Gout

Gout (Template:IPAc-en Template:Respell<ref>Template:Cite web</ref>) is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and swollen joint,<ref name="Hui2017">Template:Cite journal</ref><ref name="Dalbeth20162">Template:Cite journal</ref> caused by the deposition of needle-like crystals of uric acid known as monosodium urate crystals.<ref name="Abhishek">Template:Cite journal</ref> Pain typically comes on rapidly, reaching maximal intensity in less than 12 hours.<ref name="Lancet2010" /> The joint at the base of the big toe is affected (Podagra) in about half of cases.<ref name="PM2010">Template:Cite journal</ref><ref name="MW1">Template:Cite web</ref> It may also result in tophi, kidney stones, or kidney damage.<ref name="Dalbeth2016"/>

Gout is due to persistently elevated levels of uric acid (urate) in the blood (hyperuricemia).<ref name="Hui2017"/><ref name=Lancet2010/> This occurs from a combination of diet, other health problems, and genetic factors.<ref name="Dalbeth2016"/><ref name=Hui2017/> At high levels, uric acid crystallizes and the crystals deposit in joints, tendons, and surrounding tissues, resulting in an attack of gout.<ref name="Dalbeth2016"/> 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.<ref name="Dalbeth2016"/><ref name=Be2016>Template:Cite journal</ref> Diagnosis of gout may be confirmed by the presence of crystals in the joint fluid or in a deposit outside the joint.<ref name="Dalbeth2016"/> Blood uric acid levels may be normal during an attack.<ref name="Dalbeth2016"/>

Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, or colchicine improves symptoms.<ref name="Dalbeth2016"/><ref name=Hui2017/><ref name=Annals2017>Template:Cite journal</ref> 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.<ref name=Lancet2010>Template:Cite journal</ref> Taking vitamin C and having a diet high in low-fat dairy products may be preventive.<ref>Template:Cite web</ref><ref>Template:Cite journal</ref>

Gout affects about 1–2% of adults in the developed world at some point in their lives.<ref name=Lancet2010/> It has become more common in recent decades.<ref name="Dalbeth2016"/> This is believed to be due to increasing risk factors in the population, such as metabolic syndrome, longer life expectancy, and changes in diet.<ref name=Lancet2010/> Older males are most commonly affected.<ref name="Dalbeth2016"/> Gout was historically known as "the disease of kings" or "rich man's disease".<ref name=Lancet2010/><ref name=Dic>Template:Cite web</ref> It has been recognized at least since the time of the ancient Egyptians.<ref name=Lancet2010/>

Signs and symptoms

side view of a foot showing a red patch of skin over the joint at the base of the big toe

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).<ref name="Neogi2016"/> The metatarsophalangeal joint at the base of the big toe is affected most often, accounting for half of cases.<ref name=PM2010/> It can also involve midfoot structures, including the cuneiform bones.<ref>Template:Cite journal</ref> Other joints, such as the heels, knees, wrists, and fingers, may also be affected.<ref name="Neogi2016"/> Joint pain usually begins during the night and peaks within 24 hours of onset.<ref name="Neogi2016"/> This is mainly due to lower body temperature.<ref name="Dalbeth2016"/> Other symptoms may rarely occur along with the joint pain, including fatigue and high fever.<ref name=PM2010/><ref name=Egg2007>Template:Cite journal</ref>

Long-standing elevated uric acid levels (hyperuricemia) may result in other symptoms, including hard, painless deposits of uric acid crystals called tophi. Extensive tophi may lead to chronic arthritis due to bone erosion.<ref name=Nature2009/> Elevated levels of uric acid may also lead to crystals precipitating in the kidneys, resulting in kidney stone formation and subsequent acute uric acid nephropathy.<ref name=German09/>

