When they break through the tophi, they trigger a local immune-mediated inflammatory reaction in macrophages, which is initiated by the NLRP3 inflammasome protein complex. Activation of the NLRP3 inflammasome recruits the enzyme caspase 1, which converts pro-interleukin 1β into active interleukin 1β, one of the key proteins in the inflammatory cascade. An evolutionary loss of urate oxidase (uricase), which breaks down uric acid, in humans and higher primates has made this condition common.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. 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. The increased precipitation at low temperatures partly explains why the joints in the feet are most commonly affected. Rapid changes in uric acid may occur due to factors including trauma, surgery, chemotherapy and diuretics. The starting or increasing of urate-lowering medications can lead to an acute attack of gout with febuxostat of a particularly high risk. Calcium channel blockers and losartan are associated with a lower risk of gout compared to other medications for hypertension. Diagnosis
Gout may be diagnosed and treated without further investigations in someone with hyperuricemia and the classic acute arthritis of the base of the great toe (known as podagra). Synovial fluid analysis should be done if the diagnosis is in doubt.
Other conditions commonly complicated by gout include lead poisoning, kidney failure, hemolytic anemia, psoriasis, solid organ transplants, and myeloproliferative disorders such as polycythemia. A body mass index greater than or equal to 35 increases male risk of gout threefold. Chronic lead exposure and lead-contaminated alcohol are risk factors for gout due to the harmful effect of lead on kidney function. Medication
Diuretics have been associated with attacks of gout, but a low dose of hydrochlorothiazide does not seem to increase risk. Other medications that increase the risk include niacin, aspirin (acetylsalicylic acid), ACE inhibitors, angiotensin receptor blockers, beta blockers, ritonavir, and pyrazinamide. The immunosuppressive drugs ciclosporin and tacrolimus are also associated with gout, the former more so when used in combination with hydrochlorothiazide. Hyperuricemia may be induced by excessive use of Vitamin D supplements. Levels of serum uric acid have been positively associated with 25(OH) D. The incidence of hyperuricemia increased 9.4% for every 10 nmol/L increase in 25(OH) D (P < 0.001). Pathophysiology
Gout is a disorder of purine metabolism, and occurs when its final metabolite, uric acid, crystallizes in the form of monosodium urate, precipitating and forming deposits (tophi) in joints, on tendons, and in the surrounding tissues. Microscopic tophi may be walled off by a ring of proteins, which blocks interaction of the crystals with cells and therefore avoids inflammation. 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.