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Clinical Review Science, medicine, and the future

Is folic acid the ultimate functional food component for disease prevention?

BMJ 2004; 328 doi: (Published 22 January 2004) Cite this as: BMJ 2004;328:211

Folic acid supplementation- beware of vitamin B12 deficiency

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

Competing interests: No competing interests

30 January 2004
Stephen DH Malnick
Director, Department of Internal Medicine C
Sorel Goland
Kaplan Medical Center, Rehovot, 76100, Israel