Gout

From Wikipedia, the free encyclopedia

Gout
Classification and external resources
Uric acid
ICD-10 M10.
ICD-9 274.0 274.1 274.8 274.9
OMIM 138900 300323
DiseasesDB 29031
eMedicine med/924  orthoped/124 emerg/221 med/1112 oph/506 radio/313
MeSH D006073

Gout (also called metabolic arthritis) is a disease created by a build up of uric acid. In this condition, monosodium urate or uric acid crystals are deposited on the articular cartilage of joints, tendons and surrounding tissues due to elevated concentrations of uric acid in the blood stream. This provokes an inflammatory reaction of these tissues.

Contents

[edit] Signs and symptoms

The Gout, Cartoon by James Gillray (1799). The artist memorably illustrates the excruciating pain and swelling that are symptoms of the disease.
The Gout, Cartoon by James Gillray (1799). The artist memorably illustrates the excruciating pain and swelling that are symptoms of the disease.

Gout is characterized by excruciating, sudden, unexpected, burning pain, as well as swelling, redness, warmth, and stiffness in the affected joint. This occurs commonly in men in their toes but can appear in other parts of the body and affects women as well. Low-grade fever may also be present. The patient usually suffers from two sources of pain. The crystals inside the joint cause intense pain whenever the affected area is moved. The inflammation of the tissues around the joint also causes the skin to be swollen, tender and sore if it is even slightly touched. For example, a blanket or even the lightest sheet draping over the affected area could cause extreme pain.

Gout usually attacks the big toe (approximately 75 percent of first attacks); however, it also can affect other joints such as the ankle, heel, instep, knee, wrist, elbow, fingers, and spine. In some cases, the condition may appear in the joints of small toes that have become immobile due to impact injury earlier in life, causing poor blood circulation that leads to gout.

Patients with longstanding hyperuricemia (see below) can have uric acid crystal deposits called tophi (singular: tophus) in other tissues such as the helix of the ear. Elevated levels of uric acid in the urine can lead to uric acid crystals precipitating in the kidneys or bladder, forming uric acid kidney stones.

[edit] Diagnosis

A definitive diagnosis of gout is from light microscopy of fluid aspirated from the joints (this test may be difficult to perform) to demonstrate intracellular monosodium urate crystals in synovial fluid polymorphonuclear leukocytes. The urate crystal is identified by strong negative birefringence under polarised microscopy and its needle-like morphology. A trained observer does better in distinguishing them from other crystals.

Hyperuricemia is a common feature, although urate levels are not always raised.[1] Hyperuricemia is defined as a plasma urate (uric acid) level greater than 420 μmol/L (7.0 mg/dL) in males (or 380 μmol/L in females). However, a high uric acid level does not necessarily mean a person will develop gout. Urate is within the normal range in up to two-thirds of cases.[2] If gout is suspected, the serum urate test should be repeated once the attack has subsided. Other blood tests commonly performed are full blood count, electrolytes, renal function, thyroid function tests and erythrocyte sedimentation rate (ESR). This helps to exclude other causes of arthritis, most notably septic arthritis, and to investigate any underlying cause for the hyperuricaemia.

[edit] Pathogenesis

Gout occurs when mono-sodium urate crystals form on the articular cartilage of joints, on tendons, and in the surrounding tissues. Purine metabolism gives rise to uric acid, which is normally excreted in the urine. Uric acid is more likely to form into crystals when there is a hyperuricemia, although it is 10 times more common without clinical gout than with it.[3]

Purines can be generated by the body via breakdown of cells in normal cellular turnover, or can be ingested in purine-rich foods such as seafood. The kidneys are responsible for approximately two-third of uric acid excretion, with the gut responsible for the rest. It may be possible that defects in the kidney that may be genetically determined are responsible for the predisposition of individuals for developing gout.

There are also different racial propensities to develop gout. Gout is high among the peoples of the Pacific Islands, and the Māori of New Zealand, but rare in the Australian aborigine despite the latter's higher mean concentration of serum uric acid.[4] In the United States, gout is twice as prevalent in African American males as it is in European-Americans.[5]

A seasonal link also may exist, with significantly higher incidence of acute gout attacks occurring in the spring.[6][7]

Hyperuricemia is considered an aspect of metabolic syndrome, although its prominence has been reduced in recent classifications. This explains the increased prevalence of gout among obese individuals.

