gout gout gout (/ɡaʊt/ gowt) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crystals. pain typically comes on rapidly, reaching maximal intensity in less than 12 hours. the joint at the base of the big toe is affected (podagra) in about half of cases. it may also result in tophi, kidney stones, or kidney damage. goutother namesarthritis uratica, or podagra when of the footvideo summary (script). leading with the gout (james gillray, 1799), which depicts the pain of the artist's gout as a demon or dragon.specialtyrheumatologysymptomsjoint pain, swelling, and rednessusual onsetolder males, post-menopausal womencausesuric acidrisk factorsdiet high in meat or beer, being overweight, geneticsdifferential diagnosisjoint infection, rheumatoid arthritis, pseudogout, otherspreventionweight loss, abstinence from drinking alcohol, allopurinoltreatmentnsaids, glucocorticoids, colchicinefrequency1–2% (developed world) gout is due to persistently elevated levels of uric acid (urate) in the blood (hyperuricemia). this occurs from a combination of diet, other health problems, and genetic factors. at high levels, uric acid crystallizes and the crystals deposit in joints, tendons, and surrounding tissues, resulting in an attack of gout. gout occurs more commonly in those who regularly drink beer or sugar-sweetened beverages; eat foods that are high in purines such as liver, shellfish, or anchovies; or are overweight. diagnosis of gout may be confirmed by the presence of crystals in the joint fluid or in a deposit outside the joint. blood uric acid levels may be normal during an attack. treatment with nonsteroidal anti-inflammatory drugs (nsaids), glucocorticoids, or colchicine improves symptoms. once the acute attack subsides, levels of uric acid can be lowered via lifestyle changes and in those with frequent attacks, allopurinol or probenecid provides long-term prevention. taking vitamin c and eating a diet high in low-fat dairy products may be preventive. gout affects about 1 to 2% of adults in the developed world at some point in their lives. it has become more common in recent decades. this is believed to be due to increasing risk factors in the population, such as metabolic syndrome, longer life expectancy, and changes in diet. older males are most commonly affected. gout was historically known as "the disease of kings" or "rich man's disease". it has been recognized at least since the time of the ancient egyptians. signs and symptoms gout presenting as slight redness in the metatarsophalangeal joint of the big toe gout can present in several ways, although the most common is a recurrent attack of acute inflammatory arthritis (a red, tender, hot, swollen joint). the metatarsophalangeal joint at the base of the big toe is affected most often, accounting for half of cases. other joints, such as the heels, knees, wrists, and fingers, may also be affected. joint pain usually begins during the night and peaks within 24 hours of onset. this is mainly due to lower body temperature. other symptoms may rarely occur along with the joint pain, including fatigue and high fever. long-standing elevated uric acid levels (hyperuricemia) may result in other symptoms, including hard, painless deposits of uric acid crystals known as tophi. extensive tophi may lead to chronic arthritis due to bone erosion. elevated levels of uric acid may also lead to crystals precipitating in the kidneys, resulting in stone formation and subsequent urate nephropathy. cause black-and-white photograph of the arms and hands of a 50-year-old man, showing large tophi of sodium urate affecting the elbow, knuckles, and finger joints. the crystallization of uric acid, often related to relatively high levels in the blood, is the underlying cause of gout. this can occur because of diet, genetic predisposition, or underexcretion of urate, the salts of uric acid. underexcretion of uric acid by the kidney is the primary cause of hyperuricemia in about 90% of cases, while overproduction is the cause in less than 10%. about 10% of people with hyperuricemia develop gout at some point in their lifetimes. the risk, however, varies depending on the degree of hyperuricemia. when levels are between 415 and 530 μmol/l (7 and 8.9 mg/dl), the risk is 0.5% per year, while in those with a level greater than 535 μmol/l (9 mg/dl), the risk is 4.5% per year. lifestyle dietary causes account for about 12% of gout, and include a strong association with the consumption of alcohol, sugar-sweetened beverages, meat, and seafood. among foods richest in purines yielding high amounts of uric acid are dried anchovies, shrimp, organ meat, dried mushrooms, seaweed, and beer yeast. chicken and potatoes also appear related. other triggers include physical trauma and surgery. studies in the early 2000s found that other dietary factors are not relevant. specifically, a diet with moderate purine-rich vegetables (e.g., beans, peas, lentils, and spinach) is not associated with gout. neither is total dietary protein. alcohol consumption is strongly associated with increased risk, with wine presenting somewhat less of a risk than beer or spirits. eating skim milk powder enriched with glycomacropeptide (gmp) and g600 