Anemia of inflammation

Abstract

Anemia of inflammation (AI), also known as anemia of chronic disease (ACD), is regarded as the most frequent anemia in hospitalized and chronically ill patients. It is prevalent in patients with diseases that cause prolonged immune activation, including infection, autoimmune diseases, and cancer. More recently, the list has grown to include chronic kidney disease, congestive heart failure, chronic pulmonary diseases, and obesity. Inflammation-inducible cytokines and the master regulator of iron homeostasis, hepcidin, block intestinal iron absorption and cause iron retention in reticuloendothelial cells, resulting in iron-restricted erythropoiesis. In addition, shortened erythrocyte half-life, suppressed erythropoietin response to anemia, and inhibition of erythroid cell differentiation by inflammatory mediators further contribute to AI in a disease-specific pattern. Although the diagnosis of AI is a diagnosis of exclusion and is supported by characteristic alterations in iron homeostasis, hypoferremia, and hyperferritinemia, the diagnosis of AI patients with coexisting iron deficiency is more difficult. In addition to treatment of the disease underlying AI, the combination of iron therapy and erythropoiesis-stimulating agents can improve anemia in many patients. In the future, emerging therapeutics that antagonize hepcidin function and redistribute endogenous iron for erythropoiesis may offer additional options. However, based on experience with anemia treatment in chronic kidney disease, critical illness, and cancer, finding the appropriate indications for the specific treatment of AI will require improved understanding and a balanced consideration of the contribution of anemia to each patient's morbidity and the impact of anemia treatment on the patient's prognosis in a variety of disease settings.

Figure 1.

Pathophysiological mechanisms of AI. Systemic inflammation results in immune cell activation and formation of numerous cytokines. Interleukin (IL-6) and IL-1β, as well as lipopolysaccharide (LPS), are potent inducers of the master regulator of iron homeostasis, hepcidin, in the liver, whereas expression of the iron-transport protein transferrin is reduced. Hepcidin causes iron retention in macrophages by degrading the only known cellular iron exporter ferroportin (FP1); by the same mechanism, it blocks dietary iron absorption in the duodenum. Multiple cytokines (eg, interleukin-1β [IL-1β], IL-6, IL-10, and interferon-γ [IFN-γ]) promote iron uptake into macrophages, increase radical-mediated damage to erythrocytes and their ingestion by macrophages, and cause efficient iron storage by stimulating ferritin production and blocking iron export by transcriptional inhibition of FP1 expression. This results in the typical changes of AI (ie, hypoferremia and hyperferritinemia). In addition, IL-1 and TNF inhibit the formation of the red cell hormone erythropoietin (Epo) by kidney epithelial cells. Epo stimulates erythroid progenitor cell proliferation and differentiation, but the expression of its erythroid receptor (EpoR) and EpoR-mediated signaling are inhibited by several cytokines. Moreover, cytokines can directly damage erythroid progenitors or inhibit heme biosynthesis via radical formation or induction of apoptotic processes. Importantly, because of iron restriction in macrophages, the availability of this metal for erythroid progenitors is reduced. Erythroid progenitors acquire iron mainly via transferrin-iron/transferrin receptor (Tf/TfR)-mediated endocytosis. Erythroid iron deficiency limits heme and hemoglobin (Hb) biosynthesis, as well as reduces EpoR expression and signaling via blunted expression of Scribble (Scb). In addition, the reduced Epo/EpoR signaling activity impairs the induction of erythroferrone (Erfe), which normally inhibits hepcidin production.

Figure 2.

Evaluation and management of anemia. Evaluation and management of anemia. Once the screening blood count demonstrates anemia, an evaluation is necessary and begins with an assessment of iron status. When ferritin (SF) and/or iron saturation levels (TSAT) indicate absolute iron deficiency, referral to a gastroenterologist or gynecologist to identify a specific source of chronic blood loss may be indicated. When ferritin and/or iron saturation values rule out absolute iron deficiency, and signs of inflammation are evident, AI is likely. Depending on ferritin, transferrin saturation, or values of markers suggesting concomitant true iron deficiency, diagnostic steps to identify the disease underlying AI and/or the reason for iron deficiency should be undertaken. A nephrologist may be consulted in the case of GFR reduction and evidence for chronic kidney disease. When ferritin and/or iron saturation values are indeterminant, further evaluation to rule out absolute iron deficiency vs inflammation/chronic disease is necessary. A successful therapeutic trial of iron would confirm absolute iron deficiency. No response to iron therapy would support the diagnosis of AI, suggesting that ESA therapy may be beneficial. Reprinted from Goodnough and Schrier with permission.