Dr. Paul Anderson
This post originally appeared on Emerson Ecologics
Reference: Theodore M. Brasky, Emily White, and Chi-Ling Chen. Long-Term, Supplemental, One-CarbonMetabolism–Related Vitamin B Use in Relation to Lung Cancer Risk in the Vitamins and Lifestyle (VITAL) Cohort. J Clin Oncol 35. (2017) PMID: 28829668
Design: Retrospective analysis of prospective cohort study data
This “original report” from the Journal of Clinical Oncology grabbed a number of headlines when it was released including:
- High Doses Of Vitamin B Supplements Linked To Lung Cancer Risk[i]
- Popular Vitamin Supplement Appears To Cause Lung Cancer In Men[ii]
- Clear link between heavy vitamin B intake and lung cancer[iii]
- Vitamin B Supplements Linked To Greater Lung Cancer Risk, But Only For Some[iv]
None of those headlines sound very good and certainly have caused a number of questions from patients in our practice as well as in online forums.
From the “methods” portion of the paper the design is outlined as:
A total of 77,118 participants of the VITAL cohort, 50 to 76 years of age, were recruited between October 2000 and December 2002 and included in this analysis. Incident, primary, invasive lung cancers (n = 808) were ascertained by prospectively linking the participants to a population-based cancer registry. The 10-year average daily dose from individual and multivitamin supplements were the exposures of primary interest.
In this large, prospective analysis of older adults, we report a 30% to 40% increased lung cancer risk associated with vitamins B6 and B12 use from individual supplements in men. No association was found in women or for B vitamins from multivitamin sources. Use of vitamin B6 or B12 in high doses (mostly from individual supplements) for an extended period (10 years) was associated with an almost two-fold increased risk of lung cancer in men, and this risk was further strengthened among men who were current smokers at baseline.
The actual findings:
- The study found that “consuming high-dose individual B6 and B12 vitamin supplements over a 10-year period is associated with increased lung cancer risk, especially in male smokers.”
- The study did “not find such associations in non-smoking males nor in females regardless of smoking history.”
- The study found no association between increased lung cancer risk and folic acid supplementation.
- “High-dose” was identified as > 20 mg / day for vitamin B-6 and > 55 mcg / day for vitamin B-12
It should be noted that in the quotes from the study above, there is disagreement between “increased lung cancer risk, especially in male smokers” and did “not find such associations in non-smoking males nor in females regardless of smoking history”, in that the first statement makes one believe all males are at risk, while the second clarifies the data and non-smoking males are actually not at higher risk. This may have been an editing mistake or potentially a generalization but the effect is that the first statement over states the risk and extrapolates it to non-smoking males. This is certainly worth pointing out.
The specific risk elevations for male smokers were stratified by duration of smoking using a baseline of “1.00” for the non-supplementing group. Those former smokers who had been non-smokers for 10 or more years had a 0.54 increase, former smokers less than 10 years since quitting had a 0.92 increase and current smokers had a 1.93 increase (or almost three times the risk of a non-supplementing person).
It is certainly not surprising that lung cancer risk is elevated in smokers. It is also not an unfamiliar thought that some nutrients react differently in smokers than in non-smokers. One case in point is the confusion over vitamin E and lung cancer risk as well as vitamin A / carotenoids and lung cancer risk.
In regard to vitamin E we have studies showing that higher levels of dietary tocopherol and tocotrienol intake are associated with lower risk of lung cancer in smokers[v][vi] and others intimating that while dietary intake of vitamin E appears protective while supplemental vitamin E ‘may’ be associated with an increase in lung cancer[vii] although they state that association needs further investigation. Further confusion arises in studies suggesting tocopherols and tocotrienols may be used in lung cancer treatment.[viii]
Vitamin A and carotenoids are a similar discussion. The same ideas arise, that higher levels of carotenoids are associated with lower lung cancer risk, but also that in current smokers use of high-dose supplemental β-carotene increases lung cancer risk.[ix][x]
Why bring up Vitamins A and E when the study being discussed did not assess those as risk factors? Both are examples which I believe parallel the potential risk association between vitamins B6 and B12 reported in the Brasky paper. That parallel being a difference in nutrient metabolism in people who smoke and people who do not smoke potentially leading to these observed differences in risk.
The authors of the Brasky paper look at potential reasons for this metabolic difference in smokers and non-smokers in an effort to explain the observations. In regard to gender differences they reported other data showing that genetic polymorphisms of the MTHFR enzyme[xi] interacted differently between men and women with dietary vitamin B6 and B12 intakes, cigarette smoking, and lung cancer. Men and women have different susceptibility to tobacco induced lung cancer and supplementation with high-dose vitamins B6 and B12 for longer duration may support more rapid cell growth and promote carcinogenesis in already mutated cells in smoking men. They also point out that “Because androgen signaling regulates key enzymes involved in the one-carbon metabolism pathways, the increase of androgen levels or activity in men may lead to a more profound effect.”
