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Nutrition and age-related macular degeneration: this article explores the evidence base around dietary supplementation and ill age-related macular degeneration, including findings from the two Age-Related Eye Disease Studies (AREDS), providing a clinical decision-making aid to assist practitioners in giving supplementation and dietary modification advice.

INTRODUCTION

Age-related macular degeneration (AMD) is a multifactorial degenerative condition affecting the central area of the retina. It is the leading cause of visual impairment and blindness registration in the developed world. (1) A rapidly ageing population has raised the priority for reducing the risk of 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.

THEORETICAL CAUSES

High-resolution vision is possible due to the density of photoreceptors in the foveal area of the macula. The macula is approximately 5mm in diameter and is central in the retina. The fovea (fovea centralis) is a depression in the inner retinal surface within the centre of the macula (approximately 1.5mm in diameter) that is thinner, and contains the highest concentrations of cone photoreceptors. (3) AMD is simply the damage or loss of these photoreceptors in the macular area. Predominantly, much of the damage and/or loss of these photoreceptors occur over the age of 50, thus providing the condition with its name. The exact reason for the photoreceptor damage and loss is still a matter for debate and continuing research. The current hypotheses will be considered in turn.

Oxidative stress

Photoreceptors are exposed to an extensive amount of oxidative stress; an imbalance between the systemic production of reactive oxygen species (ROS) --chemically reactive molecules containing oxygen--and the biological system's ability to swiftly detoxify the reactive intermediates or to restore the resulting destruction. (4) The retina has antioxidant processes to delay or prevent oxidation (the removal of electrons), (5) but also generates 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. (6)

The eye is particularly susceptible to oxidative damage due to:

* The high percentage of polyunsaturated fatty acids such as docosahexaenoic acid (DHA) that are within the outer membrane of photoreceptors. These have a large amount of electrons due to their double bonding and, therefore, can be readily oxidised leading to lipid peroxidation causing loss of function and structural integrity within the membrane (5)

* The exposure to light (particularly blue) which is a strong oxidising agent, causing free radical production and cellular apoptosis (7) The eye's high oxygen consumption and blood flow (higher than the brain on a gram-for-gram basis), thereby making it very active metabolically (8)

* The chromophores it contains --molecules that absorb light in order to cause a chemical reaction --such as rhodopsin, melanin, lipofuscin and the mitochondrial respiratory enzymes

* Retinal pigment epithelial (RPE) phagocytosis which is, in itself, a free radical-producing process

Bruch's membrane changes

Bruch's membrane is a pentalaminar structure composed of several layers of elastic and collagen that separates the RPE from the choriocapillaris--the main blood supply to the outer retina. Nutrients must cross this membrane to enter the RPE and photoreceptors, which is crucial, as photoreceptors do not have their own blood supply. (9,10) Conductivity of Bruch's membrane declines with age, and the lipid content of the membrane increases. (11) This in turn, changes the diffusion characteristics of the membrane which may contribute to the onset of AMD. (12)

Vascular insufficiency

Changes to the choroidal circulation may affect the normal diffusion of substances and gases across the RPE to Bruch's membrane. Removal of waste products slows down, leading to a build-up of waste materials and a disturbance to the supply of gases and metabolites to the neural retina. (13) The RPE can then deteriorate either through ischaemia ('zone hypoxia') or as a direct consequence of the waste material, and the blood flow will decrease.

Genetics

Numerous studies have shown there is a genetic predisposition for AMD, especially in first-degree relatives. (14,15) The Y402H allele of the complement factor H (CFH) gene (chromosome 1g (31)) has been researched as it helps to regulate the body's inflammatory response by protecting against uncontrolled complement activation. The allele's polymorphism appears to exert a strong influence on the risk of developing AMD. (16) There are also many other genes on other chromosomes that have been researched for their ability to modify AMD risk. (17) However, susceptibility is determined by multiple factors that include environmental influences as well as inherited.

NUTRITION AND AMD

Because the oxidative stress theory purports to be the most popular hypothesis for the possible cause of AMD, treatment lies with antioxidant therapy in an attempt to reduce the number of circulating ROS.

