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Serum Transferrin Receptor and Its Ratio to Serum Ferritin in the Diagnosis of Iron Deficiency
Open accessAbstract
The objective of the study was to evaluate the diagnostic efficiency 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 deficiency anemia (IDA), 64 anemia of chronic disease (ACD), and 17 patients had depleted iron stores and an infectious or an inflammatory condition (COMBI). Depletion of iron stores was defined 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 deficiency 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 identification 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.
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“Steady-state levels of hemoglobin and hematocrit in healthy adults typically correlate negatively with log 10 EPO levels (21).”
From Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point (2014) · cites this paper as [21]
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McDermid, J. M., Jaye, A., van der Loeff, M. F. S., Todd, J., Bates, C. J., Austin, S. B., Jeffries, D. J., Awasana, A. A., Whittle, H. C., & Prentice, A. M. (2007) · JAIDS Journal of Acquired Immune Deficiency Syndromes · doi:10.1097/qai.0b013e31815b2d4b · Cited by 92
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Biomarkers of body iron stores and risk of developing type 2 diabetes
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Anemia of Chronic Disease and Iron Deficiency Anemia in Inflammatory Bowel Diseases
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“ferritin was shown when measured alone, the incorporation of ferritin and sTfR into 1 index (sTfR/logF) improved sensitivity and specificity drastically.(125) For example, the index succeeded to differentiate coexisting iron deficiency with ACD in a group of 96 patients with rheumatoid arthritis.”
BackgroundSerum transferrin receptor assays and their application
Worwood, M. (2002) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1258/0004563021902152 · Cited by 85
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“Concomitantly, a more complete view of iron status is obtained [32,38,48,49]; many investigators now recommend using the sTfR in conjunction with serum ferritin.”
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“…Haematology Unit, Institute of Molecular Medicine, The John Radcliffe, Oxford OX3 9DS. valuable diagnostic aid in the assessment of iron deficiency (Skikne et al, 1990; Punnonen et al, 1997); iron deficiency stimulates the synthesis of transferrin receptor and leads to an increase in sTfR levels.”
BackgroundDiagnosis of iron-deficient states
Archer, N. M., & Brugnara, C. (2015) · Critical Reviews in Clinical Laboratory Sciences · doi:10.3109/10408363.2015.1038744 · Cited by 82
Weizer‐Stern, O., Adamsky, K., Amariglio, N., Levin, C., Koren, A., Breuer, W., Rachmilewitz, E., Breda, L., Rivella, S., Ioav Cabantchik, Z., et al. (2006) · British Journal of Haematology · doi:10.1111/j.1365-2141.2006.06258.x · Cited by 80
“TFR1 expression increases in iron deficiency anaemia and in various states of enhanced erythropoiesis, including TM (Musto et al, 1993; Punnonen et al, 1997; Cazzola et al, 1999).”
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Anaemia and iron deficiency in children with inflammatory bowel disease
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“Median transferrin saturation and median ferritin at diagnosis were 6 (4, 9)% and 25 (15, 54) μg/l; at one year were 14 (8, 16)% 16 (9, 29) μg/l; and at two years were 13 (8, 25)% and 22 (17, 29) μg/l respectively.”
BackgroundIron Status is Associated with Asthma and Lung Function in US Women
Brigham, E. P., McCormack, M. C., Takemoto, C. M., & Matsui, E. C. (2015) · PLoS ONE · doi:10.1371/journal.pone.0117545 · Cited by 82
“A sTfR-F Index, which estimates total body iron, was calculated with the following equation, as previously reported [14]: sTfR/log10(ferritin).”
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Serum hepcidin levels and iron parameters in children with iron deficiency
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“These values are comparable to the AUC of serum ferritin determined in the present and previous studies [26, 27].”
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Brotanek, J. M., Gosz, J., Weitzman, M. L., & Flores, G. (2008) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/archpedi.162.4.374 · Cited by 78
“This ratio has been shown to be a useful tool for estimating total body iron stores.(63,64) However, more work is needed to validate the use of serum transferrin receptor and to establish age-specific reference ranges for this new measure in children.”
