Pathophysiology
Despite considerable research, the etiology of keratoconus remains unclear. Several sources suggest that keratoconus likely arises from a number of different factors: genetic, environmental or cellular, any of which may form the trigger for the onset of the disease. Once initiated, the disease normally develops by progressive dissolution of Bowman's layer, which lies between the corneal epithelium and stroma. As the two come into contact, cellular and structural changes in the cornea adversely affect its integrity and lead to the bulging and scarring characteristic of the disorder. Within any individual keratoconic cornea, regions of degenerative thinning coexisting with regions undergoing wound healing may be found. Scarring appears to be an aspect of the corneal degradation; however, a recent, large, multicenter study suggests abrasion by contact lenses may increase the likelihood of this finding by a factor over two.
A number of studies have indicated keratoconic corneas show signs of increased activity by proteases, a class of enzymes that break some of the collagen cross-linkages in the stroma, with a simultaneous reduced expression of protease inhibitors. Other studies have suggested that reduced activity by the enzyme aldehyde dehydrogenase may be responsible for a build-up of free radicals and oxidising species in the cornea. Whatever the pathogenetical process, the damage caused by activity within the cornea likely results in a reduction in its thickness and biomechanical strength. While keratoconus is considered a noninflammatory disorder, one study shows wearing rigid contact lenses by patients leads to overexpression of proinflammatory cytokines, such as IL-6, TNF-alpha, ICAM-1, and VCAM-1 in the tear fluid.
A genetic predisposition to keratoconus has been observed, with the disease running in certain families, and incidences reported of concordance in identical twins. The frequency of occurrence in close family members is not clearly defined, though it is known to be considerably higher than that in the general population, and studies have obtained estimates ranging between 6% and 19%. Two studies involving isolated, largely homogenetic communities have contrarily mapped putative gene locations to chromosomes 16q and 20q. Most genetic studies agree on an autosomal dominant model of inheritance. A rare, autosomal dominant form of severe keratoconus with anterior polar cataract is caused by a mutation in the seed region of mir-184, a microRNA that is highly expressed in the cornea and anterior lens. Keratoconus is diagnosed more often in people with Down's syndrome, though the reasons for this link have not yet been determined.
Keratoconus has been associated with atopic diseases, which include asthma, allergies, and eczema, and it is not uncommon for several or all of these diseases to affect one person. A number of studies suggest vigorous eye rubbing contributes to the progression of keratoconus, and patients should be discouraged from the practice. Iatrogenic keratoconus has also been observed following LASIK surgery, caused by removal of excessive stromal bed tissue.
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