Circulating Transferrin Receptor Research Articles

Iron and Parenteral Nutrition

There is ample evidence that iron is an essential trace element, but assessment of iron status and decisions on the amounts needed and the means of delivery in patients on parenteral nutrition (PN) have been unclear. Although iron requirements may diminish during acute illness, the frequent concurrence of blood loss and iron deficiency argue strongly for maintenance of levels of delivery in line with basal requirements. Maintenance of iron delivery has not been thought likely to present risk, but new data are questioning this. The needs of menstruating, pregnant, and lactating women are greater than those of adult men. The evidence favors an intravenous dose of around 1 mg of elemental iron per day in adult men and postmenopausal women. Doses of 1.5 mg/d [DOSAGE ERROR CORRECTED] in menstruating women and 2.0 mg/d [DOSAGE ERROR CORRECTED] for those in the later stages of pregnancy or lactating can be supported. A calibrated response is required in the growing child. Continued monitoring of iron status is recommended. Iron is an essential component for most PN regimens. The quantity of iron to be included should take account of predicted requirements.

Association of serum transferrin receptor concentration with markers of inflammation in Zimbabwean children

Background Clinical studies have shown that degree of erythropoiesis, the hypoxic response, and iron status each independently influences transferrin receptor concentration, but there is conflicting information regarding the effect of inflammation on transferrin receptor expression. Subjects and methods Levels of hemoglobin, reticulocytes, serum ferritin, transferrin receptors and inflammatory markers (C-reactive protein, interleukin-6 and neutrophils) were determined in 208 Zimbabwean children ≤ 5 years attending well-child clinics in a non-malaria transmission, non-hookworm area. Results In linear regression models among 147 children with ferritin > 10 ng/mL that adjusted for erythropoiesis with log 10 reticulocyte count, the hypoxic response with hemoglobin concentration and iron status with log 10 ferritin concentration, positive correlations were found between log 10 transferrin receptor concentration and log 10 C-reactive protein concentration ( P = 0.012), log 10 interleukin-6 concentration ( P = 0.011) and log 10 neutrophil count ( P = 0.013). These models predict that, with a baseline transferrin receptor concentration in the upper normal range of 8.0 mg/L and holding hemoglobin concentration and reticulocyte count constant, an increase from 1 to 10 mg/L in C-reactive protein is associated with a rise of 1.6 mg/L in transferrin receptor (95% C.I. 0.3–3.0 mg/L), an increase from 0.5-to-5.0 pg/mL in interleukin-6 with a rise of 1.9 mg/L (0.4–3.7 mg/L), and an increase from 2000 to 20,000/μL in neutrophil count with a rise of 3.6 mg/L (0.7–7.5 mg/L). Conclusion Our results suggest that inflammation leads to an increase in circulating transferrin receptor concentration that is independent of the degree of erythropoiesis, the hypoxic response and iron status.

Measurement of reticulocyte hemoglobin content to diagnose iron deficiency in Saudi children

Iron deficiency and iron deficiency anemia are common conditions in children, especially in developing countries. It is often difficult for the pediatrician to know which indices should be used in the diagnosis of these conditions in children. Reticulocyte hemoglobin (Hb) content (CHr) has been shown to be an accurate indicator of anemia, however whether its use suits the situation in developing countries or not is unclear. The aim of this study was to evaluate the value and effectiveness of using CHr as a method to diagnose iron deficiency and iron deficiency anemia in Saudi children. The samples for the study were collected from 305 children suspected to have anemia. Complete blood count, transferrin saturation (Tfsat), ferritin, circulating transferrin receptor (TfR) and CHr were measured. Three groups were defined, iron deficiency (Tfsat <20%, Hb >11 g/dL; n=120), iron deficiency anemia (Tfsat <20%, Hb <11 g/dL; (n=73) and controls (Tfsat >20%; n=112). The anemic group had significantly lower macrocytic anemia (MCV), mean corpuscular hemoglobin (MCH) and CHr. All of the variables in the anemia group were significantly lower than those of the control group except for the ferritin level. Compared to the control group, the iron deficiency group also showed significantly lower values except for transferrin receptor and the ferritin levels. CHr levels of <26 pg correlated well with anemic states. CHr together with a complete blood count may provide an alternative to the traditional hematologic or biochemical panel for the diagnosis of iron deficiency and iron deficiency anemia in young children and is cost-effective in developing countries. A CHr cut-off level of 26 pg is considered to be a reasonable indicator of anemic states.

