INTRODUCTION

Age-related macular degeneration (AMD) is one of the diseases affecting the choroid and retinal pigment epithelium (RPE) as well as the retina which has lately experienced many significant transitions. This is true for the pathogenesis, identification of risk factors, early detection of patients at risk, therapeutic options, public awareness, and socioeconomic impact.

The recent discoveries of genetic variants associated with an increased risk for AMD, especially the Y402H polymorphism of complement factor H (CFH) and a modification in the promoter region of HtrA serine peptidase 1 (HTRA1), have led to a completely new understanding of the disease.1–5 These findings clearly indicate that genetic predisposition is the key factor in the etiology of AMD. Several risk factors have been recognized in the past, but seem less relevant compared to genetic predisposition. Genetic screening for AMD will become most valuable for identifying patients with increased risk for AMD at a young age, possibly allowing early preventive measures. Therapies aiming to modulate the complement cascade, especially the alternative pathway, are currently under intensive investigation with the goal of changing the course of AMD. Paroxysmal nocturnal hematuria (PNH), a rare disease of the complement system, has been shown to be effectively and safely treated by complete inhibition of the complement system using eculizumab, and may serve as a spearhead for AMD.6 The increase in patients with nonneovascular AMD, especially in industrialized countries, demonstrates that better diagnostic tools and treatments are desperately needed for this form of AMD.

DISEASE PREVALENCE AND INFLUENCE

Several large epidemiologic studies have evaluated the prevalence of nonneovascular or so-called dry AMD. There is some variation in the prevalence of nonneovascular AMD depending on the exact definition of AMD, the age range of the populations evaluated, and genetic as well as environmental variations. Common to all studies is the higher prevalence of early AMD and an increasing prevalence with age. In the early 1990s in the USA the National Health and Nutrition Examination Survey (NHANES) showed a prevalence of 9.2% for all types of AMD in a population 40 years and older. Nonneovascular AMD is considered to make up about 85% of AMD cases. When pooling the prevalence found in large epidemiologic studies inside and outside the USA, the prevalence of AMD in the USA is estimated to be 1.75 million citizens in 2003, increasing to 2.95 million in 2020.7 So far epidemiologic studies outside the USA have indicated that the occurrence of AMD might be generally lower than in the USA, as shown for example in the Rotterdam Study and the Blue Mountains Eye Study. Recently new epidemiologic studies on AMD have shifted the focus to two new areas of interest. First, certain populations, e.g., Norway and Greenland, seem to have a significantly higher prevalence of AMD than others. In a population aged at least 60 years, born and living in Greenland, the prevalence of any form of AMD was found to be 52.3%.8 These studies indicate a strong impact of genetic and/or environmental factors and show the

socioeconomic relevance of the disease. Lately the association of variants of CFH has been confirmed in many populations.

The second focus is on the prevalence of AMD in Asia. Little was known about AMD in India and China. The reasons for an increasing prevalence of AMD in Japan have not been conclusive. Prevalence of early AMD in a Japanese population is now at the level of the Australian population evaluated in the Beaver Dam Eye Study.9 Epidemiologic studies in different Chinese populations found a prevalence of AMD above 10% and increasing with age. However, in contrast to Caucasian populations, the frequency of the CFH risk allele seems to be significantly lower in Asian populations.

Overall the impact of AMD is enhanced by increasing life expectancy in most of the large populations throughout the world. Nonneovascular AMD is commonly associated with gradual vision loss. Irreversible severe vision loss can occur, and the risk of progression to neovascular AMD should not be neglected.

RISK FACTORS

Before the discovery of a strong association of CFH and HTRA1 polymorphisms with AMD, several observational studies revealed that AMD shares a number of risk factors with atherosclerosis, among which age and smoking are the most important. However, atherosclerosis itself has not been consistently confirmed to be a risk factor for AMD. Several worldwide epidemiologic studies have found that with age there is an increasing risk for any type of AMD. Cigarette smoking is the most relevant modifiable, dose-dependent risk factor for AMD. A prospective study on cigarette smoking and risk of AMD found a risk ratio of 2.46 for current smokers (at least 20 cigarettes per day) compared to nonsmokers.10 There is evidence that smoking in addition to variants of CFH and HTRA1 multiplies the risk for AMD.11 Homozygosis for Y402H in addition to smoking increased the risk for advanced AMD to have an odds ratio (OR) of 10.2.12 Further modifiable risk factors are a high body mass index (BMI) and fat intake. A BMI of at least 30 has been shown to have an OR of 2.1 for AMD. Again, homozygosis for Y402H polymorphism was found to multiply the OR to 5.9. There is ongoing controversy about dietary fats and their associated risk for AMD. Total fat intake has been consistently associated with an increased risk for AMD or AMD progression. Inconsistency of data with regard to vegetable or animal fats and their associated risk for AMD may be due to different regional fat preferences and regional differences in fat processing. A meta-analysis on the effect of lipidlowering agents in the development of AMD found no clear evidence for an AMD risk reduction.13 Interestingly there is a growing body of evidence that higher fish/omega-3 fatty acid consumption may have a protective effect for AMD.