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“With a cutoff of 41 mg/l that would provide optimal diagnostic efficiency in anemic subjects (Punnonen et al., 1997), 74% of anemic infants would have been iron deficient.”
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Parenteral iron therapy in obstetrics: 8 years experience with iron–sucrose complex
Perewusnyk, G., Huch, R., Huch, A., & Breymann, C. (2002) · British Journal Of Nutrition · doi:10.1079/bjnbjn2002577 · Cited by 79
“A newly-studied variable, the transferrin receptor (TfR) concentration, has been introduced to diagnose Fe-deficiency anaemia reliably under these conditions ( Punnonen et al. 1997; Krafft et al. 1999; Perewusnyk et al. 1999; Rusia et al. 1999).”
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Means, R. T., Allen, J., Sears, D. A., & Schuster, S. J. (1999) · Clinical & Laboratory Haematology · doi:10.1046/j.1365-2257.1999.00224.x · Cited by 77
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High prevalence of subclinical iron deficiency in whole blood donors not deferred for low hemoglobin
Baart, A. M., van Noord, P. A. H., Vergouwe, Y., Moons, K. G. M., Swinkels, D. W., Wiegerinck, E. T. G., de Kort, W. L. A. M., & Atsma, F. (2012) · Transfusion · doi:10.1111/j.1537-2995.2012.03956.x · Cited by 76
A bone marrow report of absent stainable iron is not diagnostic of iron deficiency
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“Less frequently, iron deficiency may be assessed by measuring soluble transferrin receptor [17, 19, 20 ] and erythrocyte protoporphyrin concentration [13, 15, 16, 21].”
BackgroundRational Management of Iron-Deficiency Anaemia in Inflammatory Bowel Disease
Nielsen, O. H., Soendergaard, C., Vikner, M. E., & Weiß, G. (2018) · Nutrients · doi:10.3390/nu10010082 · Cited by 76
“, the sTfR-F index) has been recommended [78].”
BackgroundThe Measurement of Serum Transferrin Receptor
Cook, J. D. (1999) · The American Journal of the Medical Sciences · doi:10.1016/s0002-9629(15)40630-5 · Cited by 75
De Mast, Q., Van Dongen‐Lases, E. C., Swinkels, D. W., Nieman, A., Roestenberg, M., Druilhe, P., Arens, T. A., Luty, A. J., Hermsen, C. C., Sauerwein, R. W., et al. (2009) · British Journal of Haematology · doi:10.1111/j.1365-2141.2009.07664.x · Cited by 74
“In recent years, the sTfR/log ferritin index has been advocated by some authors as a useful marker for diagnosis of iron deficiency in the presence of inflammation (Punnonen et al, 1997), because sTfR is thought to be less affected by inflammation (Baillie et al, 2003; Beguin, 2003).”
BackgroundNutritional Anemias and the Elderly
Carmel, R. (2008) · Seminars in Hematology · doi:10.1053/j.seminhematol.2008.07.009 · Cited by 74
Anemia in inflammatory bowel disease: A neglected issue with relevant effects
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Markers of iron status in chronic kidney disease
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Prevalence of iron deficiency and anemia among healthy women of reproductive age in Bhaktapur, Nepal
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“Alternatively, it may be due to a hyperproliferative production of red blood cells caused by various other reasons (Punnonen et al., 1997).”
BackgroundRadtke, H., Tegtmeier, J., Röcker, L., Salama, A., & Kiesewetter, H. (2004) · Transfusion · doi:10.1111/j.1537-2995.2004.04074.x · Cited by 70
Pang, W. W., & Schrier, S. L. (2012) · Current Opinion in Hematology · doi:10.1097/moh.0b013e3283522471 · Cited by 69
“Although the serum soluble transferrin receptor (sTfR)–log ferritin index has been shown to be more sensitive than standard iron indices for identifying iron deficiency in the anemic elderly [22,23], the regular implementation of this assay is hindered by the lack of standardized reagents for the sTfR assay [24,25].”
