Medical Oncology

, Volume 23, Issue 1, pp 23–36 | Cite as

The diagnostic plot

A concept for identifying different states of iron deficiency and monitoring the response to epoetin therapy
  • Christian Thomas
  • Andreas Kirschbaum
  • Dieter Boehm
  • Lothar Thomas


Iron balance is regulated by the rate of erythropoiesis and the size of the iron stores. Anemia that accompanies infection, inflammation, and cancer (anemia of chronic disease) features normal or increased iron stores, although patients may have functional iron deficiency, namely, an imbalance between iron requirements of the erythroid marrow and the actual supply. The proportion of hypochromic red cells and the hemoglobin content of reticulocytes are direct indicators of functional iron deficiency. Biochemical markers, especially the soluble transferrin receptor/log ferritin ratio (ferritin index), are useful indicators of the iron supply to erythropoiesis. The relationship between functional iron deficiency (reticulocyte hemoglobin content) and iron supply to erythropoiesis (ferritin index) can be described in a diagnostic plot. In normoproliferative and hypoproliferative erythropoiesis, the plot allows the differentiation of classic iron deficiency from anemia of chronic disease and the combined state of functional iron deficiency with anemia of chronic disease. The therapeutic implications of the plot are to differentiate patients into those who should be administered iron supplements, epoetin, or a combination of epoetin and iron. In patients receiving epoetin therapy, the plot is an important tool for monitoring erythropoietic activity, functional iron deficiency, and adequate iron stores for new red cell production. Enhanced erythropoiesis is reflected quantitatively by the ferritin index vector. A transgression of the 1.5 (3.2) cut-off value for the ferritin index indicates that extra doses of iron need to be administered to increase the body's iron stores. A lack of increase or a reticulocyte hemoglobin content below 28 picograms indicates functional iron deficiency. The diagnostic plot is a model for differentiating iron-deficient states and predicting those patients who will respond to epoetin therapy.

