Critique 248: Association of Alcohol Consumption with Cataract Surgery — 19 April 2021

Chua SYL, Luben RN, Hayat S, Broadway DC, Khaw K-T, Warwick A, et al, on behalf of The UK Biobank Eye and Vision Consortium.   Alcohol Consumption and Incident Cataract Surgery in Two Large UK Cohorts.  Ophthalmology 2021, pre-publication.

Authors’ Abstract

Purpose: To examine the association of alcohol consumption and type of alcoholic beverage with incident cataract surgery in 2 large cohorts.

Design: Longitudinal, observational study.

Participants: We included 469,387 participants of UK Biobank with a mean age of 56 years and 23,162 participants of European Prospective Investigation of Cancer (EPIC)-Norfolk with a mean age of 59 years.

Methods: Self-reported alcohol consumption at baseline was ascertained by a touchscreen questionnaire in UK Biobank and a food-frequency questionnaire in EPIC-Norfolk. Cases were defined as participants undergoing cataract surgery in either eye as ascertained via data linkage to National Health Service procedure statistics.  We excluded participants with cataract surgery up to 1 year after the baseline assessment visit or those with self-reported cataract at baseline. Cox proportional hazards models were used to examine the associations of alcohol consumption with incident cataract surgery, adjusted for age, sex, ethnicity, Townsend deprivation index, body mass index (BMI), smoking, and diabetes status.

Main Outcome Measures: Incident cataract surgery.

Results: There were 19,011 (mean cohort follow-up of 95 months) and 4,573 (mean cohort follow-up of 193 months) incident cases of cataract surgery in UK Biobank and EPIC-Norfolk, respectively.  Compared with nondrinkers, drinkers were less likely to undergo cataract surgery in UK Biobank (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.85-0.93) and EPIC-Norfolk (HR, 0.90; 95% CI, 0.84-0.97) after adjusting for covariables.  Among alcohol consumers, greater alcohol consumption was associated with a reduced risk of undergoing cataract surgery in EPIC-Norfolk (P < 0.001), whereas a U-shaped association was observed in the UK Biobank.  Compared with nondrinkers, subgroup analysis by type of alcohol beverage showed the strongest protective association with wine consumption; the risk of incident cataract surgery was 23% and 14% lower among those in the highest category of wine consumption in EPIC-Norfolk and UK Biobank, respectively.

Conclusions: Our findings suggest a lower risk of undergoing cataract surgery with low to moderate alcohol consumption. The association was particularly apparent with wine consumption. We cannot exclude the possibility of residual confounding, and further studies are required to determine whether this association is causal in nature.

Forum Comments

Overview:  Forum reviewers were favorably impressed by these analyses, based on two prospective, very-large cohort studies in the UK, the UK Biobank study and the EPIC-Norfolk study.  They noted that the assessment of alcohol intake included information on frequency of drinking and usual amount, as well as type of beverage, from a self-administered questionnaire for one of the studies and from a food questionnaire of usual food and drink intake during the previous year for subjects in the other study.  Reviewer Ellison considered that these have been shown to be reasonable methods for estimating intake; unfortunately, whether or not the beverage was consumed with food, a measure of intake being found to be important in determining health risks (Stranges, et al; Boban, et al; Oksanen & Kokkonen; Sluik, et al), was not reported.  The key outcome measure, incident cataract surgery, was ascertained via linkage to hospital procedure records for England, Scotland, and Wales, considered a very reliable source.

A strength of the study was that there were 19,011 cases of cataract surgery during a mean follow up of 95 months in the UK Biobank study and 4,573 cases in the 193 month follow up in the EPIC study; thus, the investigators had an unusually large number of cases for these analyses.  Further, given that all subjects presumably had access to the national health programs in the UK, we can probably assume that cataract surgeries reflect the incidence of significant cataracts, and the authors a present cogent discussion of using the incidence of surgeries to estimate the occurrence of significant cataracts.  The analytic approaches used were appropriate, as adjustments were made for age, sex, ethnicity, socio-economic status (SES, derived from the Townsend deprivation index), BMI, smoking, diabetes, and physical activity, factors that may influence the development of cataract and/or the decision for surgery.

The key results were that the hazard ratio for cataract surgery for all drinkers combined vs. non-drinkers was 0.90 (95% CI 0.84-0.97) for EPIC and 0.89 (0.85-0.93) for UK Biobank.  For dose-response analyses among drinkers only, in EPIC the adjusted third and highest quartiles of alcohol intake showed reductions in risk of cataract surgery of 14% and 18%, respectively.  In UK Biobank subjects, there was a U-shaped association, with subjects reporting 1-2 and 3-4 times/week having 7%, and 6% lower risk than those who drank 1-3 times or less per month.   Daily or almost daily drinkers had 5 to 6% higher risk of cataract surgery.  All of these differences were statistically significant.

