Gout

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Gout
Classification & 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
MeSH	D006073

Gout (also called metabolic arthritis) is a disease due to an inborn disorder of the uric acid metabolism. In this condition monosodium urate crystals are deposited on the articular cartilage of joints and in the particular tissue like tendons. This provokes an inflammatory reaction of these tissues. These deposits often increase in size and burst through the skin to form sinuses discharging a chalky white material.

Normally, the human bloodstream only carries small amounts of uric acid. However, if the blood has an elevated concentration of uric acid, uric acid crystals are deposited in the cartilage and tissue surrounding joints. Elevated blood levels of uric acid can also result in uric kidney stones.

Contents 1 Signs and symptoms 2 Diagnosis 3 Pathogenesis 4 Stages of gout 5 Treatment 5.1 Attacks 5.2 Prevention 5.2.1 Additional measures 5.3 Surgery 6 Diet 7 History 8 Famous people with gout 9 Gout in fiction 10 See also 11 References 12 Footnotes 13 External links

[edit] Signs and symptoms

The classic picture is of excruciating and sudden pain, swelling, redness, warmness and stiffness in the joint. 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 draping over the affected area could cause extreme pain.

Gout usually attacks the big toe (approximately 75% of first attacks), however it can also 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 the small toes which 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 e.g. the helix of the ear. Uric acid stones can form as one kind of kidney stone in some occasions.

[edit] Diagnosis

The diagnosis is generally made on a clinical basis, although tests are required to confirm the disease.

Hyperuricemia is a common feature; however, 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, high uric acid level does not necessarily mean a person will develop gout. Additionally, 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 and erythrocyte sedimentation rate (ESR). This serves mainly to exclude other causes of arthritis, most notably septic arthritis.

A definitive diagnosis of gout is from light microscopy of joint fluid aspirated from the joint (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 bi-refringence under polarised microscopy, and their needle-like morphology. A trained observer does better in distinguishing them from other crystals.

[edit] Pathogenesis

Gout arises directly from elevated levels of uric acid within the blood. The amount of uric acid within the body is determined by the balance between the amount being produced and the amount being excreted. Uric acid is produced when purines are broken down by enzymes in the liver. Purines can be generated by the body itself (via the breakdown of cells in normal cellular turnover) or can be ingested in purine-rich foods (e.g. seafood, beer). Most people with gout, however, do not produce more than the normal amount of uric acid. Instead, most people with gout tend to be underexcretors. The kidney is responsible for about one 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. The prevalence of 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.^[3] In the United States, gout is twice as prevalent in African American males as it is in Caucasians.^[4]

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.

Many still believe that gout is caused by a combination of dietary factors and "laziness". In particular, many believe that gout develops following several years of excessive alcohol consumption combined with an ongoing lack of physical activity and a diet completely lacking in purine-neutralising foods, such as berries, as well as other specific fruit and vegetables (see below). Others have refined this theory, saying that some are genetically predisposed to gout and some are not. As a result, people who are not predisposed can live over-indulgent lifestyles and not develop gout, while others who are predisposed can develop gout, despite being physically active and having a well-rounded diet. However, most in the "genetic predisposition" school of thought nonetheless believe that the condition is much more likely to develop in the predisposed if the other factors are present over several years (excess alcohol, inactivity and failure to eat purine-neutralising foods). It is known that lead sugar was used to sweeten wine, and that chronic lead poisoning is a cause of gout,^[5][6] which condition is then known as saturnine gout, because of its association with alcohol and excess.^[7]

Gout can also 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.^[8]

[edit] Stages of gout

Gout has four distinct stages:

1. asymptomatic,
2. acute,
3. intercritical,
4. chronic.

In the first (asymptomatic) stage, plasma uric acid level increases, but there are no symptoms. The first attack of gout marks the second or acute stage. Mild attacks usually go away quickly, whereas severe attacks can last days or even weeks. After the initial attack, the person enters the intercritical stage or symptom-free interval that may last months or even years. Most gout patients have their second attack within 6 months to 2 years from their initial episode.

In the last or chronic stage, gout attacks become frequent and become polyarticular (affecting multiple joints at one time). Large tophi can also be found in many joints. In advanced cases of chronic gout, kidney damage, hypertension and kidney stones can also develop.

[edit] Treatment

[edit] Attacks

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

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

Before medical help is available, some over the counter medication can provide temporary relief to the 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. Preparation H hemorrhoidal ointment can be applied to the swollen skin to reduce the swelling temporarily. Professional medical care is needed for long term management of gout.

