Ask Dr. Andro: Are Vitamin Supplements Bad For Me (1/2)? The "wrong" Vitamin E Supplements Increase Cancer Risk.

Figure 1: This is where you, my American friends (and most Europeans), should and would get your "E's" from - it's called "food" (Eitenmiller. 2004)

With the recent publication of two studies on increased all-cause mortality in older women (Bjelacovic. 2011; Mursu. 2011) who took multivitamins (+2.4%), vitamin B6 (+4.1%), folic acid (+5.9%), iron (+3.4%), magnsium (+3.6%), zinc (+3.0%), and the "killer" copper (+18%) and increased risk of prostate cancer due to selenium and/or vitamin E supplements (Klein. 2011) on a regular basis and the huge media attention these studies,

• "Certain Dietary Supplements Associated With Increased Risk of Death in Older Women, Study Suggests"
• "Vitamin E Supplement May Increase Prostate Cancer Risk, National U.S. Study Finds"

have received, I got interested in taking a closer look at what I would usually have discarded as epidemiological guesswork and scare tactics, anyway.

How can a vitamin be bad for you? It's supposed to be a vital nutrient, goddammit!  

In that, I want to start with the 2nd of the two studies, i.e. the one on Vitamin E, which also happens to be a "true" Ask Dr. Andro question. After all, Steven Acerra posted a whole bunch of related questions on my Facebook page (remember you can always send in questions you want to have answered in this column!)

Image 1: Conflicts of interest, as declared in the paper by Klein et al.

Are medical studies "objective"? Being a scientist (in a whole different area of research, though), myself, I am well aware that financing expensive cutting edge science with the meager support from national agencies is impossible, these days. Therefore, I refuse any rash prejudgements based on the openly stated potential conflicts of interest (cf. image 1), as Steven put them forward in a follow-up comment on my facebook page. If you want to blame someone, blame the influential editors of the large journals, including the JAMA, where Klein's paper was published. Their acceptance of a paper determines whether a study appears on the SuppVersity, "only", or is taken up by a journalist from a major popular scientific magazine or, as in this case, even the Health Podcast of Time Magazine.

Other than Steven suspected, the study by Klein et al. that was published in the latest issue of JAMA (the Journal of the American Medical Association which is not particularly well know for being independent of the pharma lobby, cf. red box ;-) - despite its size - actually is a "controlled" trial... Well, as controlled as a study with 34 887 men who were randomly assigned to receive selenium (n= 8752), vitamin E (n=8737), vitamin E + selenium (n=8702) or placebo (n=8696), can be. It is part of, or  I should say, the final outcome of the so called SELECT trial, a large scale intervention that was conducted in the United States, Canada, and Puerto Rico. Data acquisition started on August 22, 2001 and ended three months ago, on July 5, 2011. The fact that the study is over is good news for all participants, because, as the bold headlines would have it, all treatments increased the participants' risk to develop cancer. Yet, what mainstream media didn't tell you is that (I quote directly from the detailed results in the paper; Klein. 2011):

The rate of prostate cancer detection was greater in all treatment groups when compared with placebo* but was statistically significant only in the vitamin E alone group. After adjustment for the marginal effects of vitamin E and selenium, the interaction between vitamin E and selenium was statistically significant (P=.02), indicating no increased risk of prostate cancer when vitamin E and selenium were taken together. The risk of Gleason 7 or greater disease was higher for all 3 interventions [vitamin E + 16%; selenium +21%; combination: +23%] but did not reach statistical significance for any group.

* I suspect this is probably about as far as most journalists read - if they even had the fulltext of the study, when they wrote their sensational and fearmongerish articles

If you compare the real findings to what you may have read in the course of the last week, it is quite obvious that half of the media reports got the results completely wrong. A quarter of the reporters obviously did not know the meaning and importance of "statistical significance" and the lousy rest does not care about information, anyway, as long as a headline could potentially increase sales or pageviews, it makes it into the magazine or onto the website.

