In this post I’ll be reviewing the book Dumping Iron by P.D. Mangan. It looks at the under discussed issue of excess iron, and how many people can dramatically improve their health by lowering their iron levels.

^ P.D. Mangan (left) and the book cover (right)

Before we get any further, it’s probably worth noting that this information is most relevant to men and post-menopausal women, who don’t regularly donate blood. Women’s monthly menstruation naturally reduces their iron levels, so excess iron generally doesn’t become an issue until they reach menopause.

This book caught my attention because it shows we could be doing everything “right” when it comes to health, such as eating well, sleeping well, exercising regularly etc. – but, if we don’t control our iron levels, we’re missing a valuable piece of the health puzzle.

The author calls iron “the secret killer”. Noting that:

  • Very few people know that excess iron accelerates aging, disease and cognitive decline – despite lots of research backing this up.
  • There are no symptoms of excess iron, unless you get to the very extremes, so if you’re not tracking your iron levels you’re unlikely to realize there’s a issue.

Personally, before coming across this book, iron levels were not on my radar. I’d had multiple blood tests over the years, which included iron biomarkers, and not one of the doctors evaluating them had flagged up my high iron levels. Presumably this was because they were still in the “reference range” (more on that later). In retrospect though, I should have had some awareness, as years ago I’d skimmed through Tim Ferriss’ ‘The 4 Hour Body’ – where he specifically notes on page 451:

“Thought bloodletting went out of fashion around the time of the Salem witch trials? Not entirely.

I’m betting on a major resurgence, and it all has to do with excess iron.

More than estrogen, it’s thought to partially explain why post-menopausal (but not pre-menopausal) women have a similar incidence of heart attack to men. I’ve donated blood since 2001 to be on the safe side.

[…]

There is ample evidence that iron reduction through phlebotomy (bloodletting) can not only improve insulin sensitivity, but also reduce cancer-specific and all-cause deaths. High iron stores have been correlated to an increased number of heart attacks in otherwise symptom-free males, and blood donation has conversely been correlated to a decrease in “cardiovascular incidents.”

There it was… a tip off about iron levels buried within the 594 pages of Tim’s 2010 book. Unfortunately I must have glossed over it at the time!

So, back to this book!

The author P.D. Mangan has managed to compile everything you might need to understand, and, treat the condition of excess iron. He has carefully backed up his statements with over 140 scientific references. Which allows you to check and verify what he’s saying, rather than taking his word for it.

The book follows this format:

  • Intro to what iron is, why we need it and why excess is toxic.
  • A six chapter deep dive into how excess iron can accelerate aging, heart disease, cancer, brain disease and cognitive decline.
  • How to measure and reduce your iron levels.

The bulk of the book (6 out of 8 chapters) is focused on the link between iron and various diseases. The good news is that measuring and reducing your iron is fairly simple and straightforward.

Below I’ve attempted to summarize some of the key information presented by P.D. in his book. Of course it’s just a tiny fraction of what he covers, but hopefully it’s enough to pique your interest to learn more.

How the Iron story began

P.D. explains how the research into excess iron began in the 1980s, when the late Dr Jerome Sullivan was puzzling over the question of why men have significantly higher risk of heart disease than women.

The above graph (via the American Heart Association) shows that beginning age 35, men have at least a 2x higher risk of heart attacks and death from coronary heart disease than women – a disparity which continues until age 65 is reached, at which point women’s risk starts to catch up.

A leading theory in the 1980s was that women’s higher levels of estrogen conferred heart disease protection. However, in Jerome’s 1981 paper titled “Iron and the sex difference in heart disease risk”, he points out that research from the Framingham study (a longitudinal study on cardiovascular disease, ongoing since 1948) showed that women’s protection from heart disease ends after surgical menopause – even if the ovaries are left in. When left in, the ovaries will continue to produce estrogen and progesterone for some years to come. To quote the specific study1:

“In the age groups 45 to 49 and 50 to 54 years, incidence rates in menopausal and postmenopausal intervals were more than double those in pre-menopausal intervals, whether menopause was natural or surgical. In surgical menopause there was excess incidence whether the ovaries were removed or not. Postmenopausal women on hormones had a doubled risk of coronary heart disease.”

