Age-related maculopathy (ARM) is the leading cause of blindness in the elderly. Although beneficial therapeutic strategies have recently begun to emerge, much remains unclear regarding the etiopathogenesis of this disorder. Epidemiologic studies have enhanced our understanding of ARM, but the data, often conflicting, has led to difficulties with drawing firm conclusions with respect to risk for this condition. As a consequence, we saw a need to assimilate the published findings with respect to risk factors for ARM, through a review of the literature appraising results from published cross-sectional studies, prospective cohort studies, case series, and case control studies investigating risk for this condition. Our review shows that, to date, and across a spectrum of epidemiologic study designs, only age, cigarette smoking, and family history of ARM have been consistently demonstrated to represent risk for this condition. In addition, genetic studies have recently implicated many genes in the pathogenesis of age-related maculopathy, including Complement Factor H, PLEKHA 1, and LOC387715/HTRA1, demonstrating that environmental and genetic factors are important for the development of ARM suggesting that gene-environment interaction plays an important role in the pathogenesis of this condition.
Age-related macular degeneration (AMD), the late stage of age-related maculopathy (ARM), is the leading cause of blindness in white individuals over 65 years of age in the Western world [
The burden of AMD to individuals and to society is expected to rise as a result of an increase in life expectancy, reduced birth rates, and the consequential demographic shift towards an elderly population [
Risk factors for ARM may be classified as modifiable and nonmodifiable. Possible modifiable risk factors for ARM include smoking, body mass index, cumulative sunlight exposure, diet, alcohol consumption, and cardiovascular disease. Possible nonmodifiable risk factors for ARM include: age, family history of ARM (early and/or late), iris color, and refractive error.
Any review of the literature assessing possible risk factors for ARM should comment upon the nature of the designs of the studies cited, and on the relative strengths and limitations of such designs [
Thus, in this article, we review the literature germane to risk for ARM, as determined by studies of various design, including case series, cross-sectional, cohort, and case-control studies (Tables
Large epidemiologic studies investigating risk for ARM.
Study | Location | Design | No. of participants |
---|---|---|---|
Beaver Dam Eye Study [ | USA (1988–2005) | Cross-Sectional | 4926 |
Prospective | 3684 (5-year) | ||
2764 (10-year) | |||
2119 (15-year) | |||
Blue Mountains Eye Study [ | Australia (1992–2004) | Cross-Sectional | 3654 |
Prospective | 2335 (5-year) | ||
1952 (10-year) | |||
Rotterdam Study [ | Holland (1990–2004) | Cross-Sectional | 6418 |
Prospective | 4953 (2-year) | ||
3406 (6.5-year) | |||
2387 (11-year) | |||
Pathologies Oculaires Liees a L’Age [ | France (1995–2000) | Cross-Sectional | 2584 |
Prospective | 1642 (3-year) | ||
Los Angeles Latino Eye Study [ | USA (2000–2003) | Cross-Sectional | 6357 |
Melbourne Visual Impairment Project [ | Australia (1992-1999) | Cross-Sectional | 5147 |
Prospective | 3271 (5-year) | ||
Reykjavik Eye Study [ | Iceland (1996–2001) | Cross-Sectional | 1045 |
Prospective | 846 (5-year) | ||
Beijing Eye Study [ | China (2001) | Cross-Sectional | 4439 |
Copenhagen City Eye Study [ | Denmark (1986–2002) | Cross-Sectional | 946 |
Prospective | 359 (14-year) | ||
Andhra Pradesh Eye Disease Study [ | India (1996–2000) | Cross-Sectional | 3723 |
Barbados Eye Studies [ | Barbados (1987–2003) | Cross-Sectional | 4631 |
Prospective | 3427 (4-year) | ||
2793 (9-year) | |||
Salisbury Eye Evaluation Project [ | USA (1993) | Cross-Sectional | 2520 |
Proyecto VER [ | USA (1997–1999) | Cross-Sectional | 4774 |
Baltimore Eye Survey [ | USA (1985–1988) | Cross-Sectional | 5308 |
Aravind Comprehensive Eye Survey [ | India (1995–1997) | Cross-Sectional | 5150 |
European Eye Study [ | 7 European Countries (2000–2003) | Cross-Sectional | 5040 |
Hisayama Study [ | Japan (1998–2003) | Cross-Sectional | 1482 |
Prospective | 961 (5-year) | ||
Framingham Eye Study [ | USA (1973–1975) | Cross-Sectional | 2940 |
National Health and Nutrition Examination Survey I [ | USA (1971–1972) | Cross-Sectional | 3056 |
National Health and Nutrition Examination Survey III [ | USA (1988–1994) | Cross-Sectional | 8270 |
Cardiovascular Health Study [ | USA (1997–1998) | Cross-Sectional | 2361 |
Atherosclerosis Risk in Communities Study [ | USA (1993–1995) | Cross-Sectional | 11532 |
MRC Trial of Assessment and Management of Older People in the Community [ | UK (1996–2000) | Cross-Sectional | 13900 |
Risk factors for ARM examined in the cited studies.
Family history of ARM |
Complement Factor H gene |
Apolipoprotein E gene |
LOC gene |
Clinical Evidence of Atherosclerosis |
Subclinical evidence of atherosclerosis |
Cigarette smoking |
Diabetes mellitus |
Hypertension and associated disease |
Cholesterol |
Obesity |
Female sex hormones |
Novel risk factors for atherosclerosis |
Systemic Diseases with Inflammatory Components |
Anti-inflammatory Medications |
Markers of Systemic Inflammation |
Intercellular Adhesion Molecule-1 |
E-Selectin |
Anti-oxidants |
Pro-oxidant status |
Refractive Error |
Iris Color |
Cataract |
Cataract Surgery |
Alcohol Consumption |
Medication Use |
Coffee Consumption |
Frailty |
Physical Activity |
Most of the cited studies have utilized a grading system of ARM, consistent with the International Classification and Grading System for ARM and AMD. According to this classification, a diagnosis of early ARM is made in the presence of soft drusen (
In this review article we have, where possible in the context of the grading systems used in the cited studies, distinguished between early ARM and late ARM (AMD). All of the cited studies comment on the prevalence of ARM, defined by the appearance of the designated lesion(s) at the time of the study examination. Where incidence of ARM was studied, it was identified by the appearance of a designated lesion at followup examination a number of years following the baseline examination where no such findings were present.
Studying ARM as a genetic disease is difficult due to the inherently age-related nature of the disease [
Many human diseases have a genetic basis, mediated through DNA sequence variation [
With regard to ARM, there is now strong evidence supporting the role of genetic background in the development of ARM [
Familial aggregation studies are designed to identify if the risk for a certain condition is higher in individuals related to the affected individual, when compared to unrelated individuals [
During the baseline examination of the Beaver Dam Eye Study, cross-sectional information was gathered regarding the siblings of participants [
The Rotterdam Study provides two population-based familial aggregation analyses, which have reported that a positive family history of ARM represents risk for this condition [
Several twin studies have also yielded information regarding the nature of heritability of ARM [
The evidence, described earlier, supporting a genetic role in the development of ARM led to a search for a susceptibility gene, or genes, responsible for ARM.
