Zollinger-Ellison syndrome

Syndrome caused by a gastrin-secreting tumor (gastrinoma) leading to excessive gastric acid hypersecretion and multiple refractory peptic ulcers.

• Causes hard-to-treat ulcers and chronic diarrhea; often appears on exams as a classic cause of refractory peptic ulcer disease, sometimes as part of MEN1.

• Severe, recurrent peptic ulcers (often multiple and in atypical locations like distal duodenum or jejunum) plus chronic diarrhea (acid inactivates pancreatic enzymes, causing malabsorption).
• Ulcers that fail to heal with standard therapy (high-dose PPI) or without H. pylori/NSAIDs history → raises suspicion for ZES.
• In 20–25% cases, part of MEN1 (patients may also show kidney stones from hyperparathyroidism or pituitary tumor signs).

1. Measure fasting gastrin level off acid suppression (gastrin >1000 pg/mL with gastric pH <2 is essentially diagnostic of ZES). If gastrin is moderately elevated (e.g. 200–1000), proceed with confirmatory testing.
2. Perform a secretin stimulation test for equivocal cases: in ZES, secretin paradoxically causes a large gastrin rise (≥120 pg/mL above baseline is a positive test).
3. Check gastric acid levels: gastric pH ≤2 (with high gastrin) supports ZES vs other causes of high gastrin like atrophic gastritis (which causes low acid/high pH).
4. Localize the gastrinoma with imaging: somatostatin receptor PET/CT (Ga-68 dotatate) is highly sensitive; also consider endoscopic ultrasound (EUS) for duodenal/pancreatic tumors.
5. Screen for MEN1 in confirmed ZES: check for hyperparathyroidism (calcium, PTH levels) and pituitary tumors (prolactin, etc).

1. High-dose PPIs are first-line to control acid hypersecretion and heal ulcers (e.g. omeprazole ~60 mg/day, much higher than standard GERD doses).
2. Surgical tumor resection if feasible: can be curative for localized gastrinomas (especially sporadic tumors >2 cm); MEN1 cases often have multiple small tumors (surgery targeted if large lesions).
3. For metastatic or unresectable ZES: use somatostatin analogs (octreotide) to reduce gastrin and slow tumor, and consider targeted therapies (e.g. everolimus, PRRT with radiolabeled octreotide) in advanced disease.

• Secretin test paradox: secretin normally inhibits gastrin, but in ZES it causes an ↑ gastrin surge (diagnostic clue).
• MEN1 – 3 P's (Pituitary, Parathyroid, Pancreas): gastrinomas (pancreatic/duodenal tumors) are one of the trio of tumors in MEN1.
• Peptic ulcers in unusual locations (e.g. post-bulbar duodenum or jejunum) or multiple ulcers → suspect ZES instead of ordinary PUD.

• Ulcers in atypical locations (distal duodenum/jejunum) or multiple ulcers that don't respond to therapy → red flag for ZES (do not just treat as routine PUD).
• Stopping PPIs for diagnostic testing can cause acid rebound – monitor closely for ulcer bleeding or perforation during workup.
• Diagnosed ZES patients should be evaluated for MEN1 signs (hypercalcemia, pituitary issues) – missing MEN1 means missing other tumors.

1. Refractory or multiple ulcers ± diarrhea → suspect ZES.
2. Hold acid-suppressing meds if possible and obtain fasting gastrin level (plus gastric pH).
3. If gastrin is modestly elevated → perform secretin stimulation test (positive = big gastrin rise).
4. If ZES confirmed biochemically → localize tumor with imaging (Ga-68 dotatate PET, EUS, CT/MRI).
5. Manage with high-dose PPI for acid control, resect tumor if localized (and screen for MEN1).

• Middle-aged patient with multiple ulcers and chronic diarrhea, very high gastrin level → Zollinger-Ellison syndrome (gastrinoma).
• Young adult with refractory ulcers plus kidney stones (hypercalcemia) → MEN1 syndrome (gastrinoma with hyperparathyroidism).
• Secretin injection leads to a marked rise in gastrin levels → positive secretin stimulation test (confirms ZES).