Epidemiology

Etiology

Risk factors

• Increased uric acid production
  • Dietary sources
    • Purine-rich foods (eg, seafood, red meat)
    • Fructose-containing & alcoholic beverages (particularly beer)
  • ↑ Cell turnover (eg, tumor lysis syndrome)
  • Lesch-Nyhan syndrome (deficiency of HGPRT)
  • ↑ Phosphoribosyl pyrophosphate activity
• Decreased uric acid clearance
  • Chronic kidney disease
  • Volume depletion
  • Diuretics (eg, thiazide)
  • Niacin
  • Cyclosporine & tacrolimus
• Rapid decline in uric acid levels
  • Xanthine oxidase inhibitors (eg, allopurinol)
  • Uricosuric drugs (eg, probenecid)

Pathophysiology

• Gout
  • An inflammatory crystal arthropathy that is caused by the precipitation and deposition of uric acid crystals in synovial fluid and tissues.
  • It is typically associated with hyperuricemia, but can also occur if uric acid levels are normal.
• Uric acid
  • An end-product of purine metabolism that is excreted by the kidneys
  • Has somewhat poor water solubility
  • Predisposes to gout
• Triggers of urate crystal deposition
  • ↑ Uric acid levels (due to insufficient excretion or increased production of purines)
  • Acidosis
  • Low temperature (e.g., cool peripheral joints)
• Crystalline arthritis: supersaturation of uric acid in extracellular fluid → intraarticular uric crystal precipitation (coated by IgGs) → phagocytosis by polymorphonuclear cells → release of inflammatory mediators and enzymes → local joint inflammation
• Chronic effects: repeated attacks → aggregations of urate crystals and giant cells (tophi) → deformities and arthritis

Clinical features

• Most common manifestation
  • Acute severe pain with overlying erythema, decreased range of motion, swelling, warmth
  • Possibly fever
  • Symptoms are more likely to occur at night, typically waking the patient.
  • Symptoms peak after 12–24 hours and regress over days to weeks.
  • Desquamation of the skin overlying the joint may be seen during the recovery from an acute gout flare.
• Location
  • Usually monoarthritis during first attacks
    • In < 20% of cases, patients present with polyarthritis during first attacks.
    • Asymmetrical distribution is common if more than one joint is affected

Diagnostics

• Synovial fluid leukocyte count
  • Gout: >2,000/mm³
  • Septic arthritis: > 50,000/mm³

Treatment

Acute gout flare

NSAIDs

• Naproxen or an alternative (e.g., indomethacin, ibuprofen)
• Contraindicated in PUD

Colchicine

• Mechanism of action: binds and stabilizes tubulin subunits → inhibits microtubule polymerization → inhibits phagocytosis of urate crystals, neutrophil activation, migration, and degranulation
• Adverse effects
  • Gastrointestinal symptoms, e.g., diarrhea, nausea, vomiting, and abdominal pain, are the most common.
  • Rhabdomyolysis , myopathy
  • Polyneuropathy
  • Cardiac toxicity, arrhythmias
  • Nephrotoxicity
  • Myelosuppression
  • CNS symptoms (e.g., fatigue, headache)

Chronic gout

• Urate-lowering therapy (ULT) is recommended for chronic gout.
  • First-line: xanthine-oxidase inhibitors (allopurinol)
  • Second-line: uricosurics (probenecid)
  • Third-line: recombinant uricase (pegloticase, rasburicase)
    • Also used in Tumor lysis syndrome
• Administer anti-inflammatory prophylaxis before initiating ULT as ULT may trigger, prolong, or worsen an acute gout flare.
  • Lowering of serum urate levels likely causes preexisting urate crystal deposits to dissolve and become mobile.

Uricosurics

• Probenecid
• Mechanism of action
  • Inhibition of uric acid reabsorption along renal proximal convoluted tubules → increased renal elimination
• Side effects
  • Nephrolithiasis#Uric acid stones
  • Hypersensitivity reactions (sulfa allergy due to being a sulfonamide derivative)