What it does in the body

Oxygen transport and storage
Red blood cells contain a protein called hemoglobin and each hemoglobin molecule contains four iron atoms. The iron in hemoglobin binds oxygen when it passes through blood vessels in the lungs and releases it in the tissues. After releasing the oxygen, hemoglobin binds carbon dioxide, the waste product of respiration, and carries it back to the lungs to be released. Red blood cells and the iron they contain, are recycled and replaced every 120 days. Another iron-containing molecule, myoglobin, carries and stores oxygen in the cells and is therefore essential for cellular activities in all body tissues.

Metabolism
Enzymes involved in many metabolic functions require iron. It is necessary for cell division and growth through its role in DNA synthesis. It is also essential for protein metabolism.

Energy production
Iron plays a role in oxygen transfer in cytochromes, protein molecules involved in the production of energy in cells.

Other functions
Thyroid hormones, which regulate metabolic processes, require iron for production. Iron is involved in the production of connective tissue and several brain neurotransmitters, and in the maintenance of a healthy immune system.

Absorption and metabolism
Healthy people absorb around 5 to 10 percent of the iron in their daily diets. Absorption is highest in childhood, and reduces with age. Iron is present in animal foods in organic 'heme' form and in plant foods in inorganic 'nonheme' form. The heme and nonheme forms of iron are absorbed by different mechanisms.¹ About 20 to 30 percent of heme iron is absorbed compared to only 2 to 5 percent of nonheme iron. Vitamin C consumed in the same meal as nonheme iron improves absorption by up to 50 percent. Vitamin A and beta carotene can also improve nonheme iron absorption.²

Iron must be in ferrous form to be absorbed and the hydrochloric acid of the stomach converts ferric iron to ferrous iron. Iron absorption is a slow process, taking between two and four hours. Iron levels in the body are regulated by absorption, rather than by excretion and low body iron levels lead to improved absorption. In cases of iron deficiency absorption efficiency increases to around 10 to 20 percent.

Various food factors affect iron absorption and the overall amount of iron absorbed from a meal will depend on the interactions between these factors. Sugars and amino acids may boost absorption. Calcium supplements, zinc supplements, oxalates in green vegetables such as spinach, and tannins in tea and coffee can reduce absorption. Phytates in unleavened whole grain bread reduce iron absorption although this may be reversed in the presence of meat and vitamin C. Milk proteins, albumin and soy proteins may also reduce absorption.

As it is highly chemically reactive, iron can cause damage to proteins and fats in cell membranes. It is therefore bound to proteins in the body to limit its toxic effects and is not excreted in the urine. A protein known as transferrin, binds to iron and is responsible for its transfer to the bone marrow. Iron is stored in the form of ferritin, mostly in the bone marrow, liver and spleen. Body iron stores depend on the iron absorbed from the diet. They are usually in the range of 300 to 1000 mg for adult women and 300 to 1500 mg for men. The levels vary considerably between people and some healthy adult women have almost no body stores. In the iron overload disorder, hemochromatosis, body iron stores may reach 30 g.

About 24 mg iron is released daily from normal breakdown of red blood cells in the liver and spleen, but most of this is conserved by the body. Iron is lost from the body through bleeding, sloughing of cells, menstrual flow and transfer to a developing fetus. Iron losses during a typical menstrual period are about 15 mg. Losses during breastfeeding are about 0.5 mg daily.

Tests which measure iron levels
There are various blood tests to measure the levels of iron in the body.

Serum ferritin
Serum ferritin is the most useful measure of iron status as it accurately reflects body stores and is the earliest laboratory measure to reflect iron deficiency. It can be used to detect iron deficiency and excess. Normal serum ferritin levels are 40 to 160 mcg per liter, with iron deficiency anemia indicated by a level of 12 mcg per liter.

Serum iron
Serum iron is the concentration of iron in the serum (clear) part of the blood. Normally it is about 100 mcg per 100 ml of blood, although this varies during the day by as much as 30 percent within a single person. Serum iron is sensitive to the day's dietary intake and is not a reliable predictor of iron status.

TIBC
Total iron-binding capacity (TIBC) is the total amount of iron that can be bound by transferrin. Normally it ranges from 250 to 450 mcg per 100 ml of blood. Transferrin saturation is calculated from serum iron and TIBC. It is an index of iron transport rather than storage. In conditions of deficiency TIBC is increased, serum iron is low and transferrin saturation is reduced (around 15 percent). In the iron overload disease, hemochromatosis, serum iron is normal, TIBC may be decreased and transferrin saturation may be 100 percent.

