Hyperhomocysteinemia: Causes

Pathogenesis (disease development)

The sulfur-containing amino acid homocysteine is formed in the organism as an intermediate product in methionine and cysteine metabolism. Depending on the methionine requirement, homocysteine is remethylated to methionine or degraded to cysteine by means of transsulfuration (exchange of sulfur between L-homocysteine and L-cysteine). Therefore, homocysteine plays an essential role in amino acid metabolism as a linking intermediate. However, the reactive amino acid has cyto-, vaso- as well as neurotoxic effects, which is why it is rapidly metabolized (metabolized) into methionine and cysteine or released into the plasma. Individuals with hyperhomocysteinemia have impaired metabolism of homocysteine, which can be metabolized or transformed in two ways in healthy individuals:

  • Synthesis of methionine by methylation (transfer of methyl groups) of homocysteine – here the enzymes methionine synthase as well as methylene tetrahydrofolate reductase require the two essential cofactors folic acid and vitamin B12.
  • Transsulfuration of homocysteine to cysteine – here the enzymes cystathionine-β-synthase as well as cystathionine-γ-synthase require pyridoxal phosphate (biologically active form of vitamin B6) as a cofactor.

Low homocysteine levels are associated with physical activity, moderate alcohol consumption and a healthy diet. Especially the latter leads to a good supply of B vitamins, which are important cofactors in homocysteine metabolism. Consequently, homocysteine serum levels are significantly regulated by three vitamins:

  • Folic acid
  • Vitamin B12
  • Vitamin B6

Furthermore, choline and betaine can help reduce hyperhomocysteinemia. Choline can be oxidized to betaine (zwitterionic trimethylglycine). Betaine is able to transfer a methyl group to homocysteine, and no other cofactors are necessary. The reaction step is catalyzed by betaine-homocysteine methyltransferase and methionine and dimethylglycerol are formed as the endpoint.

Etiology (Causes)

Biographic causes

  • Genetic burden from parents, grandparents:
    • Polymorphism of methylene tetrahydrofolate reductase (MTHFR):
      • The task of MTHFR is to convert 5,10-methylene hydrofolate (inactive folic acid form) to 5-methyl tetrahydrofolate (5-MTHF, active folic acid form).
      • Genetic cause: autosomal recessive inheritance; point mutation.
        • Replacement of the nucleic base cytosine by thymine in the MTHFR gene → amino acid alanine is replaced by valine → enzyme activity is thus reduced by circa 70%.
      • Genetic risk dependent on gene polymorphisms:
        • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
          • Genes: MTHFR
          • SNP: rs1801133 in the gene MTHFR
            • Allele constellation: CT (35% restriction of folic acid metabolism).
            • Allele constellation: TT (80-90% restriction of folic acid metabolism).
      • Distinction between heterozygous and homozygous polymorphism:
        • Heterozygous polymorphism (677CT).
          • Homocysteine levels usually within the tolerable normal range.
          • Homocysteine values of 11.9 ± 2.0 μmol/l
          • Frequency: 45-47
        • Homozygous polymorphism (677TT).
          • Leads to mild hyperhomocysteinemia
          • Homocysteine levels of 14.4 ± 2.9 μmol/l
          • Frequency: 12-15
      • Frequency of the “wild type” (677CC – normal, non-mutated gene variant): 40-50% in European-origin populations.
      • Reduction in activity of MTHFR reductase is irrelevant in the presence of sufficient folic acid supply; but in the presence of folic acid deficiency, homozygous trait carriers may experience an increase in homocysteine levels by 25% (2 to 3 µmol/l)
      • Recommended for homozygous trait carriers is the intake of the active folic acid form 5-MTHF.
    • Other genetic enzyme defects:
      • Defect of cystathionine-β-synthase (CBS), cystathionine lyase (CL), homocysteine methyltransferase (HMT), or betaine homocysteine methyltransferase (BHMT).
      • Distinction between heterozygous and homozygous genetic defects.
        • Heterozygous genetic defect
          • Leads to moderate hyperhomocysteinemia
          • Homocysteine levels ≥ 30 µmol/l
          • Occurs rarely
        • Homozygous genetic defect
          • Leads to severe hyperhomocysteinemia
          • Homocysteine levels ≥ 100 µmol/l
          • Occurs very rarely (Germany: 1: 300,000)
          • Treatment mandatory, otherwise premature death.
          • Therapy: high-dose administration of vitamin B6
  • Age – increasing age
  • Hormonal factors – postmenopausal women.

Behavioral causes

  • Nutrition
    • Micronutrient deficiency (vital substances) – vitamin B6, B12 and folic acid – see Prevention with micronutrients.
  • Pleasure food consumption
    • Alcohol – (woman: > 20 g/day; man: > 30 g/day).
    • Tobacco (smoking)
  • Psycho-social situation
    • Stress

Causes related to disease

Drugs (which, among other things, interfere with methionine-homocysteine metabolism or induce an excess demand for folic acid, B6 and B12).