Williams Hematology



Iron Compartments in Man






Dietary Iron
Iron Absorption
Transport of Iron



Role of the Monocyte-Macrophage System
Iron Excretion
Genetic Disorders Related To Iron Metabolism
Chapter References

Iron is a component of all living organisms. It plays an important role, particularly in electron transfer reactions. Much of the iron in the human body is in circulating red cells, which contain 1 mg of iron per 1 ml of packed cells. Iron is stored in the form of ferritin or hemosiderin. Smaller amounts of iron are present in myoglobin and in many enzymes. Because little iron is lost from the body, the iron content of the body is regulated by modulating iron absorption. Separate pathways exist for the absorption of heme and inorganic iron. The precise mechanism by which iron passes across the intestinal mucosa into the plasma has not yet been elucidated. The process appears to involve a ferrireductase, a divalent iron transporter DMT1, hephaestin, an integrin, and very likely the HFE protein. Iron absorption is increased in the presence of iron deficiency, and it decreases when there is iron overload. Once it enters the plasma, iron in the ferric form is bound by transferrin, which transports the metal into cells after being bound by the transferrin receptor. The transferrin receptor is internalized together with bound transferrin and iron, and the iron is released inside the cell into an acidified vacuole. The transferrin receptor then moves back to the cell surface.
Many of the proteins involved in iron transport are regulated by the amount of available iron through iron responsive elements (IREs), which exist as stem loop structures in RNA. IREs can serve to regulate either translation of mRNA or stability of mRNA. This regulation is achieved by IRPs (iron regulatory proteins). The major IRP is cytoplasmic aconitase, which binds to the IRE when it is not complexed with iron and does not bind when iron is present.

Acronyms and abbreviations that appear in this chapter include: DCT-1, divalent cation transporter 1; DMT1, divalent metal transporter 1; ECF, extracellular fluid; H, heavy; IREs, iron-responsive elements; IRPs, iron regulatory proteins; L, light; mk, microcytic anemia; TfR, transferrin receptor; sla, sex-linked anemia.

Iron is a key element in the metabolism of all living organisms. In plants, ferredoxins are essential for an early step of photosynthesis. DNA synthesis requires the enzyme ribonucleotide reductase to convert ribonucleotides to deoxyribonucleotides. Neither bacteria nor nucleated cells proliferate when the supply of iron is insufficient. Iron is a part of heme, which is the active site of electron transport in cytochromes and cytochrome oxygenase, essential coenzymes in the Krebs cycle. Heme is also the site of O2 uptake by myoglobin and hemoglobin, providing the means of O2 transport to tissues. In the root nodules of legumes hemoglobin catalyzes the fixation of atmospheric N2 by symbiotic bacteria. This is an important natural means of fertilization of soil and for synthesis of plant proteins. Heme is also the active site of peroxidases that protect cells from oxidative injury by reducing peroxides to water.
Many iron proteins are structurally related. Iron-sulfur proteins have an Fe-S cluster at the active sites. These include ferredoxins in plants, ribonucleotide reductase, aconitase, and succinic dehydrogenase. Heme proteins include hemoglobin, myoglobin, the cytochromes, cytochrome oxidase, homogentisic oxidase, peroxidases, and catalase. Iron flavoproteins include cytochrome c reductase, NADH dehydrogenase, acyl coenzyme A dehydrogenase, and xanthine oxidase. A heterogeneous group of proteins contain iron in a variety of molecular configurations.1
Aconitase catalyzes a critical, early step in the Krebs cycle, the interconversion of citric, isocitric, and cis-aconitic acids (Fig. 24-1). When iron is abundant within the cytosol, the cubane (cubelike) structure of the aconitase molecule contains a 4Fe-4S cluster (Fig. 24-2, left). In this form, it is an active enzyme. When iron is scarce, the cluster opens as 3Fe-4S.2,3 and 4 Then it is not an enzyme but the iron regulatory protein IRP-1 (Fig. 24-2, right) that interacts with iron-responsive elements (discussed later) to increase the synthesis of proteins that determine the cellular uptake of iron. Nearly half the enzymes and cofactors of the Krebs tricarboxylic acid cycle either contain iron or require its presence.

FIGURE 24-1 The interrelationship of iron metabolism and energy metabolism. Aconitase is critical to the regulation of both. Mitochondrial aconitase is a critical enzyme in the Krebs cycle (left). On the right, iron metabolism is regulated at the mRNA/ribosomal level by cytoplasmic aconitase, that, when iron-depleted becomes IRP-1.

FIGURE 24-2 The iron-sulfur cluster of aconitase. Left: The active enzyme, with its Fe-S cluster in the cubane (cubelike) structure, catalyzes the interconversion of citric, cis-aconitic, and iso-citric acids in the Krebs cycle. Right: When iron is insufficient in the cytosol, the Fe-S cluster opens; it then becomes the iron regulatory protein. (From Beinert H. and Kennedy MC,4 with permission of the Federation of American Societies for Experimental Biology, FASEB).

Several iron compartments are shown in Table 24-1 and are discussed below.


Approximately 2 g of body iron of men and 1.5 g in women is in hemoglobin, which is 0.34 percent iron by weight. One mL of packed erythrocytes contains approximately 1 mg of iron.
Iron is stored either as ferritin or as hemosiderin. The former is water-soluble; the latter is water-insoluble. Ferritin is composed of a core ferrihydrite crystal (Fe2O3 · 9 H2O)x within an apoferritin shell.5
Apoferritin is composed of 24 similar or identical subunits arranged as 12 dimers forming a dodecahedron that approximates a hollow sphere (Fig. 24-3a and Fig. 24-3b). The apoferritin monomers are of H (heavy) or L (light) type. L monomers have 15 hydrophilic residues that may bind iron, thereby promoting its retention and serving as sites for ferrihydrite crystal growth. H monomers have fewer hydrophilic residues but contribute an iron-binding histidyl to the intermonomeric pore (where iron atoms enter or exit). H monomers have ferroxidase activity, thereby enabling apoferritin to take up or release iron quite rapidly (Fig. 24-4).6,7,8 and 9 Apoferritin that is rich in H monomers takes up iron more readily but retains it less avidly than does ferritin composed predominantly of L monomers.5,10 Much of the storage iron in liver and spleen is in ferritin containing mostly L monomers.

