Role of Nutraceuticals in Managing Ophthalmic Patients
Timothy L. Schneider, M.D.
The practice of advising patients to use nutritional supplementation in eye care has met with some scrutiny within the medical community. Ample research demonstrates the positive benefits of nutritional supplements, particularly Omega-3 fatty acids, as an adjunct to standard pharmacotherapy in the care and treatment of our patients, particularly those with age-related macular degeneration (AMD) and dry eye syndrome (DES).
Dietary Omega-3 fatty acids can reduce age-related macular degeneration (AMD) according to a study published in the American Journal of Clinical Nutrition (August 8, 2008). A team of European researchers coordinated by the London School of Hygiene and Tropical Medicine, studied patients with AMD and evaluated dietary intake of fish and Omega-3 fatty acids compared with a control group. Participants’ intake of the main Omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), was obtained by linking collected dietary data with food composition tables. Findings in this study revealed that individuals who habitually consume oily fish (or who consume 300mg of DHA and EPA daily), were 70% less likely to have wet AMD. A strong inverse association between levels of DHA and EPA was demonstrated. There was no protective effect found from consumption of non-oily white fish. (1)
In a study published in the Archives of Ophthalmology (2001), it was concluded that, “higher intake of vegetable, monounsaturated, polyunsaturated fats and linoleic acid (Omega-6 fatty acids)—rather than total fat intake, may be associated with a greater risk for advanced AMD”. Conversely, diets high in Omega-3 fatty acids and fish were inversely associated with risk for AMD when intake of linoleic acid, was low. (2) The U.S Twin Study of Age-Related Macular Degeneration found that while fish consumption and Omega-3 fatty acid intake reduce the risk of AMD, cigarette smoking increases the risk. (3)
“A Systematic Review and Meta-Analysis of Dietary Omega-3 Fatty Acid and Fish Intake in the Primary Prevention of Age-Related Macular Degeneration”, (Archives of Ophthalmology, June, 2008), reviewed nine studies involving 88,974 subjects. It was found that high dietary intake of Omega-3 fatty acids was associated with an overall 38% reduction in the risk of late AMD. Further, consuming Omega-3’s at least twice weekly was associated with reduced risk of both early and late AMD. (4)
The Age-Related Eye Disease Study,(AREDS Report #20) found that higher intake of total long chain Omega-3’s and fish were positively linked to decreased likelihood of having neovascular AMD. Arachidonic Acid (AA) was the only dietary lipid directly associated with neovascular AMD prevalence. Participants getting the most dietary AA through meat, dairy and Omega-6 fatty acids were 56% more likely to have late AMD. (5) AREDS Report No. 23 recently suggested that Omega-3 fatty acid intake was associated with a decreased risk of the progression from bilateral drusen to central geographic atrophy. (6)
Additional studies suggest that other nutritional factors may play a role in slowing the onset, or limiting the effects of AMD, including AREDS Report #22. This study revealed that high dietary intake of lutein and zeaxanthin were independently associated with a reduced likelihood of having neovascular AMD. Subjects consuming the highest amount of lutein and zeaxanthin were 35% less likely to have neovascular AMD and 55% less likely to have geographic atrophy. (7)
In 2004, the Lutein Antioxidant Supplementation Trial (LAST Study) found that visual function improved with lutein alone or together with antioxidants, vitamins and minerals in male patients with atrophic AMD. (8) In another such study, the Carotenoids and Antioxidants in Age-Related Maculopathy Italian Study (CARMIS Study), the influence of short-term carotenoid and antioxidant supplementation on retinal function in non-advanced AMD was studied. Using multi-focal electroretinograms in response to 61 M-stimuli to the central 20 degrees of the visual field, pre-treatment (baseline) conditions were assessed after six and twelve months of supplementation. In non-advanced AMD eyes, a selective dysfunction in the central retina (0-5 degrees) can be improved by supplementation with carotenois and antioxidants. (9)
The Taurine, Omega-3 Fatty Acids, Zinc, Antioxidant, Lutein Study (TOZAL Study) investigated the impact of the listed nutritional supplements on visual function in patients with atrophic AMD. Seventy–six percent of the subjects receiving the nutritional supplement demonstrated stabilization or improvement of BCVA at 6 months. Subjects gained an average of 0.0541 logMAR or one-half line of visual acuity over the 6-month period, with statistically significant improvement in VA from baseline (p=0.045). (10) Although the study period was relatively short, these results align with both the LAST and CARMIS studies, and may predict a positive outcome for the AREDS 2 Trial. AREDS 2 Trial is currently underway to evaluate in a case-controlled manner, the effects of Omega-3 fatty acids, lutein, and zeaxanthin.
