Eye conditions such as 'xerophthalmia' are a common cause of childhood blindness in developing countries (Semba, 2007). These conditions are particularly associated with a vitamin A deficiency and illustrate the importance of good nutrition for eye health. Although common in developing countries conditions arising due to the lack of adequate nutrition are also not uncommon in the developed world.
It is frequently wrongly assumed that by eating a 'healthy' diet one will receive all their nutritional requirements. This text will review the role of nutritional supplementation in the most prevalent age related eye diseases Age Related Macular Degeneration (AMD) and Age Related Cataract.
Age Related Macular Degeneration
A condition commonly affecting people in the developed world found to have a strong relationship with nutrition and diet is Age Related Macular Degeneration. Globally, AMD ranks third as a cause of visual impairment with a blindness prevalence of 8.7%. It is the primary cause of visual impairment in industrialized countries (World Health Organisation 2011).
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The devastating effects of AMD (Fig.2) and our inability to treat it successfully together with evidence supporting an oxidative 'stress' aetiology has warranted further investigation in to the lifestyle changes which can potentially help prevent and improve the status of the condition. Of particular interest is the role of nutritional supplementation.
Fig.1 Normal Vision Fig.2 Effect of AMD on vision-loss of central vision
(Fig.1 & Fig.2 National Eye Institute, Eye Disease Simulations, 2011)
For us to approach the issue of AMD appropriately we need to understand the aetiology of the condition first, this being one of the issues when approaching AMD. The exact pathogenesis of AMD is yet to be fully determined, currently there are three hypotheses relating to the development of AMD. It is likely that all three hypotheses contribute to the development of the condition to different degrees. (Caffery 2003, Bartlett and Eperjesi 2003, Augustin 2005)
This theory implies that the cells in macular area do not gain a sufficient amount of nutrition to function properly due to impeded blood flow to that area as a result of narrowed arteries and poorly functioning capillaries of the choroid. This also means that the waste products produced by the normal breakdown of photoreceptors cannot be removed. The accumulation of these waste products may lead to the deterioration of the retinal pigment epithelium (RPE) and new blood vessel formation therefore causing a breakdown of macular function. (Caffery 2003, Bartlett and Eperjesi 2003, Augustin 2005)
The oxidative stress theory is based upon the breakdown of protective antioxidant systems over time within the retina. Halliwell and Gutteridge (1999) described an antioxidant as a substance which at low concentrations significantly delays or inhibits oxidation (Bartlett and Eperjesi 2003). Normal metabolic processes within the retina coupled with exposure to high energy visible light generate highly reactive and potentially damaging forms of oxygen called free radicals. A heavy free radical load (oxidative stress) results in the free radicals attacking cell membranes and cell constituents such as DNA thus resulting in cell death, mutations and ultimately destruction of tissues. It has been shown that the concentration of lipofuscin, a pigment in the RPE consisting of waste products resulting from oxidatively damaged photoreceptors, also increases with age. Photoreceptor outer segments that aren't digested in the lysosomes of the RPE remain in the RPE as this highly oxidised lipid material. It is the accumulation of this lipofuscin teamed up with free radicals that leads to the breakdown of macular function. It was postulated further to this theory that a boost in antioxidant levels may help prevent the development of AMD. (Caffery 2003, Bartlett and Eperjesi 2003, Augustin 2005)
Bruch's Membrane Deterioration
The conductivity of the Bruch's membrane decreases with age leading to the detachment of the RPE. As seen in the dry form of AMD, the resulting reduction in the exchange of metabolic material between the choroid and the RPE results in the formation of atrophic lesions within that area. The first sign that the metabolic state of the retina has been altered can be seen as the deposition of substances between the RPE and the Bruch's membrane-drusen. The blockage of nutrition due to the thickening of the Bruch's membrane acts as a stimulus for choroidal neovascularisation as seen in the 'wet' form of AMD
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Fig.3 Macular changes in AMD ('DeCleene Optometry.inc)
These blood vessels destroy the structures around them as they continue to grow creating further damage within the macula (Bartlett and Eperjesi 2003, Augustin 2005)
The role of Antioxidants in AMD prevention
The hypothesis that oxidative stress/breakdown of antioxidant systems, possibly induced by an
inadequate diet, contributes to AMD has been based on several animal and human studies. Animals with insufficiency of vitamin E have shown increased retinal damage and extensive accumulation of lipofuscin (Robison et al 1979) while an insufficiency of vitamin C in guinea pigs without any additional oxidative stress led to an increase of retinal lipid peroxidation (oxidative degradation of lipids) thus causing cell damage (Augustin 2005).