FIGURE 24-3 The quaternary structure of apoferritin. Twenty-four subunits or apoferritin monomers are joined in 12 pairs, to form a dodecahedron, or 12-sided structure, that approximates a hollow sphere. As shown in c, lower left, each monomer consists of 4 long helices (A–D) nearly parallel to each other, and a short E helix. In upper left (a), the apoferritin shell is composed of 24 monomers shown in helical configurations. In lower right (b) is a scheme for the pairing of monomers to form a dodecahedron. (From Hempstead et al,5 by permission of Journal of Molecular Biology).

FIGURE 24-4 A scheme for the uptake and oxidation of Fe++ by apoferritin. Two iron-binding sites are hypothesized within each pore channel. The outermost of these has a higher affinity for Fe++, and the innermost has a higher affinity for Fe+++. As two ferrous ions enter the pore, they are bound, then oxidized to Fe+++. The iron is then displaced to the inner binding site, where ferrihydrite (Fe2O3 · 9H2O) forms and is added to the ferrihydrite crystal in the central cavity of apoferritin. Apoferritin thus acts as a ferroxidase in the oxidation of Fe++ to Fe+++. (Crichton and Roman,8 by permission of the Journal of Molecular Catalysis.)

Apoferritin synthesis is regulated in accordance with iron sufficiency or lack, as described below in the section entitled “The Intracellular Regulation of Iron Metabolism.”
Ferritin occurs in virtually all cells of the body and also in tissue fluids. In blood plasma ferritin is present in minute concentration. It is largely composed of H monomers. The plasma (serum) ferritin concentration usually correlates with total-body iron stores, which makes this measurement important in the diagnosis of disorders of iron metabolism (see Chap. 38 and Chap. 42).
Hemosiderin occurs predominantly in macrophages of the monocyte-macrophage system (marrow, liver, and spleen). It can be seen microscopically in unstained tissue sections or marrow films as clumps or granules of golden refractile pigment. Hemosiderin contains approximately 25 to 30 percent iron by weight. Under pathologic conditions, it may accumulate in large quantities in almost every tissue of the body. Hemosiderin consists of aggregates of ferrihydrite core crystals,11,12 and 13 largely devoid of apoferritin.
The size of the storage compartment is quite variable. Normally in adult men it amounts to 800 to 1000 mg; in adult women it is a few hundred milligrams. Depletion of the storage iron occurs when iron loss exceeds iron absorption. The mobilization of storage iron involves the reduction of Fe+++ to Fe++, its release from the core crystal and its diffusion out of the apoferritin shell. As it passes from cytosol to plasma, it must be reoxidized, either by hephaestin in the cell membrane or by ceruloplasmin in plasma, before it binds to transferrin.
Myoglobin is structurally similar to hemoglobin, but it is monomeric: Each myoglobin molecule consists of a heme group nearly surrounded by loops of a long polypeptide chain containing approximately 150 amino acid residues. Myoglobin is present in small amounts in all skeletal and cardiac muscle cells, in which it may serve as an oxygen reservoir to protect against cellular injury during periods of oxygen deprivation.
The labile iron pool was postulated from studies of the rate of clearance of injected 59Fe from plasma.14,15 Iron leaves the plasma and enters the interstitial and intracellular fluid compartments for a brief time before it is incorporated into heme or storage compounds. Some of the iron reenters plasma, causing a biphasic curve of 59Fe clearance 1 to 2 days after injection. The change in slope defines the size of the labile pool, normally 80 to 90 mg of iron.
Tissue iron normally amounts to 6 to 8 mg. This comprises cytochromes and iron-containing enzymes. Although a small compartment, it is an extremely vital one that is sensitive to iron deficiency.16,17,18,19,20 and 21
From the standpoint of its total iron content, normally about 3 mg, the transport compartment of plasma is the smallest but the most active of the iron compartments: Its iron normally turns over at least 10 times each day. This is a common pathway for interchange of iron between compartments (Fig. 24-4).
Transferrins and lactoferrins comprise a group of glycoproteins that transport iron in plasma and in milk, respectively. They are single polypeptide chains with an Mr of approximately 80 kDA. Each molecule has two binding sites for Fe+++ and bicarbonate. Each is bilobed, and within each lobe the iron-binding site is in a cleft between two domains that are designated N and C (for aminoterminal and carboxy-terminal). Thus, each complete transferrin or lactoferrin molecule has two N domains and two C domains. Within each lobe, Fe+++ is bound to both the N and C domains, which fold over and enclose the Fe+++.22,23
Normally, approximately one-third of the transferrin iron-binding sites are occupied by iron. About 200 mg (2.5 µmol) of transferrin, carrying about 100 µg (1.8 µmol) of iron per deciliter is normally present in human plasma.
Apotransferrin (transferrin devoid of iron) is synthesized by hepatocytes and by cells of the monocyte-macrophage system.24,25 At least 19 genetically determined molecular variants of transferrin have been described26,27 in humans. Their iron-binding and kinetic properties seem to be identical.
The iron content of the diet is variable. An average American male ingests 10 to 20 mg of iron daily.28,29 Table 24-2 shows daily requirements that are age- and sex-specific. The amount of iron absorbed by a normal adult male need only balance the small amount that is excreted, mostly in the stool, approximately 1 mg per day. A higher iron requirement exists during growth periods or when there is blood loss. In women, iron absorbed must be sufficient to replace that lost through menstruation or diverted to the fetus during pregnancy


The iron gained by food during cooking or other food processing is in the form of simple inorganic salts or iron-amino acid complexes. Heme, as from hemoglobin and myoglobin, normally comprises about one-third of dietary iron.
Iron is absorbed at the brush border of epithelial cells of the intestinal villi, particularly in the duodenum and upper jejunum. It is absorbed in the form of heme, or as ferric or ferrous ions (Fig. 24-5). In humans little of the heme absorbed by mucosal cells passes directly into plasma.30,31 In microsomes, heme oxygenase converts heme to biliverdin, CO, and Fe+++.32,33

