Pathophysiology of Iron Homeostasis during Inflammatory States

Abstract

I nfectious and noninfectious inflammatory conditions are often associated with significant changes in systemic iron metabolism. One of the important consequences of this altered metabolic state is a decrease in plasma iron levels that is caused by reduced intestinal absorption and increased intracellular sequestration of the metal. The decrease in circulating iron can compromise erythropoiesis and ultimately lead to the development of an anemia that is usually referred to as anemia of inflammation (AI). AI is usually a mild to moderate normocytic, normochromic anemia characterized by low plasma iron concentrations in the presence of normal or elevated serum ferritin levels. It typically occurs in the setting of chronic infections and autoinflammatory states but also can accompany malignancies and chronic renal disease. Even though hypoferremia is an important factor in the development of AI, other abnormalities that are associated with inflammation, such as decreased erythropoietin production, impaired erythropoiesis, and increased erythrocyte destruction, are additional contributors to the pathogenesis of the anemia. It is also worth remembering that persistently low circulating iron levels may have adverse effects on biological processes other than erythropoiesis (eg, neurocognitive development, an issue of particular importance in infants and young children). This article will review our current understanding of the mechanisms that lead to hypoferremia in inflammatory diseases. Most of what we know about this problem is derived from studies in adult humans or from experiments in mice. It is likely that the basic pathophysiology will be very similar in infants and children, but this is an issue that deserves further investigation. We will start by summarizing the mechanisms that regulate systemic iron metabolism under normal conditions, and then describe how inflammation causes abnormalities in this process. We will conclude with a brief description of the management of inflammation-associated hypoferremia.