Age-related cataract is the leading cause of visual impairment worldwide.1–8 With longer life expectancies and an aging population throughout the world, the burden and impact of age-related cataract tend to increase, resulting in a global public health concern. The key step for the prevention of age-related cataract is to identify the risk factors for this eye condition, especially modifiable ones. Up until now, few risk factors have been consistently associated with age-related cataract except smoking9 and ultraviolet exposure.10 In a recently published meta-analysis, we found that obesity increased the risks of age-related cataract.11
Alcohol consumption is a common modifiable lifestyle factor and appears to be associated with a wide range of chronic diseases such as cancers,12 type 2 diabetes mellitus,13 and cardiovascular diseases.14 However, there is uncertainty regarding its association with age-related cataract in elderly adults. A relationship between alcohol consumption and an increased risk of cataract has been reported from cross-sectional studies,15,16 but several prospective cohort studies have not found this association.17,18
It is especially important to understand whether the association between alcohol consumption and age-related cataract is modified by the amount of alcohol consumption because there is always a U-shaped association observed in epidemiologic studies between alcohol consumption and clinical disorders. For example, light and moderate alcohol consumption appears to be protective for cardiovascular diseases whereas heavy consumption appears to be a risk factor.14 Therefore, a systematic approach to combine the results of all available studies evaluating the association of alcohol consumption with age-related cataract would be informative to answer this research question. To address this gap, we conducted a systematic review and meta-analysis of the published literatures to examine if different amount of alcohol consumption is associated with different risks of age-related cataract.
METHODS
Search Strategy and Inclusion Criteria
We conducted a systematic review and meta-analysis to examine the association of alcohol consumption with age-related cataract based on the Meta-analysis of Observational Studies in Epidemiology guidelines.19 We searched the electronic databases of PubMed and Embase for relevant articles reporting the association published up to May 2014 with the following search terms (formatted for PubMed search): (“ethanol”[MeSH Terms] OR “ethanol”[All Fields] OR “alcohol”[All Fields] OR “alcohols”[MeSH Terms] OR “alcohols”[All Fields]) AND ((“cataract’[MeSH Terms] OR “cataract”[All Fields]) OR (“cataract”[MeSH Terms] OR “cataract”[All Fields] OR (“lens”[All Fields] AND “opacity”[All Fields]) OR “lens opacity”[All Fields])). Titles and abstracts of the studies were independently scanned by two authors (YG and KF). Duplicate articles from the two databases were deleted. The extracted studies were compared, and inconsistencies were resolved by consensus. In addition, the reference lists of all identified studies were examined. This study was approved by the Medical College of Soochow University Institutional Review Board.
We included studies if they were case-control or cohort studies and if they reported alcohol consumption as an exposure variable and any subtypes of age-related cataract including cataract surgery as the outcome measure. Furthermore, we included studies only if the summary estimates such as odds ratios (ORs), relative risks (RRs), and hazard ratios with 95% confidence interval (CI) were reported in the article or allowed for the calculation of the summary estimates based on the data presented in the article. We only included studies in which age-related cataract was assessed based on lens photographs or diagnosed by ophthalmologists. We excluded studies if they were not case-control or cohort studies (e.g., cross-sectional designs or ecology studies) or if they measured cataract by questionnaires (self-reported). For cohort studies, if one study reported two results at different follow-up periods, the result with a longer follow-up period was included in the analysis. Although we did not specifically exclude non-English literature, the studies included in the final analysis were all in English.
Data Extraction and Assessment of Study Quality
For each study in the analyses, we extracted the following information: first author, publication year, study name, study design, sample size, age range of the study participants, follow-up periods (for cohort studies only), definitions of alcohol consumption and age-related cataract, summary estimates and corresponding 95% CI, and confounding factors adjusted for.
We assessed the study quality using the tool described by Sanderson et al.20 The variables examined included the methods for selecting study participants, methods for measuring exposure (alcohol consumption) and outcome variable (age-related cataract), design-specific sources of bias (excluding confounding), methods for controlling confounding, statistical methods (excluding control of confounding), and conflict of interest.
