Journal of Vascular Nursing
Volume 21, Issue 1 , Pages 30-32, March 2003

Hyperhomocysteinemia and vascular disease☆☆☆

Section of Vascular Surgery, Washington Hospital Center, Washington, District of Columbia

Article Outline

Abstract 

J Vasc Nurs 2003;21:30-2.

 

The leading cause of morbidity and mortality in the United States is cardiovascular disease as a result of atherosclerosis.1 Hyperhomocysteinemia has been demonstrated in patients with peripheral, cerebrovascular, and coronary artery disease,2 and is now considered an independent risk factor for atherosclerosis, particularly in premature atherosclerosis (before age 50 years).3

Discovered first in 1932,4 homocysteine is a sulfur-containing amino acid intermediate that is formed during the metabolism of methionine, an essential amino acid derived from dietary protein.5 Plasma homocysteine is found in the liver, muscle, and other tissues, and is metabolized by the enzyme cystathionine B-synthase to cysteine (broken further down to glutathionine and sulfate) or remethylated to methionine. The cystathionine B-synthase activity is dependent on vitamin B6, whereas the remethlation of homocysteine is dependent on both vitamin B12 and folate.6

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Mechanism of vascular disease 

Homocysteine-related dysfunction of the endothelium may be involved with the initiation and progression of atherogenesis, thrombosis, or both. Four theories currently exist concerning the effects of hyperhomocysteinemia; that it: (1) is toxic to endothelial cells, (2) stimulates smooth muscle cell proliferation, (3) is a thrombogenic agent and (4) promotes platelet aggregation. Homocysteine undergoes auto-oxidation in the plasma, whereby superoxide and hydrogen peroxide are formed that are toxic to the endothelium. Superoxide is thought to initiate lipid peroxidation at the endothelial cell surface and may contribute to oxidation of low-density lipoproteins. Thus, homocysteine may cause endothelial damage and proliferation of smooth muscle cells into the intimal wall of the artery and lipid accumulation in the arterial wall.

Vasomotor function is affected by hyperhomocysteinemia in the absence of structural vascular disease.5, 7 Researchers7 studied healthy, middle-aged adults and noted diminished endothelium-dependent vasodilation of the brachial artery in patients with hyperhomocysteinemia in response to hyperemia and nitroglycerin. Also, endothelial injury may lead to impaired release of nitric oxide, adversely affecting the relationship between the vessel wall, platelets, and macrophages.7, 8, 9, 10

Homocysteine promotes coagulation by increasing Factor V and Factor XI activity, while depressing protein C activation and increasing the binding of lipoprotein (a) in fibrin.4 Homocysteine may also inhibit heparin sulfate and thrombomodulin expression and cause platelets to aggregate. These processes increase thrombin formation and increase the propensity for thrombosis.11

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Factors influencing homocysteine 

Genetic deficiencies of the enzymes necessary for homocysteine metabolism (cystathionine B-synthase and 5, 10-methyltetrahydrofolate) cause hyperhomocysteinemia. In those patients without these enzyme deficiencies, increases in plasma homocysteinemia with age are likely related to the deficiencies of folate and vitamins B6 and B12, and deteriorating renal function,12 because normal renal function is necessary to eliminate homocysteinemia. Bostom13 found that in patients with hyperhomocysteinemia (> 13.9 μmol/L) at least 75% had end-staged renal disease. Other researchers14 have attributed elevations in homocysteine in smokers to their decreased levels of B6, B12, and folate caused by the smoking. An additional factor influencing homocysteine is liver disease from alcohol abuse, which has been shown to impair methionine metabolism causing hyperhomocysteinemia.15

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Diagnosis 

The assay of total homocysteine (μmol/L) includes homocysteine, mixed disulfides, homocysteine thiolactone, free homocysteine, and protein-bound homocysteine, where normal levels of total homocysteine are 5 to 15 μmol/L. The plasma homocysteine levels should be correlated with assays of the folic acid, and vitamin B6 and B12 levels to determine if an increase in homocysteine is related to a deficiency in these vitamins.4 Patients should have a washout period of at least 2 weeks before having their homocysteine level drawn if they have been taking vitamin supplementation or 1 month if they have been taking any of the following medications: methotrexate, estrogen supplements, anticonvulsants, or penicillamine. Estrogen may play a part in homocysteine regulation because homocysteine levels increase to a point at or near that of men after menopause.16

Hyperhomocysteinemia should be suspected in patients who present with premature atherosclerosis, especially in individuals who do not have the traditional risk factors for atherosclerosis such as smoking, hypertension, diabetes mellitus, or hyperlipidemia.14 Also, homocysteine levels should be considered in patients with asymptomatic atherosclerosis and carotid intimal wall thickening.17, 18

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Management 

Many patients with hyperhomocysteinemia can benefit from the combined vitamin supplementation of vitamins B6, B12, and folate, which significantly lowers homocysteine levels in patients with both normal and impaired renal function.14, 19, 20 Folate doses of 1 to 5 mg daily can normalize plasma homocysteine concentrations5 and has shown a greater reduction of homocysteinemia in women than men, and in patients aged less than 65 years than those aged more than 65 years.18 Recommended doses of vitamin B12 (cyanocobalamin) are 25 to 100 mcq and vitamin B6 (pyridoxine) are 5 to 10 mg by mouth daily. Smoking cessation is also recommended as a means of lowering homocysteine levels because of the associated lower levels of B6, B12, and folate that cause hyperhomocysteinemia.6

Hyperhomocysteinemia in patients with renal failure may be attributed to the decreased glomerular filtration rate and depressed tubular uptake of homocysteine.21 Thus, patients with end-stage renal disease generally require higher doses of folate (5-10 mg/day) supplementation to lower their homocysteine levels. New research has demonstrated that N-acetlycysteine taken orally (600 mg) can lower homocysteine levels by unbinding the protein-bound homocysteine, which improves its potential for metabolism.22

Normalization of homocysteine usually occurs 4 to 6 weeks after initiation of therapy, however, can occur in as little as 2 weeks. Side effects of vitamin supplementation include sensory neuropathy associated with doses of B6 (pyridoxine) greater than 500 mg/day. Patients on dialysis have reported nausea, headache, and vivid dreams when receiving folic acid supplementation.23

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Conclusion 

Preventing or limiting the affects of atherosclerosis will prolong life, prevent disability, and decrease health care costs. Because hyperhomocysteinemia is an independent risk factor in the development of atherosclerosis and is found in patients with peripheral, cerebrovascular, and coronary artery disease, establishing the magnitude of vascular disease risk associated with hyperhomocysteinemia may modify the current approaches to vascular disease prevention. Vitamin supplementation, in addition to standard risk factor management, is an inexpensive, low-risk therapy that may decrease atherosclerotic disease progression during time. However, more research is needed to determine whether hyperhomocysteinemia is a contributing cause or the result of the atherosclerotic process.24 Further longitudinal research on the effects of hyperhomocysteinemia on vascular disease expression needs to be done to evaluate whether normalizing high homocysteine concentrations with folic acid, N-acetlycysteine, and vitamin B6 and B12 supplementation will improve cardiovascular morbidity and mortality.

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References 

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☆ Address reprint requests to Debra Kohlman-Trigoboff, ACNP, CVN, Washington Hospital Center, Section of Vascular Surgery, 110 Irving St, NW NA-1041, Washington, DC 20010.

☆☆ 1062-0303/2003/$30.00 + 0

PII: S1062-0303(02)74501-9

doi:10.1067/mvn.2003.1

Journal of Vascular Nursing
Volume 21, Issue 1 , Pages 30-32, March 2003

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