Normal Purine Metabolism and Pathogenesis of Gout in Metabolic Disorders

Abstract

Background: Gout is the most common inflammatory arthropathy among adults and develops due to hyperuricemia and the long-term deposition of monosodium urate (MSU) crystals in the joints and tissues. Hyperuricemia results either from increased production of uric acid or decreased renal and intestinal excretion, with impaired urate excretion being the predominant underlying cause in most individuals. Although genetic variations in urate transporters significantly influence serum urate levels, not all individuals with hyperuricemia develop MSU crystal deposition or gout. Aim: To review and analyze the pathophysiology of gout arising from normal and disrupted purine metabolism. Materials and Methods: Using a narrative literature review approach, we examined published research on purine metabolism and the pathophysiological mechanisms of gout. Sources included Thomson Reuters, PubMed Central, Cochrane Library, Medline, Web of Science, and Google Scholar. A total of more than 670 publications were screened, of which 31 key studies relevant to the pathophysiology of gout were included in the final analysis. Results: The inflammatory response triggered by MSU crystals is primarily driven by activation of the NLRP3 inflammasome, which converts IL-1β (pro-IL-1β) and IL-18 (pro-IL-18) into their active forms, IL-1β and IL-18, thereby initiating inflammation. IL-1β and IL-18 further enhance cytokine and chemokine expression, recruiting neutrophils and other immune cells to the site of inflammation. Neutrophils not only amplify the inflammatory response but also contribute to its resolution through the formation of neutrophil extracellular traps (NETosis), which capture and degrade inflammatory mediators. Severe gout is characterized by tophus formation, chronic inflammation, and structural joint damage. Tophaceous deposits consist of aggregated MSU crystals surrounded by inflammatory cells and connective tissue and are closely associated with persistent inflammation and tissue injury. Conclusion: A clear, logically structured understanding of disease pathophysiology—including cause-and-effect mechanisms—is essential for making evidence-based decisions in diagnosis and treatment.