Deficiency
Iron deficiency may be the most common nutritional deficiency in the USA. Results from the third National Health and Nutrition Examination Survey (1988-1994) suggest that iron deficiency and iron deficiency anemia are still relatively common in toddlers, adolescent girls, and women of childbearing age. Nine percent of toddlers aged 1 to 2 years, and 9 percent to 11 percent of adolescent girls and women of childbearing age were iron deficient; of these, iron deficiency anemia was found in 3 percent and 2 percent to 5 percent, respectively. These prevalences correspond to approximately 700,000 toddlers and 7.8 million women with iron deficiency; of these, approximately 240,000 toddlers and 3.3 million women have iron deficiency anemia. Iron deficiency occurred in around 7 percent of older children or those older than 50 years, and in around 1 percent of teenage boys and young men.³

Infants under two years of age are at risk due to their rapid growth rate, low iron reserves and the low iron content of milk and other foods. Teenagers, particularly girls who menstruate, are at risk due to the large amount of iron needed for rapid growth. Deficiencies are also common in women during childbearing years as menstruation, pregnancy and lactation draw heavily on the body's iron stores. Iron deficiency is also common in the elderly as they have reduced stomach acid and therefore reduced absorption ability. Surgery also leads to anemia and this is related to the extent of the surgery.⁴

Other causes of iron deficiency include heavy menstrual periods, frequent blood donation, and diseases of the stomach or bowel which reduce absorption. Some anti-arthritis drugs, which may cause repeated small bleeds from the stomach, may also lead to deficiency. It is important to carefully investigate the source of iron deficiency as slow blood loss from the gut or the uterus may be the cause.

Symptoms of iron deficiency include anemia, fatigue, rapid heartbeat, breathlessness, inability to concentrate, giddiness, disturbed sleep, severe menstrual pain and bleeding, cracks in the corners of the mouth, eye inflammation, mouth ulcers and hair loss. Low blood plasma levels of iron can cause generalized itching especially in elderly people. Fingernails may become thin, brittle and white.

A pregnant woman with an iron deficiency is more prone to infection after delivery, spontaneous abortion and premature delivery. Iron deficiency also increases the risk of low birthweight babies, stillbirth and infant death. Infants born of anemic mothers may also be at risk of anemia.

A new National Institute of Aging study suggests that low iron levels are linked to an increased likelihood of death in elderly people. Researchers looked at the iron status of nearly 4000 men and women aged 71 and over. Results of the five-year study showed that low iron levels increased the risk of total and coronary heart disease deaths. Those with higher iron levels had decreased risk. Men with the highest iron levels had only 20 percent of the risk of dying of heart disease of those with the lowest levels. Women with the highest levels were about half as likely to die of heart disease compared to those with the lowest levels. Iron levels tend to be lower in people with chronic disease as the body's needs are higher and normal dietary intake may not be sufficient to meet the body's needs. Other research has linked high iron levels with an increased risk of heart disease. This new study suggests that the picture is not that simple.

Anemia
Anemia is the final stage of iron deficiency.  Before the red blood cells show anemia, deficiency affects iron- dependent enzymes and immune functions. Symptoms include small pale red blood cells, extreme fatigue, difficulty concentrating, breathlessness and dizziness. Symptoms of anemia can develop gradually and may continue without being recognized for some time. Hemoglobin and hematocrit blood tests may not show evidence of anemia in the early stages and serum ferritin and TIBC tests are the best and most sensitive measures of iron levels. Iron levels may also vary from day to day, and the average value from multiple tests provides the best readings.

Iron deficiency anemia is the most common nutritional deficiency in children. It can lead to depressed growth and impaired mental performance. The baby of a well-nourished mother is born with enough iron to last four months and must also obtain iron from breast milk or formula. Although it is low in iron, breast milk is high in lactose and vitamin C which enhance absorption. Infant formula is fortified with iron and vitamin C. Researchers involved in a 1997 Canadian study assessed iron status and feeding practices at 39 weeks of age in 434 infants in Vancouver. They found iron-deficiency anemia in 7 percent of infants and low iron stores in about 24 percent.⁶

Some iron-deficient people develop cravings for ice, clay, soil or other materials, a condition known as pica.

