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Current Concepts in Agerelated Macular Degeneration and Nutrition University of Milan at Bicocca June 2007 Anthony Cavallerano, OD, FAAO VA Boston Health Care System New England College of Optometry Boston, Massachusetts [email protected] Course Outline Epidemiology Risk factors Biology of AMD Evidence based studies Diet/nutritional components to AMD Clinical application/recommendations Age-related Macular Degeneration 1874 - described in medical literature “symmetrical central choroido-retinal disease occuring in senile persons” Alternaltely referred to as “senile,” “diskiform,” or “macular degeneration.” 1980 – “age-related maculopathy” End stage = “age-related macular degeneration” Vision Impairment and Eye Disease A major public health problem Growing ever larger with the aging of the US population Disproportionately incident in underserved and minority populations A significant co-morbid condition Epidemic of diabetes Cardiovascular disease Treatments target the end stage of disease Accounts for $68 billion in direct costs in the US AMD and Functional Vision Reduced Central VA Central metamorphopsia Decreased contrast Decreased color 20/40 20/80 20/200 or worse Driving privileges Reading newspaper print Difficulty reading large print Legal blindness Face recognition is difficult Ability to live independently is threatened Age-related Macular Degeneration Leading cause of irreversible blindness in older individuals in developed countries. In the US and other developed countries around the world it is reaching “epidemic” levels Patients with mild or moderate forms of the disease can develop metamorphopsia and visual impairment, whereas those with the advanced stages often experience loss of central vision leading to legal blindness. The Aging Phenomenon Age-dependent Diseases causing loss of Independence – Alliance for Aging Alzheimer’s and related demented disorders Eye Disease AMD Diabetic Eye Disease Glaucoma Osteoporosis Epidemiology Prevalence/Incidence Several studies provided information concerning the matter: NHANES FRAMINGHAM EYE STUDY WATERMEN BEAVER DAM ROTTERDAM BLUE MOUNTAIN RURAL ITALY Prevalence: In the US, 15 million people are affected 13.5 million with dry type 1.5 million with wet type As many as 200,000 new cases of neovascular (wet) AMD are diagnosed in the United States each year accounting for 90 % of severe vision loss. No accepted treatment exists for millions of patients with (dry) AMD. Blindness from AMD – A Growing Problem U.S. 2003 2030 Projected Number of Legally Blind New Cases Annually 1.2 Million 6.3 Million 200,000 500,000 As the population ages and lives longer, the number of people suffering severe vision loss will increase dramatically Pharmacological Treatments for AMD, L. Singerrman, M.D. Review of Ophthalmology, 10/03 Vision Problems in the U.S., Prevent Blindness America, 1994 Risk Factors Genetic Race Gender Age Hypertension/Diabetes Refractive error Lens opacities Sun exposure Smoking Risk Factors Genetic Studies have demonstrated familial aggregation. ABCR gene (linked to Stargardt’s disease) has been linked to some cases of AMD. Complement factor H Gene Proteins in CFH pathway found in drusen deposits Two- to four fold increased risk if gene variant is inherited from one parent Five- to seven fold increased risk from 2 parents Hagerman studied 3200 eyes with dry AMD Genetic component found in 75% of eyes Gene accounts for 30% to 50% of overall risk for developing AMD Protective form of the gene exists Risk Factors Race NHANES III reported a higher frequency in whites compared with blacks. In Baltimore Eye Survey AMD accounted for 30% of blindness among whites and 0% of blindness among blacks. Gender In the Beaver Dam study, only wet AMD was shown to be more frequent in women. Age AMD Is Directly Related To Age 30% 12% 55 to 64 16% 65 to 74 Over 75 Incidence of AMD Increases With Age 1 Beaver Dam Study Source: Yanoff: Ophthalmology, First Edition, 1999; Clinical Practice Guidelines, www.aoanet.org; www.allaboutvision.com Risk Factors Hypertension Role remains unclear Beaver Dam reported that systolic BP was associated with incidence of RPE depigmentation. Macular Photocoagulation Study reported an increased incidence of wet AMD associated with hypertension, in the 2nd eye of individuals with the disease in one eye