What causes elevated homocysteine (hyperhomocysteinemia) levels?

Causes of Elevated Homocysteine (Hyperhomocysteinemia)

Elevated homocysteine levels are primarily caused by genetic enzyme defects, nutritional deficiencies of folate, vitamin B12, and vitamin B6, renal dysfunction, hypothyroidism, and certain medications that interfere with homocysteine metabolism. 1, 2

Genetic Causes

• Cystathionine-beta-synthase (CBS) deficiency - A key enzyme in the transsulfuration pathway 3
• MTHFR gene variants - Particularly the C677T variant where cytosine is replaced by thymidine at position 677 2
  • Homozygous (TT genotype) - Found in 10-15% of the general population
  • Heterozygous (CT genotype) - Found in 30-40% of the population
• Other genetic defects in homocysteine metabolism:
  • Methionine synthase (MS) deficiency
  • Methionine synthase reductase deficiency
  • Effects in intracellular cobalamin metabolism 1

Nutritional Deficiencies

• Folate deficiency - Essential for homocysteine remethylation 1
• Vitamin B12 deficiency - Critical cofactor in homocysteine metabolism 1, 4
• Vitamin B6 deficiency - Required for the transsulfuration pathway 1
• Dietary patterns:
  • Vegetarian and vegan diets - Often associated with B12 deficiency (67% of vegans show B12 deficiency) 4
  • Poor diet quality - Insufficient intake of B vitamins 1

Medical Conditions

• Renal failure - 85-100% of dialysis patients have elevated homocysteine levels 2, 5
• Hypothyroidism - Affects homocysteine metabolism 1
• Classical homocystinuria - Inborn error of metabolism with dramatically increased homocysteine levels 1

Medications

• Drugs that interfere with folate metabolism:
  • Methotrexate
  • Phenytoin
  • Carbamazepine
• Drugs that affect B12 absorption:
  • Proton pump inhibitors
  • Metformin 3

Severity Classification

• Moderate hyperhomocysteinemia (15-30 μmol/L):

  • Poor diet
  • Mild vitamin deficiencies
  • Heterozygosity for CBS defects
  • Hypothyroidism
  • Impaired renal function
  • Medication effects 1

• Intermediate hyperhomocysteinemia (30-100 μmol/L):

  • Moderate/severe cobalamin or folate deficiency
  • Renal failure 1

• Severe hyperhomocysteinemia (>100 μmol/L):

  • Severe cobalamin deficiency
  • Homocystinuria (genetic disorders) 1

Clinical Significance

• Each 5 μmol/L increase in homocysteine increases stroke risk by 59% 2
• Elevated homocysteine is associated with 2-3 fold increased risk of atherosclerotic vascular disease 2, 6
• Hyperhomocysteinemia is linked to increased risk of:
  • Venous thromboembolism
  • Cardiovascular disease
  • Cerebrovascular disease
  • Peripheral arterial disease
  • Alzheimer's disease
  • Age-related macular degeneration 7

Diagnostic Approach

When elevated homocysteine is detected, evaluate for:

1. Nutritional status - serum/plasma folate, RBC folate, vitamin B12 levels
2. Renal function - creatinine, GFR
3. Thyroid function - TSH, free T4
4. Medication review
5. Consider methylmalonic acid (MMA) testing to differentiate folate from B12 deficiency 2

Plasma homocysteine measurement is generally more informative than MTHFR genetic testing alone, as the clinical significance depends on the actual homocysteine level rather than just the genetic status 2.