Specifically vitamin B6 has different metabolism in smokers and non-smokers which may give rise to one reason for the observed risk increase as well. They postulate a theory regarding B6 levels “serum levels differing between participants with lung cancer and participants without lung cancer because of different absorption, distribution, or catabolism of the circulating nutrient, rather than the total amount they consume” which although complex is a likely reason for the phenomenon noted.
To shorten a very long and in depth discussion of vitamin B6 metabolism, and how that is affected by cancer, I will summarize the salient points and refer to the references cited should anyone require a deeper investigation.
First “blood levels” of B6 can be specifically assayed but general use “vitamin B6” levels actually include four separate vitamers of B6 (pyridoxamine, pyridoxine, pyridoxal-5-phosphate (P5P) and 4-pyridoxate) all of which have metabolic intermediates making the total number of vitamers of B6 larger. The issue is that (if looking at a total vitamin B6 level) one sees this pool reflecting partly the active P5P as well as other vitamers which can be increased by inflammation.
Second vitamin B6 and the enzyme family aldehyde dehydrogenase (ALDH) are metabolically connected[xii] and ALDH activity has effect on cancer stem cells (CSC) and their activity[xiii], including adenocarcinoma of the lung CSC activity.[xiv]
And finally the actual metabolism of vitamin B6 is tied to both cancer protection and cancer stimulation depending on the metabolism of the individual vitamers. High circulating B6 levels (especially in the presence of high levels of the P5P producing pyridoxal kinase enzyme) is associated not only with improved outcomes in many solid and hematologic cancers but also in non-small cell lung cancer (NSCLC) as well.[xv] Conversely B6 in the presence of inflammation or smoking metabolizes in a different manner.[xvi] This metabolic difference (and association with worse cancer outcomes) is due to the effects of inflammation on B6 (and other) metabolism[xvii] as well as the effect of smoking on B6 metabolism.[xviii]
Practice Implications:
Any time there are data that point to a potential difference in disease outcome in one subset of the population versus the larger population it underscores the reality of bio-individuality as well as the need for nuanced medicine to deal with such differences. That said the following are summary points to consider when clinically incorporating this data:
- This study showed an increased risk only in male smokers, with the highest risk being in current smokers using supplemental vitamin B12 as well as vitamin B6 but not folic acid.
- Smoking is the leading risk factor for lung cancer and is associated with elevated concentrations of inflammatory markers. [xix] It is the inflammatory chemistry of the smoker that causes abnormal metabolism of vitamins B12 and B6.
- Groups considered in the study to have “elevated intake” excluded people taking a standard multi vitamin (i.e. Centrum) daily for 10 years, which by default excludes moderate dose “balanced” nutrient intake from the increased risk group. This means that the “elevated intake” group were truly consuming an odd, and normally not recommended, imbalanced group of nutrients.
- Both the metabolism of vitamin B12 and B6 are noted to be different in smokers (due to inflammatory and epigenetic changes) via the pathways mentioned above.
- Smokers generally have the lowest antioxidant and nutrient intake from diet when compared with non-smoking controls. In a study of over 6700 people current smokers had the lowest dietary antioxidant intake including fruit and vegetables. And current smokers consumed the fewest numbers of servings of all nutrient-bearing groups.[xx]This is a critical fact in assessing the drivers of the “abnormal B6 and B12 metabolism in smokers” which is at the core of the data.
- There was no increased risk in females (smokers or not) nor in non-smoking males.
- Limitations and questions:
- While some participants were taking a multi vitamin in addition to the levels of B6, B12 and folic acid studied some were not. There is no way to correct the outcomes for balanced nutrient intake versus imbalanced intake. This is of note as many of the metabolic difficulties noted for B6 or B12 can be lower in the presence of other collateral cofactors (including other flavonoids, polyphenols, vitamins and minerals).
- Another potential confounding variable is the lack of correction for antioxidant or other dietary anti-inflammatory intake. Because inflammation is an equal or greater driver (as compared with imbalanced cofactors) of abnormal metabolism of B6 and B12 it is possible that (and data referenced above confirm) that in the absence of excess inflammation the abnormal B6 and B12 metabolism may be less or not occur at all.
- This is a very real issue as cited above (Ma, et.al), smokers have much lower general nutrient intake as well as antioxidant intake than non-smokers, and have been shown in a double-blind placebo-controlled randomized crossover study to require supplemental vitamin C to keep vitamin E recycled in the primary antioxidant system used in the body.[xxi]
- Clinical considerations:
- Regardless of the patient history assure that a whole person oriented diet and nutrient approach is employed in regard to overall health promotion as well as cancer protection. This includes balancing of vitamins, minerals, antioxidants and plant and other sources of anti-inflammatory nutrients.
- If a patient is a male smoker (or former smoker) assess their supplement intake and balance carefully. Consider focusing on lowering inflammation in multiple ways (stopping smoking, antioxidant balance, inflammation modulating natural foods and supplements etc.) before using vitamins B6 or B12 in excess of a balanced multi vitamin.
- Because there are no prospective data using a balanced nutritional approach, in contrast to the single nutrients in isolation assessed in this study, inform patients of the limitations of the study and conclusions one may (and more importantly may not) draw from it.
