What is the diagnostic workup and management approach for Zollinger‑Ellison syndrome?

Zollinger-Ellison Syndrome: Diagnostic Workup and Management

When to Suspect ZES

Suspect Zollinger-Ellison syndrome in patients with severe peptic ulceration refractory to standard therapy, chronic diarrhea (present in ~50% at diagnosis), gastroesophageal reflux disease unresponsive to treatment, or epigastric pain lasting years despite acid suppression (reported in 70% at diagnosis). 1, 2, 3

Key clinical red flags include:

• Multiple or recurrent peptic ulcers in unusual locations (distal duodenum, proximal jejunum) 4
• Weight loss accompanying gastrointestinal symptoms 1, 2
• Symptoms persisting despite appropriate proton pump inhibitor therapy 3

Diagnostic Algorithm

Step 1: Discontinue Proton Pump Inhibitors

Stop PPIs for 1-2 weeks before testing to avoid false elevations of gastrin levels. 1, 3 H2 receptor antagonists should be stopped for 48 hours. 5

Step 2: Initial Biochemical Testing

Measure fasting serum gastrin level after appropriate medication washout. 1, 3

Diagnostic thresholds:

• Gastrin >1000 pg/mL combined with gastric pH <2 is diagnostic for ZES 2
• Gastrin >100 pg/mL warrants further investigation 5
• Sensitivity of fasting gastrin is 99% 5

Critical pitfall: Rule out renal failure first, as it is a common cause of hypergastrinemia that must be excluded before pursuing ZES diagnosis. 1, 3 Other causes of hypergastrinemia with hypochlorhydria include atrophic gastritis, H. pylori-associated pangastritis, gastric outlet obstruction, and vagotomy. 5

Step 3: Confirm Gastric Acid Hypersecretion

Measure gastric pH to confirm it is <2 in the setting of hypergastrinemia. 2, 6

Step 4: Secretin Stimulation Test (if needed)

When fasting gastrin is elevated but <1000 pg/mL, perform secretin stimulation test to differentiate ZES from other hypergastrinemic states. 7, 5 Administer 4 μg/kg secretin intravenously over 1 minute and measure gastrin at specific intervals. 5 Gastrinoma cells will secrete gastrin in response to secretin, while normal G cells are inhibited. 5

Step 5: Additional Biochemical Markers

• Chromogranin A: Measure after stopping PPIs for at least 14 days to avoid false positives 1
• Serum calcium and parathyroid hormone: Screen all gastrinoma patients for Multiple Endocrine Neoplasia Type 1 (MEN-1), as 20-38% of ZES cases are associated with MEN-1 1, 4, 6

Step 6: Endoscopic Evaluation

Perform esophagogastroduodenoscopy (EGD) to assess for peptic ulcer disease and esophagitis. 1 Gastrinomas are subepithelial neuroendocrine tumors arising from deeper layers, making standard mucosal biopsies non-diagnostic. 1

Tumor Localization

Primary Imaging Modality

Gallium-68 radiotracers (68Ga-DOTATOC, 68Ga-DOTANOC, 68Ga-DOTATATE) with positron emission tomography/CT is currently the standard for tumor localization. 1, 2, 8 This represents a significant advancement over traditional 111indium-octreotide scintigraphy. 8

Complementary Imaging

• Endoscopic ultrasound (EUS): Sensitivity up to 83% for pancreatic gastrinomas 1, 2; particularly useful in MEN-1 patients 8
• Multiphase CT and MRI: Important for detecting gastrinomas and assessing pancreatic disease 1
• Somatostatin receptor scintigraphy: Useful for initial evaluation 1

Anatomic consideration: The majority of gastrinomas are located in the duodenum, with the remainder in the pancreas, typically within the "gastrinoma triangle" (involving parts of duodenum, pancreas, and extra-hepatic biliary system). 1, 5

Management Approach

Medical Management of Acid Hypersecretion

High-dose PPIs are the initial treatment of choice, starting with omeprazole 60 mg/day or equivalent. 1 Initial therapy may require omeprazole 80-100 mg daily or pantoprazole 40-160 mg daily, with doses reduced once effective control is established. 6

Surgical Management

For localized sporadic gastrinomas: Surgical resection should be performed regardless of imaging results, as it is the only curative treatment and provides 5-year survival rates of 80-100% in resectable cases. 7, 5

Critical prognostic information: Metastases develop in 60% of gastrinoma patients, with likelihood correlated to primary tumor size. 7, 1, 2 Complete resection results in 10-year survival of 90% when feasible. 7

For MEN-1-associated ZES:

• First address hyperparathyroidism 5
• Surgery may be considered in selected cases 5
• Approach differs from sporadic ZES due to different natural history 4

Advanced/Metastatic Disease

For metastatic or unresectable disease, use a stepwise approach:

1. Somatostatin analogues (lanreotide autogel 60-120 mg/month or octreotide LAR 10-30 mg/month) as primary antiproliferative therapy 1

2. Liver-directed therapies for hepatic metastases: radiofrequency ablation, UAE, TACE, or SIRT 1

3. Peptide receptor radionuclide therapy (PRRT) with lutetium-177 DOTATATE for progressive disease 1

4. Everolimus off-label for uncontrolled symptoms in refractory progressive cases 1

5. Chemotherapeutic agents for progressive malignant disease 7, 1

6. Liver transplantation may be considered in young adults with high tumor burden, stable liver-only disease, and early therapy failure 1

Important caveat: Even with metastatic disease, surgical debulking may improve symptoms and survival. 7 A multidisciplinary approach including both surgical and non-surgical therapies is recommended for advanced disease. 1

Surveillance

Postoperative surveillance involves measurement of gastrin levels, followed by imaging if elevation is detected. 4