Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Folic acid is beneficial: But, how and why?
- Undurti N Das (26 January 2004)
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Folic acid supplementation- beware of vitamin B12 deficiency
- Stephen DH Malnick, Sorel Goland (30 January 2004)
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Folate and mental health
- Matthew J Taylor, John Geddes, Professor of Epidemiological Psychiatry. (4 February 2004)
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Long-term safety of folic acid supplementation is questionable
- Michal R Pijak, Frantisek Gazdik (11 February 2004)
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Folic Acid supplementation: long term safety is not an excuse for inaction
- Amanda J Neville, Elisa Calzolari, Lenore Abramsky (18 March 2004)
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Undurti N Das, Research Director UND Life Sciences, 1083 Main Street, Walpole, MA 02081, USA
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The recent review by Lucock highlighted the clinical importance of folic acid. The current resurgence of interest in folic acid can be attributed not only to the ability of folic acid to reduce plasma homocysteine levels but also to its other important actions. For instance, impaired endothelial nitric oxide (eNO) activity is an early marker for cardiovascular disease. Most risk factors for atherosclerosis are associated with impaired endothelium-dependent vasodilatation due to reduced NO production. Folic acid not only reduces plasma homocysteine levels but also enhances eNO synthesis, and shows anti -inflammatory actions. Folic acid stimulates endogenous tetrahydrobiopterin (H4B) regeneration, a co-factor necessary for eNO synthesis, inhibits intracellular superoxide generation and thus, enhances the half-life of NO. H4B, in turn, enhances NO generation and augments arginine transport into the cells. Folic acid has also been shown to increase concentrations of n-3 polyunsaturated fatty acids (PUFAs) in the tissues. This is interesting since, PUFAs also enhance eNO synthesis. In this context, the interaction between folic acid and vitamin C also needs attention. Vitamin C augments eNO synthesis by increasing intracellular H4B and stabilization of H4B. Insulin stimulates H4B synthesis, PUFA metabolism and suppresses the production of pro-inflammatory cytokine tumor necrosis factor-alpha, superoxide anion and enhances NO generation. Thus, the ability of folic acid to augment eNO generation is independent of its capacity to lower plasma homocysteine levels (1). In view of this close interaction between folic acid, H4B, vitamin C, and n-3 fatty acids and in particular to their ability to enhance eNO generation may explain why all these dietary factors are useful in vascular diseases. Availability of adequate amounts of L-arginine is also necessary for optimal production of eNO. Hence, supplementation of L- arginine along with folic acid and PUFAs may be helpful in various vascular diseases. In view of this, a judicious combination of folic acid, vitamin B12, B6, vitamin C, H4B, L-arginine, and n-3 fatty acids in appropriate amounts may form a novel approach in the prevention and management of various conditions such as hyperlipidemias, coronary heart disease, atheroslcerosis, peripheral vascular disease, and some neurodegenerative conditions. References: 1. Das UN. Folic acid says NO to vascular diseases. Nutrition 2003; 19: 686-692. Competing interests: None declared |
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Stephen DH Malnick, Director, Department of Internal Medicine C Kaplan Medical Center, Rehovot, 76100, Israel, Sorel Goland
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Following the review by Lucock on folic acid supplementation, we feel that it is appropriate to add a word of caution regarding possible concomitant vitamin B12 deficiency. While there is no doubt that folic acid deficiency is linked with hyperhomocysteinemia, concomitant vitamin B12 deficiency may also be responsible for elevations of homocysteine . Vitamin B12 deficiency can be subtle, manifesting only as an increase in homocysteine and methyl malonic acid levels in blood and urine, with levels of vitamin B12 at the lower limit of normal (1). There is variation in the levels of vitamin B12 in different populations. In the USA, data from the NHANES III survey found a mean serum B12 level of 518 pg/mL and 3% of the population had a serum B12 of less than 200pg/mL (2). In Israel a deficiency of vitamin B12 is more common than is commonly appreciated. We have reported a frequency of vitamin B12 deficiency of 30% in 130 serial patients undergoing coronary angiography (3), and another group has