Sandbox: jss

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Physiology

• In the human body, iron mainly exists as bound to protein (hemoprotein), as heme compounds (hemoglobin or myoglobin), heme enzymes, or nonheme compounds (flavin-iron enzymes, transferring, and ferritin).
• The body requires iron for the synthesis of its oxygen transport proteins, (hemoglobin and myoglobin), and for the formation of heme enzymes and other iron-containing enzymes involved in electron transfer and oxidation-reductions.
• 60% of the body iron is found in the hemoglobin present in circulating erythrocytes, 25% is contained in tranferrin and ferritin, and the remaining 15% is bound to myoglobin in muscle tissue and in a variety of enzymes involved in the oxidative metabolism and many other cell functions.
• Iron is bound and transported in the body via transferrin and stored in ferritin molecules.

• Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma from intestinal enterocytes or reticuloendothelial macrophages.
• The binding of transferrin to the cell-surface transferrin receptor (TfR) 1 results in endocytosis and uptake of iron.
• Internalized iron is transported to mitochondria for the synthesis of heme or other iron containing enzymes.
• Excess iron is stored in cytosolic ferritin.

Absorption of iron

• .Iron absorption occurs by the enterocytes in the duodenum and upper jejunum.
• In the blood, it is transported by transferrin to the cells or the bone marrow for erythropoiesis.
• Iron absorption is controlled by ferroportin which allows or does not allow iron from the mucosal cell into the plasma.
• Iron is absorbed in Fe⁺² state.

The physical state of iron entering the duodenum greatly influences its absorption. At physiological pH, ferrous iron (Fe+2) is rapidly oxidized to the insoluble ferric (Fe+3) form. Gastric acid lowers the pH in the proximal duodenum reducing Fe+3 in the intestinal lumen by ferric reductases, thus allowing the subsequent transport of Fe+2 across the apical membrane of enterocytes. This enhances the solubility and uptake of ferric iron. When gastric acid production is impaired (for instance by acid pump inhibitors such as the drug, prilosec), iron absorption is reduced substantially.

Dietary heme can also be transported across the apical membrane by a yet unknown mechanism and subsequently metabolized in the enterocytes by heme oxygenase 1 (HO-1) to liberate (Fe+2).[19] This process is more efficient than the absorption of inorganic iron and is independent of duodenal pH. It is thus not influenced by inhibitors such as phytate and polyphenols. Consequently, red meats high in hemoglobin are excellent nutrient sources of iron. Directly internalized Fe+2 is processed by the enterocytes and eventually (or not) exported across the basolateral membrane into the bloodstream via Fe+2 transporter ferroportin. The ferroportin-mediated efflux of Fe+2 is coupled by its reoxidation to Fe+2, catalyzed by the membrane-bound ferroxidase hephaestin that physically interacts with ferroportin[20] and possibly also by its plasma homologue ceruloplasmin. Exported iron is scavenged by transferrin, which maintains Fe+3 in a redox-inert state and delivers it into tissues. The total iron content of transferrin (≈3 mg) corresponds to less than 0.1% of body iron, but it is highly dynamic and undergoes more than 10 times daily turnover to sustain erythropoiesis. The transferrin iron pool is replenished mostly by iron recycled from effete RBCs and, to a lesser extent, by newly absorbed dietary iron. Senescent RBCs are cleared by reticuloendothelial macrophages, which metabolize hemoglobin and heme, and release iron into the bloodstream. By analogy to intestinal enterocytes, macrophages export Fe+2 from their plasma membrane via ferroportin, in a process coupled by reoxidation of Fe+2 to Fe+3 by ceruloplasmin and followed by the loading of Fe+3 to transferrin.[21]

Theil et al.,[21] recently reported that an independent mechanism also exists for the absorption of plant ferritins mostly present in legumes. However, the relevance of the ferritin transporter is unclear as most ferritin seems to be degraded during food processing and digestion, thereby releasing inorganic iron from the ferritin shell for absorption by the normal mechanism.[22] As one ferritin molecule contains 1000 or more iron atoms, and should also be unaffected by iron absorption inhibitors, such a mechanism would provide an important source of iron in the developing world where legumes are commonly consumed.

