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Around the Web; Back from Vacation Edition

Posted by on June 25, 2011 23 comments

A lot has happened since we last did a round-up. Here is a sampling of things we’ve found interesting:

[1] Interesting posts: Jamie Scott channeled his inner Staffan Lindeberg and performed the Vanuatu Study: “The Diet and Lifestyle of the People of Vanuatu: Paleo in Paradise”. It has a lot of pictures and descriptions of the Kitava-like Paleo diet and attractive good health of the natives. Unfortunately, fewer Melanesians are eating traditional diets, and we may not be able to observe traditional diets in native populations much longer.

Chris Masterjohn helps us understand Weston A. Price. He also did a fascinating podcast with Chris Kresser on LDL cholesterol: The Healthy Skeptic Podcast Episode 11. Speaking of cholesterol, Ned Kock reported that alcohol increases LDL cholesterol in people with the ApoE e4 allele, but decreases LDL cholesterol in people with the ApoE e2 allele.

In another post, Ned notes that a 6-foot man can be strong and healthy at 145 pounds. The moral: Be yourself; don’t think your body needs to look like someone else’s.

The opportunity to reverse Type 2 diabetes by diet was in the news, because of a UK study (Pubmed, Full text) in which 11 patients experienced normalization of beta cell function and reversal of Type 2 diabetes on a diet of 600 calories per day: 280 carb calories, 200 protein calories, and 120 fat calories per day (plus considerable fat released from adipose tissue). This is a starvation diet, below our safe minimum of 600 carb+protein calories and undoubtedly deficient in micronutrients and complex biological compounds, since it’s almost impossible to be well nourished on less than 1200 calories per day of real food. Indeed, people on the diet felt they were starving:

“It was very tough. I was hungry all the time. It was a starvation diet and food was on your mind all the time,” he said.

Many bloggers commented, including Peter Dobromylskyj, Jenny Ruhl, and Pål Jåbekk.

Melissa McEwen cured a skin condition by getting more vitamin A. Matt Stone offered a Paleo failure story, and linked to some pictures of hypothyroid faces. CarbSane found that selenium cured her insomnia; in the comments Mario argues that selenium may be protecting against metal and halogen toxicity.

Keith Woodford links to research showing that opioid peptides from cow’s milk drank by the mother can enter babies via breast milk and argues “the implications are huge”. Dr. Briffa notes that the artificial sweetener aspartame is converted to formaldehyde, a potent carcinogen, in the body. Chris Kresser discusses why it’s possible to have trouble with coconut milk. In the comments Tony Mach says the biggest BPA exposure comes from handling cash register receipts.

At Angelo Coppola’s “Latest in Paleo” blog, breastfeeding advice from a recovered boob nazi. (I may discuss this post a bit in an upcoming blog post.)

Via The Telegraph, many dishwashers are infected with fungi and deposit potentially dangerous fungal pathogens on plates and utensils. Via Craig Newmark, Top Ten Myths About Introverts.

Tom Naughton reveals that the government issued health warnings against cholesterol in the 1960s at the direction of Lyndon Johnson – who wanted to reduce the price of eggs to improve the inflation statistics!

NBA player Robert Horry leaves a poignant letter to his daughter, who died from a genetic disease.

Finally, for our academic readers, the oldest known journal rejection letter, written to Ptolemaeus in regard to his method for measuring the circumference of the earth.

[2] Don’t sleep on the sofa darling: Thursday’s post called to mind Petula Clark’s great hit:

In this video, recorded live in 2003 in Paris, Petula is 70 years old and looks great. At 78 she’s still performing. I wonder what diet she eats?

(The 1967 studio version can be heard here.)

[3] It’s safe to come out:

[4] Thank you, Pål – and thank you, readers: While we were on vacation, Pål Jåbekk of Ramblings of a Carnivore posted a very nice review of our book: “The As Good Health As Possible Diet”:

I would like there to be one diet book. One book that is constantly updated with new research. It would be The Diet Book. The book that made all other diet books superfluous. The go to place for everyone interested in achieving good health. The only book we would need….

The one book I’ve found that comes closest to being the diet book to end all other diet books is Perfect Health Diet. Had it replaced the official dietary guidelines we might actually be getting somewhere. The Perfect Health Diet book is not a perfect book, nor should it be. I think that some of the composition could be improved as well as the lay out and I would’ve liked to see some statements moderated, but content wise and information wise, Perfect Health Diet appears as a good first draft of a book with the potential to end the need for any more diet books.

I am excitedly looking forward to the second edition.

Pål is one of our favorite bloggers and a perspicacious writer on health, so this is high praise. As he says, our book is a work in progress. We are still learning, and that is why blogging is so much fun. The growth of knowledge is a cooperative process, and we continue to learn from other bloggers and from our readers.

We believe that diet should be a primary therapy for all diseases, and that with a good diet and appropriate antimicrobial therapies nearly all diseases can be cured. It’s exciting therefore to hear from readers, especially sick readers, who apply our ideas. We are grateful to readers who share their experiences with us, whether good or bad. Both successes and failures are educational.

Like Pål, we look forward to a second edition. We aim for the perfect diet, but we know that we have not yet written the perfect book. To achieve excellence, an evolutionary process is usually required. We’re most grateful to all those who apply our ideas and help us refine them.

[5] Another migraine success story: Speaking of reader feedback, it was great to hear from Rebecca Lachance on Facebook:

Just a note of thanks for helping me control migraines/headaches. Ketogenic diet has made an enormous difference in my life. Down from 24 days of headaches in February to only 4 days in June! My M.D. is suffering cognitive dissonance – thrilled with the decrease of headaches, but “suggests” a minimal dose of statins to prevent atherosclerosis – despite an HDL of 99 and TRG of 52. Obviously, I won’t be taking statins!… Thanks again.

We believe that ketogenic diets are probably therapeutic for nearly all neurological diseases, so we hope more people with brain or nerve disorders will try our version of the ketogenic diet.

[6] Don’t rush to your funeral: A Russian woman, wrongly declared dead, woke up at her own funeral and had a heart attack when she realized she was about to be buried alive.

[7] It’s good to supplement magnesium: A study in AJCN found that women in the highest quartile of dietary magnesium had a 37% lower risk of sudden cardiac death, and in the highest quartile of serum magnesium had a 77% lower risk of sudden cardiac death, than women in the top quartiles. In the same issue, a clinical trial found that supplementation of 500 mg/day magnesium was beneficial for obese people.

We recommend supplementing magnesium at 200 mg to 400 mg per day. 500 mg/day is more likely to produce an observable effect in a 4-week trial, but is more than we would recommend for long-term supplementation.

[8] My interview with Cary Nosler’s Wide World of Health: The podcast is available for download here.

[9] Getting Real at Whole Foods: This has been making the rounds, but it’s good enough for one more showing:

Via Melissa McEwen.

[10] O Primitivo on LDL, meat, and mortality: Ricardo (“O Primitivo”) of Canibais e Reis (“Cannibals and Kings” in Portuguese; inspired by Marvin Harris’s book), who was the source of the data discussed in Tuesday’s post, tried to leave a comment there but it had too many links for our spam filter and was lost. Fortunately, he emailed me with some fascinating information.

