Does Iron Overload Cause Diabetes and Heart Disease? | Kresser Institute

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Does Iron Overload Cause Diabetes and Heart Disease?

on September 27, 2017

by Chris Kresser

Iron plays an essential role in many physiological processes, including oxygen transport and mitochondrial energy production. However, more iron is not necessarily better! The overaccumulation of iron in the body, a condition referred to as iron overload, has been implicated in the development of several chronic diseases, including diabetes and heart disease. Read on to learn why iron overload promotes the development of diabetes and heart disease and how iron reduction strategies can be used to beneficially alter the course of these diseases.


What is iron overload?

Iron overload occurs when excess iron accumulates in the body. The most common cause of iron overload is hereditary hemochromatosis (HH), an autosomal recessive genetic disorder that affects between one in 200 and one in 400 individuals and is caused by mutations in the HFE C282Y and H63D genes. (1) HH is characterized by significantly enhanced intestinal iron absorption and the abnormal accumulation of iron in bodily organs. Excess iron oxidatively damages cells and tissues, essentially “rusting” the body. This generates organ toxicity and promotes chronic disease processes.

However, a negative test result for the C282Y and H63D mutations does not mean a person is “off the hook” for iron overload. In fact, carriers of HFE mutations and people with moderately elevated iron levels also have an increased risk of health complications associated with iron overload. (2) Alarmingly, research indicates that iron overload may be a significant but greatly underappreciated cause of two widely prevalent chronic diseases, diabetes and heart disease.

Iron overload is a risk factor for metabolic syndrome and diabetes

The association between iron overload and diabetes was first noted in people with hereditary hemochromatosis. However, the effects of iron overload on glucose and insulin homeostasis are not limited to those with hemochromatosis. A growing body of research indicates that moderately elevated serum ferritin levels, well within the normal laboratory reference range, are associated with abnormal blood sugar, insulin resistance, metabolic syndrome, and diabetes. (3, 4, 5, 6) In fact, the constellation of high serum ferritin, insulin resistance, and glucose dysregulation has become common enough among the general population to warrant its own name—dysmetabolic iron overload syndrome (DIOS).

Have you had your iron levels checked? If you have heart disease or diabetes you should.

While serum ferritin is the most well-studied biomarker in relation to metabolic syndrome and diabetes, another important iron regulatory hormone, hepcidin, has also been associated with these conditions. (7) Hepcidin inhibits intestinal iron absorption, and in people without HFE mutations, it is upregulated in the presence of high body iron. However, elevated hepcidin may also detrimentally alter genes that govern insulin production, thus causing this protective function to backfire. Altogether, the available evidence suggests that “normal” iron levels may not be ideal and that iron overload may affect far more people than once believed.

There are several mechanisms by which iron physiologically impacts glucose and insulin homeostasis. Iron is catalytically reactive and readily interacts with endogenously produced hydrogen peroxide in a process called the Fenton reaction. This reaction produces hydroxyl free radicals, which oxidatively damage cells and tissues, including pancreatic beta-cells. The iron-induced free radical damage sustained by pancreatic beta-cells decreases insulin synthesis and secretion, contributing to insulin resistance. (8, 9) Iron overload also decreases glucose oxidation, impairing the utilization of glucose for fuel, and increases hepatic glucose production. (10, 11) Finally, iron has a proclivity for adipocytes; the accumulation of iron in fat cells reduces their production of the insulin-sensitizing hormone adiponectin, thus inducing insulin resistance.

While the harmful effects of iron overload on glucose and insulin homeostasis are concerning, it is possible to mediate the damage. Interestingly, the induction of near iron deficiency through therapeutic phlebotomy has been found to significantly lower postprandial blood glucose, improve glucose tolerance, and increase adiponectin, indicating that reduction of iron stores may be beneficial for the treatment of metabolic syndrome and diabetes. (12, 13)

Excess iron harms the cardiovascular system

Cardiovascular disease (CVD) is the single largest cause of mortality in the world, and a growing body of evidence indicates that iron overload may play a significant role in its pathogenesis. Iron overload was first correlated with CVD in people with hereditary hemochromatosis. However, current evidence indicates that even moderately elevated body iron levels confer an increased risk of cardiovascular disease. (14)

