Biomarkers of hypochromia: the contemporary assessment of iron status and erythropoiesis

Eloísa Urrechaga, Luís Borque, Jesús F Escanero, Eloísa Urrechaga, Luís Borque, Jesús F Escanero

Abstract

Iron status is the result of the balance between the rate of erythropoiesis and the amount of the iron stores. Direct consequence of an imbalance between the erythroid marrow iron requirements and the actual supply is a reduction of red cell hemoglobin content, which causes hypochromic mature red cells and reticulocytes. The diagnosis of iron deficiency is particularly challenging in patients with acute or chronic inflammatory conditions because most of the biochemical markers for iron metabolism (serum ferritin and transferrin ) are affected by acute phase reaction. For these reasons, interest has been generated in the use of erythrocyte and reticulocyte parameters, available on the modern hematology analyzers. Reported during blood analysis routinely performed on the instrument, these parameters can assist in early detection of clinical conditions (iron deficiency, absolute, or functional; ineffective erythropoiesis, including iron restricted or thalassemia), without additional cost. Technological progress has meant that in recent years modern analyzers report new parameters that provide further information from the traditional count. Nevertheless these new parameters are exclusive of each manufacturer, and they are patented. This is an update of these new laboratory test biomarkers of hypochromia reported by different manufactures, their meaning, and clinical utility on daily practice.

