Chapter 3 Age-related macular degeneration (AMD) and cataracts
Introduction
AMD
Age-related macular degeneration (AMD) and cataracts are the 2 leading eye diseases of advanced age. AMD is the leading cause of blindness in the elderly worldwide, affecting 30–50 million people. The World Health Organization (WHO) statistics from the most recent WHO global eye disease surveys conducted in 2002 reported that 8.7% of worldwide blindness was due to AMD, the third leading cause of worldwide blindness after cataract and glaucoma.1 Conservatively, the WHO has estimated that 14 million persons worldwide could be blind or severely visually impaired because of AMD.2, 3 The majority of these impaired individuals and the millions more who are visually impaired from this condition live in developed countries.
The large population-based Beaver Dam Eye Study discovered that the prevalence of large extracellular ocular deposits known as drusen, a hallmark sign of AMD, was 2% in persons 43–54 years of age and 24% in persons over 75 years of age in the US.4 It has also been reported that late AMD is the most common cause of untreatable blindness in the Western world, with a prevalence that is 0.05% before the age of 50 years and that rises to 11.8% after 80 years of age.5
Numerous large population studies have identified important factors as to the epidemiology of AMD. The Age–Related Eye Disease Study (AREDS) found that 20.2% of individuals with an early stage diagnosis of AMD progressed to advanced disease over a 5–year period, a rate of 4.0% per year. Similar annual rates of progression, between 2.5% and 4.8%, were reported in the Rotterdam Study and Blue Mountains Eye Study (BMES) respectively.6, 7 Recently a report by Taylor and colleagues estimated that the progression rate for mild to moderate visual impairment was approximately 32%, and that the rate from moderate to severe visual impairment was 46%.8 The basis for this estimate was derived from the 2–3 year progression data that originated from the Macular Photocoagulation Study (MPS), the Treatment of AMD with Photodynamic Therapy (TAP) study and the Vertiporfin in Photodynamic (VIP) Therapy study. These reported rates are slightly higher than the rates of 16% and 17% per year reported by the Melbourne Visual Impairment Project (MVIP) study. Taylor and colleagues also showed that the incidence of mild visual impairment in individuals who were 40 years or older was 0.10% per year and, for moderate and severe visual impairment in this same group, it was 0.04% and 0.11% per year, respectively.9
However, as life expectancies are observed to increase in all parts of the world the prevalence of AMD is also expected to increase. It is likely that in the following decades, many millions of people worldwide will suffer blindness or severe visual impairment from AMD. 10–17
Cataracts
A recent review has reported that cataract, (opacification of the lens) is one of the commonest causes of loss of useful vision, with an estimated prevalence of 16 million people affected worldwide.18 Prevalence studies for cataract are made difficult by a lack of uniform grading scores for the clinically observed opacities of the lens. Several population studies have been reported though, that demonstrate an increasing risk for cataract development with increasing age.19, 20, 21,
The Framingham Eye Study from the US, reported in 1977,19 that the proportion of people with age–related cataracts causing loss of vision of 20/30 (6/9) or worse was 15·5% for all ages and 45·9% for those 75 years or older. In the 1992 Beaver Dam Eye Study,20, 21 which used a similar definition of loss of vision, the reported proportions were 38·8% of men and 45·9% of women older than 74 years.
Data from other studied populations demonstrate a wide range of rates, such as 82% of 75–85 year olds in India and 53% of 75–85 year olds in Tibet.22, 23
Lifestyle and lifetime risk factors
A recent report by the US Preventive Services Task Force has identified a number of risk factors for the prevention of AMD and cataracts (Table 3.1).24
Table 3.1 Scientifically proven robust risk factors for AMD and cataracts
| AMD | Cataracts |
|---|---|
| Older age groups | Older age groups |
| Family history | Female gender |
| White race | Black race |
| Smoking | Smoking |
| Alcohol use (heavy) | Alcohol use |
| Exposure to ultraviolet light B | |
| Diabetes (+associated pathologies) | |
| Corticosteroid use |
The reviewed epidemiological literature conclusively reports that the older ages are causal for the development of AMD and cataracts.22, 25
Genetic predispositions
Family history, white race, black race
Family history is a consistent risk factor identified in most epidemiological studies of AMD that have been conducted. Familial aggregation studies have shown that there is a genetic contribution that has been readily identified in up to 25% of AMD cases.26 Moreover, studies with twins also support a genetic basis for the disease, with the concordance of clinical features (i.e. drusen and pigmentary changes) for both early and late onset of the disease being approximately twice as high in identical (monozygotic) twins compared to non–identical (dizygotic) twins.27, 28
Numerous population studies have investigated the racial differences observed in the prevalence of AMD.29, 30, 31 Recently, in an eye disease prevalence investigation Bressler et. al.32 have described the differences in frequency of early fundus lesions associated with AMD by racial group in an extended study of the Salisbury Eye Evaluation population cohort. The study confirmed that white persons are generally more likely than black persons to have medium or large drusen, focal pigment abnormalities, and advanced AMD. Also racial differences were prominent for non–neovascular AMD features only when present in the central zone.