Cause

File:Tophaceous gout affecting the arms and hands Wellcome L0062959.jpg

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.<ref name="Dalbeth2016"/> 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%.<ref name=Lancet2010/> About 10% of people with hyperuricemia develop gout at some point in their lifetimes.<ref name="pmid18327257">Template:Cite journal</ref> 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.<ref name=Egg2007/>

Lifestyle

Dietary causes account for about 12% of gout,<ref name=Review08>Template:Cite journal</ref> and include a strong association with the consumption of alcohol, sugar-sweetened beverages,<ref>Template:Cite journal</ref> meat, and seafood.<ref name="Neogi2016"/> The dietary mechanisms and nutritional basis involved in gout provide evidence for strategies of prevention and improvement of gout, and dietary modifications based on effective regulatory mechanisms may be a promising strategy to reduce the high prevalence of gout.<ref>Template:Cite journal</ref> Among foods richest in purines yielding high amounts of uric acid are dried anchovies, shrimp, organ meat, dried mushrooms, seaweed, and beer yeast.<ref>Template:Cite journal</ref> Chicken and potatoes also appear related.<ref name=Maj2018>Template:Cite journal</ref> Other triggers include physical trauma and surgery.<ref name=Lancet2010/>

Studies in the early 2000s found that other dietary factors are not relevant.<ref name=Epi2008/><ref name=Choi2004>Template:Cite journal</ref> Specifically, a diet with moderate purine-rich vegetables (e.g., beans, peas, lentils, and spinach) is not associated with gout.<ref name=Singh2011>Template:Cite journal</ref> Neither is total dietary protein.<ref name=Choi2004/><ref name=Singh2011/> Alcohol consumption is strongly associated with increased risk, with wine presenting somewhat less of a risk than beer or spirits.<ref name="Singh2011" /><ref>Template:Cite journal</ref> Eating skim milk powder enriched with glycomacropeptide (GMP) and G600 milk fat extract may reduce pain but may result in diarrhea and nausea.<ref>Template:Cite journal</ref>

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;<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name=Life2010>Template:Cite journal</ref><ref>Template:Cite journal</ref> however, taking vitamin C supplements does not appear to have a significant effect in people who already have established gout.<ref name="Dalbeth2016"/> Peanuts, brown bread, and fruit also appear protective.<ref name=Maj2018/> This is believed to be partly due to their effect in reducing insulin resistance.<ref name=Life2010/>

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.<ref>Template:Cite journal</ref>

Genetics

Gout is partly genetic, contributing to about 60% of variability in uric acid level.<ref name=Lancet2010/> The SLC2A9, SLC22A12, and ABCG2 genes have been found to be commonly associated with gout and variations in them can approximately double the risk.<ref>Template:Cite journal</ref><ref name="Reginato2012">Template:Cite journal</ref> Loss-of-function mutations in SLC2A9 and SLC22A12 causes low blood uric acid levels by reducing urate absorption and unopposed urate secretion.<ref name=Reginato2012/> 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.<ref name=Lancet2010/>

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.<ref name=PM2010/> Other conditions commonly complicated by gout include lead poisoning, kidney failure, hemolytic anemia, psoriasis, solid organ transplants, and myeloproliferative disorders such as polycythemia.<ref name=Lancet2010/><ref name="pmid16392875">Template:Cite journal</ref> A body mass index greater than or equal to 35 increases male risk of gout threefold.<ref name=Epi2008/> Chronic lead exposure and lead-contaminated alcohol are risk factors for gout due to the harmful effect of lead on kidney function.<ref>Template:Cite journal</ref>

Medication

Diuretics have been associated with attacks of gout, but a low dose of hydrochlorothiazide does not seem to increase risk.<ref name=CFP09/> Other medications that increase the risk include niacin, aspirin (acetylsalicylic acid), ACE inhibitors, angiotensin receptor blockers, beta blockers, ritonavir, and pyrazinamide.<ref name="Dalbeth2016"/><ref name=Nature2009/> The immunosuppressive drugs ciclosporin and tacrolimus are also associated with gout,<ref name=Lancet2010/> the former more so when used in combination with hydrochlorothiazide.<ref>Template:Cite book</ref> 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).<ref>Template:Cite journal</ref>

