Gout

Gout is a form of inflammatory arthritis caused by crystals of monosodium urate that form in and around joints when the level of uric acid in the blood stays high for a long time. It is the most common inflammatory arthritis, affecting about 9.2 million adults (3.9%) in the United States^[1:1] and an estimated 55.8 million people worldwide in 2020.^[2:1]

Gout typically appears as sudden attacks, called flares, of severe pain and swelling in a single joint of the lower limb, often the base of the big toe; a flare usually settles within one to two weeks and is followed by a symptom-free period until the next one.^[3:1][4:1] Over years, untreated gout can lead to lumps of crystal called tophi and to permanent joint damage.^[3:2]

The underlying cause, a raised blood urate level (hyperuricemia), is well understood, and effective, inexpensive medicines can lower it; nevertheless, many people with gout do not receive or continue long-term treatment.^[1:2][2:2] Gout is one of the oldest recognised diseases, described in ancient Egypt and by Hippocrates.^[4:2]

Signs and symptoms

A gout flare starts abruptly with intense pain, swelling, redness and warmth, usually in one joint of the leg or foot; it can also involve tendons and fluid-filled sacs near the joint (bursae).^[3:1] Acute gout of the joint at the base of the big toe (the first metatarsophalangeal joint) has its own name, podagra.^[4:2] The English physician Thomas Sydenham, who had gout himself, described an attack that wakes the patient at about two in the morning with pain in the big toe that grows so severe the patient cannot bear the weight of the bedclothes.^[4:1]

The features that doctors treat as typical of a gout episode include pain that peaks within a day, symptoms that resolve within two weeks, complete recovery between episodes, great difficulty walking or using the joint, inability to bear touch on it, and redness over it.^[5:1]

Between flares, people with untreated gout may have no symptoms. In longstanding disease, usually after at least 10 years and with higher urate levels, deposits of crystal called tophi can form in and around joints, bone, cartilage, tendons and skin.^[3:2] Tophi are closely linked to structural damage in affected joints, and advanced gout involves chronic inflammation in addition to flares.^[3:2]

Causes and risk factors

Uric acid and hyperuricemia

Uric acid is the end product of the breakdown of purines, compounds that come both from food and from the body's own cell turnover. Most mammals convert uric acid into a highly soluble compound, allantoin, using the enzyme uricase, but humans and other apes (chimpanzees, gorillas, orangutans and gibbons) lack this enzyme.^[3:3] In mammals that do have uricase, urate levels are low and gout does not occur.^[4]

In the sodium-rich fluid outside cells, urate exists mostly as monosodium urate, which starts to form crystals once blood urate exceeds about 6.8 mg/dL.^[3:4] Cooler temperatures, pH between 7 and 9, and high sodium concentration all make urate less soluble, and joints that are already damaged, for example by injury or osteoarthritis, are more prone to crystal deposits.^[3:5]

A high urate level is necessary for gout but does not guarantee it. In one cohort, about 22% of men with blood urate above 9.0 mg/dL developed gout within five years, and in an imaging study only 24% of people with high urate but no symptoms had urate deposits visible on dual-energy CT.^[3:6]

In most people, hyperuricemia results mainly from the body excreting too little urate rather than making too much. About two-thirds of urate is excreted by the kidneys and one-third through the intestine.^[3:7]

Genetics

Differences in the genes for urate transporters, the proteins that move urate into and out of the kidney and gut, are the strongest known genetic influence on blood urate. The genes most strongly linked are SLC2A9, SLC22A12, SLC17A1 and ABCG2.^[3:8] Diet appears to have a smaller effect on urate levels and gout risk than these genetic variants.^[3:9]

Diet, body weight and other conditions

Eating more purine-rich meat and seafood is associated with a higher risk of gout, whereas purine-rich plant foods are not; alcohol and high fructose intake are also associated with gout.^[3:9] Obesity, metabolic syndrome and chronic kidney disease are risk factors, and gout is associated with cardiovascular, metabolic and kidney conditions.^[2:3] According to the Global Burden of Disease Study, high body-mass index accounted for 34.3% of the disability caused by gout worldwide in 2020, and kidney dysfunction for 11.8%.^[2:4]

