Gout

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Gout
Other namesPodagra
Video summary (script). Leading with The Gout (James Gillray, 1799) depicts the pain of the artist's gout as a demon or dragon. [1] [2]
Pronunciation
Specialty Rheumatology
Symptoms Joint pain, swelling, and redness [4]
Usual onsetOlder males, [4] post-menopausal women [5]
Causes Uric acid [5]
Risk factors Diet high in meat or beer, being overweight [4] [6]
Differential diagnosis Joint infection, rheumatoid arthritis, pseudogout, others [7]
PreventionWeight loss, vitamin C, not drinking alcohol, allopurinol [8]
Treatment NSAIDs, steroids, colchicine [5] [9]
Frequency1–2% (developed world) [8]

Gout is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot, and swollen joint. [4] [5] Pain typically comes on rapidly, reaching maximal intensity in less than 12 hours. [8] The joint at the base of the big toe is affected in about half of cases. [10] It may also result in tophi, kidney stones, or kidney damage. [4]

Inflammatory arthritis is a group of diseases which includes: rheumatoid arthritis, psoriatic arthropathy, inflammatory bowel disease, adult-onset Still's disease, scleroderma, juvenile idiopathic arthritis, and systemic lupus erythematosus (SLE).

Joint effusion effusion of watery liquid into the cavity of a joint

A joint effusion is the presence of increased intra-articular fluid. It may affect any joint. Commonly it involves the knee.

Tophus deposit of uric acid crystals, in the form of monosodium urate crystals, in people with longstanding hyperuricemia (high levels of uric acid in the blood)

A tophus is a deposit of monosodium urate crystals, in people with longstanding high levels of uric acid in the blood, a condition known as hyperuricemia. Tophi are pathognomonic for the disease gout. Most people with tophi have had previous attacks of acute arthritis, eventually leading to the formation of tophi. Chronic tophaceous gout is known as Harrison Syndrome.

Contents

Gout is due to persistently elevated levels of uric acid in the blood. [5] [8] This occurs from a combination of diet, other health problems, and genetic factors. [4] [5] At high levels, uric acid crystallizes and the crystals deposit in joints, tendons, and surrounding tissues, resulting in an attack of gout. [4] Gout occurs more commonly in those who regularly eat meat or seafood, drink beer, or are overweight. [4] [6] Diagnosis of gout may be confirmed by the presence of crystals in the joint fluid or in a deposit outside the joint. [4] Blood uric acid levels may be normal during an attack. [4]

Uric acid the end product of nucleic acid degradation

Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of purine nucleotides, and it is a normal component of urine. High blood concentrations of uric acid can lead to gout and are associated with other medical conditions, including diabetes and the formation of ammonium acid urate kidney stones.

In medicine, comorbidity is the presence of one or more additional conditions co-occurring with a primary condition; in the countable sense of the term, a comorbidity is each additional condition. The additional condition may also be a behavioral or mental disorder.

Heredity Passing of traits to offspring from the speciess parents or ancestor

Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic information of their parents. Through heredity, variations between individuals can accumulate and cause species to evolve by natural selection. The study of heredity in biology is genetics.

Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or colchicine improves symptoms. [4] [5] [11] 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. [8] Taking vitamin C and eating a diet high in low-fat dairy products may be preventive. [12] [13]

Steroid any organic compound having sterane as a core structure

A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes which alter membrane fluidity; and as signaling molecules. Hundreds of steroids are found in plants, animals and fungi. All steroids are manufactured in cells from the sterols lanosterol (opisthokonts) or cycloartenol (plants). Lanosterol and cycloartenol are derived from the cyclization of the triterpene squalene.

Colchicine medication most commonly used to treat gout

Colchicine is a medication used to treat gout and Behçet's disease. In gout, it is less preferred to NSAIDs or steroids. Other uses include the prevention of pericarditis and familial Mediterranean fever. It is taken by mouth.

