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Keratoconus
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== Pathophysiology == [[File:David G Cogan case 245 keratoconus thin stroma wrinkled endothelium.png|thumb|A specimen of keratoconic cornea taken out six years after diagnosis: thin stroma, wrinkled posterior surface]] Despite considerable research, the cause of keratoconus remains unclear.<ref name="puco"/> 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.<ref name="grayson">{{cite book | last =Arffa R| year = 1997| title = Grayson's Diseases of the Cornea. Chap. 17 | pages = 452β454| publisher = Mosby | isbn = 978-0-8151-3654-5 }}</ref><ref name="nkcf">Brown D. ''National Keratoconus Foundation: Research Overview.'' http://www.nkcf.org {{webarchive|url=https://web.archive.org/web/20040322044445/http://nkcf.org/ |date=22 March 2004 }}. Accessed 12 February 2006.</ref><ref>Warren, Catherine. What Causes Keratoconus? National Keratoconus Foundation. {{cite web |url=http://www.nkcf.org/what-is-keratoconus/ |title=What is Keratoconus Disease - Bulging Eye Disease Causes, Symptoms | NKCF |access-date=30 March 2015 |url-status=dead |archive-url=https://web.archive.org/web/20131211044918/http://www.nkcf.org/what-is-keratoconus/ |archive-date=11 December 2013}} (14 March 2015)</ref> Once initiated, the disease normally develops by progressive dissolution of [[Bowman's layer]],<ref name="epstein"/> which lies between the corneal [[epithelium]] and [[Stroma of cornea|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.<ref>{{Cite journal |last=Barr JT |last2=Wilson BS |last3=Gordon MO |last4=Rah |first4=Marjorie J |last5=Riley |first5=Colleen |last6=Kollbaum |first6=Pete S |last7=Zadnik |first7=Karla |display-authors=3 |date=January 2006 |title=Estimation of the incidence and factors predictive of corneal scarring in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study |journal=Cornea |volume=25 |issue=1 |pages=16β25 |doi=10.1097/01.ico.0000164831.87593.08 |pmid=16331035 |s2cid=220574540}}</ref><ref>{{cite web|title=The Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study Archive |url=https://vrcc.wustl.edu/clekarchive/ |url-status=dead |archive-url=https://web.archive.org/web/20070630052538/https://vrcc.wustl.edu/clekarchive/ |archive-date=30 June 2007}}</ref> A number of studies have indicated keratoconic corneas show signs of increased activity by [[protease]]s,<ref name="grayson"/> a class of [[enzyme]]s that break some of the [[collagen]] cross-linkages in the stroma, with a simultaneous reduced [[Gene expression|expression]] of protease [[Enzyme inhibitor|inhibitors]].<ref name="Spoerl1">{{cite journal |vauthors=Spoerl E, Wollensak G, Seiler T |title=Increased resistance of crosslinked cornea against enzymatic digestion |journal=Current Eye Research |volume=29 |issue=1 |pages=35β40 |date=July 2004 |pmid=15370365 |doi=10.1080/02713680490513182|s2cid=22361390 }}</ref> Other studies have suggested that reduced activity by the enzyme [[aldehyde dehydrogenase]] may be responsible for a build-up of [[free radical]]s and oxidising species in the cornea.<ref>{{cite journal |author=Gondhowiardjo TD |title=Analysis of corneal aldehyde dehydrogenase patterns in pathologic corneas |journal=Cornea |volume=12 |issue=2 |pages=146β54 |date=March 1993 |pmid=8500322 |doi=10.1097/00003226-199303000-00010 |author2=van Haeringen NJ |author3=VΓΆlker-Dieben HJ |display-authors=3 |last4=Beekhuis |first4=Houdijn W. |last5=Kok |first5=Jan H.C. |last6=Van Rij |first6=Gabriel |last7=Pels |first7=Liesbeth |last8=Kijlstra |first8=Aize|s2cid=45104769 }}</ref> Whatever the [[Pathogenesis|pathogenetical process]], the damage caused by activity within the cornea likely results in a reduction in its thickness and biomechanical strength. At an ultrastructural level the weakening of the corneal tissue is associated with a disruption of the regular arrangement of the collagen layers and collagen fibril orientation.