Age-Related Macular Degeneration - part 8 pps

In the Beaver Dam Eye Study, after controlling for age, total serum cholesterol was inversely related to early AMD in women (OR, 0.89; 95% CI, 0.80–0.98), whereas the total cholesterol/HDL cholesterol ratio was inversely related (OR, 0.89; 95% CI, 0.84–0.96) and HDL cholesterol was positively related to early AMD in men (113). The reasons for these associations are not clear although a possible explanation is selective survival. Be- cause persons with higher cholesterol levels or lower HDL cholesterol levels are at higher risk of cardiovascular death than persons with normal levels of cholesterol, a positive relationship may have been obscured. Serum cholesterol or HDL cholesterol was not related to neovascular AMD or geographic atrophy in the same study (113). The Age-Related Macular Degeneration Risk Factors Study Group found neovascular AMD, but not nonneovascular AMD, to be positively associated with high-density lipoprotein level (OR, 2.3; 95% CI, 1.1–4.7), and dietary cholesterol level (OR, 2.2; 95% CI, 1.0–4.8) (19). In the Beaver Dam Eye Study, persons with intake of saturated fat and cholesterol in the highest compared with the lowest quintile had odds ratio of 1.8 (95% CI, 1.2–2.7) and 1.6 (95% CI, 1.1–2.4) for early AMD, respectively, after adjusting for age and beer intake (118). However, no significant association between these intakes was found with late AMD (118). The findings in this study concur with the Blue Mountains Eye Study, which found that total and saturated fat intake were associated with a borderline significant increase in risk for early AMD [ORs (95% CI) for highest compared to lowest quintiles of intake, 1.60 (0.94–2.73) and 1.50 (0.91–2.48), respectively], but not for late AMD (119). A significant association (p for trend ϭ 0.05) for increasing prevalence of early AMD with increasing monounsaturated fat intake was observed. Cholesterol intake was associated with a borderline significant increase in risk for late AMD [OR (95% CI) for highest compared to lowest quintiles of intake, 2.71 (0.93–7.96); p for trend ϭ 0.04]. The Rotterdam Study (112), the Blue Mountains Eye Study (18), and the Atheroscle- rosis Risk in Communities Study (40) did not find any association between serum cholesterol or HDL cholesterol with AMD. No significant association between AMD and serum cholesterol was also found in the Framingham Eye Study (12), NHANES-I (7), and several small studies (69, 120, 421). No difference in the levels of plasma cholesterol and fatty acids was found between 65 cases of neovascular AMD and control pairs in a study by Sanders and associates (122). 4. Diabetes and Hyperglycemia The majority of studies that have investigated the relationship between diabetes and/or hyperglycemia and AMD have found no significant association (6,12,30,40,48,60,69,123). One small study by Vidaurri and associates observed an association between drusen and serum glucose in women but not in men (115). In the Beaver Dam Eye Study, diabetes was not associated with early AMD (124). In persons Ն 75 years, those with diabetes had a higher frequency of neovascular AMD (9.4%) than those without (4.7%) but both groups had similar frequencies of geographic atrophy. The relative risk of neovascular AMD in di- abetic men compared to nondiabetic men Ն 75 years was 10.2 (95% CI, 2.4–43.7); for women it was 1.1 (95% CI, 0.4–3.0). The authors suggested that the relationship of neovascular AMD in older men, but not women, might be the result of chance, in the same study, no relationship was found between glycosylated hemoglobin and any signs of AMD in nondiabetic persons (124). The Blue Mountains Eye Study found geographic atrophy to be significantly associated with diabetes (OR, 4.0; 95 CI, 1.6–10.3), but no association was found with either neovascular AMD (OR, 1.2; 95% CI, 0.4–3.5) or early AMD (OR, 1.0; Risk Factors for AMD and CNV 377 95% CI, 0.5–1.8 (125). There was also no association found between impaired fasting glucose and AMD (125). The Atherosclerosis Risk in Communities Study (40) did not find any association between AMD and diabetes. Overall, there is scant evidence in the literature to suggest a real relationship between diabetes and/or hyperglycemia and AMD. 5. Body Mass Index In the Blue Mountains Eye Study, having a body mass index (BMI) [defined as body weight in kilograms divided by height in meters squared (kg/m 2 )] either lower or higher than the accepted normal range (20–25) was associated with a significantly increased risk of early AMD (18). Low BMI (OR, 1.92; 95% CI, 1.16–3.18) conferred an increased risk for early AMD almost equal to that of obesity (OR, 1.78; 95% CI, 1.19–2.68). This association is thus difficult to explain in terms of cardiovascular risk. Although the odds ratios were similar for association with late AMD, they did not reach statistical significance. A Finnish population-based study found that a high BMI was associated with an increased risk of AMD in men but not in women (30). On the other hand, the Beaver Dam Eye Study found that BMI was associated with increased frequency of RPE degeneration, increased retinal pigment, and increased presence of pigmentary abnormalities in women but not in men (113). No association between BMI and AMD was found in the Atherosclerosis Risk in Communities Study (40). 