| | Essential fatty acids for dry eye: A review published online 25 December 2009. Abstract PurposeDry eye is a common complaint often encountered in optometric practice. However, it is a difficult condition to treat as clinical signs do not always correlate with patient symptoms. Essential fatty acids (EFA), particularly omega-3 EFA, may be effective in dealing with the underlying causes. MethodsA literature review was carried out on the PubMed, ScienceDirect and Ovid databases. Searches included keywords such as ‘dry eye’, ‘essential fatty acids’ and ‘nutrition’ to find articles relating to the treatment of dry eye syndrome (DES) with omega-3 EFAs. ResultsOmega-3 and -6 EFAs need to be consumed together within a reasonable ratio to be effective. Currently, typical diets in developed countries lack omega-3 EFA and this results in an overexposure to omega-6. Omega-3 supplementation has an anti-inflammatory effect, inhibiting creation of omega-6 prostaglandin precursors. Omega-3 EFAs also demonstrate anti-inflammatory action in the lacrimal gland preventing apoptosis of the secretory epithelial cells. Supplementation clears meibomitis, allowing a thinner, more elastic lipid layer to protect the tear film and cornea. ConclusionDietary supplementation of omega-3 EFA has already proven to be effective in coronary heart disease and arthritis. Safety is not a concern as it works synergistically with omega-6 in the body. Evidence suggests that supplementation with omega-3 EFA may be beneficial in the treatment and prevention of DES. 1. Introduction  Dry eye syndrome (DES) is thought to be a product of tear film abnormality, stemming from aqueous deficiencies or evaporation of the tear film [1], although it may also arise from lid closure abnormalities or environmental conditions (e.g. air conditioning). Current treatments are centered on the management of the tear film, and temporary relief may be achieved through instillation of artificial tears, although the effects do not last long because these topical treatments generally treat the symptoms and are unable to resolve the underlying cause [2]. Research has shown that up to 10% of the non-contact lens wearing population who are under the age of 60 have dry eye symptoms and these symptoms are even more common in older people and postmenopausal women [3]. Up to 25% of patients consulting eye care practitioners present with dry eye symptoms [4], as well as up to 50% of the 35 million contact lens wearers in the USA [5], [6], [7]. A survey of US practitioners showed that 12–21% of soft contact lens patients reduced their wearing time because of dry eye symptoms, and that 6–9% were so symptomatic that they were unable to wear lenses at all [8]. Despite the frequency of DES diagnosis is not always straightforward as clinical signs are not always reliable and lack the discrimination capabilities necessary to deal with the condition [9]. Use objective tests such as fluorescein staining, rose bengal staining, tear film breakup time and Schirmer's test showed discrepancies in sensitivity and specificity when used as diagnostic tools in the clinical setting. McCarty et al. found the Schirmer test to be least effective and did not recommend using any of the four tests individually [9]. Tear film breakup time may be the most effective measure of dry eye because it relays directly to the clinician the stability of the tear film. The National Eye Institute has defined DES as ‘a disorder of the tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort’ [10]. Dry eye syndrome can be divided into two types: evaporative and aqueous deficient [11]. While there are many factors that can lead to DES, both the evaporative and aqueous deficient types will result in increased tear osmolarity (raised concentration of tear film solutes) [12]. Evaporative dry eye may arise due to a meibomian oil deficiency or lid inadequacies such as an incomplete blink or a low blink rate (inability to properly distribute tears) [11]. A deficiency of vitamin A, which is needed for maintaining the health of epithelial tissues, may also result in evaporative dry eye [11]. Aqueous deficient DES can be further broken down to Sjögren's and non-Sjögren's dry eye. One possible cause of the non-Sjögren's type is a lacrimal gland duct