Gender and socioeconomic status have not been shown to be a risk factor for AMD, whereas ethnicity may determine the risk for AMD. Black and Hispanic populations appear to have a lower prevalence for AMD than non-Hispanic white populations. Some Asian populations appear to have a prevalence for AMD comparable to white populations in western industrialized countries. These findings have been an indicator for a strong genetic component of the disease in the past.

Ocular risk factors such as refractive error, iris color, or cataracts have been investigated for a potential associated risk for AMD, but studies have either shown no association or have been contradictory. However, the strongest controversy concerns cataract surgery and progression of AMD.14 It is mostly based on the question whether the removal of the natural lens, the major barrier to wavelengths of 300–400 nm (near ultraviolet radiation), leads to an increased risk of AMD progression. Several experimental animal studies provide compelling evidence for light toxicity on the retina. However, epidemiologic studies have been contradictory. Most modern intraocular lenses (IOLs) absorb ultraviolet radiation (below 400 nm). The value of yellow IOLs, attenuating blue light in the wavelength range 400–500 nm, in reducing the potential risk of AMD progression following cataract surgery, remains currently unclear.

A genetic component has long been suspected to be the key risk factor for AMD. But only recently genetic polymorphism in the gene encoding for the CFH located on chromosome 1q32 (region of CFH) and polymorphisms on chromosome 10 (LOC387715/PLEKHA1/ HTRA1) were detected, validated, and accounted for a large part of the genetic risk for AMD. Variations in both regions are associated with an increased risk for AMD.1–5 The associated risk for AMD varies between studies due to inclusion of different stages of AMD, different ethnic populations, and slight variations in the gene loci tested. The risk increases in patients with homozygosis and varies for different types of AMD. In particular, one important single nucleotide polymorphism (SNP) has been identified as a replacement of the amino acid tyrosine with histidine at amino acid 402 in exon 9 (Tyr402His). Individuals who carry a single copy of the histidine allele in the Y402H polymorphism have a twoto fourfold increased risk of AMD; individuals who are homozygous for the risk allele have a fiveto sevenfold increased risk fordevelopingAMD.AccordinglytheincidentrateratiosforLOC387715 were found to be 2.5 and 5.5. Subjects homozygous for both risk alleles even have a 50 times increased risk for AMD. Overall the variations at chromosome 10q26 seem to be more strongly associated with neovascular AMD than the variation at chromosome 1q32.

ETIOLOGY/PATHOGENESIS

In the past four principal pathomechanisms have been postulated for nonneovascular AMD: oxidative stress, impairment of choroidal circulation, degeneration of Bruch’s membrane, and chronic inflammation.

The oxidative stress hypothesis as a pathomechanism of AMD is based on the breakdown of protective antioxidant systems within the retina. The key mechanism by which tissue damage due to reactive radicals or light-induced singlet oxygen occurs is the formation of lipid peroxides. Photoreceptors degenerate when exposed to continuous oxidative challenge or when antioxidative defense mechanisms are impaired. Currently the strongest evidence for a correlation of oxidative stress and AMD comes from the Age-related Eye Disease Study (AREDS). It investigated the use of high-dose vitamin C and E, betacarotene, zinc, and copper on AMD and cataract. Patients with intermediate dry AMD or significant vision loss due to AMD in the second eye showed most risk reduction for progression to advanced AMD and for a three-line decrease in visual acuity.15

The choroidal circulation theory goes back to Verhoeff and Grossman, who already in 1937 linked sclerotic changes of the choriocapillaris to AMD.16 Several studies using different techniques showed an association of reduced choroidal blood flow and AMD.17–20 As mentioned previously, atherosclerosis and AMD have very similar risk factors. However, choroidal vascular changes can also – without atherosclerosis

– occur secondary to impairment of the RPE.

