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Association between vitamin D and dry eye disease: A systematic review and meta-analysis of observational studies
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Review article
Association between vitamin D and dry eye disease: A systematic review and meta-analysis of observational studies Gholamreza Askaria, Nahid Rafieb, Maryam Miraghajanic,d, Zahra Heidarie, Arman Araba,* a
Department of Community Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Department of Clinical Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran c Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran d The Early Life Research Unit, Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK e Department of Biostatistics and Epidemiology, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran b
A R T I C LE I N FO
A B S T R A C T
Keywords: Vitamin D Dry eye disease Dry eye syndrome Systematic review Meta-analysis
Purpose: A number of studies have examined the association between vitamin D and dry eye disease in different populations, but findings are inconclusive. Herein, available observational studies were systematically reviewed to elucidate the overall relationship between vitamin D and dry eye disease among adult population. Methods: PubMed, Scopus, Google scholar and ISI web of science databases were searched until January 2020 for studies assessing the association between vitamin D and dry eye disease. The Newcastle-Ottawa Quality Assessment Scale was used to examine the quality of each study. Results: A total of 14 studies out of 252 met the inclusion criteria and were included in this systematic review and meta-analysis. Serum 25(OH) D3 was lower in dry eye disease subjects compared to healthy ones (WMD −5.93; 95 % CI, −7.47 to −4.40; P < 0.001) with evidence of significant heterogeneity (I2 = 94.6 % p < 0.001). Also, in final analysis, vitamin D correlated significantly with ocular surface disease index (Fisher’s Z: −0.26; 95 % CI, −0.48 to −0.04; P = 0.018), with significant heterogeneity between studies (I2 = 59.3 %, P = 0.043). Conclusion: It was found that serum vitamin D had a significantly lower level in dry eye disease patients, and correlated with ocular surface disease index but no other dry eye disease parameter. The findings add to the existing literature supporting the concept that nutrition especially vitamin D plays an important role in human eye health. Prospective studies are needed to confirm this relationship
1. Introduction Dry eye disease (DED) manifests as ocular discomfort and visual function impairment along with tear abnormalities or ocular surface disorders [1,2]. 5%–30% of the world 50 years and older population are suffering from this condition, with women representing approximately two-thirds of those affected [3,4]. Also, its prevalence is higher among Asians compared to western populations [5]. DED patients have substantially lower vision and quality of life with symptoms often interfering with daily activities [6]. In order to design new treatment strategies for improving vision-related quality of life in patients with DES, universal research effort is at work to identify risk factors involved in DES [7]. Many factors have been linked to DED such as hormonal alterations, psychological indices, medications [8], aging, reproductive factors,
tobacco, contact lens use, ocular surgery and dry environment [9,10]. Dietary intake and inflammation (reference) are additional risk factors associated with DED [11]. Several anti-inflammatory drugs have been used to treat DED, but their value is limited because of insufficient efficacy and noticeable side effects in some cases [12,13]. Recently, anti-inflammatory dietary factors such as omega-3 fatty acids have been reported to be potentially useful for DED treatment [6]. A recent focus of efforts, devoted to discover innovative approaches for DED prevention and treatment, has been on vitamin D [14–16]. Over the last three decades, it has become clear that the role of vitamin D goes beyond calcium homeostasis and bone health. Body of evidence is increasing about the influence of VD in health and disease conditions by modulating immune and cardiovascular functions. Also, regulatory effects of VD on the proliferation and differentiation of benign and malignant tissues have been reported
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Corresponding author. E-mail addresses: [email protected] (G. Askari), nahid.rafi[email protected] (N. Rafie), [email protected] (M. Miraghajani), [email protected] (Z. Heidari), [email protected] (A. Arab). https://doi.org/10.1016/j.clae.2020.03.001 Received 9 October 2019; Received in revised form 26 February 2020; Accepted 4 March 2020 1367-0484/ © 2020 Published by Elsevier Ltd on behalf of British Contact Lens Association.
Please cite this article as: Gholamreza Askari, et al., Contact Lens and Anterior Eye, https://doi.org/10.1016/j.clae.2020.03.001
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2.4. Study quality
[17–19]. Due to the remarkable effects of vitamin D on the immune system, it could be conjectured that the immune-regulatory effects of vitamin D might influence the development of DED [20]. However, increasing body of literature has shown paradoxical relationships between vitamin D and DED. Some studies have suggested a significant association between serum vitamin D level and DED prevalence [21,22]. On the other hand, others do not support such an association [23,24]. Currently, there is insufficient evidence showing whether serum vitamin D deficiency is related to DED, and the determination of this relationship has rarely been conducted. Moreover, a relatively small sample size has been used in a majority of the studies assessing this association. To address these issues, this systematic review and meta-analysis was carried out by pooling the results from observational studies to examine the potential association between serum vitamin D and DED in patients as compared to healthy subjects in adult population. This information is important for clinicians and researchers alike as it increases knowledge on the potential usefulness of dietary modification and nutritional supplementation in DES.
The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the quality of each study [26]. The scale consists of assessment of three domains: selection (5 points), comparability (2 points) and outcome (3 points) for a total score of 10 points. Studies scoring 7–10, 5–6 and 0–4 points were identified as high, moderate and low quality, respectively. 2.5. Definition of DED assessment indices OSDI is a valid and reliable instrument in distinguishing between healthy subjects and patients with DED. OSDI score is from 0 to 100, with higher score representing greater disability and ranks patients as normal, mild to moderate and severe [27]. TBUT, a clinical measurement of evaporative DED, is recorded as the number of seconds that elapses between the last blink and the appearance of the first dry spot in the tear film. TBUT under 10 s is considered as abnormal [28]. Shirmer’s tear secretion test is performed to assess whether the eye produces enough tears to keep it moist. In order to perform this test, a paper strip is inserted into the eye for several minutes to measure the tear production. A negative test result of > 10 mm moisture on the filter paper in 5 min is considered as normal [29].
2. Methods This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guidelines and was registered on Prospero database (CRD42018099858) [25].
2.6. Statistical analysis Meta-analysis was performed using weighted mean difference (WMD) with 95 % confidence intervals (CIs) for assessing the association between serum vitamin D levels and dry eye disease. ORs with 95 % CIs were used to compute the pooled OR of vitamin D status and the risk of dry eye disease. Fisher’s Z and its SE using correlation coefficients and sample size were used to assess the association between serum 25(OH) D3 and OSDI, shirmer’s test, and TBUT. Based on heterogeneity between studies, random or fixed effects model were used. The sensitivity analyses were also performed to examine the influence of each individual study on the stability of the meta-analysis results. Each time, one study was excluded to show that study’s impact on the combined effect estimate. Subgroup analysis was also conducted based on different quality of the studies. Chi-squared (χ2) test was used to estimate heterogeneity and it was quantified using I2statistic. I2 was calculated using the formula: I2 = 100 % × (Q − df)/Q (where Q is the chi squared statistic, and df is the degrees of freedom), and an I2 value of 75 % or greater was considered as high level of inconsistency and Pvalue of < 0.05 indicated significant heterogeneity. Egger’s and Begg’s tests were conducted to estimate publication bias and also to determine the degree of funnel plot asymmetry with p < 0.05 representing significant publication bias.