6. Hematological Factors The Beaver Dam Eye Study found that, after controlling for age, sex, diabetes, and smoking history, neovascular AMD was associated with higher hematocrit values (OR, 1.09; 95% CI, 1.00–1.19) and higher leukocyte count (OR, 1.10; 95% CI, 1.00–1.19) in people 65 years of age or older (113). Blumenkranz and associates also found a higher leukocyte count in patients with neovascular AMD compared to controls (66). No association between hematocrit and AMD was found in NHANES-l (7). The Blue Mountains Eye Study found that plasma fibrinogen level was associated with late but not early AMD (18). The Eye Disease Case-Control Study found a nonsignificant increased risk of neovascular AMD with increasing plasma fibrinogen levels (6). 7. Cigarette Smoking This will be discussed under environmental factors (see below). B. Reproductive and Related Factors The relationship of cardiovascular disease to AMD has generated some interest in the effect of estrogen-related variables on the risk of AMD in women. The Eye Disease Case- Control Study found that use of postmenopausal exogenous estrogen was negatively associated with neovascular AMD (6). Current and former users of estrogen had odd ratios of 0.3 (95% CI, 0.1–0.8) and 0.6 (95% CI, 0.3–0.98) for neovascular AMD, respectively, when compared to women who never used estrogen. This is compatible with findings from a nested case-control study within the Rotterdam Study, which suggest that early artificial menopause increases the risk of late AMD (atrophic or neovascular AMD) (126). Women with early menopause after unilateral or bilateral oophorectomies had an increased risk of late AMD compared with women who had their menopause at 45 years or later. No significant excess risk was found for early spontaneous menopause and early hysterectomy. In the Blue Mountains Eye Study, a significant protective association for early AMD was 378 Au Eong and Haller found with increased years from menarche to menopause (OR, 0.97; 95% CI, 0.95–0.99) (32). Other female-specific factors including late menarche, history of hormone replace- ment therapy, and early menopause were not significantly associated with early or late AMD (32). No significant relationship, however, was found in the Beaver Dam Eye Study between years of estrogen therapy and neovascular AMD, geographic atrophy, or early AMD (127). It should be noted that because the number of cases of late AMD in the Beaver Dam Eye Study was small, the power to detect a real association is limited. Women who have ever been pregnant (parity Ն 1) had increased odds of 2.2 (95% CI ϭ 1.3–3.9) compared to women who have never been pregnant (parity ϭ 0) in the Eye Disease Case-Control Study (6). On the other hand, the Beaver Dam Eye Study docu- mented that the number of past pregnancies was significantly inversely related to soft drusen, with odds ratio of 0.94 per pregnancy (95% CI, 0.90–0.98) (127). The relationship with the number of pregnancies to any AMD was of borderline significance, the odds ratio being 0.96 per pregnancy (95% CI, 0.92–1.01). The number of pregnancies was not significantly related to neovascular AMD or geographic atrophy. Past use of birth control pills, age of menarche, or the number of years of menstruation had no significant effect on AMD in the Beaver Dam Eye Study (127). C. Dermal Elastotic Degeneration In a small case-control study, Blumenkranz and associates found a correlation between the degree of dermal elastic degeneration in sun-protected skin with the development of neovascular AMD (66). However, there was no significant difference in outdoor sun exposure as estimated by patients. In fact, cases admitted to fewer average hours outdoors weekly than controls. The authors suggested that patients with neovascular AMD may have a gen- eralized systemic disorder characterized by abnormal susceptibility of elastic fibers to photic or other as-yet unrecognized degenerative stimuli. D. Antioxidant Enzymes Recently, the POLA (Pathologies Oculaires Liees a l’Age) Study, a large-scale, population- based, cross-sectional study in southern France, found that higher levels of plasma glutathione peroxidase were significantly associated with a ninefold increase in late AMD prevalence, but not with prevalence of early AMD (128). Plasma glutathione peroxidase therefore appears to be one of the strongest indicators of late AMD ever found, but the bio- logical meaning of this finding remains to be elucidated. The authors suggest that oxidative stress may lead to the induction of antioxidant enzymes, and therefore high concentrations of antioxidant enzymes may be indicators of oxidative stress. In the same study, levels of erythrocyte superoxide dismutase activity were not associated with either early or late AMD. VIII. ENVIRONMENTAL FACTORS A. Smoking Of the environmental influences, smoking has most consistently been associated with increased risks of AMD in recent studies (6,48,129–137). However, a number of studies Risk Factors for AMD and CNV 379 (30,60,64,66,69), including