FEATURE ›› OCULAR DIETARY SUPPLEMENTATION
Ocular Dietary Supplementation — Food For Thought
Diet is one of the most important and modifiable lifestyle determinants of human health.
BY SVETLANA PILYUGINA, MD
All of us get this question in the clinic, “Doctor, should I be taking vitamins for my eyes? What should I eat to improve my eye health and prevent eye disease?” With hundreds of dietary supplements on the market and minimal FDA regulations, we need all the evidence we can find to educate ourselves and our patients.
A significant amount of epidemiologic and scientific data exists with regard to the impact of nutrition on the development and progression of AMD.1 The AREDS and AREDS2 trials2,3 have become the gold standard for defining the role of ocular nutrition. Those studies identified the key nutrients in ocular/retinal health: antioxidants, vitamin C, E, minerals zinc and copper, and dietary supplements lutein zeaxanthin and Omega-3 fatty acids. However, it’s unlikely that similarly large placebo-controlled trials will be replicated to study other common dietary supplements.
So, until we have definitive data and direction, how should we advise our patients? What substantiates the benefits of a diet rich in green leafy vegetables and fish or drinking a glass of red wine each day? What about the purported antioxidant benefits of blueberries? In this article, I’ll review the literature on nutrient supplementation on ocular health but bear in mind that this article covers merely the tip of the iceberg in an area in which there is still much to be learned.
VISION LOSS AND RETINAL CHANGES
In a busy clinical setting, we tend to focus our attention on the more severe symptoms of central vision loss universally assessed by visual acuity testing. Clinical trials on nutrient supplementation also tend to rely on visual acuity as a measurement of efficacy.4 In addition to visual acuity, however, other optical limitations exist that can affect visual performance and reduce the quality of vision including chromatic aberration, light scatter (veiling luminance) and glare. It’s well recognized that functional visual decline precedes RPE-photoreceptor complex visible changes and that patients with early AMD and minimal retinal findings often suffer from a gradual loss of contrast sensitivity, impaired reading speed and difficulty adapting to changing light conditions5 — functionalities rarely tested in the retina practice or clinical trials. These functional declines have also been observed as a result of aging changes in AMD-free retinas. These findings raise a question whether nutrient supplementation effects have not been fully revealed due to a lack of sensitivity measures in the trials conducted to date.6
Anatomic considerations support the idea of nutrient supplementation for retinal health. Lutein (L) and its optical isomer zeaxanthin (Z) and mezo-zeaxanthine (MZ) are the primary components of macular pigment and are also present in the lens. L and Z are xanthophyll carotenoids, which are pigments synthesized by plants for coloration and absorption of light energy. MZ is produced in the macula following isomerization of retinal lutein. Lutein is predominant in the parafoveal region, while Z and MZ are primarily found in the fovea.7 Lutein protects the ocular tissue by filtering the damaging 445-472 nm blue light, which attenuates chromatic aberration in the healthy eye. L and Z are also antioxidants, preventing damage from the reactive oxygen intermediates, such as free radicals and hydrogen.8 Macular pigments are derived entirely from diet and are transported to the macula from hepatocytes via high-density lipoprotein (HDL).9 Food sources include leafy green vegetables, orange and yellow fruits and vegetables, and egg yolks. Spinach, kale and collard greens contain lutein, while corn, oranges and eggs carry zeaxanthin.