Soluble transferrin receptors and ferritin in Type 2 diabetic patients

To determine circulating transferrin receptor levels (sTfR) in Type 2 diabetic patients to evaluate whether serum ferritin reflects iron body stores or inflammation in diabetic population. A total of 84 consecutive Type 2 diabetic patients and 60 healthy subjects matched by age and gender were included in this case-control study. Ferritin concentration was measured by a turbidimetric method and sTfR concentration were determined by nephelometry. Diabetic patients have higher serum ferritin levels than control subjects [114 ng/ml (12-831) vs. 74 ng/ml (11-697); P = 0.006]. However, no differences in sTfR concentrations were observed between both groups [1.27 mg/l (0.69-2.47) vs. 1.24 mg/l (0.77-2.80); P = NS]. A negative correlation between ferritin and sTfR concentration was detected in control subjects but not in diabetic patients. Serum ferritin levels are increased in Type 2 diabetic patients in the absence of a reciprocal decrease of sTfR. This finding suggests that elevated ferritin levels in Type 2 diabetes are mainly as a result of inflammatory mechanisms rather than iron overload.

Marked increase in serum transferrin receptor among Thai children with Hb-E-beta-thalassaemia.

To determine the serum transferrin receptor (sTfR) level in patients with Hb-E-beta-thalassaemia attending a paediatric haematology clinic. Sixty-four patients with Hb-E-beta-thalassaemia aged 2.9-10.8 years were attending a paediatric haematology clinic at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Circulating transferrin receptor was measured, as was the complete blood count and percentage of reticulocytes. A transfusion regimen recommended by the Thalassaemia International Federation was used whenever parents agreed to the treatment. In patients with Hb-E-beta-thalassaemia, the concentration of sTfR varied from 1.88 to 28.44 mg/L (mean +/- SD 13.99 +/- 5.37), while in the control group, it varied from 0.95 to 2.56 mg/L (mean +/- SD 1.58 +/- 0.41; n = 31). The sTfR level correlated inversely to a single measurement of haemoglobin in the same specimen (r = - 0.433; P = 0.00) and was elevated compared to the control group (P = 0.00; alpha < 0.05). In addition, the sTfR level correlated inversely to mean pre-transfusion haemoglobin (r = - 0.36; P = 0.003). The level of sTfR is elevated in children with Hb-E-beta-thalassaemia. The sTfR level can be used as an adjunct real-time assessment of erythropoietic activity, comparable with mean pre-transfusion haemoglobin. Measurement of sTfR is easy using most automated chemical analyzers, and material can be obtained from routine specimen collections. Further studies should be carried out in a larger population to verify the benefits of this test to patients.