References

    1. Swinkels DW, Janssen MCH, Bergmans J, Marx JJM. Hereditary hemochromatosis: genetic complexity and new diagnostic approaches. Clinical Chemistry. 2006;52(6):950–968.
    1. Ganz T, Nemeth E. Iron sequestration and anemia of inflammation. Seminars in Hematology. 2009;46(4):387–393.
    1. Fleming RE, Bacon BR. Orchestration of iron homeostasis. The New England Journal of Medicine. 2005;352(17):1741–1744.
    1. Weiss G, Goodnough LT. Anemia of chronic disease. The New England Journal of Medicine. 2005;352(10):1011–1023.
    1. Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and erythropoiesis. Blood. 2000;96(3):823–833.
    1. Mast A. The clinical utility of peripheral blood tests in the diagnosis of iron deficiency anemia. Bloodline. 2001;1:7–9.
    1. Coyne D. Iron indices: what do they really mean? Kidney International Supplements. 2006;(101):S4–S8.
    1. Kalantar-Zadeh K, Rodriguez RA, Humphreys MH. Association between serum ferritin and measures of inflammation, nutrition and iron in haemodialysis patients. Nephrology Dialysis Transplantation. 2004;19(1):141–149.
    1. Beerenhout C, Bekers O, Kooman JP, van der Sande FM, Leunissen KML. A comparison between the soluble transferrin receptor, transferrin saturation and serum ferritin as markers of iron state in hemodialysis patients. Nephron. 2002;92(1):32–35.
    1. Skikne BS. Serum transferrin receptor. The American Journal of Hematology. 2008;83(11):872–875.
    1. Weiss G. Iron metabolism in the anemia of chronic disease. Biochimica et Biophysica Acta. 2009;1790(7):682–693.
    1. Lankhorst CE, Wish JB. Anemia in renal disease: diagnosis and management. Blood Reviews. 2010;24(1):39–47.
    1. Cavill I, Macdougall IC. Functional iron deficiency. Blood. 1993;82(4, article 1377)
    1. Macdougall IC. Poor response to erythropoietin: practical guidelines on investigation and management. Nephrology Dialysis Transplantation. 1995;10(5):607–614.
    1. Zager RA, Johnson ACM, Hanson SY, Wasse H. Parenteral iron formulations: a comparative toxicologic analysis and mechanisms of cell injury. The American Journal of Kidney Diseases. 2002;40(1):90–103.
    1. Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. Clinical Journal of the American Society of Nephrology. 2006;1:S4–S8.
    1. Katodritou E, Zervas K, Terpos E, Brugnara C. Use of erythropoiesis stimulating agents and intravenous iron for cancer and treatment-related anaemia: the need for predictors and indicators of effectiveness has not abated. British Journal of Haematology. 2008;142(1):3–10.
    1. Locatelli F, Aljama P, Bárány P, et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrology Dialysis Transplantation. 2004;19(supplement 2):ii1–ii47.
    1. Buttarello M, Plebani M. Automated blood cell counts: state of the art. The American Journal of Clinical Pathology. 2008;130(1):104–116.
    1. Higgins JM, Mahadevan L. Physiological and pathological population dynamics of circulating human red blood cells. Proceedings of the National Academy of Sciences of the United States of America. 2010;107:20587–20592.
    1. Cullen P, Söffker J, Höpfl M, et al. Hypochromic red cells and reticulocyte haemglobin content as markers of iron-deficient erythropoiesis in patients undergoing chronic haemodialysis. Nephrology Dialysis Transplantation. 1999;14(3):659–665.
    1. Thomas C, Thomas L. Biochemical markers and hematologic indices in the diagnosis of functional iron deficiency. Clinical Chemistry. 2002;48(7):1066–1076.
    1. Mast AE, Blinder MA, Lu Q, Flax S, Dietzen DJ. Clinical utility of the reticulocyte hemoglobin content in the diagnosis of iron deficiency. Blood. 2002;99(4):1489–1491.
    1. Brugnara C. Iron deficiency and erythropoiesis: new diagnostic approaches. Clinical Chemistry. 2003;49(10):1573–1578.
    1. Macdougall IC. Merits of percentage hypochromic red cells as a marker of functional iron deficiency. Nephrology Dialysis Transplantation. 1998;13(4):847–849.
    1. Bovy C, Gothot A, Krzesinski JM, Beguin Y. Mature erythrocyte indices: new markers of iron availability. Haematologica. 2005;90(4):549–551.
    1. Bovy C, Gothot A, Delanaye P, Warling X, Krzesinski JM, Beguin Y. Mature erythrocyte parameters as new markers of functional iron deficiency in haemodialysis: sensitivity and specificity. Nephrology Dialysis Transplantation. 2007;22(4):1156–1162.
