THERAPEUTIC INSIGHTS

Nutrition for Dry Eye Therapy

Research reveals the potential of oral nutritional supplements.

Jeffrey R. Anshel, OD, FAAO

When considering treatments for dry eyes, optometrists traditionally prescribe lubricating drops or pharmaceutical agents. As science has revealed more about the genesis of degenerative diseases, however, we have learned that the ocular and periorbital glands respond to stress and degenerative change just as joint cartilage in arthritis and vessel walls in hypertension and arteriosclerosis do.¹ Age, stress and degeneration appear to be related to a build-up of free radicals in tissue at the cellular level, which results in loss of function and premature aging of tissues.² Chronic dry eye syndrome (DES) may be the result of such changes. Other stress-producing factors may be corneal surgery and contact lens wear.

One of the major contributors to the accumulation of free radicals in the lacrimal, mucus- and oil-producing glands of the eye and orbit may be nutritional deficiency.³ Data from the ARED study convinced many of the potential for nutritional supplements to restore and protect ocular tissue. Continued research over the past decade has shown that specifically targeted nutritional supplements can restore function to the glands that provide lubrication to the eye. This research identified specific nutrient antioxidants that can restore and support improved tear function.

As a result, oral nutritional formulations of essential fatty acids (EFA) are being used to treat dry eye syndrome. In this article, I describe the components of these formulations, their mechanisms of action and their effect on dry eye syndrome to assist clinicians in evaluating the various available supplements.

EFA formulations

To effectively treat DES, EFA must have the proper balance of omega 6 and omega 3 EFA from chemically stable plant oil⁴ to consistently produce series-one, tear-specific, anti-inflammatory prostaglandin (PGE1).⁵ Properly designed formulations also will block arachidonic acid cleavage to the series-two cyclooxygenase (COX2) enzyme, which can convert to a pro-inflammatory series-two prostaglandin (PGE2) without the nutrient cofactors that inhibit COX2 formation.⁶

Treatment of dry eye syndrome with EFA depends upon specific nutrient cofactors that aid the downstream metabolic conversion to antiinflammatory prostaglandins.⁷ These nutrient cofactors stimulate the production of healthy goblet cells⁸ and clearer, thinner meibomian oil. Properly designed EFA formulations also stimulate lacrimal gland secretion⁹ and the production of lactoferrin, the antiviral, antibacterial iron-binding protein that is particularly vital to the LASIK patient. In fact, dry eye nutritional formulations based on the most recent science now include iron-free lactoferrin in the product. Serum lactoferrin is released from the eyelid, and possibly from tear neutrophils during infection and inflammation, in a manner similar to serum immunoglobulin G, and by binding iron, it prevents the pathogen from obtaining sufficient iron for growth.¹⁰ Many clinicians believe tear lactoferrin levels are clinical markers for bacteria-induced dry eyes from contact lens wear and dependable predictors of LASIK outcomes.¹¹

The nutritional formulations that are designed around chemically stable omega 6 plant oils contain linolenic acid and significant amounts of gamma linolenic acid (GLA), plus the nutrient cofactors necessary to ensure the delta 6 desaturase (D6D) enzymatic metabolic conversion to the tear-specific anti-inflammatory PGE1.¹² They also contain varying amounts of omega 3 alpha linolenic acid (ALA), which converts to docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). To back up this plant-based ALA/DHA/EPA conversion, reputable formulators include small amounts of mercury-free fish oil, which contains DHA and EPA, which are necessary to block the delta-5-desaturase (D5D) enzymatic arachidonic acid cleavage of the omega 6 downstream di-homo-gamma linolenic acid (DGLA) metabolite by the COX2 enzyme.¹³ If not blocked, this enzyme can convert omega 6 DGLA and omega 3 stearidonic acid EFA to the proinflammatory series-two prostaglandins (PGE2). Early nutritional products did not address the arachidonic acid/COX2 cleavage issues as they pertain to the downstream conversion of EFA to anti-inflammatory prostaglandins.

The omega 3 EFA also requires nutrient cofactors to consistently convert downstream to DHA and EPA, which subsequently convert to the anti-inflammatory series-three prostaglandins (PGE3). PGE3 is an important site-specific anti-inflammatory, particularly for rheumatoid arthritis patients, but its effect is not as specific to tears as PGE1 from the omega 6 fatty acid metabolites.

Flax and fish oils

Some dry eye formulations are focused on the metabolic action of the omega 3 fatty acids found primarily in flax and fish oils. Many still use flax oil as a stand-alone treatment for dry eye syndrome because it contains a large amount of omega 3 and a small amount of omega 6. Unfortunately, flax oil is highly unstable¹⁴ and contains none of the nutrient cofactors necessary to ensure consistent enzymatic conversion to PGE1 or PGE3, nor does it enhance the production of tear lactoferrin. In addition, the conversion of short-chain omega 3 EFA (i.e., flax oil) does not readily convert to the longer chain EFA, such as DHA and EPA.¹⁵

Fish oil is available in two forms: the ethyl ester form and the triglyceride form, which is often referred to as the “natural” form. Raw fish oil is about 33% EPA and DHA along with other fatty acids. The most common EPA/DHA ratio in natural supplemental fish oil is 18:12, meaning the average 1,000 mg capsule of natural fish oil contains 180 mg of EPA and 120 mg of DHA. The U.S. government requires all fish oil to be mercury- and PCB-free.