First, he has compiled a database specifically correlating LDL cholesterol levels to various health conditions. This is a very valuable database and I hope he’ll blog about it before long. LDL levels are highly correlated with total cholesterol, so the results are similar to those in his total cholesterol database, but still interesting.

O Primitivo also sent links to some of his blog posts:

Plus a number of links to recent papers which I’ll leave for him to blog about.

Since he has so much good material, and many people will lack time to explore it all, let me give you one highlight. From his document on animal-vegetable ratios, the fraction of food intake from animals versus mortality:

Take that, vegetarians!

Thank you, Ricardo, for all the great information. You have a fantastic blog.

[11] The cat who didn’t bark:

[12] Quote of the week: From a comment by Chris Friederich on Chris Masterjohn’s blog:

“If people let government decide what foods they eat and what medicines they take, their bodies will soon be in as sorry a state as the souls of those who live under tyranny.” – Thomas Jefferson

[13] Who eats better, lab mice or humans?: Paleo bloggers frequently mock scientists for the “Western” diet fed to lab mice: usually some mix of sucrose, casein, and soybean oil. After watching this video, what strikes me about the ingredient lists is that the scientists are right. “Western” humans are eating an awful lot of artificially-colored animal chow:

[14] Race to the bottom continues: Via Bix at Fanatic Cook, a Japanese food scientist has learned how to make “turd burgers” – fake meat made of protein derived from bacteria in sewage, and “improved” by the addition of soy protein:

[15] Shou-Ching’s photo art: Belated Father’s Day edition:

[16] Weekly video: The United States has been losing family farms. One reason is aggressive enforcement of counter-intuitive and health-damaging farm regulations. The new movie “Farmageddon” documents how difficult it is for family farms to produce healthy food. Here is the trailer:

Farmageddon – Movie Trailer from Kristin Canty on Vimeo.

Via Scott Kustes.

Iodine and Hashimoto’s Thyroiditis, Part 2

Posted by on May 26, 2011 344 comments

Mario Renato Iwakura’s guest series on the place of iodine and selenium supplementation in treatment of hypothyroidism continues. This is part 2. Thank you Mario! – Paul

UPDATE November 2023: Since this article was written, PHD recommendations for iodine have become firm. We recommend consistent daily supplementation in the range of 150 to 225 micrograms (not milligrams) per day, plus frequent seafood consumption. The supplementation (a) ensures a healthful supply of iodine and (b) accustoms the thyroid to the presence of iodine which minimizes the risk of thyroid injury from intake of a large amount of iodine at once, possibly at a time of selenium deficiency, for example from an all-you-can-eat crab buffet. Supplementation of >1 mg high doses of iodine carries a high risk of thyroid injury, making some parts of the thyroid hypothyroid and possibly also creating nodules with hyperthyroid activity. … Although our recommendations are not in line with Mario’s, nevertheless Mario’s article is fascinating, and a few people have reported benefit from high-dose iodine. Please read his article and judge for yourself! Best, Paul

In Part I (Iodine and Hashimoto’s Thyroiditis, Part I, May 24, 2011) we looked at evidence from animal studies that iodine is dangerous to the thyroid only when selenium is deficient or in excess, and that optimizing selenium status allows the thyroid to tolerate a wide range of iodine intakes. In fact, there were some hints (such as an improved CD4+/CD8+ T cell ratio) that high iodine, if coupled with optimal selenium, might actually diminish autoimmunity.

If that holds in humans too, we should expect that populations with healthy selenium intakes should see a low incidence of thyroid disease and no effect from iodine intake on the incidence of Hashimoto’s thyroiditis. Is that the case?

Korean Study

Dr. K [1] quotes a Korean study [3] of Hashimoto’s patients. Half restricted iodine intake to less than 100 mcg/day, the other half ate their normal seaweed and iodine. Of the 23 patients who restricted iodine, 18 (78%) became euthyroid in the sense of having TSH below 4.43 mIU/L, while only 10 (46%) of the 22 that did not restrict iodine became euthyroid. There was no measurement of symptoms at all, and no report of thyroid antibody titers after iodine restriction, so we don’t know if the iodine restriction relieved the underlying autoimmune disorder.

The selection of subjects for the two groups was odd. Group 1, the iodine restricted patients, had an extremely wide range of starting TSH, averaging 38 mIU/L but with a standard deviation of 82 mIU/L. Since all subjects began with TSH above 5 mIU/L, it’s clear that many of the Group 1 members had TSH near 5 and others had TSH well over 100 mIU/L. In comparison, Group 2, the controls, averaged a TSH of 11 mIU/L with a standard deviation of 11 mIU/L – less than 1/7 the standard deviation of Group 1. Few Group 2 members had a TSH above 30.

Table 2 presents the results. Mean TSH in Group 1 was reduced a little, but it did not even come close to normal. Since 78.3% of Group 1 had TSH below 4.43 mIU/L after 3 months, the other 21.7% had to have averaged a TSH above 102.2 mIU/L at the conclusion of the study. The standard deviation of Group 1 TSH at the end of 3 months of iodine restriciton was 71 mIU/L.

Meanwhile, Group 2 members still had a much lower standard deviation at the end of the study: 19 mIU/L.

A conclusion of this study was that “the initial serum TSH concentration was significantly lower in the recovered patients than in the non-recovered patients, which suggests that the possibility of recovvery is increasingly rare as the initial hypothyroidism becomes more severe.” Since Group 1 originally had a much larger fraction of members with very low TSH than Group 2 (plus a few with extremely high TSH to raise the average TSH), and the definition of recovery was a reduction of TSH to 4.43, perhaps it is not surprising that a higher fraction of Group 1 recovered.

Further calling into question the conclusion that lower iodine intake is beneficial is another observation. Looking at Table 1, we see that Group 2 (controls) had, at baseline, much higher iodine intake and higher urinary iodine excretion. Despite this, goiter size, TSH, antimicrosomal (MSAb) and antithyroglobulin (TGAb) antibodies were all lower!

A Japanese Study

A similar study with similar results was done in Japan [4].

In Asia, high iodine intake is due to high consumption of seaweed. Seaweed is high in naturally produced bromine compounds [5][6][7], arsenic [9][12][13], and mercury [9], and can accumulate radioactive iodine [8][9][10][11]. All these substances are known to interfere with thyroid function.

Bromide levels in urine in Asia are very high and are associated with seaweed consumption [6][7]. Values of 5 to 8.1 mg/l have been observed among Japanese, and 8 to 12 mg/l among Koreans.

It is quite possible that any benefits from “iodine restriction,” i.e. seaweed restriction, were due to reduced intake of bromine, arsenic, mercury, and radioactive iodine.

A China Study

Dr. Kharrazian [2] cites a study done in China [14] comparing three different areas: one with iodine deficiency (Panshan), another where iodine is more than adequate (Zhangwu) and a third where iodine is excessive (Huanghua). More than adequate and excessive iodine was associated with increased risk for subclinical and overt hypothyroidism.

