Review Article Association of vitamin C with the risk of age-related cataract: a meta-analysis Lin Wei, Ge Liang, Chunmei Cai and Jin Lv Department of Ophthalmology, The Second Artillery General Hospital, Beijing, China ABSTRACT. Whether vitamin C is a protective factor for age-related cataract remains unclear. Thus, we conducted a meta-analysis to summarize the evidence from epidemiological studies of vitamin C and the risk of age-related cataract. Pertinent studies were identified by searching in PubMed and in Webscience. The random effect model was used to combine the results. Meta-regression and subgroups analyses were used to explore potential sources of between-study heterogeneity. Publication bias was estimated using Egger s regression asymmetry test. Finally, 15 articles with 20 studies for vitamin C intake and eight articles with 10 studies for serum ascorbate were included in this meta-analysis. The relative risk (RR) and 95% confidence interval of cataract for the highest versus the lowest category of vitamin C intake was 0.814 (0.707 0.938), and the associations were significant in America and Asia. Significant association of cataract risk with highest versus the lowest category of serum ascorbate was found in general [0.704 (0.564 0.879)]. Inverse associations were also found between serum ascorbate and nuclear cataract and posterior subcapsular cataract. Higher vitamin C intake and serum ascorbate might be inversely associated with risk of cataract. Vitamin C intake should be advocated for the primary prevention of cataract. Key words: age-related cataract meta-analysis serum ascorbate vitamin C Acta Ophthalmol. 2016: 94: e170 e176 ª 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd doi: 10.1111/aos.12688 Introduction The World Health Organization has estimated that there was 37 million blind people worldwide, and cataract is one of the major causes (Foster & Resnikoff 2005). Although cataracts can be removed surgically and replaced by an artificial intraocular lens to restore sight, many people remain blind from cataracts due to inadequate surgical services or high surgery expenses (Ono et al. 2010). Thus, identifying modifiable risk factors of cataract is important and may help to establish the preventive measures. A recent meta-analysis was reported that vitamin A and beta-carotene intake can reduce the risk of agerelated cataract (Wang et al. 2014). The opacification of the ocular lens, or cataractogenesis, may be initiated by oxidative damage from photochemically or non-photochemically generated oxygen radicals (Berman 1991). Beta-carotene, vitamin A and vitamin C as antioxidant nutrients can counteract this process due to the free radical scavenger capacity, suggesting that dietary antioxidants may play an important role in prevention. Up to now, a number of epidemiologic studies have been published to explore the relationship of vitamin C and the risk of cataract. However, the results are not consistent. Therefore, we conducted a meta-analysis to assess the cataract risk for the highest versus lowest categories of vitamin C intake and serum ascorbate level. We also assess the heterogeneity among studies and publication bias. Methods Search strategy Studies were identified by a literature search of PubMed and Web of Knowledge up to August 2014 and by handsearching in the reference lists of the computer-retrieved articles. The following search terms were used: vitamin C or serum ascorbate and cataract or lens opacities without restrictions. Moreover, we reviewed the reference lists from retrieved articles to search for further relevant studies. Two investigators searched articles and reviewed of all retrieved studies independently. Disagreements between the two investigators were resolved by consensus with a third reviewer. Inclusion criteria For inclusion, studies had to fulfil the following criteria: (i) the exposure of interest was vitamin C or serum ascorbate; (ii) the outcome of interest was age-related cataract; (iii) the subtype cataract was as an independent study when the total cataract was not observed; and (iv) multivariateadjusted RR with 95% confidence interval (CI) was provided (compared e170