Several epidemiological studies have revealed that men with serum ferritin levels above 200 µg/L have a significantly increased risk of atherosclerosis and ischemic cardiovascular disease. (15, 16) A similar association has been discovered in postmenopausal women, with high serum ferritin conferring an increased risk of cardiovascular complications. The risk for women appears to increase after menopause because the regular iron losses associated with menstruation have ceased, leading to iron accumulation. (17) Serum ferritin is also positively associated with increased carotid arterial plaque, coronary artery calcium content, and carotid arterial thickness, factors that promote the progression of atherosclerosis. (18, 19, 20)

Several studies have noted that the relationship between iron levels and CVD is stronger in people with elevated LDL concentrations and the ApoE4 gene variant, which has been linked to higher levels of oxidized LDL; this suggests that LDL may interact with ferritin, potentially through the process of lipid peroxidation, to increase the risk of CVD.

The primary mechanism by which iron harms the cardiovascular system is through the production of free radicals. In the Fenton reaction, mentioned previously in the context of iron and diabetes, iron reacts with hydrogen peroxide to create hydroxyl free radicals. Hydroxyl free radicals oxidize LDL particles and free fatty acids, contributing to the development of atherosclerosis and CVD. (21) Elevated hepcidin may also contribute to iron-induced cardiovascular damage by promoting the destabilization of fatty arterial plaques, a phenomenon implicated in the development of atherosclerosis. (22, 23)

How to assess iron overload

Serum ferritin and hepcidin are two key markers for diagnosing iron overload; however, they are also acute-phase reactants that are elevated in the inflammatory response. To distinguish between iron overload and inflammation, a handful of other tests should be performed. These include measurements of iron saturation, soluble transferrin receptor, C-reactive protein and A1-acid glycoprotein, and HFE genetic testing. An elevated iron saturation measurement is indicative of iron overload, whereas the soluble transferrin receptor level will be low when iron is present in excess. C-reactive protein and A1-acid glycoprotein are acute-phase reactants that are elevated in the inflammatory response and can be used to distinguish between iron overload and inflammation—though it’s important to note that a normal C-reactive protein does not rule out inflammation as a cause of high ferritin. HFE genetic testing can reveal whether a patient possesses HFE C282Y or H63D variants. For more information on the diagnosis of iron overload, check out the ADAPT Academy Focus Seminar on Iron Deficiency and Iron Overload.

What treatment options are available for iron overload?

Within the scientific community, the role of iron as a risk factor for diabetes and cardiovascular disease has drawn significant attention because it may be easily modifiable through dietary modification and other iron reduction strategies. Historically, phlebotomy and iron-chelating pharmaceuticals have been the frontline treatment for iron overload in people with hereditary hemochromatosis. However, recent research indicates that iron reduction may also be beneficial for people with mild to moderate iron overload. Iron chelation and phlebotomy produce improvements in insulin secretion and sensitivity, decrease glycated hemoglobin, and improve endothelial function in patients with and without hemochromatosis. (24, 25, 26, 27) For patients with severe iron overload, a prescription for therapeutic phlebotomy from a hematologist may be required; for those with milder cases, regular blood donations may be sufficient for lowering iron levels.

Specific dietary guidelines have been created for patients with hemochromatosis, and some of the recommendations may also be useful for people with mild to moderate iron overload. (28) The guidelines, developed by the Iron Disorders Institute, include the following:

  • Avoid organ meats, venison, and shellfish. These foods are all very high in heme iron.
  • Limit consumption of beef and lamb, which are also high in heme iron, to two or three times per week. Heme iron is more bioavailable than non-heme iron, present in plant foods such as legumes, grains, nuts, and seeds.
  • Limit supplemental vitamin C to 200 mg/day. Supplemental vitamin C enhances intestinal iron absorption, but vitamin C from foods is fine.
  • Avoid alcohol and sugar. Alcohol and sugar enhance intestinal iron absorption.
  • Avoid supplements/multivitamins that contain iron.
  • Eat a wide variety of fruits and vegetables. Plant foods contain polyphenols and oxalates that inhibit iron absorption and antioxidants that counteract iron-induced free radical damage.
  • Drink tea or coffee with meals. The tannins in these beverages inhibit iron absorption.