Constant exposure to light and smoking are 2 major sources of free radical damage leading to cataract and AMD. The body possesses reducing substances, such as glutathione an antioxidant enzyme found in the lens, which disarm the free radicals (Brown 2004). The body's reducing substances are aided by the antioxidant vitamins, vitamin A (beta-carotene), C and E and also by the carotenoids, lutein, zexanthin and mesoxianthin. The body's own reducing ability depletes with increasing age (Brown 2004). Hence, it has been suggested antioxidant nutrients can play a protective role against these conditions. Antioxidants neutralise these free radicals therefore reducing the harm they may cause. Antioxidants can be vitamins, minerals, enzymes such as glutathione or phytochemicals such as the carotenoids (Davies 2004). The major carotenoids include, beta-carotene, lutein and zeaxanthin, these will be discussed in due course.
Although research on other aspects relating to AMD is certainly on the go, a large proportion of research looks at the nature of oxidation and the production of free radicals. Vitamin intake is the most extensively studied. Research undertaken has been rather inconsistent in terms of results with some studies showing a positive relationship between nutrition and the progression of AMD and some not. For instance, the positive effect of zinc supplementation in subjects found by Newsome et al 1988 was not confirmed by Spur et al 1996 (Bartlett and Eperjesi 2003).
The most widely known and the largest study in this area which exhibited a positive relationship between nutrition supplementation and AMD is the Age Related Eye Disease Study (AREDS). In October 2001, the National Eye Institute published the results of a randomised placebo controlled trial which investigated the effect of high dose nutrition supplementation on both AMD and cataract. The results from the AMD branch of the study will mainly be discussed here.
3640 subjects, with an average age of 69 years, were monitored twice a year for 6.3years. Participants were grouped in to four different categories depending on the stage of the age related maculopathy/age related macular degeneration. Participants from three of the categories took part in both the cataracts and AMD branch of the study and were randomised in to four main groups of supplementation: (1) antioxidants, (2) zinc, (3) antioxidants plus zinc, (4) placebo. The antioxidants plus zinc formulation consisted of vitamin C, 500 mg; vitamin E, 400 IU; beta carotene, 15 mg; zinc, 80mg and copper, 2mg to prevent zinc induced copper deficiency aneamia. (The AREDS Research Group 2001)
With regards to the cataract branch of the study, no statistically significant effect of the antioxidant formulation was seen on the development or progression of age-related lens opacities (The AREDS Research Group, 2001).
The most notable effect relating to AMD was that of the 'antioxidants plus zinc' formulation, this was shown to have reduced the risk of disease progression by 25% over 5 years for patients with intermediate or advanced AMD. The nutrients also reduced the risk of vision loss in advanced AMD by 19%. There was also a 'suggestive' reduction in risk for those participants taking the zinc supplements alone.
The results indicate that the combination of zinc and antioxidants was 'modestly' effective in preventing the progression of AMD to an advanced state. This effect was not seen with antioxidants alone or in participants with earlier stages of the disease. The AREDS research group therefore concludes: 'individuals over the age of 55 should have dilated eye examinations to determine their risk of developing advanced AMD. Those with extensive or intermediate sized drusen, at least 1 large drusen, non-central geographic atrophy in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye, without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that used in this study' (The AREDS Research Group, 2001).
