ACP medicine, 3rd Edition


Red Blood Cell Function and Disorders of Iron Metabolism

Gary M. Brittenham M.D.1

1Professor of Pediatrics and Medicine, Columbia University College of Physicians and Surgeons

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

March 2004

Red Blood Cell Function

The red blood cell, or erythrocyte, carries oxygen from the lungs to peripheral tissues for utilization and brings carbon dioxide from tissues to the lungs for excretion.1 The mature erythrocyte dedicates more than 95% of its intracellular protein, as hemoglobin, to these tasks. Hemoglobin, the oxygen transport molecule, binds oxygen molecules at the high oxygen tensions of the pulmonary alveoli and releases oxygen molecules at low oxygen tensions to peripheral tissues.2,3 Hemoglobin also acts as a carrier of nitric oxide (NO), a third respiratory gas that seems to regulate oxygen delivery.4 The exact role of NO in the cardiorespiratory cycle is debated,5 but NO is a potent vasorelaxant that reportedly is released during arteriovenous transit, increasing blood flow and therefore oxygen transport in hypoxic tissue.4

The cell membrane of the erythrocyte is a flexible structure composed of a lipid bilayer with integral proteins. These proteins anchor the membrane to an underlying protein skeleton that maintains the biconcave discoid form of the cell.6 This shape optimizes passage of the cell through the circulatory system and permits apposition of erythrocytes and parenchymal cells across the thin endothelium of capillaries, facilitating exchange of oxygen and carbon dioxide.

In the erythrocyte, a variety of metabolic pathways maintain the iron of hemoglobin in the ferrous state, protect against oxidant damage, generate 2,3-diphosphoglycerate (2,3-DPG) to help regulate oxygen affinity, and maintain osmotic stability through a series of membrane pumps.7 Without erythrocytes, blood plasma can carry only about 5 ml O2/L; with erythrocytes containing normal hemoglobin, whole blood can transport about 200 ml O2/L or more.1


Hemoglobin is a spherical molecule composed of two pairs of dissimilar globin chains, with a heme group, ferroprotoporphyrin IX, bound covalently at a specific site in each chain.3 The major adult hemoglobin, hemoglobin A, is formed from a pair of α chains (each containing 141 amino acids) and a pair of β chains (each containing 146 amino acids) and is written as α2β2 [see Figure 1].


Figure 1. Model of Hemoglobin Molecule

A model of the hemoglobin molecule shows the relative alignment of the α chains (light gray) and β chains (dark gray). 2,3-Diphosphoglycerate (2,3-DPG), a glycolytic intermediate, binds in the central cavity of the hemoglobin and stabilizes the deoxygenated form by cross-linking the β chains, thus reducing the oxygen affinity of hemoglobin. Note that the α and β chains are in contact at two points. On oxygenation, movement of the iron atom into the plane of the heme group (colored disks) apparently triggers other structural changes in the α and β subunits as the molecule assumes the oxygenated conformation. Sliding occurs at the α1β2 interface, and the spacing between the two β chains is reduced in oxyhemoglobin. In the detail showing the structure of heme, M is methyl, V is vinyl, and P is propionic acid.

The configuration of hemoglobin shifts with oxygenation and deoxygenation.2,8 The deoxy configuration of hemoglobin is stabilized through the binding of protons and 2,3-DPG, a highly charged anion. With oxygenation of one subunit, these bonds are sequentially broken, and the resulting change in tertiary structure increases oxygen affinity of the remaining unliganded subunits.2 This phenomenon is termed cooperativity or heme-heme interaction. As oxygen is released in the tissues, a reversal of this process decreases oxygen affinity, facilitating the release of oxygen. Conformational changes also contribute to the decrease in oxygen affinity with decreasing pH.2 This effect, called the Bohr effect, is physiologically beneficial both in the lungs, where elimination of carbon dioxide raises the pH, enhancing oxygen affinity and uptake, and in tissues, where carbon dioxide uptake decreases the pH, lowering oxygen affinity and facilitating oxygen release.


Oxygen-Hemoglobin Dissociation Curve

The oxygen-hemoglobin dissociation curve [see Figure 2] is a plot of the equilibrium between oxygen and hemoglobin at various oxygen tensions (PO2).3 At sea level and at a partial pressure of oxygen of about 90 mm Hg, hemoglobin is 97% saturated in the lungs. After unloading oxygen to tissues, at a PO2 of about 40 mm Hg in mixed venous blood, the hemoglobin saturation is about 75%. The P50 (i.e., the partial pressure of oxygen at which hemoglobin is 50% saturated) is a useful measure of the oxygen affinity of hemoglobin: the higher the affinity, the lower the P50. Under normal physiologic conditions (i.e., a temperature of 37° C [98.6° F]; pH of 7.4; 2,3-DPG level of 5 mmol/L; and carbon dioxide tension [PCO2] of 40 mm Hg), the P50 of normal adult blood is 26 ± 1 mm Hg. The P50 is decreased (shifted to the left on the oxygen-hemoglobin dissociation curve) by increasing pH, decreasing 2,3-DPG, or decreasing temperature.


Figure 2. Oxygen-hemoglobin Dissociation Curve

The normal oxygen-hemoglobin dissociation curve (solid black line) is shifted by changes in temperature, pH, and the intracellular concentration of 2,3-DPG. P50 stands for 50% oxygen saturation; PO2 stands for oxygen tension.

Effects of 2,3-Diphosphoglycerate

The glycolytic intermediate 2,3-DPG, which is present in mature erythrocytes at approximately the same intracellular concentration as hemoglobin, is the most important allosteric regulator of oxygen affinity.3 With acute hypoxia, 2,3-DPG concentrations increase within hours, which shifts the oxygen-hemoglobin dissociation curve to the right. The increase in the 2,3-DPG concentration promotes delivery of oxygen to tissues but also impedes the acquisition of oxygen in the lungs. Short-term adaptation to hypoxic stress may be helped if the supply of oxygen is plentiful and the cardiopulmonary reserve is robust. At high altitude, with the cardiovascular system unable to effectively meet increased circulatory demands, or in other pathologic circumstances, increased amounts of 2,3-DPG may be counterproductive.3


Several other physiologic factors function in an integrated manner to provide an adequate supply of oxygen, including blood volume, blood viscosity, pulmonary and cardiac function, and regional blood flow.9 The concentration of circulating red blood cells depends on the production of erythropoietin by the kidney and the erythropoietic response of the erythroid marrow.10 Hemoglobin transport of NO, which binds to both heme iron and globin, may help match regional blood flow and oxygen requirements. In peripheral tissues, the erythrocyte may release NO, which would relax the microvasculature, improve blood flow, and enhance oxygen delivery.4,5 An intriguing development has been the identification of a new class of so-called hexacoordinate hemoglobins (expressed in nerve cells11 or a wide array of tissues12), whose functions are not yet established but which may facilitate oxygen transport, help protect against hypoxia, or scavenge reactive oxygen species.


After delivering oxygen, hemoglobin binds with carbon dioxide.13 Deoxyhemoglobin has a higher binding affinity for carbon dioxide than does oxyhemoglobin, facilitating unloading of carbon dioxide from tissues and pulmonary excretion.13 Most of the carbon dioxide from tissue capillaries is transported to the lungs as bicarbonate, with about 10% carried as a carbamino complex reversibly bound to the globin chains.

Iron Metabolism

Remarkable progress continues to be made in understanding disorders of iron metabolism and in improving the diagnosis and management of both iron deficiency and iron overload.14,15 In the body, iron transports and stores oxygen, carries electrons, catalyzes reactions in oxidative metabolism, and sustains cellular growth and proliferation. With iron deficiency, the body is unable to produce sufficient amounts of heme, other iron-porphyrin complexes, metalloenzymes, and other iron-containing compounds to sustain normal functions. With iron overload, excess iron can catalyze free radical reactions that can damage cellular membranes, proteins, and nucleic acids, resulting in progressive cellular and organ damage and eventual death.


The concentration of iron in the human body is carefully regulated and is normally maintained at about 40 mg Fe/kg in women and about 50 mg Fe/kg in men. Iron balance is the result of the difference between the amount of iron taken up by the body and the amount lost [seeFigure 3]. Because humans are unable to excrete excess iron, iron balance is physiologically regulated by the control of iron absorption. The two major factors that influence iron absorption are the level of body iron stores and the extent of erythropoiesis.16 If iron stores increase, absorption decreases; if stores decrease, absorption increases. Absorption also increases with increased erythropoietic activity, especially with ineffective erythropoiesis. Most of the iron in the body is located in the erythron, which consists of the totality of circulating erythrocytes and their precursors in the bone marrow. The predominant pathway of internal iron flux is a one-way flow from the plasma iron transport protein, transferrin, to the erythron, and then through the monocyte-macrophage system back to transferrin [see Figure 3]. The erythron uses about 80% of the iron passing through the transferrin compartment each day. Normally, the majority of this iron is used for hemoglobin synthesis and returned to the circulation within red blood cells. Small quantities of iron are stored in ferritin, enter the iron-containing enzymes of immature erythroid cells, or are lost in the products of ineffective erythropoiesis. At the end of their life span, senescent red cells are phagocytized by specialized macrophages in the spleen, bone marrow, and liver, which then return most of the iron to the transferrin compartment, where the cycle begins again. The phagocytosis of flawed and aged erythrocytes accounts for almost all of the storage iron normally found in the macrophages of the liver, bone marrow, and spleen. By contrast, the parenchymal cells of the liver may either take iron from, or give iron to, plasma transferrin. Under normal physiologic conditions, iron recycling is very efficient; less than 0.05% of the total body iron is acquired or lost each day.