the Framingham Eye Study (12) and NHANES-III (25), did not find an association between smoking and AMD. In fact, one study by West and associates even showed smoking to be protective (67). However, when this decreased risk of AMD associated with smoking was further investigated, no clear dose-response relationship was demonstrated. In the large case-control study by the FRANCE-DMLA Study Group, a past history of smoking, but not current smoking status, was associated with an increased risk of AMD after univariate analysis (64). After multivariate adjustment, both factors were not significantly associated with AMD. Paetkau and associates noted in their case series of 114 patients with at least one eye blind from AMD that the mean age at the onset of blindness in the first eye was 64 years in current smokers compared with 71 years in the group that had never smoked (129). How- ever, because there was no control group, confounding factors such as increased mortality in the smoking group cannot be excluded. In a Japanese case-control study, compared to male nonsmokers, the age-adjusted odds ratio of developing neovascular AMD was 2.97 (95% CI, 1.00–8.84) for male current smokers and 2.09 (95% CI, 0.71–6.13) for male former smokers (136). In addition, smoking-habit-related variables, such as use of extra filter, smoke inhalation level, age at starting smoking, duration of smoking, and the Brinkman index, defined as the numbers of cigarette smoked per day times smoking years, were found to be significantly related to an increased risk of neovascular AMD (136). The Beaver Dam Eye Study found that the relative odds for neovascular AMD in men and women who were current smokers compared with those who were former smokers or who never smoked were 3.29 (95% CI, 1.03–10.50) and 2.50 (95% CI, 1.01–6.20), respectively (131). However, there was no significant relation between smoking status and geographic atrophy. In addition, smoking status, pack-years smoked, and current exposure to passive smoking were not associated with signs of early AMD, except for a higher frequency of increased retinal pigment in men who were former smokers compared with those who had never smoked (131). The Blue Mountains Eye Study found current cigarette smoking to be significantly associated with both early and late AMD, after adjusting for the effects of age and sex (134). The odds ratio of early and late AMD when comparing current smokers to those who never smoked was 1.89 (95% CI, 1.25–2.84) and 4.46 (95% CI, 2.20–9.03), respectively. A history of having ever smoked was significant for late AMD (OR, 1.83; 95% CI, 1.07–3.13) but not early AMD (134). In addition, passive smoking among subjects who never themselves smoked, but lived with a smoking spouse, incurred a moderate but not statistically significant increase in the risk of late AMD (OR, 1.42; 95% CI, 0.62–3.26). In the POLA Study, after adjustment for age and sex, current (OR, 3.6; 95% CI, 1.1–12.4) and former smokers (OR, 3.2; 95% CI, 1.3–7.7) had an increased prevalence of late AMD when compared to nonsmokers (137). The risk of late AMD increased with increasing number of pack-years, with up to a 5.2-fold increase in risk among participants (current and former smokers combined) who smoked 40 pack-years or more (OR, 1.9; 95% CI, 0.6–6.4 for 1–19 pack-years, OR, 3.0; 95% CI, 0.9–9.5 for 20–39 pack-years, and OR, 5.2; 95% CI, 2.0–13.6 for 40 pack-years and more). In addition, the risk of late AMD re- mained increased until 20 years after cessation of smoking. However, the study found no significant associations of smoking with early AMD (soft distinct and indistinct drusen and pigmentary abnormalities) (137). Two large prospective cohort studies evaluated the relationship between smoking and AMD (133,135). In the Nurses’ Health Study with 12 years of follow-up, women who currently smoked Ն 25 cigarettes per day had a relative risk of AMD of 2.4 (95% CI, 380 Au Eong and Haller 1.4–4.0) compared with women who never smoked (135). Risk of AMD also increased with an increasing number of pack-years smoked (p for trend Ͻ 0.001). Past smokers of this amount also had a relative risk of 2.0 (95% CI, 1.2–3.4) compared to women who never smoked. Compared with current smokers, little reduction in risk was found even after quit- ting smoking for 15 or more years. In the Physicians’ Health Study, men who were current smokers of Ն 20 cigarettes per day had a relative risk of AMD of 2.5 (95% CI, 1.6–3.8) compared with men who never smoked (133). Men who were past smokers had a modest elevation in relative risk of AMD of 1.3 (95% CI, 1.0–1.7). Some have suggested that the effect of cigarette smoking on the development of AMD may be related to its effect on antioxidants in the body (136). Studies have shown that smokers have much lower plasma levels of ␤-carotene than do nonsmokers (122,138). Stryker and associates found that men and women who smoked one pack per day had 72% (95% CI, 58–89) and 79% (95% CI, 64–99) of the plasma ␤-carotene levels of nonsmokers, respectively, after accounting for dietary carotene and other variables (138). Another study also disclosed that smokers had lower plasma concentrations of total