Hyperhomocysteinemia

Signs and symptoms

Elevated levels of homocysteine have been associated with a number of disease states: more than 100 adverse outcomes have been identified.

Cardiovascular risks

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.

Neuropsychiatric illness

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.

Bone health

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.

Ectopia lentis

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.

Possible causes

B-enzyme deficiencies

A number of factors have been considered as causes of high homocysteine levels. Deficiencies of vitamins B6, B9 and B12 have been implicated. Vitamin B12 is a cofactor for the enzyme methionine synthase, which participates in the biosynthesis of S-adenosylmethionine (SAM). Vitamin B12 deficiency prevents the 5-methyltetrahydrofolate (5-MTHF) form of folate from being converted into THF due to the "methyl trap". 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).

Alcohol

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

Tobacco

Smokeless tobacco may be a risk factor for hyperhomocysteinemia.

Genetic

Genetic defects in 5-MTHF reductase can 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.

Diagnosis

A blood test can be performed to quantify total homocysteine concentration in the plasma, of which approximately 80% is generally protein-bound. Classification of hyperhomocysteinemia is defined with respect to serum concentration as follows:

• Moderate: 15–30 nmol/mL (or μmol/L)
• Intermediate: 30–100 nmol/mL
• Severe: 100 nmol/mL If total homocysteine concentration is not found to be elevated, but clinical suspicion is still high, an oral methionine loading challenge several hours prior to quantification of homocysteine concentration may be used to increased sensitivity for marginal abnormalities of homocysteine metabolism. Fasting for 10 hours is sometimes recommended prior to measurement of homocysteine levels, but this may not be necessary for diagnostic yield.

Treatment

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.

References

References

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