Gout

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Gout

Definition & Epidemiology

Gout is a form of inflammatory arthritis caused by the deposition of monosodium urate (MSU) crystals in joints and periarticular tissues, driven by sustained hyperuricemia (plasma urate >6.8 mg/dL). It affects approximately 4% of U.S. adults - roughly 5% of males and 3% of females - and prevalence increases significantly with age. Risk factors include obesity, hypertension, diabetes, chronic kidney disease, and use of thiazide diuretics or cyclosporine.

Rosen's Emergency Medicine, 10e
Robbins & Kumar Basic Pathology

Pathogenesis

Uric Acid Metabolism

Uric acid is the end product of purine catabolism. Purines are produced via two pathways:

De novo pathway: synthesis from non-purine precursors
Salvage pathway: recycling of free purine bases from dietary intake or DNA/RNA degradation

Uric acid is filtered by the glomerulus, almost completely reabsorbed by the proximal tubule, with a small fraction secreted by the distal nephron. In primary gout (~90% of cases), reduced renal excretion is the main driver (mechanism usually unknown). In secondary gout, causes include:

Overproduction: tumor lysis syndrome, HGPRT enzyme defects (partial deficiency = gout; complete absence = Lesch-Nyhan syndrome)
Reduced excretion: chronic renal disease, diuretics, cyclosporine

Crystal-Induced Inflammation

When urate crystals precipitate in a joint, the sequence is:

Resident synovial macrophages phagocytose MSU crystals
Crystals activate the NLRP3 inflammasome
Caspase-1 is activated, generating active IL-1β
IL-1β recruits neutrophils, which release cytokines, free radicals, and proteases
Crystals damage phagolysosomal membranes, causing lysosomal enzyme leakage
Result: acute synovitis, self-limited but recurrent

Only ~10% of people with hyperuricemia ever develop gout. Contributing factors include age, duration of hyperuricemia, and precipitating events (dietary purine load, alcohol, dehydration, trauma, surgery).

Robbins & Kumar Basic Pathology

Clinical Stages

Stage	Features
Asymptomatic hyperuricemia	Elevated urate, no symptoms; may persist for 20-30 years
Acute gouty arthritis	Sudden, severe monoarthritis; peaks in 1-2 days; resolves in days to weeks
Intercritical period	Symptom-free intervals between attacks; attacks become more frequent over time
Chronic tophaceous gout	Persistent joint disease; tophi form; bony erosion; joint deformity

Clinical Features

The classic presentation is podagra - acute, exquisitely painful arthritis of the first metatarsophalangeal (MTP) joint. Other commonly affected joints: knee, ankle, tarsal joints, wrists, and fingers.

Up to 20% of patients present with polyarticular involvement, or associated bursitis and tenosynovitis that can mimic cellulitis.

Tophi are gritty, chalk-like nodules of packed MSU crystals found in subcutaneous tissue, bursae, joint spaces, and soft tissues. They are generally painless but indicate chronic disease.

Acute gout of the first MTP joint showing erythema, warmth, and diffuse swelling of the forefoot

Acute podagra - marked erythema and swelling of the first MTP and forefoot. - Rosen's Emergency Medicine

Rosen's Emergency Medicine, 10e

Diagnosis

Definitive - Synovial Fluid Analysis

Joint aspiration (arthrocentesis) is the gold standard, especially for a first episode or when septic arthritis cannot be excluded. Under polarized light microscopy, MSU crystals appear needle-shaped and negatively birefringent (yellow when parallel to the polarizer axis).

Laboratory

Serum uric acid: often elevated, but not reliable during an acute attack (may be normal). Does not correlate well with flare frequency.
WBC: may be elevated (nonspecific)
Renal function: important because many treatments are nephrotoxic and there is an association between gout and renal insufficiency

Imaging

Plain X-ray: acute attacks show only soft-tissue swelling; chronic disease shows asymmetric, sclerotic-appearing punched-out bony erosions outside the joint capsule ("overhanging edge" sign)
Ultrasound: highly useful; shows the double contour sign (urate deposition on articular cartilage surface) and tophi with a characteristic "lump of sugar" appearance

Ultrasound of gout: (A) double contour sign at MTP joint (arrows), (B) tophus with heterogeneous "lump of sugar" pattern

Ultrasound findings in gout. - Rosen's Emergency Medicine

Rosen's Emergency Medicine, 10e

Management

Acute Attack

The goal is rapid anti-inflammatory treatment. Do not initiate urate-lowering therapy during an acute attack, but do continue it if already prescribed (stopping can prolong the flare).