In early 2005, three separate research groups independently identified a variant in the complement factor H (CFH) gene, known as the Y402H polymorphism, which exerts a strong influence on the risk of developing ARM [
Interestingly, interaction between tobacco use and the Y402 H gene has been recently reported, although followup studies have not replicated such findings (reported in what follows) [
Further two reports in 2005 identified other susceptibility loci, on chromosome 10q26, associated with increased risk for ARM [
Apolipoprotein E gene (ApoE) codes for apolipoproteins, which are major transporters of lipid and cholesterol in the nervous system [
Interestingly, ApoE is a ubiquitous component of drusen, and clinical manifestations of retinal degeneration are exhibited in Apolipoprotein E-deficient mice that carry an ApoE gene that has been inactivated by gene targeting [
Other genes recently discovered to be associated with an increased risk for ARM include the complement factor B gene (BF), the complement component 3 gene (C3), and the complement component 2 gene (C2) [
In conclusion, over the past decade, numerous studies have attempted to identify susceptibility genes for AMD. The discovery of a risk variant within the CFH gene and recent findings for loci PLEKHA1/LOC387715, Apo E, and BF/C2 have increased our knowledge particularly in relation to elucidating the complex gene-environment interaction in the pathogenesis of this disease. Future research is likely to clarify the exact role of these genes and identify additional susceptibility genes.
Cardiovascular disease includes coronary heart disease, cerebrovascular disease, and peripheral arterial disease. Atherosclerosis is responsible for the majority of cases of cardiovascular disease [
As early as 1937, it was hypothesized that ARM may be part of an underlying systemic vascular process and therefore associated with cardiovascular disease [
The vascular model proposes that the progressive deposition of lipid, seen in atherosclerosis, is the underlying cause of ARM [
The inflammatory model of cardiovascular disease proposes that local inflammatory responses are important in the etiology of both macular drusen and drusen-like deposits in arterial vessels [
Epidemiologic studies investigating a possible association between cardiovascular disease and ARM have typically done so by focusing on three main parameters: (1) clinical evidence of atherosclerosis in subjects with and without ARM; (2) subclinical evidence of atherosclerosis in subjects with and without ARM; (3) risk factors for atherosclerosis in subjects with and without ARM.
In most epidemiological studies, clinically important atherosclerosis was deemed to be present if subjects reported a history of angina, heart attack, or stroke. Atherosclerosis does not correlate well with cardiovascular events, which are largely atherothrombotic [
Three population-based epidemiological studies have investigated whether evidence of subclinical atherosclerosis is associated with risk for ARM, by using noninvasive techniques to measure atherosclerotic vascular changes [
In 1995, cross-sectional data from the Rotterdam Study indicated that patients with subclinical carotid atherosclerosis or peripheral atherosclerosis exhibited a significantly increased prevalence of late ARM [
In 1999, the cross-sectional Atherosclerosis Risk in Communities Study, in fact, demonstrated an association between carotid atherosclerosis and prevalence of early ARM, but not with carotid artery stiffness or pulse pressures (parameters not measured in the Rotterdam Eye Study) [
The prospective arms of the Beaver Dam Eye Study reported a statistically significant association between a higher pulse pressure and risk for late neovascular ARM (but not atrophic late ARM) [
In summary, the results of studies designed to investigate a possible association between atherosclerosis and risk for ARM are inconsistent. However, it is worth bearing in mind that these studies should be interpreted with full appreciation of their limitations, including the poor relationship between atherosclerosis and cardiovascular events, since cardiovascular events were typically used in the reported studies as a presumed indicator of underlying atherosclerosis. This shortcoming needs to be addressed in the design of future studies, if the relationship between atherosclerosis and ARM is to be elucidated.
Cigarette smoking has been established as an important risk factor in the development of cardiovascular disease [
The limitations of studies attempting to investigate the relationship between tobacco use and ARM warrant discussion. First, potential confounders in such studies include age and associations between tobacco use and other health risk behaviours, such as poor diet and increased alcohol consumption. Of the studies discussed in what follows, 15 have been adjusted for some of these potential sources of confounding [
In epidemiologic studies, smoking history is typically ascertained using an interviewer-administered questionnaire. Participants are usually classified as being nonsmokers, former smokers, or current smokers. In a number of studies, the total pack-years smoked by each participant was also calculated, and this is defined as the number of cigarettes smoked per day divided by 20, and multiplied by the number of years smoked [
The relationship between tobacco use and the prevalence and incidence of ARM has been investigated in cross-sectional, prospective cohort and case-control studies (Table
Studies investigating the relationship between tobacco use and risk for ARM.
Study | No. of cases | Outcome measure/risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval | |
---|---|---|---|---|---|---|
Cross-Sectional studies | ||||||
Beaver Dam Eye Study [ | 4771 | Current smokers versus ex-smokers or never smokers | Neovascular AMD | 2.50 | 1.01–6.20 (Females) | |
3.29 | 1.03–10.50 (Males) | |||||
Blue Mountains Eye Study [ | 3654 | Current smoker versus current nonsmoker | Late ARM | 3.92 | 2.07–7.41 | |
Early ARM | 1.75 | 1.20–2.54 | ||||
Pathologies Oculaires Liees a L’Age [ | 2196 | Current smokers | Late ARM | 3.6 | 1.1–12.4 | |
Melbourne Visual Impairment Project [ | 5147 | Smoked Cigarettes for longer than 40 years | Late ARM | 2.39 | 1.02–5.57 | |
Rotterdam Study [ | 6174 | Current smokers | Neovascular AMD | 6.6 | 2.8–15.9 | |
Los Angeles Latino Eye Study [ | 5875 | Ever smoked | Late ARM | 2.4 | 1.03–5.4 | |
Ever smoked versus never smoked | All AMD | 2.4 | ||||
Copenhagen Study Denmark [ | 773 | Atrophic AMD | 2.5 | |||
Neovascular AMD | 1.5 | NS | ||||
Chesapeake Bay, Waterman Study, USA [ | 769 | Ever smokers versus never smokers | All AMD | 0.61 | (0.35–1.05) | |
Prospective studies | ||||||
Blue Mountains Eye Study [ | 2335 | Current smoker versus never smoker | Geographic atrophy | 3.6 | 1.1–11.3 | |
Any late ARM | 2.5 | 1.0–6.2 | ||||
Beaver Dam Eye Study [ | 2764 | Current smoker | Late ARM | 0.51 | 0.18–1.46 | |
Early ARM | 1.37 | 0.98–1.94 | ||||
14752 | Current Smoker | Late ARM | 3.12 | 2.10–4.64 | ||
9523 | Current smoker | Late ARM | 2.35 | 1.30–4.27 | ||
Physician’s Health Study, USA [ | Current smokers | All AMD | 1.26 | 0.61–2.9 | ||
21157 | Current smokers | All AMD | 2.46 | 1.6–3.79 | ||
Neovascular AMD | 1.95 | 0.89–4.2 | ||||
Nurse’s Health Study, USA [ | 31843 | Currrent smokers versus never smoked | All AMD | 1.7 | 1.2–2.50 | |
Hisayama Study [ | 961 | Current or ex-smoker | ARM | 2.2 | 1.14–4.33 | |
Case-Control Studies | Case | Con | Current smokers versus never smokers | |||
France [ | 26 | 23 | Neovascular AMD | 1.25 | 0.3–4.4 | |
Eye Disease Case-Control Study [ | 421 | 615 | Neovascular AMD | 2.2 | 1.4–3.5 | |
France [ | 1844 | 1844 | All ARM/AMD | 1.09 | 0.83–1.42 | |
Neovascular AMD | 2.97 | 1.0–8.84 | ||||
Japan [ | 56 | 82 | Early ARM | 1.25 | 1.09–1.44 | |
Atrophic AMD | 1.61 | 1.06–2.42 | ||||
