Mar 30, 2022

Disclaimer 

Our Integrative Medical Advisory team has developed or collected these protocols from practitioners and supplier partners to help health care practitioners make decisions when building treatment plans. By following this protocol, you understand and accept that the recommendations in the protocol are for initial guidance and need to seek medical professional advise.  

Get Help

Elevated Homocysteine

Homocysteine is a non-essential amino acid and metabolite of methionine, an essential amino acid obtained in the diet. (20) Homocysteine is involved in vitamin B-dependent methylation cycles that generate and breakdown the universal methyl-group donor, S-adenosyl-methionine (SAMe). Disruptions in this cycle, whether caused by reduced enzymatic expression or activity of various methylation cycle proteins including methylenetetrahydrofolate reductase (MTHFR), pyridoxal-5’-phosphate (P5P), or cystathionine B-synthase (CBS), may theoretically lead to elevated levels of homocysteine. (28)

Normal homocysteine levels can range from 5-15 μmol/L, while hyperhomocysteinemia occurs when homocysteine levels are elevated beyond 15 μmol/L. (35) Hyperhomocysteinemia can be further classified as mild (16-30 μmol/L), intermediate (31-100 μmol/L), or severe (>100 μmol/L). (20)

Hyperhomocysteinemia has been linked to numerous diseases, including: 

  • Age-related conditions, such as Alzheimer’s disease, Parkinson’s disease, and stroke 
  • Endocrine-related conditions, such as diabetes, hypothyroidism, insulin resistance, and osteoporosis
  • Endothelial-related conditions, including cerebrovascular and vascular diseases
  • Other conditions, such as end-stage renal disease, various cancers, schizophrenia, and complications in pregnancy (1)(20)(28)
 

A number of factors may contribute to hyperhomocysteinemia, including:

  • Genetic polymorphisms of methylation enzymes, such as MTHFR, CBS, methionine synthase, and methionine synthase reductase
  • Nutrient deficiencies, such as folate, vitamin B6, vitamin B12, or betaine deficiencies
  • Diet and lifestyle considerations, such as excess methionine intake, smoking, excess alcohol or caffeine intake, and sedentarism (1)(33)

Folic acid and vitamin B12

0.2-0.8 mg as folic acid or 5-methylfolate (5-MTHF) per day, minimum 12 weeks for greatest benefit and maintenance for up to ~5 years, with optional 0.4-1.0 mg vitamin B12 for improved efficacy in patients with elevated homocysteine (3)(5)(6)(7)(10)(12)(15)(16)(21)(23)(34)(37)(38)

  • Folic acid provided primary effect on homocysteine reductions ranging between ~13-30% (3)(4)(5)(6)(7)(10)(12)(15)(16)(21)(22)(23)(26)(32)(34)(40)
  • Proportions of reductions in homocysteine were highly dependent on greater baseline homocysteine and lower baseline folate levels (5)(15)(16)(29)(37)
  • Higher folic acid doses ranging between 5-60 mg per day were safely used, but did not reduce homocysteine further than ingestion of 0.8 mg (16)(22)(29)(32)(40)
  • Most human evidence did not support greater folate bioavailability or efficacy in reducing homocysteine by 5-MTHF over folic acid, but it may provide extended retention of benefit upon discontinuation in patients with poor methylation capacity (2)
  • Vitamin B12 produced additional ~7% reduction in homocysteine (4)(5)(15)(16)(21) 
  • Individual trials showed benefit of adding vitamin B6 for further reductions in homocysteine, however this was not supported in meta-analyses (3)(5)(15)(16)(23)(34)
  • Males may have required higher folic acid dose ranges than women (6)
Folic Acid

Omega-3 fatty acids

200-6,000 mg (~98-2,000 mg EPA/490-1,000 mg DHA) per day, for 1-12 months in patients with hyperhomocysteinemia or elevated homocysteine within normal ranges (8)(11)(13)(17)(18)(19)(25)(30)(42)(43)

  • Reduced homocysteine by 1.18-1.58 μmol/L on average using wide dose ranges, as shown in meta-analyses (8)(18)
  • Reduced homocysteine by ~2.5-4.0 μmol/L in patients with type II diabetes, patients on hemodialysis, or healthy adults using mid-range doses of 2,000-3,600 mg per day for 1-3 months and up to one year (11)(17)(25)(30)(42)(43)
  • Reduced homocysteine by ~1.6 μmol/L over 12 months in patients younger than 65 years, previously suffering from myocardial infarction (13)
  • Adjunct therapy with folic acid, vitamin B6, and vitamin B12 improved efficacy (8)(17)
  • Adjunct aerobic exercise and cognitive stimulation may be required for benefit in some populations, including older adults with mild cognitive impairment (19)
Omega-3

N-acetylcysteine (NAC)

600 mg, 2-3 times per day, for 2-8 weeks (14)(24)(36)(41)

  • Reduced total homocysteine by 12-45% in healthy patients or patients at increased risk for CVD (9)(14)(24)(36)(39)
  • Oral formulations reduced total homocysteine in patients with end-stage renal disease by 21-25%, while intravenous formulations further reduce homocysteine during hemodialysis by ~90% (24)(27)(31)
  • Reduced SBP (~7.1 mmHg) and DBP (~3.3 mmHg) in hyperlipidemic men and SBP (~3.2 mmHg) in normolipidemic men; each 10% reduction in homocysteine is associated with 1.45-2.55 reduction in pulse pressure mmHg in patients undergoing hemodialysis (14)(27)(31)
  • Increased urinary excretion of homocysteine in its sulfonated form (36)
N-acetylcysteine

Attachments

Support your prescription with these additional resources