<ref>{{cite journal |vauthors=Daxer A, Fratzl P | year = 1997 | title = Collagen fibril orientation in the human corneal stroma and its implications in keratoconus | journal = Invest Ophthalmol Vis Sci | volume = 38 | issue = 1| pages = 121β129 | pmid = 9008637 }}</ref> While keratoconus is considered a noninflammatory disorder, one study shows wearing rigid contact lenses by people leads to overexpression of proinflammatory [[cytokine]]s, such as [[Interleukin 6|IL-6]], [[TNF-alpha]], [[ICAM-1]], and [[VCAM-1]] in the tear fluid.<ref name="pmid18650659">{{cite journal |vauthors=Lema I, DurΓ‘n JA, Ruiz C, DΓez-Feijoo E, Acera A, Merayo J |title=Inflammatory response to contact lenses in patients with keratoconus compared with myopic subjects |journal=Cornea |volume=27 |issue=7 |pages=758β63 |date=August 2008 |pmid=18650659 |doi=10.1097/ICO.0b013e31816a3591|s2cid=25238570 }}</ref> A genetic predisposition to keratoconus has been observed,<ref>{{cite journal |vauthors=Edwards M, McGhee CN, Dean S |title=The genetics of keratoconus |journal=Clinical & Experimental Ophthalmology |volume=29 |issue=6 |pages=345β51 |date=December 2001 |pmid=11778802 |doi=10.1046/j.1442-9071.2001.d01-16.x|s2cid=46643398 }}</ref> with the disease running in certain families,<ref>{{cite journal |author=Zadnik K |title=Baseline findings in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study |journal=Investigative Ophthalmology & Visual Science |volume=39 |issue=13 |pages=2537β46 |date=December 1998 |pmid=9856763 |url=http://iovs.arvojournals.org/article.aspx?articleid=2161642 |author2=Barr JT |author3=Edrington TB |display-authors=3 |last4=Everett |first4=DF |last5=Jameson |first5=M |last6=McMahon |first6=TT |last7=Shin |first7=JA |last8=Sterling |first8=JL |last9=Wagner |first9=H |url-status=dead |archive-url=https://web.archive.org/web/20161003141110/http://iovs.arvojournals.org/article.aspx?articleid=2161642 |archive-date=3 October 2016 |access-date=25 June 2016 }}</ref> and incidences reported of [[Concordance (genetics)|concordance]] in identical twins.<ref name="rabonitz"/> 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,<ref name="puco"/> and studies have obtained estimates ranging between 6% and 19%.<ref name="Merin">{{cite book | last = Merin S| year = 2005 | title = Inherited Eye Disorders: Diagnosis and Management | publisher = Taylor & Francis | location =Boca Raton | isbn = 978-1-57444-839-9}}</ref> Two studies involving isolated, largely homogenetic communities have contrarily mapped putative gene locations to [[chromosome]]s 16q and 20q.<ref name="Merin"/> Most genetic studies agree on an [[autosomal]] [[Dominant gene|dominant]] model of inheritance.<ref name="feder"/> 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.<ref>{{cite journal | doi = 10.1016/j.ajhg.2011.09.014 | vauthors = Hughes AE, Bradley DT, Campbell M, Lechner J, Dash DP, Simpson DA, Willoughby CE | year = 2011 | title = Mutation Altering the miR-184 Seed Region Causes Familial Keratoconus with Cataract | journal = The American Journal of Human Genetics | volume = 89 | issue = 5 | pages = 628β33 | pmc = 3213395 | pmid = 21996275 | df = dmy-all }}</ref> Keratoconus is diagnosed more often in people with [[Down's syndrome]], though the reasons for this link have not yet been determined.