Zollinger-Ellison Syndrome (ZES)

I. Definition, Historical Perspective & Epidemiology

Zollinger–Ellison Syndrome (ZES) is a rare disorder characterized by gastrin-secreting tumors (“gastrinomas”) of the pancreas or duodenum. These tumors lead to excessive gastric acid secretion, resulting in recurrent, treatment-resistant peptic ulcers, severe gastroesophageal reflux, and diarrhea.​

• ZES accounts for <1% of peptic ulcer disease cases.
• May occur sporadically or as part of Multiple Endocrine Neoplasia type 1 (MEN1).​
• Peak incidence: 30–60 years; men and women equally affected.

II. Pathophysiology

1. Gastrinoma Biology

• Gastrinomas are neuroendocrine tumors (NETs), most commonly in the “gastrinoma triangle” (pancreatic head, duodenum, and peripancreatic soft tissue), and less often in lymph nodes or elsewhere.​
• Malignancy: Up to 60% are malignant, capable of regional and hepatic metastasis.​

2. Mechanism—Gastrin Overproduction

• Unregulated gastrin secretion (often >10x normal baseline) causes gastric parietal cell hyperplasia and massive gastric acid hypersecretion.​
• Gastric pH is often <2, even after fasting.

3. Resultant Clinical Effects

• Recurrent, multiple, and atypical peptic ulcers: Especially duodenal ulcers distal to the bulb, or ulcers refractory to standard anti-ulcer therapy.​
• Diarrhea, steatorrhea: Acid inactivates pancreatic enzymes (impairing fat digestion) and damages mucosa, leading to nutrient malabsorption.​
• Chronic acid exposure → esophagitis, stricture, Barrett’s esophagus.

III. Clinical Features

• Severe, recurrent peptic ulcer disease (often multiple, post-bulbar)
• Gastroesophageal reflux symptoms
• Diarrhea and steatorrhea (in up to 50–75% cases; may be the only presenting sign)
• Weight loss and malnutrition with advanced disease​
• MEN1 features (pituitary, parathyroid, pancreatic tumors) in about 25% of cases

IV. Diagnosis

1. Clinical Suspicion

• Ulcers refractory to standard treatment
• Multiple or atypically located ulcers (distal duodenum, jejunum)
• Unexplained recurrent ulcers with diarrhea

2. Key Diagnostic Tests

• Fasting serum gastrin level (>10x upper limit of normal, often >1000 pg/mL): Most reliable initial test.​
  • Caution: Discontinue proton pump inhibitors (PPIs) for 1–2 weeks prior if possible (can elevate gastrin).
• Gastric pH measurement (<2): Demonstrates intact or increased acid secretion, supports diagnosis.​
• Secretin stimulation test: Secretin paradoxically increases gastrin in ZES but not in other causes of hypergastrinemia.​
• Imaging: Somatostatin receptor scintigraphy (Octreoscan), endoscopic ultrasound, CT/MRI to localize gastrinoma.​
• MEN1 evaluation: Check serum calcium, parathyroid hormone, and pituitary hormones.​

V. Differential Diagnosis

• Peptic ulcer disease due to H. pylori, NSAIDs
• Gastric outlet obstruction
• Hypercalcemia/hyperparathyroidism
• Other causes of hypergastrinemia: chronic atrophic gastritis, retained antrum, vagotomy ()​

VI. Management

A. Acid Suppression—Mainstay of Therapy

Proton Pump Inhibitors (PPIs):

• Omeprazole, pantoprazole, esomeprazole, lansoprazole​
• PPIs are the drug of choice, suppressing acid secretion by irreversibly blocking the H⁺/K⁺-ATPase in parietal cells.​
• Dosing: Often requires much higher than conventional doses (e.g., omeprazole 60–120mg/day in divided doses) to maintain gastric pH >3.​
• H2-receptor antagonists: Less effective; may require massive and inconvenient dosing.

B. Surgical and Curative Therapy

• Surgical resection of localized tumor (if feasible and no metastases).
• MEN1 patients: Surgery usually reserved for aggressive or symptomatic tumors, as multiple/microscopic tumors are the norm.​
• Liver-directed therapy: Resection, radiofrequency ablation, embolization for metastatic disease.​
• Somatostatin analogs (octreotide, lanreotide): Used for symptomatic or metastatic gastrinomas when surgery is not feasible.​
• Chemotherapy or targeted therapy: For progressive, metastatic disease; e.g., streptozocin, 5-FU, everolimus.​

C. Management of Diarrhea and Nutritional Support

• Correct fluid/electrolyte imbalance
• Pancreatic supplements if steatorrhea
• Parenteral nutrition if severe malabsorption.​

VII. Prognosis

• Survival: Dramatically improved with effective gastric acid suppression (PPIs).
• Prognostic factors: Presence of liver metastases (major determinant), MEN1 association, tumor grade.​
• Lifelong surveillance is necessary, as recurrence/metastasis can occur after long remission periods.

VIII. Pharmacological Notes (For Examinations)

• PPIs are first-line due to powerful, irreversible inhibition of gastric acid secretion.​
• Octreotide: Long-acting somatostatin analog, inhibits gastrin release.​
• Avoid abrupt withdrawal of acid suppression: Risk of severe ulcer flare or GI bleeding.
• Cholecystokinin-B/gastrin receptor antagonists: Experimental, not standard therapy.

IX. Key Learning Points

• Zollinger–Ellison Syndrome is a gastrin-secreting tumor syndrome—think of it with refractory, multiple, or post-bulbar ulcers, especially with diarrhea.
• Serum gastrin >1000 pg/mL with low gastric pH is virtually diagnostic.
• Management is primarily with high-dose PPIs; surgery for localized disease, and somatostatin analogs for unresectable or metastatic settings.
• MEN1 association is crucial—always screen for other endocrine neoplasms.

X. Table: Comparison—Peptic Ulcer Disease vs. ZES

XI. References

1. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. (2018). Chapter: Gastrointestinal Pharmacology; Hypersecretory States.
2. Katzung BG, Trevor AJ. Basic & Clinical Pharmacology. 15th ed. (2023). Chapter: Drugs Used in Acid-Peptic Disorders.
3. Harrison’s Principles of Internal Medicine. 20th ed. (2022). Chapter: Peptic Ulcer Disease and Related Disorders.
4. Ritter JM, Flower R, Henderson G, et al. Rang & Dale’s Pharmacology. 10th ed. (2023). “Drugs for gastrointestinal disorders.”