Serum ferritin (SF)
Ferritin is 24-subunit iron storage molecule that forms a hollow sphere with a capacity to hold up to 4000 iron atoms.1 Stored iron is predominantly held in reticuloendothelial cells (macrophages) and hepatocytes, but ferritin is in fact produced in many of the body’s cells, and a proportion of this is secreted into the plasma.2 Accordingly, plasma ferritin accounts for only a proportion of total body ferritin, and in thalassemia patients serum ferritin has been shown to correlate with the volume of transfused blood.2
However, the secretion of ferritin into the plasma can be mediated by a number of other factors. This means that the measurement of serum ferritin may be confounded in a number of important clinical contexts. Ascorbate deficiency and hypothyroidism reduce serum ferritin.2 Conversely, chronic inflammatory conditions, increased erythropoietin levels, hematological malignancies, liver damage, pancreatic cancer and acute inflammation may all increase serum ferritin.2 More recently, it has been proposed that ferritin may be a mediator of the inflammatory response, not merely a marker.3
Serum ferritin measurement is inexpensive and available in many hospital laboratories. Serum ferritin facilitates regular monitoring.
Comparisons of serum ferritin to liver iron stores have confirmed the correlation. When serum ferritin was compared to liver iron concentration (LIC, as measured through liver biopsy) for patients with thalassemia major, the serum ferritin level correlated positively (r = 0.73, p < 0.005).4 An alternative approach quantifying liver iron via magnetic resonance imaging has shown that serum ferritin correlates well in patients with transfusional iron overload and thalassemia major (r = 0.76, p < 0.001) and sickle cell anemia (r = 0.75, p < 0.001).5 However the same study highlighted that serum ferritin as a single measurement can be erratic due to its mediation by other physiological processes.
The relationship however is slightly less straight-forward in the context of non-transfusional iron overload. Serum ferritin levels in patients with thalassemia intermedia are significantly lower for a given liver iron concentration than in thalassemia major patients.6 Accordingly, serum ferritin levels may under-estimate the degree of bodily iron in non-transfusion-dependent thalassemia (NTDT) patients:7 such patients may require more direct approaches to iron measurement.
In patients with sickle cell disease the relationship between serum ferritin and liver iron concentration can be non-linear, especially in the range of 1500-3000 μg/L.8
Indicative serum ferritin levels in the context of iron overload, based on evidence in thalassemia major patients as described later
|Normal ferritin||<300 μg/L|
|Mild to moderate iron overload||>1000 ≤ 2500 μg/L|
|Severe iron overload||> 2500 μg/L|
Most guidelines recommend serial serum ferritin measurement every 1-3 months, although this can be adapted to individual patient needs.9-12
In transfusion-dependent thalassemia (TDT), a serum ferritin level consistently > 2,500 μg/L has been shown to increase the risk of cardiac complications and endocrine disease.13,14 While maintaining levels <1000 μg/L is associated with increased survival and less morbidity.14,15 Current practice is to initiate iron chelation therapy when the serum ferritin rises above 1000 μg/L.10
In non-transfusion dependent thalassemia (NTDT) levels > 800 μg/L were associated with increased morbidity in cross-sectional and long-term studies,16 the current recommendation is to initiate chelation therapy beyond this threshold.11
Sickle Cell Disease
Serum ferritin values higher than 3,000 were associated with liver fibrosis in SCD patients while values <1,500 μg/L indicated absence of such effects.8 The recommendation is to start chelation in patients who show levels >1,000 μg/L.17
Serum ferritin levels higher than 1,000 μg/L have been associated with decreased survival and increased risk of leukemic transformation in MDS patients.18 Several guidelines for MDS management thus recommend starting iron chelation therapy when serum ferritin levels reach values of >1,000 μg/L.12,19
- Arosio P, Ingrassia R, Cavadini P. Ferritins: a family of molecules for iron storage, antioxidation and more. Biochim Biophys Acta. 2009;1790(7):589-599.
- Jensen P-D. Evaluation of iron overload. British Journal of Haematology. 2004;124(6):697-711.
- Rosario C, Zandman-Goddard G, Meyron-Holtz EG, et al. The hyperferritinemic syndrome: macrophage activation syndrome, Still's disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med. 2013;11:185.
- Olivieri NF, Brittenham GM, Matsui D, et al. Iron-chelation therapy with oral deferipronein patients with thalassemia major. N Engl J Med. 1995;332(14):918-922.
- Brittenham GM, Cohen AR, McLaren CE, et al. Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am J Hematol. 1993;42(1):81-85.
- Musallam KM, Rivella S, Vichinsky E, et al. Non-transfusion- dependent thalassemias. Haematologica. 2013;98(6):833-844.
- Taher A, El Rassi F, Isma'eel H, et al. Correlation of liver iron concentration determined by R2 magnetic resonance imaging with serum ferritin in patients with thalassemia intermedia. Haematologica. 2008;93(10):1584-1586.
- Adamkiewicz TV, Abboud MR, Paley C, et al. Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury. Blood. 2009;114(21):4632-4638.
- Musallam KM, Angastiniotis M, Eleftheriou A, et al. Cross-talk between available guidelines for the management of patients with beta-thalassemia major. Acta Haematol. 2013;130(2):64-73.
- Cappellini MD, Cohen A, Porter J, et al. Guidelines for the management of transfusion dependent thalassemia (TDT). 3rd Ed. Nicosia, Cyprus: Thalassemia International Federation; 2014.
- Taher A, Vichinsky E, Cappellini MD, et al. Guidelines for the management of non-transfusion dependent thalassemia (NTDT). Nicosia, Cyprus: Thalassemia International Federation; 2013.
- Bennett JM, MDS Foundation's Working Group on Transfusional Iron Overload. Consensus statement on iron overload in myelodysplastic syndromes. Am J Hematol. 2008;83(11):858-861.
- Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med. 1994;331(9):574-578.
- Belhoul KM, Bakir ML, Saned MS, et al. Serum ferritin levels and endocrinopathy in medically treated patients with beta thalassemia major. Ann Hematol. 2012;91(7):1107-1114.
- Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89(10):1187-1193.
- Musallam KM, Cappellini MD, Daar S, et al. Serum ferritin level and morbidity risk in transfusion-independent patients with beta-thalassemia intermedia: the ORIENT study. Haematologica. 2014;99(11):e218-221.
- de Montalembert M, Ferster A, Colombatti R, et al. ENERCA clinical recommendations for disease management and prevention of complications of sickle cell disease in children. Am J Hematol. 2011;86(1):72-75.
- Sanz G, Nomdedeu B, Such E, et al. Abstract 640: Independent impact of iron overload and transfusion dependency on survival and leukemic evolution in patients with myelodysplastic syndrome. Blood. 2008;112:abstract 640.
- Malcovati L, Hellstrom-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943-2964.