A Hematologic “Gold Standard” for Iron-deficient States?1

In this issue of the Journal, Thomas and Thomas (1) provide a novel approach to the diagnosis of iron-deficient states. Traditionally, iron deficiency studies have used various biochemical indicators of iron metabolism to establish the absence or presence of biochemical iron deficiency and to assess the performance of a potentially novel biochemical or hematologic marker. Biochemical indicators have included serum iron, serum transferrin, transferrin saturation, serum ferritin, and serum circulating transferrin receptor (TfR) as well as various ratios of these variables. Hematologic indices that have been used to establish the presence of iron deficiency anemia have included, in addition to hemoglobin (Hb) or hematocrit (Hct), abnormal erythrocytes or reticulocyte indices that identify the presence of hypochromic and microcytic cells. Additional variables that have been investigated include zinc protoporphyrin and erythrocyte ferritin. Studies on the diagnosis of iron-deficient states have been complicated by the absence of a clear reference method to detect biochemical iron deficiency. Iron staining of bone marrow biopsy is widely quoted as a gold standard, but the invasive nature of this procedure severely limits its use. A less invasive standard for iron deficiency is based on the hematologic response to iron replacement therapy: an increase of the reticulocyte count or reticulocyte index after oral or intravenous iron replacement therapy reveals the presence of iron deficiency. The use of biochemical markers to diagnose iron-deficient states is problematic in clinical conditions such as the anemia of chronic disease (ACD). When a disturbed iron metabolism is associated with acute or chronic phase inflammatory responses, serum ferritin and transferrin concentrations are affected and not informative. Biochemical markers are also less effective in diagnosing functional iron deficiency, a transient discrepancy between iron supply and utilization that is mostly seen in individuals treated with recombinant human erythropoietin (r-HuEPO). In their report, Thomas and Thomas …

Current Literature: Reticulocyte Hemoglobin Content to Diagnose Iron Deficiency in Children

Context: Early identification of iron deficiency in children is essential to prevent the damaging long‐term consequences of this disease. However, it is not clear which indices should be included in a diagnostic panel for iron deficiency and iron deficiency anemia in children. Objectiiv: To develop an effective approach for the diagnosis of iron deficiency and iron deficiency anemia in young children. Design and Setting: Retro spective laboratory analysis, carried out over 7 weeks in 1996, using blood samples ordered by pediatricians and sent to a large metropolitan hospital for analysis. Patients: A total of 210 children (mean [SD] age, 2.9 (2.0] years; 120 were male) who had a lead screening test (complete blood cell count and plasma lead level) ordered by a primary care pediatrician. Main Outcome Measures: Levels of hemoglobin (Hb), iron, transferrin, transferrin saturation (Tfsat), ferritin, and circulating transferrin receptor (TfR) and reticulocyte Hb content (CHr) among patients with and without iron deficiency, defined as Tfsat of less than 20%, and iron deficiency anemia, defined as Tfsat of less than 20% and Hb level less than 110 g/L. Results: Of the 210 subjects, 43 (20.5%) were iron deficient; 24 of these had iron deficiency anemia. Reticulocyte Hb content and Hb levels were the only significant predictors of iron deficiency (likelihood ratio test [LRT] = 15.96; P &lt; 0.001 for CHr, and LRT = 6.59; P = 0.01 for Hb), and CHr was the only significant multivariate predictor of iron deficiency anemia (LRT = 30.43; P &lt; 0.001). Plasma ferritin level had no predictive value (P = 0.97). Subjects with CHr of less than 26 pg (optimal cutoff value based on sensitivity/specificity analysis) had lower Hb level, mean corpuscular volume, mean corpuscular Hb level, serum iron level, and Tfsat, and increased red blood cell distribution width vs those with CHr of 26 pg or more (P &lt; 0.001 for all). Conclusions: Reticulocyte Hb content level was the strongest predictor of iron deficiency and iron deficiency anemia in children. It holds promise as an alternative to biochemical iron studies in diagnosis. (JAMA 281:2225–2230, 1999)

Circulating Transferrin Receptor Assay—Coming of Age

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 …

Serum transferrin receptors are decreased in the presence of iron overload

To test the hypothesis that the quantities of circulating transferrin receptors are reduced in iron overload, we studied serum transferrin receptors and indirect measures of iron status in 150 subjects from rural Zimbabwe. We found significant inverse correlations between serum concentrations of transferrin receptors and ferritin, the ratio of ferritin to aspartate aminotransferase, and transferrin saturation (r > or = 0.44; P < 0.001). The mean +/- SD concentration of serum transferrin receptors in 23 subjects classified as having iron overload (ferritin > 300 microg/L and transferrin saturation > 60%) was 1.55 +/- 0.61 mg/L, significantly lower than the 2.50 +/- 0.62 mg/L in 75 subjects with normal iron stores (ferritin 20-300 microg/L and transferrin saturation 15-55%; P < 0.0005) and the 2.83 +/- 1.14 mg/L in 8 subjects with iron deficiency (ferritin < 20 microg/L; P = 0.001). In keeping with the regulation of transferrin receptor expression at the cellular level, our findings suggest that serum transferrin receptors are decreased in the presence of iron overload.

