Revolution Health & Wellness
(918) 935-3636
Facebook Twitter YouTube RSS

Ferritin

As Seen On

Ferritin

ferritin level functional medicine

Ferritin is the protein that binds iron. However, elevated ferritin levels suggest potential problems. Elevated ferritin is something I’ve struggled with myself and I have to manage it.

Free iron is toxic to cells as it acts as a catalyst in the formation of free radicals from reactive oxygen species, which can initiate lipid peroxidation and tissue damage.1 Because of the toxicity of free iron we need an elaborate set of protective mechanisms to bind iron. Within cells, iron is stored in a non-toxic state with the protein, ferritin.

Fenton Reaction

Oxidation via iron occurs through what is call the Fenton Reaction:

Fe2+ + H2O2 → Fe3+ + OH– + OH•

First, Fe2+ (ferrous) iron must be freed where it is normally bound. H2O2 oxidizes Fe2+ (ferrous) to Fe3+ (ferric). These reactions form hydroxyl radicals which are highly reactive and are the most potent Reactive Oxygen Species (ROS).

The Haber Weiss Reaction:

H2O2 + O2• →OH– + OH•

This reaction is catalyzed by ferrous iron converting to ferric iron:

Fe2+ → Fe3+ (copper may do this same thing going from Cu2+ → Cu3+)

Ferritin is primarily secreted from the liver and also serves as the major carrier protein for iron, transporting it via the circulation to tissues. Under steady state conditions, serum ferritin levels correlate with total body iron stores. However, when there is cellular injury (e.g., acute inflammation) to organs that contain ferritin, such as the liver, spleen, and bone marrow, ferritin levels can become elevated, even though the total ferritin content in the body is normal.2

The ferritin lab test is performed by immunoassay. Ferritin’s risk-based cut-points for insulin resistance are as below (ng/mL):

Female Male
Low <61 <147
Intermediate 61-108 147-252
High >108 >252

N.B. Ranges of ferritin used for assessment of insulin resistance and diabetes risk differ from reference ranges used to diagnose conditions specifically related to iron nutrient status, e.g., iron deficiency or hemochromatosis.

Clinical Interpretation

Increased ferritin levels are associated with insulin resistance, diabetes, and cardiovascular disease.

Many population-based studies have reported alterations in inflammatory, metabolic, and oxidative stress markers associated with high ferritin concentration.4,5 Increased iron stores are also associated with increased risk of type-2 diabetes mellitus (T2DM),1,6-8 gestational diabetes,9 prediabetes,10 and cardiovascular disease (CVD).5,11-14

Elevated circulating ferritin levels are positively associated with increased prevalence of the metabolic syndrome (MetS) and elements that contribute to it, (e.g., waist circumference),14-16 Serum ferritin shows a linear increase with an increasing number of Metabolic Syndrome features.15,17

The highest quartile of ferritin in a recent study was associated with a 3-fold risk of developing Metabolic Syndrome compared to the lowest quartile.18 In fact insulin resistance and Type-2 Diabetes are common manifestations of iron overload disorders such as hereditary hemochromatosis.19,20 These patients show evidence of oxidative stress, impaired glucose metabolism, and endothelial dysfunction that reverts with iron depletion, and recent studies have confirmed the presence of atherogenic dyslipidemia related to elevated iron stores, particularly hypertriglyceridemia, which is characteristic of Metabolic Syndrome and confers high risk for CVD.21

Multiple prospective studies have since shown that an increase in serum ferritin concentration is associated independently with glucose metabolism, insulin resistance, and increased risk of T2DM in the general population.6,7,8,22-24 High ferritin levels were a significant predictor of hypertension in a large sample of middle-aged Korean men and a representative German population sample of 1070 individuals.3,25 In the latter study, the severity of MetS was associated with increased ferritin levels, thereby indicating a causal connection. Moreover, median ferritin levels increased as the number of Metabolic Syndrome components increased in both genders, especially men, where they were elevated 2-fold.3

Studies in the Korean population have shown how men and women differ with regard to the role of ferritin in insulin resistance and glucose regulation. Interestingly, elevated ferritin concentrations were associated with increased triglyceride concentrations in Korean adult males and glucose intolerance in Korean women.26 Another study found that elevated ferritin levels were associated with insulin resistance, Type-2 Diabetes, impaired fasting glucose, and Metabolic Syndrome in Korean adult males and only impaired fasting glucose in Korean women.27 The reasons for these discrepancies are not clear, but genetic and dietary/lifestyle factors may play a role.