obstruction [11] resulting in increased tear osmolarity [13]. Some authorities suggest that the instillation of artificial tears is the mainstay of the management of DES [14]. Over the last few years artificial tears with a high lubricity index have become available and a recent report suggests that Systane (Alcon Laboratories) has the lowest coefficient of friction and therefore the highest lubricity index value when compared to GenTeal [Novartis Ophthalmics], Refresh Tears and Refresh Endura [Allergan] [15]. A recent study (n =40) compared Systane to Soothe (Alimera Sciences Inc., Alpharetta, GA) and found that while one drop of Systane increased lipid layer thickness by an average of 16%, the same amount of Soothe produced an average increase of 117% [16]. Ridder et al. reported that Sensitive Eyes (Bausch and Lomb) a low viscosity artificial tear, improved contrast sensitivity and visual acuity in a group of silicon–hydrogel contact lens wearers with evaporative DES, when compared to Clerz2 (Alcon) and GenTea, both of which have a higher viscosity than Sensitive Eyes [17]. The authors proposed that this was due to a mechanism involving aqueous supplementation and/or minimal tear layer disruption. Research has shown that dry eye and nutrition are not mutually exclusive [18], prompting interest in the use of nutritional supplementation or dietary modification for the prevention and treatment of DES. Essential fatty acids (EFAs) may enhance the lipid layer of the tear film, thus retarding evaporation [19]. Perhaps more importantly, EFAs have displayed anti-inflammatory properties in conditions such as rheumatoid arthritis [20]. The key to the beneficial intake of EFAs is the ratio in which they are consumed and absorbed [21], [22]. Industrialized society has led to the overconsumption of omega-6 EFAs, thus limiting the effectiveness of omega-3 EFAs. This literature review attempts to give an overview of the investigation of EFA supplementation as a potential treatment for DES. 2. Methods We identified pertinent articles on use of EFA supplementation for DES published in peer-reviewed journals, through a multi-staged, systematic approach. In the first stage, a computerized search of the PubMed, ScienceDirect and Ovid databases was performed to identify all relevant articles published between 1950 and December 2008. Terms and words used for the search included ‘dry eye’, ‘dry eye syndrome’, ‘essential fatty acid’ ‘fatty acid’, ‘omega 3′, ‘omega 6′ and ‘Sjögren's syndrome’. In the second stage, copies of the entire articles were obtained, where possible. Bibliographies of the retrieved articles were manually searched with use of the same search guidelines. In the third stage, articles were reviewed and information relating to the use of EFAs for DES was incorporated into the manuscript. The literature search was not limited to the English language, although no translation was required. 3. Results 3.1. Essential fatty acids Essential fatty acids are deemed to be essential because they cannot be produced in the human body. They are polyunsaturated and can be divided into two groups namely omega-3 (ω-3) and omega-6 (ω-6); omega-9 fatty acids are not considered essential as they can be synthesised in the body from unsaturated fat. Essential fatty acids contain a carboxyl group (COOH) at one end, so are among the group of compounds known as carboxylic acids. The final position at the end of the chain opposite the carboxyl group is known as ω (omega, the final letter of the Greek alphabet) and the terms omega-3 and omega-6 refer to the location of the first double-bond in relation to the ω end of the chain. Essential fatty acids can also be classified according to the number of carbon atoms and double-bonds. For example, the lipid name for alpha-linolenic acid (ALA) is 18:3 ω-3. It contains 18 carbons and three double-bonds, and the first double-bond is three carbon atoms from the ω end [23]. Table 1 lists common name and lipid name of EFAs that are important in nutrition. Alpha-linoleic acid (omega-3, ALA) and linolenic acid (omega-6, LA) are short chain polyunsaturated fatty acids (SC-PUFA), while the other EFAs listed are long chain polyunsaturated fatty acids (LC-PUFA). Short chain-PUFAs and LC-PUFAs are available from the diet, but LC-PUFAs can also be formed within the body from SC-PUFAs. Therefore, ALA and LA can be considered the most important as they are the starting point for the formation of other EFAs [23]. 