Figure 3. Body Iron Supply and Storage

The figure shows a schematic representation of the routes of iron movement in the adult.95 The area of each circle is proportional to the amount of iron contained in the compartment, and the width of each arrow is proportional to the daily flow of iron from one compartment to another. The major portion of iron is found in the erythron as hemoglobin iron (28 mg/kg in women; 32 mg/kg in men) dedicated to oxygen transport and delivery. Small amounts of erythron iron (< 1 mg/kg) are also present in heme and nonheme enzymes in developing red cells. The remainder of functional iron is found as myoglobin iron (4 mg/kg in women; 5 mg/kg in men) in muscle and as iron-containing and iron-dependent enzymes (1 to 2 mg/kg) throughout the cells of the body. Small amounts of iron are deposited within ferritin in erythroid cells, but most storage iron (5 to 6 mg/kg in women; 10 to 12 mg/kg in men) is held in reserve by hepatocytes and macrophages in the liver, bone marrow, spleen, and muscle. The small fraction of transport iron (about 0.2 mg/kg) in the plasma and extracellular fluid is bound to the protein transferrin, which carries iron to meet tissue needs throughout the body.


A number of proteins are now known to be involved in the absorption, transport, utilization, and storage of iron. Some of these proteins have more than one function.

Systemic Iron Transport

Transferrin is the physiologic carrier of iron through the plasma and extracellular fluid.15 Apotransferrin, transferrin without attached iron, is a single-chain glycoprotein with two structurally similar lobes. Binding of a ferric ion to one of these lobes yields monoferric transferrin; binding of ions to both yields diferric transferrin. The transferrin saturation is the proportion of the available iron-binding sites on transferrin that are occupied by iron atoms, expressed as a percentage. In humans, almost all the circulating plasma apotransferrin is synthesized by the hepatocyte.17 After delivering iron to cells, apotransferrin is promptly returned to the plasma to again function as an iron transporter, completing 100 to 200 cycles of iron delivery during its lifetime in the circulation.15

Cellular Iron Uptake

Specific receptors for transferrin, which are found on the surface membrane of all nucleated cells, provide the route of entry for transferrin-bound iron. The affinity of transferrin receptors is greatest for diferric transferrin, intermediate for monoferric transferrin, and almost negligible for apotransferrin. These differences in affinity contribute to the efficiency of iron delivery. Two forms of the transferrin receptor have now been identified and are designated as transferrin receptor 1 and transferrin receptor 2.15 Both consist of paired subunits, each of which can bind a molecule of transferrin. Although their extracellular structures are quite similar,18 the two forms of the receptor have important functional differences. The binding affinity of transferrin receptor 1 for diferric transferrin is about 25-fold to 30-fold greater than that of transferrin receptor 2. Expression of transferrin receptor 1 is regulated by intracellular iron levels (see below), but that of transferrin receptor 2 is not. Transferrin receptor 1 is expressed by all iron-requiring cells, whereas transferrin receptor 2 is most highly expressed on hepatocytes and developing erythroid cells. Transferrin receptor 1 is required for life in mammals19; transferrin receptor 2 cannot compensate for the absence of transferrin receptor 1. Transferrin receptor 2 seems to have other functions in maintaining iron homeostasis (see below).

The delivery of transferrin-bound iron begins with the binding of two molecules of monoferric or diferric transferrin to a transferrin receptor on the cell surface.15 The iron-transferrin-transferrin receptor complex then moves to the interior of the cell within an endosome, where it releases its iron. The dissociated iron is then taken up by the divalent metal transporter-1 (DMT1) and transported across the endosomal membrane for utilization or for storage in the cell.19 Freed of its iron, the transferrin—now apotransferrin—binds avidly to the transferrin receptor and is carried back to the cell membrane and released into the plasma.15

Cellular Iron Storage

Cellular iron storage utilizes ferritin, a protein found in the cytoplasm of virtually all cells. Ferritin is a spherical shell that can store as many as 4,500 atoms of iron in its interior. Ferritin functions both as a safe storage site for iron and as a readily accessible reserve for iron that has been acquired by the cell in excess of its immediate needs.20 Accordingly, the greatest amounts of ferritin are found in cells dedicated to iron storage (e.g., macrophages and hepatocytes) and in cells with the highest iron requirements for the synthesis of iron-containing compounds (e.g., developing erythroid cells). Apoferritin, or ferritin without attached iron, is composed of 24 oblong subunits that are designated as H (heavy) and L (light). Ferritin molecules with a greater proportion of H subunits seem to be more active in iron metabolism; ferritin molecules with a greater abundance of L subunits apparently are used for the longer-term storage of iron. A ferritin H-like protein assembled into ferritin shells has been identified within iron-loaded mitochondria of patients with impairment of heme synthesis.21 In patients with sideroblastic anemia, most of the iron in ringed sideroblasts is sequestered in mitochondrial ferritin.22

Regulation of Cellular Iron Uptake and Storage

Cellular iron uptake and storage are regulated through the synthesis of transferrin receptors and ferritin. This synthesis is coordinated by the iron-regulatory proteins IRP-1 and IRP-2 [see Figure 4]. When intracellular iron levels are low, IRP-1 and IRP-2 bind to messenger RNA (mRNA) stem-loop elements known as iron-responsive elements (IREs) in transcripts.23 Transferrin receptor synthesis is regulated by controlling the stability of cytoplasmic transferrin receptor mRNA, whereas ferritin synthesis is regulated by controlling translation of ferritin mRNA without changing the amount of ferritin mRNA in the cytoplasm. As a result, changes in the amounts of the IRPs have opposite effects on the production of transferrin receptor and ferritin, allowing iron to self-regulate its intracellular availability. IRPs also regulate mRNAs for other proteins involved in iron uptake,24 availability, release,25 and utilization.26


Figure 4. Regulation of Transferrin Receptor and Ferritin Expression

Regulation of transferrin receptor and ferritin expression by the iron regulatory proteins IRP-1 and IRP-2.

Macrophage Hemoglobin Catabolism and Iron Release

Specialized macrophages in the bone marrow, liver, and spleen selectively recognize and phagocytize erythrocytes that are senescent or damaged.27 On average, each of these macrophages can phagocytize one erythrocyte a day.28 After ingesting the erythrocyte, the macrophage lyses the erythrocyte membrane. The hemoglobin within then undergoes oxidative precipitation and rapid catabolism into heme.

Any hemoglobin released into plasma by intravascular hemolysis is rapidly bound by haptoglobin. Macrophages remove the haptoglobin-hemoglobin complex from plasma by binding29 and endocytosis; the complex is then digested in lysosomes, liberating heme.

The heme from both sources is degraded by the microsomal enzyme heme oxygenase, yielding biliverdin IXa, carbon monoxide, and iron30,31; the iron is either stored in ferritin or returned to plasma, apparently via ferroportin.27,32 The outpouring of iron from macrophages in the bone marrow, liver, and spleen to plasma apotransferrin normally constitutes the largest single flux of iron from cells in the body.30Unsaturated transferrin is not required for the release of iron from the macrophages; apotransferrin does not enter the macrophage and accepts iron only after the release of iron from the cell. Rather, a major determinant of the rate of iron exit from the macrophage is ceruloplasmin, which establishes a rate of oxidation of ferrous iron.33 After oxidation, the ferric iron can be bound and transported by transferrin back to the erythron and other iron-requiring tissues.

Other Pathways of Iron Exchange

Heme that is released into the plasma as a result of intramedullary or intravascular hemolysis is bound by hemopexin. The heme-hemopexin complex is delivered to the hepatocyte via specific receptors and internalized, and the heme is catabolized to liberate the iron.34 The hepatocyte may either donate iron to plasma transferrin or receive iron from it.35 At high transferrin saturations, iron moves from the plasma to the liver; at low saturations, iron is mobilized from hepatocyte stores and supplied to plasma transferrin. Normally, the overall magnitude of iron exchange by hepatocytes is only about one fifth that by macrophages. Other pathways of iron movement involve approximately equal exchanges: about 1 mg Fe/day is absorbed and lost, about 3 mg Fe/day is transferred between the plasma and extravascular transferrin compartments, and about 2 mg Fe/day moves between extravascular transferrin and parenchymal tissues.

Intestinal Iron Absorption

The amount of iron in the body is regulated by control of iron absorption in the proximal small intestine. Both heme iron and nonheme iron enter through the brush border of intestinal enterocytes.36 The exact means by which heme iron is absorbed are still uncertain, but nonheme iron seems to be taken up via the apical iron transporter DMT1 (the same iron transporter that provides an exit for iron from the endosome; see above) and perhaps via other routes.37 DMT1 is a proton-coupled symporter with a broad substrate range that includes other metallic cations, but its physiologic function appears to be the uptake of Fe2+.19 DMT1 is a ferrous iron transporter, but most dietary iron is in the ferric form. Duodenal cytochrome b, a heme protein highly expressed in duodenal brush border membrane, reduces luminal iron to the ferrous state for transport into enterocytes via DMT1.38 Once within the enterocyte, the absorbed iron may be transported across the basolateral membrane into the plasma or stored within ferritin and then lost when the enterocyte is exfoliated. The details of the handling of iron in the enterocyte remain obscure, but as in the macrophage, ferroportin seems to serve as the transmembrane channel for the transfer of ferrous iron into the plasma,32 and hephaestin is a ceruloplasmin homologue that is required for the efficient exit of iron from the basolateral membrane of the enterocyte into the systemic circulation.39

Regulation of Body Iron Absorption and Storage

The molecular mechanisms responsible for the regulation of body iron stores through control of iron absorption are still not understood, but some of the proteins involved have been identified. The gene HFE, which is mutated in most patients with hereditary hemochromatosis (see below), has been identified,40 but the means by which the normal gene product, HFE, regulates iron balance remains uncertain. HFE is found in crypt cells in the duodenum, in tissue macrophages, and in Kupffer cells in the liver. Two mutually exclusive functions have been suggested for HFE: decreasing iron uptake by binding to transferrin receptor (thereby competing with transferrin) and inhibiting iron release from macrophages.41,42 The relative effects of these offsetting activities may be determined by the balance between serum transferrin saturation and serum transferrin-receptor concentrations.43 Other models give the liver a central role in the regulation of iron homeostasis.44 The observations that tissue iron overload can result from mutations in two other proteins, transferrin receptor 245 (see above) and hepcidin,46 indicate that these proteins are also involved in the pathway for regulation of iron balance. Hepcidin, an antimicrobial peptide produced by hepatocytes, seems to act as an iron-regulatory hormone whose expression is inversely related to both iron absorption and macrophage iron release. In HFE-associated hereditary hemochromatosis, expression of hepcidin is not increased despite hepatic iron overload, suggesting that HFE may be involved in the regulation of hepcidin expression in response to changes in body iron stores.47 Despite these intriguing observations, elucidation of the molecular mechanisms underlying the regulation of body iron absorption and storage will likely await the identification of other key proteins involved.

