Homocysteine And Health
Homocysteine and Alzheimer’s Disease
In a 2002 study published in the New England Journal of Medicine, dementia developed in 111 study participants of which 83 were diagnosed with Alzheimer’s disease over an eight-year follow up. In those with a plasma homocysteine level greater than 14 µmol/L, the risk of Alzheimer’s disease nearly doubled. Investigators concluded, “An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer’s disease.”30
How Elevated Homocysteine Leads to Vascular Damage
If unhealthy levels of homocysteine accumulate in the blood, the delicate lining of an artery (endothelium) can be damaged.
Homocysteine can both initiate and potentiate atherosclerosis. For example, homocysteine-induced injury to the arterial wall is one of the factors that can initiate the process of atherosclerosis, leading to endothelial dysfunction and eventually to heart attacks and strokes.31,32 Several studies have shown that homocysteine can inflict damage to the arterial wall via multiple destructive molecular mechanisms.19,33,34
Homocysteine Is Linked to Congestive Heart Failure
Small clinical studies have shown that patients with congestive heart failure (CHF) suffer from elevated plasma homocysteine levels.35 Based on preclinical evidence that the myocardium may be especially susceptible to homocysteine-induced injury36 and based on observations linking homocysteine to oxidative stress37 and to left ventricular remodeling,38,39 it has been hypothesized that elevated plasma homocysteine levels would increase the risk of CHF. Accordingly, researchers investigated the relationship of plasma homocysteine concentration to the risk of CHF in a community-based sample of adults (2,491 adults, mean age 72 years, 1,547 women) who participated in the well-known Framingham Heart Study during the 1979‒1982 and 1986‒1990 examination periods and who were free of CHF or prior myocardial infarction at baseline. In one study that examined patients without any manifestation of coronary heart disease at baseline, investigators found that the association of plasma homocysteine levels with risk of CHF was maintained in men and women and concluded “an increased plasma homocysteine level independently predicts risk of the development of CHF in adults without prior myocardial infarction.”40
Reducing Homocysteine for Migraine Relief
Migraine is a debilitating disease that can be associated with elevated blood levels of homocysteine.41-43
A study showed that treatment with B-complex vitamins, including 5-MTHF, could provide relief for migraine sufferers including those with the MTHFR C677T genotype,44 which typically limits the clinical effectiveness of supplemental folic acid since individuals with this genotype do not effectively convert folic acid to its active form. People with the C677T genotype consistently have higher levels of homocysteine than those with the normal C677C genotype. Headache frequency and pain severity were also reduced. The treatment proved successful in reducing homocysteine levels and migraine disability in study participants with the MTHFR C677T genotype. Researchers have long suspected that migraine headaches have a genetic component because migraine sufferers often have family members who also have the condition. Studies suggest up to 12% of those living in the United States and Western Europe have this genetic link to migraine.45
Homocysteine’s Role in Macular Degeneration
Studies of homocysteine’s role in age-related macular degeneration (AMD: both wet and dry types) reveal a strong link between the compound and the disease.
In a group of 2,335 study participants who had evidence of AMD as detected from retinal photographs, researchers found that homocysteine blood levels >15 µmol/L were associated with an increased likelihood of AMD in participants aged <75 years. They also found a similar association for blood levels of vitamin B12 <125 pmol/L among all study participants. In participants with homocysteine levels ≤15 µmol/L, low serum B12 was associated with nearly fourfold higher odds of AMD.46
In a larger and more recent study, Harvard researchers enrolled 5,442 women who were at high risk for cardiovascular disease. The women were given a placebo or 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 per day. After an average of more than seven years of treatment and follow-up, researchers recorded 55 cases of AMD in the B-vitamin treatment group and 82 in the placebo group. Investigators concluded that in women at high risk of cardiovascular disease, daily long-term supplementation with folic acid, B6, and B12 may reduce the risk of AMD.47
Homocysteine Linked to Hearing Loss
A number of published studies suggest hearing loss may be linked to plasma homocysteine levels, which could be reduced by folic acid supplementation.
