The Iron Metabolic System

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Chapter 9 The Iron Metabolic System

Iron is one of the essential micronutrients and, as such, is required for growth, development, and normal cellular functioning. In contrast to some other micronutrients, such as water-soluble vitamins, there is a significant danger of toxicity if excessive amounts of iron accumulate in the body. A finely tuned feedback control system functions to limit this excessive accumulation by limiting absorption of iron. This chapter discusses systemic and brain iron homeostasis.

Systemic Iron Homeostasis

Dietary Forms of Iron

Iron occurs in two fundamental forms in the human diet: heme and nonheme iron.1 Heme iron refers to all forms of iron from plant and animal sources in which the iron molecule is tightly bound within the porphyrin ring structure, as is found in both myoglobin and hemoglobin. Nonheme iron refers to all other forms of iron. Nonheme iron is solubilized and ionized by gastric acid juice, reduced to the ferrous form, and kept soluble in the upper gastrointestinal tract by chelation to compounds such as citrate and ascorbic acid. The types and amounts of other materials, such as ascorbic acid, that can chelate iron to keep it in solution also determine the amount of nonheme iron in a soluble luminal pool. The number of “inhibitors” of nonheme iron absorption is substantial with phytate, polyphenols, and tannins leading the list. These inhibitors typically bind either ferric or ferrous iron in a tight complex in the lumen of the gut and make it unavailable for the absorptive proteins. Thus, a diet that contains a large amount of unrefined grains and nondigestible fibers will have poor bioavailability. In contrast, a diet that is highly refined and contains little roughage and substantial portions of meat will have a greater iron bioavailability regardless of other factors. The American diet typically contains about 50% of its iron intake from grain products in which the iron concentration is between 0.1 and 0.4 mg per serving. Some fortified cereals, however, may contain as much as 24 mg of iron in a single serving. Heme iron is more highly bioavailable than nonheme iron and its bioavailability is less affected by other components of the diet than nonheme iron. Heme iron represents only about 10% of total dietary iron intake in many Western countries.

Regulation of Absorption

There are two fundamental regulators of iron absorption in humans. The first is the total amount and form of iron compounds ingested (discussed earlier), and the second is the iron status of the individual.2 Thus, individuals with a high iron status will absorb proportionally less of any amount of iron consumed than an iron-deficient individual, and individuals with a lower iron status will absorb more of any dietary intake. This process of selective absorption is the fundamental mechanism whereby humans regulate iron balance.3 Although the details of the regulation are still not yet entirely clear, major discoveries in the last decade have added substantially to our understanding. At supraphysiological levels (as in high-dose iron supplementation) iron can apparently move across the gut via paracellular diffusion following a concentration gradient. At more physiological concentrations, as would be expected with the consumption of food, iron uptake is mediated by a series of receptors and binding proteins, which distinguish heme from nonheme iron.

Heme Iron Absorption

Heme iron is soluble in an alkaline environment; hence, no binding proteins are necessary for its luminal absorption. Specific transporters exist for heme on the surface of enterocytes, and efforts are being made to characterize this heme transporter.4 After binding to its receptor, the heme molecule is then internalized, acted on by heme oxygenase (HOX1) to release the iron to the soluble cytoplasmic pool.5 HOX1 is not induced by oral administration of hemoglobin (a source of heme) but is induced by iron deficiency, suggesting some form of feedback regulation from the iron stores “signal.”5 The distribution of HOX1 in the intestine is identical to that of maximal heme iron absorption. Heme iron absorption is far more efficient than nonheme iron absorption.6 In a typical American diet, it is reasonable to expect that overall dietary nonheme iron absorption is approximately 5% to 10% efficient, whereas heme iron absorption is nearly 40% efficient.

Nonheme Iron Absorption

Divalent metal transporter (DMT) (Fig. 9-1) is a transmembrane protein that resides on the luminal membrane, has a strong preference for divalent metals, and exists in several isoforms (DMT1 and DMT2).2,7 The nonheme iron in the lumen of the gut has variable solubility depending on the various amounts of ferric and ferrous iron and the amounts of iron-binding compounds. A membrane-bound member of the cytochrome P450 family, Dcytb, accomplishes the rapid conversion of ferric to ferrous iron. Ferrous iron binds to DMT1, is internalized by vesicular endocytosis, and finally is released into the cellular cytoplasm. This iron is then free to be transported to the basolateral membrane for export by some as-yet-undescribed, intracellular iron-binding protein(s) or it can be incorporated into ferritin.8

Ferritin plays a primary role in both iron storage and detoxification and is found both intracellularly and in a secreted form in the blood.9 Ferritin molecules are composed of two subunit types, H and L. In general, H-chain ferritin is important in ferrous iron oxidation and often increases in response to acute inflammation. H-ferritin may serve as a regulator of cellular differentiation as well as a cytoprotectant.1015 L-ferritin levels are often reflective of long-term iron storage and are involved in the enucleation of iron in the core of the mature 24-subunit protein.16

