What is Homocysteine
Homocysteine is a sulfur-containing amino acid produced as an intermediate metabolite during the breakdown of methionine, an essential amino acid, and its metabolism requires vitamins B6, B12, and folic acid as essential cofactors. 1
Biochemical Origin and Metabolism
Homocysteine is not obtained from dietary sources but is synthesized endogenously through a specific metabolic pathway 2, 3:
Production pathway: Homocysteine is generated when S-adenosyl-methionine (SAM)—the body's universal methyl donor—undergoes methylation reactions, producing S-adenosyl-homocysteine (SAH), which is then hydrolyzed to homocysteine 1
Remethylation pathway: Under conditions of methionine deficiency, homocysteine is converted back to methionine by methionine synthase (MS), which requires vitamin B12 as a cofactor and 5-methyltetrahydrofolate (5-MTHF) as a substrate 1
Transsulfuration pathway: When methionine is abundant, homocysteine is metabolized to cystathionine and then cysteine via cystathionine β-synthase (CBS), which requires vitamin B6 as an essential cofactor 1
Renal clearance: A portion of homocysteine is eliminated through the kidneys 4, 5
Normal Reference Values
Normal plasma homocysteine levels are widely accepted as <15 μmol/L, though optimal levels in healthy adults with good B-vitamin status are <12 μmol/L. 1
The classification system for elevated levels 1:
- Moderate hyperhomocysteinemia: 15-30 μmol/L
- Intermediate hyperhomocysteinemia: 30-100 μmol/L
- Severe hyperhomocysteinemia: >100 μmol/L
Adults without folic acid fortification typically have upper reference limits of 15-20 μmol/L 1
Causes of Elevated Homocysteine
The three primary nutritional causes are deficiencies in folic acid, vitamin B12, and vitamin B6, as these vitamins serve as essential cofactors in homocysteine metabolism. 2, 3, 5
Additional causes include 1, 6, 3:
- Genetic defects: Mutations in cystathionine β-synthase (CBS) or methylenetetrahydrofolate reductase (MTHFR), particularly the C677T variant
- Chronic renal failure: Decreased renal clearance leads to accumulation 1, 4
- Hypothyroidism 6
- Certain medications 6
Clinical Significance
Elevated homocysteine is associated with a 2- to 3-fold increased risk for atherosclerotic vascular disease, including stroke, coronary artery disease, and venous thromboembolism. 1, 6
The cardiovascular risk is quantifiable 1, 6:
- Each 5 μmol/L increase in homocysteine raises stroke risk by 59% (95% CI, 29-96%)
- Each 3 μmol/L decrease reduces stroke risk by 24% (95% CI, 15-33%)
- A 5 μmol/L increment confers coronary artery disease risk equivalent to a 20 mg/dL increase in cholesterol
Beyond cardiovascular disease, elevated homocysteine is associated with neurodegenerative disorders (including Alzheimer's disease and vascular dementia), pregnancy complications, osteoporosis, and venous thrombosis 2, 3, 5
Pathophysiological Mechanisms
Homocysteine causes vascular damage through multiple mechanisms, primarily oxidative stress and endothelial dysfunction. 1
Key mechanisms include 1:
- Oxidative stress: Self-oxidation of homocysteine to homocystine generates reactive oxygen species (ROS), and homocysteine induces NADPH oxidase activity, increasing superoxide radical production
- Endothelial dysfunction: Uncoupled endothelial nitric oxide synthase (eNOS) becomes a source of superoxide radicals instead of nitric oxide, leading to low NO bioavailability
- Inflammatory activation: The pro-oxidative state activates nuclear factor-kappa B (NF-κB), triggering expression of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1, promoting atherogenesis 1
Critical Testing Considerations
Blood samples for homocysteine measurement must be placed on ice immediately after collection and centrifuged with plasma separation within 30 minutes to prevent falsely elevated results from erythrocyte release. 7, 6
The patient must fast for at least 8 hours before testing 7, 6