What Homocysteine Measures
Homocysteine is a sulfur-containing amino acid that serves as a metabolic marker of methionine metabolism and vitamin B status (B12, folate, B6), and functions as an independent risk factor for cardiovascular disease, stroke, and thromboembolism. 1, 2, 3
Biochemical Function and Metabolic Position
Homocysteine is a metabolite derived from the essential amino acid methionine and exists at a critical biochemical intersection in the methionine cycle between S-adenosylmethionine (the universal methyl donor) and vitamins B12 and folic acid. 1, 3, 4
The amino acid is obtained from dietary proteins including poultry, meat, eggs, seafood, and dairy products, with homocysteine representing an intermediate metabolite in this pathway. 5
Elevated homocysteine levels signal a breakdown in methylation processes, as increased homocysteine and S-adenosylhomocysteine lead to hypomethylation of DNA and proteins, rendering vascular structures and neurons more susceptible to damage. 4
What Abnormal Levels Indicate
Vitamin Deficiency States
Homocysteine is markedly elevated in patients with cobalamin (B12), folate, or vitamin B6 deficiency, and decreases only when treated with the deficient vitamin, making it valuable for diagnosis and follow-up of these deficiency states. 6
The test compensates for weaknesses of traditional laboratory tests for vitamin deficiencies, as significant deficiencies in these cofactors are commonly seen in elderly populations with resultant increases in homocysteine with advancing age. 4, 6
Cardiovascular and Thrombotic Risk
Elevated plasma homocysteine levels are associated with a 2- to 3-fold increased risk for atherosclerotic vascular disease, including stroke, with every 5 μmol/L increase in homocysteine conferring a 59% increase in stroke risk. 1, 7
An increment of 5 μmol/L in total homocysteine confers equivalent coronary artery disease risk to a 20 mg/dL increase in plasma cholesterol, and homocysteine accounts for up to 10% of the population's coronary artery disease risk. 7
Homocysteine testing is indicated in patients with venous thromboembolism as part of comprehensive thrombophilia workup, since hyperhomocysteinemia acts as an independent and additive risk factor for thrombosis. 2
Genetic and Enzymatic Defects
Increased plasma levels often result from genetic defects in enzymes involved in homocysteine metabolism, such as deficiencies of cystathionine-synthase and methylenetetrahydrofolate reductase (MTHFR), or the thermolabile MTHFR C677T variant. 1
Decreased renal clearance in patients with chronic renal failure may contribute to hyperhomocysteinemia, making it a marker of renal function as well. 1
Normal Values and Diagnostic Thresholds
Normal range for fasting homocysteine is 5-15 μmol/L, with hyperhomocysteinemia defined as >15 μmol/L. 2, 6
Moderate hyperhomocysteinemia (15-30 μmol/L) commonly indicates poor diet, mild vitamin deficiencies, heterozygosity for enzyme defects, hypothyroidism, impaired renal function, or certain medications. 2
Intermediate hyperhomocysteinemia (30-100 μmol/L) typically results from moderate/severe folate or B12 deficiency or renal failure, while severe hyperhomocysteinemia (>100 μmol/L) usually indicates severe cobalamin deficiency or homocystinuria. 2
Clinical Testing Requirements
Fasting for at least 8 hours is mandatory for accurate homocysteine results, as non-fasting samples may be falsely elevated. 2
Blood samples must be placed on ice immediately after collection and centrifuged with plasma separation within 30 minutes to prevent falsely elevated results from erythrocyte release of homocysteine. 2
Total homocysteine in whole blood increases at room temperature due to continuous production and release from blood cells, but artificial increase is minimal if centrifuged within 1 hour or placed on ice. 6
Specific Clinical Indications for Testing
Order homocysteine testing in patients with unexplained venous thrombosis, premature vascular disease (before age 55 in men or 65 in women), suspected vitamin deficiencies, or strong family history of thrombotic events. 2
Testing is indicated when elevated homocysteine would change management, particularly when evaluating for thrombophilia alongside Factor V Leiden or prothrombin 20210A testing. 2
Routine screening of asymptomatic individuals without personal or family history of thrombosis is not recommended, nor is universal screening before oral contraceptive use unless there is personal history of thromboembolism or strong family history. 2