What causes low uric acid levels?

Causes of Low Uric Acid

Low uric acid (hypouricemia, defined as serum uric acid ≤2.0 mg/dL) results from either increased renal excretion or decreased production, with medications being the most common iatrogenic cause, followed by genetic disorders of uric acid transport and various underlying medical conditions. 1

Medication-Induced Hypouricemia

Drugs are the most important and common cause of hypouricemia in clinical practice. 1

Urate-Lowering Therapies (Overtreatment)

• Xanthine oxidase inhibitors (allopurinol, febuxostat) reduce uric acid production and commonly cause hypouricemia when dosed too aggressively 1
• Uricosuric agents increase renal uric acid excretion 1
• Uricases (rasburicase) directly catabolize uric acid into allantoin, causing rapid and profound hypouricemia 2, 1

Cardiovascular Medications

• ACE inhibitors (captopril, enalapril, ramipril) increase uricosuria by lowering net reabsorption of uric acid in the proximal tubule 3
• Losartan (angiotensin II antagonist) augments uricosuria and decreases serum uric acid 3, 4
• Low-dose aspirin modestly affects uric acid levels, though the effect is variable 2, 4

Other Medications

• Various drugs can interfere with renal tubular handling of uric acid, increasing urinary excretion 4

Genetic Causes

Renal Hypouricemia (RHU)

• Mutations in urate transporters (particularly URAT1) cause impaired tubular reabsorption of uric acid, leading to increased urinary uric acid excretion and low serum levels 5, 6
• This condition is associated with exercise-induced acute kidney injury due to vasoconstriction and intratubular uric acid precipitation 5
• Patients may develop renal stones despite low serum uric acid due to elevated urinary uric acid concentration 5

Inherited Metabolic Defects

• Defects in purine metabolism can reduce uric acid production 1

Medical Conditions Causing Hypouricemia

Hepatic Disease

• Severe hepatocellular disease impairs purine metabolism and uric acid production 1

Malignancy

• Neoplastic conditions can alter uric acid metabolism, though the mechanism varies 1

Renal Tubular Disorders

• Defective renal tubular reabsorption of uric acid from various tubular disorders increases urinary losses 1, 4
• Fanconi syndrome and other proximal tubular defects can cause hypouricemia 6

Physiological Context

Acute Inflammatory States

• Uric acid behaves as a negative acute phase reactant, temporarily decreasing during acute inflammation and stress 2
• Patients with gout may paradoxically have normal or low serum uric acid during acute attacks due to increased renal excretion 2

Volume Status

• Extracellular fluid volume is a major regulator of urate excretion; volume expansion increases uric acid clearance 4

Clinical Significance and Monitoring

Hypouricemia is not benign and requires evaluation for underlying causes. 5

Key Diagnostic Steps

• Calculate fractional excretion of uric acid to distinguish between renal losses (increased excretion) versus decreased production 6
• 24-hour urinary uric acid measurement helps identify the mechanism 4, 6
• Medication review is essential, as drugs are the most common reversible cause 1

Important Complications

• Exercise-induced acute kidney injury in patients with renal hypouricemia due to vasoconstriction and reduced renal blood flow 5
• Nephrolithiasis from elevated urinary uric acid concentration despite low serum levels 5, 4
• Impaired endothelial function as uric acid has antioxidant properties that protect against oxidative stress 5

Management Considerations for Renal Hypouricemia

• Hydration and urinary alkalinization are recommended to prevent stone formation and exercise-induced kidney injury 5
• In some cases, xanthine oxidase inhibitors may be considered to reduce oxidative stress, though this seems counterintuitive 5