at baseline. Diabetes Beaver Dam showed no relation, however, literature on the matter is otherwise scant. Ocular Risk Factors Refractive error Increased risk with hyperopia Lens opacities Beaver Dam revealed nuclear sclerosis associated with increased risk of early AMD but not late stages of the disease. FES found no relationship. Aphakia In studies of unilateral aphakia, surgical eye had more advanced disease when compared to contralateral eye. Environmental Risk Factors Sun exposure – controversial risk factor Watermen study revealed a weak association between advanced AMD and exposure to visible light. UV light did not seem to be related in the Beaver Dam, Watermen and Blue Mountain studies. Environmental Risk Factors Smoking Strong positive association between smoking and the dry and wet form. In the Nurses’ Health Study risk increased as pack years of smoking increased indicating a dose dependent relationship. AMD IS A MULTIFACTORIAL DISEASE Genetic Factors – Chr. 1*, 2, 5, 9 & 22 Cardiovascular Factors Environmental – Smoking, nutrition and sunlight exposure Hx *50 percent of AMD can be explained by variations in a gene called Complement Factor H (CFH). This gene makes a protein that regulates the immune and inflammatory responses of the body. What About Diet and Nutrition? USA Dietary Patterns (1890-2006) High simple carbohydrate consumption Soda -3.5 cans/day (only 25 % diet) - started in 1890 White Flour Baked goods - started in 1890 Potatoes - French Fries as #1 “vegetable” Low Fruit & Vegetable (micronutrient/fiber) consumption 20:1 imbalance W6:W3 fatty acids 5-10 % calories from trans fats Grain-fed & fattened cows, pigs, chickens -and stable, (perhaps slightly lower %) saturated fat consumption Progressive increase in calories to 3700/capita in 1990s (fast food and meal super-sizing) Obesity Trends* Among U.S. Adults 1990 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data www.cdc.gov <10% 10%–14% 15%–19% 20%–24% ≥25% Obesity Trends* Among U.S. Adults 2004 (*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person) No Data www.cdc.gov <10% 10%–14% 15%–19% 20%–24% ≥25% AMD - Classification Nonexudative (geographic, non-neovascular, “dry”) involves outer retinal complex Choriocapillaris RPE Photoreceptors Exudative (neovascular, “wet”) Choroidal NV Serous or hemorrhagic neurosensory or RPE detachment Both types can lead to visual loss Classification & Definition 2 clinical forms: Dry Both Exudative types can lead to visual loss. Currently less than 1% is successfully treated Dry AMD: Natural Course Drusen ↓ RPE cell change (apoptosis) ↓ 2ary atrophy of the choriocapillaris ↓ 2ary atrophy of the outer retina ↓ Geographic atrophy Choroidal Neovascular Membrane Clinical features hemorrhage lipid exudation serous elevation of RPE and sensory retina subretinal hemorrhage gray or green (dirty brown) lesion (appearance as seen through the RPE) Wet AMD Subretinal Fibrosis Clinical Features of Exudative AMD Classic CNVM (30% of CNVM) -Pattern is mainly differentiated by FA findings -Early phase reveals staining of a well demarcated lesion. -Late phase reveals leak, at times beyond the lesion borders. Clinical Features of Exudative AMD Occult CNVM (70% of CNVM) - 2 patterns recognized: -Fibrovascular PED -Late leakage of undetermined source Clinical Features of Exudative AMD RPE elevation VEGF A naturally occurring protein Stimulates angiogenesis Proinflammatory Macugen is the only FDA approved at this point to treat AMD Others being studied Current route of administration is injection IV administration likely to be next VEGF in the Normal Eye VEGF and VEGF receptors expressed in normal eye Receptors present in neural elements of inner retina High VEGF expression in retinal pigment endothelium Researchers hypothesize VEGF may be important for choriocapillaris survival and/or fenestrae maintenance Role of normal VEGF expression in the eye is unknown Kim et al. IOVS. 1999; Witmer et al. Prog Ret & Eye Res. 2002; Adamis & Shima. In press. VEGF in the Diseased Eye VEGF is implicated in: Choroidal neovascularization (CNV)/ AMD Diabetic retinopathy Retinal vein occlusion Retinopathy of prematurity Corneal neovascularization Iris neovascularization Age Related Macular Degeneration: A Pervasive Problem…An Elusive Solution Oxidative damage to the retina may be a causative factor. Until recently a lack of