Risk Factors for Age-related Macular Degeneration

Abstract

There is an increasing body of evidence as to the risk factors for age-related macular degeneration. Age and genetic make-up are the most important risk factors identified to date. Over the next decade, the different genes that are involved in the development of age-related macular degeneration will be identified. There is reasonably consistent evidence that smoking cigarettes results in increased risk of the disease. The question as to whether antioxidant vitamin and mineral supplementation prevents or delays the development of the disease will be resolved as the results of large ongoing trials become available in the next few years. Currently, there is conflicting evidence as to their benefits and some indication as to possible harm. Other risk factors such as alcohol consumption, oestrogen replacement and lifetime light exposure require further study. The study of the epidemiology of age-related macular degeneration would be facilitated by a greater standardization of methods. Studies with large numbers of late stage disease are needed in order to provide the power to investigate moderate risks. This may either be achieved by adding on macular degeneration studies to large cohort studies already in place, or by pooling data from smaller studies.

Introduction

Age-related macular degeneration is a disease involving typical lesions in the macula in older people, which cannot be attributed to infectious or inflammatory causes. The early stages of the disease are characterized by the development of drusen, which are yellow spots clinically observable on the retina, and pigmentary abnormalities with hyper- and hypo-pigmentation. Later stages of the disease comprise two types: geographic atrophy, and neovascular age-related macular degeneration. In geographic atrophy, the retinal pigment epithelium and overlying receptors degenerate. In cases of neovascular age-related macular degeneration, new vessels form under the retina, leading to the destruction of the retinal pigment epithelium. If the vessels leak, the resulting haemorrhage results in further scarring and visual loss.

Over the past 30 years there have been a number of epidemiological studies into the distribution and prevalence of eye disease, including age-related macular degeneration, in the population (Leibowitz et al., 1980; Klein and Klein, 1982; Gibson et al., 1985; Vinding, 1989; Bressler et al., 1989; Klein et al (1992), Klein et al (1995); Hirvela and Laatikainen, 1995; Pagliarini et al., 1997; Vingerling et al., 1995b; Mitchell et al., 1995; Friedman et al., 1999; Schachat et al., 1995). Details of these studies are set out in Table 1. One outcome of this work has been growing consensus as to how the disease should be classified in epidemiological studies. The International Age-Related Maculopathy Study Group brought together investigators from the large epidemiological studies and agreed a classification, which is set out in Table 2 (Bird et al., 1995). This is the terminology that is used in this paper. The Group propose an overall term “age-related maculopathy” encompassing early and late stages of the disease. Early age-related maculopathy refers to signs such as large, soft drusen and pigmentary abnormalities, that may, or may not develop into late stages of the disease. The term “age-related macular degeneration” describes geographic atrophy and neovascular age-related macular degeneration.

Age-related macular degeneration is the most important cause of visual loss in western industrialized countries. In the United Kingdom, approximately 30,000 people are registered blind or partially sighted every year, half of whom will have macular degeneration (Evans, 1995). This pattern in the registered population is reflected in Europe, North America and Australia (Bjornsson, 1981; Graf et al., 1999; Hansen, 1981; Krumpaszky and Klauss, 1992; Chan and Billson, 1991). Cataract is probably more frequent as an incident cause of visual loss but, as there is safe and effective surgery for cataract, it is less common as a prevalent cause of visual loss.

Age-related macular degeneration increased dramatically as a proportionate cause of registered visual loss in the 20th century (Evans and Wormald, 1996; Maruo et al., 1991). In 1933, just 6% of the registered population in England and Wales had “senile macular degeneration”, compared to nearly 50% in 1990 (Evans and Wormald, 1996). Most of this increase can be attributed to a combination of ageing population, declining importance of infectious causes of visual loss, and increasing effectiveness of ophthalmic surgery. However, examination of age-standardized population rates indicate an excess incidence of approximately 30%. This may reflect a real increase or simply indicate changes in the detection of this condition in parallel with its increasing importance.

Currently, there is no treatment that can restore vision in age-related macular degeneration. There are some treatments, for example, laser photocoagulation and photodynamic therapy, which can delay the progressive loss of visual function in a small proportion of people with neovascularisation (Fine et al., 2000). For that reason, there is considerable interest in possibilities for preventing the disease developing in the first place. Interest in the role of vascular factors has lead to investigations of cardiovascular disease risk factors in the development of age-related macular degeneration. It is also hypothesized that age-related macular degeneration occurs as a result of the inability of the retina to cope with the highly reactive oxygen species that are produced during visual processing. With developments in molecular biology and genetic methods, there is increasing potential for discovery of the genetic determinants that may underly the pathological mechanisms outlined above.

The aim of this paper is to investigate the epidemiological evidence behind the proposed hypotheses for the aetiology of age-related macular degeneration, namely, vascular factors, and oxidative processes. This will then be linked with what is known about the genetic determinants of the disease.

Table 3 sets out some of the epidemiological terms that will be used. Incidence refers to the number of new cases of disease arising in a cohort of people over a defined period of time. Prevalence is defined as the number of cases in a population at a given point in time. Exposure is used interchangeably with the term risk factor and refers to any agent or factor that is hypothesized or shown to have an adverse or beneficial risk on the development or progression of disease. Bias and confounding are important components of epidemiological studies that need to be addressed during their interpretation. Bias refers to any systematic error in the study design that means that the true estimate of effect is over or under-estimated. Confounding is said to occur when the observed association between exposure and disease can be attributed to another factor that is associated both with the exposure and the disease. Age is a common confounding factor.