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Elevated levels of homocysteine have been associated with a number of disease states.
Elevated homocysteine is a known risk factor for cardiovascular disease and thrombosis. It has also been shown to be associated with microalbuminuria which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction. Homocysteine degrades and inhibits the formation of the three main structural components of arteries: collagen, elastin and proteoglycans. In proteins, homocysteine permanently degrades cysteine disulfide bridges and lysine amino acid residues, affecting structure and function.
Elevated levels of homocysteine have also been linked to increased fractures in elderly persons. Homocysteine auto-oxidizes and reacts with reactive oxygen intermediates, damaging endothelial cells and increasing the risk of thrombus formation.
A study on elderly Japanese individuals who had experienced a stroke found that folate and B12 reduce the incidence of osteoporotic hip fractures.
Deficiencies of the vitamins B6, B9 and B12 can lead to high homocysteine levels.
- About 50% of homocysteine is converted back to methionine by remethylation via the methionine synthase major pathway. This requires active folate and vitamin B12, in order to donate a methyl group. Active folate is known as 5-methyltetrahydrofolate (5-MTHF).
- Another pathway for the conversion of homocysteine back to methionine also exists, involving methylation with trimethylglycine (also called betaine or abbreviated to TMG) as a methyl donor.
- The remaining homocysteine is transsulfurated to cysteine, with vitamin B6 as the co-factor.
Genetic defects in 5-MTHF reductase can consequently lead to hyperhomocysteinemia. The most common polymorphisms are known as MTHFR C677T and MTR A2756G. These polymorphisms occur in about 10% of the world's population.
The best way to prevent hyperhomocysteinemia is to eat foods which contain B6, B12, folate, and taurine, such as potatos, greens, beans, and fish. The only natural sources of B12 are from animal products. It is also found in fortified breakfast cereals and enriched soy or rice milk. Supplementation with pyridoxine, folic acid, B12, or trimethylglycine (TMG or betaine) reduces the concentration of homocysteine in the bloodstream, as does taurine supplementation.
Individuals with hyperhomocysteinemia may benefit from dietary supplementation with vitamin B6, B12, and other nutrients. Individuals with the MTHFR C677T gene polymorphism' may not respond to supplementation with folic acid because their ability to convert folic acid into its active form is impaired, and so supplementation is recommended to occur with 5-methyltetrahydrofolate instead.
N-acetyl-cysteine (NAC) has shown the ability to significantly reduce homocysteine levels. It is believed that NAC displaces homocysteine from its protein carrier in the blood, promoting the formation of cysteine.
Vitamin supplements counter the deleterious effects of homocysteine on collagen. As they inefficiently absorb B12 from food, elderly persons may benefit from taking higher doses orally such as 100 µg/day (found in some multivitamins) or by intramuscular injection.
Effectiveness of treatment
In patients who already have major disease, reducing homocysteine levels may in fact have no effect on stroke risk, the risk of a heart attack, or thromboembolic events. One study found that in patients with diabetic nephropathy, lowering homocysteine with vitamin B was in fact associated with a doubling of cardiovascular complications (heart attack, stroke, death) and a deterioration in kidney function.
Hypotheses have been offered to address the failure of homocysteine-lowering therapies to reduce cardiovascular events. When folic acid is given as a supplement, it may increase the build-up of arterial plaque. A second hypothesis involves the methylation of genes in vascular cells by folic acid and vitamin B12, which may also accelerate plaque growth. Finally, altered methylation may catalyse l-arginine to asymmetric dimethylarginine, which is known to increase the risk of vascular disease.
Effectiveness of lowering homocysteine
Despite evidence suggesting links between elevated homocysteine and a range of conditions, several studies have found equivocal benefits in maintaining low homocystein levels. There is tentative but inconclusive evidence for congestive heart failure and bone health. However, the HOPE-2 study found a statistically significant 25% reduction in the risk of stroke.
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