Can Dietary Changes and Vitamin Supplements Improve Signs and/or Symptoms of Dry Eye DiseaseIntroductionDDry eye disease (DED) was first officially defined and classified in 1995, when the report of The National Eye Institute/Industry Workshop on Clinical Trials in Dry Eye was published. This was followed by the Tear Film and Ocular Surface Society (TFOS) publications of the TFOS International Dry Eye Workshop I (TFOS DEWS I) in 2007, and TFOS DEWS II in 2017 (1). Since the first report publication in 1995, the definition of DED has evolved as new research has revealed more information about this multifaceted disease. The most current, globally acknowledged definition of dry eye disease from the TFOS DEWS II workshop (2) is as follows:“Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.” (p.278)The ocular symptoms that may accompany DED include ocular discomfort, dryness and visual disturbance, and are reported to increase in severity towards the end of the day (3).ClassificationDED can be broadly separated into two main categories: aqueous deficient and evaporative (2). Aqueous deficient DED can be further classified into Sjogren’s and non-Sjogren’s, while evaporative DED can be further classified into intrinsic or extrinsic (2). The classification of DED can be further broken down into different sub-categories as highlighted by figure 1 (1). Figure 1. ‘Major etiological causes of dry eye’ (4: p.77)EpidemiologyDespite the TFOS DEWS II workshop recently revised definition of DED, there is still no standardized definition (1). Without a standardized definition, determining the epidemiology of DED is difficult to accurately ascertain. Epidemiologic research has thus been conducted with varying diagnostic and inclusion criteria, which has resulted in a wide estimate of DED prevalence. TFOS DEWS II reports that based on signs with or without symptoms, reports of DED prevalence ranges from 5-50% (1). Additionally, there are areas of epidemiological research that need to be focused on in future research, such as DED in younger populations (1). Since age is only one of many possible risk factors contributing to DED, it would be beneficial to draw information from people of all ages affected by DED. Together, a standardized definition of DED, and expanding research to include younger participants, would provide a more accurate picture of the impact of DED.It has been estimated that overall, less than 0.1% of DED patients are managed by ophthalmologists in the UK, France, Germany, Italy, Spain, and Sweden (5). Despite this small percentage, within the UK the annual cost of ophthalmologists managing 1,000 patients with DED was estimated to be $1.10 million U.S. dollars, the major cost determinant being prescription drugs (5). Due to the financial burden that DED places on patients and their health care systems, it is worthwhile investigating the role of diet and nutritional supplements and their role in DED.It is well known that nutritional supplementation or equivalent dietary changes, can positively impact the pathogenesis of many diseases. However, advising nutritional supplements to all dry eye patients may not be physiologically and thus financially beneficial. For example, The Age-Related Eye Disease Study (AREDS) showed that only a specific patient population with age related macular degeneration benefitted from nutritional supplementation with the AREDS formula to reduce the risk of developing advanced age-related macular degeneration (AMD) (#). It may stand to reason, that not all DED patients benefit will from nutritional supplementation or dietary changes, depending on the stage of their disease, current treatment they are receiving or other factors such as genetics which may impact the absorption of nutrients.  