ReviewSoluble transferrin receptor for the evaluation of erythropoiesis and iron status
Introduction
Iron transport in the plasma is carried out by transferrin, which donates iron to cells through its interaction with a specific membrane receptor. The transferrin receptor (TfR) is a 760-amino-acid glycoprotein. The functional receptor is composed of two such monomers, linked by two disulfide bridges to form a molecule of 190,000 Da. Virtually all cells, except mature red cells, have TfR on their surface, but the largest numbers are in the erythron, placenta and liver. In a normal adult, about 80% of TfR are in the erythroid marrow. Receptor density on proliferating cells is related to the availability of iron as deprivation of iron results in prompt induction of TfR synthesis whereas excess iron suppresses TfR numbers. Therefore, the total mass of cellular TfR depends both on the number of erythroid precursors in the bone marrow and on the number of TfR per cell, a function of the iron status of the cell.
A circulating form of TfR has been found in human as well as animal serum. Serum TfR (sTfR) is a soluble truncated monomer of tissue receptor, lacking its first 100 amino acids, which circulates in the form of a complex of transferrin and its receptor [1]. A possible conformation is two receptor monomers (85 kDa) binding to one transferrin molecule (80 kDa) to give a total MW of around 250 kDa. A very small amount (although this may vary with the patient's diagnosis) of circulating TfR is in the form of an intact dimer in exosomes [2]. Soluble TfR is produced by proteolysis, mediated by a membrane-associated serine protease that occurs mostly at the surface of exosomes within the multivesicular body prior to exocytosis [3]. The bulk of sTfR measured in serum is proportional to the mass of cellular TfR [4] and originates mostly from erythroblasts and to a lesser extent from reticulocytes [5].
In this review, we will highlight the value of soluble sTfR as a quantitative measure of erythropoietic activity and as a marker of tissue iron deficiency. This will be extensively illustrated by presenting numerous examples of the practical use of this assay in the evaluation of erythropoiesis and/or iron status in an individual as well as in defined populations of patients. Potential pitfalls in the interpretation of sTfR values will be discussed.
Section snippets
Soluble TfR in normal subjects
Kohgo et al. [6] and Beguin et al. [7] were the first to measure sTfR quantitatively in human and rat serum, respectively. A number of quantitative assays have been set up to measure sTfR levels in biological fluids such as culture supernatants and plasma or serum. Some have been developed in research laboratories but several are now commercially available. The performance of these assays is highly variable but the major problem is the lack of an international standard. Therefore, although
Soluble TfR and erythropoietic activity
Erythropoietic activity has been found to be the most important determinant of sTfR levels [6], [7], [12], [13]. Decreased sTfR levels are found in situations characterized by erythroid hypoplasia (Fig. 1), such as hypertransfusion, chronic renal failure, severe aplastic anemia or after intensive chemotherapy [14]. Increased sTfR levels are seen in situations of stimulated erythropoiesis (Fig. 2), such as congenital dyserythropoietic anemia, hemolytic anemia, hereditary spherocytosis, sickle
Soluble TfR and iron status
The iron status also influences sTfR levels in serum (Fig. 3) [7]. In subjects with elevated transferrin saturation [55], [56], African iron overload [57], [58] or genetic hemochromatosis [12], [57], [59], average sTfR levels are about 20% below those measured in normal subjects but most values are still within the normal range. Iron deficiency has a much stronger impact on sTfR levels [60]. Soluble TfR levels in severely anemic iron-deficient rats increase many folds over normal values, in
Soluble TfR: a marker of iron status and/or erythropoiesis?
Within the iron-replete range, sTfR correlates with Hb but not with markers of iron status such as transferrin saturation and ferritin [8], [67], [105], [106], [107]. An inverse correlation between sTfR and ferritin may even represent an association between erythropoietic activity and iron utilization for erythropoiesis rather than an effect of iron stores on TfR expression [107]. Soluble TfR is therefore only a marker of erythropoiesis when iron stores are adequate and available and
Soluble TfR as a tumor marker
Increased expression of transferrin receptors has been documented on the surface of malignant tumors as compared to their normal counterparts. A number of studies have evaluated sTfR levels in erythroid (Fig. 4) as well as nonerythroid malignancies (Fig. 5). Soluble TfR levels are elevated in patients with myelofibrosis and myeloproliferative disorders, but are essentially within the normal range in chronic myelogenous leukemia or essential thrombocythemia, which is in keeping with our
References (136)
- et al.
Serum transferrin receptor is a truncated form of tissue receptor
J. Biol. Chem.
(1990) - et al.
Serum soluble transferrin receptor concentration is an accurate estimate of the mass of tissue receptors
Exp. Hematol.
(2001) - et al.
Higher concentrations of serum transferrin receptor in children than in adults
Am. J. Clin. Nutr.
(1999) - et al.
Intact transferrin receptors in human plasma and their relation to erythropoiesis
Blood
(1990) - et al.
Quantitative assessment of erythropoiesis and functional classification of anemia based on measurements of serum transferrin receptor and erythropoietin
Blood
(1993) - et al.
Anemia in children with cancer is associated with decreased erythropoietic activity and not with inadequate erythropoietin production
Blood
(1998) - et al.
Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis
Blood
(1996) - et al.
Red blood cell precursor mass as an independent determinant of serum erythropoietin level
Blood
(1998) - et al.
Congenital erythropoietin-dependent erythrocytosis responsive to theophylline treatment [letter; comment]
Blood
(1998) - et al.
Reduction of the clinical severity of sickle cell/beta-thalassemia with hydroxyurea: the experience of a single center in Greece
Blood Cells Mol. Dis.
(2000)
Early prediction of response to recombinant human erythropoietin in patients with the anemia of renal failure by serum transferrin receptor and fibrinogen
Blood
Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase I/II clinical trial
Blood
Prediction of response to erythropoietin treatment in chronic anemia of cancer
Blood
Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients
Blood
A comparison of the responses to recombinant human erythropoietin in normal and uremic subjects
Kidney Int.
Optimization of recombinant human erythropoietin therapy after allogeneic hematopoietic stem cell transplantation
Exp. Hematol.
Cessation of intensive treatment with recombinant human erythropoietin is followed by secondary anemia
Blood
Identification of blood erythroid markers useful in revealing erythropoietin abuse in athletes
Blood Cells Mol. Dis.
A second molybdoprotein aldehyde dehydrogenase from Amycolatopsis methanolica NCIB 11946
Arch. Biochem. Biophys.
Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency
Blood
Usefulness of serum transferrin receptor and serum ferritin in diagnosis of iron deficiency in infancy
Am. J. Clin. Nutr.
Intake and indicators of iron and zinc status in children consuming diets low in saturated fat and cholesterol: the STRIP baby study. Special Turku Coronary Risk Factor Intervention Project for Babies
Am. J. Clin. Nutr.
Serum transferrin receptor: a quantitative measure of tissue iron deficiency
Blood
Serum transferrin receptor as a new index of erythropoiesis
Blood
Response of serum transferrin receptor to iron supplementation in iron-depleted, nonanemic women
Am. J. Clin. Nutr.
Marginal iron deficiency without anemia impairs aerobic adaptation among previously untrained women
Am. J. Clin. Nutr.
Intravenous iron therapy for severe anaemia in systemic-onset juvenile chronic arthritis
Lancet
Serum transferrin receptor and transferrin receptor–ferritin index identify healthy subjects with subclinical iron deficits
Blood
Acute functional iron deficiency in obese subjects during a very-low-energy all-protein diet
Am. J. Clin. Nutr.
Prevalence of iron deficiency with and without concurrent anemia in population groups with high prevalences of malaria and other infections: a study in Cote d'Ivoire
Am. J. Clin. Nutr.
Day-to-day variation in iron status indexes is similar for most measures in elderly women with and without rheumatoid arthritis
J. Am. Diet. Assoc.
The Jeanne Manery-Fisher Memorial Lecture 1991. Maturation of reticulocytes: formation of exosomes as a mechanism for shedding membrane proteins
Biochem. Cell. Biol.
Mechanism of production of the serum transferrin receptor
Adv. Exp. Med. Biol.
Reticulocyte transferrin receptor (TfR) expression and contribution to soluble TfR levels
Haematologica
Circulating transferrin receptor in human serum
Br. J. Haematol.
Transferrin receptors in rat plasma
Proc. Natl. Acad. Sci. U. S. A.
Measurement of soluble transferrin receptor in serum of healthy adults
Clin. Chem.
Body iron stores decrease in boys during pubertal development: the transferrin receptor–ferritin ratio as an indicator of iron status
Pediatr. Res.
Regression-based reference limits for serum transferrin receptor in children 6 months to 16 years of age
Clin. Chem.
The clinical measurement of serum transferrin receptor
J. Lab. Clin. Med.
Dynamics of erythropoietic recovery after bone marrow transplantation: role of marrow proliferative capacity and erythropoietin production in autologous versus allogeneic transplants
Bone Marrow Transplant.
Serum erythropoietin in chronic lymphocytic leukemia
Br. J. Haematol.
Erythropoiesis in multiple myeloma: defective red cell production due to inappropriate erythropoietin production
Br. J. Haematol.
Influence of marrow erythropoietic activity on serum erythropoietin levels after autologous hematopoietic stem cell transplantation
Haematologica
Butyrate trials
Ann. N.Y. Acad. Sci.
Serum concentrations of transferrin receptor in hereditary hemochromatosis
Clin. Chem.
Serum erythropoietin and serum transferrin receptor levels in aplastic anaemia
Br. J. Haematol.
Assessment of erythropoiesis following renal transplantation
Eur. J. Haematol.
The clinical significance of serum transferrin receptor levels in sickle cell disease
Br. J. Haematol.
Evaluation of serum soluble transferrin receptors and erythropoietin levels as indicators for erythropoietic activity among multi-transfused beta-thalassemic patients
J. Trop. Pediatr.
Cited by (379)
Randomized Trial to Improve Body Composition and Micronutrient Status Among South African Children
2024, American Journal of Preventive MedicineComment on: Intravenous iron for critically ill children. Comparison of three dose regimens
2024, Pediatric Blood and Cancer
- 1
Yves Beguin is Research Director of the National Fund for Scientific Research (FNRS, Belgium).