Folic Acid/Folate Metabolism - An Ongoing Controversy
02/01/2017 - Product Newsletter (adapted from PN #200, Nov. 2008)
One of the biggest clinical concerns for nutritional practitioners today is the striking increase in methylene tetrahydrofolate reductase (MTHFR) polymorphisms in today's patient population. The question is: Will supplemental folic acid or supplemental folate give the best clinical result when treating these patients?
Increased folic acid intake and neural tube defects (NTD)
Mandatory fortification of flour with folic acid has been the law of the land for quite some time now. More specifically, as noted by Bar-Oz et al (Folate fortification and supplementation - Are we there yet?, Reprod Toxicol, Vol. 25, pp. 408-412, 2008):
"Folate fortification at 140 µg/100 g and 150 µg/100 g flour respectively, became mandatory in 1998 in the USA and Canada."
Other aspects of mandatory food fortification with folate can be seen in the chart below from the Bar-Oz et al paper:
The reason for this mandatory fortification program was to prevent neural tube defects (NTD) in newborns. But has this program been successful? Bar-Oz et al note:
"In the USA an estimated decline in prevalence of NTD from 10.6 cases per 10,000 live births in 1995-1996 (pre fortification) to 7.5 cases per 10,000 in 1999-2000 (post fortification) was reported. Williams et al. reported 31% decrease in the prevalence of spina bifida from 5.15 cases per 10,000 births in 1995-1996 to 3.54 cases per 10,000 births in 1998-1999, and 16% decrease in anencephaly, from 2.43 cases per 10,000 births in 1995-1996 to 2.05 cases per 10,000 births in 1998-1999... Stevenson et al. reviewed the incidence of NTD also showing a decrease from 18.9 to 9.5 per 10,000 live births over a six year period (1992-1998) coinciding with the increased periconceptional use of folic acid supplement among women of child-bearing age."
These numbers may seem impressive, but Bar-Oz et al. feel that further improvements can still be realized with increased folate:
"Our findings document that the goal of optimal prevention of NTD has not yet been achieved, and there is a considerable proportion of pregnant women at risk of having a baby with NTD. Although these NTDs are multifactorial in origin, the potentially preventable cases should not be overlooked and both folate fortification and supplementation need to be reassessed."
The authors recommend the following supplemental program for pregnant women:
"Our data is supportive of Wald's suggestion that folate supplementation of 0.4 mg/day is insufficient and that supplementation with 5 mg/day will result in almost full protection of pregnant women against preventable NTD. A 5 mg daily dose, starting when planning pregnancy will provide a booster dose whenever it is taken. We call for an urgent action in increasing fortification and supplementation as well as measures in increasing awareness and education needs to be undertaken."
Certainly, in my opinion, the rationale for supplementing pregnant women with more folic acid to enhance NTD prevention has great validity. But what of the suggestion to increase fortification? Since large percentages of men and non-pregnant women would also be affected by such a recommendation, should we be much more cautious before proceeding?
Given the general attitude of most of the public and many in the supplement industry that nutrients are "natural" and, therefore have no downside at virtually any dose, the answer to this question should be simple: "Of course not!!" In agreement, Wald et al, whose paper was referenced in the above quote (Wald NJ et al. Quantifying the effect of folic acid, Lancet, vol. 358, pp. 2069-73, December 15, 2001), state the following:
"No known or suspected adverse effects of folic acid at the proposed 5 mg daily dose have been recorded, and it has no contraindications, though women with epilepsy should have their anticonvulsant treatment reviewed. Masking of anaemia of vitamin B12 deficiency is not, in our view, an adverse effect of folic acid. It might change the presentation of the disease, but there is no indication that in practice this will result in irreversible damage."
Dose/response - Does folic acid get a free pass?