The ultimate goal of determining the role of nutritional supplements and diet and would be to develop DED supplement supported by evidence based research, and a nutrition guide for DED patients. By determining changes in diet that patients could implement, this could act as a starting point in DED management and prevention during routine sight tests with optometrists.ObjectiveThe objective of this literature review is to investigate whether or not certain dietary components including omega-3 fatty acids (FAs), vitamin D and antioxidants can alleviate DED signs and or symptoms.MethodsIn this literature review, the review question was whether or not dietary changes or supplements improve the signs and/or symptoms of DED. The following electronic databases were used to gather information: Pubmed, JAMA Network, The National Center for Biotechnology Information (NCBI), Ovid and Science Direct. The language restriction was English, and research publication date needed to be from the year 2000 and onwards. Study types to be included were both qualitative and quantitative, with no restriction on types of study designs that could be included. However, the preferred study design is double blind randomized controlled trials. The context in which the studies were conducted include optometric practice, ophthalmological practice and hospital or university settings.The condition being studied is dry eye disease. The exposures that were eligible for inclusion were various nutrients such as omega-3 FAs, vitamin D, and antioxidant. The exposures could be taken by the study participants in either supplement form or as dietary changes.  The inclusion criteria for the literature review study participants was any individual with signs and or symptoms of DED, regardless of etiology. The exclusion criteria were those without signs and or symptoms of DED. The exposures of interest for this literature review include omega-3 fatty acids, vitamins and antioxidants. The exposures could be either in the form of dietary changes or supplements/nutraceuticals. Both quantitative and qualitative study designs were included in this review. The primary outcome of interest was statistically significant reduction in the signs and/or symptoms of DED measured at the end of the study in comparison to starting values. There are no secondary outcomes of interest in this literature review. Omega-3 Fatty AcidsOmega-3 fatty acids (FAs) are polyunsaturated fatty acids (PUFAs) which the human body is not able to synthesize itself and is therefore obtained through diet. (6). There are two different forms of omega-3 FAs: one short chain form and two long chain forms. The short chain omega-3 FAs is alpha-linolenic acid (ALA) and the long chain omega-3 FAs include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (6). When ingested, short chain omega-3 FAs can be used by the body to synthesize the long chain FA, EPA (6). Arachidonic acid (AA), is an omega-6 FA and is the precursor to inflammatory mediators involved in the inflammatory cascade (7). Omega-3 FAs are of interest due to their ability to competitively inhibit the conversion of AA into pro-inflammatory molecules (7). Therefore, it is possible that dietary intake of omega-3 FAs, could help reduce underlying inflammation which is believed to play an essential etiological role in the development of dry eye disease.Dietary sources of omega-3 FAsALAEPA and DHAWalnutsSoybeansFlaxseedLinseed oilOily fish(herring, salmon, mackerel and tuna)Table 1. Dietary sources of short and long chain omega-3 FAs (6)Currently, there is conflicting results with regards to the efficacy of omega-3 FAs and the reduction of DED signs and or symptoms (6). It is interesting that for a disease in which it is recognized that inflammation plays a major etiological role, the supplementation of omega-3 FA which has anti-inflammatory properties, yields such variable results.A meta-analysis of 17 randomized clinical trials (RCTs) included a total number of 3,363 participants (6). The analysis in this study shows a significant improvement in DED signs and symptoms with omega-3 supplementation across, Schirmer test scores, tear break up time (TBUT) and corneal staining with fluorescein (6). The studies included in this meta-analysis were conducted in the United States, India, Europe, Australia, Japan and Iran. The sources and doses of omega-3 FAs varied across studies. Sources of omega-3 FAs included: EPA, DHA, krill oil, fish oil, sea buckthorn oil, flaxseed oil and borage oil. Further analysis of the study’s results revealed that location had a significant impact on results. Studies performed in India were found to have significantly greater improvements of DED symptoms and increased TBUT in comparison with the other countries included in the meta-analysis. The authors postulate that the high prevalence of vegetarian diet in India predisposes the population to lower omega-3 intake (6). To the best of their knowledge, the authors believe this to be the largest