Iron deficiency is very common and is the most common cause of anemia worldwide. It is estimated that iron-deficiency anemia affects some two billion people, causing almost one million deaths each year.

Introduction: Iron Deficiency and Iron Therapy

Introduction

Iron is vital to the human organism because of its indispensable role in oxygen transport, DNA synthesis and electron transport. 1 Consequently, vital body functions are conditional on appropriate iron stores. Hemoglobin synthesis in particular is iron-dependent. ² The human body contains approximately 3 to 4 g of iron, with hemoglobin accounting for 60% of the body's total iron. Adult individuals require a relatively constant amount of total body iron. Indeed, under usual conditions, very little iron enters or leaves the organism. Iron loss is normally limited to less than 4 mg daily, ³ reaching, on average, only 1 mg daily in men and 2 mg in women during the child-bearing years.

In humans, 80% of the iron demand is related to the daily production of 200 billion new erythrocytes, which requires approximately 20 to 24 mg of iron for the synthesis of hemoglobin. Most of this iron is provided by macrophages through the catabolism of hemoglobin of senescent red blood cells; iron released from aged erythrocytes is recovered from the plasma and delivered to the erythroid marrow (see Figure 1). ⁴ Thus, approximately 90% of iron in the circulation re-circulates, and there is little iron exchange with other tissues.

1. Iron Deficiency

Iron deficiency is the most common cause of anemia worldwide. It is estimated that iron-deficiency anemia affects some two billion people, causing almost one million deaths each year. ⁵ Iron deficiency results in the decreased synthesis of important molecules, including iron-containing enzymes, thereby inducing cellular and organic functional disturbances. If not corrected in a timely manner, iron- deficiency anemia will ensue. The consequences of iron-deficiency anemia range from impaired psychological and physical well-being and decreased occupational abilities to developmental troubles in children and increased morbidity and mortality in some patient populations. Moreover, iron deficiency is a risk factor in various medical settings because it impedes erythropoietic response to acute and chronic anemia.

1.1. Mechanisms of Iron Deficiency

Body iron homeostasis is assured by the strict balance between iron input and excretions. The only source for replacing eliminated iron is exogenous iron; an average of 1 to 2 mg are absorbed and eliminated daily under normal conditions. Iron deficiency occurs if the equilibrium between iron needs and input is not reached because of increased demands, insufficient intake, malabsorption or increased losses, mostly inherent to blood loss. Table I.1. lists the principal causes of iron deficiency.

	Table 1: Causes of iron deficiency
	Increased Demands Growth during infancy and childhood Treatment with erythropoiesis-stimulating agents Increased Losses Phlebotomy Blood donation Dialysis (particularly hemodialysis) Hemorrhage Surgery Trauma Gastrointestinal bleeding Genitourinary bleeding Respiratory tract bleeding Insufficient Intake Malnutrition Inappropriate diet with deficit in bioavailable iron and/or ascorbic acid Malabsorption Gastric resection Malabsorption syndromes (Crohn's disease and celiac disease) Drug interference (gastric antacid agents and antisecretory drugs)

Iron deficiency can be either absolute or functional. In absolute iron deficiency, the iron stores are depleted; in functional iron deficiency, iron stores, although replete, cannot be mobilized from the macrophages of the reticulo-endothelial system (RES). Functional iron deficiency occurs in inflammatory diseases because iron is trapped in the RES as a result of increased secretion of hepcidin, a hormone that controls iron release from cells (cf. Iron Metabolism section). Functional iron deficiency may also occur in response to the therapeutic use of erythropoietin (EPO), which places a significant demand on iron stores that may surpass the iron-release capacity of the RES.

1.2. Treatment Options

When iron deficiency is secondary to an underlying disease, treatment of the cause should be considered first whenever possible. Red blood cell transfusions are considered the standard treatment in life-threatening anemia when urgent correction of hemoglobin is required. However, the risks inherent to blood product use and the increasing blood product shortage-a consequence of increased surgical demand in an aging population and fewer available donors- have prompted the development of alternatives to allogeneic blood transfusions, including pharmacological agents for anemia correction.

