Biomarkers of Iron Status: Ferritin

Optimal Takeaways

Ferritin is the storage form of iron; circulating levels usually reflect storage levels, and an elevated level may indicate iron overload. However, as an acute-phase protein, ferritin can increase during inflammation, infection, cancer, and acute illness without chronic iron overload. Low ferritin levels can be seen in iron deficiency and its associated anemia, as well as hypoferritinemia without anemia. Hypothyroidism and vitamin C insufficiency may be associated with low serum ferritin as well.

Standard Range: 16 - 232 ng/mL (16 - 232 ug/L)      

The ODX Range: 45 - 79 ng/mL (45 - 79 ug/L)  

Low ferritin is seen in decreased iron storage, iron insufficiency, iron-deficiency anemia, severe protein deficiency, blood loss, menstruation, hemodialysis (Pagana 2021), and hereditary hemorrhagic telangiectasia (Locke 2022). Low ferritin may also be associated with hypoferritinemia without anemia (Al-Jafar 2017), vitamin C/ascorbate insufficiency, hypothyroidism (Knovich 2009), and bariatric surgery (Bjørklund 2021, Sandvik 2021).

High ferritin can be seen with recent transfusion, iron overload, hemosiderosis, hemochromatosis, chronic hepatitis, chronic liver disease, alcoholism, malignancy, metastatic cancer, uremia, collagen vascular disease, inflammation, infection, and megaloblastic, hemolytic, and sideroblastic anemias (Pagana 2021). Increased ferritin after menopause may be associated with insulin resistance (Kim 2012).

Overview

Ferritin is the major iron storage protein. Serum ferritin typically reflects iron stores, i.e., 1 ng/mL of ferritin in serum reflects 8 mg of iron in storage. Decreased serum levels reflect iron insufficiency, while increased levels reflect iron overload. However, as an acute-phase reactant, increased serum ferritin can also be seen with inflammation, infection, lymphoma, and metastases. Increased ferritin associated with acute illness usually peaks in 3-5 days and should be transient (Pagana 2021).

Elevated ferritin had adverse outcomes in the prospective randomized Iron and Atherosclerosis Study (FeAST) that looked at the use of phlebotomy in peripheral artery disease patients. Higher ferritin was associated with increased inflammatory biomarkers, including TNF-alpha, IL-6, and hs-CRP, disease severity, and increased mortality. Ferritin above 100 ng/mL was associated with a significantly increased risk of cardiovascular disease and type 2 diabetes, while a level as high as 127 ng/mL was associated with cancer. Those not developing cancer had significantly lower ferritin with a mean of 76.4 ng/mL. A ferritin between 70-79 ng/mL was associated with lower mortality and reduced levels of inflammatory markers (DePalma 2021).

The association of ferritin with cardiovascular disease is not always clear-cut or consistent across genders. One population-based study of 2,874 subjects suggests that ferritin of 60-65 ng/mL in women appears optimal, with cardiovascular risk more likely to increase above or below that level. However, the study did not find the same association in men (Friedrich 2009).

Another study of 5,471 individuals, the English Longitudinal Study of Ageing, found no association of elevated ferritin with cardiovascular disease in women. However, the study observed an increased cardiovascular risk and all-cause mortality in men with ferritin levels above 194 ng/mL. This effect was blunted when corrected for inflammation and lifestyle factors. Women in this study had an increased risk of all-cause mortality with lower ferritin levels of 2-44 ng/mL (Kadoglou 2017).

One longitudinal study of 70 women found a significant increase in ferritin from the pre- to the post-menopausal period, i.e., mean ferritin of 69.5 ng/mL versus a mean of 128.8 ng/mL, respectively. Higher ferritin in menopause was associated with an increased risk of Insulin resistance (Kim 2012).

Low ferritin appears to have a clearer and more robust association with adverse outcomes. Decreased ferritin reflects decreased iron, and ferritin below 30 ng/mL in healthy students was found to have a sensitivity of 100% and a specificity of 89% for bone marrow iron deficiency. Researchers also found that the optimal cut-off for predicting anemia would be cured with iron therapy was serum ferritin of 26 ng/mL (Daru 2017).

A study of whole blood donors confirmed that ferritin of 30 ng/mL or below reflected reduced erythropoiesis and was often accompanied by reduced hemoglobin, MCV, and reticulocytes (Dijkstra 2019). Iron depletion at this level is considered already advanced. It is important to rule out inflammation when evaluating iron deficiency anemia because ferritin acts as an acute phase reactant and may be falsely elevated with inflammation. Therefore transferrin saturation must also be measured (Munoz 2009). 

