Dry Eye Disease and Vitamins: A Narrative Literature Review

Abstract

Dry eye disease (DED) is a major public health problem worldwide that seriously impairs the quality of life, reduces work productivity, and poses significant economic burden. In DED, tear film instability or hyperosmolarity activates a self-perpetuating vicious cycle that may aggravate ocular surface inflammation and damage. Thus, treatment approaches should focus on interrupting this cycle and ameliorating inflammation. In addition to anti-inflammatory medications, such as corticosteroids, cyclosporine, and lifitegrast, nutrients with anti-inflammatory and anti-oxidative properties may also be effective for the treatment of DED. Evidence indicates that vitamin deficiencies may be associated with an increased risk of DED and that vitamin supplementation can be an effective treatment for DED. In the present review, we introduce the results of clinical and experimental studies on the association between vitamin deficiencies and DED. The potential efficacy of systemic and topical supplementation in the treatment of DED is also discussed.

1. Introduction

Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by the loss of tear film homeostasis [1]. DED is one of the most frequently encountered ophthalmic diseases, with a prevalence of 10% to 50% worldwide [2,3,4,5,6]. The disease can be accompanied by ocular surface symptoms, such as blurry vision, ocular pain, discomfort, grittiness, redness, and foreign body sensation that may significantly interfere with daily activities, including driving, working, reading, watching television, and using digital devices [1,7]. Thus, DED has emerged as a major public health problem in terms of quality of life impairment, productivity loss, and economic burden [2,8].

Tear film instability and hyperosmolarity, as well as ocular surface damage and inflammation, are suggested to play major etiologic roles in DED [1]. Abnormalities in tear film, such as instability and hyperosmolarity, trigger ocular surface inflammation and promote the innate immune response, which can activate a vicious self-perpetuating cycle that may eventually lead to the amplification of ocular surface inflammation and damage [4,9,10,11]. Neurosensory abnormality has also been proven to play an etiologic role in the development of DED [1].

Hence, the treatment of DED should focus on disrupting the vicious cycle of ocular surface inflammation [4,12]. Anti-inflammatory treatment using drugs, such as corticosteroids, cyclosporine A, lifitegrast, autologous serum, and doxycycline, has been used to improve dry eye signs and symptoms [4,12]. Anti-oxidative therapy as well as treatment approaches to reinforce the innate immunomodulatory and anti-inflammatory actions may also be considered effective [9,12].

Studies have shown that vitamins play an important role in maintaining ocular surface homeostasis, suggesting the possible protective effects of these vitamins against DED [13]. Vitamin A is crucial for the proliferation, differentiation, and growth of corneal and conjunctival epithelial cells [14,15]. Vitamin B is important for the regulation of the nervous system on the ocular surface [14,16]. Vitamin C has anti-inflammatory, anti-oxidative, and immunomodulatory properties [17]. Vitamin D is important for the modulation of ocular surface inflammation and immune reaction [12,13,18], and vitamin E also provides anti-oxidative defense in the ocular surface [19,20]. Previous studies have shown that vitamin deficiencies may be associated with an increased risk of DED [21,22,23,24,25,26,27,28,29,30,31,32], and the supplementation of these vitamins may be effective for improving dry eye signs and symptoms in patients with vitamin deficiency [33,34,35,36,37,38].

In this review, we aim to provide an overview of the potential association between vitamin deficiencies and DED and discuss the efficacy of vitamin supplementation in the treatment of DED.

2. Vitamin A and Dry Eye Disease

Vitamin A comprises a group of micronutrients that are widely present in food [39]. Retinol (molecular formula C₂₀H₃₀O), preformed vitamin A, is found in animal-based products, and carotenoid precursors (group of compounds comprising 4 terpenes, including 40 carbon atoms), most of which are provitamin A, are found in plant foods [12,39]. Vitamin A plays a key role in the maintenance of a healthy ocular surface and in the prevention of DED, as it is involved in the proliferation and differentiation of the ocular surface epithelium [15]. An in vitro study showed that vitamin A can promote the synthesis of eicosanoids in the human cornea and conjunctiva [40], which subsequently leads to the upregulation of secretory phospholipase A (2) group IIA genes and the expression of the mucin MUC16 gene [41]. The upregulation of MUC16 results in the production of hydrophilic membrane-associated mucin MUC16, which provides a wet-surfaced protective barrier for the corneal and conjunctival epithelium and prevents the keratinization of the ocular surface, providing protective effects against DED [41,42]. Experimental studies have shown that vitamin A facilitates corneal wound healing by attenuating the apoptosis of corneal epithelial cells and promoting the repair of epithelial defects [43,44,45]. Vitamin A also promotes tear production and improves tear film quality, which can be helpful for the treatment of DED [44,46]. In a rabbit model of ocular surface damage due to long-term anti-glaucoma medication, topical vitamin A was found to not be inferior to topical cyclosporine in improving adverse ocular surface changes [47].

