Potential benefits of vitamin A and its derivatives in glaucoma

Abstract

Vitamin A (VA), which plays a vital role in maintaining normal eye functions, has shown potential benefits in glaucoma based on accumulating evidence. The purpose of this review is to comprehensively summarize the possible role of VA and VA derivatives in the prevention and treatment of glaucoma, explore their mechanisms of action, suggest future research directions, and provide references for relevant researchers. Regarding the correlation between VA intake and glaucoma, researchers in different regions have conducted a series of studies, but most of them are cross-sectional studies. The results of different studies vary greatly and there are conflicting results, but the results of several systematic reviews and meta-analysis suggest that dietary VA intake can help reduce the risk of glaucoma. If increasing total dietary VA intake is successful as an effective prevention strategy, this would be a promising approach for primary prevention of glaucoma. Further, we summarized a large number of mechanism studies which have demonstrated the mechanisms of how VA might play a role in the prevention and treatment of glaucoma by inhibiting the oxidative stress process of trabecular meshwork and optic nerve tissue, reversing the effect of TGF-β2 on human trabecular meshwork cells and increasing intracranial pressure. Additionally, studies have also shown that VA and its derivatives could also play a role in preventing postoperative scarring and damage of the ocular surface due to the use of antiglaucoma drugs through a variety of mechanisms.

Key Messages

What is known

• Vitamin A plays an important role in maintaining the normal eye functions, such as promoting the growth of corneal and conjunctival epithelium, the viability of retinal pigment epithelial cells, and retinal phototransduction.

What is new

1. Vitamin A may play a role in the prevention and treatment of glaucoma by inhibiting the oxidative stress process of trabecular meshwork and optic nerve tissue, reversing the effect of TGF-β2 on human trabecular meshwork cells and increasing intracranial pressure.

2. Topical use of vitamin A may prevent the development of hormone-induced glaucoma by inhibiting the hormone-induced decrease in ascorbic acid levels in aqueous humor.

3. Vitamin A and its derivatives can play a role in preventing postoperative scarring and preventing the damage of antiglaucoma drugs on the ocular surface through a variety of mechanisms.

Introduction

Vitamin A (VA), also known as retinol, is an essential fat-soluble vitamin that plays a vital role in maintaining normal physiological functions of body [1]. VA plays an important role in maintaining the normal eye functions, such as promoting the growth of corneal and conjunctival epithelium, the viability of retinal pigment epithelial cells, and retinal phototransduction [2]. Thus, VA is vitally important for maintaining normal vision. Glaucoma is a group of diseases characterized by progressive retinal ganglion cell death with characteristic visual field impairment. It is the leading cause of irreversible blindness worldwide [3]. The global prevalence of glaucoma in people aged 40 to 80 years is estimated to be 3.5%, and 111.8 million people are expected to have glaucoma by 2040 [3]. The causes of glaucoma are complex and multi-factorial, including mechanical, vascular, genetic, immunological and other factors [4]. Studies have shown that decreased antioxidant capacity in the aqueous humor (AH) or at the systemic level appeared to be associated with more severe glaucomatous lesions and more advanced visual field loss [5–7]. Therefore, oxidative stress processes are thought to play an important role in glaucoma. Although many researchers have been focusing on whether VA, as a powerful antioxidant, has a preventive or adjuvant therapeutic effect on glaucoma, there are some conflicting research results that raise doubts among physicians and patients about the impact of VA on glaucoma.

The purpose of this review is to comprehensively summarize the possible role of VA and VA derivatives in the prevention and treatment of glaucoma, explore their mechanisms of action, suggest future research directions, and provide references for relevant researchers.

Method

Three databases were systematically searched for relevant references including PubMed, Embase and Web of Science from inception of electronic databases to 30 June 2024. We used a broad inclusive search strategy so as not to miss a seminal contribution. Both MeSH terms and text words were used, which included ‘vitamin A’ and ‘glaucoma’. Endnote software was used to manually filter out duplicate articles. Finally, references that met the criteria were summarized. The systematic search identified 98 potentially relevant references, of which 24 articles met the predefined inclusion criteria and were subjected to rigorous qualitative synthesis.

