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Summary Table

Feature	Detail
Risk Factors	Male sex, postmenopausal women, obesity, chronic kidney disease, high-purine diet (red meat, shellfish, organ meats), alcohol use (especially beer), thiazide/loop diuretics, cyclosporine, low-dose aspirin, tumor lysis syndrome
Etiology	Deposition of monosodium urate (MSU) crystals in joints and soft tissues due to chronic hyperuricemia (serum urate > 6.8 mg/dL)
Patient Presentation	Acute onset of excruciating monoarticular joint pain, most commonly the first metatarsophalangeal (MTP) joint, peaking within 12 to 24 hours, often waking the patient from sleep
Classic Physical Exam	Swollen, erythematous, exquisitely tender joint (podagra); tophi in chronic gout (ear helices, olecranon bursa, Achilles tendon, finger joints)
Key Diagnostic Results	Synovial fluid analysis: negatively birefringent, needle-shaped crystals under polarized light microscopy; serum uric acid may be normal during an acute flare
Management	Acute flare: NSAIDs, colchicine, or corticosteroids. Long-term urate-lowering therapy (ULT): allopurinol or febuxostat. Target serum urate < 6.0 mg/dL
Keywords	"Podagra," "needle-shaped negatively birefringent crystals," "woken from sleep by joint pain," "tophaceous," "first MTP joint"

1. Pathophysiology

Gout is fundamentally a disorder of purine metabolism resulting in chronic hyperuricemia. Uric acid is the final breakdown product of purine metabolism in humans because we lack the enzyme uricase, which in other mammals converts uric acid into the more soluble allantoin. When serum urate concentration exceeds its saturation point (approximately 6.8 mg/dL at physiologic temperature and pH), monosodium urate crystals begin to precipitate in avascular and relatively cooler peripheral tissues.

The predilection for the first MTP joint is explained by two factors: it is the coolest joint in the body (urate solubility decreases with temperature), and it experiences repetitive microtrauma from weight-bearing, which promotes crystal nucleation. This is why the classic presentation is called podagra.

Once MSU crystals deposit in the synovial space, they are phagocytosed by resident macrophages, triggering activation of the NLRP3 inflammasome. This leads to cleavage of pro-IL-1-beta into active IL-1-beta, a potent pro-inflammatory cytokine that drives the intense neutrophilic infiltration, vasodilation, and edema characteristic of an acute gout flare. The result is one of the most painful conditions in medicine, with rapid escalation to peak intensity within hours.

Hyperuricemia arises from two broad mechanisms: underexcretion of uric acid (accounting for roughly 90% of cases, commonly worsened by chronic kidney disease, diuretic use, and low-dose aspirin) and overproduction of uric acid (seen in myeloproliferative disorders, tumor lysis syndrome, Lesch-Nyhan syndrome, and high dietary purine intake). Understanding this distinction matters because it guides the choice of urate-lowering therapy.

In chronic untreated gout, persistent crystal deposition forms tophi, which are organized granulomatous collections of MSU crystals surrounded by inflammatory cells. Tophi are destructive, eroding into bone and cartilage, and can also deposit in soft tissues such as the ear helix and olecranon bursa.

2. Classification and Clinical Manifestation

Stage	Clinical Features	Key Characteristics
Asymptomatic Hyperuricemia	Elevated serum urate without symptoms	No treatment with ULT is indicated; lifestyle modification only
Acute Gouty Arthritis	Sudden monoarticular inflammation, most often the first MTP joint	Peaks in 12 to 24 hours; exquisitely tender, red, swollen joint; may have fever; self-resolves in 7 to 14 days untreated
Intercritical Gout	Symptom-free interval between flares	Crystals remain in joints despite clinical quiescence; duration between attacks shortens over time without ULT
Chronic Tophaceous Gout	Polyarticular involvement, visible tophi, joint destruction	Tophi on ear helices, olecranon, Achilles tendon, fingers; chronic pain; bony erosions on imaging with characteristic "overhanging edge" (Martel sign)

Gout can also present in atypical patterns. In elderly patients and women on diuretics, it may affect the fingers and wrists rather than the first MTP, and can mimic rheumatoid arthritis with polyarticular involvement. Gout in transplant recipients on cyclosporine tends to have an accelerated course and may present with early tophaceous disease.