Key Words

Iron deficiency anemia of chronic disease soluble transferrin receptor ferritin index diagnostic plot epoetin therapy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Moliterno AR, Spivak JL. Anemia of cancer. Hematol Oncol Clin North Am 1996; 10: 245–363.CrossRefGoogle Scholar
  2. 2.
    Van Belle SJB, Cocquyt V. Impact of haemoglobin levels on the outcome of cancers treated with chemotherapy. Crit Rev Oncol/Haematol 2003; 47: 1–11.CrossRefGoogle Scholar
  3. 3.
    Engert A. Recombinant human erythropoietin as an alternative to blood transfusion in cancer-related anemia. DMMA 2000; 5: 259–272.Google Scholar
  4. 4.
    Cazzola M, et al. Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin's lymphoma: dose finding and identification of predictors of response. Blood 1995; 86: 4446–4453.PubMedGoogle Scholar
  5. 5.
    Österborg A et al. Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-Hodgkin's lymphoma—a randomized multicenter study. Blood 1996; 87: 2675–2682.PubMedGoogle Scholar
  6. 6.
    Cazzola M, Mercuriali F, Brugnara C. Use of recombinant human erythropoietin outside the setting of uremia. Blood 1997; 89: 4248–4267.PubMedGoogle Scholar
  7. 7.
    Nowrousian MR. Recombinant human erythropoietin in the treatment of cancer-related or chemotherapy induced anaemia in patients with solid tumours. Med Oncol 1998; 15: (Suppl 1): S19-S28.PubMedGoogle Scholar
  8. 8.
    Oberhoff C, et al. Effekt von rekombinantem humanen Erythropoetin auf den Transfusionsbedarf und die Hämoglobinkonzentration bei Patienten mit soliden Tumoren und chemotherapie-induzierter Anämie. Tumordiagn u Ther 2000; 21: 15–25.CrossRefGoogle Scholar
  9. 9.
    Österborg A et al. Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, Epoetin beta, in hematologic malignancies. J Clin Oncol 2002; 20: 2486–2494.PubMedCrossRefGoogle Scholar
  10. 10.
    Vansteenkiste J, et al. Double-blind, placebo-controlled, randomized phase III trial of Darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 2002; 94: 1211–1220.PubMedGoogle Scholar
  11. 11.
    Hedenus M, et al. Efficacy and safety of darbepoetin alpha in anemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol 2003; 122: 394–403.PubMedCrossRefGoogle Scholar
  12. 12.
    Cazzola M, Beguin Y, Kloczo J, Spicka I, Coiffier B. Onceweekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and detective endogenous erythropoietin production. Br J Haematol 2003; 122: 386–393.PubMedCrossRefGoogle Scholar
  13. 13.
    Rizzo JD, et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. Blood 2002; 100: 2303–2319.PubMedCrossRefGoogle Scholar
  14. 14.
    Bokemeyer C, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004; 40: 2201–2216.PubMedCrossRefGoogle Scholar
  15. 15.
    Papadaki HA, Kritikos HD, Valatas V, et al. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-α antibody therapy. Blood 2002; 100: 474–482.PubMedCrossRefGoogle Scholar
  16. 16.
    Tilg H, Ulmer H, Kaser A, Weiss G. Role of IL-10 for induction of anemia during inflammation. J Immunol 2002: 169: 2204–2209.PubMedGoogle Scholar
  17. 17.
    Ludwiczek S, Aigner E, Theurl I, Weiss G. Cytokine-mediated regulation of iron transport in human monocytic cells. Bood 2003; 101: 4148–4154.Google Scholar
  18. 18.
    Alvarez-Hernandez X, Liceaga J, McKay IC, Brock JH, Induction of hypoferremia and modulation of macrophage iron metabolism by tumor necrosis factor. Lab Invest 1989; 61: 319–322.PubMedGoogle Scholar
  19. 19.
    Eschbach JW. Anemia management in chronic kidney disease: role of factors affecting epoetin responsiveness. J Am Soc Nephrol 2002; 13: 1412–1414.PubMedCrossRefGoogle Scholar
