Anemia is a frequent complication of chronic inflammatory diseases (e.g. cancer, rheumatoid arthritis, inflammatory bowel diseases, and congestive heart failure), as well as sepsis and chronic renal failure. In addition to blood loss, hemolysis, hepatic or endocrine disorders, nutritional deficiencies, bone marrow infiltration (cancer cells), or vitamin consumption (bacteria), this anemia may be the result of activation of the immune system by the underlying process, and certain immune and inflammatory cytokines including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-1, 6, 8 and 10[18,19
As for chronic inflammatory diseases (and sepsis), these inflammatory mediators lead to anemia through several of the following pathophysiological mechanisms[19
] (Figure ): (1) decreased RBC half-life because of dyserythropoiesis, RBC damage and increased erythrophagocytosis (TNF-α); (2) EPO responses are inadequate for the degree of anemia in most, but not all (e.g. systemic-onset of juvenile chronic arthritis) (IL-1 and TNF-α)[20
]; (3) impaired responsiveness of erythroid cells to EPO (IFN-γ, IL-1, and TNF-α); (4) inhibited proliferation and differentiation of erythroid cells (IFN-γ, IL-1, TNF-α, and α-1-antitrypsin); and (5) pathological iron homeostasis caused by increased DMT-1 (IFN-γ) and TfR (IL-10) expression in macrophages, reduced ferroportin 1 expression (IFN-γ and IL-6-induced high hepcidin levels) in enterocytes (inhibition of iron absorption) and macrophages (inhibition of iron recirculation), and increased ferritin synthesis (TNF-α, IL-1, IL-6, IL-10) (increased iron storage). All these lead to hypoferremia through iron diversion to the RES [functional iron deficiency (FID) that is characterized by low serum iron and decreased TSAT], iron-restricted erythropoiesis, and mild-to-moderate anemia.
Effects of inflammation on erythropoiesis and iron homeostasis in mammals. (-): Negative effect; (+): Positive effect.
Thus, the immunological pathophysiology of ACD includes disturbances of iron homeostasis, impaired proliferation of erythroid progenitor cells, and a blunted EPO response to anemia[19
]. However, the pathophysiology of acute inflammation-related anemia (e.g. trauma or surgery) is somewhat different. In this setting, inflammatory responses are mediated mainly by IL-6 and IL-8 (with transient contribution of TNF-α and IL-1 in some visceral surgery, such as gastrointestinal or cardiac procedures), whereas IFN-γ plasma levels are undetectable or within the normal range[21-23
]. Therefore, in most of these conditions, the two major mechanisms that lead to anemia are perioperative or traumatic blood loss and blunted erythropoiesis caused by decreased iron availability (caused by IL-6-induced high hepcidin levels), whereas EPO levels are normal or near-to-normal[24
]. Finally, with persisting decreased iron absorption and/or chronic blood loss, ACD may evolve to ACD with true ID (ACD + ID).
On the other hand, it must be borne in mind that iron is not only required for erythropoiesis and oxidative metabolism. Cellular immune responses are also dependent on the presence of iron, and specific defects in cell-mediated immunity have been described in detail, even in mild ID, including the impaired proliferation and function of lymphocytes and natural killer cells, and a depressed neutrophil respiratory burst[25,26
]. Thus, ID or FID may lead not only to a blunted erythropoiesis and chronic fatigue, but also to an inappropriate immune response. For this reason, systemic inflammatory response episodes last longer in critically ill patients with FID, and result in prolonged stay in the intensive care unit and increased morbidity[27
]. On the other hand, the effectiveness of the administration of iron sucrose, alone or in combination with EPO, has been assessed in a population of anemic, critically ill patients[28
]. Compared to those in the control group who only received folic acid, patients treated with iron sucrose experienced an amelioration of systemic inflammatory response [decreased C-reactive protein (CRP) levels]. These beneficial effects were not as evident in patients who received iron sucrose plus recombinant human EPO (rHuEPO), probably because of the persistence of FID caused by rHuEPO-enhanced erythropoietic activity.