2.1. Data source and search strategy Database search including PubMed (http://www.ncbi.nlm.nih.gov/ pubmed), Scopus (http://www.scopus.com), ISI Web of Science (http://www.webofscience.com) and Google Scholar (http://scholar. google.com) was carried out up to January 2020. The reference lists of the included articles were also reviewed to retrieve any additional studies. The following search strategy was run in PubMed and tailored to each database as necessary: “vitamin D” OR “25-Hydroxyvitamin D” OR “cholecalciferol” OR “ergocalciferol” OR “calcitriol” AND “ophtalmoxerosis” OR “xerophtalmia” OR “dry eye” OR “xeroma” OR “dry eye syndrome” OR “dry eye disease”. 2.2. Inclusion criteria Articles were considered for inclusion if they (I) were of observational design; (II) evaluated the association between serum vit D and dry eye disease and related measurement tools including OSDI, TBUT and shirmer’s test; and (III) assessed and reported means, medians or odds ratios (ORs) and the corresponding 95 % confidence intervals (CIs) for outcomes. The exclusion criteria were: gray literature without sufficient details, studies including DED and other ocular diseases at the same time, non-human studies, review articles, case reports, editorials and poster abstracts.
3. Results 3.1. Search results The initial search yielded 252 articles. After removing duplicates, 202 papers were reviewed based on title and abstract by two independent reviewers. Thirty-four papers were retrieved and reviewed based on full text, and finally 14 articles met the inclusion criteria and were entered in this systematic review and meta-analysis. The PRISMA flow diagram summarizes the results of study selection process for this systematic review and meta-analysis (Fig. 1).
2.3. Data extraction Before the screening process, all publications identified through the literature search were exported to the Endnote X8 software (Thomson Reuters, New York) and checked for duplicated publications. Titles and abstracts of each study were checked prior to full text screening by two independent reviewers (A. A & N. R). Any discrepancies in terms of the decision on a given study were resolved via discussion and, if necessary, consultation by a third reviewer (M. M). Extracted information from each study was as follows: first author name, year of publication, country, sample size, participants’ age and gender, study design and dietary assessment method.
3.2. Overview of included studies A total of 14 studies involving 44,977 participants were included in this systematic review and meta-analysis. The included observational studies were conducted between 2014 and 2019. Among the included 2
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Fig. 1. The flow diagram of study selection. Table 1 Characteristics of included studies. Author, Year
Location
Sample size (F/M)
Age
Study Design
Population health status
DAM
Quality assessment
Yang et.al., 2018 Shetty et al., 2016 Yoon et al., 2016 Jee et al, 2016 Jeon et al., 2017 Kim et al., 2017 Demirci et al., 2016 Meng et al., 2017 Shetty et al., 2016- B Galor et al., 2014 Jin et al., 2017 Kurtul et al., 2015 Yildirim et al., 2016 Khamar et al., 2019
Australia India Korea Korea Korea Korea Turkey China India USA Korea Turkey Turkey India
37/21 58/37 10108/7434 9316/7080 487/253 4808/4541 29/31 61/79 17/21 247M 57/22 48/7 98F 41/39
55.13 19-78 50.88 46.3 51 44.53 33.85 50.35 33.3 69 53.38 49 39.02 35.15
Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Case-control Cross-sectional Cross-sectional Cross-sectional Case-control Case-control Case-control
DED DED DED DED DED DED DED DED DED DED DED DED DED DED
– – – – – – – – – FFQ – Interview – –
Moderate Moderate High High High High Moderate Moderate Moderate High High Moderate High Moderate
& healthy adults & healthy adults & healthy adults & healthy adults & healthy adults & healthy adults & healthy adults & healthy adults & healthy adults & healthy adults with & without VDD with & without VDD with & without VDD & healthy adults
DAM: Dietary assessments method, DED: Dry eye disease, VDD: Vitamin D deficiency, FFQ: Food frequency questionnaire, F: Female, M: Male.
3.3. Findings from systematic review
studies, 5 were from Korea [21,30–33], 3 from Turkey [34–36], 3 from India [23,37,38] and the others were established from China [22], United states [39], and Australia [24]. Among included observational studies, 10 were of cross-sectional [21,23,24,30–34,37,39] and 4 of case control [22,35,36,38] design. Only 2 studies [35,39] examined the dietary intakes of the participants and the others did not mention anything [21–24,30–34,36–38]. Eleven studies categorized participants as dry eye disease and healthy groups [21–24,30,31,33,34,37–39], but 3 studies recruited patients with dry eye disease and grouped them as with or without vitamin D deficiency [32,35,36]. Based on the NOS, 7 studies ranked as high quality [21,30–33,36,39] and the others had moderate quality [22,22,23,24,34,35,37,38]. Characteristics of the included studies are illustrated in Table 1.
The association between serum vitamin D level and dry eye disease was investigated in 1 cross-sectional and 2 case control studies in which participants were categorized according to serum 25(OH) D levels. In first study, 92 patients (mean age 53.38 ± 13.69) with dry eye disease were recruited and divided in three groups according to serum 25(OH) D levels. TBUT and Schirmer’s tear secretion test were higher in vitamin D sufficient group compared with deficient group, but OSDI score did not show any significant difference between groups. In correlation analysis, only TBUT and Schirmer’s tear secretion test were positively correlated with serum 25(OH) D levels (r = 0.389, p = 0.001; and r = 0.428, p < 0.001, Pearson correlation test), and OSDI did not show significant correlation with serum 25 (OH) D levels (p > 0.05) [32]. 3
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3.4.2. The association between vitamin D status and dry eye disease Four studies with 44,027 subjects evaluated the association between vitamin D status sufficient vs deficient and dry eye disease [21,30,31,33]. There was no significant association between vitamin D status and dry eye disease (pooled OR: 0.96; 95 % CI, 0.91–1.02; P = 0.156). There was no significant heterogeneity between studies (I2 = 37.8 % p = 0.185). No evidence of publication bias was found (Begg’s test: P = 0.497, Egger’s test: P = 0.072) (Fig. 3).
In another case-control study assessing vitamin D deficiency and dry eye disease, thirty-four patients (mean age 51 ± 16) with vitamin D deficiency and twenty-one controls with normal vitamin D levels (mean age 47 ± 9) were included. TBUT and Schirmer’s tear secretion test results of study group were significantly lower than the control group (p < 0.05) [35]. In order to evaluate tear film function in vitamin D deficient patients, Demirici et al. recruited 30 patients with vitamin D deficiency (mean age 33.9 ± 0.9) and 30 healthy subjects (33.8 ± 0.9). In this cross-sectional study, results of TBUT and Schirmer’s tear secretion test showed significantly lower score in cases. On the other hand, OSDI was significantly higher in vitamin D deficient patients compared to healthy subjects (p < 0.001 for all) [34]. The last study demonstrated the relationship between vitamin D deficiency and dry eye disease. Fifty premenopausal women (mean age 40.28 ± 7.03) with vitamin D deficiency and forty-eight controls (37.77 ± 7.02) were included. Results of this study detected the lower scores of Schirmer’s test and TBUT, and higher scores of OSDI in vitamin D deficient patients compared to the controls (P < 0.05). Vitamin D levels were positively correlated with TBUT, Schirmer’s test, and negatively with OSDI [36].
