In a 55-year-old man with newly diagnosed hypertension and type II diabetes mellitus who was started on aspirin, metformin, lisinopril, and hydrochlorothiazide and then develops acute painful red swelling of the first metatarsophalangeal joint, which medication is most likely responsible?

Hydrochlorothiazide is Most Likely Responsible

Hydrochlorothiazide (HCTZ) is the medication most likely causing this patient's acute gout flare, as thiazide diuretics are well-established triggers for gout by reducing renal uric acid excretion and promoting hyperuricemia.

Clinical Presentation Analysis

The patient presents with classic podagra—acute monoarthritis of the first metatarsophalangeal (MTP) joint characterized by severe pain, redness, and swelling. 1, 2

• Approximately 50% of initial gout attacks involve the first MTP joint, making this the most characteristic presentation of acute gout. 1, 2
• The rapid onset of severe pain reaching maximum intensity within 6-24 hours is highly suggestive of crystal-induced inflammation rather than other causes of joint pain. 1
• The combination of first MTP joint involvement with erythema has a likelihood ratio of 30.64 for gout diagnosis, with 96% sensitivity and 97% specificity. 2

Medication Analysis

Hydrochlorothiazide (Answer D) - MOST LIKELY

• Thiazide diuretics are a well-recognized risk factor for gout, with a relative risk of 1.72. 3
• HCTZ reduces renal uric acid excretion, leading to hyperuricemia and precipitation of monosodium urate crystals in joints. 3
• In patients with type 2 diabetes treated with HCTZ, metabolic effects include significantly increased fasting glucose and HbA1c, demonstrating the drug's systemic metabolic impact that extends to uric acid handling. 4
• The timing is consistent—gout flares typically occur within days to weeks of initiating thiazide therapy in susceptible individuals. 3

Aspirin (Answer A) - Less Likely

• Low-dose aspirin (typically ≤325 mg/day for cardiovascular prophylaxis) can increase uric acid levels by inhibiting renal uric acid excretion. 3
• However, aspirin's effect on uric acid is dose-dependent and generally less pronounced than thiazides. 3
• While aspirin is listed as a risk factor for gout, its relative risk is lower than that of thiazide diuretics. 3

Metformin (Answer B) - Unlikely

• Metformin is not associated with increased gout risk and does not affect uric acid metabolism. 3
• No evidence in the literature supports metformin as a trigger for acute gout attacks. 3

Lisinopril (Answer C) - Unlikely

• ACE inhibitors like lisinopril are not associated with increased gout risk. 3
• In fact, some evidence suggests ACE inhibitors may have neutral or potentially beneficial effects on uric acid levels. 3

Diagnostic Confirmation

While the clinical presentation is highly suggestive (95% strength of recommendation for clinical diagnosis of recurrent podagra with hyperuricemia), definitive diagnosis requires joint aspiration with synovial fluid analysis demonstrating needle-shaped, negatively birefringent monosodium urate crystals under polarized light microscopy. 5, 1

• Synovial fluid crystal analysis has 84% sensitivity and 100% specificity for gout diagnosis. 3
• Gram stain and culture must be performed even when MSU crystals are identified, as gout and septic arthritis can coexist. 5, 1, 3

Common Pitfalls to Avoid

• Do not diagnose gout based on hyperuricemia alone—approximately 10% of patients with acute gout have normal serum uric acid levels during an attack, and only 22% of asymptomatic individuals with serum uric acid >9 mg/dL develop gout within 5 years. 5, 3
• Do not assume septic arthritis is excluded based on clinical appearance alone—if infection cannot be ruled out clinically, joint aspiration with Gram stain and culture is mandatory. 5, 1
• Do not delay treatment waiting for laboratory confirmation in typical presentations—clinical diagnosis is sufficient to initiate anti-inflammatory therapy. 1