Homocysteine: A risk factor of atherosclerosis

Nurse Practitioner, Apr 2000 by Bomalaski, Patricia Sullivan

More than 75 clinical and epidemiologic studies have shown a relationship between total homocysteine (tHcy) levels and coronary artery disease, peripheral arterial disease, stroke, or venous thrombosis.1 Studies in humans and animals demonstrate that homocysteine-induced atherosclerosis is characterized by substantial platelet accumulation and platelet-rich thrombus formation in areas of endothelial injury.2

Homocysteine is an intermediate amino acid in human tissue formed during the metabolism of methionine, an essential amino acid.3 The metabolic fate of tHcy may be influenced by alterations in the activities of enzymes and by serum concentrations of the B vitamins folate, pyridoxine (B6), and cobalamin (B12).4 The clinical observation linking elevated plasma tHcy concentrations with vascular disease was made by Khmer McCully, MD, who proposed the hypothesis of homocysteinemia and atherosclerotic vascular disease (ASVD).5

Hyperhomocysteinemia can be viewed as the first risk factor for atherosclerosis believed to exert its ef fects through a mechanism involving oxidative damage.2 Cholesterol and low-density lipid (LDL) cholesterol cause atherogenesis by carrying tHcy in the form of LDL-homocysteine aggregates. LDL-homocysteine aggregates are precursors of foam cells, cholesterol, and lipid deposits within developing plaques.5

An elevated plasma tHcy level is a risk factor for arterial occlusive diseases in about 13 % of patients with coronary heart disease, 35 % of patients with stroke, and 47% of patients with peripheral arterial ocelusive disease.6 Recent evidence linking moderately elevated tHcy levels to increased risk of coronary artery disease has focused attention on genetic and lifestyle determinants of tHcy levels. Recognized determinants of total plasma tHcy, such as sex and the functional state of enzymatic metabolism, are inherited, whereas age, Bl, or folate status, and renal function are acquired.7

Genetic enzyme deficiencies may more frequently account for elevated tHcy levels in patients with premature arterial disease. In the elderly, vitamin deficiencies may play a greater role.8

Some 10% of the coronary artery disease risk in the general population can be attributed to tHcy.' An increase of 5 mcmol/liter in the tHcy concentration increases the risk of coronary artery disease by 20 mg/dl in the cholesterol concentration.3 Drugs that can cause folate deficiency and may increase the tHcy level include folate antagonists such as methotrexate (used in the treatment of rheumatoid arthritis), trimethoprim (an antimicrobial), tamoxifen (an antiestrogen used in the treatment of breast cancer), and anticonvulsants (phenytoin).9 Differences in plasma tHcy levels in various populations can usually be attributed to one or more of these factors.

Laboratory Studies

Most clinical laboratories use highperformance liquid chromatography to measure a tHcy level. The cost of such assays are typically $45 to $100 per measurement. Normal fasting tHcy concentrations range from 5 to 15 mcmol/liter. Hyperhomocysteinemia has been classified as moderate at 15 to 30 mcmol/liter, as intermediate at greater than 30 to 100 mcmol/liter, and as severe at greater than 100 mcmol/liter.4 Other laboratory values measured are vitamin B 2 (normal range: 103 to 406 nmol/liter), folate (normal range: 5.4 to 16.3 nmol/liter), and vitamin B6 (normal range: 28.7 to 162 nmol/ liter) can be helpful in the diagnosis of clinically significant vitamin deficiency.4 It is customary to obtain measurements in the fasting state, similar to testing for total cholesterol.

Interventions

Vitamin supplements decrease or normalize tHcy concentrations in most cases.6 The strong epidemiologic and experimental evidence argues for treatment of hyperhomocysteinemia.6 Therapy with folic acid at doses of 400 mcg or more daily has been associated with a 30% to 42% decrease in tHcy levels.4

Patients at high risk for vascular disease or tHcy metabolism abnormalities should be screened for hyperhomocysteinemia.4 If hyperhomocysteinemia persists after vitamin B12 deficiency has been excluded and offending medications have been discontinued, folic acid supplementation of 400 mcg to 1 mg in addition to a multivitamin (without iron for males and postmenopausal females) that contains at least 400 mcg of folic acid and the U.S. recommended daily allowance of B6 and B12 may be initiated as primary therapy.

Homocysteine levels should be measured 6 to 8 weeks after initiation of tHcy-lowering therapy. If elevated levels persist despite therapy, the folic acid supplement dose may be increased to 2 mg per day and the tHcy level measured again after 6 to 8 additional weeks. Higher doses of folic acid, up to 5 mg per day, may be needed for patients with endstage renal disease or with continual folic acid loss caused by folate antagonist drugs.4

In a placebo-controlled study, a combination of multiple agents including folic acid (0.65 mg/day), vitamin B6 (10 mg/day), and vitamin B12 (0.4 mg/day) was effective in reducing tHcy levels in patients with moderate or intermediate hyperhomocysteinemia. However, increased vitamin intake from food sources (1 mg of folic acid, 12.2 mg of B6, and SO mcg of B12 per day) failed to maintain normal tHcy levels attained previously by vitamin supplements.10