Association of total antioxidants level with glaucoma type and severity

Discussion

We obtained plasma samples from 340 cases of extensively diagnosed glaucoma patients and 351 healthy controls. Our control group was carefully selected in terms of age, gender, and ethnicity. We established that they were free of glaucoma by extensive clinical examination. Age and gender are known to affect TAS levels independent of glaucoma status; therefore, age-and-gender matched control groups were selected for this study.22 In addition, as indicated in Table 3 there was no difference in the distribution of 5 different systemic co-morbidity (DM, hypertension, hypercholesterolemia, CAD, and smoking) between patients and controls thus eliminating any other factors which may influence the TAS level and allowing us to compare TAS level as independent risk factor for glaucoma. There is strong evidence of oxidative mechanisms in POAG,10 and PEG.23 However, optic nerve injury in PACG is mainly considered to be caused by increased IOP as a result of anatomic changes in the anterior,24 and posterior globe.25,26 The role of oxidative stress in PACG has perhaps therefore received limited attention, despite the fact that PACG affects 3.9 million people worldwide.1 We previously investigated the TAS level in a PACG group of patients.19 Among the 340 glaucoma cases we had 54 PEG cases, 147 POAG, and 139 PACG cases. When every group of glaucoma was compared to controls independently, we detected the following: i) TAS levels among PEG were decreased in relation to controls;18 ii) TAS level was also decreased in POAG patients versus controls, and TAS level was associated with increased cup-to-disc ratio;20,27 and iii) TAS level was almost similar in PACG patients versus controls; however, there was an inverse correlation of TAS level with IOP.19,28 From these results, it is clear that decreased TAS level plays a bigger role in PEG and POAG compared with PACG. This may indicate that oxidative stress represented indirectly by the TAS levels; play a bigger role in cases of POAG and PEG than for PACG.

Our current observation that oxidative stress may play a minor role in PACG development compared to other types of glaucoma is well supported by our previous findings in PACG.29 It is also possible that decreased levels of TAS are more linked to particular clinical indices important for PACG rather than the disease per se. Collectively, the mean total antioxidant concentration was significantly lower among cases compared with controls. This fact confirms our previous findings in the Saudi population,18-20 and agrees with the published literature. Gherghel et al30 reported decreased levels of plasma glutathione in patients with glaucoma suggesting compromised antioxidative defense. Erdurmus et al15 reported decreased serum antioxidant capacity and increased blood oxidative stress in patients with POAG and PEG. Zanon-Moreno et al31 reported a significant increase in oxidative status measured as malondialdehyde-thiobarbituric acid reactive substances (MDA-TBARS), and decreased total antioxidant activity in the aqueous humor of glaucomatous eyes than the cataract eyes. In addition; however, our current study highlights the association between type and severity of glaucoma and the mean TAS level. Our findings suggest that not only the mean TAS level may be decreased due to glaucoma, but it is also more decreased in open angle than in closed angle or pseudoexfoliation types, enforcing our earlier investigations that oxidative stress may play a minor role in PACG development compared with other types of glaucoma.29 Oxidative stress in the anterior chamber of glaucomatous eyes can be an ocular manifestation as a result of systemic insult. A study by Sorkhabi et al16 provided evidence for increased oxidative damage and decreased TAS in serum and aqueous humor of glaucoma patients suggesting that in glaucoma the increased oxidative burden in the anterior chamber of glaucomatous eyes may be due more to a faulty antioxidative defense and increased oxidative stress than to a systemic insult, compromising the trabecular meshwork and its functioning. Hence, we speculate that decreased levels of TAS, as a result of increased oxidative stress in the glaucomatous eyes, may at least in part play a role in occurrence and progression of POAG and PEG.

We also observed that the more reduced mean TAS level, the more acute or severe the glaucoma type. Additionally, the inheritance factors are playing a major role in this causative pathway, as our findings show that the prevalence of consanguinity and a family history of glaucoma are much more among both POAG and PACG groups than the PEG group. Although most of our recruited patients are usually set on anti-glaucoma medications, there was a statistically significant difference across the 3 subgroups of cases in terms of both mean IOP and number of glaucoma mediations levels. It is well established that chronic glaucoma patients suffer an increasing pattern of IOP until reaching the maximum tolerated level of medication and are indicated for surgical intervention. This fact was also true for the visual acuity level. Furthermore, our findings suggest that the mean TAS level may be used as an indicator of the severity of glaucoma, and possibly on the duration and compliance to treatment among chronic cases. Nevertheless, this area requires more investigation and recruitment of a large cohort of patients in a longitudinal multi-centric study to provide concrete evidence.

This study has its own limitations. There is a great debate in the literature regarding the role of cataract in glaucoma surgery. Visual acuity assessment as a glaucoma severity index used in our study could therefore be affected by other diseases common in these patients including cataract. However, among our subjects we did not have enough cases to compare vision with and without combined cataract. Reviewing our data, we found only 2 cases with combined cataract, where visual acuity was better than 20/40; so, it was not worth controlling for them. In addition, our current study used age at first diagnosis and self reported age at onset as a surrogate to the actual age at onset. The reason for that was to roughly estimate the duration of having glaucoma. We understand that this measurement would face a lot of potential bias. However, we think that in terms of age, it would be much more appropriate to use “age at onset” than using the “current patient age” where this approach is expected to minimize the estimation error. Although significant correlation has been reported between serum and aqueous levels of TAS,16 it should be noted that the results reflect the antioxidant status in the plasma samples and not aqueous fluid and hence require cautious interpretations. The study is purely descriptive in nature and provides no evidence of mechanistic conclusions. In a perfect scenario an ideal study group would include glaucoma patients without anti-glaucoma medications; however, these cannot be included for ethical reasons. Our findings do not necessarily indicate that low levels of TAS is a primary cause of glaucoma, but suggest future avenues for research.

In conclusion, our findings provide evidence that plasma TAS levels are decreased in patients with glaucoma, more so in open-angle and pseudoexfoliation than angle-closure glaucoma. The study adds to the growing body of evidence supporting the hypothesis that decreased antioxidative defense and/or increased oxidative stress may have a critical role in the pathogenesis of glaucoma. As far as we know, this study is unique in its approach, and may open the gate for more investigations in the area of antioxidant research in glaucoma that would yield a more in-depth understanding of the association between pathogenic mechanisms of the disease and antioxidants level, and provide a new therapeutic approach to control the increasing prevalence of blinding glaucoma.