Gout: Supplemental Information on Pathogenesis

The majority of the uric acid pool is produced from turnover of endogenous purines. Dietary purines account for the remaining minority of uric acid. Thus, only the most extreme diets are effective in decreasing serum concentrations of uric acid.

About two thirds of daily uric acid excretion is through the kidney, via a complicated renal handling mechanism. Nearly all serum uric acid is filtered through the glomerulus and the majority of this is reabsorbed in the proximal tubule. More distally, in the proximal tubule, there is secretion and again reabsorption. Overall, about 10% of the originally filtered load appears in the urine. The remainder of uric acid excretion is through the gastrointestinal (GI) tract, where it is subjected to the action of bacterial uricase, an enzyme not found in man.

The uric acid pool increases in men at puberty and in women at the menopause. The uric acid pool in men is about 1200 mg, twice that typically seen in women. Patients with gout invariably have an increased uric acid pool. Typically they have normal or increased renal excretion of uric acid. In comparison to individuals who are not hyperuricemic, most patients (over 90%) will have less uric acid appearing (when controlled for serum uric acid concentrations) in the urine than normouricemic controls. Additional factors may alter the production or renal handling of uric acid (Table 5.1). Increased cell turnover (eg, disorders such as the myelo- or lymphoproliferative disorders) increases production of uric acid. Similarly, factors which impair renal excretion, including glomerular dysfunction, or factors affecting tubular handling of uric acid (especially organic acids) increase levels of uric acid.

Uric acid has a solubility of about 6.5 mg/dL in water. Concentrations greater than this represent supersaturated solutions and make precipitation of monosodium urate possible. Usually after many years of hyperuricemia, body stores of uric acid have increased to the point that adaptation to the excess is no longer possible, and clinically discernable disease results.

Crystals of monosodium urate free in the joint activate a number of inflammatory pathways. The crystals are coated with immunoglobin G (IgG), which activates complement. Similarly, the kallikrein system is activated. As a result, there is vasodilatation and influx of neutrophils. Phagocytosed uric acid crystals stimulate neutrophils to release prostaglandins and lysosomal enzymes and induce oxidant production. Further, neutrophils are unable to digest the phagocytosed urate crystal, which ultimately results in lysosomal rupture, cell death, and spillage of cellular contents extracellularly. Simultaneously, free uric acid crystals activate mononuclear cells and synoviocytes with the production of inflammatory cytokines, including interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, which account for some of the systemic symptoms seen particularly in recurrent attacks of gout.