Age-related Eye Disease Study [ | 340 | 111 | Neovascular AMD | 1.91 | 1.57–2.33 | |
5 |
Of note, cigarette use increases the risk for both the neovascular and atrophic forms of late ARM, but neovascular ARM to a greater extent. Of the studies investigating the possible association between cigarette use and late ARM, six out of ten have found that tobacco use represents risk for the development of neovascular late ARM [
Furthermore, cigarette smoking appears to have a dose-dependent relationship with risk for ARM, reflected in the demonstration that the extent of risk rises with the number of pack years smoked in the Physician’s Health Study and in the Nurse’s Health Study [
Only one study to date has investigated whether tobacco use influences the age of onset of ARM. In the Blue Mountains Eye study, it was reported that participants who were free of late ARM at baseline but who were current smokers ultimately developed ARM on average 10 years earlier than nonsmokers, who also exhibited no signs of disease at baseline [
Finally, there is a growing body of evidence to suggest that cessation of cigarette smoking leads to a subsequent reduction in the risk for ARM. To date, 11 studies have examined the risk of ARM amongst exsmokers, reporting an increased risk of developing ARM when compared to never-smokers, but lower risk when compared to current smokers [
The results of an association between cigarette smoking and risk for ARM, however, are not entirely consistent, and some studies have failed to identify any association, or have demonstrated only a weak association between tobacco use and ARM [
Finally, although the Beaver Dam Eye Study reported a strong association between smoking and neovascular late ARM at baseline, this association was weaker at the 5-year and 10-year followup examination [
In summary, the current evidence is broadly consistent across a range of populations and study designs. Depending on the type of ARM in question (early, atrophic late ARM, or neovascular late ARM), the risk of developing ARM is two or three times amongst current smokers when compared with never smokers. Three large epidemiologic studies carried out on three different continents, and the pooled data and prospective arms of these studies, provide strong evidence in support of the view that cigarette use is associated with increased risk for ARM [
Diabetes mellitus is a known risk factor for the development of atherosclerosis [
It is interesting to note that a recent publication on glycaemic index (related to carbohydrate intake) and ARM within the AREDS study concluded that a reduced glycaemic index in nondiabetic individuals may be associated with reduced risk for ARM [
Hypertension is a known risk factor for atherosclerosis [
The association between hypertension and incident ARM has also been investigated, and most studies have failed to identify any significant relationship (Table
Studies investigating the relationship between hypertension and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Hisayama Study [ | 1482 | Hypertension (history or examination) | ARM | 1.58 | 1.03–2.41 (Males) |
Pathologies Oculaires Liees a L’Age [ | 2584 | Systolic BP (per 10 mm of Hg) | Late ARM | 1.19 | 0.98–1.43 |
Diastolic BP (per 10 mm of Hg) | Late ARM | 0.98 | 0.72–1.35 | ||
Blue Mountains Eye Study [ | 3654 | Previous diagnosis or systolic BP | Early ARM | 0.88 | 0.67–1.16 |
Late ARM | 1.06 | 0.63–1.79 | |||
Beaver Dam Eye Study [ | 4926 | Hypertension | Neovascular AMD | 0.79 | 0.44–1.42 |
Geographic atrophy | 1.07 | 0.46–2.47 | |||
Prospective Studies | |||||
9523 | Systolic blood pressure (per 2 mm of Hg) | Late ARM | 1.03 | 0.94–1.13 | |
Diastolic blood pressure (per 10 mm of Hg) | Late ARM | 0.95 | 0.79–1.16 | ||
Rotterdam Study [ | 4822 | Elevated systolic blood pressure (per 10 mm Hg increase) | ARM | 1.06 | 1.01–1.12 |
Pulse pressure (per 10 mm Hg increase) | ARM | 1.09 | 1.02–1.15 | ||
Beaver Dam Eye Study [ | 2764 | High systolic blood pressure at baseline | Retinal pigment epithelial depigmentation | 1.10 | 1.01–1.18 |
Neovascular AMD | 1.22 | 1.06–1.41 |
Hypertensive small vessel disease may lead to focal ischemic changes in the cerebral white matter [
Prolonged hypertension may be associated with changes in the retinal vasculature, such as focal arteriolar narrowing, arteriovenous nipping, as well as retinal arteriolar and venular narrowing [
Serum lipids include cholesterol and triglycerides, with cholesterol having multiple subtypes, including low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and very low density lipoprotein (VLDL) [
However, evidence for such an association from epidemiologic studies, to date, has been unimpressive, with few reports of an association between hyperlipidaemia and ARM. Nevertheless, high serum cholesterol was associated with a 2.2-fold increased risk of neovascular ARM in the Eye Disease Case-Control Study [
However, most epidemiologic studies have failed to detect an association between elevated serum lipid levels and late ARM. Moreover, some studies have shown that high LDL cholesterol and low HDL cholesterol were actually protective for prevalent and incident ARM (Table
Studies investigating the relationship between cholesterol and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Cardiovascular Health Study [ | 2361 | Serum total cholesterol (per 10 mg/dL increase) | ARM | 0.95 | 0.91–0.98 |
National Health and Nutrition Examination Survey III [ | 8270 | HDL cholesterol (per mmol/L) | Early ARM | 1.30 | 0.99–1.71 |
Triglycerides (per mmol/L) | Soft drusen | 0.88 | 0.79–0.99 | ||
Pathologies Oculaires Liees a L’Age [ | 2584 | Cholesterol (per mmol/L) | Soft drusen | 1.07 | 0.97–1.17 |
Late ARM | 0.97 | 0.71–1.31 | |||
HDL Cholesterol (per mmol/L) | |||||
Blue Mountains Eye Study [ | 3654 | Cholesterol (per 10 mg/dL) | Early ARM | 0.95 | 0.84–1.09 |
Late ARM | 1.08 | 0.92–1.27 | |||
Prospective studies | |||||
Beaver Dam Eye Study [ | 3684 | Serum Cholesterol (per 10 mg/dL increase) | Geographic Atrophy | 1.29 | 1.05–1.58 |
Rotterdam Eye Study [ | 4776 | Serum Cholesterol (per 10 mg/dL) | Early ARM | 0.96 | 0.84–1.09 |
HDL Cholesterol (per mmol/L) | Early ARM | 1.38 | 0.92–1.79 |
Epidemiologic studies and clinical trials have investigated the relationship between cholesterol-lowering agents (statins) and ARM, but until recently, no association between the use of these medications and the incidence or progression of ARM has been reported [
Any attempt to reconcile the discrepancy of the results between two similarly and well-designed prospective arms of population-based studies must take account of the differences in baseline findings between the Beaver Dam Eye Study (BDES) and the Blue Mountain Eye Study (BMES). For example, the ratio of statin users to nonusers was
Attempting to identify the causal or protective effect from data generated from a population-based study can be complex, and warrants discussion. Cross-sectional studies, in which the disease and exposure are measured at the same time, inherently lack the ability to detect a true temporal association. Cohort studies, such as the prospective arms of the Beaver Dam Eye Study, the Blue Mountains Eye Study, and the Rotterdam Eye Study, allow for such inferences. However, and in the context of an infrequent risk factor or an infrequent end-point (such as conversion to neovascular ARM) prospective population-based studies may have limited power to detect an association. Therefore, the question remained unanswered is whether statin use is protective for development, or progression, of ARM. However, further followup of large cohorts with increasing numbers taking statins should enhance our understanding of the protective role, if any, of statins for ARM. Nevertheless, and even with more prolonged followup, difficulties arising from unmeasured confounding, selective survival, and other sources of bias will mean that the result of such studies should be interpreted with appropriate caution.
