It may be taken for granted the impact that the food we eat has to our overall health. The body absorbs nutrients, such as vitamins and minerals, from the food that is consumed and uses it in several functions. These vitamins and minerals play many vital roles in reactions and metabolic pathways. Dietary iron is a mineral that is essential to several functions of the body and deficiency will result in negative effects.
Iron is an element with the symbol Fe on the periodic table. Its atomic number is 26 and its atomic mass is 55.845 g/mol (8). Synonyms of iron include: ferrum, ferrous ion, ferryl ion, and ferric ion (1,8). Iron plays an important role in the human body “existing in complex forms bound to protein (hemoprotein), as heme compounds (hemoglobin or myoglobin), heme enzymes, or nonheme compounds (flavin-iron enzymes, transferrin, and ferritin)” (1). The importance of iron in the body stems from its ability to interconvert readily between two relatively stable oxidation states (Fe2+or ferrous iron and Fe3+or ferric iron). This ability makes iron a useful component of oxygen-binding molecules in hemoglobin and myoglobin, cytochrome and diverse enzymatic reactions including DNA synthesis, lipid metabolism and free radical scavenging.
Iron plays a role in several metabolic pathways. “By exploiting the oxidation state, redox potential and electron spin state of iron, it is particularly suited to participate in a large number of useful biochemical reactions” (12). Iron is a cofactor; a non-protein essential molecule to enzymatic function. A specific enzyme that utilizes iron as a cofactor is tryptophan hydroxylase. This enzyme catalyzes the reaction of tryptophan hydroxylation to produce 5-hydroxytryptophan, which is the first step of the production of serotonin; a neurotransmitter that plays a role in regulating mood (12). Iron’s role in the reaction of tryptophan hydroxylation, “can be described in two parts: 1) reaction of the tetrahydropterin, oxygen, and the active site iron to form the reactive hydroxylating intermediate and 2) insertion of oxygen into the amino acid substrate” (12). The specific mechanism at the iron activation site involves the interaction of 4a-peroxypterin either as the formation of a Fe II-peroxypterin intermediate or the direct transfer of an oxygen atom (12). The result of hydroxylation of tryptophan is the addition of a hydroxyl group to the amino acid. Just as iron is a useful cofactor to tryptophan hydroxylase, it is a cofactor to several other enzymes as well such as: tyrosine hydroxylase, tryptophan hydroxylase, xanthine oxidase and ribonucleoside reductase (12). Without iron, these enzymes would not function properly and the reactions that they catalyze would be affected. Therefore, the body needs iron for the catalysis of metabolic reactions.
For the body to utilize iron, it must be consumed, absorbed and metabolized. Once iron is consumed, it is absorbed in the small intestine, specifically the duodenum and upper jejunum. Absorption occurs by the enterocytes, intestinal absorptive cells, via transport proteins such as divalent metal transporter 1 and heme carrier protein 1 (1). The enterocytes are responsible for reducing insoluble ferric (Fe3+) ions to absorbable ferrous (Fe2+) ions. For nonheme iron, the ionic forms (Fe2+ and Fe3+), the absorption depends on the pH at the absorption site (1). In contrast, absorption of heme iron does not depend on pH and is “metabolized in the enterocytes by heme oxygenase”. Heme iron is absorbed more easily and thus the larger source of dietary iron than non-heme (10).
Dietary iron occurs in two forms: heme and nonheme. Heme iron is only found in the flesh of animals such as meats, poultry, and fish. Heme iron accounts for about 10% of the average daily iron intake but it is so well absorbed that it contributes a significant amount of iron to the body (17). Heme iron is highly bioavailable and is not influenced by the dietary factors. Nonheme iron is found in both plant-derived and animal derived foods such as nuts, beans, vegetables and fortified grain products (16). Nonheme iron is present as either the reduced ferrous (Fe2+) form or the oxidized ferric (Fe3+) form. However, its formation of insoluble ferric complexes reduces bioavailability in the intestine. Besides, there are several dietary factors affecting nonheme iron absorption.
The MFP factor and vitamin C (ascorbic acid) enhance nonheme absorption when foods are eaten at the same meal. Some acids (citric and lactic) and sugar (fructose) will have the same effect on nonheme iron. However, some factors such as the phytates in legumes, whole grains, nuts, seeds, vegetable proteins (soybeans), calcium in milk, the polyphenols (tannic acid in tea, coffee, grain products, oregano, and red wine) have an inhibiting effect on nonheme absorption (16). The balance of iron metabolism is critical because the body lacks a mechanism for iron excretion, thus absorption is the main regulation of iron (1). Absorption of iron increases when the iron storage is empty or low. Iron absorption decreases when the iron storage is full. Once the iron is absorbed from the diet, the iron storage protein called ferritin captures iron from food and stores it in the mucosal cells in the intestine.
The absorption of intestinal iron is regulated in several ways. The first mechanism is called the dietary regulator in which the accumulation of intracellular iron reaches a threshold in which the absorptive enterocytes resist to acquire more iron (17). However, it may occur even in the presence of systemic iron deficiency. The second mechanism is termed as the stores regulator in which iron levels are sensed in response to the saturation of plasma transferrin with iron (17). The third mechanism is known as erythropoietic regulator in which iron responds to the requirements for erythropoiesis. It is achieved by sensing a soluble signal sent out by plasma from the bone marrow to the intestine (13). The protein that helps to regulate iron absorption from the small intestine and controls the release of iron from the liver, spleen and bone marrow is known as hepcidin. Hepcidin is produced in the liver. Production of hepcidin decreases in iron deficiency and increases in iron overloaded by inhibiting ferroportin I to uptake more iron (14).
