Iron metabolism

Systemic and cellular iron regulation

The control of iron homeostasis acts at both the cellular and the systemic level and involves a complex system of different cell types, transporters, and signals. To maintain systemic iron homeostasis, communication between cells that absorb iron from the diet (duodenal enterocytes), consume iron (mainly erythroid precursors), and store iron (hepatocyte and tissue macrophages) must be tightly regulated. Each of these cell types plays an essential role in the homeostatic iron cycle. The β-defensin–like antimicrobial peptide hepcidin is thought to be the long-anticipated regulator that controls iron absorption and macrophage iron release. Hepcidin is synthesized in the liver upon changes in body iron needs, anemia, hypoxia, and inflammation, and secreted in the circulation. It counteracts the function of ferroportin, a major cellular iron exporter protein in the membrane of macrophages and the basolateral site of enterocytes, by inducing its internalization and degradation. ^, Background information on these major pathways of iron exchange and the role of hepcidin in iron regulation is provided in Fig. 40.1 . Cells involved in iron homeostasis are duodenal enterocytes, hepatocytes, macrophages, and erythroid precursors. Fig. 40.2 displays these key sites in iron homeostasis and their function in more detail to illustrate the description of the pathophysiology for the different iron disorders. The iron enters the body through the diet. Most iron absorption takes place in the duodenal and proximal jejunum enterocytes in different phases. In the luminal phase iron is solubilized and converted from trivalent iron into bivalent iron by duodenal cytochrome B (DcytB). During the mucosal phase iron is bound to the brush border and transported into the mucosal cell by the iron transporter dimetal transporter (DMT1). In the cellular phase iron is either stored in cellular ferritin or transported directly to the opposite side of the mucosal side. In the last phase of iron absorption Fe ²⁺ is released into the portal circulation by the basolateral cellular exporter ferroportin. Enterocytic iron export also requires hephaestin, a multicopper oxidase homologous to ceruloplasmin (CP), which oxidases Fe ²⁺ to Fe ³⁺ for loading onto transferrin. This cellular efflux of iron is inhibited by the peptide hormone hepcidin by binding to ferroportin and subsequent degradation of the ferroportin-hepcidin complex.

The hepatocyte serves as the main storage site for surplus iron (most body iron is present in erythrocytes and macrophages). Furthermore this cell, as the main producer of hepcidin, largely controls systemic iron regulation. The signal transduction pathway runs from the membrane to the nucleus, where the bone morphogenetic protein (BMP) receptor, the membrane protein hemojuvelin (HJV), the HFE protein and transferrin receptor (TfR) -1 and -2, and matriptase-2 each plays an essential role. Through intracellular pathways, a signal is given to hepcidin transcription. The membrane-associated protease matriptase-2 (encoded by TMPRSS6 ) detects iron deficiency and blocks hepcidin transcription by cleaving HJV. The macrophage belongs to the group of reticuloendothelial cells and breaks down senescent red blood cells. During this process iron is released from heme proteins. This iron can either be stored in the macrophage as hemosiderin or ferritin, or may be delivered to the erythroid progenitor as an ingredient for new erythrocytes. The iron exporter ferroportin is responsible for the efflux of Fe ²⁺ into the circulation. In both hepatocytes and macrophages this transport requires the multicopper oxidase CP, which oxidases Fe ²⁺ to Fe ³⁺ for loading onto transferrin.

In the erythroid progenitor cell , transferrin, with iron molecules, is endocytosed via TfR1. After endocytosis the iron is released from transferrin by acidification, converted from Fe ³⁺ to Fe ²⁺ by the ferroreductase six-transmembrane epithelial antigen of prostate 3 (STEAP3), and transported to the cytosol by DMT1, where it is available mainly for heme synthesis. Apotransferrin is transported back to the cell surface and released, ready to transport additional iron. Erythropoiesis has been reported to communicate with the hepatocyte by the proteins Growth Differentiation Factor 15 (GDF15), Twisted Gastrulation 1 (TWSG1), and erythroferrone (ERFE) that inhibit signaling to hepcidin. In the mitochondria of the erythroid progenitor , heme synthesis and iron-sulfur cluster (Fe-S clusters) synthesis takes place. In the first rate-limiting step of heme synthesis, 5-aminolevulinic acid (ALA) is synthesized from glycine and succinyl-CoA by the enzyme delta-aminolevulinic acid synthase (ALAS2) in the mitochondrial matrix. The protein SLC25A38 is located in the mitochondrial membrane and is probably responsible for the import of glycine into the mitochondria and might also export ALA to the cytosol. In the heme synthesis pathway, the uroporphyrinogen III synthase (UROS) in the cytosol is the fourth enzyme. It is responsible for the conversion of hydroxymethylbilane (MHB) to uroporphyrinogen III, a physiologic precursor of heme. In the last step, ferrochelatase (FECH) located in the mitochondrial intermembrane space is responsible for the last step, that is, the incorporation of Fe ²⁺ in protoporphyrin IX (PPIX) to form heme. GATA binding factor I (GATA 1) is critical for normal erythropoiesis, globin gene expression, and megakaryocyte development and among others regulates expression of UROS and ALAS2 in erythroblasts. The enzyme glutaredoxin-5 (GLRX5) plays a role in the synthesis of the Fe-S clusters, which are transported to the cytoplasm, probably via the transporter ABCB7.

