The amount of folic acid, the synthetic form of folate, a vitamin within the family of B vitamins, in the diet of many people around world has greatly increased in the last two decades. This increase has mainly been the result of measures taken after the discovery that women with very low folate levels around the time of conception and very early in pregnancy are prone to a higher rate of certain congenital abnormalities in the newborn.
Prevention of congenital abnormalities was the pretext for initiating widespread fortification with folic acid
Since the 1990s women who are planning to be or already are pregnant have been advised to take folic acid supplements. Importantly, due the perception that folic acid supplementation in a timely manner would be hard to achieve for all women becoming pregnant, it was decided in the US and Canada to mandate fortification of all grains with folic acid from 1997 so that all women becoming pregnant have a sufficient amount of folic acid in their diet. This measure may prevent on the order of a few thousand of cases of congenital abnormalities per year in a country such as the US. However, as a side effect, the whole population (i.e. roughly 300 million in the US) has been exposed to much higher dietary folic acid level, resulting in significantly increased folate/folic acid levels inside the body (research has shown at least a two-to-three times increase compared to historical levels).
Folic acid intake significantly increased across many populations
In subsequent years, in part due to a powerful lobby by organisations such as the WHO in partnership with producers of folic acid such as Monsanto, an increasing number of countries across the globe have started mandating folic acid fortification (with the significant exception of Europe), so that a significant portion of the world population is now exposed to high amounts of folic acid in their diet. Even in countries where there is no mandatory fortification of grains (such as in Europe), fortification of food products such as breakfast products and supplement use has significantly increased folic acid intake.
Vitamin B-complex principle ignored in fortification programs
It has been known for a long time that certain B vitamin interact with each other, leading to the advice that several of them be taken together in the form of a so-called vitamin B-complex. This is especially important for the B vitamins folic acid, B6 and B12, because these vitamins have to kept in a balance and the human body has a limited capability to excrete excess amounts of these vitamins. Notably, the large-scale fortification with folic acid completely ignores the B-complex principle. As will be explained below, this relatively subtle oversight is likely to produce (and already has produced) widespread detrimental effects on the health of large populations, including increased incidence of disorders and syndromes that are associated with a high degree of morbidity and mortality.
Neurological vitamin B12 deficiency syndromes have become widespread due to high folic acid intake
Vitamin B12 is another important B-family vitamin that is exclusively found in animal-based food sources in a natural diet. Deficiency of vitamin B12 can lead to a wide range of symptoms. Some of the historically recognized symptoms are reminiscent of those of severe folic acid deficiency (a certain type of anemia and atrophy of certain mucous membranes such as the tongue), but a wide range of other symptoms (including paresthesias, neuropathy, balance problems, cognitive problems and dementia) are primarily neurological in nature and specific to vitamin B12 deficiency. It is the latter group of symptoms that, due to the impact of increased folic acid intake, has risen to prominence in recent years.
The interaction between folic acid and vitamin B12 is especially important with respect to the increase in folic acid intake. It has been known for a long time that increased folic acid intake exacerbates the neurological symptoms in persons with vitamin B12 deficiency, while masking (reducing or correcting) the hematological symptoms of vitamin B12 deficiency. This can be attested from textbooks from before the start of folic acid fortification.
[15]
Traditional used laboratory tests are no longer sensitive and have limited value for excluding vitamin B12 deficiency
It can be seen that the increase in folic acid intake may make diagnosis of vitamin B12 deficiency much more difficult, because the characteristic anemia may no longer be detectable, while the diverse spectrum of neurological symptoms (ranging from mild paresthesias, presenting for example with numbness, pains or tingling in the extremities, to severe debilitation) may be difficult to diagnose and seperate from other disorders with neurological symptoms.
Secondly, the greatly increased folic acid level may increase the “threshold” level of B12 stores inside the body below which neurological symptoms and other consequences of vitamin B12 deficiency become apparent, thus effectively increasing the prevalence of vitamin B12 deficiency, while making diagnosis even more difficult because patients with vitamin B12 levels traditionally regarded as normal may be affected. Indeed, at the time of the introduction of folic acid fortification, there was discussion in the medical community about the potential adverse affects of folic acid without also fortifying with vitamin B12, including the masking effect of folic that would make recognition and diagnosis of neurological manifestations of vitamin B12 deficiency more difficult, but this consideration was ignored and for many years received little further discussion.
