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functional medicine methylation cycleWhat is Homocysteine?

Homocysteine (Hcy) is a sulfhydryl-containing amino acid produced by intracellular demethylation of the essential amino acid methionine (Met). It is not used to make proteins but as an intermediate in methionine metabolism.

What does homocysteine do?

Serum Homocysteine isoforms are reduced to free Homocysteine, and then exogenous S-adenosylmethionine (SAM) methylates Homocysteine to form SAH and Met, a reaction catalyzed by Homocysteine methyltransferase. SAH is then hydrolyzed to Homocysteine and adenosine (ADO) by SAH hydrolase. ADO is immediately hydrolyzed into inosine and ammonia, which reacts with glutamate dehydrogenase with concomitant conversions of NADH to NAD+ measured at ΔA340nm.

Homocysteine continuously cycles through this reaction to significantly amplify the detection signal. B vitamins are important cofactors in this metabolic pathway. When methionine levels are low, methyltetrahydrofolate (from folic acid) donates methyl groups to generate methionine from Homocysteine, and vitamin B12 is also necessary for the methionine synthase-catalyzed remethylation of homocysteine into methionine. When there is excess methionine, the biologically active form of vitamin B6 catalyzes homocysteine transulfuration to cystathionine and ultimately to cysteine (excess of which is eliminated by the body).

Homocysteine and Cardiovascular Disease

Homocysteine mediates adverse effects on the blood vessels through diverse pathways:

  1. homocysteine isoforms directly damage the blood vessel walls11
  2. interactions between homocysteine and low-density lipoprotein (LDL) cholesterol contribute to subendothelial plaque genesis3
  3. post-translational modifications of LDL particles, promoting the formation of foam cells and plaque progression12
  4. increased peroxide production and reduced glutathione peroxidase activity increase endothelial cell damage13
  5. reduced nitric oxide availability results in vasoconstriction11
  6. activation of monocytes leads to cytokine secretion and inflammation3,14
  7. platelet activation and aggregation, reduced thrombomodulin expression, depressed protein-C activity, and tissue plasminogen activator cause dysregulation of the coagulation system.3,15,16

Hyperhomocysteinemia is also associated with impaired hepatic capacity to synthesize apoA-I, thereby lowering HDL particle concentrations.17

Although the association between Hcy and vascular disease is widely recognized, elevated Hcy has also been associated with the following disorders and diseases:

  1. Deficiency of folic acid or vitamins B6/B12: Elevated homocysteine levels are most commonly caused by low levels of one or all of these B vitamins. A normal homocysteine excludes significant B vitamin deficiency.15,18
  2. Liver disease: Elevated Hcy and low levels of SAM are associated with liver toxicity and cirrhosis.19,20 Homocysteine may cause liver damage, leading to the formation of fibrin, clots, and vascular complications.21
  3. Renal disease: homocysteine levels rise during renal insufficiency due to inadequate homocysteine filtration.22,23
  4. Thyroid conditions: Elevated homocysteine levels may contribute to accelerated heart disease in patients with concomitant hypothyroidism.24
  5. Alzheimer’s disease and dementia: Elevated homocysteine levels have been associated with Alzheimer’s disease incidence, indicating impaired methylation in brain tissue.25,26,27
  6. Depression: Low serum folic acid levels have been associated with depression in women.28,29 Of interest, low levels of serum folate reduce the efficacy of fluoxetine (Prozac®, an antidepressant),28 while Vitamin B6 may alleviate depression.30
  7. Erectile dysfunction: A case study described a patient with erectile dysfunction who had a genetic defect causing elevated serum homocysteine levels. Although the patient did not initially respond to treatment with sildenafil (Viagra®), subsequent supplementation with 5 mg of folic acid and 1 mg of vitamin B12 resulted in successful treatment of his erectile dysfunction with sildenafil.31 Homocysteine has been shown to reduce production of nitric oxide, a vasodilator that increases blood flow to organs such as the penis.32
  8. Ocular disease: homocysteine’s ability to damage blood vessels extends to the ocular microvasculature. Elevated homocysteine levels are associated with ocular diseases such as glaucoma and macular degeneration. Mean homocysteine levels in patients with central retinal vein occlusion were 11.6 μmol/L compared with 9.5 μmol/L in control subjects.33

Additional risk factors for elevated homocysteine levels include advanced age (often due to vitamin B12 deficiency owing to increased malabsorption with age), male sex, genetic defects of homocysteine metabolizing enzymes, diabetes mellitus, smoking, coffee intake, hyperproliferative conditions (e.g. psoriasis, rheumatoid arthritis), malignancies and drugs that affect homocysteine metabolism (e.g., some lipid-modifying drugs, anticonvulsants, folate and B12 antagonists, metformin).6,18,34,35

Should we lower Homocysteine?