Statistical Methods
We performed the meta-analysis using Stata version 12.0 (StataCorp, College Station, TX). We meta-analyzed the fully adjusted, study-specific summary estimates using a random-effects model to account for both within- and between-study variability. Age-related cataract was treated as the outcome measure, whereas alcohol consumption was analyzed as the independent variable. Heavy alcohol consumption was defined as more than two standard drinks per day, which is equal to a daily intake of 20 g of alcohol or 140 g per week. Moderate alcohol consumption was defined as less than 20 g of alcohol per day but more than never. We treated “non–alcohol drinker” as the reference category and converted summary estimates if necessary. Statistical heterogeneity among studies was evaluated using I2 statistic.21 Values of 0 to 24%, 25 to 49%, 50 to 74%, and more than 75% denote no, low, moderate, and high heterogeneity, respectively.22 Sensitivity analysis was performed to investigate the contribution of each study to the heterogeneity by sequentially removing one study and reanalyzing the pooled estimate for the remaining studies.
The RRs were used as the common measure of association across studies. Hazard ratios were directly considered as RRs. Where necessary, ORs were transformed into RRs with the following formula:
;)
in which Po is the rate of the outcome of interest in the nonexposed group.14
The SE of the resulting converted RR was then determined with the following formula:
In some studies, a single summary estimate was not available for moderate/heavy drinkers versus nondrinkers because the data were presented as only a dose-response. In these cases, we first pooled across levels of alcohol intake within the study using a random-effects model to derive a single summary estimate for moderate/heavy drinkers versus nondrinkers. The resulting single, study-specific summary estimate was then pooled with those of other studies.
We evaluated publication bias using the Egger regression asymmetry test and the Begg test. A two-sided p value of less than 0.05 was regarded as significant for all analyses.
RESULTS
We identified 1542 unique titles and abstracts in the electronic databases of PubMed and Embase. After two rounds of reviews and searching citations of retained articles, we identified 42 studies as potentially relevant for analysis, from which we retrieved 29 full text articles for review. Finally, we included 5 cohort studies17,18,23–25 and 5 case-control studies26–30 in this meta-analysis (Fig. 1). Characteristics of the 10 studies included in the meta-analysis are summarized in Table 1. Among the identified 10 studies, 4 were conducted in the United States18,24,25,29 whereas the other 6 were in Australia,23 Sweden,17 Nigeria,26 India,27 Scotland,30 and Italy.28 Of the 10 studies, 2 reported on all-female cohorts,17,24 1 reported on men only,25 and the other 7 included both men and women. Two studies26,27 did not report the findings of moderate alcohol consumption, whereas all identified studies reported the associations between heavy alcohol consumption and cataract.
TABLE 1: Characteristics of the included studies on association between alcohol consumption and age-related cataract in the meta-analysis
FIGURE 1: Flow chart describing the selection of studies.
For the assessment of study quality, we examined the variables included, methods for selecting study participants, methods for measuring exposure (alcohol consumption) and outcome variable (age-related cataract), design-specific sources of bias (excluding confounding), methods for controlling confounding, statistical methods (excluding control of confounding), and conflict of interest. In general, all studies described sampling methods in the texts, albeit in varying degrees. Six studies outlined specific exclusion criteria and provided information on nonresponders. Among the five cohort studies, three were population based and two were on specific working groups. All the five case-control studies were clinically based. Data on alcohol consumption were all self-reported and collected from questionnaires whereas only two studies diagnosed cataract based on lens photographs. In most of the included studies, cataract data were retrieved by medical records or clinically diagnosed by ophthalmologists. Age and sex were adjusted in all included studies, whereas smoking was adjusted in six studies. No studies reported conflict of interest. The detailed assessment of study quality is shown in Table 2.
