Management of Gout

Gout is among the most common causes of acute monoarticular arthritis. Estimates of prevalence in the United States are as high at 4% of the adult population. Estimates of prevalence are increasing as the population ages and obesity and diabetes become more common. Gout is predominantly a disease of adult men (sex ratio, up to 9:1), but prevalence is increasing among women. Inborn errors of purine metabolism and abnormalities of uric acid excretion account for many cases of primary gout, but lifestyle issues are becoming increasingly important. In the Nurses’ Health Study, high levels of soft-drink consumption significantly increased risk of developing gout among participating women. The expanded use of agents that decrease uric acid excretion has also markedly increased the incidence of secondary gout. In the Framingham Study, almost half of new cases were associated with thiazide diuretic use.

The primary care physician should be able to diagnose acute gout promptly, treat it effectively, prevent recurrences, and minimize the chances for the development of chronic gouty arthritis. Patients who present with asymptomatic hyperuricemia also require attention (see Chapter 155).

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and 23)

The majority of patients with primary gout have a hereditary renal defect in uric acid excretion that leads to chronic hyperuricemia (see Chapter 155). Decreased renal excretion also occurs in the context of hyperinsulinism (as seen in obesity and metabolic syndrome), renal failure, thiazide therapy, and low doses of aspirin. Overproduction may result from myeloproliferative disease, lymphoproliferative malignancies, and severe psoriasis. Increasingly appreciated are dietary sources of overproduction such as foods and beverages (especially soft drinks) heavily sweetened with highfructose corn syrup (see Chapter 155). Similarly, high alcohol consumption (particularly beer) increases urate formation. Use of thiazide and loop diuretics, obesity, cyclosporine, and hypertension also increase uric acid levels and risk of gout. In an observational study, high intakes of meat and fish compared to low intakes are associated with increased relative risks of gout (relative risks, 1.4 and 1.5, respectively), but moderate intakes of purine-rich vegetables are not. A high intake of low-fat dairy products appears to reduce risk (relative risk, 0.56) as does vitamin C, and coffee. Acute gout usually occurs after many years of sustained asymptomatic hyperuricemia. The serum becomes saturated at a uric acid concentration of 6.8 mg/dL. The higher the uric acid concentration, the greater is the risk for an acute attack, but the risk remains relatively low until very high urate levels are reached (e.g., the annual risk is 0.5% for a serum urate of 7.0 to 8.9 mg/dL and 4.9% for urate >9.0 mg/dL; see Chapter 155). The mean duration of the asymptomatic period is about 30 years. During this time, urate may be deposited in synovial lining cells and possibly also in cartilage.

Acute gout develops when uric acid crystals collect in the synovial fluid as a result of precipitation from a supersaturated state or release from the synovium. Underscoring the importance of local urate concentrations is the observation that serum uric acid is often not elevated at the time of an attack of acute gout. Trauma, a fall in temperature or pH, dehydration, starvation, excessive intake of alcohol, emotional or physical stress, and rapid changes in the serum uric acid concentration have all been implicated in the process.

The pathogenesis of the inflammatory response involves the phagocytosis of crystals by leukocytes in the synovial fluid, the disruption of lysosomes, the release of enzymatic products, the activation of the complement and kallikrein systems, and the release of leukocyte chemotactic factor.

Acute Gouty Arthritis

In men, the first attack is usually during the fifth decade; in women, it tends to be after age 60 years. The episode is typically monoarticular and abrupt in onset, often occurring at night. Symptoms and signs of inflammation become maximal within a few hours of onset and last for a few days to a few weeks. Untreated, symptoms of an acute attack can last for up to a few weeks, but attacks are usually self-limited, and recovery is complete.

The initial attack usually involves a joint of the lower extremity. In about half of patients, the first metatarsophalangeal joint is the site of inflammation (podagra). The tarsal joint (located at the instep), ankle, and knee are other common sites of initial attacks. Later episodes may involve a joint of the upper extremity, such as the wrist, elbow, or finger; shoulder or hip involvement is rare. More than 80% of attacks occur in a lower extremity; 85% of patients have at least one episode of podagra.

Polyarticular involvement is noted in about 5% of acute gouty attacks and may be confined to the upper extremities. Finger joint involvement is more common in women than in men and tends to present as a Heberden or Bouchard node. In elderly patients with gout and osteoarthritis, almost half have such nodal inflammation as the sole or initial manifestation of gout. In elderly women, the presentation of gout may be more insidious and polyarticular; multiple hand joints may be involved, with the condition resembling active rheumatoid disease.

The joint involved in an attack of acute gout appears swollen and erythematous; periarticular involvement is also common. Low-grade fever and leukocytosis may be present. A substantial
fraction of patients may be normouricemic at the time of the acute attack. During resolution, the skin overlying the affected joint often desquamates. The clinical presentation may simulate joint infection (see Chapter 145) or even cellulitis (see Chapter 190).

