How is urate formed and where, and is a uric acid lab test the same as serum urate?

Urate Formation, Location, and Relationship to Uric Acid Lab Tests

Urate is formed in the liver as the end product of purine metabolism in humans, and serum urate and uric acid lab tests are measuring the same substance, with the terms often used interchangeably in clinical practice. 1, 2

Urate Formation Process

• Urate is produced in the liver through the degradation of purines, which come from two main sources: endogenous purine nucleotide turnover (approximately two-thirds) and dietary intake (approximately one-third) 2
• The final step in purine metabolism involves the enzyme xanthine oxidase, which converts hypoxanthine to xanthine and then to uric acid 3
• In most mammals, the enzyme uricase further metabolizes uric acid to allantoin, but humans and higher primates lack functional uricase, resulting in higher serum urate levels 2, 4
• This evolutionary loss of uricase is unique to higher primates and results in serum urate levels that are approximately 10 times higher than in other mammals 2

Urate Physiology and Distribution

• Urate exists primarily as monosodium urate in the extracellular fluid at physiological pH (7.4) 5
• When serum urate levels exceed the saturation point (approximately 6.8 mg/dL or 360 μmol/L), monosodium urate crystals can form and deposit in tissues 5
• These crystal deposits primarily occur in joints, kidneys, and other tissues, forming the pathophysiological basis for gout and other urate-related conditions 5
• Approximately two-thirds of urate is eliminated via the kidneys, with the remainder excreted through the gastrointestinal tract 2, 1

Renal Handling of Urate

• Only 8-12% of filtered urate is excreted in urine, with the majority being reabsorbed in the proximal tubule 1, 2
• Urate transport in the proximal tubule is bidirectional, involving both reabsorption and secretion processes 1
• Key transporters involved in urate reabsorption include:
  • URAT1 (SLC22A12) and OAT4 (SLC22A11) on the apical membrane 1
  • GLUT9 (SLC2A9) on the basolateral membrane 1
• Key transporters involved in urate secretion include:
  • OAT1 (SLC22A6) and OAT3 (SLC22A8) on the basolateral membrane 1
  • ABCG2, NPT1 (SLC17A1), and NPT4 (SLC17A3) on the apical membrane 1

Uric Acid vs. Serum Urate: Terminology Clarification

• Uric acid and serum urate refer to the same substance but in different forms depending on pH 4
• At physiological pH in the blood (7.4), approximately 98% exists as the ionized form (urate), while at acidic urinary pH, the non-ionized form (uric acid) predominates 4
• Laboratory tests measuring "uric acid" and "serum urate" are measuring the same substance, with the terms often used interchangeably in clinical practice 5
• The saturation point for monosodium urate in serum is approximately 6.8 mg/dL (360 μmol/L), above which crystal formation may occur 5

Clinical Significance of Urate Levels

• Hyperuricemia is defined as serum urate greater than 6.8 or 7.0 mg/dL, representing the saturation point for monosodium urate 5
• The therapeutic goal for urate-lowering therapy is to maintain serum urate below 6 mg/dL (360 μmol/L) to promote crystal dissolution and prevent new crystal formation 5
• For patients with severe gout (tophi, chronic arthropathy), a lower target of less than 5 mg/dL (300 μmol/L) is recommended to facilitate faster crystal dissolution 5, 6
• Allopurinol and other xanthine oxidase inhibitors reduce serum urate by inhibiting the formation of uric acid, while uricosuric agents increase urinary excretion 3

Common Pitfalls in Urate Testing and Management

• Failure to recognize that serum urate levels fluctuate, particularly during acute gout attacks when they may be normal or even low 5
• Not adjusting allopurinol dosage in patients with renal impairment, which can increase the risk of severe adverse reactions 5
• Discontinuing urate-lowering therapy after symptom improvement, which leads to recurrence of gout flares in most patients 6
• Not providing prophylaxis against acute attacks when initiating urate-lowering therapy, which can increase the risk of flares during the first months of treatment 6

Understanding the formation, metabolism, and measurement of urate is essential for proper management of gout and other urate-related conditions, with the goal of maintaining serum levels below the saturation point to prevent crystal formation and promote dissolution of existing deposits.