Zollinger-Ellison Syndrome - Gastrinoma

Diagnostic Algorithm

  Zollinger-Ellison Syndrome Testing Algorithm

Clinical Background

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); also referred to as a gastrinoma..

Epidemiology

• Incidence – 1/1,000,000
• Age – diagnosis in 30s-40s
• Sex – M:F, equal
• Occurrence – second most common pancreatic NET

Inheritance

• Most tumors are sporadic, although 20-30% are genetic
• Multiple endocrine neoplasia type 1 (MEN1, Wermer syndrome) – heritable disorder with increased risk for NETs
  • Parathyroid gland hyperplasia or tumor, endocrine tumor of the pancreas or duodenum, and endocrine tumor of the pituitary gland
  • Autosomal dominant trait

Pathophysiology

• Neuroendocrine tumor that secretes gastrin
• Gastrin stimulates parietal gastric cells to increase in number
• Increased number of parietal cells increases the 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
• Frequently, multiple tumors are present
• Approximately 50-60% are malignant and metastasize

Clinical Presentation

• Abdominal pain with peptic ulcer disease
  • Multiple ulcers common
  • Ulcers are refractory to therapy
• Gastroesophageal reflux disease (GERD), possibly esophageal stenosis or Barrett mucosa
• Diarrhea – caused by acid secretion that inactivates pancreatic lipase and bile salts
• Hypercalcemia – if associated with MEN1
• Metastatic disease – most often hepatic

Treatment

• Control gastric acid hypersecretion
• Control tumor growth

Diagnosis

• Indications for testing – refractory peptic ulcer disease, multiple peptic ulcers, familial peptic ulcer disease, peptic ulcer disease with diarrhea
• Laboratory testing
  • Gastrin, serum fasting – usually >200 pg/mL; >1000 pg/mL virtually diagnostic
    • Elevated fasting serum gastrin in isolation is not diagnostic of ZES
  • Gastric acid analysis – increased basal acid output/secretion (BAO) ≥15 mEq (mmol/L)/hr or >5 mEq (mmol/L)/hr after acid reducing surgery
    • If BAO measurement unavailable, may measure pH of gastric fluid
    • pH ≥2 not consistent with ZES diagnosis
  • Secretin stimulation test
    • Looks for increase in serum gastrin after secretin administration
    • Not recommended for patients with acute pancreatitis
    • Avoid effects on gastrin release
      • Fasting on the day of study
      • Acid suppressive medications discontinued well in advance
    • Baseline serum gastrin samples
      • Taken 5 minutes before and immediately prior to secretin administration
    • Administration of pure porcine secretin (2 units/kg)
      • Administered intravenously over a 30-second time period
    • Serum gastrin samples
      • Initial samples at 2 and 5 minutes post-injection
      • Additional samples every 5 minutes for 20 minutes
    • Positive secretin stimulation test (increase in serum gastrin by more than 200 pg/mL) may confirm presence of gastrinoma
• Histology
  • Nested or trabecular arrangement of small- to medium-sized cells
    • Finely granular eosinophilic cytoplasm
    • Central, round to oval nuclei
    • Stippled chromatin (“salt and pepper”)
  • Immunohistochemistry – chromogranin, synaptophysin, gastrin
• Imaging studies
  • CT scan
  • Somatostatin-receptor scintigraphy
  • MRI

Differential Diagnosis

• Gastroesophageal reflux disease
• Peptic ulcer disease
• Helicobacter pylori infection
• Gastric outlet obstruction
• Pernicious anemia
• Short bowel syndrome

Pharmacogenetics and Therapeutic Drug Monitoring

Screening

Monitoring

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Immunohistochemistry Stain Offering arup005 Method: Immunohistochemistry	For fixed tissue samples, consultative services as well as immunohistochemical staining for synaptophysin, chromogranin, NSE, gastrin, AE1/AE3 (pancytokerat), PGP 9.5 are available

General References