Consuming large amounts of daily caffeine may increase the risk of glaucoma

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Consuming large amounts of daily caffeine may increase the risk of glaucoma more than three-fold for those with a genetic predisposition to higher eye pressure according to an international, multi-center study.

The research led by the Icahn School of Medicine at Mount Sinai is the first to demonstrate a dietary – genetic interaction in glaucoma.

The study results published in the June print issue of Ophthalmology may suggest patients with a strong family history of glaucoma should cut down on caffeine intake.

The study is important because glaucoma is the leading cause of blindness in the United States. It looks at the impact of caffeine intake on glaucoma, and intraocular pressure (IOP) which is pressure inside the eye. Elevated IOP is an integral risk factor for glaucoma, although other factors do contribute to this condition.

With glaucoma, patients typically experience few or no symptoms until the disease progresses and they have vision loss.

“We previously published work suggesting that high caffeine intake increased the risk of the high-tension open angle glaucoma among people with a family history of disease. In this study we show that an adverse relation between high caffeine intake and glaucoma was evident only among those with the highest genetic risk score for elevated eye pressure,” says lead/corresponding author Louis R. Pasquale, MD, FARVO, Deputy Chair for Ophthalmology Research for the Mount Sinai Health System.

A team of researchers used the UK Biobank, a large-scale population-based biomedical database supported by various health and governmental agencies. They analyzed records of more than 120,000 participants between 2006 and 2010. Participants were between 39 and 73 years old and provided their health records along with DNA samples, collected to generate data.

They answered repeated dietary questionnaires focusing on how many caffeinated beverages they drink daily, how much caffeine-containing food they eat, the specific types, and portion size. They also answered questions about their vision, including specifics on if they have glaucoma or a family history of glaucoma. Three years into the study later they had their IOP checked and eye measurements.

Researchers first looked at the relationship looked between caffeine intake, IOP and self-reported glaucoma by running multivariable analyses. Then they assessed if accounting for genetic data modified these relationships. They assigned each subject an IOP genetic risk score and performed interaction analyses.

The investigators found high caffeine intake was not associated with increased risk for higher IOP or glaucoma overall; however, among participants with the strongest genetic predisposition to elevated IOP – in the top 25 percentile – greater caffeine consumption was associated with higher IOP and higher glaucoma prevalence.

More specifically, those who consumed the highest amount of daily caffeine- more than 480 milligrams which is roughly four cups of coffee – had a 0.35 mmHg higher IOP.

Additionally, those in the highest genetic risk score category who consumed more than 321 milligrams of daily caffeine – roughly three cups of coffee – had a 3.9-fold higher glaucoma prevalence when compared to those who drink no or minimal caffeine and in lowest genetic risk score group.

Glaucoma patients often ask if they can help to protect their sight through lifestyle changes, however this has been a relatively understudied area until now. This study suggested that those with the highest genetic risk for glaucoma may benefit from moderating their caffeine intake.

It should be noted that the link between caffeine and glaucoma risk was only seen with a large amount of caffeine and in those with the highest genetic risk,” says co-author Anthony Khawaja, MD, Ph.D., Associate Professor of Ophthalmology University College London (UCL) Institute of Ophthalmology and ophthalmic surgeon at Moorfields Eye Hospital.

“The UK Biobank study is helping us to learn more than ever before about how our genes affect our glaucoma risk and the role that our behaviors and environment could play. We look forward to continuing to expand our knowledge in this area.”


Relatively high intraocular pressure (IOP) can have a negative effect on the optic nerve and is the most important cause of development and progression of glaucoma. Therefore, most studies suggest that lowering IOP in glaucoma patients can prevent glaucoma progression. However, it is also true that glaucoma development or progression can occur even if the IOP is within the normal range. Many studies have been conducted to identify other solutions for patients who cannot be managed by lowering IOP [1,2]. In addition to this, various other risk factors affecting glaucoma have been reported [3–6].

Although the effects of environmental factors on the development or progression of glaucoma may be evident, the associations are weak, with no clear evidence [3–6]. Despite the demonstrated importance of low IOP in glaucoma, patients often seek other methods that offer favorable effects on glaucoma. Many people wonder if it is possible to stabilize the glaucoma state by changing daily lifestyle in addition to pursuing IOP control.

Caffeine is a widely consumed ingredient worldwide, and studies have reported equivocal effects on glaucoma [7–11]. Some research has indicated that caffeinated coffee consumption increases the risk of glaucoma associated with elevated IOP and plasma homocysteine level [11–14]. Studies about the association of commonly consumed beverages with glaucoma demonstrated equivocal associations, and the effect could be different among ethnicities or individuals. Thus, in this study, we sought to investigate the association of consumption of coffee, tea, and soft drinks typical in Korea with open-angle glaucoma (OAG) using the data from a nationwide population-based survey.

