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Background

In 2014 the National Dry Eye Disease Guidelines for Canadian optometrists included essential fatty acids as a long term management strategy for chronic dry eye alongside topical cyclosporine[1]. Very recently the Tear Film and Ocular Surface Society published the 2017 Dry Eye Workshop II (DEWS II)[2]. Their Management and Therapy report included a review of the research on the omega-3 fatty acids EPA and DHA as well as the omega-6 fatty acids GLA[2]. DEWSII listed oral essential fatty acid supplementation in Step 1 of their Staged Management & Treatment Recommendations for Dry Eye Disease further solidifying supplementation with essential fatty acids as an effective treatment management strategy[2].

What are essential fatty acids?

Essential fatty acids are comprised of omega-3 and omega-6 fatty acids, which are physiologically distinct groups of fatty acids that are deemed “essential” – meaning we have to get them from the diet for good health, as our bodies lack the enzymes to produce them[3]. Both omega-3 and omega-6 fatty acids are important components of the phospholipid bilayer of cells and compete for incorporation into the cellular membrane[3].

Of the omega-3 fatty acids, there are 3 that stand out.

ALA is found in greater quantities in green leafy vegetables and plant oils, including nuts and seeds such as walnuts and flaxseeds. While ALA is an omega-3, to provide the health benefits commonly associated with omega-3 it must be converted into the longer-chain EPA or DHA omega-3 fatty acids. Unfortunately, the human body isn’t very efficient at converting ALA. Studies estimate that the conversion rate of ALA into EPA and DHA is about 5%[4,5]. This means that while foods like green leafy vegetables, nuts and seeds are healthy foods and sources of ALA, they are not very efficient at providing EPA and DHA
due to this limited enzymatic conversion.

Direct sources of the omega-3 EPA and DHA include marine oils, such as fish oils and algal oils. The vast majority of clinical research investigating supplementation with omega-3 fatty acids in dry eye use fish oil as the source for EPA and DHA in the intervention.

When it comes to omega-6 fatty acids, a common source is vegetable oil (eg. corn, sunflower, safflower) which contains Linoleic acid (LA) which is then converted, through a number of steps, to arachidonic acid (AA)[6]. Eggs and animal fats are direct sources of arachidonic acid. Gamma-linolenic acid (GLA) is a unique omega-6 fatty acids which is an intermediate between LA and AA. GLA is predominantly found in evening primrose, borage and black seed oils[1].

The role of omega-3 and omega-6 fatty acids in the body

Omega-3 fatty acids (specifically EPA) and the omega 6 fatty acid arachidonic acid (AA) are parent compounds in the production of eicosanoids[7]. The dietary intake of omega-3 and omega-6 fatty acids impacts the type of eicosanoids produced, with those resulting from the omega-3 being associated with an anti-inflammatory effect and those from AA being associated with a pro-inflammatory effect[7]. It is important to note that both omega-3 and omega-6 are essential, thus both are required and it is the balance of the two that plays a role in which state predominates.

Nutritional research suggests that a dietary ratio of omega-3 to omega-6 of 1:1 to 1:4, which is believed to be what historically was consumed dating back to paleolithic times is thought to be ideal[7]. The Western diet has changed significantly from the diet of our ancestors with significantly higher amounts of omega-6 being consumed leading to estimates of an omega-3 to 6 ratio today that is 1:15–20 instead of the more ideal 1:1 or 1:4[7]. Because of this it has even been suggested that the Western diet is “deficient” in omega-3 fatty acids[7,8]. This is why much research focuses on the supplementation of the omega-3 fatty acids EPA and DHA to help restore this systemic balance and ultimately impact the physiological state from the downstream effects of these essential fatty acids, this premise also applies to dry eye.[6]

What about the dry eye recommendations for essential fatty acids, including omega-6?

Given the above synopsis of omega-3 and omega-6 fatty acids it may seem counterintuitive that the National Dry Eye Disease Guidelines as well as DEWSII recommends essential fatty acids, which include omega-6 as management strategies for dry eye.

As highlighted in the National Dry Eye Disease guidelines, a specific omega-6 fatty acid stands out, gamma-linolenic acid (GLA)[1]. What makes this omega-6 fatty acid unique is that like the omega-3 fatty acids EPA and DHA it can elicit anti-inflammatory properties which in fact are different than those from EPA and DHA and can have positive effects in the body, including in dry eye[1,9]. The recommendations go further to highlight that GLA be combined with a minimum ratio of 1:1 with the omega-3 fatty acids EPA and DHA[1]. Clinical research showed that when the three fatty acids (EPA and DHA and the
omega-6 GLA) were combined, the combination “ may be utilized to reduce the synthesis of proinflammatory AA metabolites, and importantly, not induce potentially harmful increases in serum AA levels (which was seen when GLA was administered on its own)”[9]. The mechanism of action that has been suggested for this by in vivo and in vitro studies is that EPA may act as an inhibitor of delta-5 desaturase enzyme, thereby reducing the production of AA[9].

There have been numerous clinical studies conducted investigating the omega-6 GLA in dry eye, with dosages ranging from 15 to 420 mg [10–15]. As highlighted in the National Dry Eye Guidelines: “In the presence of EPA/DHA, GLA has been shown to have significant anti-inflammatory properties and to be effective in dry eye with an inflammatory component”[1]. Clinical research has investigated its effect with promising results in contact lens associated dry eye, post refractory surgery dry eye, dry eye associated with Meibomian gland dysfunction, keratoconjunctivitis sicca (KCS) associated with sjorgens syndrome
and improve the signs and symptoms of moderate to severe KCS with inflammatory components [1, 10,13,14,16–18].