- The data presented and statistics used appear valid, but are somewhat artificial in regard to what any responsible integrative practitioner would ever recommend for a patient. Given the known low intake of nutrients including antioxidants coupled with the poor antioxidant cycling status in smokers cited above, and the fact that these factors are the primary drivers of the abnormal B6 and B12 metabolism seen in smokers, there is no reason to believe that the higher risk group (male smokers, past or present) would have any increased risk if they had a balanced nutrient intake with additional antioxidant support (both dietary and supplemental).
This article first appeared on Dr. Anderson’s monthly review for Emerson Ecologics.
References
[i] http://www.iflscience.com/health-and-medicine/high-doses-of-vitamin-b-supplements-linked-to-lung-cancer-risk-but-theres-a-twist-0/
[ii] http://secondnexus.com/technology-and-innovation/b6-b12-lung-cancer-link/
[iii] https://www.sciencedaily.com/releases/2017/08/170822175515.htm
[iv] http://www.medicaldaily.com/vitamin-b-supplements-linked-greater-lung-cancer-risk-only-some-421591
[v] Chen G, Wang J, Hong X, Chai Z, Li Q. Dietary vitamin E intake could reduce the risk of lung cancer: evidence from a meta-analysis. International Journal of Clinical and Experimental Medicine. 2015;8(4):6631-6637.
[vi] Knekt P. Vitamin E and smoking and the risk of lung cancer. Ann N Y Acad Sci. 1993 May 28;686:280-7; discussion 287-8. PMID: 8512253
[vii] Wu Q-J, Xiang Y-B, Yang G, et al. Vitamin E intake and the lung cancer risk among female nonsmokers: a report from the Shanghai Women’s Health Study. International journal of cancer Journal international du cancer. 2015;136(3):610-617. doi:10.1002/ijc.29016.
[viii] Zarogoulidis P, Cheva A, Zarampouka K, et al. Tocopherols and tocotrienols as anticancer treatment for lung cancer: future nutrition. Journal of Thoracic Disease. 2013;5(3):349-352. doi:10.3978/j.issn.2072-1439.2013.04.03.
[ix] Männistö S. et.al. Dietary carotenoids and risk of lung cancer in a pooled analysis of seven cohort studies. Cancer Epidemiol Biomarkers Prev. 2004 Jan;13(1):40-8. PMID: 14744731
[x] Gallicchio L, et.al. Carotenoids and the risk of developing lung cancer: a systematic review. Am J Clin Nutr August 2008 vol. 88 no. 2 372-383
[xi] Shi Q, Zhang Z, Li G, et al: Sex differences in risk of lung cancer associated with methylenetetrahydrofolate reductase polymorphisms. Cancer Epidemiol Biomarkers Prev 14:1477-1484, 2005
[xii] Lumeng, L., and T-K. Li. 1974. Vitamin B6 metabolism in chronic alcohol abuse. Pyridoxal phosphate levels in plasma and the effects of acetaldehyde on pyridoxal phosphate synthesis and degradation in human erythrocytes. J. Clin. Invest. 53: 693-704.
[xiii] Vasiliou V, Thompson DC, Smith C, Fujita M, Chen Y. Aldehyde dehydrogenases: From eye crystallins to metabolic disease and cancer stem cells. Chemico-biological interactions. 2013;202(0):2-10. doi:10.1016/j.cbi.2012.10.026.
[xiv] Liang D, Shi Y. Aldehyde dehydrogenase-1 is a specific marker for stem cells in human lung adenocarcinoma. Med Oncol. 2012 Jun;29(2):633-9. doi: 10.1007/s12032-011-9933-9. Epub 2011 Apr 12. PMID: 21484084 DOI: 10.1007/s12032-011-9933-9
[xv] L Galluzzi, E Vacchelli, J Michels, P Garcia, O Kepp, L Senovilla, I Vitale and G Kroemer. Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses. Oncogene 32, 4995-5004 (17 October 2013) | doi:10.1038/onc.2012.623
[xvi] Ulvik A, Midttun O, Pedersen ER, et al. Evidence for increased catabolism of vitamin B-6 during systemic inflammation. Am J Clin Nutr 2014;100:250–5.
[xvii] Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883–99.
[xviii] Zuo H, et.al. Markers of vitamin B6 status and metabolism as predictors of incident cancer: The Hordaland Health Study . Int J Cancer Volume 2015 Jun 15;136(12):2932-9. doi: 10.1002/ijc.29345. Epub 2014 Nov 26. PMID: 25404109
[xix] Walser T, Cui X, Yanagawa J, et al Smoking and lung cancer: the role of inflammation. Proc Am Thorac Soc 2008;5:811–5.
[xx] Ma J. et.al. Antioxidant intakes and smoking status: data from the Continuing Survey of Food Intakes by Individuals 1994–1996. Am J Clin Nutr March 2000 vol. 71 no. 3 774-780
[xxi] Bruno RS. Et.al. Faster plasma vitamin E disappearance in smokers is normalized by vitamin C supplementation. Free Radic Biol Med. 2006 Feb 15;40(4):689-97. Epub 2005 Nov 15.