Clinical Pearls & Morning Reports
Published September 18, 2019
Responding to infection or injury by favoring host defense processes over housekeeping processes such as erythropoiesis is a beneficial evolutionary strategy that provides a useful framework for understanding anemia of inflammation. Read the Review Article here.
Q: Describe some of the biomarkers of anemia of inflammation as compared to those associated with iron-deficiency anemia.
A: Anemia of inflammation, like iron-deficiency anemia, is characterized by low serum iron levels (hypoferremia), but it differs from iron-deficiency anemia in that iron stores are preserved in marrow macrophages, as well as in splenic and hepatic macrophages that recycle senescent erythrocytes. Whereas erythrocytes in iron-deficiency anemia are often small (low mean corpuscular volume) and hemoglobin-deficient (low mean corpuscular hemoglobin concentration), the erythrocytes in anemia of inflammation most often appear normal, although they become small and pale in a subset of patients, particularly those in whom iron deficiency coexists or develops as a complication. Hypoferremia associated with elevated plasma ferritin and hepcidin levels is characteristic of anemia of inflammation, whereas in iron-deficiency anemia, hypoferremia associated with low plasma ferritin and hepcidin levels is characteristic.
Q: How does inflammation affect hepcidin synthesis?
A: The main mechanism of iron homeostasis centers on the interaction between the iron regulatory hormone hepcidin, produced by hepatocytes, and ferroportin, which is both the hepcidin receptor and the sole cellular iron exporter through which iron is transferred to blood plasma. Inflammation greatly increases hepcidin synthesis, which is important in the pathogenesis of anemia of inflammation. Hepcidin synthesis increases predominantly but not exclusively because of interleukin-6, which acts through the JAK2–STAT3 (Janus kinase 2–signal transducer and activator of transcription 3) pathway to increase the transcription of the hepcidin gene in hepatocytes. High levels of circulating hepcidin inhibit the export of cellular iron into plasma, thereby decreasing both intestinal absorption of iron and the release of iron from erythrocyte-recycling macrophages in the spleen and the liver.
A: Leukocytosis and increased production of leukocytes in the marrow are early inflammatory responses, manifested in the marrow by an increased number of myeloid precursors (ratio of myeloid to erythroid precursors, >4:1). Such reprogramming of the marrow is mediated by inflammatory cytokines (e.g., TNF-α and interferon-γ, which have been studied most extensively) that activate the transcription factor PU.1 to promote myelopoiesis and lymphopoiesis at the expense of erythropoiesis. In patients with anemia of inflammation, a moderate (approximately 25%) decrease in the erythrocyte lifespan, to approximately 90 days, has been consistently shown, originally with the use of radioactive iron tracers and currently by means of measurements of exhaled carbon monoxide, a product of heme degradation. The heterogeneity of underlying diseases in anemia of inflammation makes it likely that multiple factors contribute to the increased destruction of erythrocytes.
A: New compounds for the specific treatment of anemia of inflammation are under development. The targeted mechanisms are designed to reverse hypoferremia in anemia of inflammation by decreasing the level of hepcidin with the use of hepcidin binders or by hindering the access of hepcidin to its target ferroportin or antagonizing the signaling pathways that stimulate hepcidin production during inflammation.