Allopurinol chemical compound

Allopurinol, sold under the brand name Zyloprim among others, is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken by mouth or injected into a vein.

Gout affects about 1 to 2% of the Western population at some point in their lives. [8] It has become more common in recent decades. [4] This is believed to be due to increasing risk factors in the population, such as metabolic syndrome, longer life expectancy, and changes in diet. [8] Older males are most commonly affected. [4] Gout was historically known as "the disease of kings" or "rich man's disease". [8] [14] It has been recognized at least since the time of the ancient Egyptians. [8]

Western world Countries that identify themselves with an originally European shared culture

The Western world, also known as the West, refers to various regions, nations and states, depending on the context, most often including at least parts of Europe, Australasia, and the Americas. There are many accepted definitions, all closely interrelated. The Western world is also known as the Occident, in contrast to the Orient, or Eastern world. It might mean the Northern half of the North–South divide.

Metabolic syndrome clustering of medical conditions (giving a total of 16 possible combinations giving the syndrome)

Metabolic syndrome, sometimes known by other names, is a clustering of at least three of the five following medical conditions: central obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).

Signs and symptoms

Gout presenting as slight redness in the metatarsal-phalangeal joint of the big toe Gout2010.JPG
Gout presenting as slight redness in the metatarsal-phalangeal joint of the big toe

Gout can present in multiple ways, although the most common is a recurrent attack of acute inflammatory arthritis (a red, tender, hot, swollen joint). [7] The metatarsal-phalangeal joint at the base of the big toe is affected most often, accounting for half of cases. [10] Other joints, such as the heels, knees, wrists, and fingers, may also be affected. [7] Joint pain usually begins during the night and peaks within 24 hours of onset. [7] This is mainly due to lower body temperature. [4] Other symptoms may rarely occur along with the joint pain, including fatigue and a high fever. [10] [15]

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. [16] Elevated levels of uric acid may also lead to crystals precipitating in the kidneys, resulting in stone formation and subsequent urate nephropathy. [17]

Hyperuricemia acquired metabolic disease that has material basis in an abnormally high level of uric acid in the blood.

Hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. The amount of urate in the body depends on the balance between the amount of purines eaten in food, the amount of urate synthesised within the body, and the amount of urate that is excreted in urine or through the gastrointestinal tract. In humans, the upper end of the normal range is 360 µmol/L (6 mg/dL) for women and 400 µmol/L (6.8 mg/dL) for men.

Arthritis A type of joint disorder that involves inflammation of one or more joints

Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In some types of arthritis, other organs are also affected. Onset can be gradual or sudden.

Kidney internal organ in most animals, including vertebrates and some invertebrates

The kidneys are two bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about 11 centimetres (4.3 in) in length. They receive blood from the paired renal arteries; blood exits into the paired renal veins. Each kidney is attached to a ureter, a tube that carries excreted urine to the bladder.

Cause

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. [4] 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%. [8] About 10% of people with hyperuricemia develop gout at some point in their lifetimes. [18] 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. [15]

Lifestyle

Dietary causes account for about 12% of gout, [19] and include a strong association with the consumption of alcohol, fructose-sweetened drinks, meat, and seafood. [7] Among foods richest in purines yielding high amounts of uric acid are dried anchovies, shrimp, organ meat, dried mushrooms, seaweed, and beer yeast. [20] Chicken and potatoes also appear related. [21] Other triggers include physical trauma and surgery. [8]

Studies in the early 2000s found that other dietary factors are not relevant. [22] [23] Specifically, moderate consumption of purine-rich vegetables (e.g., beans, peas, lentils, and spinach) are not associated with gout. [24] Neither is total consumption of protein. [23] [24] Alcohol consumption is strongly associated with increased risk, with wine presenting somewhat less of a risk than beer or spirits. [24] [25] Eating skim milk powder enriched with glycomacropeptide (GMP) and G600 milk fat extract may reduce pain but may result in diarrhea and nausea. [26]