The rationale of Wald et al may seem intuitively plausible, but can it truly withstand objective, scientific scrutiny? As suggested by Paracelsus almost 500 years ago and, more recently, by many highly publicized studies suggesting adverse effects of supplemental nutrients at certain doses, the answer seems to be "No". What did Paracelsus have to say about the concept of dose and its relationship to good health?
"What is there that is not poison? All things are poison and nothing (is) without poison. Solely the dose determines that a thing is not a poison."
Furthermore, does common sense suggest that any given substance can be totally benign at any dose? I think not. Common sense suggests that everything on earth, including air and water, may be harmful at certain doses.
Thus, with the simple wisdom of Paracelsus and common sense in mind, let us review a different, less well known body of research on folic acid supplementation that suggests Wald et al may be a bit over confident in asserting folic acid is the one substance on earth exempt from the simple, time-tested wisdom of Paracelsus and common sense!
Folic acid and colorectal cancer
Not too long ago, a highly publicized study appeared in the Journal of the American Medical Association (JAMA) entitled "Folic acid for the prevention of colorectal adenomas" by Cole et al (Cole et al. JAMA, Vol. 297, No. 21, pp. 2351-2359, June 6, 2007). In this study 1021 men and women with a recent history of colorectal adenomas, but no history of large intestine carcinoma, were evaluated. For up to six years one half of the participants received 1 mg per day of supplemental folic acid; the other half received a placebo. Based on previous research, the authors hypothesized that the treatment group would experience a decreased incidence of colorectal adenomas. In contrast, Cole et al were surprised to note the following:
"In conclusion, our study indicates that folate, when administered as folic acid for up to 6 years, does not decrease the risk of adenoma formation in the large intestine among individuals with previously removed adenomas. The evidence for an increased risk of adenomas is equivocal and requires further research."
In the opinion of the authors, why did this surprising finding occur?
"Our results may have been affected by fortification of the food supply with folate, which began in 1996, shortly after enrollment in this study was initiated, and became mandatory in 1998, largely to reduce the risks of neural tube defects by increasing maternal folate levels during early pregnancy."
In the accompanying editorial, Ulrich and Potter (Ulrich CM & Potter JD. Folate and cancer - Timing is everything, JAMA, Vol. 297, No. 21, pp. 2408-2409, June 6, 2007) elaborate on the relationship between folic acid supplementation and cancer:
"Despite its central function in maintaining DNA integrity, the role of folate in cancer prevention may not be as straightforward as initially conceived. Recent experiments have suggested that the timing of folate administration during cancer progression can modify outcomes. Folate administration prior to the existence of preneo-plastic lesions can prevent tumor development, whereas provision of folate once early lesions are established appears to increase tumorigenesis. This initially counterintuitive observation may be explained by the function of folate in nucleotide synthesis. Rapidly proliferating tissues, including tumors, have an increased requirement for nucleotides; thus many cancers up-regulate folate receptors, and antifolate drugs are efficacious in cancer treatment."
Other research agrees that Americans may be over-ingesting folic acid. Quinlivan and Gregory (Quinlivan EP & Gregory JF. Effect of food fortification on folic acid intake in the United States, Am J Clin Nutr, Vol. 77, pp. 221-5, 2003) state:
"Typical intakes of folic acid from fortified foods are more than twice the level originally predicted."
"The results of this analysis are internally consistent, suggesting that the fortification of cereal-grain products in the United States has increased typical folic acid consumption by >200 µg/d, approximately twice the 70-130 µg/day increment predicted by the FDA."
If the problem is a simple issue of too much, just exactly what is it that we are ingesting too much of?
For years, we mistakenly have been using the terms "folate" and "folic acid" interchangeably. However, these terms define two distinctly different substances that are metabolized very differently by the human body. Let us begin with "folate." According to Wright et al (Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK, Br J Nutr, Vol. 98, pp. 667-675, 2007):
"Folate is a generic term for the related family of water-soluble B-group vitamins found widely in foodstuffs, mainly reduced methyl and formyl folylpolyglutamates, that have similar nutritional properties and chemical structures to those of folic acid."