Discussion
Our study indicates that drinking coffee significantly increased risk of OAG in men but not women. Conversely, no significant association was found between consumption of tea or soft drinks and risk of OAG. In addition, coffee consumption was not significantly associated with elevation of IOP.

Many studies have explored the association between caffeinated beverages and IOP or OAG, but there have been conflicting results. The plasma and aqueous levels of homocysteine may be elevated by coffee, which is associated with development of pseudoexfoliation glaucoma and OAG [8,21]. A meta-analysis of randomized controlled trials suggested that coffee consumption raises the serum levels of triglycerides and low-density lipoprotein cholesterol [22]. Another study found that it slightly increased glycosylated haemoglobin (HbA1c) [23]. Higher level of HbA1c and metabolic syndrome were suggested as risk factors for development of glaucoma [24,25]. In addition, coffee contains many ingredients, and it is possible that bioactive components other than caffeine are responsible for glaucomatous optic nerve damage. For example, the acrylamide contained in coffee probably plays a role in neurotoxicity related to conjugation of acrylamide with cysteine residues of presynaptic membrane proteins engaged in neurotransmitter release [26]. As a result, the flow of nerve impulses may be inhibited, coupled with subsequent degeneration of neurons. Oxidative stress is also caused by acrylamide [26].

In this study, there was an inverse association between consumption of soft drinks and IOP mainly in participants who consumed more than 3 cups of soft drinks per day. Excessive intake of soft drinks containing phosphorus additives could cause metabolic acidosis, which might lead to a decrease in IOP [27,28]. However, IOP reduction associated with soft drinks was seen only in women, and sex differences in the impact of soft drinks on IOP remain unknown. This may require further studies.

Caffeine is a methylxanthine derivative and is a component of both tea and coffee. Emerging data have suggested that caffeine-induced vasoconstriction and the subsequent reduction in ocular blood flow may increase the risk of glaucomatous optic neuropathy. Mathew et al reported a significant reduction in cerebral blood flow after ingestion of 250 mg caffeine under double-blind conditions [29]. Vasoconstriction induced by caffeine may result from its inhibitory effect on adenosine, which acts as a potent vasodilator. Some studies presented evidence of increased vascular resistance and decreased blood flow in the optic nerve head and choroidal–retinal circulation after caffeine administration [30,31]. It is possible that altered hemodynamic response may cause ischemic insult and render the optic nerve more sensitive to elevated IOP [32]. Indeed, vascular dysregulation is considered a pivotal factor, especially in the pathogenesis of OAG with low IOP, which is the most common type of glaucoma in Korean people [33]. Patients with OAG may show abnormal vascular responses to caffeine intake; thus, glaucomatous change may occur even with only a tiny alteration in IOP.

Some randomized controlled trials have indicated that ingestion of caffeinated coffee can lead to a significant IOP elevation in participants with or at risk for glaucoma compared with controls taking in equal volumes of fluid [14,34,35]. Kang et al reported via a prospective cohort study that overall regular coffee consumption was not associated with risk of OAG, but subgroup analyses showed a significant adverse correlation between caffeinated coffee and OAG with IOP ≥22 mmHg among those with daily consumption of five or more cups of caffeinated coffee or those with a family history of glaucoma [11]. These authors additionally showed that greater caffeine intake was more adversely related to risk of OAG with elevated IOP in those having a family history of glaucoma. However, Wu et al suggested that coffee consumption was not associated with development of glaucoma [10].

Caffeine is considered to play a role in increasing IOP after drinking coffee [36,37]. Many studies regarding the effect of caffeinated beverages on eyes have reported that caffeine may affect aqueous production and drainage. Although the mechanism is not clearly understood, theoretically, caffeine can raise IOP by inhibiting phosphodiesterase activity, resulting in higher intracellular cyclic AMP level and greater aqueous humour production in the ciliary body [38]. In an animal model of ocular hypertension, dilated intercellular spaces in the nonpigmented ciliary epithelium were observed following intravenous caffeine administration, suggesting caffeine-induced enhancement of aqueous humour transport [39]. Caffeine is also assumed to reduce aqueous humour outflow through the trabecular meshwork by decreasing smooth muscle tone [37]. Although the caffeine effect on aqueous outflow was not seen in healthy individuals, most studies conducted in participants with or at risk of glaucoma have shown a positive association between caffeine intake and IOP [36,37,40,41].