FIGURE 24-5 A scheme for the mechanism of iron uptake by epithelial cells of the duodenum and its transport across the epithelial cell to plasma of the subepithelial capillaries. At least nine proteins appear to be involved in this mechanism. They are mucin in the gastric and duodenal lumen; ferric reductase, b3-integrin, DMT1, HFE, and hephaestin, which are cell membrane proteins; ceruloplasmin and transferrin, in plasma of the capillary network. Heme appears to enter the cell directly, by means as yet unknown. The iron is released by heme oxygenase. The uptake of Fe++ at the brush border may be mediated by DMT1. Fe++ traverses the cytosol. At the ablumenal (basal) membrane, it is bound to hephaestin, a ceruloplasmin-like membrane protein that oxidizes it to Fe+++. Thus, it exits the cell, and in plasma, it is bound by monoferric-transferrin. The absorption of ferric iron is not well understood. A ferric reductase on the membrane of the brush border may reduce it to the ferrous state, enabling it to enter the cell. Fe+++ that is complexed with mucin also appears to bind to a protein of the brush border membrane that is b3-integrin. The iron-b3-integrin complex may then be internalized to form, within the cytosol, a complex with calreticulin (mobilferrin) and a flavin monooxygenase. This complex has been called paraferritin, although it neither contains nor resembles ferritin. In this complex, Fe+++ is reduced to Fe++. In the ferrous form, it may traverse the cell to be taken up by hephaestin, which oxidizes it to Fe+++ and releases it to plasma.
The avidity of villus epithelial cells for iron is “programmed” when they are in the crypts, before they migrate up the villi. In the crypts, HFE protein somehow determines whether, a few days later as absorptive cells, they will absorb little iron or much iron.

Gastric juice stabilizes dietary ferric iron, preventing its precipitation as insoluble ferric hydroxide.34,35 This may be due in part to chelation of Fe+++ by small molecules in the gastric juice, such as amino acids and keto sugars.36,37 At pH less than 3, Fe+++ is stable and binds loosely to mucin.38 Within the brush border of the epithelial cell, a transmembrane ferric reductase converts Fe+++ to Fe++.39
It is still uncertain how iron passes from the luminal to the abluminal (basal and lateral portions of the cell) membrane. This process may require a b3-integrin, mobilferrin (calreticulin or calnexin), a flavomonooxygenase,40 the divalent metal transporter DMT1 (also called Nramp2 or DCT-1 for divalent cation transporter 1), and hephaestin.
Hephaestin is a transmembrane protein of the basal membrane that is essential for the release of iron to plasma. It is structurally homologous to ceruloplasmin.41 Both are ferroxidases. Ceruloplasmin serves as a scavenger of Fe++ in plasma, converting it to Fe+++, which may then be taken up by monoferric transferrin. In the absence of plasma ceruloplasmin, ferrous iron atoms readily enter cells and are deposited in tissues throughout the body, with serious consequences (see aceruloplasminemia, Chap. 42).
Whereas the epithelial cells of villi of the duodenal mucosa are the principal site of iron absorption, the programming of these cells for rate of iron absorption occurs in the crypt epithelial cells.42 In the latter cells, HFE protein and transferrin receptor (TfR) colocalize in the perinuclear endoplasmic reticulum.43 (This localization is unique to the crypt epithelial cells of the upper small bowel. In most other cells, TfR is a membrane protein, HFE protein spans the cell membrane, and in the membrane HFE protein modulates iron uptake through its binding with TfR.) In the perinuclear endoplasmic reticulum of crypt epithelial cells, the HFE-TfR complex somehow modulates the iron-absorbing function that the cell will have as it migrates along the villus toward the lumen, becoming an absorptive cell.
Iron may also be trapped in ferritin within the epithelial cells of the gastrointestinal tract, thereby preventing its absorption when body iron stores are high.44,45,46 and 47 With the passage of time the mucosal cell advances to the tip of the villus, is sloughed and lost in the feces, together with its retained iron.
The absorption of iron is modulated to meet the body’s needs: The absorbed fraction is reduced when body iron stores are high. Yet this physiological mechanism is easily overcome by large oral doses of medicinal iron or by accidental ingestion of iron by a child. There is no “mucosal block” of iron absorption: For each increment in dose of an inorganic iron compound there is a corresponding increment in the amount of iron absorbed.48,49,50 and 51 (Fig. 24-6).

FIGURE 24-6 The relationship between oral iron dosage and amount of iron absorbed in humans. When the logarithm of the dose is plotted against the logarithm of the amount of iron absorbed, a rectilinear relationship is observed. Thus, at all levels, the greater the dose of iron, the more is absorbed, although the percent of the dose that is absorbed progressively declines. (Drawn from data of Smith and Pannacciuli.48)

Iron absorption is enhanced when there is chronic liver disease.52,53 The mechanism is unknown. Pancreatic disorders appear not to influence iron absorption.54,55,56 and 57 Bile may facilitate iron absorption.58
Oxalates, phytates, and phosphates complex with iron and retard its absorption. Many simple reducing substances increase iron absorption. Among these are hydroquinone, ascorbate, lactate, pyruvate, succinate, fructose, cysteine, and sorbitol.59,60,61,62 and 63 There is contradictory evidence concerning the effect of ethanol on iron absorption.64,65
Among the factors operating outside the alimentary tract to increase iron absorption are hypoxia, anemia, depletion of iron stores, and increased erythropoiesis. Each of these factors appears to exert an independent effect, but it is not known how they “instruct” the bowel to absorb more iron. The degree of transferrin saturation, the plasma iron concentration, the rate of plasma iron clearance, and the plasma erythropoietin concentration have each been considered as humoral messengers. The fine control of the rate of iron absorption may depend on more than one humoral mechanism.
Once an atom of iron enters the body, it is virtually in a closed system (Fig. 24-7) in which it cycles almost endlessly from the plasma to the developing erythroblast (where it is utilized in hemoglobin synthesis), thence into the circulating blood for about 4 months, and then to phagocytic macrophages. Here it is removed from hemoglobin and released back into the plasma to repeat the cycle.