But, another study [15], done in the same regions, showed that, coincidentally, Huanghua, the region with excessive iodine, and Zhangwu, the region with more than adequate iodine, had lower median serum selenium concentrations than Panshan, where iodine was deficient. Blood selenium concentrations were 83.2, 89.1 and 91.4 microg/L, respectively. So iodine consumption was inversely related to selenium consumption. Was it lower iodine, or higher selenium, that was beneficial?

TPOAb antibody levels were inversely associated with selenium levels. Patients with the highest TPOAb antibodies (>600 UI/ml) had lower selenium levels than patients with moderate and lower TPOAb antibodies (respectively 83.6, 95.6 and 92.9 UI/ml). [15]

Studies from Brazil, Sri Lanka, Turkey, and Greece

Dr K also cites a rise in Hashimoto’s incidence in Brazil, Sri Lanka, Turkey and Greece after salt iodinization began. Are these countries deficient in selenium? Well, lets see:

Brazil: The study was done in São Paulo, a city with a large Brazilian-Japanese population. Brazilian-Japanese have significant lower levels of Se than Japanese living in Japan [16].

Greece: Selenium status is one of the lowest of the Europe [17].

Turkey: Selenium status of Turkish children is found to be unusually low, only 65 ng/ml in boys and 71 ng/ml in girls [18]. Turkey is characterized by widespread iodine deficiency and marginal selenium deficiency [19].

Sri Lanka: Significant parts of the Sri Lankan female population may be selenium deficient [20].

One study, done in Egypt, measured iodine excretation in urine and its relation with thyroid peroxidase antibody (TPOAb) [21]. Although the abstract said that a significant correlation was found, this is far from reality, as we can see from Fig. 2.

Another study from Brazil [2] measured urinary iodine excretation and serum TPOAb and TgAb antibodies from 39 subjects with Hashimoto’s, none of whom were receiving treatment at the time of the study. Both antibody titers had no obvious correlation with urinary iodine.


Two discordant epidemiological studies

From the Netherlands, we have a prospective observational study looking at whether the female relatives of 790 autoimmune thyroid disease patients would progress to overt hypothyroidism or hyperthyroidism [22].

Although the relationship was not considered statistically significant, they found that women with high iodine intake (assessed through questionnaires) were 20% less likely to develop thyroid disorders.

Another study from western Australia (a region that has previously been shown to be iodine replete) measured urinary iodine concentration (UIC) of 98 women at 6 months postpartum and checked their thyroid status both postpartum and 12 years later [23]. UIC at 6 months postpartum predicted both postpartum thyroid dysfunction and hypothyroidism  12 years later:

The researchers concluded:

The odds ratio (OR) of hypothyroid PPTD with each unit of decreasing log iodine was 2.54, (95%CI: 1.47, 4.35), and with UIC < 50 lg/l, OR 4.22, (95%CI: 1.54, 11.55). In the long term, decreased log UIC significantly predicted hypothyroidism at 12-year follow-up (p = 0.002) … The association was independent of antibody status.

In short, the more iodine being excreted (and thus, presumably, the more in the diet and in the body), the less likely were hypothyroid disorders – not only at the time, but also 12 years later.

Dangers of selenium supplementation in iodine deficiency.

Selenium supplementation when iodine and selenium deficiencies are both present  can be dangerous, as the experience in northern Zaire, one of the most severely iodine and selenium deficient population in the world, shows [25].

Schoolchildren and cretins were supplemented for 2 months with a physiological dose of selenium (50 mcg Se per day as selenomethionine). Serum selenium was was very low at the beggining of the study and was similar in schoolchildren and in cretins (343 +- 190 nmil/L in schoolchildren, n=23, and 296 +- 116 nmol/L in cretins, n=9). After 2 months of selenium supplementation, the massive decrease in serum T4 in virtually every subject can be seen in fig. 4 below:

In schoolchildren, serum free thyroxin (fT4) decreased from 11.8 +- 6.7 nmol/L to 8.4 +- 4.1 nmol/L (P<0.01); serum reverse triiodothyronine (rT3) decreased from 12.4 +- 11.5 nmol/L to 9.0 +- 7.2 nmol/L; mean serum T3 and mean TSH remained stable. In cretins, serum fT4 remained the same or decreased to an undetectable level in all nine cretins; mean serum T3 decreased from 0.98 +- 0.72 nmol/L to 0.72 +- 0.29 nmol/L, and two cretins who were initially in a normal range of serum  T3 (1.32-2.9 nmol/L) presented T3 values outside the lower limit of normal after selenium supplementation; mean serum TSH increased significantly from 262 mU/L to 363 mU/L (p<0.001).

Another previous similar trial, this time done in 52 schoolchildren, reached the same results: a marked reduction in serum T4 [26][27]. This previous trial “was shown to modify the serum thyroid hormones parameters in clinically euthyroid subjects and to induce a dramatic fall of the already impaired thyroid function in clinically hypothyroid subjects” [27].

What stands out is the difference in the results between euthyroid schoolchildren and cretins/hypothyroids. Two months of selenium supplementation was probably not enough time to affect significantly the thyroid of the euthyroid schoolchildren (althougt already impacted T4 and fT4). But, in cretins and hypothyroids, where the thyroid was already more deficient, the impact was evident.

Conclusion and What I Do

Iodine and selenium are two extremely important minerals for human health, and are righly emphasized as such in the Perfect Health Diet book and blog. I believe they are fundamental to thyroid health and very important to Hashimoto’s patients.

A survey of the literature suggests that Hashimoto’s is largely unaffected by iodine intake. However, the literature may be distorted by three circumstances under which iodine increases may harm, and iodine restriction help, Hashimoto’s patients:

  1. Selenium deficiency causes an intolerance of high iodine.
  2. Iodine intake via seaweed is accompanied by thyrotoxic metals and halides.
  3. Sudden increases in iodine can induce a reactive hypothyroidism.

All three of these negatives can be avoided by supplementing selenium along with iodine, using potassium iodide rather than seaweed as the source of iodine, and increasing iodine intake gradually.

It’s plausible that if iodine were supplemented in this way, then Hashimoto’s patients would experience benefits with little risk of harm. Anecdotally, a number have reported benefits from supplemental iodine.

Other evidence emphasizes the need for balance between iodine and selenium. Just as iodine without selenium can cause hypothyroidism, so too can selenium without iodine. Both are needed for good health.

A few months after I was diagnosed with Hashimoto’s I started 50 mg/day iodine plus 200 mcg/day selenium. If I were starting today, I would follow Paul’s recommendation to start with selenium and a low dose of iodine, and increase the iodine dose slowly. I would not take any kelp, because of potential thyrotoxic contaminants.

