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Anemia of Chronic Disease

(Anemia of Chronic Inflammation)


Evan M. Braunstein

, MD, PhD, Johns Hopkins University School of Medicine

Last full review/revision Mar 2020| Content last modified Mar 2020

The 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 and transferrin are typically low to normal, while the serum ferritin value can be normal or elevated. Treatment is to reverse the underlying disorder and in some cases, to give erythropoietin.

(See also Overview of Decreased Erythropoiesis.)

Worldwide, the anemia of chronic disease is the 2nd most common anemia. Early on, the red blood cells (RBCs) are normocytic; with time they may become microcytic. The major issue is that erythropoiesis is restricted due to inappropriate iron sequestration.

Etiology of Anemia of Chronic Disease

The anemia of chronic disease occurs as part of a chronic inflammatory disorder, most often chronic infection, an autoimmune disease (especially rheumatoid arthritis), 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 increased hemophagocytosis by macrophages, occurs in patients with inflammatory diseases.
  • 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 hemoglobin (Hb) synthesis. There is thus a failure to compensate for the anemia with increased RBC production. Macrophage-derived cytokines (eg, interleukin-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 hepcidin synthesis.

Diagnosis of Anemia of Chronic Disease

  • Symptoms and signs of the underlying disorder
  • Complete blood count (CBC) and serum iron, ferritin, transferrin, and reticulocyte count

Clinical findings in the anemia of chronic disease are usually those of the underlying disorder (infection, inflammation, cancer). The anemia of chronic disease should be suspected in patients with microcytic or normocytic anemia who also have 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 (> 80 g/L) unless an additional mechanism contributes to anemia, such as concomitant iron deficiency (see table Differential Diagnosis of Microcytic Anemia Due to Decreased RBC Production) or iatrogenic phlebotomy.

A serum ferritin level of < 100 ng/mL (< 224.7 pmol/L) in a patient with inflammation (< 200 ng/mL [< 449.4 pmol/L] in patients with chronic kidney disease) suggests that iron deficiency may be superimposed on anemia of chronic disease, because serum ferritin is usually elevated as an acute-phase reactant.

Treatment of Anemia of Chronic Disease

  • Treatment of underlying disorder
  • Sometimes recombinant erythropoietin (EPO) and iron supplements

Treatment of the anemia of chronic disease requires treating the underlying disorder. Because the anemia is generally mild, transfusions usually are not required.

Recombinant EPO has been shown to be most useful in patients with chronic kidney disease. Because both reduced production of and marrow resistance to EPO occur, the recombinant EPO dose may need to be 150 to 300 units/kg subcutaneously 3 times a week. A good response is likely if, after 2 weeks of therapy, the Hb has increased > 0.5 g/dL (> 5 g/L) and the serum ferritin is < 400 ng/mL (< 898.8 pmol/L).

Iron supplements are required to ensure an adequate response to recombinant EPO. However, careful monitoring of Hb response is needed because adverse effects (eg, venous thromboembolism, myocardial infarction, death) may occur when Hb rises to > 12 g/dL (> 120 g/L).

Key Points

  • Almost any chronic infection, inflammation, or cancer can cause anemia; hemoglobin usually is > 8 g/dL (> 80 g/L) unless an additional mechanism contributes.
  • Multiple factors are involved, including shortened red blood cell 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 erythropoietin.

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