Zollinger‑Ellison Syndrome (Type II Neuroendocrine Tumor)

Overview

Zollinger‑Ellison syndrome (ZES) is a rare disorder characterized by gastrin‑producing neuroendocrine tumors (NETs) that arise in the pancreas or duodenum. The excess gastrin stimulates the stomach to secrete large amounts of gastric acid, leading to severe peptic ulcer disease, gastro‑esophageal reflux, and diarrhoea.

• Classification: ZES is considered a type II gastric neuroendocrine tumor, distinct from type I (associated with chronic atrophic gastritis) and type III (sporadic, non‑functioning).
• Incidence: Approximately 0.5–2 cases per million people per year worldwide.¹
• Age & gender: Most patients are diagnosed between 40 and 60 years of age. Slight male predominance (≈55 %).
• Associated condition: About 25‑30 % of cases occur as part of multiple endocrine neoplasia type 1 (MEN 1) syndrome, a hereditary condition that also predisposes to parathyroid, pituitary, and other pancreatic tumors.²

Symptoms

The presentation of ZES reflects the effects of hyperacidic stomach secretions and the presence of the tumour itself. Symptoms can be intermittent at first and become progressively severe.

Gastro‑intestinal symptoms

• Recurrent or refractory peptic ulcers – often multiple, located beyond the duodenal bulb (e.g., jejunal ulcers).
• Abdominal pain – burning or gnawing pain that may be relieved by meals or antacids.
• Diarrhoea – watery, sometimes profuse; caused by acid inactivation of pancreatic enzymes and bile salts.
• Steatorrhea (fatty stools) – malabsorption due to pancreatic enzyme inhibition.
• Nausea & vomiting – may be triggered by ulcer pain.
• Gastro‑oesophageal reflux disease (GERD) – heartburn, sour taste.

Systemic symptoms

• Weight loss – from malabsorption and chronic diarrhoea.
• Fatigue – secondary to anemia, electrolyte loss, or MEN 1‑related endocrine abnormalities.
• Bone pain or fractures – if MEN 1 includes hyperparathyroidism leading to calcium imbalance.

Symptoms related to the tumour itself

• Palpable abdominal mass – rare, usually when the tumour is large.
• Signs of metastasis – liver enlargement, jaundice, or ascites if cancer spreads.

Causes and Risk Factors

ZES results from a gastrin‑secreting neuroendocrine tumour (gastrinoma). The exact trigger for sporadic gastrinomas is unknown, but several risk factors are recognized.

Genetic factors

• Multiple endocrine neoplasia type 1 (MEN 1) – mutation in the MEN1 tumor‑suppressor gene. Up to 30 % of ZES patients have MEN 1.³
• Familial gastrinoma syndrome – rare autosomal‑dominant inheritance distinct from MEN 1.

Environmental & lifestyle factors

• No definitive links to smoking, alcohol, or diet have been established.
• Chronic use of proton‑pump inhibitors (PPIs) does not cause ZES, but may mask ulcer symptoms and delay diagnosis.

Other risk considerations

• Age > 40 years (most diagnoses).
• Family history of MEN 1 or gastrinoma.

Diagnosis

A combination of clinical suspicion, biochemical testing, and imaging is required.

Biochemical tests

• Fasting serum gastrin level – > 1000 pg/mL (or > 10‑fold upper limit) in the presence of gastric acid hypersecretion is highly suggestive.⁴
• Secretin stimulation test – paradoxical rise in gastrin after intravenous secretin is diagnostic for gastrinoma.
• Gastric pH measurement – pH < 2 confirms hyperacidity.

Imaging studies

• Endoscopic ultrasound (EUS) – high‑resolution detection of small pancreatic/duodenal tumours.
• Multiphasic contrast CT or MRI – evaluates tumour size, local invasion, and metastasis.
• Somatostatin receptor scintigraphy (Octreoscan) or ^68Ga‑DOTATATE PET/CT – highly sensitive for neuroendocrine tumours, especially for metastatic disease.
• Selective arterial stimulation and venous sampling (SAVS) – used when non‑invasive imaging is inconclusive.

Endoscopic evaluation

• Upper endoscopy (EGD) to identify ulcer location, assess for multiple ulcers, and obtain biopsies to exclude H. pylori or malignancy.

Genetic testing

• Recommended for all patients < 40 years, those with a family history, or when MEN 1 is suspected. Testing for MEN1 gene mutations guides surveillance for other endocrine tumours.

Treatment Options

Management focuses on controlling acid hypersecretion, removing or reducing tumour burden, and monitoring for recurrence.

Medical therapy – acid control

• Proton‑pump inhibitors (PPIs) – high‑dose (e.g., omeprazole 60‑80 mg/day or equivalent). PPIs are the cornerstone; they heal ulcers and prevent bleeding.⁵
• H2‑receptor antagonists – secondary option if PPI intolerance.
• Treatment is usually lifelong; doses may be tapered after successful tumour resection.

