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Anemia of Chronic Disease

(Iron-Reutilization Anemia)

by Alan E. Lichtin, MD

Anemia of chronic disease is a multifactorial anemia often coexistent with iron deficiency. Diagnosis generally requires the presence of chronic infection, inflammation, or cancer; microcytic or marginal normocytic anemia; and values for serum transferrin receptor and serum ferritin that are between those typical for iron deficiency and sideroblastic anemia. Treatment is to reverse the underlying disorder or, if the disorder is irreversible, to give erythropoietin.

Worldwide, anemia of chronic disease is the 2nd most common anemia. Early on, the RBCs are normocytic; with time they become microcytic. The major issue is that the marrow erythroid mass fails to expand appropriately in response to anemia.

Etiology

This type of anemia was thought to occur as part of a chronic disorder, most often infection, inflammatory disease (especially RA), or cancer; however, the same process appears to begin acutely during virtually any infection or inflammation. Three pathophysiologic mechanisms have been identified:

  • Slightly shortened RBC survival occurs via unknown mechanisms in patients with cancer or chronic granulomatous infections.

  • Erythropoiesis is impaired because of decreases in both erythropoietin (EPO) production and marrow responsiveness to EPO.

  • Intracellular iron metabolism is impaired.

Reticuloendothelial cells retain iron from senescent RBCs, making iron unavailable for Hb synthesis. There is thus a failure to compensate for the anemia with increased RBC production. Macrophage-derived cytokines (eg, IL-1β, tumor necrosis factor-α, interferon-β) in patients with infections, inflammatory states, and cancer cause or contribute to the decrease in EPO production and the impaired iron metabolism.

Diagnosis

  • Symptoms and signs of underlying disorder

  • CBC and serum iron, ferritin, transferrin, and transferrin receptor

Clinical findings are usually those of the underlying disorder (infection, inflammation, or cancer). Anemia of chronic disease is suspected in patients with microcytic or marginal normocytic anemia with chronic infection, inflammation, or cancer. If anemia of chronic disease is suspected, serum iron, transferrin, transferrin receptor, and serum ferritin are measured. Hb usually is > 8 g/dL unless an additional mechanism contributes to anemia (see also Differential Diagnosis of Microcytic Anemia Due to Decreased RBC Production). If there is infection, inflammation, or cancer, a serum ferritin level of slightly < 100 ng/mL suggests that iron deficiency is superimposed on anemia of chronic disease. However, because serum ferritin may be falsely elevated as an acute-phase reactant, the serum transferrin receptor measurement may better differentiate iron deficiency from anemia of chronic disease when serum ferritin is > 100 ng/mL.

Treatment

  • Treatment of underlying disorder

  • Recombinant EPO and iron supplements

Treating the underlying disorder is most important. Because the anemia is generally mild, transfusions usually are not required, and recombinant EPO may be offered. Because both reduced production of and marrow resistance to EPO occur, the EPO dose may need to be 150 to 300 units/kg sc 3 times/wk. A good response is likely if after 2 wk of therapy Hb has increased > 0.5 g/dL and serum ferritin is < 400 ng/mL. Iron supplements (see Iron Deficiency Anemia : Treatment) are required to ensure an adequate response to EPO. However, careful monitoring of Hb response is needed because adverse effects (eg, venous thromboembolism, MI, death) may occur when Hb rises to > 12 g/dL.

Key Points

  • Almost any chronic infection, inflammation, or cancer can cause anemia; Hb usually is > 8 g/dL unless an additional mechanism contributes.

  • Multiple factors are involved, including shortened RBC survival, impaired erythropoiesis, and impaired iron metabolism.

  • Anemia is initially marginally normocytic and then becomes microcytic.

  • Measure serum iron, transferrin, transferrin receptor, and ferritin levels.

  • Serum ferritin levels tend to be > 100 ng/mL unless iron deficiency also is present.

  • Treat the underlying disorder and give recombinant EPO.

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