The many links between elevated plasma homocysteine and diseases that afflict the elderly point to the existence of a common denominator that may be responsible for these diseases. Whether this denominator is homocysteine itself or whether homocysteine is merely a biomarker remains to be determined.

Since multiple clinical trials have demonstrated no cardiovascular event reductions despite lowering homocysteine using folic acid and B vitamin supplementation, the benefit of homocysteine-lowering strategies has been debated.4,6,15,34,36,37

However, the development of an atherosclerotic plaque takes a long time, typically 30-40 years from initial development to a clinical event. If homocysteine were a true causal contributor to this process, the time required to show a beneficial intervention effect of lowering homocysteine could take much longer than the < 5 years of follow-up characterizing the B-vitamin intervention trials.15

Thus it is possible that the homocysteine-lowering trials, although studying large numbers of patients, have been underpowered simply because the duration of follow-up has been too short in relation to the development time-frame for atherosclerotic disease.15,36 In support of this notion, a meta-analysis of the effect of B vitamins on stroke showed a full absence of any effect in short term studies (< 36 months) but a statistically significant 29% reduction in the studies with at least 36 months of follow-up.38

A large meta-analysis of more than 90 genetic and prospective studies calculated that lowering homocysteine levels by 3 µmol/L (by increased folic acid intake) would reduce the risk of ischemic heart disease by 16%, DVT by 25% and stroke by 25%.8 Lowering homocysteine levels may also increase nitrous oxide availability and reduce endothelial dysfunction.15,37 But the debate over whether plasma homocysteine can be considered a modifiable risk factor for atherosclerosis still rages.15,36

In particular, it is still unclear whether endogenous variations of plasma homocysteine within normal range are accompanied by clinically significant variations in endothelial dysfunction, oxidative stress, or the overall thrombotic state.15

Beneficial Dietary Modifications

Ingestion of Met may increase homocysteine levels since homocysteine is a Met metabolite. Indeed, homocysteine levels have been increased in experimental protocols through Met supplement ingestion.39 Foods rich in Met such as meat and eggs have been associated with increased risk of heart disease, although causality between Met content and CVD has not been established.

Diets high in fruits and vegetables that contain folic acid, beta-carotene, and vitamin C lowered homocysteine levels: in one study, healthy people consumed diets containing either one pound of fruits and vegetables or 3½ ounces of fruits and vegetables daily; homocysteine levels were 11% lower in the former group as compared with the latter after four weeks.40

Also of interest, replacing a breakfast of refined rice with whole-grain and legume powder significantly lowered homocysteine levels in men with cardiovascular disease (CVD).41 People with elevated homocysteine are typically advised to eat less processed foods, meat, and saturated fat to lower the risk of heart disease.

Beneficial Lifestyle Modifications

Cigarette smoking and coffee consumption are associated with increased homocysteine levels,42 an observation consistent with the association between smoking and caffeine consumption and increased risk of both CVD and osteoporosis. The correlation between coffee intake and increased homocysteine has been confirmed in some,43 but not all, studies.44 T

o exemplify the effects of lifestyle modification on homocysteine levels, a diverse group of people participated in a weeklong program that included a strict vegan diet, stress management, spirituality enhancement sessions, group support, and exclusion of tobacco, alcohol, and caffeine.45 B vitamin supplements known to reduce plasma homocysteine levels were not provided. Mean homocysteine levels declined by 13% after one week of lifestyle modification.

Thus a whole diet approach high in fruit and vegetables with high natural folate content is recommended to decrease plasma homocysteine levels, with the added benefit of increasing the intake of other important nutrients as well.

