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Hyperhomocysteinemia is a medical condition characterized by an abnormally high level of homocysteine in the blood, conventionally described as greater than 15 μmol / L.
As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies of vitamin B6, folic acid (vitamin B9) and vitamin B12 can lead to high levels of homocysteine.
Hyperhomocysteinemia is usually treated with supplements of vitamin B6, vitamin B9, and vitamin B12. Supplements of these vitamins; however, do not change the results.
Signs and symptoms
Elevated levels of homocysteine have been associated with a series of disease states.
Cardiovascular risks:
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 diseases and renal dysfunction.
Homocysteine degrades and inhibits the formation of the three main structural components of the arteries: collagen, elastin and proteoglycans.
In proteins, homocysteine permanently degrades cysteine disulfide bridges and lysine amino acid residues, affecting structure and function.
Neuropsychiatric disease:
There is evidence linking high levels of homocysteine and Alzheimer’s disease. There is also evidence that elevated homocysteine levels and low levels of vitamin B6 and B12 are risk factors for mild cognitive impairment and dementia.
Oxidative stress induced by homocysteine may also play a role in schizophrenia.
Bone health:
Elevated homocysteine levels have also been linked to an increase in fractures in the elderly.
Homocysteine is automatically oxidized and reacts with reactive oxygen intermediates, damaging endothelial cells and increasing the risk of thrombus formation.
Causes
Deficiencies of vitamins B6, B9 and B12 can lead to high levels of homocysteine. Vitamin B12, or cobalamin, acts as a cofactor for the enzyme methionine synthase (which is part of the biosynthesis and regeneration cycle of S-adenosylmethionine).
Deficiency of vitamin B12 prevents the 5-methyltetrahydrofolate (5-MTHF) form of folate from becoming THF due to the “methyl trap”. This alters the folate pathway and leads to an increase in homocysteine that damages the cells (for example, damage to endothelial cells may cause an increased risk of thrombosis).
Chronic alcohol consumption can also cause an increase in plasma levels of homocysteine.
Genetics:
Homocysteine is a non-protein amino acid, synthesized from methionine and recycled back into methionine or converted into cysteine with the help of group B vitamins.
Approximately 50% of homocysteine is converted back to methionine by remethylation through the main methionine synthase pathway. This requires active folate and vitamin B12 to donate a methyl group. Active folate is known as 5-methyltetrahydrofolate (5-MTHF).
There is also another route for the conversion of homocysteine to methionine, which involves methylation with trimethylglycine (also called betaine or abbreviated to TMG) as a methyl donor. The remaining homocysteine is transulfurized to cysteine, with vitamin B6 as a cofactor.
Genetic defects in 5-MTHF reductase can cause hyperhomocysteinemia.
The most common polymorphisms are known as MTHFR C677T and MTR A2756G. These polymorphisms occur in approximately 10% of the world population. Elevations of homocysteine can also occur in the rare hereditary disease homocystinuria.
Treatment
The supplements of vitamins B6, B9 or B12, although they reduce the homocysteine level, do not modify the risk of heart disease, stroke or death. This also applies to people with kidney disease on dialysis.
Hypotheses have been offered to address the failure of homocysteine reduction therapies to reduce cardiovascular events. When folic acid is given as a supplement, it can increase the buildup of arterial plaque.
A second hypothesis involves the methylation of genes in vascular cells by folic acid and vitamin B12, which can also accelerate plaque growth. Finally, altered methylation can catalyze l-arginine in asymmetric dimethylarginine, which is known to increase the risk of vascular disease.