FIGURE 24-7 The iron cycle in humans. Iron is tightly conserved in a nearly closed system in which each iron atom cycles repeatedly from plasma and extracellular fluid (ECF) to the marrow, where it is incorporated into hemoglobin. Then it moves into the blood within erythrocytes and circulates for 4 months. It then travels to phagocytes of the reticuloendothelial system, where senescent erythrocytes are engulfed and destroyed, hemoglobin is digested, and iron is released to plasma, where the cycle continues. With each cycle, a small proportion of iron is transferred to storage sites, where it is incorporated into ferritin or hemosiderin, a small proportion of storage iron is released to plasma, a small proportion is lost in urine, sweat, feces, or blood, and an equivalent small amount of iron is absorbed from the intestinal tract. In addition, a small proportion (about 10%) of newly formed erythrocytes normally is destroyed within the bone marrow and its iron released, bypassing the circulating blood part of the cycle (ineffective erythropoiesis). The numbers indicate the approximate amount of iron (in mg) that enters and leaves each of these iron compartments every day in healthy adults who do not have bleeding or other blood disorders.

The major function of the transport protein transferrin is to move iron from wherever it enters the plasma (intestinal villi, splenic sinusoids) to the erythroblasts of the marrow. It binds to TfR on the erythroblast membrane.66,67 and 68 Even this late in hemoglobin synthesis, the membrane of a reticulocyte can still bind from 25,000 to 50,000 diferric transferrin molecules per minute.
Relatively small amounts of iron are transported to other tissues, especially in a slow exchange with the iron in ferritin and hemosiderin and to a much lesser extent with other tissue forms of iron.
Diferric transferrin binds to the transferrin receptor on the cell surface,69,70,71 and 72 and the transferrin-TfR complex forms clusters in pits on the cell membrane.73,74 The complex is then internalized by endocytosis. Within the cytosol the transferrin-TfR complex is in a clathrin-coated vesicle. The vesicles fuse with endosomes, in which occur acidification and release of iron from transferrin. Transformation into lysosomes does not occur. Neither transferrin nor TfR is degraded in the process. Within the vesicle, a low pH (approximately pH 5) in the vesicle releases one iron atom.75,76 Release of the other iron atom may be mediated by ATP, other small molecules, or by hemoglobin. The process may require reduction of iron from the ferric to ferrous form. The apotransferrin-TfR complex then returns to the cell membrane, where at neutral pH, apotransferrin is released to the interstitial fluid to reenter plasma and take up more iron.74,75
TfR is a protein consisting of two subunits that are linked by disulfide bonds.77 It is a group II transmembrane protein: Its amino-terminus is on the cytoplasmic side of the membrane, and its carboxy-terminus is on the outer surface.78 Because of the role of TfR in the binding and endocytosis of diferric transferrin, control of TfR biosynthesis is a major mechanism for regulation of iron metabolism. Synthesis of TfR is induced by iron deficiency, or, experimentally, by incubation with an iron chelating agent such as desferrioxamine. Conversely, synthesis of TfR is inhibited by heme.79
The binding of diferric transferrin by TfR is modulated by another transmembrane protein called HFE. This protein was discovered through studies of hemochromatosis: Abnormalities in this protein are responsible for most cases of hemochromatosis (see Chap. 42), hence it may be called “the hemochromatosis protein.” Within the cytosol, HFE forms a complex with TfR, reducing the number of TfR sites on the cell membrane. HFE also acts at the membrane to inhibit internalization of the TfR-transferrin-iron complex.80,81 and 82
Once within the developing erythroblast, iron must be transported to mitochondria to be incorporated into heme or taken up by ferritin within siderosomes. Within the vesicle, another protein called DMT1 (divalent metal transporter 1) effects the release of Fe+++ into the cytosol, where it is taken up by mitochondria for heme synthesis (Fig. 24-8).

FIGURE 24-8 The cellular uptake and cycling or iron, shown for an erythroblast in the bone marrow. (See text for explanation.)

Within mitochondria, iron is inserted into protoporphyrin by heme synthetase (ferrochelatase). When heme synthesis is impaired, as in lead poisoning or in the sideroblastic anemias (see Chap. 63), the mitochondria accumulate excessive amounts of amorphous iron aggregates.83 The mitochondria can then be stained by the Prussian blue reaction and are seen by light microscopy as a ring of large blue siderotic granules encircling the erythroblast nucleus (ringed sideroblast). In normal marrow, siderotic granules are also demonstrable in erythroblast cytoplasm. However, these are very small, usually only one to three in number, and randomly distributed in the cytoplasm. These normal siderotic granules are ferritin aggregates located in lysosomal organelles designated siderosomes.84 Erythroblasts containing these siderotic granules are called sideroblasts and normally represent 20 to 50 percent of the erythrocyte precursors of the marrow. In iron deficiency and in anemia that accompanies chronic disorders, sideroblasts almost disappear from the marrow. Conversely, in some states of iron overload, they may become more numerous and contain more siderotic granules than normally.
The regulation of synthesis of apoferritin, TfR, ALA synthase, apotransferrin, aconitase, DMT1, and possibly other proteins that are important in iron metabolism, is at the level of translation of mRNA by ribosomes. The mRNA for each of these proteins contains one or several IREs. Each IRE consists of a stem and loop structure, in which the loop is the nucleotide sequence CAGUGC (Fig. 24-9). The apoferritin mRNA has, as its IRE, a single stem-loop structure in the 5′ (upstream) untranslated region. In contrast to the apoferritin IRE, those for TfR consist of as many as 5 stems-loops in the 3′ (downstream) untranslated portion of TfR mRNA.79,85,86,87,88 and 89

FIGURE 24-9 The stem-loop structure that is the iron-responsive element of apoferritin mRNA. (From Hentze and coworkers,112 with permission.)

