Iron and the anemia of chronic disease.

The anemia of chronic disease traditionally is defined as a hypoproliferative anemia of no apparent cause that occurs in association with an inflammatory, infectious, or neoplastic disorder, and resolves when the underlying disorder is corrected. Disordered iron metabolism as manifested by a low serum iron, decreased serum transferrin, decreased transferrin saturation, increased serum ferritin, increased reticuloendothelial iron stores, increased erythrocyte-free protoporphyrin, and reduced iron absorption, is a characteristic feature of the anemia of chronic disease and has been thought to be a major factor contributing to the syndrome. A mild shortening of red cell life span also occurs. However, we now know that impaired erythropoietin production and impaired responsiveness of erythroid progenitor cells to this hormone are also important abnormalities contributing to the anemia of chronic disease, and appear to be due to the effects of inflammatory cytokines. Increased intracellular iron may also have a role in the inhibition of erythropoietin production, since the oxygen sensor is a hemoprotein. While the role of inflammatory cytokines in the pathogenesis of anemia of chronic disease appears unequivocal, it has become apparent that disordered iron metabolism, while characteristic of this form of anemia, may not be central to its pathogenesis. It is undisputed that iron absorption is reduced, and that iron administered intravenously is rapidly sequestered in the reticuloendothelial system; however, iron delivery to the bone marrow is not impaired, and erythroid iron utilization is not markedly depressed in anemia of chronic disease. Importantly, recombinant erythropoietin therapy can correct the anemia of chronic disease, but it cannot correct the anemia due to iron deficiency. This refutes the concept that the lack of available iron is central to the pathogenesis of the syndrome. Indeed, it is highly likely that abnormalities such as reduced iron absorption and decreased erythroblast transferrin-receptor expression largely result from decreased erythropoietin production and inhibition of its activity by inflammatory cytokines.