Results

The correlation between VA intake and glaucoma

Regarding the correlation between VA intake and glaucoma, researchers in different regions have conducted a series of studies, but most of them are cross-sectional studies. As detailed in Table 1, this section systematically incorporated 11 articles meeting the predefined criteria. A cross-sectional study of 662 elderly African-American participants in the study of osteoporotic fractures suggested that higher intake of certain foods rich in VA (≥1500 μg Retinol Equivalents), vitamin C (VC,≥140 mg) and carotenoids might be related to a reduced likelihood of glaucoma in older African-American women [8]. A cross-sectional study of 581 Japanese American participants in Los Angeles showed that low VA intake was related to an increased risk of glaucoma [9]. In a prospective cross-sectional study conducted in Beijing, China, serum retinol concentrations in fasting blood samples were measured of 101 normal-tension glaucoma (NTG) patients and 138 healthy controls, and the results showed that serum retinol concentrations were lower in NTG patients [10]. In addition, a cross-sectional survey of 6742 adults in Koreans showed that insufficient intake of certain nutrients such as VA might be correlated with an increased risk of primary open-angle glaucoma (POAG) [11]. Also, a cross-sectional study of 16,770 Korean adults found that dietary nutrient intake levels such as VA were correlated with open-angle glaucoma (OAG) independent of intraocular pressure (IOP) [12]. Of course, in addition to cross-sectional studies, there are other methodologically designed surveys that provide evidence of correlation between the VA and glaucoma. For example, results from a prospective cohort study in Rotterdam, in which 3502 participants aged 55 years and older were followed for an average of 9.7 years, showed that low retinol equivalent and vitamin B1 (VB1) intake and high magnesium intake appeared to be related to an increased risk of OAG [13].

Table 1.

The correlation between VA intake and glaucoma

Literature	Study type	The number of participants	Participant type	Research conclusions
1[8]	Cross-sectional study	662	Elderly African-American women	Higher intake of certain foods rich in VA might be related to a reduced likelihood of glaucoma
2[9]	Cross-sectional study	581	Japanese American	Low VA intake was related to an increased risk of glaucoma
3[10]	Cross-sectional study	345	Chinese (101 NTG patients, 106 POAG patients and 138 control subjects)	Serum retinol concentrations were lower in NTG patients, but no positive results were obtained in POAG patients
4[11]	Cross-sectional study	6742	Korean adults	Insufficient intake of VA might be correlated with an increased risk of POAG
5[12]	Cross-sectional study	16770	Korean adults	Dietary VA intake level was correlated with OAG
6[13]	Prospective cohort study	3502	Elderly participants in Rotterdam	Low retinol equivalent intake appeared to be related to an increased risk of OAG
7[14]	Cross-sectional study	2912	Americans over age 40	Neither dietary supplementation of VA nor serum VA level was associated with glaucoma incidence
8[15]	Cross-sectional study	91	Japanese (47 NTG patients and 44 control subjects)	No statistically significant difference in serum VA content
9[16]	Controlled study	Not applicable	Rabbits	No correlation between IOP and serum VA levels
10[17]	Prospective cohort study	173230	Americans (121,701 nurses and 51,529 health professionals)	No strong association was observed between the intake of VA and the risk of POAG
11[18]	Prospective cohort study	More than 20,000	Participants were from Seguimiento Universidad de Navarra	Participants with a higher ACE-Vitamin Index had a lower risk of developing glaucoma, but when each vitamin was analyzed individually, there was no significant protective effect