Pathophysiology

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, precipitating and forming deposits (tophi) in joints, on tendons, and in the surrounding tissues.<ref name=Nature2009/> Microscopic 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">Template:Cite journal</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 inflammatory reaction in macrophages, which is initiated by the NLRP3 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 1β, one of the key proteins in the inflammatory cascade.<ref name="Dalbeth2016">Template:Cite journal</ref> An evolutionary loss of urate oxidase (uricase), which breaks down uric acid, in humans and higher primates 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">Template:Cite journal</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">Template:Cite journal</ref><ref name="pmid7783706">Template:Cite journal</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>Template:Cite web</ref> Calcium channel blockers and losartan are associated with a lower risk of gout compared to other medications for hypertension.<ref name="pmid22240117">Template:Cite journal</ref>

Diagnosis

Template:Synovial fluid analysis 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.<ref name=Egg2007/><ref>Template:Cite journal</ref> Plain X-rays are usually normal and are not useful for confirming a diagnosis of early gout.<ref name=Lancet2010/> They may show signs of chronic gout such as bone erosion.<ref name=CKS2019/>

Synovial fluid

A definitive diagnosis of gout is based upon the identification of monosodium urate crystals in synovial fluid or a tophus.<ref name="Neogi2016"/> All synovial fluid samples obtained from undiagnosed inflamed joints by arthrocentesis should be examined for these crystals.<ref name=Lancet2010/> 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.<ref name="pmid18299687">Template:Cite journal</ref> The fluid must be examined relatively soon after aspiration, as temperature and pH affect solubility.<ref name=Lancet2010/>

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.<ref name=PM2010/><ref>Template:Cite journal</ref> Thus, the diagnostic utility of measuring uric acid levels is limited.<ref name=PM2010/> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> A white blood cell count as high as 40.0×10⁹/l (40,000/mm³) has been documented.<ref name=Egg2007/>

Differential diagnosis

The most important differential diagnosis in gout is septic arthritis.<ref name=Lancet2010/><ref name=PM2010/> This should be considered in those with signs of infection or those who do not improve with treatment.<ref name=PM2010/> To help with diagnosis, a synovial fluid Gram stain and culture may be performed.<ref name=PM2010/> Other conditions that can look similar include CPPD (pseudogout), rheumatoid arthritis, psoriatic arthritis, palindromic rheumatism, and reactive arthritis.<ref name="Dalbeth2016"/><ref name=PM2010/> Gouty tophi, in particular when not located in a joint, can be mistaken for basal cell carcinoma<ref>Template:Cite journal</ref> or other neoplasms.<ref>Template:Cite journal</ref>

• Light microscopy of a touch preparation of a gout tophus, showing needle-shaped crystals.
  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.<ref>Template:Cite web Updated: Jun 30, 2020</ref>
  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.<ref>Template:Cite web Updated: Jun 30, 2020</ref>
• In contrast, CPPD (pseudogout) displays rhombus-shaped crystals with positive birefringence.
  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.
  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),<ref>Template:Cite journal</ref> sucrose, and purine-rich foods of animal origin, such as organ meats and seafood.<ref name=Be2016/> Eating dairy products, vitamin C-rich foods, coffee, and cherries may help prevent gout attacks, as does losing weight.<ref name=Be2016/><ref name=2014rev>Template:Cite journal</ref> 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.<ref name="pmid16171252">Template:Cite journal</ref>