IRP-1 (iron regulatory protein 1, or desferri-aconitase) binds to the apoferritin IRE to down-regulate apoferritin synthesis. The presence of iron in the cytosol causes IRP-1 to convert to the cubane form as aconitase, thereby displacing it from the IRE and reducing the inhibition of apoferritin synthesis.87,89,90,91,92,93,94,95 and 96 Iron also causes translocation of preformed apoferritin messenger RNA to polyribosomes, where synthesis of apoferritin occurs. The effect of binding of IRP-1 to the IREs for apotransferrin, TfR, DMT1, and ALA synthase is to increase synthesis of these proteins; conversely, when the iron content of cytosol is high, the displacement of IRP-1 from these IREs leads to decreased synthesis of these proteins. Fig. 24-10 illustrates these relationships for the regulation of synthesis of apoferritin and TfR.

FIGURE 24-10 The regulation of iron metabolism at the cytoplasmic mRNA level by interaction of iron regulatory protein (IRP-1) and the iron-responsive elements (IREs) of apoferritin mRNA (above) and transferrin receptor (TfR) mRNA (below). When the cytoplasmic iron concentration is low (left), IRP-1 binds to the IREs of both mRNAs. This represses the translation of apoferritin mRNA, thereby reducing the amount of apoferritin formed, and stabilizes and increases the translation of TfR mRNA, thereby increasing the amount of TfR formed, which in turn increases the ability of the cell to bind diferric transferrin. Conversely, when there is an abundance of iron in the cytoplasm (right), IRP-1 is displaced from both species of mRNA. This results in derepression of apoferritin synthesis and destabilization and degradation of TfR mRNA. Then, apoferritin increases within the cytosol, and there is reduction in the number of TfR molecules on the cell membrane. (Modified from: Knisely,113 by permission of Mosby/Year Book.)

There is some redundancy in iron regulatory protein: in addition to IRP-1, there is an IRP-2 that also acts on IREs. IRP-2 is structurally different; it does not contain an iron-sulfur cluster. It undergoes proteolysis when the iron concentration is low.3,97,98
In addition to mechanisms for regulation of iron metabolism at the mRNA level, there is regulation at the DNA level of the expression of the genes for proteins important in iron metabolism. As yet, little is known about these regulatory mechanisms that reside within the cell nucleus. However, present evidence indicates that the cellular uptake and metabolism of iron are predominantly regulated at the level of cytoplasmic mRNA, as described above, rather than at the level of DNA.
Destruction of aged erythrocytes and hemoglobin degradation occur within macrophages. This proceeds at a rate sufficient to release approximately 20 percent of the hemoglobin iron within a few hours. As iron is released, it is bound to transferrin and ultimately redistributed, approximately 80 percent being rapidly reincorporated into hemoglobin. Thus, about 40 percent of the hemoglobin iron of nonviable erythrocytes reappears in circulating red cells in 12 days. The rate of reutilization is normally about 19 to 69 percent in 12 days. The remainder of the iron enters the storage pool as ferritin or hemosiderin and then turns over very slowly. In normal subjects, approximately 40 percent of this iron remains in storage after 140 days. When there is an increased iron demand for hemoglobin synthesis, however, storage iron may be mobilized more rapidly.99 Conversely, in the presence of infection or other inflammatory process or malignancy, iron is much more slowly reutilized in hemoglobin synthesis.99,100,101 and 102
These perturbations in iron reutilization are believed to be due to changes in the rate of iron-release macrophages. Chronic inflammatory disease causes reduction in the rate of release of iron by phagocytic cells, increased storage of iron in the monocyte-macrophage system, slowing of delivery of iron to erythropoietic cells, and slowing of erythropoiesis. Microcytic anemia is a consequence of the reduced flow of iron from the monocyte-macrophage system to the developing erythroblasts.
In addition to their role in regulating the size of iron stores, macrophages contribute to regulation of the plasma transferrin concentration through synthesis of apotransferrin and the internalization and degradation of transferrin.103,104 and 105
The body conserves iron with remarkable efficiency: less than a thousandth of it is lost each day, an amount easily replaced if dietary sources are adequate. Almost all this iron loss occurs by way of the feces, and it normally amounts to about 1 mg per day. Exfoliation of skin and dermal appendages results in a much smaller loss, as does perspiration. Even in tropical climates, the loss of iron in sweat is minimal.106 Iron is excreted also in urine, but in very small amounts. In humans, lactation may cause excretion of about 1 mg iron daily, thus doubling the overall rate of iron excretion. Blood loss by normal menstruation contributes to negative iron balance (see Chap. 38).
While total daily iron excretion is normally about 1 mg for males and about 2 mg for menstruating women, persons with marked iron overload, as in hemochromatosis, may lose as much as 4 mg of iron daily by these mechanisms, a quantity insufficient to prevent the accumulation of storage iron.46
During the past few years, much has been learned of genetic disorders that are related to iron metabolism. Those associated with hemochromatosis are discussed in detail in Chap. 42.
A syndrome of congenital cataracts and hyperferritinemia has been reported in several families.107,108 This disorder has been attributed to mutation in the stem-loop structure of the apoferritin mRNA. Serum ferritin concentrations are thousands of µgm/L. The ferritin in these cases appears to contain only L monomers.
Deficiency of hephaestin is responsible for a congenital microcytic anemia in the sla (sex-linked anemia) inborn strain of mice.41 Microcytic anemia (mk) mice are unable to absorb iron from the intestinal tract. They also fail to respond to parenterally administered iron. Thus, their red blood cell precursors are also unable to take up iron from plasma. Remarkably, the same DMT1 mis-sense mutation that was found in mk mice, G185R, causes marked reduction in iron absorption in Belgrade laboratory rats, an inbred strain with a hereditary microcytic anemia.109,110,111

Beutler E: Iron enzymes in iron deficiency. VI. Aconitase activity and citrate metabolism. J Clin Invest 38:1605, 1959.

Paraskeva E, Hentze MW: Iron-sulphur clusters as genetic regulatory switches: the bifunctional iron regulatory protein-1. [Review] [50 refs]. FEBS Lett 389:40, 1996.

Henderson BR, Menotti E, Kuhn LC: Iron regulatory proteins 1 and 2 bind distinct sets of RNA target sequences. J Biol Chem 271:4900, 1996.

