Chapter 42: Iron Metabolism

Iron is a key element in the metabolism of nearly all living organisms. Iron is a component of heme, which is the active site of electron transport in cytochromes and cytochrome oxidase involved in mitochondrial energy generation. The heme moiety of hemoglobin and myoglobin binds O₂, providing the means to transfer O₂ from the lungs to tissues and to store it. Heme is also the active site of peroxidases that protect cells from oxidative injury by reducing peroxides to water or generate microbicidal hypochlorite in granulocytes. 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.

Table 42–1 summarizes the most important iron compartments.

HEMOGLOBIN

Hemoglobin, which is 0.34 percent iron by weight, contains approximately 2 g of body iron in men and 1.5 g in women. One mL of packed erythrocytes contains approximately 1 mg of iron. Because the life span of human erythrocytes is approximately 120 days, every day 1/120 of the iron in hemoglobin is recycled by macrophages and returned to the plasma, from where it is largely delivered to marrow erythroblasts for incorporation into newly synthesized hemoglobin.

STORAGE COMPARTMENT

Iron is stored either as ferritin or as hemosiderin. The former is water-soluble; the latter is water-insoluble. The protein ferritin is composed of 24 similar or identical subunits arranged as 12 dimers forming a dodecahedron that approximates a hollow sphere with a cavity capable of storing up to 4500 Fe atoms as hydrous ferric oxide polymers.^1,2 The ferritin subunits are of H (heavy) or L (light) type. H subunits have ferroxidase activity, thereby enabling ferritin to take up or release iron quite rapidly. Ferritin that is rich in H subunits takes up iron more readily, but retains it less avidly than does ferritin composed predominantly of L subunits. Much of the storage iron in liver and spleen is in ferritin containing mostly L subunits.

Ferritin is found in virtually all cells of the body and also in tissue fluids. In plasma ferritin is present in minute concentrations. It is glycosylated and largely composed of L subunits. Except under conditions of inflammation, the plasma (serum) ferritin concentration usually correlates with total-body iron stores, making measurement of serum ferritin levels important in the diagnosis of disorders of iron metabolism.

The size of the iron storage compartment is quite variable. Normally, in adult men, it amounts to 800 to 2000 mg; in adult women, it is a few hundred milligrams. The mobilization of storage iron from ferritin involves the reduction of Fe³⁺ to Fe²⁺, 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 to Fe³⁺, either by hephaestin or ceruloplasmin in the cell membrane or by ceruloplasmin in plasma, before it binds to transferrin. Alternatively, iron may be released from ferritin by autophagy followed by lysosomal degradation.³

Hemosiderin is found predominantly in macrophages. Microscopically, in unstained tissue sections or marrow films it appears as clumps or granules of golden refractile pigment. Under pathologic conditions, it may accumulate in large quantities in almost every tissue of the body. Hemosiderin is chemically similar to the iron core of ferritin and may be derived from ferritins whose protein shells have been digested in lysosomes.

MYOGLOBIN

Myoglobin is structurally similar to hemoglobin, but it is monomeric rather than tetrameric: Each myoglobin molecule consists of a heme group nearly surrounded by polypeptide loops of the 154 amino acid protein. It is present in small amounts in all skeletal and cardiac muscle cells, where it may serve as an oxygen reservoir to protect against cellular injury during periods of oxygen deprivation and may scavenge nitric oxide and reactive oxygen species.⁴

LABILE IRON POOL

The existence of a cellular labile iron pool was postulated from studies of the rate of clearance of injected ⁵⁹Fe from plasma.⁵ 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. It is now sometimes considered to be equivalent to the chelatable iron pool.⁶

TISSUE IRON COMPARTMENT

Tissue iron (exclusive of hemoglobin, ferritin, hemosiderin, myoglobin, and the labile compartment) normally amounts to 6 to 8 mg. This includes cytochromes and other iron-containing enzymes. Although a small compartment, it is an extremely vital one and is sensitive to iron deficiency.^7,8

TRANSPORT COMPARTMENT

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, almost entirely carried by transferrin, normally turns over at least 10 times each day. This is the common pathway for interchange of iron between compartments.