Human hepcidin is predominantly produced by hepatocytes as a 25-amino-acid (aa) peptide (molecular weight: 2789.4 Da) ^{, ,} that is secreted into the circulation. Subsequent amino-terminal processing of the 25 aa form can result in the appearance of four main smaller hepcidin forms of 24, 23, 22, and 20 amino acids. ^, These hepcidin peptides form a hairpin structure, with four intramolecular disulfide bridges. Much is still unknown about the origin of the smaller isoforms. They are thought to arise due to degradation of the full-length hepcidin in the circulation or the urine. Cleavage of hepcidin also occurs during sample storage at room temperature.

Under physiologic conditions the smaller hepcidin isoforms are present in the urine, but not in serum, other than at very low concentrations. ^, These smaller hepcidin isoforms only occur in serum in diseases that are associated with increased concentrations of hepcidin-25, such as sepsis and chronic kidney disease (reviewed in Kroot et al. ). Only the full-length 25-aa hepcidin is biologically active and induces significant hypoferremia. ^,

Hepcidin is bound to α2-macroglobulin, but the proportion of hepcidin that is freely circulating varies between 11 and 98%.

Several physiologic and pathologic processes regulate the synthesis of hepcidin (reviewed in references , , , and ). These functional signaling routes by which (1) iron status, (2) erythropoietic activity, (3) hypoxia, and (4) inflammation affect hepcidin expression are increasingly being investigated. These routes comprise four highly interconnected regulatory pathways ( Fig. 40.3 ). Situations in which demand for circulating iron is increased (particularly erythropoietic activity) elicit a decrease in hepatocellular hepcidin synthesis. These conditions include iron deficiency, hypoxia, anemia, and conditions characterized by increased erythropoietic activity. A decrease in hepcidin results in the release of stored iron and an increase in dietary iron absorption. Conversely, infection or inflammation causes an increase in hepcidin synthesis. This leads to a deficiency of iron available for erythropoiesis and is considered to be the mechanism underlying the reticuloendothelial iron sequestration, intestinal iron absorption impairment, and low serum iron concentrations characteristic of ACD.

Intracellular iron regulation

The expression of proteins involved in the uptake, storage, and release of iron from the cell is determined by the need of the cell for iron and regulated at the post-transcriptional level by iron responsive protein and iron regulatory element (IRP/IRE) network. In the cell, the IRP1 and IRP2 interact with the IRE on mRNA and affect the translation to protein. In conditions of high cellular iron (Fe) levels, the IRPs are inactive. Low cellular Fe levels, on the other hand, increase IRP activity. In the latter condition, IRPs bind to the IRE and inhibit mRNA translation (in the case of ferritin and ferroportin) or increase mRNA stability (in case of cellular iron importers such as TfR1 and DMT1). The result is that more Fe enters the cell and less Fe is stored in ferritin or leaves the cell via ferroportin. In conditions of low cellular Fe there is also less synthesis of ALAS-2, the first enzyme in the heme synthesis pathway, and less production of hypoxia-inducible factor (HIF)-2α in kidney fibroblasts, resulting in a decrease in erythropoietin (EPO) production. As such, the body decreases heme and red blood cell synthesis in case of Fe scarcity, which results in microcytic anemia (see also Chapter 76 ). Thus although key aspects of systemic Fe metabolism are regulated transcriptionally (hepcidin expression) and post-translationally (ferroportin function by hepcidin), intracellular Fe homeostasis is largely controlled by this post-transcriptional mechanism involving the IRP1/IRP2 network.