Currently I’m doing the following to try to reverse my Hashimoto’s:

  1. PHD diet and follow PHD book and blog advices to enhance immunity against infections, since infections seems to be implicated in Hashimoto’s pathology [28][29][30]. I give special attention to what Chris Masterjohn calls “traditional superfoods”: liver and other organs, bones and marrow, butter and cod liver oil, egg yolks and coconut, because these foods are high in minerals, like iodine, zinc, selenium, copper, chromium, manganese and vanadium, all of which seems to play a role in thyroid health [31];
  2. High dose iodine (50mg of Lugol’s) plus 200 mcg selenium daily. These I supplement because of their vital importance to thyroid and immune function;
  3. 3 mg LDN (low dose naltrexone) every other day to further increase immunity. LDN resources are listed below [32][33][34][35][36];
  4. Avoiding mercury and other endocrine disruptors. When I removed 9 amalgams (mercury), my TPO antibodies increased for 3 months and took another 6 months to return to previous values. I also avoid fish that have high and medium concentrations of mercury. Cod consumption increased my TPO antibodies;
  5. 1g of vitamin C daily. Since it seems to confer some protection against heavy metal thyroid disfunction [37], improve thyroid medication absorption [38] and there is some evidence that it could improve a defective cellular transport for iodine [39];
  6. Donating blood 2 to 3 times per year. In men, high levels of iron seems to impact thyroid function [40].

Final Thanks

I would like to make a special thanks to Paul Jaminet for giving me the opportunity to write this essay, for gathering many, many papers for me, and for having the patience to revise both posts and suggest many changes that made the text clearer; and to Emily Deans who kindly sent me one key study that Paul could not get.

References:

[1] Dr Datis Kharrazian. Iodine and Autoimmune Thyroid — References.  http://drknews.com/some-studies-on-iodine-and-autoimmune-thyroid-disease/.

[2] Marino MA et al. Urinary iodine in patients with auto-immune thyroid disorders in Santo André, SP, is comparable to normal controls and has been steady for the last 10 years. Arq Bras Endocrinol Metabol. 2009 Feb;53(1):55-63. http://pmid.us/19347186.

[3] Yoon SJ et al. The effect of iodine restriction on thyroid function in patients with hypothyroidism due to Hashimoto’s thyroiditis. Yonsei Med J. 2003 Apr 30;44(2):227-35. http://pmid.us/12728462.

[4] Kasagi K et al. Effect of iodine restriction on thyroid function in patients with primary hypothyroidism. Thyroid. 2003 Jun;13(6):561-7. http://pmid.us/12930600.

[5] Gribble GW. The natural production of organobromine compounds. Environ Sci Pollut Res Int. 2000 Mar;7(1):37-47. http://pmid.us/19153837.

[6] Zhang ZW et al. Urinary bromide levels probably dependent to intake of foods such as sea algae. Arch Environ Contam Toxicol. 2001 May;40(4):579-84. http://pmid.us/11525503.

[7] Kawai T, Zhang ZW et al. Comparison of urinary bromide levels among people in East Asia, and the effects of dietary intakes of cereals and marine products. Toxicol Lett. 2002 Aug 5;134(1-3):285-93. http://pmid.us/12191890.

[8] Leblanc C et al. Iodine transfers in the coastal marine environment: the key role of brown algae and of their vanadium-dependent haloperoxidase. Biochimie. 2006 Nov;88(11):1773-85. http://pmid.us/17007992.

[9] van Netten C et al. Elemental and radioactive analysis of commercially available seaweed. Sci Total Environ. 2000 Jun 8;255(1-3):169-75. http://pmid.us/10898404.

[10] Hou X et al. Iodine-129 in human thyroids and seaweed in China. Sci Total Environ. 2000 Feb 10;246(2-3):285-91. http://pmid.us/10696729.

[11] Toh Y et al. Isotopic ratio of 129I/127I in seaweed measured by neutron activation analysis with gamma-gamma coincidence. Health Phys. 2002 Jul;83(1):110-3. http://pmid.us/12075675.

[12] Miyashita S, Kaise T. Biological effects and metabolism of arsenic compounds present in seafood products. Shokuhin Eiseigaku Zasshi. 2010;51(3):71-91. http://pmid.us/20595788.

[13] Cleland B et al. Arsenic exposure within the Korean community (United States) based on dietary behavior and arsenic levels in hair, urine, air, and water. Environ Health Perspect. 2009 Apr;117(4):632-8. Epub 2008 Dec 8. http://pmid.us/19440504.

[14] Chong W, Shit Xg, Teng WP, et al. Multifactor analysis of relationship between the biological exposure to iodine and hypothyroidism. Zhongua Yi Za Zhi. 2004 Jul 17:84(14):1171-4. http://pmid.us/15387978.

[15] Tong YJ et al. An epidemiological study on the relationship between selenium and thyroid function in areas with different iodine intake. Zhonghua Yi Xue Za Zhi. 2003 Dec 10;83(23):2036-9. http://pmid.us/14703411.

[16] Karita K et al. Comparison of selenium status between Japanese living in Tokyo and Japanese brazilians in São Paulo, Brazil. Asia Pac J Clin Nutr. 2001;10(3):197-9. http://pmid.us/11708308.

[17] Thorling EB et al. Selenium status in Europe–human data. A multicenter study. Ann Clin Res. 1986;18(1):3-7. http://pmid.us/3717869.

[18] Mengüba? K et al. Selenium status of healthy Turkish children. Biol Trace Elem Res. 1996 Aug;54(2):163-72. http://pmid.us/8886316.

[19] Hincal F. Trace elements in growth: iodine and selenium status of Turkish children. J Trace Elem Med Biol. 2007;21 Suppl 1:40-3. http://pmid.us/18039495.

[20] Fordyce FM et al. Selenium and iodine in soil, rice and drinking water in relation to endemic goitre in Sri Lanka. Sci Total Environ. 2000 Dec 18;263(1-3):127-41. http://pmid.us/11194147.

[21] Alsayed A et al. Excess urinary iodine is associated with autoimmune subclinical hypothyroidism among Egyptian women. Endocr J. 2008 Jul;55(3):601-5. Epub 2008 May 15. http://pmid.us/18480555.

[22] Strieder TG et al. Prediction of progression to overt hypothyroidism or hyperthyroidism in female relatives of patients with autoimmune thyroid disease using the Thyroid Events Amsterdam (THEA) score. Arch Intern Med. 2008 Aug 11;168(15):1657-63. http://pmid.us/18695079.

[23] Stuckey BG et al. Low urinary iodine postpartum is associated with hypothyroid postpartum thyroid dysfunction and predicts long-term hypothyroidism. Clin Endocrinol (Oxf). 2011 May;74(5):631-5. doi: 10.1111/j.1365-2265.2011.03978.x. http://pmid.us/21470286.

[24] American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hyperthyroidism and Hypothyroidism. https://www.aace.com/sites/default/files/hypo_hyper.pdf.

[25] Vanderpas JB et al. Selenium deficiency mitigates hypothyroxinemia in iodine-deficient subjects. Am J Clin Nutr. 1993 Feb;57(2 Suppl):271S-275S. http://pmid.us/8427203.

[26] Contempré B et al. Effect of selenium supplementation on thyroid hormone metabolism in an iodine and selenium deficient population. Clin Endocrinol (Oxf). 1992 Jun;36(6):579-83. http://pmid.us/1424183.

[27] Contempré B et al. Effect of selenium supplementation in hypothyroid subjects of an iodine and selenium deficient area: the possible danger of indiscriminate supplementation of iodine-deficient subjects with selenium. J Clin Endocrinol Metab. 1991 Jul;73(1):213-5. http://pmid.us/2045471.