Dry Eye Syndrome
AMD is not the only ophthalmic disease that may benefit from nutritional supplements. The Women’s Health Study found a 68% reduction of dry eye syndrome (DES) in women who consumed five to six servings of tuna per week, one of the largest contributors of Omega-3’s in American diets. A high ratio of Omega-6/Omega-3 (n-6/n-3) greater than 15:1 was associated with a greater than two-fold prevalence of DES, suggesting that the ratio of inflammatory Omega-6 fatty acids (n-6) to anti-inflammatory Omega-3 fatty acids (n-3) is important. It appears that the anti-inflammatory effects of Omega-3 fatty acids may play a role in preventing DES. (11)
Cataract development appears to be altered by nutritional supplementation as well. High dietary levels of lutein and zeaxanthin resulted in a 32% lower prevalence of nuclear cataract compared to lower levels of dietary intake in women studied in the CAREDS study (12) These findings were mirrored in another study assessing dietary intake of 39,876 female health professionals looking at dietary carotenoids, and Vitamins C and E. (13)
How Does It Work?
The etiology of AMD and dry-eye syndrome (DES) appears to be multi-factorial, but inflammation likely plays a major role. Prevention and treatment appear to involve the inflammatory cascade. One of the most potent inhibitors of inflammation is Omega-3 fatty acids. Essential fatty acids are natural modulators of inflammatory activity via their metabolism to eicosanoids, locally acting hormone-like lipids involved in the control of inflammatory and immune responses. Eicosanoids are derived from three fatty-acid precursors: dihomogammalinoleic acid (20:3, n-6 DGLA), arachidonic acid (20:4, n-6 AA), and eicosapentaenoic acid (n-3 EPA). The modulation of inflammatory activity is based on the balance of these precursors. Omega-3 fatty acids suppress the biosynthesis of arachidonic acid (AA)-derived eicosanoids. Dietary intake determines the balance of Omega-3 fatty acids to Omega-6 fatty acids in cellular membranes (14) High intake of Omega-3 fatty acids results in displacement of the usually more abundant AA, with EPA and DHA. Eicosanoids derived from AA, (prostaglandins E2 and leukotriene B4) are vigorously pro-inflammatory. (11) Arachidonic acid was the only dietary lipid directly associated with neovascular AMD prevalence. (5) Prostaglandins derived from 3-series and 5-series leukotrienes from EPA are 10 to 100-fold less biologically active. (15). Omega-3 fatty acids also suppress COX-2 and have greater affinity resulting in higher formations of EPA-derived, as compared to AA-derived eicosanoids. When the ratio of n-6/n-3 is 4:1 or lower, there is a competitive inhibition of the conversion of DGLA to AA; resulting in enhanced metabolism of DGLA to the 1-series prostaglandins including PGE1 which has a number of anti-inflammatory actions. This is also thought to be one of the etiologies of DES (dry eye syndrome). (16) Similarly, it is also thought that Omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) may exhibit cytoprotective and cytotherapeutic actions contributing to a number of anti-angiogenic and neuroprotective mechanisms within the retina. (17)
Lutein and Zeaxanthin were found to reduce the likelihood of neovascular AMD, geographic atrophy, and large or extensive drusen in the AREDS Report # 22. Their potent antioxidant properties are concentrated in the ocular tissues of the retina and protect the retina from oxidative stress by absorbing blue light which can cause photochemical damage. It appears that nNOS and COX-2 expression are inhibited by lutein. (18)
What Does This Mean for the Medical Community?
Nutritional supplements have been the subject of much controversy in the established medical community. An estimated 38 million adults in the United States used dietary supplements or herbal products in 2002. (19) Dietary supplements are big business in the US. Consumer sales in 2006 were estimated at $22.5 billion, with some 60% of Americans taking at least a daily vitamin. (14) Only one-third of these patients told their healthcare providers about their use of vitamins. Many people use vitamins or other nutritional supplements in order to feel better, perform better or look better. This is the foundation of the Wellness Industry. For many years the AMA deemed the use of vitamins unnecessary, assuming that most Americans received adequate nutrition in their daily food intake. However, in 2002 the AMA reversed its stance, claiming that scientific understanding of vitamins had advanced, and that clearly, nutritional supplements may play a key role in preventing many common illnesses, including cancer, depression, heart disease, osteoporosis, dementia and macular degeneration.
Despite growing acceptance of the use of nutritional supplementation, some members of the medical community still consider these supplements to be simply a modern form of “snake oil”. Ironically, the Chinese have used snake oil for centuries to treat a multitude of ailments, primarily arthritis. Snake oil was brought to this country in the 1800’s by Chinese laborers who came to build the transcontinental railroad. Richard Kunin, M.D., in his 1989 analysis published in the Western Journal of Medicine, found the Chinese Water Snake oil to contain 20% eicosapentaenoic acid (EPA), one of the two of Omega-3 fatty acids used by our bodies. The Chinese water snake was found to have the highest concentration of Omega-3 fatty acids of any natural source. (20,26) Thus it appears that the Chinese knew more about health and wellness than was originally believed, and snake oil actually did treat disease, as research is confirming.
