Micronutrients and Age-Related Macular Degeneration

					Micronutrients and Age-Related Macular Degeneration
by Emily Y. Chew, MD Age-related macular degeneration (AMD) is the most common cause of visual impairment in the US.1 The disease is projected to increase at an alarming rate as the longevity of the American population increases.2 The treatment of AMD is currently limited with the use of laser photocoagulation,3,4 photodynamic therapy,5,6 and surgical procedures. Although the pathogenesis of AMD is unknown, there is growing evidence that oxidative stress may play a role.7,8 The results of the Age-Related Eye Disease Study (AREDS) showed that oral supplements of high dose antioxidant vitamins C, E, and beta-carotene and zinc (with copper) reduced the risk of progression to advanced AMD.9 Smoking is also a known risk factor associated with the risk of AMD and smoking is known to deplete the body’s antioxdative potential.10 These data further support the possible role of oxidative stress in AMD. Carotenoids: Lutein/Zeaxanthin The role of micronutrients in the pathogenesis of AMD was explored in 1988.11 Investigators reviewed the dietary intake of patients with and without AMD in the first NHANES (National Health and Nutritional Examination Healthy Survey) and found that participants with the highest consumption of fruits and vegetables rich in vitamins A and C reduced their risk of AMD by as much as 41% when compared to participants who did not eat such foods. The Eye Disease Case Control Study, conducted by the National Eye Institute, compared blood levels of carotenoids and other vitamins in patients who had neovascular AMD with those without AMD. 12 The study found that patients with the highest blood levels of carotenoids, compared with those with the lowest levels, had the lowest risk of macular degeneration, with reductions as high as 70 percent. Patients with moderate blood levels of carotenoids had a 50 percent risk reduction. In addition,

patients with a high dietary intake of the carotenoids lutein and zeaxanthin, found in green leafy vegetables such as spinach and collard greens, had a 43 percent or more risk reduction for AMD compared with those with low or minimal intake.13 The higher consumption of these foods was associated with a lower risk of AMD, appearing to show a dose response. The lowest risk of AMD was found in participants eating spinach six times a week when compared to those who never eat the vegetable. This association of dietary lutetin/zeaxanthin with AMD was also found in the third NHANES study.14 Lutein and zeaxanthin are the major components of the yellow pigment found in the center part of the mammalian eye. Like other vitamins, lutein and zeaxanthin are not manufactured by the body, so they must be consumed in the diet. They act as the major filter for ultraviolet radiation, and as such, might help prevent oxidative stress. In plants, lutein acts like a sunscreen; plants that are deficient in the vitamin become scorched. Lutein is often touted as a treatment for macular degeneration. However, this is based upon observational, case-controlled studies and such information is inconclusive due to unknown, confounding factors that may influence findings. For example, a person’s decision to take vitamin supplements may be associated with their socioeconomic status or with patient compliance. In other words, patients who take vitamins may, in general, be of higher socioeconomic status, or may be more compliant in taking medicines for high blood pressure or other conditions. In general, people who take dietary supplements may otherwise take better care of themselves. Age-Related Eye Disease Study (AREDS) In 1992, the National Eye Institute mounted a controlled clinical trial called the Age-Related Eye Disease Study (AREDS) to evaluate the role of antioxidant vitamins and zinc in the treatment of age-related cataract and macular degeneration.15 Only rigorous testing in controlled clinical trials that account for known and unknown confounders can determine whether a treatment is effective for a given disease or condition.