BackgroundYağcı, S., Serin, E., Acicbe, Ö., Zeren, M. İ., & Odabaşı, M. S. (2021) · International Journal of Laboratory Hematology · doi:10.1111/ijlh.13479 · Cited by 68
Iron Deficiency and Cardiovascular Disease: An Updated Review of the Evidence
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“[5] have validated all these biochemical measures of iron status versus the gold standard technique, i.”
MethodAnemia and intestinal parasite infection in school children in rural Vietnam.
Le, H. T., Brouwer, I. D., Verhoef, H., Nguyen, K. C., & Kok, F. J. (2007) · PubMed · Cited by 69
Iron nutrition in the UK: getting the balance right
Fairweather‐Tait, S. J. (2004) · Proceedings of The Nutrition Society · doi:10.1079/pns2004394 · Cited by 69
Anaemia and iron deficiency among adolescent schoolgirls in peri-urban Bangladesh
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“…operating characteristics (ROC) curve testing, has investigated the sensitivity and speci®city of SF as an indicator of iron de®ciency, and showed that a cut-off value of 41 mg=l for SF could provide the optimal diagnostic ef®ciency for iron de®ciency among anaemic subjects (Punnonen et al, 1997).”
BackgroundSerum Transferrin Receptor Concentrations during Normal Pregnancy
Choi, J. W., Im, M. W., & Pai, S. H. (2000) · Clinical Chemistry · doi:10.1093/clinchem/46.5.725 · Cited by 68
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The anaemia of chronic disease
Fitzsimons, E. J., & Brock, J. H. (2001) · BMJ · doi:10.1136/bmj.322.7290.811 · Cited by 68
“How best can we then differentiate microcytic anaemia of chronic disease from genuine iron deficiency when ferritin values are normal? Examination of the bone marrow for iron is the definitive test for iron deficiency but it is uncomfortable and expensive. The measurement of a soluble form of transferrin receptor in s…”
Cable, R. G., Steele, W. R., Melmed, R., Johnson, B., Mast, A. E., Carey, P. M., Kiss, J. E., Kleinman, S. H., Wright, D. J., & (REDS‐II), F. T. N. R. E. D. S. (2011) · Transfusion · doi:10.1111/j.1537-2995.2011.03389.x · Cited by 67
Higher concentrations of serum transferrin receptor in children than in adults
Virtanen, M. A., Viinikka, L. U., Virtanen, M., Svahn, J. C. E., Anttila, R., Krusius, T., Cook, J. D., Axelsson, I. E. M., Räihä, N. C. R., & Siimes, M. A. (1999) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/69.2.256 · Cited by 67
EPO, red cells, and serum transferrin receptor in continuous and intermittent hypoxia
KOISTINEN, P. O., Rusko, H. K., Irjala, K. M. A., Rajam, A., PENTTINEN, K., SARPARANTA, V.-P., Karpakka, J., & Lepp�luoto, J. (2000) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-200004000-00012 · Cited by 66
Self-citationChange in Transferrin Receptor Concentrations with Age
Choi, J. W., Pai, S. H., Im, M. W., & Kim, S. K. (1999) · Clinical Chemistry · doi:10.1093/clinchem/45.9.1562 · Cited by 66
“Measurement of the soluble transferrin receptor (sTfR) recently has been introduced as a new diagnostic tool for the evaluation of iron status (2, 4).”