The eating or drinking of coffee, vitamin C, and dairy products, as well as physical fitness, appear to decrease the risk. [27] [28] [29] [30] Vitamin C supplements do not appear to have a significant effect in people who already have established gout. [4] Peanuts, brown bread, and fruit also appear protective. [21] This is believed to be partly due to their effect in reducing insulin resistance. [29]

Genetics

Gout is partly genetic, contributing to about 60% of variability in uric acid level. [8] The SLC2A9 , SLC22A12 , and ABCG2 genes have been found to be commonly associated with gout and variations in them can approximately double the risk. [31] [32] Loss-of-function mutations in SLC2A9 and SLC22A12 causes low blood uric acid levels by reducing urate absorption and unopposed urate secretion. [32] 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. [8]

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. [10] Other conditions commonly complicated by gout include lead poisoning, kidney failure, hemolytic anemia, psoriasis, solid organ transplants, and myeloproliferative disorders such as polycythemia. [8] [33] A body mass index greater than or equal to 35 increases male risk of gout threefold. [22] Chronic lead exposure and lead-contaminated alcohol are risk factors for gout due to the harmful effect of lead on kidney function. [34]

Medication

Diuretics have been associated with attacks of gout, but a low dose of hydrochlorothiazide does not seem to increase risk. [35] Other medications that increase the risk include niacin, aspirin (acetylsalicylic acid), ACE inhibitors, angiotensin receptor blockers, beta blockers, ritonavir, and pyrazinamide. [4] [16] The immunosuppressive drugs ciclosporin and tacrolimus are also associated with gout, [8] the former more so when used in combination with hydrochlorothiazide. [36]

Pathophysiology

Chemical structure of uric acid Harnsaure Ketoform.svg
Chemical structure of uric acid

Gout is a disorder of purine metabolism, [8] 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. [16] Microscopic tophi may be walled off by a ring of proteins, which blocks interaction of the crystals with cells and therefore avoids inflammation. [37] 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. [37] 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. [4] [16] [37] 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. [4] An evolutionary loss of urate oxidase (uricase), which breaks down uric acid, in humans and higher primates has made this condition common. [8]

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. [16] [38] 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. [8] [39] [40] The increased precipitation at low temperatures partly explains why the joints in the feet are most commonly affected. [19] Rapid changes in uric acid may occur due to factors including trauma, surgery, chemotherapy and diuretics. [15] The starting or increasing of urate-lowering medications can lead to an acute attack of gout with febuxostat of a particularly high risk. [41] Calcium channel blockers and losartan are associated with a lower risk of gout compared to other medications for hypertension. [42]

Diagnosis

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. Gichtfuss im Roentgenbild 002.png
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.
Microscope photograph of spiked rods of uric acid crystals found in a synovial fluid sample illuminated with polarized light. Formation of uric acid crystals in the joints is associated with gout. Fluorescent uric acid.JPG
Microscope photograph of spiked rods of uric acid crystals found in a synovial fluid sample illuminated with polarized light. Formation of uric acid crystals in the joints is associated with gout.

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. [15] [43] Plain X-rays are usually normal and are not useful for confirming a diagnosis of early gout. [8] They may show signs of chronic gout such as bone erosion. [41]

Synovial fluid

A definitive diagnosis of gout is based upon the identification of monosodium urate crystals in synovial fluid or a tophus. [7] All synovial fluid samples obtained from undiagnosed inflamed joints by arthrocentesis should be examined for these crystals. [8] 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. [44] The fluid must be examined relatively soon after aspiration, as temperature and pH affect solubility. [8]

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. [10] [45] Thus, the diagnostic utility of measuring uric acid levels is limited. [10] 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. [46] 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. [47] [48] A white blood cell count as high as 40.0×109/l (40,000/mm3) has been documented. [15]