The laboratory assessment of iron status — an update

The description by Ramsay in 1957 of a practical way of determining the total iron binding capacity of serum (a measure of transferrin concentration) provided a diagnostic test for both iron deficiency and iron overload. Since 1957 the introduction of the assay for serum ferritin (in 1972) has made it possible to assess the levels of storage iron in normal subjects and assays for free erythrocyte protoporphyrin and the circulating transferrin receptor methods to evaluate iron supply for erythropoiesis. In 1957 iron metabolism in man was already well understood but its evaluation relied on measurement of tissue iron concentrations and the use of radioisotopes of iron to measure rates of erythropoiesis. The evaluation can now be carried out using the various blood assays along with the measurement of haemoglobin concentration but interpretation of the measurements in disease still requires an understanding of the way in which these measures are influenced by pathological processes.

Defective Iron Supply for Erythropoiesis and Adequate Endogenous Erythropoietin Production in the Anemia Associated With Systemic-Onset Juvenile Chronic Arthritis

Systemic-onset juvenile chronic arthritis (SoJCA) is associated with high levels of circulating interleukin-6 (IL-6) and is frequently complicated by severe microcytic anemia whose pathogenesis is unclear. Therefore, we studied 20 consecutive SoJCA patients with hemoglobin (Hb) levels <12 g/dL, evaluating erythroid progenitor proliferation, endogenous erythropoietin production, body iron status, and iron supply for erythropoiesis. Hb concentrations ranged from 6.5 to 11.9 g/dL. Hb level was directly related to mean corpuscular volume (r = .82, P < .001) and inversely related to circulating transferrin receptor (r = -.81, P < .001) suggesting that the severity of anemia was directly proportional to the degree of iron-deficient erythropoiesis. Serum ferritin ranged from 18 to 1,660 microgram/L and was unrelated to Hb level. Bone marrow iron stores wore markedly reduced in the three children investigated, and they also showed increased serum transferrin receptor and normal-to-high serum ferritin. All 20 patients had elevated IL-6 levels and normal in vitro growth of erythroid progenitors. Endogenous erythropoietin (epo) production was appropriate for the degree of anemia as judged by both the observed to predicted log (serum epo) ratio 10.95 +/- 0.12) and a comparison of the serum epo-Hb regression found in these subjects with that of thalassemia patients. Multiple regression analysis showed that serum transferrin receptor was the parameter most closely related to hemoglobin concentration: variation in circulating transferrin receptor explained 61% of the variation in Hb level (P < .001). In 10 severely anemic patients, amelioration of anemia following intravenous iron administration resulted in normalization of serum transferrin receptor. Defective iron supply to the erythron rather than blunted epo production is the major cause of the microcytic anemia associated with SoJCA. A true body-iron deficiency caused by decreased iron absorption likely complicates long-lasting inflammation in the most anemic children, and this can be recognized by high serum transferrin receptor levels. Although oral iron is of no benefit, intravenous iron saccharate is a safe and effective means for improving iron availability for erythropoiesis and correcting this anemia. Thus, while chronically high endogenous IL-6 levels do not appear to blunt epo production, they are probably responsible for the observed abnormalities in iron metabolism. Anemia of chronic disease encompasses a variety of anemic conditions whose peculiar features may specifically correlate with the type of cytokine(s) predominantly released.

