Fig. 21.41 Pathogenesis of acute gouty arthritis. Urate crystals are phagocytosed by macrophages and stimulate the production of various inflammatory mediators that elicit the inflammation characteristic of gout. Note that IL-1, one of the major pro-inflammatory cytokines, in turn stimulates the production of chemokines and other cytokines from a variety of tissue cells. LTB4, Leukotriene B4; IL-1β, interleukin 1β.
neutrophils and macrophages in the joint. These cells, in turn, release other cytokines, free radicals, proteases, and arachidonic acid metabolites. The ingested crystals also damage the membranes of phagolysosomes, leading to leakage of these mediators. Activation of complement by the alternative pathway may contribute to more leukocyte recruitment. The result is an acute arthritis, which typically remits spontaneously in days to weeks. Repeated attacks of acute arthritis lead eventually to the formation of tophi, aggregates of urate crystals and inflammatory tissue, in the inflamed synovial membranes and periarticular tissue. Severe damage to the cartilage develops and the function of the joints is compromised.
Only about 10% of patients with hyperuricemia develop clinical gout. Other factors contribute symptomatic gout:
Age of the individual and duration of the hyperuricemia. Gout usually appears after 20 to 30 years of hyperuricemia.
Genetic predisposition. In addition to the well-defined X-linked abnormalities of HGPRT, polymorphisms in genes involved with urate or ion transport and possibly inflammation are also associated with gout.
Alcohol consumption.
Obesity.
Drugs (e.g., thiazides) that reduce excretion of urate.
The distinctive morphologic changes in gout are (1) acute arthritis, (2) chronic tophaceous arthritis, (3) tophi in various sites, and (4) gouty nephropathy.
Acute arthritis is characterized by a dense inflammatory infiltrate that permeates the synovium and synovial fluid. Urate crystals are frequently found in the cytoplasm of the neutrophils and are arranged in small clusters in the synovium. They are long, slender, and needle-shaped, and are negatively birefringent. The synovium is edematous and congested, and it also contains scattered lymphocytes, plasma cells, and macrophages.
Chronic tophaceous arthritis evolves from the repetitive precipitation of urate crystals during acute attacks. The crystals encrust the articular surface and form visible chalky deposits in the synovium (
Fig. 21.42A ). The synovium becomes hyperplastic, fibrotic, and thickened by inflammatory cells and forms a pannus that destroys the underlying cartilage.