  20. 20.
    Steenvinkel P. The role of inflammation in the anaemia of end-stage renal disease. Nephrol Dial Transplant 2001; 16 (Suppl 7): 36–40.Google Scholar
  21. 21.
    Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005; 352: 1011–1023.PubMedCrossRefGoogle Scholar
  22. 22.
    Macdougall IC, Cooper A. The inflammatory response and epoetin sensitivity. Nephrol Dial Transplant 2002; 17 (Suppl 1); 48–52.PubMedCrossRefGoogle Scholar
  23. 23.
    Means RT Jr, Krantz SB. Progress in understanding the pathogenesis of anemia of chronic disease. Blood 1992; 80: 1639–1647.PubMedGoogle Scholar
  24. 24.
    Cavill I, Macdougall IC. Functional iron deficiency. Blood 1993; 82: 1377.PubMedGoogle Scholar
  25. 25.
    Andrews NC, Anemia of inflammation: the cytokine-hepcidin link. J Clin Invest 2004; 113: 1251–1253.PubMedCrossRefGoogle Scholar
  26. 26.
    Cavill I. Erythropoiesis and iron. Best Prac Res Clin Haematol 2002; 15: 399–409.Google Scholar
  27. 27.
    Thomas C, Thomas L. Anemia of chronic disease: pathophysiology and laboratory diagnosis. Lab Hematol 2005; 11: 14–23.PubMedCrossRefGoogle Scholar
  28. 28.
    Bainton DF, Finch CA. The diagnosis of iron deficiency anemia. Am J Med 1964; 37: 62–70.PubMedCrossRefGoogle Scholar
  29. 29.
    Baynes RD. Assessment of iron status. Clin Biochem 1996; 29: 209–215.PubMedCrossRefGoogle Scholar
  30. 30.
    Trey JE, Kushner I. The acute phase response and the hematopoietic system: the role of cytokines. CRC Oncol/Hematol 1995; 21: 1–18.CrossRefGoogle Scholar
  31. 31.
    Skikne BS. Circulating transferrin receptor assay—coming of age. Clin Chem 1998; 44: 7–9.PubMedGoogle Scholar
  32. 32.
    Beguin Y. Soluble transferrin receptor for the evaluation of erythropoiesis and iron status. Clin Chim Acta 2003; 329: 9–22.PubMedCrossRefGoogle Scholar
  33. 33.
    Worwood M. Serum transferrin receptor assays and their application. Ann Clin Biochem 2002; 39: 221–230.PubMedCrossRefGoogle Scholar
  34. 34.
    Beynes RD, Skikne BS, Cook JD. Circulating transferrin receptors and assessment of iron status. J Nutr Biochem 1994; 5: 322–330.CrossRefGoogle Scholar
  35. 35.
    Punnonen K, Irjala K, Rajarnäki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood 1997; 89: 1052–1057.PubMedGoogle Scholar
  36. 36.
    Suominen P, Punnonen K, Rajarnäki A, Irjala K. Serum trasnsferrin receptor and transferrin receptor-ferritin index identity healthy subjects with subclinical iron deficits. Blood 1998; 92: 2934–2939.PubMedGoogle Scholar
  37. 37.
    Malope BI, MacPhail AP, Alberts M, Hiss DC. The ratio of serum transferrin receptor and serum ferritin in the diagnosis of iron status. Br J Haematol 2001; 115: 84–89.PubMedCrossRefGoogle Scholar
  38. 38.
    Lee EJO, Park YJ, Lee HK, Kim BK. Soluble transferrin receptor (sTIR), ferritin and sTfR/log ferritin index in anemic patients with non hematologic malignancy of chronic inflammation. Clin Chem 2002; 48: 1118–1121.PubMedGoogle Scholar
  39. 39.
    Rimon E, et al. Diagnosis of iron deficiency anemia in the elderly by transferrin receptor-ferritin index. Arch Intern Med 2002; 162: 445–449.PubMedCrossRefGoogle Scholar
  40. 40.
    Cermak J, Brabec V. Transferrin receptor-ferritin index: a useful parameter in differential diagnosis of iron deficiency and hyperplastic erythropoiesis. Eur J Haematol 1998; 61: 210–212.PubMedCrossRefGoogle Scholar
  41. 41.
    Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood 2002; 99: 3505–3516.PubMedCrossRefGoogle Scholar
  42. 42.
    Krantz SB. Pathogenesis and treatment of the anemia of chronic disease. Am J Med Sci 1994; 307: 353–359.PubMedCrossRefGoogle Scholar
