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1997 89: 1052-1057

Serum Transferrin Receptor and Its Ratio to Serum Ferritin in the Diagnosis of Iron Deficiency
Kari Punnonen, Kerttu Irjala and Allan Rajamki

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Serum Transferrin Receptor and Its Ratio to Serum Ferritin in the Diagnosis of Iron Deciency
By Kari Punnonen, Kerttu Irjala, and Allan Rajama ki
The objective of the study was to evaluate the diagnostic efciency of laboratory tests, including serum transferrin receptor (TfR) measurements, in the diagnosis of iron depletion. The patient population consisted of 129 consecutive anemic patients at the University Hospital of Turku who were given a bone marrow examination. Of these patients, 48 had iron deciency anemia (IDA), 64 anemia of chronic disease (ACD), and 17 patients had depleted iron stores and an infectious or an inammatory condition (COMBI). Depletion of iron stores was dened as a complete absence of stainable iron in the bone marrow examination. Serum TfR concentrations were elevated in the vast majority of the IDA and COMBI patients, while in the ACD patients, the levels were within the reference limits reported earlier for healthy subjects. TfR measurement thus provided a reliable diagnosis of iron deciency anemia (AUCROC 0.98). Serum ferritin measurement also distinguished between IDA patients and ACD patients. However, the optimal decision limit for evaluation of ferritin measurements was considerably above the conventional lower reference limits, complicating the interpretation of this parameter. Calculation of the ratio TfR/log ferritin (TfR-F Index) is a way of combining TfR and ferritin results. This ratio provided an outstanding parameter for the identication of patients with depleted iron stores (AUCROC 1.00). In anemic patients, TfR measurement is a valuable noninvasive tool for the diagnosis of iron depletion, and offers an attractive alternative to more conventional laboratory tests in the detection of depleted iron stores. 1997 by The American Society of Hematology.

HE LEVEL of body iron stores is affected both by dietary intake and by the physiological need of iron for erythropoiesis. Consequently, iron deciency anemia (IDA) can be caused by dietary deprivation of iron or by iron malabsorbtion; importantly, it may be the rst clinical sign of increased blood loss. Unexplained iron deciency anemia warrants extensive investigations of the gastrointestinal tract, since the probability of ulcers or malignant tumors as the cause of excessive blood loss is relatively high.1 Using laboratory tests, distinguishing between iron deciency anemia and the anemia that accompanies infection, inammation, or malignancy is difcult, as the commonly used laboratory parameters do not necessarily distinguish between these common causes of anemia.2-5 The conventional laboratory tests of iron status, serum iron, transferrin/total iron-binding capacity (TIBC), transferrin saturation, and ferritin are widely used in clinical practice, although they are considerably inuenced by acute phase responses, which complicates the clinical interpretation of the test results.3-5 High sensitivity, as well as specicity, is of special importance for a test of iron status, as the further identication of the cause of the depletion of iron stores is bound to result in tedious clinical and laboratory investigations. Because the absence of stainable iron in bone marrow examination is generally regarded as the denitive marker of iron deciency, marrow examinations are generally requested to conrm iron deciency. There is an evident clinical need for noninvasive and sensitive means for the detection of iron deciency, and in recent years, the serum transferrin receptor (TfR) level has

been introduced as a promising new tool for the diagnosis of iron depletion.3,6-11 The TfR receptor is a transmembrane protein with two identical polypeptide chains, each weighing 95 kD; iron delivery to erythroblasts is mediated by the interaction of plasma transferrin with cell surface transferrin receptors.11,12 From the cell membrane the TfR-transferrin-iron complex is internalized via an endocytic vesicle, and in the intracellular compartment iron dissociates from TfR-transferrin complex.3,11,13 The iron remains in the cytosol, while the TfRtransferrin complex is recycled back to the cell surface. Virtually all cells have transferrin receptors on their surface, but in the normal adult, about 80% of them are in the erythroid marrow.12 Soluble TfR present in human plasma is a truncated form of the tissue receptor and exists as a transferrinreceptor complex.13-15 The TfR number on the cell surface reects the iron requirement, and iron deprivation has been shown to result in the prompt induction of transferrin receptor synthesis.16 We have evaluated the clinical efciency of TfR measurements in the identication of iron deciency in an extensive, consecutive patient population. The diagnostic classication of all patients was based on an examination of bone marrow using iron staining as the gold standard for iron depletion.
MATERIALS AND METHODS

