It's been a while since I've written about iron reduction, which I consider one of the most important tools in our preventive health arsenal. Given the sudden jump in heart attacks and the 'mystery' rise of cancers after the COVID gene therapy rollout commenced, I figured it's a topic well worth revisiting.
The content below was originally paywalled.
Iron is an essential mineral, but one that manifests itself as the quintessential double-edged sword. Too little iron, and you'll become anemic. That's when your endurance performance starts regressing to walking frame levels, and getting out of a chair feels like you're doing a heavy squat. It sucks.
But so too does too much iron. Excess iron accumulates in organs and tissues throughout the body, turning your physiology into a oxidation-prone fiesta of free radical debauchery. Wayward free radicals, missing the electrons they need for stability, start texting their single buddies: "Dude, you need to get down here, there's iron everywhere!"
Iron, like sugar, is also a favoured food of microbes, so high iron levels could theoretically render you more susceptible to infections. It's worth noting that diabetics, whose greater susceptibility to infections is well known, not only suffer from high blood sugar levels but also commonly exhibit high bodily iron levels.
How Do You Know if Your Iron Levels are Too High?
The best and most readily accessible marker for bodily iron stores is serum ferritin, which can be ascertained by a simple blood test.
Depending on where you live, iron deficiency is diagnosed at 15-30 mcg/l or lower, while iron overload (known in medical circles as hemochromatosis) is suspected above 200 mcg/l (females) and 300 mcg/l (males).
However, if your ferritin reading is over the upper reference limit, don't be surprised if your doctor doesn't even notice. Most doctors are trained to watch out for iron deficiency anemia, a common problem in premenopausal females, but are far less attuned to the dangers of excess iron. A close friend has had three iron tests between 2019 and 2023, with two of the readings well north of 300 mcg/l (the other was 290 mcg/l). Despite the 300+ readings being highlighted in bold and marked with a "H" (high) by the lab, his doctor didn't even mention them.
Iron Levels: Too High is Lower than Previously Thought
This is a worry, because there is a large body of evidence to show that health problems can be caused by bodily iron levels far lower than those required to produce a serum ferritin reading of 300 mcg/l.
In teenagers, serum ferritin levels average around the low 20s. In premenopausal women, who shed blood and hence iron on a monthly basis, that's about where they remain, right up until menopause.
In most men, however, average bodily iron levels start steadily rising after the teen years. As their serum ferritin rises, so too does their risk of common ailments like heart disease and cancer. Up until menopause, women enjoy lower levels of these diseases, in fact they enjoy a lower level of mortality overall.
Once they hit menopause, the party comes to an abrupt halt for the ladies. Serum ferritin levels shoot up, and their risk of cardiovascular disease quickly rises to match that of their age-matched male counterparts.
Years ago, the lower incidence of heart disease in premenopausal women was ascribed to estrogen. The inherent belief encapsulated in this untenable explanation was that estrogen was beneficial to women's cardiovascular health, yet testosterone, the primary male sex hormone, was for some strange reason either benign or even harmful to male cardiovascular health.
Either Mother Nature was a man-hating feminist, or those who propagated this self-contradictory theory were wrong.
The estrogen argument, it turns out, wasn't just self-conflicted but a willful denial of the science. You see, way back in 1978 the infamous Framingham study showed that women of child-bearing age who underwent hysterectomy - which brings menstruation to a permanent halt - suffered a marked increase in CHD, even when their ovaries (which produce most of a woman's estrogen) were left intact.
In 1981, South Carolina scientist Jerome L. Sullivan, M.D., Ph.D., proposed that decreased iron stores could explain the low incidence of CHD in premenopausal women. Sullivan cited the Framingham findings in support of his thesis, but he was ignored.
For decades, the cholesterol-obsessed mainstream ignored non-supportive evidence and kept pushing the idea that estrogen possessed some sort of magical effect against cardiovascular disease. Pharmaceutical companies made billions selling HRT concoctions to women on the basis it lowered their risk of cardiovascular disease.
That appalling charade began to unravel in 2002 when a series of HRT intervention trials began confirming estrogen did nothing to prevent cardiovascular disease. In fact, one of those studies had to be stopped early because the commonly-prescribed estrogen/progestin combo seemed to be increasing CHD deaths. Women in the HRT group also experienced higher rates of potentially fatal blood clots and biliary tract surgery.