Adequate iron stores readily available for erythropoiesis are the prerequisite for the correction of anemia in all settings. Therapeutic or prophylactic administration of iron can be considered when iron deficiency has already been established or to prevent further depletion of stores. Clinical settings with a high potential risk for the occurrence of functional iron deficiency, for example, treatment with erythropoiesis-stimulating agents (ESAs), are a case in point.

1.2.1. Oral Iron Therapy

Oral iron supplementation is adequate in some clinical conditions. In many situations, however, it has serious limitations. Intestinal iron absorption tends to be limited and non-compliance is very common because of intolerance. Side effects of oral iron salts include digestive intolerance, causing nausea, flatulence, abdominal pain, diarrhea or constipation, and black or tarry stools. Moreover, intake independent of meals is recommended for increasing iron absorption but increases digestive intolerance and, therefore, decreases compliance. Consequently, parenteral iron administration constitutes the optimal route for iron supplemenation in many patients. Because of the serious side effects associated with the intramuscular (IM) and subcutaneous (SC) routes (pain at the injection site, permanent skin staining, and hematoma following IM injection in the presence of coagulation abnormalities), these routes have been virtually abandoned in many countries, thus rendering intravenous (IV) administration the most convenient and common route for parenteral iron supplementation.

1.2.2. Intravenous Iron Therapy

Intravenous iron therapy is indispensable in patients who are intolerant to oral iron or in whom oral iron supplementation is not possible. Intravenous iron supplementation is also needed when oral iron therapy fails to provide enough iron for the correction or prevention of iron-deficiency anemia despite appropriate patient compliance. The reason for therapeutic failure may be increased erythropoiesis demands and limited intestinal iron absorption.

2. Intravenous Iron Preparations

All intravenous iron agents are colloids with spheroidal iron-carbohydrate nanoparticles. ^{6, 7} Each particle consists of an iron-oxyhydroxide core (iron[III] hydroxide) and a carbohydrate shell that surrounds and stabilizes the core (Figure I.2. 1). The chelation of iron-oxyhydroxide with a carbohydrate shell confers to the particles a structure resembling ferritin that protects the organism against the toxicity of unbound inorganic ferric iron (iron[III]). While the core chemistry is identical in all agents, the core size, shell and global size of the particles differ for each agent. Differences in core size and carbohydrate chemistry determine pharmacological and biologic differences between agents, including clearance after injection, iron release in vitro, early evidence of iron bioactivity in vivo, maximum tolerated dose and rate of infusion. At present, three classes of intravenous iron complexes are principally used in clinical practice: iron dextran, iron sucrose and ferric gluconate. In practice, the use of iron dextran is generally not recommended because of the risk of life-threatening or serious acute hypersensitivity reactions and the availability of safer agents ^{8, 9} such as ferric gluconate and iron sucrose (or iron saccharate). The former has a much lower incidence of lethal hypersensitivity; the latter has no reported lethal reactions at all.

In iron sucrose (iron(III)-hydroxide sucrose complex), the iron is tightly bound with non-covalently linked sucrose molecules; in ferric gluconate, the core is tightly bound with gluconate and weakly associated with sucrose (Figure I.2. 2). The differences in iron core size and carbohydrate chemistry account for the differences in overall molecular weight. The molecular weight of iron dextran varies from 76 to 265 kD,¹⁰ whereas iron sucrose weighs 43 kD and ferric gluconate 38 kD. ¹¹ In a recent article by Kudasheva et al.,^6, atomic force microscopy was used to distinguish the iron-oxyhydroxide core from the carbohydrate shell, thereby providing a direct determination of the core size. The authors found that the iron sucrose core is slightly bigger than that of ferric gluconate and that there is a large difference between these two iron agents and iron dextran, which has more of an ellipsoidal core (Figure I.2. 3). This study confirmed that the relative diameters of the overall iron-carbohydrate particles follow the sequence observed for overall molecular weight, i.e., iron dextran >> iron sucrose > ferric gluconate. This finding further supports that the relative diameters of the iron cores follow the same sequence. Moreover, this study provides a basis for understanding the different biologic characteristics of intravenous iron agents, particularly with relation to labile iron-a biologically active fraction of intravenous iron agents to be distinguished from free iron-which could exert biological impact prior to cellular uptake.

