Homocysteine (Hcy)

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Subject: Homocysteine (Hcy)

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Definition

  • Total Hcy is a thiol-containing amino acid, produced by the intracellular demethylation of methionine to cysteine. Elevated tHcy has primary atherogenic and prothrombotic properties. Elevations in plasma homocysteine may be the result of genetic defects; nutritional deficiencies of vitamin B6 (pyridoxine), vitamin B12, and folic acid; some chronic medical conditions such as chronic renal insufficiency; and certain drugs. The most common form of genetic hyperhomocysteinemia results from the production of a thermolabile variant of methylene tetrahydrofolate reductase (MTHFR). Homozygosity for this form of MTHFR is a relatively common cause of elevated total Hcy (tHcy) in the general population (5–14%). Highly elevated levels of tHcy are found in patients with homocystinuria (hyperhomocysteinemia), a rare genetic disorder of enzymes involved in homocysteine metabolism. These patients exhibit arterial and venous thromboembolism, severe early arteriosclerosis, mental retardation, osteoporosis, and ocular abnormalities. Moderately elevated levels of tHcy are associated with less severe genetic defects. Moderate hyperhomocysteinemia is an independent risk factor for venous and arterial thromboembolism but less profound than other well-established risk factors. Because of that, population screening for total Hcy level is not recommended.

  • Normal range: 5.0–15 μmol/L.

Use

  • Elevated levels of tHcy may be used to exclude or confirm deficiencies of vitamin B12 or folate.

    • It is recommended to test in patients using medications that interfere with folate status (methotrexate, antiepileptics), vegetarians without B12 supplementation, unexplained anemia, peripheral neuropathy or myleopathy, recurrent spontaneous abortions or infertility.

    • Testing also recommended for patients 40 years of age with coronary artery disease to exclude homocystinuria.

  • Elevations in tHcy levels have also been used as an independent risk factor of coronary or cerebral vascular disease. Treatment of moderate hyperhomocystinemia with folic acid supplementation for primary and secondary cardiovascular protection has met with inconsistent results and at present cannot be routinely recommended.

Interpretation

  • Hyperhomocystinemia has been classified as follows:

    • Moderate: 15–30 μmol/L

    • Intermediate: 30–100 μmol/L

    • Severe: >100 μmol/L

Increased In

  • Vitamin B12, vitamin B6, or folate deficiency

  • Hypothyroidism

  • Chronic renal failure

  • Coronary heart disease

Decreased In

  • Down syndrome

  • Pregnancy

  • Hyperthyroidism

  • Early diabetes

Limitations

  • The plasma (or serum) must be separated immediately on collection to avoid continuous synthesis of Hcy by red cells.

  • Samples must be immediately stored on ice and serum centrifuged immediately, before a complete clot is formed, to prevent erroneous results due to the presence of fibrin.

  • Certain drugs, such as anticonvulsants, methotrexate, or nitrous oxide, may interfere with the assay.

  • Cigarette smoking and coffee consumption increase tHcy levels.

  • Intraindividual variability is approximately 8%; it can be as much as 25% in patients with hyperhomocystinemia.

  • Generally, a single measurement of tHcy is considered adequate.

Suggested Readings

Clarke  R, Daly  L, Robinson  K Hyperhomocysteinemia: An independent risk factor for vascular disease. N Engl J Med.  1991;324:1149–1155.
Kluijtmans  LA, Young  IS, Boreham  CA Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults. Blood.  2003;101:2483–2488.
Refsum  H, Smith  AD, Ueland  PM Facts and recommendations about total homocysteine determinations: An expert opinion. Clin Chem.  2004;50:3–32.
Wierzbodi  AS. Homocysteine and cardiovascular disease: A review of the evidence. Diab Vasc Dis.  2007;4:143–149.
 
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