Clinical diagnosis is confirmed by seeing the characteristic crystals in joint fluid. Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or colchicine improves symptoms. Once the acute attack subsides, levels of uric acid are usually lowered via lifestyle changes, and in those with frequent attacks, allopurinol or probenecid provide long-term prevention.

Gout has increased in frequency in recent decades, affecting about 1-2% of the Western population at some point in their lives. The increase is believed due to increasing risk factors in the population, such as metabolic syndrome, longer life expectancyand changes in diet.

Gout was historically known as "the disease of kings" or "rich man's disease" because they could afford diets high in cheese and meat which are also high in purines, which and can elevate uric acid levels and subsequently cause gout.

Gout can present in a number of ways, although the most usual is a recurrent attack of acute inflammatory arthritis (a red, tender, hot, swollen joint).^[2] The metatarsal-phalangeal joint at the base of the big toe is affected most often, accounting for half of cases.^[3] Other joints, such as the heels, knees, wrists and fingers, may also be affected.^[3] Joint pain usually begins over 2–4 hours and during the night.^[3] The reason for onset at night is due to the lower body temperature then.^[1] Other symptoms may rarely occur along with the joint pain, including fatigue and a high fever.^[1][3]

Long-standing elevated uric acid levels (hyperuricemia) may result in other symptomatology, including hard, painless deposits of uric acid crystals known as tophi. Extensive tophi may lead to chronic arthritis due to bone erosion.^[4] Elevated levels of uric acid may also lead to crystals precipitating in the kidneys, resulting in stone formation and subsequent urate nephropathy.^[5]

Cause

Hyperuricemia is the underlying cause of gout. This can occur for a number of reasons, including diet, genetic predisposition, or underexcretion of urate, the salts of uric acid.^[2] Renal underexcretion of uric acid is the primary cause of hyperuricemia in about 90% of cases, while overproduction is the cause in less than 10%.^[6] About 10% of people with hyperuricemia develop gout at some point in their lifetimes.^[7] 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.^[1]

Lifestyle

Dietary causes account for about 12% of gout,^[2] and include a strong association with the consumption of alcohol, fructose-sweetened drinks, meat, and seafood.^[4][8] Other triggers include physical trauma and surgery.^[6] Recent studies have found dietary factors once believed associated are, in fact, not, including the intake of purine-rich vegetables (e.g., beans, peas, lentils, and spinach) and total protein.^[9][10] The consumption of coffee, vitamin C and dairy products, as well as physical fitness, appear to decrease the risk.^[11][12][13] This is believed partly due to their effect in reducing insulin resistance.^[13]

Genetics

The occurrence of gout is partly genetic, contributing to about 60% of variability in uric acid level.^[6] Two genes called SLC2A9 and ABCG2 have been found to commonly be associated with gout, and variations in them can approximately double the risk.^[14] A few rare genetic disorders, including 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.^[6]

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.^[3] Other conditions commonly complicated by gout include: polycythemia, lead poisoning, renal failure, hemolytic anemia, psoriasis, and solid organ transplants.^[6][15] A body mass index greater than or equal to 35 increases a male's risk of gout threefold.^[10] Chronic lead exposure and lead-contaminated alcohol are risk factors for gout due to the harmful effect of lead on kidney function.^[16] Lesch-Nyhan syndrome is often associated with gouty arthritis.

Medication

Diuretics have been associated with attacks of gout. However, a low dose of hydrochlorothiazide does not seem to increase the risk.^[17] Other medicines that have been associated include niacin and aspirin (acetylsalicylic acid).^[4] The immunosuppressive drugs ciclosporin and tacrolimus are also associated with gout,^[6] the former particularly when used in combination with hydrochlorothiazide.^[18]

Pathophysiology

Gout is a disorder of purine metabolism,^[6] and occurs when its final metabolite, uric acid, crystallizes in the form of monosodium urate, precipitating in joints, on tendons, and in the surrounding tissues.^[4] These crystals then trigger a local immune-mediated inflammatory reaction,^[4] with one of the key proteins in the inflammatory cascade being interleukin 1β.^[6] An evolutionary loss of uricase, which breaks down uric acid, in humans and higher primates has made this condition common.^[6]

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.^[4][19] Other factors believed important in triggering an acute episode of arthritis include cool temperatures, rapid changes in uric acid levels, acidosis,^[20][21] articular hydration, and extracellular matrix proteins, such as proteoglycans, collagens, and chondroitin sulfate.^[6] The increased precipitation at low temperatures partly explains why the joints in the feet are most commonly affected.^[2] Rapid changes in uric acid may occur due to a number of factors, including trauma, surgery, chemotherapy, diuretics, and stopping or starting allopurinol.^[1] Calcium channel blockers and losartan are associated with a lower risk of gout as compared to other medications for hypertension. ^[22]