In a 7-year follow-up of 27,548 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study, higher serum ferritin levels were associated with a significantly higher risk of Type-2 Diabetes (relative risk from highest to lowest quintile, 1.7; p = 0.002).24 Elevated serum ferritin levels have been shown to correlate with impaired fasting glucose levels in prediabetic subjects,10 and were reportedly increased in women presenting with polycystic ovary syndrome (PCOS) and/or abnormal glucose tolerance (independent of obesity).25

Mechanisms underlying the relationship between iron and diabetes risk. Although the exact mechanisms are unknown, the link between ferritin levels and risk for diabetes may be mediated via the free radical-induced oxidative stress resulting from iron overload.28 Decreases in both insulin secretion and sensitivity have been linked to iron, ultimately leading to impaired pancreatic β-cell function and β-cell apoptosis or failure.29,30 Several cross- sectional and longitudinal studies have shown that serum ferritin is associated with muscle insulin resistance, as measured by HOMA-IR or by hyperinsulinemic-euglycemic clamp.15,16,31 The finding that several markers of iron metabolism are associated with adipocyte insulin resistance (defined as the product of fasting insulin and free fatty acids) suggests that iron also contributes to the early pathogenesis of T2DM by the induction of insulin resistance in adipose tissue.32 A negative correlation between serum ferritin and adiponectin levels in this and other studies supports this conclusion.32,33

Ferritin and adiponectin 

It has been shown that the association between serum ferritin and adiponectin is independent of inflammation and that serum ferritin is an excellent predictor of serum adiponectin. Studies in cell culture, mouse models, and humans have shown that iron plays a direct, causal role in determining adiponectin levels and risk for diabetes, and that the adipocyte functions as an iron sensor.34

In subjects with diabetes, serum ferritin levels are 2-fold higher (p = 0.0004) and adiponectin levels 24% lower (p = 0.012); consistent with this, insulin sensitivity is inversely correlated with ferritin (r = 0.365, p = 0.0003) and directly correlated with adiponectin levels (r = 0.354, p = 0.0004) in the general population.34 As adiponectin is causally linked to insulin sensitivity, changes in adiponectin in response to iron are accompanied by changes in glucose tolerance and insulin sensitivity.35

Ferritin and inflammation

Ferritin is also an acute phase reactant, whose production is stimulated by infection or pro-inflammatory cytokines, and thus may be increased in people with chronic infection or inflammation, liver disease, autoimmune disorders (e.g., rheumatoid arthritis), and some types of cancer.36 Therefore, serum ferritin is a marker of both insulin resistance and chronic inflammation in patients with Metabolic Syndrome or Type-2 Diabetes.37

A normal level of C-reactive protein can be used to exclude elevated ferritin caused by acute phase reactions. In addition to regulating adiponectin, the fact that iron is also involved in determining insulin secretory capacity may explain the observed associations among iron, glucose tolerance, and Metabolic Syndrome.34 Accumulating evidence also suggests a link between serum ferritin, insulin resistance, and non-alcoholic fatty liver disease (NAFLD), which may underlie the association between serum ferritin and Metabolic Syndrome.38,39

Ferritin and Cardiovascular Disease

As stated above, iron can be incredibly toxic. Peroxidation of LDL (oxidized LDL, oxLDL) is increased by iron-mediated oxidative stress. This peroxidation contributes to dyslipidemia related (and non-lipid reactive oxygen species) endothelial dysfunction, atherosclerosis, and cardiovascular disease. However, the increased risk of cardiovascular diseaase, MI, and carotid artery disease associated with increased iron levels is genetic and not universal.53

The cardiovascular disease associated with iron is related to the severity of perfusion and functional abnormalities of coronary arteries but not always anatomic angiographic obstruction. Microvascular angina and endothelial dysfunction of the coronary arteries. Increased iron levels compound cardiovascular disease with dyslipidemia and other cardiovascular risk factors.

Interestingly, iron supplementation directly increases LDL cholesterol levels.