    1. Kotisaari S, Romppanen J, Penttilä I, Punnonen K. The Advia 120 red blood cell and reticulocyte indices are useful in diagnosis of iron-deficiency anemia. European Journal of Haematology. 2002;68(3):150–156.
    1. National kidney foundation, kidney disease outcomes quality initiative NKF-K/DOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease. The American Journal of Kidney Disease. 2006;47(5, supplement 3):S11–S145.
    1. Locatelli F, Covic A, Eckardt KU, Wiecek A, Vanholder R. Anaemia management in patients with chronic kidney disease: a position statement by the anaemia working group of European renal best practice (ERBP) Nephrology Dialysis Transplantation. 2009;24(2):348–354.
    1. Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood. 2010;116(23):4754–4761.
    1. Ervasti M, Kotisaari S, Heinonen S, Punnonen K. Use of advanced red blood cell and reticulocyte indices improves the accuracy in diagnosing iron deficiency in pregnant women at term. European Journal of Haematology. 2007;79(6):539–545.
    1. Ervasti M, Kotisaari S, Sankilampi U, Heinonen S, Punnonen K. The relationship between red blood cell and reticulocyte indices and serum markers of iron status in the cord blood of newborns. Clinical Chemistry and Laboratory Medicine. 2007;45(8):1000–1003.
    1. Suominen P, Punnonen K, Rajamäki A, Irjala K. Serum transferrin receptor and transferrin receptor-ferritin index identify healthy subjects with subclinical iron deficits. Blood. 1998;92(8):2934–2939.
    1. Stoffman N, Brugnara C, Woods ER. An algorithm using reticulocyte hemoglobin content (CHr) measurement in screening adolescents for iron deficiency. Journal of Adolescent Health. 2005;36(6):529–533.
    1. Ullrich C, Wu A, Armsby C, et al. Screening healthy infants for iron deficiency using reticulocyte hemoglobin content. The Journal of the American Medical Association. 2005;294(8):924–930.
    1. Shaker M, Jenkins P, Ullrich C, Brugnara C, Nghiem BT, Bernstein H. An economic analysis of anemia prevention during infancy. Journal of Pediatrics. 2009;154(1):44–49.
    1. Ramakers C, van der Woude DAA, Verzijl JM, Pijnenborg JMA, van Wijk EM. An added value for CHr and MCV in the diagnosis of iron deficency in postpartum anemic women. International Journal of Laboratory Hematology. 2012;34(5):510–516.
    1. Radtke H, Meyer T, Kalus U, et al. Rapid identification of iron deficiency in blood donors with red cell indexes provided by Advia 120. Transfusion. 2005;45(1):5–10.
    1. Nadarajan V, Sthaneshwar P, Eow GI. Use of red blood cell indices for the identification of iron deficiency among blood donors. Transfusion Medicine. 2008;18(3):184–189.
    1. Semmelrock MJ, Raggam RB, Amrein K, et al. Reticulocyte hemoglobin content allows early and reliable detection of functional iron deficiency in blood donors. Clinica Chimica Acta. 2012;413(7-8):678–682.
    1. Kang SH, Kim HK, Ham CK, Lee DS, Cho HI. Comparison of four hematology analyzers, CELL-DYN Sapphire, ADVIA 120, Coulter LH 750, and Sysmex XE-2100, in terms of clinical usefulness. International Journal of Laboratory Hematology. 2008;30(6):480–486.
    1. Ermens AAM, Hoffmann JJML, Krockenberger M, van Wijk EM. New erythrocyte and reticulocyte parameters on CELL-DYN Sapphire; analytical and preanalytical aspects. International Journal of Laboratory Hematology. 2012;34(3):274–282.
    1. Hoffmann JJML, van den Broek NMA, Curvers J. Reference intervals of extended erythrocyte and reticulocyte parameters. Clinical Chemistry and Laboratory Medicine. 2012;50(5):941–948.
    1. Costa O, van Moer G, Jochmans K, Jonckheer J, Damiaens S, de Waele M. Reference values for new red blood cell and platelet parameters on the Abbott Diagnostics Cell-Dyn Sapphire. Clinical Chemistry and Laboratory Medicine. 2012;50(5):967–969.
    1. Buttarello M, Temporin V, Ceravolo R, Farina G, Bulian P. The new reticulocyte parameter (RET-Y) of the Sysmex XE 2100: its use in the diagnosis and monitoring of posttreatment sideropenic anemia. The American Journal of Clinical Pathology. 2004;121(4):489–495.
    1. Canals C, Remacha AF, Sardá MP, Piazuelo JM, Royo MT, Angeles Romero M. Clinical utility of the new Sysmex XE 2100 parameter—reticulocyte hemoglobin equivalent—in the diagnosis of anemia. Haematologica. 2005;90(8):1133–1134.