Iron Deficiency


Iron deficiency designates conditions in which the body's iron requirements exceed iron supply. Iron is needed to restore physiologic loss, which is just under 1 mg/day in men and is about 1.5 mg/day in menstruating women35; iron is also needed for growth and pregnancy and to replace pathologic losses. Sequential stages of decreases in body iron can be identified [see Table 1]. A decrease in iron stores without a change in the amounts of functional iron compounds is designated as reduced iron stores. When iron stores are exhausted, patients may be described as having iron depletion. Further decrements in the level of body iron result in limited production of hemoglobin and other iron-containing functional compounds; this stage is termed iron-deficient erythropoiesis. Still further decreases in body iron produce iron deficiency anemia.

Table 1 Changes in Iron Stores and Distribution with Increased or Decreased Body Iron Content


Marrow Iron (0–6+)

Liver Iron (µmol/g, dry weight)

Plasma Ferritin (µg/L)

Plasma Transferrin Receptor (mg/L)

Plasma Iron (µg/dl)

Transferrin Saturation (%)

Protoporphyrin (µmg/dl Red Blood Cells)

Red Blood Cells

Iron deficiency anemia


< 3.0

< 12


< 40

< 10


Microcytic, hypochromic

Iron stores depletion

0 to trace amounts


< 20


< 115

< 30



Reduced iron stores


< 10.0

< 25


< 115






15.0 ± 5.0

100 ± 60

5.5 ± 1.5

115 ± 50

35 ± 15



Increased iron stores, hemochromatosis





> 150

> 60



Increased iron stores; transfusional iron overload





> 150

> 50



Massive iron overload, HLA-linked hemochromatosis






> 60



Massive iron overload; transfusional iron overload






> 90



* May be normal in some patients.


Iron deficiency is the most common nutritional deficiency worldwide. Its prevalences are highest in developing countries, where 30% to 70% of the population may be affected48; in comparison, the overall prevalence of iron deficiency is less than 20% in the industrialized countries of Europe and North America.48 In the United States, the Centers for Disease Control and Prevention estimate that the prevalence of iron deficiency is greatest in toddlers 1 to 2 years of age (7%) and in adolescent girls and adult women 12 to 49 years of age (9% to 16%).49


Iron deficiency can result from increased iron requirements, inadequate iron supply, or both [see Table 2]. Blood loss is the most common cause of increased iron requirements that lead to iron deficiency. In men and postmenopausal women, iron deficiency is almost always the result of gastrointestinal blood loss.50 In menstruating women, genitourinary blood loss often accounts for increased iron requirements. Oral contraceptives tend to decrease menstrual blood loss, whereas intrauterine devices tend to increase menstrual bleeding. Other causes of genitourinary bleeding and respiratory tract bleeding can also increase iron requirements [see Table 2]. For blood donors, each donation results in the loss of 200 to 250 mg of iron. During periods of growth in infancy, childhood, and adolescence, iron requirements may outstrip the supply of iron available from diet and stores.51 Iron loss from tissue growth during pregnancy and from bleeding during delivery and post partum averages 740 mg.35,51 Breast-feeding increases iron requirements by about 0.5 to 1 mg /day.

Table 2 Causes of Iron Deficiency

   Blood loss
   Gastrointestinal tract
      Hemorrhagic lesions (e.g., hiatal hernia, esophageal varices, gastritis, duodenitis, peptic ulcer, cholelithiasis, intrahepatic bleeding, inflammatory bowel disease, diverticulosis, hermorrhoids, or adenomatous polyp)
      Occult gastrointestinal malignancy
      Chronic ingestion of drugs (e.g., alcohol, salicylates, steroids, and nonsteroidal anti-inflammatory drugs)
      Helminthic infections (e.g., hookworm, Schistosoma mansoni, S. japonicum, or severe Trichuris trichiura)
      Other (e.g., vascular purpura with scurvy, aberrant pancreas, Meckel diverticulum, hereditary hemorrhagic telangiectasia, other vascular ectasia of the bowel, or colonic polyposis)
   Genitourinary tract
      Menstrual blood loss
      Other (e.g., uterine malignancies of fibroids, stones, infarction, infection with S. haematobium,inflammatory disease, malignancy of the urinary tract, or chronic hemoglobinuria or hemosiderinuria resulting from paroxysmal nocturnal hemoglobinuria or chronic intravascular hemolysis)
   Respiratory tract
      Chronic recurrent hemoptysis
      Idiopathic pulmonary siderosis
      Goodpasture syndrome
   Blood donation
   Infants, premature infants
   Pregnancy and lactation
   Diets with insufficient amounts of bioavailable iron
   Impaired absorption of iron
   Intestinal malabsorption (e.g., steatorrhea, sprue, celiac disease, diffuse enteritis, atrophic gastritis with achlorhydria, or pica)
   Gastric surgery

An insufficient supply of iron may contribute to the development of iron deficiency. In infants and in women with high iron requirements, diets containing inadequate amounts of bioavailable iron increase the risk of iron deficiency.51 In older children, men, and postmenopausal women, a poor supply of dietary iron is almost never the only factor responsible for iron deficiency; therefore, other etiologic factors must be sought, especially blood loss.50,52,53 Impaired absorption of iron is an uncommon cause of iron deficiency. In some patients, intestinal malabsorption of iron is only one aspect of more generalized malabsorption54 [see Table 2]. Gastric surgery, especially partial or total gastric resection or gastroenterostomy for bypass of the duodenum, may result in iron deficiency. Although absorption of dietary iron may be poor in such patients, therapeutic iron salts are usually well absorbed, and the iron deficiency can be readily corrected.

The risk of iron deficiency is especially high when iron requirements are increased and the supply of iron is inadequate. For example, infants who are fed cow's milk often become iron deficient because of the combination of increased iron losses from cow's milk-induced gastrointestinal bleeding and the small amounts of bioavailable iron in cow's milk.51,55 Women with high iron requirements because of menstruation often have diets that contain little bioavailable iron and contain inhibitors of iron absorption, such as calcium. A common mutation of the transferrin gene (designated as G277S) has been associated with a reduction in the circulating transferrin concentration and may predispose menstruating women to iron deficiency.56 The mechanism underlying this effect is unknown.


Clinical Manifestations

Patients with iron deficiency may be asymptomatic and their disorder recognized only because of abnormal results of laboratory tests.51Other patients may come to medical attention because of the manifestations of the underlying disorder that produced iron deficiency, but they may have no findings resulting from the iron deficiency. Still other patients may present with the signs and symptoms common to all anemias, such as weakness, dizziness, easy fatigability, pallor, irritability, and other indefinite and nonspecific complaints. Iron deficiency may also be associated with signs and symptoms that are unrelated to anemia, such as angular stomatitis, glossitis, postcricoid esophageal stricture or web, and gastric atrophy. In addition, a high prevalence of iron deficiency has been found in patients with the restless legs syndrome, a neurologic disorder characterized by a distressing, irresistible urge to move the legs (akathisia).57 Finally, some patients present with one or more of the limited number of signs and symptoms thought to be highly specific for iron deficiency, which include blue sclerae58 and koilonychia. Pagophagia, or pica with ice, is thought to be another highly specific symptom of iron deficiency and disappears shortly after iron therapy is begun.59 Other types of pica may accompany iron deficiency, but none is as specific a symptom as pagophagia. The nonhematologic consequences of iron deficiency are diminished exercise tolerance and work performance and impaired immunity and resistance to infection.60,61 In children, iron deficiency seems to adversely affect growth, motor development, behavior, and cognitive function51,62; these abnormalities may not be reversible with later treatment.

Laboratory Tests

Iron deficiency anemia is the only microcytic hypochromic anemia associated with lack of iron stores. In other microcytic hypochromic disorders, marrow iron stores are normal or increased. Indirect measures of body iron can be used to identify a characteristic sequence of changes that occur as body iron decreases from the iron-replete normal levels to levels found in iron deficiency anemia [see Table 2]. Measurement of the serum ferritin concentration is the most useful test for the detection of iron deficiency, because serum ferritin concentrations decrease as body iron stores decline.50 A serum ferritin concentration below 12 µg/L is virtually diagnostic of absent iron stores. In contrast, a normal serum ferritin concentration does not confirm the presence of storage iron, because serum ferritin concentration may be increased independently of body iron by infection, inflammation, liver disease, malignancy, and other conditions.63Because the serum transferrin receptor concentration seems to be unaffected by these conditions, determination of this value (or the ratio of the serum transferrin receptor concentration to the serum ferritin concentration) provides a means of distinguishing between the anemia of iron deficiency and the anemia associated with chronic inflammatory disorders.64,65,66 The concentration ratio of the serum transferrin receptor to serum ferritin can also provide a quantitative estimate of body iron stores that may be useful in monitoring iron status in patients who are highly susceptible to iron deficiency, such as infants, preschool children, and pregnant women.67 The serum iron level and serum transferrin saturation are decreased in both iron deficiency and infectious or inflammatory states and therefore are of little practical assistance in distinguishing between these conditions. An alternative approach to the detection of an impaired iron supply for erythropoiesis is the use of hematologic indices derived from automated analyzers, such as the proportion of hypochromic cells and reticulocyte cellular indices.68,69 These measurements of erythrocyte and reticulocyte indices may be particularly useful in the evaluation of iron-restricted erythropoiesis in patients with chronic renal failure or chronic disease who are treated with erythropoietin.70 An empirical trial of iron therapy may also be an effective means of establishing the diagnosis of iron deficiency.