Reviewer Skovenborg stated: “I found this study well planned, well done and well written. The authors had two large cohorts at their disposal and have thought of many of the well-known epidemiological caveats.”  He added: “The points that I found intriguing about the study include the following:

• • Against the background of inconsistent results regarding the association between alcohol consumption and cataract from previous studies, a large longitudinal cohort study with a large number of endpoints is the best way to determine the presence of a weak association.
  • A hard endpoint like cataract surgery is worth its weight in gold in an observational study.
  • Intake of alcohol was only ascertained at baseline and may be underreported or not accurately recalled; however, the possible misclassification bias is most likely nondifferential and the results were consistent across the two different cohorts studied.
  • The adjustments for sociodemographic and lifestyle factors seem to be adequate and the dose-response association makes residual confounding less likely.
  • Age-related cataract may result in part from oxidative stress to lens proteins which would make the more favourable results from intake of wine rich in antioxidants more plausible.”

Forum member Parente wrote: “I agree that this paper warrants a review.  I believe it’s important to extend the alcohol/wine & health discussion beyond the cardiology, nutrition and epidemiology spheres. Unfortunately, there’s only a single self-report of alcohol use estimation at baseline, but with ~ one-half million participants and some pretty consistent results for moderate wine intake, I find its findings persuasive.”  Reviewer Finkel agreed with the impressions of other Forum members that “This was a reasonable analysis, although I do not have ‘wild enthusiasm’ for it because of the relatively small benefit associated with moderate drinking, the non-life threatening nature of the disease, and the elective and complex factors related to the decision for having cataract surgery.”

Forum member Pająk had some similar concerns: “I share the positive impressions of the paper expressed earlier by the other Forum members.  However, the relation seems not to be very strong and authors did not debate much the plausibility.  Further, Townsend deprivation index which was used as a measure of SES could be assessed on the population basis and it relates only to a part of the complexity of social environment.  This leaves room for further discussion on the possible causality and possible residual confounding by SES.”

Does the type of alcoholic beverage matter?  As for the type of alcoholic beverage, in EPIC, the data indicate more favorable and consistent results for consumers of wine than for beer or spirits; for the top tertile versus lowest tertile of wine drinkers, the HR was 0.77 (0.69-0.85).  For UK Biobank, there were similar more favorable results for red wine and white wine, although smaller amounts of beer and spirits also showed reductions in risk of cataract surgery.  Forum members agreed with the authors that the associations with wine were stronger than those for other beverages.

Potential mechanisms for wine/alcohol effects on cataract:  Forum member Goldfinger wrote: “I find this to be a very interesting observation.  One may ponder the possible protective mechanisms involved, such as improved vascular/circulatory support, anti-inflammation/anti-oxidant protection, etc.  In the United States, cataract surgery is, for the most part, elective.  Cataract surgery, thus, is often recommended earlier in more affluent groups, and may be delayed in less affluent groups.  This is a personal presumption.  As such, I might expect to see more cataract surgeries in the more affluent group where wine drinking is supposedly more prominent.  For me, this is an interesting paradox.”  Reviewer Ellison added: “We note that in their analysis the authors did adjust for ethnicity and for the Townsend deprivation index (which uses subjects’ home address to estimate unemployment, ownership of an automobile, home ownership, and household crowding) in an attempt to take SES factors into consideration.  However, I agree with Goldfinger that residual confounding by SES is surely possible.”

Reviewer Mattivi had some cogent information on potential mechanisms: “This paper is reporting new and important results, calling for further investigation into the mechanisms involving antioxidants and anti-inflammatory agents present in our diet, which may help in the prevention or delaying the progression of eye diseases.  The protective role of several classes of polyphenols (including flavanols, anthocyanins, resveratrol) as well as other phytochemicals in the prevention of age-related eye diseases, including cataract, has been already suggested (Rhone & Basu).  The finding that both red wine and white wine are protective suggest that, as polyphenols are involved, then the wine hydroxycinnamates could be possibly involved, this being the only class of polyphenols significantly present in these wines.  (I would have expected a much higher protective effect of red wine; wine has certainly a much higher content of flavonoids than other beverages considered.)

