Definition:
Gout is a crystal-induced inflammatory arthritis caused by deposition of monosodium urate crystals in synovial joints due to hyperuricemia (serum uric acid > 6.8 mg/dL). It classically presents as sudden, severe pain, swelling, and redness in joints—most commonly the first metatarsophalangeal joint ("podagra").
Etiology:
Hyperuricemia arises due to either:
- Decreased excretion of uric acid (most common cause – 90% of primary gout):
- Chronic kidney disease (↓ GFR)
- Thiazide or loop diuretics
- Lead nephropathy
- Dehydration
- Alcohol abuse
- Increased production of uric acid:
- High purine intake (meat, seafood, alcohol)
- Increased cell turnover: leukemias, lymphomas, psoriasis
- Enzyme defects: PRPP synthetase overactivity, HGPRT deficiency (→ Lesch-Nyhan syndrome)
Pathogenesis:
- Uric acid is the end product of purine metabolism.
- When uric acid levels exceed solubility threshold, monosodium urate (MSU) crystals precipitate, particularly in:
- Cooler joints (e.g., great toe, ankle, knee)
- Crystals are phagocytosed by macrophages, triggering:
- Activation of NLRP3 inflammasome
- Release of IL-1β, TNF-α, prostaglandins → strong neutrophilic inflammation
- This leads to:
- Pain, swelling, erythema, and warmth
- Resolution occurs via: crystal coating by proteins, anti-inflammatory cytokines, neutrophil apoptosis, and macrophage clearance.