Pyridoxine in the UK

Why, when many pharmaceutical products continue as commercial successes despite clear evidence of potential harm, are essential nutrients so often condemned as harmful on the basis of weak or questionable evidence? Why are there now so many attacks in progress on the use of nutrition, on the national. the European and the international levels?

The reason is plain, and always has been: the concurrence of interests between the pharmaceutical industry, scientific academia and governments--certainly not the public interest or that of patients. In the UK at present, yet another such attack on nutritional therapy continues: the move to restrict amounts of vitamin B6 in supplements. In the last issue of the journal, we published a preliminary report of a survey that challenges one of the key assumptions on which the move is based [ 1].

THE DALTON STUDY

In 1987, a paper appeared in a Scandinavian journal, reporting a telephone survey of women attending a pre-menstrual syndrome (PMS) clinic [ 2]. The principal author was (and still is) a noted proponent of the use of progesterone in PMS. The study population consisted of all those telephoned who admitted to taking B6 supplements (172 women). Those who did not admit to taking B6 supplements were not investigated--so there were no true control subjects. Of the 172, 103 (60%) were deemed to have neurological symptoms, which were described as "consistent with the well described clinical syndrome of peripheral sensory neuropathy". These were compared with the other 69 (40%) without such symptoms, who were described as controls. Both groups were taking nearly identical doses of B6 (117 +/- 92 mg vs 116 +/- 66 mg), but the authors noted that the symptom group had been taking B6 for longer than controls (2.9 +/- 1.9 years vs 1.6 +/- 2.1 years) and reported a p-value of < 0.01 for this.

A number of criticisms have been made of the 'Dalton paper', and in the intervening decade no one has replicated the data. Indeed, it might have sunk without trace, had an expert committee in the Department of Health not used it as the basis for recommending restrictions on the sale of vitamin B6. These criticisms have been discussed in detail elsewhere 131. but to summarize them:

The study contained no true control group for comparison.

The clinical picture described is different to that reported by other studies in humans in several respects, and is not consistent with the peripheral neuropathy described with very high doses of B6.

No electrophysiological testing was performed in the study, which would have allowed comparison with the findings in other reports of B6-induced neuropathy.

In contrast to all other studies of B6 toxicity, there is no dose-response relationship with regard to severity, incidence or time-to-onset of' symptoms.

Most subjects were taking B6 for PMS, depression or menopause, all of which are recognized as causing a variety of diffuse, non-specific symptoms.

PMS is reported to respond markedly to placebo, so it is possible that the improvement on B6 withdrawal was entirely due to placebo effect.

THE COMMITTEE ON TOXICITY

Acting on a request from the Consumers' Association, the Committee on Toxicity (CoT), a committee within the Department of Health (DoH), conducted a review of the safety of vitamin B6. which it endorsed in committee and released in December 1996. Several bodies pointed out that there were serious flaws in the reasoning of this statement, the most notable being the conclusion that the observations of Dalton and Dalton were consistent with the data from laboratory studies of toxicity in animals. This appeared to arise from a simple misreading of the animal data, in which changes occurring at doses down to 50 mg per kg body weight per day were interpreted as occurring at 50 mg per day in total. This represents a difference in dose levels of at least an order of magnitude; 50 mg per kg per day for a 50-kg person (8 stone, 112 lbs) is 2500 mg per day. The response of CoT to this point was to make a post-hoc adjustment to the safety factor proposed for B6, thus arriving at the same recommendation as before, by a slightly longer route. This recommendation was that the maximum daily safe dose of B6 for humans was 10 mg.

Apart from the fact that the CoT actually used the Dalton and Dalton paper, given its recognized shortcomings, and that it is the only human study to support the claims of toxicity at such doses, the CoT's statement ignored other important data, including an extensive survey conducted for the DoH over a period of 8 years, which found no instance of' B6 toxicity at all [ 4]. The CoT also slid hastily over the issue of B6 requirements, ignoring a range of studies showing a significant prevalence of B6 deficiency in the population, with increased prevalence in vulnerable groups. In fact, studies in adults repeatedly show prevalences of vitamin B6 of around 25% [ 5].

Strangely, the statement also cited homocystinuria as an instance of inherited defects with increased B6 requirements--yet mentioned it only as a severe inborn defect, ignoring recent evidence that heterozygosity for this group of enzyme defects occurs in an estimated 30-50% of the population, and is a greater risk factor for cardiovascular disease than smoking, blood pressure or cholesterol [ 6]. Mention of this evidence would have invited the comment that normalization of homocysteine, in the 30-40% of such cases responsive to B6, can be achieved with 100 mg per day of B6, but not with 10 mg [ 7].

Concern has been expressed about the impartiality of the CoT, which meets behind closed doors. Of its 15 members, 9 have declared interests in the pharmaceutical industry, including consultancies, research awards and shareholdings.

WHAT HAPPENED NEXT

From the CoT in the DoH, responsibility for this proposal passed to the Food Advisory Committee (FAC) in the Ministry of Agriculture, Fisheries and Food (MAFF), and then passed back to the Medicines Control Agency (MCA) in the DoH. In the course of a few days last summer, the revised conclusions of the CoT were released, endorsed and formulated into proposals by the FAC, and also issued as proposed amendments to the Medicines Act by the MCA. There was also a 'fax cascade' initiated by the Chief Medical Officer in the DoH, notifying all general practitioners and all health authorities of the forthcoming amendments, and in effect warning against the use of greater doses than those recommended.