AREDS was designed to examine the natural history of macular degeneration and cataract, but an additional interest was the investigation of the nutritional aspects of these diseases through a randomized trial. Goals of the study included determining whether antioxidants or minerals could slow the progression of lens opacity in cataract, and whether these nutrients could prevent or slow the progression of AMD. The 4,757 patients in the study were randomly assigned to one of four treatment groups: placebo (a sham treatment); antioxidants; zinc; or antioxidants plus zinc. The antioxidants used in the study were vitamin C (500 mg/day), vitamin E (400 IU/day), and beta-carotene (15 mg/day or 2500 IU/day). When the AREDS was designed, lutein and zeaxanthin were not commercially available and thus not tested. Zinc (80 mg/day) was given together with copper (2 mg/day). Zinc was of interest because many patients were already taking this mineral based on the results of just a single small study done in the 1980s that showed benefit in reducing minor vision impairment.16 Because zinc at high doses can cause significant health problems, including copper deficient-anemia, in the AREDS study, copper was given to counter the harmful effects of zinc. As of 2001 when the major AREDS results were announced, the patients had been followed for an average of more than six years. Cataract After five years, cataracts developed in 29.8 percent of patients who took antioxidants and 30.4 percent who did not take antioxidants. Thus, the antioxidants were neither beneficial nor harmful in terms of cataract development, nor were they beneficial in preventing surgery for cataract. At five years, 10.5 percent who took antioxidants, and 11.3 percent who did not, underwent cataract surgery. Loss of visual acuity with cataract at five years was virtually the same in both groups — 4.7 percent in the antioxidant

group and 4.8 percent in those not taking antioxidants. These antioxidant vitamins are not recommended for the prevention or treatment of cataracts. Age-Related Macular Degeneration Four groups of patients with varying risk of AMD were enrolled in AREDS. The risk of AMD was identified by an examination of the retina to evaluate the size and the area of drusen, or yellow spots. Although people with no risk for macular degeneration normally develop a few drusen over their lifetime, patients with AMD have more and larger drusen. The four AMD groups included: 1) people thought to have no risk for macular degeneration (few or no drusen); 2) people at risk for early AMD (intermediate drusen); 3) people with intermediate risk for AMD (extensive intermediate or large drusen); and 4) people who already have AMD in one eye and one unaffected eye. Patients at low risk for macular degeneration were not given zinc because of its potential harmful effects. The study of zinc was limited to those who had early AMD or worse. In all clinical trials, some of the most valuable data includes information on the natural history of the disease. In AMD, it was found that people with small to moderate drusen had a very low risk of developing advanced disease. At five years, only 1.3 percent developed the advanced form of AMD. People at intermediate risk, who had moderate to large drusen, had an 18 percent chance of developing advanced AMD in five years. People who already had macular degeneration in one eye had the highest risk — 43 percent — of developing advanced disease. The results of the randomized, controlled clinical trial showed that 28 percent of the patients taking placebo developed advanced AMD — either the neovascular or the atrophyic form — after five years. Of those taking the combination of antioxidants and zinc, only 20 percent developed advanced disease in 5 years. The combination

treatment with zinc and antioxidants reduced the risk of advanced AMD by 25 percent while zinc alone reduced the risk by 21 percent, and antioxidants alone reduced the risk of advanced AMD by 17. The combination treatment was the best. Regarding vision loss, 29 percent of patients taking placebo developed moderate vision loss at the end of five years, whereas 23 percent of patients taking antioxidants and zinc actually had a reduction in terms of moderate vision loss. Given alone, the antioxidants and zinc were each effective to some extent in preventing macular degeneration and in preserving vision, but the combination therapy again resulted in the most beneficial effects. AREDS is the first vitamin study that has shown beneficial effects for a disease of considerable public health significance and is the first study in which a treatment has been shown to prevent the development of macular degeneration. Risks of Vitamin Therapy The risks associated with the treatment used in AREDS include: 1. Possible increased risk of lung cancer in people already at risk. As was shown in the NIH sponsored Alpha-Tocopherol Beta-Carotene Trial (ATBC trial)17 in Finland, heavy smokers who took beta carotene significantly increased their risk of developing lung cancer. In addition, the CARET Study18 (the beta-Carotene and Retinol Efficacy Trial), which followed the ATBC trial, replicated much of the findings of the former study in patients who were either heavy smokers or had exposure to asbestos. This study was also sponsored by the NIH. As in the ATBC trial, participants in CARET who took beta-carotene had an increased risk of developing lung cancer and an increased death rate. Thus, beta carotene therapy for AMD would not be recommended in smokers or others at risk for lung cancer.

