Iron is one of the most abundant metals on Earth, as well as being an essential nutrient. It is a component of several metalloproteins and plays a vital function in essential biochemical activities, such as oxygen sensing and transport, electron transfer, and catalysis. Iron exists in two steady oxidative states: ferrous (Fe2+) and ferric (Fe3+). As a result of the toxicity of free iron and its low solubility in the presence of oxygen and neutral pH conditions, organisms have been forced to develop proteins (e.g., transferrin) that are able to bind Fe3+ and maintain its stable form but, simultaneously, make it available for biological processes. The poor solubility of iron renders iron difficult to access by pathogenic microorganisms, thereby avoiding their proliferation.
The majority of iron is intracellular, bound within the iron storage proteins (ferritin and haemosiderin) or associated with proteins in the form of haem. The most abundant mammalian haemproteins, haemoglobin and myoglobin, serve as oxygen carriers in the erythroid tissue and in the muscle, respectively. Another important class of haemproteins are cytochromes, which play an important function in redox reactions and electron transport.
The adult human body contains approximately 3–5 g of iron, with more than two-thirds incorporated in the haemoglobin of developing erythroid precursors and mature red blood cells. A healthy individual absorbs daily 1–2 mg of iron from the diet, which compensates nonspecific iron losses by cell desquamation in the skin and the intestine. Furthermore, menstruating women physiologically lose iron from the blood. Recycling of iron provides the amount of iron required for erythropoiesis (30 mg/day).
The body has no effective means of excreting iron and thus the regulation of absorption of dietary iron plays a critical role
in iron homeostasis. Absorption of dietary non-haem iron involves the release of elemental iron from digested food and its maintenance in a soluble form, which is accomplished in part by gastric acid. The low pH of the gastric acid dissolves
ingested inorganic iron and facilitates its enzymatic reduction (Fe3+ is reduced to Fe2+) and then, iron is transported across the intestinal epithelium by a transporter called divalent metal transporter 1 (DMT-1), which also traffics other metal ions such as copper, zinc, and cobalt by a proton-coupled mechanism. Haem iron is absorbed into the enterocytes by a haem carrier protein 1, a membrane protein found in the intestine.
Iron is exported into the circulation, where it binds to transferrin, which is able to bind iron tightly but reversibly, and is transported to sites of use and storage. Transferrin-bound iron enters target cells (erythroid, immune, and hepatic cells) is stored as ferritin (the major iron storage protein). Later, iron is released and bound by transferrin, which transports iron to the bone marrow. This internal turnover of iron is essential to meet the requirements for erythropoiesis. Since iron is required for a number of diverse cellular functions, a constant balance between iron uptake, transport, storage, and utilization is required to maintain iron homeostasis.
Nutritional iron deficiency arises when physiological requirements cannot be met by iron absorption from the diet. Dietary iron bioavailability is low in populations consuming monotonous plant-based diets with little meat. (1) In meat, 30–70% of iron is haem iron, of which 15–35% is absorbed. (2) However, in plant-based diets in developing countries most dietary iron is non-haem iron, and its absorption is often less than 10%. The absorption of non-haem iron is increased by meat and ascorbic acid, but inhibited by phytates, polyphenols, and calcium. Because iron is present in many foods, and its intake is directly related to energy intake, and the risk of deficiency is highest when iron requirements are greater than energy needs. This situation happens in infants and young children, adolescents, and in menstruating and pregnant women. During infancy, rapid growth exhausts iron stores accumulated during gestation and often results in deficiency, if iron-fortified formula or weaning foods are not supplied. Excessive early consumption of cows’ milk can also contribute to early-childhood iron deficiency.