So What's an Optimal Serum Ferritin Level?
Iron is a crucial mineral, but we don't need huge amounts in our body to keep motoring along at optimal levels.
In teenage males and females, serum ferritin levels average around 21-23 mcg/l. This rises to around 94 mcg/l in males aged 18-45, and 124 mcg/l in men over 45, but remains in the vicinity of 25 mcg/l among premenopausal women.
After menopause, where cardiovascular risk in females rises to match that of males, the average serum ferritin level is around 89 mcg/l (see Cook 1976 and Jehn 2004). That's a heck of a way off from the 200 mcg/l target that indicates possible female hemochromatosis.
What this all indicates is that keeping bodily iron stores at more youthful levels could successfully prevent or treat common conditions like cancer and cardiovascular disease.
Iron-lowering protocols, like that outlined in the highly informative book Exposing the Hidden Dangers of Iron, typically aim to bring serum ferritin down to around 25 mcg/l, and keep it from rising above 75 mcg/l. Iron reduction data in athletes is thin on the ground, but for what it's worth, my experience after 15 years of iron reduction clearly shows that my cycling performance is noticeably and negatively impacted whenever my serum ferritin dips below 30 mcg/l. As such, I prefer the Australian male lower limit for 'normal' serum ferritin of 30 mcg/l (last time I checked, some US labs were citing 20 mcg/l as a threshold).
Now, let's take a look at some clinical trials that actually put iron-lowering to the test.
Unleash the FeAST
The Iron (Fe) and Atherosclerosis Study (FeAST) trial found promising reductions in cardiovascular and cancer incidence and mortality among men randomized to receive phlebotomy (blood withdrawal).
The FeAST study was comprised of two segments. The first was a small pilot study examining the utility of iron depletion in the secondary prevention of CHD among peripheral arterial disease patients.
Pilot trials are small, preliminary endeavors that seek to establish whether it is worthwhile conducting subsequent larger trials. In this instance, the three-month pilot study did indeed obtain results demanding further study.
Among vascular disease patients who had sufficient blood removed to reduce their average serum ferritin level from 125 mcg/l to 52 mcg/l, only one (3.4 percent) experienced an adverse cardiovascular event (angioplasty). In the control group, eight patients (42 percent), experienced heart attack, heart failure, unstable angina, or dysrhythmia (a type of abnormal and potentially fatal heart rhythm).
So the researchers, led by Leo R. Zacharski, then proceeded to a larger and longer trial, the results of which were published in 2007.
Over 1,200 patients were recruited into the study, and after a mean follow-up of 4.5 years there was a 15% relative risk reduction in overall mortality and a 12% RR reduction in the composite endpoint of death and non-fatal heart attack and stroke.
Because the differences were small and statistically non-significant, the trial was roundly reported in the media as a failure.
However, those who looked closely at the findings quickly realized the trial was anything but.
Iron Reduction: The Earlybird Gets the Greatest Benefit?
When the researchers looked at the interaction of age with iron-lowering treatment, a dramatically different picture emerged.
The mean age of the trial participants was 67 years. In the youngest age quartile (ages 43-61), there was an impressive 53% reduction in overall mortality and a 59% reduction in the composite endpoint of death and non-fatal heart attack and stroke.
In the 43-61 age group, 28 of 169 participants died, compared to 13 of 163 in the iron-reduction phlebotomy group.
In that same age group, 49 of the control subjects experienced the composite endpoint of death/non-fatal heart attack/stroke, compared to only 21 of the iron reduction subjects.
In the older age quartiles, there was little-to-no difference in these outcomes between the groups.
The researchers posited that iron reduction in the older participants may have occurred too late. The damage caused to their cardiovascular systems by free radical damage may have been too far advanced to benefit from a reduction in bodily iron stores.
Before abandoning the idea of iron reduction for those over 61, however, there's another aspect of this study that needs highlighting. For patients in the iron-reduction group, the goal was to perform regular phlebotomy to achieve ferritin levels of approximately 25 mcg/l, then to prevent subsequent ferritin levels rising much above 60 mcg/l.
