Gout

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

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 untreated, the crystals form tophi, which can cause significant tissue damage. Gout results from a combination of elevated concentrations of uric acid and overall acidity in the bloodstream. In isolation, neither elevated uric acid (hyperuricemia) nor acidity is normally sufficient to cause gout.

Contents

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.

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 with tophi on elbow and knee.

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 a normal component of blood serum. Uric acid is more likely to form into crystals when there is hyperuricemia, although hyperuricemia is 10 times more common without clinical gout than with it.[1] Gout can also occur when serum uric acid is normal, and when it is abnormally low (hypouricemia). Paradoxically, acute attacks of gout can occur together with a sudden decrease in serum uric acid, such as due to use of drugs (uricosurics, xanthine oxidase inhibitors), or total parenteral nutrition.[2] However, correlation does not imply causation. The sudden decrease may be a consequence of abrupt formation of crystals (removing uric acid from the serum), rather than a cause.

Regardless of the serum concentration of uric acid, precipitation of uric acid is markedly enhanced when the blood pH is low (acidosis). A similar pH-sensitive effect occurs in urine,[3] contributing to uric acid nephrolithiasis.

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.

Causes

Gout may be primary (including idiopathic), or secondary to (a complication of) another condition.

Primary gout

A proportion of people have mutations in the proteins responsible for the excretion of uric acid by the kidneys (four genes have so far been identified: SLC22A12, SLC2A9, ABCG2 and SLC17A3).[4]

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.[5] Some studies have established a statistical connection between gout and lead poisoning,[6] and a significant correlation between levels of lead in the body and urate excretion and gout.[7] It is known that lead sugar was used to sweeten wine, and that chronic lead poisoning is a cause of gout,[8][9] and condition is then known as saturnine gout, because of its association with lead (Saturnus was the alchemists' term for the metal lead).[10]

Diuretics (particularly thiazide diuretics) have traditionally been blamed for precipitating attacks of gout because they compete at the same transporter, but a Dutch case-control study from 2006 appears to cast doubt on this conclusion.[11]

Secondary gout

Secondary gout is a complication of other medical conditions. Medical conditions that commonly result in gout include:

Gout also can develop as co-morbidity of other diseases, including polycythaemia, intake of cytotoxics, obesity, diabetes, hypertension, renal disorders, and hemolytic anemia.

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.

Gouty tophi, particularly when not located in a joint, can be mistaken for basal cell carcinoma[12] or other neoplasm.[13]

A definitive diagnosis of gout is from light microscopy of fluid aspirated from the affected joint or other locus (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. Many physicians do not perform this test, relying instead on a variety of less specific clinical signs and laboratory tests.[14]

Hyperuricemia is a common feature of gout, so its presence supports a diagnosis of gout. However, gout can occur without hyperuricemia.[15] 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.[16] 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.

Ultrasound imaging (US) can be helpful. US signs of gouty joints include a double-contour appearance of the cartilage and a snowstorm appearance of the synovial membrane.[17] US can also be used to guide aspiration.[18]

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,[19] or intra-articular glucocorticoids administered via a joint injection.

NSAIDs such as diclofenac, etoricoxib, indomethacin, ketoprofen, naproxen or sulindac may be prescribed.[20] For those at risk of gastric irritation from NSAIDs, an additional proton pump inhibitor may be given.[21]

Colchicine remains a second line drug in the UK for those unable to tolerate NSAIDs,[21][22] but its side effect profile has resulted in its role being relegated, at least in the US, to after that of oral glucocorticoids.[23] 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.[24]

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. 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.[25] 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 crystals. Adequate hydration is a standard recommendation. However, a small study found that only icing, not heating, was beneficial.[26] 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.

Chronic joint changes

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

Extensive tophi that invade bone are associated with arthritis due to bone erosion.[27]

Prevention

Prevention of chronic gout has a different objectives than management of acute episodes (flareups). In an acute attack the objective is to reduce pain and inflammation. 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.

Diet

See Saag and Choi, 2006, an open-access review article, for detailed references and further information.[33]

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.

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.[34]

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. This has to do with the number of mitochondria per cell. Meat (particularly dark meat) and seafood are high in purine because muscle cells are packed with thousands of mitochondria, each with 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. In plants, in addition to mitochondria (in very low numbers) some cells have chloroplasts, also with their own DNA and RNA. For this reason, both relatively high-protein vegetables and dark green leafy vegetables are expected to have more purines than other vegetables. However, the contribution of these to the total purine content of plant tissues is relatively low due to the relatively low copy number. 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.[1] This is because soft drinks contain large quantities of high-fructose corn syrup (HFCS), a common sweetener in soft drinks, which results in Hyperuricemia in blood.[35][36] Hyperuricemia, in turn predispose the body for gout.[37]

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.

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:

Over the counter remedies

Epidemiology

Gout is a form of arthritis that affects mostly men between the ages of 50 and 60.

