Homocysteine and Risks for Cardiovascular Disease
by Beth A. Pletcher, MD

Homocysteine is a natural amino acid that is produced during methionine metabolism. Serum homocysteine levels in a normal population range from 5 to 15 mmol/liter in a fasting sample. There is a known association of increased serum homocysteine with coronary artery disease, stroke, and thrombosis. This was originally seen in the disorder homocystinuria where there is early death due to cardiovascular disease. Recently, there have been studies that have suggested that mild elevations of serum homocysteine levels may confer an increased risk for cardiovascular disease.

REASONS FOR MILDLY ELEVATED HOMOCYSTEINE

• Homocysteine levels in men are generally higher than in premenopausal women.

• Diets rich in animal proteins tend to increase homocysteine levels whereas diets high in plant proteins tend toward lower levels. Lower levels are associated with diets that include fruit, vegetables, and vitamin supplements.

• Vitamin deficiencies can increase homocysteine levels, especially B12 in older people and folate in younger individuals.

• Renal failure will increase homocysteine levels.

• Organ transplant patients have an idiopathic increase in homocysteine levels.

GENETIC REASONS FOR ELEVATED HOMOCYSTEINE LEVELS

• Recessive deficiency of cystathionine b-synthase or methionine synthase.

• Homozygous methylenetetrahydrofolate reductase (MTHFR) genotype.

Recent studies have shown the MTHFR mutation as an independent risk for cardiovascular disease.* Two of these studies have shown an odds ratio of 3.1 and 3.2 for development of cardiovascular disease. Other studies have shown that homozygotes for the MTHFR mutation are not at increased risk for cardiovascular disease among well nourished, predominately white middle class populations.

Serum homocysteine levels can be lowered in patients by folate and B vitamin supplementation. Generally, a daily dose of folate >400 mg is recommended, although the optimal doses of folate and B vitamins have not been well established.

DETERMINATION OF HOMOCYSTEINE LEVELS

It has been suggested that homocysteine levels should be measured on patients who have:

• Any evidence for homocystinuria, including "marfanoid habitus", dislocated lens and increased urinary homocysteine.

• Evidence of vitamin B12 or folate deficiency.

• Strong family history of myocardial infarction, stroke, peripheral arterial disease, venous thrombosis, or recurrent pulmonary embolism without other explanations. These indications, are especially relevant when dignosed in family members under 35 years of age.

• Other high risk groups include patients with renal failure or transplant patients, patients on diets for inborn errors of metabolism, or parents of children with neural tube defects. (Hyperhomocysteinemia secondary to subtle folate deficiency has been implicated as a possible mechanism for the development open neural tube defects in utero.)

*MTHFR genotyping is available to determine if the patient is at risk for elevated homocysteine levels.

REFERENCES:

Anderson JL, King GJ, Thomson MJ, Todd M, Bair TL, Muhlestein JB, Carlquist JF. A Mutation in the Methylenetetrahydrofolate Reductase Gene is Not Associated With Increased Risk for Coronary Artery Disease of Myocardial Infarction . JACC, 1997, 30(5):1205-11.

Mayer EL, Jacobsen DW, Robinson K. Homocysteine and Coronary Atherosclerosis . JACC, 1996, 27(3):517-27.

Miner SES, Evrovski J, Cole DEC. Clinical Chemistry and Molecular Biology of Homocysteine Metabolism: An Update. Clinical Biochemistry , 1997, 30(3):189-201.

Supported in part by: Project #MCJ-341007-01-0
Maternal & Child Health, Title V, Social Security Act
Health Resources/Service Administration
Department of Health and Human Services