In a 55-year-old man with newly diagnosed hypertension and type 2 diabetes mellitus started on aspirin, metformin, lisinopril, and hydrochlorothiazide, which medication is most likely responsible for an acute gout flare of the first metatarsophalangeal joint?

Hydrochlorothiazide is Most Likely Responsible

Hydrochlorothiazide (HCTZ) is the medication most likely responsible for this acute gout flare, as thiazide diuretics are well-established triggers for gout attacks by reducing renal uric acid excretion and increasing serum urate levels. 1

Mechanism and Evidence

• Thiazide diuretics like HCTZ reduce renal uric acid excretion, leading to hyperuricemia and precipitation of monosodium urate crystals in joints 1
• Diuretic use is associated with a 1.72-fold increased relative risk of gout 2
• The JNC-7 guidelines specifically note that gout occurrence is uncommon with doses ≤50 mg/day of hydrochlorothiazide or ≤25 mg of chlorthalidone, but this patient was just started on therapy, making him vulnerable to an acute flare even at standard doses 1

Clinical Presentation Confirms Gout

• The patient presents with classic podagra—acute monoarthritis of the first MTP joint with severe pain, redness, and swelling 2, 3
• Podagra has a likelihood ratio of 30.64, with 96% sensitivity and 97% specificity for gout diagnosis 3
• Pain typically peaks within 6-12 hours in acute gout attacks 2, 3

Why Not the Other Medications?

• Aspirin (Option A): While low-dose aspirin can contribute to hyperuricemia, it is a much weaker trigger compared to thiazide diuretics and is less commonly implicated in acute gout flares 2

• Metformin (Option B): Has no established association with gout or hyperuricemia 4

• Lisinopril (Option C): ACE inhibitors like lisinopril may actually have a neutral or slightly protective effect on uric acid levels, though they can reduce renal function in some patients. They are not recognized as primary gout triggers 1, 4

Risk Factor Context

This patient has multiple risk factors that amplify his gout risk:

• Hypertension (relative risk 3.93) 2, 5
• Type 2 diabetes (component of metabolic syndrome) 2, 5
• Male gender 2
• Age 55 years (peak incidence in older adults) 4

Diagnostic Confirmation Recommended

• Joint aspiration with synovial fluid analysis showing needle-shaped, negatively birefringent monosodium urate crystals under polarized light microscopy is the gold standard (sensitivity 84%, specificity approaching 100%) 2
• Gram stain and culture must be performed even if crystals are identified, as gout and septic arthritis can coexist 2
• Serum uric acid should be measured, but approximately 10% of patients with acute gout have normal uric acid levels during an attack 2

Management Implications

• Do not discontinue HCTZ abruptly during the acute flare, as this can paradoxically worsen the attack 2
• Consider alternative antihypertensive agents (ACE inhibitors, ARBs, or calcium channel blockers) for long-term management if recurrent gout becomes problematic 1
• Initiate acute anti-inflammatory therapy with NSAIDs, colchicine, or corticosteroids 2

Answer: D. Hydrochlorothiazide