3. Diagnostic Workup

Test	Role	Key Findings
Synovial fluid analysis (polarized microscopy)	Gold standard / confirmatory	Negatively birefringent, needle-shaped crystals; elevated WBC count (typically 10,000 to 70,000/microL, neutrophil-predominant)
Serum uric acid	Supportive but not diagnostic	Often elevated (> 6.8 mg/dL), but can be normal or even low during an acute flare
Joint X-ray	Baseline imaging	Early disease: normal or soft tissue swelling. Chronic gout: punched-out erosions with overhanging edges (Martel sign), preserved joint space until late
Dual-energy CT (DECT)	Advanced imaging when aspiration is not feasible	Detects urate crystal deposits with high sensitivity; useful in atypical presentations
24-hour urine uric acid	Classify as overproducer vs. underexcretor	> 800 mg/day suggests overproduction; guides ULT selection
Synovial fluid Gram stain and culture	Rule out septic arthritis	Always send when aspirating, as gout and septic arthritis can coexist

The best initial diagnostic step in any acute monoarticular arthritis is arthrocentesis with synovial fluid analysis. This is non-negotiable on the exam. The reason is twofold: it confirms the diagnosis of gout by identifying MSU crystals, and it simultaneously rules out septic arthritis, which is the most dangerous mimic of acute gout.

The finding of negatively birefringent, needle-shaped crystals under compensated polarized light microscopy is the gold standard. "Negatively birefringent" means the crystals appear yellow when parallel to the axis of the red compensator. This is the single most tested fact about gout diagnosis.

A critical exam trap: serum uric acid is not reliable during an acute flare. Uric acid levels may drop during inflammation due to the uricosuric effect of acute-phase cytokines. A normal serum urate does not rule out gout. Conversely, asymptomatic hyperuricemia alone does not diagnose gout. The diagnosis requires demonstration of crystals or, in the right clinical context, fulfillment of validated classification criteria.

For chronic gout, plain radiographs show characteristic punched-out periarticular erosions with sclerotic borders and overhanging edges. Unlike rheumatoid arthritis, joint space is relatively preserved until advanced disease, and there is no periarticular osteopenia.

4. Management and Treatment

Setting	First-Line Therapy	Dose and Details
Acute flare	NSAIDs (indomethacin preferred)	Indomethacin 50 mg TID until flare resolves; naproxen 500 mg BID is an alternative
Acute flare (NSAID contraindicated)	Colchicine	1.2 mg at onset, then 0.6 mg one hour later (total 1.8 mg on day 1); then 0.6 mg once or twice daily. Most effective within the first 36 hours
Acute flare (NSAIDs and colchicine contraindicated)	Systemic corticosteroids or intra-articular injection	Prednisone 0.5 mg/kg/day for 5 to 10 days with taper; or triamcinolone intra-articular for monoarticular flare
Refractory acute flare	IL-1 inhibitor (anakinra)	Used in patients who cannot tolerate standard therapies or have contraindications to all three first-line agents
Urate-lowering therapy (ULT)	Allopurinol (xanthine oxidase inhibitor)	Start at 100 mg/day (50 mg if CKD stage 3 or higher), titrate by 100 mg every 2 to 4 weeks to target serum urate < 6.0 mg/dL
ULT alternative	Febuxostat	40 to 80 mg/day; reserved for allopurinol intolerance or failure; carries an FDA cardiovascular warning
ULT (underexcretor phenotype)	Probenecid (uricosuric)	250 mg BID, titrate to 500 mg BID; contraindicated if CrCl < 50 mL/min or history of nephrolithiasis
Flare prophylaxis during ULT initiation	Low-dose colchicine or NSAID	Colchicine 0.6 mg once or twice daily for 3 to 6 months after starting ULT
Refractory tophaceous gout	Pegloticase (recombinant uricase)	IV infusion every 2 weeks; reserved for severe tophaceous gout failing oral ULT; risk of anaphylaxis and infusion reactions

Acute management focuses on suppressing inflammation, not lowering uric acid. The three pillars are NSAIDs, colchicine, and corticosteroids. The choice depends on comorbidities. NSAIDs are avoided in renal impairment, heart failure, and peptic ulcer disease. Colchicine must be started within 36 hours of flare onset for best efficacy and loses its benefit if initiated later. Corticosteroids are the safest option in patients with renal insufficiency.

