Review
Soluble transferrin receptor for the evaluation of erythropoiesis and iron status

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Abstract

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). A soluble form of the TfR (sTfR) has been identified in animal and human serum. Soluble TfR is a truncated monomer of tissue receptor, lacking its first 100 amino acids, which circulates in the form of a complex of transferrin and its receptor. The erythroblasts rather than reticulocytes are the main source of serum sTfR. Serum sTfR levels average 5.0±1.0 mg/l in normal subjects but the various commercial assays give disparate values because of the lack of an international standard. The most important determinant of sTfR levels appears to be marrow erythropoietic activity which can cause variations up to 8 times below and up to 20 times above average normal values. Soluble TfR levels are decreased in situations characterized by diminished erythropoietic activity, and are increased when erythropoiesis is stimulated by hemolysis or ineffective erythropoiesis. Measurements of sTfR are very helpful to investigate the pathophysiology of anemia, quantitatively evaluating the absolute rate of erythropoiesis and the adequacy of marrow proliferative capacity for any given degree of anemia, and to monitor the erythropoietic response to various forms of therapy, in particular allowing to predict response early when changes in hemoglobin are not yet apparent. Iron status also influences sTfR levels, which are considerably elevated in iron deficiency anemia but remain normal in the anemia of inflammation, and thus may be of considerable help in the differential diagnosis of microcytic anemia. This is particularly useful to identify concomitant iron deficiency in a patient with inflammation because ferritin values are then generally normal. Elevated sTfR levels are also the characteristic feature of functional iron deficiency, a situation defined by tissue iron deficiency despite adequate iron stores. The sTfR/ferritin ratio can thus describe iron availability over a wide range of iron stores. With the exception of chronic lymphocytic leukemia (CLL) and high-grade non-Hodgkin's lymphoma and possibly hepatocellular carcinoma, sTfR levels are not increased in patients with malignancies. We conclude that soluble TfR represents a valuable quantitative assay of marrow erythropoietic activity as well as a marker of tissue iron deficiency.

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

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    Yves Beguin is Research Director of the National Fund for Scientific Research (FNRS, Belgium).

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