Primary gout (Table 43-1) is due to genetically determined hyperuricemia, which is caused by urate overproduction or underexcretion. Enzyme defects causing urate overproduction, in a small percentage of patients with gout, have been well worked out. Underexcretion, found in most cases, has recently been tracked to hereditary defects in renal anion transporters of uric acid.

Secondary gout (see Table 43-1) can be due to intake of medications that decrease urate excretion or cause renal insufficiency, increased purine intake in the diet, and treatments or conditions that lead to cell breakdown and consequent purine production. Uric acid is the end product of purine degradation.

Uric acid crystals induce a classical inflammatory response via an activation of the innate immune system. Toll-like receptors are involved in recognizing urate crystals; complement, including the membrane attack complex, is activated; neutrophils and then macrophages are recruited into the joint via chemotactic factors; and cytokines [e.g., tumor necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-8] are secreted.

Gouty attacks are self-limited because of the nature of the immune system response to urate. This is related to the fact that neutrophils eventually stop entering the joint, and as monocytes mature within the joint fluid, they have been found to produce fewer proinflammatory cytokines.

URIC ACID, THE HEART, AND KIDNEY. It is clear that hyperuricemia correlates with renal disease and atherosclerosis, but it remains unclear as to what extent, if any, hyperuricemia is directly causative of each. Urate level is routinely elevated in the metabolic syndrome (i.e., insulin resistance, hypertension, central obesity, dyslipidemia, and the proinflammatory and prothrombotic state), at least in part because of high insulin levels, which decrease urate excretion. It is presently unclear whether lowering urate levels in the metabolic syndrome will ameliorate any of the clinical features of this syndrome.

The prevalence of gout is increasing, and there is a trend toward an earlier age of onset. Gout is the most common inflammatory joint disease in men older than 40 years.

Men continue to outnumber women in the incidence of gout, but after menopause, women begin to close the gap, possibly related to the loss of the uricosuric effect of estrogen.

Attacks of gout are becoming more severe and difficult to treat. This likely relates to the aging of the population, with their comorbidities contraindicating many of our therapeutic options. Aging patients have a higher incidence of renal disease and renal failure, which worsens hyperuricemia and limits the use of many of our standard agents. In patients undergoing transplantation, cyclosporine can cause an especially aggressive form of gout, with rapidly forming tophi.

Four different stages are recognized in the clinical evolution of gout.

Attacks of gout are generally of very rapid onset, often with systemic features, such as low-grade fever. After a first attack, the second may not occur for 5 to 10 years in some patients, but once the attacks begin to occur frequently, a pattern of closely spaced attacks is almost always established, and long-term spontaneous remission is rare. The classic attack of gout involves only a single joint, but as the disease evolves, it is not rare to see polyarticular attacks and involvement of contiguous joints.