  43. 43.
    Kalantar-Zadeh K, Rodriguez RA, Humphreys MH. Association between serum ferritin and measures of inflammation, nutrition and iron in haemodialysis patients. Nephrol Dial Transplant 2004; 19: 141–149.PubMedCrossRefGoogle Scholar
  44. 44.
    Skikne BS, Flowers CH, Cook JD. Serum transferrin receptor: a quantitative measure of tissue iron deficiency. Blood 1990; 75: 1870–1876.PubMedGoogle Scholar
  45. 45.
    Mast AE, Blinder MD, Gronowski AM, Chumley C, Scott MG. Clinical utility of the soluble transferrin receptor and comparison with serum ferritin in several populations. Clin Chem 1998; 44: 532–541.Google Scholar
  46. 46.
    Thomas C, Thomas L. Biochemical markers and hematologic indices in the diagnosis of functional iron deficiency. Clin Chem 2002; 48: 1066–1076.PubMedGoogle Scholar
  47. 47.
    Ahluwalia N, Skikne BS, Savin V, Chonko A. Markers of masked iron deficiency and effectiveness of erythropoietin therapy in chronic renal failure. Am J Kidney Dis 1997; 30: 532–541.PubMedGoogle Scholar
  48. 48.
    Brugnara C. Reticulocyte cellular indices: a new approach in the diagnosis of anemaias and monitoring of erythropoietic function. Crit Rev Clin Lab Sci 2000; 97: 93–130.CrossRefGoogle Scholar
  49. 49.
    McDougal IC et al. Detection of functional iron deficiency during erythropoietin treatment: a new approach. Br Med J 1992; 304: 225–226.CrossRefGoogle Scholar
  50. 50.
    McDougal IC. What is the most appropriate strategy to monitor functional iron deficiency in the dialysed patient on r-HuEPO therapy? Merits of percentage hypochromic red cells as a marker of functional iron deficiency. Nephrol Dial Transplant 1998; 13: 847–849.CrossRefGoogle Scholar
  51. 51.
    Bovy C, et al. Factors determining the percentage of hypochromic red blood cells in hemodialysis patients. Kidney Int 1999; 56: 1113–1119.PubMedCrossRefGoogle Scholar
  52. 52.
    European best practice guidelines for the management of anemia in patients with chronic renal failure. Nephrol Dial Transplant 1999: 14 (Suppl 5): 1–50.Google Scholar
  53. 53.
    Briggs C, Rogers R, Thompson B, Machin SJ. New red cell parameters on the Sysmex XE-2100 as potential markers of functional iron deficiency. Infus Ther Transfus Med 2001; 28: 256–262.CrossRefGoogle Scholar
  54. 54.
    Buttarello M, Temporin V, Ceravolo R, Farina G, Bulian P. The new reticulocyte parameter (RET-Y) of the Sysmex XE 2100. Am J Clin Pathol 2004; 121: 489–495.PubMedCrossRefGoogle Scholar
  55. 55.
    Franck S, Linssen J, Messinger M, Thomas L. Clinical utility of the RET-Y in iron-restricted erythropoiesis. Clin Chem 2004; 50: 1240–1242.PubMedCrossRefGoogle Scholar
  56. 56.
    Brugnara C, Zurakowski D, DiCanzio J, Boyd T, Platt O. Reticulocyte hemoglobin content to diagnose iron deficiency in children. JAMA 1999; 281: 2225–2230.PubMedCrossRefGoogle Scholar
  57. 57.
    Fishbane S, Shapiro W, Dutka P, Valenzuela OF, Faulbert J. A randomized trial of iron deficiency testing strategies in hemodialysis patients. Kidney Int 2001; 60: 2406–2411.PubMedCrossRefGoogle Scholar
  58. 58.
    Mittman N, et al. Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO. Am J Kidney Dis 1997; 30: 912–922.PubMedGoogle Scholar
  59. 59.
    Schaefer RM, Schaefer L. Hypochromic red blood cells and reticulocytes. Kidney Int 1999; 55 (Suppl 5): S44-S48.CrossRefGoogle Scholar
  60. 60.
    Dati F, et al. Consensus of a group of professional societies and diagnostic companies on guidelines for interim reference ranges for 14 proteins based on the standardization against the IFCC/BCR/CAP reference material (CRM 470). Eur J Clin Chem Clin Biochem 1996; 34: 517–520.PubMedGoogle Scholar