3.4.3. The correlation between serum 25(OH) D3 level and OSDI The correlation between serum 25(OH) D3 and OSDI was examined in five studies with 237 participants [22–24,32,37]. Analysis revealed significant inverse correlation between serum 25(OH) D3 and OSDI (Fisher’s Z: -0.26; 95 % CI, -0.48 to -0.04; P = 0.018). Heterogeneity between studies was significant (I2 = 59.3 %, P = 0.043). Due to few studies in this field, subgroup analysis was not performed. No evidence of publication bias was found (Begg’s test: P=0.624, Egger’s test: P =0.381) (Fig. 4). 3.4.4. The correlation between serum 25(OH) D3 level and shirmer’s test Four studies with 185 subjects evaluated the correlation between serum 25(OH)D3 and shirmer’s test [22–24,32]. There was no significant correlation between serum 25(OH)D3 and shirmer’s test (Fisher’s Z: 0.47; 95 % CI, -0.09 to -1.03; P = 0.102). Heterogeneity between studies was significant (I2 = 92.1 %, P < 0.001). Due to few studies in this field, subgroup analysis was not performed. No evidence of publication bias was found (Begg’s test: P=0.497, Egger’s test: P =0.398) (Fig. 5).
3.4. Findings from meta-analysis 3.4.1. The association between serum 25(OH)D level and dry eye disease Eight studies with 44,343 participants examined the association between serum 25OH D and dry eye among patients with DED and healthy subjects [21,22,24,30,31,33,37,38]. Overall, meta-analysis showed a significant association between serum 25(OH) D and dry eye disease (WMD -1.70; 95 % CI, -2.61 to -0.79; P < 0.001). There was evidence of heterogeneity between the effect sizes of the included studies (I2 = 94.6 % p < 0.001). So, subgroup analysis has been done based on the studies' quality. Although, there was no significant association between serum 25(OH)D and dry eye disease in the moderate quality studies (WMD -2.45; 95 % CI, -10.94 to 6.03; P = 0.571) with significant heterogeneity (I2 = 95.5 % p < 0.001), analysis in the high quality studies subgroup revealed a significant result (WMD -0.62; 95 % CI, -0.63 to 0.61; P < 0.001) with evidence of no significant heterogeneity (I2 = 0.0 % p = 986). No evidence of publication bias was found (Begg’s test: P = 0.621, Egger’s test: P = 0.463) (Fig. 2).
3.4.5. The correlation between serum 25(OH) D3 level and TBUT The correlation between serum 25(OH) D3 and TBUT was assessed in four studies with 185 participants which did not reveal significant results (Fisher’s Z: -0.14; 95 % CI, -0.79 to 0.51; P = 0.674). There was significant heterogeneity between studies (I2 = 94.1 % p < 0.001). Due to few studies in this field, subgroup analysis was not performed. No evidence of publication bias was found (Begg’s test: P = 0.486, Egger’s test: P = 0.845) (Fig. 6). 4. Discussion To the best of knowledge, no systematic review and meta-analysis
Fig. 2. Forest plot of the association between the serum 25(OH) D in dry eye disease and healthy subjects. 4
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Fig. 3. Forest plot of association between vitamin D status and dry eye disease.
Fig. 4. Forest plot of correlation between vitamin D and OSDI.
Fig. 5. Forest plot of correlation between vitamin D and Shirmer’s test. 5
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Fig. 6. Forest plot of correlation between vitamin D and TBUT.
central mechanism in the pathogenesis of ocular surface damage. Tear hyper-osmolarity leads to the death of epithelial surface cells and a cascade of inflammatory events, which contribute to the loss of mucinproducing goblet cells. This exacerbates the tear film instability and is accompanied by a circle of events that negatively affect ocular surface [47–49]. Dry eye patients' neuropathic pain such as dysesthesias and hyperalgesia could be due to either peripheral sensitization of neurons or damage to free nerve endings by inflammatory stimuli. The presence of inflammation has also been found to directly and indirectly affect the structure and function of peripheral nerves resulting in altered nociception [50]. In the other way, excited nerve fibers could release neuropeptides which in turn trigger a neurogenic inflammatory response [23]. Current evidence suggest that 25(OH) D, known as vitamin D, has been proved to have many non-calcemic properties including regulation of gene expression, antioxidant, anti-inflammatory and immune-regulatory effects [51,52]. due to vitamin D capabilities in reducing inflammation [53,54],vitamin D deficiency may therefore lead to inflammation of ocular surface and ultimately dry eye disease [24] Interleukin-6 (IL-6), known as an anti-inflammatory cytokine, is the key mediator of the inflammatory response to localized inflammation [55]. It is suggested that higher IL-6 may affect the inflammatory response and cause higher tear volume production. Consequently, dry eye, as a chronic inflammatory eye disease, might be relieved by vitamin D through the inhibition of IL-6 [24,56]. Interleukin-17 (IL-17), well known for its pathologic role in inflammatory disorders, is also involved in nociception and itis found in higher concentrations in the tears of DED patients [37]. It has been revealed that IL-17A blockers could decrease OSDI score in DED subjects [57]. On the other hand, Vitamin D and its agonists could inhibit maturation and induce tolerance in dendritic cells resulting in the halt of inflammatory processes [58]. Another mechanism proposed for beneficial effects of vitamin D in DED is its ability to improve corneal epithelial barrier function [16]. Vitamin D could affect not only tear film indices but also ocular pain or discomfort through modulating nociception by regulation of nerve homeostasis and inflammatory responses. There are several theories regarding the mechanism linking vitamin D to pain. Serotonin which can extend chronic pain response has been proved to be high in subjects with DED and vitamin D is known to affect serotonin synthesis indicating a regulatory role of vitamin D in nociception [59,60]. Also, vitamin D, by decreasing nitric oxide synthesis, a nociceptive neurotransmitter, could modulate pain [61,62]. The present study has some limitations that warrant consideration. First, significant heterogeneity was present in the analysis which could limit the generalization of findings. Heterogeneity between studies may
