Is low vitamin D a risk factor for primary open angle glaucoma?

Although the exact relationship between vitamin D and glaucoma remains uncertain, it has increasingly become apparent that low systemic levels of the vitamin may be a risk factor for primary open angle glaucoma (POAG).¹ Studies to date have not demonstrated a direct link between vitamin D deficiency and POAG, with many interacting phenotypic, genetic, epigenetic and environmental factors likely to be involved. However, they have lent significant weight to the pursual of further studies in the area.

When examining the link between vitamin D and glaucoma, it is helpful to consider the fact that the retinal ganglion cell (RGC) degeneration that occurs in the inner retina in POAG has been proposed to result from both direct and indirect damage from oxidative stress. Various reviews have explored oxidative stress and its contribution to the pathogenesis of glaucoma.^2-4

Evidence

Hypotheses for the benefits of vitamin D in glaucoma include its role as an antioxidant⁵ and in suppression of genes involved in the determination of intraocular pressure.⁶ Vitamin D has also been shown to regulate the functions of neuroprotection in the central nervous system, including the optic nerve.^7,8

Treatment with the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3, was found to ameliorate the effects of oxidative stress in human retinal pigment epithelium cells in one study.⁹ The compound led to suppression of oxidative damage and inflammation through antioxidant signalling pathways and reduced the generation of reactive oxygen species (ROS). Human retinal pigment epithelium cells also had greater survival rates and there was a reduction in the secretion of cytokines and vascular endothelial growth factor.⁹

Ultimately, the multiple complex pathways leading to RGC damage under oxidative stress are likely varied and overlapping. The apoptotic process itself generates ROS and the overall effect is a positive feedback cycle whereby excess ROS produce oxidative stress that eventually yields more ROS.¹⁰

The relationship between vitamin D and glaucoma may also be a consequence of altered vitamin D metabolism in affected individuals, or due to low vitamin D levels. Observational studies that assessed the relationship between low levels of the vitamin and POAG found a significant association between them. Serum 25(OH)D^11-15 and calcitriol¹⁶ levels were significantly lower in POAG patients than in controls, and specific metabolic processes involving vitamin D were able to differentiate cases from controls.¹⁷

Although the cross-sectional and case control studies all found POAG to be significantly associated with low vitamin D status, no causal relationship could be established between glaucoma and low vitamin D^11-15 or calcitriol deficiency.¹⁶ On the contrary, a meta-analysis¹⁸ of three vitamin D and POAG studies^11,12,16 found no significant difference in serum vitamin D levels between POAG patients and controls.

Nevertheless, there was significant between-study heterogeneity: one study was cross-sectional whereas the other two were case-control studies. There were also significant differences in sample size and vitamin D measurements, and Lv et al.’s study¹⁶ measured serum calcitriol levels as opposed to serum 25(OH)D.

Some interventional trials have shown promise^6,19,20 but results in others are conflicting.²¹ Early interventional studies found a reduction in IOP with intramuscular administration of vitamin D¹⁹ and intramuscular cod liver oil.²⁰

Treatment of non-human primates with topical vitamin D resulted in a 20% reduction in IOP in both eyes without nasolacrimal duct occlusion, a dose-dependent unilateral IOP response with nasolacrimal duct occlusion, and depressed expression of several genes associated with IOP regulation, though the mechanism for this was unclear.⁶

In one study, no difference in IOP was found with oral supplementation (20,000 IU twice per week); however, it was noted that most participants had IOP within the normal range.²¹ Accordingly, it may be beneficial for future interventional clinical trials to investigate the link between low vitamin D and glaucoma using alternative supplementation methods such as intramuscular or topical application.

Furthermore, recent genome-wide association studies (GWAS) for vitamin D levels^22,23 in combination with POAG,²⁴ IOP²⁵ or exfoliation glaucoma have been completed.²⁶ GWAS could be used for Mendelian randomisation to explore a causal effect of vitamin D levels in POAG or other types of glaucoma.

Greater sunshine exposure and lower ambient temperatures have been found to increase the likelihood of exfoliation syndrome, an extracellular deposit disorder that is the most common cause of secondary open-angle glaucoma.²⁷ However, there have been no studies to our knowledge investigating the relationship between sun exposure and POAG. Prospective cohort studies would be beneficial to further elucidate this area.

Overall, establishing the relationship between vitamin D and POAG might not only alter the way that we manage glaucoma but also help prevent this sight-threatening disease. Discovering other modifiable risk factors, particularly those that can be inexpensively treated, will have substantial outcomes.

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Brandon Huynh, MBBS, MMed(OphthSc)
E: b.huynh@live.com
Dr Huynh is based at Westmead Hospital, Sydney, Australia.

Peter Shah, BSc (Hons), MB ChB, FRCOphth, FRCP Edin, MA (Distinction)
E: peter.shah@uhb.nhs.uk
Prof. Shah is consultant ophthalmic surgeon at the University Hospitals Birmingham (UHB) NHS Foundation Trust, as well as co-director of the Birmingham Institute for Glaucoma Research, visiting professor at University College London and honorary professor of glaucoma at the Centre for Health & Social Care Improvement, University of Wolverhampton, UK.

Freda Sii, MBBS PGDip
E: sii.freda@gmail.com
Dr Sii works at the University Hospital Birmingham NHS Foundation Trust and Birmingham Institute for Glaucoma Research, Birmingham, UK.

Damien Hunter, BSc (Hons), PhD
E: damien.hunter@sydney.edu.au
Dr Hunter is based at the Centre for Vision Research, Westmead Institute for Medical Research, Sydney, Australia and the University of Sydney’s Faculty of Medicine and Health.

Nicole Carnt, BOptom, PhD
E: n.carnt@unsw.edu.au
Dr Carnt works at the Westmead Institute for Medical Research, Sydney, Australia.

Andrew White, BMedSci (Hons), MBBS, PhD, FRANZCO
E: andrew.white@sydney.edu.au
Dr White is co-chair of the Agency for Clinical Innovation: Ophthalmology Network Governing Body and head of the Department of Ophthalmology, Westmead Hospital as well as being director of the Community Eye Care Centre, Western Sydney and conjoint associate professor of the School of Optometry and Vision Sciences, UNSW.

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article and the research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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