Ice may be applied for 20–30 minutes several times a day. There are concerns that uric acid crystallization is accelerated by low temperature, but in a 2002 study in the Journal of Rheumatology^[9] patients who used ice packs had better relief of pain with no negative side effects. Keeping the affected area elevated above the level of the heart may help as well.

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; it is usually treated in a similar fashion to athlete's foot.

[edit] Prevention

Long term treatment (in frequent attacks) is antihyperuricemic therapy.

Because the body metabolizes purines into uric acid, a maintained, low-purine diet can help lower the plasma urate level. Avoiding alcohol, high-purine foods, such as meat, fish, dry beans (also lentils and peas), mushrooms, spinach, asparagus, and cauliflower can lower plasma urate levels. In addition, consuming purine-neutralizing foods, such as fresh fruits (especially cherries and strawberries) and most fresh vegetables, diluted celery juice, distilled water, and B-complex and C vitamins can also help lower plasma urate levels.

A possible "natural" cure is a berry extract supplement consisting of bilberry, blueberry or cherry extracts. The anthocyanins which give the berries their blue and purple hues, after entering the body, turn into powerful anti-inflammatories. These might be an especially preferable option to transplant patients, who frequently suffer gout due to increased toxicity and strain on the kidneys due to their immunosuppressant medication.^{[citation needed]}

The mainstay of prevention is the drug allopurinol, a xanthine oxidase inhibitor, which directly reduces the production of uric acid. However, allopurinol treatment should not be initiated during an attack of gout, as it can then worsen the attack. If a patient is on allopurinol during an attack, it should be discontinued.

The decision to use allopurinol is often a lifelong one. Patients have been known to relapse into acute arthritic gout when they stop taking their allopurinol, as the changing of their serum urate levels alone seems to cause crystal precipitation.

Allopurinol and uricosuric agents are contraindicated in patients with kidney stones and other renal conditions.

[edit] Additional measures

• Febuxostat ((2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid) - a novel non-purine inhibitor of xanthine oxidase seems to be an alternative that is superior to allopurinol; it is currently in Phase III trials.^[10]

• Probenecid, a uricosuric drug that promotes the excretion of uric acid in urine, is also commonly prescribed - often in conjunction with colchicine. Interestingly, the drug fenofibrate (which is used in treating hyperlipidemia) also exerts a beneficial uricosuric effect.^[11]

• As arterial hypertension quite often coexists with gout, treating it with losartan, an angiotensin II receptor antagonist, might have an additional beneficial effect on uric acid plasma levels. This way losartan can offset the negative side-effect of thiazides (a group of diuretics used for high blood pressure) on uric acid metabolism in patients with gout.

• It is suspected that in many cases gout may be secondary to untreated sleep apnea, when oxygen-starved cells break down and release purines as a by-product. Treatment for apnea can be effective in lessening incidence of acute gout attacks.^[12]

• A study in 2004 suggests that animal flesh sources of purine, such as beef and seafood, greatly increase the risk of developing gout. However, high-purine vegetable sources did not. Low fat dairy products such as skim milk significantly reduced the chances of gout. The study followed over 40 thousand men over a period of years, in which 1300 cases of gout were reported.^[13]

• PEG-uricase, a poly(ethylene 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

[edit] Surgery

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

[edit] Diet

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

It is well-established that a diet low in purines reduces the serum level of uric acid, the primary risk factor for gout. The solubility threshold for uric acid is approximately 6.7 mg/dl. 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). Ingestion of 500 mg of vitamin C per day has been shown to bring about a 0.5 mg/dl decrease in serum uric acid through increased excretion.

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 was associated with a 44% decrease in the incidence of gout. Consumption of purine-rich vegetables or a high protein diet had no significant correlation. Consumption of beer, which is rich in guanosine, 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 wine consumption.

Additional dietary recommendations can be made which target gout indirectly by opposing gout risk factors such as obesity, 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:
  • cherries were reported to reduce uric acid in a small study (PMID 12771324, PMID 14776685)
  • strawberries or blueberries (and other dark red/blue berries) are also reputed to be beneficial.^{[citation needed]}
  • celery extracts (celery or celery seed either in capsule form or as a tea) 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 (PMID 15035799)
  • any kinds of cheese^{[citation needed]}. Cheese has been recommended as a low-purine food [1], and dairy products have been found to reduce the risk of gout.