High folic acid level associated with cardiovascular risk in large sections of the population
An additional adverse affect of a high folic acid level in combination with a low or low-normal level of vitamin B12 is an increase of the metabolite homocysteine, which is strongly associated with cardiovascular disease. Whereas a higher level of folic acid normally causes a reduction in homocysteine, when folic acid increases to a high level, and the vitamin B12 level is on the low side (even when it is above the lower end of the reference range), the level of homocysteine actually increases as the level of folic acid increases. Especially for populations prone to lower levels of vitamin B12 (such as the elderly and vegetarians/vegans that do not supplement with sufficient amounts of vitamin B12), this may in the long term result in increased incidence of cardiovascular disease such as stroke and certain types of dementia.
Folic acid fortification and supplementation out of control, without regulation
Not only has folic acid intake increased due to mandatory grain fortification programs, significant additional amounts of folic acid are provided by fortified products such as breakfast cereals and multivitamins. The amount of extra folic acid in these products has increased significantly, among an apparent notion that the possibility of adverse affects resulting from high amounts of folic acid in the diet is virtually non-existent. A recommended maximum tolerable intake of 1000 micrograms of folic acid, without much scientific basis, has been advertised by certain regulating bodies. With the current high levels of folic acid in food products and supplements, many people probably exceed even that level, and much lower intake (even close to the range of the recommended daily allowance of 200 micrograms) is already likely to have adverse effects in many people. Many elderly, who are already prone to vitamin B12 deficiency due to decreased absorption resulting from changes in and disorders of the gastro-intestinal tract and use of acid-reducing medications, receive a large amount of folic acid through supplements or fortified products, often without a matching amount of vitamin B12.
Several high-quality research studies have established adverse effects of high folic acid intake
In recent years the adverse affects of high folic acid intake have started to be noted in scientific research studies. An increasing body of research by leading US institutions in representative population studies has established a link between increased cognitive decline in the elderly and high folate levels in those with low or normal vitamin B12 level, as well as showing that metabolite levels indicative of vitamin B12 deficiency, including increased homocysteine, are higher in those with high folic acid levels, which is applicable to the whole population.
[1][2][4][7][8][10][13][14] The implications of these studies continue to be largely ignored by regulating bodies and the medical community at large. Some studies have also identified potential adverse affects from unmetabolized circulating folic acid (as a result of high intake), with potential implications for cancer.
Effects of folate metabolism on cancer are well established
That folic acid/folate, through its effect on cell replication, can have a significant effects on cancer progression has been long established. The so-called
anti-folate medications such as methotrexate, which reduce folate/folic
acid levels inside the body, are the classic form of effective cancer
chemotherapy. Recent studies have established that therapeutic folic acid supplementation can significantly increase disease progression in common cancers such as colon cancer. Several studies have noted increases in certain cancer rates in the US
after 1997 although these have attributed to improved detection
techniques by some. Recently, an unexpected significant increase in
early-onset prostate cancer since the last decade has been noted in the
US, and similar increases have been observed for other common cancer
types. Since the increase in folic acid levels is one of the most significant
metabolic changes that has occurred since that time frame, across the
whole population, and because folic acid clearly plays a role in the metabolism of cancer, it would be prudent to carefully investigate a
possible connection. In Europe, concerns over effects on cancer rates and progression
have been a major factor in the decision not to initiate large-scale
folic acid fortification programs.
Vitamin B12 deficiency often not taken seriously in diagnosis and largely ignored as an epidemiological entity
Very few studies have attempted to investigate any potential increase in the prevalence of vitamin B12 deficiency syndromes in the general population, but a wide range of first-hand and anecdotal evidence
[3] suggests that neurological manifestations of vitamin B12 deficiency have become much more common in countries such as the US since the increase in folic acid intake started, while very often being misdiagnosed and not properly treated, with serious consequences.
Imbalance between folic acid and vitamin B12 exacerbated by supplements
An additional factor in the imbalance between folic acid and vitamin B12 is that, while folic acid levels have increased, the amount of vitamin B12 in common supplements and B12-fortified food products (such as certain products targeted at vegetarians) has hardly increased since folic acid fortification started. Because people that have low levels of vitamin B12 often have impaired absorption of vitamin B12 (but not of folic acid), and because only a small part may be absorbed even in healthy individuals, high daily doses of vitamin B12 are required to reach a healthy level that is in balance with the level of folic acid.
Forms of vitamin B12 used for treating defiency include cyanocobalamin (supplements and injections), hydroxocobalamin (injections), and methylcobalamin (supplements). For treating deficiency, research has found that 1000 micrograms (preferably a highly bio-available form such as methylcobalamin) daily taken orally may be sufficient, while the traditional intramuscular treatment with injections remains popular and may be more effective for large groups of patients.