2.1. Pharmacokinetics of intravenous Iron Preparations

After intravenous injection, iron-carbohydrate complex mixes with plasma. It is then captured by the macrophages of the reticulo-endothelial system of the spleen, the liver (whose resident macrophages are the Kupffer cells), and the bone marrow directly from the intravascular compartment. Within these phagocytes, iron is released from the iron-carbohydrate shell into a low molecular weight iron pool. From this pool, iron is either incorporated by ferritin into intracellular iron reserves or is released from the cell and bound to its transport molecule, transferrin; transferrin delivers iron to transferrin receptors that are present on the surface of cells in various tissues, particularly on erythroid precursors.

2.2. Safety of Intravenous Iron Therapy

Despite favorable pharmacokinetics and no evidence of free iron in the circulation after the injection of any of the currently available iron preparations, the presence of labile iron has given rise to a debate over the clinical implications of biologically active forms of iron before uptake by the RES.

2.2.1. Labile Iron

There are concerns about the adverse effects of labile iron, particularly in dialysis patients where intravenous iron therapy has come to play a key role in long-term anemia management. Although there is a plausible pathogenic role of labile iron in oxidant stress, atherogenesis, infection and inflammation, all these processes are also inherent to the dialytic milieu. ¹² Consequently, apart from the evidence of labile iron, its real clinical impact, both in terms of acute IV iron toxicity and long-term effects, deserves thorough examination. ¹³

2.2.1.1. Definition of Labile Iron

Labile iron lacks biochemical characterization and is, therefore, defined as the fraction of total intravenous iron with early biological activity. Labile iron is not free, ionic iron and the distinction must be made. ¹⁴ While efforts to identify free iron in iron-carbohydrate complexes have failed and no dialyzable iron has been detected after administration of these agents,¹⁴ labile iron may occur with all intravenous iron agents. The principal metabolic pathway of intravenously administered iron agents sequentially involves its initial clearance from plasma, uptake by reticulo-endothelial phagocytes, intracellular liberation of iron from the iron-carbohydrate complex, release of iron from the RES cells to circulating transferrin and, eventually, transfer from transferrin to tissue cells-particularly erythroid precursors in the bone marrow. There exists, however, a second, limited pathway seen with all intravenous iron agents where iron is donated directly from the iron-carbohydrate complex to transferrin. Possible in vitro and in vivo manifestations of labile iron could occur as a result of iron assay interference (iron agents falsely elevate the serum iron concentration measured by standard iron assays), supersaturation of transferrin (true increase in available iron for transferrin binding exceeds total transferrin iron-binding capacity), non-transferrin-bound iron, direct iron donation to transferrin, altered intracellular iron homeostasis, cytotoxicity, neutrophil function impairment, in vitro bacterial growth stimulation, and oxidant stress. However, not all attempts to demonstrate these effects have been positive and some positive results may be caused by tissue iron excess or the underlying disease. ¹³

A recent comparative study determined that the fraction of labile iron in iron-carbohydrate complexes varies from 2.5 to 5.8% with the following progression: iron dextran < iron sucrose < ferric gluconate (Figure I.2. 4). ¹⁵ This progression appears to be related to the chemistry of the intravenous iron agents. In 1992, Geisser et al. ¹¹ reported that iron release from iron-carbohydrate agents decreases as molecular weight increases. More recent studies confirm these results and provide a possible explanation through imaging and direct measurement of the core radius of iron-carbohydrate agents. ⁶ The total surface area for iron release is likely the key factor influencing the rate of iron release provided that other factors, such as the bond strength between core iron and the carbohydrate, are similar. Under these conditions, the rate of iron release per unit of surface area would be similar in all agents; consequently, for the same total amount of core iron, surface area available for iron release increases dramatically as core radius decreases (Figure I.2. 5). ¹⁵ In other words, a collection of smaller spheres offers a greater total surface area for iron release than a collection of fewer, larger spheres with an equal mass (Figure I.2. 6).