Erythropoietin production and erythropoiesis in compensated and anaemic states of hereditary spherocytosis

A compensated haemolytic state is defined by decreased red cell life-span without anaemia, i.e. by increased erythropoiesis in the absence of the physiological stimulus for erythropoietin (Epo) production. We evaluated s-Epo levels and the expansion of erythropoiesis (as measured by circulating transferrin receptor, s-TfR) in 32 patients with hereditary spherocytosis (HS) with the aim of verifying whether the enhanced erythropoiesis of compensated haemolysis was Epo-dependent. 20 of the patients (62.5%) had normal Hb values (> 12 g/dl in females and > 13 g/dl in males). Their compensated haemolytic state was the result of up to 8.2 times normal s-Epo and up to 3.9 times normal s-TfR levels, which were maintained by physiological regulation of erythropoiesis, as documented by the inverse dependence of Hb on s-Epo levels. Considering that patients with iron-deficiency anaemia represented the predicted physiological Epo response to anaemia, the observed/predicted in s-Epo ratio (O/P ratio) was calculated in HS patients with anaemia and was used as an index of the adequateness of Epo production. All the anaemic HS patients had an O/P ratio > 1, documenting inappropriately high s-Epo levels. This work demonstrates that the compensated haemolytic state of HS patients is produced by an inappropriately high s-Epo level, and that the pattern of Epo overproduction is a biological characteristic of the disease.

Circulating transferrin receptor during erythropoietin medication of anemic patients with rheumatoid arthritis.

Serum levels of the transferrin receptor (TfR) were monitored in 12 anemic patients with rheumatoid arthritis (RA) undergoing treatment with recombinant human erythropoietin (rHuEPO) for a 24-week period. Measurement of TfR was performed using an enzyme immunoassay. Compared to a mean pretreatment level of 4.2 mg/l (range 2.1-6.1 mg/l), there was an increase in the mean TfR concentrations from 2 weeks of treatment onwards to a maximum of 7.7 mg/l (range 2.1-12.3 mg/l) at 12 weeks (p < 0.01). Nine of the 12 patients responded to rHuEPO with an increase in blood hemoglobin concentration of 15 g/l or more. An increase in TfR levels was documented not only in the responders but also in the 3 nonresponders. We conclude that in anemic RA patients exogenous erythropoietin induces a swift and sustained increase in the serum concentration of TfR, which probably reflects increased expression of TfR on erythroblasts. This sustained elevation of TfR seems to occur even in patients who do not have an increase in their hemoglobin level.

Sex Differences in Iron Stores of Adolescents

We evaluated iron status and its determinants in healthy adolescents. Fasting morning blood samples from a school-based cross-sectional study were analyzed for serum ferritin (SF), serum iron, total iron-binding capacity, and circulating transferrin receptors. Physical development, chronic disease, medication, dietary intake, and physical activity were assessed using clinical examination, questionnaires, and 7-day records. The risk of having low serum ferritin values was estimated using bivariate and multivariate regression. Subjects were 867 healthy Swedish adolescents, 14- and 17-year-olds (472 boys and 395 girls). SF values increased with pubertal stage in boys but not in girls. Five percent of the boys and 15% of the girls had SF values < 12 micrograms/L. Of the 17-year-old boys, 7% compared to 1% of the 17-year-old girls had SF values > 100 micrograms/L. Forty-one percent of cases with SF values > 12 micrograms/L had serum iron values < 15 microM, and 22% had transferrin saturation values < 16%. Mean total iron intakes of the boys were high [1.6 times recommended daily allowance (RDA)] and mean intakes of the girls were adequate (0.9 times RDA). Low heme iron intakes increased the risk of low iron stores (< 12 micrograms/L) in girls but not in boys. Total iron intake or other dietary factors, physical development, or level of physical activity did not influence the risk of low SF. The findings of this study suggest that the differences in iron status between boys and girls in adolescence results primarily from biological differences other than menstrual bleeding or insufficient iron intake. Furthermore, the results question the role of SF as an indicator of iron deficiency in adolescence, in particular if age and sex are not taken into consideration. We suggest that different reference values for SF, including the cut-off limit for low SF, adjusted for age and sex, should be considered. The high iron intakes and corresponding high SF values found in the older boys are noticeable in light of the possible negative health consequences of iron overload.

