Long-COVID: Iron, Copper, Fasting, and Cooling Inflammation
Chris Masterjohn, PhD - I published two articles on iron previously, one suggesting it could play a role in post-COVID fatigue and hair loss, and the second suggesting it could play a nearly identical role in the same symptoms when resulting from COVID vaccination.
In these posts I did not recommend indiscriminate iron supplementation. Rather, I suggested it would be helpful to approach the issue by cooling residual inflammation, testing iron status, and strategically supplementing iron if justified by the testing.
Several people responded by suggesting that COVID is more likely promoting cellular iron overload (as argued by Walter Chestnut) and that it was copper, not iron, that would be the fix (drawing from The Root Cause Protocol of Morley Robbins).
In this article, I address these issues while covering a general approach to release iron that has been trapped by inflammatory processes.
COVID, Sepsis, Inflammation, and Iron Metabolism
If we look at how COVID affects iron metabolism, it appears to be wildly similar to how sepsis affects iron metabolism. Part of this is driven by microbial attacks on red blood cells and their hemoglobin. Notably, for SARS-CoV-2 to do this you would need a very severe case, since it would require the presence of virus in the blood. This is found in 44% of those on a ventilator, but only 27% of those who are merely hospitalized and only 13% of those who are diagnosed but not hospitalized. The likelihood of virus being found in the blood is probably far lower in those who self-treat at home and never receive a diagnosis. The larger impact on iron metabolism, however, is driven by inflammation in general, regardless of the cause.
While severe COVID or sepsis can involve attacks on red blood cells and their hemoglobin, thus releasing free hemoglobin, free heme, and free iron into the circulation, the inflammatory adaptations to this and the cellular defenses against it will ultimately lead to iron being trapped in ferritin.
Inflammation increases hepcidin, a hormone that controls iron metabolism that is usually increased by high iron status. Hepcidin decreases the only known cellular iron exporter, ferroportin.
In the intestines, “exporting” iron with ferroportin leads to its import into the body, because it is exported from the intestinal cell into the circulation. Thus, the decrease in ferroportin causes iron from food to be trapped in intestinal cells, which slough off into the feces every three to four days. This leads to iron being removed in the feces. In short, hepcidin decreases absorption of iron from food.
Thus, during inflammation less iron enters the body. It is essentially impossible for inflammation to lead to systemic, whole-body iron overload. Inflammation leads to a decrease in systemic, whole-body iron content.
The decrease in ferroportin in other cells, by contrast, traps the iron inside cells.
Hepcidin also increases ferritin, the long-term storage protein that sequesters iron and prevents it from doing damage.
Since macrophages are normally the primary cells that digest and turn over red blood cells, and since they are increased during inflammation, the vast majority of that trapped iron is likely to wind up stored in ferritin within macrophages.
However, if there is rampant release of free iron from microbial destruction of hemoglobin, the indiscriminate entry of free iron into other cells and the decrease in ferroportin in those same cells could trap free iron within them. They, too, will protect themselves by making more ferritin, but for some period of time the excess free iron could wreak havoc on the cell by aggravating oxidative stress and causing damage to all the major cellular structures.
However, oxidative stress exerts its own impact on iron metabolism. Like inflammation, it increases ferritin. Converse to inflammation, however, it actually increases ferroportin. Thus, while severe cases of COVID may acutely lead to increased cellular levels of free iron that cause cellular damage and death, the cellular response to this threat will be to ramp up the protective ferritin even further, trapping the iron, and to counteract the inflammatory decrease of ferroportin, increasing this protein, and allowing the efflux of any iron that cannot be trapped by ferritin.
Thus, long-term — for example, in the case of post-COVID fatigue or hair loss occurring weeks or months after recovery — any excess of cellular free iron is almost certainly corrected by trapping the iron in ferritin and exporting whatever can't be trapped.
During the period of peak inflammation, iron absorption from food has been greatly decreased. If the inflammation is remaining weeks or months later, the decreased iron absorption from food is remaining as well. This increases the probability of actual iron deficiency alongside the problem of iron being trapped.
Weeks or months after recovery, symptoms consistent with iron deficiency that can be backed up by bloodwork as described in the previous two posts, are likely to be a result of functional iron deficiency from iron being trapped in ferritin, possibly aggravated by systemic iron deficiency from long-term suppression of iron absorption from food.
