Associations between plasma levels of vitamins and cataract in the Italian-American Clinical Trial of Nutritional Supplements and Age-Related Cataract (CTNS): CTNS Report #2.

PURPOSE: To investigate the association at baseline between plasma levels of selected vitamins and the presence and type of cataract in the participants in The Italian-American Trial of Nutritional Supplements and Age-related Cataract. METHODS: At baseline, the participants (1020, 710 with "early cataract" and 310 with "no cataract," 55-75 years of age) received an ocular examination, photographic lens grading, and measurement of plasma levels of vitamins A, C, E, beta-carotene, and of red blood cell glutathione reductase activity. RESULTS: In multiple logistic models adjusted for potential confounders, high vitamin C levels were associated with a protective effect on nuclear (N) [OR: 0.54; 95% CI: 0.30, 0.97] and posterior subcapsular (PSC) cataract (OR: 0.37; 95% CI: 0.15, 0.93). High vitamin E levels were associated with increased prevalence of cortical cataract (C) (OR: 1.99; 95% CI: 1.02-3.90), PSC (OR: 3.27; 95% CI: 1.34, 7.96) and of any cataract (OR: 1.86; 95% CI: 1.08, 3.18). CONCLUSIONS: In agreement with some earlier studies, we found higher plasma levels of vitamin C to be associated with reduced prevalence of N and PSC cataracts. The finding of an increased prevalence of some types of cataract with higher levels of vitamin E was unexpected, has not been previously reported, and could be due to unadjusted confounding.

Postmenopausal estrogen use, type of menopause, and lens opacities: the Framingham studies.

BACKGROUND: Previous studies of estrogen replacement therapy and lens opacities have not reported consistent findings. OBJECTIVE: To investigate whether postmenopausal estrogen use is associated with the occurrence of age-related lens opacities (nuclear, cortical, and posterior subcapsular). METHODS: Surviving members of the original cohort of the Framingham Heart Study who also participated in the Framingham Eye Study (1986-1989) were examined for the absence or presence of lens opacities. Data from the Framingham Heart Study, including information on menopausal status (collected biennially from approximately 1948) and use of estrogen replacement therapy (collected biennially from approximately 1960) were used to examine associations between lens opacities and duration of postmenopausal estrogen use, type of menopause, and age at menopause. Five hundred twenty-nine women, aged 66 to 93 years, were included. Multivariable-adjusted odds ratios of specific types of lens opacities were calculated for (1) duration of estrogen use (never and 1-2, 3-9, and >/=10 years), (2) surgical vs natural menopause, and (3) age at menopause. RESULTS: Longer duration of postmenopausal estrogen therapy was inversely associated with the presence of nuclear lens opacities in an adjusted model. Women who had taken estrogen for 10 years or longer had a 60% reduction in risk compared with nonusers (odds ratio, 0.4; 95% confidence interval, 0.2-1.01). Longer duration of estrogen use was associated with fewer posterior subcapsular opacities at a borderline level of significance. No association was noted for cortical opacities. The risk of posterior subcapsular opacities was significantly increased for women who had undergone surgical menopause compared with women with natural menopause (odds ratio, 2.2; 95% confidence interval, 1.1-4.3). No association was noted for lens opacities and age at menopause. CONCLUSION: Data from our study and other studies suggest that a reduction in the risk of lens opacities may be an additional benefit of postmenopausal estrogen use.

Evaluation of an iris color classification system. The Eye Disorders Case-Control Study Group.

A system for classification of iris color based on standard photographs, developed for use in a multicenter study, is described. Categories of iris color are distinguished based on predominant color (blue, gray, green, light brown, or brown) and the amount of brown or yellow pigment present in the iris. Two trained readers independently graded 339 iris photographs; discrepancies in grades were adjudicated. Measures of interobserver reliability were 0.76 by kappa for exact agreement and 0.97 for weighted kappa. The distribution of iris color grades demonstrates that the system achieved an appropriate level of detail within the authors' study population, which included patients with various racial backgrounds from five urban clinical centers. This simple, reliable classification system for iris color is offered for use in clinical research.