Sex Differences in Iron Stores of Adolescents

SummaryWe evaluated iron status and its determinants in healthy adolescents. Fasting morning blood samples from a school‐based cross‐sectional study were analyzed for serum ferritin (SF), serum iron, total iron‐binding capacity, and circulating transferrin receptors. Physical development, chronic disease, medication, dietary intake, and physical activity were assessed using clinical examination, questionnaires, and 7‐day records. The risk of having low serum ferritin values was estimated using bivariate and multivariate regression. Subjects were 867 healthy Swedish adolescents, 14− and 17‐year‐olds (472 boys and 395 girls). SF values increased with pubertal stage in boys but not in girls. Five percent of the boys and 15% of the girls had SF values &lt;12 μg/L. Of the 17‐year‐old boys, 7% compared to 1% of the 17‐year‐old girls had SF values &gt; 100 μg/L. Forty‐one percent of cases with SF values &gt;12 μg/L had serum iron values &lt; 15 μM, and 22% had transferrin saturation values &lt;16%. Mean total iron intakes of the boys were high [1.6 times recommended daily allowance (RDA)] and mean intakes of the girls were adequate (0.9 times RDA). Low heme iron intakes increased the risk of low iron stores (&lt;12 μg/L) in girls but not in boys. Total iron intake or other dietary factors, physical development, or level of physical activity did not influence the risk of low SF. The findings of this study suggest that the differences in iron status between boys and girls in adolescence results primarily from biological differences other than menstrual bleeding or insufficient iron intake. Furthermore, the results question the role of SF as an indicator of iron deficiency in adolescence, in particular if age and sex are not taken into consideration. We suggest that different reference values for SF, including the cut‐off limit for low SF, adjusted for age and sex, should be considered. The high iron intakes and corresponding high SF values found in the older boys are noticeable in light of the possible negative health consequences of iron overload.

Serum transferrin receptor level is not altered in invasive adenocarcinoma of the breast.

The transferrin receptor is expressed on the surface of rapidly dividing cells that require iron as a co-factor for essential redox reactions and deoxyribonucleotide synthesis. Transferrin receptors are expressed on the surface of breast carcinoma cells but not on benign breast tumor cells. In this study, the authors investigated whether transferrin receptor concentrations in the serum were elevated in patients with invasive adenocarcinoma of the breast. The transferrin receptor was isolated and purified from human placenta by affinity chromatography. The serum transferrin receptor concentration was determined using an enzyme-linked immunosorbent assay in 19 patients with invasive breast adenocarcinoma, 12 of whom had involvement of axillary lymph nodes. These results were compared with those from 16 normal age-matched female controls. In the invasive breast cancer group, the range of transferrin receptor concentrations was 2.60-7.34 mg/L (mean, 4.44 mg/L) compared with 2.85-8.80 mg/L (mean, 5.49 mg/L) in the control group. Nine patients with in situ adenocarcinoma of the breast had transferrin receptor concentrations of 3.68-6.66 mg/L (mean, 4.94 mg/L). For both the invasive carcinoma group and the in situ group, the means were not significantly different from those of the control group (P = 0.06 and 0.32, respectively). It was concluded that the differential expression of transferrin receptor on the surface of malignant tumor cells in adenocarcinoma of the breast was not reflected by changes in circulating transferrin receptor concentrations.

