Pathophysiology of gout

Abstract

The clinical features of gout occur in response to monosodium urate (MSU) crystals. Gout should be considered a chronic disease of MSU crystal deposition. A number of pathophysiological checkpoints are required for development of gout. First, elevated urate concentrations are required: urate overproduction and underexcretion contribute to total urate balance. Overproduction occurs due to alterations in the purine synthesis and degradation pathways. Renal underexcretion is an important cause of elevated serum urate concentrations (hyperuricaemia), and occurs through alterations in the urate transporters within the renal tubule (collectively known as the urate transportasome). Gut underexcretion (extrarenal urate underexcretion) also contributes to development of hyperuricaemia. The next checkpoint is MSU crystal formation. In some individuals with evidence of MSU crystal deposition, symptomatic gout develops. The acute inflammatory response to MSU crystals represents a self-limiting sterile acute auto-inflammatory response which is mediated by the innate immune system activation. Interleukin 1 beta is the key cytokine that contributes to the acute inflammatory response to MSU crystals. In some patients, advanced gout may occur with structural joint damage. Joint damage in gout is mediated both by direct effects of MSU crystals on joint tissue and by indirect effects of joint inflammation. In addition to their central role in pathogenesis of gout, MSU crystals have a physiological role, particularly as an adjuvant or ‘danger signal’ in immune surveillance.