Mark J. Koury, MD
Dr. Koury indicated no relevant conflicts of interest.
Prince OD, Langdon JM, Layman AJ, et al. Late stage erythroid precursor production is impaired in mice with chronic inflammation. Haematologica. 2012. Epub ahead of print.
The anemia of inflammation and chronic disease (AICD) is usually a slight to moderate, hypoproliferative, normocytic anemia. Patients with AICD are often elderly or chronically ill, and the non-severe anemia can worsen co-existing cardiac, pulmonary, and vascular maladies. Some severe or prolonged AICD cases can be microcytic as a consequence of functional or absolute iron deficiency. Recent AICD studies have appropriately focused on hepcidin, the liver peptide hormone that restricts both dietary iron absorption by duodenal enterocytes and iron recycling by macrophages through the binding and down-regulation of ferroportin, the surface membrane iron exporter. Transgenic mice engineered to overexpress hepcidin have several of the features associated with AICD including anemia, hypoferremia, and iron-restricted erythropoiesis. However, the hepcidin transgenic mouse erythrocytes are microcytic rather than normocytic, and hepcidin transgenic mice do not have increased inflammatory cytokines or relatively decreased erythropoietin concentrations that have been associated with AICD in patients and in some animal models. Using a model of AICD in mice in which the experimental animals received serial turpentine injections to induce subcutaneous abscesses, Prince et al. demonstrated normal hepcidin expression, serum iron concentrations, and transferrin saturation in a chronic-phase, normocytic anemia that was associated with increases in neutrophils, platelets, interleukin-6, interleukin-1β, and intracellular reactive oxygen species (ROSs) in erythroid precursors and erythrocytes.
Although this serial-abscess model had previously demonstrated a rapid induction of hepcidin expression and hypoferremia in the first few days of abscess formation,1 erythrocyte sizes in the chronic-phase anemia varied between normocytic1 and microcytic.2 Using larger numbers of mice, Prince et al. demonstrated that the increase in hepcidin expression and hypoferremia observed in the acute phase resolve within three weeks, but slight, normocytic anemia persisted. During the chronic phase, both hepcidin expression and serum iron concentration were normal, despite a persistent elevation of interleukin-6, a known, potent inducer of hepcidin expression. Erythropoietin levels were slightly increased whereas AICD is characterized by relatively decreased erythropoietin production. The serial-abscess mice had an increased proportion of early-stage erythroblasts compared with control mice, and reticulocyte numbers were also very slightly increased. While consistent with increased erythropoietin and erythropoiesis, these results suggested a shortened erythrocyte life span, but erythrocyte lifespan was found to be normal. Ineffective erythropoiesis related to ROS-related damage was hypothesized to account for the observed increase in early-stage erythroblast production.
In the serial-abscess model, Prince et al. have demonstrated a slight, chronic, normocytic anemia with increased neutrophils and platelets that is similar to the laboratory profile observed in many patients with AICD, but unexpectedly the chronic anemia was not accompanied by increased hepcidin expression or hypoferremia. The acute response to abscess formation does increase hepcidin expression and induce hypoferremia, but both hepcidin expression and serum iron concentration normalize in the chronic phase, indicating that other factors other than hepcidin maintain the chronic anemia. Because many different chronic diseases are associated with AICD, the role of hepcidin expression will likely vary considerably, playing a larger role in those anemias with hypoferremia and microcytosis but having a lesser or only temporary role in anemias that are normocytic and have more normal serum iron values. Understanding the factors responsible for AICD as well as the period during which each factor has its greatest effect should provide more specific approaches to treatment of AICD, when it becomes symptomatic.
1. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110:1037-1044.
2. Steinbicker AU, Sachidanandan C, Vonner AJ, et al. Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood. 2011;117:4915-4923.
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