• Diagnose homocystinuria, vitamin B₁₂ deficiency, and folate deficiency

• Assess risk of cardiovascular disease (CVD), stroke, and dementia (including Alzheimer disease)

• Monitor therapy in patients with elevated homocysteine levels

Severe hyperhomocysteinemia (>100 µmol/L) is generally caused by homocystinuria, an autosomal recessive inborn error of homocysteine metabolism (often involving cystathionine-β-synthase deficiency). While symptoms are often not apparent at birth, affected individuals may develop high myopia, ectopia lentis, marfanoid habitus, mental retardation, and thromboembolism. Early diagnosis and homocysteine-lowering therapy are important to minimize the effects of this metabolic disorder.

Mild or moderate homocysteine elevation can be caused by deficiencies of cobalamin (vitamin B₁₂), folate, and vitamin B₆ (essential cofactors in homocysteine metabolism); variations in the methylenetetrahydrofolate reductase (MTHFR) gene; and certain medications, among other factors. Vitamin B₁₂ deficiency can lead to irreversible neurologic damage, folate deficiency during pregnancy may cause neural tube defects, and either can cause megaloblastic anemia. Although folate and vitamin B₁₂ can be measured directly, homocysteine is a more accurate indicator of deficiency at the tissue level.¹ Used in combination with the methylmalonic acid (MMA) assay, homocysteine measurement can differentiate between folate and vitamin B₁₂ deficiency (see below). This can be crucial because folate supplementation can mask signs of vitamin B₁₂ deficiency (such as anemia), allowing neurodegenerative processes to continue. 

Modest elevation in plasma homocysteine has also been reported as a risk factor for atherosclerotic disease in coronary, cerebral, renal, and peripheral vessels,^2,3 and for arterial and venous thrombosis.³ The greater the homocysteine level, the greater the risk.² There appears to be an additive effect with hyperlipidemia⁴ and a synergistic interaction with hypertension and smoking,⁴ as well as factor V Leiden.⁵ In 2 recent meta-analyses, the predictive value of homocysteine level for CVD risk was lower than in earlier, individual reports.^6,7 Homocysteine concentrations predict the risk of mortality in patients with known coronary artery disease; mortality ratios across quartiles of homocysteine concentrations are 1.0 (<9.0 µmol/L), 1.9 (9.0-14.9 µmol/L), 2.8 (15.0-19.9 µmol/L), and 4.5 (≥20 µmol/L).⁸ Furthermore, homocysteine may be an independent predictor of stroke and dementia, including Alzheimer disease.⁹ In the Framingham study, involving primarily people of European descent, a 5 µmol/L increase in plasma homocysteine level was associated with a 40% increase in the 8-year risk of Alzheimer disease.⁹

Supplementation with folate, vitamin B₁₂, and vitamin B₆ can lower plasma homocysteine levels in some patients with mild or moderate homocysteinemia, but this has not yet been proven to reduce the risk of a first coronary event. However, B-vitamin supplementation may reduce the risk of restenosis after coronary angioplasty,¹⁰ improve endothelial function in patients with coronary heart disease,¹¹ and reduce the rate of subclinical atherosclerosis.¹² In individuals with elevated homocysteine levels, adequate folate intake should be ensured once vitamin B₁₂ deficiency is ruled out.¹³

• Individuals with clinical evidence of homocystinuria

• Elderly individuals with clinical evidence of reduced cobalamin and folate intake

• Individuals with early (<50 years of age) evidence of CVD

• Otherwise low-risk individuals with a family history of premature CVD

1 mL refrigerated serum; 0.5 mL minimum

Alternatively, submit 1 mL refrigerated plasma (sodium heparin [royal blue-top or green-top tube] or EDTA [lavender-top tube]).

Place specimen in refrigerator or ice bath after collection. Separate serum and plasma as soon as possible. Homocysteine levels increase ~10% for every hour the serum/plasma is not separated from the RBCs at room temperature.¹⁴ Once separated, serum and plasma are stable for 4 days at room temperature, 2 weeks at 2-8° C, and 6 months at -20° C.

• Competitive immunochemiluminometric assay (ICMA)

• Measures total homocysteine (ie, protein-bound, oxidized, and free, reduced homocysteine)

• Analytical sensitivity: 2.0 µmol/L

• Analytical specificity: does not cross-react with carbamazepine, phenytoin, 6-azauridine,
  anthopterin, adenosine, l-cysteine, or gluthathione; cross-reaction is 0.6% with S-adenosyl-l-methionine and 6.1% with cystathionine

• CPT code*: 83090

The following are some of the conditions associated with increased homocysteine levels: homocystinuria (cystathionine-β-synthase deficiency); vitamin B₁₂ (MMA increased) and folate deficiency (MMA not increased); CVD; chronic renal disease (typically 9-50 µmol/L); increasing age; male sex; MTHFR mutations; hypothyroidism; selected malignancies (eg, breast, ovarian, and pancreatic cancer); diets rich in methionine (high meat intake); cigarette smoking; and treatment with corticosteroids, methotrexate, nitrous oxide, cyclosporine, vitamin B₆ antagonists (isoniazid, azauridine, penicillamine, procarbazine), and anticonvulsants (phenytoin, carbamazepine).

Homocysteine levels are low (typically <9 µmol/L) in individuals who are pregnant (except in cases of fetal neural tube defect), <15 years of age, or taking oral contraceptives or hormone replacement therapy.

Treatment with S-adenosylmethionine may cause falsely elevated homocysteine levels, and human anti-mouse antibodies (HAMA) may also interfere with measurement.