has been published to evaluate the relationship between vitamin D and DED. Therefore, all observational studies which assessed the association between vitamin D and DED were collected. In this analysis, vitamin D correlated with OSDI but not shirmer’s test and TBUT. Also, DED did not prove to associate with vitamin D status (sufficient/deficient). Furthermore, individuals with DED showed significantly lower serum 25(OH) D3 level compared to healthy subjects. OSDI is the most common survey tool for the assessment of symptoms related to dry eye disease and their effects on vision [40]. This analysis revealed significant negative correlation between vitamin D and OSDI, which is consistent with previous interventional studies but there is inconsistency among findings of the observational studies [22–24,32,37,41]. A probable explanation for non-significant correlation between vitamin D and OSDI might be related to the nature of the inclusion criteria of DED subjects with high OSDI score and no variation in magnitude [24]. Furthermore, all of the included studies in this analysis ranked as medium quality with small sample sizes, which limited the interpretation of the final results [22–24,32,37]. TBUT is a valid technique for quantifying tear film instability which is affected by tear secretion and evaporative rate [42]. There was no significant correlation between vitamin D and TBUT which is in line with previous reports [24,37] except for an interventional study which revealed beneficial impact of vitamin D administration on TBUT [41]. Furthermore, all of the included studies in this section ranked as medium quality with small sample sizes [22,24,32,37]. Shirmer tear secretion test has been performed to assess the tear quantity and the integrity of lacrimal secretion systems [43]. The findings were consistent with previous documents which proved insignificant correlations between vitamin D and shirmer’s test [24,37]. There is a previous report which is not in line with the present results and has revealed beneficial impact of vitamin D on shirmer’s test score [41]. Alternative explanations for non-significant association between vitamin D status and DED may include vitamin D receptor dysfunction [44]; difficult accessibility of serum vitamin D to the cornea because of its lack of vasculature [31]. It has been shown that serum vitamin D levels do not reflect the levels in lacrimal fluids [31,45]. Vitamin D and its role in the pathogenesis of dry eye disease has been the subject of many recent evidences. Studies have shed lights on the association between vitamin D, DED and related mechanisms [21,31,32]. The underlying cause of DED includes inflammation which appears as discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface [46,47]. As proposed in the Dry Eye Workshop (DEWS) report, osmolarity is also reported to be one of the most objective assessments for dry eye disease and is considered as the 6
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be explained by number of the participants, participant’s differences in terms of serum vitamin D levels, and adjusted models. Moreover, the nature of cross sectional studies makes it impossible to draw causal link between variables. Since, it is a snapshot of the population, it could be altered overtime and include Neyman bias (prevalence-incidence bias), which is another form of selection bias and is highlighted in longer lasting disorders [63]. Third, small sample size was used in the included studies except in four articles [21,30,31,33]. Moreover, studies did not consider seasonal variation in serum vitamin D levels. There is no previous systematic review and meta-analysis assessing the association between vitamin D and dry eye disease in observational studies which could be considered as a strength.
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Florez, Effect of a Mediterranean dietary pattern and vitamin D levels on Dry Eye syndrome, Cornea 33 (5) (2014) 437–441. [40] B.E. Dougherty, J.J. Nichols, K.K. Nichols, Rasch analysis of the ocular surface disease index (OSDI), Invest Ophthalmol Vis Sci 52 (12) (2011) 8630–8635. [41] S.H. Bae, Y.J. Shin, H.K. Kim, J.Y. Hyon, W.R. Wee, S.G. Park, Vitamin D supplementation for patients with dry eye syndrome refractory to conventional treatment, Sci Rep 6 (2016) 33083. [42] C.G. Begley, N. Himebaugh, D. Renner, H. Liu, R. Chalmers, T. Simpson, et al., Tear breakup dynamics: a technique for quantifying tear film instability, Optom Vis Sci 83 (1) (2006) 15–21. [43] N.B. Carlson, D. Kurtz, D. Kurtz, C. Hines, Clinical procedures for ocular examination, McGraw-Hill, New York, 2004. [44] J.C. Waterhouse, T.H. Perez, P.J. Albert, Reversing bacteria‐induced vitamin D receptor dysfunction is key to autoimmune disease, Ann N Y Acad Sci 1173 (1) (2009) 757–765. [45] X. Lu, M.A. Watsky, Effects of vitamin D receptor knockout on cornea epithelium gap junctions, Invest Ophthalmol Vis Sci 55 (5) (2014) 2975–2982.
5. Conclusions It was found that serum vitamin D has negative correlation with OSDI but not TBUT or Shirmer’s test. Moreover, analysis revealed significant association between vitamin D and DED. Further prospective cohort studies and clinical trials are needed to better understand the relationship between vitamin D and DED. Funding This research received no external funding. Ethical approval All analyses were based on previous published studies; thus, no ethical approval is required. Declaration of Competing Interest The authors declare no conflict of interest. References [1] N. Yokoi, Y. Sonomura, H. Kato, A. Komuro, S. Kinoshita, Three percent diquafosol ophthalmic solution as an additional therapy to existing artificial tears with steroids for dry-eye patients with Sjögren’s syndrome, Eye 29 (9) (2015) 1204. [2] L.L. Marshall, J.M. Roach, Treatment of dry eye disease, Consult Pharm 31 (2) (2016) 96–106. [3] A. Janine, The epidemiology of dry eye disease: report of the epidemiological subcommittee of the international dry eye workshop, Ocul Surf 5 (2) (2007) 93–107. [4] D.A. Schaumberg, D.A. Sullivan, J.E. Buring, M.R. Dana, Prevalence of dry eye syndrome among US women, Am J Ophthalmol 136 (2) (2003) 318–326. [5] D.-H. Jeon, H. Yeom, J. Yang, J.S. Song, H.K. Lee, H.C. Kim, Are serum vitamin D levels associated with dry eye disease? Results from the study group for environmental eye disease, J Prev Med Public Health 50 (6) (2017) 369. [6] P.A. Rouen, M.L. White, Dry eye disease: prevalence, assessment, and management, Home Healthc Now 36 (2) (2018) 74–83. [7] K.-S. Na, K. Han, Y.-G. Park, C. Na, C.-K. Joo, Depression, stress, quality of life, and dry eye disease in Korean women: a population-based study, Cornea 34 (7) (2015) 733–738. [8] I.V. Lollett, A. Galor, Dry eye syndrome: developments and lifitegrast in perspective, Clin Ophthalmol (Auckland, NZ) 12 (2018) 125. [9] G. Ren, H. Li, W. Qiao, H. Shen, Y. Zhuang, T. Shao, et al., Possible association of killer cell immunoglobulin-like receptor genotypes and haplotypes with dry eye disease in a Han Chinese population, Mol Vis 21 (2015) 948. [10] J.-H. Lee, W. Lee, J.-H. Yoon, H. Seok, J. Roh, J.-U. Won, Relationship between symptoms of dry eye syndrome and occupational characteristics: the Korean National Health and Nutrition Examination Survey 2010–2012, BMC Ophthalmol 15 (1) (2015) 147. [11] A. Liu, J. Ji, Omega-3 essential fatty acids therapy for dry eye syndrome: a metaanalysis of randomized controlled studies, Med Sci Monit 20 (2014) 1583. [12] M.A. Jackson, K. Burrell, I.B. Gaddie, S.D. Richardson, Efficacy of a new prescription-only medical food supplement in alleviating signs and symptoms of dry eye, with or without concomitant cyclosporine A, Clin Ophthalmol 5 (2011) 1201. [13] H. Emmungil, M. Kalfa, F.Y. Zihni, G. Karabulut, G. Keser, S. Sen, et al., Interstitial cystitis: a rare manifestation of primary Sjögren’s syndrome, successfully treated with low dose cyclosporine, Rheumatol Int 32 (5) (2012) 1215–1218. [14] R.A. Elizondo, Z. Yin, X. Lu, M.A. Watsky, Effect of vitamin D receptor knockout on cornea epithelium wound healing and tight junctions, Invest Ophthalmol Vis Sci 55 (8) (2014) 5245–5251. [15] R.Y. Reins, S.D. Hanlon, S. Magadi, A.M. McDermott, Effects of topically applied
