Baseline Cataract Type and 10-Year Mortality in the Italian-American Case-Control Study of Age-related Cataract

Sally L. Williams1, Luigina Ferrigno2, Paolo Mora1, Francesco Rosmini2 and Giovanni Maraini2

1 Ophthalmology, Department of Science, ORL-Odonto-Oftalmologiche, University of Parma, Parma, Italy.
2 Laboratory for Epidemiology and Biostatistics, Istituto Superiore di Sanità, Roma, Italy.

Received for publication October 12, 2001; accepted for publication February 25, 2002.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Age-related cataract is reported to be associated with increased risk of death. The authors investigated the association of presence and type of cataract with mortality in the participants of the Italian-American Case-Control Cataract Study (Parma, Italy, 1987–1989), which included 1,008 persons aged 45–79 years who had age-related cataract and 469 who had clear lenses. Slit-lamp and retroillumination lens photographs were taken at baseline and graded with the Lens Opacities Classification System II. During 10 years of follow-up (range, 8.9–11.8 years; 11,318 person-years), the authors collected information on 1,429 participants and documented 339 deaths. After adjustment for age, sex, and other mortality risk factors, mixed cataracts with a nuclear/posterior subcapsular component were significantly associated with higher risk of death by Cox proportional hazards regression analyses. Hazard ratios were 2.26 (95% confidence interval (CI): 1.07, 4.76) for nuclear/posterior subcapsular and 1.62 (95% CI: 1.01, 2.61) for cortical/nuclear/posterior subcapsular opacities. In multivariate analysis, mixed types of opacity (any) were associated with increased mortality for malignancy (hazard ratio = 1.81, 95% CI: 1.04, 3.15) and "other" causes (hazard ratio = 2.29, 95% CI: 1.07, 4.92). These findings are compatible with the hypothesis that mixed types of cataract with a nuclear/posterior subcapsular component are indicators of accelerated aging. Am J Epidemiol 2002;156:127–31.

aging; cataract; mortality

Abbreviations: Abbreviations: CI, confidence interval; HR, hazard ratio.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Increased mortality has been reported by some studies (15) but not by others (6) to be associated with cataract or cataract surgery in diabetic or young patients and also in elderly nondiabetic persons. More recent studies using photographic cataract grading reported that nuclear opacities (7) or any type of age-related cataract (5) is independently associated with decreased survival. We report here the predictors of mortality in the participants of the Italian-American Case-Control Study of Cataract after a follow-up period of 10 years. Our objectives were to determine the risk of death associated with the presence and type of lens opacity, the influence of different confounding factors, and the relative distribution of cause-specific mortality in persons with and without cataract.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Participants
The Italian-American Case-Control Study of Cataract (8) was a clinic-based study conducted in Parma, Italy, from 1987 to 1989, with a total of 1,008 cases and 469 controls who were aged between 45 and 79 years. All participants were White. Participants were recruited from the three ophthalmic clinics of the National Health Service that provide ophthalmic care in Parma (8). Subjects qualified as cases if both pupils could be dilated to at least 6 mm, at least one eye had an age-related lens opacity, and there were no conditions other than cataract that might account for any vision loss present. Participants qualified as controls if both lenses were graded as having no lens opacities with a pupil dilation of at least 6 mm, both eyes had 6/6 best corrected visual acuity, and there was an eligible control diagnosis. Data on physiologic, medical, behavioral, nutritional, and biochemical variables were collected by direct measurements and interviews (8).

Grading of lens status
At baseline, Zeiss slit-lamp (C. Zeiss, Oberkochen, Germany) and Neitz retroillumination (Kowa Optimed, Inc., Torrance, California) lens photographs were taken and graded with the Lens Opacities Classification System II (9). The system, which uses standard reference photographs for each type of opacity, provides ordinal scores for grading the presence and severity of nuclear opalescence (scale: 0–IV), cortical opacities (scale: 0–V), and posterior subcapsular opacities (scale: 0–IV). Grading was performed simultaneously and independently by two masked graders. Disagreements were resolved by consensus. Reproducibility was monitored periodically with very good agreement.

For the present study, cortical, nuclear, and posterior subcapsular cataracts were defined as present at baseline if at least one eye had a grade of >I for a given opacity type. Gradable lens photographs of all eligible eyes were available in 1,460 participants (99 percent), and follow-up information was collected on 1,429 participants (97 percent): 438 with no lens opacities, 517 with pure cortical, 99 with pure nuclear, 16 with pure posterior subcapsular, and 359 with mixed types of cataract or aphakia. Thirty-seven participants had one aphakic or pseudophakic eye at baseline.