[28] Benvenga S et al. Homologies of the thyroid sodium-iodide symporter with bacterial and viral proteins. J Endocrinol Invest. 1999 Jul-Aug;22(7):535-40. http://pmid.us/10475151.

[29] Wasserman EE et al. Infection and thyroid autoimmunity: A seroepidemiologic study of TPOaAb. Autoimmunity. 2009 Aug;42(5):439-46. http://pmid.us/19811261.

[30] Tozzoli R et al. Infections and autoimmune thyroid diseases: parallel detection of antibodies against pathogens with proteomic technology. Autoimmun Rev. 2008 Dec;8(2):112-5. http://pmid.us/18700170.

[31] Neve J. Clinical implications of trace elements in endocrinology. Biol Trace Elem Res. 1992 Jan-Mar;32:173-85. http://pmid.us/1375054.

[32] David Gluck, MD. Low Dose Naltrexone information site. http://www.lowdosenaltrexone.org/.

[33] LDN Yahoo Group. http://groups.yahoo.com/group/lowdosenaltrexone/.

[34] LDN World Database. Where LDN users share their experience with various diseases. http://www.ldndatabase.com/.

[35] Those Who Suffer Much Know Much. A colection of LDN users testimonies. http://www.ldnresearchtrustfiles.co.uk/docs/2010.pdf.

[36] Elaine A. More. The Promise Of Low Dose Naltrexone Therapy: Potential Benefits in Cancer, Autoimmune, Neurological and Infectious Disorder. http://www.amazon.com/Promise-Low-Dose-Naltrexone-Therapy/dp/0786437154.

[37] Gupta P, Kar A. Role of ascorbic acid in cadmium-induced thyroid dysfunction and lipid peroxidation. J Appl Toxicol. 1998 Sep-Oct;18(5):317-20. http://pmid.us/9804431.

[38] Absorption of thyroid drug levothyroxine improves with vitamin C. The Endocrine Society. News Room. http://www.endo-society.org/media/ENDO-08/research/Absorption-of-thyroid-drug.cfm.

[39] Abraham, G.E., Brownstein, D.. Evidence that the administration of Vitamin C improves a defective cellular transport mechanism for iodine: A case report. The Original Internist, 12(3):125-130, 2005. http://www.optimox.com/pics/Iodine/IOD-11/IOD_11.htm.

[40] Edwards CQ et al. Thyroid disease in hemochromatosis. Increased incidence in homozygous men. Arch Intern Med. 1983 Oct;143(10):1890-3. http://pmid.us/6625774.

Iodine and Hashimoto’s Thyroiditis, Part I

Posted by on May 24, 2011 239 comments

Mario Renato Iwakura is a Brazilian engineer and Hashimoto’s thyroiditis patient who is intimately familiar with the hypothyroidism literature. Mario has graciously agreed to do a guest series on the place of iodine and selenium supplementation in treatment of hypothyroid disorders. I’m very excited to have Mario’s thoughts, as he’s extremely smart and passionately engaged with the science. — Paul

Most doctors believe that iodine supplementation will aggravate autoimmune (Hashimoto’s) thyroiditis. This view is supported by observations that the incidence of Hashimoto’s hypothyroidism tends to increase in populations that increase their iodine intake. (The incidence of hyperthyroidism, on the other hand, increases as iodine intake decreases.). However not all epidemiological studies support this association [1][2][3][4].

Dr. Datis Kharrazian (“Dr. K”), whose 2010 book “Why Do I Still Have Thyroid Symptoms?”[5] is popular among Hashimoto’s patients, vehemently opposes the use of iodine in Hashimoto’s [5][6][7]. Chris Kresser of The Healthy Skeptic [8] has argued this point of view in his post “Iodine for hypothyroidism: like gasoline on a fire?”. And there’s little doubt that some patients have experienced bad consequences from high-dose iodine.

On the other side, doctors such as Dr. Guy E. Abraham [9], Dr. David Brownstein [10], Jorge D. Flechas [11] and Dr. David Derry [12] have claimed success prescribing high doses of iodine for Hashimoto’s and for breast and thyroid cancers.

Can these experiences by reconciled? What we will try to do is demonstrate that iodine acts synergistically with selenium, and that it is imbalances between the two that damage the thyroid.

First, Some Background

Thyroid peroxidase or thyroperoxidase (TPO) is an enzyme expressed mainly in the thyroid that liberates iodine for addition onto tyrosine residues on thyroglobulin (TG) for the production of the thyroid hormones thyroxine (T4) or triiodothyronine (T3).

The human body normally has low levels of auto-antibodies against both TG and TPO, which serve some physiological function. Autoimmune thyroiditis features high levels of these auto-antibodies, leading to immune attacks on the thyroid.

High levels of  thyroid auto-antibodies are positively associated with hypothyroidism symptoms [13][14]. TPO antibodies and TSH levels are strongly associated with progression of subclinical hypothyroidism to overt hypothyroidism [3], as can be see in Table 3 below:

Selenium Can Cure An Iodine Excess

Dr. K said in his book and site that “iodine stimulates the production and activity of the thyroid peroxidase (TPO) enzyme” [5][7]. Since TPO is a target of autoimmune attack in Hashimoto’s patients, this might worsen the disease [5][6][7]. In his book he also states that excessive iodine will shut down TPO activity [5], but he neither cites a reference nor states what level of iodine intake will cause this to happen.

In fact, excess iodine combined with selenium insufficiency will reduce (not increase, not shut down) TPO activity [15]. Let’s look at a study that had seven groups: normal iodine and lab-chow selenium only (NI), excess iodine and lab-chow selenium only (EI), and five groups with excess iodine and steadily increasing levels of selenium added to water (IS1 to IS5). TPO activity was reduced by excess iodine (EI), but returned to control levels (NI) with moderate selenium (IS1 and IS2). With excess iodine and excessive selenium (IS3 to IS5), TPO activity was also decreased, as we can see from table 2 below.

Some other studies have also demonstrated this reduced TPO activity at high iodine intakes [23][24].

This study [15] also showed a picture (fig. 1) of thyroid follicles from rats receiving normal iodine diet (NI), excessive iodine (EI) and excessive iodine plus 0.2 mg/L selenium (IS2). Thyroid follicles from the excessive iodine group (EI) are enlarged, a characteristic of goiter. But, there is virtually no difference between the first and last picture! If selenium and iodine are increased together, no goiter occurred.

Note that the IS2 level of selenium, which protects against iodine toxicity, corresponds in a person who drinks 1-2 liters per day to a selenium dose of 200 to 400 mcg per day – which happens to be the Perfect Health Diet “plateau range” for selenium.

Selenium Can Cure Autoimmunity

Another paper, also from China, looked at the effects of selenium in an animal model of iodine induced autoimmune thyroiditis [16].

There were three groups of mice, a healthy control group, and groups with iodine induced autoimmune thyroiditis without (AIT) and with (AIT+Se) selenium. The AIT+Se group was given high iodine (AIT only) for 8 weeks to induce the disease, and then, for 8 weeks more, they were given iodine plus selenium. After 8 weeks of selenium supplementation their thyroid follicles were almost fully recovered, as we can see below, even though high-dose iodine had continued:

The AIT group has enlarged cells characteristic of goiter and dead tissue; the AIT-Se group thyroid section resembles a normal thyroid. Thyroid weight doubled in the AIT group, proof of goiter, but returned to normal after selenium supplementation.