Nutrients that are considered beneficial for AMD include:

* Vitamin C--this is a water-soluble antioxidant that can protect against free radical-mediated oxidative tissue damage

* Vitamin E--these are 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. Tocopherol is one of the compounds in the vitamin E group: the four common forms of tocopherol include: alpha, beta, gamma and delta. In the human retina, the alpha form is the most predominant in high concentrations. (18) A relationship has been found between high plasma vitamin E levels and a reduced risk of AMD. (5) Good sources of vitamin E include almonds, safflower oil, and corn oil

* 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 dehydronase 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, (19) 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 omega-3), 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 omega-3), the precursor to DHA and the other major dietary omega-3 LCPUFA, can exert similar actions to DHA. (20) Rich sources of omega-3 fatty acids include flaxseeds, walnuts, sardines, and salmon

* 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. 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 21

* Certain other xanthophylls (lutein, meso-zeaxanthin and zeaxanthin) form the macular pigment, responsible for its characteristic yellow appearance (see Figure 1). The largest concentration of lutein and zeaxanthin lie at the fovea, and reduce with eccentricity. (22) The measurement of macular pigment (MP) has recently become the focus of AMD research--some studies have shown those with low MP density are at risk of AMD compared with age-matched controls (23,24)

* 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. (25) Studies have shown that in xanthophyll-free animals, foveal protection has been absent, but became evident after supplementation of the nutrients. (26) The methods used to prevent oxidation are firstly the energy transfer to the carotenoid which will quench singlet oxygen due to the conjugate double bond within their molecular structure, and secondly the reaction with peroxy radicals that are involved in lipid peroxidation

* Xanthophylls are abundant in dark green leafy vegetables such as spinach and kale, as well as yellow and orange fruits and vegetables such as peppers (27)

NUTRITION STUDIES

The most significant clinical breakthrough in positive antioxidant intervention was the Age-Related Eye Disease Study (AREDS) in 2001. (28) The AREDS team investigated a combination of high dose nutrient supplementation on AMD and cataracts over a period of six years. The AREDS formulation of vitamin C 500mg, vitamin E 400IU, beta-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 nonsubfoveal 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, and the incidence of advanced AMD in this group was very low (<1%). 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 ophthalmologists and other 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 encompassed the carotenoids lutein and zeaxanthin to the original AREDS supplement formulation, plus omega-3 fatty acids. (29) 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 [less than or equal to] 0.823mg per day dietary intake of lutein and zeaxanthin at the start of the study, 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. (30)

Investigators have suggested that beta-carotene may have masked 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. It can, therefore, be concluded that lutein and zeaxanthin may be useful substitutes for beta-carotene in the original formulation. These results can form the standard of care for all patients with or at risk of AMD.

PATIENT SURVEY

Research has shown that the opinions of eye care professional are divided on the topic of nutrition and AMD. (31-33) There are no clear-cut guidelines currently for either patient or practitioner to follow, and the complexity of AREDS 2 has only added to the lack of clarity. A recent survey of AMD patients revealed that they felt they had insufficient information and support from eye care practitioners regarding nutrition, and this has led to confusion over which foods are beneficial for eye health, and when and what nutritional supplements to take. (34) Participants in the survey displayed a lack of understanding about the link between nutrition and eye health, and this was demonstrated in a food diary where participants overwhelmingly ate too few of the important nutrients that would be beneficial for their condition. (35)

In order to help patients receive the same consistent advice from all eye care practitioners, there must be consensus in when and what dietary advice to give, and which nutritional supplements to advise. The only formulations that are supported by large-scale clinical trials are those used in the AREDS and AREDS 2 studies. The inclusion and exclusion criteria for these s tudies can be used to decide when nutritional supplementation is appropriate. Because of the intricacy of the AREDS 2 study, practitioners would benefit from a tool to assist in the clinical decision making process; an aid in the form of a flowchart has been designed by Aston University researchers for this very reason (see Figure 2).

CLINICAL DECISION-MAKING FLOWCHART

The flowchart starts with the results found in ophthalmoscopy. If a patient has a 'normal' macular appearance, but has a family history of AMD, a branch of decisions will determine whether they would benefit from dietary modification. If the patient has an abnormal macula, the branches on the flowchart determine whether the patient fits into the AREDS 2 inclusion criteria for nutritional supplementation, or whether they would benefit from dietary modification only. If the findings are not related to AMD, referral for an ophthalmological opinion is advised. The final outcomes are split into either dietary modification or supplementation advice. Advice 1 refers to dietary modification--the patient can incorporate 150g (one cup or one large handful) of cooked spinach or kale, or two cooked eggs into their diet each day. These can be eaten either alone or as part of a recipe.