From the Central Laboratory, Departments of Clinical Chemistry and Hematology, University Hospital of Turku, Turku, Finland. Submitted March 14, 1996; accepted September 16, 1996. Address reprint requests to Kari Punnonen, MD, PhD, Department of Clinical Chemistry, University Hospital of Turku, Kiinamyllynkatu 4-8, 20520 Turku, Finland. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. section 1734 solely to indicate this fact. 1997 by The American Society of Hematology. 0006-4971/97/8903-0013$3.00/0
1052

Patients. The patient population consisted of 129 consecutive anemic adult patients at the University Hospital of Turku who underwent a bone marrow examination because of anemia. The purpose of the examinations was to dene the type of anemia and to determine iron stores. Anemia was dened as a hemoglobin concentration of less than 128 g/L in men and 117 g/L in women, which constitutes the lower 2.5% reference limits in our hospital. All blood samples were obtained before any blood transfusions, and patients on oral iron therapy were excluded from the study population. Patients with hematological malignancies were also excluded from this study, as certain hematological malignancies have been reported to be associated with an elevated serum TfR regardless of the iron status of the patients.14,17 Additionally, patients who had hemolytic anemia or dened deciency of vitamin B12 or folic acid were excluded from the study population, as these conditions may be associated with elevated TfR levels irrespective of iron status.18 The patients were assigned to one of three groups on the basis of the bone marrow
Blood, Vol 89, No 3 (February 1), 1997: pp 1052-1057

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TRANSFERRIN RECEPTOR AND IRON DEFICIENCY 1053

Table 1. Laboratory Tests of Iron Status in the Three Anemic Patient Groups
IDA (n 48) ACD (n 64) COMBI (n 17)

RESULTS

Hemoglobin, g/L MCV, Iron, mmol/L Transferrin, g/L Ferritin, mg/L TfR, mg/L TI Transferrin saturation, % TfR/log ferritin

93 { 16 (96) 75 { 9 (75) 8 3.3 21 6.2 2.7 { { { { { 11 (4) 0.4 (3.3) 55 (11) 3.5 (5.0) 3.9 (1.3)

102 { 12 (103) 90 { 7 (91) 10 1.9 342 1.8 5.2 { { { { { 6 (9) 0.5 (1.8) 385 (195) 0.6 (1.8) 2.9 (4.9)

88 { 20 (90) 78 { 9 (79) 6 2.6 87 5.1 2.7 { { { { { 3 (6) 0.6 (2.4) 167 (23) 2.0 (4.7) 1.6 (1.8)

12 { 17 (5.7) 6.8 { 6.5 (5.4)

23 { 13 (21) 0.8 { 0.3 (0.8)

12 { 7 (8) 3.8 { 1.9 (3.2)

Results are mean { SD (median).