Medications

As of 2020, allopurinol is generally the recommended preventative treatment if medications are used.<ref name=Fitz2020>Template:Cite journal</ref><ref name="ACR2021">Template:Cite journal</ref> A number of other medications may occasionally be considered to prevent further episodes of gout, including probenecid, febuxostat, benzbromarone, and colchicine.<ref name="Annals2017" /><ref name=Lancet2016>Template:Cite journal</ref><ref>Template:Cite journal</ref> Long term medications are not recommended until a person has had two attacks of gout,<ref name=Review08/> unless destructive joint changes, tophi, or urate nephropathy exist.<ref name=German09>Template:Cite journal</ref> It is not until this point that medications are cost-effective.<ref name=Review08/> They are not usually started until one to two weeks after an acute flare has resolved, due to theoretical concerns of worsening the attack.<ref name=Review08/> They are often used in combination with either an NSAID or colchicine for the first three to six months.<ref name=Lancet2010/><ref name="Annals2017" />

While it has been recommended that urate-lowering measures should be increased until serum uric acid levels are below 300–360 μmol/L (5.0–6.0 mg/dL),<ref name=Fitz2020/><ref>Template:Cite journal</ref> there is little evidence to support this practice over simply putting people on a standard dose of allopurinol.<ref>Template:Cite journal</ref> If these medications are in chronic use at the time of an attack, it is recommended that they be continued.<ref name=PM2010/> Levels that cannot be brought below 6.0 mg/dL while attacks continue indicates refractory gout.<ref>Template:Cite journal</ref>

While historically it is not recommended to start allopurinol during an acute attack of gout, this practice appears acceptable.<ref name=Rob2016>Template:Cite journal</ref> Allopurinol blocks uric acid production, and is the most commonly used agent.<ref name=Review08/> Long term therapy is safe and well-tolerated and can be used in people with renal impairment or urate stones, although hypersensitivity occurs in a small number of individuals.<ref name=Review08/> The HLA-B*58:01 allele of the human leukocyte antigen B (HLA-B) is strongly associated with severe cutaneous adverse reactions during treatment with allopurinol and is most common among Asian subpopulations, notably those of Korean, Han-Chinese, or Thai descent.<ref>Template:Citation</ref>

Febuxostat is only recommended in those who cannot tolerate allopurinol.<ref>Template:Cite web</ref> There are concerns about more deaths with febuxostat compared to allopurinol.<ref name=FDA2019>Template:Cite web</ref> Febuxostat may also increase the rate of gout flares during early treatment.<ref>Template:Cite journal</ref> However, there is tentative evidence that febuxostat may bring down urate levels more than allopurinol.<ref name=Coch2014Feb>Template:Cite journal</ref>

Probenecid appears to be less effective than allopurinol and is a second line agent.<ref name=Review08/><ref name=Lancet2016/> Probenecid may be used if undersecretion of uric acid is present (24-hour urine uric acid less than 800 mg).<ref name=agabegi2nd251>Template:Cite book</ref> It is, however, not recommended if a person has a history of kidney stones.<ref name=agabegi2nd251/> Probenecid can be used in a combined therapy with allopurinol is more effective than allopurinol monotherapy.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Pegloticase is an option for the 3% of people who are intolerant to other medications.<ref name=FDA2010>Template:Cite web</ref> It is a third line agent.<ref name=Lancet2016/> Pegloticase is given as an intravenous infusion every two weeks,<ref name=FDA2010/> and reduces uric acid levels.<ref>Template:Cite journal</ref> Pegloticase is useful decreasing tophi but has a high rate of side effects and many people develop resistance to it.<ref name=Lancet2016/> Using lesinurad Template:Val plus febuxostat is more beneficial for tophi resolution than lesinural Template:Val with febuxostat, with similar side effects. Lesinural plus allopurinol is not effective for tophi resolution.<ref>Template:Cite journal</ref> Potential side effects include kidney stones, anemia and joint pain.<ref>Template:Cite journal</ref> In 2016, it was withdrawn from the European market.<ref>Template:Cite web</ref><ref name=Pres2017>Template:Cite journal</ref>