Beinert J, Kennedy MC: Aconitase, a two-faced protein: enzyme and iron regulatory factor. FASEB J 7:1442, 1993.

Hempstead PD, Yewdall SJ, Fernie AR, et al: Comparison of the three-dimensional structures of recombinant human H and horse L ferritins at high resolution. JMB 268:424, 1997.

Hoy TG, Harrison PM, Shabbir M, Macara IG: The release of iron from horse spleen ferritin to 1,10-phenanthroline. Biochem J 137:67, 1974.

Jones T, Spence R, Walsh C: Mechanism and kinetics of iron release from ferritin by dihydroflavins and dihydroflavin analogues. Biochemistry 17:4011, 1978.

Crichton RR, Roman F: A novel mechanism for ferritin iron oxidation and deposition. J Mol Catal 4:75, 1978.

Crichton RR, Roman F, Roland F, et al: Ferritin iron deposition and mobilisation. J Mol Catal 7:267, 1980.

Harrison PM, Arosio P: The ferritins: molecular properties, iron storage function and cellular regulation. [Review] [477 refs]. Biochim Biophys Acta 1275:161, 1996.

Richter GW: Electron microscopy of hemosiderin: Presence of ferritin and occurrence of crystalline lattices in hemosiderin deposits. J Biophys Biochem Cytol 4:55, 1958.

Fischbach FA, Gregory DW, Harrison PM, Hoy TG, Williams JM: On the structure of hemosiderin and its relationship to ferritin. J Ultrastruct Res 73:495, 1971.

Hoy TG, Jacobs A: Ferritin polymers and the formation of haemosiderin. Br J Haematol 49:593, 1981.

Pollycove M, Mortimer R: The quantitative determination of iron kinetics and hemoglobin synthesis in human subject. J Clin Invest 40:753, 1961.

Hosain F, Marsaglia G, Finch CA: Blood ferrokinetics in normal man. J Clin Invest 46:1, 1967.

Beutler E: Iron enzymes in iron deficiency. I. Cytochrome C. Am J Med Sci 234:517, 1957.

Beutler E, Blaisdell RK: Iron enzymes in iron deficiency. III. Catalase in rat red cells and liver with some further observations on cytochrome C. J Lab Clin Med 52:694, 1958.

Beutler E, Blaisdell RK: Iron enzymes in iron deficiency. V. Succinic dehydrogenase in rat liver, kidney and heart. Blood 15:30, 1960.

Jacobs A: Iron-containing enzymes in the buccal epithelium. Lancet 2:1331, 1961.

Dallan PR, Sunshine P, Leonard Y: Intestinal cytochrome response with repair of iron deficiency. Pediatrics 39:863, 1967.

Srivastava SK, Sanwal GG, Tewari KK: Biochemical alterations in rat tissue in iron deficiency anemia and repletion with iron. Indian J Biochem 2:257, 1965.

Bailey S, Evans RW, Garratt RC, et al: Molecular structure of serum transferrin at 3.3-A resolution. Biochemistry 27:5804, 1988.

Van Haeringen B, de Lange F, van Stokkum IHM, et al: Dynamic structure of human serum transferrin from transient electric birefringence experiments. Proteins: Structure, Function Genet 23:233, 1998.

Haurani FI, Meyer A, O’Brien R: Production of transferrin by the macrophage. J Reticuloendothel Soc 14:309, 1973.

Thorbecke GJ, Liem HH, Knight S, Cox K, Muller-Eberhard U: Sites of formation of the serum proteins transferrin and hemopexin. J Clin Invest 52:725, 1973.

Giblett ER: Genetic Markers in Human Blood. Philadelphia, Davis, 1969.

Aisen P: The transferrins, in Iron in Biochemistry and Medicine, edited by A Jacobs, M Worwood, p 87. Academic, New York, 1980.

Moore CV: Iron nutrition and requirements. Ser Haematol 6:1, 1965.

Pennington JAT, Young BE, Wilson DB, Johnson RD, Vanderveen JE: Mineral content of foods and total diets: the selected minerals in foods survey, 1982 to 1984. J Am Diet Assoc 86:876, 1986.

Turnbull A, Cleton F, Finch CA: Iron absorption. IV. The absorption of hemoglobin iron. J Clin Invest 41:1897, 1962.

Weintraub R, Weinstein MB, Huser H-J, Rafal S: Absorption of hemoglobin iron: the role of a heme-splitting substance in the intestinal mucosa. J Clin Invest 47:531, 1968.

Conrad ME, Benjamin BI, Williams HL, Foy AL: Human absorption of hemoglobin-iron. Gastroenterology 53:5, 1967.

Raffin SB, Woo CH, Roost KT, Price DC, Schmid R: Intestinal absorption of hemoglobin iron-heme cleavage by mucosal heme oxygenase. J Clin Invest 54:1344, 1975.

Beutler F, Fairbanks VF, Fahey JL: Clinical Disorders of Iron Metabolism. Grune & Stratton, New York, 1963.

Jacobs A: Gastric factor in iron absorption. Lancet 1:1313, 1968.

Van Campen D: Enhancement of iron absorption from ligated segments of rat intestine by histidine, cysteine, and lysine: Effects of removing ionizing groups and of stereoisomerism. J Nutr 103:139, 1973.

Davis PS, Deller DJ: Prediction and demonstration of iron chelating ability of sugars. Nature 212:405, 1966.

Conrad ME, Umbreit JN, Moore EG: A role for mucin the absorption of inorganic iron and other metal cations. A study in rats. Gastroenterology 100:129, 1991.

Eckmekcioglu C, Fkeyertag J, Marktl W: A ferric reductase activity is found in brush border membrane vesicles isolated from Caco-2 cells. J Nutr 126:2209, 1996.

Conrad ME, Umbreit JN, Moore EG, Heiman D: Mobilferrin is an intermediate in iron transport between transferrin and hemoglobin in K562 cells. J Clin Invest 98:1449, 1996.

Vulpe CD, Kuo YM, Murphy TL, et al: Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nature Genet 21:195, 1999.