TABLE 2: Assessment of methodological quality of included studies on association between alcohol consumption and age-related cataract
In the meta-analysis of 10 studies, the associations between moderate alcohol consumption and age-related cataract were marginally nonsignificant (pooled RR, 0.88; 95% CI, 0.74 to 1.05; I2 = 82.1%) (Fig. 2), whereas heavy alcohol consumption was associated with an increased risk of age-related cataract (pooled RR, 1.26; 95% CI, 1.06 to 1.50; I2 = 58.9%) (Fig. 3).
FIGURE 2: Random-effects meta-analysis evaluating the association between moderate alcohol consumption and cataract. ID, identification.
FIGURE 3: Random-effects meta-analysis evaluating the association between heavy alcohol consumption and cataract. ID, identification.
Subgroup analyses were performed on study designs (cohort studies vs. case-control studies) and confounders adjusted for (studies adjusted for smoking vs. studies that did not adjust for smoking). The association between heavy alcohol consumption and cataract was stronger in case-control studies than in cohort studies. Adjusting for smoking as a potential confounder attenuated the association between heavy alcohol consumption and cataract. (Table 3).
TABLE 3: Associations of alcohol consumption and age-related cataract stratified by study design and confounders adjusted for
Omission of individual studies revealed that no single study had a particular influence on the pooled estimate. There was no evidence of publication bias as indicated by a nonsignificant Egger test (all p > 0.05) and Begg test (all p > 0.05) in all analyses.
DISCUSSION
In this systematic review and meta-analysis, we found that heavy alcohol consumption significantly increased the risk of age-related cataract, whereas moderate alcohol consumption may be protective for this ocular condition, although the finding was marginally nonsignificant. Clinically, the findings indicated that information on a patient’s alcohol drinking history might be valuable to general physicians and ophthalmologists when there is a diagnosis of age-related cataract and should be collected on a routine basis in eye clinics. Ophthalmologists should be aware that risk of age-related cataract appears to vary by the amount of alcohol consumption.
Our study indicated that there may be a U-shaped association between alcohol consumption and age-related cataract, which is commonly observed in studies assessing the association between alcohol consumption and cardiovascular diseases. These findings may not be surprising as there are some shared risk factors between age-related cataract and clinical cardiovascular diseases. A large retrospective case-control study31 of adults older than 50 years who underwent cataract surgery in Israel found that all risk factors for cardiovascular diseases were significantly more prevalent in cataract patients in univariate analysis. Meanwhile, multivariate analysis also revealed a significant association of the exposures related to cataractogenesis including diabetes, carotid artery disease, systemic arterial hypertension, peripheral vascular disease, smoking, ischemic heart disease, chronic renal failure, hyperlipidemia, and Ashkenazi origin. In addition, the Blue Mountain Eye Study found that baseline cardiovascular disease or vascular risk factors such as obesity, hypertension, or angina were associated with incident age-related cataract.32 Therefore, the effects of alcohol consumption on cardiovascular system and lens may share common pathways in pathophysiology.
The biological plausibility behind the observed association has not been elucidated, and we offer several possible explanations. Oxidative stress is well known to be involved in the pathogenesis of cataract.33 Heavy alcohol consumption could induce microsomal enzyme cytochrome CYP2E1 in the liver.34 Metabolism of ethanol by cytochrome CYP2E1 could produce free radicals, which may also lead to aggregation of lens proteins, leading to cataract formation in elderly adults. Alternatively, maintenance of calcium homeostasis is essential for normal functioning of the lens. Several lens enzymes are calcium dependent and higher calcium levels are shown to induce cataract in vitro, in both animal and human studies.35 Acute alcohol exposure increases calcium permeability of lens fiber cell membrane and inhibits calcium pumps on lens fiber cells, resulting in higher intracellular lens calcium levels.36 This disruption in calcium homeostasis may lead to cataract formation.
