Ask the Hematologist March-April 2007

A 72-year-old man is referred for iron deficiency anemia not responding to iron therapy. His past history is notable for longstanding rheumatoid arthritis. Physical examination is consistent with rheumatoid arthritis. Repeated stool tests are heme negative. Laboratory studies show a hematocrit of 29 percent with normocytic indices, normal white blood cell and platelet counts, a low serum iron concentration, and an elevated serum ferritin concentration.

The term “anemia of chronic disease” (ACD) refers to an underproduction anemia characterized by a low serum iron concentration despite adequate reticuloendothelial iron stores (generally shown by a normal or increased serum ferritin concentration). This term is frequently criticized because it does not indicate the mechanism producing anemia, and because anemias associated with some disorders that are chronic (i.e., hypothyroidism) do not result from ACD. The advantage of the term is its long usage — most hematologists and internists understand what ACD means. The most frequently suggested alternative, “anemia of inflammation,” has the advantage of indicating the pathophysiologic mechanism underlying the syndrome, but its meaning in clinical terms is less established. One group has defined it as anemia with an elevated serum ferritin concentration in the appropriate clinical setting. It is clear that both ACD and “anemia of inflammation” refer to the same clinical and pathophysiologic entity.

In ACD, a modest decrease in RBC survival creates a demand for increased red cell production which cannot be met (because of impaired mobilization and utilization of reticuloendothelial iron) and an impaired erythropoietic response. The impaired erythropoietic response has two components — a blunted erythropoietin increment in response to anemia and a relative resistance of erythroid progenitors to erythropoietin. All of these processes are induced by the cytokines that mediate the inflammatory response — cytokine activation is the feature linking the syndromes associated with ACD.

Shortened RBC survival in ACD may result from selective hemolysis of young RBC induced by erythropoietin deficiency (neocytolysis). The iron abnormalities of ACD are due to the cytokine-induced peptide hepcidin. Hepcidin binding causes degradation of the iron export protein ferroportin; iron is then retained in reticuloendothelial cells where it is unavailable for erythropoiesis.

Hypoferremia may cause ACD to be confused with iron deficiency anemia. This is more likely in that minority of ACD patients with mild microcytosis. Demonstration of reticuloendothelial iron stores rules out iron deficiency. Ferritin is an acute-phase reactant and can be elevated to variable degrees by concurrent inflammation. However, even with significant inflammation, a serum ferritin concentration greater than 100 µg/L is unlikely in iron-deficient individuals, and a serum ferritin concentration greater than 200 µg/L essentially rules out iron deficiency. Other tests, such as the serum soluble transferrin receptor concentration or the reticulocyte hemoglobin concentration, may help resolve difficult cases. Although the serum erythropoietin concentration in ACD patients tends to be lower than would be predicted from the degree of anemia, its measurement is rarely helpful in diagnosing ACD in individual patients.

Depending on the patient’s specific clinical circumstances and the degree of anemia, therapy of ACD may not be necessary. The standard approach is to treat the associated clinical syndrome — as disease activity decreases, the hematocrit generally improves. If more active correction of anemia is required, an extensive literature indicates the effectiveness of recombinant erythropoietin in ACD. The use of routine iron supplementation with erythropoietin therapy of ACD is debated, but a number of reports suggest it enhances the response to erythropoietin. Iron therapy by itself does not correct ACD; if a patient with ACD develops superimposed iron deficiency, iron replacement can correct that component of the anemia.