Ferritin

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):

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

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