^ Dr Jerome Sullivan 1944-2013 (left) and his Iron hypothesis abstract (right)

A similar Canadian longitudinal study also duplicated similar results2.

So let’s just recap:

  • If women’s protection from heart disease was down to hormones, you’d expect it to continue after surgical removal of the uterus, assuming the ovaries (hormone producing part) were left alone. However, maintaining hormone function doesn’t seem to help.
  • Similarly, if it was the hormones providing protection, you’d expect hormone replacement therapy to confer reduced risk, but it also doesn’t.
  • If it was all about aging, then you wouldn’t expect early menopause to increase risk – but it does.

If you’re like me, and haven’t read much on menopause before this, then it’s worth pausing for a second just to clarify a few things.

Natural menopause occurs in women around the ages of 45-55, and is the result of running out of viable oocyte’s (an oocyte being an immature egg). At which point, women’s periods stop, and their ability to become pregnant ends.

It’s also possible to force menopause to begin early through surgery called a “hysterectomy”. These come in a few forms (source):

  • Partial hysterectomy – removing the cervix
  • Total or Simple hysterectomy – removing the uterus and the cervix
  • Radical Hysterectomy: removes the uterus, cervix, ovaries, fallopian tubes and possible upper portions of the vagina and affected lymph glands

So as you see, hysterectomy methods don’t always remove the ovaries, which produce the hormones. However, all of them will stop women’s periods occurring (and end their ability to become pregnant).

The studies cited above found that all hysterectomies increase women’s risk of heart disease risk – even if their ovaries were left intact such that their hormones were minimally impacted.

So if it isn’t hormones, what could it be?

Jerome Sullivan’s hypothesis was that pre-menopausal women had lower levels of stored iron, due to their monthly menstruation. Whereas men and post-menopausal women didn’t have this mechanism for lowering iron (menstruation), and thus their higher iron levels accelerated their risk of heart disease.

How does menstruation lower iron levels?

Each month a women has her period, she loses on average 50ml of blood3. Over the course of a year, this equates to slightly more than 1 blood donation.

Within blood are lots of iron-containing proteins called hemoglobin – approximately 60-70% of the iron stores of the human body4.

So by losing blood, one also loses iron.

Verifying this hypothesis?

Sullivan goes on to point out the hypothesis can be tested using phlebotomy. Phlebotomy is the extraction of blood – such as is in blood donations. If the risk of heart disease decreases in a cohort of age/health matched people who donate blood vs those who do not, then this would suggest the hypothesis is correct.

There are two studies that come close to this. If you’re interested – expand the box below to read about them.

1) The first study we’ll look at was completed in Finland in 19985.

It studied 2,862 men (aged 42–60 years) for almost 9 years. One man (0.7%) out of 153 men who had donated blood in 24 months preceding the baseline examination experienced an acute heart attack, whereas 316 men (12.5%) of 2,529 non-blood donors had an acute heart attack. When they adjusted for for age and all other predictive coronary disease risk factors, blood donors had a 88% reduced risk of acute myocardial infarction, compared with non-blood donors.

2) The second study (named FeAST) was completed in the USA in 2005.  It studied 1277 males, mean age 67, all with peripheral arterial disease. They were randomized into a control and phlebotomy group, with the aim to get the phlebotomy group down to ~25-60 ng/ml ferritin levels – the typical level of pre-menopausal women. A substudy analysis of the results6 found that in the younger participants (age 43-61) phlebotomy significantly improved all-cause mortality (their primary study outcome) and significantly reduced death, heart attacks and strokes (secondary outcome).