Gout is a form of arthritis that affects mostly men between the ages of 50 and 60. The high levels of uric acid in the blood are caused by protein rich foods. Alcohol intake often causes acute attacks of gout and hereditary factors may contribute to the elevation of uric acid. Typically, persons with gout are obese, predisposed to diabetes and hypertension, and at higher risk of heart disease. Gout is more common in affluent societies due to a diet rich in proteins, fat, and alcohol. When it follows as a consequence of other health conditions such as renal failure, it is often regardless of the person's lifestyle.[8] Lin, et al have statistical evidence linking gout to lead poisoning[9] and lead level in the body is significantly correlated with urate excretion and gout.[10] It is known that lead sugar was used to sweeten wine, and that chronic lead poisoning is a cause of gout,[11][12] which condition is then known as saturnine gout, because of its association with alcohol and excess.[13]

Gout also can develop as co-morbidity of other diseases, including polycythaemia, leukaemia, intake of cytotoxics, obesity, diabetes, hypertension, renal disorders, and hemolytic anemia. This form of gout is often called secondary gout. Diuretics (particularly thiazide diuretics) have traditionally been blamed for precipitating attacks of gout, but a Dutch case-control study from 2006 appears to cast doubt on this conclusion.[14]

Gout with tophi on elbow and knee.
Gout with tophi on elbow and knee.

[edit] Treatment

[edit] Acute attacks

The first line of treatment should be pain relief. Once the diagnosis has been confirmed, the drugs of choice are indomethacin, other nonsteroidal anti-inflammatory drugs (NSAIDs), oral glucocorticoids[15], or intra-articular glucocorticoids administered via a joint injection.

Colchicine was previously the drug of choice in acute attacks of gout, as it impairs the motility of granulocytes and can prevent the inflammatory phenomena that initiate an attack. Colchicine should be taken within the first 12 hours of the attack and usually relieves the pain within 48 hours, although side effects (gastrointestinal upset such as diarrhea and nausea) can complicate its use. NSAIDs are the preferred form of analgesia for patients with gout.

A randomized controlled trial found similar benefit from nonsteroidal anti-inflammatory drugs and oral glucocorticoids; however, less adverse drug reactions occurred in the glucocorticoids group.[16] In the nonsteroidal anti-inflammatory drugs group, each patient initially received diclofenac (75 mg) intramuscularly, indomethacin 50 mg orally, and acetaminophen 1 g orally. The patient was received a 5-days of indomethacin (50 mg orally every 8 hours for 2 days, followed by indomethacin 25 mg every 8 hours for 3 days), and acetaminophen 1 g every 6 hours as needed. The glucocorticoids patients received prednisolone 30 mg orally, and acetaminophen 1 g orally. The patient was then given prednisolone 30 mg orally once per day for five days.

Before medical help is available, some over-the-counter medications can provide temporary relief from pain and swelling. NSAIDs such as ibuprofen can reduce the pain and inflammation slightly, although aspirin should not be used as it can worsen the condition. This is because aspirin raises plasma uric acid levels even at low doses by inhibiting uric acid secretion in the renal tubules[citation needed]. Aspirin also reduces vasodilatation due to inhibition of prostaglandin PGE2 and PGI2 synthesis in the renal medulla and glomeruli respectively (see mechanism of action of aspirin). This may be a contra-indication for the use of aspirin for gout pain as well.

The anti-hemorrhoidal ointment Preparation H can reduce gout-induced skin swelling temporarily. Ice may be applied for 20 to 30 minutes several times a day, and a randomized controlled trial found that patients who used ice packs had better relief of pain without side effects.[17] Since gout is caused by crystals, it has been suggested that keeping very well hydrated and heating the affected joint in hot water (rather than cooling with ice) will promote the dissolution and clearance of the urate crytals.[18] Keeping the affected area elevated above the level of the heart also may help. Professional medical care is needed for long-term management of gout.

Due to swelling around affected joints for prolonged periods, shedding of skin may occur. This is particularly evident when small toes are affected and may promote fungal infection in the web region if dampness occurs, and treatment is similar to that for common athlete's foot.

Some sufferers of gout report an aggravation of the condition in the knees and toes associated with long periods of immobility, such as when sitting at a computer desk for long hours. Sufferers who notice early swelling or early pain may appear to be able to arrest the aggravation when medical treatment is applied before the condition gets worse. Where this is the case, a medically prescribed anti-inflammatory oral treatment taken with food and bed rest may provide relief within 6 to 8 hours.

Another possibility is use of acetazolamide, one of the first diuretics discovered. This drug inhibits the action of carbonic anhydrase on the proximal convoluted tubules within the kidneys, which effectively inhibits reabsorption of bicarbonate, thus alkalinizing the urine. After two to three days of usage, the diuretic effects of this drug decline because of increased downstream reabsorption of ions and water by the renal tubules; however, the alkalinization of urine persists, and this basic urine attracts weak acids such as uric acid and cystine into the urine, thus increasing their urinary excretion.35

[edit] Chronic joint changes

For extreme cases of gout, surgery may be necessary to remove large tophi and correct joint deformity.

