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What Causes Macular Degeneration?

By Liji Thomas, MD

Macular cells are specialized photoreceptors, both cones and rods, though cones far outnumber rods at this focus. The condition called macular degeneration is caused by a mix of factors, both environmental and hereditary.

The causes of AMD include a complex interaction of advancing age, genetic factors, local inflammation as well as systemic inflammatory conditions.

AMD is predominantly a disease of age, as it is mostly found after the age of 60, and is second only to diabetic retinopathy as the cause of legal blindness in people between 45 and 65 years. If the population above 50 is taken as a whole, AMD accounts for the majority of cases of central vision loss and legal blindness.  

It has been found that several genes indicate a higher risk of AMD. One of these genes is the CFH gene, on chromosome 1, which contains a region showing polymorphism for an allele that increases the chances of developing AMD more than 7 times in homozygous individuals.

The same region also binds heparin and C-reactive protein. Other genes which are found to be associated with a higher risk of AMD include C3, C2, CFB, and CX3CR1. However, because of the unknown relationship between genetic and environmental factors, genetic testing is not currently widely recommended.

Another recent discovery is the role that inflammation plays in the genesis of AMD. Research shows a significantly higher level of specific types of CD lymphocytes in these patients, as compared to people without AMD.

Subretinal fibrosis, which occurs in a subset of patients with neovascular AMD, is associated with a higher circulating percentage of CD4+ lymphocytes, in contrast to patients without this finding.

AMD patients show higher levels of many proteins that form part of the complement cascade. They also demonstrate the presence of active inflammation, in the form of chemicals which induce inflammation, such as the interleukins IL-1α, IL-1β, and IL-17.

Additionally, a higher neutrophil: lymphocyte ratio is found in patients with AMD. This relative neutrophilia may account for several phenomena associated with AMD, such as the increase in pro-inflammatory molecules, the activation of T-cells, the heightened immune state, and neovascularization associated with this condition.

With regard to the pathophysiology, AMD may be either atrophic or neovascular. In the early stages of atrophic AMD, visual acuity remains unchanged.  Later, the loss of photoreceptor cells, the degeneration of retinal pigment epithelium, and the breakdown of the capillaries that supply the chorionic layer, result in failing vision.

In neovascular AMD, on the other hand, the growth of fragile new blood vessels into the retina interferes with the proper transmission of light, and this accounts for the loss of central vision. These new capillaries may grow under the pigmentary layer, or in the subretinal space. Sometimes they are found to grow within the retina itself, in a condition called retinal angiomatous proliferation.

The mechanism by which neutrophils induce the formation of new vessels in the retina may be by their production of matrix metalloproteinases (MMPs) which degrade the retinal pigment epithelial membrane, and by the release of molecules like vascular endothelial growth factor (VEGF) and IL-8.

The new retinal vessels formed are easily disrupted, and the resulting hemorrhages cause subretinal fibrosis, leading to permanent loss of vision at the center of the visual field. This is a characteristic of late stage AMD.

Further Reading

Last Updated: Dec 7, 2015

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