Obesity is an established risk factor for cardiovascular disease, and many studies have shown that obesity is a risk factor for hypertension and lipid abnormalities, and, therefore, predisposes to atherosclerosis [
Body mass index (BMI) is defined as the body weight in kilograms divided by the height in meters squared, and is the most commonly used measure of obesity in epidemiologic studies [
Evidence to date from other studies is less convincing (Table
Studies investigating the relationship between obesity and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Beaver Dam Eye Study [ | 4926 | BMI | Neovascular AMD | 1.02 | 0.97–1.08 |
Geographic atrophy | 1.06 | 0.98–1.14 | |||
Blue Mountains Eye Study [ | 3654 | BMI | Early ARM | 1.78 | 1.19–2.68 |
BMI | Early ARM | 1.92 | 1.16–3.18 | ||
Pathologies Oculaires Liees a L’Age [ | 2584 | BMI | Late ARM | 2.29 | 1.00–5.23 |
Retinal pigmentary abnormalities | 1.54 | 1.05–2.26 | |||
Prospective Studies | |||||
Beaver Dam Eye Study [ | 3583 | BMI | Retinal Pigmentary Abnormalities | 1.03 | 1.00–1.06 |
9523 | BMI | Late ARM | 0.87 | 0.51–1.47 |
In the cross-sectional POLA study, participants with a BMI
In the cross-sectional arm of the Blue Mountains Eye Study, a high BMI and a low BMI were both associated with an increased risk of prevalent early ARM [
Two recent, nonpopulation-based, prospective studies have reported a two-fold increased risk of incident ARM in obese subjects. The Physicians’ Health Study, a prospective study of male physicians in USA, reported a two-fold increased incidence of early ARM amongst obese subjects [
In conclusion, conclusive evidence that BMI represent risk for ARM is still lacking. However, there appears to be a growing body of evidence in support of the view that obesity is an important determinant for the development and/or progression of ARM.
Obesity may be a marker of lack of physical activity, and such a lack of physical activity is associated with increased risk of several factors that predispose to cardiovascular disease, including hypertension, weight, and lipid profile [
There is a growing debate amongst epidemiologists about the role of female sex hormones in the etiopathogenesis of cardiovascular disease. The observation that the risk of cardiovascular disease is lower amongst women than amongst men before the menopause, but rises in postmenopausal women, is well documented. Indeed, observational studies have reported that hormone replacement therapy, in the form of exogenous estrogen, is protective against cardiovascular disease [
A number of mechanisms have been put forward to explain the putative protective effect of female sex hormones for cardiovascular disease [
However, results from recent randomized controlled studies, including the Heart and Estrogen/Progestin Replacement Study (HERS) [
Epidemiologic studies have used a number of ways to measure exposure to estrogen (Table
Studies investigating the relationship between female sex hormones and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Beaver Dam Eye Study [ | 4926 | Number of pregnancies | Early ARM | 0.95 | 0.92–1.01 |
Hormone replacement therapy usage | Late ARM | 0.94 | 0.63–1.39 | ||
Blue Mountains Eye Study [ | 3654 | Years from menarche to menopause | Early ARM | 0.97 | 0.95–0.99 |
Los Angeles Latino Eye Study [ | 5875 | Use of oral contraceptive pills | Early ARM | 0.5 | 0.4–0.8 |
Use of hormone replacement therapy | Early ARM | 0.8 | 0.6–1.2 | ||
Pathologies Oculaires Liees a L’Age [ | 2584 | Hormone replacement therapy | Late ARM | N/A | N/A |
Salisbury Eye Evaluation Project [ | 1458 | Current use of hormone replacement therapy | Early ARM | 0,7 | 0.3–1.5 |
Late ARM | 0.6 | 0.1–2.9 | |||
Aravind Comprehensive Eye Survey [ | 5539 | Age at menarche 14+ | ARM | 2.3 | 1.2–4.7 |
Age at menopause | ARM | 1.5 | 0.3–8.1 | ||
Endogenous estrogen exposure | ARM | 2.2 | 0.4–12.0 | ||
Prospective Studies | |||||
Beaver Dam Eye Study [ | 3684 | Hormone replacement therapy (3+ years) | Early ARM | 0.98 | 0.56–1.73 |
Late ARM | 1.30 | 0.36–5.21 | |||
Rotterdam Study [ | 4616 | Early menopause following oophorectomy | ARM | 3.8 | 1.1–12.6 |
9523 | Time from menarche to menopause per year | Late ARM | 0.99 | 0.95–1.03 | |
Hormone replacement therapy | Late ARM | 1.00 | 0.40–2.45 |
The cross-sectional arm of the Beaver Dam Eye Study found that high parity (i.e., decreased exposure to endogenous estrogen) was associated with an increased prevalence of early ARM [
Incidence data from prospective studies is similarly unconvincing. Five-year incident data from the Beaver Dam Eye Study provided little evidence of any association between exposure to estrogen and incident ARM [
In summary, reports of studies designed to investigate an association between exposure to estrogen (whether exogenous or endogenous) and ARM are inconsistent. Longitudinal analyses of prospective cohorts are required to enhance our understanding of the association, if any, between estrogen and risk for ARM. Well-designed, randomized controlled studies are needed to investigate the putative beneficial effect of HRT on incidence and/or progression of ARM.