  61. 61.
    d'Onofrio G, Zini G, Ricerca BM, Mancini S, Mango G. Automated measurement of red blood cell microcytosis and hypochromia in iron deficiency and β thalassemia trait. Arch Pathol Lab Med 1992; 116: 84–89.PubMedGoogle Scholar
  62. 62.
    NKF-K/DOQI Clinical Practice Guidelines For Anemia Of Chronic Kidney Disease: Update 2000. Am J Kidney Dis 2001: 37 (Suppl 1): S182–S238.Google Scholar
  63. 63.
    Tarnq DC, Huang TP. Determinants of circulating soluble transferrin receptor level in chronic haemodialysis patients. Nephrol Dial Transplant 2002; 17: 1063–1069.CrossRefGoogle Scholar
  64. 64.
    Sunder-Plassmann G, Hörl WH. Erythropoietin and iron. Clin Nephrol 1997; 47: 141–157.PubMedGoogle Scholar
  65. 65.
    Nissenson AR, Charytan C. Controversies in iron management. Kidney Int 2003; 87: (Suppl 87): S64-S71.CrossRefGoogle Scholar
  66. 66.
    Auerbach M, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, openlabel, randomized trial. J Clin Oncol 2004; 22: 1301–1307.PubMedCrossRefGoogle Scholar
  67. 67.
    Henry DH, et al. Intravenous ferric gluconate (FG) for increasing response to epoetin (EPO) in patients with anemia of cancer chemotherapy—results of a multicenter, randomized trial. Blood 2004: 104: ASH Meeting, Abstract 3696.Google Scholar
  68. 68.
    Cazzola M, et al. Prediction of response to recombinant human erythropoietin (r-HuEPO) in anemia of malignancy. Haematologica 1996; 81: 434–441.PubMedGoogle Scholar
  69. 69.
    Ludwig H, et al. Prediction of response to erythropoietin treatment in chronic anemia of cancer. Blood 1994; 84: 1056–1063.PubMedGoogle Scholar
  70. 70.
    Henry D, Abels R, Larholt K. Prediction of response to recombinant human erythropoietin (r-HuEPO/epoietin α) therapy in cancer patients. Blood 1995; 85: 1876–1878.Google Scholar
  71. 71.
    Kaneko Y, Miyazaki S, Hirasawa Y, Gejyo F, Suzuki M. Transferrin saturation versus reticulocyte hemoglobin content for iron deficiency in Japanese hemodialysis patients. Kidney Int 2003; 63: 1086–1093.PubMedCrossRefGoogle Scholar
  72. 72.
    Flowers CH, Skikne BS, Covell AM, Cook JD. The clinical measurements of serum transferrin receptor. J Lab Clin Med 1989; 119: 385–390.Google Scholar
  73. 73.
    Chiang WC, Tsai TJ, Chen YM, Lin SL, Hsieh BS. Serum soluble transferrin receptor reflects erythropoiesis but not iron availability in erythropoietin-treated chronic hemodialysis patients. Clin Nephrol 2002; 58: 363–369.PubMedGoogle Scholar
  74. 74.
    Deira J, et al. Soluble transferrin receptor levels in haemodialysis patients. Nephrol Dial Transplant 2003; 18: 1945–1946.PubMedCrossRefGoogle Scholar
  75. 75.
    Katodritou E, et al. Prediction of response to r-HuEPO in anemic multiple myeloma patients using a combination of sTfR-F index and hypochromic erythrocytes. Clin Chem 2005; 50: in press.Google Scholar
  76. 76.
    Brugnara C, et al. Effect of subcutaneous recombinant human erythropoietin in normal subjects: development of decreased reticulocyte hemoglobin content and iron-deficient erythropoiesis. J Lab Clin Med 1994; 123: 660–667.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2006

Authors and Affiliations

  • Christian Thomas
    • 1
  • Andreas Kirschbaum
    • 2
  • Dieter Boehm
    • 3
  • Lothar Thomas
    • 4
  1. 1.Urologische Klinik und Poliklinik der Universität MainzMainzGermany
  2. 2.Klinik und Poliklinik für Herz- und Thoraxchirurgie Universitätsklanik WürzburgWürzburgGermany
  3. 3.Klinik für Operative Intensivmedizin KrankenhausFrankfurtGermany
  4. 4.Krankenhaus Nordwest, LaboratoriumsmedizinFrankfurtGermany

Personalised recommendations