carotenoids, ␣- carotene, and ␤-carotene than nonsmokers (122). In addition, a recent study found that smokers have significantly lower macular pigment density compared to nonsmoking matched controls (87). In summary, data from several large population-based studies (131,132,134,137), case-control studies (6,48,36), and two large prospective cohort studies (133,135) provide convincing evidence that cigarette smoking is a risk factor for AMD. The strongest risk is for current smokers, suggesting that there may be potential benefits of targeting antismok- ing patient education, especially for those who are current smokers and have signs of early AMD (134). B. Sunlight Exposure Exposure to sunlight has long been suggested as a risk factor for AMD. Short-term expo- sures to longer-wavelength ultraviolet and blue light can cause retinal damage in animals (139). There are some similarities between long-term changes seen in laboratory animals exposed to shorter-wavelength visible light and changes seen in patients with AMD (81,140–145). It is theorized that light may lead to the generation of reactive oxygen species in the outer retina and/or choroid (81), perhaps by photoactivation of protoporhyrin (146). The activated forms of oxygen may, in turn, cause lipid peroxidation of the photoreceptor outer segment membranes, leading to the development of AMD. Tso and Woodford have shown that short exposure of intense visible light can pro- duce atrophy at the photoreceptor level in nonhuman primates (147), but these animals did not develop histopathological changes of drusen, diffuse thickening of Bruch’s membrane, or choroidal neovascularization seen in clinicopathological studies of AMD (148). In addition, the short, intense light exposure used in animal studies is different from the typical chronic exposure to light that occurs in people in their lifetime. The only animal model for light-induced deposits in Bruch’s membrane is that of Gottsch and co-workers, who have proposed that photosensitization of choriocapillary endothelium with blood-borne photo- sensitizers such as protoporphyrin IX is a mechanism for the histopathological features seen in AMD (146,149). The epidemiological evidence of an association between light exposure and AMD is lacking, with only a few clinical studies showing a positive association between sun exposure and late AMD. A small Spanish case-control study found a higher sun exposure index Risk Factors for AMD and CNV 381 in AMD cases compared to controls (150). In the Chesapeake Bay Watermen Study, an association between late AMD (geographic atrophy or diskiform scarring) and ocular exposure in the previous 20 years to blue or visible light (OR, 1.36; 95% CI, 1.00–1.85) was found in phakic men (96). However, no positive association was seen for early AMD (large drusen or RPE abnormalities) (96). In addition, there was no association between ultraviolet-A or ultraviolet-B exposure and any degree of AMD in the same population (67,96). The Beaver Dam Eye Study found that leisure time outdoors in summer was significantly associated with the presence of neovascular AMD when both men and women were analyzed together (OR ϭ 2.26, 95% CI ϭ 1.06–4.81) (151). Time spent outdoors in summer was significantly associated with the prevalence of increased retinal pigment in men (OR ϭ 1.44, 95% CI ϭ 1.01–2.04) but not in women (OR ϭ 0.93, 95% CI ϭ 0.63–1.38). Use of sunglasses and hats with brims was inversely associated with the prevalence of soft indistinct drusen in men (OR ϭ 0.61, 95% CI ϭ 0.38–0.98) but not in women (OR ϭ 0.99, 95% CI ϭ 0.69–1.45). The association between light exposure and AMD is not consistent across the study since an association was found in men only, and involved only a specific subset of light exposure (time spent outdoors in summer but not in winter) and a specific subset of early AMD (151). A number of case-control studies, including the Eye Disease Case-Control Study (6), failed to show an association between sunlight exposure and AMD (48,152). An Australian case-control study in fact showed that control subjects had greater median annual ocular sun exposure (865 h) than cases (723 h) (p Ͼ 0.0001) (152). Despite analysis stratified by sun sensitivity, sun exposure was greater in control subjects than in cases with AMD (152). In summary, there is currently no convincing research data to support strategies to reduce light exposure to the eye for the prevention of AMD. However, since there is little, if any, risk to a person wearing sunglasses, and ultraviolet-light exposure has been associated with the presence of cataract (95), it is reasonable to suggest that individuals wear sunglasses for comfort and to reduce exposure of ultraviolet light to ocular structures. It must be emphasized, however, that there is no published data to indicate whether the wearing of sunglasses is of any benefit in preventing any eye disease, including AMD. C. Nutritional Factors 1. Micronutrients The potential role of nutritional supplements to reduce the incidence or severity of AMD has received a great deal of attention (80,92). The lack of an effective treatment for the majority of cases of AMD, coupled with the public’s perception