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Prof. Dr. med. Wolfgang Korte/Prof. Dr. med. Arnold von Eckardstein

2. Dezember 2021

Modern challenges to diagnose iron deficiency

Webinar of Thursday 28. October 2021, 17.30–19.00 h

Keywords: Iron deficiency, ferritin, reference ranges, clinical decision limits, clinical laboratory reports

Prof. Dr. med. Wolfgang Korte

Prof. Dr. med. Wolfgang Korte
CEO and Medical Director
Centre for Laboratory Medicine St. Gallen

Laboratory assessment of iron status and Swiss Consensus

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Take Home Messages
  • The assessment of iron stores and requirement can be challenging and iron deficiency is not a clearly defined term. Although iron staining of bone marrow is the gold-standard, serum ferritin is the most important indicator of iron deficiency,1 despite the following limitations:
    • Different methods of measurement lead to different serum ferritin concentrations.2 Whether or not this leads to comparable therapeutic decision is however still debated.
    • Serum ferritin is an acute-phase protein and reacts strongly to the inflammatory process. Thus, different biomarkers are used to define iron deficiency, each showing differing performances in different clinical settings.
    • Different ferritin cut-off values are necessary to define iron deficiency, depending on the population or disease. For instance, the European Society for Cardiology defines iron deficiency for patients with heart failure as ferritin < 100 mcg/L, or < 100–300 mcg/L with transferrin saturation < 20%, while serum ferritin level < 30 mcg/L is considered to be the most sensitive and specific test for the identification of iron deficiency in the healthy population.1, 3
  • As iron deficiency is no longer a homogenous term, a Delphi process was initiated to define consensus statements, in regards to the diagnostics and treatment of iron deficiency.1
Prof. Dr. med. Arnold von Eckardstein

Prof. Dr. med. Arnold von Eckardstein
Professor at the Medical Faculty of Zurich University and Chair of the Institute for Clinical Chemistry
University Hospital Zurich

What is meant by «normal»?

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Take Home Messages
  • The term «normal value» is diffuse and must not be used. Instead, we should rather differentiate the following two approaches:
    1. There is a conventional approach using reference values and ranges:
      • This is usually defined with the 2,5th and 97,5th percentiles. This also means that 5% of values measured in healthy individuals are not normal.
      • Examples of reference ranges: blood cell counts, hemoglobin, hematokrit, electrolytes, enzyme activities (e. g. AST, ALT, CK, LDH), metabolites (e. g. bilirubin).
      • The reference ranges should be adapted to influencing factors that cannot be modified such as age, sex, genetic factors.
    2. The conventional approach is more and more frequently complemented by diagnostic decision cut-offs:
      • A ROC-curve does not only compare the diagnostic quality of tests but will also help to identify optimal diagnostic cut-offs if sensitivity and specificity are equally valued.4
      • However, in most clinical situations, the optimal cut-off should either rule-out (i. e. high sensitivity) or rule-in (i. e. high specificity), rather than to compromise both.5
      • The desirable concentration of cut-off points for flagging abnormal plasma lipid (risk thresholds) should be defined in laboratory reports as recommended by guidelines (for example total cholesterol ≥ 5,0 mmol/L).6
      • Similarly, the decision limits to diagnose iron deficiency should be defined such as to reflect the different ferritin cut-offs depending on the clinical situation.7 An example is the differential laboratory report from the USZ, which flags the ferritin and makes the distinction between healthy patient and patient at risk (ferritin < 100 mcg/L) (ex: heart failure, inflammatory bowel disease, elective surgery).
      • Finally, there is an increasing number of examples in which diagnostic cut-off values vary depending on indication (ex: ferritin > 30 mcg/L to rule-out absolute iron deficiency, versus ferritin > 100 mcg/L to rule out functional iron deficiency).8
  • With advances in science there is a considerable need to indicate these differences in clinical (laboratory) reports.


  1. Nowak A et al. Swiss Delphi study on iron deficiency. Swiss Med Wkly 2019; 149: w20097.
  2. Karakochuk CD et al. Comparison of four immunoassays to measure serum ferritin concentrations and iron deficiency prevalence among non-pregnant Cambodian women and Congolese children. Clin Chem Lab Med. 2017 Jan 1; 55 (1): 65–72.
  3. McDonagh TA et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21; 42 (36): 3599–3726.
  4. Twerenbold R et al. Optimal Cutoff Levels of More Sensitive Cardiac Troponin Assays for the Early Diagnosis of Myocardial Infarction in Patients With Renal Dysfunction. Circulation. 2015 Jun 9; 131 (23): 2041–50.
  5. Twerenbold R et al. Clinical Use of High-Sensitivity Cardiac Troponin in Patients With Suspected Myocardial Infarction. J Am Coll Cardiol. 2017 Aug 22; 70 (8): 996–1012.
  6. Nordestgaard BG et al. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points-a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J. 2016 Jul 1; 37 (25): 1944–58.
  7. von Haehling S et al. Iron Deficiency in Heart Failure: An Overview. JACC Heart Fail. 2019 Jan; 7 (1): 36–46.
  8. Fried R, Goede J, von Eckardstein A, Korte W. Definition des Eisenmangels in klinischer Medizin und Labormedizin. pipette. 2021 Mar; (1–2): 21–2.

The webinar was supported by Vifor Pharma AG and Axon Lab AG.

E 11/2021 CH-FCM-2100403


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