Transferrin

Transferrin is a dumbbell-shaped glycoprotein with a Mr of approximately 80 kDa where each of the two globular domains contains a binding cleft for Fe³⁺.^9,10,11 Normally, approximately one-third of the transferrin iron-binding sites are occupied by iron. Human plasma normally contains approximately 25 to 45 μM (200 to 360 mg/dL) transferrin, capable of binding 50 to 90 μM iron but carrying only 10 to 30 μM (50 to 180 mcg/dL) iron. Apotransferrin (transferrin devoid of iron) is synthesized by hepatocytes and by cells of the monocyte–macrophage system.^12,13

CONTENT

Average American adult men and women ingest 9 to 10 mg and 12 to 14 mg of iron daily, respectively.¹⁴ 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/day.¹⁵ More iron is needed during growth periods or after blood loss. In women, iron absorbed must be sufficient to replace that lost through menstruation or diverted to the fetus or milk during and after pregnancy. Table 42–2 shows the age- and gender-specific recommended dietary allowances for iron.¹⁶

BIOAVAILABILITY

In meat-eaters in Western countries, heme from hemoglobin and myoglobin normally comprises approximately 15 percent of dietary iron but is much more efficiently absorbed than nonheme iron, and promotes the absorption of nonheme iron.¹⁷ The absorption of nonheme dietary iron is strongly affected by iron-binding components of food. Oxalates, phytates, and phosphates complex with iron and retard its absorption, whereas simple reducing substances, such as hydroquinone, ascorbate, lactate, pyruvate, succinate, fructose, cysteine, and sorbitol, increase iron absorption.¹⁸ Iron-fortified cereals are major sources of iron in countries where fortification is practiced, but cooking in iron pots may also provide important exogenous iron.¹⁷ Gastric acid secretion, the transit time, and mucus secretion all play roles in iron absorption. Red wine, contrary to popular belief, inhibits iron absorption, probably because of the presence of polyphenols.¹⁹ In mice, alcohol suppresses the response of hepcidin to iron,²⁰ and this may contribute to iron loading that is seen in some alcoholic subjects.

Iron normally enters the body through the gastrointestinal tract, mostly through the enterocytes of the duodenum. The amount of iron absorbed is normally tightly regulated according to body needs. Active erythropoiesis and/or iron deficiency increase absorption; iron overload and systemic inflammation decrease absorption. Nevertheless, the amount of iron absorbed increases with the administered dose even though the percentage absorbed decreases (Fig. 42-1). Accidental or deliberate ingestion of large doses of medicinal iron can therefore cause iron intoxication.

MECHANISM OF TRANSPORT ACROSS THE INTESTINAL MUCOSA

Heme Iron

Understanding the mechanism of iron absorption has been made more difficult by the fact that the pathways for the uptake of inorganic iron and of heme by enterocytes are different but seem to merge within the intestinal cell where heme is converted to inorganic iron. How much heme (if any) is exported intact by enterocytes and bound by plasma heme-binding protein hemopexin is not clear, but hemopexin knockout mice show minor retention of iron in duodenal enterocytes without any effect on systemic iron homeostasis,²¹ arguing against a major contribution from this mechanism, at least in mice. Efforts to identify the apical heme import mechanism in enterocytes have not yet been definitive.²²

Ferric Iron

Following the reduction of ferric iron to ferrous iron, in part by duodenal cytochrome b (dcytb) reductase,²³ ferrous iron is transported into the intestinal villus cell by the divalent metal transporter (DMT)-1.^24,25 How iron transits within the enterocytes is not yet known. Basolateral export of ferrous iron is mediated by ferroportin^26,27,28 in association with hephaestin²⁹ and plasma ceruloplasmin³⁰ to oxidize iron to the ferric state. Ferric iron is taken up by plasma apotransferrin. Figure 42–2 illustrates some of the steps that are thought to regulate iron transport across the mucosal cell.

