What is the diagnostic work‑up and treatment for a patient with refractory peptic ulcer disease, multiple or recurrent gastric/duodenal ulcers, or ulcer‑related symptoms (abdominal pain, nausea, vomiting, watery diarrhea) suggestive of Zollinger‑Ellison syndrome?

Zollinger-Ellison Syndrome: Diagnostic Work-Up and Treatment

For patients with refractory peptic ulcer disease or multiple/recurrent ulcers, initiate diagnostic work-up with fasting serum gastrin level measurement after stopping proton pump inhibitors for 1-2 weeks, and if ZES is confirmed, start high-dose PPI therapy (omeprazole 60 mg/day or equivalent) while pursuing tumor localization with Gallium-68 PET imaging. 1, 2, 3

Initial Clinical Suspicion

Suspect ZES in patients presenting with:

• Severe peptic ulceration refractory to standard therapy 1, 2
• Chronic diarrhea (occurs in approximately 50% at diagnosis) 1, 2
• Epigastric pain lasting years despite acid-suppressive therapy (reported in 70% at diagnosis) 1, 2
• Gastroesophageal reflux disease refractory to standard therapy 1, 2
• Multiple or atypically located ulcers (e.g., jejunal ulcers) 4, 5
• Weight loss 1, 2

Critical pitfall: The average time between symptom onset and diagnosis exceeds 5 years because symptoms overlap with common gastrointestinal disorders. 6, 3

Diagnostic Algorithm

Step 1: Rule Out Common Causes of Hypergastrinemia

Before pursuing ZES diagnosis, exclude: 1, 3

• Renal failure (common cause of hypergastrinemia) 1
• Atrophic gastritis 7, 3
• H. pylori-associated pangastritis 3
• Gastric outlet obstruction 3
• Vagotomy or retained antrum syndrome 3

Step 2: Biochemical Confirmation

Medication withdrawal protocol: 1, 3

• Stop PPIs for 1-2 weeks (10-14 days minimum)
• Stop H2 antagonists for 48 hours
• Warning: In suspected gastrinoma patients, PPI withdrawal must be supervised as it is dangerous to stop without medical oversight 7

Diagnostic criteria: 1, 2, 3

• Fasting serum gastrin >1000 pg/mL combined with gastric pH <2 is diagnostic
• Gastrin >100 pg/mL warrants further investigation (sensitivity 99%) 3
• Measure basal acid output: >15 mEq/h in intact stomach or >5 mEq/h in gastrectomized patients 8

Secretin stimulation test: 4, 3

• Administer 4 μg/kg secretin IV over 1 minute
• Measure gastrin levels at specific intervals post-infusion
• This is the best test to distinguish ZES from other hypergastrinemic conditions 4
• Secretin stimulates gastrinoma cells to secrete gastrin while inhibiting normal G cells 3

Additional biochemical testing: 1

• Serum chromogranin A (CgA) after stopping PPIs for at least 14 days (to avoid false positives) 1
• Serum calcium and parathyroid hormone to screen for MEN-1 in all gastrinoma patients 1
• Fasting calcium, parathyroid hormone, and prolactin measurements 7

Step 3: Endoscopic Evaluation

Perform esophagogastroduodenoscopy (EGD) to: 1

• Assess for peptic ulcer disease and esophagitis
• Evaluate gastric and duodenal mucosa
• Obtain gastric biopsy to exclude atrophic gastritis 7

Important caveat: Gastrinomas are subepithelial neuroendocrine tumors arising from deeper layers, making standard mucosal biopsies non-diagnostic. 1

Step 4: Tumor Localization

Primary imaging modality: 1, 2, 3

• Gallium-68 radiotracers (especially DOTATOC) with PET is currently the standard for tumor localization, offering high sensitivity and specificity

Additional imaging studies: 1, 4, 3

• Multiphase CT and MRI scans for pancreatic disease detection and staging 1
• Endoscopic ultrasound (EUS) with sensitivity up to 83% for pancreatic gastrinomas (substantially lower for duodenal lesions) 1, 2, 3
• Somatostatin receptor scintigraphy for initial evaluation 1

Anatomic considerations: 3

• The majority of gastrinomas are located in the duodenum (not pancreas) 7, 1
• Most arise within the "gastrinoma triangle" involving parts of the duodenum, pancreas, and extra-hepatic biliary system 1, 3

Critical point: 50% of gastrinomas are not evident on preoperative imaging studies, but with increased awareness of duodenal tumors, gastrinoma can be found in 80-90% of patients at surgery. 4

Treatment Strategy

Medical Management: Acid Suppression

Initial therapy: 1, 8

• High-dose PPIs are the treatment of choice
• Start with omeprazole 60-80 mg/day (or up to 100 mg/day) 1, 8
• Alternative: pantoprazole 40-160 mg/day 8
• Once effective control established, doses can be greatly reduced in long-term treatment 8

Alternative considerations: 7

• P-CABs (potassium-competitive acid blockers) may be useful in very high-dose PPI scenarios to reduce ulcers and ulcer complications, though supporting evidence is presently scant 7

Intravenous PPIs: 8

• Administer when patients cannot take oral therapy, particularly in acute conditions

Surgical Management

For sporadic localized gastrinomas: 1, 4, 5

• All patients with sporadic gastrinoma without unresectable metastatic disease should undergo exploratory laparotomy for potential curative resection
• Surgery should be performed irrespective of imaging results 3
• Complete resection results in 10-year survival of 90% (less likely if large primary) 7

For MEN-1 associated ZES: 1, 4, 5

• Work-up and treatment of hyperparathyroidism is required first 3
• Surgery remains controversial but may be an option for selected cases 4, 3
• All patients should be considered candidates for MEN-1 syndrome screening 7, 1

For metastatic disease: 7, 4

• Metastases develop in 60% of patients, with likelihood correlated to primary tumor size 7, 2
• Surgery may be the most effective treatment if most or all tumor can be resected (debulking may improve symptoms and survival) 8, 4

Advanced/Metastatic Disease Management

Somatostatin analogs: 7, 1, 8

• Lanreotide autogel 60-120 mg/month or octreotide LAR 10-30 mg/month as primary antiproliferative therapy 1
• Useful for reducing gastric acid hypersecretion, serum gastrin, and gastric ECL cells 8

Liver-directed therapies: 1

• Radiofrequency ablation, UAE, TACE, and SIRT for hepatic metastases

Peptide receptor radionuclide therapy (PRRT): 1

• Lutetium-177 DOTATATE may be considered for progressive disease
• Careful observation required for acute aggravation of symptoms during or after PRRT 1

Chemotherapy: 7, 1, 8

• Indicated only for malignant progressive disease 8
• Everolimus can be used off-label for uncontrolled symptoms in refractory cases with progressive disease 1

Liver transplantation: 1

• May be considered in early therapy failure in young adults with high tumor burden, stable liver-only disease

Multidisciplinary approach: 1

• Required for advanced disease including both surgical and non-surgical therapies

Key Clinical Pitfalls to Avoid

1. Do not measure gastrin levels while patient is on PPIs – this causes false elevations and diagnostic confusion 1, 3

2. Do not rely on mucosal biopsies alone – gastrinomas are subepithelial and require deeper tissue sampling 1

3. Do not assume negative imaging excludes gastrinoma – 50% are not visible preoperatively, but can be found at surgery 4

4. Do not forget MEN-1 screening – all gastrinoma patients require evaluation for associated endocrinopathies 7, 1

5. Do not stop PPIs abruptly in suspected cases – withdrawal must be medically supervised due to risk of severe complications 7