    1. Brugnara C, Schiller B, Moran J. Reticulocyte hemoglobin equivalent (Ret He) and assessment of iron-deficient states. Clinical and Laboratory Haematology. 2006;28(5):303–308.
    1. Thomas C, Kirschbaum A, Boehm D, Thomas L. The diagnostic plot: a concept for identifying different states of iron deficiency and monitoring the response to epoetin therapy. Medical Oncology. 2006;23(1):23–36.
    1. Thomas L, Franck S, Messinger M, Linssen J, Thomé M, Thomas C. Reticulocyte hemoglobin measurement—comparison of two methods in the diagnosis of iron-restricted erythropoiesis. Clinical Chemistry and Laboratory Medicine. 2005;43(11):1193–1202.
    1. David O, Grillo A, Ceoloni B, et al. Analysis of red cell parameters on the Sysmex XE 2100 and ADVIA 120 in iron deficiency and in uraemic chronic disease. Scandinavian Journal of Clinical and Laboratory Investigation. 2006;66(2):113–120.
    1. Garzia M, Di Mario A, Ferraro E, et al. Reticulocyte hemoglobin equivalent: an indicator of reduced iron availability in chronic kidney diseases during erythropoietin therapy. Laboratory Hematology. 2007;13(1):6–11.
    1. Mast AE, Blinder MA, Dietzen DJ. Reticulocyte hemoglobin content. The American Journal of Hematology. 2008;83(4):307–310.
    1. MacOni M, Cavalca L, Danise P, Cardarelli F, Brini M. Erythrocyte and reticulocyte indices in iron deficiency in chronic kidney disease: comparison of two methods. Scandinavian Journal of Clinical and Laboratory Investigation. 2009;69(3):365–370.
    1. Miwa N, Akiba T, Kimata N, et al. Usefulness of measuring reticulocyte hemoglobin equivalent in the management of haemodialysis patients with iron deficiency. International Journal of Laboratory Hematology. 2010;32(2):248–255.
    1. Préfontaine G, Darveau M, Ahnadi C, et al. Reticulocyte hemoglobin content in 13 critically ill patients: a preliminary study. Transfusion Alternatives in Transfusion Medicine. 2008;10(4):182–188.
    1. Fernández R, Tubau I, Masip J, Muñoz L, Roig I, Artigas A. Low reticulocyte hemoglobin content is associated with a higher blood transfusion rate in critically ill patients: a cohort study. Anesthesiology. 2010;112(5):1211–1215.
    1. Schoorl M, Snijders D, Schoorl M, Boersma WG, Bartels PCM. Temporary impairment of reticulocyte hemoglobin content in subjects with community adquired pneumonia. International Journal of Laboratory Hematology. 2012;34(4):390–395.
    1. Urrechaga E, Borque L, Escanero JF. Potential utility of the new sysmex XE 5000 red blood cell extended parameters in the study of disorders of iron metabolism. Clinical Chemistry and Laboratory Medicine. 2009;47(11):1411–1416.
    1. Urrechaga E, Borque L, Escanero JF. Percentage of hypochromic erythrocytes as potential marker of iron availability. Clinical Chemistry and Laboratory Medicine. 2012;50(4):685–687.
    1. Urrechaga E, Borque L, Escanero JF. Erythrocyte and reticulocyte indices in the assessment of erythropoiesis activity and iron availability. International Journal of Laboratory Hematology
    1. Buttarello M, Pajola R, Novello E, et al. Diagnosis of iron deficiency in patients undergoing hemodialysis. The American Journal of Clinical Pathology. 2010;133(6):949–954.
    1. Urrechaga E. The new mature red cell parameter, low haemoglobin density of the Beckman-Coulter LH750: clinical utility in the diagnosis of iron deficiency. International Journal of Laboratory Hematology. 2010;32(1):e144–e150.
    1. Urrechaga E, Borque L, Escanero JF. Erythrocyte and reticulocyte indices on the LH 750 as potential markers of functional iron deficiency. Anemia. 2010;2010:7 pages.625919
    1. Urrechaga E, Borque L, Escanero JF. Low Hemoglobin Density (LHD %) potential marker of iron availability. International Journal of Laboratory Hematology. 2012;34(1):47–51.
    1. Urrechaga E, Borque L, Escanero JF. Assessing iron status in CKD patients: new Laboratory parameters. In: Gööz M, editor. Chronic Kidney Disease. 1st edition. Zagreb, Croatia: InTech; 2012. pp. 225–250.
    1. Ptolemy AS, Rifai N. What is a biomarker? Research investments and lack of clinical integration necessitate a review of biomarker terminology and validation schema. Scandinavian Journal of Clinical and Laboratory Investigation. 2010;70(s242):6–14.

Source: PubMed

3
Abonner