Multiple studies have shown that dietary L and Z intake is associated with an increase in serum L concentration,10 and elevated serum L and Z concentration is, in turn, associated with increased macular pigment optical density (MPOD).11,12 Measurements of MPOD are being investigated as a possible method of objective documentation of the impact of nutritional supplementation on the retina.13 Ongoing research suggests that elevations in MPOD are linked to the improvement of the functional abnormalities of the central retina in early AMD patients who are taking lutein and zeaxanthin supplements.14,15
OMEGA-3 FATTY ACIDS
Another group of structural retinal molecules derived primarily from diet are Omega-3 fatty acids. A brief biochemistry review is in order: monounsaturated fatty acids contain one double bond (e.g. olive oil), polyunsaturated fatty acids contain at least two double bonds and are classified by the position of the first double bond. Omega-3 fatty acids have the first double bond 3 carbon atoms away from the methyl terminal and the Omega-6 have it six carbon atoms away. The essential fatty acids (e.g. linoleic Omega-6 and lionenic Omega-3) cannot be synthesized by the body and must be supplied in the diet. They are used directly for energy production or for synthesis of long chain polyunsaturated fatty acids (LCPUFAs). Dietary sources of Omega-6 include soybean, sunflower and corn oils, egg yolks and meat. The long chain Omega-3 fatty acids — DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) — can be found in seaweed and several types of cold water fish, including tuna, salmon and sardines.
The outer retina has a high concentration of diet-derived LCPUFAs, especially DHA, located mainly in the photoreceptor outer segments which are constantly shed and turned over during the visual cycle. DHA plays a critical role in resynthesis of regenerating membranes, photoreceptor differentiation and regeneration of rhodopsin.16 DHA concentration gradient also exists in the subretinal space. EPA suppresses various compounds in the inflammatory cascade and both have been shown to reduce oxidative stress and have anti-angiogenic properties.17,18 A detailed review of all studies involving Omega-3 is outside the scope of this article, but one interesting finding deserves a mention. A group from the University of Montreal presented a pilot study during the 2013 ASRS Meeting demonstrating that 200 mg DHA and 400 mg EPA supplementation in wet AMD patients was associated with lower intravitreal anti-VEGF A levels versus those in the control group as confirmed by office-based vitreous biopsy. Once again, this finding lends support to a continued recommendation of Omega-3 use in VEGF-mediated ocular conditions.
Bilberry extract is among the most popular “ocular health” supplements worldwide. Bilberry (Vaccinium myrtillus) is an edible berry containing 15 subtypes of flavonoid anthocyanosides, water-soluble glycosides with potent, antioxidant-free radical scavenger properties. Blueberry also falls into the anthocyanoside group and has been advocated by many. Whether the claims of efficacy are substantiated or not remains largely unknown. For instance, the hypothesis that bilberry anthocyanosides improve normal night vision in healthy subjects isn’t supported by evidence from rigorous clinical studies.19 But a study of bilberry effects on retinal inflammation in endotoxin-induced uveitis mouse model does demonstrate inhibition of inflammatory cytokines and prevention of decrease in rhodopsin levels, elucidating the potential molecular mechanism of its action by antioxidant photoreceptor protection.20 There are other studies demonstrating its inhibitory effect on angiogenesis via deactivation of angiotensin converting enzymes in the vascular endothelial cells, which is certainly an intriguing idea that suggests it may have a role as an adjunct in the treatment of neovascular ocular disorders.21
Resveratrol is a polyphenolic flavonoid abundant in the skin of berries, red grapes and red wine. The beneficial effects of resveratrol within the eye are claimed to be extensive. Known primarily as a potent antioxidant, it is also said to be anti-apoptotic, anti-tumorigenic, anti-inflammatory,22 vasorelaxant and anti-angiogenic.23 The majority of these claims are based on in vitro and animal studies, because in vivo human studies may be limited by poor resveratrol bioavailability when administered orally. Nonetheless, some studies deserve mention. In a mouse model of retinal ischemic injury induced by high intraocular pressure, resveratrol treatment attenuated both ischemic-induced loss of retinal function and reduced ischemia-mediated thinning of the retina.24,25 Oral supplementation of resveratrol showed promising beneficial effects on vessel leakage, pericyte loss and VEGF protein expression in diabetic mouse retina models as compared to controls.24,25
Finally, a curious study of a mouse retinal detachment model demonstrated that resveratrol inhibited retinal caspase activation, aiding in the prevention of photoreceptor loss in a setting of retinal detachment,26 leaving us with a question whether a glass of red wine may be the earliest needed intervention for our patients presenting with a detached retina.