IRON RECYCLING

Role of the Monocyte–Macrophage System

In humans, the destruction and production of erythrocytes generates most of the iron flux in and out of plasma (20 to 25 mg/day recycled in adults compared to 1 to 2 mg/day absorbed). Iron from other cell types is likely also recycled, but this source contributes little to iron flux and has not been studied. Destruction of aged erythrocytes and hemoglobin degradation occur within macrophages (Chap. 32). This proceeds at a rate sufficient to release approximately 20 percent of the hemoglobin iron from the cell to the plasma compartment within a few hours. Approximately 80 percent of this iron is rapidly reincorporated into hemoglobin. Thus, 20 to 70 percent of the hemoglobin iron of nonviable erythrocytes reappears in circulating red cells 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.³¹ Conversely, in the presence of infection or another inflammatory process (e.g., ulcerative colitis or malignancy), iron is more slowly reused in hemoglobin synthesis and is associated with anemia (Chap. 37).^32,33

Erythrophagocytosis

As human erythrocytes age during their average 120-day life span, they shrink, stiffen, and their membranes accumulate markers of senescence.³⁴ These changes eventually trigger phagocytosis by splenic or hepatic sinusoidal macrophages. Macrophages also take up the products of intravascular hemolysis, including hemoglobin (bound by haptoglobin) and heme (bound by hemopexin), using specific endocytic receptors for the complexes.³⁵ The vesicles involved in phagocytosis and endocytosis must fuse with lysosomes to digest cellular materials or protein complexes and to free heme from hemoglobin. The membrane complex of nicotinamide adenine dinucleotide phosphate (NADPH) cytochrome c reductase, heme oxygenase 1, and biliverdin reductase releases ferrous iron from heme and simultaneously protects erythrophagocytosing macrophages from heme-induced toxicity.³⁶ The subcellular location of the conversion of heme to iron is not known with certainty. Heme oxygenase 1 is mostly located in the endoplasmic reticulum in erythrophagocytic macrophages³⁷ with the catalytic face in the cytosol, and little, if any, heme oxygenase in the phagosomal membrane. Moreover, the phagosomal membrane is enriched in the heme transporter HRG1,³⁸ and macrophage heme has a signaling role in inducing various proteins involved in macrophage iron metabolism, indicating that it may leave the phagosome, and the heme oxygenase-1–mediated release of iron may occur in the cytoplasm. However, the ferrous iron transporter Nramp1, and perhaps DMT-1, may also participate in subcellular iron transport.³⁹ Ultimately, depending on systemic iron requirements, the released ferrous iron is either exported to plasma via ferroportin⁴⁰ or trapped in macrophage cytoplasmic ferritin. By a mechanism potentially important at the low oxygen tensions found in some tissues, plasma ceruloplasmin^41,42,43 catalyzes the conversion of ferrous to ferric iron, the form of iron loaded to plasma transferrin for systemic distribution.

SYSTEMIC IRON HOMEOSTASIS

The mechanism by which body iron content is regulated by the modulation of iron absorption has been a subject of intense interest for the past 65 years. It has now become clear that intestinal iron absorption, plasma iron concentrations, and tissue distribution of iron are subject to endocrine regulation similar to that of other simple nutrients, for example, glucose or calcium, albeit in a somewhat more complex fashion.

Hepcidin and Ferroportin

Hepcidin, a 25-amino-acid peptide hormone with 4 disulfide bonds,^44,45,46,47 is produced predominantly by hepatocytes and plays a central role in systemic iron homeostasis. Hepcidin regulates plasma iron concentrations by controlling the absorption of iron by the intestinal epithelial enterocytes and its release from iron-recycling macrophages and hepatocytes involved in iron storage. The structural similarity of hepcidin and a class of antimicrobial peptides termed defensins suggests that the hormone evolved from the latter to modulate iron homeostasis as a mechanism of body defense against microorganisms. Overexpression of hepcidin results in marked iron-deficiency anemia in mice⁴⁸ and a refractory anemia resembling the anemia of chronic inflammation in humans,⁴⁹ and injection of synthetic hepcidin rapidly lowers plasma iron concentrations.⁵⁰ As many microorganisms are dependent on plasma iron for survival in the circulation, hepcidin can exert host defense. In fact, patients with iron overload and high plasma iron levels are susceptible to such infections, such as with Yersinia enterocolitica (Chap. 43).

Hepcidin exerts its iron-regulatory effect by binding to ferroportin, a transmembrane iron-export protein expressed on enterocytes, macrophages, and hepatocytes. Once hepcidin has bound to ferroportin, the ferroportin is internalized and undergoes proteolysis.^40,51 With membrane ferroportin depleted, iron cannot be exported from the enterocyte, the macrophage or the hepatocyte into the plasma (Fig. 42–3). This results in decreased iron absorption from the gastrointestinal tract and a fall in the plasma iron concentration. Hepcidin production is stimulated by inflammatory cytokines such as interleukin (IL)-6,^52,53 and the overproduction of hepcidin is one of the factors in the pathogenesis of the anemia of chronic inflammation (Chap. 37).

