Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter

IMPACT FACTOR 2018: 3.638

CiteScore 2018: 2.44

SCImago Journal Rank (SJR) 2018: 1.191
Source Normalized Impact per Paper (SNIP) 2018: 1.205

See all formats and pricing
More options …
Volume 57, Issue 2


Baseline hepcidin measurement in the differential diagnosis of anaemia for elderly patients and its correlation with the increment of transferrin saturation following an oral iron absorption test

Fleur Wolff
  • Corresponding author
  • Department of Clinical Chemistry, LHUB-ULB, rue Haute, 322, 1000 Brussels, Belgium, Phone: +32-2-5553692, Fax: +32-2-5556655
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Sandra De Breucker / Thierry Pepersack / Nathalie Compté / Christian Mélot / Béatrice Gulbis / Frédéric Cotton
Published Online: 2018-07-28 | DOI: https://doi.org/10.1515/cclm-2018-0551



Anaemia is often multifactorial in the elderly, with a frequent association between iron deficiency anaemia (IDA) and anaemia of chronic disease (ACD). The primary objective of our study was to investigate whether baseline hepcidin measurement could be useful for identifying iron deficiency (ID) in anaemic elderly patients. The secondary objective was to assess whether baseline hepcidin concentrations correlated with the relative increase of transferrin saturation (TS) after an oral iron absorption test (OIAT).


Blood samples were collected between 7:30 am and 10:00 am in 328 geriatric outpatients, 102 underwent the OIAT. Types of anaemia were classified according biochemical and clinical criteria. TS and hepcidin were measured at baseline and 4 h after the iron dose. The ability of baseline hepcidin measurement to highlight ID in elderly anaemic patients was assessed using a receiver operator curve (ROC) analysis. Correlations between baseline hepcidin levels and the increment of TS following the OIAT were investigated using the Spearman coefficient.


Among 328 included patients, 78 (23.8%) suffered from anaemia; 13 (4.0%), 19 (5.8%), 27 (8.2%) and 19 (5.8%) patients fulfilled criteria for IDA, IDA/ACD, ACD and unexplained anaemia, respectively. By multivariable analysis, creatinine, C-reactive protein, ferritin, Delta TS and Delta hepcidin were independently associated with baseline hepcidin concentrations. The area under the ROC curve (95% confidence interval) was 0.900 (0.830–0.970) for baseline hepcidin measurement. Baseline hepcidin levels correlated negatively with the relative increase in TS with a Spearman coefficient of −0.742.


Baseline hepcidin levels could be a useful tool to identify ID in anaemic elderly patients and may predict acute iron response following OIAT.

Keywords: anaemia; hepcidin; iron


  • 1.

    Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG, Woodman RC. Prevalence of anaemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anaemia. Blood 2004;104:2263–8.PubMedCrossrefGoogle Scholar

  • 2.

    Petrosyan I, Blaison G, Andrès E, Federici L. Anaemia in the elderly: an aetiologic profile of a prospective cohort of 95 hospitalised patients. Eur J Intern Med 2012;23:524–8.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 3.

    Chua AC, Klopcic BR, Ho DS, Fu SK, Forrest CH, Croft KD, et al. Dietary iron enhances colonic inflammation and IL-6/IL-11-Stat3 signaling promoting colonic tumor development in mice. PLoS One 2013;11:e78850.Web of ScienceGoogle Scholar

  • 4.

    Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood 2009;113:5277–86.CrossrefWeb of SciencePubMedGoogle Scholar

  • 5.

    Barron BA, Hoyer JD, Tefferi A. A bone marrow report of absent stainable iron is not diagnostic of iron deficiency. Ann Hematol 2001;80:166–9.PubMedCrossrefGoogle Scholar

  • 6.

    Casale G, Bonora C, Migliavacca A, Zurita IE, de Nicola P. Serum ferritin and ageing. Age Ageing 1981;10:119–22.PubMedCrossrefGoogle Scholar

  • 7.

    Olivé A, Juncà J. Elevated serum ferritin levels: associated diseases and clinical significance. Am J Med 1996;101:120.Google Scholar

  • 8.

    Joosten E, Hiele M, Ghoos Y, Pelemans W, Boogaerts MA. Diagnosis of iron-deficiency anemia in a hospitalized geriatric population. Am J Med 1991;90:653–4.Google Scholar

  • 9.

    Harms K, Kaiser T. Beyond soluble transferrin receptor: old challenges and new horizons. Best Pract Res Clin Endocrinol Metab 2015;29:799–810.Web of ScienceCrossrefPubMedGoogle Scholar

  • 10.