Assessment of study variables
Data on the body mass index, hand-grip strength, systemic blood pressure, and blood antioxidant index were obtained by direct measurement at baseline. The antioxidant index was constructed using plasma selenium, vitamin E, and red blood cells’ glutathione peroxidase levels (8). Information on age, sex, behavioral, nutritional, medical, and environmental variables, in particular smoking, alcohol use, medication use, history and duration (years) of diabetes, arthritis, cardiovascular disease, and hypertension was collected at baseline. Medical variables were validated using medical records review when possible. Cataract type was defined according to the lens status of both eyes. If bilateral, the opacity with the higher grade was selected.

Assessment of mortality and causes of death
Of the 1,460 participants in the case-control study with lens photographs, those who died after baseline were identified by consulting the files of the Parma Registry Office with a censoring cutpoint set at November 4, 1998. Of the 123 participants who lived outside Parma or who had moved to a different area after the case-control study, living status or death was assessed for 92 of the 123 participants (75 percent) by direct telephone contact with the participants or their relatives and by consulting the files of their local Registry Office. Information on living status or death was obtained for 1,429 participants (97 percent). For those who died in Parma or in the suburban areas, the main cause of death and the relative code based on the International Classification of Diseases, Ninth Revision, were obtained from the Azienda Unità Sanitaria Locale in Parma, where all death certificates are stored. The cause of death was obtained for all of the 339 participants who died.

Statistical analyses
The major outcome variable was death within the follow-up interval from baseline to November 4, 1998. For the survival analysis, person-time was calculated as the months from baseline examination to death or to November 4, 1998. As a first step, Cox proportional hazard models were created to calculate age- and sex-adjusted hazard ratios for 10-year mortality. Age was modeled as a continuous variable. The final model included variables found or known to be significantly associated with increased mortality: hand-grip strength (lower, medium, and upper tertile); smoking history (never, past, current); topical or systemic steroid use (yes/no); and number of medical visits within 5 years before baseline (0–2, 3–5, 6–10, and >10). Because the assumptions for the proportional hazard analysis were not valid for the group of pure posterior subcapsular opacities and also in consideration of the very small sample (n = 16) of participants with this type of cataract, they were not included in the Cox model.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Between the baseline examination and the censoring cutpoint of the case-control study, 66 deaths were recorded among the 438 subjects with clear lenses (15.1 percent) and 273 deaths were recorded among the 991 subjects with cataract (27.5 percent) for whom this information could be obtained. The median follow-up time for survivors was 10.4 years (range, 8.9–11.8 years). Persons without cataract were younger than persons with cataract (median age, 65 and 69 years, respectively), and there were more females with cataract (62 percent) than without cataract (55.9 percent). The overall mortality rate (23.6 percent) was slightly higher than that registered in the general population of the same sex and age range in the Parma district (21.3 percent) (10). Table 1 reports age- and sex-adjusted hazard ratios for mortality by the presence and type of cataract and by selected risk factors. A significant association with increased mortality is present for mixed nuclear/posterior subcapsular cataracts (hazard ratio (HR) = 2.11, 95 percent confidence interval (CI): 1.04, 4.25), for cortical/nuclear/posterior subcapsular cataracts (HR = 1.61, 95 percent CI: 1.02, 2.52), and for mature cataract/aphakia (HR = 1.93, 95 percent CI: 1.21, 3.08). Smoking, poor hand-grip strength, and an increased mean number of annual medical visits in the 5 years prior to baseline were also statistically associated with increased mortality. In multivariate analysis (table 2), after further adjustment for smoking, hand-grip strength, cortisone use, and number of medical visits, the association between mortality and mixed cataracts with a nuclear/posterior subcapsular component was confirmed (HR = 2.26, 95 percent CI: 1.07, 4.76 for nuclear/posterior subcapsular cataracts; HR = 1.62, 95 percent CI: 1.01, 2.61 for cortical/nuclear/posterior subcapsular cataracts). The association between mature cataract/aphakia and increased mortality was no longer present. After adjusting for the same variables, we investigated the possible influence of cataract severity but no clear gradient was detected (table 3), although there was a tendency of earlier opacities to be more associated with mortality.


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TABLE 1. Ten-year mortality by selected characteristics at baseline, Italian-American Cataract Study, Parma, Italy, 1987–1998
 

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TABLE 2. Risk of death by cataract type, Italian-American Cataract Study, Parma, Italy, 1987–1998
 

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TABLE 3. Risk of death by severity of cataract, Italian-American Cataract Study, Parma, Italy, 1987–1998
 
Causes of death were classified as malignancies (n = 128; 38 percent), cardiovascular diseases (n = 128; 38 percent), and "other" (n = 83; 24 percent). After adjustment for age, sex, smoking, hand-grip strength, cortisone use, and number of medical visits, mixed cataracts (any) showed a significant positive association with malignancies (HR = 1.81, 95 percent CI: 1.04, 3.15) and "other" causes (HR = 2.29, 95 percent CI: 1.07, 4.92). No association was detected with death for cardiovascular disease (HR = 1.03, 95 percent CI: 0.57, 1.87) (table 4).