3.2. Availability Linolenic acid (omega-6) is available in the following common oils: corn, peanut, safflower, rapeseed, sunflower, and other common sources of omega-6 EFAs are poultry, eggs, cereals and whole-grain breads [24] such that it has become almost impossible to avoid their consumption. Part of the reason for this is that early research into the benefits of omega-3 and omega-6 EFAs showed positive results, but the results for omega-3 were more subtle and omega-6 was regarded as being most important for growth and development [25]. Omega-3 EFAs are found in fish and fish oils, as well as seeds, oils, green leafy vegetables such as broccoli and spinach, nuts and beans [23]. Table 2 illustrates the fish sources of omega-3 EFAs; dark, cold water fish are best in this regard. | | |  | Fish | Serving size | Amount of omega-3 fat | |
|---|
| Atlantic Salmon or Herring | 3oz cooked | 1.9g | | | Blue Fin Tuna | 3oz cooked | 1.5g | | | Sardines, tinned | 3oz in tomato sauce | 1.5g | | | Anchovies, tinned | 2oz drained | 1.2g | | | Atlantic Mackerel | 3oz cooked | 1.15g | | | Salmon, tinned | 3oz drained | 1.0g | | | Swordfish | 3oz cooked | 0.9g | | | Sea Bass (mixed species) | 3oz cooked | 0.65g | | | Tuna, white meat tinned | 3oz drained | 0.5g | | | Sole, Flounder, Mussels | 3oz cooked | 0.4g | | | Wild Catfish, crabmeat, clams | 3oz cooked/steamed | 0.3g | | | Prawns | 6 pieces | 0.15g | | | Atlantic Cod, Lobster | 3oz cooked/steamed | 0.15g | | | Trout, Orange roughly | 3oz cooked | <0.1g | | | | |
Flaxseed is one of the best botanical sources of ALA (omega-3). The omega-3/omega-6 ratio in flaxseed is approximately 1:0.3. Table 3 compares four common nuts and seeds to show which deliver the most omega-3 EFA. 3.3. Ideal ratio of essential fatty acids It was in 1970 that studies of the Eskimos in Greenland provided an insight into the usefulness of EFAs. Despite a diet high in fat, this Eskimo population had a low incidence of cardiovascular disease and acute myocardial infarction [11]. Dietary analysis was carried out to see if solutions to common problems of developed countries such as thrombosis and atherosclerosis could be found and it was noted that the Eskimos displayed low levels of low density lipoproteins and very low density lipoproteins. Eskimos were also found to have very low levels of arachidonic acid (AA, omega-6) in their blood, and high concentrations of eicosapentaenoic acid (EPA, omega-3) [11]. This is in contrast to typical diets in developed countries where greater amounts of AA (omega-6) are consumed. Besides cardiovascular health, EFAs have also been found to benefit brain function [12], [25], [26], stroke [21], bipolar disorder [21] and as treatment for inflammatory problems such as joint pain [27]. However a balance needs to be struck as results are not as favourable when the omega-3/omega-6 ratio decreases [13]. Conversion of LA (omega-6) to AA (omega-6) competes with the conversion of ALA (omega-3) to EPA (omega-3) and then to docosahexaenoic acid (DHA, omega-3) [28]. In other words, consumption of excess LA (omega-6) generates excess AA (omega-6) in relation to EPA and DHA (omega-3). Current estimates of the omega-3/omega-6 EFA ratio in developed countries are as low as 1:25 with recommendations to the public that it should be much higher (ideally 1:4) [29]. Due to the apparent inability to consume enough omega-3 EFAs through the diet there is now a large selection of oral omega-3 supplements available to augment dietary intake. Table 4 lists a selection of common omega-3 EFA supplements that are readily available, each with varying amounts of EPA (omega-3) and DHA (omega-3). | | | | Supplement name | Amount of EPA, DHA (in one soft gel or capsule) | |
|---|