One study conducted from September 2000 to December 2004 in 728 older men and women in the Netherlands (which does not have mandatory folic acid fortification) found that at initiation, the median threshold for hearing in the low frequency range (0.5 to 2 kHz) was 11.7 decibels (dB), and 34.2 dB in the high frequency range (4 to 8 kHz). By the end of the study, the thresholds had increased for both folic acid and placebo groups. In other words, a louder noise was required to get study participants to hear it. However, the increase was lower in the supplemented group in the low frequency range (1.0 vs. 1.7 dB increase for folic acid and placebo groups, respectively). There was no significant difference in threshold decline in the higher frequency region. Thus, folic acid supplementation slowed the decline in hearing of the speech frequencies typically associated with aging.48
Researchers studied the levels of homocysteine in 28 male patients (mean age 37) with noise-induced hearing loss. Homocysteine levels of subjects with noise-induced hearing loss were significantly higher compared to healthy controls, suggesting a causal link between increased homocysteine levels and noise-induced hearing loss.49
Flawed Studies Lead to Confusion over B-Vitamins and Heart Disease
A 2010 review of several large randomized, double-blind, placebo-controlled trials that used various B-vitamin therapies for reducing cerebrovascular risk (VISP study)50 and secondary cardiovascular disease risk (HOPE 2,51 NORVIT,52 WAFACS,53 and WENBIT54 studies) concluded that B-vitamin treatments effectively decrease plasma homocysteine levels and stroke risk, although such treatments failed to reduce cardiovascular risk.2 A meta-analysis of randomized clinical trials comprising 16,958 participants with preexisting vascular disease found that folic acid supplementation had no effect on the risk of cardiovascular disease or all-cause mortality.55
Critical examinations of such studies that failed to show a reduction of cardiovascular events in patients treated with B vitamins have revealed numerous design and methodological flaws including limited statistical power, relatively short duration of follow-up, and insufficient number of cardiovascular events.56-58 In addition, three of the studies were secondary prevention trials and therefore were not designed to test the ability of B vitamins to prevent heart attacks in healthy people. The most egregious flaw in these trials, however, is that they all failed to use high enough doses of B vitamins to reduce study participants’ homocysteine levels to the optimal target range of <8 µmol/L.
Additional B-vitamin studies in patients undergoing balloon angioplasty and vascular stenting reveal the critical importance of lowering homocysteine levels to Life Extension’s recommended optimal target range. Two studies that failed to use high enough doses of folic acid, B6, and/or B12 to achieve optimal homocysteine reduction saw restenosis rates rise in some patients who received vitamin therapy.59,60 In contrast, a prospective, double-blind, randomized trial (the “Swiss Heart Study”) examined the effects of folic acid, vitamin B6, and vitamin B12 treatment in 553 patients who underwent angioplasty.61 Investigators observed a significant reduction in the need for revascularization of the target lesion at 1 year (9.9% in the treatment group vs. 16.0% in the control group). Significantly, the Swiss Heart Study is the only randomized controlled trial to date in which treatment reduced study participants’ average plasma homocysteine levels (7.5 µmol/L) to within the range recommended by Life Extension (<8 µmol/L).
Stroke Protection from B-Vitamin Therapy
The 2009 HOPE-2 trial for homocysteine therapy and stroke risk, which randomized 5,522 adults with known cardiovascular disease to a daily treatment regimen of B-vitamin therapy (2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12) for five years, achieved reduction in stroke risk of 25%.51 HOPE-2 was the first large randomized, double blind, placebo-controlled trial to use clinically adequate doses of vitamin B12. It included high-risk participants with and without history of cerebrovascular disease drawn from countries with and without folic acid food fortification. Significantly, homocysteine concentration decreased by 2.2 µmol/L in the B-vitamin therapy group and increased by 0.80 µmol/L in the placebo group.
