Iron Sequestration and Anemia of Inflammation

Abstract

Anemia of chronic disease, also called anemia of inflammation, is characterized by hypoferremia due to iron sequestration that eventually results in iron-restricted erythropoiesis. During the last decade, the molecular mechanisms of iron sequestration have been found to center on cytokinestimulated overproduction of the iron-regulatory hormone hepcidin. The inflammatory cytokine IL-6 is a particularly prominent inducer of hepcidin but other cytokines are likely to contribute as well. Hepcidin excess causes the endocytosis and proteolysis of the sole known cellular iron exporter, ferroportin, trapping iron in macrophages and iron-absorbing enterocytes. The supply of iron to hemoglobin synthesis becomes limiting, eventually resulting in anemia. Depending on the details of the underlying disease, other inflammation-related mechanisms may also contribute to anemia. Hypoferremia in infection and inflammationAs described more than sixty years ago, serum iron concentrations markedly decrease in humans 1 and in dogs 2 during the first few days of systemic infection or inflammation. More recent experimental studies in human volunteers injected with moderate doses of lipopolysaccharide 3 showed approximately a 50% decrease in serum iron by 24 hours. In another group of human subjects, a 3hr infusion of interleukin 6 (IL-6) was followed by an average 30% drop in serum iron 2 hrs later 4 . The rapid development of hypoferremia was also observed in mice with experimental meningococcal infection 5 or inflammation induced by turpentine 6 or LPS 7 . As suggested by the deleterious effects of iron supplementation during experimental infections 8,9 , the hypoferremia probably contributes to host defense against infection, likely by decreasing the iron supply to invading microbes. Hypoferremia of inflammation is caused by iron sequestration in macrophagesAs discussed elsewhere in this issue, normally most of the iron delivered to plasma (about 20-25 mg/day) is provided by macrophages involved in recycling senescent erythrocytes, and only 1-2 mg/day comes from iron absorption in the duodenum, with additional variable amounts delivered from stored iron in hepatocytes. Studies with iron-radiolabeled damaged erythrocytesCorrespondence to: Tomas Ganz, PhD, MD, CHS 37-055, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690, Tel. 310-825-6112, FAX 310-206-8766, E-mail: tganz@mednet.ucla.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. documented that inflammation or infection led to delayed appearance of radioactive iron in circulation and the a...

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