Measurement error in assessing the size of posterior subcapsular cataracts from retroillumination photographs.

Twenty-six eyes with posterior subcapsular opacities of various sizes were photographed with the Neitz-Kawara Retroillumination camera. The outline of the opacity in a single photograph of each opacity was traced onto a transparent plastic overlay twice by two independent outliners. Two methods were used to estimate the area within the outlines of the opacities. In the first, a transparent overlay with a standard grid was used to count the number of boxes within the outlines. The second method used computer planimetry to estimate the area within the tracings. We estimated the measurement error associated with a single outlining of an opacity and the contribution of the measurement error to overall sample size requirements in studies comparing the mean areas of posterior subcapsular opacities. Variability in the measurement techniques contributed fewer than 20 additional subjects to overall sample size estimates, a small contribution to total sample size requirements in most studies. An outliner's inherent variability in outlining an opacity was a much larger contributor to the measurement error than was variability in assessing the area of the outline of the opacity. While within outliner variability was similar for the two persons outlining the opacities, there were systematic differences in the way the two traced the outlines. Variability from the use of separate photographs of the same opacity taken by different photographers was minimal.

Location and severity of cortical opacities in different regions of the lens in age-related cataract.

PURPOSE: To examine the distribution of cortical opacities across the lens in the Italian-American Natural History Study of Age-Related Cataract and to study the association between an index of sunlight exposure and the location of cortical cataract within the lens. METHODS: Lens photographs of one eye of 731 persons with cortical opacities (503 with pure and 228 with mixed types of opacity) were included in the analysis. A radial grid superimposed on the photographs was used to assess presence, location, and severity of wedge-shaped cortical opacities. RESULTS: Both the prevalence and the extent of cortical opacities were highest in the inferior-nasal quadrant and lowest in the superior-nasal quadrant of the lens. In polychotomous logistic regression, persons with the greatest excess areal involvement in the inferior half of the lens were more likely to have high exposure to sunlight, as measured by a sunlight index, than persons with excess involvement in the superior half of the lens (odds ratio, 1.73; 95% confidence interval 1.03, 2.93). Excess areal involvement of the inferior lens also was associated with the pure type of cortical cataract and with the total extent of the opacity. CONCLUSIONS: Age-related cortical opacities occur more frequently inferiorly than superiorly and, to a lesser extent, nasally than temporally. Possibly higher exposure of these lens segments to sunlight may explain this preferential location of cortical opacities.

The effect of cataract severity and morphology on the reliability of the Lens Opacities Classification System II (LOCS II).

Data collected from 3646 eyes in the Italian-American Natural History Study of Age-Related Cataract were used to investigate whether the reliability of the Lens Opacities Classification System II (LOCS II) by the severity of the opacity that is being graded or is influenced by the presence and severity of coexisting opacities. Reliability was assessed by comparing the slit-lamp gradings of two clinical examiners (346 eyes) and the gradings performed at the slit lamp with gradings of photographs (3646 eyes). The severity of cortical and nuclear opacities did not affect the reproducibility of slit-lamp gradings, but clinical grading of posterior subcapsular opacities became more reliable as the severity of the posterior subcapsular opacities increased. More advanced coexisting opacities decreased the agreement in the slit-lamp diagnosis of nuclear, but not cortical or posterior subcapsular, opacities. Comparisons of clinical and photographic gradings showed very good to excellent agreement for nuclear and cortical opacities, regardless of the severity of the specific opacity or the severity of the coexisting opacities. Agreement in diagnosing posterior subcapsular opacities was decreased in eyes with milder posterior subcapsular opacities and in eyes with more severe coexisting nuclear and/or cortical opacities. The effect of the severity of the opacity being graded and the severity of coexisting opacities on the reliability of the LOCS II must be considered in studies that use the system to classify and grade cataracts.