Although bone marrow examination is now seldom performed solely for the assessment of iron status, the diagnosis of iron deficiency can almost always be verified by direct assessment of marrow iron stores. If no iron stores are present, the diagnosis of iron deficiency is established; if hemosiderin (an intracellular granule that stores iron-containing molecules) is found, iron deficiency is excluded. In addition, with iron deficiency, marrow sideroblasts will be absent or present in low numbers (less than 10% of the number of normoblasts).


Therapy for iron deficiency anemia should both correct the hemoglobin deficit and replace storage iron [see Sidebar, Iron Replacement Therapy]. Oral and parenteral replacement therapies yield similar results,50,51 but for almost all patients, oral iron is the treatment of choice.50 Oral iron therapy is effective, safe, and inexpensive.71 Because of the risk of local and systemic adverse reactions, parenteral iron should be used only in the small number of patients who cannot absorb or tolerate oral iron or whose iron requirements cannot be met by oral therapy because of chronic, uncontrollable bleeding or other blood loss. In severe iron deficiency anemia, red cell transfusions are needed in rare instances to prevent cardiac or cerebral ischemia. Red cell transfusions may also sometimes be necessary for patients whose chronic rate of iron loss exceeds the rate of replacement possible with parenteral therapy. Although the majority of patients take oral iron without difficulty, 10% to 20% experience side effects related to iron—most commonly, gastrointestinal complaints. Despite manufacturers' claims, there are no clinically significant differences between different iron salts.

Iron Replacement Therapy



Treatment of choice for iron deficiency anemia

Initial therapy to correct iron deficiency anemia

Ferrous iron salt (e.g., ferrous sulfate) given separately from meals in two or three divided doses; for example, ferrous sulfate tablets, 325 mg three times a day, or ferrous gluconate tablets, 300 mg two or three times a day

Continued therapy to replace iron stores

Ferrous iron salt given as a single daily dose of approximately 60 mg of elemental iron until the plasma ferritin concentration is > 50 µg/L (often requires 6 mo or more of treatment)

Management of side effects

Gastrointestinal side effects are the most common (10%–20% of patients) and usually can be managed symptomatically by (1) giving iron with or immediately after meals, (2) reducing the amount of iron in each dose, or (3) reducing the dose frequency to once daily



Chronic, uncontrollable blood loss producing iron needs that cannot be met by oral iron therapy

Malabsorption of iron

Intolerance of oral iron despite repeated modifications in dosage regimen


Immediate, life-threatening anaphylactic reactions

Delayed but severe serum sickness-like reactions with fever, urticaria, adenopathy, myalgias, and arthralgias

Exacerbation of rheumatoid arthritis and related conditions

Local reactions with intramuscular iron (skin staining, muscle necrosis, phlebitis, and persistent pain at injection site)


Iron dextran is the only currently available parenteral preparation; a 0.5 ml test dose is to be given at least 1 hr before every intramuscular or intravenous injection of iron dextran, but the value of this precaution is limited because anaphylaxis is not dose dependent and can occur with the test dose

Administration and dosage

Parenteral iron may be administered either intramuscularly (limited to 2 ml or 100 mg of iron per injection) or intravenously (as an undiluted injection, as a total-dose infusion, or as an additive to total parenteral nutrition); because of the risks of therapy, recommendations of the manufacturers and recent-study recommendations for treatment should be reviewed carefully before parenteral iron is given

Iron deficiency can almost always be treated effectively. Alleviation of symptoms often occurs within the first few days of treatment. With uncomplicated iron deficiency, the initial hematologic response—a mild reticulocytosis—usually begins within 3 to 5 days after the start of therapy, reaches a maximum within 8 to 10 days, and declines thereafter. After the first week, the hemoglobin concentration begins to increase and is usually normal within 6 weeks. Microcytosis may not resolve completely for as long as 4 months. If the iron deficiency is treated with oral iron at a dosage of 200 mg/day or less, the serum ferritin concentration remains below 12 µg/L until the anemia is corrected and then gradually rises as storage iron is replenished. If the response to iron therapy is not complete and characteristic, review and reevaluation of the patient is mandatory.50 One of the most common problems is mistaking the anemia of chronic disease for the anemia of iron deficiency. Recovery may be retarded by coexistent disorders, including other nutritional deficiencies; liver or kidney disease; infectious, inflammatory, or malignant disorders; or continued occult blood loss. In the event of incomplete recovery in a patient who is being treated with oral iron, the form and dosage of iron used should be reviewed, compliance evaluated, and the possibility of malabsorption considered.

Iron Overload


Iron overload arises from a sustained excess of iron supply over iron requirements and causes characteristic patterns of changes in functional, transport, and storage iron. The amount of body iron is normally controlled by regulation of dietary iron absorption. Iron overload develops with conditions that modify or circumvent the regulation of intestinal iron absorption. Because humans have no physiologic means of eliminating excess iron, any persistent increase in intake may eventually result in iron overload. When the extent of iron accumulation exceeds the body's ability to safely sequester the surplus iron, characteristic patterns of tissue damage develop. The precise manifestations of iron overload depend on the underlying abnormality responsible but generally are governed by the magnitude of the body iron burden; the rate at which the increase in body iron has occurred; the distribution of the excess iron between storage sites in macrophages and potentially more harmful deposits in parenchymal cells; and the coexistence of conditions that may ameliorate (e.g., ascorbate deficiency) or worsen (e.g., alcohol use or hepatitis) the outcome. The most common consequences of iron overload are liver disease, pancreatic disease (associated with diabetes mellitus), cardiac dysfunction, endocrine disorders (associated with gonadal insufficiency), arthropathy, and, with some forms of iron overload, specific neurologic abnormalities.

Increased iron absorption may develop because of primary disorders leading to abnormal control of iron absorption, such as hereditary hemochromatosis, or as a secondary consequence of acquired or inherited conditions, such as chronic liver disease or the iron-loading anemias. Iron overload may also result from chronic red blood cell transfusion, which bypasses intestinal control of iron uptake [see Table 3].

Table 3 Causes of Iron Overload


Hereditary hemochromatosis
  HFE associated (type 1)
  Non-HFE associated
   Transferrin receptor 2 associated (type 3)
Juvenile hemochromatosis (type 2)
  Chromosome 1q21 associated (type 2A)
  Hepcidin associated (type 2B)
Autosomal dominant hemochromatosis
  Ferroportin 1 associated (Type 4)
  Ferritin H-subunit mRNA A49U mutation


Iron-loading anemias (refractory anemias with
  hypercellular erythroid marrow)
Chronic liver disease
Porphyria cutanea tarda
Insulin resistance-associated hepatic iron overload
African dietary iron overload*
Medicinal iron ingestion*
Parenteral iron overload
   Transfusional iron overload
   Inadvertent iron overload from therapeutic


Neonatal hemochromatosis
Hereditary tyrosinemia (hypermethionemia)
Cerebrohepatorenal syndrome
GRACILE (Fellman) syndrome

  of iron

Idiopathic pulmonary hemosiderosis
Renal hemosiderosis
Associated with neurologic abnormalities
  Pantothenate kinase-associated neurodegeneration
   (formerly Hallervorden-Spatz syndrome)
  Friedreich ataxia

* May have a genetic component.
GRACILE—growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death


By far the most common forms of primary iron overload are those related to mutations in the HFE gene. Some of the genes responsible for less common forms of primary iron overload have now been identified, providing valuable insights into the control of iron metabolism. Testing for mutations in the HFE gene has become an essential step in the evaluation of primary iron overload, and continued progress is anticipated in genetic characterization of these disorders.

HFE-Associated Hereditary Hemochromatosis


Hereditary HFE-associated hemochromatosis (hemochromatosis type 1), an autosomal recessive disease, is the most common genetic disorder in persons of northern European descent.72 Data from the Third National Health and Nutrition Examination Survey (NHANES III) suggest that in the United States, 9.54% of the non-Hispanic white population is heterozygous and 0.30% is homozygous for the most common mutation in HFE, C282Y (see below).73

Etiology and genetics

The discovery of HFE, the gene on chromosome 6p21.3 that is mutated in most cases of hereditary hemochromatosis,40 has revolutionized both the understanding and the diagnosis of this disorder. Although the underlying mechanism is still not understood, a defect in the HFE protein results in an inappropriate increase in iron absorption that leads to a progressive buildup of body iron. Initially, the overload has a predominantly parenchymal pattern of deposition, with iron first accumulating in hepatocytes; subsequently, the iron builds up in the pancreas, heart, and other organs.74,75 Characteristically, macrophage iron levels in the bone marrow may be normal or even decreased despite severe parenchymal iron deposition [see Table 1].