Before selenium was given to the AIT+Se group, serum TgAb antibodies were elevated, but they returned to normal after selenium supplementation:

An interesting aspect of this study was the changing population of immune cells. A specialized subpopulation of T cells, negative regulatory T cells or Tregs, helps establish and maintain self-tolerance by suppressing response to self-antigens and suppressing excessive immune responses deleterious to the host. Deficits in Treg cell numbers or function lead to autoimmune diseases [17].

In this study, CD4+CD25+Foxp3+ Treg Cells were reduced by high iodine, but returned much of the way toward normal after 8 weeks of selenium even though high iodine intake continued. The implication is that selenium-iodine balance may be needed to maintain proper Treg cell populations, and that selenium supplementation may restore normal regulation of autoimmunity.

The researchers concluded:

“In the present study, we observed that Se supplementation increased the frequency  of CD4+CD25+Foxp3+ T cells and enhanced expression of Foxp3 in vivo. These changes were accompanied by suppressed TgAb titers and reduced thyroiditis. Thus the benefit of Se treatment may be due to the increase of CD4+CD25+ regulatory T cells.”

Under What Circumstances Does Excess Iodine Induce Autoimmunity?

In the previous study high doses of iodine were used to induce autoimmune thyroiditis. Let’s look more closely into the circumstances in which that happens.

It’s often said that excessive iodine in Hashimoto’s triggers an immune response characterized by proliferation of T lymphocytes, a disrupted Th1/Th2 axis, and altered CD4/CD8 levels. Pathogenesis of autoimmune disease is believed to begin with the activation of T cell autoaggression (turning them into “allergized T cells”).

Our next study, also from China, showed that excess iodine can indeed cause such an autoimmune pathology, but only if there is a deficiency in selenium [18].

Mice in 5 groups were orally administrated different combinations of iodine and selenium for 30 days. Four groups had no selenium but varying amounts of iodine in their water:  0 μg/L (group I), 1500 μg/L (group II), 3000 μg/L (group III), and 6000 μg/L (group IV). The fifth group had 6000 μg/L iodine plus 0.3 mg/L selenium (group V).

In Group IV, high-dose iodine at 6000 μg/L caused a proliferation of lymphocytes. But this was completely abolished by the addition of selenium to water in Group V:

Normally there are relatively stable population of T cells and their subgroups in tissue till immune function is in disorder. As we can see from Fig. 1, increasing iodine increased T lymphocytic reproductive activity, and was clearly high in group IV. But group V, which also received selenium, had the same values as the control group (I).

Subjects with Hashimoto’s also have a lower ratio of CD4+ to CD8+ lymphocytes than controls [19][20]. From fig. 2, we can see that iodine supplementation in groups II and III actually increased the CD4+ to CD8+ ratio, until the onset of autoimmune symptoms at very high doses in Group IV when the ratio decreased. However, group V, which had the highest iodine intake but with selenium as well, had the highest CD4+ to CD8+ ratio of all groups.  This suggests that high-dose iodine and selenium together may actually diminish the autoimmune syndrome compared to the low levels in the controls.

Another marker of autoimmune thyroiditis is the relative strength of the Th1 and Th2 responses, as indicated by the markers interferon-gamma and interleukin-4 (Th2). Th1(IFN-γ)/Th2(IL-4) ratios are increased in Hashimoto patients [21][22], and related with severity of Hashimoto’s disease [22].

As we can see from Fig. 3, the group with the highest iodine intake but no selenium (IV) was the only group that had clearly higher Th1/Th2 ratio. High iodine plus selenium in group V had similar Th1/Th2 ratios than control group (I).

The researchers concluded:

“The results revealed that there was no significant difference in the immunotoxicity between interventional group (group V) and control group (group I), indicating that adequate selenium has a favorable interventional effect on excessive iodine intake.”

Conclusion

Excess iodine intake can cause an autoimmune thyroiditis that bears all the characteristics of Hashimoto’s. However, in animal studies this occurs only if selenium is deficient or in excess. Similarly, in animal studies very high iodine intake can exacerbate a pre-existing autoimmune thyroiditis, but only if selenium is deficient or in excess.

With optimal selenium status, thyroid follicles are healthy, goiter is eliminated, and autoimmune markers like Th1/Th2 ratio and CD4+/CD8+ ratio are normalized over a wide range of iodine intake. It seems that optimizing selenium intake provides powerful protection against autoimmune thyroid disease, and provides tolerance of a wide range of iodine intakes.

In the next post in this series (Iodine and Hashimoto’s Thyroiditis, Part 2, May 26, 2011), we’ll transition from animals to humans. Does epidemiological evidence suggest that these animal findings are transferable to humans?

References:

[1] F. Aghini-Lombardi et al. The spectrum of thyroid disorders in an iodine-deficient community: the Pescopagano Survey. J. Clin. Endocrinol. Metab. 84, 561–566 (1999). http://pmid.us/10022416.

[2] Marino MA et al. Urinary iodine in patients with auto-immune thyroid disorders in Santo André, SP, is comparable to normal controls and has been steady for the last 10 years. Arq Bras Endocrinol Metabol. 2009 Feb;53(1):55-63. http://pmid.us/19347186.

[3] Strieder TG et al. Prediction of progression to overt hypothyroidism or hyperthyroidism in female relatives of patients with autoimmune thyroid disease using the Thyroid Events Amsterdam (THEA) score. Arch Intern Med. 2008 Aug 11;168(15):1657-63. http://pmid.us/18695079.

[4] Stuckey BG et al. Low urinary iodine postpartum is associated with hypothyroid postpartum thyroid dysfunction and predicts long-term hypothyroidism. Clin Endocrinol (Oxf). 2011 May;74(5):631-5. doi: 10.1111/j.1365-2265.2011.03978.x. http://pmid.us/21470286.

[5] Dr. Datis  Kharrazian. Why Do I Still Have Thyroid Symptoms? When My Lab Tests Are Normal: A Revolutionary Breakthrough In Understanding Hashimoto’s Disease and Hypothyroidism.

[6] Dr. Datis  Kharrazian. Iodine and Autoimmune Thyroid — References. http://drknews.com/some-studies-on-iodine-and-autoimmune-thyroid-disease/.

[7] Dr. Datis  Kharrazian. Iodine and Hashimoto’s. http://drknews.com/iodine-and-hashimotos/.

[8] Chris Kresser. Iodine for hypothyroidism: like gasoline on a fire?. http://thehealthyskeptic.org/iodine-for-hypothyroidism-like-gasoline-on-a-fire.

[9] Dr. Guy E. Abraham. http://www.optimox.com/.

[10] Dr. Brownstein. Iodine, Why You Need It. https://www.drbrownstein.com/homePage.php.

[11] Dr. Jorge D. Flechas. http://cypress.he.net/~bigmacnc/drflechas/index.htm.