The regulation of hepcidin production seems to be entirely transcriptional. In humans and laboratory rodents, hepcidin mRNA and plasma hepcidin levels increase in parallel with iron-loading and inflammatory stimuli,^44,54,55 and are decreased by erythropoietic activity⁵⁶ and iron deficiency.⁵⁷

Regulation of Hepcidin by Iron

Both elevated plasma iron concentrations and increased liver stores are sensed in the intact organism and regulate hepcidin transcription,^58,59 but the relevant mechanisms are only partially understood. For reasons that are not understood, involving perhaps the complex interactions of hepatocytes with other liver cells, isolated hepatocytes do not show consistently increased hepcidin synthesis after iron treatment, although small effects were observed when the cells were freshly harvested from mice.⁶⁰ Important clues are provided by hereditary disorders in which hepcidin transcription is dysregulated. As indicated in Table 42–3, impairment of the function of several genes is associated with iron overload in humans and in experimental animals. In addition to genes that encode the hormone hepcidin itself and its receptor, ferroportin, or encode proteins primarily involved in iron transport, there are a number of genes whose products are likely to function in iron sensing, signal transduction and transcriptional regulation. These include human hemochromatosis protein (HFE), transferrin receptor-2, bone morphogenetic proteins (BMPs), BMP receptor and its signaling pathway, and hemojuvelin, all of which encode proteins that normally stimulate hepcidin transcription to prevent iron overload. In the best-supported model, hepcidin transcription is regulated in an iron-dependent manner by the BMP pathway. Complexes of HFE, transferrin receptor-1, and transferrin receptor-2 may be involved in sensing the concentration of iron-transferrin and interact in as yet unknown manner with the BMP receptor to stimulate the transcription of hepcidin.^61,62,63,64 Hemojuvelin, whose autosomal recessive mutations cause a very severe form of hereditary hemochromatosis, serves as a coreceptor for the BMPs.^65,66 A soluble fragment of hemojuvelin acts as an inhibitor of the interaction of BMP with the receptor, but it is not clear whether it has a physiologic regulatory role.^67,68 Regulation of hepcidin transcription itself is complex, involving the formation of a complex of liver-specific and response-specific transcription factors bound to a distal BMP-RE2/bZIP/HNF4α/COUP region and to the proximal BMP-RE1/STAT region of the hepcidin promoter, possibly by physical association of the two regions.⁶⁹ A pathway that inhibits the transcription of hepcidin exists as well. Tmprss6 (also called matriptase 2) is a membrane serine protease that inhibits hepcidin transcription, likely by proteolysis of hemojuvelin.^70,71 This function was discovered when random mutagenesis in mice produced an iron-deficient animal with mutagenized Tmprss6.⁷² Subsequently, humans with mutations of the Tmprss6 orthologue were shown to manifest iron-refractory iron-deficiency anemia that does not respond to oral iron and only partially to parenteral iron therapy.⁴⁹

Regulation of Hepcidin by Erythropoiesis

Intestinal iron absorption is increased severalfold after hemorrhage or erythropoietin administration, and is chronically increased in patients with ineffective erythropoiesis but not in aplastic anemia.⁷³ These observations led to the hypothesis that the marrow generates an “erythroid regulator”⁷³ that modulates intestinal iron absorption. Later studies in mouse models⁵⁶ provided evidence that the erythroid regulator is a marrow-derived suppressor of hepcidin. Erythroferrone is an erythropoietin-induced erythroblast-secreted glycoprotein that acts on hepatocytes to suppress their hepcidin production and is required for rapid suppression of hepcidin after hemorrhage or erythropoietin administration.⁷⁴ It also contributes to hepcidin suppression and iron overload in murine models of β-thalassemia intermedia. Growth differentiation factor 15 (GDF15), a member of the BMP family, may also contribute to pathologic hepcidin suppression in anemias with ineffective erythropoiesis.⁷⁵

Regulation of Hepcidin by Inflammation

Within hours after the onset of systemic infection, plasma iron concentration decreases. The response is thought to contribute to host defense, particularly against microbes with high dependence on environmental iron.⁷⁶ This response, hypoferremia of inflammation, is also triggered by noninfectious causes of acute and chronic inflammation. Hypoferremia of inflammation is mediated by cytokine-induced increase in plasma hepcidin concentrations⁵⁴ causing hepcidin-induced sequestration of iron in macrophages. The main human cytokine responsible for hepcidin induction is IL-6^52,53 acting via the JAK2-STAT3 pathway,^77,78,79 but other cytokines including activin B may also contribute.⁸⁰ Chronic inflammation impairs iron supply to erythropoiesis and combines with other effects of inflammation to cause anemia of inflammation (anemia of chronic disease, see Chap. 37).