    Rimon E, Levy S, Sapir A, Gelzer G, Peled R, Ergas D, et al. Diagnosis of iron deficiency anemia in the elderly by transferrin receptor-ferritin index. Arch Intern Med 2002;162:445–9.PubMedCrossrefGoogle Scholar

  • 11.

    Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003;101:2461–3.CrossrefPubMedGoogle Scholar

  • 12.

    Thomas C, Kobold U, Balan S, Roeddiger R, Thomas L. Serum hepcidin-25 may replace the ferritin index in the Thomas plot in assessing iron status in anemic patients. Int J Lab Hematol 2011;33:187–93.CrossrefWeb of SciencePubMedGoogle Scholar

  • 13.

    Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002;110:1037–44.CrossrefPubMedGoogle Scholar

  • 14.

    Kobune M, Miyanishi K, Takada K, Kawano Y, Nagashima H, Kikuchi S, et al. Establishment of a simple test for iron absorption from the gastrointestinal tract. Int J Hematol 2011;93:715–9.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 15.

    Busti F, Campostrini N, Martinelli N, Girelli D. Iron deficiency in the elderly population, revisited in the hepcidin era. Front Pharmacol 2014;5:83.Web of SciencePubMedGoogle Scholar

  • 16.

    Heeren TJ, Lagaay AM, von Beek WC, Rooymans HG, Hijmans W. Reference values for the Mini-Mental State Examination (MMSE) in octo- and nonagenarians. J Am Geriatr Soc 1990;38:1093–6.PubMedCrossrefGoogle Scholar

  • 17.

    Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH, et al. Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res 1992;41:237–48.CrossrefPubMedGoogle Scholar

  • 18.

    Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser 1968;405:5–37.PubMedGoogle Scholar

  • 19.

    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604–12.CrossrefGoogle Scholar

  • 20.

    Joosten E, Demuynck M, Detroyer E, Milisen K. Prevalence of frailty and its ability to predict in hospital delirium, falls, and 6-month mortality in hospitalized older patients. BMC Geriatr 2014;14:1.Web of SciencePubMedCrossrefGoogle Scholar

  • 21.

    Wolff F, Deleers M, Melot C, Gulbis B, Cotton F. Hepcidin-25: measurement by LC-MS/MS in serum and urine, reference ranges and urinary fractional excretion. Clin Chim Acta 2013;423:99–104.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 22.

    Katz MH. Multivariable analysis. A practical guide for Clinicians. Cambridge: Cambridge University Press, 1999.Google Scholar

  • 23.

    Mast AE, Blinder MA, Gronowski AM, Chumley C, Scott MG. Clinical utility of the soluble transferrin receptor and comparison with serum ferritin in several populations. Clin Chem 1998;44:45–51.PubMedGoogle Scholar

  • 24.

    Karlsson T. Evaluation of a competitive hepcidin ELISA assay in the differential diagnosis of iron deficiency anaemia with concurrent inflammation and anaemia of inflammation in elderly patients. J Inflamm (Lond) 2017;14:21.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 25.

    Girelli D, Nemeth E, Swinkels DW. Hepcidin in the diagnosis of iron disorders. Blood 2016;127:2809–13.Web of ScienceCrossrefGoogle Scholar

  • 26.

    Kroot JJ, Tjalsma H, Fleming RE, Swinkels DW. Hepcidin in human iron disorders: diagnostic implications. Clin Chem 2011;57:1650–69.Web of ScienceCrossrefPubMedGoogle Scholar

  • 27.

    den Elzen WP, de Craen AJ, Wiegerinck ET, Westendorp RG, Swinkels DW, Gussekloo J. Plasma hepcidin levels and anemia in old age. The Leiden 85-Plus Study. Haematologica 2013;98:448–54.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 28.

    Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. Immunoassay for human serum hepcidin. Blood 2008;112:4292–7.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 29.

    Galesloot TE, Vermeulen SH, Geurts-Moespot AJ, Klaver SM, Kroot JJ, van Tienoven D, et al. Serum hepcidin: reference ranges and biochemical correlates in the general population. Blood 2011;117:e218–25.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 30.

    Koziol JA, Ho NJ, Felitti VJ, Beutler E. Reference centiles for serum ferritin and percentage of transferrin saturation, with application to mutations of the HFE gene. Clin Chem 2001;47:1804–10.PubMedGoogle Scholar

  • 31.

    Goyal H, Mohanty S, Sharma M, Rani A. Study of anemia in nondialysis dependent chronic kidney disease with special reference to serum hepcidin. Indian J Nephrol 2017;27:44–50.PubMedCrossrefGoogle Scholar

  • 32.

    Darshan D, Frazer DM, Wilkins SJ, Anderson GJ. Severe iron deficiency blunts the response of the iron regulatory gene Hamp and pro-inflammatory cytokines to lipopolysaccharide. Haematologica 2010;95:1660–7.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 33.