[12] Dr. David Derry. Breast Cancer and Iodine : How to Prevent and How to Survive Breast Cancer.

[13] Ott J et al. Hashimoto’s thyroiditis affects symptom load and quality of life unrelated to hypothyroidism: a prospective case-control study in women undergoing thyroidectomy for benign goiter. Thyroid. 2011 Feb;21(2):161-7. Epub 2010 Dec 27. http://pmid.us/21186954.

[14] Díez JJ, Iglesias P. Relationship between thyrotropin and body mass index in euthyroid subjects. Exp Clin Endocrinol Diabetes. 2011 Mar;119(3):144-50. Epub 2010 Nov 17. http://pmid.us/21086247.

[15] Xu J et al. Supplemental Selenium Alleviates the Toxic Effects of Excessive Iodine on Thyroid. Biol Trace Elem Res. 2010 Jun 2. http://pmid.us/20517655.

[16] Xue H et al. Selenium upregulates CD4(+)CD25(+) regulatory T cells in iodine-induced autoimmune thyroiditis model of NOD.H-2(h4) mice. Endocr J. 2010 Jul 30;57(7):595-601. Epub 2010 Apr 27. http://pmid.us/20453397.

[17] Sakaguchi S et al. Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006 Aug;212:8-27. http://pmid.us/16903903.

[18] Chen X et al. Effect of excessive iodine on immune function of lymphocytes and intervention with selenium. J Huazhong Univ Sci Technolog Med Sci. 2007 Aug;27(4):422-5. http://pmid.us/17828501.

[19] Gopalakrishnan S et al. The role of T-lymphocyte subsets and interleukin-5 blood levels among Indian subjects with autoimmune thyroid disease. Hormones (Athens). 2010 Jan-Mar;9(1):76-81. http://pmid.us/20363725.

[20] Zeppa P et al. Flow cytometry phenotypization of thyroidal lymphoid infiltrate and functional status in Hashimoto’s thyroiditis. Anal Quant Cytol Histol. 2006 Jun;28(3):148-56. http://pmid.us/16786724.

[21] Colin IM et al. Functional lymphocyte subset assessment of the Th1/Th2 profile in patients with autoimmune thyroiditis by flowcytometric analysis of peripheral lymphocytes. J Biol Regul Homeost Agents. 2004 Jan-Mar;18(1):72-6. http://pmid.us/15323363.

[22] Nanba T et al. Increases of the Th1/Th2 cell ratio in severe Hashimoto’s disease and in the proportion of Th17 cells in intractable Graves’ disease. Thyroid. 2009 May;19(5):495-501. http://pmid.us/19415997.

[23] Müller K et al. Effect of iodine on early stage thyroid autonomy. Genomics. 2011 Feb;97(2):94-100. http://pmid.us/21035537.

[24] Man N et al. Long-term effects of high iodine intake: inhibition of thyroid iodine uptake and organification in Wistar rats. Zhonghua Yi Xue Za Zhi. 2006 Dec 26;86(48):3420-4. http://pmid.us/17313856.

Can Endurance Exercise Promote Cancer?

Posted by on May 11, 2011 50 comments

I got into a bit of trouble in the comments a few weeks back when I joked that Grete Waitz may have died from marathoning. Steve replied:

Paul, you said “… marathoning (from which Grete Waitz just died at 57)”

Gee. The news said cancer. How confident are you that she died “from” running marathons?

Of course, not confident at all. Maybe if she’d been a sprinter she would have died at 54. Maybe if Lance Armstrong had been a couch potato he would still have had testicular cancer metastasized to his brain and lung at age 25.

A few days ago I got an email. Two highly fit endurance athletes, both of whom have always tended to their health and been careful to eat “healthy” (i.e. vegetable and whole grain rich, meat and fat poor) diets, have contracted cancers in the prime of life and been given less than a year to live. My correspondent asked, “Why?”

Let’s look into this. Is it possible that endurance exercise, especially if combined with a high-carb diet, may promote cancer?

Oxidative Damage to DNA and Cancer

Human DNA is constantly being damaged and repaired. It’s been estimated that over the course of a cell cycle – that is, from the time a cell is formed to the time it divides into two daughter cells – a human cell develops 5,000 single-stranded DNA breaks due to oxidative damage from reactive oxygen species (ROS). The vast majority are repaired by the body’s DNA repair machinery. [1]

However, in typical human cells 0.1% or 5 are not successfully repaired; instead a corresponding break is created in the complementary DNA strand, resulting in a double-strand break. In people with Bloom syndrome, an inherited condition which creates a strong predisposition to cancer, fully 1% or 50 are not successfully repaired. [1]

The double-strand break leads to a re-arrangement or “translocation” of parts of the chromosome. Usually, this does not break the coding region for a protein, but it does break non-coding regions resulting in changes to gene expression.

These sorts of genetic changes are observed both in cancer and in aging. [1] In short, oxidative damage to DNA is considered a risk factor for cancer development.

Oxidative Damage to DNA Has Been Specifically Linked to Endurance Exercise

Diets and activities that increase oxidative stress – for instance, diets deficient in antioxidant minerals – can therefore increase cancer risk. And diets and activities that minimize oxidative stress can minimize cancer risk and facilitate recovery.

Endurance exercise generates oxidative stress. Marathon running “caused a large increase in the tissue content of oxidized glutathione (189%) at the expense of reduced glutathione (-18%).” [2]

Moreover, endurance exercise damages DNA:

Both a systemic inflammatory response as well as DNA damage has been observed following exhaustive endurance exercise….

Extremely demanding endurance exercise has been shown to induce both a systemic inflammatory response [15, 42, 53, 71] as well as DNA damage [21, 36, 58, 62, 80]….

Exercise-induced DNA damage in peripheral blood cells appear to be mainly a consequence of an increased production of reactive oxygen and nitrogen species (RONS) during and after vigorous aerobic exercise [58]. Besides oxidative stress, other factors such as metabolic, hormonal and thermal stress in addition to the ultra-structural damage of muscle tissue are characteristic responses to prolonged strenuous exercise, that can lead to the release of cytokines, acute phase proteins and to the activation or inhibition of certain lines of the cellular immune system [15, 29]. [3]

There seems to be a big difference between moderate exercise and exercise to exhaustion. Moderate exercise actually protects DNA by upregulating DNA repair:

Sato et al. showed that acute mild exercise as well as chronic moderate training does not result in DNA damage, but rather leads to an elevation in the sanitization system of DNA damage [66]. [3]

However, endurance exercise leads to increased DNA damage:

Increased levels of DNA strand breaks were observed after exhaustive treadmill running in subjects of different training status [22, 45]….

