| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Editoral |
University of Kansas Medical Center, Department of Medicine, Division of Hematology, 3901 Rainbow Blvd., Kansas City, KS 66160, Fax (913) 588-3996
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)(2)(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 µg/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).
Circulating transferrin receptor concentrations do not differ between healthy males and females (15)(16). Allen et al. (13), however, have found that concentrations are slightly higher in blacks than nonblacks. They also report that the concentrations vary in populations living at different altitudes, the higher concentrations occurring at higher altitudes. These differences make it necessary for individual laboratories to establish their own reference values. The effect of altitude on transferrin receptor concentrations reflects differences in bone marrow erythroid activity. Various studies, including ferrokinetic data, indicate that circulating receptor concentrations vary according to the intensity of erythropoiesis (16)(18), with erythroid bone marrow precursors accounting for at least two-thirds of circulating receptor concentrations. Transferrin receptor concentrations are decreased in disorders with reduced erythropoiesis such as aplastic anemia or after bone marrow ablation for hematopoietic stem cell transplantation (15)(16)(19). The concentrations may also be reduced in iron-overload disorders, as described by Khumalo et al. (20) in the current issue of Clinical Chemistry, reflecting the overall decreased transferrin receptor production at the cellular level. Transferrin receptor concentrations are increased in disorders with expanded erythropoiesis, such as hemolytic anemias (15)(16)(18), and in conditions associated with ineffective erythropoiesis, such as myelodysplastic syndromes and megaloblastic anemias (21)(22).
The main value of the transferrin receptor assay is in the differential diagnosis of microcytic anemias (4)(23). Circulating transferrin receptor concentrations increase in tissue iron deficiency (15)(24)(25), reflecting the degree of iron deficiency in the erythroid precursors of the marrow. In a study in which iron-deficiency anemia was gradually induced in generally healthy subjects by serial phlebotomy, serum ferritin declined as iron stores decreased, and circulating transferrin receptor concentrations increased only once the iron stores were depleted, before changes in the other accepted markers of tissue iron deficiency, e.g., transferrin saturation, mean red cell volume, and erythrocyte protoporphyrin concentrations (26). By the time that anemia developed, none of these accepted markers had appreciably deviated from their "normal" reference intervals. In summary, when iron stores decline, serum ferritin concentrations drop until iron stores are depleted, at which time the ferritin concentration falls below the lower limit of the reference interval. With further iron loss, and as iron-deficient erythropoiesis begins, circulating transferrin receptor concentrations begin to increase and continue to do so as the severity of iron-deficient erythropoiesis increases, reflecting the increasing numbers of receptors on the erythroid cells of the bone marrow. The ratio of transferrin receptor to ferritin displays an inverse linear relationship to iron status, covering the spectrum from usual iron stores in health to substantial functional iron deficiency (25)(26). The adequate investigation of microcytic anemia includes measurement of serum ferritin. Assay of transferrin receptor with calculation of the transferrin receptor:ferritin ratio is a useful addition to this evaluation.
The measurement of transferrin receptors is especially valuable in physiological conditions in which iron stores are depleted, making it difficult to clearly distinguish iron-deficient erythropoiesis from depleted iron stores. Such situations are commonly encountered in childhood and adolescence and during pregnancy (27)(28)(29), when iron stores are uniformly low to absent but iron-deficient erythropoiesis is not necessarily present. In pregnancy the hemoglobin concentration is physiologically decreased, and evaluation is further complicated by low specificity of the routine laboratory measurements of iron-deficient erythropoiesis. In these situations, transferrin receptor concentrations increase only if tissue iron deficiency is present, allowing early identification of individuals who have true iron-deficient erythropoiesis (27) and who require aggressive iron-replacement interventions.
One of the main difficulties encountered in the laboratory evaluation of microcytic anemias is distinguishing iron-deficiency anemia from anemia of chronic disease, especially when both disorders are simultaneously present. Conventional laboratory measurements of iron status are often unable to clearly differentiate between these disorders, making it necessary to do a bone marrow examination to evaluate iron stores and establish a definitive diagnosis. Because circulating transferrin receptor concentrations do not increase in anemia secondary to inflammatory disorders (30)(31), they are helpful for distinguishing anemia of chronic disease from iron-deficiency anemia (30)(32). Furthermore, in situations where iron-deficiency anemia coexists with anemia of chronic disease, transferrin receptor concentrations increase secondary to the underlying iron deficiency, abrogating the need for a bone marrow examination (33)(34). Suominen et al. (14) confirmed these previous observations. Mast et al. (35), reporting in the current issue, suggest that a serum ferritin <30 µg/L in patients with anemia and concurrent inflammatory disease indicates that iron deficiency is present and that the measurement of transferrin receptor does not provide additional information in this situation. From these findings, when serum ferritin concentrations are >30 µg/L in patients with frank inflammatory disease, measurement of circulating transferrin receptor is warranted to exclude concurrent iron deficiency. Transferrin receptors concentrations are also increased in other causes of microcytic anemia, including sideroblastic anemia and the thalassemias; however, these diseases can be distinguished from iron-deficiency anemia by ferritin concentrations being within the reference interval or greater.