Differential diagnosis

The most important differential diagnosis in gout is septic arthritis. [8] [10] This should be considered in those with signs of infection or those who do not improve with treatment. [10] To help with diagnosis, a synovial fluid Gram stain and culture may be performed. [10] Other conditions that can look similar include pseudogout, rheumatoid arthritis, psoriatic arthritis, and reactive arthritis. [4] [10] Gouty tophi, in particular when not located in a joint, can be mistaken for basal cell carcinoma [49] or other neoplasms. [50]

Prevention

Both lifestyle changes and medications can decrease uric acid levels. Dietary and lifestyle choices that are effective include reducing intake of purine-rich foods of animal origin such as meat and seafood, alcohol, and fructose (especially high fructose corn syrup). [6] Eating dairy products, vitamin C, coffee, and cherries may help prevent gout attacks, as does losing weight. [6] [51] 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. [52]

Medications

A number of medications are useful for preventing further episodes of gout, including allopurinol, probenecid, febuxostat, benzbromarone, and colchicine. [11] [53] [54] Long term medications are not recommended until a person has had two attacks of gout, [19] unless destructive joint changes, tophi, or urate nephropathy exist. [17] It is not until this point that medications are cost-effective. [19] They are not usually started until one to two weeks after an acute flare has resolved, due to theoretical concerns of worsening the attack. [19] They are often used in combination with either an NSAID or colchicine for the first three to six months. [8] [11]

Urate-lowering measures should be increased until serum uric acid levels are below 300–360 µmol/l (5.0–6.0 mg/dl) and continue indefinitely. [8] [19] [55] If these medications are in chronic use at the time of an attack, it is recommended that they be continued. [10] Levels that cannot be brought below 6.0 mg/dl while attacks continue indicates refractory gout. [56]

While historically it is not recommended to start allopurinol during an acute attack of gout, this practice appears acceptable. [57] Allopurinol blocks uric acid production, and is the most commonly used agent. [19] 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. [19]

Febuxostat is only recommended in those who cannot tolerate allopurinol. [58] There are concerns about more deaths with febuxostat compared to allopurinol. [59] Febuxostat may also increase the rate of gout flares during early treatment. [60] However, there is tentative evidence that febuxostat may bring down urate levels more than allopurinol. [61]

Probenecid appears to be less effective than allopurinol and is a second line agent. [19] [53] Probenecid may be used if undersecretion of uric acid is present (24-hour urine uric acid less than 800 mg). [62] It is, however, not recommended if a person has a history of kidney stones. [62] Pegloticase is an option for the 3% of people who are intolerant to other medications. [63] It is a third line agent. [53] Pegloticase is given as an intravenous infusion every two weeks, [63] and reduces uric acid levels. [64] Pegloticase is useful decreasing tophi but has a high rate of side effects and many people develop resistance to it. [53] [65] Potential side effects include kidney stones, anemia and joint pain. [66] In 2016 it was withdrawn from the European market. [67] [68]

Lesinurad reduces blood uric acid levels by preventing uric acid absorption in the kidneys. [69] It was approved in the United States for use together with allopurinol, among those who were unable to reach their uric acid level targets. [70] Side effects include kidney problems and kidney stones. [69] [71]

Treatment

The initial aim of treatment is to settle the symptoms of an acute attack. [72] Repeated attacks can be prevented by medications that reduce serum uric acid levels. [72] Tentative evidence supports the application of ice for 20 to 30 minutes several times a day to decrease pain. [73] Options for acute treatment include nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and steroids. [19] While steroids and NSAIDs work equally well, steroids may be safer. [74] Options for prevention include allopurinol, febuxostat, and probenecid. Lowering uric acid levels can cure the disease. [8] Treatment of associated health problems is also important. [8] Lifestyle interventions have been poorly studied. [73] It is unclear whether dietary supplements have an effect in people with gout. [75]