| Carlson Super Omega-3 Fish Oils | 300mg EPA, 200mg DHA | | | Carlson Norwegian Cod Liver Oil | 460–500mg EPA, 500–550mg DHA per 5ml liquid | | | Coromega Omega-3 Fish Oil | 350mg EPA, 230mg DHA per packet | | | CVS Natural Fish Oil Concentrate, 1000mg | 180mg EPA, 120mg DHA | | | GNC Preventative Nutrition Omega Complex | 60mg EPA, 40mg DHA | | | Dale Alexander Omega-3 Fish Oil Concentrate | 234mg EPA, 125mg DHA | | | Health from the Sun: The Total EFA™ Essential Fatty Acid Dietary Supplement | 72mg EPA, 46mg DHA | | | Nature's Bounty Cold Water Salmon Oil, 1000mg | 80mg EPA, 120mg DHA | | | Natures Bounty Natural Fish Oil 1000mg Cholesterol Free | 180mg EPA, 120mg DHA | | | OLAY vitamins essential balanced omega 3/6, Enteric Coated for Better Digestion | 93.6mg EPA, 187mg DHA | | | OmegaBrite 100% Natural Advanced Omega 3 Formula, 500mg | 375mg EPA, 55mg DHA | | | PhytoPharmica ESKIMO-3 Naturally Stable Fish Oil | 70mg EPA, 42mg DHA | | | Puritan's Pride Cholesterol Free Fish Oil 1200mg | 216mg EPA, 144mg DHA | | | Puritan's Pride Cholesterol Free Natural Fish Oil EPA 1000mg | 180mg EPA, 120mg DHA | | | Puritan's Pride Triple Omega 3-6-9 Flax, Fish and Borage Oil | 120mg EPA, 80mg DHA | | | Rexall Flax, Fish, Borage Oil | 120mg EPA, 80mg DHA | | | Spring Valley Fish Oil, 1200mg | 216mg EPA, 144mg DHA | | | Sundown Fish Oil, 100mg | 180mg EPA, 120mg DHA | | | The Vitamin Shoppe Essential Oils & Fatty Acids EPA-DHA Omega-3 Fish Oil 500 | 300mg EPA, 200mg DHA | | | Triomega Omega-3 | 333.3mg EPA, 167mg DHA | | | Vitamin World Cholesterol Free Fish Oil 1200mg | 216mg EPA, 144mg DHA | | | Vitamin World Naturally Inspired Omega-3 Fish Oil 1000mg Cholesterol Free | 180mg EPA, 120mg DHA | | | Vitamin World Naturally Inspired Super EPA Natural Fish Oil 1000mg Cholesterol Free | 300mg EPA, 200mg DHA | | | Vitamin World Triple Omega 3-6-9 Flax, Fish & Borage Oil | 120mg EPA, 80mg DHA | | | | |
3.4. Effect of omega-6 EFA supplementation on DES Before there was a clear understanding of the mechanism by which EFAs could alleviate DES symptoms and signs, dietary supplements containing EFAs for use as a DES treatment were commercially available. Many of these contained omega-6 as well as omega-3 EFAs despite the fact that omega-6 EFA results in excess AA (omega-6) in the body which can lead to heart disease, stroke and other degenerative diseases [30]. 3.5. Lipid layer Pinna et al. investigated the role of LA (omega-6) and GLA (omega-6) in meibomian gland dysfunction (MGD). Meibomian gland secretion is important in stabilizing the tear film and MGD is a common cause of dry eye [31]. 3.6. Decreased inflammation One intervention study that was primarily focused on improving fatigue in people with Sjögren's syndrome, found no change in eye dryness with GLA (omega-6) supplementation [32]. However, a review of other studies demonstrated an improvement in lacrimal function in people suffering from Sjögren's syndrome who were supplemented with GLA (omega-6) [18]. Aragona et al., found the same results when using LA (omega-6) and GLA (omega-6). The group receiving treatment showed significantly higher levels of prostaglandin E1 (PGE1) in their tears as well as a considerable improvement in the ocular surface and symptoms after one month of treatment compared with a placebo group. Fifteen days after cessation, the PGE1 levels decreased and the signs and symptoms returned. The researchers concluded that LA (omega-6) and GLA (omega-6) played a major role in relieving the ocular discomfort and corneal epithelial defects associated with dry eye, as well as increasing the PGE1 levels [33]. Studies using LA (omega-6) and GLA (omega-6) as anti-inflammatory agents on the ocular surface of patients with aqueous deficient keratoconjunctivitis sicca as well as in topical preservative-free substitute tears have also reported a reduction in dry eye symptoms. A significant decrease in conjunctival lissamine green staining as well as a decrease in symptoms and in ocular surface inflammation was found in the group of subjects receiving LA, GLA and artificial tears while no statistically significant change between the groups was found for tear break up time or Schirmer's test [34]. 3.7. Increased tear secretion Improvement in reports of DES symptoms and an increase in tear production have been reported after six months of omega-6 EFA treatment [35]. 