found a frequency of vitamin B12 deficiency of 22.3% in Ashkenazi Jews and 40 % in patients with Gaucher’s disease (4). Furthermore, in a group of 650 hospitalized geriatric patients in Israel, 15% had a vitamin B12 level less than 200 pg/mL and these patients had a higher incidence of cerebrovascular disease (5). As a result, in Israel, the HMOs have responded to the widespread deficiency of vitamin B12 by lowering the normal levels of their laboratories (6). Since folic acid supplementation may be deleterious in the presence of undiagnosed vitamin B12 deficiency (7), we suggest that vitamin B12 levels be determined prior to administration of folic acid. Another approach may be the use of multi-vitamin tablets. The use of a "folate" supplement consisting of 1 mg of folic acid, 400 µg of vitamin B12 and 10 mg of pyridoxine has been shown to both reduced the levels of homocysteine and decrease the rate of restenosis following angioplasty (8). The cost–effectiveness of these approaches may differ from country to country depending on the prevalence of vitamin B12 deficiency. 1. Green R. Metabolite assays in cobalamin and folate deficiencies. Balliere's Clin Hematol 1995; 8: 533-66. 2. Wright JD, Bialostosky K, Gunter EW, Carroll MD, Najjar MF, Bowman BA, Johnson CC. Blood folate and vitamin B12: United States, 1988-94. Vital Health Stat 11, 1998; 243: 1-78. 3. Goland S, Ayzenberg O, Kuznitz F, Shimoni S, Caspi A, Malnick S. A high incidence of Vitamin B12 deficiency in Israeli patients undergoing coronary angiography. Cardiovasc Drugs Ther. 2003;17(2):191 4. Gielchinsky Y, Elstein D, Green R, Miller JW, Elstein Y, Algur N, et al. High prevalence of low serum vitamin B12 in a multi-ethnic Israeli population. Br J Haematol 2001; 115: 707-9. 5. Shahar A, Feiglin L, Shahar DR, Levy S, Selighson U. High prevalence and impact of subnormal vitamin B12 levels in Israeli elders admitted to a geriatric hospital. J Nutr Health Aging 2001; 5:124-7. 6. Gielchinsky Y, Elstein D, Abrahamov A, Zimran A. How B12 deficiency can impact on the individual and how society can impact on B12 deficiency. IMAJ 2001; 3:672-4. 7. Babior BM, Bunn HF. Megaloblastic Anemias. In Harrison’s Principles of Internal Medicine 15th Edition. Eds. Braunwald E, Hauser SL, Fauci AS, Longo DL, Jameson JL, Jasper DL. McGraw-Hill, NY 2001. pp.674-680. 8. Schnyder G., Roffi M, Pin R, Pin R, Hess OM . Decreased Rate of Coronary Restenosis after Lowering of Plasma Homocysteine Levels. N Engl J Med 2001; 345: 1593-600 Competing interests: None declared |
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Matthew J Taylor, Senior House Officer University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, John Geddes, Professor of Epidemiological Psychiatry.
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Lucock is to be congratulated for his interesting and timely review of folic acid [1]. However, in considering the likely effects of mass use of folate, it is unfortunate that there is no mention made in the text of the potential benefits to mental health. Associations between folate status and mood have been known for some time, with folate deficiency considered a treatable cause of depression. Emerging evidence from randomised trials suggests that the augmentation of conventional antidepressant treatments with folate may improve outcome, and this effect may be seen even in those with normal baseline folate levels [2]. Observational studies also find associations between folate status and dementia [3], although at present trials of dietary supplementation in this area are not conclusive [4]. The effects on health of fortification with folate may not be limited to birth defects, vascular disease, and cancers. 1. Lucock M. Is folic acid the ultimate functional food component for disease prevention? Br Med J 2004;328:211-214. 2. Taylor MJ, Carney S, Geddes J and Goodwin G. Folate for depressive disorders (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd. 3. Ebly EM, Schaefer JP, Campbell NR, Hogan DB. Folate status, vascular disease and cognition in elderly Canadians. Age Ageing 1998;27:485-91. 4. Malouf R, Grimley Evans J, Areosa Sastre A. Folic acid with or without vitamin B12 for cognition and dementia (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd. Competing interests: None declared |
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Michal R Pijak, Slovak Medical University Limbova 12, 83303 Bratislava, Frantisek Gazdik
