GOUT

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gout urate crystals joint tophi pathology

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GOUT

Definition & Epidemiology

Gout is a crystal-induced arthropathy caused by the deposition of monosodium urate (MSU) crystals in joints and periarticular tissues, secondary to persistent hyperuricemia. It affects approximately 4% of adults in the United States (~5% of males, ~3% of females), with prevalence increasing with age. It is the most common form of inflammatory arthritis in adults.

Risk factors: obesity, hypertension, diabetes mellitus, thiazide diuretics, cyclosporin use, chronic kidney disease, purine-rich diet (red meats, shellfish, anchovies, beer, legumes).

Pathophysiology

Uric Acid Metabolism

Uric acid is the end product of purine catabolism. Purines are synthesized via:

De novo pathway — synthesis from nonpurine precursors
Salvage pathway — recycling of free purine bases (diet or DNA/RNA degradation)

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

Causes of hyperuricemia:

Mechanism	Examples
Reduced excretion (most common, ~90%)	Idiopathic, CKD, diuretics, cyclosporin
Overproduction	HGPRT deficiency (Lesch-Nyhan syndrome), tumor lysis syndrome, myeloproliferative disorders

Lesch-Nyhan syndrome: Complete absence of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) → inability to salvage purines → severe hyperuricemia + neurological manifestations (self-mutilation, intellectual disability, spasticity).

Crystal-Induced Inflammation

MSU crystals precipitate in supersaturated extracellular fluid (especially in joints)
Resident macrophages phagocytose crystals → activate NLRP3 inflammasome
Inflammasome activates caspase-1 → IL-1β and TNF-α release
IL-1β drives neutrophil recruitment to the synovium
Neutrophils release cytokines, free radicals, and proteases; lysosomal enzyme leakage destroys cartilage
Neutrophils lower local pH → further urate precipitation (self-amplifying cycle)

Clinical Stages

Stage	Features
Asymptomatic hyperuricemia	Elevated urate, no symptoms; may last 20–30 years
Acute gouty arthritis	Sudden-onset monoarthritis; peak 1–2 days; self-limiting within 1–2 weeks
Intercritical (interval) gout	Asymptomatic periods between attacks; attacks become more frequent over time
Chronic tophaceous gout	Tophi form; permanent joint damage; polyarticular

Acute Attack Features

Podagra — first metatarsophalangeal (MTP) joint is the classic site (most common)
Also: knee, ankle, tarsal joints, wrist, fingers
Up to 20% have polyarticular involvement
Severe pain (at rest and with movement), erythema, swelling, warmth — can mimic cellulitis
Systemic fever possible → must rule out septic arthritis

Clinical Images

Confirmed gout in the second MCP joint mimicking hand cellulitis — Rosen's Emergency Medicine

Chronic tophaceous gout — MTP joint cross-section

Sagittal cross-section of the first MTP joint: extensive MSU crystal tophi with bone erosion and cartilage destruction

Chronic tophaceous gout of the knee: chalky yellow-white MSU deposits on articular surfaces and synovium

Tophi

Aggregates of monosodium urate crystals + inflammatory tissue forming in:

Synovial membranes, periarticular tissues
Bursae, joint space, subcutaneous tissue (especially helix of ear, Achilles tendon, olecranon bursa)
Generally painless but cause bony erosion and joint deformity
May ulcerate, discharging chalky-white material

Diagnosis

Synovial Fluid Analysis (Gold Standard)

Negatively birefringent, needle-shaped crystals under polarized light microscopy
Leukocytosis in synovial fluid (neutrophil predominance)
Arthrocentesis mandatory for first attack; can treat empirically if established gout + not systemically unwell

Serum Uric Acid

Unhelpful during acute attacks — can be normal during a flare and elevated without symptoms
Useful for monitoring urate-lowering therapy (target < 6 mg/dL)

Imaging

Plain X-ray: soft tissue swelling (acute); asymmetric sclerotic "punched-out" erosions outside the joint capsule with overhanging edges (chronic)
Ultrasound: "double contour sign" (urate coating cartilage surface); "lump of sugar" appearance of tophi
Dual-energy CT (DECT): color-coded urate deposits; highly specific

Ultrasound double contour sign and tophus

Ultrasound: (A) Double contour sign in MTP joint; (B) Tophus with "lump of sugar" appearance — Rosen's Emergency Medicine

Renal Function

Always check — gout is associated with renal insufficiency, and most treatments are nephrotoxic.

