New knowledge of the pathogenesis of gout.

The clinical features of gout have been well-recognised since ancient times. Knowledge of its underlying metabolic causes began towards the end of the eighteenth century with the discovery of uric acid in urinary calculi and gouty tophi, and during the nineteenth century Sir Alfred Garrod showed that the blood of gouty subjects contained an excess of uric acid which became deposited in crystalline form in the joints. The later work of Emil Fischer, establishing that uric acid was a purine compound and thus potentially related to the nucleic acid constituents adenine and guanine, and the improved methodology of uric acid determination by Folin and Dennis completed this part of the story. Other developments during the twentieth century have included, firstly, the realisation that hyperuricaemia and gout have many different causes; secondly, a swift advance, gained by biochemical, isotope, and cell-culture techniques, in our knowledge of purine metabolism, including the discovery by Seegmiller and his colleagues in 1967 of the first specific enzymatic defect (HGPRT deficiency) responsible for one special type of gout; and, thirdly, from the therapeutic aspect, a remarkable facility to control both the acute gouty attack and the level of uric acid in the blood. People who develop gout have usually lived for many years, unknown to themselves, with a raised plasma level of uric acid (asymptomatic hyperuricaemia), until eventually crystals of sodium urate precipitated in a joint provoke a sudden tissue reaction which leads to the first attack of acute gouty arthritis. Acute attacks each last for only short periods. They are followed by intervals of widely varying duration of complete freedom from symptoms (intercritical gout). Nevertheless, hyperuricaemia persists. In time, in some untreated individuals, joints may no longer return to their normal state; deposits of urate (tophi) form around the joints and elsewhere, and the patient enters the stage of chronic tophaceous gouty arthritis. The phases in the pathogenesis of gout therefore consist of (1) hyperuricaemia with an increased total uric acid pool; (2) deposition of urate crystals; and (3) an inflammatory response leading to gouty arthritis. This paper outlines our present ideas about these three phases.