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Clinical Chemistry 49:10 1573–1578 (2003)

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Iron Deficiency and Erythropoiesis: New Diagnostic Approaches
Carlo Brugnara
Iron deficiency anemia is one of the most common diseases worldwide. In the majority of cases, the presence of hypochromic microcytic anemia and biochemical evidence for depletion of body iron stores makes the diagnosis relatively straightforward. However, inseveral clinical conditions, classic biochemical indices such as serum iron, transferrin saturation, and ferritin may not be informative or may not change rapidly enough to reflect transient iron-deficient states (functional iron deficiency), such as the ones that develop during recombinant human erythropoietin (r-HuEPO) therapy. The identification and treatment of iron deficiency in settings suchas r-HuEPO therapy, anemia of chronic disease, and iron deficiency of early childhood may be improved by the use of red cell and reticulocyte cellular indices, which reflect in almost real time the development of iron deficiency and the response to iron therapy. In the anemia of chronic disease, measurements of plasma cytokines and iron metabolism regulators such as hepcidin (when available) maybe helpful in the characterization of the pathophysiologic basis of this condition. The ratio of serum transferrin receptor (sTfR) to serum ferritin (R/F ratio) has been shown to have excellent performance in estimating body iron stores, but it cannot be used widely because of the lack of standardization for sTfR assays. The combination of hematologic markers such as reticulocyte hemoglobincontent, which decreases with iron deficiency, and R/F ratio may allow for a more precise classification of anemias.
© 2003 American Association for Clinical Chemistry

Iron deficiency anemia attributable to nutritional deficiency and/or blood loss still remains the most common, treatable anemia in the world. Once the cause for the underlying blood loss or dietary deficiency is identified,

thefinding of anemia with microcytic hypochromic erythrocytes in conjunction with abnormal serum biochemical indices (low iron, low transferrin saturation, low ferritin) usually leads to the administration of oral iron supplements with improvement of anemia in the vast majority of cases. In the last decade, major fundamental advances have shed new light on the physiologic and pathologic connectionsbetween iron metabolism and erythropoiesis. We now understand in greater detail some of the interactions among the multiple genes and other factors that regulate erythropoiesis (1 ). The molecular nature and functional properties of the major iron transporters have been identified (2, 3 ). We have begun to unravel the mechanism responsible for the characteristic microcytic hypochromic features ofirondeficient erythrocytes. Heme-regulated eIF2 kinase (HRI)1 has emerged as a key regulatory step that controls the synthesis of - and -globins in erythroid cells and inhibits the translation initiation factor eIF2 when the intracellular concentration of heme is decreased (4 ). Additionally, it has been found that suppression of - and -globin synthesis by HRI is responsible for the reduction inhemoglobin (Hb) content of iron-deficient erythrocytes. Because they are unable to turn off globin synthesis, iron-deficient HRI / mice develop a hyperchromic, normocytic anemia. The entire HRI regulatory mechanism is itself part of a larger complex regulatory system that promotes survival of cells exposed to stressful conditions (5 ). New and safer preparations of intravenous iron, such as iron sucroseand ferric gluconate, are now available for the correction of deficiencies unresponsive to oral iron. An expanded repertoire of hematologic and biochemical

Children’s Hospital Boston, Department of Laboratory Medicine, 300 Longwood Ave., Boston, MA 02115. Fax 617-713-4347; e-mail carlo. brugnara@tch.harvard.edu. Received May 14, 2003; accepted July 11, 2003.

1 Nonstandard abbreviations:...