The changing landscape of iron deficiency.

Iron deficiency (ID) with or without anemia is common worldwide. ID is a broad definition encompassing decreased total body iron (absolute deficiency) as well as reduced iron supply to erythropoietic and/or other organs with preserved stores (functional iron deficiency, FID), as it occurs in inflammation. Increased iron needs unbalanced by iron supply, low iron intake, reduced absorption and chronic blood loss, often in combination, are the main causes of absolute ID, easily diagnosed by low ferritin levels. In all these cases hepcidin synthesis is repressed, while in FID is augmented by inflammatory cytokines, causing iron sequestration in stores. Because of increased ferritin levels diagnosis of ID in the latter condition may be tricky: global clinical evaluation, accepted threshold of iron tests together with response to iron treatment may be of help. Search and removal of the responsible cause(s) is as important as diagnosing ID or FID. The response to oral iron treatment is suboptimal when hepcidin levels are high. Future research is needed to establish/validate markers for improved diagnosis of complex cases and to test the therapeutic value of drugs under development aimed at interfering with the altered iron trafficking.