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, 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, heart failure, or cancer; however, the same process appears to begin acutely during virtually any infection or inflammation, including trauma and critical illness 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. Further, inflammatory cytokines can impair erythroid proliferation and differentiation via radical formation and/or induction of apoptosis.
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, interleukin-6, tumor necrosis factor-alpha, interferon-gamma) in patients with infections, inflammatory states, and cancer contribute to the decrease in EPO production and impaired iron availability by increased 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 (or total iron binding capacity), 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.
If the diagnosis is not clear following standard iron studies, soluble transferrin receptor (sTFR) and sTFR-ferritin index (elevated in iron deficiency) and/or reticulocyte hemoglobin content (ret-He), which is low in iron deficiency, may help identify concomitant iron deficiency and anemia of chronic disease, although these test results may also be subject to confounding effects of inflammation or pre-analytical variables.
In patients with possible inflammation and in whom other causes of anemia have been excluded, erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) may be obtained because these test results are nonspecific markers of inflammation.
Treatment of Anemia of Chronic Disease
Treatment of underlying disorder
Sometimes iron supplements in patients with concomitant iron deficiency
Treatment of the anemia of chronic disease requires treating the underlying disorder. Because the anemia is generally mild, transfusions usually are not required.
Iron supplementation may be helpful because iron deficiency can occur in patients with anemia of chronic disease, and iron studies are often difficult to interpret when these conditions coexist. However, in patients without suspected concomitant iron deficiency and in patients with acute, uncontrolled infection, iron supplementation is generally avoided.
Recombinant human erythropoietin or erythropoiesis-stimulating agents (ESAs) may be considered in patients with end-stage or chronic kidney disease, select patients with chemotherapy-induced anemia, and some patients before elective surgery.
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 availability.
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.