that over-the-counter nutritional supplements are relatively harmless, creates the potential for widespread use of these supplements in the absence of demonstrated effectiveness (153). Because of possible, but as yet unproven, benefits of antioxidant vitamins in cancer, cardiovascular, and other chronic diseases, vitamin supplement usage in the United States has increased steadily in recent years. It is estimated that more than half of the adult population in the United States uses dietary supplements, including supplements of antioxidant vitamins, at a cost of approximately $12 billion annually (21). Although epidemiological studies provide support for a protective role of nutritional antioxidants in the prevention of AMD, results of prospective randomized clinical trials are necessary before firm conclusions can be drawn about the balance of benefits and risks of nutritional supplements for the prevention of AMD. In fact, use of nutritional supplement has been shown to have deleterious effects in some nonophthalmic medical trials. The Al- 382 Au Eong and Haller pha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study found a higher incidence of lung cancer among men who received ␤-carotene than among those who did not (change in incidence, 18%; 95% CI, 3–36%) (154). There were also more deaths due to lung cancer, ischemic heart disease, and ischemic and hemorrhagic stroke among recipients of ␤-carotene, with an increased overall mortality of 8% (95% CI, 1–16%). Those randomized to vitamin E supplementation had higher rates of hemorrhagic stroke, but there was no overall difference in mortality rates or cancer incidence (154). In the Carotene and Retinol Efficacy Trial (CARET), participants who were given ␤-carotene and vitamin A supplements had a 28% (95% CI, 4–57%) increased incidence of lung cancer and a 17% (95% CI, 3–33%) higher mortality compared to those who were not (155). a. Antioxidants. Some have suggested that antioxidants and a variety of trace minerals necessary for the proper functioning of some key enzyme systems may reduce the risk of AMD (81, 156, 157). Photochemical damage from light can induce the production of activated forms of oxygen, which in turn can cause lipid peroxidation of the photoreceptor outer segment membranes. Antioxidants, such as vitamin C, vitamin E, ␤-carotene, and glutathione, and antioxidant enzymes, such as selenium-dependent glutathione peroxidase, in theory could act as singlet oxygen and free-radical scavengers and thereby prevent cel- lular damage (158). There is considerable interest in determining whether free radicals con- tribute to the pathogenesis of AMD and whether high levels of these antioxidants may pro- tect against AMD. This hypothesis is supported by findings of disruption of retinal photoreceptors in nonhuman primates with deficiencies of vitamins A and E (159) and a protective effect of vitamin C in reducing the loss of rhodopsin and photoreceptor cell nu- clei in rats exposed to photic injury (160). Many studies have used serum levels of micronutrients to investigate the relationship of these micronutrients and AMD. Unfortunately, high and low levels are defined differ- ently for most studies. Most have defined the high and low categories on the basis of percentile categories, i.e., those individuals with serum concentrations above a given percentile were categorized as high and those below a given percentile were categorized as low. Blumenkranz and associates reported in their small case-control study that the serum levels of vitamins A, C, and E were not different in cases of neovascular AMD and in controls (66). In another case-control study, serum levels of vitamin E in cases and controls were similar but serum selenium was significantly lower in cases compared to controls (p ϭ 0.02) (69). The Eye Disease Case-Control Study found that persons with carotenoid scores in the medium and high percentile groups, compared with those in the low group, had markedly reduced levels of risk of neovascular AMD, with levels of risk reduced to one-half (OR, 0.5; 95% CI, 0.4–0.8) and one-third (OR, 0.3; 95% CI, 0.2–0.6), respectively (5). Similarly, except for lycopene, higher levels of individual carotenoids (lutein/zeaxanthin, ␤-carotene, ␣-carotene, or cryptoxanthin) were associated with statistically significant reductions in risk of neovascular AMD. In addition, there was a progressive decrease in risk of neovascular AMD with increasing levels of carotenoids and increasing levels of the antioxidant index. However, no statistically significant overall association was seen with neovascular AMD and serum levels of vitamin C, vitamin E, and selenium in the study (5). West and associates examined the relationship between plasma levels of retinol, ascorbic acid, ␣-tocopherol, and ␤-carotene in 630 participants of the Baltimore Longitu- dinal Study on Aging (161). They found a favorable association between plasma antioxidants and AMD. Their data suggest that only ␣-tocopherol was significantly associated with a protective effect (OR for middle vs. lowest quartiles, 0.50; 95% CI, 0.32-0.79; OR for highest vs. lowest quartile, 0.43; 95% CI, 0.25-0.73). This is consistent with