A 38-year-old woman from Mumbai with a 3-month history of epigastric pain and nausea is found to be H. pylori positive. She denies NSAID use and has no alarm features. Upper endoscopy shows a 0.8 cm duodenal ulcer with a clean base (Forrest III). She is started on omeprazole 20 mg daily, amoxicillin 1 g twice daily, and clarithromycin 500 mg twice daily for 14 days. After 4 weeks, she reports persistent epigastric discomfort. Repeat endoscopy shows ulcer healing but a new 1.2 cm gastric ulcer with a clean base. H. pylori serology is negative. What is the most likely diagnosis?

Explanation

## Clinical Red Flags **Key Point:** A patient with successful H. pylori eradication (negative serology) who develops a NEW gastric ulcer while on PPI therapy is highly suspicious for Zollinger–Ellison syndrome (ZES). ### Why This Presentation Is Atypical 1. **Duodenal ulcer healed** — H. pylori eradication was successful (confirmed by negative serology) 2. **NEW gastric ulcer appeared** — despite ongoing PPI therapy and H. pylori clearance 3. **Multiple ulcers in different sites** — suggests underlying acid hypersecretion rather than H. pylori or NSAIDs 4. **Young age, no NSAID history** — low pre-test probability of NSAID ulcer ## Zollinger–Ellison Syndrome (ZES) **High-Yield:** ZES is a gastrin-secreting neuroendocrine tumor (usually in the gastrinoma triangle: junction of cystic and common bile ducts, junction of duodenum and pancreas) causing severe, refractory peptic ulcer disease. ### Diagnostic Criteria for ZES | Finding | ZES | |---------|-----| | **Fasting serum gastrin** | > 1000 pg/mL (highly suggestive); 100–1000 pg/mL (needs further testing) | | **Gastric pH** | < 2 (confirms acid hypersecretion) | | **Secretin stimulation test** | Paradoxical rise in gastrin > 200 pg/mL above baseline (gold standard) | | **Basal acid output (BAO)** | > 15 mEq/hr (or > 20 mEq/hr if prior acid-reducing surgery) | | **Ulcer characteristics** | Multiple, refractory, unusual locations (distal duodenum, jejunum) | **Clinical Pearl:** A patient on PPI therapy with a fasting gastrin level should have the PPI withheld for 1 week before testing (PPIs falsely elevate gastrin). However, if clinical suspicion is high, proceed with secretin stimulation without stopping PPI. ### Next Steps in This Patient 1. **Measure fasting serum gastrin** (on PPI — acceptable if high suspicion) 2. **Confirm gastric pH < 2** (even on PPI, ZES patients often have pH < 2 due to massive acid production) 3. **Secretin stimulation test** — if gastrin 100–1000 pg/mL 4. **Imaging** — CT/MRI abdomen, endoscopic ultrasound (EUS) to localize gastrinoma 5. **Genetic testing** — ~25% of gastrinomas are associated with MEN-1 syndrome **Mnemonic:** **ZES = Zone of Extreme Secretion** — gastrin-secreting tumor causing severe, refractory ulcers in unusual locations. ## Why Other Diagnoses Are Less Likely **Refractory H. pylori infection:** H. pylori serology is negative, confirming eradication. Refractory infection would show persistent H. pylori on repeat serology or stool antigen. **NSAID-induced ulcer:** Patient explicitly denies NSAID use, and NSAID ulcers typically do not develop AFTER successful H. pylori eradication in a patient on PPI therapy. **Idiopathic gastric ulcer (post-eradication):** While benign gastric ulcers can occur post-eradication, the appearance of a NEW ulcer in a different site while on PPI therapy is not typical of simple idiopathic ulcer and warrants investigation for ZES. [cite:Harrison 21e Ch 297; Robbins 10e Ch 17]