Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness registration in the developed world (figure 1).1 A rapidly ageing population has raised the priority of reducing the risk for age-related eye diseases that impair sight and quality of life. As there are currently 9.7 million people aged 65 and older in the UK and by 2020 one in five UK citizens will be aged 65 or older,2 it is imperative that more AMD research is conducted and additional help is given to those with the condition.
Figure 1: Atrophic ‘dry’ age-related macular degeneration
Theoretical causes
AMD is a multifactorial degenerative condition. The reasons for the photoreceptor damage and loss is still a matter for debate and on-going research. The current hypotheses involve Bruch’s membrane changes, vascular insufficiency, genetics and oxidative stress.
The eye is particularly susceptible to oxidative damage. Photoreceptors are exposed to an extensive amount of oxidative stress;3 the retina has antioxidant processes to delay or prevent oxidation (the removal of electrons),4 but they also generate activated forms of oxygen known as free radicals (any atom or molecule that has one or more unpaired electron). Free radicals try to become stable by taking electrons from other molecules, thereby damaging them and causing a cytotoxic oxidative chain. Studies have shown that mean plasma levels of oxidative biomarkers appear to be higher in AMD patients than in case-control matches.5
Figure 2: Rich sources of omega-3 fatty acids
Nutrition and AMD
Nutrients that have been investigated with respect to AMD include:
- Zinc: this metallic element is very concentrated in human tissue, especially in the retina and RPE. It is important as it acts as a cofactor for retinal dehydrogenase and catalase, both of which are antioxidant enzymes. A low concentration of zinc can compromise macrophages and through increased apoptosis, T and B lymphocytes also become reduced. Zinc deficiency can result in an increased vitamin A uptake,6 causing toxicity, and lipid peroxidation and damage to lipid membranes. In the human body, zinc stimulates the protein metallothionein in the intestinal wall, causing it to bind to dietary copper and preventing copper absorption. For this reason, zinc is often supplemented alongside copper.
- Omega-3 fatty acids: docosahexaenoic acid (DHA,C22:6), the major dietary and structural omega-3 long-chain polyunsaturated fatty acid (LCPUFA) of the retina may modulate metabolic processes and stop the effects of environmental exposure that activate molecules implicated in the pathogenesis of retinal diseases. These processes and exposures include chronic light exposure, oxidative stress, ischaemia, inflammation, cellular signalling mechanisms, and ageing. Eicosapentaenoic acid (EPA, C20:5), the precursor to DHA and the other major dietary omega-3 LCPUFA, can exert similar actions to DHA.7 Rich sources of omega-3 fatty acids include flaxseeds, walnuts, sardines, and salmon (figure 2)
- Vitamin C: A water-soluble antioxidant that can protect against free radical-mediated oxidative tissue damage
- Vitamin E: A group of eight fat-soluble compounds that have many biological functions – the most important being a distinctive antioxidant ability to stop the production of ROS when fat undergoes oxidation. Sources of vitamin E include almonds, and safflower and corn oils. Tocopherol is one of the compounds in the vitamin E group; the four common forms of tocopherol include α, β, ϒ, and δ. In the human retina, the alpha form is the most predominant in high concentrations.8 A relationship has been found between high plasma vitamin E levels and a reduced risk of AMD.5
- Carotenoids: these are organic pigments found in plants, algae, fungi and some bacteria. They cannot be synthesised by humans or animals, and so have to be consumed in the diet. The two types of carotenoids are xanthophylls (oxygen containing) and carotenes (hydrocarbons only). In humans, four carotenoids (beta-carotene, alpha-carotene, gamma-carotene, and beta-cryptoxanthin) have vitamin A activity (meaning they can be converted to retinal); these and other carotenoids can also act as effective antioxidants. Beta-carotene in particular is able to reduce single oxygen radicals.9 Certain other xanthophylls (lutein, mesozeaxanthin and zeaxanthin – figure 3) form the macular pigment, responsible for its characteristic yellow appearance (see figure 4). The largest concentration of lutein and zeaxanthin lie at the fovea, and reduce with eccentricity.10 The measurement of macular pigment (MP) has sometimes shown those with low MP density (MPOD) are at risk of AMD compared with age-matched controls. However, measuring MPOD is difficult in practice, and results may not be reliable.11
