World Health Organization Chronic Disease Definition

Iron and anemia of chronic disease. Anemia of chronic disease (ACD) is the most frequent anemia found in hospitalized patients, often occurring in subjects suffering from chronic inflammatory disorders. The underlying diversion of iron traffic leads to a withdrawal of the metal from the sites of erythropoiesis and the circulation to the storage compartment in the reticuloendothelial system, thus resulting, at the same time, in hypoferremia and hyperferritinemia. Proinflammatory and anti-inflammatory cytokines, acute-phase proteins, and radicals are prominently involved in causing these disturbances of iron homeostasis. The role of these factors, as well as the pathophysiological reasons for the development of ACD, is discussed in this review.

Keywords

• iron homeostasis
• inflammation
• hypoferremia
• erythropoiesis

APPENDIX

ACD

anemia of chronic disease

e-ALAS

erythroid amino-levulinate synthase

IFN-γ

interferon-gamma

IL

interleukin

iNOS

inducible nitric oxide synthase

IRE

iron responsive elements

IRPs

iron regulatory proteins

NO

nitric oxide

TfR

serum transferrin receptor

Th-1

T-helper type-1 cells

TNF-β

tumor necrosis factor-β

Iron is a Janus-faced molecule that, on one hand, is an essential cofactor for enzymes in the mitochondrial respiration chain, in the citric acid cycle or for DNA synthesis, as well as a central molecule for binding and transporting oxygen by hemoglobin and myoglobin

. On the other hand, cellular accumulation of metabolically active iron may be detrimental to cells and surrounding tissues because iron is also able to catalyze the formation of highly toxic hydroxyl radicals by the "Haber-Weiss" reaction

^,

. Therefore, tight regulation of iron homeostasis is an absolute requirement for maintaining essential cellular functions while avoiding cellular damage. Thus far, many proteins, molecules, hormones and, last but not least, iron itself have been demonstrated to affect iron metabolism by various mechanisms at different regulatory levels

, which is also detailed elsewhere in this issue.

Some of these factors may become dominant over others in cases of chronic inflammatory diseases, thus leading to disturbances of iron metabolism. Therefore, patients suffering from a chronic infectious or tumor disease or an autoimmune disorder frequently develop a moderate anemia, which is termed "anemia of chronic disease" (ACD). This normochromic/microcytic anemia is clinically characterized by reduced serum iron concentrations and transferrin saturation, whereas iron stores, as reflected by ferritin levels, are often increased

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Although ACD is probably the most frequent anemia in hospitalized patients, the underlying mechanisms are still elusive. In addition to various other factors such as repression of erythropoiesis, a blunted response to erythropoietin, and erythrophagocytosis, disturbances of iron homeostasis appear to be prominently involved in the development of anemia under chronic inflammatory conditions

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. This review focuses on mechanisms that contribute to the diversion of iron traffic underlying ACD, leading to the withdrawal of iron from the sites of erythropoiesis and from serum to the iron storage sites in the reticuloendothelial system.

THE TH-1/TH-2 PARADIGM AND IRON HOMEOSTASIS

In prior years, evidence has accumulated for the existence of two CD 4+ T-helper cell subsets in humans, each of which produce a typical set of cytokines that regulate different immune effector functions and cross-react with each other

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. T-helper cells type 1 (Th-1) produce interferon (IFN)-γ, interleukin (IL)-2, and lymphotoxin [tumor necrosis factor (TNF)-β]. These cytokines activate macrophages, thus contributing to the formation of proinflammatory cytokines, such as TNF-α, IL-1, or IL-6, and the induction of cytotoxic immune effector mechanisms of macrophages. By contrast, Th-2 cells produce IL-4, IL-5, IL-10, and IL-13, which induce a strong antibody response but also inhibit various macrophage functions

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T-helper cells type 1 (Th-1)–derived cytokines have been demonstrated to also affect iron homeostasis by different mechanisms, although the data available so far are conflicting.

Interleukin-1 and TNF-α are able to induce hypoferremia by modulating macrophage iron metabolism

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. This is primarily exerted by an effect of the cytokines on the expression of the iron storage protein ferritin

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. For example, it was demonstrated that IL-6 enhances TfR expression on hepatocytes, whereas it had no effect in Kupffer cells

, and similarly IL-1 and TNF-α affect iron uptake by increasing TfR expression in fibroblasts

, whereas just the opposite is true for monocytic cells

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In contrast, IFN-γ may rather depress TfR expression by transcriptional and post-transcriptional mechanisms

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, whereas at the same time, a translational repression occurs because of the formation of the short-lived radical nitric oxide (NO) via stimulation of the interaction of iron regulatory proteins (IRPs) with an RNA stem loop structure, iron responsive elements (IRE), as detailed later here

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In summary, proinflammatory cytokines appear to cause hypoferremia via the induction of ferritin synthesis and iron storage in macrophages and hepatocytes, whereas IFN-γ tries to keep iron out of macrophages. This makes sense, given the inhibitory effects of iron on IFN-γ–mediated pathways (discussed later in this article).