Influence of type and severity of pure forms of age-related cataract on visual acuity and contrast sensitivity. Italian American Cataract Study Group.

PURPOSE: To compare the relationship between logMAR visual acuity (VA) and cataract severity and between contrast sensitivity (CS) and cataract severity in pure types of age-related lens opacities. METHODS: Analysis included patients followed in the ongoing Italian-American Study of the Natural History of Age-Related Cataract. Lens opacities were classified and graded according to the Lens Opacities Classification System II (LOCS II). Visual acuity was measured with the Early Treatment Diabetic Retinopathy Study Chart. Contrast sensitivity was measured with the Pelli-Robson chart. RESULTS: Data from 1,076 eyes were used for the analysis (366 clear lenses; 550, 124, and 36 eyes with cortical, nuclear and posterior subcapsular cataract, respectively). In age-adjusted analyses, increasing severity of all three cataract types was associated with progressively higher logMAR VA, which translates into poorer acuity, and lower CS scores. For both VA and CS, the effect of increasing severity was greatest for nuclear and least for cortical opacities. After adjusting for age and VA, CS scores were no longer associated with cataract type and severity, with the exception of advanced cortical opacities. CONCLUSIONS: Increased cataract severity, as determined by LOCS II grading, is strongly associated with both VA and CS scores. Contrast sensitivity scores obtained from testing at low spatial frequency do not seem to offer additional information over standard VA testing in early cortical and posterior subcapsular opacities nor in nuclear cataracts.

Glutathione S-transferase M1 genotype and age-related cataracts. Lack of association in an Italian population.

PURPOSE: To investigate possible associations between the gene number and allelic forms of glutathione S-transferase M1 (GSTM1) and the occurrence of nucleic and cortical age-related cataracts. METHODS: Patients with cortical cataract, nuclear cataract, mixed and cortical cataract, and no cataract were sytematically selected from subjects evaluated in the Italian-American Study of the Natural History of Age-Related Cataract. The patients were typed for the A, B, and null alleles of GSTM1 using a variation of the amplification refractory mutation system. RESULTS: Forty-nine percent of patients (50/102) with cortical cataracts, 45% (13/29) with nuclear cataracts, 51% (36/71) with mixed nuclear and cortical cataracts, and 50% of controls (49/98) were homozygous for the null GSTM1 allele. Twenty-five percent of patients (26/102) with cortical cataracts, 24% (7/29) with nuclear cataracts, 31% with mixed nuclear and cortical cataracts, and 27% of controls (26/98) displayed only the A allele for GSTM1. Twenty-four percent of patients (24/102) with cortical cataract, 24% (7/29) with nuclear cataracts, 14% (10/71) with mixed nuclear and cortical cataract, and 18% of controls showed only the B allele for GSTM1. Two percent of patients (2/102) with cortical cataracts, 7% (2/29) with nuclear cataracts, 4% (3/71) with mixed nuclear and cortical cataracts, and 5% of controls (5/98) showed both A and B alleles for GSTM1. CONCLUSIONS: No associations between the GSTM1 alleles, including the null allele, and cataracts were detected in this study.

A dose-response effect between a sunlight index and age-related cataracts. Italian-American Cataract Study Group.

To explore the existence of a dose-response relationship between sunlight exposure and risk of age-related cataracts, we analyzed data collected from 1008 patients with cataracts and 469 control subjects enrolled in the Italian-American Case-Control Study of Age-Related Cataracts. Fourteen variables related to sunlight exposure history were included in the questionnaire administered to the study participants. A sunlight index was constructed and its relationship to the presence of cataracts was modeled by logistic regression. After adjustments for potential confounding variables and for age and sex, a significant dose-response effect (P = 0.01) was detected between the sunlight exposure index and the presence of pure cortical cataracts. With the exception of corticonuclear cataracts, all the other mixed types of opacity also showed a dose-response association with the sunlight index. These data support the hypothesis that sunlight exposure is a risk factor in the development of cortical cataracts, and demonstrate the existence of a dose-response relationship in this association.