Given that homeostatic regulation of IOP is mainly achieved by aqueous outflow control, IOP may increase significantly in eyes with impaired outflow facility after exposure to provocative factors such as caffeine or fluid intake. The Blue Mountains Eye Study, a population-based, cross-sectional study, demonstrated the significant effect of coffee consumption on IOP elevation, especially in participants with OAG [42]. Li et al reported that caffeine had little effect on IOP in normal individuals, while patients with ocular hypertension or glaucoma showed significant IOP elevation [7]. Glaucoma patients show higher resistance to aqueous outflow in comparison with people of similar ages without glaucoma, and this finding may further explain the mechanism of IOP elevation in eyes with OAG after coffee consumption [43]. In our study, there was no significant difference in IOP according to coffee consumption between normal participants and glaucoma patients. Given that most study patients had OAG without high IOP, which indicates relatively normal outflow facilities, our study supports lack of influence on IOP by caffeine.

Dietary intake of phytochemicals and flavonoids in tea has been observed to have antioxidant and neuroprotective effects associated with health benefits [44]. Wu et al reported that individuals who drink hot tea had a lower risk of developing glaucoma [10]. Based on self-reported questionnaires, participants drinking at least one cup of hot tea daily showed a lower risk of glaucoma compared with those not drinking hot tea, whereas consumption of caffeinated coffee or soft drinks was not significantly associated with overall glaucoma risk. Tea contains less caffeine than coffee but more flavonoids and phytochemicals, which have been suggested to play a protective role in development or progression of glaucoma [45–47]. However, the effect of tea consumption on glaucoma remains unclear. In our study, which was performed with a larger group of participants from a single ethnic population, the results support a positive association between coffee consumption and risk of OAG. Conversely, regarding the effect of tea or soft drinks on OAG, we could not find any significant association. Differences in study methodology and ethnicity in study participants might account for this discrepancy.

In our study, the adverse association between coffee consumption and OAG was observed particularly in men, whereas this association was not significant in women. We cannot explain why this is, though men and women have different body structures and serum hormone levels. Some studies have reported difference in prevalence and risk factors of OAG between men and women [4–6,48]. One study reported that serum glutamate concentration was significantly higher in men than in women, possibly due to the effects of estrogen and progesterone [49].

The tissue responses of men and women for glaucomatous insult seem fundamentally different. Estrogen-related effects such as IOP reduction or neuroprotection have been suggested as possible mechanisms to explain the sex difference [50,51]. Regarding coffee consumption and OAG, Kang et al. showed that increasing intake of caffeine was significantly related to higher risk of OAG in women, not in men, but this association was only statistically significant in a group of women with high IOP (≥22 mmHg) [11]. Conflicting results from our study may be due to differences in study population (cohort-based vs. population-based) and methodology (incident vs. prevalent OAG). Overall, there have been controversies about sex predilection in OAG, and the mechanism of the sex-specific association remains unknown. Further studies are warranted to disclose the underlying pathophysiology.

Our study had some limitations. Because this study was an observational and cross-sectional design, the incidence of OAG and the causality between beverage consumption and OAG could not be determined. We could not analyze the types of tea consumed or the drink methods of beverage due to lack of data on aspects including beverage size. Since caffeinated beverage is not the same as caffeine, the association of caffeinated beverage with OAG should not be equated with that of caffeine. Considering the nature of a questionnaire, because the survey used depends on recall, the information obtained was likely not completely accurate. Furthermore, the role of family history, which is a strong risk factor for OAG, could not be evaluated in the association between coffee consumption and risk of OAG.

However, there was a clear distinction between people who do not drink coffee and those who drink it, and our results showed that coffee has a detrimental relationship with OAG in Koreans. Unmeasured or residual confounding factors may contribute to unexpected analytical bias. In addition, the visual field was examined by FDT rather than by Humphrey field analysis, which is the test of choice for visual field testing. However, FDT is a fast, reliable, large-scale screening method that can detect glaucomatous visual field defects earlier than standard automated perimetry [52,53].

Angle status was assessed using Van Herick methods, not gonioscopic examination. Although this study has limitations, the strengths of our study include its representation of a South Korean population and its relatively large sample size and high response rate.

Additional consideration should be given to the fact that epidemiologic studies investigating the effects of caffeine on glaucoma are complicated due to the difficulty in estimating dietary caffeine intake, great individual variability in caffeine sensitivity, and poor understanding of pathological processes in the eye [54,55].

Furthermore, ethnic differences in the prevalence of glaucoma as well as in physiological response to caffeine have been reported consistently, which suggest the need for research on the relationship between caffeine intake and OAG in different ethnicities [56–58].

The main stressor for glaucomatous damage is relatively higher IOP than that tolerable for the optic nerve. The threshold of response to stress is different depending on age, sex, ethnicity, and other factors. In this population-based study with data from KNHANES, we identified a significant association between coffee consumption and risk of OAG, particularly in men, while consumption of tea or soft drinks was not significantly associated with OAG.

According to these results, a limitation on drinking coffee may be helpful for decreasing the risk of OAG. Further studies are required to find the mechanisms and determine the sex differences in caffeine effects on OAG. If further studies are carried out and good results are revealed, precise advice to the patient will be available.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371211/


Journal information: Ophthalmology

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