Vitamin A deficiency due to poor nutrition or malabsorption is a major public health problem worldwide that can eventually lead to blindness, particularly in the developing world [12,13,48]. Vitamin A deficiency can also lead to DED by causing goblet cell loss, leading to mucin deficiency and corneal epitheliopathy [21,22,48,49]. Long-term deficiency may result in metaplasia and the keratinization of the corneal and conjunctival epithelial cells, which can eventually lead to keratomalacia or corneal ulceration [13,50,51].

The systemic administration of vitamin A, both oral and parenteral, was shown to be helpful for improving ocular surface damage and DED [33,34,52,53]. Alanazi et al. [34] reported that the short-term oral supplementation of vitamin A (1500 mg daily for 3 days) resulted in improved tear quality [34]. In patients with xerophthalmia, high-dose systemic vitamin A supplementation led to increased goblet cell density and improved corneal epitheliopathy [52,53]. Systemic vitamin deficiency may result in mucin deficiency caused by conjunctival goblet cell loss, and the supplementation of vitamin A can lead to increased goblet cell density and the improvement of ocular surface mucin deficiency [54].

Topical application of vitamin A may also be useful for the treatment of DED [55,56,57,58,59,60]. Soong et al. [58] showed that topical vitamin A may be effective for the reversal of conjunctival keratinization [58]. Tseng et al. [59] reported that vitamin A ointment improved visual acuity, dry eye symptoms, rose Bengal staining scores, and Schirmer scores [59]. It is remarkable that vitamin A ointment resulted in the reversal of conjunctival squamous metaplasia [59]. Vitamin A ointment was also found to be more effective in preventing ocular surface damage than a moisture chamber in patients in an intensive care unit [61]. Selek et al. [57] demonstrated that vitamin A emulsion improved Schirmer scores and tear break-up time (TBUT), suggesting its potential efficacy for DED. In patients with DED caused by the long-term application of prostaglandin analogue anti-glaucoma medication, vitamin A palmitate improved goblet cell density and dry eye symptoms [56]. Kim et al. [60] reported that both vitamin A and cyclosporine A 0.05% eye drops were effective for improving Schirmer scores, TBUT, blurred vision, and goblet cell density [60]. Yang et al. [62] reported that the application of vitamin A palmitate gel after strabismus surgery facilitated the proliferation of the conjunctival goblet cells and improved dry eye signs, such as Schirmer scores, fluorescein staining scores, TBUT, and dry eye symptoms. However, these studies used various forms and concentrations of topical vitamin A. Therefore, further studies are necessary for the development of an optimal formulation of topical vitamin A.

3. Vitamin B and Dry Eye Disease

Vitamin B complexes are a group of water-soluble vitamins that mostly have coenzyme activities which might be helpful for the maintenance of ocular surface homeostasis and prevention of DED [16]. Several micronutrients in the vitamin B group were shown to be associated with DED, particularly DED related to neuropathic ocular pain (NOP) [12,13,23,24,35,63,64]. Vitamin B1 (thiamine; molecular formula C₁₂H₁₇N₄OS+) has an anti-oxidative function and promotes the metabolism of carbohydrates, the synthesis of proteins, and the production of neurotransmitters [16]. Vitamin B2 (riboflavin; molecular formula C₁₇H₂₀N₄O₆) also has anti-oxidant activity and was shown to have protective effects against cataracts [65]. Vitamin B6 (pyridoxine; molecular formula C₈H₁₁NO₃) is important for immune system regulation and the production of neurotransmitters [16]. Vitamin B12 (cobalamin; molecular formula C₆₃H₈₈CoN₁₄O₁₄P) can facilitate nerve regeneration and remyelination [16]. Thus, deficiency in these vitamins can result in impaired nerve survival and regeneration, leading to peripheral and central sensitization and neuropathic pain leading to dry eye symptoms [16]. Accumulated stress and repetitive noxious nerve injury may result in maladaptive neuroplastic changes in somatosensory pathways that lead to neuropathic pain caused by the sensitization of peripheral and central somatosensory pathways [2,66,67,68].