Serum zinc and serum lipid profiles in 778 adults.

There has been increasing use of high-dosage zinc supplementation in the population, in particular as a potential treatment for age-related macular degeneration. We examined the relationship between fasting serum zinc and serum lipid levels in 778 adults, aged 22 to 80 years, who were control subjects in a multicenter, clinic-based case-control study. The samples were taken during 1987 to 1990, a time when vitamin/mineral supplementation was becoming increasingly common. We found that higher serum zinc levels, most notably those above the highest quintile, were associated with higher levels of total serum cholesterol, low-density-lipoprotein cholesterol, and triglycerides. No significant trend was noted for high-density-lipoprotein cholesterol. Previous studies demonstrated that high-dosage zinc supplements raise serum zinc levels. The possibility that use of such supplements can adversely affect serum lipid profiles suggests that chronic ingestion of such supplements should not be done without adequate medical supervision.

Systemic hypertension and age-related maculopathy in the Framingham Study.

Analysis of data on 1,828 subjects from the Framingham Heart and Eye Studies shows a small and consistent significant association between age-related maculopathy and systemic hypertension. The association was found using blood pressure and medical history data collected both 25 years before the eye examination and concurrently with the eye examination. Prevalence of age-related maculopathy progressively increases with increasing duration of systemic hypertension. Previous epidemiologic studies of the association between systemic blood pressure and age-related maculopathy have produced conflicting results. The failure of some studies to detect an association may have resulted from inadequate sample sizes to detect the small relative risks and problems in determining the duration of the systemic hypertension.

Lens opacities and senile maculopathy.

Analysis of data from a population survey, the Framingham Eye Study, shows that when the various senile lens changes are pooled, no associations with senile maculopathy are evident. Subgroup analysis shows the relative risk of senile maculopathy to be lower than 1.00 in the presence of nuclear sclerosis for all age groups and greater than 1.00 for persons between 52 and 74 years in the presence of cortical changes. Nuclear-cortical interaction tests are highly significant, indicating that nuclear sclerosis and cortical opacities have opposite effects on the relative risk of senile maculopathy.

Pseudoexfoliation, intraocular pressure, and senile lens changes in a population-based survey.

The prevalence rate of pseudoexfoliation among persons in the Framingham Eye Study, a population-based survey, increased from 0.6% for ages 52 to 64 years to 2.6% for ages 65 to 74 years to 5.0% for ages 75 to 85 years. Age-adjusted rates showed a statistically significant 2.3 to 1.0 female to male ratio. Pseudoexfoliation was associated with higher intraocular pressure levels and more frequent senile lens changes, but the latter relationship was not statistically significant. The age-specific prevalence rates for the Framingham population are similar to those reported from a mass screening of subjects in Norway, where the condition is thought to be especially common. Some of the previously reported geographic variations in prevalence rates may be due to differences in disease definitions, subject selection, and examination conditions.

Factors affecting outcome and predictability of radial keratotomy in the PERK Study.

The Prospective Evaluation of Radial Keratotomy (PERK) study used a standardized surgical technique that included a central clear zone with a diameter of 4.0, 3.5, or 3.0 mm. Multiple regression analysis of the outcome in one eye from each of 411 patients disclosed that the diameter of the central clear zone, patient age, and depth of the incision scar were the major factors affecting the change in refraction one year after surgery. Preoperative factors examined that did not have a significant influence on the outcome were sex, average central keratometric power, corneal thickness, corneal diameter, intraocular pressure, and ocular rigidity. The predictability of radial keratotomy, ie, the precision with which the outcome can be estimated, was measured by the 90% confidence interval for the change in refraction based on the regression equation. The width of this interval within each clear zone group was as follows: 4.0 mm, 2.49 diopters; 3.5 mm, 3.38 D; 3.0 mm, 4.12 D. For all 411 eyes, the 90% confidence interval was approximately 3.50 D wide. Thus, the surgeon could be 90% certain that an individual patient's refraction would be within 1.75 D of the predicted value one year after surgery.

