What is homocysteine?

Homocysteine: Definition and Clinical Significance

Homocysteine is a sulfur-containing amino acid that is a metabolite of methionine, with elevated levels (>15 μmol/L) being an independent risk factor for cardiovascular disease, stroke, and cognitive disorders. 1, 2

Biochemical Structure and Metabolism

Homocysteine exists in several forms in the body:

• Free homocysteine (contains a sulfhydryl group)
• Homocystine (homocysteine-homocysteine disulfide)
• Homocysteine-cysteine disulfide
• Protein-bound homocysteine (approximately 70% of total) 1

Homocysteine is metabolized through two main pathways:

1. Remethylation pathway: Converts homocysteine back to methionine using:

   • Folate (vitamin B9)
   • Vitamin B12 (cobalamin)
   • Methylenetetrahydrofolate reductase (MTHFR) enzyme

2. Transsulfuration pathway: Converts homocysteine to cysteine using:

   • Vitamin B6 (pyridoxine)
   • Cystathionine β-synthase (CBS) enzyme 3, 4

Clinical Significance and Classification

Homocysteine levels are classified as:

• Normal: 5-15 μmol/L
• Moderate hyperhomocysteinemia: 15-30 μmol/L
• Intermediate hyperhomocysteinemia: 30-100 μmol/L
• Severe hyperhomocysteinemia: >100 μmol/L 2, 5

Causes of Elevated Homocysteine

1. Genetic factors:

   • Cystathionine β-synthase (CBS) deficiency
   • Methylenetetrahydrofolate reductase (MTHFR) mutations (particularly C677T)
   • Methionine synthase defects 4, 6

2. Nutritional deficiencies:

   • Folate deficiency
   • Vitamin B12 deficiency
   • Vitamin B6 deficiency 7, 6

3. Other factors:

   • Chronic kidney disease (85-100% of hemodialysis patients have hyperhomocysteinemia)
   • Advanced age
   • Smoking
   • High animal protein diet 2, 6

Clinical Implications

Elevated homocysteine is associated with:

• Cardiovascular disease: Independent risk factor for coronary artery disease
• Cerebrovascular disease: Increased risk of stroke
• Venous thrombosis: Both arterial and venous thrombotic events
• Cognitive disorders: From mild cognitive decline to Alzheimer's disease
• Pregnancy complications: Neural tube defects 2, 3, 7

Measurement Considerations

Measuring total plasma homocysteine (tHcy) requires:

• Precise sample collection
• Immediate placement of blood samples on ice
• Centrifugation and plasma freezing within 30 minutes of collection
• Specialized laboratory analysis using HPLC or GC-MS techniques 1

Management Approach

For patients with elevated homocysteine:

1. Identify and treat underlying causes
2. Nutritional supplementation:
   • Folate: 0.4-1 mg/day (normal), 1-5 mg/day (CKD)
   • Vitamin B12: 0.5 mg daily (provides additional 7% reduction)
   • Vitamin B6 supplementation 2
3. Lifestyle modifications:
   • Smoking cessation
   • Diet modifications 2

Important Caveats

• Despite the effectiveness of B-vitamin supplementation in reducing homocysteine levels, multiple randomized controlled trials have failed to demonstrate that lowering homocysteine reduces cardiovascular events or mortality 2
• Inappropriate supplementation without identifying the cause can be harmful 1
• Patients with MTHFR 677TT genotype may benefit from 5-methyltetrahydrofolate (5-MTHF) instead of folic acid 2