Previous studies have indicated that abnormalities in the neurosensory system may play an important role in the pathophysiology of DED, [2,67,68,69] and that the dry eye workshop II (DEWS II) included neurosensory abnormalities in the definition of DED in 2017. [1] NOP can develop in association with pathologic changes in the peripheral and central nervous systems that result from chronic nerve damage caused by insults, including ocular surface damage and tear film instability [66,70]. Discrepancies between dry eye signs and symptoms are frequently observed in patients with DED [66,67,68], and NOP may, at least in part, explain this phenomenon [67,68,69].

These findings suggest that vitamin B deficiency may have an influence on DED associated with NOP, and the supplementation of micronutrients can improve DED, particularly NOP-associated DED [12,13,14,23,64]. An experimental study showed that vitamin B12 might be important for the trophic regulation of nerve regeneration [14]. Shetty et al. [35] introduced a case of NOP recalcitrant to the conventional treatment of DED, including artificial tears and topical cyclosporine, in which vitamin B12 deficiency was incidentally detected and where parenteral vitamin B12 administration resulted in a dramatic improvement in NOP. Ozen et al. [23] also reported that vitamin B12 supplementation for 3 months in patients with vitamin B12 deficiency and NOP led to improvements in ocular surface disease index (OSDI) scores, tear secretion, and tear film stability, and that the efficacy of vitamin B12 was superior to that of conventional treatments, such as artificial tears and cyclosporine. These findings suggest that vitamin B12 deficiency may play a role in neurosensory abnormalities leading to DED, and supplementation with vitamin B12 can be effective for NOP [12,23]. Moreover, several studies have reported an association between vitamin B12 deficiency and Sjögren syndrome [24,63,71], suggesting the possible existence of other mechanisms underlying the association between vitamin B12 and DED.

Ren et al. [64] reported that oral vitamin B1 and mecobalamin, a form of vitamin B12, improved both dry eye symptoms and signs [64]. Yang et al. [72] showed that the nebulization of vitamin B (twice a week for 3 months) onto the ocular surface led to decreased OSDI, increased TBUT, and improved corneal staining scores. They also demonstrated that vitamin B nebulization resulted in an increased density of epithelial cells and the sub-basal nerve plexus and a decreased number of dendritic cells [13]. The topical application of vitamin B12 and citicoline in patients with diabetes mellitus (DM) and DED was also shown to be effective for the recovery of ocular surface environment, corneal sensation, and sub-basal nerve plexus density [73]. Macri et al. [74] reported that treatment with eye drops containing preservative-free hyaluronic acid 0.15% and vitamin B12 improved both the signs and symptoms of DED and decreased oxidative stress. However, the effects of vitamin B12 alone cannot be evaluated by these data.

Horrobin reported that the oral supplementation of vitamin B6 and C resulted in improved tear secretion [75] in n patients with ocular surface damage due to chronic exposure to preservatives in glaucoma medication. Nebbioso et al. [76] showed that the use of food supplements containing vitamins B1 and B2 resulted in an improvement in both DED symptoms and signs [76]. Further studies are needed to elucidate the effect of each vitamin on DED.

4. Vitamins C and E and Dry Eye Disease

Vitamin C is a water-soluble vitamin composed of six carbons that has the molecular formula C₆H₈O₆ [77]. It has anti-oxidative, anti-inflammatory, and immunomodulatory functions, which can be helpful for the prevention of DED [17]. Human tear film contains high vitamin C levels, which may be helpful for anti-oxidative and anti-inflammatory defense on the ocular surface [78]. Vitamin C has been assumed to have a therapeutic role in the repair of corneal wounds [79]. An experimental study using a rat model recently showed that vitamin C improved corneal edema and alleviated inflammation after corneal injury caused by ultraviolet B exposure [80]. Li et al. [81] reported that topical vitamin C attenuated corneal inflammatory cell infiltration, promoted limbal stem cell proliferation, and decreased corneal neovascularization after corneal alkali burns in a mouse model.

Vitamin E comprises a group of fat-soluble compounds composed of a chromanol ring with a side chain at the C2 position [82] that also have anti-oxidative activity, which may also be helpful for antioxidant defense on the ocular surface and in the of DED [19]. An experimental study using a rabbit model recently showed that vitamins C and E demonstrated similar effects on corneal wound healing [20].