convincing clinical trial data had obscured a possible association between antioxidant/zinc supplementation and reduced AMD risk. The need for a large, randomized, placebocontrolled clinical trial was clear. NEI AREDS Study began Age-Related Eye Disease Study (AREDS) AMD Study Objective To evaluate the effect of high-dose vitamins C and E, beta-carotene and zinc formulations on age-related macular degeneration (AMD) progression and visual acuity. AREDS AMD Study Protocol Double-masked trial Enrollment started November 1992 Enrolled 3,640 study participants Subjects were 55-80 years of age Subject were followed every 6 months until April 2001 Average follow-up was 6.3 years 57 % of subjects already taking multivitamins; 67 % chose to add Centrum® Population Classifications Utilized in Study Category 1: Category 2: Category 3: Category 4: No AMD: Essentially free of AMD, with less than 5 small drusen (<63 u) and 20/32 vision or better in both eyes Mild AMD: Mild or borderline AMD (multiple small drusen, single or nonextensive intermediate drusen (63 or 124 u pigment abnormalities, or any combination of these) in one or both eyes, with 20/32 vision or better in both eyes Moderate AMD: Absence of advanced AMD in both eyes and at least one eye with 20/32 vision or better with at least one large drusen (125 u), extensive intermediate drusen, geographic atrophy not involving the center of the macula, or any combination of these Advanced AMD: Visual acuity of 20/32 or better and no advanced AMD (geographic atrophy involving the center of the macula or features of choroidal neovascularization) in the study eye; fellow eye had either lesions of advanced AMD or <20/32 vision and AMD abnormalities sufficient to explain reduced visual acuity. No AMD - Very Low Risk Category 1 - No or Few Drusen Early AMD - Low Risk 2 % rate of progression to advanced AMD at 5 years Category 2 - multiple small drusen, single or nonextensive intermediate drusen (63 or 124 u) pigment abnormalities. Intermediate AMD Category 3 – large drusen Advanced AMD Neovascular Geographic Atrophy AREDS: US Public Health Impact Estimate the 5 year risk reduction with an intervention with an (OR of 0.75) or 25 % risk reduction. 8 million at risk for advanced AMD 1.3 million would develop advanced AMD in the next 5 years 328,788 patients would avoid advanced AMD (2/3 Neovascular and 1/3 geographic) with antioxidants. ARVO 2002 #2903 Bressler et al. Primary Vision Outcome Estimated Probability 3 or More Line VA Loss—AMD Categories 3 and 4 40% Placebo Antioxidants Zinc Antioxidants + Zinc 30% 29% 20% 23% 10% 0% A 19% Risk Reduction 0 1 2 3 4 Years 5 6 7 Data on file, AREDS. Progression to Advanced AMD Estimated Probability AMD Categories 3 and 4 by Treatment Group 40% Placebo Antioxidants Zinc 28% Antioxidants + Zinc 30% 20% 20% 10% P vs. A+Z – p<0.01 0% A 25% Risk Reduction 0 1 2 3 4 Years 5 6 7 Data on file, AREDS. AREDS - AMD TRIAL NEI Conclusions and Recommendations If they have extensive intermediate-sized drusen, at least one large drusen, non-central GA in one or both eyes, advanced AMD in one eye, or vision loss due to AMD in one eye, and they are without contraindications (smoking) they should consider taking a supplement of antioxidants plus zinc such as that used in the AREDS study AREDS 10/12/01 press release “The supplements are not a cure for AMD, nor will they restore vision already lost from the disease”……….. AREDS Recommendations Supplement Intermediate AMD Advanced AMD Excellent Safety Avoid beta carotene in smokers Encourage adherence Data on file, AREDS. Intermediate Advanced Treatment Options for Dry AMD Dry Macular Degeneration AREDS: Approx 25% decrease in risk of developing wet when one eye already wet Would mean approx. 