milk fat extract may reduce pain but may result in diarrhea and nausea. physical fitness, healthy weight, low-fat dairy products, and to a lesser extent, coffee and taking vitamin c, appear to decrease the risk of gout; however, taking vitamin c supplements does not appear to have a significant effect in people who already have established gout. peanuts, brown bread, and fruit also appear protective. this is believed to be partly due to their effect in reducing insulin resistance. other than dietary and lifestyle choices, the recurrence of gout attacks is also linked to the weather. high ambient temperature and low relative humidity may increase the risk of a gout attack. genetics gout is partly genetic, contributing to about 60% of variability in uric acid level. the slc2a9, slc22a12, and abcg2 genes have been found to be commonly associated with gout and variations in them can approximately double the risk. loss-of-function mutations in slc2a9 and slc22a12 causes low blood uric acid levels by reducing urate absorption and unopposed urate secretion. the rare genetic disorders familial juvenile hyperuricemic nephropathy, medullary cystic kidney disease, phosphoribosylpyrophosphate synthetase superactivity and hypoxanthine-guanine phosphoribosyltransferase deficiency as seen in lesch–nyhan syndrome, are complicated by gout. medical conditions gout frequently occurs in combination with other medical problems. metabolic syndrome, a combination of abdominal obesity, hypertension, insulin resistance, and abnormal lipid levels, occurs in nearly 75% of cases. 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 chemical structure of uric acid 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. 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 synovial fluid examination typewbc (per mm3) % neutrophilsviscosityappearance normal<2000hightransparent osteoarthritis<5000<25highclear yellow trauma<10,000<50variablebloody inflammatory2,000–50,00050–80lowcloudy yellow septic arthritis>50,000>75lowcloudy yellow gonorrhea~10,00060lowcloudy yellow tuberculosis~20,00070lowcloudy yellow inflammatory: gout, rheumatoid arthritis, rheumatic fever 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. plain x-rays are usually normal and are not useful for confirming a diagnosis of early gout. they may show signs of chronic gout such as bone erosion. synovial fluid a definitive diagnosis of gout is based upon the identification of monosodium urate crystals in synovial fluid or a tophus. all synovial fluid samples obtained from undiagnosed inflamed joints by arthrocentesis should be examined for these crystals. under polarized light microscopy, they have a needle-like morphology and strong negative birefringence. this test is difficult to perform and requires a trained observer. the fluid must be examined relatively soon after aspiration, as temperature and ph affect solubility. blood tests hyperuricemia is a classic feature of gout, but nearly half of the time gout occurs without hyperuricemia and most people with raised uric acid levels never develop gout. thus, the diagnostic utility of measuring uric acid levels is limited. hyperuricemia is defined as a plasma urate level greater than 420 μmol/l (7.0 mg/dl) in males and 360 μmol/l (6.0 mg/dl) in females. other blood tests commonly performed are white blood cell count, electrolytes, kidney function and erythrocyte sedimentation rate (esr). however, both the white blood cells and esr may be elevated due to gout in the absence of infection. a white blood cell count as high as 40.0×109/l (40,000/mm3) has been documented. differential diagnosis the most important differential diagnosis in gout is septic arthritis. this should be considered in those with signs of infection or those who do not improve with treatment. to help with diagnosis, a synovial fluid gram stain and culture may be performed. other conditions that can look similar include cppd (pseudogout), rheumatoid arthritis, psoriatic arthritis, palindromic rheumatism, and reactive arthritis. gouty tophi, in particular when not located in a joint, can be mistaken for basal cell carcinoma or other neoplasms. light microscopy of a touch preparation of a gout tophus, showing needle-shaped crystals. uric acid crystals in polarized light, showing negative birefringence, with yellow color when aligned parallel to the axis of the red compensator, and blue when aligned perpendicularly to it. in contrast, cppd (pseudogout) displays rhombus-shaped crystals with positive birefringence. gout on x-rays of a left foot in the metatarsal-phalangeal joint of the big toe. note also the soft tissue swelling at the lateral border of the foot. prevention risk of gout attacks can be lowered by complete abstinence from drinking alcoholic beverages, reducing the intake of fructose (e.g. high fructose corn syrup) and purine-rich foods of animal origin, such as organ meats and seafood. eating dairy products, vitamin c-rich foods, coffee, and cherries may help prevent gout attacks, as does losing weight. gout may be secondary to sleep apnea via the release of purines from oxygen-starved cells. treatment of apnea can lessen the occurrence of attacks. medications as of