Zollinger-Ellison (ZE) Syndrome

Snapshot

• A 42-year-old male executive complains of upper abdominal pain. He says he is under considerable stress at work and smokes a pack of cigarettes daily. He has no history of shortness of breath, swelling of the feet, chest pain, or allergies. Further history reveals that the pain is worse at night and often wakens him from sleep. It occurs between meals and is subsided by drinking milk and avoiding spicy foods. On 1 occasion he vomited blood. Testing reveals serum gastrin level of 1000 pg/ml (normal < 300 pg/ml).

Introduction

• Clinical definition
  • syndrome characterized by the secretion of gastrin by duodenal or pancreatic neuroendocrine tumors (gastrinomas) 
• Epidemiology
  • demographics
    • annual incidence is 0.5-2 per million 
    • high incidence in men compared to women
  • only 25% of gastrinomas arise in the pancreas with the majority occurring in the duodenum
• Pathogenesis
  • excessive gastrin secretion from gastrinoma leads to high gastric acid output
    • gastrin has trophic action on gastric parietal cells and histamine-secreting enterochromaffin-like cells  
  • high gastric acid secreting overwhelms the neutralizing capacity of pancreatic bicarbonate secretion, resulting in low pH of intestinal contents
    • the low pH inactivates pancreatic digestive enzymes and thus interferes with the emulsification of fat by bile acids
    • results in maldigestion and malabsorption
  • high serum gastrin concentrations inhibit the absorption of sodium and water by the small intestine
• Associated conditions
• multiple endocrine neoplasia type 1 (MEN1) 

Presentation

• Symptoms
  • peptic ulcer disease 
  • heartburn
  • weight loss
  • diarrhea
• Physical exam
• abdominal tenderness

Imaging 

• Upper endoscopy 
• Contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI)
• Somatostatin receptor scintigraphy
• Endoscopic ultrasound
• usually indicated prior to surgical resection as it has greater sensitivity in detecting small tumors

Studies 

• Fasting serum gastrin concentration and gastric pH 
  • best initial test
  • serum gastrin value > 10 times the upper limit of normal (> 1000 pg/mL) in the presence of gastric pH < 2 is diagnostic
• Secretin stimulation test
  • indicated in patients with elevated gastrin/low gastrin pH that do not meet the diagnostic criteria 
  • differentiates gastrinomas from other causes of hypergastrinemia (e.g., antral G-cell hyperplasia)
  • patients with gastrinomas will have a dramatic rise in serum gastrin following secretin stimulation (normal gastric G cells are inhibited by secretin)
• Calcium infusion study
  • indicated in patients with strong clinical suspicion despite a negative secretin stimulation test
• MEN1 evaluation
  • serum parathormone levels
  • ionized calcium levels
• prolactin levels

Differential 

• Antral G-cell hyperplasia  
  • distinguishing factors
    • poor response to secretin stimulation ltest
• absence of gastrinoma on imaging

Treatment

• First-line
  • medical management with proton pump inhibitors (e.g., omeprazole) and H2-receptor anatagonists (e.g., ranitidine)
  • surgical resection
    • eliminates need for antisecretory medical therapy and protects against the morbidity and mortality of metastasis
• Second-line
  • octreotide (rarely required)
  • reoperation
• indicated in patients with intractable symptoms who fails dietary and medical therapy

Complications

• Stricture
• Perforation  
• Metastatic gastrinoma
  • liver is the most common site
  • most common cause of morbidity and mortality