Interestingly, thus far, hardly any attention has been paid to the role of Th-2–derived cytokines on iron homeostasis. In activated murine macrophages, IL-4 and IL-13 have recently been demonstrated to modulate iron metabolism by two different pathways

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: (1) by opposing IFN-γ–mediated IRP activation via NO formation, thus increasing ferritin translation; and (2) by an augmentation of TfR mRNA expression, which is most likely due to reversing the inhibitory effect of IFN-γ on TfR mRNA transcription. Therefore, Th-2–derived cytokines are able to increase iron uptake and storage in activated macrophages.

From this point of view, it appears reasonable that Th-1– and Th-2–derived cytokines may collaborate in inducing hypoferremia/hyperferretinemia in a way that Th-2–derived cytokines primarily enhance TfR-mediated iron uptake in activated macrophages, which is then stored in ferritin that has been effectively produced following stimulation with proinflammatory cytokines.

SHORT-LIVED RADICALS

Recently, it has been shown that short-lived radicals such as hydrogen peroxide (H₂O₂) or nitric oxide (NO)—both of which are produced during inflammatory responses associated with ACD—are able to influence cellular iron homeostasis. NO and H₂O₂ stimulate the binding affinity of cytoplasmic proteins (IRPs) to RNA stem loop structures (IRE)

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. One IRE is present within the 5′ untranslated regions of L-ferritin, H-ferritin mRNA, and erythroid amino-levulinate synthase (e-ALAS) mRNA, whereas five IREs have been detected within the 3′ untranslated region of TfR mRNA

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. Binding of IRP-1 and IRP-2 to IREs within the 5′ untranslated region of target mRNAs results in a translational repression of their expression, whereas interaction with the IREs in the 3′ region enhances TfR mRNA stability by protecting it from digestion by a specific RNase. Therefore, circumstances that stimulate IRE-binding affinity of IRPs, such as NO formation, oxidative stress, or iron deprivation states, enhance iron uptake, whereas iron consumption and iron storage are reduced. In contrast, increased cellular iron concentrations as well as inhibition of NO or H₂O₂ formation result in loss of IRE-binding function of IRPs, thus leading to derepression of ferritin and eALAS mRNA translation while the TfR mRNA half-life is reduced. This, in turn, leads to iron consumption and storage while iron uptake is blocked

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It is worth noting that the effects of NO and H₂O₂ on IRP activation are of a different nature. While H₂O₂ activates IRP-1 but not IRP-2

by a poorly understood fast-reacting mechanism involving kinase/phosphatase pathways, NO stimulates IRE-binding activity of both IRPs at least in macrophages with an albeit slower kinetic, which is comparable to that observed after pharmacological induction of iron deprivation by means of iron chelators

. This suggests that NO and H₂O₂ may be involved in different regulatory properties of iron homeostasis during inflammatory conditions

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. Moreover, induction of oxidative stress on addition of a glutathione-depleting drug to hepatic cells was also shown to stimulate ferritin synthesis by a transcriptional mechanisms

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However, cytokines may overcome the regulatory effects of these radicals. Apart from other mechanisms, oxygen radicals are formed by macrophages stimulated with IFN-γ, TNF-α and/or lipopolysaccharide (LPS), and murine macrophages or human hepatocytes also generate NO after treatment with the same stimuli, due to the induction of a cytokine-inducible form of NO synthase (NOS type II). Nevertheless, as stated earlier here, these cytokines have also direct effects on iron homeostasis, acting sometimes proximally from regulation by the IRE/IRP system. In activated murine macrophages and hepatocytes producing high amounts of NO after stimulation with IFN-γ and LPS, ferritin expression is inhibited translationally due to NO-mediated activation of IRPs, whereas NO is not able to stabilize TfR mRNA under such conditions

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However, the question remains of how radicals may be involved in the development of ACD. The observation that iron by itself also modulates the expression of NOS II by transcriptional mechanisms provided evidence for the existence of an autoregulatory loop in macrophages that links the maintenance of iron homeostasis with the formation of NO

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Besides its effect on cellular iron homeostasis, NO may contribute to the development of ACD by other mechanisms. First, NO is able to inhibit heme biosynthesis. This may be achieved on one hand by NO-mediated stimulation of high-affinity binding of IRP-1 to the IRE within the 5′ untranslated region of e-ALAS mRNA, thus resulting in translational repression of e-ALAS mRNA expression

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Whether H₂O₂ may be involved in similar regulatory loops or have similar effects on e-ALAS expression or erythropoiesis remains to be shown.

