Serum Transferrin Receptors are Decreased in the Presence of Iron Overload (Enzymes and Protein Markers‪)‬

Iron balance in humans is regulated fundamentally by the rate of erythropoiesis and by the size of the iron stores [1]. The concentration of soluble transferrin receptors in the plasma reflects the degree of erythropoiesis, being increased in states of enhanced erythropoiesis and decreased with reduced erythropoiesis [2]. Circulating transferrin receptors also reflect the body's iron status, in that the concentration of transferrin receptors is increased in the presence of iron-deficiency anemia [3-5], but whether serum transferrin receptors are decreased with iron overload states is not clear. On one hand, Huebers et al. [6] reported serum transferrin receptor concentrations within the normal reference interval in 7 treated patients with idiopathic hemochromatosis, and Baynes et al. [7] found normal concentrations in 14 patients with hereditary hemochromatosis and 49 black Africans with dietary iron overload. On the other hand, Thorstensen and Romslo [8] reported low serum transferrin receptor concentrations in 19 men with increased transferrin saturations in comparison with that in 800 men with normal saturation values, and Ledue and Craig [9] observed low concentrations of receptor in 7 subjects with hereditary hemochromatosis. Furthermore, Centis et al. [10] found a significant negative correlation between serum transferrin receptor concentrations and ferritin concentrations in 230 patients who had been cured of thalassemia by bone marrow transplantation. Circulating transferrin receptors are derived by proteolytic cleavage from transferrin receptors expressed on the cell surface X11]. On the basis of current understanding of regulation of transferrin receptor expression at the cellular level, we hypothesized that serum transferrin receptor concentrations would be reduced in iron overload states. Intracellular iron influences the translation of ferritin mRNA and the stability of transferrin receptor mRNA [12,13]. This regulation occurs by means of an interaction between the iron regulatory protein (IRP)', a molecule that senses changes in the chelatable intracellular iron pool X14-16], and iron-responsive elements (IREs) located on untranslated regions of ferritin and transferrin receptor mRNAs X16-18]. When intracellular iron is ample, IRP has aconitase activity and does not bind to the IREs; this results in increased ferritin mRNA translation and increased transferrin receptor mRNA degradation. Conversely, in iron deprivation, IRP loses aconitase activity and binds to IREs, causing a repression in ferritin mRNA translation and increased transferrin receptor mRNA stability X19]. Thus at the cellular level, transferrin receptor expression is decreased when iron supply is ample and increased when iron supplies are curtailed [15,20,211. In keeping with these observations in vitro, patients with secondary iron overload and with hereditary hemochromatosis have been determined to have decreased transferrin receptor expression in hepatocytes and other cells [22-24].