Aetiology

Epidemiological studies have demonstrated that increasing age, family history, and current cigarette smoking are strong risk factors for age-related macular degeneration (AMD).[14] Other risk factors that have been identified include history of cardiovascular disease, high body mass index, previous cataract surgery, and hypertension.[14]​ Studies have found that people who consume foods higher in fruit, vegetables, legumes, wholegrains, and fish and lower in red meat (e.g., Mediterranean diet, Oriental-type diet) have a lower risk of AMD than people who consume foods that do not have these characteristics (e.g., Western-type diet with higher intake of red meat, processed meat, and high-fat dairy products).[15][16][17][18]​​​

Genetic studies have identified more than 50 polymorphisms that predispose individuals to AMD.[19]​ Examples include polymorphisms in and around genes that encode components of the alternative complement pathway such as complement factor H (CFH).[20]​ Polymorphisms in the CFH gene, together with a susceptility locus in the region of ARMS2 and HTRA1, are the major genetic risk factors for AMD.[19][20]​ Other polymorphisms have been identified in genes relating to oxidative stress, lipid metabolism, and neovascularisation.

Pathophysiology

Normal ageing of the eye is associated with changes to the retina including thickening of Bruch’s membrane (the membrane separating the retinal pigment epithelium [RPE] from the choroid) and the development of hard drusen.[21][22]​​​​ In the early and intermediate stages of AMD, larger soft drusen and subretinal drusenoid deposits (also referred to as reticular pseudodrusen) can develop alongside pigmentary changes to the RPE.[21][23]

Oxidative stress can occur with normal ageing of the eye due to an imbalance between the generation of reactive oxygen species and antioxidant defences.[24]​ People with AMD may be more susceptible to oxidative damage or may be more exposed to oxidative stress.[25]​ Oxidative damage may contribute to processes including inflammation, dysregulated lipid metabolism, mitochondrial damage, and dysfunction of the RPE, and RPE cell death in AMD.[24][26]​ However, the exact mechanisms underlying the role of oxidative stress in the pathogenesis of AMD are not yet fully understood.[22][27]

Inflammation also seems to be an important component of the AMD disease process. Drusen may trigger chronic inflammation, including the recruitment of macrophages and involvement of the complement system.[21][23]

In neovascular AMD, hypoxia of the RPE may lead to increased production of vascular endothelial growth factor by RPE cells, which is the major stimulus for macular neovascularisation (MNV).[21][28]​ The proliferation of abnormal blood vessels into the macula can result in macular oedema, subretinal haemorrhage, and fibrous scarring.[23] Neovascularisation in AMD was previously described as choroidal neovascularisation (CNV), but the term MNV is now used to reflect that neovascularisation can originate in the retina.[29][30]​​​​​

  • Type 1 MNV, previously known as occult CNV, originates in the choriocapillaris and grows into the sub-RPE space. Polypoidal choroidal vasculopathy is a subtype that involves a branching vascular network and polyps.

  • Type 2 MNV, previously known as classic CNV, originates in the choroid and grows into the sub-retinal space.

  • Type 3 MNV, previously known as retinal angiomatous proliferation, originates in the retinal circulation and grows into the outer retina.

It is thought that geographic atrophy may result from metabolic stress leading to RPE cellular damage and secondary loss of adjacent photoreceptors and choriocapillaris.[31]

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