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(2009) 20–25. [55] E. Fattori, M. Cappelletti, P. Costa, C. Sellitto, L. Cantoni, M. Carelli, et al., Defective inflammatory response in interleukin 6-deficient mice, J Exp Med 180 (4) (1994) 1243–1250. [56] H.S. Oldenburg, M.A. Rogy, D.D. Lazarus, K.J. van Zee, B.P. Keeler, R.A. Chizzonite, et al., Cachexia and the acute‐phase protein response in inflammation are regulated by interleukin‐6, Eur J Immunol 23 (8) (1993) 1889–1894. [57] U.N.I.o. Health, The effects of a single intravenous administration of secukinumab (AIN457) or canakinumab (ACZ885) in dry eye patients, (2012). [58] M. Barragan, M. Good, J.K. Kolls, Regulation of dendritic cell function by vitamin D, Nutrients 7 (9) (2015) 8127–8151. [59] P. Chhadva, T. Lee, C.D. Sarantopoulos, A.S. Hackam, A.L. McClellan, E.R. Felix, et al., Human tear serotonin levels correlate with symptoms and signs of dry eye, Ophthalmology 122 (8) (2015) 1675–1680. [60] R.P. Patrick, B.N. Ames, Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior, FASEB J 29 (6) (2015) 2207–2222. [61] J. Bartley, Post herpetic neuralgia, schwann cell activation and vitamin D, Med Hypotheses 73 (6) (2009) 927–929. [62] I. Tegeder, R. Scheving, I. Wittig, G. Geisslinger, SNO-ing at the nociceptive synapse? Pharmacol Rev 63 (2) (2011) 366–389. [63] K.A. Levin, Study design III: cross-sectional studies, Evid-based Dent 7 (1) (2020) 24–25 0000.
[46] S. Kaštelan, M. Tomić, J. Salopek-Rabatić, B. Novak, Diagnostic procedures and management of dry eye, Biomed Res Int 2013 (2013). [47] N. Listed, The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye Workshop, Ocul Surf 5 (2) (2007) 75–92. [48] W. Stevenson, S.K. Chauhan, R. Dana, Dry eye disease: an immune-mediated ocular surface disorder, Arch Ophthalmol 130 (1) (2012) 90–100. [49] C. Baudouin, P. Aragona, E.M. Messmer, A. Tomlinson, M. Calonge, K.G. Boboridis, et al., Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting, Ocul Surf 11 (4) (2013) 246–258. [50] A. Ellis, D. Bennett, Neuroinflammation and the generation of neuropathic pain, Br J Anaesth 111 (1) (2013) 26–37. [51] S. Shab-Bidar, T.R. Neyestani, A. Djazayery, M.-R. Eshraghian, A. Houshiarrad, Aa. Gharavi, et al., Regular consumption of vitamin D-fortified yogurt drink (Doogh) improved endothelial biomarkers in subjects with type 2 diabetes: a randomized double-blind clinical trial, BMC Med 9 (1) (2011) 125. [52] S. Nagpal, S. Na, R. Rathnachalam, Noncalcemic actions of vitamin D receptor ligands, Endocr Rev 26 (5) (2005) 662–687. [53] M. Froicu, V. Weaver, T.A. Wynn, M.A. McDowell, J.E. Welsh, M.T. Cantorna, A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases, Mol Endocrinol 17 (12) (2003) 2386–2392. [54] D. Hughes, R. Norton, Vitamin D and respiratory health, Clin Exp Immunol 158 (1)
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Contact Lens and Anterior Eye journal homepage: www.elsevier.com/locate/clae
Review article
Association between vitamin D and dry eye disease: A systematic review and meta-analysis of observational studies Gholamreza Askaria, Nahid Rafieb, Maryam Miraghajanic,d, Zahra Heidarie, Arman Araba,* a
Department of Community Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Department of Clinical Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran c Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran d The Early Life Research Unit, Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK e Department of Biostatistics and Epidemiology, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran b
A R T I C LE I N FO
A B S T R A C T
Keywords: Vitamin D Dry eye disease Dry eye syndrome Systematic review Meta-analysis
Purpose: A number of studies have examined the association between vitamin D and dry eye disease in different populations, but findings are inconclusive. Herein, available observational studies were systematically reviewed to elucidate the overall relationship between vitamin D and dry eye disease among adult population. Methods: PubMed, Scopus, Google scholar and ISI web of science databases were searched until January 2020 for studies assessing the association between vitamin D and dry eye disease. The Newcastle-Ottawa Quality Assessment Scale was used to examine the quality of each study. Results: A total of 14 studies out of 252 met the inclusion criteria and were included in this systematic review and meta-analysis. Serum 25(OH) D3 was lower in dry eye disease subjects compared to healthy ones (WMD −5.93; 95 % CI, −7.47 to −4.40; P < 0.001) with evidence of significant heterogeneity (I2 = 94.6 % p < 0.001). Also, in final analysis, vitamin D correlated significantly with ocular surface disease index (Fisher’s Z: −0.26; 95 % CI, −0.48 to −0.04; P = 0.018), with significant heterogeneity between studies (I2 = 59.3 %, P = 0.043). Conclusion: It was found that serum vitamin D had a significantly lower level in dry eye disease patients, and correlated with ocular surface disease index but no other dry eye disease parameter. The findings add to the existing literature supporting the concept that nutrition especially vitamin D plays an important role in human eye health. Prospective studies are needed to confirm this relationship
1. Introduction Dry eye disease (DED) manifests as ocular discomfort and visual function impairment along with tear abnormalities or ocular surface disorders [1,2]. 5%–30% of the world 50 years and older population are suffering from this condition, with women representing approximately two-thirds of those affected [3,4]. Also, its prevalence is higher among Asians compared to western populations [5]. DED patients have substantially lower vision and quality of life with symptoms often interfering with daily activities [6]. In order to design new treatment strategies for improving vision-related quality of life in patients with DES, universal research effort is at work to identify risk factors involved in DES [7]. Many factors have been linked to DED such as hormonal alterations, psychological indices, medications [8], aging, reproductive factors,
tobacco, contact lens use, ocular surgery and dry environment [9,10]. Dietary intake and inflammation (reference) are additional risk factors associated with DED [11]. Several anti-inflammatory drugs have been used to treat DED, but their value is limited because of insufficient efficacy and noticeable side effects in some cases [12,13]. Recently, anti-inflammatory dietary factors such as omega-3 fatty acids have been reported to be potentially useful for DED treatment [6]. A recent focus of efforts, devoted to discover innovative approaches for DED prevention and treatment, has been on vitamin D [14–16]. Over the last three decades, it has become clear that the role of vitamin D goes beyond calcium homeostasis and bone health. Body of evidence is increasing about the influence of VD in health and disease conditions by modulating immune and cardiovascular functions. Also, regulatory effects of VD on the proliferation and differentiation of benign and malignant tissues have been reported
⁎
Corresponding author. E-mail addresses: [email protected] (G. Askari), nahid.rafi[email protected] (N. Rafie), [email protected] (M. Miraghajani), [email protected] (Z. Heidari), [email protected] (A. Arab). https://doi.org/10.1016/j.clae.2020.03.001 Received 9 October 2019; Received in revised form 26 February 2020; Accepted 4 March 2020 1367-0484/ © 2020 Published by Elsevier Ltd on behalf of British Contact Lens Association.