In patients with DM, the oral supplementation of vitamins C (1000 mg/day) and E (400 IU a day) for 10 days resulted in an improvement in TBUT and Schirmer scores, ab increase in conjunctival goblet cell density, and the restoration of conjunctival squamous metaplasia, which might have been caused by a reduction in oxidative damage to the ocular surface [83,84]. A prospective randomized trial also revealed that oral antioxidant supplementation, including with vitamins A, C, and E, led to an improvement in TBUT, Schirmer scores, corneal fluorescein staining scores, and tear reactive oxygen species level [85].

Fogagnolo et al. [86] reported that topical vitamin E combined with coenzyme Q10 may be effective for the recovery of corneal subbasal nerve flexus and the stability of the ocular surface after cataract surgery [86]. Serrano-Morales et al. [87] showed that eye drops containing 0.1% cross-linked hyaluronic acid, coenzyme Q10, and vitamin E had a similar efficacy in improving tear film stability and dry eye symptoms compared to a higher dose of carmellose eye drops in menopausal women taking antidepressants, suggesting the possible efficacy of vitamin E [87]. The topical application of vitamin E combined with coenzyme Q10 was also helpful for the restoration of the homeostasis of the ocular surface and tear film stability in pediatric patients and eyes exposed to chlorinated water [88,89].

Li et al. [90] recently demonstrated that the use of a mixture of 3% diquafosol and vitamin E (tocopherol 0.005% or 0.01%) eye drops was superior to 3% diquafosol eye drops for the improvement of the tear film and lipid layer, the recovery of the corneal epithelium, the amelioration of ocular surface inflammation, and an increase in conjunctival goblet cell density, suggesting that vitamin E alone might have an effect in treating DED [90].

However, it is difficult to determine the effect of vitamins C or E alone using these data, and further studies are necessary for the evaluation of the effect of each vitamin.

5. Vitamin D and Dry Eye Disease

Vitamin D is a fat-soluble vitamin with the molecular formula C₂₈H₄₄O (vitamin D2, or ergocalciferol) and C₂₇H₄₄O (vitamin D3, or cholecalciferol) that can be obtained from animal products, such as fish, oil, and eggs, or synthesized in the skin through exposure to sunlight [12]. It plays an important role in modulating inflammation and immune reactions on the ocular surface, which can be helpful for the alleviation of dry eye signs and symptoms [12,13,18]. In an in vitro study using cultured human corneal epithelial cells (HCECs), Rein et al. [18] showed that the treatment of HCECs with vitamin D led to an increased expression of antimicrobial peptides and decreased inflammatory mediators [18]. Vitamin D also facilitates the proliferation and differentiation of corneal epithelial cells; thus, it is important for the maintenance and recovery of corneal epithelial barrier function [91]. Furthermore, the micronutrient is one of the key factors in the modulation of systemic calcium absorption, which is important for secretory function in both the salivary and lacrimal glands [25]. In the human cornea, a specific vitamin D receptor (VDR) is present in epithelial cells and stroma, and vitamin D can be metabolized to active metabolite calcitriol by the enzyme 1-alpha-hydroxylase [92]. An in vitro study showed that calcitriol attenuated the inflammation and oxidative stress responses in cultured HCECs [93]. An experimental study showed that topical calcitriol decreased corneal inflammation and attenuated the expression of inflammatory mediators, suggesting that vitamin D supplementation may be an effective treatment for DED [94].

Sethu et al. [95] demonstrated that serum vitamin D levels had a positive correlation with tear vitamin D levels in healthy human patients, and that the concentration of vitamin D was higher in tears than in the serum [95]. Serum vitamin D concentration was significantly correlated with tear production, stability, and dry eye symptoms [26,96].

Meng et al. [97] also reported that single nucleotide polymorphisms in the VDR gene may increase the risk of DED, suggesting the possible role of vitamin D deficiency in the pathogenesis of DED [97]. Shetty et al. [98] showed that resveratrol can restore the increased oxidative stress and decreased vitamin D level in HCECs in hypertonic conditions by activating VDR expression and Notch signaling [98]. Animal studies revealed that the absence of VDR led to a defect in stem cells, suggesting that vitamin D is also essential for limbal stem cell function and corneal epithelial regeneration [92,93]. Vitamin D was also shown to be effective in the suppression of ocular surface inflammation and the attenuation of corneal neovascularization and meibomian gland injury in animal experimental studies [99,100].