A high-yield management principle: do not start, stop, or change the dose of ULT during an acute flare. Rapid changes in serum urate can worsen or prolong the attack by destabilizing existing crystal deposits. If a patient is already on ULT when a flare occurs, continue it at the same dose and treat the inflammation.

Urate-lowering therapy is indicated for patients with recurrent flares (two or more per year), tophi, urate nephropathy, or radiographic changes of gout. Allopurinol is the first-line agent. It is critical to start at a low dose and titrate gradually because rapid urate reduction can paradoxically trigger flares. Patients of Southeast Asian, African American, or Korean descent should be screened for HLA-B*5801 before starting allopurinol due to the risk of severe hypersensitivity reaction, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

When initiating ULT, flare prophylaxis with low-dose colchicine (0.6 mg daily or BID) or a low-dose NSAID should be co-prescribed for at least 3 to 6 months to prevent mobilization flares.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Is Similar	Key Discriminator
Pseudogout (CPPD disease)	Acute monoarticular arthritis in an older patient; can affect the knee, wrist	Synovial fluid shows rhomboid-shaped, positively birefringent crystals (blue when parallel); chondrocalcinosis on X-ray; tends to affect the knee and wrist rather than the first MTP
Septic arthritis	Acute monoarticular hot, swollen joint with fever; may coexist with gout	Synovial fluid WBC > 50,000 with positive Gram stain/culture; no crystals (though gout and infection can coexist); the patient appears more systemically ill; always send cultures even if crystals are found
Cellulitis	Erythema, warmth, swelling over a joint	Diffuse skin involvement without a discrete joint effusion; no crystals on aspiration; skin findings extend beyond the joint capsule
Rheumatoid arthritis	Polyarticular joint involvement in chronic/tophaceous gout can mimic RA	RA is symmetric, involves MCP and PIP joints, has positive RF/anti-CCP; gout has tophi and urate crystals; RA shows periarticular osteopenia, gout shows punched-out erosions with overhanging edges
Reactive arthritis	Acute monoarticular or oligoarticular lower-extremity arthritis	History of preceding GI or GU infection; associated with urethritis, conjunctivitis, and enthesitis; no crystals on synovial fluid

6. Traps and High-Yield Pearls

The single most common way students lose points on gout questions is by using serum uric acid to diagnose or rule out an acute flare. A normal uric acid during a flare does not exclude gout, and an elevated uric acid in an asymptomatic patient does not mean the patient has gout. The diagnosis hinges on crystal identification from synovial fluid.

The second major trap involves crystal identification. Students frequently confuse gout with pseudogout. The mnemonic is straightforward: gout crystals are Needle-shaped and Negatively birefringent (yellow when parallel). Pseudogout crystals are Rhomboid-shaped and Positively birefringent (blue when parallel). If the vignette describes "rhomboid" or "weakly positive birefringence," the answer is CPPD, not gout.

Another common error is initiating allopurinol during an acute flare or failing to provide flare prophylaxis when starting ULT. The exam tests whether you understand that acute management addresses inflammation (NSAIDs, colchicine, steroids) while chronic management addresses hyperuricemia (allopurinol, febuxostat), and these two goals should not be conflated.

Finally, do not forget to screen for HLA-B*5801 in at-risk populations before prescribing allopurinol. A vignette describing a patient of Southeast Asian descent who develops a severe drug rash after starting allopurinol is testing this exact concept. The core competency being assessed across gout questions is the ability to distinguish crystal types, sequence the diagnostic workup correctly (always aspirate first), and separate acute anti-inflammatory treatment from long-term urate-lowering strategy.

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