Zollinger-Ellison Syndrome - Gastrinoma

Last Literature Review: August 2017 Last Update:

Medical Experts




Laura Smy, PhD, MLT (Canada)
Former Clinical Chemistry Fellow, University of Utah, Department of Pathology, School of Medicine

Zollinger-Ellison syndrome (ZES) is characterized by refractory peptic ulcer disease, diarrhea, and gastric acid hypersecretion as a result of a functional pancreatic or duodenal neuroendocrine tumor (NET). ZES is also referred to as gastrinoma.


Indications for Testing

  • Refractory peptic ulcer disease
  • Multiple peptic ulcers
  • Familial peptic ulcer disease
  • Peptic ulcer disease with diarrhea

Criteria for Diagnosis

  • National Comprehensive Cancer Network (NCCN), 2017
    • Elevated fasting serum gastrin (FSG) >10x upper limit of normal, and
    • Gastric pH <2

Laboratory Testing

  • Gastrin testing – patient should be off antacids and proton pump inhibitors 10 days to 2 weeks (may substitute H2 blockers until 48 hours before testing)
    • FSG
      • >10x upper limit of normal or >1000 pg/mL suggestive of gastrinoma
    • Stimulated gastrin testing (secretin, calcium) – value of provocative tests alone is limited (Oberg, 2017)
      • Secretin stimulation test – especially recommended for indeterminate FSG findings (200-1000 pg/mL)
        • Identify increase in serum gastrin after secretin administration
        • Positive secretin stimulation test (increase in serum gastrin by ≥120 pg/mL) confirms the need to search for presence of gastrinoma
        • ≥90% sensitive and specific
        • Normal cells are inhibited by secretin – gastrinoma cells secrete gastrin in response to secretin
        • Not recommended for patients with acute pancreatitis
        • Avoid external effects on gastrin release – must fast for 12 hours before beginning the study
        • Testing protocol
          • Collect serum gastrin samples – 15 minutes and 1 minute before secretin administration
          • Administer human secretin 0.4 mcg/kg of body weight intravenously over a 1 minute time period
          • Collect serum samples at 1, 2, 5, 10, and 30 minutes postinjection
          • Peak should occur at 10 minutes
      • Calcium stimulation testing – may be helpful for patients with a negative secretin test result
  • Gastric acid analysis (not available at ARUP Laboratories)
    • Evaluate stomach acid pH
    • Evaluate basal acid output (BAO)/secretion (National Cancer Institute [NCI], 2015; Oberg, 2017)
      • ≥10-15 mEq (mmol/L)/hr (or >5 mEq (mmol/L)/hr after acid-reducing surgery
      • Overnight acid output – ≥100 mmol
      • Ratio of BAO to maximum acid output (MAO) – ≥0.6
  • Human chorionic gonadotropin (HCG) levels – may be elevated in gastrinoma patients
  • General tumor markers – suggestive of pancreatic tumor (Oberg, 2017)
    • Chromogranin A – limited in diagnosis; typically indicated for follow-up (see Monitoring)
      • May be clinically informative but not recommended for diagnosis (Oberg, 2017; Strosberg, 2017)
      • Sensitivity – 60-90% in metastatic disease; 50% in early disease
  • Genetic testing


  • Definitive diagnosis requires biopsy and pathologist examination
    • Useful immunohistochemical stains may include chromogranin A, synaptophysin, and Ki-67 (Mib-1)
    • For detailed descriptions, including recommended tests, refer to ARUP’s Immunohistochemistry Stain Offerings

Imaging Studies

  • Computed tomography (CT) scan/endoscopic ultrasound/magnetic resonance imaging (MRI)
    • Identify tumor location and confirm diagnosis
    • Endoscopic ultrasound – 67% sensitivity
  • Somatostatin-receptor scintigraphy – ~85% sensitivity

Differential Diagnosis

  • Gastroesophageal reflux disease
  • MEN1 (Wermer syndrome)
  • Peptic ulcer disease
  • Helicobacter pylori infection
  • Gastric outlet obstruction
  • Pernicious anemia
  • Short bowel syndrome
  • Achlorhydria
  • Pancreatic cancer
  • Malabsorption syndromes
  • Renal failure
  • Use of proton pump inhibitors or antacids


  • Secretin test may be repeated for follow-up after surgery
  • General tumor markers – may be suggested for surveillance after resection (Oberg, 2017)
    • Chromogranin A – indicated for follow-up
    • Pancreatic polypeptide – serum test used in management of patients
    • Alpha (α) subunit pituitary glycoprotein hormones – serum test used in management of patients



  • Incidence – ~1/million; gastrinoma and somatostatinomas together account for ~10% of functional pancreatic neuroendocrine tumors (PNET) (National Comprehensive Cancer Network [NCCN], 2017)
  • Age – diagnosis in 30s-50s
  • Sex – M≥F (slight)
  • Occurrence – second most common PNET


  • 20-30% are genetic and associated with syndromes – usually multiple endocrine neoplasia type 1 (MEN1)
  • MEN1 (Wermer syndrome) – heritable disorder with increased risk for neuroendocrine tumors (NETs)
    • Parathyroid gland hyperplasia or tumor, endocrine tumors of the pancreas or duodenum, and endocrine tumors of the pituitary gland
    • Autosomal dominant


  • NET that secretes gastrin
  • Gastrin stimulates parietal gastric cells to increase in number
  • Increased number of parietal cells increases basal and maximal acid secretion
  • Increased acid secretion leads to ulcers and diarrhea
  • Most tumors (>80%) occur in the duodenum and in the head of the pancreas
  • Multiple tumors are frequently present
  • Large percent are malignant and metastasize

Clinical Presentation

  • Diagnosis is delayed an average of 4-6 years after symptom onset
  • Abdominal pain with recurrent peptic ulcer disease
    • Multiple ulcers common
    • Ulcers are refractory to therapy
  • Gastroesophageal reflux disease, possibly esophageal stenosis or Barrett mucosa
  • Diarrhea/steatorrhea – caused by acid secretion that inactivates pancreatic lipase and bile salts
  • Hypercalcemia – if associated with MEN1
  • Metastatic disease – often hepatic; most common presentation
  • 25% of affected patients present without peptic ulcer disease and have secretory diarrhea as the primary manifestation


Additional Resources