While phlebotomy, pharmaceutical iron chelators, and dietary changes are currently the prevailing treatment options for iron overload, a wide variety of natural compounds have also been investigated for their iron-reducing potential. Green tea catechins have been found to chelate iron and scavenge free radicals; these dual roles may be beneficial for simultaneously reducing iron-overload and combating free radical damage in people with diabetes and CVD. (29, 30) Quercetin, a phytochemical found in a wide variety of fruits and vegetables, also inhibits intestinal iron absorption and reduces iron-induced free radical damage. (31, 32) Curcumin, an herb that has been lauded for its many health-promoting properties, has also demonstrated an ability to chelate iron. (33, 34) A handful of other herbs and plant compounds have demonstrated iron-chelating and free radical-scavenging activity, including Chinese skullcap, pycnogenol, and Ligusticum wallichi. (35, 36, 37) Finally, the iron-binding protein apolactoferrin binds and sequesters iron outside of the bloodstream and is protective against iron-mediated free radical damage. This protein occurs naturally in the body but can be supplemented in a form derived from cow’s milk. (38) While more research is needed to determine the clinical efficacy of these natural iron-binding compounds, the available evidence is promising and suggests that non-pharmaceutical iron-reduction strategies may soon be viable treatment options for patients with moderate iron overload.

Now I want to hear from you! Have you observed a relationship between iron overload, diabetes, and heart disease in your patients? Do you have experience with any of the iron-reduction strategies outlined in this article? Let me know in the comments below.

14 Comments

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  1. Fantastic article! In my experience there is an increase in iron infusions especially amongst teenage girls. My personal experience was an iron infusion following a prolonged undiagnosed chronic infection (salmonella java). Followed by years of high iron, I had episodes of high fasting BSL’s, elevated CRP, high visceral fat, extremely low BMR, joint pain and a known carrier of haemachromatosis gene. I wonder if my years of prolonged elevated iron contributed to my issues and whether we should be so quick to infuse iron.

  2. As a pediatrician, I almost never see iron overload or even normal serum ferritin. I often see iron deficiency anemia and extremely low ferritin levels in children and teens on the average American processed food diet, drinking milk with every meal. If adults have issues with high ferritin, I suppose you could suggest they simply drink a glass of milk with each meal. It’s highly effective at inhibiting iron absorption in children!

  3. Hi Dr. Kresser,
    Thank you for the excellent articles about iron. We have followed you for some time now. After studying iron for nearly twenty years I shake my head at the same nonsensical comments made by some clinicians that you mention in your cover email. As a patient advocacy organization, we have worked tirelessly to bring awareness to the medical community about the importance of elevated serum ferritin only to have our efforts diminished in importance by a study flawed with ascertainment bias, but one that delivers the message to physicians that no harm is taking place until serum ferritin reaches 1,000ng/mL. That’s like getting a diagnosis of cancer and waiting until it metastasizes to begin therapy. Please keep up the good work and we will continue to promote your excellent posts and articles to our members and contacts. Think ferro-toxicity; that’s a word used by members of our scientific and medical advisory board who know the dangers of excess iron.
    Take care, Cheryl Garrison, Executive Director, Iron Disorders Institute

  4. Did you mention the differences between bioavailable and not? Not just for iron but for copper? Did you mention ceruloplasmin and how important it is to control iron and keep it in circulation and behanpving properly?

    Have toy ever read the nearly 70 articles written about iron by the magnesium Man, Morley Robbins?

    Check out gotmag.org

    • Also, do you realize that the bio-available copper in liver is necessary for healthy ceruloplasmin levels and while you caution against taking more than 200 mg of vitamin C, do you realize that only applies to synthetic vitamin C (aka ascorbic acid). Real vitamin C from food sources contains copper as part of its molecule that again promotes healthy ceruloplasmin levels and is necessary to control iron. Real vitamin C also contain natural bioflavonoids which store effective blocking agents or chelators of iron.

  5. Chris:
    So I am missing the ideal functional ranges for the metrics you are referring to here. Can you please address?
    Serum Iron
    Ferritin
    TIBC
    Transferrin

    Thank you. I signed up for the Adapt Academy for my pharmacists in my business. Still trying to decide the best way to use it for them but excited for the opportunity to present it to them!