The dietary supplement industry apparently is doing quite well: an FDA report on Nutritional Supplement sales in the U.S. shows sales reached $11.5 billion in 2012, and are expected to reach $15.5 billion by 2017, with those over the age of 65 being the primary consumers. At the same time, this is the group most afflicted by the impact of the age related eye disorders. In the U.S., 11.5% of the population is affected by some degree of AMD.27 The socioeconomic benefits of AMD prevention are enormous. It has been reported that the projected visual impairment and blindness from AMD by 2050 may be reduced by 17.6% if vitamin prophylaxis is given in addition to the standard treatments for neovascular AMD.28 In 2012, total direct medical expenditures associated with macular degeneration and cataract, plus the related expected costs of post-procedure nursing care/assisted living services due to reduced vision were almost $16.97 billion and are expected to average $20.55 billion per year from 2013 to 2020 according to the report by Sullivan and Frost.29 This study further determined that if every person over age 55 were to take lutein and zeaxanthin supplements at the recommended preventive daily intake levels, avoidable expenditures related to AMD would average $57.4 million per year from 2013 to 2020. Additionally, an average of $966.6 million per year in net avoided medical costs and nearly $7.73 billion in cumulative net savings from 2013 to 2020 could be realized after accounting for the cost of dietary supplement intervention. With the AREDS2 data and other supporting studies behind us, these astounding numbers demand attention.
Supplements may be referred to as “all natural” and thought of by patients as “just vitamins” but they’re not always innocuous. Here are some key considertions to keep in mind when recommending these commonly used ocular supplements.
Vitamin C in high doses may increase the risk of renal stone formation in susceptible patients.30 Excessive Vitamin E may have an association with fatigue, muscle weakness, and has been suggested as a factor in increasing hemorrhagic stroke rates;31 it must also be used with caution in patients on anticoagulant medications and those receiving chemotherapy.32 Beta carotene and increased risk of lung cancer in smokers or prior smokers is well known.33,34 Excess Zinc leads to copper deficiency anemia, decreased HDL levels,35 stomach upset and genitourinary complications in men.36 In addition, the antithrombotic effects of fish oil are also well known.37 The risk of mercury contamination in fish oil supplements should be an important consideration when selecting a particular supplement.
Finally, the absence of strict regulatory oversight allows for an overabundance of “miracle cures.” As such, our role as physicians is to guide and caution against false promises by increasing patients’ awareness. The National Center for Complementary and Alternative Medicine is an excellent resource on the validity of many claims related to nutritional supplements. ConsumerLab is an independent firm that tests supplements to determine if they contain the promised ingredients, and specific product manufacturers can be reviewed. In 2013, FDA instituted the Dietary Supplement and Nonprescription Drug Consumer Protection Act (Public Law 109-462), requiring the reporting of adverse events associated with any dietary supplement distributed in the U.S.
So the next time your proliferative diabetic retinopathy patient informs you that he’s controlling his glucose with cinnamon bark, you may want to educate him in office or have him check out this article, “Beware of Illegally Sold Diabetes Treatments.” (Available at http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm361487.htm)
EDUCATE YOURSELF, EDUCATE YOUR PATIENTS
The above are ideas and thoughts are raised by the increasing awareness of the important role nutrition is playing in our health. As it was once said “the food you eat can be either the safest and most powerful form of medicine, or the slowest form of poison.” Until clear-cut scientific data is available, we’ll continue to exercise the art of medicine — interpreting the existing science and using our best judgment to help guide our patients to the best course of action for their ocular health and wellness. NRP
In 2012, total direct medical expenditures associated with macular degeneration and cataract, plus the related expected costs of post-procedure nursing care/assisted living services due to reduced vision were almost $16.97 billion and are expected to average $20.55 billion per year from 2013 to 2020.
