Etiology
Epidemiological studies have demonstrated that increasing age, family history, and current cigarette smoking are strong risk factors for AMD.[9] Other risk factors that have been identified include history of cardiovascular disease, high body mass index, previous cataract surgery, hypertension, and low dietary intakes of vitamins (A, C, and E), omega-3 fatty acids, lutein, and zinc.[9][10] One study showed that people with a Western-type diet had a higher risk of AMD than those with an Oriental-type diet.[11] Another study found that red meat intake was associated with an increased risk of late AMD, whereas fruit intake was found to be protective.[12]
Genetic studies have identified a series of polymorphisms that predispose to AMD. Polymorphisms in and around genes that encode components of the alternative complement pathway, especially CFH (complement factor H), have a major effect on risk. There is also a very important susceptibility locus in the ARMS2/HTRA1 region, and a number of other genetic associations have been identified with milder effects.[13] By analyzing genotype, clinical features, and known risk factors, it is now possible to predict with reasonable accuracy the likelihood of progression to late AMD.[14]
Pathophysiology
The involvement of the complement pathway and studies of the pathology of AMD implicate inflammatory processes in the disease process.[15] In addition, there is clear evidence that oxidative stress plays an important role.[16] However, the precise role of these processes in the initiation and progression of the condition remains unclear. Accumulation of iron, which is a known trigger of oxidative stress, within cells of the retinal pigment epithelium (RPE) could be involved in cellular damage.[17]
Deposition of extracellular material along the inner aspect of Bruch's membrane, the membrane separating the RPE from the choroids, plays a central role. This buildup of material alters the permeability of Bruch's membrane, resulting in decreased nutrient delivery to RPE cells and secondary metabolic stress.[18]
It is thought that metabolic stress leads to RPE cellular damage and secondary loss of adjacent photoreceptors and choriocapillaris, resulting in geographic atrophy.[19]
Ischemia of the RPE may lead to increased production of vascular endothelial growth factor by RPE cells, which is the major stimulus for neovascularization of the choriocapillaris. Choroidal neovascular vessels break through Bruch's membrane and are prone to leakage, leading to subretinal and intraretinal fluid accumulation.
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