A global study looking at the role that iron plays in 900 diseases has uncovered the impact of both low and high iron levels—and the news is mixed.
People with high iron levels are not only protected against anaemia but are also less likely to have high cholesterol, according to an international study led by Imperial College London, the University of South Australia (UniSA) and University of Ioannina.
In a paper published today in PLOS Medicine, researchers used genetic and clinical data from approximately 500,000 people in the UK Biobank, looking at the role of iron status and its impact on health.
Iron deficiency is well documented, with approximately 1.2 billion people worldwide living with anaemia, leading to serious health problems if left untreated.
What is less known is the impact of excess iron where the body stores too much iron, which can lead to liver disease, heart problems and diabetes in extreme cases.
Around 25 to 65 per cent of differences between individuals in iron levels are due to genetic factors, according to UniSA geneticist Dr. Beben Benyamin, joint first author of the paper.
“We used a statistical method, called Mendelian randomization that employs genetic data to better estimate the causal effect of iron status on 900 diseases and conditions. Through this, we found a link between excess iron and a reduced risk of high cholesterol,” Dr. Benyamin says.
“This could be significant given that raised cholesterol is a major factor in cardiovascular disease and stroke, causing around 2.6 million deaths each year according to the World Health Organization.”
However, it’s a double-edged sword: high iron levels could also lead to a greater risk of bacterial skin infections, such as cellulitis and abscesses.
Previous studies have found that bacteria need iron to survive and flourish, but the Biobank study is the first to use large scale population data to support the link between iron overload and bacterial skin infections.
Cellulitis affects around 21 million people each year, resulting in more than 17,000 deaths worldwide, making it a global health priority.
Co-lead author of the paper, Dr. Dipender Gill from Imperial College London, says a great strength of the study is its ability to “rapidly and efficiently determine the effect of genetically-raised iron status on hundreds of clinically relevant outcomes using data that has already been captured”.
“We identified the previously established protective effect of higher iron status on traits related to anaemia, and further showed protective effects related to risk of high cholesterol levels and detrimental effects on risk of skin and soft tissue infections.”
Clinical trials have been undertaken to manipulate iron status in anaemic patients but, to date, no trials have targeted iron levels to prevent or treat skin infections or regulate cholesterol.
Trial data is essential before iron manipulation is recommended for these disorders.
“In this study we have provided population-based evidence that iron is associated with certain diseases.
The next step is to investigate whether direct manipulation of iron levels improve health outcomes though clinical trials,” Dr. Benyamin says.
“Associations of genetically determined iron status across the phenome: a Mendelian randomization study” is published in PLOS Medicine.
Iron is an essential mineral, integral in the production of energy and the creation of blood cells.
If pregnant women don’t get it, they can’t deliver oxygen and nutrients to their growing babies.
If kids don’t get it, they shortchange their mental and physical development.
If adults don’t get it, their basic day-to-day physiological function falls apart.
Without adequate iron, our antioxidant defenses, our immunity, and our metabolic function all suffer. Hell, most countries even mandate the fortification of refined flour with large amounts of iron to prevent these tragedies.
Iron also has a dark side.
A large body of observational evidence links elevated iron levels to diseases and disease states like type 2 diabetes, heart disease, insulin resistance, inflammation, Alzheimer’s disease, hypertension, fatty liver, hypothyroidism, arthritis, and cancer.
You name it, it’s probably linked to elevated iron. And as much as I’d like to, I can’t dismiss these connections as non-causal.
For one, iron is inherently reactionary:
The very same proclivity for electron exchange that makes iron so integral in biochemical reactions that address stress and support health means it can also create free radicals that damage DNA, cells, blood lipids, and increase stress and harm health.
Two, there’s a little something called hereditary hemochromatosis.
Hereditary hemochromatosis is a genetic condition increasing a person’s absorption and retention of dietary iron.
This has benefits in certain contexts—carriers have a natural resistance to the bubonic plague, as one effect of hemochromatosis is to render white immune cells iron-deficient and thus resistant to the plague which feeds on iron—but it’s mostly negative in today’s relatively plague-free world.
