Circulating Transferrin Receptor Assay--Coming of Age (Editorial‪)‬

Transferrin receptors are transmembrane proteins present on the surface of most cells. Under normal circumstances, the iron required for cellular metabolism is acquired via transferrin receptors. Several recent reviews detail the methods of iron acquisition, the intracellular throughput of transferrin receptors, and the controlling mechanisms in the cell's quest to acquire and store iron [1-3]. The cells of different organ systems show considerable differences in the concentration of cellular transferrin receptor, the highest concentrations being found in cells of organs with the highest iron requirements, such as the erythroid bone marrow and placenta [4]. The concentration of cell surface transferrin receptor is carefully regulated by transferrin receptor mRNA according to the internal iron content of the cell and its individual iron requirements. Iron-deficient cells contain increased numbers of receptor, while receptor numbers are downregulated in iron-replete cells [4, 5]. Transferrin receptor was identified in serum [6] after investigators recognized that the molecule was secreted into culture media in reticulocyte and erythroleukemia cell models [7, 8], and the concentrations of secreted receptor were found to correlate with the total receptor content of the cells. Subsequent studies showed that serum concentrations of transferrin receptor increase in iron-deficiency anemia, making it a useful marker in the diagnosis of microcytic anemias [9]. Circulating transferrin receptor is a truncated form of tissue receptor [10], produced by proteolytic cleavage of cellular receptor, and for the most part circulates attached to transferrin [11, 12]. The reference interval for concentration of circulating receptor varies between different assay systems, depending on the choice of calibrators. In this issue of Clinical Chemistry, the transferrin receptor assay recently approved by the US Food and Drug Administration is described by Allen et al. [13]. The calibrators used in this enzyme immunoassay system are purified transferrin receptors isolated from serum, and the assay displays a reference interval of 0.57-2.8 [micro]g/L. A second assay system, described in a previous issue by Suominen et al. [14], has a reference interval of 1.3-3.3 mg/L; the nature of the calibrators used in this assay is not specified. Other previously described assay systems, utilizing transferrin-bound transferrin receptor calibrators isolated from intact placental transferrin receptor, report reference intervals for serum transferrin receptor of ~3.5-8.5 mg/L [15, 16]. The calibrators utilized in these latter assay systems may more closely simulate the in vivo circumstance of circulating transferrin receptor, which ordinarily circulates attached to transferrin and is not found in appreciable amounts in the unbound state. It is hoped that collaborative efforts will be made to establish optimal calibrators that can be made available to all users of transferrin receptor assays, as has been achieved with other proteins, e.g., ferritin [17].