    Price EA, Mehra R, Holmes TH, Schrier SL. Anemia in older persons: etiology and evaluation. Blood Cells Mol Dis 2011; 46:159–65.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 34.

    McCranor BJ, Langdon JM, Prince OD, Femnou LK, Berger AE, Cheadle C, et al. Investigation of the role of interleukin-6 and hepcidin antimicrobial peptide in the development of anemia with age. Haematologica 2013;98:1633–40.CrossrefWeb of SciencePubMedGoogle Scholar

  • 35.

    Kroot JJ, van Herwaarden AE, Tjalsma H, Jansen RT, Hendriks JC, Swinkels DW. Second round robin for plasma hepcidin methods: first steps toward harmonization. Am J Hematol 2012; 87:977–83.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 36.

    van Santen S, van Dongen-Lases EC, de Vegt F, Laarakkers CM, van Riel PL, van Ede AE, et al. Hepcidin and hemoglobin content parameters in the diagnosis of iron deficiency in rheumatoid arthritis patients with anemia. Arthritis Rheum 2011; 63:3672–80.CrossrefWeb of ScienceGoogle Scholar

  • 37.

    Bergamaschi G, Di Sabatino A, Albertini R, Costanzo F, Guerci M, Masotti M, et al. Serum hepcidin in inflammatory bowel diseases: biological and clinical significance. Inflamm Bowel Dis 2013;19:2166–72.CrossrefWeb of SciencePubMedGoogle Scholar

  • 38.

    Karlsson T. Mass spectrometry evaluation of the hepcidin-25 assay in the differential diagnosis of iron deficiency anaemia with concurrent inflammation and anaemia of inflammation in elderly patients. Eur J Haematol 2015;95:467–71.Web of SciencePubMedCrossrefGoogle Scholar

  • 39.

    Girelli D, Trombini P, Busti F, Campostrini N, Sandri M, Pelucchi S, et al. A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis. Haematologica 2011;96:500–6.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 40.

    Hwang SI, Lee YY, Park JO, Norton HJ, Clemens E, Schrum LW, et al. Effects of a single dose of oral iron on hepcidin concentrations in human urine and serum analyzed by a robust LC-MS/MS method. Clin Chim Acta 2011;412:2241–7.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 41.

    Zimmermann MB, Troesch B, Biebinger R, Egli I, Zeder C, Hurrell RF. Plasma hepcidin is a modest predictor of dietary iron bioavailability in humans, whereas oral iron loading, measured by stable-isotope appearance curves, increases plasma hepcidin. Am J Clin Nutr 2009;90:1280–7.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 42.

    Roe MA, Collings R, Dainty JR, Swinkels DW, Fairweather-Tait SJ. Plasma hepcidin concentrations significantly predict interindividual variation in iron absorption in healthy men. Am J Clin Nutr 2009;89:1088–91.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 43.

    Young MF, Glahn RP, Ariza-Nieto M, Inglis J, Olbina G, Westerman M, et al. Serum hepcidin is significantly associated with iron absorption from food and supplemental sources in healthy young women. Am J Clin Nutr 2009;89:533–8.Web of ScienceCrossrefPubMedGoogle Scholar

  • 44.

    Bregman DB, Morris D, Koch TA, He A, Goodnough LT. Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia. Am J Hematol 2013;88:97–101.Web of ScienceCrossrefPubMedGoogle Scholar

  • 45.

    van der Vorm LN, Hendriks JC, Laarakkers CM, Klaver S, Armitage AE, Bamberg A, et al. Toward worldwide hepcidin assay harmonization: identification of a commutable secondary reference material. Clin Chem 2016;62:993–1001.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 46.

    Itkonen O, Parkkinen J, Stenman UH, Hämäläinen E. Preanalytical factors and reference intervals for serum hepcidin LC-MS/MS method. Clin Chim Acta 2012;413:696–701.Web of SciencePubMedCrossrefGoogle Scholar

  • 47.

    Lefebvre T, Dessendier N, Houamel D, Ialy-Radio N, Kannengiesser C, Manceau H, et al. LC-MS/MS method for hepcidin-25 measurement in human and mouse serum: clinical and research implications in iron disorders. Clin Chem Lab Med 2015;53:1557–67.Web of SciencePubMedGoogle Scholar

About the article

Received: 2018-03-27

Accepted: 2018-06-29

Published Online: 2018-07-28

Published in Print: 2018-12-19

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 57, Issue 2, Pages 250–258, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2018-0551.

Export Citation

©2019 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Yelena Z. Ginzburg
Hematology, 2019, Volume 2019, Number 1, Page 327

Comments (0)

Please log in or register to comment.
Log in