It is estimated that 15% of white women 80 years of age and older, will develop neovascular AMD or geographic atrophy. The number of persons stricken with AMD will increase by nearly 2.95 million by 2020. In 2004, it was estimated that 7.3 million people had early stages of AMD. (21)
Estimated cost of a single Lucentis® (ranibizumab) injection for the treatment of neovascular AMD is in the neighborhood of $1,950.00. Trials showed twelve injections per year to be most effective in improving vision, which totals $23,500.00 per eye per year.(22) AMD has a profound impact not only on one’s economic position, but also on quality of life. One-third of all patients with AMD were found to have clinical depression secondary to severe reduction in quality of life. (23) If only a small percentage of the ophthalmic community embraces the findings of the AREDS, CARMIS, TOZAL and LAST studies, and present nutritional supplementation as an adjunct to patient care, hundreds of thousands of patients’ lives may be positively affected. When measuring the risks of taking a product such as TOZAL™ , (AmeriSciences®, Houston, TX) versus developing neovascular AMD, the risk/benefit ratio strongly favors use of such nutritional supplementation. Patients will find a way to use these products, and we as physicians need to direct them to only the highest quality pharmaceutical-grade products with high bioavailability and highest likelihood of success. It is not enough that we recommend our patients eat fish with their AREDS-formula vitamin. Research from the American Journal of Clinical Nutrition (Aug. 2008), showed that 26 servings of cod were required to equal the EPA and DHA content of twice weekly servings of farm-raised salmon. (500mg EPA + DHA/d)
Should We Wait Until 2012 For the Results of the AREDS 2 Study?
Omega-3’s have been suggested to decrease the risk for AMD, dementia, depression, coronary artery disease, arthritis, hyperlipidemia, and even cancer. Unpublished data from the Framingham Heart Study suggest that > 180 mg/d of dietary DHA is associated with a 50% reduction in dementia risk.(24) Greg M. Cole, a researcher at the University of California, Los Angeles, who sees great promise in using Omega-3 fatty acids to prevent Alzheimer’s disease and other forms of age-related dementia, expresses concern that current clinical trials lack funding to target the most promising patient population—people who have not yet started to show signs of those problems. “The risk of Alzheimer’s doubles with every five years after age 65,” he says, “and we’ve got a generation of 75 million people heading into that. We can’t afford to miss something that might help with prevention just because we couldn’t find the money to study it.” (15,25)
An ophthalmology practice with three retina-specialists was recently asked about their treatment of patients with AMD and offered three very different views: The first retina specialist stated that until the results of the AREDS 2 clinical trial are known, he could not recommend additional nutritional supplements besides an AREDS-formula vitamin. His partner stated that he simply advises his AMD patients to take a daily multiple vitamin. The third partner stated that he recommends AREDS-formula vitamins with Omega-3 fatty acids. This retina group runs the gamut of practice patterns with regard to nutritional supplementation, from an AREDS ‘denier’ to Omega-3 ‘embracer’.
With so much new evidence suggesting that nutritional supplements may play a major role in the prevention and treatment of several ophthalmic diseases, we as physicians must ask ourselves, “What is our role in this industry? Ophthalmology must become active in the wellness of our patients. The data supporting Omega-3’s for its myriad potential benefit on the eyes, heart, lipid levels, and brain is reason enough to recommend them to our patients. As U.S. healthcare continues to struggle with regard to health-care-delivery systems and reimbursement, the biggest missing piece is that M.D.’s are not playing an active role in wellness and the prevention of disease. Physicians must facilitate patient education and provide them with wise choices regarding products which are safe and highly bio-available. Many physicians have a ‘comfort threshold’ which needs to be reached before prescribing a new medication, therapy or supplement to our patients. That threshold is reached through familiarizing ourselves with current research, discussion with colleagues and personal experience. Risk of treatment must be weighed versus the possible benefit to our patients. Nutritional supplements pose very little risk. Of course, communication with our patients about taking any new medication or supplement is critical to its proper use and adherence. The possible benefit in terms of maintaining independence, preserving vision, health care and personal cost savings, and lightening the burden on family care-givers are positive beyond measure. There will always be skeptics who are wary as to whether it is the physician’s place to suggest or recommend nutritional supplements. As more and more research support nutritional supplementation, NOT recommending them may pose the biggest risk. Omission of this treatment option may not play well into the premise of the Hippocratic oath: “Do No Harm”.
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