In a study of infants aged six months, frequency of iron deficiency anaemia was lowest in infants fed iron-fortified formula (about 1%) but occurred in 15% of breastfed infants, and 20% of infants fed cows’ milk or non-fortified formula. (3) In the USA, the introduction of iron-fortified weaning foods in the 1970s was associated with a reduction in the frequency of iron deficiency anaemia in infants and pre-school children. (4) In many developing countries, plant-based weaning foods are rarely fortified with iron, and the frequency of anaemia exceeds 50% in children younger than four years.(6) In school age children, iron status typically improves as growth slows and diets become more varied. The frequency of iron deficiency begins to rise again, mainly in female individuals, during adolescence, when menstrual iron losses are superimposed with needs for rapid growth.
Because a 1 mL loss of blood translates into a 0∙5 mg loss of iron, heavy menstrual blood loss (>80 mL per month in about 10% of women) sharply increases the risk for iron deficiency (5). Other risk factors for iron deficiency in young women are high parity, use of an intrauterine device, and vegetarian diets (6). During pregnancy, iron requirements increase three-fold because of expansion of maternal red-cell mass and growth of the foetal–placental unit. The net iron requirement during pregnancy is about 1 g (equal to that contained in about 4 units of blood), most of which is needed in the last two trimesters (7). During lactation, because only about 0∙25 mg of iron per day is excreted into breast milk and most women are amenorrhoeic, iron requirement is low—only half of that of non-pregnant, non-lactating women.
Increased blood loss from gastrointestinal parasites aggravates dietary deficiencies in many developing countries. Infections with whipworm and hookworm cause intestinal blood loss and are important causes of iron deficiency anaemia. (8-11) Revised estimates indicate that hookworms afflict more than 700 million people in tropical and subtropical regions. In endemic areas, hookworm infection is estimated to account for 35% of iron deficiency anaemia and 73% of its severe form, and deworming decreases the occurrence of anaemia.
Iron deficiency anaemia can also be caused by impaired iron absorption. Gastric acid is needed to maintain ferric iron forms in solution, and achlorhydria might be a substantial cause of iron deficiency, mainly in elderly people, in whom atrophic gastritis is common (12) Other common causes of lowered iron absorption and iron deficiency are mucosal atrophy in coeliac disease (13,14) and, possibly, Helicobacter pylori infection (15).
The imbalance of iron homeostasis is associated with the development of several diseases. For instance, iron can be toxic and damaging when it is in excess and accumulates in different human organs. This excess iron in the body is usually associated with some iron-overloading disorders, such as hereditary haemochromatosis (HH) and thalassemias. On the other hand, low levels of iron in the right place could lead, for example, to the development of ID anaemia (IDA). Therefore, a proper balance of iron concentration must be achieved.
Although iron is indispensable for life, its excess can be toxic to tissues. Iron has the ability to produce oxygen free radicals under aerobic conditions, which turns it into a potential harmful component. In diseases of iron overload (e.g., HH), the generation of free radicals leads to tissue damage and organ failure.
Sources of iron
The richest sources of haem iron in the diet include lean meat and seafood. Dietary sources of non-haem iron include nuts, beans, vegetables, and fortified grain products. Haem iron has a greater bioavailability than non-haem iron and other dietary components have less effect on the bioavailability of haem iron than non-haem iron. The bioavailability of iron is approximately 14 to 18% from mixed diet that includes substantial amounts of meat, seafood and vitamin C, which enhances the bioavailability of non-haem iron, and 5 to 12% and vegetarian diets.
In addition to ascorbic acid, meat, poultry, and seafood can enhance non-haem iron absorption, whereas phytate (present in grains, and beans) and certain polyphenols in some non-animal foods (such as cereals and legumes) can have the opposite effect. Unlike other inhibitors of iron absorption, calcium might reduce the bioavailability of both forms of iron. However, the effects of enhancers and inhibitors of iron absorption or attenuated by a typically mixed Western diet, so they have little effect on most people’s iron status.