meta-analysis to date that investigates the role of omega-3 FAs on the signs and symptoms of DED (6). While this meta-analysis provides evidence to support that omega-3 FAs can improve DED, it also reveals the many differences in methodologies between the studies. In particular, the variation in sources of omega-3, inclusion criteria and ethnicity of participants. All of these factors may influence study results and are very possibly contributing to the conflicting evidence to support whether or not omega-3 FAs are beneficial for people suffering with DED. It may be best, therefore, to take a more one on one approach when evaluating the evidence for omega-3 FAs, considering these factors and looking for similarities between studies with similar methodologies. For example, comparing the results of a study that allowed participants to continue current dry eye treatments, to another study where participants were only allowed the exposures of interest, will likely provide conflicting results. Therefore, when considering study results clinicians should keep in mind the source of omega-3 used, inclusion criteria and ethnicity of participants.Omega-3 FAs are available from a variety of sources, which includes oily fish, walnuts, flaxseed, linseed oil and soybeans (6). It is important to be aware of the sources of omega-3 FAs used in research, as not all sources may be equivalent, as some may be more bioavailable than others. In a randomized, double-masked, placebo-controlled clinical trial, omega-3 from both fish oil and krill oil were compared against each other and a placebo oil (olive oil) (10). It was found that moderate supplementation with either fish or krill oil significantly improved DED signs and symptoms over a 3-month period (10). Additionally, krill oil was found to be more efficacious in improving DED symptoms and decreasing inflammatory markers compared to fish oil supplementation. Krill oil also has better stability, which is conferred by the antioxidant astaxanthin, a carotenoid, which is found in krill oil (10). In a different study, the bioavailability of fish oil and krill oil were compared (11). The results showed no significant differences in total plasma levels of EPA and DHA between fish and krill oils supplementation (11). However, this study was conducted for only 28 days, in comparison to the 3-month period the other study took place over. It is important that clinicians evaluate the inclusion criteria for study participants when considering the applications of the study results with their own patients’ individual needs. While there are few reported adverse effects of omega-3 supplementation (6), some patients may be less responsive than others to the possible beneficial anti-inflammatory effects on their DED. In a recent study, The Dry Eye Assessment and Management (DREAM) Study Research Group evaluated whether or not omega-3 supplementation improved signs and symptoms of DED in 535 participants over 12 months (9). This study was designed to reflect the real-world applications of the benefits of omega-3 FAs on DED (9). Unlike the inclusion criteria of most studies, patients in the DREAM study were allowed to continue current DED treatments. Treatments included various modalities, such as artificial tears, cyclosporin drops and warm lid soaks for the 12-month duration of the study. The study results show that in patients with moderate to severe DED, there was no significant benefit of omega-3 FA supplementation in comparison to the placebo (olive oil). Both the treatment group and the placebo group displayed improvements in DED signs and symptoms, and the authors concluded that there was no statistical difference in improvement between groups (9). The results of this study suggest that for patients already receiving treatment for moderate to severe DED, omega-3 FA supplementation may be of no additional benefit. By no means should this study be taken as conclusive evidence that omega-3 FAs have no beneficial anti-inflammatory properties for people suffering with DED. Instead, this information can help guide clinicians as to which patients might benefit most from supplementation of omega-3 FAs.Vitamin DVitamin D is a fat-soluble vitamin with anti-inflammatory and immunomodulatory properties (11, 12,), which may have applications to managing the signs and symptoms of DED (12). Vitamin D is available from 