Agent	Notes
NSAIDs (first-line)	Indomethacin, naproxen, ibuprofen. Start promptly; continue 24h after resolution. Avoid in PUD, GI bleeding, renal insufficiency.
Colchicine	Inhibits microtubule formation, blocking crystal-induced inflammation. Effective, but narrow therapeutic window; contraindicated in renal/hepatic insufficiency; GI side effects common.
Corticosteroids	Prednisone 40 mg/day x 5-7 days, or intra-articular injection (most effective for monoarticular disease; do not use if septic arthritis possible). Avoid concurrent oral steroids + NSAIDs (GI risk).
Combination therapy	Intra-articular steroid + colchicine or NSAID reasonable for severe/polyarticular disease.

Non-pharmacologic: ice, elevation, oral hydration, avoidance of triggers.

Rosen's Emergency Medicine, 10e

Long-Term / Urate-Lowering Therapy (ULT)

Target serum urate: <6 mg/dL in symptomatic patients (some guidelines target <5 mg/dL for tophaceous disease).

Drug	Class	Key Points
Allopurinol	Xanthine oxidase inhibitor (purine analog)	First-line. Start 100 mg/day; titrate up by 50 mg every 4 weeks. Dose-adjust for renal impairment. Avoid or reduce azathioprine dose if co-prescribed.
Febuxostat	Xanthine oxidase inhibitor (non-purine analog)	Use in allopurinol-intolerant patients. 40 or 80 mg/day; no dose adjustment for renal impairment. Caution: a large RCT showed higher all-cause and CV mortality vs. allopurinol in high-CV-risk patients.
Probenecid	Uricosuric agent	Increases renal urate excretion. Avoid in uric acid overproducers and nephrolithiasis.
Pegloticase	Recombinant pegylated uricase	Converts uric acid to allantoin (more soluble). For refractory/tophaceous gout. FDA-approved 2010. Risk of infusion reactions and loss of efficacy due to anti-drug antibodies.

ULT should not be started during an acute flare. When initiating, co-prescribe low-dose colchicine or NSAIDs for 3-6 months as prophylaxis against flare precipitation.

Comprehensive Clinical Nephrology, 7e

Lifestyle Modifications

Reduce purine-rich foods: red meat, organ meats, shellfish, anchovies, beer
Avoid fructose-sweetened beverages
Increase hydration
Reduce alcohol (especially beer)
Weight loss in obese patients
Review and discontinue precipitating medications (thiazides, low-dose aspirin) when feasible

Differential Diagnosis

Septic arthritis: fever + joint swelling; must be excluded by arthrocentesis (joint fluid Gram stain/culture); never treat empirically as gout without ruling this out
Pseudogout (CPPD): calcium pyrophosphate crystals; positively birefringent (blue when parallel); chondrocalcinosis on X-ray; associated with hyperparathyroidism, hemochromatosis, hypothyroidism
Reactive arthritis: follows GI/GU infection; asymmetric oligoarthritis
Rheumatoid arthritis: symmetric, small-joint, chronic; RF/anti-CCP positive

Special Situations

Transplant patients: Cyclosporine significantly reduces renal urate excretion. NSAIDs should be avoided. Allopurinol and febuxostat interact dangerously with azathioprine (reduce AZA dose by ~25% and monitor CBC closely, or switch to mycophenolate). Pegloticase may be an option for refractory cases. - Comprehensive Clinical Nephrology, 7e

Renal impairment: Allopurinol start at lower doses (100 mg/day); titrate cautiously due to oxypurinol accumulation. Febuxostat does not require dose adjustment.

Lesch-Nyhan syndrome: Complete HGPRT deficiency - causes severe hyperuricemia plus neurologic manifestations (self-mutilation, cognitive impairment, choreoathetosis). Classified as secondary gout. - Robbins & Kumar Basic Pathology

Recent Evidence (2024-2026)

A recent systematic review (PMID 39794008) found that SGLT2 inhibitors reduce hyperuricemic events, providing an additional benefit in diabetic patients with gout or at risk. An additional meta-analysis (PMID 39961457) confirmed a significant association between psoriasis/psoriatic arthritis and hyperuricemia/gout, suggesting shared inflammatory pathways and the need for uric acid monitoring in psoriatic patients.

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