Hyperhomocysteinemia

Hyperhomocysteinemia is a medical condition characterized by an abnormally high level of total homocysteine (that is, including homocystine and homocysteine cysteine disulfide) in the blood, conventionally described as above 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 homocysteine levels. Other possible causes of hyperhomocysteinemia include genetics, excessive methionine intake, and other diseases. Hyperhomocysteinemia is typically managed with vitamin B6, vitamin B9 and vitamin B12 supplementation. Hyperhomocysteinemia is a risk factor for cardiovascular disease; supplements of these vitamins may slightly reduce stroke outcome but not myocardial infarction, death from any cause or adverse events.

Elevated levels of homocysteine have been associated with a number of disease states.

Elevated homocysteine is a known risk factor for cardiovascular disease as well as 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.

Evidence exists linking elevated homocysteine levels with vascular dementia 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.

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.

Homocystinuria is the second most common cause of heritable ectopia lentis. Homocystinuria is an autosomal recessive metabolic disorder most often caused by a near absence of cystathionine b synthetase. It is associated with intellectual disability, osteoporosis, chest deformities, and increased risk of thrombotic episodes. Lens dislocation occurs in 90% of patients, and is thought to be due to decreased zonular integrity due to the enzymatic defect. Lens dislocation in homocystinuria is usually bilateral and in 60% of cases occurs in the inferior or nasal direction.

Deficiencies of vitamins B6, B9 and B12 can lead to high homocysteine levels. This disrupts the folate pathway and leads to an increase in homocysteine which damages cells (for example, damage to endothelial cells can result in increased risk of thrombosis).

Chronic consumption of alcohol may also result in increased plasma levels of homocysteine.

Smokeless tobacco is implicated as risk factor for hyperhomocysteinemia. Smoking also causes hyperhomocysteinemia

Homocysteine is a non protein amino acid, synthesized from methionine and either recycled back into methionine or converted into cysteine with the aid of the B group vitamins. 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. The homozigote mutation G;G also called C;C (it is equivalent) occurs in about 10% of the population of european ethnicity (white caucasians). Elevations of homocysteine can also occur in the rare hereditary disease homocystinuria.

Vitamins B6, B9, or B12 supplements (alone or combined) lower homocysteine level and might slightly reduce the risk of stroke but not of myocardial infarction compared to standard care or placebo in clinical trials.