Immune system
Immune response can be impaired in iron-deficient people. Chronic yeast infections and herpes infections are more common in those who have low levels of iron in their diets. Certain types of immune cells rely on iron to generate the oxidative reactions that allow these cells to kill off bacteria and other pathogens. When iron levels are low these cells cannot function properly.

Athletes
Heavy exercise may lead to iron deficiency with distance runners particularly at risk. "Sports anemia" is often used to describe a low hemoglobin condition which impairs exercise tolerance and is relatively common at the beginning of training. Symptoms of iron deficiency in athletes include reduction in exercise time, increased heart rate, decreased oxygen consumption and increased blood lactic acid. The deficiency may result from increased metabolic requirements, increased red blood cell breakdown and increased iron losses in sweat. However, unless a person is iron-deficient, supplements do not appear to improve athletic performance. After adaptation, the anemia seems to subside. It may be due to inadequate dietary intake of iron or the use of protein for tasks other than red blood cell production during the early training stages. Iron intake of athletes needs to be carefully monitored.

Other symptoms
Iron deficiency has also been associated with Plummer-Vinson syndrome where a thin web-like membrane grows across the top of the esophagus, making it difficult to swallow. This disease, once fairly common in Sweden, has been eliminated with the use of iron supplements.
Marginal iron deficiency may also contribute to sleeping difficulties, headaches, rheumatoid arthritis and restless legs syndrome
Low iron levels may increase the risk of menstrual difficulties including behavioral changes and sweating and dizziness, decreased efficiency, poor performance at work and daytime napping. Iron deficiency can also adversely affect the heart. Iron-deficient people have abnormal electrocardiogram readings.

Sources
Good sources include liver, meat, beans, nuts, dried fruits, poultry, fish, whole grains or enriched cereals, soybean flour and most dark green leafy vegetables. Flour is enriched with iron. Cooking in cast iron pots can increase the level of iron in food by as much as 20 times, although this form of iron may not be well-absorbed. Acidic foods such as chili and spaghetti sauce are especially good at leaching out the iron from cooking pots. The longer the food cooks in the pot the more iron is absorbed. The substitution of aluminum, stainless steel or plastic pots has reduced iron intake.

Those who choose not to eat red meat, which is the best source of dietary iron, should include dark green leafy vegetables, dried beans and whole cereal grains in their diet. A vegetarian diet is often high in vitamin C which helps in iron absorption.

Recommended dietary allowances

Because the iron from red blood cells is recycled and re-used, recommended requirements are small for healthy men and postmenopausal women. Iron requirements increase in pregnancy due to the increase in the mother's blood volume and the demands of the developing baby. (See table)

Iron intakes in North America and Europe average around 5 to 7 mg per 1000 calories. Thus those on low calorie diets may be at risk of deficiency.

Supplements
Iron supplements come in a variety of preparations including syrups, tablets, capsules and injections. These contain varying forms and amounts of iron. Ferrous salts are absorbed better than ferric salts. Ferrous fumarate and ferrous succinate contain the most iron (31.2 and 32.6 mg per 100 mg respectively). Ferrous succinate and ferrous sulfate (the most common) may be the most easily absorbed forms of iron but ferrous sulfate can cause gut irritation. Ferrous gluconate and ferrous fumarate are also well-absorbed and usually less irritating.

Iron supplements are also available in the form of ferritin, an iron protein complex. The hydrolyzed protein chelate form of iron (most effective with the amino acid cysteine) may cause the least side effects but may not be as well- absorbed as other forms. Supplements are usually best absorbed on an empty stomach and people may vary in their tolerance to different iron salts.

Women of childbearing age, the elderly, adolescents, athletes and alcoholics may benefit from supplements. Women who have heavy menstrual blood loss and who use intra-uterine contraceptive devices may need extra iron. The contraceptive pill reduces menstrual blood flow and may lead to decreased iron requirements.

Vegetarians may also benefit from iron supplements as they avoid easily absorbed iron sources such as meat and seafood. In addition, there are compounds in plant fiber which lead to reduced iron absorption. However, increased vitamin C may compensate.