“The mechanisms suggested have recently been reviewed (Kaur, et al) and they are multiple, each involving several different classes of phytochemicals, which can act as (i) antioxidants or ROS scavengers; (ii) aldose reductase inhibitors; (iii) antiglycating agents; or (iv) inhibitors of lens epithelial cell apoptosis.  Grape was reported in this review to contain compounds capable of acting via all these four putative mechanisms.  Another recent review (Hilliard, et al) has suggested another mechanism of action involving the flavonoids, via the activation of Nrf2 and the inhibition of MMP-9.  MMP production may be attenuated by the Nrf2 pathway or by the Nrf2 inhibition of NFkB pathway activation. This paper suggests that Nrf2 might be a therapeutic target specifically for lens cataract formation.

“I am not personally convinced of a direct role of the native flavonoids.  Among these only a small amount of anthocyanins can eventually reach the eye in their native form.  Maybe other dietary metabolites and catabolites of the polyphenols, such as the alkyl chatechols and other simple phenolics, should be considered in future studies.  The activation of the Nrf2 cell defense pathway by the microbial catabolites of dietary polyphenols (Senger, et al) is an intriguing mechanism, which certainly deserves further investigation.”

Forum member Parente also furnished further details on potential mechanisms: “Prof. Mattivi’s analysis is illuminating.  To add to the potential impact of this article, I would note the heightened interest in ophthalmology regarding micronutrients and diet beyond age-related macular degeneration (e.g., AREDS2), extending recently to cataract (Motlagh Moghaddam, et al) and glaucoma, especially regarding the role of  neuroprotection, (Guymer, et al).  This interest is further evidenced by the recent FDA approval of a novel class of ocular pressure-lowering medications, the first since 1996, i.e., rho-kinase inhibitors, e.g., netarsudil (launched in 2018), whose actions include increasing nitric oxide levels to aid vasodilation and trabecular meshwork relaxation (Tanna, et al).

“However, in part due to their low stability/solubility in ocular aqueous, the literature regarding the role of polyphenols in ocular disease and cataract is sketchy, and rigorous studies are lacking. A 2012 Cochrane review of studies on antioxidants to prevent or slow cataract progression basically concluded case closed and recommended no further studies due to lack of evidence for supplemental antioxidant vitamins C, E and beta-carotene (Mathew, et al).  Notwithstanding, the present article by Chua, et al opens up a fertile discussion given the substantial morbidity of cataract, which globally accounts for most cases of blindness (Flaxman, et al) and is a leading cause of moderate to severe vision impairment.  Despite older US adults’ access to cataract surgery, cataract surgeons and Medicare coverage, cataracts remain a substantial contributor to diminished quality of life and independence and heighten risk for motor vehicle crashes and falls with their attendant societal and social/familial costs. We can, and should, do better.”

References from Forum Critique

Boban M, Stockley C, Teissedre P-L, Restani P, Fradera U, Stein-Hammer C, Ruf J-C.  Drinking pattern of wine and effects on human health: why should we drink moderately and with meals?  Food Funct 2016;7:2937-2942.  doi: 10.1039/c6fo00218h.

Flaxman SR, Bourne RRA, Resnikoff S, Ackland P, Braithwaite T, Cicinelli MV, et al, on behalf of the Vision Loss Expert Group of the Global Burden of Disease Study.  Global causes of blindness and distance vision impairment 1990–2020: a systematic review and meta-analysis.  Lancet Glob Health 2017;5:e1221–1234. doi.org/10.1016/S2214-109X(17)30393-5

Guymer C, Wood JPM, Chidlow G, Casson RJ.  Neuroprotection in glaucoma: recent advances and clinical translation.  Clinical & Experimental Ophthalmology 2019;47:88–105.  doi: 10.1111/ceo.13336

Hilliard A, Mendonca P, Russell TD, Soliman KFA.  The Protective Effects of Flavonoids in Cataract Formation through the Activation of Nrf2 and the Inhibition of MMP-9. Nutrients 2020; 12:3651.  doi:10.3390/nu12123651

Kaur A, Gupta V, Christopher AF, Malik MA, Bansal P.  Nutraceuticals in prevention of cataract – An evidence based approach. Saudi Journal of Ophthalmology 2017;31:30–37.   DOI: 10.1016/j.sjopt.2016.12.001

Mathew MC, Ervin A-M, Tao J, M Davis RM.  Antioxidant vitamin supplementation for preventing and slowing the progression of age-related cataract.   Cochrane Database Syst Rev 2012;6:CD004567.  doi: 10.1002/14651858.CD004567.pub2.

