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BLOG: November 2009

 Folic acid studies: message in a bottle?

Folic acid studies   Folic acid cancer risk

For a while, we thought of folic acid - the most common synthetic form of vitamin B9, or folate - as a good friend of our health. Then, just as we stepped into this new century, a string of folic acid studies came to unexpected result: not only that this vitamin doesn't necessarily give us protective aura we thought it does, it can even partner with the most feared of all our health enemies - cancer.

On the other hand, some other recent studies came to the opposite conclusion: vitamin B9 does have cancer-protective effect.

 A glance at several of these studies illustrates the controversy:

1 data on 712 breast cancer cases and as many control subjects from the Nurse's Health Study showed 27% lower risk in those with highest vs. lowest blood level of folate, and as much as 89% lower among women who consume one or more alcohol drinks a day; for vitamin B6 plasma level risk reduction was 30%, and for vitamin B12 64%, but only among premenopausal women (Zhang et al, 2003)

2 study of 27,111 male Finnish smokers, 50-69y, between 1985 and 2002 found no relation between their estimated folate intake and prostate cancer; vitamin B6 intake showed mild protective effect, while vitamin B12 was associated with 36% higher cancer incidence (Weinstein et al, 2006)

3 a study of 81,922 Swedish woman and men, based on a 96-item food-frequency questionnaire in 1997, with 6.8 years mean follow-up, had 2.3 times lower incidence of pancreatic cancer in the highest dietary folate intake group (>300μg/d) than in the lowest intake group (Larsson et al, 2006)

4 data on 24,500 women participants (55-74y) within the PLCO cancer screening trial implies 19% higher risk of breast cancer in those taking >400μg/d of supplemental folic acid vs. those reporting no supplemental intake, and 32% higher for those with the highest supplemental intake vs. lowest (no significant relation for highest dietary folate intake); in women with high alcohol intake, the risk was greatest in the group with lowest total folate intake (Stolzenberg-Solomon et al, 2006)

5 study on 869 cases and 1,174 controls within European Prospective Investigation into Cancer and Nutrition cohort found no significant association between prostate cancer incidence and circulating levels of folic acid and vitamin B12, except in the subgroup with advanced stage prostate cancer, in which elevated B12 level was associated with 69% higher cancer incidence (Johansson et al, 2007)

6 a study on 11,699 Swedish woman 50y and older, during 9.5-year follow-up, found 44% lower breast cancer incidence in group with highest folate intake (both, dietary only and dietary + supplemental) vs. that in the lowest intake group (Ericson et al, 2007)

7 a study on 5442 US female health professionals 42 y and older, with preexisting cardiovascular disease or 3 or more coronary risk factors, in the 1998-2005 period, found no significant relation between high supplemental intake of folic acid (400μg/d), vitamin B12 (2.4μg/d) and vitamin B6 (1.5mg/d), and incidence of total invasive cancer, or breast cancer (Zhang et al, 2008)

8 data on 848 incident cases of invasive breast cancer and as many controls (>45y) from the Women's Health Study produced risk ratio for the highest vs. lowest plasma level group of 1.42, 0.91 and 1.29 for vitamin B9, B6 and B12, respectively (Lin et al, 2008)

9 Norwegian study of a total of 6837 patients with ischemic heart disease treated between 1998 and 2005, and followed till 2007, came up with 21% higher cancer incidence, 38% higher cancer mortality and 18% higher all-cause mortality in two groups (about half of all participants) receiving either folic acid (0.8mg/d), vitamin B12 (0.4mg/d) and vitamin B6 (40mg/d), or only folic acid and B12 (same doses), than in the other half of participants receiving either B6 alone (same dose) or placebo (Ebbing et al, 2009)

It can be said that the general anticipation going into these studies, based on both, biological role of folate and indications of positive effects of (mainly) dietary folate, was positive. In other words, it was expected that it will show increased cancer-protective effect at its higher intake/plasma levels. Turned out, the majority of studies - 6 out of 9 cited above -

had either neutral, or negative outcome.

Against most everyone's wishes and expectations, the picture of vitamin B9 as cancer-protective nutrient was undergoing drastic change.

Among the 3 above studies with positive results, i.e. concluding that vitamin B9 does have protective effect, two are from Sweden, and the third did not subject participants to supplemental regime, merely used the measured plasma levels of the vitamin. That offers some clues, as to possible explanation for inconsistent and controversial results (Ulrich CM, Folate and cancer prevention: a closer look at a complex picture, 2007).

Average folate level in the Swedish population is significantly lower than in the U.S. for two reasons: they don't have mandatory folic acid fortification of grain products, and their supplemental use in general, and for folic acid in particular, is significantly lower. Good illustration of the magnitude of difference in the folate status is that the highest folate level group in #6 study (Sweden) starts from 349μg/d up, vs. more than double that, 853μg/d and up in study #4 (U.S.).

The fact that excess folate - particularly in the form of folic acid - can fuel cancerous growth is long known. And so is the fact that its deficiency can have similar effect. This suggests as quite likely that high folate level in Sweden is still not excessive, remaining within its protective range. Over here, however,

 it has reached excess level,
and may have become detrimental to health

(such assumption is also consistent with results of animal studies, in which modest folic acid supplementation has generally protective effect, while excessive supplementation tends to encourage cancerous growth).

This basic discrepancy reflects as apparent inconsistency, or contradiction, in study results.

Another point of the folate controversy is well illustrated by the finding in study #1, that women regularly consuming alcohol have

nearly ten times higher risk of developing breast cancer

if their folate level is low, compared to the risk level when their folate level is high. High dietary/supplemental folate intake in this case protects from deficiency caused by folate antagonist, alcohol.

The magnitude of difference in the risk level due to this single factor indicates how difficult it is to design well controlled study, starting from obtaining reliable, complete data on participants' actual vitamin B9 intakes, to properly accounting for all potentially relevant factors hidden in their lifestyle and/or individual biochemistry. Good part of inconsistencies in study results may be attributable to these limitations.

Nevertheless, the big picture emerging from the data we have is clear enough. The bottom line is that mandatory food fortification in the U.S. did cause significant rise in folic acid level in the general population, and that it may be causing more harm than good. Its main goal - reduction in neural tube defect incidence - could arguably be accomplished with action focused on those who really need it: expecting mothers.

The segment of population that may be put at increased risk by excess folate intake resulting from fortification combined with self-styled supplementation is likely to be significantly larger.

So, what comes to us from these studies is sort of message in a bottle: someone's in the trouble, and needs help. That is a message that we are sending to ourselves.

As you may have noted, in addition to folic acid, high levels of vitamin B12 are also implicated in elevated risk for some cancers. These findings spell out for us a simple message, which shouldn't be hard to understand: Avoid excesses, be it nutrient intake or anything else, and keep it as natural as you can.

Following article expands on this disturbing, but not really unexpected folic acid cancer controversy.