Serum ferritin = iron stores (and cardiovascular disease risk). 3/22 studies show a positive correlation with iron and cardiovascular disease. A Finnish study showed that a ferritin >200 doubles the risk of cardiovascular disease. Ferritin x 10 = iron stores.

Increased serum iron levels are associated with a stepwise increase in all cause mortality in the setting of acute coronary syndrome (ACS).54,55

A controlled reduction of body iron stores reduce peripheral artery disease (PAD), heart attack (MI), and stroke (CVA).56 Lower iron burdens and controlled phlebotomy improved cardiovascular outcomes of peripheral artery disease, MI, CVA, and life expectancy. In other words, give blood to get your iron levels down.

Ferritin levels of 76.5 ng/mL had the lowest event rate for cardiovascular disease57

Other conditions where ferritin levels may be high

Serum ferritin levels are usually high in patients with

  • hemochromatosis
  • hemosiderosis
  • chronic disease processes (e.g., cirrhosis or hepatitis)
  • alcoholism
  • thalassemia
  • conditions that cause increased red blood cell turnover,
  • chronic blood transfusions.
  • adult-onset Still’s disease
  • porphyria
  • hemophagocytic lymphohistiocytosis
  • infections and inflammatory diseases (e.g., rheumatoid arthritis or lupus)
  • leukemia
  • excessive dietary intake of iron
  • periods of acute malnourishment40

Treatment Considerations

Screening and treatment for hereditary hemochromatosis are recommended, especially in patients with abnormal liver function tests (expanded iron studies and/or genetic testing for hereditary hemochromatosis). Postmenopausal women tend to have higher ferritin levels and are at greater risk for insulin resistance, Metabolic Syndrome, and NAFLD. 41

Body iron can be reduced by iron depletion therapies, such as dietary restriction, iron chelators, or phlebotomies. Repeat phlebotomy, in particular, has been shown to be an effective, though not widely employed, therapy for type-2 diabetics with elevated ferritin.42-43 A healthy diet is important, including plenty of antioxidant-rich fresh fruit and vegetables, plus treatment for insulin resistance/prediabetes/inflammation as necessary.