Medications are also among the risk factors for gout.^[2] In a gout registry, women more often had kidney disease and used thiazide diuretics or other diuretics, while men more often reported eating foods associated with gout.^[2:5]

Mechanism

Urate crystals can sit in tissue without causing symptoms. A flare begins when immune cells in the joint react to the crystals. The process has three broad stages: initiation, recruitment of white blood cells, and self-resolution. Initiation depends on the NLRP3 inflammasome, a protein complex in monocytes and macrophages that, when activated by the crystals, releases the inflammatory signalling molecule interleukin-1β (IL-1β).^[6:1]

White blood cells called neutrophils are then drawn into the joint, where they swallow urate crystals and release their DNA and proteins as web-like neutrophil extracellular traps (NETs).^[3:10] Flares then subside on their own, typically within two weeks.^[6:1][3:1]

Diagnosis

The definitive test for gout is finding monosodium urate crystals in fluid drawn from a symptomatic joint or bursa, or in material from a tophus. Under the 2015 classification criteria of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR, since renamed the European Alliance of Associations for Rheumatology), this finding alone is sufficient to classify someone as having gout.^[5:2] The crystals are identified with compensated polarized light microscopy, a technique introduced by Daniel McCarty and Joseph Hollander; the same method later identified the calcium pyrophosphate crystals of the related condition sometimes called pseudogout.^[4:3]

When joint fluid is not examined, the criteria assign points for the pattern of joints involved (including the first metatarsophalangeal joint), the character and time course of episodes, the presence of tophi, blood urate level, and imaging. Imaging evidence can include a "double-contour sign" of urate coating cartilage on ultrasound, urate deposits colour-coded on dual-energy CT, or gout-related joint damage on X-rays.^[5:1]

Management

Treatment has two separate goals: relieving the pain and inflammation of flares, and lowering blood urate over the long term so that crystals dissolve and flares stop. The recommendations below follow the 2020 ACR guideline, which graded each recommendation as strong or conditional.^[1:3]

Treating flares

The ACR strongly recommends colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or glucocorticoids (by mouth, injected into the joint, or into muscle) as first-line treatment, in preference to interleukin-1 inhibitors or ACTH. Applying ice is conditionally recommended as an add-on.^[1:4] When colchicine is used, a low dose is strongly preferred to a high dose because it works as well with fewer side effects.^[1:5]

Urate-lowering therapy

Long-term urate-lowering therapy (ULT) is strongly recommended for anyone with tophi, joint damage from gout visible on imaging, or two or more flares a year.^[1:6] The main strong recommendations are:^[1:3]

The ACR conditionally recommends continuing ULT indefinitely rather than stopping it.^[1:7] Allopurinol and febuxostat work by blocking xanthine oxidase, the enzyme that makes uric acid, while uricosuric drugs such as probenecid increase the amount of urate the kidneys excrete.^[4:4][4:5] For people whose urate stays above target despite these drugs and who still have frequent flares or tophi, switching to pegloticase, an injected form of the uricase enzyme humans lack, is strongly recommended.^[1:8]

Allopurinol can rarely cause a severe allergic reaction. A gene variant, HLA-B*5801, greatly increases this risk, and testing for it before starting allopurinol is conditionally recommended for people of Southeast Asian descent (for example Han Chinese, Korean or Thai) and for African American patients.^[1:9]

For people with high urate but no history of flares or tophi (asymptomatic hyperuricemia), the ACR conditionally recommends against urate-lowering drugs.^[1:10]

Lifestyle and other medicines

The ACR conditionally recommends that people with gout limit alcohol, purine-rich foods and high-fructose corn syrup, and that those who are overweight try to lose weight; it conditionally recommends against vitamin C supplements.^[1:11] Research on the causes of hyperuricemia suggests that diet has a smaller effect on urate levels than genetic variation.^[3:9] For people who need blood-pressure medication, the ACR conditionally recommends switching from hydrochlorothiazide where feasible and preferring losartan, which modestly increases urate excretion.^[1:12][4:5]