2 sources: sunlight and food (14). When exposed to direct sunlight, the body is able to synthesize Vitamin D. However, in the UK there is not enough sunlight between the months of early October to early March to obtain the required amount of vitamin D (14). Children over the age of 1 year, and adults (including pregnant and breastfeeding women and people who are at risk of vitamin D deficiency), require 10 micrograms of vitamin D a day (14). From food, vitamin D is found predominantly in oily fish, meat and eggs. It is important to note that in the UK, milk is not fortified as it is in other countries and is therefore not a good source of vitamin D (14).Sources of Vitamin DOily Fish: salmon, sardines, herring, mackerelRed meatLiverEgg yolksFortified foods (such as fat spread & most cereals)Table 2. Dietary sources of vitamin D (14).There has been a recent interest in the association between vitamin D supplementation and DED. Research has demonstrated that patients with low serum vitamin D levels might be at higher risk of developing DED (12, 13). Due to the increased risk of the development DED in patients with auto-immune diseases, it is possible that the immunomodulatory and anti-inflammatory properties of vitamin D supplementation could help reduce the risk of DED in these patients (12).Decreased serum levels of vitamin D have been shown to significantly reduce TBUT, Schirmer test scores and ocular surface disease index (OSDI) scores. (13).Vitamin D may be a beneficial supplement for patients with vitamin D deficiency and DED that has responded poorly to conventional treatment. Bae et al (15) investigated the effect of intramuscular injection of cholecalciferol (vitamin D3) on the signs and symptoms of DED in participants whose DED was not manageable with artificial tears or liposic EDO. Patients with autoimmune diseases, history of corneal surgery or disease, and corneal opacities were excluded from this study. The results showed an improvement of both DED signs and symptoms over a ten-week period (15). Vitamin D supplementation was associated with significantly improved TBUT, fluorescein staining score, hyperaemia of the eyelid margins, Schirmer test scores, OSDI score and the vision analogue pain score (15). Sub analysis showed that both men and women had increased TBUT, however, only women demonstrated a significant improvement in fluorescein staining scores and tear secretion (15). Out of 104 participants, 21 were male and 84 were female. The gender imbalance in this study could contribute to the statistically different results when stratified by gender. It would be beneficial to conduct a larger trial with equal male to female participants to investigate whether this was a result of gender bias, or if there is perhaps an underlying biological mechanism in which women respond better to vitamin D supplementation with regards to DED. DED signs and symptoms may not always correlate in severity (16). There are some patients who experience exaggerated symptoms of DED, but present with little to no signs of the disease (16). In a study by Shetty et al (16), inflammatory cytokines were measured in patients with DED symptoms, but little to no signs of DED. The authors postulate that low serum vitamin D levels might influence inflammatory cytokines or alter corneal pain perception in DED, which could result in fewer signs of DED, but with out of proportion symptoms (16). Diagnosing and managing these patients could prove difficult. The study found a significant correlation between lower serum vitamin D levels and altered inflammatory cytokines in patients with little to no signs of DED, but who were presenting with out of proportioned symptoms (16). DiscussionWeaknesses in studies-          Different grading scales-          Lack of standardized definition-          Comparison between studies that are not equivalent and drawing conclusions-           Future Research/Areas of Interest-          Anti-inflammatory diets-          Sugar intake; not only adding anti-inflammatory supplements/food to diet but reducing/eliminating pro-inflammatory foods. From the studies evaluated in this literature review, evaluation of current diet was not taken into account.-          Including genetic analysis regarding omega-3 FA serum levels in future research involving omega-3 FAs and its impact on dry eye disease.Conclusion(1) Nelson JD, Craig JP, Akpek EK, Azar DT, Belmonte C, Bron AJ, et al. TFOS DEWS II Introduction. The Ocular Surface. 