examination and clinical data. Forty-eight patients (32 women and 16 men) who fullled the morphologic criteria of iron deciency and who had no stainable iron in the bone marrow were classied as having IDA. Sixty-four anemic patients (37 women and 27 men) were classied as having anemia of chronic disease (ACD), and these patients all had stainable iron in the bone marrow. Of these 64 patients, 34 had recurrent or chronic infections, while the remaining 30 had other chronic diseases (ie, nonhematological malignancies and inammatory diseases such as rheumatoid arthritis). Those patients who had no iron in the bone marrow together with an infectious disease, a chronic inammatory disease (eg, rheumatoid arthritis or colitis ulcerosa) or a nonhematological malignancy were placed in a COMBI group (n 17). In addition, two iron-decient patients who had a C-reactive protein (CRP) value above 20 mg/L were regarded as having an accompanying inammatory or infectious condition and were included in the COMBI group. Preliminary results concerning a small subgroup of the patients (n 36) have been reported earlier.19 Samples and analytical methods. Bone marrow was aspirated from the sternal bone or iliac crest. The smears were stained using the May-Gru nwald-Giemsa method (Orion Diagnostica, Helsinki, Finland), and the iron stores were stained by the Prussian blue method. Blood counts were measured with an automated analyzer (Technicon H*2, Technicon Instruments Corp, Tarrytown, NY). Serum transferrin receptor assays were performed using a commercially available kit based on a polyclonal antibody in a sandwich enzyme immunoassay (EIA) format (Clinigen; R&D Systems, Minneapolis, MN). According to the assay kit from the manufacturer, the central 95th percentile of the reference distribution of TfR concentration is 0.85 to 3.05 mg/L (n 1,000). Ferritin (reference range, 15 to 306 mg/L for men, 5 to 103 mg/L for women, according to the manufacturer) was measured using a radioimmunoassay (Spectria, Orion Diagnostics). Transferrin (reference range, 2.1 to 3.4 g/L for men, 2.0 to 3.1 g/L for women20) was measured with a Behring Nephelometer (Behringwerke AG, Marburg, Germany) together with antibodies provided by Dakopatts (Dakopatts, Glostrup, Denmark). Serum iron (reference range, 10 to 40 mmol/L) was measured using an Iron FZ assay (Hoffmann-LaRoche, Basel, Switzerland) based on a guanidine hydrochloride/Ferrozine reaction. The transferrin index (TI) was calculated as iron (mmol/L)/transferrin (g/L), as recently suggested by Beilby et al.21 Percent transferrin saturation was calculated as [iron/(transferrin 1 23)] 1 100. Statistical analysis. Receiver operating characteristics (ROC) curves were visualized and the corresponding areas under the curves were calculated using the GraphROC for Windows software package.22 The areas under the ROC curves (AUCROC) were compared with each other using a software mathematically based on a method described earlier.23-25 The P values (one-tailed test) corresponding to the calculated z scores were drawn from a table of normal distributions.

The results for blood counts and iron status markers for the 129 anemic patients are summarized in Table 1. Serum iron was not a reliable indicator of iron depletion (Table 2). When the study population was analyzed as a whole (n 129), serum transferrin distinguished fairly well between iron-decient and ACD patients (Table 2). However, in a considerable proportion of the iron-decient patients, the transferrin concentration was within the reference limits of a healthy population (see Materials and Methods), making the clinical interpretation of the transferrin concentrations difcult. The area under the ROC curve (AUCROC) provided by Transferrin-Index (TI, iron/transferrin),21 or the percentage transferrin saturation [iron/(transferrin 1 23) 1 100] in the identication of iron-decient patients was 0.82. For comparison, the corresponding AUCROC for red cell mean corpuscular volume (MCV) was 0.88. In male and female IDA patients, the median serum ferritin concentrations were 13 mg/L (mean { standard deviation [SD], 37 { 94) and 9 mg/L (mean { SD, 12 { 9), respectively. In male and female ACD patients, the median ferritin concentrations were 195 mg/L (mean { SD, 364 { 310) and 169 mg/L (mean { SD, 326 { 440), respectively. There have been no previous reports of any signicant differences in TfR concentrations between male and female patients; the present ndings are consistent with this, as for instance, in male and female ACD patients, the median TfR concentrations were 1.9 g/L (mean { SD, 1.9 { 0.7) and 1.7 g/L (mean { SD, 1.8 { 0.5), respectively. As neither ferritin nor TfR concentrations differed signicantly between male and female patients, the results have been analyzed and presented without distinction between male and female patients. Serum ferritin measurements distinguished between IDA and ACD patients (AUCROC 0.98); however, the optimal decision limit for the interpretation of ferritin measurements was considerably above the conventional lower reference limit, which is based on evaluations of apparently healthy populations (Tables 1 through 3 and Fig 1). TfR concentrations were elevated in the vast majority of IDA and COMBI patients, and the serum TfR concentration was found to be a good indicator of iron deciency, as demonstrated by the