Two missense mutations in the HFE gene, usually designated as C282Y and H63D, are responsible for up to 85% of the cases of hereditary hemochromatosis in the United States73; in other areas of the world, the percentage ranges from about 60% to almost 100%.75 In the United States, 15% or more of patients with primary iron overload have neither of these mutations but are clinically indistinguishable from patients who do have one of these mutations.40 Some of these patients are found to have other mutations in the HFE gene. Patients without evidence of mutations on chromosome 6p are classified as having non-HFE-associated hereditary hemochromatosis. The proportion of patients with non-HFE-associated hemochromatosis is higher in populations from southern Europe.76

Clinical manifestations

Homozygotes for hereditary hemochromatosis may have no distinctive clinical manifestations, especially at younger ages. In homozygotes who present with hereditary hemochromatosis in middle age or later, the classic tetrad of clinical signs is liver disease, diabetes mellitus, skin pigmentation, and gonadal failure.74,75 Arthropathy may be an early manifestation of the disease and is frequently present in patients with advanced disease. Cardiac failure may develop and may even be the presenting symptom in untreated homozygotes. Body iron stores have usually increased from the normal amount of 1 g or less to 15 to 20 g or more by the time symptoms of parenchymal damage occur, usually in middle or late life. Additional increases in body iron may be fatal, although some patients are able to tolerate a total iron accumulation of as much as 40 to 50 g or more.77 Men are affected at younger ages than women, presumably because of iron losses during menstruation and childbearing. Environmental factors (e.g., dietary iron content, blood donation or loss, and alcohol use) and coexisting disorders (e.g., viral hepatitis) may greatly influence the rate and severity of organ damage.74 The penetrance of HFE-associated hereditary hemochromatosis is a subject of controversy. In a study of 41,038 patients attending a health-appraisal clinic in the United States, the results were interpreted as showing that less than 1% of homozygotes develop frank clinical hemochromatosis,78,79 although this interpretation has been questioned.80 The Hemochromatosis and Iron Overload Screening (HEIRS) study of more than 100,000 adults should help clarify both the penetrance and the prevalence of HFE-associated hemochromatosis and other forms of iron overload in the United States.81

Screening and diagnostic tests

Screening for hereditary hemochromatosis can use both phenotypic and genotypic methods and is indicated for patients with chronic liver disease or symptoms and signs associated with iron overload.75,82 Phenotypic screening can provide biochemical evidence of iron overload, but no single test or combination of tests will identify all patients who are genetically susceptible to iron loading.78 Genotypic screening for the most common HFE mutations, C282Y and H63D, in populations of northern European ancestry can identify a majority of those patients at risk for the development of primary iron overload. In pedigree studies, genotyping should replace HLA typing in the assessment of siblings of a C282Y homozygote.75 In addition, genotyping the spouse of a C282Y homozygote is a cost-efficient strategy that leads to a more selective investigation of children for the hemochromatosis gene. Nonetheless, such limited genetic screening will not detect other mutations associated with iron loading; is less useful in other population groups, such as those originating from southern Europe,76 Africa,83 or Asia; and provides no indication of the extent of iron excess. Population screening has been advocated82,84 but has not been undertaken generally because of uncertainties about disease penetrance78; the disease burden and natural history of iron overload; and a variety of ethical, legal, and social concerns.75,78

Measurement of the serum transferrin saturation is usually recommended as the initial phenotypic screening determination.75,82,84,85Although individual laboratories may have their own reference ranges, a persistent value of 45% or higher is often recommended as a threshold value for further investigation. The serum ferritin concentration is then used as a biochemical indicator of iron overload, and in the absence of complicating factors, increased concentrations suggest increased iron stores.74 Genetic testing should then be considered in patients with abnormal elevations in transferrin saturation, serum ferritin, or both. The exact role of genetic testing in screening and diagnosis depends in part on the population being examined because of variations in the proportion of patients with hereditary hemochromatosis who have HFE mutations.

Once genetic testing has identified a patient as homozygous for the C282Y mutation (i.e., C282Y/C282Y), an elevated transferrin saturation establishes the diagnosis of hereditary hemochromatosis.85 Liver biopsy, formerly a standard part of the diagnostic process, is no longer needed in most cases. Liver biopsy is indicated to detect cirrhosis if the serum ferritin level is above 1,000 µg/L86; biopsy may also be considered in patients with hepatomegaly, patients with abnormal findings on liver function tests, and patients who are older than 40 years.74,85,87

Patients who are heterozygous for the C282Y mutation and wild type (i.e., C282Y/wild type) have serum transferrin saturations and serum ferritin concentrations that are similar to those of wild-type homozygotes (i.e., wild type/wild type),88,89 and these patients do not develop clinically important iron overload.88 Consequently, finding a persistently elevated level of transferrin saturation, serum ferritin concentration, or both in a C282Y/wild type heterozygote should lead the clinician to search for other causes of iron overload.85

In patients who are heterozygous for the C282Y mutation and H63D, the other major HFE mutation (i.e., C282Y/H63D), mild to moderate iron overload may develop, but the penetrance of this genotype is even less than that of C282Y/C282Y homozygotes.74,75,85,87Heterozygotes for H63D (i.e., H63D/wild type) may have elevated transferrin saturation levels90 but do not develop iron overload. Homozygotes for H63D (i.e., H63D/H63D) also may have elevated transferrin saturation levels, but the risk of clinically important iron overload is slight.90 Less common mutations of the HFE gene have been identified91; S65C heterozygotes with either C282Y (i.e., S65C/C282Y) or H63D (i.e., S65C/H63D) may develop mild iron overload.

Several diagnostic approaches can be pursued in patients with phenotypic evidence of iron overload who are neither homozygous for C282Y (C282Y/C282Y) nor heterozygous for C282Y and H63D (C282Y/H63D). These approaches include further genetic testing for less common HFEmutations and for non-HFE mutations associated with iron loading; noninvasive assessment of the liver iron concentration92; and liver biopsy, which permits a definitive diagnosis of hereditary hemochromatosis regardless of genotype.74,85,87 Evaluation of the biopsy specimen should include quantitative determination of the nonheme iron concentration, histochemical evaluation of the pattern of iron deposition, and pathologic assessment of tissue injury. Calculation of the hepatic iron indexhepatic iron concentration (expressed as µmol Fe/g of liver, dry weight) divided by the age of the patient in years—may be helpful in distinguishing homozygotes for hereditary hemochromatosis from heterozygotes or from patients with increased body iron associated with chronic (usually alcoholic) liver disease.74,87In the absence of other causes of iron overload, a hepatic iron index greater than 1.9 is evidence for hereditary hemochromatosis. In patients with evidence of increased body iron levels, further evaluation should be directed toward detecting complications of iron overload and may include liver function tests, assessment of glucose tolerance and hormonal function, cardiac examination, joint and bone x-rays, and, especially if cirrhosis is present, screening for hepatocellular carcinoma.74,85,87


The treatment of choice for hereditary hemochromatosis is phlebotomy to reduce the body iron levels to normal or near-normal and maintain them in that range.74,85,87 In patients with hereditary hemochromatosis who develop cardiac failure, the use of both phlebotomy and chelation therapy has been suggested. Phlebotomy therapy should be started as soon as the diagnosis of the homozygous state for hereditary hemochromatosis has been established; postponement only increases the risk of organ damage from iron overload. The phlebotomy program should remove 500 ml of blood (containing 200 to 250 mg of iron) once weekly or, for heavily loaded patients, twice weekly until the patient is iron deficient.85 Before each phlebotomy, the hematocrit or hemoglobin concentration should be measured. Initially, the hematocrit and hemoglobin levels will decline by about 10% of their initial values but may then rise as the rate of erythropoiesis increases to match the demands of phlebotomy. Measurements of serum ferritin, iron, and transferrin saturation should be done regularly to follow the progress of iron removal. As iron is removed, the serum ferritin concentration will decrease progressively but the serum transferrin saturation will remain raised until iron stores are almost exhausted. Finally, when all the storage iron has been removed, the ferritin concentration will fall to less than 12 µg/L, the serum iron concentration and transferrin saturation will drop, and the hemoglobin concentration will decrease to less than 10 g/dl for 2 weeks without further phlebotomy. In patients with hereditary hemochromatosis, prolonged treatment is often needed. For example, if the initial body iron burden is 25 g, complete removal of the iron burden with weekly phlebotomy may require 2 years or more. After the iron load has been completely removed, a lifelong program of maintenance phlebotomy is required to prevent reaccumulation of the iron burden.85 Typically, phlebotomy of 500 ml of blood every 3 to 4 months is needed. The goal of maintenance phlebotomy should be to maintain a serum ferritin concentration of less than about 50 µg/L.

If phlebotomy therapy removes the iron load before diabetes mellitus or cirrhosis develops, the patient's life expectancy is normal.93 If cirrhosis develops, however, the risk of hepatocellular carcinoma is increased by more than 200-fold.74 In hereditary hemochromatosis, hepatomas develop almost exclusively in patients with hepatic cirrhosis and are the ultimate cause of death in 20% to 30% of these patients, even after successful removal of the iron burden. Phlebotomy therapy is almost always indicated for patients with hereditary hemochromatosis, even when cirrhosis or organ damage is already present, because further progression of the disease can be stopped and alleviation of some organ dysfunction is possible.

