What triggers a gout attack?

Updated: Jan 26, 2021
  • Author: Bruce M Rothschild, MD; Chief Editor: Herbert S Diamond, MD  more...
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Answer

A gout attack may be triggered either by release of crystals (eg, from partial dissolution of a microtophus caused by changing serum urate levels) or by precipitation of crystals in a supersaturated microenvironment (eg, release of urate as a consequence of cellular damage). In either situation, it is believed, naked urate crystals then interact with intracellular and surface receptors of local dendritic cells and macrophages, triggering a danger signal to activate the innate immune system. [11]

This interaction may be enhanced by immunoglobulin G (IgG) binding. [12, 13] Triggering of these receptors, including Toll-like receptors, followed by intracellular signaling by the NLRP3 inflammasome, results in the release of interleukin (IL)-1β, which in turn initiates a cascade of proinflammatory cytokines, including IL-6, IL-8, neutrophil chemotactic factors, and tumor necrosis factor (TNF)-α. [14, 15] Neutrophil phagocytosis leads to another burst of inflammatory mediator production.

Chatfield et al reported that the interaction of urate crystals with lysosomes results in the formation of web-like chromatin structures known as neutrophil extracellular traps (NETs) and subsequent cell death (NETosis), via a mechanism independent of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The urate crystal–induced NETs are enriched for actin and are resistant to degradation by serum and DNase; they coat the crystals with DNA, which then persist in tissues as gouty tophi.​ [16]

Subsidence of an acute gout attack results from multiple mechanisms, including the clearance of damaged neutrophils, change in the properties of urate crystals, and the production of anti-inflammatory cytokines such as IL-1 receptor antagonist (IL-1RA), IL-10, and transforming growth factor (TGF)-β. [13, 17, 18, 19]


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