O.K., time to go back to Biochem 101. Remember all those proteins, metabolic pathways, enzymes, and cofactors you had to memorize first year in medical school? Probably not. However, it turns out that some of that information may actually be useful in its application to causes and prevention of atherosclerotic vascular disease. One of those proteins, homocysteine, is coming under increasing study in its relationship to vascular disease. It may help explain the presence of vascular disease in patients without other obvious risk factors.
In the late 1960's a researcher studying two children with extensive arterial thrombosis and atherosclerosis, found elevated levels of homocysteine in their plasma and urine. He postulated that hyperhomocysteinemia might be a causative factor for atherosclerosis. This information went largely unnoticed for many years. However, there is now increasing information that would support this theory and homocysteine has become one of the new buzz words in the field of vascular disease in the past few years.

Homocysteine is an intermediate protein involved in the conversion of the amino acid methionine to cysteine and in the remethylation of homocysteine to form methionine (see figure 1). Folic acid (folate) is a major substrate in the process and some of the key enzymes in the pathways have vitamin B6 or vitamin B12 as cofactors. There exist, therefore, several potential sites for metabolic disorders to arise with the net effect of resulting in elevated levels of homocysteine in the blood.

The children studied in the late 60's most likely had a very rare homozygous form of cystathionine beta-synthase deficiency. However, the heterozygous form of this disease can also lead to hyperhomocysteinemia and may be present in up to 1% of the general population. A thermolabile variant of methylenetetrahydrofolate reductase deficiency may be present in up to 13% of the population. There are also many other potential causes of hyperhomocysteinemia. All in all, increased homocysteine levels are seen in 5-7% of the general population.

Elevated homocysteine levels in the blood have been shown experimentally to produce endothelial injury primarily through oxidation type reactions. It has also been shown to promote platelet accumulation in areas of endothelial injury. Other studies have shown homocysteine to enhance factors VII and VI activity, increase synthesis of thromboxane B2 and platelet levels of thromboxane A2, depress protein C activation, and to block tPA binding to endothelial cells.

Epidemiologic studies have shown associations between hyperhomocysteinemia and cardiovascular disease, peripheral vascular disease, cerebrovascular disease, and venous thromboembolism. Studies are now underway to determine what influence lowering homocysteine levels will have on the incidence or progression of vascular disease.

Normal homocysteine levels fall in the range of 5-15 micromol/L. Age and gender specific "normals" have yet to be worked out though men tend to have higher levels than women and levels tend to increase slightly with age. Values of 15-30 are considered to be mildly elevated. Values greater than 100 represent severe elevation. Levels should generally be obtained fasting. If fasting levels are in the normal range in individuals thought to be at risk, hyperhomocysteinemia can be unmasked by an ingested methionine challenge.

The relationship of folic acid and the B vitamins to the metabolism of homocysteine can make for relatively simple treatment of hyperhomocysteinemia in many patients. Significant improvements in homocysteine levels can be accomplished using folate and sometimes vitamins B6 and B12 as well. In the absence of actual deficiencies of these vitamins, folate alone may be all that's necessary. Recommended doses of folate range from 1-5 mg/day depending on response. Response times to see reductions in plasma homocysteine levels can be 6-8 weeks so followup bloodwork should not be done any sooner than 8 weeks past initiation of treatment. Do not expect normalization of levels in renal failure patients or in those patients with severe key enzyme deficiencies. B12 levels should always be checked first before initiating treatment even with folate alone as B12 deficiencies can be masked. B6 supplementation is usually in the range of 50-100 mg/day. B6 is very plentiful in many common food sources but 10-50% can be lost in food processing and storage procedures.

Should all patients with vascular disease be tested for hyperhomocysteinemia? Probably not. Average cost for a homocysteine level is currently around $140. However, for those patients with premature atherosclerosis, atherosclerosis in the absence of other known risk factors, or with unexplained thromboembolic events, testing is certainly appropriate. Whether or not treatment of hyperhomocysteinemia will result in prevention of further disease or thromboembolic events is unproven as yet. Prospective studies are now underway to answer this. However, treatment is relatively easy and inexpensive and has the potential to make a major impact on public health.