Of course, Dr. Jerome Sullivan’s hypothesis combined with the two studies above is not sufficient evidence alone. Instead, the idea was to share ‘the beginnings story’ for how the field began.

Fortunately, in the 40 years since, there has been much more research – which P.D. covers in his book.

Below, we’ll look at further research, before discussing how to measure and improve your iron levels.

Iron, and why too much of it is a health problem

Iron is essential to human life. For example, it’s crucial to hemoglobin’s ability to transport oxygen around our bodies. When our iron levels get too low, it impacts our energy levels and overall health.

^ Diagram showing how our bodies utilize dietary iron – study source

However, iron is also highly reactive, and can interact with other elements to produce free radicals. Which can then go on to damage whatever they’re close to – such as cell membranes or DNA.

To prevent this damage from happening, proteins sequester (store away) iron. For iron to be moved about the body, it’s sequestered in “transferrin”, and when it’s inside cells it’s sequestered in “ferritin”. Unfortunately, despite the bodies ability to sequester iron, as iron levels rise, the risk of damage appears to also.

For example, the graph below shows results from a Danish study tracking the median survival of men with varying ferritin levels7. As levels go above 200 mcg/L – median age of survival decreases.

^ Median survival based on ferritin levels – from this study in Denmark

Personally I think this graph is a powerful demonstration of the effect of rising ferritin levels, so it’s worth examining to ensure it’s understood. The original Danish study tracked people of varying ages for 20+ years, and noted when they died. This particular sub-study (link) measured ferritin levels in samples of frozen blood from examinations of the study participants made between 1981-1983.

Then for the analysis above, it broke people up into 4 groups, based upon those ferritin results, and looked at how long they lived. The numbers next to each of the lines represent the median age of the group. So for >600 mcg/L (which is the same as ng/ml) the median age was 55, then for 400-599 mcg/L it was 72, for 200-399 it was 76, and lastly for <200 it was 79. As a reminder, the median value is the middle number in a list when ranked in order of size (e.g. lowest to highest or highest to lowest).

Generally speaking, we can see that the lower the ferritin levels were at the time of measurement, the longer the study participants lived. We can see that even a number of those with >600 mcg/L ferritin lived into their 90s, it’s just a relatively smaller number than the other, lower ferritin groups.

Among potential criticisms of this study, one could be that the elevated ferritin levels measured are simply a sign of underlying disease/inflammation, which is causing elevated ferritin. Therefore it could be the underlying disease causing the earlier deaths, rather than iron itself. Given that this is an observational study, showing association, rather than a randomized controlled trial, that hypothesis is not impossible.

However, further research since this study, suggests that ferritin reduction may improve survival rates. A specific examples is the randomized controlled trial of ferritin reduction in patients with peripheral arterial disease, where phlebotomy as an intervention improved the survival rate of the (younger) participants89.

What does modern medicine think of this issue?

Despite a large body of evidence showing that ferritin accelerates aging and disease there seems to be a general lack of awareness around the subject. In particular, the issue centers around what constitutes “excess”. Doctors are well trained on the subject of hemochromatosis, a hereditary disease which leads to extreme excess of iron. They’re also well trained on anemia, which is iron deficiency. Unfortunately, that leaves a large gap in the middle which is not monitored.

At the time of writing, “normal ranges” include:

Ferritin Range (Men) Ferritin Range (Women) Source
24 to 336 ng/ml 11 to 307 ng/ml Mayo Clinic
30-400 ng/ml 15 to 150 ng/ml LabCorp
16 – 400 ng/ml 16 – 400 ng/ml UK NHS hospital

As you can see, ferritin isn’t considered an issue by these mainstream institutions until it reaches the 300-400 levels. This is despite the Danish study above (and other research) showing a clear link between >200 ng/ml and increased disease.

The reason that we focus on ferritin as a measure of excess iron in the body, is that it’s primarily in the ferritin protein that excess iron gets stored.

So, what are optimal ferritin values?

