Gout is a common disorder of uric acid metabolism that can lead to deposition of monosodium urate (MSU) crystals in soft tissue, recurrent episodes of debilitating joint inflammation, and, if untreated, joint destruction and renal damage. Gout is definitively diagnosed based on the demonstration of urate crystals in aspirated synovial fluid.
Improvements in early diagnosis and the availability of definitive treatment have significantly improved the prognosis of gout, as evidenced by the declining incidence of disabling chronic tophaceous gout. However, tophaceous gout may still develop because of misdiagnosis, poor management, medication intolerances, and/or poor patient compliance.
For additional information on gout, see Medscape’s Gout Resource Center.
Although the presence of urate crystals in the soft and synovial tissues is a prerequisite for a gouty attack, the fact that urate crystals can also be found in synovial fluid in the absence of joint inflammation suggests that the mere presence of intrasynovial urate crystals is not sufficient to cause flares of gouty arthritis.
One explanation for this may lie in the observation that clumps or microtophi of highly negatively charged and reactive MSU crystals are normally coated with serum proteins (apolipoprotein [apo] E or apo B) that physically inhibit the binding of MSU crystals to cell receptors.1, 2 A gout attack may be triggered by either a release of uncoated crystals (eg, due to partial dissolution of a microtophus caused by changing serum urate levels) or precipitation of crystals in a supersaturated microenvironment (eg, release of urate due to cellular damage). From either source, naked urate crystals are then believed to interact with intracellular and surface receptors of local dendritic cells and macrophages, serving as a danger signal to activate the innate immune system.3
This interaction may be enhanced by immunoglobulin G (IgG) binding.4, 5 Triggering of these receptors, including Toll-like receptors, NALP3 inflammasomes, and the triggering receptors expressed on myeloid cells (TREMs) by MSU, results in the production of interleukin (IL)–1, which in turn initiates the production of a cascade of pro-inflammatory cytokines, including IL-6, IL-8, neutrophil chemotactic factors, and tumor necrosis factor (TNF)–alpha.6 Neutrophil phagocytosis leads to another burst of inflammatory mediator production.
Subsidence of an acute gout attack is due to multiple mechanisms, including the clearance of damaged neutrophils, recoating of urate crystals, and the production of anti-inflammatory cytokines including, IL-1RA, IL-10, and transforming growth factor (TGF)–beta.7, 8, 9, 5
Approximately 1% of the general population have gout.
Gout has a worldwide distribution; regional differences may reflect environmental, dietary, and genetic influences.
Gout is associated with considerable morbidity. Acute episodes of gout often lead to incapacitation.
Untreated chronic tophaceous gout can lead to severe joint destruction.
MSU deposition in the kidney can result in inflammation and fibrosis, leading to reduced renal function or chronic renal nephropathy.
Hyperuricemia and gout are associated with an increased overall likelihood of mortality. Whether this is directly attributable to hyperuricemia or gout or to gout-associated diseases (eg, insulin resistance, type 2 diabetes mellitus, abdominal obesity, hypercholesterolemia, hypertension) has been much debated. Although no evidence has shown that gout or hyperuricemia causes any of these disorders, elevated urate levels have been shown to correlate with blood pressure in adolescents,10 and, among middle-aged men, hyperuricemia with gout was a significant independent risk for death due to cardiovascular disease.11
Gout is slightly more prevalent in blacks than in whites.
The prevalence of gout is 13.6 cases per 1000 men and 6.4 cases per 1000 women.
This difference is largely a consequence of age at onset because estrogenic hormones have a mild uricosuric effect; therefore, gout is unusual in premenopausal women.
As a rule, uric acid levels are elevated for 20 years before the onset of gout.