A number of emerging risk factors for atherosclerosis have recently been identified. These “novel” risk factors include lipid-related factors, inflammatory markers, and infectious agents. [
Apolipoproteins and lipoproteins are essential in the transport of cholesterol and lipids. Apolipoprotein E has three common alleles (
Inflammatory markers that have been implicated as risk factors for cardiovascular disease include C-reactive protein, interleukins, serum amyloid A, vascular and cellular adhesion molecules, and white blood cell count [
Homocysteine is an amino acid, which is formed as a by-product of the metabolism of the essential amino acid methionine [
Infectious agents, such as cytomegalovirus,
It has also been postulated that ARM may represent an ocular manifestation of chronic inflammatory processes [
The inflammatory model proposes that some form of tissue injury leads to a localized inflammatory response in the retina, involving human leukocyte antigen (HLA) and the complement system [
The human immune system contains both innate and adaptive components [
A number of case-control and cohort studies have provided evidence in support of the view that inflammatory changes are etiologically important for ARM. Until recently, however, the evidence from large population-based epidemiological studies has been less consistent in this regard (Table
Studies investigating the relationship between indicators of inflammation and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Atherosclerosis Risk in Communities Study | 11264 | White blood cell count | Early and late ARM | N/A | N/A |
National Health and Nutrition Examination Survey III [ | 8270 | Serum albumin | Early ARM | 0.97 | 0.95–1.00 |
Cardiovascular Health Study [ | 2361 | Serum albumin | Early ARM | 0.59 | 0.39–0.92 |
Plasma Fibrinogen | Early ARM | N/A | N/A | ||
Cardiovascular Health Study [ | 2755 | C-reactive protein | Early and Late ARM | 1.24 | 0.87–1.78 (4th Quartile) |
Beaver Dam Eye Study [ | 2764 | Gout | Early ARM | 0.69 | 0.41–1.16 |
Late ARM | 2.18 | 1.06–4.47 | |||
Emphysema | Early ARM | 1.11 | 0.49–2.51 | ||
Late ARM | 2.55 | 0.74–8.81 | |||
Beaver Dam Eye Study [ | 3684 | NSAIDs | Early ARM | 1.04 | 0.78–1.38 |
Aspirin | Early ARM | 1.08 | 0.79–1.48 | ||
Oral steroids | Early ARM | 0.80 | 0.28–2.28 | ||
Blue Mountains Eye Study [ | 2313 | Steroids or NSAIDs | Early ARM | 1.2 | 0.8–1.6 |
Late ARM | 0.9 | 0.4–1.9 | |||
Beaver Dam Eye Study [ | 2764 | White blood cell count | Early ARM | 1.03 | 0.98–1.10 |
Late ARM | 0.99 | 0.86–1.14 | |||
Serum albumin | Early ARM | 0.91 | 0.64–1.29 | ||
Late ARM | 0.52 | 0.24–1.14 |
The Beaver Dam Eye Study demonstrated an association between the 10-year incidence of ARM and high white blood cell count and with low serum albumin [
Plasma fibrinogen is a well-established marker of systemic inflammation, and elevated fibrinogen levels are seen in association with arthritis, diabetes mellitus, and certain cardiovascular risk factors [
In 2004, Seddon et al. demonstrated raised CRP levels in association with intermediate and advanced ARM, when compared with a control proband [
More recent epidemiologic studies have been able to investigate the role of complement factor H Y402H polymorphism with respect to ARM. The Rotterdam Study tested for the CFH Y402H polymorphism in a total of 5681 individuals (11363 alleles), and identified this polymorphism in 36.2% [
Other, and more novel, markers for inflammation have also been examined with respect to ARM. In two samples of participants from the Beaver Dam Eye Study, no association was found between serum amyloid A, interleukin-6, or tumor necrosis factor and the prevalence or incidence of ARM [
Animals release energy from dietary carbohydrates, proteins, and lipids by cellular oxidative processes. These processes include the tricarboxylic acid (TCA) cycle and oxidative phosphorylation [
Reactive oxygen intermediates (ROIs) is a term used to describe free radicals, hydrogen peroxide, and singlet oxygen. These molecules are produced in the cell as by-products of oxidative processes, and result in cytotoxic oxidative chain reactions. An increase in the production of ROIs is seen in association with aging, and in association with inflammation, cigarette smoking, and irradiation [
Cells have multiple mechanisms to protect against the effects of oxygen toxicity [
Oxidative processes occur in the retina, and it is postulated that they are etiologically important in the pathogenesis of ARM [
In other words, it appears that oxidative damage of the retina may represent a common pathway, which is important for the development of ARM, and which is not inconsistent with other hypothesized etiologies and/or risk-factors for ARM, including cumulative light damage, inflammatory processes, hemodynamic abnormalities, and genetic predisposition.
Although much of the work on oxidative processes in relation to ARM has been laboratory-based, there is now a growing number of epidemiologic studies investigating the role, if any, of oxidative processes in the pathogenesis of ARM.
Such epidemiologic studies tend to investigate parallels between the prevalence (and/or incidence) of ARM and antioxidant or pro-oxidant status [
Antioxidant status is assessed by evaluating defense mechanisms against oxidative stress. Such measures may include dietary intake of relevant antioxidants, or serum or tissue (e.g., macular pigment optical density) levels of such antioxidants [
Vitamin C (ascorbic acid) is thought to be essential for protection against disease processes caused by oxidative stress. It is the most effective aqueous phase antioxidant in human blood [
Studies investigating the relationship between vitamin C and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
National Health and Nutrition Examination Survey I [ | 3082 | Dietary intake | Early and late ARM | 1.15 | 0.79–1.66 |
Blue Mountains Eye Study [ | 2900 | Dietary Intake | Early ARM | 0.9 | 0.5–1.4 |
Late ARM | 1.3 | 0.5–3.4 | |||
Prospective Studies | |||||
Beaver Dam Eye Study [ | 1968 | Dietary intake | Early ARM | 0.8 | 0.5–1.2 |
Late ARM | 0.6 | 0.2–2.0 | |||
Blue Mountains Eye Study [ | 1989 | Dietary intake | Early ARM | 2.3 | 1.3–4.0 |
Rotterdam Study [ | 4170 | Dietary intake of vitamin C in combination with vitamin E, | Early and late ARM | 0.65 (Hazard Ratio) | 0.46–0.92 |
Baltimore Longitudinal Study of Aging [ | 678 | Fasting plasma level | Early and late ARM | 0.55 | 0.28–1.08 |
Pathologies Oculaires Liees a L’Age [ | 1791 | Fasting plasma level | Late ARM | 0.89 | 0.32–2.5 |
The Age-Related Eye Disease Study (AREDS) provided evidence that, in addition to zinc, antioxidant supplementation may slow ARM progression in relatively advanced early ARM cases [
Cross-sectional data from the Beaver Dam Eye Study also showed that a high dietary intake of vitamin C was negatively associated with early ARM, but this finding was not statistically significant [
Serum levels of vitamin C have also been examined in relation to risk for ARM. Cross-sectional data from the Baltimore Longitudinal Study of Aging reported a nonsignificant protective effect associated with high levels of plasma vitamin C, but this finding was not replicated in the POLA study [
In summary the relationship between vitamin C and ARM remains unclear. The majority of studies have failed to demonstrate a clear association between either dietary intake or serum levels of vitamin C and ARM (OR 0.6–1.15).
Vitamin E is the major antioxidant of cellular membranes [
The Beaver Dam Eye Study showed that the prevalence of early ARM was lower for people in the highest versus lowest quintiles for dietary intake of vitamin E (Table
Less evidence has been published on the association, if any, between serum levels of vitamin E and ARM. Vitamin E is transported by lipoproteins, and it is increasingly recognized that plasma
Therefore, the body of evidence that vitamin E is protective for ARM remains inconsistent.