Interval (Intercritical) Gout

An asymptomatic period of several years typically follows an acute attack before a second episode of acute gout takes place. The original joint or another joint may be involved in subsequent attacks. Over time, the asymptomatic intervals between acute episodes shorten. In more advanced disease, polyarticular attacks are not uncommon, and resolution may be slower and less complete. Urate crystals may remain in the joint fluid.

Chronic Gouty Arthritis (Tophaceous Gout)

This form of gout takes years to develop. Tophi are typically noted an average of 10 years after the initial attack of acute gout. The risk for chronic gout is a function of the duration and severity of hyperuricemia. Tophi represent sodium urate collections surrounded by foreign body giant-cell inflammatory reactions. They can occur in a variety of sites, including the synovium, subchondral bone, olecranon bursa, Achilles tendon, and subcutaneous tissue of the extensor surfaces of the arm. Eventually, cartilage erodes, joints become deformed, and chronic arthritis ensues. The joints of the lower extremities and hands are most commonly affected. In elderly women, the fingers may be the sole sites of involvement by gouty disease; the condition may be mistaken for rheumatoid disease, with morning stiffness and tenderness and swelling of the metacarpophalangeal and proximal interphalangeal joints. The process is insidious; the patient notes progressive aching and stiffness. Tumescences may develop over joints of the foot and make wearing shoes difficult. Fortunately, the incidence of tophaceous gout has declined markedly with the introduction of effective antihyperuricemic agents. Chronic gouty arthritis develops in fewer than 15% of patients with acute gout.

Complications

The incidence of nephrolithiasis among patients with clinical gout is small; the risk for new stone formation in a patient with new onset of gout is less than 1% per year and is unrelated to the initial serum urate concentration or degree of uric acid control. Factors other than the serum urate concentration are important in stone formation and include a family history of stone formation, urine pH, hydration status, and possibly the amount of uric acid excreted by the kidneys (see Chapter 135). Stone formation is rarely dangerous; the risk for obstructive uropathy is less than 0.02%.

Concerns about the development of chronic renal failure as a complication of chronic hyperuricemia have been laid to rest by long-term studies (see Chapter 155). Lead intoxication is a cause in some populations; in others, it is concurrent hypertension, diabetes, cardiovascular disease, or underlying primary renal disease. Acute renal failure is a risk in patients undergoing chemotherapy for lymphoproliferative or myeloproliferative disease. A treatment episode may produce a uric acid load sufficient to precipitate uric acid crystals in renal tubules and elsewhere in the urinary tract, leading to acute oliguria.

Unresolved is the relation between elevations in uric acid and cardiovascular event risk. Epidemiologic studies find elevations in uric acid strongly associated with cardiovascular disease, but their role as an independent cardiovascular risk factor remains the subject of debate since such levels often occur in the context of the metabolic syndrome and other major coronary heart disease risk factors (see Chapters 18 and 31). Conversely, such cardiovascular risk factors can compromise renal function and predispose to hyperuricemia and gout (see also Chapter 155).

DIAGNOSIS (9,12,19,24,25)

Definitive diagnosis requires joint fluid examination and the finding of characteristic, negatively birefringent crystals (see Chapter 145). However, in everyday primary care practice, joint fluid examination is impractical, making necessary clinical diagnosis. A group of investigators examined the clinical variables commonly relied upon by primary care physicians (e.g., male gender, previous patient-reported arthritis attack, onset within 1 day, joint redness, first metatarsophalangeal joint involvement, serum uric acid level, and concurrent hypertension or cardiovascular disease). These were found collectively to have a positive predictive value for gout of 0.64 and a negative predictive value of 0.87. Assigning scores to each of these diagnostic variables based on an estimate of their independent predictive value allowed development of a decision rule for ruling in and ruling out gout. A score of less than four ruled out gout; a score greater than eight had a positive predictive value of 80% or more. While such decision rules require more validation, they do provide some estimate of the accuracy of clinical diagnosis.

When classic podagra appears in a patient with a prior history of gout and the other characteristic clinical features mentioned are present, a clinical diagnosis can be made with reasonable confidence. But when acute monoarticular arthritis occurs in a less typical site, the full range of diagnostic possibilities must be considered (see Chapter 145). A chronic active polyarticular presentation in an older woman can be confusing because it may resemble rheumatoid disease, especially if confined to the fingers. A clue is the presence of Heberden or Bouchard nodes; the presence of tophi is another clue. Joint aspiration for crystal identification is needed to confirm the diagnosis. Similarly, in interval (intercritical) gout, joint aspiration and synovial fluid analysis can help to establish the diagnosis, even in the absence of an acutely inflamed joint. Aspiration can be performed on a joint that is identified by history as having been previously inflamed. The serum uric acid level alone is not helpful diagnostically because it can be normal in the presence of active inflammatory disease.