Interpreting raised serum ferritin levelsBMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h3692 (Published 03 August 2015) Cite this as: BMJ 2015;351:h3692
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I peruse with interest the article "Interpreting raised serum ferritin levels".(1)
I agree that the interpretation of raised serum ferritin is relevant. But, depending upon the clinical background, the interpretation of normal level of serum ferritin (M:40-300 microgram(mcg)/L, W: 20-200 mcg/L) is also equally important and at times challenging. Like in patients with many chronic diseases serum ferritin <100 mcg/L and in patients with heart failure ferritin level <300 mcg/L indicates iron deficiency.(2)
This is important as in many patients (with/without anemia with normal serum ferritin levels) iron deficiency is commonly missed and iron is never supplemented: a missed therapeutic (and easily correctable) opportunity with tremendous morbidity benefits.(3)
1.BMJ 2015;351:h 3692
2.Camaschella C. Iron-deficiency anemia.N Engl J Med 2015;372:1832-1843
3.Anker SD, Comin Colet J,Filippatos G, et al.Ferric carboxymaltose in patients with heart failure and iron deficiency.N Engl J Med 2009;361:2436-2448
Competing interests: No competing interests
Koperdanova and Collis provide a concise and pragmatic approach to interpreting a raised ferritin level, a commonly elevated biochemical marker in a range of acute and chronic diseases (1). We would like to give a specific mention to Adult onset-Still’s Disease (AOSD). AOSD is a rare multisystem inflammatory disorder typically presenting in adults under the age of 45, chracterised by daily fevers, arthritis and an evanescent macular/maculopapular rash. The variable and non-specific presentation of AOSD often delays diagnosis for a period of weeks to months, once diagnosed there is a range of treatment options available.
AOSD commonly produces a ferritin level that well exceeds the upper limit of normal. One recent European retrospective observational study of 57 AOSD patients reported a raised serum ferritin level in 82% of patients with a mean serum ferritin level of 8745 μg/L (standard deviation 19,867, range 80–130,000 μg/L) (2). It is important to note that due its low specificity, a raised serum ferritin is not included in the diagnostic criteria of AOSD (3), however we feel the connection between AOSD and markedly elevated ferritin is worth highlighting, given the younger age and non-specific nature of most AOSD presentations that may contribute to a delayed diagnosis.
1. Koperdanova M, Cullis JO. Interpreting raised serum ferritin levels. BMJ. 2015;351:h3692.
2. Gerfaud-Valentin M, Maucort-Boulch D, Hot A, Iwaz J, Ninet J, Durieu I, et al. Adult-onset still disease: manifestations, treatment, outcome, and prognostic factors in 57 patients. Medicine (Baltimore). 2014 Mar;93(2):91–9.
3. Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol. 1992 Mar;19(3):424–30.
Competing interests: No competing interests
Why does serum contain ferritin?
In a recent article, Koperdanova and Cullis 1 rehearsed the various interpretations of raised serum ferritin levels. In fact the most interesting question 2 is why does ferritin appear in serum at all?
All modern network models of iron metabolism (e.g. 3-7) have iron being passed from the gut to peripheral cells via blood (serum) bound to transferrin, a well-established iron-transporting molecule that is present in serum at ca 0.6-3.3 g.L-1 8. By contrast, ferritin is an intracellular iron storage compound 3 5 7; its normal range for serum is at levels 10,000-100,000 times lower than that for transferrin, being from very small levels to up to 300 microg.L-1 in men and slightly lower in women 2.
While it was once thought that serum ferritin levels might reflect liver iron stores, our modern understanding (and the systems biology models) recognise, as indeed do Koperdanova and Cullis 1, that it is far more commonly an inflammatory marker. All the evidence, however, it that it appears in serum by dint simply of cell death, and is thereby a cell death marker 2.