to the lowest quantile, the RR for the highest quantile of vitamin C or serum ascorbate and age-related cataract risk). Accordingly, the following exclusion criteria were also used: (i) reviews and (ii) repeated or overlapped publications. Data extraction The following data were collected from all studies independently by two investigators: the design type (case control study, cohort study, cross-sectional study or randomized controlled trials), the first author s last name, publication year, location where the study was performed, sample size and number of cases, variables adjusted for in the analysis, RR (OR) estimates with corresponding 95% CI for the highest versus lowest categories of vitamin C or serum ascorbate, respectively. For studies that reported results from various covariate analyses, we abstracted the estimates based on the model that included the most potential confounders. If there was disagreement between the two investigators about eligibility of the data, it was resolved by consensus with a third reviewer. Quality analysis Two authors separately graded the quality of the studies using the STROBE checklist (22 items) (von Elm et al. 2007). This analysis was carried out with the articles published in journals. The studies from conferences included in the review, with data sent by the authors, were not quality graded. Disagreements between the two investigators were resolved by consensus with a third reviewer. heterogeneity among included studies. I 2 describes the proportion of total variation attributable to between-study heterogeneity as opposed to random error or chance, and I 2 values of 0%, 25%, 50% and 75% represent no, low, moderate and high heterogeneity, respectively (Higgins et al. 2003). Meta-regression with restricted maximum likelihood estimation was performed to assess the potentially important covariate exerting substantial impact on between-study heterogeneity (Higgins & Thompson 2004). Publication bias was estimated using Begg s test (Begg & Mazumdar 1994) and Egger s regression asymmetry test (Egger et al. 1997). A study of influence analysis (Tobias 1999) was conducted to describe how robust the pooled estimator is to the removal of individual studies. An individual study is suspected of excessive influence, if the point estimate of its omitted analysis lies outside the 95% CI of the combined analysis. All the statistical analyses were performed with STATA version 10.0 (Stata Corporation, College Station, TX, USA). Two-tailed p 0.05 was accepted as statistically significant. Results The search strategy identified 364 articles from PubMed and 482 articles from the Web of Knowledge. Nineteen articles (Leske et al. 1991; Robertson et al. 1991; Vitale et al. 1993; Tavani et al. 1996; Lyle et al. 1999; Simon & Hudes 1999; Jacques et al. 2001; Taylor et al. 2002; Valero et al. 2002; Ferrigno et al. 2005; Rodriguez-Rodriguez et al. 2006; Yoshida et al. 2007; Christen et al. 2008, 2010; Dherani et al. 2008; Tan et al. 2008; Rautiainen et al. 2010; Ravindran et al. 2011; Zheng Selin et al. 2013) were used in this meta-analysis. The detailed steps of our literature search are shown in Fig. 1. For vitamin C intake, data from 15 articles with 20 studies (11 prospective studies, seven case control studies, one randomized controlled trial and one cross-sectional study) were used including 16 205 cataract cases. Ten studies were carried out in the, two in Spain, two in Japan, two in Sweden, two in Italy, one in India and one in Australia. Inverse association of vitamin C intake with risk of cataract was reported in seven studies. For serum ascorbate, data from eight articles with 10 studies (three prospective studies, six cross-sectional studies and one case control study) were used including 7305 cataract cases. Seven studies were carried out in, two in India and one in Spain. Inverse association of serum ascorbate with risk of cataract was reported in Statistical analysis The pooled measure was calculated as the inverse variance-weighted mean of the natural logarithm of multivariateadjusted RR with 95% CI for the highest versus lowest levels to assess the association of vitamin C or serum ascorbate and cataract risk. A randomeffects model was used to combine study-specific RR (95% CI), which considers both within-study and between-study variation (DerSimonian & Laird 1986). The Q test and I 2 of Higgins and Thompson (Higgins & Thompson 2002) were used to assess Fig. 1. The detailed steps of our literature search. e171
