......Gout

Gout (metabolic arthritis) is a disease created by a buildup of uric acid. In this condition, crystals of monosodium urate or uric acid are deposited on the articular cartilage of joints, tendons and surrounding tissues. These crystals cause inflammation and pain, both severe. If unchecked, the crystals form tophi, which can cause significant tissue damage. Gout results from a combination of elevated concentrations of uric acid and and overall acidity in the bloodstream. In isolation, neither elevated uric acid (hyperuricemia) nor acidity is normally sufficient to cause gout.
Signs and symptoms
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 long-standing 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
Pathophysiology
Gout occurs when crystals of uric acid, in the form of mono-sodium urate, precipitate on the articular cartilage of joints, on tendons, and in the surrounding tissues. Uric acid is likely to form into crystals when there is hyperuricemia, although hyperuricemia is 10 times more common without clinical gout than with it.[1] Precipitation of uric acid is markedly enhanced when the blood pH is low (acidosis).

Uric acid is a product of purine metabolism, and in humans is normally excreted in the urine. Purines are generated by the body via breakdown of cells in normal cellular turnover, and also are ingested as part of a normal diet. The kidneys are responsible for approximately two-third of uric acid excretion, with the gut responsible for the rest.

Gout may be primary (idiopathic), or secondary to a disease or other condition that has gout as one of its complications. Secondary gout is associated with:

Metabolic syndrome
Leukemia
Inborn errors of purine-pyrimidine metabolism

Diagnosis

Clinically, gout can be hard to distinguish from several other conditions, including chondrocalcinosis. Chondrocalcinosis is a very similar disease, caused by deposition of calcium pyrophosphate rather than uric acid.

Hyperuricemia is a common feature of gout, so its presence supports a diagnosis of gout. However, gout can occur without hyperuricemia.[2] 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.[3] 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.

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.

Treatment
Acute attacks
The first line of treatment should be pain relief. Once the diagnosis has been confirmed, the drug options are of nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine and oral glucocorticoids,[4] or intra-articular glucocorticoids administered via a joint injection.

NSAIDs such as diclofenac, etoricoxib, indomethacin, ketoprofen, naproxen or sulindac may be prescribed.[5] For those at risk of gastric irritation from NSAIDs, an additional proton pump inhibitor may be given.[6]

Colchicine remains a second line drug in the UK for those unable to tolerate NSAIDs,[6][7] but its side effect profile has resulted in its role being relegated, at least in the US, to after that of oral glucocorticoids.[8] 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 (single injection of diclofenac and then oral indomethacin) as from the oral glucocorticoid prednisolone; however, less adverse drug reactions occurred in the glucocorticoid group.[9]

Another possibility is 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.

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.[10] Since gout is caused by crystals, it has been suggested[citation needed] 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 crystals. Adequate hydration is a standard recommendation. However, a small study found that only icing, not heating, was beneficial.[11] Keeping the affected area elevated above the level of the heart also may help.[citation needed] 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.


[edit] Chronic joint changes
For extreme cases of gout, surgery may be necessary to remove large tophi and correct joint deformity
Prevention
Prevention of chronic gout has a different objectivs than management of acute episodes (flareups). In an acute attack the objective is to reduce pain and inflamation. The objective of prevention is to stop any future attacks and associated cumulative tissue damage. Prevention strategies include reducing the supply of purine, dissolving crystals of uric acid so the uric acid can return to the blood, and increasing the excretion of uric acid from the blood into the urine (without causing lithiasis there). Prevention tactics involve careful diagnosis of the factors contributing to the gout, followed by appropriate use of medication, diet, and over the counter remedies
Medication
Prescription drugs used to treat gout belong to several functional classes. These include xanthine-oxidase inhibitors, uricosurics, and urate oxidases. One of the most widely used is the xanthine-oxidase inhibitor allopurinol.

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.[12] However, allopurinol and azathioprine (Imuran) used together present a risk of a potentially fatal drug interaction, a severe risk of allopurinol use which is of importance to transplant patients being treated with azathioprine for immunosuppression. [13]
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.[14]
Probenecid, a uricosuric drug, often is prescribed for gout in conjunction with colchicine.[citation needed]
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.
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.[15]
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
Ethylenediaminetetraacetic acid (EDTA), a chelator of lead, has successfully increased uric acid excretion.[16] 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.
History
The first written description of gout dates from 2,600 BC, when Egyptians noted gouty arthritis of the big toe. Around 400 BC, the Greek physician Hippocrates also commented on gout.[50] 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."

Around 200 AD, the Roman gladiatorial surgeon Galen described gout as a discharge of the four humors of the body in unbalanced amounts into the joints. The word "gout" was initially used by Randolphus of Bocking, around 1,200 AD. It is derived from the Latin word "gutta", meaning "a drop" (of liquid).[50]

The Dutch scientist Antonie van Leeuwenhoek described the microscopic appearance of urate crystals in 1679.[50] In 1848 English physician Alfred Baring Garrod realised that excess uric acid in the blood was the cause of gout.[51]

Historical treatments for gout include gin