Pathophysiology

Gout is a term that is used to describe a collection of disorders caused by the deposition of monosodium urate crystals in body tissue. The condition has become increasingly more common in the United States in the past 2 decades, in part because of the nation’s obesity crisis and a greater frequency of high blood pressure. Gout can be classified as primary or secondary. Primary gout, which affects males 10 times more often than females, is caused by an inborn error of purine metabolism that results in the overproduction or underexcretion of uric acid. Secondary gout is associated with hyperuricemia that results from other diseases or drugs that interfere with uric acid secretion. Secondary gout arises from a multitude of causes, including endocrine disorders, lead poisoning, high-dose salicylates (more than 3 g/day), myeloproliferative disorders, and chronic renal disease. Obese patients seem to have earlier onset of gout.

The basic pathology of gout generally is classified into one of two categories: overproduction or underexcretion of uric acid. A 24-hour urine collection is used to differentiate overproducers from underexcreters of uric acid.

Disease Process

Four phases generally are recognized in the development of gout. The first is asymptomatic hyperuricemia, which, as the name implies, is not associated with any clinical symptoms. Evidence suggests that the higher an individual’s serum uric acid level, the greater is the likelihood that acute gout will develop. Acute gouty arthritis, the next phase, typically presents as a sudden, exquisitely painful monoarthropathy. Although any synovial joint can be affected, the most common site for this painful manifestation is the metatarsophalangeal joint of the great toe. The third phase, the intercritical period, is the period between acute attacks. Most individuals who develop gout have a second episode of gout within 6 months to 2 years of the first attack. Untreated gout tends to result in more frequent, severe attacks of longer duration. However, some patients will never have a second attack. Finally, chronic tophaceous gout can occur. Tophi are sodium urate crystals that are deposited in the soft tissues and can occur in up to 50% of patients with gout. They tend to appear at any time from 2 or 3 years to 10 years after the onset of gout. The most common locations for tophi are synovium, prepatellar and olecranon bursae, the Achilles tendon, and the helix of the ear.

Hyperuricemia, defined as serum urate level >6 mg/dl in men and >7 mg/dl in women, is the strongest risk factor for development of gout. The higher the serum urate level, the greater is the incidence of acute gouty arthritis. Hyperuricemia alone, however, is not diagnostic. Studies involving acute gout attacks have found that uric acid levels have been low to normal in 12% to 43% of patients. Key risk factors for gout include hypertension, thiazide and loop diuretics, obesity, and alcoholism. These risk factors seem to be additive in terms of risk. Other risk factors for developing gout include age older than 60, family history, lead exposure (patients who consume “moonshine” whiskey have an even greater risk because moonshine tends to have a high lead content), and the use of other medications (e.g., low-dose aspirin [<2 g/day], cyclosporine, tacrolimus, ethambutol, pyrazinamide, nicotinic acid). Dietary intake of meat and seafood has been shown to significantly increase the risk that a gout attack will occur; consumption of dairy products is associated with the lowest risk of attacks. Excessive alcohol consumption—specifically beer and spirits, but not wine—is associated with increased risk of an attack. Conditions such as thyroid problems, kidney disease, anemia, hyperlipidemia, diabetes, vascular disease, trauma, surgery, and radiation treatment also may serve as triggers for gout.

Up to 90% of individuals with gout are underexcreters of uric acid. Normally, the kidneys turn over approximately 700 mg/dl of uric acid per day. Of that amount, about 10% is excreted. Normal serum uric acid in males ranges from 2 to 7 mg/dl; the normal range for females is 2 to 6 mg/dl. Any factor that interferes with the glomerular and renal tubular reabsorption of uric acid can result in elevated serum uric acid levels.

Overproduction of uric acid is much less common. It is often the result of another disease, frequently one associated with excessive rates of cell turnover. Hemolytic anemias, myeloproliferative and lymphoproliferative diseases, and psoriasis are examples of processes that may cause secondary gout resulting from overproduction of uric acid. Some inherited diseases and genetic abnormalities can cause primary gout through overexcretion of uric acid.

The most important differential diagnosis to be made in a patient with gout is the exclusion of a septic joint. Synovial fluid aspiration and examination help confirm the diagnosis. Fluid is sent for WBC and differential, crystal analysis, and Gram stain with culture. Examination of joint fluid with the use of a polarized microscope will reveal the presence of crystals. The presence of birefringent crystals in the synovial fluid does not exclude the possibility of infection because gout and infection can coexist in a joint.

Standardized Guidelines

Evidence-Based Recommendations

No firm evidence-based guidelines have been put forth regarding when in the course of gout it is most appropriate to start urate-lowering therapy. This is essentially up to the patient and the clinician.

Cardinal Points of Treatment

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