[edit] Prevention

[edit] Medications

  • Allopurinol is a xanthine-oxidase inhibitor, widely used in the prevention of attacks of gout, and well tolerated. It is safe to use in patients with renal impairment and urate stones.[19]
  • Sulfinpyrazone is an uricosuric. It is less widely used than allupurinol, and must not be used in patients with renal impairment, or a high urate excretion rate.[20]
  • Febuxostat ((2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid) - a non-purine inhibitor of xanthine oxidase seems to be an alternative that is superior to allopurinol at reducing serum urate levels, but not at reducing attacks of gout; it is currently in Phase III trials.[21]
  • Probenecid, a uricosuric drug that promotes the excretion of uric acid in urine, is also commonly prescribed - often in conjunction with colchicine. The drug fenofibrate (which is used in treating hyperlipidemia) also exerts a beneficial uricosuric effect.[22]
  • Gout is suspected to be secondary to untreated sleep apnea in some cases, caused by the release of purines as a by-product of the breakdown of oxygen-starved cells. Treatment for apnea can therefore be effective in lessening incidence of acute gout attacks.[23]
  • A 2004 study suggests that animal flesh sources of purine (such as beef and seafood) greatly increase the risk of developing gout. However, high-purine vegetable sources (such as asparagus, cauliflower, spinach, and green peas) did not. Dairy products such as milk and cheese significantly reduced the chances of gout. The study followed over 40000 men over a period of 12 years, in which 1300 cases of gout were reported.[24]
  • PEG-uricase, a polyethylene glycol ("PEG") conjugate of recombinant porcine uricase (urate oxidase), which breaks down the uric acid deposits is being studied in Phase III clinical trials for the treatment of severe, treatment-refractory gout in the United States in 2006.Pipeline
  • Sodium bicarbonate (baking soda) is a traditional remedy,[25] thought to work by raising blood pH (lowering blood acidity). However, the added sodium may be inappropriate for some people.
  • Ethylenediaminetetraacetic acid (EDTA), a chelator of lead, has successfully increased uric acid excretion.[26] This should be an advantageous treatment for those people whose gout was caused by lead poisoning. Care should be taken to increase intake of trace essential elements since chelation often remove these elements also.
  • Potassium supplements should be advantageous to treat gout. Gout can be triggered by the same agents that cause potassium losses such as fasting, surgery, and potassium losing diuretics.[27] A potassium deficiency can increase urate levels in the blood.[28]
  • Research from the University of British Columbia suggests long-term coffee consumption is associated with a lower risk of gout. [29]Other studies extend this benefit to tea and other caffeinated foods and drinks.[30]

[edit] Diet

See Saag and Choi, 2006, an open-access review article, for detailed references and further information.[31]

The serum level of uric acid is the primary risk factor for gout. The serum level is the result of both intake (diet) and output (excretion). Diet should be low fat and low protein.

[edit] Reduce intake of purines

The solubility threshold for uric acid is approximately 6.7 mg/dl; above this threshold crystals may form. Healthy subjects in the Normative Aging Study who had serum levels of uric acid over 9.0 mg/dl suffered a 22% incidence of gout over six years, compared to less than one percent for those with 7.0-8.9 mg/dl. The average uric acid level in men is 5.0 mg/dl, and substitution of a purine-free formula diet reduces this to 3.0 mg/dl. A purine-restricted diet lowers the level nearly as much (1-2 mg/dl).

A diet low in purines reduces the serum level of uric acid, unless these levels are caused by other health conditions and not as responsive to dietary changes. For notable sources of dietary purines, see "Foods to avoid" section below.

Protein is a crude proxy for purines; a more precise proxy is muscle. Apart from the notable dietary purines above, the main source of dietary purines is DNA and RNA, via their bases adenine and guanine. All sources of dietary protein supply some purines, but some sources provide far more purines than others. Meat (particularly dark meat) and seafood are high in purine because muscle cells are packed with mitochondria, which have their own DNA and RNA. In a large prospective study, high consumption of meat and seafood were found associated with an elevated risk of gout onset (41% and 50%, respectively). High consumption of dairy products, high in protein but very low in DNA and RNA, was associated with a 44% decrease in the incidence of gout. Consumption of the more purine-rich vegetables or a high protein diet per se had no significant correlation.

Men who consume two or more sugary soft drinks a day have an 85% higher risk of gout compared with those who drink less than one a month. [2] This is because soft drinks contain large quantities of high-fructose corn syrup (HFCS) (read label on any soft drink), which results in Hyperuricemia in blood.[32][33] Hyperuricemia, in turn predispose the body for gout.[34]

Consumption of beer is associated with a 49% increase in relative risk per daily 12-oz serving. By contrast, consumption of spirits was associated with only a 15% increase in relative risk, and no association at all was found with consumption of wine.

