Tuesday, January 30, 2018

Iron Overload: A Myth in Healthy People?

tl;dr: Oft-mentioned iron overload does not appear to be a problem in healthy humans, only in those with genetic defects. Iron is steadily lost through normal mechanisms and regained through dietary intake. Deficiency is the problem in healthy people.

So sometimes I get curious.


Now many people in the health communities I participate in get very concerned about iron overload—more below—but the basic concern has been that people keep eating iron in red meat, say; and there's no way to get rid of it, so at some point it will hit toxic levels and start to do damage. There are a number of genetic conditions where high iron levels do appear to cause damage, so this could be a reasonable concern. People even proactively give blood to lower their iron stores. But that all depends on the notion that you have no way of getting rid of excess iron.

I poked around half-heartedly, but didn't find anything.

Iron retention per year
Dumping iron

Today I got a little more curious about it, and found "Body iron excretion by healthy men and women" (Hunt 2009), which is an update of the last study done on the topic, in 1968 (Green 1968).
"On the basis of turnover rates, these subjects needed to replace as little as 2% and as much as 95% of their body iron annually!"
They used radioactive iron to measure iron turnover, which was the same method used as Green. Seems a reasonable way to do it.

Oddly, the primary mechanism for the body to shed iron is through shedding skin cells (!), exfoliation in the scientific jargon. There are also losses through bile (feces), urine, and shedding cells in the gut. Iron must be pretty hard to come by, as the body is mainly concerned with keeping it, and getting rid of it seems to be incidental to other body functions.

Hunt notes that shedding iron seems to be a somewhat random process, it's not homeostatically regulated like uptake is. (Although they saw a 40-fold variation in loss, so there may be some regulation process going on, it seems unlikely to me that such an important nutrient would be dumped randomly. But Hunt does not report a mechanism.)

One of the reasons Hunt did his study was because Green hadn't looked at women, so Hunt did. Obviously women (who menstruate) lose more iron than men do, and are more at risk from anemia (iron deficiency), consequently. I should mention that most of the iron in the body is contained in hemoglobin in the red blood cells, and the next biggest functional use of iron is in the mitochondria, in the cytochrome C molecule, which I have discussed before. There are also iron stores in the body.

Based on Hunt and Green, I think it's safe to say that the body is perfectly capable of getting rid of iron.

95% loss per annum would get the job done. 

Iron uptake

The known regulator of iron stores in the body is through uptake during digestion. That's sort of outside the scope of this, basically, but there's also a wide variation in iron uptake, depending on iron need and digestive capability.

The US RDA for iron was based on Green, which was a male-only study:
"Current US dietary recommendations for iron use the body weights and the daily iron losses of the subjects of Green et al (2) to derive an average estimated iron loss of 14 ยตg/kg...."
"This reduction, together with the tendency in the present study for the men to (nonsignificantly) increase their body iron in 3 y may mean that dietary recommendations for men in Western countries may best focus on preventing body iron accumulation rather than iron deficiency."
So that's where what I think the myth comes in. Are men in Western countries really at risk of iron overload?

Iron overload

Hunt noted that Green had measured a pretty wide variation of losses in his study—Green was in South Africa:
"Green et al... measured basal iron losses of 0.95 ± 0.30 mg/d for white men in the United States, 0.90 ± 0.31 mg/d for Mestizo men in Venezuela. and 1.02 ± 0.22 mg/d for Indian men in South Africa. Higher and more variable losses of 2.42 ± 1.09 and 2.01 ± 0.94 mg/d for Bantu men in Johannesburg and Durban, South Africa, respectively, were attributed to greater than normal body iron stores in the Bantu population."
From "Body iron excretion in man" (Green 1968), a rather important paper, as noted above.

So, if you're looking for evidence of iron overload, that seems to be the place to look for it. From Walker, 1953:
"Among the South African Bantu, the intake of iron is often very high—as much as 200 mg. per diem. This high intake is due mainly to the uptake of the element from iron utensils occuring during the preparation of their usual foods (particularly fermented cereal products)."
Dang, that's 100-fold what Green reported them losing per day! They must be like Tetsuo, The Iron Man!



[Don't watch that, it's really weird. Included for referential comprehensiveness.]

However, their high intake and status appears to have little effect:
"...there appears to be no evidence that iron overload per se is detrimental to well-being."
If the Bantu are eating that much iron and seeing no ill effects, then I think we in the West can worry less about it.

Genetic iron management diseases

The Bantu (and other Africans) do get a disease of iron overload, known as siderosis. However that appears to be genetic, and not from diet:
"Researchers originally believed that the popular, iron-rich beer caused cases of African iron overload. However, many individuals that drank the beer did not develop the disorder and some individuals that did not drink the beer did develop it. This led researchers to speculate that a mutation of a gene or genes involved in the transport or breakdown (metabolism) of iron must play a role in the development of African iron overload. Such a gene has not yet been identified."
That's from the Rare Diseases site, 2013. So it's similar to the iron overload disease that most are familiar with, hemochromatosis.

So just to wrap this up, I'm including two more links, from the CDC and from Merck.

CDC: Recommendations to Prevent and Control Iron Deficiency in the United States

Merck Manual: Secondary Iron Overload (Secondary Hemochromatosis)

As noted in those two links, virtually all instances of iron overload appear to be genetically caused. It's even possible to have iron overload (in storage) and be anemic (not enough iron in the blood) at the same time, interestingly as noted in the second link, but again from a genetic problem.

Conclusion

Hunt, again:
"Despite this substantial range in iron excretion, homeostatic control mechanisms were effective at maintaining body iron homeostasis for most subjects, with substantially impaired iron-status indexes in only one menstruating woman... These considerable differences in iron excretion and resulting requirements can generally be appropriately met by physiologic control of iron absorption, provided that dietary iron is accessible and reasonably bioavailahle."
Iron, like most important things, is tightly, homeostatically regulated by the body. As a creature that appears to have evolved on a diet of large amounts of heme-rich ruminant meat, we are unlikely to be susceptible to iron poisoning via that route, that is, via a diet far higher in heme iron than what most humans alive today eat. So unless you have an actual genetic problem, it's not necessary to manually regulate things like air, water, or your body's iron stores.

All that said, as I discuss in the cytochrome C link far above, iron is related to the diseases associated with the metabolic syndrome. But that's because it's a catalyst for the oxidation of omega-6 polyunsaturated fats. But the evidence for that beyond what I've already posted will have to be dealt with in another post.



Refs:

Hunt, Janet R, Carol Ann Zito, and LuAnn K Johnson. "Body iron excretion by healthy men and women." The American Journal of Clinical Nutrition 89.6 (2009): 1792-1798. doi: 10.3945/ajcn.2009.27439

Green, Ralph, Fatima Mayet, Clement Finch, Miguel Layrisse, et al. "Body iron excretion in man"
The American Journal of Medicine (1968), Volume 45 , Issue 3 , 336 - 353

A.R.P. Walker, Ulla B. Arvidsson; "Iron “overload” in the South African Bantu", Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 47, Issue 6, 1 November 1953, Pages 536–548, https://doi.org/10.1016/S0035-9203(53)80006-4

African Iron Overload, National Organization for Rare Disorders (NORD), 2013