Advice 2 refers to supplementation--the supplement type can be narrowed down to the AREDS 2 formulation, which consists of lutein = 10mg, zinc = 25mg, zeaxanthin = 2mg, copper = 2mg, vitamin C = 500mg, vitamin E = 400IU. (26)

To date, there are few supplements that are 'pure' AREDS 2 formulations, so practitioners need to look carefully to check these contain the necessary AREDS 2 ingredients, as many have varying amounts of the formulation and may contain extra carotenoids or ingredients such as omega-3 or meso-zeaxanthin.

There are currently no known risks with taking an AREDS 2 supplement. Having the correct dose is very important, as some AMD patients do not realise that there is no increased effect by double or triple dosing. It is important to refer to the specific supplement for dosing information, as they can vary between brands. It would be wise to advise a patient to inform their GP when taking supplements with prescribed medication so any potential interactions may be uncovered.

A simple balanced diet, generally, will not provide the required amounts of lutein and zeaxanthin as standard portions of many vegetables and fruits will not provide enough. Examples of the amounts of lutein available in different foods can be found in Table 1. Please note that lutein and zeaxanthin are extracted from foods together, so a small amount of zeaxanthin will be incorporated with each 10mg of lutein.

Up until recently, eggs have been linked to increased cholesterol and the Food Standards Agency's advice was to limit consumption. However, this advice has now been altered and consumption may be unlimited. The guidance for older adults is to make sure that egg yolks are fully cooked to avoid risk of salmonella poisoning. (36)

As the flowchart uses the exact AREDS 2 inclusion criteria, supplementation can only be recommended if the drusen are larger than 125[micro]m. Since this is a difficult size to evaluate, a retinal marker has been used to help gauge the size. The average central retinal artery can vary between 140-170[micro]m, (3) and so underestimation of drusen is unlikely using this marker.

The flowchart has been evaluated positively with both qualified and student optometrists, and is available for all practitioners to use. The flowchart is available to download at: www.aston.ac.uk/lhs/research/ health/org/amdnutrition/

CONCLUSION

Antioxidant therapy and dietary modification can slow down the progression of AMD. Giving consistent nutrition advice is an important part of optometric practice, and practitioners have a valuable tool to enable them to decide when and what nutrition advice to give.

Course code: C-41769 Deadline: September 5, 2015

LEARNING OBJECTIVES

To be able to explain to patients about the role of nutrition in AMD (Group 1.2.4)

To be able to give appropriate nutritional advice in response to changes in ocular status (Group 2.2.5)

To be able to manage patients with AMD (Group 6.1.9)

LEARNING OBJECTIVES

To be able to explain to patients about the role of nutrition in AMD (Group 1.2.4)

To understand the use of nutritional supplements for patients with AMD (Group 8.1.5)

LEARNING OBJECTIVES

To understand when it is appropriate to recommend nutritional supplements for patients with AMD (Group 1.1.2)

To be aware of the latest evidence relating to use of nutritional supplements for patients with AMD (Group 4.1.5)

Rebekah Stevens is a doctoral researcher at Aston University, investigating nutrition and AMD. She also teaches final-year undergraduate optometrists in primary care and binocular vision clinics.

Dr Hannah Bartlett is a senior lecturer at Aston University. Her research interests are focused on the role of nutrition in the prevention of onset and progression of ocular disease.

Table 1

Dietary sources
of lutein
1cup=150g

Food                      Serving size   Lutein (mg)

Kale, cooked              1 cup          20.5
Collard greens, cooked    1 cup          15.4
Spinach, cooked           1 cup          12.6
Turnip greens, cooked     1 cup          12.1
Broccoli, cooked          72 cup         4
Spinach, raw              1 cup          3.6
Aubergine, raw            1 cup          2.6
Peas, cooked              1 cup          2.2
Broccoli, raw             1 cup          2.1
Corn, cooked              72 cup         1.5
Lettuce, cos or romaine   1 cup          1.5
Brussels sprouts          72 cup         1.1
Papaya                    1 papaya       0.3
Peach                     1 peach        0.2
Apple                     1 apple        0.04
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Title Annotation:CET//MACULAR DEGENERATION
Author:Stevens, Rebekah; Bartlett, Hannah
Publication:Optometry Today
Article Type:Report
Date:Aug 8, 2015
Words:2992
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