findings Risk Factors for AMD and CNV 383 from a small Spanish case-control study (150). There was a suggestion of a protective effect with ascorbic acid and ␤-carotene in the Baltimore Longitudinal Study on Aging, but their effects were not statistically significant (161). No protective effect was noted for retinol. For late AMD (neovascular AMD or geographic atrophy), no significant protective effect was observed for any plasma micronutrient. An antioxidant index constructed of ascorbic acid, ␣-tocopherol, and ␤-carotene, controlled for age and sex, suggested that high values were protective for AMD compared with low values. It is now generally recognized that plasma ␣-tocopherol level should be expressed in terms of its concentration within lipids or lipoproteins (162–164). For this reason, the POLA Study correlated ocular findings with both plasma ␣-tocopherol and lipid-standard- ized ␣-tocopherol levels (17). The study found a weak negative association between late AMD and plasma ␣-tocopherol level, which was not statistically significant (p ϭ 0.07), but this relationship was strengthened when ␣-tocopherol-lipid ratio instead of plasma level was used (p ϭ 0.003). After adjusting for confounding factors, the odds ratios (95% CI) for late AMD in persons with ␣-tocopherol-lipid ratio in the highest and middle quintiles, compared with those with ratio in the lowest quintile, were 0.18 (0.05–0.67) and 0.46 (0.22–0.95), respectively. The odds ratios (95% CI) for any sign of early AMD in persons with ␣-tocopherol-lipid ratio in the highest and middle quintiles, compared with those with ratio in the lowest quintile, were 0.72 (0.53–0.98) and 0.78 (0.61–1.00), respectively. No association was found with plasma retinol and ascorbic acid levels or with red blood cell glutathione values (17). Data from NHANES-I, collected between 1971 and 1972, suggest that the frequency of consumption of fruits and vegetables characterized as rich in vitamin A is inversely related to the prevalence of AMD, after adjustment for medical and demographic factors (7). The Eye Disease Case-Control Study evaluated the relationship of dietary intake of carotenoids, and vitamins A, C, and E, with neovascular AMD (89). Those in the highest quintile of carotenoid intake, after adjusting for other risk factors of AMD, had an odds ratio of 0.57 (95% CI ϭ 0.35–0.92) for neovascular AMD compared with those in the lowest quintile. Among the specific carotenoids, the strongest association with a reduced risk for neovascular AMD was found with lutein and zeaxanthin, which are primarily obtained from dark-green, leafy vegetables. Intake of vitamin C was associated with a small but nonsignificant reduction in risk of neovascular AMD. No reduction in risk was found with intake of vitamin A or E. The Blue Mountains Eye Study, using a validated 145-item semiquantitative food frequency questionnaire, found no significant associations between early or late AMD and dietary intakes of carotene, vitamin A, or vitamin C, from combined diet and supplement, after adjusting for age, sex, current smoking, and AMD family history (165). There were no statistically significant trends for decreasing AMD prevalence with increasing intake of any antioxidant. Consumption of supplements was also not significantly associated with either early (OR, 1.0; 95% CI, 0.7–1.4) or late (OR, 1.2; 95% CI, 0.6–2.3) AMD. In addition, a nested case-control study within the Blue Mountains Eye Study did not find any association between AMD or serum ␣-tocopherol or ␤-carotene (166). Similarly, no significant associations between the intake of vitamin C or E or carotenoids from the diet or supplements and the prevalence of early or late AMD were observed in the Beaver Dam Eye Study (167). However, in a nested case-control study within the Beaver Dam Eye Study population-based cohort, low levels of serum lycopene, but not other carotenoids (␣-carotene, ␤- carotene, ␤-cryptoxanthin, or lutein and zeaxanthin), was related to an increased likelihood of AMD (OR, 2.2; 95% CI, 1.1–4.5) (168). 384 Au Eong and Haller The association between self-selection for antioxidant vitamin supplement use and incidence of AMD was examined among 21,120 participants in the Physicians’ Health Study I who did not have a diagnosis of AMD at baseline (8). A total of 279 incident cases of AMD with vision loss to 20/30 or worse were confirmed during an average follow-up of 12.5 years. Compared to nonusers of vitamin supplements, persons who reported taking vitamin E supplements at baseline had a nonsignificant 13% reduced risk of AMD (RR, 0.87; 95% CI, 0.53–1.43), after adjusting for other risk factors. Users of multivitamins had a nonsignificant 10% reduced risk of AMD (RR, 0.90; 95% CI, 0.68–1.19). No reduced risk of AMD was observed for users of vitamin C supplements (RR, 1.03; 95% CI, 0.71–1.50). b. Zinc. Zinc has received attention because of its high concentration in ocular tis- sues, particularly the sensory retina, RPE, and choroid (169), and its role as a cofactor for numerous metalloenzymes, including retinol dehydrogenase and catalase (170). In addition, there are some reports of zinc deficiency in the elderly, the population subgroup