Beneficial Supplementations

Vitamins B6, B12, and folic acid are essential cofactors in homocysteine metabolism to Met and cysteine, and therefore supplementation has consistently lowered plasma homocysteine.3,6,15,18,37 Oral administration of folic acid (0.5-5 mg/day) reduces fasting homocysteine levels by 25-30%, while supplementation with vitamin B12  (0.02-1 mg/day) yields an additional 7% reduction in homocysteine levels.46

Folic acid supplementation lowers homocysteine levels most significantly in healthy individuals.47,48 However, a decrease of serum homocysteine of 3 µmol/L is achievable by daily intake of ~0.8 mg folic acid and should reduce risk of ischemic heart disease by 16%, DVT by 25% and stroke by 24%.8

In 1996, the FDA required that all enriched flour, rice, pasta, cornmeal, and other grain products contain 140 µg of folic acid per 3.5 ounces.49 This level of fortification has led to a measurable decrease in serum homocysteine levels.50

However, higher levels of folic acid fortification result in further homocysteine reductions, suggesting that the FDA-mandated supplementation is inadequate to optimally protect people against hyperhomocysteinemia. Therefore, if one wishes to optimally reduce homocysteine levels, despite the current lack of level I evidence supporting CV risk reduction,36,37 folic acid supplements should complement the FDA-mandated fortification program.

Vitamin B2 (riboflavin) supplementation (1.6 mg per day) lowered homocysteine levels by 22-40% in individuals with a genetic variant of an enzyme involved in folic acid metabolism (the 677C>T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene.51 Approximately 10% of the population are homozygous for this genetic variant and could benefit from riboflavin supplementation.52,53

An alternative therapy is supplementation with methylated folic acid, the active form of folate. Specific methyl donors such as TMG/ betaine (1.5-6 g per day; 1.5 g usual standard diets) and choline (2 g per day or 2.6 g daily provided as 34 g of soy lecithin) may also lower homocysteine supplements, are other potential aids to the conversion of homocysteine to methionine (simultaneously lowering serum homocysteine). Doctors have traditionally considered supplementation with these nutrients only when vitamin B6, vitamin B12, and folate supplementation fail to reduce homocysteine to optimal levels, but they can be key methyl donors in the presence of MTHFR mutations which impair methylation ability.52

Despite the beneficial health effects of supplementation with B vitamins, it is important to note that there are possible dual effects on atherosclerosis, with the intrinsic beneficial effects of homocysteine-lowering being offset by detrimental effects of unmetabolized synthetic folic acid and/or stimulation of inflammation (and possibly proliferation) in existing atherosclerotic lesions by B vitamins.15,36 These factors may partly explain why clinical trials on homocysteine lowering failed to report improvement in CV risk and clinical outcome, and are currently under intense investigation. Following current recommendations, the target plasma homocysteine level is ≤ 10 µmol/L.15,18,34,36,57

In patients with CVD or high-risk for CVD events, a high homocysteine level may be used as a prognostic factor for CVD events and mortality:

  • Mild to moderate hyperhomocysteinemia indicates high risk for CVD and usually stems from poor diet, mild folate/B12/B6 deficiency, hypothyroidism, impaired renal function, or certain drugs.15,18,34,57 When the cause of moderate hyperhomocysteinemia is established, then the best treatment is reversal of this cause.
  • Increased tHcy combined with low B vitamin levels indicates a potential vitamin deficiency: supplement with a multivitamin containing moderate amounts of folic acid (0.2-0.8 mg), B6 (2-25 mg) and B12 (3-100 µg/day).18
  • Switch to high-dose B vitamins only if homocysteine clearly remains elevated and there is no MTHFR mutation (in which case riboflavin or supplementary methyl donors such as 5-MTHF or betaine may lower tHcy).
  • Intermediate hyperhomocysteinemia (fasting plasma tHcy 30-100 µmol/L) is usually the result of moderate/severe vitamin B12 or folate deficiency, homozygous enzyme defects in homocysteine metabolism, or renal failure.34,57 Again, diagnosis and reversal of the respective cause should be the main priority, while most patients respond well to folate alone or in combination with B12, B6 and possibly betaine. Use of all 4 supplements reduces homocysteine in people with renal failure. Notably, high doses of vitamin B12 are required for normalization of homocysteine levels after renal failure.23
  • Severe vitamin B12 deficiency and homocystinuria are the main causes of severe hyperhomocysteinemia (fasting plasma tHcy >100 µmol/L) and should be treated accordingly (0.02-1 mg/day of B12, 5-25 mg/day of B6 and 1-5 mg/day of folic acid),18 since it is associated with an increased pro-thrombotic state.

Long-term treatment with high doses of folic acid may mask pernicious anemia caused by vitamin B12 deficiency. The high folate may correct the anemia but allow the neuropathy to progress undiagnosed, leading eventually to irreversible degeneration of the spinal cord. It is therefore important to measure B12 levels before the start of folate treatment and/or treat with folate and B12 together.


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