Body iron distribution

Most of the body Fe (3 to 5 g) is found in heme-containing oxygen transport and storage proteins, including hemoglobin (>2.5 g) and myoglobin (130 mg). Small amounts ( 150 mg) are incorporated into enzymes with active sites containing heme or Fe-sulfur clusters, including peroxidases, catalases, ribonucleotide reductase, and enzymes of the Krebs cycle and the electron transport chain. Most nonheme Fe (1 g in adult men) is stored as ferritin or hemosiderin in macrophages and hepatocytes. Only a very small amount (3 mg) of Fe is bound to the circulating serum protein transferrin. An estimate of the average amount of iron contained in each of these compartments for an average male is presented in Table 40.1 and in the literature.

Each milliliter of blood contains 0.4 to 0.5 mg of Fe incorporated into Hb. Therefore an adult male body contains approximately 2.5 g of Fe as part of Hb (see Table 40.1 ). ^, Cellular Fe in excess of immediate needs is stored as an Fe oxide within the nanocavity of ferritin and a partially degraded form of ferritin known as hemosiderin.

Ferritin is a protein, which was first isolated in 1937 from the spleen of a horse by the French scientist Laufberger. Subsequently ferritin was found to be a highly conserved, ubiquitous protein that can accommodate up to 4500 iron atoms. In humans, ferritin is a heteropolymer of 24 subunits of two types, heavy/heart (H) and light/liver (L), which assemble to make a hollow spherical shell, which can take up atoms of Fe stored as ferric oxyhydroxide phosphate. ^, The ferroxidase activity of H-ferritin converts Fe ²⁺ to Fe ³⁺ , which is necessary for Fe deposition into the nanocage. L-ferritin induces Fe nucleation. L-ferritin is predominant in Fe-storing tissues (liver, reticuloendothelial), whereas H-ferritin is preferentially expressed in cells with a significant antioxidant activity (brain, heart). Different proportions of ferritin subunits give rise to the heterogeneity of the holo-protein in various tissue types.

Fe ²⁺ is delivered to ferritin by cytoplasmic chaperones. The release of Fe from ferritin is mediated by multiple mechanisms among which are autophagy and lysosomal degradation of ferritin. ^, Physiologically, degradation of ferritin is coupled to the supply of metabolic Fe availability under Fe-limiting conditions. Ferritin is present in nearly all cells of the body and provides a reserve of Fe that is readily available for formation of Hb and other heme proteins. Fe bound to ferritin is shielded from body fluids and thus is unable to cause oxidative damage, as would occur if it were in a free ionic form. In men, the total body content of stored Fe, mostly as ferritin, is approximately 1000 mg; in healthy premenopausal women, Fe stores are typically lower. The expression of ferritin is tightly regulated at the transcriptional and post-transcriptional level by a variety of factors including Fe, cytokines, hormones, and oxidative stress. ^,

After the development of the first immunoassays for the measurement of ferritin in serum in the 1970s, ferritin levels were shown to reflect body Fe stores by studies employing quantitative phlebotomy, radio-Fe retention, and bone marrow aspirate. In particular, it is now widely accepted that 1 μg/L of serum ferritin corresponds to approximately 8 to 10 mg of stored Fe. However, when comparing individuals of widely differing body weight, conversion of 120 μg serum ferritin/kg tissue storage Fe is preferable because ferritin is a concentration measurement. Serum ferritin differs from tissue ferritin in that it is glycosylated, contains mostly L-chains, and is Fe-poor (mostly apoferritin). Serum ferritin reflects both reticuloendothelial and parenchymal Fe stores. However, despite its long history of use in the assessment of body Fe stores, the source and detailed secretory pathway of serum ferritin from cells are not completely understood, although animal studies suggest that macrophages contribute significantly to serum ferritin concentrations. Also, the receptor interactions and the cellular effects of serum ferritin are unclear and topics of active debate.

Hemosiderin is an aggregated and partially deproteinized ferritin that is formed when ferritin is partially degraded. In contrast to ferritin, hemosiderin is insoluble in aqueous solutions—a difference that has been used traditionally to distinguish these two Fe storage compounds. Fe is only slowly released from hemosiderin, possibly because it occurs in relatively large aggregates and therefore has a much smaller surface-to-volume ratio. Like ferritin, hemosiderin is found predominantly in cells of the liver, spleen, and bone marrow.