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It should be noted that these results are relevant to those who already have AMD to a moderate degree. This study does not apply to those patients who have early or no form of macular degeneration. The AREDS investigators further stated that the two carotenoids lutein and zeaxanthin were also considered for inclusion in to the AREDS formulation, however these weren't readily available for manufacture at the time (The AREDS Research Group, 2001). In all, this trial has formed an excellent foundation for research in to the role of food supplementation in AMD as many studies have had contradictory outcomes. Furthermore, the trial highlights the need for further investigation in to the role of nutritional supplements along with lutein and zeaxanthin in the prevention of the very onset of the disease.
It is difficult to simply compare the results of various studies undertaken investigating this topic as a large number of different variables need to be considered. Variables include aspects such as the research population, form/concentration/combination of the nutrient(s) used, and the stage of the condition within the subjects, each of these will have an effect on the results to different degrees.
Taking the example of the contradiction between the AREDS results and those of the vitamin E, Cataract and Age Related Maculopathy trial where no significant relationship was found between antioxidant supplementation and AMD progression, we find, the difference in conclusions could perhaps suggest that supplementation with vitamin E is only effective in combination with other nutrients (Bartlett and Eperjesi 2003, Taylor et al 2002).
Function and Clinical value of Lutein and Zeaxanthin
Evidence supporting the protective role of carotenoids in the retina has increased over recent years. There are three carotenoids of primary interest, lutein, zeaxanthin and meso-zeaxanthin, known as xanthophylls and these make up the macular pigment. These macular pigments are regarded as effective antioxidants, thought to provide protection against cellular damage by neutralizing free radicals hence reducing the risk of AMD. It has been shown that the xanthophylls (oxygenated carotenoids) have superior antioxidant properties compared to hydrocarbon carotenoids such as beta-carotene. 'The yellow macular pigments also absorb blue and UV light, thus providing a buffer to protect the retinal photoreceptors' together with extending the protection of the retina already provided by the crystalline lens towards the middle end of the visible spectrum. It is this function of the carotenoids which has spurred interest and research in to the role of the xanthophylls in to the prevention of AMD. (Bartlett and Eperjesi 2003, Voke 2010)
Lutein and zeaxanthin are not actually synthesized by the human body and are obtained by dietary intake. Meso-zeaxanthin, on the other hand, is formed via a conversion process of lutein and is not found in the typical diet. Lutein and zeaxanthin are found in high concentrations in leafy green vegetables, marigolds, maize and coloured fruits such as mangoes and peaches. It is now well established that the density of lutein and zeaxanthin can be increased with dietary changes (Voke, 2010). Researchers have conducted studies on this basis to examine the role of these carotenoids in AMD.
Fig.4 From 'Humbleseed'
Lutein supplements of 10 mg per day were shown to improve visual function in the 'Lutein Antioxidant Supplementation Trial' where the role of lutein was investigated in the progression of atrophic AMD. A group of 90 individuals with atrophic AMD were randomised in to three groups (1) 10mg Lutein, (2) 10mg lutein plus antioxidants, (3) Placebo and were monitored over a 12 month period. Investigators reported a significant improvement in visual acuity, glare recovery and contrast sensitivity in both the treatment groups. Combining with other antioxidants appeared to give an added improvement to contrast sensitivity (Richer et al, 2002). The Dietary Anciliary Study of the Eye Disease Case-Control Study (EDCCS) also found similar results where lutein and zeaxanthin from foods were associated with a decreased risk of AMD whereas beta-carotene from foods was not. Investigators found that participants with a daily intake of lutein above 6mg had a decreased risk of neovascular AMD (Seddon 2007).
