Discussion
The results of the meta-analysis showed that people who have excess body weight will have higher IOP values than the normal weight sample (0.93 (95% CI: 0.67 to 1.18)). This finding is in line with a meta-analysis by Liu et al, who examined the relationship between body adipose levels and the risk of glaucoma. From 15 included studies, it was found that overweight samples assessed by BMI, waist circumference and adiposity had a 1.19 (95% CI: 1.04 to 1.37) times higher risk of suffering from glaucoma caused by an increase in IOP. The conclusion of the meta-analysis by Liu et al illustrates that body adipose levels associated with excess body weight can increase the risk of increased IOP that might lead to glaucoma.15 This was found to be in line with previous primary studies which reported that there was a difference in scores between overweight patients compared with those with normal weight and IOP values.16–22
Besides, based on the subgroup analysis of dividing the studies into overweight, obese and morbidly obese subgroups, it showed a subtotal mean difference of 0.60 (95% CI 0.48 to 0.72) in the overweight subgroup, 1.02 (95% CI 0.60 to 1.44) in the obese subgroup and 1.25 (95% CI 0.96 to 1.54) in the morbidly obese subgroup, which indicated that the higher patient weight classification will lead to higher IOP values.
‘Excess body weight can increase IOP’ is explained in two theories, namely ‘mechanical’ and ‘vascular’. Based on the mechanical theory, obesity can lead to an increase in IOP by causing an increase in intraorbital adipose tissue, blood viscosity and episcleral venous pressure,23 where fat accumulation in obesity leads to a decrease in aqueous humour outflow.24 The vascular theory suggests that eyes with poor vascular supply to the optic nerve will be more susceptible to damage when having elevated IOP. Changes in autonomic and endothelial function can result in abnormal blood flow to the eye and unstable perfusion that impairs vascular supply. Obesity was found to be a factor of vascular endothelial dysfunction and autonomic dysfunction.23
The mechanical theory is supported by Stojanov et al, who reported on the conclusion of their research, that the sample with BMI >30 kg/m2 had an average IOP value of 15.96 mm Hg compared with those with a normal BMI (18.5–24.9 kg/m2) who only have an average IOP of 12.99 mm Hg. The increase in IOP values in obese patients is associated with a buildup of retrobulbar adipose tissue (RAT) volume, where the obese sample has a thicker RAT (mean 6.23 cm3) than in the normal sample which has a mean RAT of 4.85 cm3. Furthermore, Stojanov et al explained that RAT can affect IOP due to the ‘mass effect’ mechanism, where the buildup of RAT can directly or indirectly affect episcleral venous pressure which can cause outflow dysfunction in Schlemm’s canal, further triggering an increase in IOP.22 In addition, increased blood viscosity in obese samples in the form of an increase in blood cell count, haemoglobin and haematocrit was associated with resistance to outflow in the episcleral vein, further causing an increase in venous pressure that might reduce aqueous humour outflow, resulting in an increase in IOP.18
In addition, a study by Oner and Karadağ stated that in obese patients, there was a thinning of choroidal thickness which results in abnormalities in the choroidal vascular bed that had an impact on ocular pulse amplitude (OPA). OPA itself can show choroidal flow perfusion and intraocular blood flow with a measurement using optical coherence tomography or dynamic contour tonometry (DCT). OPA is defined as the difference between diastolic and systolic IOP which reflects choroidal pulsatile flow in the form of a difference in IOP. However, in the study by Oner and Karadağ, it was found that there was a decrease in the value of OPA. In the obese group measured using DCT, OPA was found to be 2.19±0.53 mm, while in normal weight patients, OPA was found to be 2.10±0.74 mm. This shows that ocular blood flow is impaired in the obese group that is shown by a decrease in OPA, which can cause obese patients to experience accelerated visual damage due to glaucoma.19 This is also supported by a study done by Vulsteke et al, who reported that lower OPA values in obese patients as measured by DCT were associated with visual field defects due to severe glaucoma, and increased risk factors for visual organ defects.25 In a study by Karadag et al, it was also found that the lowest OPA values were experienced in the obese group (average 2.1 mm) and in the normal weight group (2.7 mm). Therefore, the decreased OPA value in obese subjects may indicate that the obese group is more prone to experiencing increased IOP values and glaucoma who are more likely to suffer from accelerated visual disability than normal weight subjects without glaucoma.11
The vascular theory is based on several studies that have examined the mechanisms underlying the microvascular changes associated with obesity, which obesity is known to cause inflammation that results in the release of many cytokines. Findings of Yilmaz et al found that adipose accumulation in obese patients causes an increase in the secretion of many molecules such as endothelin-1 (ET-1) and angiotensin-II, and also decrease of nitric oxide (NO).26 NO, an endothelium-derived vasodilator molecule, was found to be decreased in obesity and has been shown to result in impaired dilatation of the vasculature. NO vasodilator molecule of endothelial origin regulates the ocular blood flow and has a positive effect on IOP regulation.27 NO signals regulate aqueous humour outflow from the anterior chamber through the trabecular meshwork and Schlemm’s canal by decreasing the volume of trabecular meshwork cells, decreasing the cell volume of Schlemm’s canal and relaxing cells in the canalicular outflow system.28 Levels of vasoconstrictor molecules such as ET-1 were also found to increase in serum in relation to BMI.29 ET-1 affects directly and through reduced ocular blood flow causes degeneration of retinal ganglion cells (RGCs) which causes increased IOP. Furthermore, ET-1-induced vasoconstriction results in decreased ocular blood flow affecting RGCs.30