If every person over age 55 were to take lutein and zeaxanthin supplements at the recommended preventive daily intake levels, avoidable expenditures related to AMD would average $57.4 million per year from 2013 to 2020.
An average of $966.6 million per year in net avoided medical costs and nearly $7.73 billion in cumulative net savings from 2013 to 2020 could be realized after accounting for the cost of dietary supplement intervention.
SOURCE: FROST & SULLIVAN
1. Velez-Montoya R, Oliver SC, Olson JL, Fine SL, Quiroz-Mercado H, Mandava N. Current knowledge and trends in age-related macular degeneration: genetics, epidemiology, and prevention. Retina 2014;34(3):423-441.
2. Age-related Eye Disease Study Research Group. A randomized placebo-controlled, clinical trial of high dose supplementation with Vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119(10):1417-1436.
3. Age-related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA 2013;309(19):2005-2015.
4. Christen WG, Glynn RJ, Manson JE, et al. Effects of multivitamin supplement on cataract and age-related macular degeneration in a randomized trial of male physicians. Ophthalmology 2014;121(2):525-534.
5. Midena E, Degli Angeli M, Blarzino C, Valenti M, Segato T. Macular function impairment in eyes with early age-related macular degeneration. Invest Ophthalmol Vis Sci 1997;38(2):469-477.
6. Dimitrov PN, Robman LD, Varsamidis M, et al. Visual function tests as potential biomarkers in age-related macular degeneration. Invest Ophthalmol Vis Sci 2011;52(13):9457-9469.
7. Carpentier S, Knaus M, Suh M. Associations between lutein, zeaxanthin and age-related macular degeneration. Crit Rev Food Sci Nutr 2009;49(4):313-326.
8. Hollyfield JG, Bonilha VL, Rayborn ME, et al. Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 2008;14(2):194-198.
9. Li B, Vachali P, Bernstein PS. Human ocular carotenoid-binding proteins. Photochem Photobiol Sci 2010;9(11):1418-1425.
10. Rock CL, Thornquist MD, Neuhouser ML, et al. Diet and lifestyle correlates of lutein in the blood and diet. J Nutr 2002;132(3):525S-530S.
11. Dawczynski J, Jentsch S, Schweitzer D, Hammer M, Lang GE, Strobel J. Long term effects of lutein, zeaxanthin and omega-3-LCPUFAs supplementation on optical density of macular pigment in AMD patients: the LUTEGA study. Graefes Arch Clin Exp Ophthalmol 2013;251(12):2711-2723.
12. Johnson EJ, Chung HY, Caldarella SM, Snodderly DM. The influence of supplemental lutein and docosahexaenoic acid on serum, lipoproteins, and macular pigmentation. Am J Clin Nutr 2008;87(5):1521-1529.
13. Bernstein PS, Delori FC, Richer SP, van Kuijk FJ, Wenzel AJ. The value of measurement of macular carotenoid pigment optical densities and distributions in age-related macular degeneration and other retinal disorders. Vision Res 2010;50(7):716–728.
14. Ma L, Dou HL, Huang YM, et al. Improvement of retinal function in early age-related macular degeneration after lutein and zeaxanthin supplementation: a randomized, double-masked, placebo-controlled trial. Am J Ophthalmol 2012;154(4):625-634.
15. Ma L, Yan SF, Huang YM. Effect of lutein and zeaxanthin on macular pigment and visual function in patients with early age-related macular degeneration. Ophthalmology 2012;119(11):2290-2297.
16. Querques G, Forte G, Souied EH. Retina and omega-3. J Nutr Metab E-pub ahead of print Oct. 31, 2011.
17. Sangiovanni JP, Agron E, Meleth AD, et al. Omega-3 long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: AREDS report 30, a prospective cohor study from the Age-Related Eye Disease Study. Am J Clin Nutr 2009;90:1601-1607.