2. Skin yellowing. Beta-carotene increased the yellowing of the skin. This discoloration has no health consequence. 3. Genital/urinary problems. Zinc use increased hospitalizations for genital and urinary problems. The most common problem was prostate enlargement in men. 4. Possible adverse effects on cholesterol levels. Although the AREDS study found no treatment effect on cholesterol, previous studies have reported that zinc may cause a decrease in HDL (―good‖) cholesterol or an increase in LDL (―bad‖) cholesterol. 5. Anemia from Zinc. The AREDS showed no increase in anemia in those patients taking zinc. Overall, the AREDS study showed that, at the 6-year follow-up, combination therapy with zinc and antioxidants proved beneficial for AMD with fairly few side effects. Patients enrolled will be followed for additional years to assess long-term effects. Who Should Take Vitamin Therapy for AMD? The American Academy of Ophthalmology recommends that people over age 65 have a yearly eye exam with pupil dilation to screen for cataract, glaucoma, and macular degeneration. People who are not at risk for AMD, and even those at the low risk end — those with few drusen — need not take vitamins since, in five years’ time, only one percent of people in this group develop the disease. This risk is determined by the ophthalmologist following a dilated eye exam. Patients who have a family history of AMD may not necessarily be in the higher risk group for AMD and may not benefit from taking these supplements.

It is estimated that about 55 million people over the age of 55 in the United States today may be at risk for macular degeneration. Of these, eight million are at high risk and are the people who are likely to benefit from combination zinc and antioxidant therapy. If all eight million people at high risk for AMD took supplement therapy, more than 300,000 of them could be saved from advanced AMD in the next five years. References 1 Congdon N, O’Colmain B, Klaver CC, Klein R, Munoz B, Friedman DS, Kempen J, Taylor HR, Mitchell P; Eye Disease Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122:477-851 2. Thylefors B. A global initiative for the elimination of avoidable blindness. Am J Ophthalmol. 1998;125:90-93. 3. Macular Photocoagulation Study Group. Argon laser photocoagulation for senile macular degeneration. Arch. Ophthalmol. 1982;100:912–918. 4. Macular Photocoagulation Study Group, 1986. Argon laser photocoagulation for neovascular maculopathy. Threeyear results from randomized clinical trials. Arch. Ophthalmol. 1986;104:694–701. 5. TAP Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials-TAP report. Treatment of age-related macular degeneration with photodynamic therapy .(TAP) Study Group. Arch Ophthalmol. 1999; 117:1329-45 6. Verteporfin therapy of subfoveal choroidal neovascularization in agerelated macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization-

verteporfin in photodynamic therapy report 2. Am J Ophthalmol. 2001; 131:541-60. 7. Young, R.W., 1988. Solar radiation and age-related macular degeneration. Surv. Ophthalmol. 1988;32; 252–269. 8. Beatty, S., Koh, H.-H., Henson, D., Boulton, M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv. Ophthalmol. 2000; 45: 115–134. 9. Age-related Eye Disease Study Research Group. A randomized, placebocontrolled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001;119: 1439-52. 10. Age-Related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case-control study in the agerelated eye disease study: age-related eye disease study report number 3. Ophthalmology. 2000; 107:2224-32. 11. Goldberg J, Flowerdew G, Smith E, et al. Factors associated with agerelated macular degeneration. An analysis of data from the first National Health and Nutrition Examination Survey. Am J Epidemiol. 1988;128:70010. 12. The Eye Diseases Case-Control Sutdy Group. Antioxidant status and Neovascular age related macular degeneration. Arch Ophthalmol. 1993;111:1701-1708. 13. Seddon J, Ajani U, Sperduto R, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. JAMA. 1994;272:1413-20. Erratum in: JAMA. 1995;273:622.

14. Mares-Perlman JA, Fisher AI, Klein R, et al. Lutein and zeaxanthin in the diet and serum and their relation to age-related maculopathy in the third national health and nutrition examination survey. Am J Epidemiol. 2001;153(5):424-432. 15. The Age-Related Eye Disease Study Research Group. Design Paper, the Age-Related Eye Disease Study (AREDS): Design implication. AREDS Report no. 1. Control Clin Trials 1999;20:573-600. 16. Newsome DA, Swartz M, Leone NC, Elston RC, Miller E. Oral zinc in macular degeneration. Arch Ophthalmol. 1988;106:192-198. 17. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029-1035. 18. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of betacarotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med.1996;334:1150-1155. Emily Y. Chew, MD, Division of Epidemiology and Clinical Research, National Eye Institute/National Institutes of Health, Bethesda, MD.

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