Figure 3: Chemical structures of the three macular carotenoids: Lutein, RR-zeaxanthin (‘zeaxanthin’), and meso-zeaxanthin. From Nolan et al.28
Figure 4: Xanthophylls are responsible for the yellowed appearance of the macula
As well as being antioxidants, the xanthophylls act directly to absorb damaging blue and near-ultraviolet light around the 400-450nm end of the spectrum, protecting the outer retina, RPE and choriocapillaris from oxidative damage.12 Studies have shown that in xanthophyll-free animals, foveal protection has been absent, but became evident after supplementation of the nutrients.13
Oxidation is prevented by firstly transferring energy to the carotenoid which will quench singlet oxygen due to the conjugate double bond within their molecular structure, and secondly by reacting with peroxy radicals that are involved in lipid peroxidation. Xanthophylls are plentiful in dark green leafy vegetables such as spinach and kale, as well as yellow and orange fruits and vegetables such as peppers (figure 5).14
Nutrition studies
The largest clinical breakthrough in positive antioxidant intervention was the Age-Related Eye Disease Study (AREDS), published in 2001.15 The AREDS team investigated a combination of high dose nutrient supplementation on participants with AMD or cataracts over a period of six years. The AREDS formulation of vitamin C 500mg, vitamin E 400IU, b-carotene 15mg, and zinc (zinc oxide 80mg and cupric oxide 2mg) showed a 25% risk reduction in progression to advanced AMD over five years in patients with intermediate AMD (extensive intermediate drusen in one or both eyes, one or more large drusen in at least one eye, or non-subfoveal geographic atrophy in one eye) or advanced AMD (subfoveal geographic atrophy or choroidal neovascular membrane) in one eye. The risk of losing vision of three or more lines was also reduced by 19% with this combination treatment. The AREDS formulation showed no effect in preventing the development of large drusen in participants who had small drusen at baseline. It is not known whether it was one or all of the nutrients working in tandem that gave these positive results. Because of the high dosage of zinc, and the inclusion of beta-carotene (linked with lung cancer in smokers), some eye professionals became concerned with the safety of the formulation and were reluctant to advise patients to use it.
The AREDS team recently released the results for AREDS 2, which incorporated the carotenoids lutein and zeaxanthin to the original AREDS supplement formulation, plus omega 3 fatty acids.16 The study found that adding lutein and zeaxanthin to the original formula did not further reduce the risk of progression to advanced AMD. However, a subset of participants who took the AREDS formulation with beta-carotene substituted out for lutein and zeaxanthin, had their risk of progression to advanced AMD reduced by 18% compared to those participants who took the AREDS formulation that contained beta-carotene but no lutein and zeaxanthin. In addition, participants who had ≤0.823mg per day dietary intake of lutein and zeaxanthin at the start of the study, but who took the AREDS 2 formulation, were 25% less likely to develop advanced AMD compared with participants with similar dietary intake who did not take the supplementation.17
Researchers have suggested that beta-carotene may have screened the effects of lutein and zeaxanthin in the overall analysis because it competes for absorption in the body – participants who took beta-carotene along with lutein and zeaxanthin had lower serum levels compared with those who only took lutein and zeaxanthin. Investigators concluded that lutein and zeaxanthin can be useful substitutes for beta-carotene in the original formulation. The results of the AREDS 1 and 2 trials provide evidence to support specific nutritional supplementation for certain AMD patients. There is little evidence to support the wealth of other nutritional supplements that are available and marketed towards AMD patients. At Aston we have been working on projects looking at the awareness of nutrition and supplementation among AMD patients, and what we can do to ensure patients have access to accurate information.