There is evidence to support antioxidant and zinc supplements confer some benefit in reducing the risk of progression of AMD. The carotenoids, lutein and zeaxanthin also appear to confer significant protection. Individuals affected by AMD may benefit from a nutritional supplement containing vitamin A, C and E along with zinc. Patients should be encouraged to make positive lifestyle changes such as reducing the intake of alcohol and smoking, two factors which greatly reduce the antioxidant defence mechanisms within the body along with reducing the risk of developing conditions associated with AMD such as hypertension. AMD is a multifactorial condition and it is likely those with an inherited predisposition (positive family history) for the condition will develop it only with exposure to appropriate environmental factors (Bartlett and Eperjesi, 2003).
The following regime (Fig.5) could be recommended for those judged to be at risk of, or in the early to moderate stages of AMD:
Regime for patients with moderate AMD. From Brown 2004
One should bear in mind that some of the vitamins and minerals can be toxic if taken in excess therefore the upper limit of consumption must not be exceeded (See table below for recommended intake limits). In particular vitamin C in excess is now seen as harmful. Official limits have not yet been set for the carotenoids. Possible adverse effects associated with the intake of carotenoid supplements need to be investigated before their use can be recommended to prevent the progression of AMD.
Fig.6 Table of recommended intakes. From Brown 2004
Overall, these findings may represent a breakthrough in the approach to AMD. However, as mentioned, further investigation is needed regarding various aspects including the prevention of the onset of the condition. The AREDS 2 study (commencing 2008) which is currently underway may help us find some of the answers we are seeking. It has been designed to assess the effects of oral supplementation of lutein and zeaxanthin and/or long-chain omega-3 fatty acids (DHA and EPA) on the progression to advanced AMD. An additional goal of the study is to assess whether forms of the AREDS nutritional supplement with reduced zinc and/or no beta-carotene work as well as the original supplement in reducing the risk of progression to advanced AMD. (The AREDS 2 Research Group 2011)
SUPPLEMENTS AND AGE RELATED CATARACT
According to the latest assessment by W.H.O, age related cataract is responsible for 48% of world blindness this represents about 18 million people around the globe. Although cataracts can be surgically removed, surgical services are insufficient in many countries and cataract remains the leading cause of blindness. As the expected lifespan of humans increases the number of people with cataract, as with AMD, is growing. Cataract is a significant cause of low vision in both developed and developing countries. (W.H.O 2011)
Researchers have been driven to investigate the preventative measures for the development of such a commonly occurring condition. Comprehensive prevention of cataract development is not known as of yet however reduction of cigarette smoking, ultraviolet light exposure, and alcohol consumption have been suggested to prevent or rather delay the development of cataract. Positive lifestyle changes to decrease the risks of developing diabetes and hypertension which are identified as additional risk factors for developing cataracts are also encouraged. (W.H.O 2011)
As with the retina the lens is under threat of oxidative damage by free radicals. These free radicals are generated by normal metabolic processes together with exposure to sunlight. Oxidative damage to the lens occurs as a result of the effect of the free radicals on the lens proteins and lipids and may also be from the phototoxic effect of sunlight (Brown 2004). Pollution in the atmosphere and cigarette smoke are also major sources of free radicals. Thus, cigarette smoking is indeed an obvious risk factor for cataract and AMD.
Vitamin C is the most concentrated in the aqueous humor than in any other body fluid. This indicates that vitamin C is particularly important to the lens. Given that the level of vitamin C in the aqueous can be increased with increased dietary intake, it seems that the lens would benefit from an increased intake of vitamin C. Therefore, there is a rational basis for enhancing the antioxidant status of the eye by nutritional means to prevent cataract and promote eye health. (Brown 2004)
The lens possesses repair mechanisms both at a cellular level and a biochemical level which encourages the search for nutrient prevention of age related cataract. A process called 'annealing' means that damaged lens fibre cells are able to seal off their defective parts to prevent the spread of the opacity along the fibre (See Below). Lens repair at a molecular level is due to antioxidant substances neutralising the free radicals allowing the generation of normal proteins and lipids. It is therefore logical to consider boosting the antioxidant potential in the lens by increased antioxidant nutrient intake. (Brown 2004)
Fig. 7 & 8 Annealing of lens fibres and Example of a Posterior Subcapsular cataract From Brown 2004
Vitamins and other nutrients may have a direct action in protecting the lens or indirectly by promoting systemic health to benefit the eye secondarily. Studies investigating the effects of supplementation with antioxidants on the progression of cataracts have been rather inconsistent in their outcomes.
