Current issues of ACP Journal Club are published in Annals of Internal Medicine


Elevated total homocysteine levels increased the risk for vascular disease

ACP J Club. 1998 Jan-Feb;128:21. doi:10.7326/ACPJC-1998-128-1-021

Source Citation

Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Report. JAMA. 1997 Jun 11;277:1775-81.



To determine whether homocysteine (Hcy) is an independent risk factor for vascular disease in men and women.


Case-control study.


19 clinical centers in 9 European countries.


750 patients who were ≤ 60 years of age with proven vascular disease: 383 with coronary artery disease, 211 with cerebrovascular disease, and 156 with peripheral vascular disease. 800 adults without vascular disease served as controls. Exclusion criteria were recent major systemic disease or nitric oxide exposure; nonatherosclerotic vascular disease; diabetes; renal, hepatic, or thyroid disease; cardiomyopathy; pregnancy; use of anticonvulsant medication; psychiatric illness; or chronic alcohol abuse.

Assessment of risk factors

Data were collected on major vascular risk factors, diagnostic information, and drug and vitamin use. Total fasting plasma Hcy (fasting) levels, total Hcy levels after loading with L-methionine (100 mg/kg) (loading), difference between fasting and loading Hcy (increase), plasma levels of active vitamin B6, serum cobalamin levels, and erythrocyte folate levels were measured. Relative risks for vascular disease were calculated for the top quintile compared with the other quintiles of Hcy levels.

Main outcome measures

Total vascular disease, coronary heart disease, cardiovascular disease, and peripheral vascular disease.

Main results

Data were adjusted for major risk factors and analyses were stratified by age and sex. Mean fasting and loading Hcy levels were higher in patients with vascular disease than in control patients. Elevated Hcy levels, either fasting or post-methionine loading, were independently associated with increased risks for total and individual vascular diseases (Table). Similar associations were seen for men and women. Vitamin B6 levels were lower in patients with vascular disease. The groups did not differ for cobalamin or erythrocyte folate levels.


Elevated fasting and post-methionine loading total homocysteine levels were strongly and independently associated with increased vascular disease.

Source of funding: Primarily from the European Community, with funding from 14 other agencies and companies.

For article reprint: Dr. I.M. Graham, The Adelaide Hospital, Peter Street, Dublin 8, Ireland. FAX 353-1-454-2182.

Table. Adjusted relative risks and 95% CIs for elevated homocysteine levels and vascular disease

Homocysteine All vascular disease Coronary heart disease Cerebrovascular disease Peripheral vascular disease
Fasting 1.9 (1.4 to 2.8) 2.0 (1.4 to 2.8) 1.7 (1.1 to 2.7) 1.7 (1.0 to 2.9)
Loading 1.8 (1.4 to 2.4) 2.0 (1.4 to 2.8) 1.9 (1.2 to 2.9) Not significant


In 1992, 2 rather distinct forms of hyper-homocysteinemia were hypothesized: fasting and post-methionine loading (1). Animal experiments (2), human observations (3), and recent population-based data (4) support this hypothesis. The European Concerted Action Project (COMAC) found that approximately 30% of persons with hyper-homocysteinemia had isolated post-methionine-loading hyperhomocysteinemia, with normal fasting Hcy levels providing further confirmation of this hypothesis. More important, the COMAC data suggest that isolated post-methionine-loading hyperhomocysteinemia is not a biochemical curiosity but an independent risk factor for cardiovascular disease.

The COMAC data are important for testing the hypothesis that lowering Hcy levels will reduce cardiovascular disease. If all patients at risk for mild to moderate hyper-homocysteinemia are to be identified, methionine loading is indicated. A valid 2-hour methionine-loading protocol is now available (5). The COMAC project also found that active vitamin B6 levels (but not serum cobalamin or erythrocyte folate levels) were lower in patients with vascular disease. This finding, as well as reports that vitamin B6 is more effective than folic acid in reducing Hcy levels after methionine loads (3), strongly supports the inclusion of vitamin B6 in treatment regimens used to lower Hcy levels in clinical trials.

Results of Vitamin Intervention in Stroke Prevention and of other clinical trials will provide more definitive information about whether the identification and treatment of hyperhomocysteinemia is warranted and, if so, how they are best accomplished.

Andrew G. Bostom, MD, MS
Memorial Hospital of Rhode IslandPawtucket, Rhode Island, USA

Andrew G. Bostom, MD, MS
Memorial Hospital of Rhode Island
Pawtucket, Rhode Island, USA


1. Selhub J, Miller JW. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr. 1992; 55:131-8.

2. Miller JW, Nadeau MR, Smith D, Selhub J. Vitamin B-6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats. Am J Clin Nutr. 1994;59:1033-9.

3. Brattstrom L, Israelsson B, Norrving B, et al. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment. Atherosclerosis. 1990;81:51-60.

4. Bostom AG, Jacques PF, Nadeau MR, et al. Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study.Atherosclerosis. 1995;116:147-51.

5. Bostom AG, Roubenoff R, Dellaripa P, et al. Validation of abbreviated oral methionine-loading test. Clin Chem. 1995;41(6 Pt1):948-9.