Studies investigating the relationship between vitamin E and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Pathologies Oculaires Liees A L’Age [ | 2157 | Lipid-standardized plasma level | Late ARM | 0.18 | 0.05–0.07 |
Prospective Studies | |||||
Beaver Dam Eye Study [ | 1968 | Dietary intake | 0.7 | 0.5–1.1 | |
1.5 | 0.5–4.6 | ||||
Beaver Dam Eye Study [ | 1709 | Dietary intake in the past | Large drusen | 0.4 | 0.2–0.9 |
Dietary intake at baseline | Large drusen | 0.8 | 0.4–1.7 | ||
Rotterdam Study [ | 4170 | Dietary intake | Early and late ARM | 0.92 (Hazard Ratio) | 0.84–1.0 |
Vitamin A (retinol) is vital for the regeneration of rhodopsin in the retina, and is therefore essential for vision [
Studies investigating the relationship between vitamin A and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
National Health and Nutrition Examination Survey I [ | 3082 | Dietary intake | Early and late ARM | 0.74 | 0.50–1.10 |
Pathologies Oculaires Liees a L’Age [ | 2157 | Plasma Level | Late ARM | 0.6 | 0.17–2.12 |
Prospective Studies | |||||
Blue Mountains Eye Study [ | 2900 | Dietary intake | Early ARM | 1.2 | 0.7–2.0 |
Late ARM | 1.2 | 0.5–3.3 | |||
Blue Mountains Eye Study [ | 1989 | Dietary intake | Early ARM | 0.9 | 0.6–1.6 |
Carotenoids are naturally occurring pigments [
In the Beaver Dam Eye Study, dietary intake of carotenoids was unrelated to the prevalence of early or late ARM (Table
However, the macular carotenoids are likely to be more relevant to risk for ARM than B carotene, especially since B-carotene is not found in the human neurosensory retina. Foods that are rich in lutein and zeaxanthin include leafy green vegetables, corn, green peppers, and egg yolks [
Serum levels of
In summary, the relationship between ARM and dietary intake (and serum levels) of macular carotenoids remains unclear. However, recent reports from AREDS and the Blue Mountains Eye Study do suggest that dietary intake of lutein and zeaxanthin may be protective for ARM.
Studies investigating the relationship between dietary and serum levels of carotenoids and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
National Health and Nutrition Examination Survey III [ | 8222 | Dietary intake of lutein and zeaxanthin | Pigmentary abnormalities | 0.1 (Younger age groups) | 0.1–0.3 |
Serum level of lutein and zeaxanthin | Early ARM | 1.0 | 0.6–1.5 | ||
Prospective Studies | |||||
Beaver Dam Eye Study [ | 1709 | Dietary intake of pro-vitamin A carotenoids | Large drusen | 0.53 | 0.3–1.0 |
0.45 | 0.2–1.0 | ||||
Blue Mountains Eye Study [ | 2900 | Dietary intake of carotene | Early ARM | 0.7 | 0.4–1.1 |
Late ARM | 0.7 | 0.3–2.0 | |||
Blue Mountains Eye Study [ | 1989 | Dietary intake of | Early ARM | 1.3 ( | 0.8–2.2 |
1.2 ( | 0.7–2.1 | ||||
Rotterdam Study [ | 4170 | Dietary intake of | Early and late ARM | 0.65 | 0.46–0.92 |
Pathologies Oculaires Liees a L’Age [ | 899 | Plasma Levels of zeaxanthin | Early and Late ARM | 0.07 | 0.01–0.58 |
Combined plasma level of lutein and zeaxanthin | Early and late ARM | 0.21 | 0.05–0.79 |
Several antioxidant enzymes form vital components of cellular defense mechanisms against oxidative stress [
The final aspect of antioxidant status that has been evaluated in population-based epidemiologic studies with respect to ARM is that of the trace element, zinc is an essential cofactor for antioxidant enzymes. Food rich in zinc includes meat, poultry, fish, whole grains, and dairy products [
The retrospective arm of the Beaver Dam Eye Study detected a weak protective effect for individuals in the highest quintile of dietary intake of zinc when compared with those in the lowest quintile (Table
Studies investigating the relationship between zinc and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Beaver Dam Eye Study [ | 1968 | Dietary intake | Early ARM | 0.6 | 0.4–1.0 |
Beaver Dam Eye Study [ | 1709 | Dietary intake | Early ARM | 0.7 | 0.5–1.0 |
Late ARM | 1.1 | 0.3–4.1 | |||
Blue Mountains Eye Study [ | 2900 | Dietary intake | Early ARM | 0.8 | 0.5–1.3 |
Late ARM | 1.0 | 0.4–2.8 | |||
Blue Mountains Eye Study [ | 1989 | Dietary intake | Early ARM | 1.3 | 0.7–2.7 |
Rotterdam Study [ | 4170 | Dietary intake | Early and late ARM | 0.91 | 0.83–0.98 |
Aspects of pro-oxidant status that have been evaluated with respect to risk for ARM in population-based epidemiologic studies include exposure to light and dietary intake of fatty acids.