3.8. Effect of omega-3 EFA supplementation on dry eye Milijanovic et al., confirmed the link between omega-3 EFA and DES, without dismissing the function of omega-6. However, for both EFA groups to perform desirably, a balance between the two must be found. A high intake ratio of omega-3 to omega-6 EFA resulted in a decreased likelihood of suffering from DES in women [36]. It is thought that this ratio ideally should be at least 1:4 and preferably 1:2.3 [19]. However, the ratio is typically much lower (1:10–30) in a diet typical of developed countries which tends to be high in meat and processed food. It was shown that women with lower than a 1:15 omega-3/omega-6 EFA ratio had a 2.5 times greater prevalence of DES [36]. If too much omega-6 EFA is ingested due to a diet high in processed meats and low in unprocessed oils and omega-3 EFA-containing fish, then increased levels of pro-inflammatory PGE2, and low levels of anti-inflammatory agents PGE1 and PGE3, may lead to dry eye [31]. Supplementary omega-3 EFA may be taken as it is often lacking in the diet. Individuals with the highest intake of omega-3 EFA showed a 20% decrease in the likelihood of suffering from DES as opposed to those with a low intake of omega-3 EFA. In one study, women who ate at least five servings of tuna per week compared to those eating only one were 68 times less likely to suffer from DES [36]. Having said this, the UK Food Standards Agency advise that females who are pregnant, breastfeeding, or who may one day become pregnant should limit oily fish consumption to two servings per week to avoid over consumption of pollutants that these fish concentrate [37]. Dietary supplementation with omega-3 EFAs has proved to be very effective in the treatment of DES, and new trials are emerging to test the use of omega-3 EFA as a topical agent. Rashid et al., tested the effect of EFAs on induced dry eye in mice using three formulations (ALA (omega-3) only, LA (omega-6) only, LA/ALA combination). The LA only and LA/ALA combination proved to be insignificant and symptoms were the same as those mice who received the placebo. However, the ALA treatment produced a considerable reduction in ocular inflammation and symptoms, and a decrease in corneal staining. These cells occur in response to inflammation and the expression of pro-inflammatory interleukin-1 (IL-1α) and tumour necrosis factor (TNF-α) [38]. Linolenic acid (omega-6) and ALA/LA combinations do not counter the already high amount of omega-6 EFA in the body. This will not offset the pro-inflammatory status already present. However, ALA (omega 3) on its own will act as an anti-inflammatory and bring about a shift in ocular condition. 3.9. Lipid layer Omega-3 EFAs also play an important role in the synthesis of meibum, the oil secreted by meibomian glands. People with omega-3 EFA deficiency typically have a thicker meibomian gland secretion [39]. The use of omega-3 EFA supplements results in clearing and thinning of meibomian gland secretions which in turn improves symptoms of dry eye [39]. This finding correlates to the earlier finding by Pinna et al., on the use of LA and GLA in MGD. In addition it is thought that omega-3 EFA may affect the polar portion of the tear film's lipid layer by increasing the omega-3 EFA present or altering the omega-3/omega-6 ratio [40]. 3.10. Decreased inflammation Once omega-3 EFA is consumed enzymes elongate it producing PGE3 and leukotriene B5 (LTB5), both of which have anti-inflammatory properties. In addition, omega-3 EFA from fish (EPA), ‘blocks the gene expression of pro-inflammatory cytokines TNF-α, IL-1α, IL-1β, proteoglycan degrading enzymes (aggrecanases) and cyclooxygenase (COX-2)’ [12] as shown in Fig. 1. Individuals with dry eye tend to have increased levels of TNF-α and IL-1α in the tear film [41]. The overall result when gene expression is blocked is a decrease in inflammation, which may explain why omega-3 EFA is successful in the treatment of MGD. As previously discussed, omega-3 EFAs block the gene expression of TNF-α, which is important in decreasing apoptosis. It has been shown that increased TNF-α in the lacrimal glands is responsible for lacrimal gland apoptosis, which leads to a decrease in tear production and an increase in tear film osmolarity. Increase in tear film osmolarity causes an increase in TNF-α which causes apoptosis to rise, further increasing tear film osmolarity. Furthermore, DHA (omega-3) helps to prevent lacrimal gland and ocular surface cells from apoptosis caused by TNF-α. When combined with DHA, vitamin E prevents apoptosis. Docosahexaenoic acid can also help combat DES by increasing synapse function which decreases with age [42]. A decrease in synapse function lends to easier inhibition of signal transduction at the synapse by pro-inflammatory cytokines leading to dry eye [12]. 