I saw this article with responses about the consumption of folic acid. What do people think about the responses? Especially the one who says that there shouldn't be a limit to the amount of folic acid taken. bmj.com/content/329/7479/13...
I have been taking 5mg folic acid per day due to low levels of Folate but I don't know if this is a good idea or not. Some doctors' responses say it is ok.
Folic Acid
A minority of those of us who have worked in the field (I am now retired from active participation but researched pteridine biochemistry for almost forty years ) have been concerned about food supplementation with folic acid as an alternative to elective medication. When I was drawing attention to possible dangers ten years ago it was not a popular standpoint. My principal argument at that time was that it could precipitate neurological disease in those, particularly the elderly, with vitamin B12 deficiency but above that I believe we should be conservative about medication through food or water. The article in The British Medical Journal puts a different slant on the issue.
The report that high doses of folic acid are associated with neoplasia should not come as a complete surprise. Folic acid, pteroyl-L-monoglutamic acid, is a product of the pharmaceutical industry which rarely occurs in nature. Folic acid is a substrate for dihydrofolate reductase, first being reduced to dihydrofolate and then tetrahydrofolate. If large enough doses of folic acid are given then some will enter cells unchanged be polyglutamated and retained as are all folates and some antifolates eg methotrexate.
To my knowledge there are a very few situations where folic acid administration can be immediately harmful and they are exceedingly rare, one is dihydropteridine reductase deficiency, a failure in the salvage of quinonoid dihydrobiopterin to tetrahydrobiopterin. The effects of folate administration in that particular disorder serve to underline the complexities of folate interactions with other pteridines and the minor pathways or back-up mechanisms in one carbon transfers. Iatrogenic disturbance of folate metabolism will at least alter purine and pyrimidine synthesis with all that that entails. In view of the role of folates in cellular replication throughout the body, if there was to be an increase in the number of malignancies then one would expect that to manifest itself in the commonest, which in women is breast cancer.
There are benefits as well as side effects to all medication. These have to be weighed carefully against each other but the individuals who suffer have more right to complain when food is medicated unasked than when they swallow tablets they have accepted.
The increase in breast cancer among those taking high doses of folic acid during pregnancy coincides with reports of increasing malignancies among children. This might not be a coincidence,
The downside of vitamin medication is an important fundamental issue of which I am sure you are aware.
Competing interests: None declared
Competing interests: No competing interests
19 December 2004
Robert J Leeming
Honorary Senior Clinical Fellow
Clin Chem Childrens Hospital Birmingham B5 6NH
the challenge of practising patience
An intriguing study, although I share Professor Oakley's concerns should a non significant finding impair the proven effectiveness of an important global public health initiative. It strikes me that, prespecified hypotheses notwithstanding, the authors approach is the only way we shall ever be able to answer this particular research question. It would be unethical, not to mention financially irresponsible to recreate such a high quality, large, and blinded cohort. The obvious and simple answer would be; 'Practise patience, have another look when more women have died!' As a young man this philosophy sits uneasily with me, I want the answer NOW. However, although it galls me to acknowledge this, sometimes we do just have to wait.........
Competing interests: None declared
Competing interests: No competing interests
16 December 2004
richard jl baxter
General practitioner
the albany practice, brentford healeth centre, boston manor road, brentford, tw8 0px
Folic acid does not cause pernicious anemia
Dr. Kapil importantly notes the effectiveness of folic acid fortification of grains to improve public health. It is unfortunate that nutrition guidelines include a "tolerable upper intake level" of 1000 micrograms a day of synthetic folic acid. The tolerable upper level is not needed and often leads to inferences that are simply wrong--not based on the actual data.
Dr. Kapil's letter says that folic acid causes pernicious anemia. This is, of course, simply wrong. Unfortunatley this mistaken inference often raises its head in discussions of mandatory folic acid fortification of flour. Pernicious anemia is caused by the absence of intrinsic factor that leads to impaired absorption of vitamin B12. This impaired absorption can lead to very low serum levels and tissue levels of vitamin B12. It is this severe depletion of vitamin B12 that causes clinically symptomatic pernicious anemia. Since pernicious anemia can be and usually is a progressive disease, if a patient is not treated with sufficient vitamin B12, the patient will become get sicker. If a patient is not treated with vitamin B12 and is treated with folic acid, penicillin or other drugs that are not vitamin B12, the patient will become sicker. The patient not treated with vitamin B12 becomes sicker because severe vitamin B12 deficiency is toxic, not because they take other medicine, including folic acid. Unfortunately, studies conducted in the early 1950s continue to be misunderstood.
