This article includes discussion of hyperhomocysteinemia, hyperhomocystinemia, homocysteinemia, homocystinemia, hereditary homocystinuria, and homocysteine elevation. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
In this article, the author discusses hyperhomocysteinemia and review developments in the understanding of its relationship with cerebrovascular disease and dementia. Although folic acid, vitamin B12, and vitamin B6 lower homocysteine levels, many recent randomized, controlled trials suggest that treatment with these vitamins does not clearly lower the risk of vascular disease.
• Severe hyperhomocysteinemia is associated with arterial and venous vascular disease.
• Many observational studies suggest mildly elevated homocysteine levels appear to be associated with an increased risk of ischemic stroke and dementia.
• Despite the observational studies, the results of several randomized, controlled clinical trials have not demonstrated risk reduction of stroke or dementia with the administration of homocysteine-lowering B vitamins.
Historical note and terminology
Hyperhomocysteinemia is defined as elevation of plasma total concentration of homocysteine and disulfide adducts of homocysteine collectively termed "homocyst(e)ine" or "total homocysteine." The hypothesis that hyperhomocysteinemia is a risk factor for vascular disease was proposed in 1969 by McCully, who observed advanced arteriosclerosis in children with rare inherited disorders causing markedly elevated levels of total plasma homocysteine (McCully 1969). There has been a resurgence of interest in hyperhomocysteinemia because of the recognition that even moderately elevated concentrations of total plasma homocysteine are associated with increased risk of stroke, cardiovascular disease, and venous thrombosis (den Heijer et al 1998; Sacco et al 1998; Eikelboom et al 1999).
Categorizing homocysteine levels into severe, moderate, and normal ranges is useful. Severe hyperhomocysteinemia is defined as a fasting total plasma homocysteine concentration greater than 100 µM. Moderate hyperhomocysteinemia is defined as a fasting total plasma homocysteine concentration between 15 µM and 100 µM. Growing clinical evidence suggests that total plasma homocysteine concentrations in the "high-normal" range, ie, between 10 µM and 15 µM, also may be associated with increased risk of vascular disease (Jacobsen 1996). Mean fasting concentrations of total plasma homocysteine are usually less than or equal to 10 µM, with the 95th percentile at approximately 15 µM.
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