Gout usually involves single specific joints, usually including some of the small joints of the extremities. The most typical location is the metatarsal-phalangeal joint of the great toe, which is affected in about 75% of patients. The knee and ankle are involved in about 50% of patients. One third or more of patients have more than one joint involved during their first attack. The disease is 7 times more common in males than females. Acute attacks are frequently accompanied by fever and leukocytosis. Attacks of gout typically respond to colchicine as specific therapy.

Laboratory tests useful in diagnosis of gout

Serum uric acid. Patients with gout usually have elevated serum uric acid levels. However, 7%-8% have uric acid levels within reference limits at the time of the first attack. Some studies have shown elevated serum uric acid levels in about 10% of patients with RA, 15% of patients with pseudogout, and about 15% of patients with septic arthritis. Therefore, elevated serum uric acid levels are not diagnostic for gout, and normal serum uric acid levels do not conclusively rule out gout. On the other hand, positive latex test results for rheumatoid factor have been reported in 7%-11% of patients with primary gout. Serum uric acid reference values are sex related, with values in males about 1mg/100 ml higher than values in females. One report indicates considerable week-to-week variation (about 30%-40%) in serum uric acid values in the same individual. Stress has been reported to raise uric acid levels. One investigator found that serum uric acid levels increased after exposure to sunlight.

Although elevation of serum uric acid is traditionally associated with gout, the majority of serum uric acid elevations are not due to gout. By far the most frequent cause of hyperuricemia, especially in hospitalized patients, in renal disease with azotemia.

Disorders of hyperuricemia can be divided into those due to increased intake, those due to decreased excretion, and those due to increased production.

Increased intake. Increased intake of purine-rich food usually does not produce hyperuricemia by itself, although it may affect the clinical symptoms of gout or add to the effect of other hyperuricemic agents.

Decreased excretion. Uric acid is excreted predominantly through the kidneys, with about 25% excreted by the GI tract. There is good correlation between severely decreased renal function, as indicated by elevated blood urea nitrogen (BUN) or serum creatinine levels (Chapter 13) and increase in the serum level of uric acid, although the correlation is not linear. According to the literature, more than 90% of patients with elevated BUN and serum creatinine levels also have elevated serum uric acid values. However, when I examined the laboratory work of 156 newly admitted patients with elevated BUN levels, serum creatinine levels, or both, 31% of the patients had uric acid values within the reference range (even in those patients with BUN and creatinine levels both elevated, 31% still had normal uric acid levels). On the other hand, of a total of 222 patients, 30% had normal BUN and creatinine levels but elevated uric acid levels. Besides chronic renal disease, acute renal failure, and severely decreased renal blood flow, other conditions associated with hyperuricemia due to decreased renal excretion include treatment with certain drugs (including most diuretics, but especially the thiazides), ketoacidosis of diabetes or starvation, lactic acidosis, toxemia of pregnancy, lead poisoning, alcoholism, and hypothyroidism. In some of these conditions increased renal tubular reabsorption of urate is a major factor, with or without decreased renal function.

Increased production. Increased uric acid production can be demonstrated by increased uric acid excretion, if renal function is adequate. The standard method of evaluation is a 24-hour urine collection. Most investigators place the patient on a severely restricted (or “purine-free”) purine diet before collecting the urine specimen (e.g., 4 days of diet, with the specimen collected on the fourth day and collection completed before the diet is terminated). The test is more accurate when the patient is asymptomatic, since acute inflammation may increase urine excretion of urate. Under these controlled conditions, the most commonly accepted upper limit of the reference range is 600 mg/24 hours (3,570 mmol/day). About 15%-25% of patients with primary gout have increased excretion of uric acid. The other 75%-85% have normal production and urine excretion levels. Conditions in which a substantial number of patients have increased uric acid production, increased excretion of uric acid, and hyperuricemia, include myeloproliferative syndromes (chronic myelocytic leukemia, polycythemia vera, etc.), chronic lymphocytic leukemia, myeloma, various malignancies (including the aforementioned leukemias and lymphomas), tumor or tissue cell destruction from chemotherapy or radiation therapy (including the tumor lysis syndrome), sickle cell anemia and severe hemolytic anemias, extensive psoriasis (30%-50% cases), sarcoidosis (30%-50% cases), and a congenital enzymatic defect in uric acid metabolism known as the “Lesch-Nyhan syndrome.”

There is also an association of hyperuricemia with hypertension (22%-27% without renal disease), diabetes mellitus, obesity, and atherosclerotic heart disease. In some of these associated conditions there is a demonstrable etiology for hyperuricemia and in some there is not. One report indicates that up to 20% of males on long-term coumarin therapy develop elevated serum uric acid.

Measurement of urine uric acid to creatinine clearance ratio on a midmorning urine specimen has been proposed as a means to circumvent the problems involved with 24-hour urine collection. However, there is rather poor correlation between results obtained by the two methods in the same patients. One reason may be a reported diurnal variation in uric acid excretion, with about 40%-45% of daily quantity found in the 8 hours between 8 A.M. and 4 P.M.

The two most common laboratory assay methods for uric acid assay are colorimetric (based on uric acid reduction of phosphotungstic acid reagent) and enzymatic (using the specific enzyme uricase). Various reducing substances, such as levodopa and large quantities of glucose, ascorbic acid, acetaminophen, caffeine, and theophylline, can falsely elevate the colorimetric method.

Joint fluid aspiration. The most accurate readily available laboratory test for gout is demonstration of uric acid crystals in synovial fluid aspirated from an acutely inflammed joint. The needlelike crystals of sodium monophosphate may be seen within neutrophils or lying free. These may be seen with the ordinary microscope but are best visualized using compensated polarized light. With the color compensator, urate crystals exhibit negative birefringence (yellow against a red background, with the axis of the crystal parallel to the axis of the compensator). When injected into a joint, some steroids form needlelike crystals that may mimic nonpolarized uric acid crystals. It has been reported that uric acid crystals cannot be demonstrated in joint aspirates from about 15% of patients with acute gout.