Some medical drugs are purine-based. Notable among these are the purine-analog antimetabolite drugs, sometimes used as chemotherapy agents.

[edit] Increase output of uric acid

As mentioned above, medicines to induce uric acid output are called uricosuric drugs. Two such drugs are Probenecid and Sulfinpyrazone.

[edit] Other approaches

Additional dietary recommendations can be made which reduce gout indirectly, hypertension, cardiovascular disease, diabetes, and metabolic syndrome.

The following suggestions do not meet with universal approval among medical practitioners.

Low purine diet:

  • To lower uric acid:
    • bing cherries were reported to reduce uric acid in a small study.[35][36]
    • celery extracts (celery or celery seed either in capsule form or as a tisane/infusion) is believed by many to reduce uric acid levels (although these are also diuretics).[citation needed] Celery extracts have been reported to act synergistically with anti-inflammatory drugs.[37]
    • Cheese has been recommended as a low-purine food,[38] and dairy products have been found to reduce the risk of gout.
    • Carbonated beverages and sugar have also been recommended as a low-purine food, [39] even though it was established that men who consume two or more sugary soft drinks a day have an 85% higher risk of gout compared with those who drink less than one a month. [3]
    • Dietary supplements Quercetin, a flavonoid, can decrease uric acid levels. Quercetin can be taken with bromelain to improve its absorption. In addition, Pantothenic acid (vitamin B5) is said to help with the excretion process of uric acid. [40]
  • Food to avoid:
  • To avoid dehydration:
    • Drink plenty of liquids, especially water, to dilute and assist excretion of urates;
    • Avoid diuretic foods or medicines like aspirin(aspirin should be avoided by those suffering from gout, unless specified by a qualified physician), vitamin C, tea and alcohol. The role of diuretics in triggering gout has been disputed.[51]
  • Moderate intake of purine-rich vegetables is not associated with increased gout.[24]

[edit] History

Writing ca. 30 AD, Aulus Cornelius Celsus appeared to recognize many of the features of gout, including its link with a urinary solute, late onset in women, linkage with alcohol, and perhaps even prevention by dairy products. [4] "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." and "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. Upon the commencement of pain blood should be let; for when this is carried out at once in the first stages it ensures health, often for a year, sometimes for always. Some also, when they have washed themselves out by drinking asses' milk, evade this disease in perpetuity; some have obtained lifelong security by refraining from wine, mead and venery for a whole year; indeed this course should be adopted especially after the primary attack, even although it has subsided."

The Roman gladiatorial surgeon Galen described gout as a discharge of the four humors of the body in unbalanced amounts into the joints. The Latin term for a drop, as a drop of discharge, is gutta -- the term gout descends from this word.

[edit] Notable sufferers

Notable sufferers of gout have included:

[edit] Royalty and nobility

[edit] Government and politics

[edit] Military and navy

[edit] Fine and performing arts

[edit] Literature

[edit] Science and mathematics

[edit] Sports

[edit] Philosophy

[edit] Religion

[edit] See also

[edit] References

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  3. ^ Virsaladze D, Tetradze L, Djavashvili L, Esakia N, Tananashvili D. (2007). "Levels of uric Acid in serum in patients with metabolic sypfoirefudvhfduyvcjvhfgndrome.". Georgian Med News 146: 34–7. PMID 17595458. 
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  25. ^ The British Pharmaceutical Codex. Published by direction of the Council of the Pharmaceutical Society of Great Britain, 1911. Sodium
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  51. ^ Janssens HJ, van de Lisdonk EH, Janssen M, van den Hoogen HJ, Verbeek AL (2006). "Gout, not induced by diuretics? A case-control study from primary care". Ann. Rheum. Dis. 65 (8): 1080-3. doi:10.1136/ard.2005.040360. PMID 16291814. 
  52. ^ Ordi J, Alonso P, de Zulueta J et al. (2006). "The severe gout of Holy Roman Emperor Charles V". N Engl J Med 355 (5): 516–20. doi:10.1056/NEJMon060780. PMID 16885558. 

35.) Katzung, Bertram G. Basic and Clinical Pharmacology, 10th edition. New York: McGraw Hill Medical, 2007. pp. 242

[edit] External links

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other, NEC: Muscle weakness - Rheumatism - Myalgia - Neuralgia - Neuritis - Panniculitis - Fibromyalgia
Osteopathies
Chondropathies
See also congenital conditions (Q65-Q79, 754-756)
v • d • e
Inborn errors of purine-pyrimidine metabolism (E79, 277.2)
Purine metabolism
Anabolism
Catabolism
Pyrimidine metabolism
Anabolism
Catabolism