There are 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.[58] In the United States, gout is twice as prevalent in African American males as it is in European-Americans.[59]

A seasonal link also may exist, with significantly higher incidence of acute gout attacks occurring in the spring.[60][61]

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.[62] 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).[62]

The Dutch scientist Antonie van Leeuwenhoek described the microscopic appearance of urate crystals in 1679.[62] In 1848 English physician Alfred Baring Garrod realised that excess uric acid in the blood was the cause of gout.[63]

Historical treatments for gout include gin.

See also

References

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  50. ↑ The British Pharmaceutical Codex. Published by direction of the Council of the Pharmaceutical Society of Great Britain, 1911. Sodium
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  60. ↑ Schlesinger N, Gowin KM, Baker DG, Beutler AM, Hoffman BI, Schumacher HR (February 1998). "Acute gouty arthritis is seasonal". J. Rheumatol. 25 (2): 342–4. PMID 9489831. 
  61. ↑ Gallerani M, Govoni M, Mucinelli M, Bigoni M, Trotta F, Manfredini R (October 1999). "Seasonal variation in the onset of acute microcrystalline arthritis". Rheumatology (Oxford) 38 (10): 1003–6. doi:10.1093/rheumatology/38.10.1003. PMID 10534553. http://rheumatology.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10534553. 
  62. ↑ 62.0 62.1 62.2 Pillinger, MH; Rosenthal P, Abeles AM (2007). "Hyperuricemia and gout: new insights into pathogenesis and treatment". Bulletin of the NYU Hospital for Joint Diseases 65 (3): 215–221. PMID 17922673. http://www.nyuhjdbulletin.org/Permalink.aspx?permalinkId=0c3ec9d1-8cc8-49d5-850d-4c5a55cb0669. 
  63. ↑ Storey GD (October 2001). "Alfred Baring Garrod (1819-1907)". Rheumatology (Oxford, England) 40 (10): 1189–90. PMID 11600751. http://rheumatology.oxfordjournals.org/cgi/content/full/40/10/1189. 

External links

Antigout preparations (M04)
Uricosurics
primary: Probenecid · Sulfinpyrazone · Benzbromarone · Isobromindione
secondary: Fenofibrate · Guaifenesin
Xanthine oxidase inhibitors
purine analogues: Allopurinol · Oxypurinol · Tisopurine
other: Febuxostat · Inositols (Phytic acid, Myo-inositol)
Mitotic inhibitors
Other
Cinchophen · Urate oxidase (Rasburicase)
Diseases of the musculoskeletal system and connective tissue (M, 710-739)
Arthropathies
Arthritis
(monoarthritis/
polyarthritis)
Septic arthritis

Seronegative spondyloarthropathy: Reactive arthritis · Psoriatic arthritis

Rheumatoid arthritis: Juvenile idiopathic arthritis · Adult-onset Still's disease · Felty syndrome

Crystal arthropathy: Gout · Chondrocalcinosis

Osteoarthritis: Heberden's node · Bouchard's nodes

Palindromic rheumatism
Specific joints
Upper limb
shoulder (Winged scapula, Adhesive capsulitis, Rotator cuff tear, Subacromial bursitis) · elbow (Cubitus valgus, Cubitus varus) · hand (Wrist drop, Boutonniere deformity, Swan neck deformity)
Lower limb
hip (Protrusio acetabuli, Coxa valga, Coxa vara) · leg (Unequal leg length) · patella (Luxating patella, Chondromalacia patellae) · foot (Bunion/hallux valgus, Hallux varus, Hallux rigidus, Hammer toe, Foot drop, Flat feet, Club foot)
General terms
Valgus deformity · Varus deformity
Synovium and tendon
Synovitis/Tenosynovitis (Calcific tendinitis, Stenosing tenosynovitis, Trigger finger, DeQuervain's syndrome) · Irritable hip · Ganglion cyst
Bursa
Bursitis (Olecranon, Prepatellar, Trochanteric, Subacromial) · Baker's cyst
Other
Hemarthrosis · Arthralgia · Osteophyte · Hypermobility
Dorsopathies
spinal curvature (Kyphosis, Lordosis, Scoliosis) · Scheuermann's disease · Spondylolysis · Torticollis · Spondylolisthesis
Spondylopathies (Ankylosing spondylitis, Spondylosis, Spinal stenosis) · Schmorl's nodes · Degenerative disc disease · Coccydynia · Back pain (Radiculopathy, Neck pain, Sciatica, Low back pain)
see also congenital
Inborn errors of purine-pyrimidine metabolism (E79, 277.2)
Purine metabolism
Anabolism
Adenylosuccinate lyase deficiency - Myoadenylate deaminase deficiency
Nucleotide salvage
Lesch-Nyhan syndrome/Hyperuricemia - Adenine phosphoribosyltransferase deficiency
Catabolism
Adenosine deaminase deficiency - Purine nucleoside phosphorylase deficiency - Xanthinuria - Gout
Pyrimidine metabolism
Anabolism
Orotic aciduria
Catabolism
Dihydropyrimidine dehydrogenase deficiency
see also nucleotide metabolism, intermediates