Lexicon
Homocysteine
Definition
Homocysteine is a sulfhydryl-containing amino acid that is not acquired through the diet but is synthesized as an intermediate metabolite in the methionine cycle. [1] Hyperhomocysteinemia is well established as an independent risk factor for atherosclerotic vascular disease, including coronary artery disease, cerebrovascular disease, and peripheral arterial disease. [2] [3] In 1969, McCully first reported severe atherosclerotic lesions in patients with severe hyperhomocysteinemia and hypothesized a pathogenic link between hyperhomocysteinemia and atherogenesis. [4]
How it works
Homocysteine metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B12, and transsulfuration to cystathionine, which requires vitamin B6 as pyridoxal-5'-phosphate. [5] Elevated plasma homocysteine reduces nitric oxide bioavailability and promotes endothelial dysfunction through oxidative stress, endoplasmic reticulum stress, and chronic inflammatory and prothrombotic conditions. [6] The homozygous MTHFR C677T mutation reduces enzyme activity and is associated with higher homocysteine levels, while heterozygous carriers have mildly raised levels. [7] In cerebral small vessel disease research, homocysteine is classified among inflammatory markers reflecting vascular inflammation and endothelial dysfunction, a category showing relatively robust associations with small vessel disease, especially in stroke patients [8]
Connected concepts
How it's measured
Homocysteine is measured as total plasma homocysteine, and although measurement precision has improved over recent decades, universal guidelines for its determination remain lacking. [3] Plasma total homocysteine can serve as a second-line biomarker of vitamin B12 status, but it is less specific than methylmalonic acid. [9]
What levels mean
Plasma homocysteine is classified as normal between 5 and 15 μmol/L, slightly elevated from 15 to 30 μmol/L, moderate from 30 to 100 μmol/L, and severe hyperhomocysteinemia above 100 μmol/L. [1] Moderate hyperhomocysteinemia in the range of 15 to 30 μmol/L is only a modest predictor of cardiovascular risk, whereas thromboembolic manifestations are relatively frequent with intermediate or severe hyperhomocysteinemia above 30 μmol/L. [10] Every 5 μmol/L increase in blood homocysteine is linearly associated with about a 15% increase in the relative risk of Alzheimer-type dementia. [11] In cystathionine beta-synthase deficiency, keeping the plasma total homocysteine concentration below 100 μmol/L, and preferably below 120 μmol/L, is recommended to avoid serious complications.
Community knowledge
## Clinical Case Example
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- 1.Guieu R, Ruf J, Mottola G. Hyperhomocysteinemia and cardiovascular diseases. Ann Biol Clin (Paris) · 2022
- 2.Hashimoto T, Shinohara Y, Hasegawa H. [Homocysteine metabolism]. Yakugaku Zasshi · 2007
- 3.Maron BA, Loscalzo J. Homocysteine. Clin Lab Med · 2006
- 4.Cattaneo M. Hyperhomocysteinemia and thrombosis. Lipids · 2001
- 5.Selhub J. Homocysteine metabolism. Annu Rev Nutr · 1999
- 6.Lai WK, Kan MY. Homocysteine-Induced Endothelial Dysfunction. Ann Nutr Metab · 2015
- 7.
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