Table 2. AUCROC Values (SE) for Parameters of Iron Status

IDA / COMBI v ACD IDA v ACD COMBI v ACD

MCV Iron Transferrin TI (iron/transferrin) Ferritin TfR TfR/ferritin TfR/log ferritin

0.89 (0.03) 0.71 (0.05) 0.94 (0.02) 0.82 (0.04) 0.96 (0.02) 0.98 (0.01) 0.98 (0.01) 1.00 (0.001)

0.90 0.71 0.98 0.84 0.98 0.98 1.00 1.00

(0.03) (0.05) (0.01) (0.04) (0.01) (0.01) (0.00) (0.00)

0.86 0.68 0.84 0.79 0.89 0.98 0.94 1.00

(0.05) (0.07) (0.05) (0.06) (0.07) (0.01) (0.04) (0.01)

Separate values concerning the identication of patients with depleted iron stores have been calculated for the whole patient population (IDA / COMBI v ACD), for the population containing patients with uncomplicated IDA patients and ACD patients (IDA v ACD), and for the patient population in which all had an infectious or inammatory disease (COMBI v ACD).

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1054 KI PUNNONEN, IRJALA, AND RAJAMA

Table 3. Ability of Ferritin, TfR, TfR/Ferritin Ratio and TfR-F Index to Identify Patients With Iron Deciency
IDA v ACD IDA / COMBI v ACD COMBI v ACD

Ferritin

TfR

TfR 1 100/ Ferritin

TfR-F Index

Ferritin

TfR

TfR 1 100/ Ferritin

TfR-F Index

Ferritin

TfR

TfR 1 100/ Ferritin

TfR-F Index

False negative False positive True negative True positive Sensitivity Specicity Positive PV Negative PV Efciency

1 1 63 47 0.98 0.98 0.98 0.98 0.98

3 4 60 45 0.94 0.94 0.92 0.95 0.94

1 1 63 47 0.98 0.98 0.98 0.98 0.98

0 0 64 48 1.00 1.00 1.00 1.00 1.00

6 1 63 59 0.91 0.98 0.98 0.91 0.95

4 4 60 61 0.94 0.94 0.94 0.94 0.94

3 1 63 62 0.95 0.98 0.98 0.95 0.97

1 0 64 64 0.98 1.00 1.00 0.98 0.99

5 1 63 12 0.71 0.98 0.92 0.93 0.93

1 4 60 16 0.94 0.94 0.80 0.98 0.94

2 1 63 15 0.88 0.98 0.94 0.97 0.96

1 0 64 16 0.94 1.00 1.00 0.98 0.99

An efciency curve for the distinction between ACD and IDA patients was generated for each parameter, and the maximum point of the curve was used as a cutoff limit in all patient populations. The cutoff limits based on the efciency curves were 41 mg/L for ferritin, 2.7 mg/L for TfR, 4.5 for TfR 1 100/ferritin, and 1.5 for the TfR-F Index. PV predictive value.

scattergram in Fig 2 and by the ROC curve in Fig 3 (AUCROC 0.98). In the ACD patients, the levels were within the reference limits reported earlier for healthy subjects.19 TfR measurements effectively identied iron deciency, even in the presence of an accompanying inammatory or infectious condition (Tables 2 and 3, Fig 2); furthermore, the statistical comparison of the ROC curves indicates that TfR measurements distinguished between the COMBI and the ACD pa-

tients more effectively than ferritin measurements (P .033). Earlier, the calculation of the TfR/ferritin ratio was reported to reect the depletion of iron stores in response to phlebotomies.7 In the present patient material, the calculation of the TfR/ferritin ratio as such only slightly improved diagnostic sensitivity and specicity compared with the use of TfR or ferritin alone (Tables 2 and 3). However, both sensitivity and specicity were improved by logarithmic transfor-

Fig 1. Serum ferritin concentrations in anemic patients. IDA (irondeciency anemia) (n ! 48) and ACD (anemia of chronic disease) (n ! 64). Those patients who had depleted iron stores together with an infectious disease, a chronic inammatory disease, or a nonhematological malignancy were assigned to the COMBI group (n ! 17). The lower reference limits of the serum ferritin assay are indicated separately for male (() and female (&) subjects by horizontal bars.