However, there are some contradictory findings. A cross-sectional study in the United States of 2912 participants aged 40 years or older who were interviewed about dietary supplement use during the preceding 30-day period and whose serum vitamin levels were measured showed that neither dietary supplementation of VA and vitamin E (VE) nor serum VA and VE levels were associated with glaucoma incidence [14]. A cross-sectional study in Japan compared serum levels of antioxidant vitamins in 47 subjects with NTG and 44 control subjects and found no statistically significant difference in serum VA content [15]. In addition, the prospective cross-sectional study conducted in Beijing, China as described previously also included 106 patients with POAG. Unlike the results of NTG patients, there was no statistical difference in serum retinol concentration between the POAG group and the healthy control group [10]. A controlled study in the rabbits also found no correlation between IOP and serum VA levels in rabbits fed either pure VA or beta-carotene [16]. It is worth mentioning that two large cohort studies have also produced negative results. Based on a cohort that included 76,200 nurses and a follow-up study that included 40,284 health professionals in the United States, researchers examined the association between dietary antioxidant consumption and the risk of POAG in participants over 40 years of age followed for 10–16 years. No strong association was observed between the intake of antioxidants such as VA and the risk of POAG [17]. The Seguimiento Universidad de Navarra cohort included more than 20,000 participants followed for more than 20 years. The researchers extracted vitamin intake from the participants’ diets and vitamin supplements, and calculated the index including VA, VC and VE (ACE-Vitamin Index). The results found that participants with a higher ACE-Vitamin Index had a lower risk of developing glaucoma, but when each vitamin was analyzed individually, there was no significant protective effect [18].

Several investigators performed meta-analyses of the numerous clinical studies to increase statistical power. In 2018, a systematic review involving 36 studies concluded that dietary intake of VA and VC showed a beneficial association with OAG; however, the results on vitamin levels in the blood did not show a clear relationship with OAG [19]. Similarly, the data of a meta-analysis conducted in 2022 showed that high-dose intake of VA and vitamin B (VB) but not VC, vitamin D (VD), or VE was associated with a low prevalence of glaucoma [20]. Li et al. [21] used an umbrella review to integrate meta-analytic results on the association between non-ocular factors and glaucoma. Studies suggest that consuming VA through diet is associated with a reduced risk of glaucoma, though the correlation is weak. We believe that well-designed, higher quality randomized controlled trials, as well as large-scale cohort studies, are needed to further provide strong evidence for whether and how VA intake alters the risk of glaucoma.

The use of VA may assist in the prevention and treatment of glaucoma and possible related mechanisms

VA may inhibit oxidative stress in the pathogenesis of glaucoma

More and more evidence showed that there were a large number of reactive oxygen species in the AH and trabecular meshwork (TM) tissues of glaucoma patients, which confirmed the chronic exposure to oxidative stress [22]. The lack of antioxidant mechanism leads to human trabecular meshwork cells (HTMCs) death and chronic inflammatory infiltration, resulting in loss and rearrangement of HTMCs, which further leads to obstruction of AH drainage via TM, and ultimately leads to increase in IOP [23, 24]. Some scholars have also found that oxidative stress was also involved in optic nerve damage [25–27]. Moreover, studies have shown that low antioxidant capacity of AH or systemic level was associated with more severe glaucomatous damage and greater severity visual field loss [6, 7]. Therefore, oxidation process is thought to exert important roles in the pathogenesis and development of glaucoma. It is well known that antioxidants can inhibit the occurrence of oxidation events and repair the damage caused by oxidation [28]. Therefore, in theory, antioxidant supplementation to resist TM damage and protect the optic nerve and intraocular vessels may be of great benefit in the treatment of glaucoma [29, 30]. It is well known that some common nutrients in the daily diet have direct or indirect antioxidant effects, such as VA, VC and VE. As far as VA is concerned, although there is no direct evidence that VA itself has antioxidant activity, researchers generally believe that VA plays an indirect antioxidant role due to its influence on the transcription of key genes in the anti-oxidation reaction process [31].

Additionally, a clinical study evaluated the effect of several antioxidants on IOP after the closed eyelid test (CET), a predictive test for glaucoma. The results showed that IOP increased after CET, and taking various antioxidants 1 hour in advance could reduce IOP, and the effect of VA was more significant than that of VE and VC [32]. The researchers suggested that high IOP induced by CET might be a response to mixed stress, oxidative and thermic, with degenerative effects on TM, and the antioxidant VA could inhibit this process. Therefore, appropriate supplementation of VA may help to inhibit the oxidative stress process in the pathogenesis of glaucoma.