Unfortunately, that's not how things worked out. The average iron reduction participant had 72% of the calculated amount of blood removed over the course of follow-up. The mean ferritin level across follow-up visits was reduced from 121.4 to 79.7 mcg/l in these subjects (it remained unchanged in the control group).
In iron reduction patients having 50% or greater compliance with the phlebotomy protocol, the mean mean ferritin level at follow-up was 58.3 mcg/l.
In a subsequent analysis, the researchers reported compliance with phlebotomy was better among the younger subjects. Older age and higher ferritin at entry were both significant predictors of poorer compliance with phlebotomy and rising mean follow-up ferritin levels. In other words, those who needed iron reduction the most were the least likely to comply with the protocol. Lower mean follow-up ferritin levels were associated with improved outcomes in both the iron-reduction patients and across the entire cohort.
We can only wonder at how more impressive the results would have been in the younger group had the original ferritin targets been achieved - and whether the benefits seen in that group would have extended into the older groups.
Iron Reduction vs Cancer
A year after the FeAST researchers published the cardiovascular and overall mortality results, they published an eye-opening paper on what happened to cancer rates among participants.
Well, it should have been eye-opening, but it seems much of the medical profession is in a pharma-induced coma.
Patients in the iron reduction group were 35% less likely to develop cancer. Among the study participants who did develop cancer, those in the iron reduction group had 61% lower cancer-specific and 51% lower all-cause mortality, respectively.
Patients with known malignancies were excluded at baseline. During 4.5-years of follow-up, 98 subjects were diagnosed with new malignancies. Of these, 60 occurred in control patients and 38 in iron reduction patients. Risk of lung, colorectal, upper aerodigestive, prostate, and other cancers was lower with iron reduction. The sole exception was bladder cancer, which for reasons unknown was higher in the iron reduction group.
This time, the benefit was not limited to younger patients. What was associated with reduced cancer risk was adherence to the phlebotomy protocol. Mean ferritin levels across all follow-up visits among iron reduction patients were lower in patients who did not develop cancer (76.4 mcg/l) than in those who did (127.1 mcg/l)
Further analysis by the researchers suggested a reduced risk of new cancer in patients with over 60% compliance with phlebotomy, corresponding to a ferritin level of less than 54.8 mcg/l. Seventy-five percent of new cancers occurred among patients having mean ferritin levels during follow-up of greater than 57 mcg/l.
In a world where mainstream cancer therapies quite literally involve poisoning and radiating the unfortunate patient, a non-toxic and minimally invasive procedure with the potential to more than halve cancer mortality should be deluged with research funding, and researchers should be tripping over themselves to investigate it further.
The ability to halve overall CVD mortality – in any age group - is the kind of result other CHD interventions can only dream about. Again, it should have CVD researchers salivating with excitement and writing up research grant applications at a furious pace.
Sadly, the drug-centric world of Western medicine has overwhelmingly showed little interest in exploring iron reduction further.
Not all researchers remain so blind, however. Some researchers have been examining the effect of iron reduction in chronic hepatitis C patients, with promising results.
Phlebotomy versus Hepatitis C and Liver Cancer
Hepatitis C is an infectious disease that attacks the liver, causing inflammation. It can lead to cirrhosis, end-stage liver disease, liver cancer, and sometimes death.
In 2014, researchers from the Division of Gastroenterology and Hepatology, Nihon University School of Medicine, Japan, reported on 96 chronic hepatitis C patients who either agreed or refused to receive phlebotomy. This was therefore a non-randomized study, with a patient follow-up of eight years.
The phlebotomy group was, on average six years younger (55 vs 61), but had far more males and far higher serum ferritin levels at baseline (270 mcg/l vs 139 mcg/l) than the non-phlebotomy group. The liver enzymes AST and ALT were also significantly higher in the phlebotomy group at baseline.
Regardless of their phlebotomy status, all patients were treated with glycyrrhizin injection and oral ursodeoxycholic acid. None of the 96 patients had previously received interferon therapy, a common treatment that is not always effective and produces a range of side effects.
Depending on the individual patient’s condition and blood pressure, phlebotomy was performed to remove 100-400 ml of blood every 1-4 weeks.
All patients were assessed two or three times each year for possible hepatic cellular carcinomas (HCC). Follow-up for cancer incidence was 8 years, while clinical markers such as serum ferritin and liver enzymes were monitored for 5 years.
