What causes elevated homocysteine (homocysteine) levels in the blood?

Causes of High Levels of Homocysteine

Elevated homocysteine levels (hyperhomocysteinemia) are primarily caused by genetic enzyme deficiencies, nutritional deficiencies of B vitamins, and various medical conditions that affect homocysteine metabolism. 1

Genetic Causes

• Cystathionine β-synthase (CBS) deficiency

  • Most common cause of severe hyperhomocysteinemia (homocystinuria)
  • Enzyme involved in the transsulfuration pathway 1

• Methylenetetrahydrofolate reductase (MTHFR) deficiency

  • Common thermolabile variant (677C→T) found in 30-40% of the population (heterozygous) and 10-15% (homozygous)
  • Homozygosity increases risk for hyperhomocysteinemia but accounts for only about one-third of cases 1

• Defects in cobalamin (vitamin B12) cofactor synthesis 1

Nutritional Deficiencies

• Folate (vitamin B9) deficiency

  • Most important nutritional cause of elevated homocysteine
  • Essential for homocysteine metabolism via the remethylation pathway 1, 2

• Vitamin B12 (cobalamin) deficiency

  • Cofactor for methionine synthase in the remethylation pathway 1

• Vitamin B6 (pyridoxine) deficiency

  • Cofactor for cystathionine β-synthase in the transsulfuration pathway 1

Medical Conditions

• Renal failure/impairment

  • Decreased renal clearance of homocysteine contributes to hyperhomocysteinemia 1
  • Even with folic acid treatment, hyperhomocysteinemia often persists in these patients 3

• Age-related factors

  • Elderly individuals often have impaired homocysteine metabolism 2

Lifestyle and Dietary Factors

• High methionine intake

  • Methionine-rich diet can increase homocysteine levels 3, 2

• Tea and coffee consumption

  • Can increase homocysteine concentrations by up to 20% 2

• High-protein meals

  • Can cause transient increases in homocysteine levels 2

Medication Effects

• Certain drugs
  • Some medications can interfere with homocysteine metabolism 3, 4

Clinical Significance

Hyperhomocysteinemia is defined as a fasting total plasma homocysteine (tHcy) level >15 μmol/L, with graded increased risks even at levels between 10-15 μmol/L 1. It is associated with:

• Increased risk of atherosclerotic vascular disease (2-3 fold)
• Venous thrombosis
• Coronary, cerebral, and peripheral vascular disease
• Increased carotid intima-media thickness and stenosis 1

Diagnostic Considerations

When evaluating elevated homocysteine levels:

• Precise sample collection is critical (blood samples must be placed on ice immediately)
• Plasma should be separated and frozen within 30 minutes of collection
• Testing requires specialized laboratory methods 1

Treatment Approach

Treatment should target the underlying cause:

• CBS deficiency: pyridoxine with additional folic acid and betaine if necessary
• Folic acid and vitamin B12 deficiencies: appropriate supplementation
• Primary hyperhomocysteinemia: folic acid (0.5-5 mg/day)
• Post-methionine loading hyperhomocysteinemia: combination of pyridoxine and folic acid 3

In renal failure, folic acid treatment (1-5 mg/day) can help but may not normalize levels completely 3.