Epidemiology

The Global Burden of Disease Study 2021 estimated that 55.8 million people had gout in 2020, an age-standardised prevalence of 659.3 per 100,000 and an increase of 22.5% since 1990.^[2:1] Prevalence was 3.26 times higher in males than in females and rose with age.^[2:6] The highest rates were in high-income North America (1,719.8 per 100,000) and Australasia (1,424.4 per 100,000).^[2:7] The study projects 95.8 million cases by 2050, a rise of 72.6%.^[2:8]

Some populations carry a much heavier burden. In New Zealand, Māori and Pacific peoples develop severe gout at younger ages than New Zealand Europeans, with more frequent flares, more hospital admissions and more tophi.^[2:9]

Historically regarded as a disease of men, gout becomes more common in women after menopause; the Roman writer Seneca already remarked on gout in women during the reign of Nero.^[4]

History

Podagra was identified by the Egyptians in 2640 BC, and Hippocrates, in the fifth century BC, called it "the unwalkable disease".^[4:2] Among his aphorisms on the condition are that eunuchs do not get gout and that a woman does not get it unless her menstruation has stopped.^[4] The Roman physician Galen was the first to describe tophi.^[4]

The English word comes from the Latin gutta, "drop", reflecting the medieval theory that an excess of one of the four humours dripped into the joint. The first recorded use of "gout" for podagra is attributed to the medieval Dominican monk Randolphus of Bocking.^[4:6] Because it was associated with rich food and drink that only the wealthy could afford, gout became known as the "disease of kings".^[4:7] Satirists such as James Gillray and George Cruikshank made it a subject of caricature.^[4]

The chemistry of gout was worked out between the 17th and 19th centuries. Antonie van Leeuwenhoek described needle-shaped crystals from a tophus under his microscope in 1679; the Swedish chemist Carl Wilhelm Scheele identified uric acid in a kidney stone in 1776; and William Hyde Wollaston found urate in a tophus from his own ear in 1797. The physician Alfred Baring Garrod devised a "thread test" to detect uric acid in blood and concluded in 1859 that deposited urate was "the cause, and not the effect" of gouty inflammation.^[4:8]

Colchicine, from the autumn crocus (Colchicum autumnale), was first used specifically for gout by the Byzantine physician Alexander of Tralles in the sixth century AD. It fell out of favour because of Sydenham's opposition to purgatives and was rediscovered in 1763.^[4:9] Uricosuric drugs came into use at the end of the 19th century; high-dose salicylates were later replaced by probenecid and similar drugs.^[4:5] The development of allopurinol, the first xanthine oxidase inhibitor, by George Hitchings and Gertrude Elion was recognised in their 1988 Nobel Prize in Physiology or Medicine, and allopurinol became the most widely used urate-lowering drug.^[4:4]

Analysis: gout and human agency

This section is an evaluation by Agpedia contributors, based on the sources cited above.

Gout is unusual among chronic diseases in that its cause is understood, it can be confirmed with a simple test, and cheap oral drugs can prevent flares and joint damage if taken long term to a target urate level.^[1:2][1:3] Yet only a third to half of people with gout receive urate-lowering therapy, and fewer than half of those keep taking it; the ACR guideline reports no increase in its use over two decades.^[2:2][1:2] Recurrent flares that make walking impossible for days at a time, and progressive joint damage, directly limit people's ability to work and move freely, so this treatment gap is a preventable loss of agency.

The long cultural framing of gout as a self-inflicted "disease of kings" caused by overindulgence^[4:7] sits uneasily with current evidence that genetic variation in urate handling matters more than diet.^[3:9] A framing that emphasises personal blame may discourage people from seeking effective drug treatment, and it obscures the heavier burden borne by groups such as Māori and Pacific peoples in New Zealand.^[2:9] Whether stigma is a measurable cause of undertreatment is not established by the sources cited here; studies linking patient beliefs about gout to treatment uptake and persistence would help settle the question.