• Food to avoid:
  • foods high in purines
    • limit food high in protein such as meat, fish, poultry, or tofu to 8 ounces (226 grams) a day. Avoid entirely during a flare up.^{[citation needed]} Tofu has been proposed as a safe source of protein for gout patients due to its small and transient effect on plasma urate levels. (PMID 9598181)
    • Tamarind^{[citation needed]}
    • sweetbreads, kidneys, liver, brains, or other offal meats[2] (PMID 7904493)
    • sardines and anchovies [3]
    • Seafood (PMID 15014182)
    • alcohol. (PMID 15094272) Some claim that this applies especially to beer, on the basis that brewer's yeasts are very rich in purine. In view of the fact that most modern commercial beer contains trace amounts of yeast, this claim requires substantiation. Others claim that red wine is particularly bad for gout^{[citation needed]}, though again it is difficult to find an explanation. Alcohol may also reduce the rate of uric acid excretion.^{[citation needed]}
    • meat extracts, consommés, and gravies[4]

• To avoid dehydration:
  • Drink plenty of liquids, especially water, to dilute and assist excretion of urates;
  • Avoid diet sodas (these act as diuretics in many people, causing uric acid to concentrate in the blood which can then easily precipitate)^{[citation needed]}
  • Use sparingly diuretic foods or medicines like aspirin, vitamin C, tea and alcohol. The role of diuretics in triggering gout has been disputed (PMID 16291814)
• Folklore has it that Joe-Pye weed flushes uric acid quickly, but continued use can damage the liver or kidneys^{[citation needed]}
• Another folk remedy is the use of oenomel, a drink with honey and unfermented grape juice.^{[citation needed]}
• Moderate intake of purine-rich vegetables is not associated with increased gout.^[13]

[edit] History

Gout was traditionally viewed as a disease of the decadent and indolent, because the foods which contribute to its development were only available in quantity to the wealthy. The stereotypical victim was a lazy, obese middle-aged man who habitually overindulged in rich foods and alcohol, with port wine consumption often cited as a specific cause. This stereotype is especially evident when gout is referred to as "The Disease of Kings".

Perhaps due to the traditional relationship between wealth and literacy, gout is one of the most commonly-reported maladies in history.

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] Famous people with gout

One of the most famous sufferers of gout was Henry VIII. Others include John Calvin, Charles Spurgeon, Kublai Khan, Nostradamus, John Milton, Queen Anne, Isaac Newton, Gottfried Leibniz, Henry Fielding, Samuel Johnson, Charles IV, Holy Roman Emperor, Charles V, Holy Roman Emperor,^[14] Pablo Neruda, Alfred Lord Tennyson, George IV, John Hancock, Thomas Jefferson, Karl Marx, William Pitt, 1st Earl of Chatham, Benjamin Disraeli, Kirk Reuter, Peter Paul Rubens, Osbert Sitwell, Lennart Torstenson, Peter Gomes, Alexander Hamilton, George Mason, Benjamin Franklin, Wilkie Collins, Henry James, Frederick the Great, Don Nelson, Jared Leto, Pope Clement VIII, Steven Susko, David Wells, Joseph Conrad, Harry Kewell and Curt Schilling.

Piero di Cosimo de' Medici was dubbed "Piero il Gottoso"; literally "Piero The Gouty".

The Roman poet Ennius wrote "numquam poetor nisi podager" — "I never write poetry unless I am suffering from gout." He used the enforced idleness caused by his arthritis to compose poetry.

The surgical treatment of his gout led Mel Brooks to create his famous persona, the 2000 Year Old Man.

Jared Leto developed gout after gaining 65 lbs. to play Mark David Chapman in the film Chapter 27.

According to a 1997 paper in Nature,^[15] a T-Rex dubbed "Sue" could have suffered from gout.