The Linxian Cataract Study, two controlled nutrition intervention trials, completed in the rural communes of Linxian, China, found that vitamin/mineral supplements may decrease the risk of nuclear cataract. Subjects were given multiple vitamin and mineral supplements in different combinations, nutrients studied include vitamin C, beta carotene and vitamin E. However, investigators concluded additional research is needed in less nutritionally deprived populations before these findings can be translated into general nutritional recommendations (Sperduto et al, 1993). In addition to this, the Roche European American Cataract Trial (REACT) involving Boston, Bradford and Oxford found a 'small deceleration in the progression of age related cataract'. This was a placebo controlled study in which half the subjects were given a combination of vitamin A (beta-carotene), vitamin C and vitamin E daily (The REACT Group, 2002).
In India however, where an association between nutritional status and cataract might seem more likely, a study showed that antioxidant supplementation with beta carotene and vitamins C and E did not affect cataract progression in a population with a high prevalence of cataract whose diet is generally deficient in antioxidants (Gritz et al, 2006). As discussed earlier, the AREDS also found no effect of food supplements on cataract progression.
To conclude, 'research in to the role of nutritional supplements and the development of age related cataract provide only weak support for multivitamins or other vitamin supplements' (Seddon 2007).
A vitamin supplement given to individuals already with early stages of cataract is likely to have a minor effect in reducing the rate of progression, as shown in the REACT study. It seems likely that a nutritional supplement when given to individuals with poor nutrition may have a significant impact in preventing cataract where as a nutritional supplement when given to people with good nutrition would have a weak impact, if any, in preventing cataract. (Brown 2004)
Scientific literature contains a growing body of information regarding the role of food supplements in the development of age related eye disease. Both AMD and cataract are similar in their oxidative aetiology, occurring as a result of normal metabolic processes along with cumulative exposure to light, air pollution, cigarette smoke and alcohol. It is well understood that the density of the antioxidants within the eye can be increased with dietary changes. As the body's own antioxidant ability becomes less efficient with increasing age, there is a rational basis for investigating the prospect of boosting the antioxidant state of the eye with nutritional supplements to prevent eye disease and promote eye health.
Mounting evidence suggests that intake of antioxidant vitamins and minerals may neutralise the destructive effects of reactive oxygen species in the eye. This in turn could possibly prevent or delay the onset of a whole series of conditions, including AMD and Cataracts. Nutrition is now seen as a significant factor in such eye diseases and nutritional supplements have been shown to play a role in the management of eye disease through various studies, as discussed.
People of all ages should be encouraged to maintain a healthy lifestyle with a diet full of a variety of coloured fresh fruit and vegetables, avoiding 'insults' to nutrition such as smoking and excess alcohol consumption. In view of the present state of knowledge, middle-aged and elderly patients may benefit from a nutritional supplement so that they get an adequate daily intake of various vitamins and minerals and carotenoids. For patients affected by AMD, a supplement formulation of vitamin A, C and E with carotenoids and zinc may be recommended. For patients affected by the beginning of cataract, a formulation of vitamin A, C and E is likely to have an effect in slowing the progression, but no effect is likely in advanced cataract. Further investigation in the form of randomised clinical trials, these being the gold standard in clinical research, is required to identify the precise role of nutritional supplements within AMD, Cataract and other conditions. (Brown 2004, Eperjesi 2004)