The combined effect of these moves would be that:

Daily doses of B6 over 50 mg would only be available on prescription.

Daily doses between 11 and 49 mg would only be available from pharmacies.

Since then, there has been something of a groundswell of public opinion, with petitions against the proposals being signed by tens of thousands of consumers, plus submissions by industry groups and professional and scientific bodies, including the BSAENM. Although this has led to a free debate on the subject in Parliament being granted, the Food Safety Minister is evidently still determined to push this legislation through, citing as grounds "advice from our independent scientists". The 'independent scientists' in question, the CoT, are standing by their previous statement, despite criticisms that include protest from the authors of one of the key animal studies that their data are being misused. Indeed, only Dalton, of all the scientists cited, has been prepared to endorse the CoT's conclusions.

OTHER INTERESTS

If these amendments to legislation go through, people who need B6, or wish to try it, at doses over 50 mg per day, will be forced to find a doctor willing to prescribe it. After the fax cascade, representatives of general practitioners advise us that few, if any, GPs will be willing to prescribe such doses. Since non-medical practitioners are not able to prescribe, the only people who would be able, willing and competent to do so would be medical practitioners such as those represented by the BSAENM. This could, therefore, be a highly profitable move for us. Despite this, nobody from our membership has done anything other than to campaign vigorously against the proposed legislation--because it is clear to us that it is against the interests of patients and the public.

Consider the instance of homocysteine. An elevated serum homocysteine (> 15.8 mcM vs < 14.1) gives a relative risk of MI of 3.4 (95% confidence interval 1.3-8.8) after adjustment for diabetes, angina, aspirin, hypertension, raised body mass index and abnormal total cholesterol or high-density lipoprotein ratios [ 6]. Administering vitamins B6, B12 and folic acid can correct the raised homocysteine in probably 80-90% of such individuals [ 8].

Cardiovascular disease is the largest killer of males in the Western world. The pharmaceutical industry offers a number of preparations designed to control or suppress the symptoms and markers of such disease. Of the 25 best-selling drugs worldwide, 8 are cardiovascular preparations (statins, calcium antagonists and ACE inhibitors), whose combined annual sales exceed US$11 billion [ 9]. If a simple cocktail of vitamins can reduce risk more than anything else, it clearly threatens the massive profits from these.

A NEW SURVEY

In this issue of the journal, we publish the preliminary report of a survey conducted last autumn, in the US and UK, which sought to replicate the Dalton study [ 1]. A total of 135 completed questionnaires were received, of which 13 had to be rejected as unusable. The principal findings on the 122 questionnaires (Dalton considered 172 individuals) were:

Symptoms such as those described by Dalton were very common: 60% of all responders admitted to at least one of the 'Dalton symptoms'.

They were even more common in PMS or depression: 75% of PMS or depression sufferers reported such symptoms vs 44% of non-sufferers.

Taking B6 did not significantly increase the frequency of such symptoms: of PMS/depression sufferers, 81% of B6 takers vs 70% of non-takers reported symptoms (Chi2 - 0.963, not significant).

In B6 takers the large majority of these symptoms started before taking B6: 82% of patients reported that all symptoms started before they began taking B6.

The author, Alan Gaby, points out that such symptoms could be caused by a wide range of nutritional and endocrine problems, and that the evidence of' this survey suggests that B6 toxicity is a very unlikely cause, compared to PMS, depression or these other problems. Since Dalton did not control for other causes of symptoms, this report appears to shed important new light on the issue. We urge the CoT, the FAC and, indeed, all medical practitioners to consider the implications of these findings carefully, before they make any decisions on a set of proposals that appear to be designed to damage the 'health of the nation'.
REFERENCES

[1] Gaby AR. The safety of vitamin B6. J Nutr Environ Med 1997; 7: 385.

[2] Dalton K, Dalton MJT. Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol Scand 1987; 76: 8-11.

[3] Vitamin B6 and peripheral neuropathy. Submission by the BSAENM to CoT, Feb 1997.

[4] Shaw D, Kolev S, Leon C. Toxicological problems resulting from exposure to traditional medicines and food supplements. Traditional Remedies Surveillance Project, Medical Toxicology Unit, Guy's and St Thomas' Hospital Trust, London, 1996.

[5] Bender DA. Vitamin B6 requirements and recommendations. Eur J Clin Nutr 1989; 43: 289-309.

[6] Stampfer MJ, Malinow MR, et al. A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA 1992; 268: 877-81.

[7] Dudman NPB, Wilcken DEL, et al. Disordered methionme/homocysteine metabolism in premature vascular disease: its occurrence, cofactor therapy, and enzymology. Arterioscl Thromb 1993; 13:1253-60,

[8] van den Berg M, Franken DG, et al. Combined vitamin B6 plus folic acid therapy in young patients with arteriosclerosis and hyperhomocysteinemia. J Vase Surg 1994; 20: 933-40.

[9] Med Ad News 1997: 16: 59.

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By DAMIEN DOWNING MBBS BSAENM, PO Box 3AP, London W1A 3AP, UK

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