  6. Hi Chris, I’m quite interested in this topic, given that my mother and I both have elevated ferritin levels, as well as high cholesterol.
    We follow a mostly whole foods paleo-style diet and we have both started to donate blood regularly, which has helped improve our ferritin levels.
    I’m curious about your thoughts regarding the dietary guidelines put together by the Iron Disorders Institute. Do you agree that people with iron overload should be avoiding shellfish, organ meats and venison completely, whilst also limiting their intake of beef and lamb? Given that these are amongst the most nutrient-dense foods available to us, I’ve not considered limiting my consumption of them up until this point.

    Thank you for this insightful article, and all of your hard work, it is very much appreciated!

    Best regards,

    Alexander

    PS : It was a great pleasure and privilege to meet you, and to see you speak at the Re-Find Health event in London a couple of months ago!

  7. I require at least a double dose of iron to stay out of getting anemia symptoms. As a regular runner, I’ve had multiple instances of low iron symptoms that have to be resolved by my taking a 2x to 3x dose of organic iron. It’s important to me because being low in iron reduces my libido and makes my restless legs worse. It’s all a nice theory that doesn’t appear to work for me.

  8. Dear Dr. Kresser,

    Based on my personal experience as a patient, I think that identifying the underlying cause(s) of excess iron, at least to the extent possible, can help to determine how best to reduce iron load. Here’s a list of possible causes of excess iron from Makker et al 2015 ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4327557/ ):

    Genetic Iron Overload
    (1) Type 1 hemochromatosis – HFE hemochromatosis.
    (2) Type 2 hemochromatosis – juvenile hemochromatosis: (a) type 2A – mutation in hemojuvelin gene; (b) type 2B – mutation in hepcidin gene.
    (3) Type 3 hemochromatosis – transferrin receptor 2 hemochromatosis.
    (4) Type 4 hemochromatosis – ferroportin disease: (a) type 4A – with low transferrin saturation; (b) type 4B – with high transferrin saturation.
    (5) A(hypo)transferrinemia.
    (6) Aceruloplasminemia.

    Acquired Iron Overload
    (1) Iatrogenic: (a) multiple blood transfusions; (b) parenteral iron therapy; (c) oral iron therapy.
    (2) Chronic liver disease: (a) alcoholic liver disease; (b) hepatitis B and C; (c) porphyria cutanea tarda.
    (3) Anemias: (a) thalassemia major; (b) chronic hemolytic anemia; (c) pyruvate kinase deficiency.
    (4) Others: (a) dysmetabolic hyperferritinemia.

    Heterozygous mutations in BMP6 pro-peptide (http://www.gastrojournal.org/article/S0016-5085(15)01619-4/fulltext ) were added to the list of genetic causes in 2016.

    It’s important to determine whether or not the iron excess is being driven by low hepcidin/high ferroportin activity, as in HFE , Type 2, and Type 3 hemochromatosis and thalassemia (e.g., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895089/) , or, alternatively, by high hepcidin/low ferroportin activity, as in anaemia of chronic illness and Type 4A hemochromatosis (aka ferroportin loss-of-function disease.)

    HFE hemochromatosis and other conditions driven by low hepcidin and high ferroportin activity will be helped by things that increase hepcidin and/or reduce ferroportin activity; for example, quercetin and resveratrol. However, if high hepcidin or low ferroportin activity are underlying problems, then quercetin and reservatol may make things worse by further suppressing ferroportin activity.

    Another caveat with regard to genetic testing is that only HFE C282Y gene testing may be available in some countries, and only C282Y and H63D in others. In some jurisdictions, patients may be able to get more genes tested (e.g., a “hemochromatosis panel” that looks for a number of hemochromatosis-related mutations) but these panels do not cover the most recently identified mutations causing hereditary iron overload and they obviously can’t test for mutations that haven’t yet been identified.

    So gene testing can be helpful if it’s positive, but negative results don’t mean anything other than none of the mutation(s) that were tested for were found.

    However, the clinical presentation, including age and sex and presence or absence of factors known to either increase or decrease iron levels (e.g., type and amount of dietary iron, other dietary factors, menses, blood donation, etc.) along with tests showing the nature and distribution of excess iron can be helpful in narrowing down underlying causes.

