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Homocysteine

Homocysteine is a sulfur-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

Enzyme deficiencies

  • Cystathionine B-synthase
  • Methionine synthase
  • Methylenetetrahydrofolate reductase
  • Folate
  • Vitamin B12
  • Vitamin B6
  • Increasing age
  • Male gender
  • Tobacco use
  • Physical inactivity
  • Postmenopausal
  • Impaired renal function
  • SLE
  • Malignant neoplasms
  • Hyperproliferative disorders
  • Severe psoriasis
  • Hypothyroidism
  • Diabetes mellitus
  • Transplantation

Vitamin deficiencies

  • Folate
  • Vitamin B12
  • Vitamin B6

Increased methionine consumption

Demographics

  • Increasing age
  • Male Gender
  • Tobacco use
  • Physical inactivity
  • Postmenopausal

Chronic medical disorders

  • Impaired renal function
  • SLE
  • Malignant neoplasms
  • Hyperproliferative disorders
  • Severe psoriasis
  • Hypothyroidism
  • Diabetes mellitus
  • Transplantation

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
  • Cyclosporine

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. The therapeutic goal for these patients is to reduce their homocysteine levels below 12 umol/L.

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. Reference range is 0 - 12 umol/L. Plasma homocysteine levels of 12 mmol/L or above are considered elevated.

Hcy Level

Interpretation

<12

Optimal

12-15

Borderline

16-30

Moderate elevation

>30

Significant elevation

Several caveats need to be considered when interpreting homocysteine levels:

  • Homocysteine exhibits diurnal variation with the highest levels occurring in the evening.
  • Homocysteine levels may increase 10% within 6 to 8 hours after a high protein meal.
  • Specimens drawn in the supine position are ~10% lower than those drawn sitting.
  • Homocysteine is released from red blood cells after venipuncture. Levels will increase at a rate of 1 umol/L per hour if the specimen is not stored on ice and centrifuged immediately.
  • After centrifugation, plasma samples are stable for >4 days at room temperature.
  • Homocysteine levels decrease during pregnancy to a mean concentration of 5 umol/L.
  • The within person variability during over one year is approximately 8% in a healthy person and 25% in patients with high Homocysteine levels.
  • A critical difference between serial samples is >25%.

Specimen requirement is one 5 mL lavender top tube of blood. Fasting is no longer considered necessary, since postprandial values do not differ significantly from fasting levels. The tube should be centrifuged immediately or placed in ice. Homocysteine measurements are stable up to 8 hours on specimens kept in ice and 2 hours at room temperature. Improper handling allows Hcy to leach out of red cells and falsely elevate plasma levels.

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