Please cite this article as: Gholamreza Askari, et al., Contact Lens and Anterior Eye, https://doi.org/10.1016/j.clae.2020.03.001
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2.4. Study quality
[17–19]. Due to the remarkable effects of vitamin D on the immune system, it could be conjectured that the immune-regulatory effects of vitamin D might influence the development of DED [20]. However, increasing body of literature has shown paradoxical relationships between vitamin D and DED. Some studies have suggested a significant association between serum vitamin D level and DED prevalence [21,22]. On the other hand, others do not support such an association [23,24]. Currently, there is insufficient evidence showing whether serum vitamin D deficiency is related to DED, and the determination of this relationship has rarely been conducted. Moreover, a relatively small sample size has been used in a majority of the studies assessing this association. To address these issues, this systematic review and meta-analysis was carried out by pooling the results from observational studies to examine the potential association between serum vitamin D and DED in patients as compared to healthy subjects in adult population. This information is important for clinicians and researchers alike as it increases knowledge on the potential usefulness of dietary modification and nutritional supplementation in DES.
The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the quality of each study [26]. The scale consists of assessment of three domains: selection (5 points), comparability (2 points) and outcome (3 points) for a total score of 10 points. Studies scoring 7–10, 5–6 and 0–4 points were identified as high, moderate and low quality, respectively. 2.5. Definition of DED assessment indices OSDI is a valid and reliable instrument in distinguishing between healthy subjects and patients with DED. OSDI score is from 0 to 100, with higher score representing greater disability and ranks patients as normal, mild to moderate and severe [27]. TBUT, a clinical measurement of evaporative DED, is recorded as the number of seconds that elapses between the last blink and the appearance of the first dry spot in the tear film. TBUT under 10 s is considered as abnormal [28]. Shirmer’s tear secretion test is performed to assess whether the eye produces enough tears to keep it moist. In order to perform this test, a paper strip is inserted into the eye for several minutes to measure the tear production. A negative test result of > 10 mm moisture on the filter paper in 5 min is considered as normal [29].
2. Methods This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guidelines and was registered on Prospero database (CRD42018099858) [25].
2.6. Statistical analysis Meta-analysis was performed using weighted mean difference (WMD) with 95 % confidence intervals (CIs) for assessing the association between serum vitamin D levels and dry eye disease. ORs with 95 % CIs were used to compute the pooled OR of vitamin D status and the risk of dry eye disease. Fisher’s Z and its SE using correlation coefficients and sample size were used to assess the association between serum 25(OH) D3 and OSDI, shirmer’s test, and TBUT. Based on heterogeneity between studies, random or fixed effects model were used. The sensitivity analyses were also performed to examine the influence of each individual study on the stability of the meta-analysis results. Each time, one study was excluded to show that study’s impact on the combined effect estimate. Subgroup analysis was also conducted based on different quality of the studies. Chi-squared (χ2) test was used to estimate heterogeneity and it was quantified using I2statistic. I2 was calculated using the formula: I2 = 100 % × (Q − df)/Q (where Q is the chi squared statistic, and df is the degrees of freedom), and an I2 value of 75 % or greater was considered as high level of inconsistency and Pvalue of < 0.05 indicated significant heterogeneity. Egger’s and Begg’s tests were conducted to estimate publication bias and also to determine the degree of funnel plot asymmetry with p < 0.05 representing significant publication bias.
2.1. Data source and search strategy Database search including PubMed (http://www.ncbi.nlm.nih.gov/ pubmed), Scopus (http://www.scopus.com), ISI Web of Science (http://www.webofscience.com) and Google Scholar (http://scholar. google.com) was carried out up to January 2020. The reference lists of the included articles were also reviewed to retrieve any additional studies. The following search strategy was run in PubMed and tailored to each database as necessary: “vitamin D” OR “25-Hydroxyvitamin D” OR “cholecalciferol” OR “ergocalciferol” OR “calcitriol” AND “ophtalmoxerosis” OR “xerophtalmia” OR “dry eye” OR “xeroma” OR “dry eye syndrome” OR “dry eye disease”. 2.2. Inclusion criteria Articles were considered for inclusion if they (I) were of observational design; (II) evaluated the association between serum vit D and dry eye disease and related measurement tools including OSDI, TBUT and shirmer’s test; and (III) assessed and reported means, medians or odds ratios (ORs) and the corresponding 95 % confidence intervals (CIs) for outcomes. The exclusion criteria were: gray literature without sufficient details, studies including DED and other ocular diseases at the same time, non-human studies, review articles, case reports, editorials and poster abstracts.
3. Results 3.1. Search results The initial search yielded 252 articles. After removing duplicates, 202 papers were reviewed based on title and abstract by two independent reviewers. Thirty-four papers were retrieved and reviewed based on full text, and finally 14 articles met the inclusion criteria and were entered in this systematic review and meta-analysis. The PRISMA flow diagram summarizes the results of study selection process for this systematic review and meta-analysis (Fig. 1).
2.3. Data extraction Before the screening process, all publications identified through the literature search were exported to the Endnote X8 software (Thomson Reuters, New York) and checked for duplicated publications. Titles and abstracts of each study were checked prior to full text screening by two independent reviewers (A. A & N. R). Any discrepancies in terms of the decision on a given study were resolved via discussion and, if necessary, consultation by a third reviewer (M. M). Extracted information from each study was as follows: first author name, year of publication, country, sample size, participants’ age and gender, study design and dietary assessment method.