References

  1. Corti MC, Gaziano M, Hennekens CH. Iron status and risk of cardiovascular disease. Ann Epidemiol 1997;7:62–68.
  2. Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta 1996;1275:161-203.
  3. Wrede CE, Buettner R, Bollheimer LC, et al.. Association between serum ferritin and the insulin resistance syndrome in a representative population. Eur J Endocrinol 2006;154(2):333-40.
  4. Tuomainen TP, Diczfalusy U, Kaikkonen J, Nyyssonen K, Salonen JT. Serum ferritin concentration is associated with plasma levels of cholesterol oxidation products in man. Free Radic Biol Med 2003;35:922–8.
  5. Tsimikas S, Willeit J, Knoflach M, et al. Lipoprotein-associated phospholipase A2 activity, ferritin levels, metabolic syndrome, and 10-year cardiovascular and non-cardiovascular mortality: results from the Bruneck study. Eur Heart J 2009;30:107-115.
  6. Forouchi NG, Harding AH, Allison M, et al. Elevated serum ferritin levels predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective study. Diabetologica 2007;50:949-56.
  7. Jehn ML, Guallar E, Clark JM, et al. A prospective study of plasma ferritin level and incident diabetes. The Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 2007;165:1047–1054.
  8. Fernandez-Real JM, Lopez-Bermejo A, Ricart W. Cross-talk between iron metabolism and diabetes. Diabetes 2002;51(8):2348-2354.
  9. Afkhami-Ardekani M, Rashidi M. Iron status in women with and without gestational diabetes mellitus. J Diabetes Complications 2009;23(3):194-198.
  10. Sharifi F, Nasab NM, Zadeh HJ. Elevated serum ferritin concentrations in prediabetic subjects. Diabetes Vasc Dis Res 2008;5:15–18.
  11. Salonen JT, Nyyssonen K, Korpela H et al. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 1992;86:803–811.
  12. Kiechl S, Willeit J, Egger G, et al. Body iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck study. Circulation 1997;96:3300-3307.
  13. Olesnevich ME, Kuczmarski MF, Mason M, Fang C, Zonderman AB, Evans MK. Serum ferritin levels associated with increased risk for developing CHD in a low-income urban population. Public Health Nutr 2012;10:1-8.
  14. Suárez-Ortegón MF, Arbeláez A, Mosquera M, Méndez F, Aguilar-de Plata C. C-Reactive Protein, waist circumference, and family history of heart attack are independent predictors of body iron stores in apparently healthy premenopausal women. Biol Trace Elem Res 2012;148(2):135-8.
  15. Jehn M, Clark JM, Guallar E. Serum ferritin and risk of the metabolic syndrome in US adults. Diabetes Care 2004;27:2422-8.
  16. Syrovatka P, Kraml P, Potockova J, et al. Relationship between increased body iron stores, oxidative stress and insulin resistance in healthy men. Ann Nutr Metab 2009;54:268-274.
  17. Bozzini C, Girelli D, Olivieri O, Martinelli N. Prevalence of body iron excess in the metabolic syndrome. Diabetes Care 2005;28:2061-2063.
  18. Leiva A, Mujica V, et al. High levels of iron status and oxidative stress in patients with metabolic syndrome. Biol Trace Elem Res. 2013;151(1):1-8.
  19. McClain DA, Abraham D, Rogers J, et al. High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis. Diabetologia 2006;49:1661–9.
  20. Gaenzer H, Marschang P, Sturm W, et al. Association between increased iron stores and impaired endothelial function in patients with hereditary hemochromatosis. J Am Coll Cardiol 2002;40:2189–94.
  21. Merono T, Rosso LG, Sorroche P, et al. High risk of cardiovascular disease in iron overload patients. Eur J Clin Invest 2011;41(5):479–486.
  22. Salonen JT, Tuomainen TP, Nyyssonen K, Lakka HM, Punnonen K. Relation between iron stores and non-insulin dependent diabetes in men: case-control study. BMJ 1998;317:727.
  23. Jiang R, Manson JE, Meigs JB, et al. Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. JAMA 2004;291:711-7.
  24. Montonen J, Boeing H, Steffen A, et al. Body iron stores and risk of type 2 diabetes: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. Diabetologica 2012;55:2613-2621.
  25. Martinez-Garcia MA, Luque-Ramirez M, et al. Body iron stores and glucose intolerance in premenopausal women. Diabetes Care 2009;32:1525-1530.
  26. Kang H-T, Linton JA, Shim J-Y. Serum ferritin level is associated with the prevalence of metabolic syndrome in Korean adults: The 2007– 2008 Korean National Health and Nutrition Examination Survey. Clinica Chimica Acta 2012;413:636–641.
  27. Kim C-H, Kim H-K, et al. Association of elevated serum ferritin concentration with insulin resistance and impaired glucose metabolism in Korean men and women. Metabolism Clinical and Experimental 2011;60:414–420.
  28. Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006;440:944-948.
  29. McClain D, et al. High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis. Diabetologica 2006;49(7):1661-1669.