The Salisbury Eye Evaluation study has also reported racial differences in lens opacities, confirming that cataract was a highly significant problem in the African–American population more so than in the white population.33, 34
Smoking
There is robust evidence that causally associates AMD and cataract to smoking.22, 35, 36, 37
Alcohol
A recent systematic review and meta-analysis has concluded that heavy alcohol consumption that consists of more than 3 standard drinks per day is associated with an increased risk of early AMD.38 The link between alcohol and cataract is less robust — a relationship between alcohol consumption and an increased risk of cataract has been reported from cross–sectional studies, but with several prospective cohort studies failing to confirm this association.39, 40
Exposure to UVB
Over-exposure to ultraviolet B has also been concluded to be causally associated to lens opacifications as reported by numerous studies.41, 42, 43
Diabetes
The prevalence and causes of visual impairment in an epidemiologic study of aged, urban individuals in Denmark reported that diabetic retinopathy in that country has a prevalence of 5.6%.44 A recent study from the US has reported that the prevalence of diabetic retinopathy among persons with diagnosed diabetes was 9.9% and in that survey of self-reported age-related eye diseases there were approximately 1.3 million people in the US with diabetic retinopathy.45
Steroid and/or corticosteroid medications
The association of cataract with systemic corticosteroid therapy was first postulated in 1960.46 Later reviews of the scientific literature concluded that steroids remained a risk for the development of cataract.47, 48 Recently a report on steroid–induced posterior subcapsular cataracts concluded that it remains a serious concern even though some reports indicated that the evidence for glucocorticoid–protein adduct formation in the lens was inconclusive.49
Obesity
A prospective cohort study in a hospital–based retinal practice investigated and followed up patients that were 60 years or older, with some sign of non–advanced AMD and visual acuity of 20/200 or better in at least 1 eye.50 This study documented that overall and abdominal obesity increased the risk for progression to advanced AMD, and more physical activity tended to decrease risk.
Recently the association between changes in waist–hip ratio, a measure of abdominal obesity, and AMD in a total of 12 515 persons aged 45–64 years, from a population–based cohort study from 1987 to 1989, was followed up over 6 years.51
High glycaemic index foods (versus low glycaemic index foods)
As has been previously demonstrated in this section and within the framework of cellular metabolic dysfunction, dietary factors are known risk factors for AMD. The National Health and Nutrition Examination Survey (NHANES III) demonstrated that, in the population over 65 years of age, 18–20% have diabetes, with 40% having either diabetes or its precursor form of impaired glucose tolerance. Hyperglycaemia itself can promote the formation of advanced glycation end products. Hyperglycaemia damages blood vessels leading to various micro– and macro–vascular diseases such as diabetic retinopathy, which is the main microvascular complication of diabetes and the most common cause of blindness in working populations.52
The Blue Mountain Eye Study reported on the risk associated with high glycaemic index foods in its study population.53 The study concluded that a high glycaemic index diet was a risk factor for early AMD; the recognised precursor of sight-threatening late AMD. It was also noted that low glycaemic index foods, such as oatmeal, could protect against early AMD. This was consistent with an earlier study that advised that persons at risk of AMD progression, especially those at high risk of advanced AMD, could benefit from consuming smaller amounts of refined carbohydrates.54
A recent dietary/food composition and consumption study investigated a number of nutritional factors and the risk of AMD.55 It was reported that consuming diets that provided low glycaemic index foods and higher intakes of nutrients were associated with the greatest reduction in risk for prevalent drusen and advanced AMD.
Environmental
Sunlight/UVB exposure
There is no total accord on the role of light exposure in the development of AMD. A 10-year prospective study has demonstrated that prolonged exposure to sunlight may be associated with increased risk of earlier development of AMD but not AMD progression.56, 57 Furthermore, this study also found a protective effect from the use of a hat and sunglasses in reducing the incidence of early AMD. An earlier Australian case control study, however, had failed to find a link between sunlight exposure and AMD.58
Pesticide exposure
It has been reported that exposure to pesticides may increase the risk of macular degeneration. Studies from Japan have linked organophosphate exposure to Saku disease, which involves retinal degeneration and other adverse ocular effects.59 Moreover, in an early study from India the prevalence of macular degeneration was higher among pesticide workers exposed to the organophosphate fenthion than among unexposed controls.60
Physical activity
AMD
As part of the Beaver Dam Eye population-based study, a 15-year cumulative incidence of AMD was determined through 4 examination phases at 5-year intervals.61 The study showed that there was a protective effect of physical activity for incident exudative AMD, independent of body mass index and other confounders. Moreover the study also suggested a possible modifiable behaviour that might be protective against developing AMD.