In contrast, Wright et al state the following about "folic acid":
"Folic acid (pteroylmonoglutamic acid), though rarely occurring in nature, is the most oxidized and stable form of a vitamin used extensively for supplements and food fortification purposes."
To further clarify the difference between folate and folic acid, consider the diagram below from Biochemical, Physiological, Molecular Aspects of Human Nutrition, Second Edition (Stipanuk MH. Saunders, St. Louis, 2006). Note the basic structure of folates can be divided into three parts. First, on the left, there are two connected rings called a pteridine structure. In the middle is para-aminobenzoic acid (PABA). On the right is glutamate. The chemical formula on top denotes folic acid. The chemical formula below it denotes folates.
With this basic structure in mind, consider the following contrasts:
- Folates are in the "reduced" form. This means that the pteridine structure in folates contains many more hydrogens than does the pteridine structure in folic acid. The lack of hydrogens in the folic acid means that it is an "oxidized" form.
- Folates are "polyglutamates." This means that folates contain many repeating glutamates on the right hand side. In contrast, folic acid contains only one, making folic acid a "monoglutamate."
- Folates are found in foods. Folic acid is rarely found in food. Knowing this, you may wonder why the folic acid form is used in supplements? The reason has to do with point #1 above. Given the need for a supplement shelf life of two years or more, stability is important. Since folic acid exists in an "oxidized" form, it is very stable. In contrast, folates exist in a "reduced" state containing many more hydrogens, and are less stable.
Folic acid is a much more simple structure than the folates found in food. When ingested, it therefore needs to go through several conversions in the human body before it can be fully utilized. Until recently, it was falsely assumed that the human body could accomplish this conversion quite easily, no matter how much folic acid was ingested. In fact, recent research makes it clear that the human body is limited in terms of how much folic acid it can convert to fully functional folates at any one time. Therefore, can large intakes of processed foods fortified with folic acid lead to a state where large amounts of unconverted folic acid are circulating throughout the body? Emerging research is demonstrating this to be true. Could this unconverted folic acid be related to some of the adverse findings reported above concerning colorectal cancer? Some very sobering research suggests that this also might be true.
Absorption of folic acid versus food folates
I always find it interesting to note two of the "sacred cows" in clinical nutrition:
- Food-based "natural" forms of nutrients
are always absorbed better than supplemental "synthetic" forms.
- The higher the rate of absorption, the better.
Next, consider the old saying that goes:
"No generalization is worth a damn, including this one."
When considering folic acid versus food folates, this saying could not be more applicable in relation to the two "sacred cows" mentioned above. In what way? Consider the following:
Absorption - Generally it has been my feeling that the contrast between "natural" and "synthetic" has been vastly overemphasized, reflecting more a need to create a marketing advantage rather than to objectively educate about efficacy-based clinical nutrition. The research I am about to present suggests that the "synthetic" folic acid versus the "natural" food folates is a notable exception to this belief. In fact, "synthetic" folic acid is absorbed much better than "natural" food folate. In agreement, McKillop et al (The rate of intestinal absorption of natural food folates is not related to the extent of folate conjugation, Am J Clin Nutr, Vol. 84, pp. 167-73, 2006) state the following:
"The bioavailability of dietary folates from a mixed diet is considered to be ≤50% of that of folic acid, but published estimates of folate bioavailability vary greatly, ranging anywhere from 10% to 98% of that of folic acid."
Of course, the next question that needs to be asked is: "Is that a good thing or a bad thing?" The answer to this question leads to a reanalysis of sacred cow #2.
Is a higher rate of absorption always better? - As "sacred cow" #2 suggests, the answer is often "Yes". However, this "sacred cow" is based on the outmoded assumption discussed above that nutrients, being part of the human economy, have no downside at any dose. In fact, as I have stated time and time again, this is never true. In the case of folic acid, high levels of absorption could be particularly detrimental if the human body has only a limited capacity to metabolize folic acid into useful forms.