Nutritional education for AMD patients
In our survey of Macular Society members, we showed they all felt they needed more nutrition-related advice, particularly relating to nutrition.18 Although some of the participants needed to rely on others for support and felt they had considerable visual impairment, the desire to remain independent and improve their vision is evidenced through seeking the services of the Macular Society, and using other healthcare professionals such as dieticians and specialist doctors.
The majority of participants of the survey agreed that specific foods can affect general health, and participants also agreed that specific foods affect eye health. The results of the specific food questions show the majority of participants felt the vegetables and fruit were beneficial for eye health, and these perceptions were generally accurate. However, apart from a few individuals who mentioned specific nutrients in regard to specific foods (eg lutein in kale), most participants were not able to identify why these foods helped promote eye health, or gave vague responses such as ‘I read it somewhere’. This suggests that participants, who would be expected to be well-informed, were not clear about the links between diet and eye health.
The majority of participants in this study reported they did not have enough information on nutrition and its relationship to AMD. As expected, all participants reported they had received information from organisations such as the Macular Society. In contrast, not all the participants reported getting information from their ophthalmologist, which is consistent with previous studies.1,19 The data reported here shows there are clear gaps in the knowledge patients have of AMD risk factors.20 A lack of information might also explain why four percent of the participants were not sure what type of AMD they were suffering from. Patients appear to be actively seeking advice but not all are getting it from sources such as ophthalmologists or optometrists. These findings are similar to results from the Royal College of Ophthalmologists audit of AMD services in March 200921 which found that there was an insufficiency of resources to deliver adequate AMD services.
With regard to eye professionals, data shows although more than 60% of respondents reported they frequently provide dietary and supplement advice to patients with established AMD and those at risk of AMD, the nutritional advice given only consisted of leafy green vegetables and oily fish recommendations without the specificity of amounts or type of vegetables to eat, and type of supplement recommended did not comply with current best research evidence, based on the findings of the Age-Related Eye Disease Study (AREDS).22 The results reported in the present study reinforce those of the survey and the Royal College of Ophthalmologists, and provide further evidence that greater support and information provision for AMD patients is needed.
More than 75% of participants reported taking a nutritional supplement (mainly on a once-per-day basis) – this is a larger number than other studies into supplement usage have found.23-25 The majority of patients who were taking ocular supplements were not taking an exact AREDS formulation, and were taking an incorrect dosage or combining it with one or two other brands with the same formulation (maybe believing that more might be better). This pattern of supplementation could reflect a lack of information from healthcare professionals, with only a third of patients having discussed nutritional supplementation with their ophthalmologist, while some participants had not discussed supplementation with anyone at all.
Those participants in the study who reported not taking any supplements listed the primary reason as not believing they would be effective, and hence were unwilling to spend much money on an unproven supplement. The high number of nutritional supplements marketed towards people with AMD makes it difficult for both patients and health professionals to navigate this issue for the prevention or treatment of the condition.26 There are currently no clear supplement guidelines for health professionals to use, and since the AREDS 2 results have been released, there is a need for unified guidelines for all health professionals.
In a separate study in focus groups performed recently,27 patients with AMD were asked where or who had provided nutritional advice to them. The majority of focus group participants responded that they had read advice from sources such as the media, but only two participants had advice from eye-care professionals. The same participants were asked where they would like to receive nutritional information from. All participants responded they would like information to come directly from eye care professionals and they felt they could implicitly trust what they were advised to do by them. This was in preference to any other format of advice – leaflet, video, audio recording, or SMS reminders.
Summary
Patients with AMD would appreciate greater clarity from eye care professionals regarding nutritional changes to their diet and supplementation. All eye care professionals need to be providing consistent advice to patients ideally face-to-face. In part two of this series, the evaluation of a clinical decision-making aid will be discussed, which can help eye care professionals provide more specific advice to patients.
Dr Hannah Bartlett is a reader and Dr Rebekah Stevens is a teaching fellow in the Department of Vision Science, Aston University.
References
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