<ref>{{cite journal |author=Rabinowitz YS |title=Keratoconus |journal=Survey of Ophthalmology |volume=42 |issue=4 |pages=297β319 |year=1998 |pmid=9493273 |doi=10.1016/S0039-6257(97)00119-7}}</ref> Researches also have shed light on the role of hormones in the pathophysiology of keratoconus. Hormones such as [[androgen]], [[prolactin]], [[estrogen]] and [[progesterone]] have been shown to influence corneal biomechanics and tissue remodeling, potentially affecting the integrity of the cornea in individuals predisposed to keratoconus.<ref>{{cite journal |title=Serum androgens and prolactin levels in patients with keratoconus |journal=Clin Exp Optom |date=2023 |doi=10.1080/08164622.2022.2081067 |pmid=35680612 |url=https://pubmed.ncbi.nlm.nih.gov/35680612/ |ref=10.1080/08164622.2022.2081067 |last1=Jamali |first1=Hossein |last2=Heydari |first2=Mojtaba |last3=Masihpour |first3=Nasrin |last4=Khosravi |first4=Amir |last5=Zare |first5=Mousa |last6=Shams |first6=Mesbah |last7=Omrani |first7=Gholamhossein Ranjbar |volume=106 |issue=5 |pages=484β488 |s2cid=249545241 }}</ref> Moreover, fluctuations in hormonal levels during puberty and pregnancy have been associated with the onset or exacerbation of keratoconus in some cases. Keratoconus has been associated with [[Atopic syndrome|atopic diseases]],<ref name=RobbinsCotranPath /> which include [[asthma]], [[allergies]], and [[eczema]], and it is not uncommon for several or all of these diseases to affect one person. Keratoconus is also associated with [[Alport syndrome]], [[Down syndrome]] and [[Marfan syndrome]].<ref name=RobbinsCotranPath>{{cite book|last=Kumar|first=Vinay|title=Robbins Basic Pathology|year=2007|publisher=Saunders/Elsevier|location=Philadelphia|isbn=978-1-4160-2973-1|chapter=Eye: Cornea, Degenerations and Dystrophies|edition=8th}}</ref> A number of studies suggest vigorous eye rubbing contributes to the progression of keratoconus, and people should be discouraged from the practice.<ref>{{cite journal |author=Koenig SB |title=Bilateral recurrent self-induced keratoconus |journal=Eye & Contact Lens |volume=34 |issue=6 |pages=343β4 |date=November 2008 |pmid=18997547 |doi=10.1097/ICL.0b013e31818c25eb}}</ref><ref>{{cite journal |vauthors=McMonnies CW, Boneham GC |title=Keratoconus, allergy, itch, eye-rubbing and hand-dominance |journal=Clinical & Experimental Optometry |volume=86 |issue=6 |pages=376β84 |date=November 2003 |pmid=14632614 |doi=10.1111/j.1444-0938.2003.tb03082.x|doi-access=free }}</ref><ref>{{cite journal |vauthors=Bawazeer AM, Hodge WG, Lorimer B |title=Atopy and keratoconus: a multivariate analysis |journal=The British Journal of Ophthalmology |volume=84 |issue=8 |pages=834β6 |date=August 2000 |pmid=10906086 |pmc=1723585 |doi=10.1136/bjo.84.8.834}}</ref><ref>{{cite journal |vauthors=Jafri B, Lichter H, Stulting RD |title=Asymmetric keratoconus attributed to eye rubbing |journal=Cornea |volume=23 |issue=6 |pages=560β4 |date=August 2004 |pmid=15256993 |doi=10.1097/01.ico.0000121711.58571.8d|s2cid=40534579 }}</ref><ref>{{cite journal |vauthors=Ioannidis AS, Speedwell L, Nischal KK |title=Unilateral keratoconus in a child with chronic and persistent eye rubbing |journal=American Journal of Ophthalmology |volume=139 |issue=2 |pages=356β7 |date=February 2005 |pmid=15734005 |doi=10.1016/j.ajo.2004.07.044}}</ref><ref>{{cite journal |vauthors=Lindsay RG, Bruce AS, Gutteridge IF |title=Keratoconus associated with continual eye rubbing due to punctal agenesis |journal=Cornea |volume=19 |issue=4 |pages=567β9 |date=July 2000 |pmid=10928781 |doi=10.1097/00003226-200007000-00034|s2cid=8978974 }}</ref> Keratoconus differs from [[ectasia]], which is caused by [[LASIK]] eye surgery. [[Post-LASIK Ectasia]] has been associated with the excessive removal of the eye's [[Stroma of cornea|stromal bed]] tissue during surgery.
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