Vitamin D and its Relationship to Ocular Diseases: A Systematic Review

Abstract Introduction  Vitamin D plays a vital role in the proper functioning of various systems of the human body. Conventionally, it is known that its deficiency can impair, among other factors, calcium homeostasis, bone metabolism, and immune system regulation. Besides having anti-inflammatory and antiangiogenic properties, 25(OH)D also acts in maintaining the integrity of the human retina, favoring the idea of it being a protective factor for certain ocular diseases. Objective  Therefore, the purpose of this review was to collect data from the literature which support the importance of vitamin D for ocular health. Methods  Through the Scientific Electronic Library Online and the National Library of Medicine databases, a compendium was created on the subject. Results  In total, 31 articles in English published between 2016 and 2020 were found. These articles were reviewed and categorized by diseases in order to study each disorder thoroughly. It is noticed that 25(OH) D is, in fact, a potential protective factor against such diseases, including diseases that affect both the surface of the cornea and the ocular tissues that have vitamin D receptors. Conclusion  Vitamin D is a protective hormone in the eye, and its deficiency is related to a variety of ocular diseases. Therefore, the supplementation of 25(OH)D can be considered as a complementary treatment for patients with these diseases, since it brings relevant benefits.


Introduction
Vitamin D is one of the essential organic substances for the maintenance of various systems of the body.This hormone can be synthesized in the skin, with the action of ultraviolet rays or obtained through the intake of animal-origin foods, such as fish or egg yolk, for example.It plays a key role in calcium homeostasis, bone metabolism, and immune system regulation.Thus, it is essential that its levels are in the appropriate parameters.[1][2][3] This vitamin is characterized by its fat-soluble com-pounds, which can be of two types: ergocalciferol (D2), synthesized in the skin over ergosterol, and cholecalciferol (D3), from cholesterol.Both types are transported to the liver where they are modified through hydroxylation and form calcidiol that travels to the kidney where, similarly, the metabolically active form of vitamin D (calcitriol) is formed.Before going through this activation process, vitamin D is absorbed by the small intestine through passive diffusion, then incorporated by lipid, and enters the lymphatic system and bloodstream, where it binds to a protein and is carried to the liver and kidney to be activated.Thus, the biological effect of vitamin D is triggered from its connection, in active form, with specific cell receptors.2 Vitamin D deficiency may occur in the serum level or in other fluids-such as tears-for reasons such as a diet-lacking vitamin D and, mainly, insufficient sun exposure.Individuals who have certain conditions-suffer recurrent falls and fractures, pregnant women, breastfeeding women, persons over 60 years old, with dark skin, osteoporosis or metabolic bone diseases, cancers, diabetics, and obesity, among others -are more prone to have the deficiency.3 Vitamin D, according to recent studies, in addition to having anti-inflammatory, antiangiogenic properties contributing to good blood circulation that carries oxygen to the retina, also has an effect of maintaining the integrity of the human retina.Such effects would probably explain the results obtained by researchers that have associated a higher concentration of 25 (OH)D with a lower incidence of ocular diseases such as retinoblastoma (RB), age-related macular degeneration, dry eye syndrome, myopia, vernal keratoconjunctivitis (VKC) in children, keratoconus, cataract, glaucoma, and uveitis.4 Based on the above, the aim of the study is to analyze the association between vitamin D deficiency and the incidence of ocular pathologies through a systematic review of con-ducted research and studies that have correlated 25(OH)D with such ocular diseases.

Materials and Methods
Through a systematic review of scientific articles and me-thodical analysis of their content, we designed a review study that correlates with the most recent studies on the role of vitamin D in the incidence of ocular pathologies.Through the Scientific Electronic Library Online and the National Library of Medicine databases, a compendium of articles was created that associated the mentioned factors.These articles were reviewed and categorized by diseases in order to study each disorder thoroughly.The ocular diseases analyzed were myopia, cataract, diabetic retinopathy, age-related macular degeneration (AMD), glaucoma, diabetic retinopathy, age-related cataract, uveitis, dry eye syndrome, and VKC, and RB.The keywords used in the databases were the names of the main ocular diseases-mentioned above-(in English), "elec-trochemiluminescence" and "ocular diseases"; these were crossed with one of the following words: "Vitamin D" and "25-hydroxyvitamin D" (►Fig.1).
In total, 31 articles written in English published between 2016 and 2020 and with human participants only were reviewed; analysis and report of such articles were per-formed between the dates 28 February, 2020 and 3 April, 2020 (►Table 1).

