A 55-year-old man with a 10-year history of gout is admitted with acute flank pain and hematuria. Imaging reveals multiple radiopaque stones in both kidneys. His serum uric acid is 9.5 mg/dL, and 24-hour urine uric acid is 1200 mg/day (normal <800 mg/day). He has never received urate-lowering therapy. On further questioning, he reports a family history of gout in his father and two brothers. Which of the following is the most likely diagnosis?

Explanation

## Diagnosis of Uric Acid Overproduction Gout with Nephrolithiasis **Key Point:** The combination of recurrent gout, elevated serum uric acid, *elevated 24-hour urinary uric acid* (>800 mg/day), uric acid kidney stones, and positive family history indicates **primary gout with uric acid overproduction**. ### Differential Diagnosis of Hyperuricemia | Feature | Overproduction Gout | Underexcretion Gout | Secondary Gout | Tumor Lysis | |---------|-------------------|-------------------|-----------------|-------------| | **24-h urine uric acid** | >800 mg/day | <800 mg/day | Variable | Markedly ↑ | | **Serum uric acid** | ↑↑ | ↑ | ↑ | ↑↑↑ (acute) | | **Kidney stones** | Uric acid (radiopaque if monosodium urate) | Rare | Rare | Possible | | **Family history** | Often positive (genetic) | Less common | Absent | No | | **Acute presentation** | Gout attacks over years | Gout attacks | Acute (post-chemo) | Acute (post-chemo) | | **Enzyme defect** | PRPP synthetase ↑ or HGPRT ↓ | Renal transporter | Underlying disease | N/A | **High-Yield:** The **24-hour urine uric acid of 1200 mg/day** is the diagnostic discriminator. This is markedly elevated and indicates **uric acid overproduction**, not underexcretion. Most patients with gout (90%) have underexcretion; only 10% overproduce uric acid. ### Mechanism of PRPP Synthetase Superactivity ```mermaid flowchart TD A[PRPP synthetase superactivity]:::action --> B[↑ PRPP availability] B --> C[↑ De novo purine synthesis] C --> D[↑ Hypoxanthine & Guanine production] D --> E[↑ Xanthine oxidase substrate] E --> F[↑ Uric acid production]:::urgent F --> G[Hyperuricemia] G --> H[Gout attacks + Uric acid stones]:::outcome I[Positive family history]:::outcome --> J{Genetic inheritance?}:::decision J -->|X-linked or Autosomal dominant| K[PRPP synthetase gene mutation]:::outcome ``` **Clinical Pearl:** PRPP synthetase superactivity is an **X-linked or autosomal dominant** inherited condition. The family history (father and two brothers affected) strongly suggests genetic transmission. This is the most common genetic cause of primary gout with overproduction. **Mnemonic:** **PRPP-OG** = PRPP synthetase Overactivity → Gout - **P**urine synthesis ↑ - **R**ecurrent gout attacks - **P**ositive family history - **P**rimary (not secondary) disease - **O**verproduction (high 24-h urine uric acid) - **G**enetic (inherited) ### Why This Is Not Secondary Gout **Warning:** Secondary gout (from CKD, malignancy, or tumor lysis) typically presents acutely or with a clear precipitant. This patient has a 10-year history of gout with family history—classic for primary gout. CKD would cause *underexcretion*, not overproduction.