MethodMarković, M., Majkić‐Singh, N., Ignjatović, S., & SINGH, S. (2007) · International Journal of Laboratory Hematology · doi:10.1111/j.1365-2257.2006.00875.x · Cited by 65
Garcia-Casal, M. N., Pasricha, S.-R., Martinez, R. X., Lopez-Perez, L., & Peña-Rosas, J. P. (2018) · Archives of Medical Research · doi:10.1016/j.arcmed.2018.12.005 · Cited by 62
Diagnosing iron deficiency: Controversies and novel metrics
Rusch, J. A., van der Westhuizen, D. J., Gill, R. S., & Louw, V. J. (2023) · Best practice & research. Clinical anaesthesiology · doi:10.1016/j.bpa.2023.11.001 · Cited by 80
Reduced risk for placental malaria in iron deficient women
Senga, E. L., Harper, G., Koshy, G., Kazembe, P. N., & Brabin, B. J. (2011) · Malaria Journal · doi:10.1186/1475-2875-10-47 · Cited by 61
“It has good sensitivity and specificity (> 70%) for reduced bone marrow iron stores in Malawian children with severe anaemia (Hb < 5g/dl) irrespective of the presence of infection [15].”
BackgroundCinti, S., Matteis, R. D., CERESI, E., Picó, C., OLIVER, J., OLIVER, P., Palou, A., OBRADOR, A., & MAFFEIS, C. (2001) · Gut · doi:10.1136/gut.49.1.155 · Cited by 63
Canals, C., Remacha, A. F., Sardà, M. P., Piazuelo, J., Royo, T., & Romero, M. R. (2005) · PubMed · Cited by 62
Iron deficiency: From diagnosis to treatment
Polin, V., Coriat, R., Perkins, G., Dhooge, M., Abitbol, V., Leblanc, S., Prat, F., & Chaussade, S. (2013) · Digestive and Liver Disease · doi:10.1016/j.dld.2013.02.019 · Cited by 64
Srinivasan, B., O’Dell, D., Finkelstein, J. L., Lee, S., Erickson, D., & Mehta, S. (2017) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2017.07.038 · Cited by 62
Serum transferrin receptor in children and adolescents with inflammatory bowel disease
Revel‐Vilk, S., Tamary, H., Broide, E., Zoldan, M., Dinari, G., Zahavi, I., Yaniv, I., & Shamir, R. (2000) · European Journal of Pediatrics · doi:10.1007/s004310000491 · Cited by 62
“The TfR/ferritin ratio has been previously shown to improve the assessment of iron status [1, 22], identify subclinical iron deficit [1, 23] and diAerentiate between IDA and ACD [5, 7, 10, 20, 21 ].”
BackgroundMethodRapid identification of iron deficiency in blood donors with red cell indexes provided by Advia 120
Radtke, H., Meyer, T., Kalus, U. J., Röcker, L., Salama, A., Kiesewetter, H., & Latza, R. (2004) · Transfusion · doi:10.1111/j.1537-2995.2005.04205.x · Cited by 61
McDade, T. W., & Shell‐Duncan, B. (2002) · Journal of Nutrition · doi:10.1093/jn/132.12.3760 · Cited by 58
Roy, C. N., Weinstein, D. A., & Andrews, N. C. (2003) · Pediatric Research · doi:10.1203/01.pdr.0000049513.67410.2d · Cited by 60
“Some authors have proposed that the ratio of the serum transferrin receptor to the log of serum ferritin provides a useful index (2).”
BackgroundLevels of some Acute-Phase Proteins in the Serum of Patients with Cancer during Radiotherapy
Koç, M., Tayşi, S., Sezen, O., & Bakan, N. (2003) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.26.1494 · Cited by 60
Joosten, E., van Loon, R., Billen, J., Blanckaert, N. J. C., Fabri, R., & Pelemans, W. (2001) · American Journal of Hematology · doi:10.1002/ajh.10014 · Cited by 59
Iron Deficiency Anemia in Women Across the Life Span
Friedman, A. J., Chen, Z., Ford, P., Johnson, C. A., López, A. M., Shander, A., Waters, J. H., & Wyck, D. V. (2012) · Journal of Women s Health · doi:10.1089/jwh.2012.3713 · Cited by 61
Beyond soluble transferrin receptor: Old challenges and new horizons
Harms, K., & Kaiser, T. (2015) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2015.09.003 · Cited by 59
“Therefore, by applying the ferritin index, the combination of sTfR and ferritin measurements provided the highest sensitivity and specificity compared with isolated measurements of sTfR and ferritin [65].”