In men, uric acid levels rise at puberty, and the peak age of onset of gout in men is in the fourth to sixth decade of life. In women, uric acid levels rise at menopause, and peak age of onset in women is in the sixth to eighth decade of life. Gout is unlikely to present in premenopausal women or in men younger than 30 years who do not have renal insufficiency or a genetic abnormality of purine metabolism (eg, hypoxanthine-guanine phosphoribosyltransferase deficiency, phosphoribosylpyrophosphate synthetase superactivity). The higher prevalence of gout in elderly persons may also reflect an increased prevalence of metabolic syndrome, high rates of diuretic treatment for hypertension and congestive heart failure, and the use of low-dose acetylsalicylic acid. Tophi are typically detectable clinically approximately 10 years after the first gout attack.
Cyclosporin A can cause an accelerated form of gout, even in premenopausal women, that can present after only a few years of hyperuricemia, particularly if the patient is also receiving diuretics.
Acute monoarticular arthritis is the initial presentation of gout in 90% of patients.
In early gout, only 1 or 2 joints are usually involved. Typically, they are the smaller, lower-extremity joints. Podagra (inflammation of the first metatarsophalangeal joint) is the initial joint manifestation in 50% of cases. Eventually, it is involved in 90% of cases. Podagra is not synonymous with gout. Podagra may be observed in patients with pseudogout, sarcoidosis, gonococcal arthritis, psoriatic arthritis, and reactive arthritis.
The attacks begin abruptly and reach maximum intensity within 8-12 hours. The joints are red, hot, and exquisitely tender; even a bed sheet on the swollen joint is uncomfortable. Untreated, the first attacks resolve spontaneously in less than 2 weeks.
A history of intermittent inflammatory arthritis, in which the joints return to normal between attacks, is typically caused by crystalline disorders and is characteristic of gouty arthritis early in its course.
Gout initially presents as polyarticular arthritis in 10% of patients. Elderly women, particularly women with renal insufficiency on a thiazide diuretic, can develop polyarticular arthritis as the first manifestation of gout. These attacks may occur in coexisting Heberden and Bouchard nodes. Such patients may also develop tophi more quickly, occasionally without prior episodes of acute gouty arthritis.12, 13, 14
The pattern of symptoms in untreated gout change over time.
The attacks become more polyarticular.
Although more joints may become involved, inflammation in a given joint may become less intense.
More proximal and upper-extremity joints become involved.
Attacks occur more frequently and last longer.
Eventually, patients may develop chronic polyarticular arthritis, sometimes nearly symmetrical, that can resemble rheumatoid arthritis. Indeed, chronic polyarticular arthritis that began as an intermittent arthritis should prompt consideration of a crystalline disorder in the differential diagnoses.
Although gout typically causes joint inflammation, it can also cause inflammation in other synovial-based structures such as bursae and tendons.
Tophi are collections of urate crystals in the soft tissues. They develop in more than half of patients with untreated gout and may be reported as lumps or nodules. While the classic location of tophi is along the helix of the ear, they can be found in multiple locations, including the fingers, toes, in the olecranon bursae, and along the olecranon, where they can resemble rheumatoid nodules. The finding of a rheumatoid nodule in a patient with a negative rheumatoid factor result or a history of drainage from a nodule should prompt consideration of gout in the differential diagnoses. Tophi are not commonly found during the first gout episode. They tend to develop after 10 years in untreated patients who develop chronic gouty arthritis. Tophi tend to develop earlier in women, particularly those receiving diuretics.12, 13, 14
Acute flares of gout can result from situations that lead to increased levels of serum uric acid, such as the consumption of beer or liquor, overconsumption of foods with high purine content, trauma, hemorrhage, dehydration, or the use of medications that elevate levels of uric acid. Acute flares of gout also can result from situations that lead to decreased levels of serum uric acid, such as the use of radiocontrast dye or medications that lower the levels of uric acid, including allopurinol and uricosurics.
Patients with gout are profoundly more likely to develop renal stones than are healthy individuals (by a factor of 1000); therefore, they may have a history of renal colic. Indeed, renal stones may precede the onset of gout in 40% of affected patients. While 80% of these patients may have stones composed entirely of uric acid, 20% may develop calcium oxalate or calcium phosphate stones with a uric acid core.
