Free iron as a cause of inflammation

At this point many of you are likely familiar with the idea that while short term inflammation is a normal response to illness, chronic inflammation is harmful. It causes the gut to become more permeable allowing toxins into the body, negatively alters gene expression, and damages the nervous system, all of which contribute to disease over time. There are a number of different factors that trigger inflammation in the body, but in this post I want to focus on one that I've found not many people are aware of... unbound iron in the bloodstream.

I'm sure you know that iron is one of the primary mineral nutrients used by the body. In fact, you have 3.5-4 grams of iron in your body at any given time. About 70% of iron goes into oxygen transporting proteins like hemoglobin or myoglobin, about 6% is used as a cofactor in things like energy production or protein synthesis, and about 25% is stored. Depending on how much iron you consume in your diet you likely have a 0.5-3 years supply of iron stored, typically in the protein ferritin.

There are many different aspects of iron use and storage, if these processes don't work correctly this results in the release of "free iron" (unbound iron) in the blood, tissue, and even cell mitochondria. Free iron is easily converted into iron oxide (rust), which is extremely inflammatory!

Thankfully the body has ways of avoiding this, the process requires four primary nutrients:

1. Copper

 Copper is actually one of the most essential nutrients in the body, it is even used in part of the electron transport chain, which mitochondria use to make energy. Iron and copper go hand in hand in the body, primarily because copper goes into the formation of the protein ceruloplasmin, which is required to make iron usable! Copper also fuels the reticuloendothelial system (RES), which is how the body recycles iron. In fact, it's been estimated that up to 24 out of 25 milligrams of iron used by the body per day come from this recycling system! Copper is also necessary for the proteins ferroportin and hephaestin, which essentially acts as gatekeepers, letting iron in and out of cells.

2. Retinol

Retinol is the active form of vitamin A, and works to make sure copper functions correctly in the system. A moment ago I mentioned the main copper-dependent protein, ceruloplasmin. Ceruloplasmin has both an active and inactive form, the active form is known as ferroxidase. Interestingly, the ferroxidase form is actually what loads iron into the storage protein (ferritin) I mentioned early. Retinol makes copper bioavailable by loading it into ceruloplasmin, then converting ceruloplasmin into its active form ferroxidase, which makes iron bioavailable. Retinol also plays a key role in the RES iron-recycling system. Without retinol, iron cannot be transported from the tissue storage to the bone marrow where red blood cells are synthesized!

3. Vitamin C

Vitamin C plays a complex role in iron dysregulation. First off, I want to be clear that you should NOT supplement synthetic forms of vitamin C such as absorbic or citric acid. These synthetic forms actually inactive ceruloplasmin, which as we've already discussed is essential in the body. Food sources of vitamin C or food source extracts (i.e. acerola cherry or rosehip extract) contain the enzyme tyrosinase that activates ceruloplasmin. Beyond that Vitamin C greatly increases the ability of iron to be absorbed from food. It is also an antioxidant, which helps prevent the conversion of iron to inflammatory iron oxide rust.

4. Magnesium

Magnesium may well be the single most important mineral in the body. It is a cofactor for thousands of processes in the body. While it doesn't have the direct effects that copper and retinol have on iron regulation, it works in the background as a stabilizer. It necessary for the production of detox molecules like glutathione (selenium and zinc help here too), which help regulate how copper and iron are utilized. Magnesium is used to manage stress/inflammation, so when iron is dysregulated the body burns through its magnesium stores rapidly. When recovering from chronic inflammation, or really any illness, maintaining a surplus of magnesium is essential. For supplementation, magnesium chloride works best, as it is the form that's most well-absorbed.

Maybe you've read this and think (or know) you're dealing with iron dysregulation, so what can you do about it?

The easiest action you can take is eating more foods high in retinol and copper. Organ meats are the most dense souce, beef liver for example often contains more than 40x the daily requirement for retinol. Others options like chicken liver, or even high quality cod liver whole or in oil work as well. If organ meats aren't appetizing eating seafood, eggs, or dairy (especially butter) are other good sources of copper and retinol. If you're worried you might not be getting enough of either nutrient, I highly recommend using a nutrition-tracking app like Cronometer for a week or so.

Non-animal sourced vitamin A like beta-carotene will NOT work well here unfortunately, most people convert them to retinol very poorly and vitamin A deficiencies are common in vegans, plant foods are also fairly low in bioavailable copper. All animal products should be organic, grassfed, and/or wild-caught whenever possible to avoid exposure to pesticides like atrazine, glyphosate, or other toxins commonly used in industrial agriculture and factory farming. If money is an issue try looking for a local farm with good practices, they'll often work with you here.

If you're using synthetic vitamin C supplements its best to switch to food sources or extracts as I mentioned above. Essentially everyone will need to be supplementing magnesium with the toxic/stressful environment most of us are exposed to daily. Magnesium chloride is the most well absorbed form, I use pure crystals dissolved in water personally. If you do supplement it, stay below the point of it causing laxative effect, as this pulls water into the bowel and dehydrates you. B-vitamins are also important for managing iron and inflammation. B12, folate, and thiamine (B1) are some of the most important here. I recommend thiamine especially to everyone, as thiamine and magnesium work together for energy production in the mitochondria, I'll go into this in depth another time.

A number of other inflammatory factors also contribute to iron dysregulation and chronic inflammation. These include: sources of fructose, sucrose, and other processed carbs, industrial grains like wheat, corn, and soy, fluoridated water, all plant/seed oils (except olive, coconut, avocado, and black seed oil), and most drugs including caffeine, nicotine, and alcohol. The more of these you consume the more inflammation you're likely experiencing. Cut out whatever you can and give your body the nutrient dense foods I've discussed to support it!

One other practice that can also help the body detox excess iron is donating blood. With proper retinol and copper intake, blood donation actually start cycling out iron from storage proteins to make new blood cells. This process helps maintain maximum oxygen transport, and prevents iron levels from getting to the point of being inflammatory. This may be how the practice of "blood letting" used in medieval Europe to treat illness originated. For men or women who don't menstruate every three months is a good approximate blood donation schedule. Women who do menstruate naturally eliminate free iron every month, so they should only donate about once or twice per year. I want to be clear that I mean full blood donation, not plasma.

The last thing I want to touch on briefly is light. UV rays from sunlight trigger the conversion of cholesterol into vitamin D, which is actually activates ferroxidase function! Sunlight also has numerous other benefits, for example the red/infrared part of the spectrum stimulates melatonin production throughout the body. In mitochondria melatonin is the primary antioxidant. Among many other functions it prevents iron from being oxidized so it can be bound into iron-sulfur clusters, which are essential cofactors for a variety of processes.

Artificial light on the other hand is harmful to the body. It has been shown to break down retinol in the eyes and body, which can lead to inflammatory iron dysregulation over time. Spend as much time as you can out in the sun during the day (yes, even if it's cloudy) and avoid artificial light as much as possible. If you're up after sunset firelight is your best alternative (wine bottle oil lamps are a good way to save money on candles), if firelight isn't an option incandescent or blacklight bulbs work as well.