In this context, the amount of vitamin B12 in common supplements (0.5 to 25 micrograms, frequently 2.6 micrograms or less) has remained virtually negligible, with the more significant amount of folic acid in supplements, which has increased over the years, exacerbating the significant imbalance between folic acid and vitamin B12, and even people aware of the need to supplement B12 may not be doing so sufficiently. Although supplements with more effective higher doses of vitamin B12 have become more widely available, they are used by a small minority when compared to common mainstream supplements.
Changed clinical picture has caused confusion and gross underdiagnosis of vitamin B12 deficiency
Not only has the incidence of vitamin B12 deficiency greatly increased, its clinical presentation has also significantly changed. Whereas before the age of folic acid fortification hematologic signs such as megaloblastic anemia were much more prominent, now because of the masking effect of folic acid clear hematologic signs are uncommon and neurological symptoms dominate, exacerbated by high folic acid intake which has also greatly moved upward the serum B12 level below which symptoms may develop. This has resulted in massive confusion among doctors and explains the high rate of underdiagnosis and misdiagnosis of vitamin B12 deficiency and the recognition in recent official guidelines that levels above the low end of the reference range can produce serious symptoms of vitamin B12 deficiency. There is no definite test to confirm or exclude the diagnosis of a vitamin B12 deficiency syndrome, especially with its modern presentation with neurological symptoms, typically a high folic acid level, but a serum B12 level, as well as other metabolite levels related to B12 deficiency, that often are not below the low end of the reference range.
Symptoms of vitamin B12 deficiency syndromes widespread but hard to diagnose, commonly attributed to another diagnosis
To give one example of widespread misdiagnosis, it is likely that a not insignificant number of elderly patients (and increasingly, not so elderly) diagnosed with Alzheimer's disease are in fact suffering from dementia due to long-term unrecognized B12 deficiency, often of a subtle form without clear laboratory abnormalities and thus requiring a higher index of suspicion for diagnosis, but nevertheless entirely preventable and treatable when caught in time. Other common incorrect diagnoses for neurological symptoms caused by vitamin B12 deficiency include diabetic neuropathy, idiopathic neuropathy (treated with expensive medication, which may reduce symptoms but does not stop progression, instead of vitamin B12), fibromyalgia, developmental disorders such as autism in children, other forms of dementia, multiple sclerosis and other neurological disorders, psychiatric illness, and general attributions to obesity or old age. Often neurological symptoms due to B12 deficiency are attributed to a co-existing or pre-existing diagnosis (e.g. diabetes or fibromyalgia). Even when vitamin B12 deficiency is diagnosed or suspected, it is often regarded as a relatively unimportant footnote in a patient's medical record and consequently easily overlooked or forgotten and not properly treated, which is at odds with the serious, largely irreversible, progressive neurological syndrome that it actually is when proper treatment does not occur.
Reasons for lack of recognition of risks of high folic acid, and underdiagnosis of vitamin B12 deficiency
A number of reasons can be put forward for the lack of recognition of the potential adverse affects of folic acid in the medical community and in popular media, and the lack of insight and gross underdiagnosis of vitamin B12 deficiency:
- Many doctors still view vitamin B12 deficiency as a primarily hematological disease (looking for megaloblastic anemia) and have little awareness of its increasingly common presentation with a diverse range of neurological symptoms, without clear hematological signs, that requires a higher index of suspicion for diagnosis and treatment.
- The knowledge of the adverse affects of high folic acid levels and folic acid fortification and its impact on vitamin B12 deficiency symptoms and the changed clinical picture is not widespread.
- Many doctors stiffly adhere to reference ranges, neglecting to diagnose or treat vitamin B12 deficiency when the B12 level is above the low end of the reference range; as described earlier, the threshold B12 level below which symptoms may develop has increased, so reference ranges which may have been relevant before the age of folic acid fortification are no longer relevant.