Non-HFE-Associated Hereditary Hemochromatosis

Clinically, non-HFE-associated hereditary hemochromatosis is indistinguishable from hereditary hemochromatosis associated with HFEmutations. Genetically, the non-HFE disorder is heterogeneous. One subset of this autosomal recessive disorder, designated as hemochromatosis type 3, is caused by mutations of the gene encoding transferrin receptor 2 on chromosome 7q22.45

Juvenile Hemochromatosis

Juvenile hemochromatosis, designated as hemochromatosis type 2, is a rare autosomal recessive disorder in which severe iron overload develops before age 30. The two sexes are affected equally, and patients may present with cardiomyopathy, hypogonadism, impaired glucose tolerance, or some combination of these manifestations.94 Genetically, two subtypes have so far been distinguished. Type 2A shows linkage to chromosome 1q21, but the responsible gene has not yet been identified.95 Type 2B is caused by mutations in the gene for hepcidin on chromosome 19q13.46

Autosomal Dominant Hemochromatosis

Hemochromatosis with an autosomal dominant pattern of inheritance is also genetically heterogeneous, and at least one variety has been designated as hemochromatosis type 4. Several families have been identified with iron overload associated with mutations in the ferroportin gene (SLC11A3) on chromosome 2q32. Characteristically, initial iron accumulation is predominantly reticuloendothelial and the serum ferritin concentration is increased, with relatively low transferrin saturation; mild anemia early in life has been reported in a number of those affected. Some, but not all, of those with ferroportin mutations have also developed parenchymal iron overload.96 A single Japanese family has been described with autosomal dominant iron overload ascribed to a point mutation (A49U) in the iron-responsive element (IRE) of H-ferritin mRNA.97 Autosomal dominant hemochromatosis has also been reported in a Melanesian kindred, but the genetic basis has not been determined.98

Atransferrinemia and Aceruloplasminemia

Iron overload may also result from two rare autosomal recessive disorders in which the synthesis of plasma proteins vital for iron transport is absent or almost absent. In atransferrinemia, dietary iron is readily absorbed and circulates as nontransferrin plasma iron but cannot be used for erythropoiesis because of the lack of a physiologic means of transport into developing erythroid cells; affected persons die unless they receive transferrin infusion or blood transfusion.99 In aceruloplasminemia, the deficiency of ceruloplasmin ferroxidase activity results in iron accumulation in the liver, pancreas, and brain, with smaller amounts of excess iron found in the spleen, heart, kidney, thyroid, and retina. Patients present with progressive neurodegeneration of the retina and basal ganglia and with diabetes mellitus in middle age.100


Secondary iron overload may result from increased gastrointestinal absorption of iron, from transfusion of red blood cells, from inadvertent iatrogenic parenteral administration of iron, or from some combination thereof. Despite the progress made in understanding genetically determined increases in intestinal iron uptake, the pathophysiologic mechanisms responsible for the increased absorption of iron in secondary iron overload are still obscure.

Iron-Loading Anemias

The iron-loading anemias include congenital dyserythropoietic anemia, pyruvate kinase deficiency, thalassemia major (Cooley anemia) and thalassemia intermedia, hemoglobin E-β-thal assemia, a variety of forms of sideroblastic anemia, some myelodysplastic anemias, and other anemic disorders in which the incorporation of iron into hemoglobin is impaired. In patients with iron-loading anemias, severe iron overload may develop as a result of increased gastrointestinal iron absorption. Any red cell transfusions these patients receive will contribute to the iron loading. Because the extent of ineffective erythropoiesis, not the severity of the anemia, seems to determine the rate of iron loading, severe iron overload may develop in patients with only slight or mild anemia.101 The clinical manifestations and pathology that may develop in patients with iron-loading anemias are similar to those seen in hereditary hemochromatosis, including liver disease, diabetes mellitus, endocrine disorders, and cardiac dysfunction.102 Suppression of hepcidin synthesis by anemia, hypoxia, or both has been suggested as a potential mechanism for the increased iron absorption,103 but the distinctive influence of ineffective erythropoiesis remains to be explained.

Other Causes and Forms of Absorption-Related Iron Overload

Chronic liver disease

Some patients with chronic liver disease, including those with alcoholic cirrhosis and those with portacaval shunting, may experience minor or modest degrees of iron loading as a result of increased dietary iron absorption.74 The mechanisms responsible for the increased gastrointestinal iron uptake have not been identified, although ineffective erythropoiesis and hyperferremia associated with alcohol-induced folate and sideroblastic abnormalities have been proposed as etiologic factors.104 Body iron stores are increased only to a minor degree, typically to 2 to 4 g, but in alcoholic cirrhosis, the higher the liver iron, the shorter the survival.

Porphyria cutanea tarda

Symptomatic patients with porphyria cutanea tarda, a hepatic porphyria, usually have a modest increase in body iron levels that almost always is the result of increased gastrointestinal absorption.102 In patients who are of European ancestry, HFE mutations are common and may contribute to the pathogenesis of both the familial and the sporadic forms of the disorder.105

Insulin resistance-associated hepatic iron overload

An iron-overload syndrome characterized by an increased serum ferritin level with a normal transferrin saturation level in association with glucose or lipid metabolic abnormalities, or both, was first described in 1997106 and has come to be known as insulin resistance-associated hepatic iron overload.107 The iron overload is typically mild or moderate, and the histologic appearance is distinct from that of HFE-associated hemochromatosis.

African dietary iron overload

In sub-Saharan Africa, iron overload in association with greatly increased dietary iron intake from a fermented maize beverage home-brewed in steel drums has been described. Iron burdens may be as great as those found in hereditary hemochromatosis, and patients may develop liver disease (with cirrhosis and hepatoma), pancreatic disease (with diabetes mellitus), endocrine disorders, and cardiac dysfunction. Although increased dietary iron intake was long considered the sole cause of the increased iron absorption in this disorder, a series of pedigree studies has suggested that a genetic component may be involved and may be common in populations of African ancestry.83

Medicinal iron ingestion

Ingestion of iron supplements can undoubtedly contribute to the body iron burden of patients with iron-loading disorders, but the extent to which orally administered iron can increase the body iron stores of normal individuals remains uncertain. Although some case reports have described iron accumulation in patients who have taken medicinal iron for long periods, the potential involvement of an unrecognized iron-loading mutation in these individuals cannot be excluded.

Transfusional and Other Parenteral Iron Overload

Etiology and diagnosis An adequate transfusion program can sustain life in patients with severe chronic refractory anemia, but transfusion therapy alone produces a progressive accumulation of the iron contained in transfused red cells.108,109 Iron accumulation from transfusion initially occurs predominantly in macrophage sites, followed by redistribution to parenchymal tissues. In patients with severe congenital anemias, such as thal assemia major and the Blackfan-Diamond syndrome, regular transfusions can prevent death from anemia in infancy and permit normal growth and development during childhood. Treatment of acquired transfusion-dependent anemias, such as aplastic anemia, pure red cell aplasia, and hypoplastic or myelodysplastic disorders, among others, may result in the development of marked iron overload. If the transfusion-dependent anemia includes erythroid hyperplasia with ineffective erythropoiesis, increased gastrointestinal iron absorption may add to the iron loading. In such cases, dietary iron uptake may be minimized by suppression of erythropoiesis with an adequate transfusion program. Although sickling disorders (e.g., sickle cell anemia and sickle cell-β-thal assemia) are not transfusion-dependent, these patients may acquire a considerable iron load from repeated transfusions for the prevention of stroke, painful crises, and other recurrent complications.110 Because humans lack a physiologic means of eliminating excess iron, iron contained in transfused red cells progressively accumulates and eventually damages the liver, heart, pancreas, and other organs; death usually occurs from cardiac failure. In younger patients, the iron burden results in growth failure and, in adolescence, delayed or absent sexual maturation. Parenteral medicinal iron may needlessly add to the iron burden in patients with refractory microcytic anemias who are misdiagnosed as iron deficient.


About 200 to 250 mg of iron is added to the body iron load with each unit of transfused red cells. Most transfusion-dependent patients require 200 to 300 ml/kg of blood a year; for example, a 70 kg adult requires about two to three units of blood every 3 to 4 weeks, adding about 6 to 10 g of iron a year. The severity of iron toxicity seems to be related to the magnitude of the body iron burden. Almost all patients who have been treated with transfusion alone and have received 100 or more units of blood (about 20 to 25 g of iron) have developed cardiac iron deposits, often in association with signs of hepatic, pancreatic, and endocrine damage.108,109 For patients who are transfusion dependent or severely anemic, the only way to prevent iron overload is treatment with a chelating agent capable of complexing with iron and permitting its excretion. The only iron-chelating agent now available for clinical use in North America is deferoxamine B, a siderophore produced by Streptomyces pilosus. Clinical trials with deferoxamine have documented the effectiveness of iron chelation as therapy for iron overload, demonstrating that regular iron chelation can decrease the body iron burden, alleviate organ dysfunction, and improve survival.108 Although toxic side effects can occur, especially with intensive therapy, deferoxamine has been a remarkably safe drug, even with near-lifelong use in some patients.109

Iron chelation therapy should be started early to prevent the accumulation of toxic amounts of iron in vulnerable tissues and to maintain body iron stores at concentrations associated with a low risk of early death and clinical complications. The longer chelation therapy is delayed, the greater the risk of iron toxicity. Because deferoxamine is poorly absorbed after oral administration and rapidly eliminated from the circulation, deferoxamine must be given by slow subcutaneous or intravenous infusion over 9 to 12 hours each day at least 5 days a week to be optimally useful in the treatment of patients with transfusional iron overload.108,109 In patients with thalassemia major and other congenital refractory anemias who have been transfusion dependent from early infancy, chelation therapy is best started after about 10 to 20 transfusions, usually when the patient is 3 or 4 years of age.108,109 Deferoxamine is administered by slow subcutaneous infusion at a dosage not exceeding 25 mg/kg/day to minimize the risk of growth retardation. In older patients and adults with acquired refractory anemias who require regular transfusion and in patients with sickle cell disease who are chronically transfused for prevention of complications, early therapy also seems prudent, beginning after transfusion of 10 to 20 units of blood. The usual dosage of deferoxamine in these older patients is not more than 50 mg/kg/day, given over 9 to 12 hours by slow subcutaneous infusion at least 5 days a week. In some patients who are unable to tolerate the local pain and discomfort of subcutaneous infusion or who need rapid reduction of high body iron burdens, deferoxamine may be administered intravenously through implantable venous access ports. Compliance with these near-daily regimens of prolonged parenteral infusions may be difficult, and lack of compliance is the chief obstacle to effective iron chelation therapy. Administration of ascorbic acid can enhance deferoxamine-induced iron excretion but carries the risk of an internal redistribution of iron from relatively benign storage sites in macrophages to a potentially toxic pool in parenchymal cells. Although the evidence is anecdotal, large doses of ascorbic acid should be regarded as hazardous in patients with iron overload. Although deferoxamine is a generally safe and nontoxic drug in the iron-loaded patient, systemic complications have been reported, including allergic anaphylactoid reactions, infections, visual abnormalities and auditory dysfunction, and growth retardation.108,109 As a result, regular evaluation for drug toxicity should be included in the management of any patient receiving deferoxamine, including annual audiograms, retinal examination, and assessment of growth in children and adolescents. The risk of many of these complications may be minimized by adjusting the deferoxamine dose to the magnitude of the body iron load. New and promising chelating agents are in development111 or in clinical trials,112 but none is yet available for clinical use.

