EDTA sample. Should be sent to lab within 30 minutes of collection.
Homocysteine is a sulphur-containing amino acid derived from the essential amino acid, methionine. Two major biochemical pathways can metabolize homocysteine. When methionine is in excess, homocysteine is directed to the transsulfuration pathway, where it is irreversibly conjugated to serine by cystathionine beta- synthase (CBS) in a process requiring vitamin B6 as a cofactor. Under conditions of negative methionine balance, homocysteine is remethylated in a process requiring methionine synthase (MS), vitamin B12 and methyltetrahydrofolate. This pathway also requires an adequate supply of folate and the enzyme methylene tetrahydrofolate reductase (MTHFR). Genetic deficiencies of these enzymes or vitamin deficiencies can lead to elevated plasma homocysteine levels.
Hereditary homocystinuria is a genetic defect caused by a deficiency of one of the major enzymes (MTHFR, MS, or CBS) controlling homocysteine catabolism. It is a relatively rare disorder, occurring once in every 200,000 births. Affected individuals excrete large amounts of homocysteine in urine and have grossly elevated plasma levels of homocysteine, ranging from 50 to 500 umol/L. Patients with this disease have mental retardation, skeletal abnormalities, and early onset of atherosclerosis. They respond to treatment with vitamins: B6 and/or betaine for CBS deficiency; B12 for MS deficiency; folinic acid, betaine, and B12 for MTHFR deficiency.
Elevated homocysteine levels are too common in the general population to be caused by one of these rare enzyme defects. Up to 20% of elderly patients have homocysteine levels above 16 umol/L. Homocysteine elevation is caused by either heterozygous deficiency of CBS or MTHFR or from suboptimal intake of the three B-vitamins that serve as cofactors for the enzymes that metabolize homocysteine: folic acid, pyridoxine (B6) and cobalamin (B12). Inadequate dietary intakes of these nutrients can lead to “subclinical” vitamin deficiencies that can produce mild elevations in homocysteine levels. Anyone who is folate deficient probably has elevated homocysteine. One half of individuals with vitamin B6 levels below 70% of optimal, have homocysteine levels above 13 umol/L. The association between vitamin B12 deficiency and high homocysteine is not as strong. Until recently, these deficiencies were thought to be benign, but recent epidemiological studies have linked increased homocysteine levels with heightened risk for vascular disease.
Accumulating data from epidemiological studies suggests that individuals with even moderately elevated levels of homocysteine (fasting levels >16 umol/L) have small to moderate increased risks of cardiovascular disease. An elevated homocysteine level has been associated with upper and lower limb deep vein thrombosis, superior and inferior vena caval thrombosis, portal vein thrombosis, retinal vein and artery occlusion, and coronary artery disease. Most studies have demonstrated that persons with cardiovascular disease have 10-30% higher homocysteine levels than persons without cardiovascular disease. The relative risk for coronary heart disease has ranged between 1.3 and 30. Results from prospective studies have demonstrated a much weaker association between elevated homocysteine concentrations and cardiovascular disease. The relative risk has ranged between 0.9 and 4.5. The differences between epidemiological and prospective studies may suggest that homocysteine is predominantly a biomarker of atherosclerosis. Homocysteine rises with increasing cholesterol, systolic blood pressure and smoking. Another possibility is that elevated homocysteine is not a primary risk factor for atherosclerosis, but is a late stage predictor of clinical disease among patients with atherosclerosis.
|Causes of High Homocysteine|
• Cystathionine B-synthase
• Methionine synthase
• Methylenetetrahydrofolate reductase
• Vitamin B12
• Vitamin B6
|Increased methionine consumption|
• Increasing age
• Male gender
• Tobacco use
• Physical inactivity
|Chronic medical disorders
• Impaired renal function
• Malignant neoplasms
• Hyperproliferative disorders
• Severe psoriasis
• Diabetes mellitus
|Acute Phase Response Drugs
• Anticonvulsants (phenytoin, carbamazepine)
• Folate antagonists (methotrexate)
• Vitamin B12 antagonists (nitrous oxide)
• Vitamin B6 antagonists
• Chlosterol lowering (cholestyramine, colestipol, nicotinic acid)
• Thiazide diuretics
Homocysteine levels should be assessed in high-risk patients including those with thrombosis, hypothyroidism, impaired renal function, system lupus erythematosis or a significant family history of premature atherosclerosis.
Homocysteine can circulate in the plasma by itself, be oxidized to the disulfide homocystine (Hcy-Hcy), or bound to cysteine (Hcy-Cys). All three of these compounds may be partially protein bound. All of these species are converted to free homocysteine prior to measurement. The reported result represents the plasma total homocysteine concentration. Homocysteine exhibits diurnal variation with the highest levels occurring in the evening.
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