Can Hydrochlorothiazide (HCTZ) cause gout?

Can Hydrochlorothiazide Cause Gout?

Yes, hydrochlorothiazide (HCTZ) definitively causes hyperuricemia and can precipitate gout by reducing renal uric acid excretion, though clinical gout attacks remain relatively uncommon at standard doses ≤50 mg/day. 1, 2

Mechanism of Action

HCTZ elevates serum uric acid through two primary mechanisms:

• Decreased renal excretion: HCTZ blocks sodium and chloride reabsorption in the distal tubule, which secondarily decreases uric acid excretion by the kidneys 1, 2
• Biochemical effect: The drug directly decreases the excretion of uric acid while increasing calcium excretion 2

The FDA drug label explicitly states that "hyperuricemia or acute gout may be precipitated in certain patients receiving thiazide diuretics." 2

Clinical Evidence and Risk Quantification

The risk of gout with HCTZ is dose-dependent and clinically significant:

• Current use of thiazide diuretics increases the risk of incident gout with an adjusted odds ratio of 1.70 (95% CI 1.62-1.79) compared to past use 3
• Risk becomes significant at doses ≥25 mg/day, with an adjusted relative risk of 1.99 (95% CI 1.21-3.26) for thiazide monotherapy and 2.29 (95% CI 1.55-3.37) when combined with other antihypertensives 4
• At standard doses ≤50 mg/day, while uric acid elevation is common, actual gout attacks remain uncommon 1
• Combined use of loop diuretics with thiazides carries the highest risk (adjusted OR 4.65) 3

Clinical Management Algorithm

For patients with established gout currently on HCTZ:

1. First-line approach: The 2020 American College of Rheumatology conditionally recommends switching HCTZ to an alternative antihypertensive when feasible 1

2. Preferred alternative agents:

   • Losartan is the preferred substitute as it has uricosuric effects that actively lower uric acid levels 1
   • Calcium channel blockers (e.g., amlodipine) do not adversely affect uric acid levels 5, 1

3. When HCTZ cannot be discontinued: Initiate or optimize urate-lowering therapy (allopurinol or febuxostat) targeting serum uric acid <6 mg/dL (or <5 mg/dL for severe gout) 1

For patients without gout on HCTZ:

• Monitor for signs of hyperuricemia, particularly in high-risk patients (those with obesity, chronic kidney disease, metabolic syndrome, or family history of gout) 6, 7
• Keep doses at or below 50 mg/day to minimize gout risk while maintaining antihypertensive efficacy 1, 4
• Consider proactive switching to losartan in patients with multiple gout risk factors 1

Important Clinical Caveats

Do not discontinue HCTZ reflexively in all patients:

• The decision must weigh cardiovascular benefits against gout risk, particularly in patients with established cardiovascular disease where HCTZ provides proven mortality benefit 1
• In diabetic patients, one trial showed decreased morbidity and mortality with benazepril plus amlodipine versus benazepril plus HCTZ, providing additional rationale for switching 5
• The absolute risk of clinical gout remains relatively low at standard therapeutic doses, so asymptomatic hyperuricemia alone does not mandate discontinuation 1

Avoid common pitfalls:

• Do not treat asymptomatic hyperuricemia caused by HCTZ without considering medication adjustment first 4
• Recognize that serum uric acid monitoring can serve as a surrogate marker for medication compliance but routine monitoring is not required in asymptomatic patients 5
• Be aware that patients with pre-existing gout have substantially higher risk of acute attacks when exposed to thiazides 5, 7