When you get results from a blood test, they will be compared against a reference range. A reference range isn’t based on what is optimal for humans, but instead it’s based on what the central 95% of a reference population are within10.

This means that we need to look elsewhere for what is optimal.

Research done by iron researcher Leo Zacharski states:

“Optimal (minimum risk) serum ferritin levels appear to range from a low of about 15 ng/ml to about 80-100 ng/ml at an upper limit11

Emphasis on 80-100 ng/ml being an upper limit – not a target to aim for.

Their conclusion is based on 2 pieces of evidence:

1) Their study data showed that as ferritin levels rose, hemoglobin only rose until a ferritin level of 80-100 ng/ml then hemoglobin plateaued and started decreasing. Suggesting that the body utilizes as much iron as it can for hemoglobin, but once hemoglobin levels can’t rise further (~14gm/dl), extra iron isn’t of benefit.

^ Image via study paper

2) This aligned with various studies suggesting that risk of cardiovascular disease and cancer increase over 100 ng/ml. See the box below for specific examples.

  • Heart Disease – A study that diagnosed patients as having one or more coronary arteries with >= 50% blockage, found that those with these blockages had average ferritin of 73, vs 121 for those without.12
  • Stroke – Ferritin levels >137 increased risk of ischemic stroke, in a study of postmenopausal women.13
  • Cancer – In a 6-year study looking at the effects of iron reduction through phlebotomy, the ferritin levels in those not developing cancer vs those developing cancer were 76 ng/mL versus 127 ng/mL respectively (p=0.017)14
  • Type 2 Diabetes – A study that tracked male patients for 17 years, found the risk of type 2 diabetes markedly increased at a ferritin level of 18515. A separate study looked at women over an 11 year period and found that those who developed type 2 diabetes had an average ferritin level of 109, versus 71.5 for the controls.16

Similarly, a 2021 study concludes, quote17:

“Based upon experimental and epidemiologic data, we suggest testing the hypotheses that optimal ferritin levels for cardiovascular mortality reduction range from 20 to 100 ng/mL

How to reduce your iron levels?

P.D. explains that the most effective way to lower ferritin levels is to donate blood. Or, if you’re ineligible to donate blood, to get it drawn by a phlebotomist, then discarded.

^ Patiently donating blood (source)

The reason that this works is that our bodies store the majority of their iron in the hemoglobin of red blood cells. So by extracting blood we remove iron containing hemoglobin – which our bodies then have to replace. They replace it by drawing from iron stores (ferritin) and from iron in our diet. Thus lowering ferritin and our bodies overall iron levels.

Research on blood donor ferritin levels shows that 2 donations per year makes a significant difference to their ferritin range18.

^ Image from this paper, which utilizes data from this Danish study

How much will a blood donation decrease ferritin roughly? A frequently cited number is 30 ng/ml19. Although this is just an estimate, it provides a starting point for back of the napkin maths. You can estimate that at a ferritin of level of 200 ng/ml, you’ll need on the order of 4 blood donations to get under 100 ng/ml.

Fortunately, at home finger prick ferritin tests are cheap and widely available, so one can test their ferritin levels as they go.

^ Example of at home ferritin tests – image source

If you’re interested in donating blood, the best place to start is to check you’re eligible to donate to your countries blood donor service. These include:

What if you’re ineligible to donate blood?

There are many reasons why someone may be ineligible to donate blood. Although this makes getting rid of blood slightly more difficult, it won’t stop you. The term for people whose profession it is to puncture veins and draw blood is phlebotomists. Whilst most phlebotomists work permanently in hospitals and clinics, there are still a number who work independently, and will come to your home to provide phlebotomy services.

The terms to search in Google will be something like “mobile phlebotomist” or “phlebotomists near me”. Then it’ll be a case of inquiring about their prices and availability for drawing blood. You should explain you’d like to make the equivalent of a blood donation (~450ml), which can then be carefully disposed of. Make sure to cross check the details of any prospective phlebotomist with review services to understand their reputation.