Myoglobin closely resembles a single Hb subunit. Because myoglobin does not form tetramers, it lacks the allosteric oxygen-binding properties of Hb.

Fe in the circulation is bound to free sites on the plasma iron-transport protein transferrin. Transferrin keeps Fe nonreactive in the circulation and extravascular fluid, and delivers it to cells with transferrin receptors. Transferrin was discovered by the Americans Drs. Schade and Caroline as a saturable Fe-binding component in human plasma capable of inhibiting growth of Shigella dysenteriae. Transferrin is a glycoprotein with an approximate molecular mass of 80 kDa and two homologous high-affinity binding sites for ferric (Fe ³⁺ ) iron. Each site can bind one atom of trivalent iron together with one ion of HCO ₃ ⁻ . The iron atoms are incorporated one at a time and appear to bind randomly at either or both of the two sites. The functional differences between the two binding sites led to the Fletcher-Huehns hypothesis, according to which the two sites of transferrin behaved differently, the one delivering iron preferentially to erythroid cells, and the other to nonerythroid tissues. Transferrin experts in the 1970s and 80s were obsessed with this hypothesis; however, recent findings have not confirmed it, demonstrating instead that the 2 monoferric forms of transferrin (Tf) have functionally distinct effects on erythropoiesis and systemic iron regulation.

The apotransferrin- Fe ³⁺ complex is called monoferric or diferric (= holo) transferrin. Because the transferrin iron binding capacity normally largely exceeds plasma iron concentrations, transferrin-bound iron is the only physiologic source available to most cells. High transferrin saturation facilitates parenchymal iron disposition. Cells regulate the intake of transferrin-bound iron by altering the expression of surface transferrin receptor 1 (TfR1). TfR1 is transmembrane glycoprotein composed of a 190 kDa (under nonreducing conditions) homodimer that binds two holotransferrin molecules with high affinity, or monoferric transferrin with a lower affinity, one by each subunit. Its rate of synthesis is elevated in case of increased requirements of the cell for iron. In patients in whom transferrin becomes highly saturated, as in patients with iron loading anemias (see “Disorders of Erythroid Maturation” section below), untreated hemochromatosis, other severe iron overload disorders, or patients who received multiple blood transfusions, or are supplemented with high-dose oral iron due to iron deficiency, additional iron released into the circulation is bound to low-molecular-weight compounds (e.g., citrate). This so-called non–transferrin-bound iron (NTBI) is readily taken up by certain cell types, including hepatocytes and cardiomyocytes, and contributes to oxidant-mediated cellular injury. A fraction of the circulating NTBI is redox-active and designated labile plasma Fe. Although there are methods for measuring serum NTBI and labile plasma Fe, insufficient standardization and clinical correlation currently limit clinical use of these measurements. ^{, ,}

Iron deficiency

ID and IDA, defined when anemia and iron deficiency co-exist, are global health problems and common medical conditions seen in everyday clinical practice. Approximately half of the estimated 1 billion subjects with anemia worldwide have iron deficiency. ^{, ,} Prevalence of anemia is highest in South Asia and Central, West, and East Sub-Saharan Africa. The iron-amenable share of anemia burden is highest where few other causes of anemia exist, that is, in Central Asia (65%), South Asia (55%), and Andean Latin America (62%).

ID is particularly a disorder of children and premenopausal women in low- and middle-income countries, but it can also occur in men and in developed countries and people of all ages. ^{, ,} In the United States, 11% of preschool children, 14.7% of premenopausal women, and 18% of pregnant women have ID. ^,

In children, iron deficiency is frequently caused by the increased physiologic needs for dietary iron for growth and development. In adults, and especially premenopausal women, iron deficiency is almost always the result of chronic blood loss or pregnancy.

IDA is associated with impaired quality of life, work productivity, aerobic exercise capacity, ^, restless leg syndrome, and fatigue, and there is also a relationship between iron status and depression, and neurocognitive function in children, ^, pregnancy outcomes, and physical exercise performance. Fe deficiency also affects immune function and the susceptibility to infections. ^, Furthermore, Fe deficiency is a predictor of mortality in patients with nondialysis chronic kidney disease, heart failure, and coronary artery disease and treating Fe deficiency in patients with heart failure improves quality of life.