2.2.1.2. Clinical Implications of Labile Iron

Early experience with the administration of inorganic unprotected ferric iron (iron[III]) provides information about true free iron reactions (the structure of iron-carbohydrate complexes currently used in clinical practice protects the organism against the toxicity of unbound inorganic ferric iron; see above I.2.1. Intravenous Iron Preparations). Very small intramuscular doses of ferrous ammonium citrate induce acute adverse events such as nausea, vomiting, cramps, back pain, chest pain and hypotension. ^{7, 16} The structure of iron-carbohydrate complexes allows for the administration of much higher doses and there is no direct evidence of free iron in any intravenous iron-carbohydrate agents; however, the reported side effects that characterize free iron reactions, including gastrointestinal disturbances, back or chest pain and hypotension, closely resemble the adverse effects of any IV iron preparation infused too quickly or in excess. ¹³

A recent review on the safety of intravenous iron agents predicts that iron-carbohydrate agents of a larger overall molecular weight will likely be associated with greater safety at high doses and rapid infusion rates. These free-iron-like reactions account for many of the serious acute adverse events reported with intravenous iron agents. Consequently, based on recent comparative studies,^{6, 15} if labile iron can cause a free iron-like reaction, the size of the labile iron fraction may be dose-limiting; thus, the maximum tolerated dose and rate of infusion would be inversely related to the labile iron fraction and follow the sequence: iron dextran > iron sucrose > ferric gluconate.11 A recent review on the safety of intravenous iron agents in clinical practice supports this relationship and predicts that iron-carbohydrate agents having a larger overall molecular weight will likely be associated with greater safety at high doses and rapid infusion rates. ¹⁷ Transferrin supersaturation is theoretically possible after intravenous iron infusion. If this is the case, patients with low serum total iron-binding capacity may experience iron supersaturation associated with related labile iron reactions (hypotension, cramps, diarrhea or chest pain) at the recommended upper limits of infusion rates. In such patients, lower doses and slower infusion rates are recommended for subsequent intravenous iron administration. ¹⁵

2.2.2. Allergic Reactions

Although uncommon, anaphylactic reactions with iron dextran preparations are not exceptional occurrences and are potentially life-threatening. Bailie et al. ¹⁸ compared systemic hypersensitivity reactions (anaphylaxis, anaphylactoid reactions, upper airway angioedema and urticaria) following the intravenous administration of iron dextran, iron gluconate and iron sucrose by analyzing reports received by the Food and Drug Administration (FDA) Freedom of Information (FOI) database between 1997-2002. All-event reporting rates for iron dextran, iron gluconate and iron sucrose were 29.2, 10.5 and 4.2 reports/million 100-mg dose equivalents, respectively; all-fatal-event reporting rates were 1.4, 0.6 and 0.0 reports/million 100-mg dose equivalents, respectively (Figure I.2. 7). These results are consistent with those published by Fishbane, who reported that the frequency of fatal anaphylactic reactions was 0.61% with iron dextran versus 0.04% and 0% with iron gluconate and iron sucrose, respectively (Figure I.2. 8). ¹⁹

2.2.3. Is There a Risk of Iron Overload with Intravenous Iron Therapy?

Intravenous iron therapy to manage acute or chronic anemia does not expose patients to iron overload when administered in accordance with recommendations for use and EBPG [European Best Practice Guidelines] for the Management of Anemia in Patients with Chronic Renal Failure with respect to monitoring biological markers of iron status, in particular SF (serum ferritin) < 800 ?g/L. ⁹ Transfusions in patients with chronic anemia traditionally meant that they were exposed to large amounts of iron, which was primarily bound to the macrophages, then to the hepatocytes in cases of very significant overload. Since the advent of recombinant human erythropoietin (rHuEPO) use in association with parenteral iron, repeated transfusions in patients with chronic anemia are avoided. The iron in intravenous preparations such as iron sucrose does not bind to the hepatocytes but to the Kupffer cells.9 Thus, there is no evidence regarding the development of parenchymal lesions from iron overload attributable to intravenous iron therapy. Furthermore, if SF exceeds the recommended upper limit during intravenous iron therapy, the levels will rapidly decrease after discontinuation of intravenous iron supplementation.