At a time when patients with pernicious anemia were treated successfully with injectable liver extract, about 500 patients in 3 studies were deliberately removed from effective threapy (injections of liver extract) and placed on an inappropriate and ineffective therapy for pernicious anemia--folic acid in very high doses--up to 50,000 micrograms a day. Although not known at the time that folic acid would be ineffective therapy, we now know that folic acid is ineffective therapy for vitamin B12 deficiency caused by pernicious anemia. The findings from these 500 patients were that about 25% remained well, about 25% had the onset of anemia, about 25% had the onset of anemia and neuropathy and about 25% had the onset of only neuropathy. Perhaps the 25% who remained well had folate deficiency responsible for the orignial symptoms and signs that led to an inappropriate diagnosis of pernicious anemia. Those who developed anemia and or neuropathy had the usual clinical presentations of clinical disease from pernicious anemia that is undiagnosed and untreated with vitamin B12. Given what we know about pernicious anemia, the most reasonable interpretation of the data in these old studies is that folic acid is not an effective therapy for pernicious anemia, that untreated, clinically symptomatic pernicious anemia requires vitamin B12 therapy and the disease will progress if not treated and will reappear if effective therapy with vitamin B12 is discontinued. An additional inference is that folic acid in very substantial doses--50,000 micrograms a day for weeks, is safe, as these patients did not develop disease other than that that could be reasonable attributed to severe vitamin B12 deficiency that would occur if one removed effective vitamin B12 therapy from patients diagnosed with the anemia and or neuropathy of pernicious anemia.
It is time to remove from nutritional guidelines any tolerable upper intake level for folic acid. The existing science does not provide a rational base for the need for a tolerable upper intake level. As long as this misunderstanding provided the fodder to warn medical students and physicians that it is important to determine whether a patient with a macrocytic anemia was caused by folate deficiency and or B12 deficiency and then treat with the appropriate drugs, there was perhaps no pressing reason to correct the mistaken inferences handed down in textbooks for generations. Times have changed. We know know that folate deficiency is widespread, is present in all countries and causes, in addition to folate deficiency anemia, also spina bifida and anencephaly. Folate deficiency is the main reason for increases in homocysteine concentrations and is likely the cause of substantial mortality and morbidity from cardiovascular disease in every country. The evidence linking folate deficiency to causing mutation and cancer has grown in the last few years. When mandatory folic acid fortification is discussed, those opposed to it erroneously put in the discussion that folic acid is harmful to people with vitamin B12 deficiency, for which the data simply does not exist to support this contention. Unfortunately such arguments have either limited the amout of folic acid that was added to flour--the United States and Canada--or have been the major reason fortification has not been required- -the United Kingdom, Europe, New Zealand, and Australia. We now know that limiting the folic acid concentration is responsible for children being born unnecessarily with severe birth defects and that having no fortification is responsible for children also being born unnecessarily with severe birth defects and for adults to unnecessarily have folate deficiency anemia and unnecessarily high homocyteines causes about as many unnecessary deaths a year as occur from vehicular crashes.
It is time to let the idea of masking and that folic acid causes pernicious anemia to be discarded so that we can speed up the rate at which we implement the mandatory folic acid fortification programs that will rid the world of folate deficiency diseases.
Competing interests: Please see commentary
Competing interests: No competing interests
13 December 2004
Godfrey P. Oakley, Jr.
Research Professor of Epidemiology, Rollins School of Public Health of Emory University
1558 Clifton Road NE Altanta GA 30345
Effectiveness at the public health intervention level of Folic acid suppplementation
The neural tube defects (NTD) are more often than not of unknown etiology. Genetic factors, nutritional deficiencies, or drugs are among the identifiable causes of those defects. For example, a decrease in folic acid intake has been repeatedly associated with an increased risk of NTD. The geographic distribution of NTD also supports folic acid deficiency as an etiologic factor: they prevail in colder, darker climates with reduced availability of fruits and vegetables. In India all women of childbearing age to consume at least 0.5 mg folic acid per day but no more than 1 mg/day except under physician's supervision, since such a dose can mask B12 deficiency, causing pernicious anemia. The richest sources of folate in foods are liver, legumes, and green vegetables. The folic acid should be given as a supplement, especially by women at high risk, such as women on antiepileptic drugs or those having a history of NTD births. Folic acid fortification of foods has been used in few countries. Enriched cereal or grain products are fortified by 0.14 mg folic acid per 100 g of grain, which means that enriched breads, rolls, buns, flour, rice, macaroni, and cornmeals would increase the average dietary intake to 0.3 mg per day. Since folic acid supplementation does not eliminate all cases of NTD, prenatal diagnosis using alpha-fetoprotein testing and ultrasound should still be offered to high-risk women Amongst all the micronutrient interventions through food fortification , the iodized salt and folic acid fortification are only two, which have shown effectiveness at the public health intervention level and should be aggressively promoted .
Competing interests: None declared
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