Fe not only plays a key role as an oxygen carrier in the heme group of hemoglobin but is also found in cytochromes and myoglobin; this may explain why iron deficiency has effects beyond that of anemia. This was appreciated already in the 19th century. ^, More recently several studies showed that iron supplementation reduces fatigue in nonanemic women with low ferritin levels, ^, in iron-deficient women may benefit exercise performance, and reduces restless legs syndrome. In addition, in children oral iron improves anemia and may improve cognitive performance in older children, but evidence is lacking for effects on cognitive development in younger children. ^{, ,}

ID was recognized as “chlorosis,” a term derived from the Greek word meaning green, by Johannes Lange in 1554. ^{, ,} This condition became well known as the green sickness, probably because of the greenish pallor occurring in teenage “virgineus” girls. The disease preoccupied many clinicians between the middle of the 17th century and the end of the 19th century, and yet is not seen today. Therefore currently most people believe that chlorosis resulted from a combination of factors affecting adolescent girls: the demands of growth and the onset of menses, an inadequate diet, and a legacy of poor iron stores from early childhood. In the early 1830s, anemia, hypochromia, and lack of iron in the blood were linked to this disorder. Other distinguishing clinical features ascribed to a lack of iron at that time were epithelial changes involving the tongue and nails and achlorhydria. Today, anemia most often affects women with poor diets, multiple pregnancies, or menstrual irregularities. In 1832, the French physician Pierre Blaud described the response of chlorosis to his famous pills (ferrous sulfate plus potassium carbonate). But the use of iron in the treatment of chlorosis received a major setback when the chemist Bunge in 1902 ascribed the effect of iron as a placebo effect. All doubt was resolved in 1932 by Heath et al., who found that hemoglobin levels increased upon intramuscular and subcutaneous injections with iron. Even today, ferrous sulfate remains a cornerstone of modern treatment of iron deficiency.

IDA is generally an acquired condition due to blood loss, malabsorption, insufficient iron intake, or combinations of these. Some patients with chronic disease are especially vulnerable to develop absolute iron deficiency, for instance patients with gastro-intestinal tumors because of blood loss. Patients with advanced chronic kidney disease are also at risk of negative iron balance as a result of reduced dietary intake, impaired absorption from the gut, and increased iron losses. In addition, patients with chronic kidney disease also often have a functional iron deficiency because the available circulating iron cannot keep pace with the requirements of pharmacologically stimulated erythropoiesis.

More recently, the elucidation of systemic iron homeostasis has also led to the discovery of a rare (autosomal recessive) inherited disorder, iron-refractory iron deficiency anemia (IRIDA), an IDA that does not improve with oral iron supplementation. IRIDA is caused by mutations in TMPRSS6 , the gene encoding matriptase 2, which inhibits the signaling pathway that activates hepcidin. ^, To date, pathogenic TMPRSS6 defects have been identified in over 65 IRIDA families of different ethnic origin. Typical findings include marked microcytosis, extremely low transferrin saturation (TSAT), and low-normal ferritin and high hepcidin/TSAT ratio in the absence of inflammation. ^, The diagnosis is confirmed by bi-allelic pathogenic defects in the TMPRSS6 gene. Rarely also mono-allelic defects have been described. IRIDA is a rare disease and is likely to be overlooked. Knowledge of this condition is valuable, since it prevents unnecessary, invasive, and expensive diagnostic procedures and forms an indication for intravenous iron treatment. Population studies and studies in Tmprss6-haploinsufficient mice suggest an association of variants in TMPRSS6 with susceptibility to develop iron deficiency and anemia, especially in the presence of other risk factors such as blood loss, inflammation, and infection. IRIDA due to a defect in matriptase-2 should be distinguished from other causes of IDA refractory to iron supplementation, among which are disorders of the gastrointestinal tract, such as Helicobacter pylori infection and (partial or total) gastrectomy and gastric bypass (bariatric) surgery. ^,

An emerging cause of iron deficiency is obesity. It has been largely attributed to functional iron deficiency associated with low-grade inflammation which induces hepcidin levels and subsequent hepcidin-mediated decrease of iron uptake from the food and less release from reticuloendothelial system stores.

