Gout

Definition & Epidemiology

Gout is a crystal-induced arthropathy caused by the deposition of monosodium urate (MSU) crystals in joints and periarticular tissues, resulting from sustained hyperuricemia. It affects approximately 4% of adults in the US — ~5% of males and ~3% of females — and is more prevalent in older adults.

Risk factors:

Obesity, hypertension, diabetes
Thiazide diuretics, cyclosporin
Purine-rich diet: red meats, beer, legumes, shellfish, anchovies
Chronic kidney disease

Pathophysiology

Hyperuricemia (plasma urate >6.8 mg/dL) is necessary but not sufficient for gout — only ~10% of hyperuricemic patients develop gout.

Uric acid is the end product of purine catabolism. It accumulates via:

Mechanism	Examples
Reduced excretion (90% of primary gout)	Unknown basis; CKD
Overproduction	HGPRT deficiency (Lesch-Nyhan syndrome), tumor lysis syndrome

Inflammatory cascade:

MSU crystals precipitate in supersaturated joint fluid
Synovial macrophages phagocytose crystals → activate the inflammasome → caspase-1 → active IL-1β
IL-1β recruits neutrophils → cytokines, free radicals, proteases, lysosomal enzyme release
Acute arthritis (self-limiting over days–weeks)
Repeated attacks → tophi (aggregates of urate crystals + inflammatory tissue) → cartilage destruction

Clinical Stages

Stage	Features
Asymptomatic hyperuricemia	Elevated urate, no symptoms; may persist 20–30 years
Acute gout flare	Sudden severe monoarthritis; peaks in 1–2 days; resolves in ~1 week
Intercritical gout	Symptom-free intervals between attacks
Chronic tophaceous gout	Persistent tophi, polyarticular involvement, bony erosions

Most common joint: First metatarsophalangeal (MTP) joint — podagra. Knee, ankle, tarsal joints, and hands also affected. Up to 20% have polyarticular involvement. Systemic symptoms (fever) can mimic septic arthritis.

Tophi are gritty, chalk-white nodules of MSU crystals found in subcutaneous tissue, bursae, or joint spaces — generally painless until they erode bone.

Chronic tophaceous gout: chalky white MSU crystal deposits in the first MTP joint with bone erosion

Cross-section of first MTP joint in chronic tophaceous gout showing extensive MSU deposits (chalky white masses) with subchondral bone destruction.

Periarticular tophus at the elbow showing pale yellow-white MSU crystal deposits in fibrous tissue

Large periarticular tophus excised from the elbow — chalky urate concretions within fibrofatty tissue.

Diagnosis

Arthrocentesis (gold standard): Synovial fluid shows negatively birefringent needle-shaped MSU crystals under polarizing microscopy.
Serum uric acid: Unreliable — attacks can occur with normal uric acid; many hyperuricemic patients are asymptomatic.
WBC: May be elevated (non-specific).
Renal function: Important — gout is associated with renal insufficiency and many treatments are nephrotoxic.
Imaging:
- Plain X-ray (acute): soft-tissue swelling only; (chronic): asymmetric, sclerotic "overhanging edge" erosions outside the joint capsule.
- Ultrasound: "Double contour sign" (urate coating cartilage); tophi appear as a "lump of sugar."
- Dual-energy CT (DECT): highly specific for urate deposits.

Ultrasound of gout: double contour sign at MTP joint (A) and tophus with "lump of sugar" appearance (B)

Ultrasound of gout. (A) Double contour sign at a metatarsophalangeal joint. (B) Tophus with characteristic "lump of sugar" appearance.

Management

Acute Flare

All three options (NSAIDs, colchicine, corticosteroids) are effective; choose based on comorbidities:

Drug	Notes
NSAIDs (indomethacin, naproxen, ibuprofen)	First-line; start promptly; relief in ~24h; avoid in peptic ulcer, GI bleeding, renal insufficiency
Colchicine	Inhibits microtubule formation → blocks crystal-driven inflammation; contraindicated in renal/hepatic insufficiency; narrow therapeutic window; GI side effects common
Corticosteroids (oral or intra-articular)	Prednisone 40 mg/day × 5–7 days; intra-articular most effective for single joint; avoid if septic arthritis cannot be excluded

Do not start urate-lowering therapy during an acute flare, but continue existing therapy if already prescribed.
Non-pharmacologic: ice, elevation, oral hydration, rest of inflamed joint.

Long-Term Urate-Lowering Therapy (ULT)

Target: serum urate <6 mg/dL (symptomatic patients).

Drug	Mechanism	Key Points
Allopurinol	Xanthine oxidase inhibitor (purine analog)	Start 100–200 mg/day; titrate slowly (q4 weeks); dose-adjust for eGFR; risk of severe allopurinol hypersensitivity syndrome (DRESS) — higher in HLA-B*5801 carriers
Febuxostat	Xanthine oxidase inhibitor (non-purine analog)	40–80 mg/day; no renal dose adjustment; higher CV mortality vs. allopurinol in high-CV-risk patients (CARES trial); use for allopurinol-intolerant patients
Probenecid	Uricosuric (increases renal urate excretion)	Avoid in underexcretors with renal impairment or urolithiasis
Pegloticase	Recombinant pegylated uricase; converts urate → allantoin	FDA-approved for refractory gout (2010); risk of infusion reactions and antibody-mediated loss of efficacy

Note: Allopurinol and febuxostat both inhibit azathioprine metabolism — if co-prescribed, reduce azathioprine dose by ~25% and monitor CBC closely (or switch to mycophenolate, which doesn't interact).

Prophylaxis During ULT Initiation

Starting ULT can trigger acute flares by mobilizing urate deposits. Cover with low-dose colchicine (0.5–0.6 mg/day) or low-dose NSAIDs for 3–6 months.

Secondary Causes to Consider

Lesch-Nyhan syndrome: Complete HGPRT deficiency → severe hyperuricemia + neurologic features (self-mutilation, choreoathetosis, intellectual disability)
Tumor lysis syndrome: Rapid cell lysis from chemotherapy → urate overproduction
Medications: Thiazide diuretics, loop diuretics, cyclosporin, low-dose aspirin
CKD: Impaired urate excretion

Gout vs. Pseudogout (CPPD)

Feature	Gout	Pseudogout (CPPD)
Crystal type	Monosodium urate	Calcium pyrophosphate
Crystal appearance	Needle-shaped, negatively birefringent	Rhomboid, positively birefringent
Most common joint	First MTP (podagra)	Knee
X-ray finding	Erosions, tophi	Chondrocalcinosis
Associations	Hyperuricemia, diet, CKD	Hemochromatosis, hypothyroidism, hyperparathyroidism

Sources: Robbins & Kumar Basic Pathology; Rosen's Emergency Medicine; Comprehensive Clinical Nephrology, 7th Ed.

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