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Most patients suffering from chronic infections, chronic inflammations, or some malignancies develop a mild to moderate anemia. This anemia, designated anemia of chronic disease or anemia of 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 inhibitory effects of inflammatory cytokines on erythrocyte production. Among the cytokines, interleukin-6 has a central role, acting by increasing the production of the iron-regulatory hormone hepcidin by hepatocytes. 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.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: ACD, anemia of chronic disease; AI, anemia of inflammation; CRP, C-reactive protein; EPO, erythropoietin; Hgb, hemoglobin; IDA, iron-deficiency anemia; IL, interleukin; TNF, tumor necrosis factor.

The terms anemia of chronic disease (ACD) or anemia of chronic disorders refer to mild to moderately severe anemias (hemoglobin [Hgb] 7–12) 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 anemia of chronic disease but develops within days of the onset of illness. An anemia similar to AI is seen in some elderly patients in the absence of a identifiable chronic disease.3

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 erythrocytes are usually normocytic and normochromic but can be mildly hypochromic and microcytic. Anemia of critical illness2 can develop acutely (within days) in intensive care settings where the effects of infection or inflammation are exacerbated by disease-related or iatrogenic blood loss or red cell destruction, which by themselves are not sufficiently severe to cause anemia. Anemia of aging3 is diagnosed in the elderly when a normocytic normochromic anemia with low iron and preserved iron stores develops without an identified underlying disease. Elderly patients in this defined subset typically have an elevated sedimentation rate and/or elevated C-reactive protein (CRP), a high plasma interleukin (IL)-6 concentration, and frailty.

Physicians have known about the pale appearance of patients with chronic infections for hundreds of years. In 19th-century Europe, tuberculosis was the major killer, and the pallor associated with this disease was romanticized in the art literature of the time. The first measurements of red cell mass revealed the association between inflammation and anemia. Discussing “the alterations ...

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