Additional Rare or Uncommon Forms of Iron Overload

Perinatal iron overload occurs in several forms. Neonatal hemochromatosis is a heterogeneous group of disorders associated with severe congenital hepatic disease and deposits of iron in the liver, pancreas, heart, and other extrahepatic sites, with evidence of autosomal recessive inheritance in some cases.113 Several rare metabolic abnormalities of the neonate may be associated with abnormal iron deposition, including hereditary tyrosinemia (hypermethioninemia); Zellweger cerebrohepatorenal syndrome114; the tricho-hepato-enteric syndrome; and the GRACILE (or Fellman) syndrome.113

Focal sequestration of iron is found in other rare disorders, including idiopathic pulmonary hemosiderosis and renal hemosiderosis. Such abnormal iron deposition is associated with neurologic abnormalities in Friedreich ataxia, in pantothenate kinase-associated neurodegeneration (formerly Haller vorden-Spatz syndrome), and in neuroferritinopathy.115 Finally, hyperferritin emia with autosomal dominant congenital cataract116 is a disorder of iron metabolism in which affected family members present with early-onset, bilateral nuclear cataracts and moderately elevated serum ferritin concentrations.116 The body iron level is normal in these patients, but overload is often suspected because of the elevated serum ferritin concentrations.


Figure 1 Seward Hung.

Figure 2 Marcia Kammerer.

Figure 3 Seward Hung.

Figure 4 Dimitry Schidlovsky.