Results and Discussion
From the analyzed studies, a correlation between serum or tear Vitamin D levels and ocular diseases is observed.25(OH) D is a protective factor against such diseases, including diseases that affect both the corneal surface (such as dry eye syndrome) and the ocular tissues that have vitamin D receptors (VDRs; e.g., AMD, glaucoma, myo-pia, and uveitis).15,16 Specifically, in the cornea, the protective factors occur, after the interaction of the active form of vitamin D with its receptor, by the generation of a greater transepithelial resistance of human corneal epithelial cells, helping to maintain the shape and integrity of the cornea 24 since the vitamin deficiency is closely linked to tear hyperosmolarity and tear film dysfunction 19 ; on the contrary, in different ocular tissues, there are protective factors associated with different effects, such as anti-inflammatory and antiangiogenic.The anti-inflammatory effect happens because the im-mune system cells possess a large amount of VDR receptors and the active CYP27B1 gene that produces 1-alpha-hydrox-ylase, an enzyme that acts in the synthesis of calcitriol (active form of vitamin D). 19 Calcitriol is responsible for modulating the expression of several inflammatory cytokines, fighting the inflammatory process and neurodegeneration-factors that cause intense pain in patients with glaucoma, for example.It was also observed that this effect can occur by inhibiting the Langerhans cells migration into the cornea.[32][33][34] As for its anti-angiogenic action, the 1.25(OH) 2 D 3 form inhibits specific stages of the angiogenic process, and the probable causative mechanism is related to the induction of apoptosis in angiogenic epithelial cells.However, it is note-worthy that the effect of such a mechanism in ocular diseases still requires further studies.Uveitis can affect the quality of life negatively, not only because of poor visual functioning but also because of associated systemic disorders treatments.Devilliers et al cite that the immunological privilege of certain ocular compartments explains the character of the very rapid evolution of certain infections, including in the immuno-competent (a thinking in particular of necrotizing retinitis); it is known that vitamin D strengthens the immune system ocular.35 Li et al conducted a systematic review seeking to relate the degree of glaucoma to serum concentrations of vita-min D. Although many publications have reported a dif-ference in serum vitamin levels between patients with glaucoma and normal subjects, the association between serum vitamin levels and glaucoma in humans remains controversial.36 In addition, searches report vitamin D exerts some inverse relation with some of the major ophthalmic diseases such as AMD and glaucoma.37-39 Vitamin D has antineoplastic through influencing cell differentiation, apoptosis regulation, anti-angiogenesis, and cell cycle arrest in various tumors.Animal studies suggested that vitamin D analogs inhibited RB tumor growth in athymic mice by increasing apoptosis, which is associated with the upregulation of both the p53 and p21 proteins.40 Regarding the cornea, it is important to highlight that low serum concentrations of vitamin D are a problem that affects the whole world.It is estimated that one billion people are deficient or insufficient serum concentrations of vitamin D. It is estimated that one billion people are deficient or insuffi-cient serum concentrations of vitamin D. Studies reveal that at the same time, 10 million people around the world are blind due to severe corneal problems illness.Dealing with epithelial tissue, communication of the epithelial communicating junction.Patients with a low dosage of vitamin D may lead to increased gap junction communication and thus cause a mismatch in the epithelial health of the cornea, associated with epithelial regeneration.Other studies dem-onstrated that elevated epithelial calcium concentrations stimulate gap junction connectivity in corneal epithelial cells, and it depends on vitamin D to increase the absorption of calcium by the body.41 This study presents, as limiting factors, the short number of studies involving the relationship between the variables mentioned-which is why several ocular pathologies were included in this review; in addition, the studies under analysis are not standardized (they have, mainly, study design, method, ocular disease, biological matrix, and differ-ent population sample).It is observed, therefore, through several studies, that vitamin D is a protective factor in the eye and its deficiency is related to ocular diseases such as dry eye syndrome,  Clinical and demographic data were collected in addition to blood (for vitamin D) and single nucleotide polymorphisms (SNPs) of vitamin D receptors (VDR).
In DES patients, higher frequencies of Apa-1 and lower frequencies of Taq-1 were found.
There was no significant association between Bsm-1 and Fok-1 with DES.
SNPs of VDR genes (Apa-1 and Taq-1) have demonstrated to be associated with higher risks of DES.The following parameters were analyzed: time of UVB exposure, eye refractive error, SNPs of genes of the vitamin D metabolism, serum vitamin D levels and years of education.
In those aged 14 to 39 years, there was an inverse association with myopia; however, there was no independent relationship of myopia with 25(OH)D or with genes of its metabolism.
It was concluded that increased UVB exposure, particularly in adolescents and young adults, reduced myopia risks; however, no direct relationship between myopia and vitamin D or related genes was found.
Park and Choi 2017 21  Ophthalmic Epidemiology Cross-sectional study.Participants: 16,086 adults aged 40 years or older who had serum 25(OH)D levels test and who had never been diagnosed with or had never undergone to cataract surgery.
The study used a database, performing odds ratio (OR) and a 95% confidence interval.Serum 25(OH)D levels are inversely associated with the risk of incidence of nuclear cataract (P < 0.001).
There is an inverse relationship between nuclear cataract and vitamin D levels in serum; however, further studies relating such vitamin and the development of nuclear cataract are necessary.

