Zollinger-Ellison syndrome

Introduction

Zollinger-Ellison Syndrome is a rare condition caused by gastrin-secreting neuroendocrine tumours known as gastrinomas, typically located in the duodenum or pancreas. These tumours result in excessive gastric acid secretion, leading to peptic ulcer disease, malabsorption, and diarrhoea. ZES may occur sporadically or in association with Multiple Endocrine Neoplasia type 1 (MEN1).

Peak Incidence

• Most commonly presents between 30 and 50 years of age.

Pathophysiology

• Gastrinomas cause excessive secretion of gastrin, a hormone that stimulates acid production.
• The resulting hyperacidity leads to mucosal damage, ulcer formation, and inactivation of pancreatic enzymes, contributing to malabsorption.
• Around 20–30% of cases are associated with MEN1, in which multiple endocrine tumours (pituitary, parathyroid, and pancreatic) may coexist.

Symptoms

• Epigastric pain (similar to peptic ulcer disease).
• Heartburn, nausea, and vomiting.
• Diarrhoea – due to acid inactivation of pancreatic enzymes.
• Steatorrhoea – may occur with significant malabsorption.
• Weight loss.
• Symptoms of hypercalcaemia (if associated with MEN1):
  • Bone pain.
  • Polyuria and polydipsia.
  • Cognitive disturbances (e.g. confusion, depression).
  • Constipation and nausea.

Signs

• Epigastric tenderness on palpation.
• Pallor – due to chronic gastrointestinal blood loss.
• Signs of malnutrition – weight loss, muscle wasting.
• Signs of upper GI bleeding – haematemesis, melaena.
• Signs of MEN1 (if present):
  • Visual disturbances – due to pituitary tumours.
  • Hypercalcaemia – from parathyroid involvement.

Diagnosis

Initial Investigation

• Fasting serum gastrin level – first-line test:
  • Levels >10× the upper limit of normal are highly suggestive of ZES.

Confirmatory Testing

• Secretin stimulation test:
  • In ZES, gastrin paradoxically increases after secretin administration (typically >200 pg/mL).

Endoscopy

• Multiple or refractory duodenal ulcers.
• Hypertrophy of gastric rugal folds.

Imaging

• CT or MRI – to localise gastrinoma.
• Somatostatin receptor scintigraphy (SRS) – highly sensitive for detecting neuroendocrine tumours.
• Endoscopic ultrasound (EUS) – helpful for pancreatic lesions.

MEN1 Assessment

• Serum calcium and parathyroid hormone (PTH) – to evaluate for hyperparathyroidism.
• Pituitary hormone panel – if clinically indicated.
• Genetic testing – for MEN1 mutations.

Complications

• Peptic ulcer disease – may lead to bleeding, perforation, or gastric outlet obstruction.
• Malabsorption – secondary to acid-induced enzyme inactivation and mucosal damage.
• Oesophagitis – due to chronic acid reflux.
• Gastrointestinal bleeding.
• Metastasis – ~50% of gastrinomas are malignant, often spreading to the liver and lymph nodes.
• Hypercalcaemia – if MEN1-associated.
• Recurrence – after surgery or initial tumour control.

Management

Specialist Referral

• All suspected or confirmed cases of ZES should be referred to tertiary care for multidisciplinary management (gastroenterology, endocrinology, surgery).

Medical Therapy

• Proton pump inhibitors (PPIs) – High-dose therapy (e.g. omeprazole 40–60 mg twice daily) to control acid hypersecretion.
• Somatostatin analogues (e.g. octreotide) – Useful in metastatic disease to suppress hormone secretion and slow tumour growth.
• Hypercalcaemia management (if present):
  • IV fluids – to enhance renal calcium excretion.
  • IV bisphosphonates (e.g. pamidronate, zoledronate) – to inhibit bone resorption.
  • Calcitonin – second-line agent with a rapid onset of action.

Surgical Management

• Curative resection – of localised gastrinoma if possible.
• Liver metastases – may require surgical resection or liver-directed therapies (e.g. embolisation).
• MEN1-associated ZES – surgery is often less effective due to multifocal disease.

Chemotherapy

• Considered for metastatic or unresectable tumours:
  • Doxorubicin.
  • 5-fluorouracil (5-FU).

Surveillance

• Lifelong follow-up is required:

  • Monitor gastrin levels, endoscopic findings, and imaging to detect recurrence or progression.
  • Assess for MEN1-related tumours if relevant.