Why does the body have such difficulty in metabolizing folic acid?
Before answering this question, I would like to review the findings of the research discussed so far:
- Supplemental folic acid is different than food folates.
- High intakes of folic acid are correlated with increased risk of colorectal cancer in patients with a history of colorectal adenomas.
- Due to increased ingestion in the U.S. of processed foods fortified with folic acid, intake of folic acid is higher than what was originally intended.
- Folic acid (the synthetic form) is absorbed better than food folates, the natural form.
What can we conclude from this? It is very possible that high intakes of the highly absorbable synthetic form may overwhelm the body's metabolic ability, leading to increased circulating unmetabolized folic acid and the corresponding problems I have discussed. However, does direct proof exist that the body has limited ability to metabolize folic acid compared with food folates? As you will see, the answer to this question is "Yes".
All folate forms are metabolized in two sites, the gut and the liver. The limiting factor in the metabolism of folic acid is an enzyme common to both sites, dihydrofolate reductase (DHFR), which converts folic acid to dihydrofolate. Subsequent enzymatic conversions lead to the formation of 5-methyltetrahydrofolate, the folate form that is actually used in cellular functions that require folate. Unfortunately, this enzyme has low activity in man, as stated by Powers (Folic acid under scrutiny, Br J Nutr, Vol. 98, pp. 665-666, 2007):
"Importantly, in human subjects, some tissues, including liver, have a limited capacity to reduce folic acid, because of a low activity of DHFR, and are unable to reduce high concentrations of folic acid."
What is the net effect when large intakes of folic acid combine with limited enzymatic conversion ability? Powers states:
"This would be expected to increase the appearance of unmetabolized folic acid in the circulation in the situation of high or repeated doses of folic acid."
Wright et al provide more detail on this crucial aspect of folic acid metabolism:
"...since human subjects uniquely amongst mammals and birds have a reduced dihydrofolate reductase activity (and a poor ability to reduce folic acid), it is hypothesized that even a modest regular daily intake of physiological doses of folic acid could eventually saturate the preliminary liver folate-monoglutamate pool. This would result in the subsequent chronic appearance of unmatabolised folic acid in the systemic circulatory blood system which arguably, according to circumstance, increasingly looks as though it can induce polar 'Jekyll and Hyde' health effects."
I will conclude this discussion on folic acid metabolism, and what can go wrong when too much folic acid is ingested, with this excellent overview by Mason et al (A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: A hypothesis, Cancer Epidemiol Biomarkers Prev, Vol. 16, No. 7, pp. 1325-9, July 2007):
"The fact that a pharmaceutical form of folate, folic acid, has been used for fortification may be of importance. Folic acid is converted to a natural biological form of the vitamin as it passes through the intestinal wall, with enzymatic reduction and methylation resulting in the circulating form of the vitamin, 5-methyltetrahydrofolate. Nevertheless, it has been known for some years that oral doses of folic acid in physiologic quantities can saturate this conversion mechanism, resulting in detectable levels of circulating folic acid, and there has been some concern that this oxidized, nonsubstituted form of folate might feasibly be detrimental because it is not a naturally occurring coenzymatic form of the vitamin."
At what daily intake will unmetabolized folic acid start to appear in the bloodstream?
Sweeney et al (Folic acid fortification and public health: Report on threshold doses above which unmetabolised folic acid appear in serum, BMC Public Health, Vol. 7, No. 41, 2007) suggest that in Americans ingesting both folic acid-containing supplements and food fortified with folic acid, unmetabolized folic acid could start appearing at levels of intake just above 200 µg per day:
"Based on the cumulative evidence to date in this and other studies it seems that the threshold dose above which unmetabolised folic acid appears in serum lies around 200 µg. The intervals between repeated exposures also seem to be an important factor as an accumulative effect is observed if repeated doses are consumed close together."