Characterization and Quantitation of the Circulating Forms of Serum Transferrin Receptor Using Domain-Specific Antibodies

To characterize the nature of the immunoreactive transferrin receptor in human serum, antisera were developed to peptide sequences of the extracellular domain of human transferrin receptor between amino acids 107 and 120 and the intracellular domain between amino acids 40 and 54. Antisera against the extracellular domain exhibited reactivity against both purified intact receptor and immunopurified circulating receptor, whereas antisera against the intracellular domain reacted only with intact receptor. Using competitive binding enzyme-linked immunosorbent assays, transferrin receptor in ultracentrifuged sera from normal subjects and patients with sickle cell anemia could be detected with antisera against the extracellular but not the intracellular domain. When the pellet obtained by ultracentrifugation of these sera was assayed after solubilization in 1% teric (polyoxyethylene-9-lauryl ether), only 0.6% of total serum receptor was detected in normal subjects and 3.8% in subjects with sickle cell disease. Roughly equal amounts of this pelleted immunoactivity were detected with antibodies against the extracellular and intracellular domains. These results indicate that less than 1% of transferrin receptor in normal human sera is intact receptor consistent with an exosomal origin and that virtually all circulating transferrin receptor is in the form of a truncated extracellular domain.

Characterization and quantitation of the circulating forms of serum transferrin receptor using domain-specific antibodies

To characterize the nature of the immunoreactive transferrin receptor in human serum, antisera were developed to peptide sequences of the extracellular domain of human transferrin receptor between amino acids 107 and 120 and the intracellular domain between amino acids 40 and 54. Antisera against the extracellular domain exhibited reactivity against both purified intact receptor and immunopurified circulating receptor, whereas antisera against the intracellular domain reacted only with intact receptor. Using competitive binding enzyme-linked immunosorbent assays, transferrin receptor in ultracentrifuged sera from normal subjects and patients with sickle cell anemia could be detected with antisera against the extracellular but not the intracellular domain. When the pellet obtained by ultracentrifugation of these sera was assayed after solubilization in 1% teric (polyoxyethylene-9-lauryl ether), only 0.6% of total serum receptor was detected in normal subjects and 3.8% in subjects with sickle cell disease. Roughly equal amounts of this pelleted immunoactivity were detected with antibodies against the extracellular and intracellular domains. These results indicate that less than 1% of transferrin receptor in normal human sera is intact receptor consistent with an exosomal origin and that virtually all circulating transferrin receptor is in the form of a truncated extracellular domain.

The Transferrin Receptor: Its Diagnostic Value and its Potential as Therapeutic Target

Transferrin receptors are present on almost all mammalian cells. The receptor participates in the cellular acquisition of iron from transferrin by receptor-mediated endocytosis. Receptor abundancy is generally regulated by two factors: i) cellular iron status and ii) cell growth. These two factors form the basis for the utilization of transferrin receptor determination as a diagnostic tool. In the assessment of body iron status and erythropoietic activity the measurement of circulating transferrin receptor has proved to be of value as a measure of mild tissue iron deficiency, to distinguish iron deficiency anemia from the anemias of chronic disease, and as a sensitive index of iron deficiency during pregnancy. Histochemical analysis of the presence and abundancy of the transferrin receptor will continue to serve as an additional tool in special cases to distinguish between malignant and normal cell growth, and to provide additional information about the biological behaviour of tumor cells. Finally, the transferrin receptor holds a potential as a target for direct and indirect drug delivery in the therapy of malignant cell growth.

Serum transferrin receptor for the detection of iron deficiency in pregnancy

Measurements of circulating transferrin receptor provide a sensitive quantitative index of tissue iron deficiency in otherwise healthy subjects. This investigation was undertaken to examine the diagnostic utility of this new iron index in pregnancy. A battery of iron-related measurements, including serum transferrin receptor concentrations, was performed on 176 women in third-trimester pregnancy who were attending a university prenatal clinic. The mean receptor concentration of 5.96 +/- 2.37 mg/L (+/- 1 SD) did not differ significantly from concentrations in nonpregnant individuals and the frequency distributions were likewise comparable. Elevations in serum receptor greater than 8.5 mg/L occurred only in women with depleted iron stores defined by serum ferritin concentrations. Abnormal concentrations were found in 11 of 13 women with overt iron-deficiency anemia. Our findings indicate that serum receptor concentrations are not influenced by pregnancy per se and are a sensitive index of iron deficiency. By combining serum receptor and serum ferritin measurements, the entire spectrum of iron status in pregnancy can be assessed.