Once an atom of iron enters the blood plasma from dietary iron absorption, it is virtually trapped in the body (Fig. 42–4) and cycles almost endlessly from the plasma to the developing erythroblast (where it is used in hemoglobin synthesis), thence into the circulating blood for approximately 4 months, and then to macrophages. Here it is removed from heme by heme oxygenase and released back into the plasma to repeat the cycle.

The major function of the transport protein transferrin is to move iron from wherever it enters the plasma (intestinal villi, splenic and hepatic sinusoids) to the erythroblasts of the marrow and to other sites of use.

ENDOCYTOSIS OF TRANSFERRIN

Diferric (holo)transferrin binds to the transferrin receptor (TfR)-1 on the cell surface and the holotransferrin–TfR1 complex forms clusters in pits on the cell membrane.⁸¹ The complex is then internalized by endocytosis (Fig. 42–5). Within the cytosol the holotransferrin-TfR1 complex is in a clathrin-coated vesicle. The vesicles fuse with endosomes and become acidified to pH 5 which releases iron from transferrin. Iron-depleted (apo)transferrin and TfR1 remain complexed as they return to the cell membrane, where at neutral pH, apotransferrin separates from its receptor and is released to the interstitial fluid to reenter plasma and take up more iron.

The TfR is a protein consisting of two subunits that are linked by disulfide bonds.⁹ Its aminoterminus is on the cytoplasmic side of the membrane, and its carboxyl-terminus is on the outer surface. Because of the role of TfR1 in the binding and endocytosis of diferric transferrin, control of TfR1 biosynthesis is a major mechanism for regulation of iron metabolism. Synthesis of TfR1 is induced by iron deficiency. Iron inhibits TfR1 synthesis by destabilizing TfR1 mRNA by a mechanism that involves the iron-responsive element (IRE)/iron-regulatory protein (IRP) regulatory system (Fig. 42–6).^82,83 TFR1 binds to HFE,⁶¹ using a binding site that overlaps that of holotransferrin. According to a current model of iron sensing, high concentrations of holotransferrin would therefore displace HFE from its complex with TfR1, leaving HFE to signal to the BMP receptor complex to increase hepcidin transcription. This model is supported by studies in which the expression of HFE or its binding site on TfR1 are manipulated.⁶¹

A second TfR, TfR2, also endocytic for holotransferrin, is not thought to be involved in delivering iron to cells but its hepatic expression is necessary for normal hepcidin expression and regulation.⁸⁴ TfR2 influences the BMP complex and its signaling pathway to regulate hepcidin transcription but the molecular mechanism of this effect is not yet understood. TfR2 is also expressed in erythroid precursors where it interacts with the erythropoietin receptor and negatively modulates erythropoiesis, perhaps putting a brake on erythrocyte production during iron deficiency.⁸⁵