Fig 2. Serum TfR concentrations in anemic patients. For abbreviations, see text to Fig 1. The central 95th percentile of the reference distribution for the TfR assay is shown with horizontal bars.

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TRANSFERRIN RECEPTOR AND IRON DEFICIENCY 1055

consisting of consecutive anemia patients subjected to a bone marrow examination. Iron deciency was dened as a complete absence of stainable iron in bone marrow. Serum iron and iron saturation of transferrin are of limited value in the diagnosis of IDA, as the corresponding AUCROC values, consistent with earlier studies,26 do not reect proper diagnostic sensitivity and specicity. This is apparently due to the interference of the acute-phase response in serum iron and transferrin concentrations. Serum ferritin has been widely used to dene iron depletion. In this study population, ferritin measurements (AUCROC 0.98) and even serum transferrin (AUCROC 0.98) distinguished effectively between patients with uncomplicated IDA and those with ACD, but the optimal decision limit for the interpretation of both ferritin and transferrin measurements was found to be considerably above the conventional reference limits, which are based on the evaluation of apparently healthy populations. It is evident that the ability of ferritin to distinguish between IDA and ACD is due not only to the decrease in serum ferritin level in IDA patients but, to a considerable extent, to the increase in serum ferritin caused by the acute phase responses associated with chronic inammatory disease. The ROC curves produced on the basis of the present patient material (Table 2) are in good agreement with those generated earlier on the basis of meta-analysis for ferritin and iron saturation of transferrin.26 Based on the present data, it can be statistically
Fig 3. ROC curves for TfR, ferritin, and TfR-F Index (TfR/log ferritin ratio) in the identication of iron-decient patients. The ROC curves are shown separately for the whole patient population (n ! 129) (A) and for the distinction between the ACD (n ! 64) and COMBI (n ! 17) patients (B). TfR-F Index -, TfR , ferritin .

mation of the ferritin value, and we suggest that this parameter be referred to the TfR-Ferritin Index (TfR-F Index). The calculation of the TfR/log ferritin ratio (TfR-F Index) provided an outstanding parameter for the identication of irondecient patients (Table 3, Figs 3 and 4). When the whole study population (n 129) was analyzed, the TfR-F Index provided an AUCROC value of 1.00. Consequently, when subgroups were analyzed, the AUCROC values were 1.00 for the distinction between the ACD (n 64) and IDA groups (n 48), and 1.00 for the distinction between the ACD and COMBI groups (n 17) (Tables 2 and 3, and Figs 3 and 4).
DISCUSSION

The clinical situation in which serum transferrin receptor (TfR) measurements have been suggested to be especially useful is the differentiation between IDA and ACD.2,11 The distinction between IDA and the anemia that accompanies infection, inammation, or malignancy is difcult, as the laboratory parameters commonly used do not necessarily distinguish these common causes of anemia. In the present study, we have evaluated the clinical efciency of both TfR measurements and a variety of more conventional laboratory tests in the identication of patients with iron deciency. Every attempt was made to avoid any bias due to preselection of patients by using a clinically relevant study population

Fig 4. The TfR-F Index (TfR/log ferritin ratio) in anemic patients. For explanation of the abbreviations, see text in Fig 1. The median values for each patient group (IDA, 5.4; COMBI, 3.2; ACD, 0.8) are indicated by horizontal bars.

