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Norberg B. Focus on folate – folic acid, vitamin B12, and cancer [editorial]. Rondel 2010; 30. URL: http://www.rondellen.net

Focus on folate
Folic acid, vitamin B12, and cancer

Summary

Transient treatment with low doses of vitamin B12 and folic acid appeared to cause an increase of new cancer, cancer mortality, and total mortality in 6837 Norwegians with coronary heart disease, observed for 7-8 years (Tables 1,2). This conclusion was derived from the follow-up of two randomised, prospective, and double-blinded trials of homocysteine lowering by B vitamins (1-3). Folic acid plays the role of “first suspect”. For the time being, vitamin B12 is acquitted short of evidence (5). The observed risk increase is expected to have implications for food fortification with vitamin B12 and folic acid, for supplementation in health foods, and for prophylaxis and treatment of deficiency states.

Historical account

The first signals that folic acid may have a negative influence on incidence and course of tumour diseases appeared more than 50 years ago (4). The fear was confined to a limited number of connoisseurs. Ordinary clinicians in my generation were unaware of the risks. We were awakened by a public comment at the homocysteine conference in Sorrento 2001 from Victor Herbert (cf 6). During recent years, folic acid has sometimes been interpreted as a protection against cancer, sometimes as a risk for cancer (5).

The role of folic acid in cancer development was elucidated by the follow-up of two Norwegian studies on homocysteine lowering by B vitamins in patients with coronary heart disease (Tables 1,2), NORVIT (1) and WENBIT (2). The preliminary results of the follow-up were presented at the homocysteine conference in Prague 2009 (7); the suspicions against folic acid were confirmed.

The final report appeared in JAMA during the last weeks of November, 2009 (3). Thus, it is possible to analyse results and implications in more detail.

Therapy

Group 1

Group 2

Group 3

Group 4

B12

Folic acid

Pyridoxin

Placebo

0.4 mg

0.8 mg

40 mg

0.4 mg

0.8 mg

40 mg

Table 1: Intervention groups in NORVIT (1) and WENBIT (2). The trials were designed to elucidate the effects of homocysteine lowering by B vitamins in patients with coronary heart disease. The present follow-up study (3) comprised 6837 participants, divided into four intervention groups.

Variable	Hazard ratio	Confidence intervall 95%	P
Incidence of cancer	1,21	1,03 – 1,41	p=0,02
Mortality of cancer	1,38	1,07 – 1,79	p=0,01
Total mortality	1,18	1,04 – 1,33	p=0,01

Table 2: Follow-up of NORVIT and WENBIT in order to elucidate the effect of B vitamin therapy on future tumour disease (3). Exposure for vitamin B12 and folic acid during trials was 38 months (median value). Corresponding values for observation time were 88 months concerning diagnosis of new cancer and death in cancer, 98 months concerning total mortality. Hazard ratio with confidence intervals and probability values are shown for participants with coronary heart disease treated with vitamin B12 and foli acid, compared with participants treated with placebo or pyridoxin, which did not affect homocysteine values, cancer morbidity or all-cause mortality.

Time period, patient material, and scope

NORVIT and WENBIT were conducted in the period 1998-2005 (1-3). NORVIT recruited patients in the wake of an acute myocardial event. WENBIT recruited patients with a stable coronary disease. The homocysteine values of the patients were at baseline mainly around 12-15 micromol/L.

The aim of the basic trials was to lower plasma homocysteine by treatment with B vitamins in monotherapy or in combinations (Table 1). Homocysteine lowering was obtained in trial groups treated with vitamin B12 and folic acid but not in those treated with only placebo or pyridoxin. However, homocysteine lowering was not associated with improvement of coronary heart disease (1,2).

When the preliminary results of NORVIT appeared in 2005, the fear increased that folic acid might worsen incipient tumour disease. Thus, WENBIT was stopped before the agreed size and date set in the design (2).

The present study (3) represents a combination of the patients in NORVIT and WENBIT for long-term follow-up; the design of the studies were identical, although the patients of the two trials were in different stages of coronary heart disease.

Results

An impressive proportion of original patients (92%) participated in the present study (3). A covariance was found between treatment with vitamin B12 and folic acid and increased numbers of diagnosed cancer, mortality in cancer, and total mortality. The increase of relative risks were moderate (Table 2). Smokers and ex-smokers bore mainly the burden of the unfavourable outcome.

Discussion

The editorial comments in JAMA on the Norwegian observations are cautious and balanced (5). Other studies suggest that flour fortification with folic acid reduces the risk of cancer. However, this interpretation is not shared by all scientists (8).