at greatest risk of AMD (171). Data from NHANES-III suggest that persons aged Ն71 years, together with young children aged 1–3 years and adolescent females aged 12—19 years, were at the greatest risk of inadequate zinc intakes (172). It has been hypothesized that zinc deficiency in elderly persons may cause the loss of zinc-dependent coenzymes in the RPE, resulting in the development or worsening of AMD (173). Newsome and associates conducted a prospective, randomized, double-blind, placebo-controlled trial that investigated the effects of oral zinc administration on the visual acuity outcome in 151 subjects with early to late AMD (174). They showed that eyes in zinc-treated group had significantly less visual loss than the placebo group after a follow-up of 12–24 months. In addition, there was less accumulation of drusen in the zinc- treated group compared with the placebo group. However, in another double-masked, randomized, placebo-controlled trial, oral zinc supplementation did not have any short-term effect on the course of AMD in patients who have neovascular AMD in one eye (175). The Beaver Dam Eye Study found that people in the highest quintile, compared to those in the lowest quintile, for intake of zinc from foods had lower risk of early AMD (OR ϭ 0.6, 95% CI ϭ 0.4–1.0) (167). A lower serum level of zinc was found in AMD cases compared to controls in a small Spanish case-control study (150). However, zinc intake was un- related to late AMD in the same study. The Eye Disease Case-Control Study did not find any significant relationships between serum zinc levels or zinc supplementation and risk of neovascular AMD (6). This concurs with findings from the Blue Mountains Eye Study (165). c. Randomized Trials of Antioxidant Vitamins and Age-Related Macular Degenera- tion. The most reliable, and only direct, method of testing the potential protective effects of nutritional supplements is to conduct randomized clinical trials. A small prospective randomized clinical trial showed that a specific 14-component antioxidant-mineral capsule (Ocuguard, Twin Lab, Inc., Ronkonkoma, NY) taken twice daily stabilized but did not im- prove dry AMD over one and a half years (176,177). Several large-scale randomized clinical trials including the Age-Related Eye Disease Study (AREDS) (153,173), the Physi- cians’ Health Study II (PHS II) (178), the Vitamin E, Cataract, and Age-related macular degeneration Trial (VECAT) (179), the Women’s Health Study (WHS) (180), and the Women’s Antioxidant Cardiovascular Study (WACS) (181), have been designed to address the issue of antioxidant vitamins and AMD (Table 7). Results of these major trials should provide the strongest evidence to support or to refute an association of antioxidant intake with AMD. Of these trials, AREDS, sponsored by the National Eye Institute (National Institutes of Health, Bethesda, MD), is the first to be completed (173). Risk Factors for AMD and CNV 385 386 Au Eong and Haller Table 7 Some Ongoing Large-Scale Randomized Trials Addressing the Balance of Risks and Benefits of Antioxidant Vitamins for Age-Related Macular Degeneration Name of randomized trial Details of trial Remarks Age-Related Eye Disease Study (AREDS (153,173) Physicians’ Health Study II (PHS II) (178) Vitamin E, Cataract, and Age- Related Macular Degeneration Trial (VECAT) (179) Women’s Health Study (WHS) (21,180) Women’s Antioxidant Cardiovascular Study (WACS (21,181) Sponsored by the National Eye Institute of the National Institutes of Health. Trial was completed in 2001 with follow-up of participants currently planned until at least 2006. PHS II is sponsored by BASF AG. Approximately half of the PHS II cohort is comprised of participants of the PHS I cohort, which was sponsored by the National Institutes of Health. Sponsored by the National Health and Medical Research Council of Australia and other sources. Has been funded by the National Eye Institute to extend its investigation to include AMD and cataract. Has been funded by the National Eye Institute to extend its investigation to include AMD and cataract. A multicenter prospective, double-blind, randomized clinical trial evaluating the role of antioxidant micronutrients (␤-carotene, vitamins E and C, and/or zinc) in AMD and cataract. Patients with early AMD to advanced unilateral AMD were randomized to receive either antioxidants, minerals, combination therapy, or placebo. 4,757 individuals aged 55–80 years at baseline were enrolled. Morbidity and mortality associated with the supplements were monitored. Endpoints include doubling of visual angle and morphological progression of AMD. A randomized, double-blind, placebo-controlled trial enrolling 15,000 willing and eligible physicians 55 years and older. It will test alternate-day ␤-carotene, alternate-day vitamin E, daily vitamin C, and a daily multivitamin in the prevention of AMD as well as cataract, total and prostate cancer, and cardiovascular disease. A 4-year randomized, placebo-controlled, double-masked trial of vitamin E on the rate of progression of cataract and AMD in 1204 elderly Australian volunteers. A randomized, double-blind, placebo-controlled trial of vitamin E and low-dose aspirin in the prevention of cancer and cardiovascular disease among 39,876 apparently healthy, postmenopausal U.S. female health professionals. A randomized, double-blind, placebo-controlled, secondary prevention trial to test antioxidant vitamins (␤-carotene, vitamin C, vitamin E) and a combination of folate, vitamin B 6 , and vitamin B 12 among 8171 female health professionals, aged 40 or older, who are at high risk for cardiovascular disease. [...]