The amount of ferritin that is synthesized by the enterocyte is regulated specifically by iron regulator proteins (IRP1 and IRP2), which bind with high affinity to an iron response element (IRE) located in the 5′-untranslated end of the ferritin mRNA.8,17 There is also a similar set of IREs on the 3′ end of the mRNA for transferrin receptor (TfR) and DMT1 that allows for a reciprocal regulation of iron storage and iron uptake. This iron responsive element/iron-regulatory protein (IRE-IRP) system of regulation, however, is also susceptible to oxidative stress because nitric oxide may alter the affinity of this regulator of protein translation.1820 The amount of IRP1 is, in turn, dependent on the cytosolic free iron concentration. In the presence of cytosolic iron, IRP1 becomes cytoplasmic aconitase with the iron in a 4 iron (Fe)–4 sulfur (S) complex. In the absence of iron, the IRP1 (now a 3Fe-4S complex) binds to the IREs of various iron proteins to regulate the translation of the mRNA transcripts.

A second iron regulatory protein, IRP2, is produced and metabolized in a distinctly different fashion than IRP1 and appears to be quite sensitive to oxygen partial pressure.22 IRP2, like IRP1, is sensitive to cytosolic-free iron and has somewhat different binding affinities to IREs than IRP1.8 Lower duodenal levels of ferritin mRNA are found in iron-deficient subjects and higher duodenal levels of ferritin mRNA found in secondary iron overload support the role of mucosal ferritin as a major regulator of iron absorption.21 Thus, enterocyte ferritin is the mucosal “iron sink” and can serve as a means of limiting iron absorption as the enterocytes are sloughed off the tip of the microvillus in 3.4 days.

Thus, it is now reasonable to assume the IRPs are the principal iron sensors in the enterocyte and determine the fate of iron movement for export or storage in ferritin.22 Consistent with this hypothesis is the fact that the concentrations of mucosal cell ferritin mRNA and ferritin protein in patients with familial hemochromatosis are lower than those of patients with secondary iron overload.21,23,24

Basolateral Membrane Iron Export

Ferroportin functions as the cellular iron exporter and also contains an IRE (like ferritin, and DMT1, TfR) and interacts, in some undefined fashion, with the hemochromatosis gene (HFE) protein on the abluminal enterocyte surface. Mutant forms of this protein are associated with very severe iron overload.25 Recent studies have identified a 25–amino acid protein, called hepcidin, which is secreted by hepatocytes in amounts proportional to iron stores.25 Hepcidin binds to another transmembrane protein, ferroportin, followed by its internalization and destruction.26

Plasma Transport and Storage

The ferroportin protein releases ferrous iron into the plasma pool where association with hephaestin and ceruloplasmin acts in a redox couple to form ferric iron. Hephaestin, a membrane-bound ferroxidase, has 50% amino acid homology with ceruloplasmin, another ferroxidase that is found in plasma.27 Mutations in the ceruloplasmin gene cause an autosomal recessive disease known as aceruloplasminemia. This disease is characterized by iron accumulation and clinically is often manifest by diabetes and degeneration of the retina and basal ganglia.28

Once ferric iron has been formed by either hephaestin or ceruloplasmin, it binds to transferrin (Tf). Tf is produced in a number of cells, but the liver is the primary donor to the plasma pool. The rate of production of Tf is affected by the iron status of the individual via transcriptional regulation.2 Individuals with depleted iron stores and a plasma Fe concentration of less than 40 to 60 µg/dL will have increased Tf production and increased plasma Tf concentration by nearly 100%. The two binding sites on Tf are nearly identical in binding affinity for iron (Kd = 10−22 mol/L). In vivo, Tf is normally 25% to 50% saturated with iron, but in iron deficiency, it can be less than 5% in the extreme.29 One of the criteria for establishing iron deficiency is for the transferrin saturation (TSAT) to be less than 15%.3 At this level of saturation, there is insufficient delivery of iron to bone marrow to maintain normal rates of erythropoiesis. Thus, under normal physiological circumstances, the iron-binding capacity of plasma is always in excess of iron concentration. The rate and location of the uptake of iron from the plasma pool are proportional to the number of TfRs expressed on plasma membranes.2 The normal concentration of iron in the human body is between 30 and 40 mg/kg, but nearly 85% of the nonstorage iron is found in the erythroid mass. The storage iron concentration in the body varies from 0 to 15 mg/kg depending on the gender and iron status of the individual. The liver contains more than 60% of the storage pool of iron with the metal sequestered inside the 24-subunit protein, ferritin. The core of this ferritin molecule can contain up to 4000 atoms of iron as ferric-hydrite. The amount of ferritin produced is determined by the IRP-IRE interaction previously described in the enterocyte. The remaining 40% of stored iron is found in muscle tissues and cells of the reticuloendothelial system.3 Normally, 95% of the stored iron in liver tissue is found in hepatocytes as ferritin. Iron in hemosiderin constitutes the remaining 5% and is found predominantly in Kupffer cell lysosomal remnants. During iron overload, however, the mass of hemosiderin iron in the liver accumulates at 10 times the rate of ferritin iron.30

