What causes hyperuricemia (high uric acid levels)?

What Causes High Uric Acid (Hyperuricemia)

Hyperuricemia results from either decreased renal excretion (most common, ~90% of cases) or increased production of uric acid, with the dominant mechanism being impaired kidney clearance below 6 mL/min. 1, 2

Primary Mechanisms

Decreased Renal Excretion (Most Common)

• Underexcretion is the dominant cause of hyperuricemia, occurring when renal uric acid clearance falls below 6 mL/min 1, 2
• Normal kidneys clear approximately 500 mg of uric acid daily; when this mechanism fails, serum levels rise 1
• Uric acid has poor solubility at the distal tubular pH of approximately 5, facilitating crystal formation when concentrations exceed the saturation point of 6.8 mg/dL 3, 1
• Impaired renal excretion may be primary (idiopathic) or secondary to identifiable disorders 2

Increased Production (Less Common)

• Overproduction is defined as 24-hour urinary uric acid excretion >1000 mg/day on a regular diet 1
• Occurs when purine nucleic acids are catabolized to hypoxanthine, then xanthine, and finally to uric acid by xanthine oxidase, overwhelming normal renal clearance capacity 1
• Genetic enzyme deficiencies (such as hypoxanthine-guanine phosphoribosyltransferase deficiency) cause accelerated uric acid generation 4

Secondary Causes and Risk Factors

Medications That Elevate Uric Acid

• Thiazide and loop diuretics are prime examples of drugs that elevate serum urate levels 1
• Niacin significantly raises uric acid 1
• Calcineurin inhibitors increase uric acid 1
• Low-dose aspirin modestly elevates serum urate 1

Metabolic and Lifestyle Factors

• Obesity and metabolic syndrome are key contributors, with hyperuricemia occurring in approximately 25% of hypertensive patients and metabolic syndrome present in 40% 1
• High-fructose foods and purine-rich diets increase uric acid production 1
• Excessive alcohol consumption, particularly beer, elevates uric acid through multiple mechanisms 1, 5

Medical Conditions

• Chronic kidney disease creates a bidirectional relationship—both causing and resulting from hyperuricemia 1
• Hypertension is commonly associated with hyperuricemia (25% prevalence) 1
• Hypothyroidism contributes to elevated uric acid 5
• Tumor lysis syndrome from chemotherapy causes massive uric acid release due to rapid cell lysis, particularly in hematologic malignancies like Burkitt's lymphoma, acute lymphoblastic leukemia, and acute myeloid leukemia 6, 1

Specific Clinical Scenarios

• Starvation or reducing diets cause hyperuricemia 7
• Renal dialysis is associated with elevated uric acid 7
• Neoplastic disease treatment where rapid tissue mass resolution occurs 7
• Familial juvenile hyperuricemic nephropathy due to uromodulin gene abnormality 4, 8

Classification System

Hyperuricemia (serum urate level >7 mg/dL) is classified into three types: 4

1. Overproduction type: Excessive purine-rich diet consumption, enzyme deficiencies, cytolysis from chemotherapy
2. Underexcretion type: Familial juvenile hyperuricemic nephropathy, abrupt weight loss from low-calorie diets
3. Mixed type: Glucose-6-phosphatase deficiency, excessive alcohol consumption

When to Evaluate for Overproduction

The American College of Rheumatology recommends screening for uric acid overproduction in specific scenarios: 1

• Gout onset before age 25
• History of urolithiasis (kidney stones)
• Family history of early-onset gout or kidney disease

Important Clinical Pitfalls

• Serum uric acid behaves as a negative acute phase reactant, temporarily decreasing during acute inflammation and stress 3, 1, 9
• Approximately 10% of patients with crystal-proven gout have normal serum uric acid levels during acute attacks due to increased renal excretion 1
• Asymptomatic hyperuricemia alone is not an indication for treatment with urate-lowering therapy 7
• The theoretical saturation point for monosodium urate crystal formation is approximately 6.8 mg/dL, above which precipitation may begin 3