Researchers conducting a retrospective analysis confirmed the diagnostic accuracy of using ferritin to detect iron deficiency anemia, including using it as an alternative to bone marrow aspiration. They found that a cut-off of 41 ng/mL had a sensitivity and specificity of 98% in the absence of inflammation or infection (Asif 2016).

However, hypoferritinemia can also be seen without anemia (HWA), in which RBCs, hemoglobin, and CBC in general are within range. This condition may present with classic symptoms of fatigue, general weakness, hair loss, and depression despite a normal CBC (Al-Jafar 2017).

Low serum ferritin may also be associated with vitamin C/ascorbate insufficiency and hypothyroidism (Knovich 2009). Ascorbate increases iron absorption by making it soluble at a variety of gastrointestinal pH levels and its insufficiency can jeopardize iron absorption (Skolmowska 2022). In hypothyroidism, iron absorption may be impaired by increased production of hepcidin, a peptide hormone that blocks iron absorption (Garofalo 2023).

References

Al-Jafar, Hassan A. “HWA: Hypoferritinemia without anemia a hidden hematology disorder.” Journal of family medicine and primary care vol. 6,1 (2017): 69-72. doi:10.4103/2249-4863.214986

Asif, Naveed et al. “Diagnostic Accuracy of Serum Iron and Total Iron Binding Capacity (TIBC) in Iron Deficiency State.” Journal of the College of Physicians and Surgeons--Pakistan : JCPSP vol. 26,12 (2016): 958-961.

Bjørklund, Geir et al. “Iron Deficiency in Obesity and after Bariatric Surgery.” Biomolecules vol. 11,5 613. 21 Apr. 2021, doi:10.3390/biom11050613

Daru, Jahnavi et al. “Serum ferritin as an indicator of iron status: what do we need to know?.” The American journal of clinical nutrition vol. 106,Suppl 6 (2017): 1634S-1639S. doi:10.3945/ajcn.117.155960

DePalma, Ralph G et al. “Optimal serum ferritin level range: iron status measure and inflammatory biomarker.” Metallomics : integrated biometal science vol. 13,6 (2021): mfab030. doi:10.1093/mtomcs/mfab030

Dijkstra, Angelique et al. “Repeat whole blood donors with a ferritin level of 30 μg/L or less show functional iron depletion.” Transfusion vol. 59,1 (2019): 21-25. doi:10.1111/trf.14935

Friedrich, Nele et al. “Is serum ferritin within the reference range a risk predictor of cardiovascular disease? A population-based, long-term study comprising 2874 subjects.” The British journal of nutrition vol. 102,4 (2009): 594-600. doi:10.1017/S000711450922085X

Garofalo, Vincenzo et al. “Relationship between Iron Deficiency and Thyroid Function: A Systematic Review and Meta-Analysis.” Nutrients vol. 15,22 4790. 15 Nov. 2023, doi:10.3390/nu15224790

Kadoglou, Nikolaos P E et al. “The association of ferritin with cardiovascular and all-cause mortality in community-dwellers: The English longitudinal study of ageing.” PloS one vol. 12,6 e0178994. 7 Jun. 2017, doi:10.1371/journal.pone.0178994

Kim, Catherine et al. “Changes in iron measures over menopause and associations with insulin resistance.” Journal of women's health (2002) vol. 21,8 (2012): 872-7. doi:10.1089/jwh.2012.3549

Knovich, Mary Ann et al. “Ferritin for the clinician.” Blood reviews vol. 23,3 (2009): 95-104. doi:10.1016/j.blre.2008.08.001

Lee, Mark Hong et al. “Cut-off values of serum ferritin and TIBC saturation for the evaluation of gastrointestinal neoplasms in adult anemic patients.” International journal of hematology vol. 96,2 (2012): 214-21. doi:10.1007/s12185-012-1129-3

Locke, Tran, et al. “Hereditary Hemorrhagic Telangiectasia (HHT).” StatPearls, StatPearls Publishing, 11 June 2022.

Muñoz, Manuel et al. “An update on iron physiology.” World journal of gastroenterology vol. 15,37 (2009): 4617-26. doi:10.3748/wjg.15.4617 

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Sandvik, Jorunn et al. “Iron Deficiency and Anemia 10 Years After Roux-en-Y Gastric Bypass for Severe Obesity.” Frontiers in endocrinology vol. 12 679066. 22 Sep. 2021, doi:10.3389/fendo.2021.679066

Skolmowska, Dominika, and Dominika Głąbska. “Effectiveness of Dietary Intervention with Iron and Vitamin C Administered Separately in Improving Iron Status in Young Women.” International journal of environmental research and public health vol. 19,19 11877. 20 Sep. 2022, doi:10.3390/ijerph191911877