NSAIDs

NSAIDs are the usual first-line treatment for gout. No specific agent is significantly more or less effective than any other. [19] Improvement may be seen within four hours and treatment is recommended for one to two weeks. [8] [19] They are not recommended for those with certain other health problems, such as gastrointestinal bleeding, kidney failure, or heart failure. [76] 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. [35] For those at risk of gastric side effects from NSAIDs, an additional proton pump inhibitor may be given. [77] There is some evidence that COX-2 inhibitors may work as well as nonselective NSAIDs for acute gout attack with fewer side effects. [78] [79]

Colchicine

Colchicine is an alternative for those unable to tolerate NSAIDs. [19] At high doses, side effects (primarily gastrointestinal upset) limit its usage. [80] At lower doses, which are still effective, it is well tolerated. [35] [81] Colchicine may interact with other commonly prescribed drugs, such as atorvastatin and erythromycin, among others. [80]

Steroids

Glucocorticoids have been found to be as effective as NSAIDs [82] [83] and may be used if contraindications exist for NSAIDs. [19] [84] They also lead to improvement when injected into the joint. [19] A joint infection must be excluded, however, as steroids worsen this condition. [19] There were no short-term adverse effects reported. [85]

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. [86] They, however, may work less well than usual doses of NSAIDS. [86] The high cost of this class of drugs may also discourage their use for treating gout. [86]

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. [15] 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. [8] [87] It is unclear whether medications that lower urate affect cardiovascular disease risks. [88] This may be partly due to its association with insulin resistance and obesity, but some of the increased risk appears to be independent. [87]

Without treatment, episodes of acute gout may develop into chronic gout with destruction of joint surfaces, joint deformity, and painless tophi. [8] 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. [8] 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. [8] Other forms of chronic kidney dysfunction may occur. [8]

Epidemiology

Gout affects around 1–2% of the Western population at some point in their lifetimes and is becoming more common. [8] [19] Some 5.8 million people were affected in 2013. [89] Rates of gout approximately doubled between 1990 and 2010. [16] 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. [22] 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%. [76]

In the United States, gout is twice as likely in males of African descent than those of European descent. [90] Rates are high among Pacific Islanders and the Māori, but the disease is rare in aboriginal Australians, despite a higher mean uric acid serum concentration in the latter group. [91] It has become common in China, Polynesia, and urban sub-Saharan Africa. [8] 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. [92]

History

Antonie van Leeuwenhoek described the microscopic appearance of uric acid crystals in 1679. Anthonie van Leeuwenhoek (1632-1723). Natuurkundige te Delft Rijksmuseum SK-A-957.jpeg
Antonie van Leeuwenhoek described the microscopic appearance of uric acid crystals in 1679.

The term "gout" was initially used by Randolphus of Bocking, around 1200 AD. It is derived from the Latin word gutta, meaning "a drop" (of liquid). [93] According to the Oxford English Dictionary, this is derived from humorism and "the notion of the 'dropping' of a morbid material from the blood in and around the joints". [94]

Gout has been known since antiquity. Historically, it was referred to as "the king of diseases and the disease of kings" [8] [95] or "rich man's disease". [14] The first documentation of the disease is from Egypt in 2,600 BC in a description of arthritis of the big toe. Greek physician Hippocrates around 400 BC commented on it in his Aphorisms , noting its absence in eunuchs and premenopausal women. [93] [96] Aulus Cornelius Celsus (30 AD) described the linkage with alcohol, later onset in women and associated kidney problems:

Again thick urine, the sediment from which is white, indicates that pain and disease are to be apprehended in the region of joints or viscera... Joint troubles in the hands and feet are very frequent and persistent, such as occur in cases of podagra and cheiragra. These seldom attack eunuchs or boys before coition with a woman, or women except those in whom the menses have become suppressed... some have obtained lifelong security by refraining from wine, mead and venery. [97]

In 1683, Thomas Sydenham, an English physician, described its occurrence in the early hours of the morning and its predilection for older males:

Gouty patients are, generally, either old men or men who have so worn themselves out in youth as to have brought on a premature old age—of such dissolute habits none being more common than the premature and excessive indulgence in venery and the like exhausting passions. The victim goes to bed and sleeps in good health. About two o'clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle, or instep. The pain is like that of a dislocation and yet parts feel as if cold water were poured over them. Then follows chills and shivers and a little fever... The night is passed in torture, sleeplessness, turning the part affected and perpetual change of posture; the tossing about of body being as incessant as the pain of the tortured joint and being worse as the fit comes on. [98]

Dutch scientist Antonie van Leeuwenhoek first described the microscopic appearance of urate crystals in 1679. [93] In 1848, English physician Alfred Baring Garrod identified excess uric acid in the blood as the cause of gout. [99]

Other animals

Gout is rare in most other animals due to their ability to produce uricase, which breaks down uric acid. [100] Humans and other great apes do not have this ability, thus gout is common. [15] [100] Other animals with uricase include fish, amphibians and most non-primate mammals. [101] The Tyrannosaurus rex specimen known as "Sue" is believed to have suffered from gout. [102]

Research

A number of new medications are under study for treating gout, including anakinra, canakinumab, and rilonacept. [103] Canakinumab may result in better outcomes than a low dose of a steroid, but costs five thousand times more. [104] A recombinant uricase enzyme (rasburicase) is available but its use is limited, as it triggers an immune response. Less antigenic versions are in development. [15]

Related Research Articles

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Rasburicase pharmaceutical drug

Rasburicase is a medication that helps to clear uric acid from the blood. It is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Urate oxidase is known to be present in many mammals but does not naturally occur in humans. Rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain. The cDNA coding for rasburicase was cloned from a strain of Aspergillus flavus.

Uricosuric medications (drugs) are substances that increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. In general, this effect is achieved by action on the proximal tubule of the kidney. Drugs that reduce blood uric acid are not all uricosurics; blood uric acid can be reduced by other mechanisms.

Probenecid chemical compound

Probenecid, also sold under the brand name Probalan, is a medication that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.

Hypouricemia

Hypouricemia is a level of uric acid in blood serum that is below normal. In humans, the normal range of this blood component has a lower threshold set variously in the range of 2 mg/dL to 4 mg/dL, while the upper threshold is 530 micromol/L (6 mg/dL) for women and 619 micromol/L (7 mg/dL) for men. Hypouricemia usually is benign and sometimes is a sign of a medical condition.

Acute uric acid nephropathy is a rapidly worsening (decreasing) kidney function that is caused by high levels of uric acid in the urine (hyperuricosuria).

Febuxostat chemical compound

Febuxostat, sold under the brand names Uloric among others, is a medication used long-term to treat gout due to high uric acid levels. It is generally only recommended in those who cannot take allopurinol. When initially started, medications such as NSAIDs are often recommended to prevent gout flares. It is taken by mouth.

Hyperuricosuria

Hyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. For men this is at a rate greater than 800 mg/day, and for women, 750 mg/day. Notable direct causes of hyperuricosuria are dissolution of uric acid crystals in the kidneys or urinary bladder, and hyperuricemia. Notable indirect causes include uricosuric drugs, rapid breakdown of bodily tissues containing large quantities of DNA and RNA, and a diet high in purine.

SLC22A12 mammalian protein found in Homo sapiens

Solute carrier family 22, member 12, also known as SLC22A12 and URAT1, is a protein which in humans is encoded by the SLC22A12 gene.

A xanthine oxidase inhibitor is any substance that inhibits the activity of xanthine oxidase, an enzyme involved in purine metabolism. In humans, inhibition of xanthine oxidase reduces the production of uric acid, and several medications that inhibit xanthine oxidase are indicated for treatment of hyperuricemia and related medical conditions including gout. Xanthine oxidase inhibitors are being investigated for management of reperfusion injury.

Pegloticase is a medication for the treatment of severe, treatment-refractory, chronic gout. It is a third line treatment in those in whom other treatments are not tolerated. The drug is administered by infusion intravenously.

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