Age-related changes in Bruch’s membrane are considered to compromise transport of nutrients and metabolic substances to and from the RPE. Degeneration and thickening of Bruch’s membrane with formation of drusen initiate or at least contribute to AMD. Drusen are the characteristic changes of early AMD. These deposits exceed those related to the normal aging process. They are located between the inner collagenous layer of Bruch’s membrane and the basement membrane

of the RPE. Despite the fact that degenerative changes of the RPE are regarded as the primary cause for the formation of drusen,21,22 there is indication that a variable degree of drusen composition are of choroidal origin. Interestingly, apolipoprotein E (apoE)-deficient mouse and mouse on a high-fat diet show deposits in Bruch’s membrane that are similar to AMD. A polymorphism of the apoE gene was found to be a risk factor for AMD.23

The role of inflammation in AMD has moved over the last years increasingly into the center of interest. Evidence for a role of inflammation in AMD was found not only in the retina (recruited macrophages, microglia) and in the blood (C-reactive protein (CRP), fibrinogen) but also in drusen, which were shown to contain complement activators, complement fragments, and membrane attack complex. In 2001, Hageman and co-workers outlined their model on the role of inflammation in AMD, proposing activation and recruitment of choroidal dendritic cells by locally injured RPE cells and subsequent drusen formation.24 Membranoproliferative glomerulonephritis type II, a rare disease showing activation of the alternate complement pathway and drusen undistinguishable from AMD, was the link to CFH.

Early in 2005 four different groups outlined a strong association of a SNP on chromosome 1q32 and AMD. This Y402H variant in the CFH gene seems to affect the physiologic function of CFH. CFH is a regulator of the alternative complement pathway that blocks C3 activation to C3b and also degrades C3b (Figure 17.1). The absence or malfunction of CFH seems to lead to an increased activation of the alternative complement pathway, likely related to the presence of complement proteins in drusen, as described above. It is currently unclear why this specific variant leads to protein deposition in the retina. Further polymorphisms have been found around CFH that are likely to be associated with AMD. Interestingly CRP is also a binding partner of CFH, and the CRP-binding site of CFH is located in the domain containing the Y402H polymorphism. Patients homozygous for Y402H were found to have a 2.5 times higher level of CRP in their RPE and choroid. The role of CRP in the interplay between CFH and AMD is however not well understood.

In addition to the alternative complement pathway, polymorphisms in neighboring genes on chromosome 10 (PLEKHA1, LOC387715, and HTRA1) have shown association with AMD. The three genes appear to be in linkage disequilibrium. In Asian populations, where neovascular AMD occurs more commonly, a polymorphism in the HTRA1 promoter seems to be far more frequent than variants of CFH. HTRA1 itself is a stress-inducible heat shock serine protease. A role of HTRA1 in the inhibition of the angiogenic tumor growth factor-β (TGF-β) has been proposed, but the mechanisms of action remain unclear.

Further polymorphisms of apoE, complement factor B (CFB) and component C2 (part of the classic complement pathway) have shown evidence for an association with AMD, but less strong than polymorphisms of CFH and the promoter of HTRA1.

The recent findings implicate that genetic predisposition is the key factor in the pathogenesis of AMD. Some relations to pathomechanisms and risk factors postulated in the past appear more evident than others.

DIAGNOSIS AND ANCILLARY TESTING/ DIFFERENTIAL DIAGNOSIS

The diagnosis of nonneovascular AMD is commonly made by retinal examination, showing the characteristic drusen, focal hyperor depigmentations, and/or areas of atrophy of the RPE. Retinal imaging and subsequent planimetric evaluation has been commonly used to evaluate nonneovascular AMD. Fluorescein angiography (FA) characteristically shows staining of drusen, window defects in areas of RPE atrophy, and focal fluorescein blockage in areas of hyperpigmentation. FA is generally used to exclude neovascular AMD. Within recent years two newer imaging modalities have become valuable in cases with nonneovascular AMD. Fundus autofluorescence (FAF) imaging enables topographic mapping of lipofuscin distribution in the RPE.25 FAF patterns have been associated with different degrees of RPE atrophy progression. It is however unclear if FAF pattern can serve as a predictive

Pharmacotherapy to Amenable Diseases Retinal • 3 section

Degeneration Macular related-Age neovascular • 17 chapterNon