2017; 15 (3): 269-275. Available from: http://dx.doi.org/10.1016/j.jtos.2017.05.005 [Accessed Feb 2nd, 2019](2) Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK et al. TFOS DEWS II Definition and Classification Report. The Ocular Surface. 2017; 15 (3): 276-283. Available from: http://dx.doi.org/10.1016/j.jtos.2017.05.008 [Accessed Feb 2nd, 2019](3) Begley CG, Chalmers RL, Mitchell GL, Nichols KK, Caffery B, Simpson T, et al. Characterization of Ocular Surface Symptoms From Optometric Practices in North America. Cornea. 2001; 20(6): 610-618. Available from: https://insights.ovid.com/crossref?an=00003226-200108000-00011 [Accessed Feb 2rd, 2019](4) The Definition and Classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye Workshop. The Ocular Surface. 2007; 5(2): 75-92. Available from: https://doi.org/10.1016/S1542-0124(12)70081-2 [Accessed Feb 2nd, 2019 ](5) Clegg JP, Guest JF, Lehman A, Smith AF. The Annual Cost of Dry Eye Syndrome in France, Germany, Italy, Spain, Sweden and the United Kingdom Among Patients Managed by Ophthalmologists. Ophthalmic Epidemiology. 2006; 13: 263-275. Available from: https://doi.org/10.1080/09286580600801044 [Accessed Feb 5th, 2019](6) Giannaccare G, Pellegrini M, Sebastiani S, Bernabei F, Roda M, Taroni L, et al. Efficacy of omega-3 Fatty Acid Supplementation for Treatment of Dry Eye Disease: A Meta-Analysis of Randomized Clinical Trials. Cornea. 2019; 38(5): 565-573. Available from https://insights.ovid.com/pubmed?pmid=30702470 [Accessed Feb 5th, 2019](7) James MJ, Gibson A, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. The American Journal of Clinical Nutrition. 2000; 71(1): 343S-8S. Available from: https://doi.org/10.1093/ajcn/71.1.343s [Accessed Feb 5th, 2019](8) Hom MM, Asbell P, Barry B. Omegas and Dry eye: More Knowledge, More Questions. Optometry and Vision Science. 2015; 92(9): 948-956. Available from https://www.ncbi.nlm.nih.gov/pubmed/26164311 [Accessed Feb 5th, 2019](9) Asbell PA, Maguire MG, Pistilli M, Ying GS, Szczotka-Flynn LB, Hardten DR et al. n-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease. New England Journal of Medicine. 2018; 378(18): 1681-1690. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29652551. [Accessed Feb 15th,2019](10) Deinema LA, Vingrys AJ, Wong CY, Jackson DC, Chinnery HR, Downie LE et al. A Randomized, Double-Masked, Placebo-controlled Clinical Trial of Two Forms of Omega-3 Supplements for Treating Dry Eye Disease. American Academy of Ophthalmology. 2016; 124(1): 43-52. Available from http://dx.doi.org/10.1016/j.ophtha.2016.09.023. [Accessed March 7th](11) Yurko-Mauro K, Kralovec J, Bailey-Hall E, Smeberg V, Stark JG, Salem N. Similar eicosapentaenoic acid and docosahexaenoic acid plasma levels achieved with fish oil or krill oil in a randomized double-blind four-week bioavailability study. Lipids in Health and Disease. 2015; 14(99). Available from https://www.ncbi.nlm.nih.gov/pubmed/26328782 [Accessed on March 7th].(12) Kurtul BE, Aydinli MS. The association of vitamin D deficiency with tear break up time and Schirmer testing in non-Sjogren dry eye. Eye. 2015; 29: 1081-1084. Available from https://www.ncbi.nlm.nih.gov/pubmed/26066054 [Accessed March 7th](13) Meng, YF, Lu J, Xing Q, Tao JJ, Xiao P. Lower Serum Vitamin D Level Was Associated with Risk of Dry Eye Syndrome. Medical Science Monitor. 2017; 23: 2211-2216.(14) Vitamins and Minerals: Vitamin D. NHS. Page last reviewed 03/03/2017. Available from https://www.nhs.uk/conditions/vitamins-and-minerals/vitamin-d/. [Accessed March 7th](15) Bae SH, Shin YJ, Kim HK, Hyon JY, Wee WR, Park SG. Vitamin D Supplementation For Patients with Dry Eye Syndrome Refractory to Conventional Treatment. Scientific Reports. 2016; 6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27698364. [Accessed April 2nd](16) Shetty R, Sethu W, Chevour P, Deshpande K, Pahuja N, Nagaraja H et al. Lower Vitamin D Level and Dising Tear Cytokine Profile Were Observed in Patients with Mild Dry Eye Signs but Exaggerated Symptoms. Translational Vision Science and Technology. 2016; 5(6): 1-8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156440/. [Accessed April 2nd].Get Help With Your EssayIf you need assistance with writing your essay, our professional essay writing service is here to help!Find out more