18. SanGiovanni JP, Chew EY. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog Retin Eye Res 2005;24(1):87-138.
19. Anthocyanosides of Vaccinium myrtillus (Bilberry) for night vision -- a systematic review of placebo-controlled trials. Surv Ophthalmol 2004;49(1):38-50.
20. Miyake S, Takahashi N, Sasaki M, Kobayashi S, Tsubota K, Ozawa Y. Vision preservation during retinal inflammation by anthocyanin-rich bilberry extract: cellular and molecular mechanism. Lab Invest 2012;92(1):102-109.
21. Matsunaga N, Tsuruma K, Shimazawa M, Yokota S, Hara H. Inhibitory actions of bilberry anthocyanidins on angiogenesis. Phytother Res 2010;24(Suppl 1):S42-S47.
22. Kubota S, Kurihara T, Mochimaru H, et al. Prevention of ocular inflammation in endotoxin-induced uveitis with resveratrol by inhibiting oxidative damage and nuclear factor-kappaB activation. Invest Ophthalmol Vis Sci 2009;50(7):3512–3519.
23. Bola C, Bartlett H, Eperjesi F. Resveratrol and the eye: activity and molecular mechanisms. Graefes Arch Clin Exp Ophthalmol E-pub ahead of print: March 21, 2014.
24. Kim YH, Kim YS, Roh GS, Choi WS, Cho GJ. Resveratrol blocks diabetes-induced early vascular lesions and vascular endothelial growth factor induction in mouse retinas. Acta Ophthalmol 2012;90(1):e31-37.
25. Kim YH, Kim YS, Kang SS, Cho GJ, Choi WS (2010) Resveratrol inhibits neuronal apoptosis and elevated Ca2+/calmodulin-dependent protein kinase II activity in diabetic mouse retina. Diabetes 2010;59(7):1825-1835.
26. Huang W, Li G, Qiu J, Gonzalez P, Challa P. Protective effects of resveratrol in experimental retinal detachment. PLoS One. Published Sept. 11, 2013; DOI: 10.1371/journal.pone.0075735.
27. Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122(4):564-572.
28. Rein DB, Witterborn JS, Zhang X, Honeycutt AA, Lesesne SB, Saaddine J; Vision Health Cost-Effectiveness Study Group. Forecasting age-related macular degeneration through 2050: the potential impact of new treatments. Arch Ophthalmol 2009;127(4):533-540.
29. Christopher Shanahan, M.S. Robert de Lorimier, Ph.D. Care Cost Savings Resulting from the Targeted Use of Dietary Supplements: An Economic Case for Promoting Increased Intake of Key Dietary Supplements as a Means to Combat Unsustainable Health Care Cost Growth in the United States. Frost and Sullivan Report available at Frost.com.
30. Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J Am Soc Nephrol 2004;15(12):3225-3232.
31. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007;297(8): 842-857.
32. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst 2008;100(11):773-783.
33. Omenn GS. Chemoprevention of lung cancers: lessons from CARET, the beta-carotene and retinol efficacy trial, and prospects for the future. Eur J Cancer Prev 2007;16(3):184-191.
34. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330(15):1029-1035.
35. Hooper PL, Visconti L, Garry PJ, Johnson GE. Zinc lowers high-density lipoprotein-cholesterol levels. JAMA 1980;244(17):1960-1961.
36. Johnson AR, Munoz A, Gottlieb JL, Jarrard DF. High dose zinc increases hospital admissions due to genitourinary complications. J Urol 2007;177(2):639-643
37. Bender NK, Kraynak MA, Chiquette E, Linn WD, Clark GM, Bussey HI. Effects of marine fish oils on the anticoagulation status of patients receiving chronic warfarin therapy. J Thromb Thrombolysis 1998;5(3):257-261.
Dr. Pilyugina is a Director of the Retina Division at the Assil Eye Institute, a multispecialty group practice in Los Angeles, and a member of the Retinal Consultants of Southern California Medical Group. She is the Chief Editor of New Retinal Physician.