A recent study tested whether the risk of AMD could be decreased with vigorous physical activity.62 This was a prospective study of self–reported clinically diagnosed macular degeneration in male (n = 29 532) and female (n = 12 176) runners followed prospectively for 7.7 years. The study reported that higher doses of vigorous exercise (running — risk for AMD decreased 10% per km per day increment in running distance) was associated with a lower incident AMD risk independent of weight, cardiorespiratory fitness, and cigarette use. Hence, compared to men and women running < 2 km per day, those averaging 2 to 4 km per day had 19% lower adjusted risk, and those averaging ≥ 4 km per day had 42% to 54% lower adjusted AMD risk.
Cataracts
Similarly, a prospective study investigated physical activity and incident cataract.63 The risk for incident cataract increased with BMI, such that the risk in men > 27.5 kg/m2 was 88% larger than in men < 20 kg/m2. Men’s cataract risk declined significantly in relation to running distance, even when adjusted for BMI. Men who ran ≥64 km/week had 35% lower risk for cataract than those reporting < 16 km/week (28% lower risk when adjusted for BMI). Furthermore, men with greater cardiorespiratory fitness were at significantly less risk for development of cataract than were the least fit men.
Nutrition
Diets
Vegetables
Early descriptive reports64 hypothesised that there was an inverse relationship between increased consumption of foods rich in certain carotenoids (an important constituent of the retinal pigments), in particular dark green, leafy vegetables, and a decreased risk of developing advanced or exudative AMD.
A recent descriptive study that measured the regular dietary intake of antioxidants and the associated lowered risk of incident AMD reported that an above-median intake of all 4 nutrients — beta–carotene, vitamin C, vitamin E, and zinc — from foods was associated with a 35% reduced risk for incident AMD in elderly persons.65
In a further prospective observational study of plant food consumption from a large cohort of female health professionals, higher dietary intakes of lutein and/or zeaxanthin (refer also to later sections this chapter) and vitamin E from food and supplements were associated with significantly decreased risks of cataract.66
Meats
A recent epidemiological study has shown that higher consumption of fresh and processed red meat intake was positively associated with early AMD.67 Specifically the study reported that consumption of chicken ≥ 3.5 times/week versus <1.5 times/week was inversely associated with late AMD. Moreover that the data suggested that different meats may differently affect AMD risk and that hence this may be a target for lifestyle modification.
Fats (animal fats versus fish fats)
A cross-sectional study that assessed whether dietary intake of fat or fish is associated with AMD showed that the amount and type of dietary fat intake may be associated with AMD.37, 68 That this could be the situation was apparent from a recent study that evaluated the associations between past dietary fat intake and the prevalence of AMD and found that a diet low in trans–unsaturated fat and rich in omega–3 fatty acids and olive oil may reduce the risk of AMD.69
A prospective cohort study was undertaken to advise patients with a high risk for advanced forms of AMD about preventive measures through an evaluation program of the relationships between dietary fat intake and the progression of early or intermediate AMD to the advanced stages of the disease associated with visual loss. This study showed that:70
An AREDS study that examined the association of dietary omega-3 long-chain polyunsaturated fatty acid and fish intake with incident neovascular AMD and central geographic atrophy (CGA) reported that the data strongly suggested that dietary omega-3 long-chain polyunsaturated fatty acid intake was associated with a decreased risk of progression from bilateral drusen to CGA.71
A systematic review and meta-analysis from the same year confirmed that consumption of fish and foods rich in omega-3 fatty acids may be associated with a lower risk of AMD. However, it also reported that there was insufficient evidence from the current literature, with few prospective studies and no randomised clinical trials, to support their routine consumption for AMD prevention.72
In an elderly Australian cohort from 2009, 3654 participants that were examined at baseline and 2454 participants who were examined 5 and/or 10 years later were assessed for AMD.73 The study provided significant evidence for protection against early AMD from regular consumption of fish. Greater consumption of omega-3 polyunsaturated fatty acids and low intakes of foods rich in linoleic acid afforded a similar protection. It was also noted that regular consumption of nuts may also reduce AMD risk.
Salt consumption
A large Australian population-based cross-sectional study74 of 2873 patients (mean age 65 years), from the Blue Mountains area, reported that low intakes of salt in the diet reduced the risk of cataracts. Of these participants, 620 already had cortical cataracts, 350 had nuclear cataracts and 160 had posterior subcapsular cataracts. After controlling for additional risk factors for cataract formation, people with the highest quintile of sodium intake had twice the risk of developing posterior subcapsular cataracts than those in the lowest quintile of sodium intake.