Regulation of iron homeostasis

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.[11] As the body lacks a defined mechanism for the active excretion of iron, iron balance is mainly regulated at the point of absorption.[23,24]

Hepcidin is a circulating peptide hormone secreted by the liver that plays a central role in the regulation of iron homeostasis. It is the master regulator of systemic iron homeostasis, coordinating the use and storage of iron with iron acquisition.[25] This hormone is primarily produced by hepatocytes and is a negative regulator of iron entry into plasma [Figure 2]. Hepcidin acts by binding to ferroportin, an iron transporter present on cells of the intestinal duodenum, macrophages, and cells of the placenta. Binding of hepcidin induces ferroportin internalization and degradation.[26] The loss of ferroportin from the cell surface prevents iron entry into plasma [Figure 2a]. Decreased iron entry into plasma results in low transferrin saturation and less iron is delivered to the developing erythroblast. Conversely, decreased expression of hepcidin leads to increased cell surface ferroportin and increased iron absorption[27] [Figure 2c]. In all species, the concentration of iron in biological fluids is tightly regulated to provide iron as needed and to avoid toxicity, because iron excess can lead to the generation of reactive oxygen species.[28] Iron homeostasis in mammals is regulated at the level of intestinal absorption, as there is no excretory pathway for iron.

Figure 2

Hepcidin-mediated regulation of iron homeostasis. (a) Increased hepcidin expression by the liver results from inflammatory stimuli. High levels of hepcidin in the bloodstream result in the internalization and degradation of the iron exporter ferroportin. ...

Plasma hepcidin levels are regulated by different stimuli, including cytokines, plasma iron, anemia, and hypoxia. Dysregulation of hepcidin expression results in iron disorders. Overexpression of hepcidin leads to the anemia of chronic disease, while low hepcidin production results in hereditary hemochromatosis (HFE) with consequent iron accumulation in vital organs [Figure 2]. Most hereditary iron disorders result from inadequate hepcidin production relative to the degree of tissue iron accumulation. Impaired hepcidin expression has been shown to result from mutations in any of 4 different genes: TfR2, HFE, hemochromatosis type 2 (HFE2), and hepcidin antimicrobial peptide (HAMP). Mutations in HAMP, the gene that encodes hepcidin, result in iron overload disease, as the absence of hepcidin permits constitutively high iron absorption. The role for other genes (TFR2, HFE, and HFE2) in the regulation of hepcidin production has been unclear.[27]

Storage

Ferritin concentration together with that of hemosiderin reflects the body iron stores. They store iron in an insoluble form and are present primarily in the liver, spleen, and bone marrow.[2] The majority of iron is bound to the ubiquitous and highly conserved iron-binding protein, ferritin.[18] Hemosiderin is an iron storage complex that less readily releases iron for body needs. Under steady state conditions, serum ferritin concentrations correlate well with total body iron stores.[29] Thus, serum ferritin is the most convenient laboratory test to estimate iron stores.

Excretion

Apart from iron losses due to menstruation, other bleeding or pregnancy, iron is highly conserved and not readily lost from the body.[30] There are some obligatory loss of iron from the body that results from the physiologic exfoliation of cells from epithelial surfaces,[30] including the skin, genitourinary tract, and gastrointestinal tract.[3] However, these losses are estimated to be very limited (≈1 mg/day).[31] Iron losses through bleeding can be substantial and excessive menstrual blood loss is the most common cause of iron deficiency in women.

BIOAVAILABILITY

Dietary iron occurs in two forms: heme and nonheme.[23] The primary sources of heme iron are hemoglobin and myoglobin from consumption of meat, poultry, and fish, whereas nonheme iron is obtained from cereals, pulses, legumes, fruits, and vegetables.[32] Heme iron is highly bioavailable (15%-35%) and dietary factors have little effect on its absorption, whereas nonheme iron absorption is much lower (2%-20%) and strongly influenced by the presence of other food components.[23] On the contrary, the quantity of nonheme iron in the diet is manyfold greater than that of heme-iron in most meals. Thus despite its lower bioavailability, nonheme iron generally contributes more to iron nutrition than heme-iron.[33] Major inhibitors of iron absorption are phytic acid, polyphenols, calcium, and peptides from partially digested proteins.[23] Enhancers are ascorbic acid and muscle tissue which may reduce ferric iron to ferrous iron and bind it in soluble complexes which are available for absorption[23]

