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1 From the Clinical Trial Service Unit and the Epidemiological Studies Unit, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford, United Kingdom.
2 The author's work on homocysteine is supported in part by a European Union BIOMED demonstration project: BMH4-98-3549.
3 Address reprint requests to R Clarke, 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.au.uk.
See corresponding article on page 338.
Folate deficiency was traditionally diagnosed by the presence of macrocytic anemia and abnormal red blood cell precursors in the bone marrow in individuals with low folate concentrations. Similarly, vitamin B-12 deficiency was once diagnosed on the basis of a similar hematologic picture, but also on the basis of a specific form of neuropathy in individuals with low vitamin B-12 concentrations. Clinical studies carried out by Lindenbaum et al (1) showed that the neurologic symptoms in persons with vitamin B-12 deficiency frequently occur without anemia. The reported neurologic symptoms associated with vitamin B-12 deficiency include neuropsychiatric disorders, paresthesias, ataxia, memory loss, weakness, and personality and mood changes. Vitamin B-12 and folate share a metabolic pathway to supply methyl groups to all cells. A deficiency of either vitamin results in a raised homocysteine concentration, which has been used as a diagnostic test of metabolically significant vitamin B-12 and folate deficiency. Elevated blood concentrations of methylmalonic acid (MMA) occur in vitamin B-12 deficiency but not in folate deficiency. Both homocysteine and MMA concentrations are positively and equally correlated with blood creatinine concentrations. Epidemiologic studies suggest that metabolically significant vitamin B-12 deficiency in the elderly is much more common than is widely believed (2, 3). New immunoassays for homocysteine determination may provide a simple and reliable method for screening high-risk populations for vitamin B-12 deficiency. These immunoassays for homocysteine determination compare favorably with HPLC and gas chromatography–mass spectrometry assay methods, with CVs <5% when the immunoassays are run on an IMx platform (Abbott Laboratories, Chicago) (4).
Elevated blood concentrations of homocysteine are a risk factor for coronary artery disease, stroke, and thromboembolic diseases, and these associations appear to be independent of other major risk factors for these diseases (5, 6). Across the range of plasma homocysteine concentrations encountered in Western countries, lower homocysteine concentrations are associated with lower risks of vascular disease. Prospective studies of patients with vascular disease show that the differences in homocysteine concentrations often precede the onset of disease, which appears to argue against homocysteine concentrations being a marker of subclinical disease. Observational studies of vascular disease cannot exclude confounding as a result of dietary or other factors. Several large-scale clinical trials are under way to assess the effects on cardiovascular disease risk of lowering homocysteine concentrations by folic acid–based vitamin supplements (7, 8). The results of such trials are required before widespread screening for elevated homocysteine concentrations can be advocated to reduce cardiovascular disease risk.
The relevance of metabolically significant vitamin deficiency in frail elderly is a separate issue because of the hazards associated with vitamin B-12 deficiency in this population. The evidence that elevated homocysteine may be a risk factor for dementia is limited. A few retrospective studies of elderly individuals compared vitamin and homocysteine concentrations in persons with dementia and in control subjects free of the disease. We found a significant association of histologically confirmed Alzheimer disease and vascular dementia with moderately elevated serum homocysteine concentrations and with reduced blood concentrations of folate and vitamin B-12 (8). The case-control differences in folate concentrations were greater than those for vitamin B-12 comparisons. Individuals with elevated homocysteine concentrations had radiologic evidence of more rapid cerebral atrophy over a 3-y follow-up period. The latter observation supports the suggestion that the associations are more likely to be causal than a consequence of the disease. Prospective studies are required to confirm whether differences in homocysteine concentrations precede the onset of dementia. Further studies are required to determine whether vitamin B-12, folate, or both are relevant. Ultimately, clinical trials are needed to determine the therapeutic relevance for risk of dementia, if any, of treatment of high-risk populations with folic acid and vitamin B-12.
Clinicians are careful to avoid treating patients who have low vitamin B-12 concentrations with folic acid, which prevents the anemia but allows the neurologic symptoms to progress. In the United States, the proportional changes in folate and homocysteine concentrations achieved by folate fortification were found to be greater than anticipated (9). Hence, the potential for unforeseen hazards of masking vitamin B-12 deficiency are much greater than suggested originally. The prevention of undiagnosed vitamin B-12 deficiency may well require selective screening and treatment of individuals in high-risk elderly populations. But population strategies to reduce homocysteine concentrations by combined food fortification with folate and vitamin B-12 may be more cost-effective and feasible (10).
The report by de Jong et al (11) in this issue of the Journal illustrates the magnitude of change in concentrations of both homocysteine and MMA that can be achieved by vitamin-enriched diets in frail elderly persons. In this 17-wk trial that included 165 elderly persons who complied with dietary instructions and attended follow-up, daily dietary supplementation with enriched foods containing 0.25 µg folic acid and 2.5 µg vitamin B-12 was associated with reductions in blood concentrations of homocysteine of 25% and in MMA of 30%. A trial designed to detect changes in cognitive function would have required a much larger sample and a longer duration of treatment to have any realistic chance of detecting effects of diets enriched with folic acid and vitamin B-12. The metabolic results of this trial are important and suggest that interventions of this type could resolve some of the problems associated with masking of vitamin B-12 deficiency caused by fortifying staple foods with folic acid. The study by de Jong et al showed that small amounts of vitamin B-12 appear to be efficacious. Further research is required to develop strategies for combined fortification of flour with folic acid and vitamin B-12 and to determine the amounts of vitamin B-12 to add to flour to ensure absence of deficiency in the population. In addition, the technical aspects of food fortification with vitamin B-12 must be considered.
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