All EPA/DHA concentrated fish oil is molecularly distilled, most as an ethyl ester, and this includes the triglyceride fish oils. Fish oil fatty acids are concentrated by molecular distillation, which separates the fatty acids from the glycerol backbone using ethanol (pure alcohol). This reaction results in an ester compound. Instead of being esterified to glycerol, the fatty acids are now esterified to ethanol and produce ethyl ester.

This method is applied to create fish oil supplements with a higher concentration of omega 3 fatty acids EPA/DHA. This method is the only method used for extremely high concentrations of EPA/DHA (up to 90%). The most common ethyl ester EPA/DHA concentration is about 50% or 35:20.

The FDA approved highly concentrated (90%) prescription fish oil (Lovaza [formerly Omacor]; Reliant Pharmaceuticals), which is in the ethyl ester form, not the concentrated triglyceride form. To date, most published omega 3 fish oil studies have been done on the ethyl ester form.^16-21

Concentrated triglyceride fish oil is also molecularly distilled before chemically or enzymatically forcing the fatty acids back onto the glycerol backbone, turning it into an altered triglyceride. This final process, too, creates a new-to-nature-molecule. Thus, the only “real” natural fish oil is the oil in the fish! Once it is removed and processed, it is no longer “natural.” No recent studies show that the triglyceride form is more readily absorbed or effective in humans.

Expand your options

Including nutrition for dry eye patients will expand your options to treat this common disorder. With judicious use of advanced formula oral nutritional supplements, many patients have regained the comfort they had lost to dry eye syndrome. OM

1. Luo L, Li DQ, Corrales RM, Pflugfelder SC. Hyperosmolar saline is a proinflammatory stress on the mouse ocular surface. Eye Contact Lens. 2005;31:186-193.
2. Masoro EJ. Theories of aging. In: Free Radicak in aging, Yu, BY (ed.); CRC Press, Inc. Boca Raton, FL, L] 1993.
3. Smith VA, Rishmawi H, Hussein H, Easty DL. Tear film MMP accumulation and corneal disease. Br J Ophthalmol. 2001;85:147-153.
4. Wu D, Meydani M, Leka LS, et al. Effect of dietary supplementation with black currant seed oil on the immune response of healthy elderly subjects. Am J Clin Nutr. 1999;70:536-543.
5. Horrobin DF, Campbell A. Sjogren's syndrome and the sicca syndrome: the role of prostaglandin El deficiency. Treatment with essential fatty acids and vitamin C: Med Hypotheses. 1980;6:225-232.
6. Jiang Q, Elson-Schwab, Courte-manche?, Ames BN. Gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells: Proc Natl Acad Sei USA. 2000;97:11494-11499.
7. Plummer SM, Holloway KA, Manson MM, etal. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signaling complex. Oncogene. 1999;18:6013-6020.
8. Tei M, Spurr-Michaid SJ, Tisdale AS, Gipson IK. Vitamin A deficiency alters the expression of mucin genes by the rat ocular surface epithelium. Invest Ophthalmol Vis Sei. 2000;41:82-88.
9. Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea. 1998;17:584-589.
10. LASIK Techniques-Pearls and Pitfalls: J. Kevin Belville and Ronald J. Smith. Slack Incorporated: Thorofare, NJ; 2004.
11. Solomon A, Dursun D. Pflugfelder SC: Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci. 2001;42:2283-2292.
12. Bordoni A, Hrelia S, Lorenzini A, et al. Dual influence of aging and vitamin B6 deficiency on delta-six desaturation of essential fatty acids in rate liver microsomes. Prostaglandins Leukot Essent Fatty Acids. 1998;58:417-420.
13. Volker D, Fitzgerald P, Major G, Garg M. Efficacy offish oil concentrate in the treatment of rheumatoid arthritis. J Rheumatol. 2000;27:2343-2346.
14. Tzen J, Cao Y, et al: Lipids, proteins, and structure of seed oil bodies from diverse species. Plant Physiol. 1993;101:267-276.
15. Brenna, JT, Salem N Jr, Sinclair AJ, Cunnane SC; International Society for the Study of Fatty Acids and Lipids. α-Linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans. Prostaglandins Leukot Essent Fatty Acids. 2009;80:85-91.
16. Sadovsky R, Collins N, Tighe AP, Safeer RS, Morris CM, Brunton SA. Dispelling the myths about omega-3 fatty acids. Postgrad Med. 2008;120:92-100.
17. Gosai P, Liu U, Doyle RT, et al. Effect of omega-3 acid ethyl esters on the steady-state plasma pharmacokinetics of rosuvastatin in healthy adults. Expert Opin Pharmacother. 2008;9:2947-2953.
18. Nordoy A, Barstad L, Connor WE, Hatcher L. Absorption of the n-3 eicosapentaenoic and docosahexaenoic acids as ethyl esters and triglycerides by humans. Am J Clin Nutr. 1991;53:1185-1190.
19. Bryhn M, Hansteen H, Schanche T, Aakre SE. The bioavailability and pharmacodynamics of different concentrations of omega-3 acid ethyl esters. Prostaglandins Leukot Essent Fatty Acids. 2006;75:19-24.
20. Beckermann B, Baneke M, Seitz I. Comparative bioavailability of eicosapentaenoic acid and docasahexaenoic acid from triglycerides, free fatty acids and ethyl esters in volunteers. Arzneimittelforschung. 1990;40:700-704.
21. Lawson LD, Hughes BG. Absorption of eicosapentaenoic acid and docosahexaenoic acid from fish oil triacylglycerols or fish oil ethyl esters co-ingested with a high-fat meal. Biochem Biophys Res Commun. 1988;156:960-963.