No matter what the press says: You better know your vitamins E before taking the wrong one

Figure 2: Natural RRR alpha-tocopherol and synthetic SRR alpha tocopherol which is one of the isomers in the -50% less potent all-rac-alpha tocopherol, which is the "vitamin E" the 34,887 men in the large scale trial conducted by Klein et al. have received at a dose of 400IU per day  (figure from Traber. 2011)

This leaves us with just one "unexpected" result to be explained, i.e. a statistically significant increase in cancer risk with 400IU of supplemental "vitamin E" per day. In case you've noticed the quotation-marks before and after vitamin E, in the previous sentence, you already know where this is heading. After all, you would assume that the scientists would use the most potent weapons from their arsenal in their battle against prostate cancer - wouldn't you? Trial "S0000 Selenium and Vitamin E in Preventing Prostate Cancer" (clinical trials identifier: NCT00006392) sponsored by the Southwest Oncology Group, however, relied on the cheap all-rac-alpha-tocopheryl acetate of which Max K. Horwitt had shown back in 1980, already, that "all-rac-alpha-tocopheryl acetate may have no more than half the biological potency of d-alpha-tocopheryl acetate" (Horwitt. 1980). About, 19 years later Horwitt, then over 90 years old (!), was still fighting a fight against the medical establishment who maintained that the cheap synthetic form of vitamin E would have at least a 73.5% the activity of the naturally occurring form. In a letter to the editors of the American Journal of Clinical Nutrition he writes (Horwitt. 1999):

Now in my 90th y, I doubt whether I will ever see the proper correction made in the official values of the tocopherols. Having introduced the term equivalent as used by committees of dietary allowance, I prefer that this designation be used to describe the potency of the tocopherols. In the recommended dietary allowances, l mg RRR-a-tocopherol has a biological value of 1.0 a-tocopherol equivalents. Accordingly, in modified US Pharmacopoeia vitamin E units, RRR-a-tocopherol should have a value of 1.0, all-rac-a-tocopherol a value of 0.5, RRR-a-tocopheryl acetate a value of 0.91, and all-rac-a-tocopheryl acetate a value of 0.455.

Meanwhile, the USDA has changed their calculations in the USDA National Nutrient Database for Standard Reference, according to release #20 (USDA. 2008), the all-rac-alpha-tocopheryl acetate 
is now officially classified as -55% less potent than natural tocopherol. Now, the chance to pick the worst of the four vitamin E's was 25% and *bang* Klein et al. nailed it. Can this be coincidence - I guess if it was you could call it "bad luck".

Supplementation may offset the natural balance by exchanging natural gamma tocopherols for cheap synthetic alpha-tocopherols

"Bad luck", also because supplementation with high doses of alpha-tocopherol has been shown to hinder "normal" incorporation of gamma-tocopherols into VLDL particles, to increase hepatic clearance of gamma-tocopherols and, in the end, to deplete plasma gamma-tocopherol levels, as well (Jiang. 2011). Now, if you have a less potent type of vitamin E, you obviously have to supplement more (to achieve a potency equivalent to 400IU you obviously need +55% more all-rac than natural tocopherol!)... but does that really matter? Oh yes it does! As gamma tocopherol and not alpha-tocopherol is "the vitamin E" which inhibits cyclooxygenase activity and, thus, possess heart-healthy anti-inflammatory properties. No wonder that Jiang et al. report in a 2001 review that...

1. plasma gamma-tocopherol concentrations are inversely associated with increased morbidity and mortality due to CVD. 
2. serum concentrations of  gamma-tocopherol, but not of alpha-tocopherol, were lower in CVD patients than in healthy control subjects. 
3. in a concomitant cross-sectional study of Swedish and Lithuanian middle-aged men,  plasma gamma-tocopherol concentrations were twice as high in the Swedish men, but that the Swedish men had a 25% lower incidence of CVD-related mortality. In contrast, this inverse correlation was not observed with alpha-toco-pherol. 

... and the list goes on. Now, you will probably say "But Dr. Andro, those men got cancer from vitamin E, not cardiovascular disease!" and, as always, you are right, BUT the evidence that gamma- not alpha-tocopherol (or at least a "natural" mix of both) is cancer protective is even more conclusive than the one on the CVD-protective effect of the former.

What are normal ratios of alpha- to gamma-tocopherol? While we hardly can say which ratios are optimal, we know that the "normal" ratio of serum alpha- to gamma-tocopherol levels for Americans who do not take any supplements is 5:1 (alpha:gamma). According to Chopra and Baghavan his ratio further increases to greater than 20-fold in people taking vitamin E supplements (Chopra. 1999).

High gamma-tocopherol levels reduce risk of prostate cancer by -500% [no typo!]

In 2000 Helzlsouer et al. analyzed the blood of 10 456 male residents of Washington County and found that (Helzlsouer. 2000)...

For gamma-tocopherol, men in the highest fifth of the distribution had a fivefold reduction in the risk of devel-oping prostate cancer than men in the lowest fifth (Ptrend = .002).