Lesinurad reduces blood uric acid levels by preventing uric acid absorption in the kidneys.<ref name=Pro2018>Template:Cite web</ref> It was approved in the United States for use together with allopurinol, among those who were unable to reach their uric acid level targets.<ref name="zurampic">Template:Cite web</ref> Side effects include kidney problems and kidney stones.<ref name=Pro2018/><ref name=EMA2018>Template:Cite web</ref>

Treatment

The initial aim of treatment is to settle the symptoms of an acute attack.<ref name="pmid16707532">Template:Cite journal</ref> Repeated attacks can be prevented by medications that reduce serum uric acid levels.<ref name="pmid16707532"/> Tentative evidence supports the application of ice for 20 to 30 minutes several times a day to decrease pain.<ref name=Moi2013>Template:Cite journal</ref> Options for acute treatment include nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and glucocorticoids.<ref name=Review08/> While glucocorticoids and NSAIDs work equally well, glucocorticoids may be safer.<ref>Template:Cite journal</ref> Options for prevention include allopurinol, febuxostat, and probenecid. Lowering uric acid levels can cure the disease.<ref name=Lancet2010/> Treatment of associated health problems is also important.<ref name=Lancet2010/> Lifestyle interventions have been poorly studied.<ref name=Moi2013/> It is unclear whether dietary supplements have an effect in people with gout.<ref>Template:Cite journal</ref>

NSAIDs

NSAIDs are the usual first-line treatment for gout. No specific agent is significantly more or less effective than any other.<ref name=Review08/> Improvement may be seen within four hours and treatment is recommended for one to two weeks.<ref name=Lancet2010/><ref name=Review08/> They are not recommended for those with certain other health problems, such as gastrointestinal bleeding, kidney failure, or heart failure.<ref name=JFP09/> While indometacin has historically been the most commonly used NSAID, an alternative, such as ibuprofen, may be preferred due to its better side effect profile in the absence of superior effectiveness.<ref name=CFP09>Template:Cite journal</ref> For those at risk of gastric side effects from NSAIDs, an additional proton pump inhibitor may be given.<ref>Template:Cite journal</ref> There is some evidence that COX-2 inhibitors may work as well as nonselective NSAIDs for acute gout attack with fewer side effects.<ref>Template:Cite journal</ref><ref name=":1">Template:Cite journal</ref><ref name=":2">Template:Cite journal</ref><ref name=":3">Template:Cite journal</ref>

Colchicine

Colchicine is an alternative for those unable to tolerate NSAIDs.<ref name=Review08/> At high doses, side effects (primarily gastrointestinal upset) limit its usage.<ref name="FDA Warning">Template:Cite web</ref> At lower doses, which are still effective, it is well tolerated.<ref name=CFP09/><ref>Template:Cite journal</ref><ref name=":2" /><ref name=":3" /> Colchicine may interact with other commonly prescribed drugs, such as atorvastatin and erythromycin, among others.<ref name="FDA Warning" />

Glucocorticoids

Glucocorticoids have been found to be as effective as NSAIDs<ref name=":1" /><ref name="pmid17276548">Template:Cite journal</ref> and may be used if contraindications exist for NSAIDs.<ref name=Review08/><ref name=":0">Template:Cite journal</ref> They also lead to improvement when injected into the joint.<ref name=Review08/> A joint infection must be excluded, however, as glucocorticoids worsen this condition.<ref name=Review08/> There were no short-term adverse effects reported.<ref>Template:Cite journal</ref>

Others

Interleukin-1 inhibitors, such as canakinumab, showed moderate effectiveness for pain relief and reduction of joint swelling, but have increased risk of adverse events, such as back pain, headache, and increased blood pressure.<ref name=Siv2014>Template:Cite journal</ref> They, however, may work less well than usual doses of NSAIDS.<ref name=Siv2014/> The high cost of this class of drugs may also discourage their use for treating gout.<ref name=Siv2014/> Template:Further

