What are the causes of low urate levels?

Causes of Low Urate Levels

Low serum urate levels (hypouricemia) are primarily caused by genetic abnormalities in urate transporters or by conditions that lead to overexcretion or underproduction of uric acid.

Definition and Normal Range

Hypouricemia is generally defined as serum urate levels below the normal range. While the normal range varies between populations, urate is typically soluble up to a concentration of about 404 µmol/L (6.8 mg/dL) 1. Most laboratories calculate their own cut-off level for normal urate as the mean plus two standard deviations from their local healthy population, calculated separately for men and women 1.

Primary Causes of Low Urate Levels

Genetic Disorders

1. Defects in Urate Transporters:

   • URAT1/SLC22A12 deficiency: The most common cause of renal hypouricemia, particularly in Japanese populations 2
   • GLUT9/SLC2A9 deficiency: Another transporter involved in urate reabsorption whose deficiency leads to renal hypouricemia 2

2. Enzyme Deficiencies:

   • Xanthine oxidoreductase deficiency: Results in xanthinuria, a rare condition with marked hypouricemia due to inability to convert xanthine to uric acid 2
   • Molybdenum cofactor sulfurase deficiency: Causes combined deficiency of xanthine oxidoreductase and aldehyde oxidase, leading to severe hypouricemia 2

Overexcretion of Uric Acid

1. Renal Conditions:

   • Familial renal hypouricemia: Genetic disorder causing increased renal clearance of uric acid 3
   • Fanconi syndrome: Generalized proximal tubular dysfunction leading to increased uric acid excretion 3

2. Metabolic Conditions:

   • Diabetes mellitus: Can cause increased renal excretion of uric acid 3
   • SIADH (Syndrome of Inappropriate ADH secretion): Volume expansion leads to increased uric acid clearance

Secondary Causes of Low Urate Levels

Medication-Induced

1. Uricosuric Drugs:

   • Probenecid: Blocks renal tubular reabsorption of urate 3
   • Benzbromarone: Enhances urinary excretion of uric acid 3
   • High-dose aspirin: Has uricosuric effects
   • Losartan: Angiotensin receptor blocker with uricosuric properties 4

2. Drugs Affecting Uric Acid Production:

   • Allopurinol: Xanthine oxidase inhibitor that prevents conversion of xanthine to uric acid 1, 3
   • Rasburicase: Recombinant urate oxidase that converts uric acid to allantoin, which is more soluble 1

Physiological States

1. Pregnancy: Increased glomerular filtration rate can lead to increased uric acid clearance

2. Acute Illness:

   • Uric acid can behave as a negative acute phase reactant, being temporarily lowered during episodes of acute inflammation and stress 1
   • Increased renal excretion of uric acid during acute inflammatory episodes 1

Other Conditions

1. Malnutrition: Decreased protein intake leads to decreased purine intake and uric acid production

2. Wilson's disease: Copper toxicity may interfere with uric acid metabolism

3. Neoplastic diseases: Some malignancies can alter uric acid metabolism

Clinical Significance and Complications

While hyperuricemia is more commonly recognized due to its association with gout, hypouricemia can also lead to significant clinical problems:

1. Exercise-induced acute kidney injury: Particularly in patients with renal hypouricemia due to mutations in urate transporters 4

2. Increased risk of urolithiasis: Paradoxically, some forms of hypouricemia can be associated with stone formation 5

3. Xanthine stones: In patients with xanthine oxidase deficiency, xanthine can accumulate and form stones 2

Diagnostic Approach

When evaluating a patient with low urate levels, consider:

1. Medication review: Identify any drugs that may affect uric acid metabolism or excretion

2. Renal function assessment: Measure creatinine clearance, uric acid clearance, and fractional excretion of uric acid 6

3. 24-hour urine collection: To determine if hypouricemia is due to overexcretion (increased uric acid in urine) or underproduction (decreased uric acid in both serum and urine) 6, 3

4. Family history: Especially important for identifying genetic causes of hypouricemia

5. Genetic testing: For suspected hereditary renal hypouricemia or xanthinuria

Management Considerations

Management depends on the underlying cause and presence of complications:

1. Asymptomatic hypouricemia: Often requires no specific treatment

2. Prevention of exercise-induced acute kidney injury: Adequate hydration before exercise in patients with renal hypouricemia

3. Medication adjustment: Consider modifying or discontinuing medications that may be causing hypouricemia if clinically appropriate

4. Treatment of underlying conditions: Address any primary disorders causing the low urate levels

Remember that while hyperuricemia has been extensively studied due to its association with gout and cardiovascular disease, hypouricemia has received less attention but may still have important clinical implications that warrant proper evaluation and management.