Most of the hemochromatosis literature focuses on homozygotes (carriers of two copies of the gene) and specific “iron overload-related diseases,” which include cirrhosis, liver fibrosis, liver cancer, elevated liver enzymes, “physician-diagnosed symptomatic hemochromatosis,” or finger arthritis.
Those are bad conditions to have, to be sure, but that’s not even a complete list. Homozygous carriers of the mutation also have greater risks for diabetes, arthritis, fatigue, liver disease, and frailty and muscle loss.
They’re more likely to experience neurodegenerative diseases like Parkinson’s and Alzheimer’s. Even heterozygous carriers (those who carry just one copy of the variant) have an elevated risk of iron overload compared to the general population.
Okay, okay. But couldn’t it be that the hemochromatosis gene is increasing disease risk through another, non-iron route?
Perhaps high iron is just a marker of disease, not a cause. After all, most genes are pleiotropic—they have more than one effect.
Probably not. The most reliable treatment for hereditary hemochromatosis is phlebotomy. Literally removing iron from the body by draining blood is the first (and often only necessary) line of defense against hereditary iron overload. And it works really well.
Besides, phlebotomy may also be beneficial in people without clinical iron overload or hemochromatosis.
It’s the most effective way to reduce iron stores and tends to increase insulin sensitivity
In insulin resistant men with fatty liver, blood donation normalized insulin sensitivity and liver enzymes. In meat eaters, blood donation reduced ferritin levels to match those of lacto-ovo-vegetarians and improved insulin sensitivity.
One study even tested the effect of randomized phlebotomy on cancer incidence.
After four and a half years, those subjects placed in the phlebotomy group lived longer, had less cancer, and had lower ferritin levels than the subjects who didn’t donate blood.
I can’t argue with the research, but the idea that a primary component of a food we’ve been eating for millions of years and to which we may even owe much of our brainpower—the iron in meat—still rankles.
Is iron truly inherently “bad,” or is there anything about our modern environment that makes it so?
Possible Modern Influences On Iron Levels
One factor is that we don’t shed as much blood as before.
Most men engage in far fewer bouts of direct violent conflict. Most people have fewer parasites feasting on their blood. And when’s the last time you exchanged blood oaths with anyone?
We have fewer opportunities to bleed, in other words.
That’s why regular phlebotomy can be such a useful tool for men (and some women) with too much iron in their bodies—it emulates all the bloodletting we used to do in a controlled, safe fashion.
Less Intense Activity
We use iron to generate energy.
The more physical activity in which we engage, the more iron we utilize.
This is usually couched in warnings for female athletes engaged in intense training, but it can also explain the beneficial effects of exercise in people with iron overload.
There are even cases of “mild exercise” causing iron deficiency, so everything that increases energy expenditure—walking, gardening, hiking—will at least subtly reduce iron stores. More activity, less iron sitting around idle getting into trouble.
Too Many Seed Oils
I strongly suspect that the unprecedented dissemination of high-omega-6 seed oils throughout our food systems, our body fat, and our cellular membranes are exacerbating—if not causing—the relationship between excess iron and various diseases.
Take the supposedly ironclad (pun intended) relationship between heme iron and colon cancer, which is mediated by iron’s peroxidative alteration of fatty acids in the colon.
In animal studies that seek to show this relationship, you can’t get the colon cancer to “take” unless you feed the animal high-PUFA oils along with their heme iron.
In one study, feeding heme iron to rats promoted colon cancer only when fed alongside high-PUFA safflower oil. Feeding MUFA-rich and far more oxidatively-stable olive oil alongside the heme prevented the colon carcinogenesis.
In another paper, only mice consuming fish oil-based and safflower oil-based diets exhibited carcinogenic fecal peroxides after eating heme iron; a coconut oil-based group of mice had no negative reaction to heme.
Among a cohort of US nurses, where PUFA intake is around 7% of calories and comes from seed oil, iron intake has moderate links to colon cancer. Among a cohort of Swedish women, where PUFA intake is under 5% of calories with a greater proportion coming from fish, the association is far weaker.
Journal information: PLoS Medicine
Provided by University of South Australia