Table 1. Characteristics of studies on vitamin C and age-related cataract risk. First author (year) Country Study design Cases, age STROBE score RR (95% CI) for highest versus lowest category Adjustment for covariates Leske et al. (1991) Robertson et al. (1991) Vitale et al. (1993) Case control 945, 40 79 16 Vitamin C intake 0.73 (0.32 1.73) for PSC 0.80 (0.50 1.29) for cortical 0.48 (0.24 0.99) for nuclear 0.72 (0.46 1.12) for mixed Canada Case control 40, Na 16 Vitamin C intake 0.30 (0.12 0.75) Cross-sectional 431, 40 15 1.31 (0.65 2.6) for nuclear 1.01 (0.45 2.26) for cortical Tavani et al. (1996) Italy Case control 207, Na 16 Vitamin C intake 0.8 (0.4 1.3) Lyle et al. (1999) Simon & Hudes (1999) Jacques et al. (2001) Cohort 246, 43 84 18 Vitamin C intake 0.9 (0.5 1.5) for nuclear Cross-sectional 416, 60 74 15 0.74 (0.56 0.97) Cohort 163, 53 73 19 Vitamin C intake 0.31 (0.16 0.58) for nuclear 0.54 (0.28 1.02) for nuclear Valero et al. (2002) Spain Case control 343, 55 74 16 Vitamin C intake 0.70 (0.44 1.13) 0.30 (0.18 0.51) Taylor et al. (2002) Ferrigno et al. (2005) Cohort 332, 53 73 19 Vitamin C intake 0.89 (0.55 1.45) for cortical 0.64 (0.29 1.42) for PSC 1.4 (0.86 2.52) for cortical 0.74 (0.32 1.68) for PSC Cross-sectional 710, 55 75 15 0.74 (0.42 1.15) Rodriguez-Rodriguez et al. (2006) Spain Cohort 91, Na 18 Vitamin C intake 0.082 (0.009 0.753) Yoshida et al. (2007) Japan Cohort 216, 45 64 19 Vitamin C intake 0.65 (0.42 0.97) for males 0.59 (0.43 0.89) for females Tan et al. (2008) Australia Cohort 308, 49 19 Vitamin C intake 1.16 (0.76 1.78) Christen et al. (2008) Cohort 2031, 45 17 Vitamin C intake 0.94 (0.81 1.09) Adjusted for age and sex Na Adjusted for age, sex, diabetes and plasma cholesterol Adjusted for age, sex, education, smoking status, diabetes, body mass index and calorie intake Adjusted for age, energy intake, pack-years of smoking and reported amount of alcohol consumed per week Adjusted for age, race, BMI, level of physical activity, education, alcohol consumption, history of smoking, diabetes, self-reported steroid use in the past week, consumption of vitamin A supplements and riboflavin intake Adjusted for age at examination, pack-years smoked through 1990, history of hypertension through 1990, BMI in 1980, summertime sunlight exposure in 1980 and usual alcohol intake between 1980 and the date of examination Adjusted for age, sex, energy intake and season of blood collection for the blood analyses Adjusted for age at examination, pack-years smoked through 1990, history of hypertension through 1990, BMI in 1980, summertime sunlight exposure in 1980, and usual alcohol intake between 1980 and the date of examination Adjusted for age, gender, alcohol use, smoking, family history, diabetes, hypertension, sunlight index, body mass index and date of recruitment Na Adjusted for age, BMI, history of hypertension and diabetes, alcohol intake, cigarette smoking and PHC area Adjusted for age, sex, hypertension, smoking, diabetes, education and use of inhaled steroids Adjusted for age, randomized treatment assignment, smoking, alcohol use, BMI, exercise, e172
Table 1. (Continued) First author (year) Country Study design Cases, age STROBE score RR (95% CI) for highest versus lowest category Adjustment for covariates Dherani et al. (2008) India Cross-sectional 821, 50 15 0.64 (0.48 0.85) Christen et al. (2010) RCT 1174, 50 14 Vitamin C intake 1.02 (0.91 1.14) Rautiainen et al. (2010) Sweden Cohort 2497, 49 83 18 Vitamin C intake 1.25 (1.05 1.50) Ravindran et al. (2011) India Case control 4098, 60 15 Vitamin C intake 0.78 (0.62 0.98) 0.61 (0.51 0.74) Zheng Selin et al. (2013) Sweden Cohort 2963, 45 79 19 Vitamin C intake 1.21 (1.04 1.41) postmenopausal hormone use, history of hypertension, history of hypercholesterolemia, history of diabetes, family history of myocardial infarction before the age of 60 and history of eye exam in the last 2 years Adjusted for age, sex, smoking, BMI and average systolic blood pressure Adjusted for age, PHS cohort, and vitamin E, b-carotene and multivitamin treatment assignment Adjusted for age, waist circumference, smoking, alcohol consumption, steroid medication use, educational level and hormone replacement therapy use Adjusted for age, dietary energy intake, study centre, tobacco use, current fuels, BMI, diastolic blood pressure, outdoor exposure, diabetes and socio-economic status Adjusted for age, smoking, abdominal obesity, alcohol intake, fruit and vegetable intake, physical activity and self-reported health PSC, posterior subcapsular cataract; RCT, randomized controlled trials; Na, not available; RR, relative risk. four studies. The detailed characteristics of the 19 articles are shown in Table 1. Vitamin C intake and risk of age-related cataract High vitamin C intake versus low intake was significantly associated with the risk of cataract (summary RR = 0.814, 95% CI = 0.707 0.938, I 2 = 70.7%) (Fig. 2). For the subgroup analyses by