Polyunsaturated fatty acids are particularly susceptible to free radical damage, and it is noteworthy that the photoreceptor membranes of both rods and cones contain a lipid bilayer [
A number of studies have investigated dietary intake of total fat, saturated fat, and polyunsaturated fat with respect to ARM (Table
Studies investigating the relationship between dietary fat/fish intake and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
National Health and Nutrition Examination Survey III [ | 7883 | Total fat intake (percentage of total energy) | Early ARM | 1.4 | 0.9–2.2 |
Late ARM | 0.7 | 0.2–2.6 ( | |||
Blue Mountains Eye Study [ | 2900 | Energy-adjusted intake of cholesterol | Late ARM | 2.71 | 0.93–7.96 |
Frequency of fish consumption per week | Late ARM | 0.52 | 0.22–1.24 (1/wk) | ||
0.47 | 0.20–1.11 (2–4/wk) | ||||
0.46 | 0.12–1.68 ( | ||||
Prospective Studies | |||||
Beaver Dam Eye Study [ | 2152 | Saturated fat %kJ | Early ARM | 1.8 | 1.2–2.7 |
Cholesterol Mg/4200 kJ | Early ARM | 1.6 | 1.1–2.4 | ||
Blue Mountains Eye Study [ | 2335 | Total dietary fat | Early ARM | 0.92 | 0.53–1.59 |
Late ARM | 1.19 | 0.36–3.94 | |||
Frequency of fish consumption per week | Early ARM | 0.58 | 0.37–0.90 (1/wk) | ||
Late ARM | 0.25 | 0.06–1.00 (3/wk) |
The retina is subjected to high levels of cumulative irradiation with visible light over a lifetime. Exposure to ambient light is known to result in retinal injury, and a number of laboratory studies indicate that oxidative stress plays a role in this process [
Unfortunately, it is difficult to accurately measure cumulative and lifetime exposure to visible light. The Beaver Dam Eye Study investigated how exposure to sunlight relates to prevalence and incidence (5 and 10 years) of ARM and found significant associations between extended exposure to summertime sun and the 10-year incidence of early ARM [
Studies investigating the relationship between cumulative sunlight exposure and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Beaver Dam Eye Study [ | 4926 | Amount of time spent outdoors in summer | Retinal pigmentary changes | 1.44 | 1.01–2.04 (men) |
Amount of leisure time spent outdoors in summer | Late ARM | 2.19 | 1.12–4.25 (men) | ||
Pathologies Oculaires Liees a L’Age [ | 2584 | Ambient solar Radiation | Early ARM | 0.73 | 0.54–0.98 |
Leisure exposure to sunlight | Early ARM | 0.80 | 0.64–1.00 | ||
Prospective Studies | |||||
Beaver Dam Eye Study [ | 3684 | Amount of leisure time spent outdoors aged 13–19 years and aged 30–39 years | Early ARM | 2.09 | 1.19–3.65 |
Beaver Dam Eye Study [ | 2764 | Amount of leisure time spent outdoors aged 13–19 years, aged 30–39 years and at baseline examination | Early ARM | 2.20 | 1.02–4.73 |
Average annual UV-B exposure | Early ARM | 0.83 | 0.62–1.10 | ||
Late ARM | 1.00 | 0.54–1.82 |
It has been proposed that refractive error may be etiologically important for the development of ARM [
The pathophysiologic mechanisms for any association between refractive error and ARM remain unclear. Hypermetropic eyes typically have a smaller axial length than emmetropic or myopic eyes, and have a tendency towards increased scleral thickness [
A number of case-control studies have looked at the association between hypermetropia and ARM [
Studies investigating the relationship between refractive error and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Blue Mountains Eye Study [ | 3654 | Each diopter of increase in mean spherical equivalent | Early ARM | 1.1 | 1.0–1.2 |
Late ARM | 1.0 | 0.9–1.1 | |||
Rotterdam Study [ | 6209 | Each diopter of increase towards hypermetropia | Early ARM | 1.09 | 1.04–1.14 |
Late ARM | 1.09 | 1.01–1.19 | |||
Beijing Eye Study [ | 4439 | Hypermetropia | Early ARM | N/A | 1.1–1.34 |
Late ARM | 0.76–1.05 | ||||
Prospective Studies | |||||
Blue Mountains Eye Study [ | 2335 | Each diopter of increase in mean spherical equivalent | Early ARM | 1.1 | 0.98–1.15 |
Late ARM | 1.1 | 0.9–1.2 | |||
Beaver Dam Eye Study [ | 3684 | Hypermetropia +1.00 diopter or more | Early ARM | 0.86 | 0.62–1.19 (Right Eye) |
0.75 | 0.55–1.03 (Left Eye) | ||||
Late ARM | 2.09 | 0.30–14.49 (Right Eye) | |||
3.56 | 0.59–21.74 (Left Eye) | ||||
Beaver Dam Eye Study [ | 3306 | Hypermetropia +1.00 diopter or more | Early ARM | 0.9 | 0.7–1.1 |
Late ARM | 1.2 | 0.6–2.3 | |||
Rotterdam Study [ | 4935 | Each diopter of increase towards hypermetropia | Early and late ARM | 1.05 | 1.01–1.10 |
Similarly, the Beaver Dam Eye Study failed to identify a relationship between refractive status and either the 5-or 10-year incidence of ARM (early or late) [
Iris color is related to skin pigmentation, and therefore a relationship, if any, between iris color and ARM must be interpreted with full appreciation of the possibility that any observed association between iris color and ARM may actually reflect ethnicity-based differences for this condition.
Subjects with nonblue irides have increased tissue concentrations of melanin, and this is also evident in the choroid [
Initial case-control studies suggested that brown-colored irides were associated with a reduced risk for ARM [
Studies investigating the relationship between iris color and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Copenhagen City Eye Study [ | 924 | Brown versus blue iris color | Drusen and decreased vision | 0.7 | N/A |
Blue Mountains Eye Study [ | 3654 | Blue versus brown iris colour | Early ARM | 1.45 | 1.1–1.9 |
Late ARM | 1.69 | 1.0–2.9 | |||
Early ARM | 1.06 | 0.76–1.47 (Right eye) | |||
1.15 | 0.85–1.56 (Left eye) | ||||
Prospective Studies | |||||
Beaver Dam Eye Study [ | 3684 | Brown iris Color | Late ARM | 1.61 | 0.60–4.33 (Right eye) |
0.99 | 0.41–2.37 (Left eye) | ||||
Beaver Dam Eye Study [ | 2764 | Blue versus brown iris color | Soft indistinct drusen | 1.53 | 1.19–1.97 |
Retinal pigment abnormalities | 0.58 | 0.41–0.82 |
There is a strong correlation between hair color and iris color, thus prompting a number of researchers to investigate hair color with respect to risk for ARM. The Beaver Dam Eye Study showed that people with brown hair were less likely to develop early ARM, in the form of pigmentary abnormalities, when compared to those with blond hair [
Cataract and ARM are the most frequent causes of decreased vision in older people. Of the numerous cataract subtypes, the most commonly seen are nuclear sclerosis, cortical lens opacities, and posterior subcapsular cataracts. The prevalence of lens opacification rises with increasing age and may therefore have risk factors common with ARM. Alternatively, cataracts could, in theory at least, have a protective effect against ARM due to their light-absorbing properties.