Supplements
Vitamins and minerals
AMD
Antioxidants (Beta-carotene, vitamin C, vitamin E, Zinc)
The Beaver Dam Eye Study pointed to the importance of micronutrients in the prevention of progression of eye diseases. Significant, but modest, inverse associations were observed between intakes of pro–vitamin A carotenoids and dietary vitamin E and the incidence of large drusen and between zinc and the incidence of pigmentary abnormalities. No significant inverse associations though were found between antioxidants or zinc intake and the incidence of overall early AMD.75
Randomised placebo-controlled trials (by the AREDS study group) investigating high levels of antioxidant consumption of vitamins and minerals such as C and E, beta-carotene, and zinc have reported that people without contraindications, such as smoking, should consider taking a supplement of antioxidants plus zinc that could be of benefit in preventing progression of AMD.76
Systematic reviews provide additional recommendations that include that people with AMD, or early signs of the disease, could experience some benefit from taking supplements as used in the AREDS trial.77 The author also alluded to the potential harms of high-dose antioxidant supplementation which included an increased risk of lung cancer in smokers with beta-carotene, heart failure in people with vascular disease or diabetes using high dose vitamin E, and hospitalisation for genitourinary conditions for those people using high dose zinc.77, 78
Recent randomised trials with single vitamins, namely beta–carotene, has demonstrated no beneficial or harmful effects on the incidence of AMD.79 These randomised data relative to 12 years of treatment among a large population of apparently healthy men indicated that long-term supplementation with beta-carotene neither decreased nor increased the risk of AMD.
The evidence is somewhat contentious though given that systematic reviews have reported that there is insufficient evidence to support the role of dietary antioxidants, including the use of dietary antioxidant supplements, for the primary prevention of early AMD or to delay its progression.78, 80
However, while there is no definitive treatment presently available for AMD, the most recent evidence recommends that vitamin supplements with high doses of antioxidants used for primary prevention may reduce the incidence of AMD.81 This together with previous research by the National Eye Institute (AREDS) and others suggest benefit in the secondary prevention of dry AMD for some patients and some improvement in visual acuity.
B Group Vitamins
Observational epidemiologic and clinical studies indicate a direct association between homocysteine concentration in the blood and the risk of AMD.78, 82, 83, 84
A recent US study conducted a randomised double-blind placebo-controlled trial including 5442 female health care professionals 40 years or older with pre-existing cardiovascular disease or 3 or more cardiovascular disease risk factors. They examined the effect of combined folic acid (2.5mg/day), pyridoxine hydrochloride (vitamin B6 50mg/day), and cyanocobalamin (vitamin B12, 1mg/day) therapy to lower homocysteine levels versus placebo. A total of 5205 of these women did not have a diagnosis of AMD at baseline.81 At the end of the study they reported that after an average of 7.3 years of treatment and follow-up, there were 55 cases of AMD in the combination treatment group and 82 in the placebo group. For visually significant AMD, there were 26 cases in the combination treatment group and 44 in the placebo group These randomised trial data from a large cohort of women at high risk of cardiovascular disease indicates that daily supplementation with a combination of folic acid, pyridoxine, and cyanocobalamin may significantly reduce the risk of AMD.
Vitamin D
A cross-sectional association study of serum vitamin D and early and advanced AMD, assessed from non-mydriatic fundus photographs, were evaluated in the third National Health and Nutrition Examination Survey.85 This was a multistage nationally representative probability sample of non-institutionalised individuals (n = 7752; 11% with AMD). This study showed that consistent use versus non-use of vitamin D from supplements was inversely associated with early AMD only in individuals who did not consume milk daily. Moreover, even though additional studies are required to confirm these results, it was concluded that this study provided evidence that vitamin D may protect against AMD.
Cataract
Antioxidants (Vitamins C, E)
Population studies investigating the use of antioxidant vitamins and cataract incidents reported that the results provided significant evidence that there was a lower risk for cataract among users of multivitamin supplements and a stronger relationship for long-term use.86, 87 A nutritional assessment study of long-term intake of vitamins and carotenoids reported that the data support a role for vitamin C in diminishing the risk of cortical cataracts in women aged < 60 years and for carotenoids in diminishing the risk of posterior subcapsular cataracts in women who had never smoked.88
Randomised clinical trials with antioxidants have also been conducted for the prevention of cataract. The AREDS group has also reported that the use of a high-dose formulation of vitamin C, vitamin E, and beta-carotene in a relatively well-nourished older adult cohort had no apparent effect on the 7-year risk of development or progression of age-related lens opacities or visual acuity loss.89
Furthermore, an additional large randomised trial of apparently healthy female health professionals with 9.7 years of treatment and follow-up indicated that 600IU natural-source vitamin E taken every other day provided no benefit for age-related cataract or subtypes.90
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