Many different measurements have been advocated for the diagnosis of iron deficiency. Originally, emphasis was placed on the red blood cell indices; hypochromic and microcytemic anemia was generally considered to be synonymous with iron deficiency in the first half of the twentieth century. Subsequently, techniques such as staining of marrow with Perls Prussian Blue to allow visualization of ferric iron and measurement of (1) serum iron, (2) iron-binding capacity (and later transferrin), (3) serum ferritin, (4) erythrocyte Zn-protoporphyrin (ZnPP), (5) soluble transferrin receptor (sTfR), (6) percent hypochromic red cells and reticulocyte Hb content, and (7) hepcidin were reported and used for their utility in diagnosing iron deficiency. Although most of these parameters readily identify severe, uncomplicated iron deficiency, the large number of tests advocated for the diagnosis of iron deficiency reflects the fact that none by itself is sufficient to detect mild iron deficiency or iron deficiency in a clinically complex setting or in populations exposed to malaria, HIV, tuberculosis, and other infections. ^{, , ,} Interpretation and definition of common clinical decision limits and development of guidelines is further complicated by (i) lack of standardization of many parameters, that is, for ferritin, sTfR, ZnPP, reticulocyte-Hb content parameters, and hepcidin and (ii) reliance on original studies performed in different clinical settings and populations. As a result, studies and expert and international guidelines differ in the conclusions that they draw regarding advantages of one method over another, and overall diagnostic strategies. Overall, a low ferritin level is a sensitive and specific indicator of iron deficiency uncomplicated by other diseases. A low transferrin saturation (<15 to 20%) indicates an iron supply that is insufficient to support normal erythropoiesis. However, simple correlations between the various tests of iron status do not exist. Therefore in determining iron status it is important to consider the whole picture rather than relying on single tests ( Table 40.3 ). For the diagnosis of iron-deficient states, plotting the different biochemical markers and erythrocyte parameters has been proposed, but this alternative approach is not widely used in clinical practice. ^, In less complex clinical settings, the diagnosis of iron deficiency can be defined in three progressive stages, each characterized by its own combination of test results ( Fig. 40.4 ).

Anemia of chronic disease

ACD, also named anemia of inflammation, is an iron distribution disorder. Although the global prevalence of ACD is unknown, country-level studies suggest it is common. ^, It is often observed in patients with infectious and inflammatory diseases, among which are patients with chronic kidney disease, inflammatory bowel disease, chronic heart failure, malignancies, and hepatic diseases. ^{, ,} The pathogenesis comprises three principal abnormalities: shortened erythrocyte survival, erythroid suppression, and disturbances in iron metabolism. ACD is characterized by so-called functional iron deficiency, that is, maldistribution of body iron stores, with ample reticuloendothelial iron contents relative to parenchymal iron stores, with low circulating iron (hypoferremia) and subsequent iron–restricted erythropoiesis. ^, Thus whereas in IDA the iron supply depends on the absolute amount of iron stores, in ACD, the supply depends on its rate of mobilization. The pathophysiology of these iron-related aspects in ACD can be attributed to cytokine-induced increase in hepcidin synthesis. ^{, , ,} A more specific descriptive, but rarely used, designation for functional iron deficiency that captures these aspects is therefore “hypoferremic anemia with reticuloendothelial siderosis.”

Functional Fe deficiency is a state of Fe-restricted erythropoiesis in which there is insufficient Fe mobilization from the (otherwise adequate) body Fe stores to meet the Fe demands of the erythroid precursors. This is especially the case in conditions with increased erythroid Fe demands, as is for instance observed in some subjects with chronic kidney disease after treatment with erythropoiesis–stimulating agents. In fact, since the widespread introduction of erythropoiesis–stimulating agents, it is recognized that supplemental Fe is necessary to optimize hemoglobin response and allow adjustment of the dose of these agents, for both economic reasons and recent concerns about safety.

ACD is a typically normocytic, normochromic anemia. It is diagnosed when serum Fe concentrations are low despite adequate Fe stores, as evidenced by serum ferritin that is not low. In the setting of inflammation, it may be difficult to differentiate ACD from IDA, and the two conditions may coexist.

Iron overload

Iron overload disorders are typically insidious, causing progressive and sometimes irreversible tissue damage before clinical symptoms develop (see also Chapter 44 on iron overload). With increased awareness, however, the consequences of iron toxicity can be attenuated or prevented. Iron overload disorders can be categorized according to whether the underlying pathophysiologic defect is in the hepcidin-ferroportin axis, erythroid maturation, or in iron transport. There are also some less common disorders that do not fit into these categories (see Table 40.2 ). Iron overload may also develop as a consequence of multiple red blood cell transfusions and parenteral iron supplementation.