Iron supplementation is likely to provide a useful band-aid while addressing the root cause if the iron deficiency is only a functional one. Iron supplementation is likely to be necessary if suppression of iron absorption has led to a systemic, whole-body iron deficiency.
In either case, though, iron will need to be released from ferritin as part of addressing the root cause. How do we achieve that?
Releasing Iron From Ferritin
Ferritin degradation occurs as part of the broader process of autophagy, where a cell will “eat” parts of itself, releasing the raw materials of those components to be used for other things.
However, ferritinophagy, the process of digesting ferritin, is regulated independently by cellular iron status. When the cell runs low in iron, it will send ferritin into the general autophagy system. When the cell has plenty of iron, it will stop this process even if autophagy is proceeding normally. The cellular iron abundance, in fact, will itself cause more ferritin to be made, and if whole-body iron status is also abundant, the hormone hepcidin will increase ferritin production even further.
If the reason ferritin is elevated is because of enduring inflammation, then simply removing the inflammation will lower the synthesis of ferritin. Ferritinophagy will take over the rest naturally.
Thus, cooling inflammation has to be the top priority. This is addressing the root cause.
This is what I had suggested for cooling post-COVID inflammation previously:
Some things that may help include the specific Italian lactoferrin product Lattoglobina or, much more easily obtained, two scoops of whey protein (explained here); 1000 milligrams per day of curcumin; or 1000 milligrams of black seed oil once or twice per day. Maintaining good vitamin D status should be a priority even as a preventative, and may help restrain IL-6 from elevating during COVID in the first place. Given the data suggesting omega-3 fatty acids help hasten recovery from COVID, and given that they are essential to resolving inflammation, anyone recovering post-COVID should make sure to get 600 mg per day of the sum of EPA and DHA per day.
The role of copper in this process is as a cofactor for two autophagy-activating proteins. Copper deficiency compromises autophagy across the board because of this role, so it is important to have healthy copper status.
We don't want excess copper, however. Excess copper causes oxidative stress and this will indeed elicit even more autophagy, but in that case the autophagy will just be doing damage control to mop up the effects of copper toxicity.
Keeping serum copper in the middle third of the normal range, with a sweet spot around 120 mcg/dL, is likely to help keep autophagy capacity in its sweet spot as well.
Fasting is another way to stimulate autophagy. My preferred “stack” to enhance the effect of fasting is exercise. During the fasting state, if not avoiding all supplements, at least avoid protein, amino acids (especially arginine and leucine), SAMe, and methyl donors, as these all activate MTOR, which opposes autophagy. Some people use other supplements, such as resveratrol, to enhance the effect of fasting. Given that the half-life of resveratrol is up to 9 hours, which could keep it in one's system for two days, I think this is only appropriate to use for multi-day fasts.
Iron supplementation, by providing the iron our cells need, is likely to slow the degradation of stored ferritin. However, I believe it is appropriate if one is experiencing iron deficiency symptoms.
Let's do a little thought experiment where we assume the maximal effect of inflammation. Roughly 20 milligrams per day of iron comes from internal iron recycling, and roughly 1-2 mg comes from food (since food iron usually has low absorption). Extended inflammation could, in one month, theoretically trap the amount of iron it would normally take one or two years to obtain from food, all while shutting down absorption of iron from food for that month. That is, it could trap 30 days times 20 milligrams while shutting down the 1-2 milligrams per day from food. That's 600 milligrams of trapped iron, which would take 300-600 days to get from food, and 30-60 milligrams of iron from food that hasn't been absorbed.
Releasing it would take a month at 20 milligrams per day. If the extended inflammation persisted for even longer, it would take even longer to reverse. That is, to whatever degree iron that should be released during recycling is being trapped, reversing the effect will take as long as it's been going on for.
In real life, we won't have maximal effects. But if we trapped half the iron that should have been utilized for six months, we will still have to spend six months reversing this when we get iron cycling back to normal.
Iron supplementation will help this. If inflammation is keeping iron absorption very low, taking in more of it will help compensate. If inflammation has been successfully cooled, a window will open where food absorption could be higher than normal, and supplementing during this time will take advantage of that.
Since reversing the effects of inflammation will take time, and since quality of life can be greatly disrupted by symptoms of iron deficiency, I believe it makes sense to strategically supplement iron when labs and symptoms make it make sense to do so. In particular, 18 milligrams per day of iron bisglycinate can be used when iron saturation is consistently below 30%, with the aim to get it between 30 and 40%.