However, contrary to these findings, there are also studies showing that excess VA can lead to increased phosphorylation of α-synuclein and elevated levels of oxidative stress, ultimately promoting neuronal death, underscoring the importance of appropriate doses [33].

VA may assist in the treatment of glaucoma by reversing the role of transforming growth factor β2 (TGF-β2) in the pathogenesis of glaucoma

Substantial evidence has shown that TGF-β is thought to exert important roles in the development of a variety of eye diseases, including glaucoma. Much evidence indicated that TGF-β can lead to TM dysfunction by inducing the transformation of HTMCs into myofibroblast-like structures, promoting extracellular matrix (ECM) accumulation, increasing cross-linked actin networks, accelerating apoptosis and cell aging, increasing oxidative stress and other mechanisms, and ultimately leading to increased resistance to AH outflow [7, 34–36]. There are three subtypes of TGF-β: TGF-β1, TGF-β2 and TGF-β3, of which TGF-β2 is the main subtype in AH [37, 38]. Multiple independent studies and meta-analyses have reported higher concentrations of TGF-β2 in AH in POAG patients than in controls [39–41]. It is believed that TGF-β2 plays an important role in the pathogenesis of glaucoma. Intervention of HTMCs with TGF-β2 is also a common cell disease model in basic research of glaucoma. Researchers have investigated the effects of all-trans retinoic acid (ATRA), a derivative of VA, on TGF-β2-treated two-dimensional (2D) and three-dimensional (3D) cultures of HTMCs [42]. The results showed that ATRA inhibited TGF-β2-induced increase in the barrier function and metabolic reserve from the mitochondrial oxidative phosphorylation to the glycolysis in 2D HTMCs. In addition, ATRA had significant shrinking and softening effects on 3D HTM spheroids in the absence and presence of TGF-β2.

VA may assist in the treatment of glaucoma by increasing intracranial pressure (ICP)

Professor Wang Ningli's team first proposed the concept of trans-lamina cribrosa pressure difference in 2011 [43]. The anterior surface of the lamina cribrosa was affected by IOP, while the posterior surface of the lamina cribrosa and the retrobulbar optic nerve were affected by ICP. According to the laws of mechanics, the stress within the lamina cribrosa is dependent on the forces on both sides (IOP and ICP) and its thickness. The difference between IOP and ICP is the net pressure within the lamina cribrosa, also known as the trans-lamina cribrosa pressure difference. It acts on the lamina cribrosa, causing changes in the structure and morphology of the lamina cribrosa, increasing the mechanical load of the optic disc, crushing the optic nerve fibers passing through the lamina cribrosa, thereby causing damage to the optic nerve axons and resulting in irreversible loss of visual function [44–47]. It is obvious, then, that a lower ICP leads to a larger trans-lamina cribrosa pressure difference, and the optic nerve is more susceptible to damage.

Emerging evidence support this, with some studies observed a reduced in ICP in POAG patients, especially NTG patients [43, 48–51], and lower ICP values were associated with more severe disease conditions [43, 52–55]. In general, the study largely support the impact of ICP reduction on the development and progression of glaucoma, indicating that low ICP could be an important factor involved in the development of glaucoma. In a retrospective study, VA was found to increase ICP [56], suggesting that the increase in ICP may also be a mechanism by which VA may assist in the treatment of glaucoma.

Supplementation of VA and its derivatives may help prevent scar formation after glaucoma filtering surgery and possible related mechanisms

In clinical practice, surgery is often required for glaucoma patients whose IOP is not well controlled by drugs or laser surgery, and filtering surgery is still the gold standard, but postoperative filtering bleb scar formation often leads to surgical failure [57, 58]. Anti-mitotic drugs such as mitomycin C and 5-fluorouracil can be used to reduce the degree of postoperative scarring, but their substantial side effects limit their application [59]. Therefore, alternative strategies that are safe and more effective in preventing scarring are needed. Recently, some evidence suggested that VA and its derivatives might be potential drugs to prevent scarring.

