Zollinger-Ellison Syndrome

Zollinger-Ellison syndrome is gastric acid hypersecretion caused by an autonomous gastrin secreting neuroendocrine tumour (gastrinoma), producing severe, recurrent or refractory peptic ulceration, diarrhoea and reflux.

Incidence is about 0.5 to 3 for each million people each year. Peak age is 40 to 60 years. About 20% to 30% occur in multiple endocrine neoplasia type 1.

Sites are the duodenum in 50% to 70% (often under 1 cm and multiple, mainly in MEN1) and pancreas in 25% to 40%. Over 50% are malignant, and liver metastases are the main adverse prognostic factor.

Pathophysiology.

Gastrin stimulates enterochromaffin like cells and parietal cell mass, causing acid secretion that overwhelms duodenal buffering, damages the mucosa and inactivates pancreatic enzymes, producing steatorrhoea.

Epigastric pain, multiple or distal (beyond the bulb) ulcers, ulcers refractory to or recurring on acid suppression, complications (bleeding, perforation, stricture), watery diarrhoea that improves with acid suppression, weight loss and reflux with oesophagitis. Hypercalcaemia and pituitary or pancreatic features point to MEN1.

Red flags.

• Ulcer complications.
• Ulcers without Helicobacter pylori or non-steroidal drug use.
• Hepatic metastases.
• Family history of MEN1.

Measure fasting serum gastrin and gastric pH. A gastrin over 10 times the upper limit with gastric pH under 2 is diagnostic. Hold proton pump inhibitors for 1 week (and H2 blockers for 2 days) only under specialist supervision, because of rebound ulcer risk.

If gastrin is raised and pH is uncertain, perform a secretin stimulation test (secretin 0.4 microgram/kg IV, with gastrin at baseline and at 2, 5, 10, 15 and 30 minutes): a rise of 120 pg/mL or more within 15 minutes is diagnostic. Basal acid output over 15 mmol/h (10 mmol/h after acid reducing surgery) supports the diagnosis. Localise with gallium-68 DOTATATE positron emission tomography, endoscopic ultrasound, CT or MRI. Test calcium, parathyroid hormone and prolactin for MEN1.

Differential diagnosis.

• Hypergastrinaemia from proton pump inhibitor use.
• Atrophic gastritis and pernicious anaemia.
• Helicobacter pylori infection.
• Antral G-cell hyperplasia.
• Retained gastric antrum.
• Renal failure.
• Gastric outlet obstruction.

Control acid first, then resect the tumour when possible.

• Omeprazole:
  • 60 mg orally once daily initially; adjust every 1 to 2 weeks to keep basal acid output under 10 mmol/h (under 5 mmol/h after acid reducing surgery) and symptoms controlled, with divided doses for amounts over 80 mg
  • Lifelong unless cured; maximum 120 mg daily
  • Monitor symptoms, magnesium, vitamin B12, calcium and bone density; use specialist titration in severe hepatic impairment
• Pantoprazole (when oral intake is not possible): 80 mg IV every 12 hours; short term only; maximum 240 mg daily; monitor magnesium and symptoms; reduce in severe hepatic impairment.

Surgery: resect sporadic duodenal and pancreatic tumours when localised (enucleation or pancreatoduodenectomy). In MEN1, treat hyperparathyroidism first, since correcting hypercalcaemia lowers gastrin; resect pancreatic tumours over 2 cm.

Metastatic disease:

• Lanreotide: 120 mg deep subcutaneously every 28 days; continue until progression; maximum 120 mg every 14 days; monitor glucose, gallstones and heart rate; start at 60 mg in moderate to severe hepatic or renal impairment.
• Everolimus: 10 mg orally once daily; until progression or toxicity; maximum 10 mg daily; monitor glucose, lipids, pneumonitis and infection; reduce to 5 mg daily in moderate hepatic impairment.
• Lutetium-177 dotatate: 7.4 GBq IV every 8 weeks for 4 doses with amino acid infusion; monitor blood counts, renal function and liver function; avoid when creatinine clearance is under 30 mL/min.

Liver directed therapy (resection, embolisation or ablation) is used for liver metastases.

Monitoring. Symptoms and acid output yearly, gastrin and chromogranin A, imaging every 6 to 12 months, and bone density.

Referral and escalation. Endocrine and neuroendocrine tumour multidisciplinary team, genetics for MEN1, and surgery.