Waheed A, Parkkila S, Saarnio J, et al: Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Proc Natl Acad Sci USA 96:1579, 1999.

Parkkila S, Waheed A, Britton RS, et al: Immunohisotchemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals a unique pattern of expression in gastrointestinal tract. Proc Natl Acad Sci USA 94:2534, 1997.

Conrad ME Jr, Crosby WH: Intestinal mucosal mechanisms controlling iron absorption. Blood 22:406, 1963.

Hartman RS, Conrad ME, Jr., Hartman RE, Joy RJT, Crosby WH: Ferritin containing bodies in human small intestinal epithelium. Blood 22:397, 1963.

Crosby WH, Conrad ME Jr, Wheby MS: The rate of iron accumulation in iron storage disease. Blood 22:429, 1963.

Wheby MS, Crosby WH: The gastrointestinal tract and iron absorption. Blood 22:416, 1963.

Smith MD, Pannacciulli IM: Absorption of inorganic iron from graded doses: Its significance in relation to iron absorption tests and the ‘mucosal block’ theory. Br J Haematol 4:428, 1958.

Bonnet JD, Hagedorn AB, Owen CA Jr: A quantitative method for measuring gastrointestinal absorption of iron. Blood 15:36, 1960.

Brown EB Jr, Dubach R, Moore CV: Studies in iron transportation and metabolism. XI. Critical analysis of mucosal block by large doses of inorganic iron in human subjects. J Lab Clin Med 52:335, 1958.

Beutler E, Kelly BM, Beutler F: The regulation of iron absorption. II. Relationship between iron dosage and iron absorption. Am J Clin Nutr 11:559, 1962.

Murray MJ, Stein N: A gastric factor promoting iron absorption. Lancet 1:614, 1968.

Smith RS: Iron absorption in cystic fibrosis. Br Med J 1:608, 1964.

Biggs JC, Davis AE: The exocrine pancreas and iron absorption. Aust Ann Med 15:36, 1966.

Kavin H, Charlton RW, Jacobs P, Green R, Torrance JD, Bothwell TH: Effect of the exocrine pancreatic secretions on iron absorption. Gut 8:556, 1967.

Murray MJ, Stein N: Does the pancreas influence iron absorption? A critical review of information on iron absorption. Gastroenterology 51:694, 1966.

Balcerzak SP, Peternel WW, Heinle EW: Iron absorption in chronic pancreatitis. Gastroenterology 53:257, 1967.

Wheby MS, Conrad ME, Hedberg SE, Crosby WH: The role of bile in the control of iron absorption. Gastroenterology 42:319, 1962.

Herndon JF, Rice EG, Tucker RG, VanLoon EJ, Greenberg SM: Iron absorption and metabolism. III. The enhancement of iron absorption in rats by D-sorbitol. J Nutr 64:615, 1958.

Hallberg L, Sölvell L: Iron absorption studies: [1] Determination of the absorption rate of iron in man. [2] Absorption of a single dose of iron in man. [3] Iron absorption during constant intragastric infusion of iron in man. [4] Effect of iron and transferrin intravenously on iron absorption and turnover in man (Sölvell alone). Acta Med Scand 168(suppl 358):1, 1960.

Pollack S, Kaufman RM, Crosby WH: Iron absorption: effects of sugars and reducing agents. Blood 24:577, 1964.

Slatkavitz CA, Clydesdale FM: Solubility of inorganic iron as affected by proteolytic digestion. Am J Clin Nutr 47:487, 1988.

Taylor PG, Martinez-Torres C, Romano EL, Layrisse M: The effect of cysteine-containing peptides released during meat digestion on iron absorption in humans. Am J Clin Nutr 43:68, 1986.

Charlton RW, Jacobs P, Seftel H, Bothwell TH: Effect of alcohol on iron absorption. Br Med J 2:1427, 1964.

Celada A, Rudolf H, Donath A: Effect of single ingestion of alcohol on iron absorption. Am J Hematol 5:225, 1978.

Jandl JH, Inman JK, Simmons RL, Allen DW: Transfer of iron from serum iron-binding protein to human reticulocytes. J Clin Invest 38:161, 1959.

Katz JH: The delivery of iron to the immature red cell: a critical review. Ser Haematol 6:15, 1965.

Jandl JH, Katz JH: The plasma-to-cell cycle of transferrin. J Clin Invest 42:314, 1963.

Bergamaschi G, Eng MJ, Huebers HA, Finch CA: The effect of transferrin saturation on internal iron exchange. Proc Soc Exp Biol Med 183:66, 1986.

Konopka K, Mareschal JC, Crichton RR: Iron transfer from transferrin to ferritin mediated by polyphosphate compounds. Biochim Biophys Acta 677:417, 1981.

Octave JN, Schneider YJ, Crichton RR, Trouet A: Transferrin protein and iron uptake by isolated rat erythroblasts. FEBS Lett 137:119, 1982.

Morgan EH, Baker E: Role of transferrin receptors and endocytosis in iron uptake by hepatic and erythroid cells. Ann NY Acad Sci 526:65, 1988.

Cheng TPO: Redistribution of cell surface transferrin receptors prior to their concentration in coated pits as revealed by immunoferritin labels. Cell Tissue Res 244:613, 1986.

Dautry-Varsait A: Receptor-mediated endocytosis: the intracellular journey of transferrin and its receptor. Biochemie 68:375, 1986.

Dautry-Varsat A, Ciechanover A, Lodish HF: pH and the recycling of transferrin during receptor mediated endocytosis. Proc Natl Acad Sci USA 80:2258, 1983.

Chan RYY, Loh TT: Perturbation of intracellular pH by DIDS on endocytosis of transferrin and iron update in rabbit reticulocytes. Biochem Biophys Res Commun 150:1256, 1988.

Schneider C, Williams JG: Molecular dissection of the human transferrin receptor. J Cell Sci 3(suppl):139, 1985.

Zerial M, Melancon P, Schneider C, Garoff H: The transmembrane segment of the human transferrin receptor functions as a signal peptide. EMBO J 5:1543, 1986.

