A 52-year-old man with a 10-year history of peptic ulcer disease presents with persistent epigastric pain and diarrhea despite proton pump inhibitor therapy. Serum gastrin level is elevated at 850 pg/mL (normal <100). Which investigation is most appropriate to confirm Zollinger–Ellison syndrome?

## Diagnosis of Zollinger–Ellison Syndrome **Key Point:** The secretin stimulation test is the gold-standard confirmatory investigation for Zollinger–Ellison syndrome (ZES). In ZES, secretin paradoxically causes a rise in serum gastrin (>200 pg/mL above baseline), whereas in other causes of hypergastrinemia (e.g., pernicious anemia, atrophic gastritis), gastrin levels fall or remain unchanged. ### Pathophysiology of the Secretin Response In normal physiology, secretin inhibits gastrin release. However, gastrin-secreting tumors (gastrinomas) are autonomous and do not respond to normal feedback inhibition. Secretin may even stimulate these tumors directly, causing paradoxical elevation of serum gastrin. ### Diagnostic Algorithm for Elevated Fasting Gastrin | Finding | Interpretation | Next Step | |---------|-----------------|----------| | Fasting gastrin <100 pg/mL | Normal | No further testing | | Fasting gastrin 100–1000 pg/mL | Equivocal | Secretin stimulation test | | Fasting gastrin >1000 pg/mL | Highly suggestive of ZES | Secretin test + imaging | | Secretin test: ↑ gastrin >200 pg/mL | Confirms ZES | Localize tumor (CT/MRI/EUS) | | Secretin test: ↓ or ↔ gastrin | Rules out ZES | Consider other causes | **High-Yield:** The secretin stimulation test has ~90% sensitivity and ~100% specificity for ZES. It is the single most reliable confirmatory test when fasting gastrin is borderline or mildly elevated (100–1000 pg/mL). ### Why This Patient Needs Secretin Testing Although this patient's fasting gastrin (850 pg/mL) is elevated, it is not diagnostic by itself. Elevated gastrin can occur in: - Zollinger–Ellison syndrome (autonomous gastrin secretion) - Pernicious anemia (loss of acid feedback) - Atrophic gastritis (G-cell hyperplasia) - Chronic renal failure (impaired gastrin clearance) - Post-gastrectomy states Secretin stimulation definitively separates ZES from these mimics. **Clinical Pearl:** In ZES, gastric pH is typically <2 (high acid output), whereas in achlorhydria-related hypergastrinemia (pernicious anemia), pH is >4. This distinction helps guide the secretin test interpretation. [cite:Harrison 21e Ch 297]