In addition, Koçak et al also reported that in patients with obesity class III or with BMI >40 with normal IOP, a decrease in RGC and retinal nerve fibre layer thickness was found and has been associated with optic nerve damage that could lead to normotension glaucoma.31 As for Newman-Casey et al, obese patients with hyperleptinemia can have oxidative injury to the trabecular meshwork, thereby disrupting the outflow of the aqueous humour of the eye, which leads to an increase in IOP.32 Furthermore, in the study by Teberik et al,17 it was also found that the thickness of the retinal nerve fibre layer was significantly reduced in the obese group compared with the control group (72.7±13.6 mm vs 85.05±52.6 mm; p=0.024), which manifested as RGC damage induced by oxidative stress expression in obese patients that could lead to damage of optic nerves.
In addition, central corneal thickness (CCT) was also found to be increased in obese patients. Based on a study of Su et al, CCT was obtained from 3239 individuals. CCT was found greater in individuals with higher BMI (p=0.038), greater IOP (p<0.001), greater axial length (p=0.005) and greater radius of corneal curvature (p<0.001). Based on the results of this research, CCT was found to be associated with higher IOP as well as higher BMI.33
In summary, the relationship between excess body weight as a risk factor for increased IOP values has the following mechanisms: (1) mechanical theory in the form of increased episcleral venous pressure, intraorbital adipose and blood viscosity resulting in an increase in IOP; (2) vascular theory in the form of vascular endothelial dysfunction and autonomic dysfunction resulting in increased IOP (figure 3).
Figure 3The mechanism of excess body weight on the increase in intraocular pressure.
However, one recent study also found a significant correlation between underweight patients who are more susceptible to primary open-angle glaucoma (POAG). Na et al found that compared with normal weight patients (BMI 18.5–23 kg/m2), the risk ratio of POAG increased by 12.9% in underweight patients; however, when compared with obese patients, it was only found to be increased by 3.4%, 6.0% and 8.0% for obese patient class I, class II and class III, respectively. Therefore, people who have more or less body weight are at risk of open-angle glaucoma. One explanation for the effect of underweight is adipose tissue depletion, which has the effect of increasing levels of adiponectin and adipocyte-derived factor. It is said that lower adiponectin levels in individuals who are obese or in individuals who are underweight can increase the risk of atrial fibrillation (AF). AF is a condition with an irregular and rapid heart rate which can cause poor systemic blood flow, one of which is associated with an impact on episcleral venous blood flow leading to an increase in IOP. Therefore, BMI has been shown to have a U-shaped relationship with the risk of AF.34 35
In addition, a potential factor is reduced muscle mass and arterial stiffness. Arterial stiffness increases as muscle mass reduces and ageing happens. Previous studies have shown that increased arterial stiffness has an association with glaucoma and may contribute to the pathogenesis of glaucoma. Low muscle mass, which is affected by a low BMI, may be significantly associated with arterial stiffness and glaucoma.36
The strength of this study is that it not only presents the statistical results of the latest meta-analysis on the effect of excess body weight on IOP but also presents a comprehensive theory about several mechanisms that cause excess body weight from mechanical and vascular aspects. However, the limitation of this study is that it only focuses on the effect of excess body weight on IOP. Although we have eliminated several factors that can influence IOP, such as several systemic diseases, we realise that many other factors influence IOP and have not been identified in this study, such as CCT, OPA, RAT, inflammatory cytokines and genetic factors. The second limitation is that each study does not have a standardised classification related to BMI; this is partly because some studies come from Asia and Europe, so the BMI classification used is different. In addition, the tools used to measure IOP in this study are varied and not standardised, so it is possible that there will be differences in IOP measurement results between studies.
Furthermore, further studies are needed to assess obesity as a direct risk factor for glaucoma. In addition, studies on the relationship between low body weight and IOP should also be carried out to complete a comprehensive understanding of the relationship between BMI and IOP. The relationship between underweight and glaucoma in other studies has not been widely studied, and the population-based study by Na et al is the first study to independently evaluate the effect of underweight on the risk of developing POAG.35