    For example, there are three ways I can think of to get an idea of whether or not someone has iron overload involving ferroportin underactivity:
    1. Someone has iron overload with high ferritin but low-normal or even low transferrin saturation, along with low normal or slightly low hemoglobin. An MRI shows extra iron concentrated more in the bone marrow and spleen than in the liver. As the extra iron is removed by phlebotomy, it takes longer and longer for the hemoglobin to get back up high enough for the next phlebotomy. As the person gets close to being de-ironed, he or she may have to wait for the hemoglobin to recover for a month or even longer between phlebotomies.
    2. Someone has an inflammatory condition or other condition that raises hepcidin. Hepcidin reduces ferroportin activity by kicking ferroportin off its working position on the cell membrane into the middle of the cell (internalizing it), where the ferroportin is then broken down. If at all possible, one wants to fix the inflammatory condition to correct the inhibition of ferroportin activity caused by inflammation.
    3. Genetic testing has identified one or more mutations on the SLC40A1 gene or other genes known to cause ferroportin underactivity (“loss of function.”) This testing is not done in Canada, where I live. Tests commercially available in the US check for some but not all of the mutations known to cause ferroportin underactivity. There are also likely to be more mutations that cause ferroportin underactivity that haven’t been identified yet, because more of these mutations are being discovered every year.

    I hope some of this might be helpful – let me know if you want any references on any of the above. If it’s of interest, I’ve also started putting together a list of whatever I can find as having been shown to either increase or decrease ferroportin activity and am happy to share, but I’m afraid so far it’s been slim pickings.

    All the best,
    Gillian Arsenault MD

  9. Staying a live and well became so frustrating; especially when I am not responsible. I was perfectly healthy until my 40’s (now 60), until I was diagnosed with Hasimoto and g6pd deficiency, that resulted in high ferritin levels and intermittent anemia due to hemolysis. Based on the above recommendation, I should stay clear of organ meats and consume little amounts of beef, lamb and seafood and focus on legumes, grains, nuts, and seeds. But what is one to do, if he can’t eat the above due to an autoimmune issues (plus a host of vegetables) and food allergies, where even green tea and coffee should be avoided? In particular, since I already switched to Primal a number of years ago and currently to keto. Naturally, I don’t consume any sugars nor do I supplement with vitamin C and I’ve donated blood 3 times this year and scheduled for a blood test a no of months from now… last ferritin measured at ~350

    I would also like to get your opinion, on the relationship between magnesium (deficiency) and vitamin D as they relate to Iron overloads. The last 5 years proved challenging as far as dealing with leg cramps and finding a helpfully supplement was a challenge, until I came across magnesium chloride, which at last is working.

  10. Thank you for this article. I am disappointed, however, that it doesn’t mention the ideal ferritin level of women (pre and post menopausal). I have been taking an iron supplement and wonder now if that is a good idea, and at what ferritin level I should stop.

  11. I have one copy of the C282Y – tested for when blood tests showed high ferritin levels – however the high ferritin levels were due to high inflammation from Polymyalgia Rheumatica. So essentially had high ferritin, but lowish iron and my other inflammation markers were only slightly high.

  12. hello – I started out anemic and ended up with iron overload due to IV’s of iron to correct the anemia. The Dr. didn’t monitor my iron levels in my blood. I did 19 IV’s of iron, 1cc each…$100 per week / $400 per month. over the course of 3 months or so. I ended up with off the charts Ferritin 492,UIBC of 389, TIBC of 511, LDH of 259 (an indicator of organ breakdown and cancer, etc.) and totally screwed up glucose (I am now insulin resistant). Perhaps not coincidentally I also developed a melanoma during these months which luckily I caught at stage 1A and which I have to have Mohs surgery to remove. Today I donated blood to reduce my Iron and I am on chelators now. I am wondering if the removal of the excess Iron will fix the problems in my body since I do not have the natural tendency for extra iron? I am wondering if I did permanent damage to my organs? During this time I have been utterly exhausted and weak. And scared as I thought I was I was doing everything possible to make myself feel better, not worse. Has any research been done on Iron Overload due to external Iron being introduced to the body?? thank you for any info or advice,
    -jane

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