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Homocysteine and B Vitamins Reduce the Risk of AMD
Abstract & Commentary
By Dónal P. O'Mathúna, BS (Pharm), MA, PhD. Dr. O'Mathúna is Senior Lecturer in Ethics, Decision- Making & Evidence, School of Nursing, Dublin City University, Ireland; he reports no financial relationship to this field of study.
Source: Christen WG, et al. Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: The Women's Antioxidant and Folic Acid Cardiovascular Study. Arch Intern Med 2009; 169:335-341.
The risk of age-related macular degeneration (AMD) has been associated with homocysteine concentration in the blood in observational epidemiologic studies. Randomized controlled trials (RCTs) of interventions to lower homocysteine levels in AMD are lacking. This RCT sought to establish whether a combined regimen of folic acid (2.5 mg/d), pyridoxine hydrochloride (vitamin B6, 50 mg/d), and cyanocobalamin (vitamin B12, 1 mg/d) impacted the incidence of AMD in women. The RCT included 5,205 female health care professionals 40 years or older with pre-existing cardiovascular disease or three or more cardiovascular disease risk factors and without diagnosed AMD. After an average of 7.3 years of treatment, 55 women in the treatment group had AMD and 82 in the placebo group (relative risk [RR], 0.66; 95% confidence interval [CI], 0.47-0.93; P = 0.02). For visually significant AMD, there were 26 cases in the combination treatment group and 44 in the placebo group (RR, 0.59; 95% CI, 0.36-0.95; P = 0.03). The authors concluded that women at high risk of cardiovascular disease may have a reduced risk of AMD by taking daily supplements of folic acid, pyridoxine, and cyanocobalamin.
Age-related macular degeneration (AMD) is the leading cause of severe, irreversible vision loss in Americans. It is the most common cause of poor sight in people older than 60 years of age, but rarely leads to complete loss of vision. The macula is a small area at the center of the retina directly behind the pupil. A very important part of the eye, it is responsible for what we see directly in front of us. It permits seeing fine detail when reading and writing, and is also important in seeing color. AMD is the term used for a variety of conditions arising when the cells of the macula become damaged and stop working. At it develops, central vision is impaired, but usually enough peripheral vision remains to allow people to continue daily activities. As AMD progresses, vision becomes generally blurry, colors are lost from sight, and people can no longer see items in the middle of their vision. No treatments for AMD currently exist.
A number of cross-sectional and case-control studies have found a direct association between homocysteine concentration in the blood and risk of AMD. Homocysteine is an amino acid that is not obtained from the diet, but is an intermediate formed during metabolism of another amino acid, methionine. High levels of homocysteine (greater than 2.0 mg/L) have been associated with increased risk of atherosclerosis and cardiovascular disease (CVD). These high levels are believed to cause vascular endothelial dysfunction. Recent data suggest that atherosclerosis and endothelial dysfunction may play a role in the development of AMD.
Other data have shown that deficiencies in folic acid, pyridoxine hydrochloride, and cyanocobalamin can lead to high plasma levels of homocysteine. Administration of these supplements lowers homocysteine blood levels.1 The Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS) hypothesized that increasing the levels of these supplements could lower blood levels of homocysteine and reduce the risk of AMD.
Only women without a diagnosis of AMD at baseline were included. Each year they completed a questionnaire, which included a question about whether they had received a diagnosis of AMD since the last questionnaire. If they had, permission was sought to examine their medical records related to the diagnosis. Detailed information was then sought in writing from the ophthalmologists and optometrists.
As noted in the abstract, significant differences were found between the intervention group and the placebo group. A beneficial effect on total AMD incidence began to appear after approximately two years of supplementation. For visually significant AMD, the benefit started to appear after about four years. Blood homocysteine levels were not obtained from all participants, but only from a subset of 300 participants. These indicated that those taking the supplements had homocysteine levels 18.5% lower than those on placebo, an average difference of 0.31 mg/L (P < 0.001). This may have been the cause of the reduced risk of AMD, but other factors may have been involved.
The only previous recommendation that could be given to patients to reduce their risk of AMD was to avoid cigarette smoking. The WAFACS is the first RCT to use these supplements as an intervention to reduce the risk of AMD. As the first such study, it will need to be replicated to increase confidence in its findings. Some concern was raised by the authors as the larger WAFACS study and others did not find any benefit from these supplements on CVD, even though CVD and AMD were expected to benefit through similar mechanisms.2 Some caution is therefore necessary in implementing the findings, although it is possible that lowering elevated homocysteine levels has a greater impact on eye vasculature. Given the widespread problem of AMD and that the supplements used are readily available and safe, women at increased risk of cardiovascular disease may be able to reduce their risk of AMD using daily supplements of folic acid, pyridoxine hydrochloride, and cyanocobalamin.
1. Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: A meta-analysis of the randomized trials. Am J Clin Nutr 2005;82:806-812.
2. Albert CM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: A randomized trial. JAMA 2008;299:2027-2036.