INTRACELLULAR IRON HOMEOSTASIS

Each cell must regulate its iron uptake and subcellular distribution, both to assure adequate iron for a multitude of cellular enzymes and to prevent excessive iron accumulation that could be injurious or deny adequate iron to other cells. Accordingly, the synthesis of key cellular proteins involved in iron transport, storage, and use is regulated posttranscriptionally by cellular iron concentrations.^82,83 The mRNA for each of these proteins contains one or several IREs. If the IRE is located at the 5′ end of the mRNA, it serves to regulate translation; 3′ IREs regulate the stability of the mRNA. Each IRE consists of a stem and loop structure, in which the loop is the nucleotide sequence CAGUG (Fig. 42–7). IRE/IRP–regulated mRNAs include those encoding ferritin, TfR1, aminolevulinic acid (ALA) synthase, transferrin, aconitase, DMT-1, and ferroportin. The ferritin mRNA has, as its IRE, a single stem–loop structure in the 5′ (upstream) region. In contrast to the ferritin IRE, there are as many as five stems–loops in the 3′ untranslated portion of TfR mRNA. The IREs are targeted by specific RNA-binding proteins, IRPs. IRP-1 is cytoplasmic aconitase with four iron-sulfur clusters and the ability to bind iron, which is required for its aconitase activity; IRP-2 is highly homologous to IRP-1 but differs by the presence of a 73-amino-acid insertion in the N-terminus and a lack of aconitase activity. In the absence of iron, IRP-1 binds to IREs, but in its presence becomes a cytoplasmic aconitase and does not bind IREs. IRP-2 (as well as, to some extent, IRP-1) undergoes ubiquitination and proteasomal degradation in the presence of iron.^86,87 The effect of binding of IRPs to 5′ IREs is to inhibit protein translation; the effect of binding of IRPs to 3′ IREs is to increase the stability of the mRNA and thus to enhance the synthesis of the gene product. Figure 42–6 illustrates these relationships for the regulation of synthesis of ferritin and TfR. The net effect of the IRE/IRP system is to balance cellular iron uptake with storage, use, and in some cell types, export of iron.

IRON IN THE ERYTHROBLAST

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, STEAP3 (six-transmembrane epithelial antigen of prostate 3) effects the reduction of ferric (Fe³⁺) to ferrous (Fe²⁺) iron, and another protein, DMT-1 (the same transporter as in intestinal iron absorption), transports Fe²⁺ into the cytosol, where it is taken up by mitochondria by a complex of mitoferrin-1, ABCB10 (ATP-binding cassette [ABC] transporter in the inner membrane of mitochondria) and ferrochelatase for heme synthesis.⁸⁸ Physical interaction between mitochondria and endosomes (“kiss and run”) may also be required.⁸⁹

Mitochondrial Iron

Mitochondria, working together with cellular cytoplasm, supply each cell with heme. Although heme synthesis is important for all cells, erythroblasts synthesize much more heme than any other cell type. The final steps of heme synthesis take place in mitochondria, where iron is inserted into protoporphyrin by the enzyme ferrochelatase. When heme synthesis is impaired, as in lead poisoning or in the sideroblastic anemias (Chap. 59), the mitochondria accumulates excessive amounts of amorphous iron aggregates. 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, iron-replete marrow, (much smaller) siderotic granules are also demonstrable, scattered in the cytoplasm of about one-third of erythroblasts. These normal siderotic granules are ferritin aggregates located in lysosomal organelles designated siderosomes.⁹⁰ Erythroblasts containing these siderotic granules, sideroblasts, normally represent 20 to 50 percent of the erythrocyte precursors of the marrow and as visualized by light microscopy. In iron deficiency and in the 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 excessive numbers of granules, some of which may be considerably larger than normal.

Mitochondrial Ferritin

Ring sideroblasts contain a ferritin isoform, mitochondrial ferritin (Chap. 59), which is a product of an intronless, IRE-lacking, ferritin gene on chromosome 5q23.1 that is specifically targeted to mitochondria by a 60-amino-acid-leader sequence.^1,91 Mitochondrial ferritin lacks IRE and, thus, is not subject to iron-dependent translational control. Its function appears to be to reduce the labile iron pool and decrease the level of reactive oxygen species. Mitochondrial ferritin has limited tissue expression and is found in high concentrations in the mitochondria of normal testes and in the sideroblasts of patients with sideroblastic anemia (Chap. 59).⁹²

The body conserves iron with remarkable efficiency. Most iron loss occurs by way of desquamated intestinal cells in the feces and it normally amounts to approximately 1 mg/day,^15,93 less than one-thousandth of total-body iron. Exfoliation of skin and dermal appendages and perspiration result in much smaller losses. Even in tropical climates, the loss of iron in sweat is minimal.⁹⁰ Very small amounts of iron are lost in the urine. Lactation may cause excretion of approximately 1 mg iron daily, thus doubling the overall rate of iron loss. Blood loss by normal menstruation contributes to negative iron balance.

Although total daily iron loss is normally approximately 1 mg for males,¹⁵ it averages approximately 2 mg for menstruating women. Persons with marked iron overload, as in hemochromatosis, may lose as much as 4 mg of iron daily, probably because of the shedding of iron-laden cells, principally macrophages.