When the body needs iron, ferritin releases iron from the enterocytes to the transferrin, an iron transport protein. It is achieved by transporting the internalized Fe2+ to the bloodstream through the basolateral membrane via another transporter named ferroportin. The Fe2++is re-oxidized to Fe3++during the transport. The transferrin carries the iron as an iron-transferrin complex and circulates in the plasma until it binds with specific transferrin receptors on erythroid cells in the bone marrow and other tissues. The iron-transferrin-transferrin receptor complex is internalized into the cell through endocytosis. The iron is released from the transferrin and transferrin returns back to plasma to pick up more iron (5). The bone marrow incorporates iron into hemoglobin of red blood cells where iron-containing hemoglobin is able to carry oxygen from lungs to tissues. Iron in hemoglobin can help the red blood cells to maintain their shape and functionality. However, lifespan of the red blood cells is about 4 months. After that, the liver and spleen will dismantle the old red blood cells and remove them from the blood. Iron will be re-attached to the transferrin which transports iron back to bone marrow for making new red blood cells (15). Iron is recycled and reused. The surplus of iron is stored in the protein ferritin, primarily in liver and other storage location is in the bone marrow and spleen.
Ferritin is constantly made and supplies iron to bone marrow and other tissues. When the supply of iron is excessively high, liver will convert some ferritin into hemosiderin. Hemosiderin is an iron storage complex which less readily releases iron (1). Storing excess iron in hemosiderin protects the body against the free iron that could attack cell lipids, DNA and proteins (1). However, if the body does not need iron and the iron is not absorbed, the iron will be excreted in feces.
In order to take in the adequate amount of iron and for these metabolic processes to occur, it is important to know how much should be consumed. The recommended daily intake for infants from birth to 6 months old is 0.27 milligram (mg). For infants between 7 to 12 months, the daily intake is 11 mg. Young children aged 1 to 3 years old needs about 7 mg while 4 to 8 years old need about 10 mg. Daily intake for preteen (9-13 years old) is 8 mg. However, females during puberty (14- 18 years old) require 15 mg and adult women (19 to 50 years) in their reproductive years need 18 milligrams a day due to blood loss during menstruation. Additional iron (27 mg) is needed during pregnancy to support the growth of the fetus, added blood volume and blood loss during delivery. However, women after menopause need only 8 mg per day. The recommended daily intake for male adolescent (14 to 18 years old) and adult men after 19 years old is 11 mg (16). Without meeting the nutritional requirements for iron, deficiency can occur and lead to negative effects.
Iron deficiency is the most common nutrient deficiency. It accounts for 30% of world population, mostly found in toddlers, adolescent girls and women of childbearing age (18). Iron deficiency is a state of having depleted iron stores, meaning that ron storage in ferritin and hemosiderin is progressively diminished and no longer meets the needs of normal iron turnover. It then leads to a shortage of iron supply to tissues which results in a decrease in transferrin saturation and an increase in transferrin receptors in the circulation and on the surface of the cells (18). When iron-deficiency results in a low hemoglobin concentration, iron deficiency anemia occurs (IDA). IDA is characterized by pale (hypochromic) and small (microcytic) red blood cells. Since IDA leads to a decrease in hemoglobin synthesis, the red blood cells are not able to carry enough oxygen from the lungs to tissues which causes the energy metabolism in the cells to decrease (3).
According to the World Health Organization (WHO), iron deficiency and iron deficiency anemia have a significant impact on cognitive performance, work capacity and productivity and pregnancy (18). WHO reported that iron deficiency anemia is related to delay in psychomotor development, impaired cognitive performance, lower IQ scores, weakness, tiredness, headaches, apathy, pallor, poor resistance to cold temperature, increased maternal mortality, prenatal and perinatal infant loss and prematurity, and increased morbidity from infectious diseases. It is reported that “leukocytes have a reduced capacity to kill ingested microorganism and lymphocytes a decreased ability to replicate when stimulated by mitogen” (18).
Another iron deficiency related disorder is known as pica. It is especially common among women and children in low-income groups (7). Pica is a craving for and consumption of nonfood substances such as clay, baby powder, chalk, ash, ceramics, paper, paint chips, or charcoal. In fact, those substances commonly craved and consumed inhibit iron absorption making pica associated with iron deficiency (7).
Iron supplementation is the most common way to treat iron deficiency and iron deficiency anemia. Usually oral iron therapy is the first choice because it is simple, inexpensive and relatively effective in treating iron deficiency. However, noncompliance is common. Long course treatment (3 to 4 weeks) and limited intestinal absorption makes the oral iron therapy less ideal. Treatment with intravenous (IV) iron therapy is an alternative to the oral iron therapy. The advantage of IV iron therapy is “faster higher increases of hemoglobin levels and body iron stores” (19). Intravenous ferric carboxymaltose is a stable complex, not predisposed to anaphylactic reactions and allows administration of large doses (15mg/kg maximum of 1000 mg/infusion) in a single shot. It also has a shorter therapeutic session (15 minutes infusion) that makes IV iron therapy more appealing (19). Taking supplements between meals, before bedtime, or on an empty stomach enhance iron absorption. However, constipation is a common side effect. Moreover, iron supplementation always works better with an iron-rich, absorption enhancing diet.
Iron is a critical mineral to the body with many functions including: supporting metabolism, cofactors to enzymes to aid in metabolic reaction, and aiding normal cellular growth and development. Careful iron balance and adequate iron intake are important to prevent iron deficiency and iron deficiency anemia. As is important with adequate nutritional intake of iron, it is also important to consume the recommended amounts of all vitamins and minerals. A well balanced diet can meet these nutritional requirements, which will aid in metabolic pathways needed for proper bodily function.