  30. Cooksey RC, et al. Dietary iron restriction or iron chelation protects from diabetes and loss of beta-cell function in the obese (ob/ob lep -/-) mouse. Am J Physiol Endocrinol Metab 2010;298(6):E1236-1243.
  31. Haap M, Fritsche A, Mensing HJ, Haring HU, Stumvoll M. Association of high serum ferritin concentration with glucose intolerance and insulin resistance in healthy people. Ann Intern Med 2003;139:869-871.
  32. Wiazlo N, van Greevenbroek MJ, Ferreira I, et al. Iron metabolism is associated with adipocyte insulin resistance and plasma adiponectin. Diabetes Care 2013; 36(2):309-15.
  33. Ku B-J, Kim S-Y, Lee T-Y, Park K-S. Serum ferritin is inversely correlated with serum adiponectin level: population-based cross-sectional study. Dis Markers 2009;27(6):303-310.
  34. Gabrielsen JS, Gao Y, Simcox JA, et al. Adipocyte iron regulates adiponectin and insulin sensitivity. J Clin Invest 2012;122(10):3529-40.
  35. Kubota N, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 2002;277(9):25863-25866.
  36. Kim MK, Baek KH, Song KH, Kang MI, Choi JH, et al. Increased serum ferritin predicts the development of hypertension among middle-aged men. Am J Hypertens 2012;25(4):492-7.
  37. Rajpathak SN, Crandall JP, Wylie-Rosett J, et al. The role of iron in type 2 diabetes in humans. Biochim Biophys Acta 2009;1790:671-81.
  38. Zelber-Sagi S, Nitzan-Kaluski D, Halpern Z, Oren R. NAFLD and hyperinsulinemia are major determinants of serum ferritin levels. J Hepatol 2007;46:700-707.
  39. Trombini P, Piperno A. Ferritin, metabolic syndrome and NAFLD: Elective attractions and dangerous liaisons. J Hepatol 2007;46:549-552.
  40. Papillard-Marrechal S, Sznaider M, et al. Iron metabolism in patients with anorexia nervosa: elevated serum hepcidin concentrations in the absence of inflammation. Am J Clin Nutr 2012;95(3):548-54.
  41. Cho GJ, Shin JH, Yi KW, Park HT, Kim T, Hur JY, Kim SH. Serum ferritin levels are associated with metabolic syndrome in postmenopausal women but not in premenopausal women. Menopause 2011;18(10):1120-4.
  42. Gabrielsen JS, Gao Y, Simcox JA, Huang J, Thorup D, et al. Adipocyte iron regulates adiponectin and insulin sensitivity. J Clin Invest 2012;122(10):3529-40.
  43. Hatunic M, Finucane FM, Norris S, Pacini G, Nolan JJ. Glucose metabolism after normalization of markers of iron overload by venesection in subjects with hereditary hemochromatosis. Metabolism 2010;59(12):1811-5.
  44. Fernández-Real JM, Peñarroja G, Castro A, García-Bragado F, Hernández-Aguado I, Ricart W. Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function. Diabetes 2002;51(4):1000-4.
  45. Mirza NM, Palmer MG, Sinclair KB, McCarter R, He J, Ebbeling CB, Ludwig DS, Yanovski JA. Effects of a low glycemic load or a low-fat dietary intervention on body weight in obese Hispanic American children and adolescents: a randomized controlled trial. Am J Clin Nutr 2013;97:276-285.
  46. Yki-Ja¨rvinen H. Nutritional modulation of nonalcoholic fatty liver disease and insulin resistance: human data. Curr Opin Clin Nutr Metab Care 2010;13(6):709-14.
  47. Bradley U, Spence M, Courtney CH, McKinley MC, Ennis CN, McCance DR, McEneny J, Bell PM, Young IS, Hunter SJ. Low-fat versus low-carbohydrate weight reduction diets: effects on weight loss, insulin resistance, and cardiovascular risk: a randomized control trial. Diabetes 2009;58(12):2741-8.
  48. Ross R, Janssen I, Dawson J, Kungl AM, Kuk JL, Wong SL, Nguyen-Duy TB, Lee S, Kilpatrick K, Hudson R. Exercise-induced reduction in obesity and insulin resistance in women: a randomized controlled trial. Obes Res 2004;12(5):789-798.
  49. O’Hagan C, De Vito G, Boreham CA. Exercise prescription in the treatment of type 2 diabetes mellitus : current practices, existing guidelines and future directions. Sports Med 2013;43:39-49.
  50. Davidson LE, Hudson R, Kilpatrick K, Kuk JL, McMillan K, Janiszewski PM, Lee S, Lam M, Ross R. Effects of exercise modality on insulin resistance and functional limitation in older adults: a randomized controlled trial. Arch Intern Med 2009;169(2):122-131.
  51. Williams MA, Haskell WL, et al. American Heart Association Council on Clinical Cardiology; American Heart Association Council on Nutrition, Physical Activity, and Metabolism. Resistance exercise in individuals with and without cardiovascular disease: 2007 update: a scientific statement from the American Heart Association Council on Clinical Cardiology and Council on Nutrition, Physical Activity, and Metabolism. Circulation 2007;116:572-584.
  52. Aguilar RB. Evaluating treatment algorithms for the management of patients with type 2 diabetes mellitus: a perspective on the definition of treatment success. Clin Ther 2011;33(4):408-24. Moore EM, Mander AG, Ames A, et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 2013;36(10):2981-7.
  53. NEJM 2012;366:348-59
  54. Clin Cardiol 2013;36:139
  55. Am Heart J 2013;165:744
  56. J of Nutritional Biochemistry 2013;24:1634
  57. Am Heart J 2011;162:949