Editing Gout (section)

==Pathophysiology==
[[File:Harnsäure Ketoform.svg|thumb|upright=1.2|alt=structure of organic compound: 7,9-dihydro-1H-purine-2,6,8(3H)-trione|Chemical structure of [[uric acid]]]]

Gout is a disorder of [[purine metabolism]],<ref name="Lancet2010" /> and occurs when its final metabolite, [[uric acid]], crystallizes in the form of monosodium urate, [[Precipitation (chemistry)|precipitating]] and forming deposits (tophi) in joints, on tendons, and in the surrounding tissues.<ref name=Nature2009/> Microscopic [[tophus|tophi]] may be walled off by a ring of proteins, which blocks interaction of the crystals with cells and therefore avoids inflammation.<ref name="LB&R">{{cite journal |last1=Liu-Bryan |first1=Ru |last2=Terkeltaub |first2=Robert |date=2006 |title=Evil humors take their Toll as innate immunity makes gouty joints TREM-ble |journal=Arthritis & Rheumatism |volume=54 |issue=2 |pages=383–386 |doi=10.1002/art.21634 |pmid=16447213 |doi-access=free }}</ref> Naked crystals may break out of walled-off tophi due to minor physical damage to the joint, medical or surgical stress, or rapid changes in uric acid levels.<ref name="LB&R"/> When they break through the tophi, they trigger a local [[immune]]-mediated [[inflammation|inflammatory]] reaction in [[macrophages]], which is initiated by the [[NLRP3]] [[inflammasome|inflammasome protein complex]].<ref name="Dalbeth2016"/><ref name="Nature2009" /><ref name="LB&R"/> Activation of the NLRP3 inflammasome recruits the enzyme [[caspase 1]], which converts pro-interleukin 1β into active [[interleukin-1 beta|interleukin 1β]], one of the key proteins in the inflammatory cascade.<ref name="Dalbeth2016">{{cite journal|last1=Dalbeth|first1=N|author1-link= Nicola Dalbeth |last2=Merriman|first2=TR|last3=Stamp|first3=LK|title=Gout|journal=Lancet|date=April 2016|volume=388|issue=10055|pages=2039–2052|doi=10.1016/S0140-6736(16)00346-9|pmid=27112094|s2cid=208790780|type=Review}}</ref> An evolutionary loss of [[urate oxidase]] (uricase), which breaks down uric acid, in humans and higher [[primate]]s has made this condition common.<ref name="Lancet2010" />

The triggers for precipitation of uric acid are not well understood. While it may crystallize at normal levels, it is more likely to do so as levels increase.<ref name="Nature2009" /><ref name="pmid17595458">{{cite journal |vauthors=Virsaladze DK, Tetradze LO, Dzhavashvili LV, Esaliia NG, Tananashvili DE |title=[Levels of uric acid in serum in patients with metabolic syndrome] |language=ru |journal=Georgian Med News|issue=146 |pages=35–37 |year=2007 |pmid=17595458 |trans-title=Levels of uric acid in serum in patients with metabolic syndrome }}</ref> Other triggers believed to be important in acute episodes of arthritis include cool temperatures, rapid changes in uric acid levels, [[acidosis]], articular hydration and [[extracellular matrix]] proteins.<ref name="Lancet2010" /><ref name="pmid12672211">{{cite journal|vauthors=Moyer RA, John DS | title = Acute gout precipitated by total parenteral nutrition| journal = The Journal of Rheumatology| volume = 30| issue = 4| pages = 849–850| year = 2003| pmid = 12672211}}</ref><ref name="pmid7783706">{{cite journal|vauthors=Halabe A, Sperling O | title = Uric acid nephrolithiasis| journal = Mineral and Electrolyte Metabolism| volume = 20| issue = 6| pages = 424–431| year = 1994| pmid = 7783706}}</ref> The increased precipitation at low temperatures partly explains why the joints in the feet are most commonly affected.<ref name="Review08" /> Rapid changes in uric acid may occur due to factors including trauma, surgery, [[chemotherapy]] and diuretics.<ref name="Egg2007" /> The starting or increasing of urate-lowering medications can lead to an acute attack of gout with [[febuxostat]] of a particularly high risk.<ref name=CKS2019>{{cite web |title=Gout |url=https://cks.nice.org.uk/gout#!scenario:1 |website=NICE |access-date=22 August 2019 |archive-date=28 October 2016 |archive-url=https://web.archive.org/web/20161028200324/http://cks.nice.org.uk/gout#!scenario:1 |url-status=live }}</ref> [[Calcium channel blocker]]s and [[losartan]] are associated with a lower risk of gout compared to other medications for [[hypertension]].<ref name="pmid22240117">{{cite journal|vauthors=Choi HK, Soriano LC, Zhang Y, Rodríguez LA | title=Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study | journal=BMJ | year= 2012 | volume= 344 |pages= d8190 | pmid=22240117 | doi=10.1136/bmj.d8190 | pmc=3257215}}</ref>