3.2. Overview of included studies A total of 14 studies involving 44,977 participants were included in this systematic review and meta-analysis. The included observational studies were conducted between 2014 and 2019. Among the included 2
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Fig. 1. The flow diagram of study selection. Table 1 Characteristics of included studies. Author, Year
Location
Sample size (F/M)
Age
Study Design
Population health status
DAM
Quality assessment
Yang et.al., 2018 Shetty et al., 2016 Yoon et al., 2016 Jee et al, 2016 Jeon et al., 2017 Kim et al., 2017 Demirci et al., 2016 Meng et al., 2017 Shetty et al., 2016- B Galor et al., 2014 Jin et al., 2017 Kurtul et al., 2015 Yildirim et al., 2016 Khamar et al., 2019
Australia India Korea Korea Korea Korea Turkey China India USA Korea Turkey Turkey India
37/21 58/37 10108/7434 9316/7080 487/253 4808/4541 29/31 61/79 17/21 247M 57/22 48/7 98F 41/39
55.13 19-78 50.88 46.3 51 44.53 33.85 50.35 33.3 69 53.38 49 39.02 35.15
Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Case-control Cross-sectional Cross-sectional Cross-sectional Case-control Case-control Case-control
DED DED DED DED DED DED DED DED DED DED DED DED DED DED
– – – – – – – – – FFQ – Interview – –
Moderate Moderate High High High High Moderate Moderate Moderate High High Moderate High Moderate
& healthy adults & healthy adults & healthy adults & healthy adults & healthy adults & healthy adults & healthy adults & healthy adults & healthy adults & healthy adults with & without VDD with & without VDD with & without VDD & healthy adults
DAM: Dietary assessments method, DED: Dry eye disease, VDD: Vitamin D deficiency, FFQ: Food frequency questionnaire, F: Female, M: Male.
3.3. Findings from systematic review
studies, 5 were from Korea [21,30–33], 3 from Turkey [34–36], 3 from India [23,37,38] and the others were established from China [22], United states [39], and Australia [24]. Among included observational studies, 10 were of cross-sectional [21,23,24,30–34,37,39] and 4 of case control [22,35,36,38] design. Only 2 studies [35,39] examined the dietary intakes of the participants and the others did not mention anything [21–24,30–34,36–38]. Eleven studies categorized participants as dry eye disease and healthy groups [21–24,30,31,33,34,37–39], but 3 studies recruited patients with dry eye disease and grouped them as with or without vitamin D deficiency [32,35,36]. Based on the NOS, 7 studies ranked as high quality [21,30–33,36,39] and the others had moderate quality [22,22,23,24,34,35,37,38]. Characteristics of the included studies are illustrated in Table 1.
The association between serum vitamin D level and dry eye disease was investigated in 1 cross-sectional and 2 case control studies in which participants were categorized according to serum 25(OH) D levels. In first study, 92 patients (mean age 53.38 ± 13.69) with dry eye disease were recruited and divided in three groups according to serum 25(OH) D levels. TBUT and Schirmer’s tear secretion test were higher in vitamin D sufficient group compared with deficient group, but OSDI score did not show any significant difference between groups. In correlation analysis, only TBUT and Schirmer’s tear secretion test were positively correlated with serum 25(OH) D levels (r = 0.389, p = 0.001; and r = 0.428, p < 0.001, Pearson correlation test), and OSDI did not show significant correlation with serum 25 (OH) D levels (p > 0.05) [32]. 3
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3.4.2. The association between vitamin D status and dry eye disease Four studies with 44,027 subjects evaluated the association between vitamin D status sufficient vs deficient and dry eye disease [21,30,31,33]. There was no significant association between vitamin D status and dry eye disease (pooled OR: 0.96; 95 % CI, 0.91–1.02; P = 0.156). There was no significant heterogeneity between studies (I2 = 37.8 % p = 0.185). No evidence of publication bias was found (Begg’s test: P = 0.497, Egger’s test: P = 0.072) (Fig. 3).
In another case-control study assessing vitamin D deficiency and dry eye disease, thirty-four patients (mean age 51 ± 16) with vitamin D deficiency and twenty-one controls with normal vitamin D levels (mean age 47 ± 9) were included. TBUT and Schirmer’s tear secretion test results of study group were significantly lower than the control group (p < 0.05) [35]. In order to evaluate tear film function in vitamin D deficient patients, Demirici et al. recruited 30 patients with vitamin D deficiency (mean age 33.9 ± 0.9) and 30 healthy subjects (33.8 ± 0.9). In this cross-sectional study, results of TBUT and Schirmer’s tear secretion test showed significantly lower score in cases. On the other hand, OSDI was significantly higher in vitamin D deficient patients compared to healthy subjects (p < 0.001 for all) [34]. The last study demonstrated the relationship between vitamin D deficiency and dry eye disease. Fifty premenopausal women (mean age 40.28 ± 7.03) with vitamin D deficiency and forty-eight controls (37.77 ± 7.02) were included. Results of this study detected the lower scores of Schirmer’s test and TBUT, and higher scores of OSDI in vitamin D deficient patients compared to the controls (P < 0.05). Vitamin D levels were positively correlated with TBUT, Schirmer’s test, and negatively with OSDI [36].
3.4.3. The correlation between serum 25(OH) D3 level and OSDI The correlation between serum 25(OH) D3 and OSDI was examined in five studies with 237 participants [22–24,32,37]. Analysis revealed significant inverse correlation between serum 25(OH) D3 and OSDI (Fisher’s Z: -0.26; 95 % CI, -0.48 to -0.04; P = 0.018). Heterogeneity between studies was significant (I2 = 59.3 %, P = 0.043). Due to few studies in this field, subgroup analysis was not performed. No evidence of publication bias was found (Begg’s test: P=0.624, Egger’s test: P =0.381) (Fig. 4). 3.4.4. The correlation between serum 25(OH) D3 level and shirmer’s test Four studies with 185 subjects evaluated the correlation between serum 25(OH)D3 and shirmer’s test [22–24,32]. There was no significant correlation between serum 25(OH)D3 and shirmer’s test (Fisher’s Z: 0.47; 95 % CI, -0.09 to -1.03; P = 0.102). Heterogeneity between studies was significant (I2 = 92.1 %, P < 0.001). Due to few studies in this field, subgroup analysis was not performed. No evidence of publication bias was found (Begg’s test: P=0.497, Egger’s test: P =0.398) (Fig. 5).
3.4. Findings from meta-analysis 3.4.1. The association between serum 25(OH)D level and dry eye disease Eight studies with 44,343 participants examined the association between serum 25OH D and dry eye among patients with DED and healthy subjects [21,22,24,30,31,33,37,38]. Overall, meta-analysis showed a significant association between serum 25(OH) D and dry eye disease (WMD -1.70; 95 % CI, -2.61 to -0.79; P < 0.001). There was evidence of heterogeneity between the effect sizes of the included studies (I2 = 94.6 % p < 0.001). So, subgroup analysis has been done based on the studies' quality. Although, there was no significant association between serum 25(OH)D and dry eye disease in the moderate quality studies (WMD -2.45; 95 % CI, -10.94 to 6.03; P = 0.571) with significant heterogeneity (I2 = 95.5 % p < 0.001), analysis in the high quality studies subgroup revealed a significant result (WMD -0.62; 95 % CI, -0.63 to 0.61; P < 0.001) with evidence of no significant heterogeneity (I2 = 0.0 % p = 986). No evidence of publication bias was found (Begg’s test: P = 0.621, Egger’s test: P = 0.463) (Fig. 2).
