## Diagnosis: Zollinger-Ellison Syndrome (ZES) **Key Point:** The clinical triad of severe peptic ulcer disease, elevated fasting gastrin (>1000 pg/mL or 10-fold elevation above normal), and gastric pH <2 is highly suggestive of ZES. However, elevated gastrin alone is not diagnostic—it can occur with PPI use, atrophic gastritis, and achlorhydria. **High-Yield:** The **secretin stimulation test** is the gold standard confirmatory test for ZES. In ZES, secretin paradoxically causes an increase in serum gastrin by ≥200 pg/mL above baseline (or ≥110% increase). In other causes of hypergastrinemia (e.g., G-cell hyperplasia, retained antrum), gastrin decreases or remains unchanged. ### Why Secretin Stimulation Test? 1. **Mechanism:** Secretin normally inhibits gastrin release in healthy individuals. In gastrinoma (ZES), the tumor cells are autonomous and respond paradoxically with increased gastrin secretion. 2. **Sensitivity & Specificity:** >90% sensitivity and >90% specificity for ZES diagnosis. 3. **Clinical Pearl:** This is the single most specific test to differentiate ZES from other causes of hypergastrinemia. ### Investigation Algorithm for Suspected ZES ```mermaid flowchart TD A[Severe/Refractory PUD + Elevated Gastrin]:::outcome --> B{Fasting Gastrin >1000 pg/mL?}:::decision B -->|Yes| C[Likely ZES]:::outcome B -->|No| D{Gastrin 100-1000 pg/mL?}:::decision D -->|Yes| E[Repeat gastrin after PPI washout for 1 week]:::action E --> F{Gastrin still elevated?}:::decision F -->|Yes| G[Perform Secretin Stimulation Test]:::action F -->|No| H[Alternative diagnosis]:::outcome G --> I{Gastrin rise ≥200 pg/mL?}:::decision I -->|Yes| J[Confirm ZES]:::outcome I -->|No| K[Rule out ZES]:::outcome ``` **Clinical Pearl:** Always measure gastric pH before secretin stimulation—ZES requires pH <2. If pH >2, the diagnosis is unlikely. [cite:Harrison 21e Ch 297]
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