Rouault T, Rao K, Harford J, Mattia E, Klausner RD: Hemin chelatable iron, and the regulation of transferrin receptor biosynthesis. J Biol Chem 260:14862, 1985.

Recalcati S, Pometta R, Levi S, Conte D, Cairo G: Response of monocyte iron regulatory protein activity to inflammation: abnormal behavior in genetic hemochromatosis. Blood 91:2565, 1998.

Andrews NC, Levy JE: Iron is hot: an update on the pathophysiology of hemochromatosis. Blood 92:1845, 1998.

Salter-Cid L, Brunmark A, Li Y, et al: Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: implications for cellular iron homeostasis. Proc Natl Acad Sci USA 96:5434, 1999.

Fawwaz RA, Winchell HS, Pollycove M, Sargent T: Hepatic iron deposition in humans. I. First-pass hepatic deposition of intestinally absorbed iron in patients with low plasma latent iron-binding capacity. Blood 30:417, 1967.

Cartwright GE, Deiss A: Sideroblasts, siderocytes, and sideroblastic anemia. N Engl J Med 292:185, 1975.

Casey JL, Di Jeso B, Rao KK, Rouault TA, Klausner RD, Harford JB: Deletional analysis of the promotor region of the human transferrin receptor gene. Nucl Acids Res 16:629, 1988.

Müller EW, Kühn LC: A stem-loop in the 3′ untranslated region mediates iron-dependent regulation of transferrin receptor mRNA stability in the cytoplasm. Cell 53:815, 1988.

Casey JL, Hentze MW, Koeller DM, et al: Iron-responsive elements: Regulatory RNA sequences that control mRNA levels and translation. Science 240:924, 1988.

Casey JL, Di Jeso B, Rao K, Klausner RD, Harford JB: Two genetic loci participate in the regulation by iron of the gene for the human transferrin receptor. Proc Natl Acad Sci USA 85:1787, 1988.

Casey JL, Di Jeso B, Rao K, Rouault TA, Klausner RD, Harford JB: The promoter region of the human transferrin receptor gene. Ann NY Acad Sci 526:54, 1988.

Rouault TA, Hentze MW, Caughman SW, Harford JB, Klausner RD: Binding of a cytosolic protein to the iron-responsive element of human ferritin messenger RNA. Science 241:1207, 1988.

Hentze MW, Caughman SW, Casey JL, et al: A model for the structure and functions of iron-responsive elements. Gene 72:201, 1988.

Rouault TA, Hentze MW, Haile DJ, Harford JB, Klausner RD: The iron-responsive element binding protein: a method for the affinity purification of a regulatory RNA-binding protein. Proc Natl Acad Sci USA 86:5768, 1989.

Leibold EA, Guo B: Iron-dependent regulation of ferritin and transferrin receptor expression by the iron-responsive element binding protein. Annu Rev Nutr 12:345, 1992.

Tang CK, Chin J, Harford JB, Klausner RD, Rouault TA: Iron regulates the activity of the iron-responsive element binding protein without changing its rate of synthesis or degradation. J Biol Chem 267:24466, 1992.

Haile DJ, Rouault TA, Tang CK, Chin J, Harford JB, Klausner RD: Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster. Proc Natl Acad Sci USA 89:7536, 1992.

Kühn LC, Hentze MW: Coordination of cellular iron metabolism by post-transcriptional gene regulation. J Inorg Biochem 47:183, 1992.

Rouault T, Klausner R: Regulation of iron metabolism in eukaryotes. Curr Top Cell Reg 35:1, 1997.

Henderson BR, Kuhn LC: Differential modulation of the RNA-binding proteins IRP-1 and IRP-2 in response to iron. IRP-2 inactivation requires translation of another protein. J Biol Chem 270:20509, 1995.

Noyes WD, Bothwell TH, Finch CA: The role of the reticulo-endothelial cell in iron metabolism. Br J Haematol 6:43, 1960.

Haurani FI, Burke W, Martinez EJ: Defective reutilization of iron in the anemia of inflammation. J Lab Clin Med 65:560, 1965.

Haurani FI, Young K, Tocantins LM: Reutilization of iron in anemia complicating malignant neoplasms. Blood 22:73, 1963.

O’Shea MJ, Kershenobich D, Tavill AS: Effects of inflammation on iron and transferrin metabolism. Br J Haematol 25:707, 1973.

MacSween RNM, MacDonald RA: Iron metabolism by reticuloendothelial cells in vitro uptake of transferrin-bound iron by rat and rabbit cells. Lab Invest 21:230, 1969.

MacDonald RA, MacSween RNM, Pechet GA: Iron metabolism by reticuloendothelial cells in vitro: physical and chemical conditions, lipotrope deficiency, and acute inflammation. Lab Invest 21:236, 1969.

Hemmaplardh D, Morgan EH: Transferrin and iron uptake by human cells in culture. Exp Cell Res 87:207, 1974.

Green R, Charlton R, Seftel H, Bothwell T: Body iron excretion in man: a collaborative study. Am J Med 45:336, 1968.

Beaumont C, Leneuve P, Devaux I, et al: Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract. Nature Genet 11:444, 1995.

Girelli D, Corrocher R, Bisceglia L, et al: Hereditary hyperferritinemia-cataract syndrome caused by a 29-base pair deletion in the iron responsive element of ferritin L-subunit gene. Blood 90:2084, 1997.

Fleming MD, Trenor CC III, Su MA, et al: Microctyic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nature Genet 16:383, 1997.

Su MA, Trenor CC, Fleming JC, Fleming MD, Andrews NC: The G185R mutation disrupts function of the iron transporter Nramp2. Blood 92:2157, 1998.

Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC: Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proceedings of the Natl Acad Sci USA 95:1148, 1998.

Hentze MW, Rouault TA, Wright-Caughman S, Dancis A, Harford JB, Klausner RD: A cis-acting element is necessary and sufficient for translational regulation of human ferritin expression in response to iron. Proc Natl Acad Sci USA 84:6730, 1987.

Knisely AS: Neonatal hemochromatosis. Adv Pediatr 39:383, 1992.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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