Currently, ongoing studies with NOS II knock-out mice will hopefully contribute to the definition of the part NO plays among all other factors orchestrating iron metabolism under chronic inflammatory conditions.

ACUTE PHASE PROTEINS AND HORMONES

Some of the activating effects exerted by cytokines such as IL-1 or IL-6 on ferritin mRNA expression have been proposed to occur as part of the acute phase response in the liver in order to contribute to detoxification of iron by promoting its storage, thus preventing the catalyzation of toxic radical reactions by the metal

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WHY ANEMIA OF CHRONIC DISEASE?

Because ACD is very frequently occurring under chronic inflammatory conditions, it is tempting to speculate about what could be the body's idea causing these diversions of iron traffic that underlie this disease.

Iron and immunity

Iron has multiple effects on cell-mediated immunity. On one hand, it differently modulates the proliferation and differentiation of lymphocyte subsets, whereas, on the other hand, it strongly affects the immune potential of macrophages

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On the contrary, IL-4 and IL-13 may reduce Th-1–mediated immune effector function by increasing intracellular iron content via stimulation of TfR expression, which may be part of their anti-inflammatory and macrophage-deactivating function

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Iron withholding

Because of the multiple functions of iron in metabolism outlined in the beginning of this article, this metal is an essential growth factor for proliferating tissues and microorganisms. Therefore, withholding iron from invading pathogens and tumor cells would limit their growth by affecting their energy metabolism or DNA synthesis

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. Furthermore, decreased formation of hemoglobin by withholding iron from the erythron and inhibition of erythropoiesis by cytokines reduces the oxygen transport capacity of the blood, thus decreasing the overall oxygen supply that may primarily affect rapid proliferating (malignant) tissues and microorganisms.

Other mechanisms

Besides the underlying mechanism of iron perturbations in ACD, other factors not discussed in this review may also contribute to ACD. Bacterial toxins and cytokines, such as TNF-α, have been proposed to decrease erythrocyte survival and to cause an increased phagocytosis of these cells by splenic macrophages. This is compatible with the observation that during inflammatory states an increase of erythrocyte-derived iron in splenic macrophages and Kupffer cells takes place

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Alternatively, ACD may just be seen as a disease occurring as a side effect of an ongoing immune response. Cytokines not only affect iron metabolism, as shown herein, but they also exert inhibitory effects on erythropoiesis by blocking proliferation and differentiation of erythroid progenitor cells, affecting their ability to respond to erythropoietin and causing deficiency in the production of erythropoietin

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^,

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.

TREATMENT OF ANEMIA OF CHRONIC DISEASE

Finally, the question remains of how ACD should be treated. There is a wide consensus in literature that the superior treatment of ACD is the cure of the underlying disease. The supply of iron to such patients is controversial

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, and should be avoided (at least in my opinion) in patients with chronic infectious or tumor diseases for several reasons. On one hand, supplementation of iron would promote growth and proliferation of tumor cells and microorganisms underlying the chronic inflammatory disease causing ACD

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; on the other hand, cell-mediated immune effector mechanisms may be weakened by the action of iron

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• PubMed
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^,

^,

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^,

. Moreover, it is questionable how much iron may pass over into the erythron due to the withholding mechanism outlined in this review. On the contrary, supplementation of iron to ACD patients with an autoimmune disorder may be rather beneficial

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^,

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, most likely because of the described inhibitory actions of iron on cytokine actions and macrophage-mediated cytotoxicity, although the contribution of the metal to the formation of toxic radicals has to be taken into account

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via induction of the binding of hypoxia regulatory factors to the erythropoietin promoter.

Recombinant erythropoietin is a widely used therapeutic approach for ACD (discussed in this issue)

^6.

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• PubMed
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^,

. However, response rates to the therapy with erythropoietin are sometimes low. This may refer, in part, to the fact that a prominently stimulated immune activation will inhibit erythropoiesis very efficiently via the action of cytokines, whereas, on the other hand, iron is withdrawn from the erythron and shifted into the reticuloendothelial system by the mechanisms described earlier in this article. However, erythropoietin is able to up-regulate TfR expression on erythroid progenitor cells via transcriptional and post-transcriptional mechanisms and therefore affects iron balance

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. It remains to be seen whether sequential administration of erythropoietin and iron (such as 48 hr later) will favor a more efficient uptake of iron into erythroid progenitors and consecutive stimulation of erythropoiesis, so that the detrimental effects of this metal on the growth of pathogens and down-regulation of immune effector function can be minimized.

ACKNOWLEDGMENTS

Support by grant FWF 12186 from the Austrian Research Funds is gratefully acknowledged. I thank Dr. Jeremy Brock for critical reading of the manuscript.

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