Zollinger-Ellison Syndrome (Gastrinoma)

Zollinger-Ellison Syndrome is caused by gastrin-secreting neuroendocrine tumors called gastrinomas, leading to:

• Hypergastrinemia: Excessive gastrin hormone levels.
• Gastric Acid Hypersecretion: Resulting in mucosal damage.
• Refractory Peptic Ulcers: Ulcers resistant to standard therapy.

Prevalence

• Age of Onset: Typically between 30–50 years old.
• Gender: Male > Female (2:1 ratio).
• Sporadic cases: 80%
• MEN-1 syndrome: 20%

Association with MEN 1

• Multiple Endocrine Neoplasia type 1 (MEN 1):
  • Occurs in ∼25% of ZES cases.
  • Mnemonic for MEN 1 Tumors: "3 P's"
    • P: Parathyroid adenomas (hyperparathyroidism)
    • P: Pancreatic endocrine tumors (gastrinomas, insulinomas)
    • P: Pituitary adenomas

Risk Factors

• Family History: Especially MEN 1 syndrome.
• Genetic Mutations: Mutations in the MEN1 gene.

Gastrinoma Characteristics

• Location:
  • "Gastrinoma Triangle": Junction of cystic and common bile ducts, duodenal-jejunal junction, and the neck of the pancreas.
  • Most Common Sites:
    • Duodenum (∼70% of cases)
    • Pancreas (∼25% of cases)
    • Ectopic sites (e.g., lymph nodes, stomach)
• Nature:
  • Neuroendocrine tumors.
  • Malignancy: Over 60% are malignant but typically slow-growing.

Mechanism

• Gastrin Overproduction:
  • Gastrin stimulates parietal cells to secrete gastric acid (HCl).
  • Leads to hyperacidity.
• Gastric Acid Hypersecretion:
  • Causes mucosal injury resulting in peptic ulcers.
  • Inactivates pancreatic enzymes leading to malabsorption.
• Clinical Manifestations:
  • Refractory peptic ulcers.
  • Diarrhea and steatorrhea (fatty stools) due to malabsorption.

• Peptic Ulcer Disease
  • Multiple ulcers
  • Resistant to standard therapy
  • Unusual locations (distal duodenum)
  • Severe symptoms despite PPI use
• Diarrhea
  • Present in 70% of cases
  • Can be watery or steatorrhea
  • Due to acid inactivation of pancreatic enzymes
• Other Features
  • GERD symptoms
  • Weight loss (Inactivation of pancreatic enzymes leads to impaired digestion and malabsorption.)
  • Upper GI bleeding (Due to a bleeding peptic ulcer)
  • MEN-1 related symptoms if present

Initial Evaluation

• Suspicion in Patients With:
  • Recurrent, multiple, or refractory peptic ulcers.
  • Ulcers distal to the duodenal bulb.
  • Diarrhea and steatorrhea.
  • No NSAID use or H. pylori infection.

Laboratory Tests

• Fasting Serum Gastrin Level:
  • FSG > 1000 pg/mL with gastric pH ≤ 2 confirms ZES.
  • FSG 100–1000 pg/mL requires further testing.
• Gastric pH Measurement:
  • Gastric pH ≤ 2: Supports diagnosis.
  • Gastric pH > 2: Makes ZES unlikely.
• Secretin Stimulation Test:
  • Indication: Inconclusive FSG levels.
  • Procedure: Administer secretin intravenously.
  • Positive Test: Rise in gastrin > 120 pg/mL over baseline.
  • Note: In normal individuals, secretin inhibits gastrin release.

Imaging Studies

• Localizing the Tumor:
  • Somatostatin Receptor Scintigraphy (Octreotide Scan):
    • Preferred for detecting primary gastrinomas and metastases.
  • Endoscopic Ultrasound (EUS):
    • Useful for detecting pancreatic and duodenal tumors.
  • CT/MRI Scans:
    • Assess for metastases, especially in the liver.

Assessment for MEN 1 Syndrome

• Parathyroid Hormone (PTH) Levels:
  • Detect hyperparathyroidism.
• Calcium Levels:
  • Hypercalcemia supports MEN 1.
• Pituitary Hormone Levels:
  • Prolactin, growth hormone, ACTH.

Medical Management

• Proton Pump Inhibitors (PPIs):
  • High-dose PPIs are first-line to control gastric acid hypersecretion.
  • Examples: Omeprazole, lansoprazole.
• Somatostatin Analogues:
  • Octreotide may reduce gastrin levels and control symptoms.
  • Useful in metastatic or inoperable cases.

Surgical Management

• Tumor Resection:
  • Localized Disease:
    • Surgical exploration and resection of gastrinomas.
  • Criteria for Surgery:
    • Sporadic gastrinomas without metastasis.
    • Gastrinomas > 2 cm in patients with MEN 1.
• Liver Metastases:
  • Debulking Surgery: Removal of as much tumor as possible.
  • Liver Transplantation: Considered in select cases.

• Biochemical Monitoring
  • Gastrin levels: Every 3-12 months
  • Calcium/PTH if MEN-1
  • Vitamin B12 levels
• Imaging
  • Annual cross-sectional imaging
  • Somatostatin scanning every 3 years