Motlagh Moghaddam EA, Motarjemizadeh G, Ayremlou P, Zarrin R.  Major dietary patterns in relation to age-related cataract. Clin Nutr ESPEN 2021;41:325-330. doi:10.1016/j.clnesp.2020.11.008.

Oksanen A, Kokkonen H.  Consumption of Wine with Meals and Subjective Well-being: A Finnish Population-Based Study.  Alcohol Alcohol 2016;51:716-722. doi: 10.1093/alcalc/agw016.

Rhone M, Basu A.  Phytochemicals and age-related eye diseases.  Nutrition Reviews 2008;66:465-472. DOI: 10.1111/j.1753-4887.2008.00078.x

Senger DR, Li D, Jaminet SC, Cao S.  Activation of the Nrf2 Cell Defense Pathway by Ancient Foods: Disease Prevention by Important Molecules and Microbes Lost from the Modern Western Diet. PLOS ONE 2016;11:e0148042, doi:10.1371/journal.pone.0148042

Sluik D, Bezemer R, Sierksma A, Feskens E.  Alcoholic Beverage Preference and Dietary Habits: A Systematic Literature Review, Critical Reviews in Food Science and Nutrition 2016;56:2370-2382,  DOI: 10.1080/10408398.2013.841118

Stranges S, Wu T, Dorn JM, Freudenheim JL, Muti P, Farinaro E, et al.  Relationship of Alcohol Drinking Pattern to Risk of Hypertension. A Population-Based Study. Hypertension 2004;44:813-819.  https://doi.org/10.1161/01.HYP.0000146537.03103.f2

Tanna AP, Johnson M.  Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension. Ophthalmology 2018;125:1741-1756.  doi:10.1016/j.ophtha.2018.04.040)

Forum Summary

This was a well-done analysis of a very large number of cases of cataract surgery in the UK; there were reasonable measures of the exposure (alcohol consumption), including the amount and type of beverage consumed, and appropriate potentially confounding factors were taken into consideration.  However, data on the consumption of alcohol with or without food were not available. The use of national registries of cataract surgery provide an appropriate approach for estimating the main outcome of the analyses, and the results probably reflect the incidence of clinically significant cataract occurrence in these populations.

The key results were that there was a small but highly significant lower risk of cataract surgery among moderate drinkers.  Red and white wine consumers showed more consistent and significantly lower risks of cataract surgery than consumers of other beverages.  (In one of the two studies included in the analysis, small amounts of beer and spirits also showed a lower risk than that of non-drinkers.) There were too few heavy drinkers in these studies to determine the extent to which such drinking might affect risk.  We appreciate that residual confounding, especially by factors that relate to subjects choosing to have surgical treatment of their cataracts, could still be present in these results.

Forum reviewers conclude that, in agreement with the investigators of this study, the data indicate a small but statistically and clinically significant decrease in the risk of cataract surgery for low-to-moderate drinkers, versus non-drinkers.  A lowering of risk was especially clear for wine drinkers, in comparison with consumers of beer and spirits.  There is an extensive literature regarding potential mechanisms by which constituents of the diet, especially those present in wine, may influence the development of cataracts.  Among these are antioxidants or ROS scavengers, aldose reductase inhibitors, antiglycating agents, and inhibitors of lens epithelial cell apoptosis.  However, the ultimate reason for the lower risk of cataract surgery associated with wine consumption found in this study has not been clearly delineated.

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Comments on this critique by the International Scientific Forum on Alcohol Research have been provided by the following members:

Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark

Harvey Finkel, MD, Hematology/Oncology, Retired (Formerly, Clinical Professor of Medicine, Boston University Medical Center, Boston, MA, USA)

Matilda Parente, MD, consultant in molecular pathology/genetics and emerging technologies, San Diego, CA, USA

R. Curtis Ellison, MD, Professor of Medicine, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

Tedd Goldfinger, DO, FACC, Desert Cardiology of Tucson Heart Center, University of Arizona School of Medicine, Tucson, AZ, USA

Professor Andrzej Pająk, Epidemiology and Population Studies, Jagiellonian University Medical College, Kraków, Poland

Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy

Fulvio Mattivi, MSc, CAFE – Center Agriculture Food Environment, University of Trento, via E. Mach 1,  San Michele all’Adige, Italy

Creina Stockley, PhD, MSc Clinical Pharmacology, MBA; Principal, Stockley Health and Regulatory Solutions; Adjunct Senior Lecturer, The University of Adelaide, Adelaide, Australia

Pierre-Louis Teissedre, PhD, Faculty of Oenology–ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France