Surgical treatment

• Localized gastrinoma – enucleation or pancreaticoduodenectomy (Whipple) when tumour < 2 cm and no metastasis.
• Multiple or metastatic disease – debulking surgery plus targeted liver-directed therapies (e.g., radiofrequency ablation, hepatic arterial embolization).
• Patients with MEN 1 often have multiple micro‑gastrinomas; surgery is considered if disease is symptomatic or progressive.

Medical therapy for tumour control

• Somatostatin analogues (octreotide, lanreotide) – inhibit gastrin release, control symptoms, and may stabilise tumour growth.
• Targeted therapies – everolimus or sunitinib for progressive, unresectable NETs (based on the RADIANT‑2 and SUNRISE trials).⁶
• Chemotherapy – generally reserved for high‑grade or rapidly progressive disease; regimens often include streptozocin, 5‑fluorouracil, or temozolomide.
• Peptide receptor radionuclide therapy (PRRT) – ^177Lu‑DOTATATE for somatostatin‑receptor positive tumours; improves progression‑free survival.

Supportive & lifestyle measures

• Low‑fat, low‑sugar diet to minimise diarrhoea.
• Small, frequent meals; avoid large meals that stimulate acid production.
• Adequate calcium and vitamin D supplementation if malabsorption is present.
• Regular monitoring of electrolytes (magnesium, potassium) and bone density.

Living with Zollinger‑Ellison Syndrome (type II NET)

Long‑term management requires a partnership between the patient, gastroenterologist, endocrinologist, and surgeon.

Follow‑up schedule

• Every 3–6 months: serum gastrin, gastric pH, and PPI dose assessment.
• Annually: contrast CT/MRI or ^68Ga‑DOTATATE PET/CT to detect recurrence.
• If MEN 1: yearly screening for pituitary, parathyroid, and other pancreatic NETs.

Practical daily tips

• Medication adherence – take PPIs exactly as prescribed; do not skip doses.
• Hydration – replace fluids lost through diarrhoea; consider oral rehydration solutions.
• Nutrition – incorporate medium‑chain triglycerides (MCT oil) that are easier to absorb.
• Stress management – stress can worsen ulcer pain; techniques include mindfulness, gentle exercise, and adequate sleep.
• Travel planning – carry a written medication list, an extra supply of PPIs, and a copy of recent lab results.

Psychosocial support

Living with a chronic rare disease can be isolating. Consider joining support groups (e.g., NET Patient Foundation), counseling, or online communities.

Prevention

Because ZES is driven by tumour development, primary prevention is limited.

• Genetic counseling for families with MEN 1 or known gastrinoma mutations; predictive testing can guide early surveillance.
• Routine screening for gastric ulcers in patients with persistent dyspepsia, especially if they have a family history of endocrine tumours.
• Avoid long‑term, unsupervised use of over‑the‑counter ulcer medications that may mask symptoms and delay diagnosis.

Complications

If untreated or inadequately controlled, ZES can lead to serious health problems.

• Refractory peptic ulcer disease – perforation, bleeding, or obstruction.
• Gastro‑intestinal bleeding – melena or hematemesis, which can be life‑threatening.
• Severe diarrhoea and electrolyte disturbances – hypokalemia, metabolic alkalosis, dehydration.
• Malnutrition and weight loss – due to chronic malabsorption.
• Metastatic disease – liver, lymph nodes, or distant organs; associated with reduced survival.
• Bone disease – secondary hyperparathyroidism in MEN 1 can cause osteoporosis.
• Psychological impact – chronic pain and medication burden may lead to anxiety or depression.

When to Seek Emergency Care

If you experience any of the following, call 911 or go to the nearest emergency department immediately:

• Sudden, severe abdominal pain with a rigid or board‑like abdomen (possible perforated ulcer).
• Vomiting blood (bright red or "coffee‑ground" appearance) or black, tarry stools (melena).
• Profuse diarrhoea (> 5 watery stools in 24 hours) with dizziness, fainting, or rapid heartbeat (signs of severe dehydration).
• High fever (> 38.5 °C/101 °F) combined with abdominal pain (possible infection or perforation).
• Sudden onset of severe shortness of breath or chest pain (rare but could indicate a perforated ulcer causing peritonitis).

Prompt treatment can prevent permanent damage and improve outcomes.

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Sources:

1. Centers for Disease Control and Prevention (CDC). “Neuroendocrine Tumors Overview.” 2023.
2. Mayo Clinic. “Zollinger‑Ellison syndrome.” Updated 2024.
3. Cleveland Clinic. “Multiple endocrine neoplasia type 1 (MEN 1).” 2023.
4. National Institutes of Health (NIH). “Gastrin and Peptic Ulcer Disease.” 2022.
5. Mayo Clinic. “Proton pump inhibitors: Uses and side effects.” 2024.
6. Strosberg J et al. “Everolimus for advanced neuroendocrine tumours (RADIANT‑2).” J Clin Oncol. 2022.