Despite a marginally nonsignificant association, our analysis revealed that moderate alcohol consumption may reduce the risk for age-related cataract. A population-based cohort study has shown that light to moderate alcohol consumption could reduce the risk of atherosclerosis of blood vessels.37 The protection afforded by light to moderate alcohol consumption may possibly be attributed to antithrombotic effects and inhibition of the atherogenic action of high levels of low-density lipoprotein cholesterol. The atherosclerosis of local blood vessels may reduce the risk of cataract by supplying the lens with more oxygen and nutrients.
We have noticed that smoking is a confirmed risk factor for age-related cataract and the observed association between alcohol consumption and age-related cataract may be confounded by smoking status. The subgroup analysis in our study found that pooling the studies that had adjusted for smoking as a potential confounder attenuated the associations between alcohol consumption and age-related cataract but did not alter the trend. Considering that there are only six studies that had adjusted for smoking in this review, we cannot confirm whether smoking is a confounder for the association between alcohol consumption and age-related cataract. More well-designed cohort studies in nonsmokers are warranted to confirm if alcohol consumption is independently related to cataract.
During the peer-review process of this article, another meta-analysis on the association between alcohol intake and age-related cataract was published by Wang and Zhang.38 However, the hypotheses, methods for study selection, and statistical analyses between our study and theirs were completely different. First, our hypothesis was that the risk of cataract is modified by the amount of alcohol consumption whereas theirs was that the risk of cataract differs between alcohol drinkers and nondrinkers. Therefore, the main analyses as shown in the forest plots of the two articles were completely different. In addition, some studies39,40 included in the article by Wang and Zhang were not included in our analysis because these studies did not report the amount-stratified analysis on the association between alcohol consumption and cataract. Second, we included both case-control and cohort studies whereas the article by Wang and Zhang only included cohort studies. Although we acknowledge that cohort design provides stronger evidence than case-control design, we think that it is important to include case-control studies in this meta-analysis, especially when the number of studies identified is small. Finally, we believe that a stratified analysis for the studies that did and did not adjust for smoking status should be performed on this research topic because smoking is a well-established risk factor for age-related cataract and is always associated with alcohol intake. Therefore, smoking may be an important confounder for the association between alcohol intake and age-related cataract.
There are several strengths of the meta-analysis. From epidemiologic perspectives, only case-control or cohort studies were included, which results in the analysis having a higher evidence level than those including cross-sectional studies or ecologic studies. In addition, the sample sizes of the included studies are large and the follow-up periods of the cohort studies are relatively longer (at least 5 years). Limitations of this meta-analysis should also be acknowledged. First, the potential biases in the original studies, methodological issues, and different strategies for adjusting for confounders could affect the results from this meta-analysis. The observed association may have been confounded by other unadjusted factors or selection bias. Second, the number of the contributing studies was small such that the results of subgroups analysis may not be robust. Third, different studies reported different outcomes of age-related cataract, which make it impossible for us to perform subgroup analysis on different cataract subtypes including nuclear, cortical, and posterior subcapsular cataract. Finally, publication bias could be of concern because studies that report statistically significant results are more likely to get published than studies that report nonsignificant results, and this could have distorted the findings of our meta-analyses. Although the Egger test and the Begg test indicated little evidence of publication bias in this meta-analysis, the estimation may not be accurate enough as the number of the studies is small.
In conclusion, this systematic review and meta-analysis of 10 epidemiologic studies demonstrated that effect of alcohol consumption on age-related cataract is not linear and varies by the amount of alcohol consumption. Moderate consumption appears to be protective for age-related cataract with marginally nonsignificant association, whereas heavy alcohol consumption is a risk factor for this eye condition. The results of the meta-analysis suggest that lifestyle changes in alcohol intake would help alter the incidence and associated costs of age-related cataract, subsequently changing visual functioning and health-related quality of life.
Chen-Wei Pan
School of Public Health
Medical College of Soochow University
199 Ren Ai Rd
Suzhou 215123
China
e-mail: [email protected]
ACKNOWLEDGMENTS
Authors Yu Gong and Kehong Feng contributed equally to the work presented and therefore should be considered equivalent first authors.
Received July 31, 2014; accepted February 6, 2015.
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