Iron in health and disease
Iron deficiency anaemia
Iron deficiency anaemia IDA is usually seen as a continuous process, comprising three elementary steps: iron depletion, iron-deficient erythropoiesis (IDE), and IDA. Basically, IDA occurs when ID is sufficiently severe to the point of reducing erythropoiesis. IDA is the most frequent type of chronic anaemia. Iron is an essential mineral for several metabolic reactions in our body. IDA is associated with several conditions, such as preterm delivery, defects in cognitive and psychomotor development, impaired work capacity, diminished growth, alterations in bone mineralization, and diminished immune response (16–19). Furthermore, increased oxidative stress in patients with IDA has been reported (20,21). Iron is an essential cofactor for enzymes involved in several cellular processes, namely in antioxidant metabolism. Therefore, the increased oxidative stress, and consequent DNA damage, seems to play a critical role in the pathogenesis of IDA.
The high frequency of iron deficiency anaemia in the developing world has substantial health and economic costs. In an analysis of ten developing countries, the median value of physical productivity losses per year due to iron deficiency was about US$0∙32 per head, or 0∙57% of the gross domestic product. In the WHO African subregion, it is estimated that if iron fortification reached 50% of the population, it would avert 570 000 disability-adjusted life years (DALYs) every year. During the first two trimesters of pregnancy, iron deficiency anaemia increases the risk for preterm labour, low birthweight, infant mortality, and predicts iron deficiency in infants after four months of age. Estimates are that anaemia accounts for 3∙7% and 12∙8% of maternal deaths during pregnancy and childbirth in Africa and Asia, respectively.
Data for the adverse effects of iron deficiency on cognitive and motor development in children are equivocal because environmental factors limit their interpretation. Several studies reported adverse effects of iron deficiency anaemia on infant development that might be only partly reversible. Other studies suggest that no convincing evidence exists that iron deficiency anaemia affects mental or motor development in children younger than two years, but that iron deficiency adversely affects cognition in school children. Anaemic school-children have decreased motor activity, social inattention, and decreased school performance. Whether adverse effects of iron deficiency on neuromotor development are due to anaemia or absence of iron in the developing brain is unclear.
Iron is an indispensable nutrient in the life of several organisms, including bacteria. Bacteria require iron and other transition metals so that they can replicate, and eventually cause disease. Therefore, the withholding of iron is an effective strategy of the host in the prevention of infection, a process commonly referred as nutritional immunity (22). As previously stated, the poor solubility of iron is an important chemical property in this context. Nevertheless, there are some iron-binding proteins that maintain low levels of free, circulating iron, as well as hinder the uptake of iron by bacteria, including transferrin, lactoferrin, and siderocalin. Both transferrin and lactoferrin have great affinity for iron. Moreover, most of the iron-binding sites of these proteins are normally unoccupied, thus making the amount of free iron very small to support bacterial growth. Therefore, the antimicrobial properties of these two proteins have been solely attributed to their ability to sequester iron (23,24). However, and in the case of lactoferrin, new insights emerged regarding to its antimicrobial properties. It is now well established that lactoferrin possesses bactericidal activity against a wide range of microorganisms. Nevertheless, these bactericidal properties appear to be iron independent and are probably a result of a direct interaction of lactoferrin with bacterial surface (25,26).
During infection, bacteria secrete iron chelating compounds called siderophores, which allow the uptake of iron from the host. Siderocalin is released by neutrophils at sites of infection and inflammation, and blocks bacterial proliferation through binding to bacterial siderophores, which prevents iron uptake by bacteria (27).
Iron deficiency anaemia increases susceptibility to infections, mainly of the upper respiratory tract, which happen more often and have a longer duration in anaemic than in healthy children. (28)
The response to iodine prophylaxis is reduced in goitrous children with deficiencies of both iodine and iron, probably because of impairment of the haem-dependent enzyme, thyroid peroxidase (29)
In adults, physical activity is reduced, and manual labourers in developing countries are more productive if they are given iron and treated for hookworm and other infections. Iron deficiency, even in the absence of anaemia, might cause fatigue and reduce work performance (31)
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Keywords:- iron, anaemia, cognitive function, infection, goitre,Vitamin A, fatigue