Toxic effects of excess intake
Large doses of iron can cause deterioration of the gut lining, vomiting and diarrhea, liver damage, abdominal and joint pain, weight loss, fatigue, excess thirst and hunger. Immediate medical attention is necessary. It is important to keep iron supplements out of reach of children as doses as low as 3 g can cause death in children and every year there are a few cases of fatal poisoning.

Constipation is the most common side effect associated with iron supplements, although diarrhea can also occur. Side effects can be reduced if the iron supplements are taken in small divided doses with meals. Doses of 25 to 75 mg per day have been taken without side effects, although those with iron overload or kidney disorders might develop symptoms at lower doses.

In most people iron absorption becomes less efficient as blood levels reach optimum and dietary excesses pass out in feces. Accumulation is possible; however, as excesses are not easily excreted once absorbed. Heme iron absorption may be less affected by the iron status of the individual than nonheme iron absorption, making it easier to overdose on diets high in animal foods.

Hemochromatosis
Hemochromatosis is the term used to refer to iron overload disorders. It may be hereditary, due to excessive intake or due to chronic alcoholism. Hereditary hemochromatosis is an inherited condition of defective iron metabolism in which the body lacks the ability to limit iron absorption from the diet and stores greater than normal amounts. This iron is stored in the liver, heart, pancreas, skin and other organs and can generate free radicals which cause serious damage. In the US, the disorder is known to affect 1.5 million people. Many experts believe hemochromatosis is under-diagnosed and may occur in as many as one in 200 people. The effects are usually seen in men over 50 years of age as the disease can often go undetected until mid-life when iron levels reach five to 50 times normal amounts. The initial symptoms are fatigue, achy joints and weakness. Other symptoms include heart disorders, joint pain, cirrhosis of the liver, diabetes and excessive skin pigmentation.

Researchers involved in the Framingham Heart Study have found high iron intakes to be common in elderly people with around 91 percent of study participants having intakes above the recommended dietary levels. Only one percent of the people had iron deficiency anemia.

Iron accumulation can contribute to a variety of disorders such as cancer, heart disease, arthritis, osteoporosis, diabetes and psychiatric illnesses. The liver is particularly susceptible to the toxic effects of iron as it is the major site of iron storage in the body. Treatment for hemochromatosis involves repeated bleeding (phlebotomy) to remove excess iron. Therapy for hemochromatosis may also involve a diet rich in bread and cereals, and fruit and vegetables. The amount of meat and alcohol should be limited. Tea or coffee may be drunk with meals as this will reduce iron absorption. Foods and supplements rich in vitamin C, such as fruit and fruit juice, should be avoided with meals.

Early therapy is very important to prevent complications and increase the chance of normal life expectancy. A test is advisable for those with a family history of hemochromatosis.

Cardiovascular disease
The evidence from many scientific studies suggests that high iron levels (above 200 mcg per liter blood ferritin), may lead to an increase in the risk of cardiovascular disease. The increased risk may be due to oxidative damage to the heart and blood vessels and increased oxidation of LDL cholesterol.

A study published in 1998 in the American Journal of Epidemiology suggests that men and women, particularly those over 60, are at increased risk of heart disease if they have high levels of iron in their diets. The study, which was conducted in Greece, involved 329 patients with heart disease and 570 people of similar age who were admitted to hospital with minor conditions believed to be unrelated to diet. Results showed that for every 50 mg increase in iron intake per month, men over 60 were 1.47 times more likely to have heart disease than their peers. In women over 60, the risk was even higher, with a 3.61-fold risk for every 50 mg increase.⁷

In a paper published in 1997, Austrian researchers involved in the Bruneck study investigated the links between serum ferritin concentrations and the five-year progression of carotid atherosclerosis in 826 men and women aged 40 to 79 years old. Serum ferritin was one of the strongest risk predictors of overall progression of atherosclerosis, probably due to increased oxidation of LDL cholesterol. Changes in iron stores during the follow-up period modified atherosclerosis risk, in that a lowering was beneficial and further iron accumulation exerted unfavorable effects. High serum ferritin and LDL cholesterol also increased the risk of death from cardiovascular disease.⁸

Another study published in 1998 in the American Heart Association journal Circulation suggests that men with high levels of stored iron in the body have an increased risk of heart attack. The Study, which was done in Finland, involved 99 men who had had at least one heart attack and 99 healthy men matched for background and age. The results showed that those men with the highest iron levels had almost three times the risk of heart attack when compared with those with the lowest levels.⁹