In conclusion, there is growing evidence that strenuous exercise can lead to DNA damage that with few exceptions [36] is predominantly observed not before 24 h after the resolution of exercise [21, 44, 45, 80]. [3]

In addition, strenuous endurance exercise induces hormonal and other changes which might promote cancer. An Ironman triathlon has significant effects on hormones and inflammatory markers, some of which persist for more than 19 days post-race:

Briefly, as described in details elsewhere [42], there were significant (P<0.001) increases in total leukocyte counts, MPO, PMN elastase, cortisol, CK activity, myoglobin, IL-6, IL-10 and hs-CRP, whereas testosterone significantly (P<0.001) decreased compared to pre-race. Except for cortisol, which decreased below pre-race values (P<0.001), these alterations persisted 1 d post-race (P<0.001, P<0.01 for IL-10). Five days post-race CK activity, myoglobin, IL-6 and hs-CRP had decreased, but were still significantly (P<0.001) elevated. Nineteen days post-race most parameters had returned to pre-race values, with the exception of MPO and PMN elastase, which had both significantly (P<0.001) decreased below pre-race concentrations, and myoglobin and hs-CRP, which were slightly, but significantly higher than pre-race [42]. [3]

In the opinion of the authors of this review, the biggest problem is production of reactive oxygen and nitrogen species (RONS) by damaged immune cells:

The most conclusive picture that emerges from the available data is that oxidative stress seems to be the main link between exercise-induced inflammation and DNA damage…. DNA damage in peripheral immuno-competent cells, indeed, most likely resulted from an increased generation of RONS due to initial systemic inflammatory responses or the delayed inflammatory processes in response to muscle damage (Fig. 1). [3]

What About High-Carb Diets?

Do high-carb diets contribute?

During strenuous exercise mitochondria produce oxidation products:

The mitochondrial electron transport system can trigger the formation of superoxide leading to increased production of H2O2 by superoxide dismutase [49], [50]. [4]

In a normal person at rest, about 1-2% of the oxygen utilized by mitochondria ends up in superoxide. [4]

Before we go further let’s take a brief detour into mitochondrial chemistry: specifically, something called the electron transport chain.

Here’s a stylized view:

Source: Wikipedia.

The main point for our purposes is that there are two points of entry into the chain, one that goes through complex I and one that bypasses it.

Glucose metabolism favors entry via complex I, while fatty acid metabolism is relatively more favorable to entry via complex II. Quantitatively, glucose metabolism produces 5 NADH molecules (entering at complex I) for every one succinate molecule (entering at complex II), while fatty acid metabolism produces only 2 NADH for every one succinate.

High-carb dieting tends to habituate the body to metabolism of glucose. Therefore, it increases utilization of complex I.

This is significant because complex I is vulnerable to production of excess oxidative stress under some circumstances.

In principle, every mitochondrial complex has the potential to operate cleanly with minimal production of superoxide. However, if mitochondrial function is in any way impaired, so that operation of a complex is inhibited, then ROS production can rise substantially.

If for some reason electrons cannot flow properly through the electron transport chain, then they leave as superoxide:

One factor which may sensitise cells to increased DNA damage is impaired mitochondrial function [74]…. Reduced electron flow through the mitochondrial respiratory chain, particularly through the inhibition of complex I or complex III, favours the enhanced production of superoxide and H2O2 [75]. Together, with the age-dependent increase in oxidative stress and decline in NAD+ and ATP content, we found a tendency to the reduction in the activity of the respiratory complexes with age in all organs. Sipos et al. (2003) showed that mitochondrial formation of H2O2 due to complex I inhibition is more clinically relevant than ROS production due to inhibition of complex III and IV in situ [76]. [4]

What exactly did Sipos et al. find?  They state:

ROS formation was not detected until complex III was inhibited by up to 71 +/- 4%, above that threshold inhibition, decrease in aconitase activity indicated an enhanced ROS generation. Similarly, threshold inhibition of complex IV caused an accelerated ROS production. By contrast, inactivation of complex I to a small extent (16 +/- 2%) resulted in a significant increase in ROS formation, and no clear threshold inhibition could be determined. [5]

Basically, superoxide can be generated in complexes I, III, and IV. However, in complexes III and IV, there is a high threshold of inhibition of electron transport before any superoxide is produced. In complex I, there is no threshold:  even very slight inhibition will generate ROS. This means that during practical living, the great majority of excess ROS is produced from complex I.

This means that high-carb dieting, which increases utilization of complex I, will tend to generate oxidative stress if there is any inhibition of complex I.

But in endurance exercise, there is inhibition of complex I. To name just one pathway, exercise increases levels of the hormone DHEA, and DHEA inhibits complex I. [6]

It looks like high-carb diets and endurance exercise may be a bad combination.

Are Whole Grains Especially Bad?

There may be specific problems with grain toxins. For instance, wheat germ agglutinin, a wheat toxin that is very effective at distributing itself through the body through transcytosis, is able to damage mitochondria:

WGA induced a loss of transmembrane potential, disruption of the inner mitochondria membrane, and release of cytochrome c and caspase-9 activation after 30 min of cell interaction. [7]

At high doses in test tubes this can lead to cell death. It’s conceivable that at physiological levels WGA damage to mitochondria might mildly inhibit complex I and increase oxidative stress.

Of course, any deficiency in antioxidant minerals zinc and copper, which dismutate superoxide to hydrogen peroxide which is then disposed of by glutathione peroxidase (a selenium containing enzyme), would increase oxidative stress. Wheat contains phytic acid which chelates minerals and reliance on wheat as a calorie source may impair antioxidant status.

Conclusion

I don’t want to exaggerate the risks of endurance sports. With the exception of melanoma [8], there isn’t a clear increase in cancer incidence among marathon runners. And if this post seemed a bit tortuous, it’s because there’s no simple “smoking gun” pathway connecting endurance exercise to cancer.

On the other hand, endurance exercise is probably not as healthy, in terms of cancer risk, as shorter-duration activities. Also, the risk may rise substantially on high-carb or wheat-based diets. There are at least a few plausible mechanisms, not all of which I’ve discussed here, that might connect endurance exercise on grain-based high-carb low-fat diets to cancer.

References

[1] Vilenchik MM, Knudson AG. Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12871-6. http://pmid.us/14566050.

[2] Cooper MB et al. The effect of marathon running on carnitine metabolism and on some aspects of muscle mitochondrial activities and antioxidant mechanisms. J Sports Sci. 1986 Autumn;4(2):79-87. http://pmid.us/3586108.

[3] Neubauer O et al. Exercise-induced DNA damage: is there a relationship with inflammatory responses? Exerc Immunol Rev. 2008;14:51-72. http://pmid.us/19203084.

[4] Braidy N et al. Age related changes in NAD+ metabolism oxidative stress and sirt1 activity in wistar rats. PLoS One. 2011 Apr 26;6(4):e19194. http://pmid.us/21541336.

[5] Sipos I et al. Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals. J Neurochem. 2003 Jan;84(1):112-8. http://pmid.us/12485407.

[6] Safiulina D et al. Dehydroepiandrosterone inhibits complex I of the mitochondrial respiratory chain and is neurotoxic in vitro and in vivo at high concentrations. Toxicol Sci. 2006 Oct;93(2):348-56. http://pmid.us/16849397

[7] Gastman B et al. A novel apoptotic pathway as defined by lectin cellular initiation. Biochem Biophys Res Commun. 2004 Mar 26;316(1):263-71. http://pmid.us/15003540.

[8] Ambros-Rudolph CM et al. Malignant melanoma in marathon runners. Arch Dermatol. 2006 Nov;142(11):1471-4. http://pmid.us/17116838.