What are the causes of hyperuricemia?

Causes of Hyperuricemia

Hyperuricemia results from two primary mechanisms: decreased renal excretion of uric acid (the dominant cause) or increased uric acid production, with many cases involving both pathways simultaneously. 1, 2, 3

Primary Mechanisms

Decreased Renal Excretion (Most Common)

Impaired renal excretion is the dominant cause of hyperuricemia in most patients. 2, 3 This mechanism involves:

• Idiopathic underexcretion - The most common form, related to genetic variations in uric acid transporters, particularly URAT1 (urate transporter 1), which exchanges urate with other organic anions in the kidney. 2
• Uromodulin gene mutations - Cause familial juvenile hyperuricemic nephropathy (ADTKD-UMOD), characterized by inappropriately decreased fractional urate excretion beginning in childhood before significant kidney dysfunction develops. 1
• Renal damage or chronic kidney disease - Directly impairs the kidney's ability to excrete uric acid. 4, 5

Increased Uric Acid Production

Overproduction accounts for a smaller proportion of cases but is clinically important:

• Genetic enzyme deficiencies - Hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) deficiency (Lesch-Nyhan syndrome) and glucose-6-phosphatase deficiency cause excessive purine metabolism. 4, 3
• Rapid cell turnover - Hematologic malignancies (acute and chronic leukemia, lymphoma, polycythemia vera, multiple myeloma) and chemotherapy-induced tumor lysis syndrome dramatically increase uric acid production. 1, 4
• Myogenic hyperuricemia - Increased conversion of hypoxanthine in skeletal muscles, frequently associated with hypertension. 6

Secondary Causes: Medications

The ACR specifically recommends evaluating and eliminating non-essential medications that elevate serum urate levels. 1 Key offending agents include:

• Diuretics - Thiazide and loop diuretics are prime examples of medications causing hyperuricemia through decreased renal excretion. 1, 4
• Niacin - Reduces renal uric acid excretion. 1
• Calcineurin inhibitors - Used in transplant patients, these significantly elevate uric acid levels. 1
• Low-dose aspirin (≤325 mg daily) - Modestly elevates serum urate, though discontinuation is not recommended when used for cardiovascular prophylaxis due to negligible impact on gout management. 1

Secondary Causes: Comorbidities

The ACR recommends a specific comorbidity checklist for all gout patients to identify reversible causes. 1 Important associations include:

• Metabolic syndrome components - Obesity, hypertension, hyperlipidemia, and diabetes mellitus. 1, 7, 5
• Renal disease - Both acute and chronic kidney disease impair uric acid excretion. 4, 5
• Hypothyroidism - Associated with elevated uric acid levels. 5
• Psoriasis - Increased cell turnover contributes to hyperuricemia. 4

Dietary and Lifestyle Factors

• Excessive alcohol consumption - Particularly beer and spirits, which increase uric acid production and decrease excretion. 7, 3
• High purine diet - Red meat and seafood consumption elevates uric acid levels. 7
• Fructose-rich foods and beverages - Sugar-sweetened drinks increase uric acid production. 7
• Starvation or rapid weight loss - Low-calorie diets can precipitate hyperuricemia through increased ketone production that competes with uric acid for renal excretion. 4, 3
• Obesity - Visceral fat accumulation due to overnutrition is a major risk factor. 7, 5, 8

Special Clinical Scenarios

Early-Onset Hyperuricemia

For patients with gout onset before age 25 or history of urolithiasis, the ACR specifically recommends screening for uric acid overproduction through 24-hour urine uric acid evaluation. 1 This identifies:

• Genetic enzyme deficiencies requiring specialized management. 1
• Familial forms like ADTKD-UMOD, where hyperuricemia and gout often affect multiple family members. 1

Renal Dialysis

Patients undergoing renal dialysis commonly develop hyperuricemia due to impaired clearance. 4

Environmental Exposures

Pesticide exposure has been identified as a risk factor for hyperuricemia. 5

Clinical Pitfall

The ACR recommends referral to a specialist when the etiology of hyperuricemia remains unclear despite initial evaluation, as this may indicate rare genetic disorders or complex pathophysiology requiring specialized investigation. 1