- In countries where many physicians have some financial interest in the particular diagnosis they make and the treatments they prescribe, such as the US and many other Western countries, diagnosing vitamin B12 deficiency is unpopular and often missed because there is “no money in it"; there is much more monetary gain from treating symptoms with expensive medication or operations as opposed to the cheap (but sometimes cumbersome, when intramuscular injections are prescribed) supplementation treatment associated with a diagnosis of vitamin B12 deficiency. For example, neurologists may be caught up in an environment where promotion of diagnoses such as idiopathic or unspecified neuropathy results in increasingly prevalent prescription of expensive medication that only treats symptoms, creating a self-perpetuating cycle of increasing monetary gain for both the pharmaceutical companies involved and the doctors themselves. Given such an environment, a doctor may become reluctant or even hostile to considering vitamin B12 deficiency syndromes in a differential diagnosis. In this context, the relative lack of sensitivity of common laboratory tests for diagnosing or excluding vitamin B12 deficiency can lead to premature dismissal of the possibility of a B12 related syndrome based on a simplistic interpretation of one or more test results.
- The treatment of vitamin B12 deficiency is often misunderstood; instead
of long-term supplementation with a high amount vitamin B12, some
doctors still prescribe small amounts of B12 and stop treatment when the
amount climbs above low-end of the reference range (which goes against
all guidelines), or stop treatment for a long time when a relatively
high B12 level is found after an injection (which is a trivial and
expected finding, and guidelines dictate that treatment should be
continued).
- In general, doctors are bombarded with promotional information about expensive medications to be used for treating certain symptoms, while updated guidelines for recognizing and treating vitamin B12 deficiency, when they exist at all, only reach a small minority of doctors.
- In popular conception, the notion that a “healthy" vitamin such as folic acid that can prevent congenital abnormalities can have adverse affects seems to be difficult to understand due to the (very superficially) inferred contradiction. This misconception seems to extend even to many medical professionals and researchers.
- Some people from vegetarian, vegan or health food circles view folic acid as an infallible “veggie vitamin” and are uncomfortable with the need for vitamin B12 because it is naturally derived from animal sources; this results in damaging downplaying of the need for sufficient vitamin B12 among vegetarians/vegans, use of supposed plant-based sources of vitamin B12 that do not actually contain biologically active vitamin B12, and in some cases misguided perceptions can reach further: on one occasion in 2013 all references to adverse affects of folic acid, and mentions of its relation to vitamin B12 in the English Wikipedia article on folic acid were removed on grounds of a “conspiracy by the meat industry”.
- Nutritional deficiencies, when not associated with classic and overt laboratory value abnormalities (which, as explained earlier, are commonly absent even in serious cases of vitamin B12 deficiency), are often crudely dismissed as being associated with alternative therapies involving vitamins such naturopathy for which there is little scientific evidence.
- Certain large corporations that dominate the production and sale of folic acid have a large financial interest in the continuing increase in folic acid production and consumption in the US and worldwide. Such a corporation typically has well-funded lobbying and promotional divisions that may directly or indirectly influence the food industry, the supplement industry, government-related regulating agencies as well as the medical community itself, including medical research.
Grass-roots education efforts among the public from direct experience with vitamin B12 deficiency
In the face of the widespread reluctance by the medical community to seriously consider vitamin B12 deficiency in symptomatic individuals, direct experience by the members of the public of vitamin B12 deficiency symptoms, experience of the difficulty of obtaining a proper diagnosis, and experience of the positive effects of proper treatment has lead to the appearance of numerous "grass-roots" patient groups and websites focused on vitamin B12 deficiency based in various countries, including active message forums. In some cases, people with direct experience of the tragic consequences of delayed diagnosis (for example, of a family member) have been motivated to start websites and provide information and education about pitfalls relating to the diagnosis. In several countries, books have been published on the subject of vitamin B12 deficiency, often with numerous first-hand accounts of the detrimental and often tragic consequences of misdiagnosis or delayed diagnosis.
[3]
Increased use of commercial supplements with high amounts of vitamin B12
Commercial companies have appeared in countries such as the US selling specific high-end supplements for the treatment of neuropathy and other symptoms, containing a large amount of vitamin B12 as one of the ingredients. Although the link with vitamin B12 deficiency may not be directly made by the company, it is likely that vitamin B12 is the active ingredient and that such a supplement is in fact effective in treating/resolving symptoms because the neuropathy symptoms are in fact due to a vitamin B12 deficiency syndrome in a large proportion of customers, so that using the supplement will have the effect of treating and correcting the deficiency. The popularity of such supplements in an indirect way provides evidence of the widespread existence vitamin B12 deficiency syndromes, even from an economical market theory standpoint.
Large-scale detrimental effects of imbalance between folic acid and vitamin B12 increasing, drastic measures urgently needed
Meanwhile, the detrimental effects resulting from the imbalance between folic acid and vitamin B12 in large sections of the general population of many countries have already produced suffering on a large scale, there's potential for it get worse. For example, given the accelerated cognitive decline now seen in the elderly with high folate levels and low or normal B12 levels, what will be the effect on the younger population that is being exposed to this imbalance in the long term? Will there be a massive epidemic of premature dementia in 10-20 years time?
