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INTRODUCTION

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SUMMARY

Most patients suffering from chronic infection, chronic inflammation, or some with various malignancies develop a mild to moderate anemia. This anemia, designated anemia of chronic disease or anemia of chronic inflammation, is characterized by a low serum iron level, a low to normal transferrin level, and a high to normal ferritin level. The anemia is caused by the direct and indirect inhibitory effects of inflammatory cytokines on erythrocyte production. Among the cytokines, interleukin-6 has a central role, acting by increasing hepatocyte production of the iron-regulatory hormone hepcidin. Hepcidin then blocks the release of iron from macrophages and hepatocytes, causing the characteristic hypoferremia associated with this anemia, and limiting the availability of iron to the developing erythrocytes. Effective treatment of the underlying disease restores normal erythropoiesis. When this is not possible, and treatment is necessary, therapeutic trials have revealed that the anemia is often responsive to pharmacologic doses of erythropoietin.

Anemia of chronic kidney disease presents similarly to anemia of inflammation but because the kidneys are the predominant site of erythropoietin production, the pathogenesis of this anemia is frequently dominated by relative erythropoietin deficiency, where erythropoietin concentrations in serum are lower than expected for the severity of anemia. Systemic inflammation from underlying renal disease, or induced by dialysis treatments and their complications, contributes to pathogenesis in a manner similar to anemia of inflammation. Circulating hepcidin concentrations may also rise because of its decreased renal clearance. Suppressive effects of uremia on erythropoiesis and blood losses from hemodialysis may contribute to anemia in end-stage renal disease. A combination of erythropoiesis–stimulating agents and intravenous iron is usually effective in reversing anemia but overtreatment may worsen overall outcomes.

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Acronyms and Abbreviations:

ACD, anemia of chronic disease; AI, anemia of inflammation; CKD, chronic kidney disease; CPG, clinical practice guideline; CRP, C-reactive protein; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; IDA, iron-deficiency anemia; IL, Interleukin; KDIGO, The Kidney Disease Improving Global Outcomes; sTfR, soluble transferrin receptor; TfR, transferring receptor; TNF, tumor necrosis factor.

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DEFINITION AND HISTORY

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The term anemia of chronic disease (ACD) or anemia of chronic disorders refers to mild to moderately severe anemia (hemoglobin [Hgb] 7 to 12 g/dL) associated with chronic infections and inflammatory disorders and some malignancies.1 The newer name, anemia of inflammation (AI), is not only more reflective of the pathophysiology of ACD but also includes anemia of critical illness,2 a condition that presents similarly to ACD but develops within days of the onset of illness. An anemia similar to AI is seen in some older individuals in the absence of an identifiable chronic disease; this condition is sometimes referred to as unexplained anemia of elderlies or anemia of aging (Chap. 9).3

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AI is characterized by inadequate erythrocyte production in the setting of low serum iron and low iron-binding capacity (i.e., low transferrin) despite preserved or even increased macrophage iron stores in the marrow. The ...

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