Several clinical studies have shown that lower serum vitamin D levels were associated with an increased risk of DED [25,26,27,28,29,30,31,32]. A meta-analysis conducted in 2020 revealed that patients with DED had lower serum vitamin D concentrations compared to a control group by an average of 4 ng/mL [101]. This study also confirmed that vitamin D deficiency is associated with an increased OSDI score and decreased tear secretion [101]. A recent study demonstrated that vitamin D deficiency (<20 ng/dL) was associated with lower Schirmer scores and TBUT and higher OSDI scores [102]. Aksoy et al. [103] revealed that type 1 DM in pediatric patients was associated with the deterioration of tear parameters, such as the Schirmer test, corneal staining scores, TBUT, and the tear meniscus height and area measured using anterior segment optical coherence tomography, and that the phenomenon is more marked when accompanied by vitamin D deficiency [103]. Fukuoka et al. [104] reported that vitamin D intake may be associated with decreased MGD prevalence among a Japanese population [104]. Decreased vitamin D levels were also associated with an increased risk of NOP [29,105].

Vitamin D supplementation may be effective, particularly in cases accompanied by vitamin D deficiency in which conventional DED treatments were not effective [37]. Bae et al. [37] showed that systemic vitamin D supplementation in these patients resulted in a significant improvement in the Schirmer test, corneal staining, TBUT, lid margin hyperemia, and dry eye symptoms [37]. Daily oral supplementation of vitamin D (50,000 units a day for 8 weeks followed by 1500–2000 units a day for 24 weeks) in patients with vitamin D deficiency and obstructive MGD resulted in improved Schirmer scores, TBUT, corneal staining scores, tear osmolarity, meibomian gland expressibility score, eyelid margin scores, and OSDI scores [106].

Yang et al. [38] also reported significant improvements in DED symptoms and corneal staining scores after 2 months of vitamin D supplementation [38]. Hwang et al. [107] showed that vitamin D deficiency was associated with the decreased therapeutic efficacy of artificial tears, while systemic vitamin D supplementation enhanced the efficacy of topical artificial tears in these patients [107]. Another study reported that the intramuscular supplementation of vitamin D (50,000 units of 25(OH)D3 intramuscularly, once weekly, for 8 weeks) resulted in an improvement in tear osmolarity [36].

Arita et al. [108] reported that the application of vitamin D analogue ointment on the eyelid resulted in improvements in TBUT, meibum grade, meibomian gland plugging, and lid margin vascularity, suggesting that topical vitamin D might also be effective for the treatment of obstructive MGD [108]. An ophthalmic solution containing vitamin A, vitamin D, and omega-3 was shown to be effective in improving ocular surface inflammation and tear film stability and in facilitating the healing of ocular surface damage in both evaporative and non-evaporative DED [109]. Similar effects were also observed in patients with DED who had undergone cataract surgery [110].

6. Current Perspectives

The studies introduced in the present review suggest that vitamin deficiency may result in DED; thus, serum vitamin levels should be checked in patients with DED, particularly those who are refractory to conventional treatment [13].

To date, multiple studies have provided evidence that vitamin supplementation may be effective for the treatment of DED, particularly for vitamins A and D. Although several studies have shown that vitamins B, C, and E may also be helpful for the treatment of DED, we believe that further studies are needed to elucidate the mechanism underlying the effect of these vitamins and evaluate the specific effect of each vitamin on different types of DED—i.e., aqueous deficiency, lipid deficiency, and mucin deficiency. Further prospective studies are necessary to establish guidelines for the indication, composition, dose, and duration of vitamin supplementation.

Regarding the safety of vitamin supplementation, short-term systemic administration for 28 days or less may be associated with a low risk of side effects [13,56]. However, long-term supplementation with vitamin A may be associated with an increased risk of hypercalcemia, osteoporosis, and teratogenicity [13,111], while long-term topical supplementation of vitamin A may increase the risk of meibomian gland disorder and blepharoconjunctivitis [112]. Although other vitamins apparently have high safety profiles, attention should be paid to avoid an overdose of these vitamins [13].

In conclusion, this review shows that vitamin deficiencies may lead to DED, and that vitamin supplementation may improve dry eye signs and symptoms and promote the recovery of healthy ocular surfaces. Further prospective studies with large populations are needed to elucidate the mechanism of action associated with DED of each vitamin and to establish guidelines for the indication and optimal regimen of vitamin supplementation.