Factors enhancing iron absorption

A number of dietary factors influence iron absorption. Ascorbate and citrate increase iron uptake in part by acting as weak chelators to help to solubilize the metal in the duodenum [Table 1].[34] Iron is readily transferred from these compounds into the mucosal lining cells. The dose-dependent enhancing effect of native or added ascorbic acid on iron absorption has been shown by researchers.[34] The enhancing effect is largely due to its ability to reduce ferric to ferrous iron but is also due to its potential to chelate iron.[35] Ascorbic acid will overcome the negative effect on iron absorption of all inhibitors, which include phytate,[36] polyphenols,[37] and the calcium and proteins in milk products,[38] and will increase the absorption of both native and fortification iron. In fruit and vegetables, the enhancing effect of ascorbic acid is often cancelled out by the inhibiting effect of polyphenols.[39] Ascorbic acid is the only absorption enhancer in vegetarian diets, and iron absorption from vegetarian and vegan meals can be best optimized by the inclusion of ascorbic acid-containing vegetables.[40] Cooking, industrial processing, and storage degrade ascorbic acid and remove its enhancing effect on iron absorption.[41]

Table 1

Factors that could influence iron absorption

The enhancing effect of meat, fish, or poultry on iron absorption from vegetarian meals has been shown,[42] and 30 g muscle tissue is considered equivalent to 25 mg ascorbic acid.[33] Bjorn-Rasmussen and Hallberg[43] reported that the addition of chicken, beef, or fish to a maize meal increased nonheme iron absorption 2-3-fold with no influence of the same quantity of protein added as egg albumin. As with ascorbic acid, it has been somewhat more difficult to demonstrate the enhancing effect of meat in multiple meals and complete diet studies. Reddy et al.,[44] reported only a marginal improvement in iron absorption (35%) in self-selected diets over 5 days when daily muscle tissue intake was increased to 300 g/day, although, in a similar 5-day study, 60 g pork meat added to a vegetarian diet increased iron absorption by 50%.[45]

Factors inhibiting iron absorption

In plant-based diets, phytate (myo-inositol hexakisphosphate) is the main inhibitor of iron absorption.[23] The negative effect of phytate on iron absorption has been shown to be dose dependent and starts at very low concentrations of 2-10 mg/meal.[37,46] The molar ratio of phytate to iron can be used to estimate the effect on absorption. The ratio should be 1:1 or preferably, 0.4:1 to significantly improve iron absorption in plain cereal or legume-based meals that do not contain any enhancers of iron absorption, or, 6:1 in composite meals with certain vegetables that contain ascorbic acid and meat as enhancers.[47]

Polyphenols occur in various amounts in plant foods and beverages, such as vegetables, fruit, some cereals and legumes, tea, coffee, and wine. The inhibiting effect of polyphenols on iron absorption has been shown with black tea and to a lesser extent with herbal teas.[48,49] In cereals and legumes, polyphenols add to the inhibitory effect of phytate, as was shown in a study that compared high and low polyphenol sorghum.[23]

Calcium has been shown to have negative effects on nonheme and heme iron absorption, which makes it different from other inhibitors that affect nonheme iron absorption only.[50] Dose-dependent inhibitory effects were shown at doses of 75-300 mg when calcium was added to bread rolls and at doses of 165 mg calcium from milk products.[51] It is proposed that single-meal studies show negative effects of calcium on iron absorption, whereas multiple-meal studies, with a wide variety of foods and various concentrations of other inhibitors and enhancers, indicate that calcium has only a limited effect on iron absorption.[52]

Animal proteins such as milk proteins, egg proteins, and albumin, have been shown to inhibit iron absorption.[53] The two major bovine milk protein fractions, casein and whey, and egg white were shown to inhibit iron absorption in humans.[54] Proteins from soybean also decrease iron absorption.[55]

Competition with iron

Competition studies suggest that several other heavy metals may share the iron intestinal absorption pathway. These include lead, manganese, cobalt, and zinc Table 1. As iron deficiency often coexists with lead intoxication, this interaction can produce particularly serious medical complications in children.[56]

Lead is a particularly pernicious element to iron metabolism.[57] Lead is taken up by the iron absorption machinery (DTM1), and secondarily blocks iron through competitive inhibition. Further, lead interferes with a number of important iron-dependent metabolic steps such as heme biosynthesis. This multifaceted influence has particularly dire consequences in children, were lead not only produces anemia, but can impair cognitive development. Lead exists naturally at high levels in ground water and soil in some regions, and can clandestinely attack children's health. For this reason, most pediatricians in the U.S. routinely test for lead at an early age through a simple blood test.