Glaucoma filtering surgery can stimulate the proliferation, migration and differentiation of human conjunctival fibroblasts (HConFs) and human Tenon fibroblasts (HTFs), and promote the secretion of ECM. This is an important process in scar formation [60–62]. Multiple studies have shown that all-trans-retinoic acid (ATRA), a derivative of VA, has anti-fibrotic potential because it inhibits the effects of TGF-β [63]. Scientists are also focusing on the effect on HConFs. ATRA has been reported to inhibit TGF-β-induced HConFs-mediated collagen gel contraction through the SMAD signaling pathway [64]. Further results have shown that ATRA inhibited HConFs migration, proliferation and ECM synthesis, and promoted HConFs apoptosis by inhibiting the PI3K/AKT signaling pathway [65]. Some studies have also shown that it also has a regulatory effect on HTFs cell function. Also, it was reported that ATRA can inhibit HTFs-mediated TGF-β-induced collagen gel contraction. It may be achieved by weakening the formation of actin stressed fibers and focal adhesions, inhibiting the signaling of MAPKs, c-Jun and Smads, reducing the production of MMP-1 and MMP-3, and stimulating the production of TIMP-1 [64, 66]. Therefore, ATRA may effectively inhibit the scar formation after glaucoma filtering surgery by regulating the cell function of HConFs and HTFs.

Retinoic acid is a derivative of VA that plays a part in eye development and tissue repair [67]. The availability of retinoic acid in the anterior chamber is considered to be a determinant of pathological changes associated with primary congenital glaucoma [68]. R667, an agonist of retinoic acid receptor γ (RARγ), was found to inhibit TGF-β1-induced contraction and ECM synthesis in HTFs cultured in a 3D collagen gel. Further, it was found that R667 reduced IOP in a rat model of glaucoma filtering surgery. Therefore, RARγ agonists may have clinical value in inhibiting scar formation after filtering surgery [69].

VA may prevent ocular surface damage caused by antiglaucoma drugs and possible related mechanisms

A previous published review by our team systematically summarized relevant studies on various ocular damage caused by topical use of antiglaucoma drugs [70], such as eyelid dermatitis, subconjunctival fibrosis, conjunctival inflammation, conjunctival epithelial changes, tear film instability, corneal surface and endothelial damage, etc. [71, 72]. A large body of evidence shows that VA can affect the growth and differentiation of cells, and plays an essential role in maintaining the health of human epithelial cells such as conjunctival and corneal epithelial cells [73, 74], and it is also a key factor regulating the production of mucin in corneal limbal epithelial cells [75].

The goblet cells (GCs) in the conjunctival epithelium is the most vulnerable target of ocular surface toxic damage. Previous evidence suggests that GC density is reduced in patients with long-term use of antiglaucoma drugs [76, 77]. The protective effect of VA against a decline in GC density was demonstrated as early as the twentieth century [78]. Recently, findings suggested that concomitant topical VA (retinyl palmitate 0.05% and polysorbate 80 1%; four times daily) therapy exerted beneficial effects on the ocular surface in rabbits undergoing prolonged (≥3 weeks) multidrug antiglaucoma regimens. VA application significantly increased the GC density and improve the impression cytology grades of rabbit conjunctiva [79]. In addition, results from a prospective cohort study also suggested that local application of 0.1% VA palmitate twice daily can effectively relieve dry eye caused by long-term use of prostaglandin analogs (PAGs) by increasing GC density and reduce toxicity to the conjunctiva [80].

Corneal damage is also a common side effect of topical eye medication use. A randomized controlled experimental study in rabbits showed that VA palmitate could promote the repair of mechanical defects of corneal epithelium and the formation of intracellular connections. It can also promote the regeneration of GCs and rebuild the connections within conjunctival epithelial cells [81]. VA has also been found to stimulate rabbit corneal epithelial cells and keratocytes release hyaluronic acid [82]. An animal study investigated the effect of VA on the apoptosis of corneal epithelial cells in mouse models of dry eye induced by benzalkonium chloride (BAC), and the results showed that VA could inhibit BAC-induced upregulation of Bax and Bcl-2 expression in epithelial cells of dry eye mice, and thus inhibit the apoptosis of epithelial cells [83].