What are the possible specific adverse effects of continuous exposure to unmetabolised folic acid?
Published reports suggest many. The first report I would like to point out is a paper by Troen et al (Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmeno-pausal women, J Nutr, Vol. 136, pp. 189-194, 2006). The following was considered:
"We evaluated dietary and supplemental intakes of folate and folic acid in relation to an index of immune function, natural killer cell (NK) cytotoxicity, among 105 healthy, postmenopausal women."
The findings were quite sobering:
"Unmetabolized folic acid was detected in 78% of plasma samples from fasting participants. We found an inverse relation between the presence of unmetabolized folic acid in plasma and NK cytotoxicity. NK cytotoxicity was ~23% lower among women with detectable folic acid. This inverse relation was stronger among women ≥ 60 y old and more pronounced with increasing unmetabolized folic acid concentrations."
This connection between unmetabolized folic acid and decreased NK cell activity may have tremendous significance in terms of the relationship between colon cancer and folic acid intake, as suggested in the Cole et al paper discussed earlier. It indicates direct cause and effect for a phenomenon that some wanted to dismiss as pure coincidence when the study was first published.
What other adverse effects might be linked with excessive levels of unmetabolized folic acid?
Wright et al suggest potential masking of the anemia of vitamin B12 deficiency. Lucock and Yates (Folic acid - vitamin and panacea or genetic time bomb, Nature Rev Genetics, Vol. 6, pp. 235-240, 2005) suggest an adverse effect on certain genes involved in folate metabolism. Finally, Smith et al (Is folic acid good for everyone?, Am J Clin Nutr, Vol. 87, pp. 517-33, 2008) suggest that unmetabolized folic acid in pregnant women could potentially cause adverse genetic effects in their offspring.
Some parting thoughts
It is currently in vogue with reports such as this to end with a recommendation for total elimination of the substance being criticized. I cannot emphasize enough that this could not be further from the truth!! As suggested by Paracelsus, the dose determines the poison. Therefore, just because a substance causes harm at a high dose, it does not mean that we should condemn it at any dose. (If this were the case, water, one of history's most deadly substances at excessive doses, would have been banned eons ago.) As suggested by the very positive research on neural tube defects, folic acid deserves a rightful place in the diet and supplements of Americans. However, given the ever increasing amounts of consumption via processed foods, I feel there is a need to proceed more cautiously than we have in the past, supplementing folic acid based on determination of individual need rather than on an attitude of "give it to everyone because it can't hurt and it might help." In agreement, Mason et al state the following:
"It is extremely important that the public and the scientific community not misconstrue either these observations or the nature of our interpretations. We do not propose to ignore or negate the very compelling body of scientific evidence that has been accrued over the past 15 years that indicates that supplemental folic acid protects against neural tube defects and that habitually high intakes of dietary folate are protective against colorectal cancer. Indeed, due to the strength of the existing epidemiologic and preclinical observations in conjunction with the known biological effects of folate, several of us remain strong advocates of this latter hypothesis. Instead, by presenting these data, we wish to highlight the potential complexity of the response to this nutrient and emphasize prior observations that have been made in both preclinical and clinical studies that indicate that administering high doses of folic acid to susceptible individuals or in an inappropriate time frame may accelerate the growth of existing neoplasms."
YouTube: What you Should Know About Folic Acid by Dr. Moss 6.41 minutes https://www.youtube.com/watch?v=_QFl7BnWhpQ&t=12s
Product Tip of the Week: Folic Acid vs. L-%-MTHF by Dr. Moss 2.52 minutes
LIVE PRESENTATION: I will be giving a 2 ½ hour presentation on the above material, plus discussion about the MTHFR Polymorphism. This presentation will contain new, current material:
As I hope you now realize, the issue of folic acid supplementation has become increasingly more complicated with the advent of ever-increasing intakes of processed foods containing folic acid. Gone are the days when we could delude ourselves with the "if a little is good more is better" platitude.
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