Normally, serum ferritin is assessed via an antibody test, that detects only the protein. Where measurements to measure its iron content as well 9-11, the serum ferritin itself is found to have lost almost all its iron 2. The free iron thereby liberated can prove cytotoxic, both by catalysing the Fenton reaction to produce hydroxyl radicals 4 12-14, and by the awakening of dormant microbes whose lipopolysaccharide can produce the inflammation characteristic of such diseases 15-17.
We think that it is time for a re-evaluation of what serum ferritin measurements are really telling us.
Douglas B. Kell  & Etheresia Pretorius 
 School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, 131, Princess St, MANCHESTER M1 7DN, Lancs, UK
 Department of Physiology, Faculty of Health Sciences, University of Pretoria, Arcadia 0007, South Africa.
We thank the Biotechnology and Biological Sciences Research Council (grant BB/L025752/1) as well as the National Research Foundation (NRF) of South Africa for supporting this collaboration.
1. Koperdanova M, Cullis JO. Interpreting raised serum ferritin levels. BMJ 2015;351:h3692.
2. Kell DB, Pretorius E. Serum ferritin is an important disease marker, and is mainly a leakage product from damaged cells. Metallomics 2014;6(4):748-73.
3. Hower V, Mendes P, Torti FM, Laubenbacher R, Akman S, Shulaev V, et al. A general map of iron metabolism and tissue-specific subnetworks. . Mol Biosyst 2009;5:422-43.
4. Kell DB. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med Genom 2009;2:2
5. Chifman J, Kniss A, Neupane P, Williams I, Leung B, Deng Z, et al. The core control system of intracellular iron homeostasis: A mathematical model. J Theor Biol 2012;300:91-9.
6. Mitchell S, Mendes P. A Computational Model of Liver Iron Metabolism. PLoS Comp Biol 2013;9(11):e1003299.
7. Chifman J, Laubenbacher R, Torti SV. A systems biology approach to iron metabolism. Adv Exp Med Biol 2014;844:201-25.
8. Helander A. Absolute or relative measurement of carbohydrate-deficient transferrin in serum? Experiences with three immunological assays. Clin Chem 1999;45(1):131-5.
9. Watanabe K, Yamashita Y, Ohgawara K, Sekiguchi M, Satake N, Orino K, et al. Iron content of rat serum ferritin. J Vet Med Sci 2001;63(5):587-89.
10. Yamanishi H, Iyama S, Yamaguchi Y, Kanakura Y, Iwatani Y. Relation between iron content of serum ferritin and clinical status factors extracted by factor analysis in patients with hyperferritinemia. Clin Biochem 2002;35(7):523-9.
11. Konz T, Añón Alvarez E, Montes-Bayon M, Sanz-Medel A. Antibody labeling and elemental mass spectrometry (inductively coupled plasma-mass spectrometry) using isotope dilution for highly sensitive ferritin determination and iron-ferritin ratio measurements. Anal Chem 2013;85(17):8334-40.
12. Kell DB. Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples. Arch Toxicol 2010;577:825-89. .
13. Pretorius E, Kell DB. Diagnostic morphology: biophysical indicators for iron-driven inflammatory diseases. Integrative Biol 2014;6(5):486-510.
14. Kell DB, Pretorius E. The simultaneous occurrence of both hypercoagulability and hypofibrinolysis in blood and serum during systemic inflammation, and the roles of iron and fibrin(ogen). Integr Biol 2015;7:24-52.
15. Potgieter M, Bester J, Kell DB, Pretorius E. The dormant blood microbiome in chronic, inflammatory diseases. FEMS Microbiol Rev 2015;39:567-91.
16. Kell DB, Potgieter M, Pretorius E. Individuality, phenotypic differentiation, dormancy and ‘persistence’ in culturable bacterial systems: commonalities shared by environmental, laboratory, and clinical microbiology. F1000Res 2015;4:179.
17. Kell DB, Pretorius E. On the translocation of bacteria and their lipopolysaccharides between blood and peripheral locations in chronic, inflammatory diseases: the central roles of LPS and LPS-induced cell death Integr Biol 2015:online, DOI: 10.1039/c5ib00158g.
Competing interests: No competing interests