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1056 KI PUNNONEN, IRJALA, AND RAJAMA

estimated22 that in anemic patients who do not have an accompanying infection or inammatory disease, a cut-off limit of 41 mg/L for serum ferritin provides optimal diagnostic efciency. However, this estimation is apparently no longer valid if we assume that the iron-decient patient has another disease accompanied by an acute phase reaction (ie, the COMBI group), so that the diagnostic usefulness of ferritin measurements is reduced (Tables 2 and 3). In the interpretation of ferritin results, the conventional population-based reference limits are not very useful, as for instance in female IDA patients (n 32), the lower reference limit of ferritin concentrations provided only 22% sensitivity in the identication of iron deciency. On the other hand, it is obvious that the need for disease-specic decision limits is difcult to meet. In conclusion, the measurement of serum ferritin may provide a rational basis for the identication of iron deciency; the interpretation of the ferritin levels, however, requires careful diagnostic classication of the patients and knowledge of all the factors that may cause changes in serum ferritin levels. The proinammatory cytokines tumor necrosis factor-a and interleukin-6 have been suggested to reduce TfR expression under in vitro experimental conditions.27 On the basis of the present study, TfR measurements are able to distinguish between patients with IDA and those with ACD. The nding suggests that in ACD patients the potentially increased cytokine production does not greatly affect the TfR response caused by iron depletion; this is consistent with earlier reports.2 A major advantage of TfR measurements over serum ferritin is the apparent specicity of the biological response to changes in iron status and erythropoiesis. The present study suggests that when compared with ferritin, the clinical interpretation of TfR measurements is simpler. When hemolysis or megaloblastosis can be excluded, the TfR measurement should be an attractive alternative to more conventional tests of iron status. The serum ferritin level varies with iron stores, while TfR is assumed to reect reliably the degree of tissue iron supply.3,11 The TfR/ferritin ratio has been suggested to be a good estimate of body iron in individual subjects,7 but no studies of a representative patient population have so far been published. In the present study, we evaluated a variety of possibilities of combining the TfR and ferritin parameters; the results suggest that calculation of the TfR/ferritin ratio does not considerably improve diagnostic efciency compared with TfR alone (Tables 2 and 3). However, logarithmic transformation of the ferritin values and calculation of the TfR/log ferritin ratio (the TfR-F Index) provided an outstanding indicator of iron depletion, as demonstrated by the scattergram and the corresponding ROC curves (Figs 3 and 4). This TfR-F Index takes advantage of the relationship between two phenomena, ie, an increase in TfR and a decrease in the ferritin concentration. This parameter consists of two variables, which in general, are inuenced by the body iron stores, the availability of iron for erythropoiesis, and the total mass of erythroid bone marrow. This study shows that, while serum TfR measurements are useful in the diagnosis of iron deciency and in the differential diagnosis of various types of anemia, the combi-

nation of TfR and ferritin measurements provides the highest sensitivity and specicity. It may be predicted that these measurements are likely to replace the conventional parameters of iron status, ie, serum iron, transferrin, and ferritin alone, in clinical laboratories. They would be especially useful at outpatient clinics, where bone marrow examinations are often either not available or are regarded as an invasive means of identifying patients with depleted iron stores.
REFERENCES