Because the bone marrow has by far the greatest daily demand for iron, that is where greater than 80% of the plasma iron ends up on a daily basis. It is estimated that nearly 20 mg of Fe per day goes to the bone marrow for insertion into erthryoblasts in the porphyrin ring structure to form hemoglobin. As the plasma pool of iron is frequently less than 4 mg of iron, it is easy to compute that the half-life of an iron molecule in plasma is quite short. The other contributors to the plasma pool of iron apart from the gastrointestinal are macrophages, other reticuloendothelial (RE) cells, and hepatocytes. Iron turnover is primarily mediated by destruction of senescent erythrocytes by the reticuloendothelial system.31 Erythrocytes, which contain about 80% of the body’s functional iron, have a mean functional lifetime of 120 days in humans. At the end of their functional lifetime, they are recognized as senescent by changes in the structure of their membranes and are catabolized at extravascular sites by Kupffer cells and spleen macrophages. After phagocytosis, the globin chains of hemoglobin are denatured, which releases bound heme. Intracellular unbound heme is ultimately degraded by heme oxygenase, which liberates iron. About 85% of the iron derived from hemoglobin degradation is re-released to the body in the form of iron bound to Tf or ferritin. Each day, 0.66% of the body’s total iron content is recycled in this manner.32 Smaller contributions are made to plasma iron turnover by the degradation of myoglobin and iron-containing enzymes. Macrophage release of iron is affected by hepcidin, which alters the export of iron to the plasma pool.26

Iron Losses

The low solubility of iron at physiological pH precludes urinary excretion as a major mechanism of maintaining iron homeostasis. Thus, in contrast to most other trace minerals whose homeostasis in maintained by excretion, the primary mechanism of maintaining whole body iron homeostasis is to regulate the amount of iron absorbed so that it approximates iron losses. Iron losses can vary considerably with the gender of the individual. In males, total iron losses from the body have been calculated to be 1 mg/day. For premenopausal females, this loss is slightly higher. The predominant route of loss is from the gastrointestinal tract and amounts to 0.6 mg/day in men.32 Fecal iron losses derive from shed enterocytes, extravasated red blood cells, and biliary heme breakdown products, which are poorly absorbed. Urogenital and integumental iron losses have been estimated to be greater than 0.1 mg/day and 0.3 mg/day, respectively, in men.31 Menstrual iron loss, estimated from an average blood loss of 33 mL/month, equals 1.5 mg/day but may reach as high as 2.1 mg/day.33 Oral contraceptives reduce this loss and intrauterine devices increase it.34,35 Pregnancy is associated with losses approximating 1 g, which consist of a basal loss of 230 mg iron, increased maternal red cell mass of 450 mg iron, fetal needs of 270 to 300 mg iron, and placenta, deciduas, and an amniotic fluid iron content of 50 to 90 mg. A number of clinical and pathological conditions are attended by varying amounts of blood loss. These conditions include hemorrhage, hookworm infestation, peptic gastric or anastomotic ulceration, ulcerative colitis, colonic neoplasia, infant feeding with cow’s milk, aspirin, nonsteroidal anti-inflammatory drugs or corticosteroid administration, and hereditary hemorrhagic telangiectasia (see Bothwell3 for review). In addition to these conditions, a significant amount of iron (210 to 240 mg/unit) can be lost with regular blood donation.

Brain Iron Homeostasis

Many of the basic mechanisms (e.g., TfR, Tf, DMT1, ferroportin, hepcidin) operating to manage iron in systemic organs also operate within the brain. In this section, we review what is known about the cellular regulation of iron within the brain and the movement of iron across the blood-brain barrier (BBB).

The normal adult brain has a high concentration of iron (approximately 60 mg) in a distinct pattern of distribution. Hallgren and Sourander36 studied iron content in approximately 100 autopsy brains, establishing the standard reference for brain region iron quantification. They found the globus pallidus, red nucleus, substantia nigra, and putamen to contain the greatest amounts of iron, followed by the dentate nucleus, caudate nucleus, and frontal white matter. They also noted that iron content is low in all brain regions at birth and increases to a fairly constant value by about age 40. More recent studies by Bartzokis and colleagues37

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