Zollinger-Ellison Syndrome: Causes, Symptoms & Treatment

What is Zollinger-Ellison Syndrome?

Zollinger-Ellison Syndrome (ZES) is a rare but serious medical condition first described in 1955 by surgeons Robert Zollinger and Edwin Ellison. It is caused by a hormone-secreting tumor called a gastrinoma, which releases excessive amounts of the hormone gastrin. This causes the stomach lining to produce abnormally large quantities of hydrochloric acid, leading to severe peptic ulcers and other complications.

ZES affects men slightly more often than women and typically presents between the ages of 20 and 60. It is estimated to affect 0.5 to 4 people per million per year, making it a rare condition.

Causes

ZES is caused by a gastrinoma – a neuroendocrine tumor that secretes gastrin. Gastrinomas are most commonly found in:

• The duodenum (small intestine) – in approximately 70% of cases
• The pancreas – in approximately 25% of cases
• Less commonly in lymph nodes or the stomach wall

Around 20–30% of ZES cases occur as part of the inherited condition Multiple Endocrine Neoplasia Type 1 (MEN1), where multiple endocrine glands are simultaneously affected. Gastrinomas may be benign or malignant; approximately 60–90% show malignant potential at the time of diagnosis.

Symptoms

The symptoms of ZES are primarily caused by the extreme overproduction of gastric acid and include:

• Peptic ulcers: Often located at unusual sites (e.g., the jejunum), multiple, or resistant to standard treatment
• Upper abdominal pain: Burning or stabbing pain in the upper abdomen
• Heartburn and acid reflux: Acid flowing back into the esophagus
• Nausea and vomiting
• Diarrhea: Watery or fatty stools due to inactivation of digestive enzymes
• Weight loss resulting from malabsorption and reduced appetite
• Gastrointestinal bleeding in cases of ulcer complications

Diagnosis

Diagnosing ZES requires a combination of laboratory tests and imaging studies:

Laboratory Tests

• Fasting serum gastrin level: Markedly elevated gastrin levels (above 1,000 pg/ml are highly suspicious)
• Gastric pH measurement: Confirmation of extreme acid overproduction (basal acid output > 15 mEq/h)
• Secretin stimulation test: A paradoxical rise in gastrin levels after secretin administration is a hallmark sign of gastrinoma

Imaging Studies

• Endoscopy (gastroscopy): Detection of ulcers, often multiple or atypically located
• CT scan and MRI: Used to localize the tumor
• Somatostatin receptor scintigraphy (SRS) or DOTATATE-PET/CT: Highly sensitive methods for tumor localization
• Endoscopic ultrasound (EUS): Particularly sensitive for small pancreatic tumors

Treatment

Medical Management

The primary goal of medical treatment is to control excess gastric acid secretion:

• Proton pump inhibitors (PPIs) such as omeprazole or pantoprazole at high doses: First-line treatment to suppress acid production
• H2 blockers: May be used as an alternative or adjunct, though less commonly today

Surgical Treatment

When feasible, surgical removal of the gastrinoma is the preferred approach, especially for solitary, localized tumors without distant metastases. Complete resection may lead to cure in selected patients.

Treatment in MEN1

In patients with concurrent MEN1, the management strategy is more complex due to the presence of multiple tumors. Symptom control often takes priority in these cases.

Systemic Therapy for Metastatic Disease

• Somatostatin analogues (e.g., octreotide, lanreotide): Inhibit hormone secretion and help control tumor growth
• Chemotherapy or targeted therapies (e.g., everolimus, sunitinib) for advanced gastrinomas
• Peptide receptor radionuclide therapy (PRRT) for somatostatin receptor-positive tumors

Prognosis

Prognosis depends largely on the tumor stage and whether complete surgical resection is possible. For localized tumors, the outlook after successful surgery is favorable. In metastatic cases, the disease is not curable, but modern therapies can often control it for many years. The widespread use of potent acid-suppressing medications has significantly reduced the previously life-threatening complications caused by peptic ulcers.

References

1. Jensen RT, Niederle B, Mitry E et al. – Gastrinoma (duodenal and pancreatic). In: Neuroendocrine Tumours of the Gastrointestinal Tract. Springer, 2006.
2. Ellison EC, Johnson JA – The Zollinger-Ellison syndrome: a comprehensive review of historical, scientific, and clinical considerations. Current Problems in Surgery, 46(1):13–106, 2009. PubMed PMID: 19059208.
3. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) – Zollinger-Ellison Syndrome. U.S. Department of Health and Human Services, 2023. Available at: https://www.niddk.nih.gov