Hyperuricemia in Glycogen Storage Disease Type I
Hyperuricemia in GSD I results from two primary mechanisms: increased uric acid production due to accelerated ATP degradation triggered by hypoglycemia and elevated glucagon levels, combined with decreased renal clearance of urate. 1, 2
Pathophysiologic Mechanisms
Increased Uric Acid Production
The overproduction of uric acid in GSD I occurs through multiple interconnected pathways:
Hypoglycemia-induced ATP breakdown: When blood glucose falls below 70 mg/dL in GSD I patients, there is rapid activation of ATP degradation to its breakdown products, ultimately generating uric acid 1, 2
Glucagon-mediated purine degradation: The glucagon response to hypoglycemia directly stimulates ATP breakdown, with pharmacologic doses causing a 90% increase in urinary uric acid excretion and a 65% increase in radioactivity from labeled adenine nucleotides 2
Accelerated de novo purine synthesis: Studies using [1-14C]glycine incorporation demonstrate that patients with GSD I have markedly elevated purine synthesis rates (0.68% incorporation) compared to controls with GSD III (0.18% incorporation) 3
Decreased Renal Clearance
Impaired urate excretion: Patients with GSD I demonstrate severely reduced renal urate clearance (1.1-3.1 ml/min) with fractional excretion as low as 11.3% 2
Lactate competition: The marked lactic acidosis characteristic of GSD I (blood lactate increases rapidly when glucose drops below 40-50 mg/dL) competes with uric acid for renal tubular secretion, further reducing urate clearance 1
Clinical Significance
This distinguishes GSD I from other glycogen storage diseases, as GSD III, VI, and IX characteristically have normal blood lactate and normal uric acid levels. 1
Key Differentiating Features
- GSD I: Hyperuricemia present with hyperlactatemia 1, 4
- GSD III: Normal uric acid and lactate despite similar hepatomegaly and hypoglycemia 1
- GSD VI and IX: Normal lactate levels, though postprandial elevations can occur 1
Therapeutic Implications
Glucose therapy reduces hyperuricemia: Continuous intravenous glucose infusion for one month improved both serum urate levels and renal urate clearance in GSD I patients, demonstrating the direct role of hypoglycemia in urate metabolism 2
Nocturnal feeding improves urate handling: Addition of nocturnal nasogastric feeding decreased de novo purine synthesis and increased fractional renal uric acid excretion from 11.3% to 26.3% 3
Somatostatin suppresses glucagon-mediated effects: Somatostatin infusion suppressed the hypoglycemia-induced increases in serum urate and urinary oxypurine excretion by reducing plasma glucagon levels from 81.3 to 52.2 pg/ml, despite persistent hypoglycemia 2
Clinical Pitfall
Do not perform glucagon stimulation testing in suspected GSD I patients, as it significantly worsens metabolic acidosis and can cause acute decompensation while providing minimal diagnostic value. 1, 4 When inadvertently performed, glucagon causes a significant increase in blood lactate but little to no increase in blood glucose, confirming the diagnosis but at substantial risk to the patient 1