It can be seen that VA can not only maintain the integrity of the ocular surface, but also prevent the damage of antiglaucoma drugs and their preservatives on the ocular surface.

Discussion

This review makes a systematic summary of relevant clinical research and basic research work. Overall, there are some contradictions in the results of different studies. Due to the different types of study designs and the varying inclusion criteria, the resulting data quality is uneven and difficult to compare across studies. However, in general, it can still be seen that VA has certain benefits for the prevention and treatment of glaucoma, anti-scarring after surgery and even preventing the damage of antiglaucoma medications on ocular surface health. Although conclusive evidence remains elusive, the unique association between serum VA and glaucoma has attracted considerable academic attention. However, we posit that analysis of tear and AH may prove more effective for early diagnosis and prediction. It must be pointed out that our analysis reveals that the majority of extant investigations remain cross-sectional in design, whose derived data exhibit inherent methodological constraints. We maintain that implementing longitudinal or interventional study designs is necessary. For example, well-designed randomized controlled trials are needed to further determine whether VA intake alters the risk of glaucoma, and further large-scale cohort studies are needed to determine how VA alters the risk of glaucoma.

If the above questions can be answered, then the most important question will be in what form and at what dosage to supplement. Humans cannot synthesize VA and must obtain it from the diet. If it is obtained solely through diet, it is necessary to consider whether the amount of VA ingested is sufficient to play a role in preventing or even assisting in the treatment of glaucoma. If increasing total dietary VA intake is successful as an effective prevention strategy, this would be a promising approach for primary prevention of glaucoma. If the dietary channel unable meet the needs for prevention and treatment, additional supplementation is needed, then oral or local drug effect is better is also a question that needs to continue to explore. High intake of VA is known to cause nausea, vomiting, headaches, and dry scaly skin. Too much VA stored in the body can lead to serious health problems, such as liver damage, osteoporosis and nervous system disorders. Therefore, the appropriate amount of supplementation seems to be very important, and a lot of evidence of evidence-based medicine is still needed to prove it. Topical use of VA appears to have more potential for combating ocular surface damage caused by antiglaucoma drugs and their preservatives, as well as anti-scarring after glaucoma filtering surgery. In addition, it is worth mentioning that topical application of VA seems to prevent the occurrence of hormone-induced glaucoma in patients with topical application of hormone drugs, which was the result of a 1982 study [84]. This phenomenon is quite understandable because numerous studies have shown that the underlying mechanisms of hormone-induced glaucoma include the ECM remodeling of the TM, effect on TGF-β, oxidative stress, and etc. [85, 86]. But there is no further evidence of large-sample controlled clinical trials. If its effect is confirmed, hormone-induced glaucoma will be prevented in the first place.

Conclusion

In general, VA may have certain benefits for the prevention and treatment of glaucoma, anti-scarring after surgery and even preventing the damage of antiglaucoma medications on ocular surface health. However, the optimal form and dosage for rational VA supplementation and administration remain unclear. Future well-designed, large-sample randomized controlled trials are still required to further validate these parameters.

Author contributions

Conceptualization, Xinyue Zhang and Xuanchu Duan; writing—original draft preparation, Xinyue Zhang and Honghao Yang; writing—review and editing, Xiaoyu Zhou, Jiahao Xu, Jiawei Chen, Li Liao, and Ping Wu; supervision, Xuanchu Duan; project administration, Xuanchu Duan; funding acquisition, Xinyue Zhang, Xiaoyu Zhou and Xuanchu Duan. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Hunan Engineering Research Center for Glaucoma with Artificial Intelligence in Diagnosis and Application of New Materials, grant number 2023TP2225; Changsha Municipal Natural Science Foundation, Grant Number kq2208495; the Natural Science Foundation of Hunan Province, China, Grant Number 2023JJ40004, 2023JJ40003 and 2023JJ70014; the Science and Technology Foundation of Aier Eye Hospital Group, China, Grant Number AR2206D4, AR2206D2 and AR2206D5; and the Hunan Province “little lotus” science and technology talent special, Grant Number Grant No. 2023TJ-X24. The APC was funded by 2023JJ40003.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.