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Reply to NJ Wald et al

Clinical Trial Service Unit and
Epidemiological Studies Unit
Nuffield Department of Clinical Medicine
Radcliffe Infirmary
Oxford, OX2 6HE
United Kingdom
E-mail: Robert.Clarke{at}ctsu.ox.ac.uk

John Grimley Evans

Department of Clinical Geratology
Radcliffe Infirmary
Oxford
United Kingdom

Dear Sir:

Vitamin B-12 deficiency caused by either intrinsic factor deficiency or hypochlorhydria chiefly affects the elderly. Vitamin B-12 deficiency may present as macrocytic anemia, but it also causes neuropathy, including (if the deficiency is severe) subacute combined degeneration of the spinal cord (1). The neurologic symptoms may occur in the absence of anemia in 20-30% of cases (1). The diagnosis of vitamin B-12 deficiency is complicated by the limitations of the current vitamin B-12 assay techniques, whereby a low serum vitamin B-12 concentration does not always indicate vitamin B-12 deficiency. Persons with biologically significant vitamin B-12 deficiency almost always have elevated plasma concentrations of homocysteine or methylmalonic acid (1). Consequently, measurement of blood concentrations of either metabolite among persons with low or borderline concentrations of vitamin B-12 may be used to identify those at high risk of vitamin B-12 deficiency. Using these assays to identify persons with vitamin B-12 deficiency, we found that, among those aged 65-74 and 75 y, respectively, 10% and 20% were at high risk of vitamin B-12 deficiency (2).

Folic acid supplementation can prevent anemia among persons with vitamin B-12 deficiency, but it does not prevent damage to the nerves, spinal cord, or brain. Hence, universal, mandatory, folic acid fortification may delay the diagnosis of vitamin B-12 deficiency (ie, result in the "masking" of vitamin B-12 deficiency) and allow the progression of vitamin B-12-related damage to peripheral nerves, spinal cord, and brain. It is not correct, as Wald et al (3) suggest, to dismiss the hazards of masking vitamin B-12 deficiency among elderly persons.

There is a biochemical basis for the masking of vitamin B-12 deficiency by folic acid (4). The methylenetetrahydrofolate reductase enzyme is responsible for the formation of 5-methyltetrahydrofolate, the primary circulating form of folate and carbon donor for homocysteine remethylation to methionine. The reaction catalyzed by this enzyme is irreversible, and the only way the product, once formed, can be recycled in the cell is to be converted back to tetrahydrofolate by the vitamin B-12-dependent enzyme methionine synthase. If folic acid is supplied to vitamin B-12-deficient persons, it can be converted directly to dihydrofolate and tetrahydrofolate in the bone marrow, which allows hematopoiesis, but not in cells elsewhere. Thus, folic supplementation of vitamin B-12-deficient persons can prevent anemia and thereby mask the diagnosis of neuropathy.

A relevant document on folic acid fortification in the United Kingdom is the report from the Committee on Medical Aspects of Food and Nutrition Policy, entitled "Folic Acid and the Prevention of Disease" (5). This study concluded that mandatory fortification of flour with 240 µg folic acid/100 g flour could be beneficially and safely introduced, subject to 2 conditions. The first condition is that technical means be devised to ensure fortification at a target concentration, rather than at a minimal concentration, and the second condition is that means be instituted to identify and protect elderly persons who are vitamin B-12 deficient. The first condition has not been achieved and may be unachievable; the second would render the first unnecessary. It is to meeting the second condition that our research was directed (2).

The conclusion of the Committee on Medical Aspects of Food and Nutrition Policy was based on the need to prevent folic acid intakes >1 mg/d in elderly persons in whom there might be undiagnosed vitamin B-12 deficiency, the prevalence of which was unknown at the time of the report. The report recognized that the evidence suggesting that people with vitamin B-12 deficiency are at risk of harm if exposed to folic acid concentrations >1 mg/d was incomplete but also that, for ethical reasons, complete evidence was unobtainable. In view of the high prevalence of vitamin B-12 and folate deficiencies reported in the elderly, we suggest that routine screening of elderly persons (particularly those aged 75 y) for vitamin B-12 and folate deficiencies may be indicated (2). If the methods used for screening elderly persons for vitamin B-12 deficiency also detected other, treatable abnormalities, so much the better.

REFERENCES

1. Lindenbaum J, Healton EB, Savage DE, Brust JCM, Garrett TJ, Podell ER. Neuropsychiatric diseases caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720-8.[Abstract]
2. Clarke R, Refsum H, Birks J, et al. Screening for vitamin B-12 and folate deficiency in older persons. Am J Clin Nutr 2003;77:1241-7.[Abstract/Free Full Text]
3. Wald NJ, Law M, Hoffbrand V. Vitamin B-12 and folate deficiency in older persons. Am J Clin Nutr 2004;79:336-7.
4. Scott JM, Weir DG. Folic acid, homocysteine and one-carbon metabolism: a review of the essential biochemistry. J Cardiovasc Risk 1998;5:223-8.[Medline]
5. Committee on Medical Aspects of Food and Nutrition Policy (COMA). Folic acid and the prevention of disease. London: Her Majesty's Stationery Office, 2000.

This article has been cited by other articles:

				N. J Wald, M. Law, and A V. Hoffbrand Folic acid fortification in the prevention of neural tube defects Am. J. Clinical Nutrition, December 1, 2004; 80(6): 1665 - 1665. [Full Text] [PDF]

This Article Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clarke, R. Articles by Evans, J. G. Search for Related Content PubMed Articles by Clarke, R. Articles by Evans, J. G. Agricola Articles by Clarke, R. Articles by Evans, J. G.