Although patients with gout often have other risk factors for renal disease, including hypertension and diabetes, chronic urate nephropathy can contribute to renal insufficiency. Chronic urate nephropathy in patients with chronic tophaceous gout can result from the deposition of urate crystals in the medullary interstitium and pyramids, resulting in an inflammatory reaction that can lead to fibrotic changes. This process is characterized by hyperuricemia that is disproportional to the degree of renal impairment and is associated with a benign urinary sediment.
Lead intoxication can damage the renal tubules, leading to impaired proximal tubular function with resultant hyperuricemia and gout.
Because gout is frequently present in patients with the metabolic syndrome (eg, insulin resistance or diabetes, hypertension, hypertriglyceridemia, and low levels of high-density lipoproteins) and because the presence of these associated disorders can lead to coronary artery disease, these problems should be sought and treated in patients diagnosed with gout.
Importantly, ask about a history of peptic ulcer disease, renal disease, or other conditions that may complicate the use of the medications used to treat gout.
During an acute gout attack, examine all joints to determine if the patient’s arthritis is monoarticular or polyarticular.
Involved joints have all the signs of inflammation: swelling, warmth, erythema, and tenderness.
The erythema over the joint may resemble cellulitis; the skin may desquamate as the attack subsides.
The joint capsule becomes quickly swollen, resulting in a loss of range of motion of the involved joint.
During an acute gout attack, patients may be febrile, particularly if it is an attack of polyarticular gout.
Look for sites of infection that may have seeded the joint and caused an infectious arthritis that can resemble or coexist with acute gouty arthritis.
The presence of tophi suggests long-standing hyperuricemia.
Gout develops in the setting of excessive stores of uric acid in the form of monosodium urate. Uric acid is an end-stage by-product of purine metabolism. Lacking uricase, humans remove uric acid primarily by renal excretion. When excretion is insufficient to maintain serum urate levels below the saturation level of 6.8 mg/dL (with some variability depending on temperature and pH), hyperuricemia may develop, and urate can crystallize and deposit in soft tissues. Ninety percent of patients with gout develop excess urate stores due to an inability to excrete sufficient amounts of normally produced uric acid in the urine (underexcretion). The remaining patients either overconsume purines or produce excessive amounts of uric acid endogenously (overproduction).
In rare cases, overproduction of uric acid is primary, due to a genetic disorder. These disorders include hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome), glucose-6-phosphatase deficiency (von Gierke disease), fructose 1-phosphate aldolase deficiency, and PP-ribose-P synthetase variants.
Overproduction of uric acid may also occur in disorders that cause high cell turnover with release of purines. These disorders include myeloproliferative and lymphoproliferative disorders, psoriasis, chemotherapy (tissue lysis), hemolytic anemias, pernicious anemia, ineffective erythropoiesis (as in B-12 deficiency), excessive exercise, and obesity.
Overproduction of uric acid can occur from overconsumption of foods high in purines.
Common causes of secondary gout due to underexcretion of uric acid include renal insufficiency, lead nephropathy (saturnine gout), starvation or dehydration, hypothyroidism, hyperparathyroidism, drugs (including diuretics and cyclosporine A), and chronic ethanol (especially beer and hard liquor) abuse. These disorders should be identified and corrected, if possible.
Individual gout flares are often triggered by acute increases or decreases in urate levels that may lead to the production, exposure, or shedding of crystals that are not coated with apo B or apo E. This can result from acute alcohol ingestion, acute overindulgence in foods high in purines, rapid weight loss, starvation, trauma, or hemorrhage. Medications that increase uric acid levels via effects on renal tubular transport include diuretics and low-dose aspirin. Gout flares can also result from agents that lower levels of uric acid, including the use of radiocontrast dyes and medications such as allopurinol or uricosurics.