The only possible conclusion is that action on a massive scale to restore the physiologic balance between folic acid and vitamin B12 in the US population, and the population of most other countries of the world, is needed with the highest possible urgency. This may not be easy; options include cessation of general folic acid fortification of grains or drastically reducing the amount of fortified folic acid, drastically reducing the amount of folic acid in most supplements and individually fortified food products, general fortification of grains with significant amounts of vitamin B12, drastically increasing the amount of vitamin B12 in fortified food products and supplements, and a massive compaign to raise awareness among the general public, the food industry, the supplement industry, and especially the medical community.
References
In chronological order, latest first:
(1) Catherine F Hughes, Mary Ward, Leane Hoey, Helene McNulty, 'Vitamin B12 and ageing: current issues and interaction with folate', Ann Clin Biochem 2013 50 (4) 315-329
(2) Low-normal B12 levels are associated with accelerated cognitive decline in the elderly, especially those with high folate levels: Martha Savaria Morris, Jacob Selhub, Paul F. Jacques, 'Vitamin B-12 and Folate Status in Relation to Decline in Scores on the Mini-Mental State Examination in the Framingham Heart Study', Journal of the American Geriatrics Society, 2012 60 (8) 1457
(3) A first-hand account of the prevalence and misdiagnosis of
vitamin B12 deficiency in the US from the perspective of ER staff, as
well as general overview of vitamin B12 deficiency, and a call for
action: Sally M. Pacholok and Jeffrey J. Stuart, 'Could it be B12? An
epidemic of misdiagnoses', second edition, Linden Publishing, 2011
(4) Amanda F MacFarlane, Linda S Greene-Finestone, Yipu Shi, 'Vitamin B-12 and homocysteine status in a folate-replete population: results from the Canadian Health Measures Survey', Am J Clin Nutr 2011 94 (4) 1079-1087
(5) Ponnusamny Saravanan, Chitranjan S Yajnik, 'Role of maternal vitamin B12 on the metabolic health of the offspring: a contributor to the diabetes epidemic?', British Journal of Diabetes & Vascular Disease, 2010 10 (3) 109-114
(6) A. David Smith et al, 'Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial', PLOS ONE Sep 8 2010
(7) Clinical consequences of B12 deficiency may be worsened by high folic acid intake and unmetabolized folic acid: Martha Savaria Morris, Paul F Jacques, Irwin H Rosenberg, Jacob Selhub, 'Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors', Am J Clin Nutr 2010 91 (6) 1733-1744
(8) Joshua W Miller, Marjorie G Garrod, Lindsay H Allen, Mary N Haan, Ralph Green, 'Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate', Am J Clin Nutr 2009 90 (6) 1586-1592
(9) Christine C. Tangney, Yuxiao Tang, Denis A. Evans, Martha Clare Morris, 'Biochemical indicators of vitamin B12 and folate insufficiency and cognitive decline', Neurology Jan 27, 2009 vol. 72 no. 4 361-367
(10) Jacob Selhub, Martha Savaria Morris, Paul F Jacques, Irwin H Rosenberg, 'Folate–vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency', Am J Clin Nutr 2009 89 (2) 702S-706S
(11) Renee D Kalmbach, Silvina F Choumenkovitch, Aron M Troen, Ralph D'Agostino, Paul F Jacques, Jacob Selhub, 'Circulating folic acid in plasma: relation to folic acid fortification', Am J Clin Nutr 2008 88 (3) 763-768
(12) Helga Refsum, A. David Smith, 'Are we ready for mandatory fortification with vitamin B-12?', AM J Clin Nutr 2008 88 (2) 253-254
(13) A. David Smith, Young-In Kim, Helga Refsum, 'Is Folic Acid Good for Everyone?', Am J Clin Nutr 2008 87 (3) 517-533
(14) Jacob Selhub, Martha Savaria Morris, Paul F. Jacques, 'In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations', PNAS vol. 104 no. 50 2007
(15) Stuart Roath and Samuel Gross, (quote) 'In the solely B12-deficient patient, folate administration will produce a modest hematologic response and a marked impairment in the neurological abnormalities', in Medical Diagnosis and Therapy, M. Gabriel Khan (ed), Lea & Febiger, 1994
Updated November 11, 2014.
