Altered iron metabolism and the anemia of chronic disease: a role of immune activation.

Recently, Means and Krantz showed that the inhibition of erythroid colony-forming units caused by interferon-y (IFN-y) can be corrected invitro by recombinant human erythropoietin (EPO).' In vivo, the pathogenetic mechanism of the anemia of chronic disease (ACD) is not yet understood. Because this symptom is very common, many attempts have been made to explore the factors involved and to establish treatment modalities. In vitro results suggest that IFN-7 could he responsible for the development of ACD. We earlier found correlations between the anemia of patients with hematologic disorders and the degree of cellular immune activation, measured by increased serum IFN-y and neopterin concentrations.2 Similar correlations could be found in various clinical conditions such as chronic pneumonia3 and gynecologic ~ a n c e r . ~ A potential mechanism involved in the development of ACD is the shift of iron towards the storage compartment. Because activated macrophages are able to influence the iron metabolism in vitro, they seem to play a crucial role? We recently found a significant correlation between the levels of neopterin and ferritin in patients with malignant disorders6 A negative correlation, on the other hand, existed between neopterin and the degree of anemia, confirming results described previously.2 Likewise, serum iron was correlated with neopterin in a negative manner. Finally, a significant correlation was found between iron concentrations and the hemoglobin content of the single erythrocyte, pointing to the development of a hypochromic population of erythrocytes. During follow-up, successful treatment of patients was associated with decreasing neopterin and ferritin concentrations and an increase of serum iron and hemoglobin. Thus, the reduction of immune activation seems to improve the changes described above. From these findings we assume that the ACD is mediated by IFN-y. The fact that tumor-associated anemia, eg, in multiple myeloma, can be corrected by EP07 appears to confirm the in vitro results of Means and Krantz.' The striking similarity of the findings in chronic inflammatory and in malignant disorders6 supports the idea of a common pathogenetic mechanism and underlines the central role of activated macrophages in this puzzling network. It would be interesting to know whether a correlation exists between the degree of immune activation and the responsiveness of tumorassociated anemia to EPO treatment.