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TABLE 4. Association between cataract type and selected causes of death, Italian-American Cataract Study, Parma, Italy, 1987–1998
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Previous studies have produced evidence supporting the association between cataract or cataract extraction and increased mortality. However, the Physicians’ Health Study failed to detect an association between self-reported cataract and mortality in 18,669 participants after more than 12 years of follow-up (6). Studies that utilized a precise classification of cataract type and severity found increased mortality to be associated with practically any type of opacity. Any nuclear/posterior subcapsular and cortical cataracts and mixed opacities have been found, in different studies, to be independent predictors of increased mortality (4, 5, 7, 1113). The results of our study, after a 10-year follow-up, support the hypothesis of a relation between the existence of age-related mixed lens opacities with a nuclear/posterior subcapsular component and decreased survival. We found these types of cataract to be significant predictors of mortality even after adjusting for other possible factors of decreased survival. We did not detect an association between mortality and pure forms of cataracts. A moderate increase in risk for mortality with increased severity of nuclear opacity was reported by West et al. (7). We have not been able to identify such a gradient. At least four population studies have reported increased mortality of diabetics with cataract, but existing evidence also supports increased mortality in nondiabetic cataract patients (1, 4, 12, 1416). In our population, there was no interaction between diabetes and cataract that resulted in increased mortality, but this may have resulted from the systematic exclusion of diabetics with any sign of retinopathy that could have caused a reduction in visual acuity. Misclassification might explain our inability to detect an association between the number of comorbid conditions and mortality because other conditions were not ascertained.

Our study has several strengths such as the relatively long follow-up period, the use of a reliable cataract classification system, 97 percent complete mortality follow-up, and a single reference group (persons with clear lenses) at baseline in the principal analyses. We attempted to minimize the influence of unadjusted confounding by including in the analysis all the variables that we found to be associated with increased mortality. The study also has some limitations mainly deriving from not being a population study. In spite of our precautions to get comparable cases and controls, we could have enrolled more sick people in the case group than in the controls, and the adjustments made in the analyses may not have been adequate to compensate for the imbalance. Although not new, our data add to previous findings, and their consistency with those of other studies suggests that the association between decreased survival and the presence of some types of age-related lens opacities is real. We found a significant association between increased mortality and mixed cataracts with a nuclear/posterior subcapsular component, the type of opacity most frequently leading to surgery (17). Our finding is consistent with the results of the studies that found an association between cataract surgery and increased mortality (2, 3, 13, 16).

We found that mixed cataracts (any) have a significantly increased relative risk of mortality for cancer. We cannot at the moment offer any reasonable interpretation for this association that is similar to the association for mixed nuclear opacities found by West et al. (7).

Previous studies on cause-specific mortality reported an association of cortical cataract with cardiovascular risk factors (18). A recent prospective study (13) of 60,657 participants reported, during 10 years of follow-up, a significant association between cataract extraction and higher risk for coronary heart disease, which entirely explained the increased overall mortality. In our multivariate analysis, we found no association between cardiovascular mortality and pure or mixed cataract types. A possible explanation for the difference in findings between the two studies may be the different study design, our smaller sample size, or some information bias such as misclassification in the attribution of the diagnoses on the death certificate.

At present the possible mechanisms to explain the association between cataract and decreased survival are at least in part hypothetical. It is tempting to recall that the available evidence indicates oxidative damage to be involved in the opacification of the aging eye lens and also, in other tissues, in other age-related degenerative diseases (19). It seems reasonable to imagine that the condition of transparency of the lens might be a biologic predictor of senescence more reliable than simple chronologic age.


    ACKNOWLEDGMENTS
 
Supported by Cofin98, Ministero dell’Universita e della Ricerca Scientifica e Tecnologica (MURST), and National Eye Institute contracts N01-EY-6-2110 and N01-EY-6-2111.

Presented in part as an abstract at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), Ft. Lauderdale, Florida, April 29–May 4, 2001.


    NOTES
 
Correspondence to Dr. Giovanni Maraini, Oftalmologia, Università di Parma, via Gramsci 14, 43100 Parma, Italy (e-mail: maraini{at}unipr.it). Back


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 RESULTS
 DISCUSSION
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