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Inconsistency in ferritin reference intervals across laboratories: a major concern for clinical decision making

  • Steef Kurstjens EMAIL logo , Andrea D. van Dam , Ellis Oortwijn , Wendy P.J. den Elzen , Firmin Candido , Ron Kusters , Anoeska Schipper , Yvo F.C. Kortmann , Ron M.C. Herings , Maarten Kok , Johannes Krabbe , Bauke A. de Boer , Anne-Margreet de Jong and Marieke A.M. Frasa
Published/Copyright: October 14, 2024
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 63 Issue 3

Abstract

Objectives

Iron deficiency anemia is a significant global health concern, diagnosed by measuring hemoglobin concentrations in combination with plasma ferritin concentration. This study investigated the variability in ferritin reference intervals among laboratories in the Netherlands and examined how this affects the identification of iron-related disorders.

Methods

Ferritin reference intervals from 52 Dutch ISO15189-certified medical laboratories were collected. Ferritin, hemoglobin and mean corpuscular volume data of non-anemic apparently healthy primary care patients, measured by four laboratory platforms (Beckman, Abbott, Siemens, and Roche), were collected (n=397,548). Median ferritin levels were determined per platform, stratified by sex and age. The proportion of ferritin measurements outside of the reference interval was calculated using the reference intervals from the 52 laboratories (using a total of n=1,093,442 ferritin measurements). Lastly, ferritin data from 3,699 patients as captured in general practitioner (GP) data from the PHARMO Data Network were used to assess the variation of abnormal ferritin measurements per GP.

Results

Median plasma ferritin concentrations were approximately four times higher in men and twice as high in postmenopausal women compared to premenopausal women. Moreover, there are substantial differences in the median plasma ferritin concentration between the four platforms. However, even among laboratories using the same platform, ferritin reference intervals differ widely. This leads to significant differences in the percentages of measurements classified as abnormal, with the percentage of ferritin measurements below the reference limit in premenopausal women ranging from 11 to 53 %, in postmenopausal women from 3 to 37 %, and in men from 2 to 19 %. The percentage of ferritin measurements above the reference limit in premenopausal women ranged from 0.2 to 11 %, in postmenopausal women from 3 to 36 % and in men from 7 to 32 %.

Conclusions

The lack of harmonization in ferritin measurement and the disagreement in plasma ferritin reference intervals significantly impact the interpretation of the iron status of patients and thereby the number of iron disorder diagnoses made. Standardization or harmonization of the ferritin assays and establishing uniform reference intervals and medical decision limits are essential to reduce the substantial variability in clinical interpretations of ferritin results.

Keywords: ferritin; iron disorders; iron deficiency; reference interval; harmonisation; standardisation
Corresponding author: Steef Kurstjens, PhD, Laboratory of Clinical Chemistry and Laboratory Medicine, Dicoon BV, Location Canisius Wilhelmina Hospital, Nijmegen, The Netherlands, E-mail:

Acknowledgments

The authors would like to thank employees of the PHARMO Institute for the support in analyzing and interpretation of the results as well as all the healthcare providers for contributing information to the PHARMO Data Network.

  1. Research ethics: Laboratory data were anonymized, and the requirement for informed consent was waived by the local ethics board (METC Brabant, number NW2023-81).

  2. Informed consent: Laboratory data were anonymized, and the requirement for informed consent was waived by the local ethics board (METC Brabant, number NW2023-81).

  3. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. S.K., M.F., BdB. and A.d.J. initiated the study. S.K., E.O., A.S., M.K., J.K., BdB., R.H. and A.d.J. collected laboratory data. A.v.D., A.S. and S.K. analyzed the data. All authors were involved in the design of the study, provided input and improved the manuscript. M.F., M.K., J.K., B.d.B., A.d.J. and R.K. supervised the project. S.K. wrote the paper with input from all authors.

  4. Use of Large Language Models, AI and Machine Learning Tools: ChatGPT v4.0 was used to improve grammar and spelling.

  5. Conflict of interest: The authors state no conflict of interest.

  6. Research funding: None declared.

  7. Data availability: Data are available from the corresponding author upon reasonable request.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/cclm-2024-0826).

Received: 2024-07-18
Accepted: 2024-09-24
Published Online: 2024-10-14
Published in Print: 2025-02-25

© 2024 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2024-0826
Keywords for this article
ferritin; iron disorders; iron deficiency; reference interval; harmonisation; standardisation

Articles in the same Issue

  1. Frontmatter
  2. Editorials
  3. Multi-cancer early detection: searching for evidence
  4. High sensitivity cardiac troponin assays, rapid myocardial infarction rule-out algorithms, and assay performance
  5. Reviews
  6. Consensus statement on extracellular vesicles in liquid biopsy for advancing laboratory medicine
  7. Copeptin as a diagnostic and prognostic biomarker in pediatric diseases
  8. Opinion Papers
  9. The Unholy Grail of cancer screening: or is it just about the Benjamins?
  10. Critical appraisal of the CLSI guideline EP09c “measurement procedure comparison and bias estimation using patient samples”
  11. Tumor markers determination in malignant pleural effusion: pearls and pitfalls
  12. Contribution of laboratory medicine and emerging technologies to cardiovascular risk reduction via exposome analysis: an opinion of the IFCC Division on Emerging Technologies
  13. Guidelines and Recommendations
  14. Recommendations for European laboratories based on the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease
  15. Genetics and Molecular Diagnostics
  16. Expanded carrier screening for 224 monogenic disease genes in 1,499 Chinese couples: a single-center study
  17. General Clinical Chemistry and Laboratory Medicine
  18. How do experts determine where to intervene on test ordering? An interview study
  19. New concept for control material in glucose point-of-care-testing for external quality assessment schemes
  20. Vitamin B12 deficiency in newborns: impact on individual’s health status and healthcare costs
  21. Analytical evaluation of eight qualitative FIT for haemoglobin products, for professional use in the UK
  22. Colorimetric correcting for sample concentration in stool samples
  23. Reference Values and Biological Variations
  24. Assessment of canonical diurnal variations in plasma glucose using quantile regression modelling and Chronomaps
  25. Inconsistency in ferritin reference intervals across laboratories: a major concern for clinical decision making
  26. Establishing the TSH reference intervals for healthy adults aged over 70 years: the Australian ASPREE cohort study
  27. Hematology and Coagulation
  28. The EuroFlow PIDOT external quality assurance scheme: enhancing laboratory performance evaluation in immunophenotyping of rare lymphoid immunodeficiencies
  29. Clinical value of smear review of flagged samples analyzed with the Sysmex XN hematology analyzer
  30. Cardiovascular Diseases
  31. Evidence for stability of cardiac troponin T concentrations measured with a high sensitivity TnT test in serum and lithium heparin plasma after six-year storage at −80 °C and multiple freeze-thaw cycles
  32. Letters to the Editor
  33. Impact of high-sensitivity cardiac troponin I assay imprecision on the safety of a single-sample rule-out approach for myocardial infarction
  34. Why is single sample rule out of non-ST elevation myocardial infarction using high-sensitivity cardiac troponin T safe when analytical imprecision is so high? A joint statistical and clinical demonstration
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