Prognosis

Without treatment, an acute attack of gout usually resolves in five to seven days; however, 60% of people have a second attack within one year.<ref name=Egg2007/> Those with gout are at increased risk of hypertension, diabetes mellitus, metabolic syndrome, and kidney and cardiovascular disease and thus are at increased risk of death.<ref name=Lancet2010/><ref name=Rh2008>Template:Cite journal</ref> It is unclear whether medications that lower urate affect cardiovascular disease risks.<ref>Template:Cite journal</ref> This may be partly due to its association with insulin resistance and obesity, but some of the increased risk appears to be independent.<ref name=Rh2008/>

Without treatment, episodes of acute gout may develop into chronic gout with destruction of joint surfaces, joint deformity, and painless tophi.<ref name=Lancet2010/> These tophi occur in 30% of those who are untreated for five years, often in the helix of the ear, over the olecranon processes, or on the Achilles tendons.<ref name=Lancet2010/> With aggressive treatment, they may dissolve. Kidney stones also frequently complicate gout, affecting between 10 and 40% of people, and occur due to low urine pH promoting the precipitation of uric acid.<ref name=Lancet2010/> Other forms of chronic kidney dysfunction may occur.<ref name=Lancet2010/>

• Gouty tophus of left metatarsophalangeal joint, causing hallux valgus
  Gouty tophus of left metatarsophalangeal joint, causing hallux valgus
• Gouty tophi presenting as nodules on the finger and helix of the ear
  Gouty tophi presenting as nodules on the finger and helix of the ear
• Tophus of the knee
  Tophus of the knee
• Tophii on the toe and ankle
  Tophii on the toe and ankle
• Gout complicated by ruptured tophi, the exudate of which tested positive for uric acid crystals
  Gout complicated by ruptured tophi, the exudate of which tested positive for uric acid crystals
• Gout in the big toe of left foot, compared to the healthy right foot
  Gout in the big toe of left foot, compared to the healthy right foot
• Gout in the joint of the big toe
  Gout in the joint of the big toe
• Gross pathology of a large tophus
  Gross pathology of a large tophus

Epidemiology

Gout affects around 1–2% of people in the Western world at some point in their lifetimes and is becoming more common.<ref name=Lancet2010/><ref name=Review08/> Some 5.8 million people were affected in 2013.<ref name=GBD2015>Template:Cite journal</ref> Rates of gout approximately doubled between 1990 and 2010.<ref name=Nature2009>Template:Cite journal</ref> This rise is believed to be due to increasing life expectancy, changes in diet and an increase in diseases associated with gout, such as metabolic syndrome and high blood pressure.<ref name=Epi2008>Template:Cite journal</ref> Factors that influence rates of gout include age, race, and the season of the year. In men over 30 and women over 50, rates are 2%.<ref name=JFP09>Template:Cite journal</ref>

In the United States, gout is twice as likely in males of African descent than those of European descent.<ref>Template:Cite web</ref> Rates are high among Polynesians, but the disease is rare in aboriginal Australians, despite a higher mean uric acid serum concentration in the latter group.<ref name="pmid10225809">Template:Cite journal</ref> It has become common in China, Polynesia, and urban Sub-Saharan Africa.<ref name=Lancet2010/> Some studies found that attacks of gout occur more frequently in the spring. This has been attributed to seasonal changes in diet, alcohol consumption, physical activity, and temperature.<ref>Template:Cite journal</ref>

Taiwan, Hong Kong and Singapore have relatively higher prevalence of gout. A study based on the National Health Insurance Research Database (NHIRD) estimated that 4.92% of Taiwanese residents have gout in 2004. A survey hold by the Hong Kong government found that 5.1% of Hong Kong resident between 45–59 years and 6.1% of those older than 60 years have gout. A study hold in Singapore found that 2,117 in 52,322 people between 45–74 years have gout, roughly equals to 4.1%.<ref>Template:Cite journal</ref>

History

A man wearing a long, curly wig and a full robe is sitting, looking out. His left arm rests on a small table, with his left hand holding a box. Behind him is a globe.