Another meta-analysis that focused on a subset of seven of 12 randomized studies added a randomized trial from China to assess the efficacy of folic acid supplementation in stroke prevention. Study investigators found that folic acid supplementation significantly reduced the risk of stroke by 18%.62
Additional Studies on Homocysteine Reduction and Vascular Disease
A number of controlled studies that found positive effects of B-vitamin therapy on vascular disease yielded the following results:
- Folate supplementation improved arterial function in patients with peripheral arterial disease.63 Two measures of arterial health, brachial pressure index (ABPI) and pulse wave velocity (PWV), were measured; ABPI improved significantly in all patients receiving folate compared with controls, while PWV improved significantly in individuals receiving an active form of folic acid (5-MTHF), and tended to be improved in those taking folic acid, compared with controls.
- Twenty hypercholesterolemic adults taking Lovastatin were given a daily folate supplement (5 mg) for eight weeks while 20 patients received a placebo64; only the folate-supplemented group experienced decreased blood levels of homocysteine.
- Reducing blood levels of homocysteine through B-vitamin therapy was shown to improve endothelial function in renal transplant recipients with hyperhomocysteinemia.65 Investigators assigned 36 stable renal transplant recipients with hyperhomocysteinemia to either a B-vitamin treatment group (5 mg folic acid, 50 mg vitamin B6, and 1,000 mcg vitamin B12 per day) or to a control group (placebo only) for six months. Investigators found that homocysteine significantly decreased in the B-vitamin treatment group compared with baseline (12.6 vs. 20.1 µmol/L); no significant changes in homocysteine levels were observed in the control group. Vasodilatation responses were significantly improved in the treatment group compared to controls.
- Folic acid treatment in patients undergoing hemodialysis (10 mg three times weekly after dialysis treatment for six months) lowered plasma homocysteine levels while it significantly increased total plasma antioxidant capacity levels.66 Twenty patients receiving placebo treatment showed no statistically significant effect on any of the parameters studied.
- A study treated liver transplant recipients with 5-methyltetrahydrofolate (5-MTHF; 1 mg) versus folic acid (1 mg) versus placebo in an 8-week double-blind placebo-controlled trial. Investigators observed a significant decrease of total serum homocysteine in the 5-MTHF group by week 8; they found no significant decrease of total serum homocysteine in either the folic acid group or the placebo group. The effects of 5-MTHF (active folate) were found to be significantly more potent than folic acid at lowering elevated homocysteine levels in liver transplant recipients.67
- A randomized study in 103 patients at increased risk of heart attack or stroke investigated the effect of daily supplementation of folic acid (5 mg) on carotid artery intima-media thickness (IMT). Study participants were randomized to receive either a daily dose of 5 mg folic acid or placebo. After 18 months of folic acid supplementation, participants in the active treatment group saw their homocysteine levels significantly reduced, compared to a significant increase in the placebo group. Investigators noted significant regression of carotid IMT in the treatment group compared to significant IMT progression in the placebo group.68
- A controlled study was carried out to assess whether folic acid supplementation could produce a reduction in homocysteine levels and improvement in endothelial function in patients with unstable angina (UA) and hyperhomocysteinemia.3 Investigators treated patients with 5 mg of folic acid for eight weeks, rechecking homocysteine, folic acid, and vitamin B12 levels at the end of four and eight weeks. Plasma homocysteine levels were significantly higher in patients with UA than in patients without UA at baseline (19.2 vs. 10.7 µmol/L), whereas plasma levels of folic acid and vitamin B12 were significantly lower. After eight weeks of folic acid supplementation, homocysteine levels were reduced by 55.3% in the 22 UA patients with hyperhomocysteinemia. Flow-mediated dilation, an indirect measure of endothelial function, also improved significantly after eight weeks of treatment with folic acid.
- A 2008 study examined carotid artery atherosclerosis as determined by measurements of carotid IMT and plaque calcification in 923 patients with vascular disease or diabetes.69 Study investigators found an inverse association between plasma folate and plaque calcification score; there was a trend toward an inverse association with IMT as well.