Meng et al 2019 6 Medical Science Monitor
Case-control study.There were 140 participants; 70 with DES and 70 healthy controls.
Blood samples (for vitamin D) and clinical data were collected.DES symptoms were analyzed using parameters.Serum 25(OH)D levels were significantly lower in cases than in controls.There were significant relationships: direct of 25(OH)D with ST and inverse with OSDI and TBUT.
Vitamin D deficiency was related to DES and its symptoms.It is indicated, therefore, that vitamin D can act favorably and adjunctively for the patient with DES.

McKay et al 2017 22
Ophthalmology Cross-sectional study.neovascular AMD; however, the OR is low.Furthermore, after Bonferroni correction, there was no direct association between SNPs and AMD (at any stage).
SNPs and AMD and, therefore, there is no basis for the association between vitamin D and AMD.
Li et al 2017 23  Nutrients Systematic review with metaanalysis 19 case-control studies with humans which associated vitamins B6, B12 or D with glaucoma were selected.Of these, nine related to POAG; four on normal tension glaucoma (NTG) and six on exfoliative glaucoma (EXG).
Articles were selected from online databases.The keywords were: "glaucoma" (in the title) and "vitamin" (in the abstract).
The difference in the levels of these vitamins between glaucoma patients and control ones was not significant after performing the meta-analysis, as there were contrasting results among studies; however, the sample size and study location may have influenced the outcome.
There is no association of vitamins (B6, B12 and D) in blood with the different types of glaucoma.However, more studies on the subject are necessary, particularly multicentered and with larger samples.Through a database, the study used clinical information and serum 25(OH)D levels.
Separating groups by time of sunlight exposure, it was observed that those with an exposure longer than 2 hours had a significantly lower risk of myopia.Those with higher 25(OH)D levels had lower prevalence of myopia.
Fewer hours of sun exposure and low 25(OH) D levels result in a higher incidence of myopia in Korean adults.

Fig. 1
Fig.1Flowchart of the choice of articles for review.Note: n refers to the number of articles.

Table 1
Summary of articles used in the manuscript

Table 1 (
Continued) Vitamin D and Ocular Diseases Review dos Reis Zuniga et al. 59

Table 1 (
Continued)Participants underwent an analysis of (among other) parameters for DES and serum 25(OH) D levels.Compared to the control group, patients with signs of DES (lower vitamin D levels) had higher OSDI; 25(OH)D was not significantly related to TBUT and ST.Low vitamin D levels provoke severe DES symptoms in patients with mild signs of the disease.Blood and tear samples (for 25(OH)D in such) were collected.Significant data showed that 25(OH)D levels were, on average, twice as high in tears as in serum and that there is a positive correlation between serum and tear fluid 25(OH).Higher 25(OH)D levels were observed in the tear fluid than in the serum.It is suggested to consider tear vitamin D levels to study its role with reference to ocular surface diseases.OH)D levels and SNPs of VDRs (Cdx-2, Fok I, Bsm I and Taq I) were measured by blood collection.The levels of 25(OH)D in patients with POAG were significantly lower than in the age-matched control group.Significant differences in the allelic frequency of Bsm I genotypes (higher frequencies of "B" Allele) and Taq I (higher frequency "t" allele) were detected between the groups.Vitamin D deficiency and presence of BsmI 'B' and Taq I 't' alleles are relevant risk factors for glaucoma.However, additional studies on the causes of these noted changes between groups and its possible association with vitamin D are essential.
Vitamin D and Ocular Diseases Review dos Reis Zuniga et al. 61