^ Example of someone getting phlebotomy in the comfort of their home

Alternatives to blood donation?

P.D. notes that there *are* alternatives to blood donation for getting ferritin levels down – but they’re less researched and may be slower. Speed is somewhat of the essence when it comes to excess iron, as the damage appears to be a function of elevation level over time. Reduce the time elevated, reduce the potential damage.

Low iron diets

Red meat, and particularly organ meats, are high in iron. Therefore a low iron diet would minimize red meats, replacing them with lower iron forms of protein and nutrients.

You’ll notice in the image below that there are many food sources of iron that aren’t meat. A suggestion P.D. makes for those is to consume them with foods that reduce iron absorption, such as tea, red wine, eggs and dairy. Although these iron absorption inhibitors only work with non-heme iron, ie – iron that doesn’t come from meat.

^ Image from MyFoodData

Fortified Flour

White flour (but not wholemeal, or non-wheat flour) in countries such as the USA and UK is “fortified” with iron, such that it contains small amounts of iron filings. It will mention this on the ingredients like so:

If you type into YouTube “iron in cereal” you’ll find videos demonstrating how to extract the iron with a magnet, such as this one – https://www.youtube.com/watch?v=oQ5lzpAw2qE.

So on top of avoiding red meat, you’d also want to be cognizant of products containing white flour, if you’re in a country that fortifies it. Interestingly, Denmark has banned fortified food (link).

Iron Chelators

Chelators are compounds that can bind metals to them for later excretion. Examples P.D. gives are:

  • Quercetin – a plant flavonol
  • Curcumin – an extract of turmeric
  • Inositol hexaphosphate (also known as IP6) – which is commonly extracted from rice bran
  • ECGC – a green tea extract
  • Theaflavin – from black tea

Unfortunately there haven’t yet been comprehensive trials on these to test the dose and duration required to lower ferritin levels. So it’s not possible to estimate, for example, how much is needed, for how long, to reduce ferritin by 30 ng/ml.

Other compounds worth mentioning that can reduce iron:

Aspirin – it’s thought the mechanism of iron reduction action is through the (small amount) of intestinal bleeding that aspirin induces.

Lactoferrin – another iron chelator – not mentioned in the book.

Calcium channel blockers – these are typically prescribed to lower blood pressure, but they also appear to inhibit iron absorption.2021

So whilst there are a lot of options when it comes to compounds that will chelate iron – they’re not as tried and tested as compared to phlebotomy.

Pharmaceutical iron chelators

Just to give a quick mention to some prescription only iron chelators called:

Whilst these are iron chelators, they can cause potentially bad side effects. So they’re available via prescription only, and are reserved for the extreme iron disorders such as haemochromatosis and thalassemia.

These aren’t mentioned in the book for that reason – and from my brief research – I don’t see a reason to take health risks with them if iron reduction can be achieved in the other, safer ways.

How to test your iron levels?

To test the bio-marker of excess iron we’ve been looking at, ferritin, you can use at-home fingerprick tests. US Examples include:

It’s also possible to do regular blood tests at a clinic. WalkInLab ferritin tests are available at both Quest and Labcorp locations.

Similarly, UK at-home fingerprick tests are available from:

Roundup

Hopefully the above gives you a feel for the content covered in P.D. Mangan’s incredible book.

Personally I find the iron issue both simultaneously simple and complex – at the same time.

The simple part is that, on balance, I think excess iron is bad, and 1 to 2 donations per year should cut most people’s risk dramatically.

The complex part is that there’s a lot of nuance available to discuss – such as:

  • Which diseases it definitely exacerbates at which thresholds.
  • How individual variance in “tolerance” affects these thresholds.
  • What the interplay is between iron and other diseases. For example, does diabetes exacerbate the issue?

Whilst I find those intellectually curious questions. The key point is that most men and postmenopausal should track their ferritin level over time – and take steps to get it down if it strays too high.