In the phlebotomy group, the mean ferritin level dropped from 270 mcg/l at baseline to 63 mcg/l after five years. This average included five phlebotomy patients whose ferritin was not successfully controlled.
In the non-phlebotomy group, the mean ferritin level dropped from 139 mcg/l at baseline to 74 mcg/l after five years.
AST and ALT levels dropped in the phlebotomy group, but not the control group.
Of the 96 study patients, 19 were diagnosed with HCC during the follow-up period. HCC developed in four (10.3%) patients in the phlebotomy group and 15 (30.0%) patients in the non-phlebotomy group.
In a multivariate analysis that considered phlebotomy, age, platelet count and AST, ALT and AFP levels, phlebotomy was the only variable associated with HCC incidence. It also returned an impressive hazard ratio of 0.13.
In this study, the upper limit of a normal ferritin level was also defined as 200 mcg/l for women and 300 mcg/l for men. In contrast to the control subjects, no phlebotomy patient with a normal serum ferritin level at baseline developed HCC during the study.
Among patients with a high baseline serum ferritin level, the incidence of HCC in the phlebotomy group was far lower than that observed in the non-phlebotomy group.
Taken together with the FeAST results, these findings suggest that keeping iron at youthful levels is something we should be taught to do in early adulthood.
Adverse Effects
In the FeAST study, six patients experienced "minor vasovagal events" attributed to the drop in blood volume (in some folks, the sudden reduction in blood volume can cause lightheadedness and fainting).
In the Japanese Hep C study, complaints of feeling cold in the extremities prompted phlebotomy to be stopped in one patient. No significant adverse events occurred in other patients.
Other side effects that have been reported at the lower end of the normal serum ferritin range include hair thinning and restless leg syndrome. I can't comment on the former, having being inspired by Marco Pantani to shave my tufts back in the noughties. I have noticed restless leg syndrome on the couple of occasions my ferritin dipped below 30 - you can tell the next morning when you wake up and you've kicked your bed sheets all over the place.
Low serum ferritin levels may also exacerbate depressive symptoms, so if you suffer from depression then you need to tread carefully.
Before You Start, Check That You Even Need to Start
It is extremely important to get your iron status checked before engaging in phlebotomy or any other form of iron reduction. Statistically, premenopausal women are at far higher risk of iron deficiency than iron overload. Highly active endurance athletes (not taking EPO) tend to have lower ferritin levels than sedentary folks. While serum ferritin rises with age, average levels begin to decline after 70, possibly an artifact of greater longevity in those with lower bodily iron stores.
The bottom line is you can't tell your iron status by looking in the mirror or reading an internet article. The last thing you want is to begin iron reduction when you are already near the low end of normal or, heaven forbid, already deficient.
You need to get the requisite blood work done. Obviously, any blood test for this purpose should include serum ferritin, as that is the key marker you will be monitoring. I'd also recommend including transferrin saturation and hemoglobin at a minimum, and watching to ensure they stay within normal range.
Each standard blood donation will drop your serum ferritin an average 30 mcg/l. That's a yardstick, not a set-in-stone figure, so don't rely on it alone to calculate how many blood withdrawals you need. Personally, I get my blood retested when this figure predicts I have at least two withdrawals left to hit the target. Waiting until you have only one predicted withdrawal left is too late, because you might already be too close to the lower end of normal range.
Ideally, you'd have your iron status monitored regularly throughout your iron reduction protocol.
You'll also need to monitor your iron levels once your target 'trough' level has been achieved to ensure they don't travel back out of the ideal range.
Obviously, controlling your bodily iron stores requires a lot more thought and pro-activity than popping the latest wonder drug or supplement. But my personal experience (marked improvements in glycemic control and gastrointestinal health) and the results of the above studies suggest iron reduction could be a far more effective - and often free - method for fighting chronic disease.
If you’d like to learn more, the aforementioned book Exposing the Hidden Dangers of Iron is a great starting resource. It was written by Dr Eugene Weinberg, who passed away in early 2019 just a few days after his 97th birthday
If you've tried iron reduction, share your experiences - positive or negative - in the comments section below. I'll also do my best to answer any questions you might have.
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