2.2.4. Intravenous Iron Therapy and Infection

Iron is an essential nutrient for bacterial growth and intravenous iron agents provide iron in abundance. Indeed, intravenous iron agents appear to be able to enhance bacterial growth in vitro, a matter of particular concern in hemodialysis patients who frequently require chronic intravenous iron supplementation. However, clinical trials have not shown any increased risk of infection associated with intravenous iron preparations. In a 1999 review of the literature pertaining to infection and use of supplemental iron, Fishbane¹⁹ found no causal relationship between serum ferritin levels, iron supplementation and infection based on the findings of the EPIBACDIAL study, a large-scale, multicenter prospective study conducted on 988 hemodialysis patients. ²⁰ A more recent investigation showed no evidence of a connection between incidence of bacteremia and intravenous iron supplementation. ²¹ In his review, Fishbane noted that the more important the number of covariates, the lower the associated risk between infection and iron administration. He did not rule out that more exhaustive studies could even demonstrate a protective role for supplemental iron in infection.

The EPIBACDIAL study cites four risk factors for bacteremia in hemodialysis patients: 1) type of vascular access; 2) history of bacteremia; 3) current immunosuppressive treatment; and 4) corpuscular hemoglobin. In this particular study, only 5% of patients presented with SF levels > 1000 ?g/L. In multivariate analysis, neither intravenous iron administration nor weekly amounts of iron in the subgroup of patients treated with intravenous iron were risk factors for bacteremia. Anemia severity did, however, increase the risk for bacteremic episodes. ²²

	There is no additional risk of infection if intravenous iron supplementation is administered at therapeutic doses and with the appropriate monitoring of biological parameters. According to the EBPG for the Management of Anemia in Patients with Chronic Renal Failure, SF in this patient population should not exceed 800 ?g/L for a prolonged period.

A retrospective analysis by Aronoff et al. found that the mortality rate from infection or sepsis among patients treated with iron sucrose compared favorably with that of the overall hemodialysis population in the Unites States. Hospitalization rates from infection among patients who received iron sucrose were significantly lower than those seen in the hemodialysis population. ²³

Nevertheless, as a precaution, intravenous iron administration should be withheld in patients with ongoing bacteremia.

There is no additional risk of infection if intravenous iron supplementation is administered at therapeutic doses and with the appropriate monitoring of biological parameters. According to the EBPG for the Management of Anemia in Patients with Chronic Renal Failure, SF in this patient population should not exceed 800 ?g/L for a prolonged period.

2.2.5. Intravenous Iron Therapy and Oxidative Stress

In the physiological state, free radicals are indispensable for cellular energy production. However, excessive amounts of free radicals may cause deleterious cellular and tissue effects called oxidative stress. Consequently, the body controls the production of free radicals through several mechanisms aimed at their neutralization. Acute iron administration, whether intravenous^{24, 25} or oral, as well as iron deficiency^{26, 27} induce the manifestation of oxidative stress markers. Such manifestations are related to the labile iron fraction-to be distinguished from free iron, which has not been found with any of the current intravenous iron preparations-and are modest and transient. Moreover, not all studies have shown these effects. Although chronic, repeated intravenous iron administration may produce pro-oxidant effects that are longer lasting, the real clinical impact remains hypothetical. Nevertheless, the question of increased risk of cardiovascular disease and atherogenesis related to oxidative stress in chronic renal failure patients receiving long-term intravenous iron supplementation has been raised. However, only indirect evidence relating intravenous iron to atherogenesis is available. ¹⁷ No clinical study has shown an increase in atheromatous lesions or cardiovascular impairment attributable to intravenous iron therapy. Therefore, although the evidence calls for caution when administering long-term intravenous iron therapy, a possible modest increase in risk must be weighed against the serious and well-documented health consequences of failing to correct iron deficiency. ²⁸

2.2.6. Intravenous Iron Therapy and Cancer

Unlike arsenic, chromium or nickel, the carcinogenicity of iron is still under debate. The association between iron overload with cancer risk in humans has been under increased scrutiny in recent decades. ²⁹ Epidemiological studies on the association of iron with cancer remain inconclusive. The concerns are mostly focused on a possible risk associated with dietary iron in colorectal cancer, the increased risk of developing hepatocellular carcinoma in hereditary hemochromatosis and related hepatic iron overload and cirrhosis, and association between occupational exposure to iron and kidney, lung and stomach cancers. The risk of iron-induced sarcoma by repeated intramuscular injections of iron dextran has also been raised. ²⁹ As for the therapeutic use of intravenous iron, such risks remain theoretical. Moreover, intravenous iron therapy has not been associated with a tumor incidence increase.


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