Antonie van Leeuwenhoek described the microscopic appearance of uric acid crystals in 1679.<ref name="Pillinger"/>

The English term "gout" first occurs in the work of Randolphus of Bocking, around 1200 AD.<ref>Template:Cite book</ref> It derives from the Latin word Template:Lang, meaning "a drop" (of liquid).<ref name="Pillinger"/> According to the Oxford English Dictionary, this originates from humorism and "the notion of the 'dropping' of a morbid material from the blood in and around the joints".<ref>Template:Cite web</ref>

Gout has been known since antiquity. Historically, wits have referred to it as "the king of diseases and the disease of kings"<ref name=Lancet2010/><ref>Template:Cite web</ref> or as "rich man's disease".<ref name=Dic/> The Ebers papyrus and the Edwin Smith papyrus, (Template:Circa) each mention arthritis of the first metacarpophalangeal joint as a distinct type of arthritis. These ancient manuscripts cite (now missing) Egyptian texts about gout that are claimed to have been written 1,000 years earlier and ascribed to Imhotep.<ref>Schwartz, Stephan A. "Disease of distinction." Explore 2, no. 6 (2006): 515–519. - "Both the Ebers and Edwin Smith Papyri describe a condition that is clearly gout.[...] They were written about 1552 BC but contain information taken from texts a thousand years earlier, and ascribed to Imhotep, a kind of ancient world Leonardo da Vinci, and the great overarching figure of Egyptian medicine."</ref> Greek physician Hippocrates around 400 BC commented on it in his Aphorisms, noting its absence in eunuchs and premenopausal women.<ref name="Pillinger">Template:Cite journal</ref><ref>Template:Cite web</ref> Aulus Cornelius Celsus (30 AD) described the linkage with alcohol, later onset in women and associated kidney problems: Template:Blockquote

Benjamin Welles, an English physician, authored the first medical book on gout, A Treatise of the Gout, or Joint Evil, in 1669.<ref>Template:Cite book</ref> In 1683, Thomas Sydenham, an English physician, described its occurrence in the early hours of the morning and its predilection for older males: Template:Blockquote

In the 18th century, Thomas Marryat distinguished different manifestations of gout:

The Gout is a chronical disease most commonly affecting the feet. If it attacks the knees, it is called Template:Linktext; if the hands, Template:Linktext; if the elbow, Onagra; if the shoulder, Template:Linktext; if the back or loins, Lumbago.<ref>Template:Cite book</ref>

Dutch scientist Antonie van Leeuwenhoek first described the microscopic appearance of urate crystals in 1679.<ref name="Pillinger"/> In 1848, English physician Alfred Baring Garrod identified excess uric acid in the blood as the cause of gout.<ref name="pmid11600751">Template:Cite journal </ref>

Other animals

Gout is rare in most other animals due to their ability to produce uricase, which breaks down uric acid.<ref name=Animals01>Template:Cite journal</ref> Humans and other great apes do not have this ability; thus, gout is common.<ref name=Egg2007/><ref name=Animals01/> Other animals with uricase include fish, amphibians and most non-primate mammals.<ref name=Choi2005>Template:Cite journal</ref> The Tyrannosaurus rex specimen known as "Sue" is believed to have had gout.<ref name="Rothschild">Template:Cite journal</ref>

Research

A number of new medications are under study for treating gout, including anakinra, canakinumab, and rilonacept.<ref>Template:Cite journal</ref> Canakinumab may result in better outcomes than a low dose of a glucocorticoid, but costs five thousand times more.<ref>Template:Cite journal</ref> A recombinant uricase enzyme (rasburicase) is available but its use is limited, as it triggers an immune response. Less antigenic versions are in development.<ref name=Egg2007/>

See also

• List of people known as the Gouty

External links

• Template:Cite EB1911
• Template:Cite web