Donating blood may help prevent a heart attack according to a 1998 study reported in the American Journal of Epidemiology. The results of a Finnish study showed that middle aged men who gave blood had an 88 percent lower risk of heart attack than those who had not donated. In a group of 2862 men, less than 1 percent of the blood donors had heart attacks compared with 12.5 percent of the non-donors.¹⁰

Cancer
Some studies have shown that iron can inhibit tumor development while others have shown that it might enhance it. Iron may increase the risk of cancer through its effect on free radical formation. In some population studies, high iron levels have been associated with an increased risk of throat and gastrointestinal cancers while others have not shown links.¹¹ Results from a study assessing the links between body iron stores and cancer in 3287 men and 5269 women participating in the first National Health and Nutrition Examination Survey (NHANES I) found an increased risk with high iron levels.¹² Some experts believe that the findings of increased risk are due to causes such as defects in iron metabolism, rather than diet alone.

Other disorders
High iron levels may also worsen the joint inflammation associated with rheumatoid arthritis. High iron levels may also lead to an increased risk of infection as iron is necessary for bacterial growth. Vitamin A supplementation may help to control the adverse effects in areas where infections are prevalent.¹³

Therapeutic uses of supplements

Prevention and treatment of deficiency
Iron supplements are used to treat cases of iron deficiency anemia, generalized itching and impaired mental performance in the young. The usual dose for treatment of deficiency is 100 mg per day in adults and 2 mg per kg of body weight per day in children. Doses are low to start with and increased gradually to reduce side effects. It may take one to two months to correct anemia and iron supplements may be needed for a further several months afterwards to replenish iron stores.

Pregnancy
Iron supplements are often recommended for pregnant women due to the high demands of the developing baby and may also be useful after pregnancy. During the last three months of pregnancy, 3 to 4 mg of iron are transferred to the baby each day. The number of red blood cells in the mother's blood increases by 20 to 30 percent. It is often very difficult to meet these increased needs from diet alone, and many doctors recommend iron supplements. They are particularly important for women with low iron stores. Iron is also very important for women who are breastfeeding, especially if they are recovering from blood loss during delivery or depletion of body stores during pregnancy. Breastfeeding causes needs to increase by around 0.5 to 1 mg per day.

Mental function
Iron supplements may improve verbal learning and memory in those susceptible to iron deficiency even in those who are not anemic. In a study published in The Lancet in 1996, researchers at Johns Hopkins University evaluated 78 adolescent girls with non-anemic iron deficiency and measured their cognitive ability, memory and concentration. The girls were then divided into two groups, some were given a placebo and some were given iron supplements. After eight weeks, measurements showed an increase in iron levels in the supplement group while the levels in the placebo group remained low. Tests showed that the girls who took the iron supplements performed better on the verbal learning and memory tests than the girls who took placebo. Both groups scored the same on tests measuring their ability to pay attention and concentrate. There was a direct relationship between how much the blood iron levels went up and the ability to learn.¹⁴

Interactions with other nutrients
Iron in the ferric form oxidizes vitamin E and reduces its effectiveness. Ferrous forms of iron do not usually interact with vitamin E. Vitamin E may reduce the possible harmful oxidative effects of iron.
Iron competes with magnesium, copper, calcium and zinc for absorption in the intestine, and excess intake of one of these minerals could produce a deficiency of the others. Nicotinic acid seems to enhance iron utilization.¹⁵

Interactions with drugs
Antacids, anti-arthritis drugs, allopurinol for gout, aspirin, and cholestyramine may decrease iron absorption and should be taken several hours apart from supplements. Iron may decrease absorption of thyroxin, tetracyclines, penicillamine, ciprofloxacin or norfloxacin.

Elevated serum levels of iron may reduce the effectiveness of interferon therapy for the hepatitis C virus.

Cautions
Children should not be given large doses of iron supplements. Iron is an important nutrient for bacteria and supplements should be avoided during acute infections, particularly in the young.

Iron supplements should be avoided in cases of peptic ulcers and inflammatory bowel disease as iron can have a corrosive effect and exacerbate these conditions. Blood transfusion recipients and sufferers of thalassemia, hemochromatosis and hepatitis should also avoid iron supplements. Iron preparations by injection may cause a flare-up of rheumatoid arthritis.

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