  1. Klinken S: Red blood cells. Internat J Biochem Cell Biol 34:1513, 2002
  2. Yonetani T, Park SI, Tsuneshige A, et al: Global allostery model of hemoglobin: modulation of O(2) affinity, cooperativity, and Bohr effect by heterotropic allosteric effectors. J Biol Chem 277:34508, 2002
  3. Hsia CC: Respiratory function of hemoglobin. N Engl J Med 338:239, 1998
  4. McMahon TJ, Moon RE, Luschinger BP, et al: Nitric oxide in the human respiratory cycle. Nat Med 8:711, 2002
  5. Schechter AN, Gladwin MT: Hemoglobin and the paracrine and endocrine functions of nitric oxide. N Engl J Med 348:1483, 2003
  6. Discher DE, Carl P: New insights into red cell network structure, elasticity, and spectrin unfolding—a current review. Cell Mol Biol Lett 6:593, 2001
  7. Jacobasch G: Biochemical and genetic basis of red cell enzyme deficiencies. Baillieres Best Pract Res Clin Haematol 13:1, 2000
  8. Henry ER, Bettati S, Hofrichter J, et al: A tertiary two-state allosteric model for hemoglobin. Biophys Chem 98:149, 2002
  9. Leach RM, Treacher DF: The pulmonary physician in critical care: 2: oxygen delivery and consumption in the critically ill. Thorax 57:170, 2002
  10. Fisher JW: Erythropoietin: physiology and pharmacology update. Exp Biol Med (Maywood) 228:1, 2003
  11. Trent JT 3rd, Watts RA, Hargrove MS: Human neuroglobin, a hexacoordinate hemoglobin that reversibly binds oxygen. J Biol Chem 276:30106, 2001
  12. Burmester T, Ebner B, Weich B, et al: Cytoglobin: a novel globin type ubiquitously expressed in vertebrate tissues. Mol Biol Evol 19:416, 2002
  13. Geers C, Gros G: Carbon dioxide transport and carbonic anhydrase in blood and muscle. Physiol Rev 80:681, 2000
  14. Andrews NC: Disorders of iron metabolism. N Engl J Med 341:1986, 1999
  15. Aisen P, Enns C, Wessling-Resnick M: Chemistry and biology of eukaryotic iron metabolism. Int J Biochem Cell Biol 33:940, 2001
  16. Finch C: Regulators of iron balance in humans. Blood 84:1697, 1994
  17. Zakin MM, Baron B, Guillou F: Regulation of the tissue-specific expression of transferrin gene. Dev Neurosci 24:222, 2002
  18. Trinder D, Baker E: Transferrin receptor 2: a new molecule in iron metabolism. Int J Biochem Cell Biol 35:292, 2003
  19. Andrews NC: A genetic view of iron homeostasis. Semin Hematol 39:227, 2002
  20. Arosio P, Levi S: Ferritin, iron homeostasis, and oxidative damage. Free Radic Biol Med 33:457, 2002
  21. Levi S, Corsi B, Bosisio M, et al: A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem 276:24437, 2001
  22. Cazzola M, Invernizzi R, Bergamaschi G, et al: Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. Blood 101:1996, 2003
  23. Rouault TA: Systemic iron metabolism: a review and implications for brain iron metabolism. Pediatr Neurol 25:130, 2001
  24. Hubert N, Hentze MW: Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci USA 99:12345, 2002
  25. Abboud S, Haile DJ: A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275:19906, 2000
  26. Cairo G, Recalcati S, Pietrangelo A, et al: The iron regulatory proteins: targets and modulators of free radical reactions and oxidative damage. Free Radic Biol Med 32:1237, 2002
  27. Knutson M, Wessling-Resnick M: Iron metabolism in the reticuloendothelial system. Crit Rev Biochem Mol Biol 38:61, 2003
  28. Kondo H, Saito K, Grasso JP, et al: Iron metabolism in the erythrophagocytosing Kupffer cell. Hepatology 8:32, 1988
  29. Kristiansen M, Graversen JH, Jacobsen C, et al: Identification of the haemoglobin scavenger receptor. Nature 409:198, 2001
  30. Wilks A: Heme oxygenase: evolution, structure, and mechanism. Antioxid Redox Signal 4:603, 2002
  31. Baranano DE, Wolosker H, Bae BI, et al: A mammalian iron ATPase induced by iron. J Biol Chem 275:15166, 2000
  32. Pietrangelo A: Physiology of iron transport and the hemochromatosis gene. Am J Physiol Gastrointest Liver Physiol 282:G403, 2002
  33. Hellman NE, Gitlin JD: Ceruloplasmin metabolism and function. Annu Rev Nutr 22:439, 2002
  34. Tolosano E, Altruda F: Hemopexin: structure, function, and regulation. DNA Cell Biol 21:297, 2002
  35. Bothwell TH, Charlton RW, Cook JD, et al: Iron Metabolism in Man. Blackwell, London, England, 1979
  36. Miret S, Simpson RJ, McKie AT: Physiology and molecular biology of dietary iron absorption. Annu Rev Nutr 23:283, 2003
  37. Conrad ME, Umbreit JN: Pathways of iron absorption. Blood Cells Mol Dis 29:336, 2002
  38. McKie AT, Latunde-Dada GO, Miret S, et al: Molecular evidence for the role of a ferric reductase in iron transport. Biochem Soc Trans 30:722, 2002
  39. Anderson GJ, Frazer DM, McKie AT, et al: The expression and regulation of the iron transport molecules hephaestin and IREG1: implications for the control of iron export from the small intestine. Cell Biochem Biophys 36:137, 2002
  40. Feder JN, Gnirke A, Thomas W, et al: A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399, 1996
  41. Fleming RE, Sly WS: Mechanisms of iron accumulation in hereditary hemochromatosis. Annu Rev Physiol 64:663, 2002
  42. Drakesmith H, Sweetland E, Schimanski L, et al: The hemochromatosis protein HFE inhibits iron export from macrophages. Proc Natl Acad Sci USA 99:15602, 2002
  43. Townsend A, Drakesmith H: Role of HFE in iron metabolism, hereditary haemochromatosis, anaemia of chronic disease, and secondary iron overload. Lancet 359:786, 2002
  44. Frazer DM, Anderson GJ: The orchestration of body iron intake: how and where do enterocytes receive their cues? Blood Cells Mol Dis 30:288, 2003
  45. Camaschella C, Roetto A, Cali A, et al: The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 25:14, 2000
  46. Roetto A, Papanikolaou G, Politou M, et al: Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 33:21, 2003
  47. Bridle KR, Frazer DM, Wilkins SJ, et al: Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 361:669, 2003
  48. Ramakrishnan U, Yip R: Experiences and challenges in industrialized countries: control of iron deficiency in industrialized countries. J Nutr 132:820S, 2002
  49. Iron Deficiency—United States, 1999–2000. MMWR Morb Mortal Wkly Rep 51:897, 2002
  50. Goddard AF, McIntyre AS, Scott BB: Guidelines for the management of iron deficiency anaemia. British Society of Gastroenterology. Gut 46(suppl 3–4):IV1, 2000
  51. Recommendations to prevent and control iron deficiency in the United States. MMWR Recomm Rep 47(RR-3):1, 1998
  52. Willoughby JM, Laitner SM: Audit of the investigation of iron deficiency anaemia in a district general hospital, with sample guidelines for future practice. Postgrad Med J 76:218, 2000
  53. Mukhopadhyay D, Mohanaruban K: Iron deficiency anaemia in older people: investigation, management and treatment. Age Ageing 31:87, 2002
  54. Annibale B, Capurso G, Chistolini A, et al: Gastrointestinal causes of refractory iron deficiency anemia in patients without gastrointestinal symptoms. Am J Med 111:439, 2001
  55. Sandoval C, Berger E, Ozkaynak MF, et al: Severe iron deficiency anemia in 42 pediatric patients. Pediatr Hematol Oncol 19:157, 2002
  56. Lee PL, Halloran C, Trevino R, et al: Human transferrin G277S mutation: a risk factor for iron deficiency anaemia. Br J Haematol 115:329, 2001
  57. Earley CJ: Clinical practice. Restless legs syndrome. N Engl J Med 348:2103, 2003
  58. Kalra L, Hamlyn AN, Jones BJ: Blue sclerae: a common sign of iron deficiency? Lancet 2:1267, 1986
  59. Rector WG Jr: Pica: its frequency and significance in patients with iron-deficiency anemia due to chronic gastrointestinal blood loss. J Gen Intern Med 4:512, 1989
  60. Haas JD, Brownlie T 4th: Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship. J Nutr 131:676S, 2001
  61. Oppenheimer SJ: Iron and its relation to immunity and infectious disease. J Nutr 131:616S, 2001
  62. Grantham-McGregor S, Ani C: A review of studies on the effect of iron deficiency on cognitive development in children. J Nutr 131:649S, 2001
  63. Cook J: The nutritional assessment of iron status. Arch Latinoam Nutr 49:11S, 1999
  64. Cook JD: The measurement of serum transferrin receptor. Am J Med Sci 318:269, 1999
  65. Malope BI, MacPhail AP, Alberts M, et al: The ratio of serum transferrin receptor and serum ferritin in the diagnosis of iron status. Br J Haematol 115:84, 2001
  66. Beguin Y: Soluble transferrin receptor for the evaluation of erythropoiesis and iron status. Clin Chim Acta 329:9, 2003
  67. Cook JD, Flowers CH, Skikne BS: The quantitative assessment of body iron. Blood 101:3359, 2003
  68. Brugnara C: Reticulocyte cellular indices: a new approach in the diagnosis of anemias and monitoring of erythropoietic function. Crit Rev Clin Lab Sci 37:93, 2000
  69. Thomas C, Thomas L: Biochemical markers and hematologic indices in the diagnosis of functional iron deficiency. Clin Chem 48:1066, 2002
  70. Goodnough LT, Skikne B, Brugnara C: Erythropoietin, iron, and erythropoiesis. Blood 96:823, 2000
  71. McDiarmid T, Johnson ED: Are any oral iron formulations better tolerated than ferrous sulfate? J Fam Pract 51:576, 2002
  72. Milman N, Pedersen P: Evidence that the Cys282Tyr mutation of the HFE gene originated from a population in Southern Scandinavia and spread with the Vikings. Clin Genet 64:36, 2003
  73. Steinberg KK, Cogswell ME, Chang JC, et al: Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA 285:2216, 2001
  74. Powell LW: Hereditary hemochromatosis and iron overload diseases. J Gastroenterol Hepatol 17(suppl):S191, 2002
  75. Bomford A: Genetics of haemochromatosis. Lancet 360:1673, 2002
  76. Barosi G, Salvaneschi L, Grasso M, et al: High prevalence of a screening-detected, HFE-unrelated, mild idiopathic iron overload in Northern Italy. Haematologica 87:472, 2002
  77. Adams PC, Deugnier Y, Moirand R, et al: The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis. Hepatology 25:162, 1997
  78. Beutler E, Felitti VJ, Koziol JA, et al: Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 359:211, 2002
  79. Beutler E: The HFE Cys282Tyr mutation as a necessary but not sufficient cause of clinical hereditary hemochromatosis. Blood 101:3347, 2003
  80. Ajioka RS, Kushner JP: Clinical consequences of iron overload in hemochromatosis homozygotes. Blood 101:3351, 2003
  81. McLaren CE, Barton JC, Adams PC, et al: Hemochromatosis and Iron Overload Screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults. Am J Med Sci 325:53, 2003
  82. Niederau C, Strohmeyer G: Strategies for early diagnosis of haemochromatosis. Eur J Gastroenterol Hepatol 14:217, 2002
  83. Gordeuk VR: African iron overload. Semin Hematol 39:263, 2002
  84. Adams P, Brissot P, Powell LW: EASL International Consensus Conference on Haemochromatosis. J Hepatol 33:485, 2000
  85. Brissot P, Guyader D, Loreal O, et al: Clinical aspects of hemochromatosis. Transfus Sci 23:193, 2000
  86. Morrison ED, Brandhagen DJ, Phatak PD, et al: Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med 138:627, 2003
  87. Pietrangelo A: Haemochromatosis. Gut 52(suppl 2):ii23, 2003
  88. Moirand R, Guyader D, Mendler MH, et al: HFE based re-evaluation of heterozygous hemochromatosis. Am J Med Genet 111:356, 2002
  89. Beutler E, Felitti V, Gelbart T, et al: Haematological effects of the C282Y HFE mutation in homozygous and heterozygous states among subjects of northern and southern European ancestry. Br J Haematol 120:887, 2003
  90. Gochee PA, Powell LW, Cullen DJ, et al: A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology 122:646, 2002
  91. Pointon JJ, Wallace D, Merryweather-Clarke AT, et al: Uncommon mutations and polymorphisms in the hemochromatosis gene. Genet Test 4:151, 2000
  92. Brittenham GM, Badman DG: Noninvasive measurement of iron: report of an NIDDK workshop. Blood 101:15, 2003
  93. Niederau C, Fischer R, Purschel A, et al: Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 110:1107, 1996
  94. De Gobbi M, Roetto A, Piperno A, et al: Natural history of juvenile haemochromatosis. Br J Haematol 117:973, 2002
  95. Roetto A, Totaro A, Cazzola M, et al: Juvenile hemochromatosis locus maps to chromosome 1q. Am J Hum Genet 64:1388, 1999
  96. Cazzola M, Cremonesi L, Papaioannou M, et al: Genetic hyperferritinaemia and reticuloendothelial iron overload associated with a three base pair deletion in the coding region of the ferroportin gene (SLC11A3). Br J Haematol 119:539, 2002
  97. Kato J, Fujikawa K, Kanda M, et al: A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload. Am J Hum Genet 69:191, 2001
  98. Eason RJ, Adams PC, Aston CE, et al: Familial iron overload with possible autosomal dominant inheritance. Aust N Z J Med 20:226, 1990
  99. Sheth S, Brittenham GM: Genetic disorders affecting proteins of iron metabolism: clinical implications. Annu Rev Med 51:443, 2000
  100. Nittis T, Gitlin JD: The copper-iron connection: hereditary aceruloplasminemia. Semin Hematol 39:282, 2002
  101. Cazzola M, Beguin Y, Bergamaschi G, et al: Soluble transferrin receptor as a potential determinant of iron loading in congenital anaemias due to ineffective erythropoiesis. Br J Haematol 106:752, 1999
  102. Bottomley SS: Secondary iron overload disorders. Semin Hematol 35:77, 1998
  103. Nicolas G, Chauvet C, Viatte L, et al: The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 110:1037, 2002
  104. Conrad ME, Barton JC: Anemia and iron kinetics in alcoholism. Semin Hematol 17:149, 1980
  105. Bygum A, Christiansen L, Petersen NE, et al: Familial and sporadic porphyria cutanea tarda: clinical, biochemical and genetic features with emphasis on iron status. Acta Derm Venereol 83:115, 2003
  106. Moirand R, Mortaji AM, Loreal O, et al: A new syndrome of liver iron overload with normal transferrin saturation. Lancet 349:95, 1997
  107. Chitturi S, George J: Interaction of iron, insulin resistance, and nonalcoholic steatohepatitis. Curr Gastroenterol Rep 5:18, 2003
  108. Olivieri NF, Brittenham GM: Iron-chelating therapy and the treatment of thalassemia. Blood 89:739, 1997
  109. Porter JB: Practical management of iron overload. Br J Haematol 115:239, 2001
  110. Files B, Brambilla D, Kutlar A, et al: Longitudinal changes in ferritin during chronic transfusion: a report from the Stroke Prevention Trial in Sickle Cell Anemia (STOP). J Pediatr Hematol Oncol 24:284, 2002
  111. Wong C, Richardson DR: beta-Thalassaemia: emergence of new and improved iron chelators for treatment. Int J Biochem Cell Biol 35:1144, 2003
  112. Nisbet-Brown E, Olivieri NF, Giardina PJ, et al: Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 361:1597, 2003
  113. Kelly AL, Lunt PW, Rodrigues F, et al: Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism. J Med Genet 38:599, 2001
  114. Goldfischer S, Grotsky HW, Chang CH, et al: Idiopathic neonatal iron storage involving the liver, pancreas, heart, and endocrine and exocrine glands. Hepatology 1:58, 1981
  115. Ponka P: Rare causes of hereditary iron overload. Semin Hematol 39:249, 2002
  116. Cazzola M: Hereditary hyperferritinaemia/cataract syndrome. Best Pract Res Clin Haematol 15:385, 2002

Editors: Dale, David C.; Federman, Daniel D.