HUMAN REQUIREMENTS

During early infancy, iron requirements are met by the little iron contained in the human milk.[58] The need for iron rises markedly 4-6 months after birth and amounts to about 0.7-0.9 mg/day during the remaining part of the first year.[58] Between 1 and 6 years of age, the body iron content is again doubled.[58] Iron requirements are also very high in adolescents, particularly during the period of growth spurt. Girls usually have their growth spurt before menarche, but growth is not finished at that time. In boys there is a marked increase in hemoglobin mass and concentration during puberty. In this stage, iron requirements increase to a level above the average iron requirements in menstruating women[58] [see Table 2].

Table 2

Iron requirements of 97.5% of individuals in terms of absorbed irona, by age group and sex (World Health Organization, 1989)

The average adult stores about 1-3 g of iron in his or her body. A fine balance between dietary uptake and loss maintains this balance. About 1 mg of iron is lost each day through sloughing of cells from skin and mucosal surfaces, including the lining of the gastrointestinal tract.[59] Menstruation increases the average daily iron loss to about 2 mg per day in premenopausal female adults.[60] The augmentation of body mass during neonatal and childhood growth spurts transiently boosts iron requirements.[61]

Wolters Kluwer -- Medknow Publications

Review on iron and its importance for human health

Nazanin Abbaspour, Richard Hurrell, and Roya Kelishadi

Additional article information

Abstract

It is well-known that deficiency or over exposure to various elements has noticeable effects on human health. The effect of an element is determined by several characteristics, including absorption, metabolism, and degree of interaction with physiological processes. Iron is an essential element for almost all living organisms as it participates in a wide variety of metabolic processes, including oxygen transport, deoxyribonucleic acid (DNA) synthesis, and electron transport. However, as iron can form free radicals, its concentration in body tissues must be tightly regulated because in excessive amounts, it can lead to tissue damage. Disorders of iron metabolism are among the most common diseases of humans and encompass a broad spectrum of diseases with diverse clinical manifestations, ranging from anemia to iron overload, and possibly to neurodegenerative diseases. In this review, we discuss the latest progress in studies of iron metabolism and bioavailability, and our current understanding of human iron requirement and consequences and causes of iron deficiency. Finally, we discuss strategies for prevention of iron deficiency.

Keywords: Anemia, human iron requirement, iron bioavailability, iron deficiency, iron metabolism

INTRODUCTION

From ancient times, man has recognized the special role of iron in health and disease.[1] Iron had early medicinal uses by Egyptians, Hindus, Greeks, and Romans.[2,3] During the 17th century, iron was used to treat chlorosis (green disease), a condition often resulting from the iron deficiency.[4] However, it was not until 1932 that the importance of iron was finally settled by the convincing proof that inorganic iron was needed for hemoglobin synthesis.[5] For many years, nutritional interest in iron focused on its role in hemoglobin formation and oxygen transport.[6] Nowadays, although low iron intake and/or bioavailability are responsible for most anemia in industrialized countries, they account for only about half of the anemia in developing countries,[7] where infectious and inflammatory diseases (especially malaria), blood loss from parasitic infections, and other nutrient deficiencies (vitamin A, riboflavin, folic acid, and vitamin B12) are also important causes.[8]

Biochemistry and physiology

In contrast to zinc, iron is an abundant element on earth[2,9] and is a biologically essential component of every living organism.[10,11] However, despite its geologic abundance, iron is often a growth limiting factor in the environment.[9] This apparent paradox is due to the fact that in contact with oxygen iron forms oxides, which are highly insoluble, and thus is not readily available for uptake by organisms.[2] In response, various cellular mechanisms have evolved to capture iron from the environment in biologically useful forms. Examples are siderophores secreted by microbes to capture iron in a highly specific complex[12] or mechanisms to reduce iron from the insoluble ferric iron (Fe+3) to the soluble ferrous form (Fe+2) as in yeasts.[13] Many of the mechanisms found in lower organisms, have analogous counterparts in higher organisms, including humans. In the human body, iron mainly exists in complex forms bound to protein (hemoprotein) as heme compounds (hemoglobin or myoglobin), heme enzymes, or nonheme Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences

Wolters Kluwer -- Medknow Publications

Review on iron and its importance for human health

Nazanin Abbaspour, Richard Hurrell, and Roya Kelishadi

Additional article information

Abstract

It is well-known that deficiency or over exposure to various elements has noticeable effects on human health. The effect of an element is determined by several characteristics, including absorption, metabolism, and degree of interaction with physiological processes. Iron is an essential element for almost all living organisms as it participates in a wide variety of metabolic processes, including oxygen transport, deoxyribonucleic acid (DNA) synthesis, and electron transport. However, as iron can form free radicals, its concentration in body tissues must be tightly regulated because in excessive amounts, it can lead to tissue damage. Disorders of iron metabolism are among the most common diseases of humans and encompass a broad spectrum of diseases with diverse clinical manifestations, ranging from anemia to iron overload, and possibly to neurodegenerative diseases. In this review, we discuss the latest progress in studies of iron metabolism and bioavailability, and our current understanding of human iron requirement and consequences and causes of iron deficiency. Finally, we discuss strategies for prevention of iron deficiency.

Keywords: Anemia, human iron requirement, iron bioavailability, iron deficiency, iron metabolism

INTRODUCTION

From ancient times, man has recognized the special role of iron in health and disease.[1] Iron had early medicinal uses by Egyptians, Hindus, Greeks, and Romans.[2,3] During the 17th century, iron was used to treat chlorosis (green disease), a condition often resulting from the iron deficiency.[4] However, it was not until 1932 that the importance of iron was finally settled by the convincing proof that inorganic iron was needed for hemoglobin synthesis.[5] For many years, nutritional interest in iron focused on its role in hemoglobin formation and oxygen transport.[6] Nowadays, although low iron intake and/or bioavailability are responsible for most anemia in industrialized countries, they account for only about half of the anemia in developing countries,[7] where infectious and inflammatory diseases (especially malaria), blood loss from parasitic infections, and other nutrient deficiencies (vitamin A, riboflavin, folic acid, and vitamin B12) are also important causes.[8]

Biochemistry and physiology

In contrast to zinc, iron is an abundant element on earth[2,9] and is a biologically essential component of every living organism.[10,11] However, despite its geologic abundance, iron is often a growth limiting factor in the environment.[9] This apparent paradox is due to the fact that in contact with oxygen iron forms oxides, which are highly insoluble, and thus is not readily available for uptake by organisms.[2] In response, various cellular mechanisms have evolved to capture iron from the environment in biologically useful forms. Examples are siderophores secreted by microbes to capture iron in a highly specific complex[12] or mechanisms to reduce iron from the insoluble ferric iron (Fe+3) to the soluble ferrous form (Fe+2) as in yeasts.[13] Many of the mechanisms found in lower organisms, have analogous counterparts in higher organisms, including humans. In the human body, iron mainly exists in complex forms bound to protein (hemoprotein) as heme compounds (hemoglobin or myoglobin), heme enzymes, or nonheme compounds (flavin-iron enzymes, transferring, and ferritin).[3] The body requires iron for the synthesis of its oxygen transport proteins, in particular hemoglobin and myoglobin, and for the formation of heme enzymes and other iron-containing enzymes involved in electron transfer and oxidation-reductions.[14,3] Almost two-thirds of the body iron is found in the hemoglobin present in circulating erythrocytes, 25% is contained in a readily mobilizable iron store, and the remaining 15% is bound to myoglobin in muscle tissue and in a variety of enzymes involved in the oxidative metabolism and many other cell functions.[15]

Iron is recycled and thus conserved by the body. Figure 1 shows a schematic diagram of iron cycle in the body. Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma mainly from intestinal enterocytes or reticuloendothelial macrophages. The binding of iron-laden transferrin to the cell-surface transferrin receptor (TfR) 1 results in endocytosis and uptake of the metal cargo. Internalized iron is transported to mitochondria for the synthesis of heme or iron-sulfur clusters, which are integral parts of several metalloproteins, and excess iron is stored and detoxified in cytosolic ferritin.

Figure 1

Iron is bound and transported in the body via transferrin and stored in ferritin molecules. Once iron is absorbed, there is no physiologic mechanism for excretion of excess iron from the body other than blood loss, that is, pregnancy, menstruation, or ...

METABOLISM

Absorption

The fraction of iron absorbed from the amount ingested is typically low, but may range from 5% to 35% depending on circumstances and type of iron.[3]

Iron absorption occurs by the enterocytes by divalent metal transporter 1, a