300,000 less people per year developing wet Formulation: Vitamin C 500mg, Vit. E 400IU, Beta Carotene 15mg Zinc 80mg, Copper 2mg Note: Smokers unable to take formulation increase risk of lung cancer with high dose beta-carotene Chance of Progressing to Advanced AMD 15 - 18% 0.3 Probability of Advanced AMD Advanced AMD 0.2 0.1 0 1 2 3 4 5 Years 15% - 18% of intermediate AMD patients will progress to advanced AMD within 5 years Source: Arch Ophthalmology, October, 2001 Current Atrophic AMD intervention Decrease smoking Avoid obesity Exercise Avoid exposure to bright sunlight (blueblockers-yellow tint) Increase plant food (spinach) consumption Follow www. MyPyramid.Gov & SuperFoods Rx book by Steve Pratt, MD ……… Avoid or control hypertension. Avoid high Fe(II) intake; give blood 3x/year (Lutein based multivitamin/multimineral) Omega 3 fatty acids A glass of red wine and blueberries/cherries Soy (genistein), oranges, bananas & vitamin D against neovascularization (wet AMD) 14 Super Foods Blueberries Sardine Citrus Pumpkin Yogurt Oats Legumes Spinach Turkey Breast Broccoli Walnuts Tomato Green Tea Soy Daily sunlight and/or 1000 IU vitamin D daily also is very important for general health Additional Emerging Epidemiological Associations Cardiovascular Disease Plant Food Consumption Obesity and Physical Inactivity C-reactive Protein Fish & nut intake (vs. trans fat) Aspirin ? Cholesterol yes & statins ? Alcohol Iron status Lycopene Carotenoid found in tomatoes Ten times more potent than Vitamin E Inherent putative anti-inflammatory effects Thought to be protective for: AMD Prostate disease Cancers Cardiovascular disease National Eye Institute AREDS II Study The primary objective of AREDS II is to determine whether oral supplementation of lutein or omega-3, alone, together or in combination decrease the risk of progression to advanced AMD as compared to placebo 4,000 patients 40-60 sites 5 year study duration Start date: April 2006 AREDS II Effect on progression to Advanced AMD with lutein (10 mg and 2 mg of zeaxanthin) AND Omega-3 (1 gm daily) Refine formulation of original AREDS formula including Remove beta-carotene due to risk to smokers Reduce zinc from 80mg to 40mg daily Concern re: ? Risk for Alzheimer’s disease AREDS II Randomized, clinical, trial Lutein/Zeaxanthin Lutein/Zeaxanthin Omega-3 Fatty Acids Begin 2006 DHA/EPA AREDS II Local Sites Beth Israel Deaconess Medical Center Boston, MA Jorge Arroyo, MD, MPH 617-667-3391 Massachusetts Eye and Ear Infirmary Boston, MA Johanna Seddon, MD 617-573-4010 New England Medical Center Boston, MA Elias Reichel, MD 617-636-5489 Ophthalmic Consultants of Boston Boston, MA Jeffrey Heier, MD 617-314-2608 Zeaxanthin and Lutein May Help to Reduce Oxidative Stress Lutein (and Zeaxanthin) Anti-oxidant carotenoids in the vitamin A family, also known as xanthophylls Lutein can be converted to zeaxanthin in the body Most dominant pigments in the macular region of the retina Retinoprotective Lutein reduces blue light damage to photoreceptors by filtering blue light Protects against perioxidation of fatty acids in the photoreceptor membrane Protects the blood vessels supplying the macular region Protective for cataract LUTEIN BIOLOGICAL ACTIONS Only carotenoid found in ocular tissue Accumulates in both lens and macula Primary component of the yellow macular pigment Protects the macula by Filtering out blue light Acting as an antioxidant Providing structural integrity to photoreceptors The eye selectively concentrates Lutein (yellow colored pigment) in the macula region Macula Pigment Optical Density is the amount of Zeaxanthin & Lutein in the macula The eye conserves these carotenoids KEY LUTEIN (macula pigment) Lutein is the key carotenoid in the diet. 6 mg. intake per day led to a 43% reduction in severe AMD prevalence (1994 JAMA study). Diet plays a role in lutein deposited in the macula. Lutein protects by blocking blue light and functioning as an antioxidant. AMD patients have less macula lutein in vivo or on autopsy. MPOD is 20% lower in females. MPOD is lower in individuals with light-colored irises. MPOD is lower in smokers. AREDS compatible Lutein based Antioxidant Supplements If you meet high risk AREDS criteria B & L PreserVision® w lutein gel caps– 1 cap twice per day (or equivalent components & dose used in the National Eye Institute AREDS study) General mail order comprehensive multivitamin with lutein www.PurityProducts.com “Perfect MultiFormula” 1-800-281-7781 www. MedOp.com “Whole Body Formula” 1-800-358-7797 www. Lef.org “Two per day” –superior to Centrum® 1-800-544-4440 Fish (sardines, herring, salmon, chunk tuna) or cod liver oil Healthy Life Style Diet Exercise Smoking Alcohol consumption French paradox Blood pressure/lipid profile Conclusion Many new treatments Most likely will see combinations of different treatments along with more aggressive prevention Bottom line: AMD is still debilitating, and we must be quick to diagnose, treat, and offer low vision when needed QUESTIONS THANK YOU