The Norwegian observations (1-3) are compatible with a series of prospective Scandinavian studies, which demonstrated a correlation between cancer risk and vitamin B12/folate levels in the upper parts of the reference range (9-11).

The effect of transient treatment with vitamin B12 and folic acid in the Norwegian studies (1-3) is shocking to Swedes; in Sweden, folic acid in 5 mg prescription tablets is routine for deficiency treatment. The practice represents a relict from the introduction of folic acid around 1950.

Prescription-free folic acid was restricted to oral doses below 1 mg in USA in 1972 (12). The restriction was due to fear of masking deficiency of vitamin B12 by stronger dosage. Furthermore, the risk of cancer loomed in the background (4).

Is homocysteine dead as a risk factor for vascular disease? Frankly, nearly gone (13)! Though, a subgroup analysis from HOPE-2 suggested a beneficial effect of homocysteine lowering concerning stroke (14).

It is reasonable to assume that the future role of homocysteine will be a sensitive screening test for incipient deficiency of vitamin B12 and/or folate. A homocysteine value below 10 micromol/L excludes actual deficiency. On the other hand, a homocysteine value above 20 micromol/L suggests incipient deficiency (cf 16,17).

Another crucial question is the everyday supplementation and prophylaxis with folic acid and vitamin B12 in order to avoid future deficiency. The present study (3) is certainly a warning shot through the head of the enthusiasts within the health food and prophylaxis branches.

Bo Norberg
norberg.bo@gmail.com

References

1. Böna KH, Njolstad I, Ueland PM et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med, 2006; 354:1578-1588

2. Ebbing M, Bleie O, Ueland PM et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA, 2008; 300:795-804

3. Ebbing M, Bönaa KH, Nygård O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 2009; 302(19):2119-2126

4. Kim Y-I. Folate: a magic bullet or a double edged sword for colorectal cancer prevention. Gut 2006; 55:1387-9

5. Drake BF, Colditz GA. Assessing cancer prevention studies – A matter of time. JAMA 2009; 302(19);2152-2153

6. Scott JM. Victor Herbert (1927-2002). J Nutr 2004; 134:1678-1680

7. Ebbing M, Böna KH, Nygard O, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njölstad I, Refsum H, Vollset SE. Cancer incidence, cancer mortality and all-cause mortality after treatment with folic acid and vitamin B12 in ischemic heart disease patients. Oral presentation (O70) at the 7^th International Conference on Homocysteine Metabolism, Prague 21-25 June, 2009

8. Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH. 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. 2007; 16:1325-9

9. Van Guelpen B, Hultdin J, Johansson I, Hallmans G, Stenling R, Riboli E, Winkvist A. Low folate levels may protect against colorectal cancer. Gut 2006; 55:1461-6

10. Hultdin J, Van Guelpen B, Bergh A, Hallmans G, Stattin P. Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: a prospective study. Int J Cancer. 2005; 113:819-24

11. Johansson M, Van Guelpen B, Vollset SE, Hultdin J, Bergh A, Key T, Midttun O, Hallmans G, Ueland PM, Stattin P. One-carbon metabolism and prostate cancer risk: prospective investigation of seven circulating B vitamins and metabolites. Cancer Epidemiol Biomarkers Prev. 2009; 18:1538-43

12. Lee GR, Bitchell TC, Forster J, Athens JW, Lukens JN (eds). Wintrobe´s Clinical Hematology, pp.777-9 Ed 9, Philadelphia: Lea & Febiger; 1993

13. Bozzano LA. Folic acid supplementattion and cardiovascular disease: The state of the art. Amer J Med Sci 2009; 338:48-49

14. Saposnik G, Ray JG, Sheridan P, et al. Homocysteine lowering therapy and stroke risk, severity, and disability: Additional findings from the HOPE-2 trial. Stroke 2009; 40:1365-1372

15. Schedvin G, Jones I, Hultdin J, Nilsson TK. A laboratory algorithm with homocysteine as the primary parameter reduces the cost of investigation of folate and cobalamin deficiency. Clin Chem Lab Med 2005; 43(10):1065-8

16. Norberg B. Provocative proposal – global guidelines for oral vitamin B12 therapy [editorial]. Rondel 2006; 26. URL: http://www.rondellen.net/publisher26_eng.htm

17. Nilsson M. Advice for assessors – how to read context and content of the Nyholm paper [editorial]. Rondel 2009; 29. URL: http://www.rondellen.net/publisher29_eng.htm

Published March 29, 2009