What are the causes of hypouricemia in adults?

Causes of Hypouricemia in Adults

Hypouricemia in adults results from either uric acid underproduction (hereditary xanthinuria, severe liver disease) or renal overexcretion (hereditary renal hypouricemia, drug-induced, Fanconi syndrome), with hereditary renal hypouricemia being the most common cause of persistent asymptomatic hypouricemia, particularly in Asian populations. 1, 2

Definition and Classification

Hypouricemia is defined as serum uric acid levels below 2.0 mg/dL (119 μmol/L). 1, 2, 3 The condition is classified into two major categories based on mechanism:

Underproduction Type (Decreased Uric Acid Formation)

Hereditary xanthinuria is the primary genetic cause of uric acid underproduction. 1, 4

• Mechanism: Autosomal recessive mutations in xanthine oxidase lead to minimal uric acid production with accumulation of xanthine. 1
• Clinical features: Patients present with very low serum urate levels (often 0 mg/dL), xanthine stones, hematuria, and potential chronic kidney failure. 1, 4
• Key diagnostic clue: Serum uric acid of 0 mg/dL strongly suggests underproduction type hypouricemia. 4

Severe hepatocellular disease impairs purine metabolism and uric acid synthesis. 3

Alkaptonuria is a rare metabolic disorder that can present with hypouricemia. 4

Overexcretion Type (Increased Renal Uric Acid Loss)

Hereditary renal hypouricemia (RHUC) is the most common cause of persistent asymptomatic hypouricemia, particularly in Japan where over 100 cases have been identified. 1, 2

• Type 1 RHUC: Caused by defects in the SLC22A12 gene encoding human urate transporter 1 (hURAT1). 1, 2
• Type 2 RHUC: Caused by defects in the SLC2A9 gene encoding GLUT9 transporter. 1, 2
• Diagnostic markers: Hypouricemia (<119 μmol/L) plus fractional excretion of uric acid >10%. 1
• Critical complications: Exercise-induced acute kidney injury and nephrolithiasis. 1, 5, 2

Drug-induced hypouricemia is an important iatrogenic cause. 3

• Urate-lowering therapies: Overtreatment with xanthine oxidase inhibitors (allopurinol, febuxostat), uricosuric agents (probenecid), and uricases (rasburicase). 6, 3
• Other medications: Various drugs not primarily used for gout treatment can decrease uric acid levels through effects on renal tubular transport. 3
• Specific concern with rasburicase: This recombinant urate oxidase can cause profound hypouricemia and is contraindicated in G6PD-deficient patients due to risk of hemolytic anemia and methemoglobinemia. 6

Fanconi syndrome and other tubulopathies cause generalized proximal tubular dysfunction with uric acid wasting. 4

• Nephropathic cystinosis is a specific cause identified in pediatric series that extends into adulthood. 4
• Distal renal tubular acidosis can present with hypouricemia and metabolic acidosis. 4

Neoplastic conditions may cause secondary hypouricemia through various mechanisms. 3

Diagnostic Approach Algorithm

Step 1: Confirm persistent hypouricemia with serum uric acid <2.0 mg/dL on at least 3 separate occasions. 4

Step 2: Calculate fractional excretion of uric acid (FEUA):

• FEUA >10% indicates renal overexcretion type. 1
• FEUA <10% suggests underproduction type. 1

Step 3: For underproduction type:

• Check for serum uric acid of 0 mg/dL (strongly suggests xanthinuria). 4
• Obtain urine xanthine and hypoxanthine levels. 1
• Assess liver function tests for hepatocellular disease. 3
• Consider genetic testing for xanthine dehydrogenase deficiency. 1, 4

Step 4: For overexcretion type:

• Review medication list for urate-lowering drugs or other causative agents. 3
• Screen for tubulopathy with urinalysis, urine glucose, phosphate, amino acids. 4
• Obtain genetic testing for SLC22A12 and SLC2A9 mutations if hereditary RHUC suspected. 1, 5, 2
• Evaluate for systemic diseases causing tubular dysfunction. 4

Critical Clinical Pitfalls

Exercise-induced acute kidney injury in RHUC is a life-threatening complication that clinicians must recognize. 1, 5, 2

• Patients with RHUC who develop acute kidney injury after exercise present with nonspecific clinical and histological features. 5
• A "wait-and-see" approach with supportive therapy is recommended rather than invasive procedures like renal biopsy, as outcomes are generally excellent. 5
• Genetic confirmation should follow clinical stabilization. 5

Diagnostic delay is common in patients with isolated hypouricemia compared to those presenting with metabolic acidosis or other symptoms. 4

Hypouricemia in 22q11.2 deletion syndrome context should not be confused with hypocalcemia, which is the predominant metabolic abnormality in this population requiring monitoring. 6

Iatrogenic hypouricemia from rasburicase requires special blood handling: samples must be placed immediately on ice to prevent continued ex vivo enzymatic degradation of uric acid, which can falsely lower measured levels. 6