Circulating transferrin receptor concentrations are also helpful in predicting an erythroid response to erythropoietin replacement in patients with the anemia of chronic renal failure. A low transferrin receptor value combined with a high-normal to above-normal ferritin value (indicating decreased erythroid activity with adequate iron stores) suggests that a response to erythropoietin replacement is likely, whereas an increased receptor value with a low-normal or low ferritin value predicts a lack of response to erythropoietin because of underlying iron deficiency (36) and suggests that aggressive iron replacement with intravenous iron may be necessary for obtaining an adequate hemoglobin response. Because increased erythropoiesis results in an increased concentration of transferrin receptor, as does iron-deficient erythropoiesis, transferrin receptor measurement does not by itself allow the detection of iron-deficient erythropoiesis in patients who are on erythropoietin replacement. However, a >20% increase in receptor concentration over baseline within 2 weeks of starting or escalating a dose of erythropoietin is an early predictor of response to a particular erythropoietin dose, and indicates that an increase in hemoglobin is likely to follow.
Details of the performance of two commercial assays for circulating transferrin receptor have been presented in this journal (13)(14). The assay system described by Allen et al. has been approved for use in the US by the FDA. The availability of such assays, together with serum ferritin measurement, allows a comprehensive evaluation of iron status and aids in the diagnosis of microcytic anemias, obviating the need to do a bone marrow examination to evaluate iron status in many circumstances. Because both assays require only very small samples, <100 µL of serum in each, they lend themselves to use in pediatric patients as well as adults, and are also extremely valuable in performing epidemiological studies of iron status. Widespread availability of these assays may lead to further applications in a variety of different circumstances and diseases.
References
The following articles in journals at HighWire Press have cited this article:
|
|
 |
|
  J. W. Choi Sensitivity, Specificity, and Predictive Value of Serum Soluble Transferrin Receptor at Different Stages of Iron Deficiency Ann. Clin. Lab. Sci., October 1, 2005; 35(4): 435 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. I. Takala, P. Suominen, R. Isoaho, S.-L. Kivela, M. Lopponen, O. Peltola, A. Rajamaki, and K. Irjala Iron-Replete Reference Intervals to Increase Sensitivity of Hematologic and Iron Status Laboratory Tests in the Elderly Clin. Chem., September 1, 2002; 48(9): 1586 - 1589. [Full Text] [PDF]
|
|
|
|
|
|
P. Suominen, A. Virtanen, M. Lehtonen-Veromaa, O. J. Heinonen, T. T. Salmi, M. Alanen, T. Mottonen, A. Rajamaki, and K. Irjala Regression-based Reference Limits for Serum Transferrin Receptor in Children 6 Months to 16 Years of Age Clin. Chem., May 1, 2001; 47(5): 935 - 937. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Olivares, T. Walter, J. D Cook, E. Hertrampf, and F. Pizarro Usefulness of serum transferrin receptor and serum ferritin in diagnosis of iron deficiency in infancy Am. J. Clinical Nutrition, November 1, 2000; 72(5): 1191 - 1195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. T. Goodnough, B. Skikne, and C. Brugnara Erythropoietin, iron, and erythropoiesis Blood, August 1, 2000; 96(3): 823 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Choi, M. W. Im, and S. H. Pai Serum Transferrin Receptor Concentrations during Normal Pregnancy Clin. Chem., May 1, 2000; 46(5): 725 - 727. [Full Text] [PDF]
|
|
|
|
|
|
J. W. Choi, S. H. Pai, M. W. Im, and S. K. Kim Change in Transferrin Receptor Concentrations with Age Clin. Chem., September 1, 1999; 45(9): 1562 - 1563. [Full Text] [PDF]
|
|
|
|
|
|
P. Suominen, K. Punnonen, A. Rajamaki, R. Majuri, V. Hanninen, and K. Irjala Automated Immunoturbidimetric Method for Measuring Serum Transferrin Receptor Clin. Chem., August 1, 1999; 45(8): 1302 - 1305. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