[edit] Gout in fiction

• Benjamin Franklin, who was afflicted with gout, wrote a fictionalized account of a conversation he had with a "Madam Gout," where they listed together all the reasons why he was afflicted, in the literary piece Dialogue Between Franklin and The Gout [5]
• In Jules Verne's The Vanished Diamond (L’Étoile du sud, 1884), one of the main characters, John Watkins, is suffering from gout.
• In an episode of King of the Hill, Bobby Hill, age 13, eats nothing but chopped liver for awhile and develops Gout. Hank Hill, Bobby's father, is shocked when he finds out, saying "that's an old man's disease!"
• In an episode of Lost In Space, Will Robinson encounters Hamish Rhu-Glamis, a Scotsman executed in 1497, but who was suffering gout at the time of his death. Will's mother Maureen attempts to treat the gout when Hamish is made living again by passage through a space warp.
• In George Eliot's Middlemarch, Tertius Lydgate publishes a book on gout.
• In an episode of Everybody Hates Chris, Chris's father has gout in the episode "Everybody Hates The Gout."
• In Archie Comics, the school principal Mr. Weatherbee was a long time sufferer of gout.
• In The Dukes of Hazzard, Boss Hogg regularly suffers from gout brought on by obesity, rich food and drink, and inactivity.
• In an episode (Angel Gabriel Blue) of Keeping Up Appearances, Richard has a fungus infection on his feet, but Hyacinth prefers to tell everyone it's gout because it "afflicts those who over-indulge on finer living".
• In the movie Captain Blood (1935), Dr. Peter Blood (Errol Flynn), a physician convicted of treason for treating a rebel against the crown (despite treating men of both sides) and thus sentenced to a life of slavery in Port Royal, Jamaica, tends to Governor Steed's (George Hassell) gouty foot.
• Jiggs, husband of Maggie, in George McManus' long defunct comic strip 'Bringing Up Father'. Jiggs ate large amounts of wonderfully rich food, especially corned beef and cabbage, bringing on very painful attacks of gout in the foot.
• Matthew Bramble, an invalid gentleman in Tobias Smollett's c. 1750 novel 'Humphry Clinker', suffers from a number of ailments, including gout. He reluctantly takes the waters of Bath to attempt a cure.
• In Jane Austen's last novel, Persuasion, Admiral Croft, arrives at Bath with orders "to walk to keep off the gout."
• In the high fantasy series "A Song of Ice and Fire", Prince Doran Martell suffers from a chronic case of gout.
• In Charles Dickens's Bleak House, the stereotype of Gout associated with the aristocracy is reinforced through the character Lord Dedlock and the male line of ancestors in the Dedlock family and is repeatedly referred to as the "family gout".
• In the Adam Sandler song Lunch Lady Land are these lyrics: "I wear this hair net because my red hairs are falling out. / I wear these brown orthopedic shoes because I've got a bad case of gout!".
• In the song "Great Big Stuff" from the Broadway musical "Dirty Rotten Scoundrels" gout is mentioned in one of the lyrics.
• In the comic strip "Katzenjammer Kids", the Captain often suffered from gout, always drawn in the form of a huge bandaged up foot.
• Gout is mentioned in the song "Impossible" from the musical "A Funny Thing Happened on the Way to the Forum".
• In Laurel and Hardy's Perfect Day (1929) the father is suffering from gout and has his left foot heavily wrapped up. This foot is hit at least 20 times by falling objects, closing doors, and so on throughout the episode.
• In Calvin and Hobbes, when Calvin is forging a one dollar bill, Hobbes remarks that "Ol' George has the gout, I see." This is a criticism of Calvin's forgery skills. (Strip dated November 3, 1987)
• The character of the Lawyer, Mr. Bruff, in Wilkie Collins' book The Moonstone is described as suffering from an attack of gout.

[edit] See also

• Pseudogout is a very similar disease, but caused by deposition of calcium pyrophosphate, not uric acid.

[edit] References

• Clements, Thomas. Book of Gout. 
• Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL (eds.) (2005). Harrison's Principles of Internal Medicine, 16th ed., New York: McGraw-Hill. ISBN 0-07-139140-1. 
• Kumar P, Clark M (eds.) (1998). Clinical Medicine, 4th ed., Philadelphia: W.B. Saunders. ISBN 0-7020-2458-9. 
• Porter, Roy and Rousseau, G. S. (1998). Gout: The Patrician Malady. Yale University Press. ISBN 0-300-07386-0. 

[edit] Footnotes

[edit] External links

• American College of Rheumatology (March 23, 2007). Retrieved on 2007-03-23.- (ACR Fact Sheet on Gout)
• Answers and Questions on Gout. U.S. National Institutes of Health—National Institute of Arthritis and Musculoskeletal and Skin Diseases (March 23, 2007). Retrieved on 2007-03-23.
• Diet and gout. A-Z Health Guide. webMD.com (July 01, 2004). Retrieved on 2006-09-18.
• Purine content in food. British Dalmatian Club. Retrieved on 2006-09-18.
• Gout. Health in Plain English. Retrieved on 2006-09-18. - (with pictures)
• Gout. ArthritisMD (2005). Retrieved on 2006-09-18. - (research based arthritis articles by physicians)
• Investigational Medications for Gout. Retrieved on 2006-11-03. - (Saviant Pharmaceuticals web site)
• Gout: Natural Treatments. Retrieved on 2006-11-07. - (written by naturopathic physician)
• I Cured My Gout (2007-0103). Retrieved on 2007-03-20. - (site claiming that gout is cured by baking soda)