With p = 0.002 the chance that this was "coincidence" is exactly  125x smaller (0.2%) than Klein et al.'s chance (25%) to pick the worst alpha-tocopherol variety there is for their large scale intervention. And while this is only an epidemiological study, we have more than enough in-vitro and animal data to confirm the anti-cancer effect of gamma-tocopherol:

Prostate cancer:
• Jiang. 2004:  "... gammaT and mixed vitamin E forms induce cell death by interrupting the de novo sphingolipid pathway in a prostate cancer cell line"
• Campbell. 2009: Growth arrest (40%) in PC-3 prostate cancer cells through the regulation of fatty acid metabolism and PPAR gamma mRNA and protein upregulation was achieved with gamma-tocopherol within 6 h.
• Jiang. 2011: Sphingolipid promoting effects of gamma-tocopherol induces apoptosis and autophagy in prostate cancer cells

Colon cancer:
• Campbell 2006: In-vitro study on human colon-cancer cell lines; "treatment with RRR-gamma-tocopherol resulted in significant cell death for all cancer cell lines tested, while RRR-alpha-tocopherol did not [...] RRR-gamma-tocopherol may aid chemotherapy without toxic effects to normal cells demonstrated by most chemotherapeutic agents"

Other cancers:
• Yu. 2009: Mouse model (human breast cancer) + in-vitro studies > "α-tocopherol not only failed to exhibit anticancer properties but it reduced anticancer actions of γ-tocopherol in vivo and γ-tocopherol and α-TEA in vitro."; what is important to note, though is that the all-trans-variety used in the Klein study did at least inhibit proliferation and increase apoptosis (programmed cell death) in vivo.
• Yang. 2010: "[I]nhibition of inflammation as well as of cancer formation and growth in the lung and colon in animal models" by tocopherol supplement with  57% gamma-T
• Ju. 2010a: "In cell culture, the growth of H1299 cells [lung cancer] was inhibited by tocopherols with their effectiveness following the order of delta-T > gamma-TmT > gamma-T, whereas alpha-T was not effective."
• Ju. 2010b: "... recent results have demonstrated that a gamma-tocopherol-rich mixture of tocopherols inhibits colon, prostate, mammary and lung tumorigenesis in animal models, suggesting that this mixture may have a high potential for applications in the prevention of human cancer"

And directly referring to the "partly negative" outcomes of studies into the potentially beneficial effects of "vitamin E" supplements (which were almost exclusively conducted with alpha-tocepherol-only products), Reiter el al. wrote in a 2009 review (Reiter. 2009):

As pointed out in this review, more and more evidence indicates that γT and other vitamin E forms than αT have unique bioactivities that may be important for maintaining and improving human health (Dietrich et al. 2006; Jiang et al. 2001). For example, γT is a stronger inhibitor of cyclooxygenase and possibly lipoxygenase than αT. Furthermore, γT traps reactive nitrogen species more efficiently than αT. Some of these in vitro effects are slowly being confirmed in vivo, but more studies are needed here. In addition, γT but not αT exhibits anti-proliferative and pro-apoptotic effects on cancer but not normal epithelial cells (Jiang et al, 2004). [...] Thus, despite the undisputed anti-inflammatory effects of α- and γT, the recent large-scale interventional studies aimed at reducing diseases associated with chronic inflammation have been disappointing, but may be explained by the complex interaction of the different vitamin E forms with inflammatory signaling, xenobiotic transformation, and as yet undefined pathways.

I think I do not have to point out that with what we know today about the necessary synergy of the vitamins E (including the tocotrienols, which I deliberately left out, in order not to overcomplicate things) and the results of a 2003 study by Huang (Huang. 2003), which showed that supplementation with 400IU of RRR-alpha-tocopheryl acetate (remember due to the fact that this is the more potent variety, the actual dose in µg was -50% lower than in the Klein study)

reduced serum gamma-tocopherol concentrations by a median change of -58% [95% CI = (51%, 66%), P < 0.0001], and reduced the number of individuals with detectable delta-tocopherol concentrations (P < 0.0001),

initiating a similar study as Klein et al. did 10 years ago, would border physical injury resulting from negligence, today. And although the use of isolated forms of vitamin E, which you will find in most of the cheap multivitamin tablets you can buy at the supermarket, could also be involved in the negative effect "certain dietary supplements" (including multivitamins) were reported to have on the health of "older women" in the 2nd study, I mentioned in the introduction, I will address this issue in an individual installment in a follow up to this post in the course of the next week. So stay tuned for more.