Prevalence of myopia in the United States.

Data from the 1971 to 1972 National Health and Nutrition Examination Survey were used to estimate myopia prevalence rates for persons in the United States between the ages of 12 and 54 years. When persons were classified by the refractive status of their right eye, 25% were myopic. Significantly lower prevalence rates were found for male subjects than for female subjects and for blacks than for whites. Myopia prevalence rose with family income and educational level. The importance of income and educational level may result from their association with near work, a factor that has been implicated in the pathogenesis of myopia.

Relationship between refractive error and visual acuity in the Prospective Evaluation of Radial Keratotomy (PERK) Study.

As part of the Prospective Evaluation of Radial Keratotomy (PERK) study, we examined the relationship between post-operative refractive error and visual acuity without correction. We included 394 eyes (one eye per patient) with refractive errors ranging from -3.00 to +3.00 diopters one year after radial keratotomy. Within each 1-D range of the spherical equivalent of the refractive error, the visual acuity spanned five to ten Snellen lines. For visual acuities of 20/16 to 20/50, the refractive error spanned 3 to 5 D. Additionally, operated eyes had a better average uncorrected visual acuity than unoperated eyes with a similar refractive error. Within the narrow range of refraction between -2.00 and -2.50 D, the mean uncorrected visual acuity was 20/125 for 56 unoperated eyes and 20/63 for 29 operated eyes, a difference of three Snellen lines.

Age-related cataract in the Tibet Eye Study.

The Tibet Eye Study was designed to estimate the prevalence of age-related cataract in Duilong-Deqing County, west of Lhasa, China (altitude, 4000 m). Previous reports have suggested an unusually high prevalence of age-related cataract in Tibet. A two-stage probability sample of persons aged 20 years or older from the 35 townships of the county targeted 2884 persons for inclusion in the study; 2665 (92.4%) were examined. Age-related cataract was diagnosed when (1) visual acuity was worse than 6/12 (20/40) because of nuclear or cortical (including posterior subcapsular) opacities, or (2) aphakia associated with a history of age-related cataract was present in either eye. The prevalence of age-related cataract among persons aged 20 to 39 years was 0.2%; among persons 40 years old or older, the prevalence was 11.8%. Cortical cataracts were by far the most common type of cataract diagnosed. Age- and sex-adjusted prevalence in Tibet was 60% higher than the prevalence in a similar, previously conducted study of 6951 person in Shunyi County, northeast of Beijing (altitude, 50 m). A second, independent slit-lamp classification of lens status was conducted in the Tibet Eye Study using standard photographs previously described. Age-specific cataract prevalence was similar with the two examination techniques. Results from the Tibet Eye Study support previous suggestions of a high prevalence of age-related cataract in Tibet.

Dietary fat and risk for advanced age-related macular degeneration.

OBJECTIVE: To evaluate the relationship between intake of total and specific types of fat and risk for advanced age-related macular degeneration (AMD), the leading cause of irreversible blindness in adults. DESIGN: A multicenter eye disease case-control study. SETTING: Five US clinical ophthalmology centers. PATIENTS: Case subjects included 349 individuals (age range, 55-80 years) with the advanced, neovascular stage of AMD diagnosed within 1 year of their enrollment into the study who resided near a participating clinical center. Control subjects included 504 individuals without AMD but with other ocular diseases. Controls were from the same geographic areas as cases and were frequency-matched to cases by age and sex. MAIN OUTCOME MEASURES: Relative risk for AMD according to level of fat intake, controlling for cigarette smoking and other risk factors. RESULTS: Higher vegetable fat consumption was associated with an elevated risk for AMD. After adjusting for age, sex, education, cigarette smoking, and other risk factors, the odds ratio (OR) was 2.22 (95% confidence interval [CI], 1.32-3.74) for persons in the highest vs those in the lowest quintiles of intake (P for trend,.007). The risk for AMD was also significantly elevated for the highest vs lowest quintiles of intake of monounsaturated (OR, 1.71) and polyunsaturated (OR, 1.86) fats (Ps for trend,.03 and.03, respectively). Higher consumption of linoleic acid was also associated with a higher risk for AMD (P for trend,.02). Higher intake of omega-3 fatty acids was associated with a lower risk for AMD among individuals consuming diets low in linoleic acid, an omega-6 fatty acid (P for trend,.05; P for continuous variable,.03). Similarly, higher frequency of fish intake tended to reduce risk for AMD when the diet was low in linoleic acid (P for trend,.05). Conversely, neither omega-3 fatty acids nor fish intake were related to risk for AMD among people with high levels of linoleic acid intake. CONCLUSION: Higher intake of specific types of fat--including vegetable, monounsaturated, and polyunsaturated fats and linoleic acid--rather than total fat intake may be associated with a greater risk for advanced AMD. Diets high in omega-3 fatty acids and fish were inversely associated with risk for AMD when intake of linoleic acid was low.