A recent (2017) systematic review and meta-analysis on the efficacy of nutritional supplementation with omega-3 and omega-6 fatty acids in dry eye syndrome concluded, similarly to the National Dry Eye Guidelines, that while omega-3 fatty acids should be the main component of oral supplements it may be combined with lower amounts of omega-6[15].

Given the significant increase in research showing positive results with supplementation of essential fatty acids in dry eye and their inclusion in dry eye management guidelines (including DEWSII), while there is still more research to be done to determine ideal dosage ranges and ratios there is little doubt that essential fatty acids (including the omega-3 fatty acids EPA and DHA and the omega-6 fatty acid GLA) are now an accepted and effective mainstream management option for dry eye.

References

  1. Prokopich L. National Dry Eye Disease Guidelines for Canadian Optometrists. Can J Optomtry. 2014;76(Suppl.1):1–31. https://opto.ca/sites/default/files/resources/documents/cjo_dry_eye_supplement_2014.pdf.
  2. Jones L, Downie LE, Korb D, et al. TFOS DEWS II Management and Therapy Report. Ocul Surf. 2017;15(3):575–628. doi:10.1016/j.jtos.2017.05.006.
  3. Simopoulos AP. Evolutionary aspects of Diet: The omega-6/omega-3 ratio and the brain. Mol Neurobiol. 2011;44(3):203–215. doi:10.1007/s12035-010-8162-0.
  4. Plourde M, Cunnane SC. Extremely limited synthesis of long chain polyunsaturates in adults: implications for their dietary essentiality and use as supplements. Appl Physiol Nutr Metab. 2007. doi:10.1139/H07-034.
  5. Thomas Brenna J, to Brenna CJ. Efficiency of conversion of a a-linolenic acid to long chain n-3 fatty acids in man. 1363.
  6. Jones L, Downie LE, Korb D, et al. TFOS DEWS II Management and Therapy Report. Ocul Surf. 2017;15(3):575–628. doi:10.1016/j.jtos.2017.05.006.
  7. Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother. 2002;56(8):365-379. doi:10.1016/S0753-3322(02)00253-6.
  8. Barabino S, Horwath-Winter J, Messmer EM, Rolando M, Aragona P, Kinoshita S. The role of systemic and topical fatty acids for dry eye treatment. Prog Retin Eye Res. 2017;61:23–34. doi:10.1016/j.preteyeres.2017.05.003.
  9. Barham JB, Edens MB, Fonteh AN, Johnson MM, Easter L, Chilton FH. Addition of eicosapentaenoic acid to gamma-linolenic acid-supplemented diets prevents serum arachidonic acid accumulation in humans. J Nutr. 2000;130(8):1925–1931. http://www.ncbi.nlm.nih.gov/pubmed/10917903. Accessed December 21, 2017.
  10. Brignole-Baudouin F, Baudouin C, Aragona P, et al. A multicentre, double-masked, randomized, controlled trial assessing the effect of oral supplementation of omega-3 and omega-6 fatty acids on a conjunctival inflammatory marker in dry eye patients. Acta Ophthalmol. 2011;89(7):591–598. doi:10.1111/j.1755-3768.2011.02196.x.
  11. Jackson MA, Burrell K, Gaddie IB, Richardson SD. 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. 2011;5(1):1201–1206. doi:10.2147/OPTH.S22647.
  12. Barabino S, Rolando M, Camicione P, et al. Systemic linoleic and gamma-linolenic acid therapy in dry eye syndrome with an inflammatory component. Cornea. 2003;22(2):97–101. doi:10.1111/j.1467–8470.1988.tb00584.x.
  13. Aragona P, Bucolo C, Spinella R, Giuffrida S, Ferreri G. Systemic omega-6 essential fatty acid treatment and PGE1 tear content in Sjögren’s syndrome patients. Investig Ophthalmol Vis Sci. 2005;46(12):4474–4479. doi:10.1167/iovs.04-1394.
  14. Kokke KH, Morris JA, Lawrenson JG. Oral omega-6 essential fatty acid treatment in contact lens associated dry eye. Contact Lens Anterior Eye. 2008;31(3):141–146. doi:10.1016/j.clae.2007.12.001.
  15. Molina-Leyva I, Molina-Leyva A, Bueno-Cavanillas A. Efficacy of nutritional supplementation with omega-3 and omega-6 fatty acids in dry eye syndrome: a systematic review of randomized clinical trials. Acta Ophthalmol. 2017;95(8):e677-e685. doi:10.1111/aos.13428.
  16. Pinna A, Piccinini P, Carta F. Effect of Oral Linoleic and Y-Linolenic Acid on Meibomian Gland Dysfunction. Cornea. 2007;26(3):260–264. doi:10.1097/ICO.0b013e318033d79b.
  17. Macrì A, Giuffrida S, Amico V, Iester M, Traverso CE. Effect of linoleic acid and Y-linolenic acid on tear production, tear clearance and on the ocular surface after photorefractive keratectomy. Graefe’s Arch Clin Exp Ophthalmol. 2003;241(7):561–566. doi:10.1007/s00417-003-0685-x.
  18. Sheppard JD, Singh R, McClellan AJ, et al. Long-term Supplementation With n-6 and n-3 PUFAs Improves Moderate-to-Severe Keratoconjunctivitis Sicca. Cornea. 2013;32(10):1297–1304. doi:10.1097/ICO.0b013e318299549c.