It has been hypothesized that cataracts may provide protection against ARM by absorbing blue light, and thus reducing oxidative damage to the retina [
As sunlight has been putatively implicated in the pathogenesis of ARM, the possibility that cataract surgery results in increased risk of ARM has been postulated. Indeed, ophthalmologists often observe the development of neovascular AMD shortly following cataract surgery. Such a hypothesis has prompted lens manufacturers to incorporate a blue-light filter into the intraocular lens. However, the benefit of such blue-filtering intraocular lenses has yet to be established [
Early population-based epidemiological studies have reported inconsistent findings on the relationship between cataract and ARM (Table
Studies investigating the relationship between cataract and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Framingham Eye Study [ | Nuclear sclerosis | Early and late ARM | N/A | ||
Cortical lens opacity | Early and late ARM | N/A | |||
National Health and Nutrition Examination Survey I [ | 3087 | Opacity without visual impairment | ARM | 1.80 | 1.40–2.30 |
Cataract | ARM | 1.14 | 0.84–1.55 | ||
Blue Mountains Eye Study [ | 3654 | Nuclear Sclerosis | Early ARM | 1.0 | 0.6–1.9 |
Late ARM | 1.6 | 0.5–5.3 | |||
Cortical lens Opacity | Early ARM | 1.4 | 0.9–2.2 | ||
Late ARM | 1.7 | 0.7–4.2 | |||
Posterior Subcapsular lens Opacity | Early ARM | 1.1 | 0.4–2.7 | ||
Late ARM | 3.0 | 1.0–9.3 | |||
Beaver Dam Eye Study [ | 4926 | Nuclear sclerosis | Early ARM | 1.96 | 1.28–3.01 |
Late ARM | 1.38 | 0.52–3.63 | |||
ProspectiveStudies | |||||
Beaver Dam Eye Study [ | 2764 | Any lens opacity | Early ARM | 1.30 | 1.04–1.63 |
Copenhagen City Eye Study [ | 359 | Any lens opacity | Early and late ARM | 2.8 | 1.2–6.2 |
However, these limitations have been addressed in more recent studies. In 1994, the Beaver Dam Eye Study published evidence indicating that nuclear sclerosis was associated with an increased prevalence of early ARM, but not of late ARM [
Evidence for a relationship between cataract surgery and ARM is, however, more consistent (Table
Studies investigating the relationship between cataract surgery and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Salisbury Eye Evaluation Project + Proyecto VER + Baltimore Eye Survey (Pooled data) [ | 2520 + 4774 + 4396 | Previous cataract surgery | Late ARM | 1.7 | 1.1–2.6 |
Andhra Pradesh Eye Study [ | 3723 | Previous cataract surgery | Early and late ARM | 3.79 | 2.1–6.78 |
Prospective Studies | |||||
Beaver Dam Eye Study [ | 3684 | Previous cataract surgery | Late ARM | 2.80 | 1.03–7.63 |
Beaver Dam Eye Study [ | 2764 | Previous cataract surgery | Early ARM | 1.36 | 0.82–2.23 |
Late ARM | 3.81 | 1.89–7.69 | |||
Blue Mountains Eye Study + Beaver Dam Eye Study (Pooled data) [ | 3684 + 2335 | Previous cataract surgery | Late ARM | 5.7 | 2.4–13.6 |
Blue Mountains Eye Study [ | 1952 | Previous cataract surgery | Late ARM | 3.3 | 1.1–9.9 |
In conclusion, the relationship between cataract and cataract surgery and AMD has been the subject of much debate over recent years. With regard to cataract and ARM, some studies show cataract to be negatively associated with ARM, others having equivocal results. With regard to cataract surgery and ARM, some studies show it to be beneficial in AMD patients, whereas others show cataract extraction to have deleterious effects and result in progression of disease. At this time however, it is not possible to draw reliable conclusions from the available data to determine whether cataract surgery is beneficial or harmful in people with AMD. Physicians will have to make practice decisions based on best clinical judgment until appropriate studies are conducted and reported.
The association, if any, between alcohol consumption and ARM has been investigated in a number of studies.
Alcohol has been shown to have both harmful and beneficial effects with respect to a number of conditions, and may exert deleterious effects by interfering with cellular defense mechanisms against oxidative processes [
However, investigation of the association between alcohol and cardiovascular disease has also revealed a number of mechanisms whereby alcohol may actually exert beneficial effects. Putative mechanisms leading to a protective effect of alcohol include increased HDL cholesterol, decreased platelet aggregation [
Initial evidence from the Beaver Dam Eye Study revealed that consumption of beer in the past year was associated with an increased prevalence of pigmentary changes at the macula, and of neovascular AMD (Table
Studies investigating the relationship between alcohol and risk for ARM.
Study | No. of cases | Measure of risk factor | Type of ARM | Odds ratio or relative risk | 95% confidence interval |
---|---|---|---|---|---|
Cross-Sectional Studies | |||||
Beaver Dam Eye Study [ | 4926 | Consumption of beer in the past year | Pigmentary changes | 1.13 | 1.02 |
Neovascular AMD | 1.41 | 1.41 | |||
Blue Mountains Eye Study [ | 3654 | Consumption of spirits | Early ARM | 1.61 | 1.07–2.41 |
Consumption of beer | Early ARM | 1.42 | 0.86–2.35 | ||
Late ARM | 0.89 | 0.32–2.48 | |||
National Health and Nutrition Examination Survey 1 [ | 3072 | Consumption of wine | Early and Late ARM | 0.81 | 0.67–0.99 |
Los Angeles Latino Eye Study [ | 5875 | “Heavy” consumption of alcohol ( | Geographic atrophy | 12.7 | 1.5–104.6 |
Neovascular AMD | 5.8 | 1.3–25.8 | |||
Andhra Pradesh Eye Study [ | 3723 | “Light” alcohol drinkers versus non-drinkers | Early and late ARM | 0.38 | 0.19–0.76 |
Prospective Studies | |||||
Beaver Dam Eye Study [ | 3534 | Consumption of | Early ARM | N/A | N/A [Power 0.08 (10.6% Incidence versus 6.9% Incidence)] |
Reykjavik Eye Study [ | 846 | Current alcohol consumption | Soft drusen | 0.48 | 0.28–0.82 ( |
0.34 | 0.16–0.72 ( | ||||
Copenhagen City Eye Study [ | 359 | Alcohol consumption | Early ARM | 4.6 | 1.1–19.2 |
Other studies have also investigated the effects of total alcohol consumption with respect to age related maculopathy. Cross-sectional data from the Reykjavik Eye Study found that current alcohol consumption was associated with decreased risk of drusen formation, and increased risk of pigmentary changes, at the macula [
The association between use of certain medications and risk of ARM has been investigated in a number of population-based epidemiologic studies [
Certain medications, such as chloroquine and chlorpromazine, are well known to have toxic effects on the human retina [
A review of studies investigating the relationship between ARM and hormone replacement therapy and lipid-lowering agents has already been discussed.
The Beaver Dam Eye Study investigated the association, if any, between medication use and the 5-year incidence of early ARM [
Due to the difficulties and limitations in the studies designed to investigate associations between medication usage and ARM, data from the Beaver Dam Eye Study, the Blue Mountains Eye Study, and the Rotterdam Study has been pooled [
Intake of caffeine has been shown to have a vasoconstrictive effect on the retinal capillary circulation at the macula [
ARM can also be considered to be part of a global aging process, as well as a specific disease entity. In this context, markers of frailty or biologic aging may be relevant to risk for ARM. Such markers include gait-time, handgrip strength, peak expiratory flow rate, and the ability to stand from a sitting position without using the arms. The Beaver Dam Eye Study has examined the relationship between these markers and ARM [
Meaningful comment on risk for ARM has been greatly facilitated by a large number of studies of varying design that have been published over the last twenty years. Our review of case series, large-scale population-based studies, cohort, cross-sectional, and case-control studies strongly indicate that age, tobacco use, and family history of ARM represent indeed the risk for this condition. Further, there is a growing body of evidence that cataract surgery and obesity also represent risk for ARM, especially the neovascular form of this disease.
However, population-based epidemiologic studies have failed to consistently demonstrate associations between ARM and a myriad of other potential risk factors. It should be noted that the low prevalence of late ARM in the general population makes the detection of relationships with potential risk factors for its development particularly difficult in the context of population-based studies. Moreover, identification of relationships may also be confounded where disease expression is strongly determined by genetic background. Indeed, our recently enhanced understanding of the genetic basis of ARM will inform the design and interpretation of future studies attempting to investigate risk for ARM, and the role of gene-environment interaction in the etiopathogenesis of this condition.
References for this review were identified through a comprehensive systematic literature search of the electronic MEDLINE database (1966–2008) using the Pubmed search service. Further articles, abstracts, and textbook references generated from reviewing the bibliographies of the initial search were selectively included. To ensure the up-to-date nature of our review article, current issues of
The authors have no proprietary or commercial interest in any product or concept discussed in this article.