Low-dose aspirin and risks of cataract in a randomized trial of US physicians.

Observational studies have raised the question of a possible benefit of aspirin on the development of cataract. The Physicians' Health Study, a randomized double-masked placebo-controlled trial among 22,071 male physicians, aged 40 to 84 years, provided the opportunity to collect information about whether low-dose aspirin therapy (325 mg on alternate days) affects the development or extraction of cataract. There were 173 age-related cataracts among those physicians assigned to aspirin therapy and 180 among those given placebo (relative risk, 0.95; 95% confidence interval, 0.74 to 1.22). Cataract extractions were less frequent in the aspirin than in the placebo group, but this difference was not statistically significant (relative risk, 0.80; 95% confidence interval, 0.56 to 1.15). Among younger men (aged 40 to 59 years), the relative risks were 0.62 (95% confidence interval, 0.40 to 0.94) for cataract development and 0.67 (95% confidence interval, 0.38 to 1.31) for cataract extraction. These randomized trial data tend to exclude any large benefit of aspirin. While the overall findings concerning cataract development seem to be null, the data on extraction of age-related cataract, while not statistically significant, cannot exclude a possible small to moderate benefit of alternate-day aspirin therapy on the extraction of age-related cataract.

The Linxian cataract studies. Two nutrition intervention trials.

OBJECTIVE: To determine whether the vitamin/mineral supplements used in two cancer intervention trials affected the risk of developing age-related cataracts. DESIGN: Two randomized, double-masked trials with a duration of 5 to 6 years and end-of-trial eye examinations. SETTING: Rural communes in Linxian, China. PARTICIPANTS: In trial 1, 2141 participants aged 45 to 74 years, and, in trial 2, 3249 participants aged 45 to 74 years. INTERVENTIONS: Multivitamin/mineral supplement or matching placebo in trial 1; factorial design to test the effect of four different vitamin/mineral combinations in trial 2 (retinol/zinc, riboflavin/niacin, ascorbic acid/molybdenum, and selenium/alpha-tocopherol/beta carotene). MAIN OUTCOME MEASURES: Prevalence of nuclear, cortical, and posterior subcapsular cataracts in treatment groups at end of trials. RESULTS: In the first trial, there was a statistically significant 36% reduction in the prevalence of nuclear cataract for persons aged 65 to 74 years who received the supplements. In the second trial, the prevalence of nuclear cataract was significantly lower in persons receiving riboflavin/niacin compared with persons not receiving these vitamins. Again, persons in the oldest group, 65 to 74 years, benefited the most (44% reduction in prevalence). No treatment effect was noted for cortical cataract in either trial. Although the number of posterior subcapsular cataracts was very small, there was a statistically significant deleterious effect of treatment with riboflavin/niacin. CONCLUSIONS: Findings from the two trials suggest that vitamin/mineral supplements may decrease the risk of nuclear cataract. Additional research is needed in less nutritionally deprived populations before these findings can be translated into general nutritional recommendations.