1. Rockey DC, Cello JP: Evaluation of the gastrointestinal tract in patients with iron-deciency anemia. N Engl J Med 329:1691, 1993 2. Ferguson BJ, Skikne BS, Simpson KM, Baynes RD, Cook JD: Serum transferrin receptor distinguishes the anemia of chronic disease from iron deciency anemia. J Lab Clin Med 119:385, 1992 3. Cazzola M, Beguin Y: New tools for clinical evaluation of erythron function in man. Br J Haematol 80:278, 1992 4. Harju E, Pakarinen A, Larmi T: A comparison between serum ferritin concentration and the amount of bone marrow stainable iron. Scand J Clin Lab Invest 44:555, 1984 5. Burns ER, Goldberg SN, Lawrence C, Wenz B: Clinical utility of serum tests for iron deciency in hospitalized patients. Am J Clin Pathol 93:240, 1990 6. Kohgo Y, Niitsu Y, Kondo H, Kato I, Tsushima N, Sasaki K, Hirayama M, Numata T, Nishisato T, Urushizaki I: Serum transferrin receptor as a new index of erythropoiesis. Blood 70:1955, 1987 7. Skikne BS, Flowers CH, Cook JD: Serum transferrin receptor: A quantitative measure of tissue iron deciency. Blood 75:1870, 1990 8. Flowers CH, Skikne BS, Covell AM, Cook JD: The clinical measurement of serum transferrin receptor. J Lab Clin Med 114:368, 1989 9. Thorstensen K, Egeberg K, Romslo I, Dalhoj J, Wiggers P: Variations in serum erythropoietin and transferrin receptor during phlebotomy therapy of hereditary hemochromatosis: A case report. Eur J Haematol 47:219, 1991 10. Thorstensen K, Romslo I: The transferrin receptor: Its diagnostic value and its potential as therapeutic target. Scand J Clin Lab Invest 53:113, 1993 11. Cook JD, Skikne BS, Baynes RD: Serum transferrin receptor. Annu Rev Med 44:63, 1993 12. Huebers HA, Finch CA: The physiology of transferrin and transferrin receptors. Physiol Rev 67:520, 1987 13. Ahn J, Johnstone RM: Origin of a soluble truncated transferrin receptor. Blood 81:2442, 1993 14. Huebers HA, Beguin Y, Pootrakul P, Einspahr D, Finch CA: Intact transferrin receptors in human plasma and their relation to erythropoiesis. Blood 75:102, 1990 15. Shih YJ, Baynes RD, Hudson BG, Flowers CH, Skikne BS, Cook JD: Serum transferrin receptor is a truncated form of tissue receptor. J Biol Chem 265:19077, 1990 16. Rao KK, Shapiro D, Mattia E, Bridges K, Klausner RD: Effects of alterations in cellular iron on biosynthesis of the transferrin receptor in K562 cells. Mol Cell Biol 5:595, 1985 17. Beguin Y, Lampertz S, De Groote D, Igot D, Malaise M, Fillet G: Soluble CD23 and other receptors (CD4, CD8, CD25, CD71) in serum of patients with chronic lymphocytic leukemia. Leukemia 7:2019, 1993 18. Carmel R, Skikne BS: Serum transferrin receptor in the megaloblastic anemia of cobalamin deciency. Eur J Haematol 49:246, 1992 19. Punnonen K, Irjala K, Rajama ki A: Iron deciency anemia

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TRANSFERRIN RECEPTOR AND IRON DEFICIENCY 1057

is associated with high serum levels of transferrin receptor. Clin Chem 40:774, 1994 20. Rajama ki A, Irjala K, Aitio A: Immunochemical determination of serum transferrin. Scand J Haematol 23:227, 1979 21. Beilby J, Olynyk J, Ching S, Prins A, Swanson N, Reed W, Harley H, Garcia-Webb P: Transferrin index: An alternative method for calculating the iron saturation of transferrin. Clin Chem 38:2078, 1992 22. Kairisto V, Poola A: Software for illustrative presentation of basic clinical characteristics of laboratory tests - GraphROC for Windows. Scand J Clin Lab Invest 222:43, 1995 (suppl 55) 23. Hanley JA, McNeil BJ: The meaning and use of the area under a receiver operating characteristics (ROC) curve. Radiology 143:29, 1982

24. Beck JR, Schultz EK: The use of relative operating characteristic (ROC) curves in test performance evaluation. Arch Pathol Lab Med 110:13, 1986 25. Forsstro m J: Machine learning in clinical medicine by knowledge acquisition from patient databases (Dissertation). University of Turku, Turku, Finland, Departments of Medicine and Clinical Chemistry, 1992 26. Guyatt GH, Oxman AD, Ali M, Willan A, McIlroy W, Patterson C: Laboratory diagnosis of iron-deciency anemia: An overview. J Gen Intern Med 7:145, 1992 27. Fahmy M, Young SP: Modulation of iron metabolism in monocyte cell line U937 by inammatory cytokines: Changes in transferrin uptake, iron handling and ferritin mRNA. Biochem J 296:175, 1993

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