study design, the association between the highest category of vitamin C intake versus the lowest category and cataract risk was significant in the case control studies (RR = 0.681, 95% CI = 0.549 0.845), but not in the cohort studies for the highest category of vitamin C intake versus the lowest category and cataract risk. In subgroup analyses of geographic locations, when we restricted the analysis to America, Europe and Asia, significant associations were found in America (RR = 0.845, 95% CI = 0.730 0.978) and Asia (RR = 0.761, 95% CI = 0.592 0.979), but not in the Europe. Subgroup analysis by cataract type suggested that significant association was found in nuclear cataract (RR = 0.618, 95% CI = 0.420 0.909, I 2 = 81.8%); however, no association was found in posterior subcapsular cataract (PSC) (RR = 0.881, 95% CI = 0.743 1.045, I 2 = 0.9%) and cortical cataract (RR = 1.014, 95% CI = 0.883 1.163, I 2 = 0.0%) (Table 2). and risk of age-related cataract Highest serum ascorbate levels versus lowest levels were significantly associated with the risk of cataract (RR = 0.704, 95% CI = 0.564 0.879, I 2 = 61.6%) (Fig. 3). For the subgroup analyses by study design, the association was significant in the cross-sectional studies (RR = 0.693, 95% CI = 0.592 0.810), but not in the cohort studies. Subgroup analysis by cataract type suggested that significant associations were found in nuclear cataract (RR = 0.587, 95% CI = 0.347 0.995, I 2 = 75.0%) and PSC (RR = 0.478, 95% CI = 0.348 0.655, I 2 = 7.5%), but not in cortical cataract (Table 2). Influence analysis and publication bias Influence analysis showed that no individual study had excessive influence on the above-mentioned pooled effect. Egger s test and Begg s test showed no evidence of significant publication bias between cataract risk and vitamin C intake and serum ascorbate (Table 3). Discussion The findings from this meta-analysis indicate that highest vitamin C intake is associated with a reduced risk of cataract, especially in America and Asia. We also found a significant association between vitamin C intake and e173
Fig. 2. The multivariate-adjusted risk of age-related cataract for the highest versus lowest categories of vitamin C intake. Table 2. Summary risk estimates of the association between vitamin C and age-related cataract risk. Subgroups Cases Studies RR (95% CI) I 2 (%) p heterogeneity Food 16 205 20 0.814 (0.707 0.938) 70.7 0.000 Cataract type Nuclear 1659 6 0.618 (0.420 0.909) 81.8 0.000 Cortical 1314 5 1.014 (0.883 1.163) 0.0 0.663 PSC 627 5 0.881 (0.743 1.045) 0.9 0.401 Study design Prospective 9398 11 0.844 (0.683 1.044) 79.1 0.000 Case control 1535 7 0.681 (0.549 0.845) 0.0 0.564 Geographic locations America 4931 11 0.762 (0.629 0.923) 64.3 0.002 Europe 6101 5 1.014 (0.779 1.321) 67.8 0.015 Asia 5173 4 0.761 (0.592 0.979) 51.9 0.100 Serum 7305 10 0.704 (0.564 0.879) 61.1 0.006 Cataract type Nuclear 1230 4 0.587 (0.347 0.995) 75.0 0.007 Cortical 875 5 0.730 (0.462 1.153) 69.1 0.012 PSC 471 4 0.478 (0.348 0.655) 7.5 0.355 Study design Prospective 495 3 0.850 (0.459 1.574) 61.6 0.074 Cross-sectional 6476 6 0.693 (0.592 0.810) 20.7 0.278 Geographic locations America 2052 7 0.852 (0.669 1.086) 26.5 0.226 Others 5253 3 0.531 (0.383 0.737) 71.0 0.032 PSC, posterior subcapsular cataract; RR, relative risk. nuclear cataract. Inverse association was also found between serum ascorbate and risk of cataract, especially in cross-sectional studies. The associations were significant in nuclear cataract and PSC for the highest versus lowest categories of serum ascorbate. Between-study heterogeneity is common in meta-analysis (Munafo & Flint 2004), and exploring the potential sources of between-study heterogeneity is the essential component of metaanalysis. For vitamin C intake and serum ascorbate with the risk of agerelated cataract, evidence of heterogeneity was found in the pooled results. The between-study heterogeneity might arise from publication year, study region, study design and disease type. Thus, we used meta-regression to explore the causes of heterogeneity for covariates. However, no covariate had a significant impact on between-study heterogeneity for the above-mentioned covariates. Considering that the pooled meta-analysis was fraught with face the e174