About P.D. Mangan

P.D. Mangan is a 66 year old Californian, with a background in microbiology. He currently works as a writer and health educator. Primarily utilizing his Twitter account to share ideas with his 100,000+ followers. His writing on iron and other topics can be found at his blog roguehealthandfitness.com.

At 66, P.D. is at the age where some people’s bodies and brains start breaking down. Yet, despite that, he appears fit, healthy and cognitively sharp, so I’d posit he’s doing something right! You can find his book Dumping Iron on Amazon, and his blog at Rogue Health & Fitness.

References:

  1. Menopause and coronary heart disease. The Framingham Study – McNamara et al. (1978)
  2. Early and surgical menopause associated with higher Framingham Risk Scores for cardiovascular disease in the Canadian Longitudinal Study on Aging – Velez et al. (2021)
  3. The blood loss during normal menstruation – Fowler et al. (1936)
  4. The roles of iron in health and disease – Yang et al. (2001) – see paper intro section
  5. Donation of Blood Is Associated with Reduced Risk of Myocardial Infarction: The Kuopio Ischaemic Heart Disease Risk Factor Study – Nyyssonen et al. (1998)
  6. Ferritin levels, inflammatory biomarkers, and mortality in peripheral arterial disease: A substudy of the Iron (Fe) and Atherosclerosis Study (FeAST) Trial – Zacharski et al. (2010)
  7. Total and Cause-Specific Mortality by Moderately and Markedly Increased Ferritin Concentrations: General Population Study and Metaanalysis – Ellervik et al. | 2014 | Clinical Chemistry
  8. Effect of controlled reduction of body iron stores on clinical outcomes in peripheral arterial disease – Zacharski et al. | 2011 | American Heart Journal
  9. Effect of An Interaction Between Age and Ferritin Level on Clinical Outcomes In Peripheral Arterial Disease (PAD) – Zacharski et al. | 2010 | Blood
  10. Reference Intervals – Barker A, Jones G (2008)
  11. Ferritin and Percent Transferrin Saturation Levels Predict Type 2 Diabetes Risk and Cardiovascular Disease Outcomes – Zacharski et al. (2017)
  12. Association of increased ferritin with premature coronary stenosis in men – Ghanbili et al. (2001)
  13. Serum Ferritin Is a Risk Factor for Stroke in Postmenopausal Women – van der Schouw et al. (2005)
  14. Ferritin and Percent Transferrin Saturation Levels Predict Type 2 Diabetes Risk and Cardiovascular Disease Outcomes – Zacharski et al. (2017)
  15. Body iron stores and the risk of type 2 diabetes in middle-aged men – Hu et al. | European Journal of Endocrinology | 2004
  16. Body Iron Stores in Relation to Risk of Type 2 Diabetes in Apparently Healthy Women – Meigs et al. | JAMA | 2004
  17. Optimal Serum Ferritin Level Range: iron status measure and inflammatory biomarker – Ralph G DePalma, O’Leary et al. | 2021 | Metallomics
  18. The Risk of Too Much Iron: Normal Serum Ferritin Levels May Represent Significant Health Issues – William Ware (2013)
  19. The Risk of Too Much Iron: Normal Serum Ferritin Levels May Represent Significant Health Issues – William R. Ware (2013)
  20. Amlodipine Reduces Cardiac Iron Overload in Patients with Thalassemia Major: A Pilot Trial – Saad et al | 2013 | The American Journal of Medicine
  21. A randomized trial of amlodipine in addition to standard chelation therapy in patients with thalassemia major – Saad et al. | 2016 | Blood

Posted by John Alexander

Hi, I'm John, a researcher and writer.

With a keen interest in health and longevity.

Note: not an MD or PhD.

Hope you enjoy the site. If you've suggestions for content you'd like to see - let me know.

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Stevan
Stevan
3 months ago

Thanks for the writeup John, easy article to go through