Management

Acute Attack

Drug	Notes
NSAIDs (first-line)	Indomethacin, naproxen, ibuprofen; start promptly, continue 24 hrs after resolution; avoid in PUD, GI bleeding, renal insufficiency
Colchicine (second-line)	Must be started within 36 hours of attack onset; inhibits NLRP3 inflammasome, tubulin polymerization, neutrophil migration; narrow therapeutic window; avoid in renal/hepatic insufficiency; GI side effects common
Corticosteroids	Oral (prednisone 40 mg/day × 5–7 days) or intra-articular; preferred when NSAIDs/colchicine contraindicated; do NOT combine oral steroids + NSAIDs
Combination therapy	Intra-articular steroid + colchicine or NSAID for severe/polyarticular disease
Non-pharmacologic	Ice, elevation, oral hydration, rest, avoid triggers

Long-standing urate-lowering drugs (allopurinol, febuxostat, probenecid) should NOT be initiated during an acute attack but may be continued if already prescribed.

Urate-Lowering Therapy (ULT) — Chronic Gout

Indications:

≥ 2 attacks/year
Chronic kidney disease
Nephrolithiasis
Presence of tophi

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

Drug Class	Drug	Mechanism	Notes
Xanthine oxidase inhibitors (first-line)	Allopurinol	Inhibits xanthine oxidase → ↓ uric acid synthesis	Start at 100–200 mg/day; titrate slowly; adjust for renal function; risk of severe hypersensitivity (allopurinol hypersensitivity syndrome, especially in HLA-B*5801 carriers)
	Febuxostat	Non-purine xanthine oxidase inhibitor	40–80 mg/day; no renal dose adjustment; higher CV mortality than allopurinol in high-CV-risk patients (CARES trial) — use with caution
Uricosuric agents	Probenecid	Blocks proximal tubule urate reabsorption	Second-line; avoid in nephrolithiasis
Uricase	Pegloticase	Converts urate → allantoin (more soluble)	IV; refractory tophaceous gout; FDA-approved 2010; anti-drug antibodies cause loss of efficacy + infusion reactions

Key drug interaction: Allopurinol and febuxostat inhibit xanthine oxidase → block azathioprine metabolism → risk of severe myelosuppression. If combination required, reduce azathioprine dose by ~25% and monitor CBC closely. Alternatively, switch to mycophenolate.

Prophylaxis When Starting ULT

Initiation of ULT can precipitate an acute flare due to rapid urate level changes. Co-prescribe:

Low-dose colchicine, or
Low-dose NSAIDs, or
Low-dose corticosteroids

Continue for at least 6 months after starting ULT.

Secondary Gout — Special Populations

Post-Transplant Gout

Risk factors: pre-transplant hyperuricemia, CKD, diuretics, cyclosporin (> tacrolimus)
Acute management: ice, rest + colchicine / increased corticosteroids / NSAIDs (NSAIDs used cautiously)
ULT: allopurinol starting at 100–200 mg/day; dose-titrate every 4 weeks

Tumor Lysis Syndrome

Rapid cell lysis after chemotherapy → massive purine release → secondary gout/urate nephropathy
Prevented/treated with rasburicase (recombinant uricase) or allopurinol prophylaxis

Differential Diagnosis

Condition	Distinguishing Features
Septic arthritis	Fever, very high synovial WBC (>50,000), positive culture
Pseudogout (CPPD)	Calcium pyrophosphate crystals — positively birefringent, rhomboid-shaped; chondrocalcinosis on X-ray; associated with hemochromatosis, hypothyroidism, hyperparathyroidism
Rheumatoid arthritis	Symmetric, RF/anti-CCP positive, morning stiffness
Cellulitis	No crystals, responds to antibiotics, no joint effusion

Key Drug: Colchicine — Mechanism Summary

Colchicine binds tubulin → depolymerizes microtubules → impairs:

Neutrophil chemotaxis and adhesion
NLRP3 inflammasome activation → ↓ IL-1β, IL-18
Mast cell degranulation

Adverse effects: nausea, vomiting, diarrhea (dose-limiting); chronic use → myopathy, neutropenia, aplastic anemia, alopecia. Metabolized by CYP3A4 and P-glycoprotein — significant drug interactions (clarithromycin, itraconazole, verapamil, amiodarone increase colchicine toxicity).

Sources: Robbins & Kumar Basic Pathology; Rosen's Emergency Medicine; Goodman & Gilman's Pharmacological Basis of Therapeutics; Lippincott Illustrated Reviews: Pharmacology; Comprehensive Clinical Nephrology 7e

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