Fig. 3. The multivariate-adjusted risk of age-related cataract for the highest versus lowest categories of serum ascorbate. Table 3. Publication bias between vitamin C and age-related cataract risk. Publication bias method Vitamin C p-value Egger Food 0.175 Serum 0.411 Begg Food 0.156 Serum 0.474 problem of heterogeneity, subgroup analyses by the type of study design, cataract type and geographic locations were performed to explore the source of heterogeneity. However, the between-study heterogeneity persisted in some subgroups, suggesting the presence of other unknown confounding factors. The methods of cataract diagnosis used were different, such as Neitz CT-R, Topcon SL-7e, International Classification of Diseases, self-report, hospital diagnosis, etc. These different methods may cause the between-study heterogeneity. In addition, different adjustments made in analysis for other covariates such as other antioxidant micronutrients intake or blood levels, supplements use, socio-demographic, lifestyle variables may be the reason for the high between-study heterogeneity. Age-related cataract is a complex aetiology and pathophysiology disease generated by the combined effects of genes and environmental factors. Thus, other genetic and environmental variables, as well as their possible interaction, may well be the potential contributors to the heterogeneity observed. Among the antioxidant nutrients, vitamin C received considerable early interest as a possible anticataract agent, in part because it is known to be an effective antioxidant at low partial pressures of oxygen (Burton & Ingold 1984), conditions found in the lens, but also because it is readily available in fruits and vegetables and is not associated with any harmful effects, even in the very large doses used to treat patients with erythropoietic protoporphyria (Bendich 1988; Mathews-Roth 1988). In addition, also, evidence from human studies has demonstrated that elevated intake or enhanced serum concentrations of antioxidant vitamins may have a protective role against the degeneration of the ageing lens after oxidative insult (Jacques et al. 1988; van der Pols 1999). An increase in ocular lens protein modification subject to chronic oxidative stress and the lack of optimum intake of antioxidant micronutrients by the lens and surrounding fluids are crucial factors in cataractogenesis (Varma 1991; Taylor et al. 1995). Vitamin C and ascorbic acid can neutralize reactive oxygen species which are formed as a natural consequence of normal biochemical activity and may reduce oxidative DNA damage and genetic mutation (Frei 1994). As a meta-analysis of published studies, our findings showed some advantages. First, a major strength of this study was the large number of participants included in this analysis, and this may derive in a more precise estimation of the relationship between vitamin C and age-related cataract risk. Second, no significant publication bias was found. However, there were some limitations in this meta-analysis. First, as a meta-analysis of observational studies, we cannot rule out that individual studies may have failed to control for potential confounders, which may introduce bias in an unpredictable direction. Second, many case control e175
studies were included in this metaanalysis. Overstated association may be expected from the case control studies because of recall or selection bias, and early symptoms in patients may have resulted in a change in dietary habits. Further studies with cohort design are wanted to confirm this association between serum ascorbate with the risk of age-related cataract. Third, we found a significant association between vitamin C intake and age-related cataract risk in the America, from which most of the included studies (11 of 20). Only two studies came from Spain (Valero et al. 2002; Rodriguez-Rodriguez et al. 2006), two from Sweden (Rautiainen et al. 2010; Zheng Selin et al. 2013) and one from Italy (Tavani et al. 1996), in which we found no significant association, probably due to the little number of studies included. Due to this limitation, the results are applicable to the America for vitamin C intake and age-related cataract risk, but cannot be extended to European populations. 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Zheng Selin J, Rautiainen S, Lindblad BE, Morgenstern R & Wolk A (2013): High-dose supplements of vitamins C and E, low-dose multivitamins, and the risk of age-related cataract: a population-based prospective cohort study of men. Am J Epidemiol 177: 548 555. Received on September 19th, 2014. Accepted on January 12th, 2015. Correspondence: Lin Wei Department of Ophthalmology The Second Artillery General Hospital Xicheng District Beijing 100088, China Tel: +86 139 10927809 Fax: +86 010 66343115 Email: 964483941@qq.com e176