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EDITOR-We share Lucock´s (1) concerns related to the fact that "the form of folate in supplements and in fortified foods is pteroylmonoglutamate (PGA), a form that does not occur in nature". The author is rightly critical of increasing tendency among clinicians to give supraphysiological doses of PGA. In this regard, we would like to note that in Slovakia the single PGA is available only in 10 mg capsules. This dose is more than 20 times that needed to give maximal concentrations of the normal form of vitamin in plasma. Moreover, physicians are regularly prescribing up to 30mg/day of PGA according to the Prescription Drug Information. The major concern, as Lucock point out, is that "we do not know the long-term biological effects of exposure to unmodified synthetic folate". In fact, there is evidence that neurological complications in patients with vitamin B12 deficiency (2) are not the only possible risk of folate supplementation. For example, animal and some clinical studies have suggested that folate supplementation in higher doses may increase cancer risk and accelerate tumor progression (3). Because the long-term effects of PGA are not known, the best way of folate supplementation is through natural food. Those who are healthy and live healthy life (including eating natural food rich in folate) do not need to take folate in its synthetic supplement form. In certain situations, however, as is the case for some aged individuals and alcoholics, supplements containing recommended amounts of PGA may be warranted. (4,5) Nevertheless, the countries that adopted a policy of folate fortification of foods should provide monitoring of the benefits and possible harms of such fortification. Michal R Pijak, consultant in rheumatology, allergy and clinical
immunology,
1. Lucock M. Is folic acid the ultimate functional food component for disease prevention? BMJ 2004;328:211-4. 2. Reynolds EH. Benefits and risks of folic acid to the nervous system. J Neurol Neurosurg Psychiatry 2002;72:567-71. 3. Kim YI. Role of folate in colon cancer development and progression. J Nutr. 2003;133:3731S-3739S. 4. Bailey LB. Folate, methyl-related nutrients, alcohol, and the MTHFR 677C-->T polymorphism affect cancer risk: intake recommendations. J Nutr 2003;133:3748S-3753S. 5. Wharton B, Booth I. Fortification of flour with folic acid. BMJ 2001;323:1198-9. Competing interests: None declared |
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Amanda J Neville, IMER Registry Coordinator University of Ferrara, Medical Genetics Section, Via L Borsari 74 , 44100 Ferrara (FE) Italy, Elisa Calzolari, Lenore Abramsky
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Lucock’s clinical review and the Rapid Responses that have followed show the need to understand both the benefits and concerns regarding folic acid supplementation. EUROCAT (the European Surveillance of Congenital Anomalies) has documented the folic acid policy in 17 European countries of which it is made up. The health benefits, especially the prevention of congenital anomalies such as neural tube defects, are clear and the EUROCAT Report ( EUROCAT - Publications & Data ) provides recommendations for a strategy across Europe. EUROCAT proposes (1)monitoring pregnant women to identify the level of compliance with recommendations on taking folic acid supplementation in different countries (2) consideration of mandatory fortification of a staple food with folic acid and (3) monitoring prevalence rates for specified congenital anomalies in relation to levels of periconceptional folic acid supplementation in different countries . While caution regarding possible long term effects of folic acid supplementation is needed, failure to implement a proven preventive treatment is not the answer. It is no longer ethical to rely on a secondary prevention policy based on the termination of affected pregnancies - a heartbreaking alternative in a wanted pregnancy - given the body of evidence now available regarding the preventative effects of folic acid. Careful scientific monitoring of supplementation projects is required in order to ensure that we gain the health benefits whilst identifying any long term ill effects on health. Lucock rightly mentions the vast amount of published literature which makes it difficult for workers in the field to keep up to date and fully informed. The mass communication of the health benefits and any ill effects of folic acid requires effective national and international networks. To this end the Italian Superior Institute of Health is creating a national network for the promotion of folic acid for the prevention of Congenital defects http://www.cnmr.iss.it/. We look to authoritative journals such as the BMJ to continue with reviews such as Lucock’s to ensure the correct focus on benefits and concerns regarding folic acid supplementation. Sincerely, Amanda J Neville, Elisa Calzolari and Lenore Abramsky Competing interests: None declared |
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