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Anemia of Chronic Disease

(Anemia of Chronic Inflammation)

By Evan M. Braunstein, MD, PhD, Instructor of Medicine, Johns Hopkins School of Medicine

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Anemia of chronic disease is a multifactorial anemia. Diagnosis generally requires the presence of a chronic inflammatory condition, such as infection, autoimmune disease, kidney disease, or cancer. It is characterized by a microcytic or normocytic anemia and low reticulocyte count. Values for serum iron transferrin are typically low to normal, while ferritin can be normal or elevated. Treatment is to reverse the underlying disorder and in some cases, 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 erythropoiesis is restricted due to inappropriate iron sequestration.

Etiology

This type of anemia occurs as part of a chronic inflammatory disorder, most often chronic infection, autoimmune disease (especially RA), kidney disease, or cancer; however, the same process appears to begin acutely during virtually any infection or inflammation, including trauma or post-surgery. (See also Anemia of Renal Disease.)

Three pathophysiologic mechanisms have been identified:

  • Slightly shortened RBC survival, thought to be due to release of inflammatory cytokines, occurs in patients with cancer or chronic granulomatous infections.

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

  • Iron metabolism is altered due to an increase in hepcidin, which inhibits iron absorption and recycling, leading to iron sequestration.

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-1-beta, tumor necrosis factor-alpha, interferon-beta) in patients with infections, inflammatory states, and cancer contribute to the decrease in EPO production and the impaired iron metabolism by increasing hepatic synthesis of hepcidin.

Diagnosis

  • Symptoms and signs of underlying disorder

  • CBC and serum iron, ferritin, transferrin, and reticulocyte count

Clinical findings are usually those of the underlying disorder (infection, inflammation, or cancer). Anemia of chronic disease should be suspected in patients with microcytic or normocytic anemia with chronic illness, infection, inflammation, or cancer. If anemia of chronic disease is suspected, serum iron, transferrin, reticulocyte count and serum ferritin are measured. Hb usually is > 8 g/dL unless an additional mechanism contributes to anemia, such as concomitant iron deficiency (see Table: Differential Diagnosis of Microcytic Anemia Due to Decreased RBC Production).

A serum ferritin level of < 100 ng/mL in the setting of inflammation (< 200 ng/mL in patients with renal failure) suggests that iron deficiency may be superimposed on anemia of chronic disease. However, serum ferritin may be falsely elevated as an acute-phase reactant.

Treatment

  • Treatment of underlying disorder

  • Sometimes recombinant erythropoietin (EPO) and iron supplements

Treating the underlying disorder is most important. Because the anemia is generally mild, transfusions usually are not required. Recombinant EPO has been shown to be most useful in the setting of chronic kidney disease. 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 normocytic and then can become microcytic.

  • Serum iron and transferrin are typically decreased, while ferritin is normal to increased.

  • Treat the underlying disorder and consider recombinant EPO.

* This is the Professional Version. *