3.4.5. The correlation between serum 25(OH) D3 level and TBUT The correlation between serum 25(OH) D3 and TBUT was assessed in four studies with 185 participants which did not reveal significant results (Fisher’s Z: -0.14; 95 % CI, -0.79 to 0.51; P = 0.674). There was significant heterogeneity between studies (I2 = 94.1 % p < 0.001). Due to few studies in this field, subgroup analysis was not performed. No evidence of publication bias was found (Begg’s test: P = 0.486, Egger’s test: P = 0.845) (Fig. 6). 4. Discussion To the best of knowledge, no systematic review and meta-analysis
Fig. 2. Forest plot of the association between the serum 25(OH) D in dry eye disease and healthy subjects. 4
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Fig. 3. Forest plot of association between vitamin D status and dry eye disease.
Fig. 4. Forest plot of correlation between vitamin D and OSDI.
Fig. 5. Forest plot of correlation between vitamin D and Shirmer’s test. 5
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Fig. 6. Forest plot of correlation between vitamin D and TBUT.
central mechanism in the pathogenesis of ocular surface damage. Tear hyper-osmolarity leads to the death of epithelial surface cells and a cascade of inflammatory events, which contribute to the loss of mucinproducing goblet cells. This exacerbates the tear film instability and is accompanied by a circle of events that negatively affect ocular surface [47–49]. Dry eye patients' neuropathic pain such as dysesthesias and hyperalgesia could be due to either peripheral sensitization of neurons or damage to free nerve endings by inflammatory stimuli. The presence of inflammation has also been found to directly and indirectly affect the structure and function of peripheral nerves resulting in altered nociception [50]. In the other way, excited nerve fibers could release neuropeptides which in turn trigger a neurogenic inflammatory response [23]. Current evidence suggest that 25(OH) D, known as vitamin D, has been proved to have many non-calcemic properties including regulation of gene expression, antioxidant, anti-inflammatory and immune-regulatory effects [51,52]. due to vitamin D capabilities in reducing inflammation [53,54],vitamin D deficiency may therefore lead to inflammation of ocular surface and ultimately dry eye disease [24] Interleukin-6 (IL-6), known as an anti-inflammatory cytokine, is the key mediator of the inflammatory response to localized inflammation [55]. It is suggested that higher IL-6 may affect the inflammatory response and cause higher tear volume production. Consequently, dry eye, as a chronic inflammatory eye disease, might be relieved by vitamin D through the inhibition of IL-6 [24,56]. Interleukin-17 (IL-17), well known for its pathologic role in inflammatory disorders, is also involved in nociception and itis found in higher concentrations in the tears of DED patients [37]. It has been revealed that IL-17A blockers could decrease OSDI score in DED subjects [57]. On the other hand, Vitamin D and its agonists could inhibit maturation and induce tolerance in dendritic cells resulting in the halt of inflammatory processes [58]. Another mechanism proposed for beneficial effects of vitamin D in DED is its ability to improve corneal epithelial barrier function [16]. Vitamin D could affect not only tear film indices but also ocular pain or discomfort through modulating nociception by regulation of nerve homeostasis and inflammatory responses. There are several theories regarding the mechanism linking vitamin D to pain. Serotonin which can extend chronic pain response has been proved to be high in subjects with DED and vitamin D is known to affect serotonin synthesis indicating a regulatory role of vitamin D in nociception [59,60]. Also, vitamin D, by decreasing nitric oxide synthesis, a nociceptive neurotransmitter, could modulate pain [61,62]. The present study has some limitations that warrant consideration. First, significant heterogeneity was present in the analysis which could limit the generalization of findings. Heterogeneity between studies may
has been published to evaluate the relationship between vitamin D and DED. Therefore, all observational studies which assessed the association between vitamin D and DED were collected. In this analysis, vitamin D correlated with OSDI but not shirmer’s test and TBUT. Also, DED did not prove to associate with vitamin D status (sufficient/deficient). Furthermore, individuals with DED showed significantly lower serum 25(OH) D3 level compared to healthy subjects. OSDI is the most common survey tool for the assessment of symptoms related to dry eye disease and their effects on vision [40]. This analysis revealed significant negative correlation between vitamin D and OSDI, which is consistent with previous interventional studies but there is inconsistency among findings of the observational studies [22–24,32,37,41]. A probable explanation for non-significant correlation between vitamin D and OSDI might be related to the nature of the inclusion criteria of DED subjects with high OSDI score and no variation in magnitude [24]. Furthermore, all of the included studies in this analysis ranked as medium quality with small sample sizes, which limited the interpretation of the final results [22–24,32,37]. TBUT is a valid technique for quantifying tear film instability which is affected by tear secretion and evaporative rate [42]. There was no significant correlation between vitamin D and TBUT which is in line with previous reports [24,37] except for an interventional study which revealed beneficial impact of vitamin D administration on TBUT [41]. Furthermore, all of the included studies in this section ranked as medium quality with small sample sizes [22,24,32,37]. Shirmer tear secretion test has been performed to assess the tear quantity and the integrity of lacrimal secretion systems [43]. The findings were consistent with previous documents which proved insignificant correlations between vitamin D and shirmer’s test [24,37]. There is a previous report which is not in line with the present results and has revealed beneficial impact of vitamin D on shirmer’s test score [41]. Alternative explanations for non-significant association between vitamin D status and DED may include vitamin D receptor dysfunction [44]; difficult accessibility of serum vitamin D to the cornea because of its lack of vasculature [31]. It has been shown that serum vitamin D levels do not reflect the levels in lacrimal fluids [31,45]. Vitamin D and its role in the pathogenesis of dry eye disease has been the subject of many recent evidences. Studies have shed lights on the association between vitamin D, DED and related mechanisms [21,31,32]. The underlying cause of DED includes inflammation which appears as discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface [46,47]. As proposed in the Dry Eye Workshop (DEWS) report, osmolarity is also reported to be one of the most objective assessments for dry eye disease and is considered as the 6
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be explained by number of the participants, participant’s differences in terms of serum vitamin D levels, and adjusted models. Moreover, the nature of cross sectional studies makes it impossible to draw causal link between variables. Since, it is a snapshot of the population, it could be altered overtime and include Neyman bias (prevalence-incidence bias), which is another form of selection bias and is highlighted in longer lasting disorders [63]. Third, small sample size was used in the included studies except in four articles [21,30,31,33]. Moreover, studies did not consider seasonal variation in serum vitamin D levels. There is no previous systematic review and meta-analysis assessing the association between vitamin D and dry eye disease in observational studies which could be considered as a strength.
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