BackgroundMethodCavill, I. A. J. (2002) · Best Practice & Research Clinical Haematology · doi:10.1053/beha.2002.0004 · Cited by 59
Kolbe-Busch, S., Lotz, J., Hafner, G., Blanckaert, N. J. C., Claeys, G., Togni, G., Carlsen, J., Röddiger, R., & Thomas, L. (2002) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2002.091 · Cited by 58
Mechanism of Anemia in Schistosoma mansoni–Infected School Children in Western Kenya
Butler, S. E., Muok, E. M. O., Montgomery, S. P., Odhiambo, K., Mwinzi, P. N. M., Secor, W. E., & Karanja, D. M. S. (2012) · American Journal of Tropical Medicine and Hygiene · doi:10.4269/ajtmh.2012.12-0248 · Cited by 58
“surement of sTfR levels and its ratio to SF in patients with intermediate serum ferritin values, it is possible to identify which mechanism(s) of anemia is in effect.(13,15) Independently,”
BackgroundBlock, C. E. M. D., Campenhout, C. M. V., Leeuw, I. H. D., y Keenoy, B. M., Martin, M., Hoof, V. O. V., & Gaal, L. F. V. (2000) · Diabetes Care · doi:10.2337/diacare.23.9.1384 · Cited by 58
Erythropoietic activity and soluble transferrin receptor level in neonates and maternal blood
Choi, J., Kim, C., & Pai, S. (2000) · Acta Paediatrica · doi:10.1080/080352500750043981 · Cited by 57
Potential Utility of Ret-Y in the Diagnosis of Iron-Restricted Erythropoiesis
Franck, S., Linssen, J., Messinger, M., & Thomas, L. (2004) · Clinical Chemistry · doi:10.1373/clinchem.2004.030254 · Cited by 57
Erythropoietin and iron-restricted erythropoiesis
Goodnough, L. T. (2007) · Experimental Hematology · doi:10.1016/j.exphem.2007.01.026 · Cited by 58
Serum Hepcidin in Inflammatory Bowel Diseases: Biological and Clinical Significance
Bergamaschi, G., Di Sabatino, A., Albertini, R., Costanzo, F., Guerci, M., Masotti, M., Pasini, A., Massari, A., Campostrini, N., Corbella, M., et al. (2013) · Inflammatory Bowel Diseases · doi:10.1097/mib.0b013e31829a6e43 · Cited by 56
“These parameters are believed to reflect iron status and iron supply to erythropoiesis even in the presence of inflammation.(17,18) A validated method using surface-enhanced laser desorption/ ionization time-of-flight mass spectrometry measured serum hepcidin isoforms (hepcidin-25 and hepcidin-20), as described with r…”
Method
Metadata
- Authors
- Punnonen, K., Irjala, K., & Rajamäki, A.
- Affiliations
- Turku University Hospital (FI)
- From the Central Laboratory, Departments of Clinical Chemistry and Hematology, University Hospital of Turku, Turku, Finland.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 1997-02-01
- Volume
- 89
- Issue
- 3
- Pages
- 1052-1057
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W1924847619
- Cited by
- 859
- References
- 28
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 19 · 2023: 20 · 2022: 10 · 2021: 26 · 2020: 29 · 2019: 25 · 2018: 37 · 2017: 22 · 2016: 28 · 2015: 44 · 2014: 35 · 2013: 30 · 2012: 45
- FWCI
- 13.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Hematological disorders and diagnostics
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- serum transferrin receptor, serum ferritin, iron deficiency anemia, anemia of chronic disease, iron depletion, diagnostic accuracy, inflammatory diseases
- MeSH terms
- Adult, Anemia, Blood Cell Count, Bone Marrow, Chronic Disease, Female, Ferritins, Humans, Iron, Male, Receptors, Transferrin, Staining and Labeling, Anemia, Iron-Deficiency
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