... of developing age-related macular degeneration in NHANES-1 J Am Geriatr Soc 19 98: 46:1–7 Ajani U, Willett W, Miller D, Haller J, Yannuzzi L, Blair N, Burton T, Seddon J Alcohol consumption and neovascular age-related macular degeneration (abstr) Am J Epidemiol 1993;1 38: 646 1 68 169 170 171 172 173 174 175 176 177 1 78 179 180 181 182 183 184 185 186 187 Risk Factors for AMD and CNV 188 189 190 191 192... Rosenthal FS Visible light and risk of age-related macular degeneration Trans Am Ophthalmol Soc 1990 ;88 :163–173 Delcourt C, Carriere I, Ponton-Sanchez A, Lacroux A, Covacho MJ, Papoz L et al Light ex- 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 Risk Factors for AMD and CNV 99 100 101 102 103 104 105 106 107 1 08 109 110 111 112 113 114 115 116 117 1 18 119 120 121 401 posure and the... Gaudio AR High-risk characteristics of fellow eyes of patients with unilateral neovascular age-related macular degeneration Ophthalmology 19 98; 105:441–447 Roy M, Kaiser-Kupfer M Second eye involvement in age-related macular degeneration: a four-year prospective study Eye 1990;4 :81 3 81 8 Macular Photocoagulation Study Group Five-year follow-up of fellow eyes of patients with age-related macular degeneration. .. factors, and age-related maculopathy: the Blue Mountains Eye Study Arch Ophthalmol 19 98; 116: 583 – 587 Hyman L, Schachat AP, He Q, Leske C Hypertension, cardiovascular disease, and age-related macular degeneration Age-Related Macular Degeneration Risk Factors Study Group Arch Ophthalmol 2000;1 18( 3):351–3 58 Ferris FL Senile macular degeneration: review of epidemiologic features Am J Epidemiol 1 983 ;1 18: 132–151... self-reported and surrogate-reported cataract and age-related macular degeneration in the Beaver Dam Eye Study Am J Epidemiol 1991;134:14 38 1446 Melrose MA, Magargal LE, Lucier AC Identical twins with subretinal neovascularization complicating senile macular degeneration Ophthalm Surg 1 985 ;16:6 48 651 Meyers SM, Zachary AA Monozygotic twins with age-related macular degeneration Arch Ophthalmol 1 988 ;106:651–653... Biol Sci 1 982 ; 216(1202):71 85 Bone RA, Landrum JT Macular pigment in Henle fiber membranes: a model for Haidinger’s brushes Vision Res 1 984 ;24(2):103–1 08 Snodderly DM Evidence for protection against age-related macular degeneration by carotenoids and antioxidant vitamins Am J Clin Nutr 1995;62(Suppl):1448S– 1461S Young RW Solar radiation and age-related macular degeneration Surv Ophthalmol 1 988 ;32(4):252–269... Antioxidant status and neovascular age-related macular degeneration Eye Disease Case-Control Study Group Arch Ophthalmol 1993;111:104–109 Risk factors for neovascular age-related macular degeneration The Eye Disease Case-Control Study Group Arch Ophthalmol 1992;110:1701–17 08 Goldberg J, Flowerdew G, Smith E, Brody JA, Tso MO Factors associated with age-related macular degeneration An analysis of data... and age-related maculopathy: the Blue Mountains Eye Study Ophthalmology 19 98; 105 (8) :1359– 1363 Chaine G, Hullo A, Sahel J, Soubrane G, Espinasse-Berrod M-A, Schutz D et al Case-control study of the risk factors for age-related macular degeneration Br J Ophthalmol 19 98; 82(9):996–1002 Sandberg MA, Gaudio AR, Miller S, Weiner A Iris pigmentation and extent of disease in patients with neovascular age-related. .. vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no 8 Arch Ophthalmol 2001;119(10):1417–1437 Newsome DA, Swartz M, Leone NC, Elston RC, Miller E Oral zinc in macular degeneration Arch Ophthalmol 1 988 ;106(2):192–1 98 Stur M, Tittl M, Reitner A, Meisinger V Oral zinc and the second eye in age-related macular degeneration Invest Ophthalmol Vis Sci 1996;37(7):1225–1235... degeneration Arch Ophthalmol 1 989 ;107(6):675 87 9 Vinding T Pigmentation of the eye and hair in relation to age-related macular degeneration: an epidemiological study of 1000 aged individuals Acta Ophthalmol (Copenh) 1990; 68( 1):53– 58 Tsang NCK, Penfold PL, Snitch PJ, Billson F Serum levels of antioxidants and age-related macular degeneration Doc Ophthalmol 1992 ;81 (4): 387 –400 Klein R, Klein BEK, Jensen . West SK. Epidemiology of age-related macular degeneration. Mol Vis 1999;5:26. 5. Antioxidant status and neovascular age-related macular degeneration. Eye Disease Case-Con- trol Study Group. Arch. Fine (1 984 ) (197) Holz et al. (1994) (1 98) Bressler et al. (1995) (199) 98/ 49 142/71 126 patients 483 patients 61 (29 81 ) 58 (16– 78) 68 NA 20/20 OU in 21 patients (43%) 20/25 to 20/40 OU in 18 patients. large-scale randomized clinical trials including the Age-Related Eye Disease Study (AREDS) (153,173), the Physi- cians’ Health Study II (PHS II) (1 78) , the Vitamin E, Cataract, and Age-related macular degeneration

Định dạng
Số trang	56
Dung lượng	378,83 KB