3.11. Increased tear secretion Together, DHA (omega-3) and EPA (omega-3) work to prevent omega-6 EFAs being converted into AA, allowing dihomo-gamma-linoleic acid (DGLA) to be converted to PGE1. Along with PGE3 (from omega-3), PGE1 is anti-inflammatory [33]. Like PGE3, PGE1 is an anti-inflammatory that inhibits TNF-α, IL-1β and IL-6 [43]. Dihomo-gamma-linoleic acid has also been shown to reduce pro-inflammatory eicosanoids such as leukotrienes B4 and C4 which are formed by AA [31]. When the omega-3/omega-6 ratio is 1:4 or higher, there is competitive inhibition of the conversion of DGLA to AA resulting in more PGE1 [36]. As a result of this, it has been suggested that omega-3 and omega-6 EFA be given together [33] as more anti-inflammatory eicosanoids can be produced by DGLA and EPA with less inflammation caused by those formed by AA [36]. 4. Discussion Until now, the symptoms of DES have been treated with moderate success, but long term solutions are needed. Artificial tears are a stopgap that mask symptoms, but do not resolve underlying problems. The use of EFAs in DES needs to further be investigated, particularly as EFAs have already shown their usefulness in heart disease, inflammatory diseases and arthritis [20]. The key to unraveling the potential benefits of EFAs is to firstly gain a clearer understanding of their interactions and to ensure that appropriate amounts of each EFA are consumed. For example, an ideal balance of omega-3/omega-6 should be 1:2.3; this ratio needs to be reached because these two groups of EFAs perform distinct and complementary functions. Omega-6 EFAs are the precursors of eicosanoids and prostaglandins that act as natural healers, but can lead to problems such as thrombosis and coronary heart problems. An excess of omega-6 EFAs, such as in the typical diet of developed countries, allows for a disproportionate response of pro-inflammatory prostaglandins that will not be blocked by its natural omega-3 EFA anti-inflammatory counterpart [44]. A comparison of the consumption of omega-3 and omega-6 EFA across different countries sheds light on their relationship with inflammation and heart disease. In the USA, between 70 and 80% of EFA consumed is omega-6 [45], [46] and coronary heart disease rates are 200 per 100,000 [46]. On the other hand, the Japanese consumption of EFA consists of only 35–40% omega-6 [46], [47], and Japan has about one quarter of the heart disease rate of the USA [46]. In Greenland where omega-3 EFAs are plentiful in the diet, heart disease is almost non-existent [46]. The importance of omega-3 EFAs cannot be underestimated and in DES the advantages are threefold: (1) restoration of the lipid layer, (2) decreased inflammation and apoptosis, and (3) increased tear secretion. Apoptosis of the acini and epithelial cells of the lacrimal glands can lead to decreased secretory function [48]. Supplementation with anti-inflammatory omega-3 EFA counters the under-challenged pro-inflammatory omega-6 EFA, increasing the secretion from the lacrimal gland. Omega-3 EFAs also clear meibomitis allowing a thinner more fluid lipid to be secreted from the meibomian glands. This in turn will better protect the tear film and retard evaporation [19]. It is prudent to address any safety issues. Theoretically, an excess of omega-3 EFAs could cause bleeding due to their anti-thrombotic properties [19] therefore individuals that suffer from bleeding disorders should seek medical advice before taking omega-3 EFA supplements. 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Ophthalmic Research Group, School of Life & Health Sciences, Aston University, Birmingham B4 7ET, UK  Corresponding author at: Vision Sciences Building, School of Life & Health Sciences, Aston University, Birmingham B4 7ET, UK. Tel.: +44 121 204 4182; fax: +44 121 204 4048.
PII: S1367-0484(09)00153-2 doi:10.1016/j.clae.2009.11.002 © 2009 British Contact Lens Association. Published by Elsevier Inc. All rights reserved. | |
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