Zollinger‑Ellison Syndrome (Gastrinoma)

Overview

Zollinger‑Ellison syndrome (ZES) is a rare disorder in which one or more tumors called gastrinomas secrete excessive amounts of the hormone gastrin. The high gastrin levels stimulate the stomach to produce large volumes of acid, leading to severe peptic ulcer disease, gastro‑esophageal reflux, and diarrhea.

Who it affects: Most patients are adults between 30 and 60 years old, but the condition can occur at any age, including children (particularly in familial cases). Men and women are affected equally.

Prevalence: ZES occurs in about 1–3 per million people worldwide. Approximately 20–25 % of cases are associated with the inherited syndrome multiple endocrine neoplasia type 1 (MEN‑1).^[1]

Symptoms

Symptoms arise from acid hypersecretion and the tumor itself. They can be intermittent early on and become more constant as the disease progresses.

• Recurrent abdominal pain – Often described as burning or gnawing, typically worse when the stomach is empty.
• Peptic ulcers – Ulcers may be multiple, large, and located in unusual sites such as the distal duodenum, jejunum, or even the ileum.
• Diarrhea – Acid inactivates pancreatic enzymes and damages the intestinal mucosa, leading to watery, often foul‑smelling stools.
• Steatorrhea (fatty stools) – Result of malabsorption due to pancreatic enzyme inactivation.
• Weight loss – From chronic diarrhea, malabsorption, and decreased appetite.
• Heartburn / GERD – Excess acid refluxes into the esophagus.
• Nausea and vomiting – May accompany ulcer pain.
• Gastrointestinal bleeding – Ulcers can erode blood vessels, causing melena or hematemesis.
• Ulcer perforation – A medical emergency presenting with sudden severe abdominal pain and rigid abdomen.
• Gastric outlet obstruction – Rarely, swelling or scarring from ulcers can block the pylorus.
• Non‑specific symptoms such as fatigue, anemia (from chronic blood loss), and electrolyte disturbances (e.g., low potassium from diarrhea).

Causes and Risk Factors

Underlying cause

Gastrinomas arise from neuroendocrine cells in the pancreas or duodenum. The majority (≈85 %) are duodenal, while the remainder are pancreatic. The tumor’s uncontrolled gastrin secretion drives the disease.

Genetic risk factors

• Multiple Endocrine Neoplasia type 1 (MEN‑1) – An autosomal‑dominant mutation in the MEN1 gene; up to 25 % of ZES patients have MEN‑1.
• Familial gastrinoma syndrome – Rare, inherited form not linked to MEN‑1.

Other risk factors

• Age 30–60 (peak incidence)
• Male or female (no gender predilection)
• History of other neuroendocrine tumors

What does NOT cause ZES?

Common conditions such as chronic NSAID use, *Helicobacter pylori* infection, or simple acid reflux do **not** cause gastrinomas, although they can coexist and worsen symptoms.

Diagnosis

Diagnosing ZES requires a combination of clinical suspicion, biochemical testing, imaging, and sometimes endoscopic evaluation.

1. Biochemical tests

• Fasting serum gastrin level – A level > 1,000 pg/mL (normal < 100 pg/mL) is highly suggestive, especially when gastric pH < 2.^[2]
• Secretin stimulation test – Paradoxical rise in gastrin after an intravenous secretin injection confirms ZES when fasting gastrin is equivocal.
• Gastric pH measurement – Persistent acidity (pH < 2) supports hypersecretion.

2. Imaging studies

• Somatostatin receptor scintigraphy (Octreoscan) or Ga‑68 DOTATATE PET/CT – Highly sensitive for locating gastrinomas.
• Multiphasic contrast‑enhanced CT or MRI – Provides anatomical detail for surgical planning.
• Endoscopic ultrasound (EUS) – Excellent for small pancreatic lesions (< 2 cm).

3. Endoscopy

Upper endoscopy (EGD) is performed to assess ulcer burden, obtain biopsies to rule out malignancy, and sometimes to place feeding tubes if obstruction occurs.

4. Staging

If malignancy is suspected, the tumor is staged using the TNM system (Tumor size, Nodes, Metastasis) and assessed for liver involvement, the most common site of metastasis.

Treatment Options

Management aims to control acid hypersecretion, remove or shrink the tumor, and monitor for recurrence.

1. Acid‑suppression therapy (first‑line)

• Proton pump inhibitors (PPIs) – High‑dose omeprazole, esomeprazole, or pantoprazole (e.g., 60–120 mg/day) effectively normalize gastric pH in > 90 % of patients.^[3]
• H2‑blockers – May be added for breakthrough symptoms but are less potent than PPIs.

Patients typically need lifelong high‑dose PPIs; abrupt discontinuation can precipitate severe ulceration.

2. Surgical management

• Curative resection – Preferred for solitary, localized tumors. Pancreaticoduodenectomy (Whipple) or enucleation depending on location.
• Debulking surgery – For metastatic disease; reduces tumor burden and gastrin output.
• Enucleation of duodenal gastrinomas – Often successful because these tumors are usually small.

Operative success rates: 70–80 % cure for non‑MEN‑1 sporadic gastrinomas; lower (≈30–50 %) in MEN‑1 due to multifocal disease.^[4]

3. Medical therapy for tumor control

• Somatostatin analogues (octreotide, lanreotide) – Bind to somatostatin receptors, inhibiting gastrin release and sometimes shrinking tumors.
• Targeted therapy – Everolimus (mTOR inhibitor) or sunitinib (tyrosine‑kinase inhibitor) for progressive metastatic neuroendocrine tumors.
• Chemotherapy – Generally reserved for high‑grade, poorly differentiated tumors.

4. Management of complications

• Iron, B12, and folate supplementation for anemia.
• Electrolyte replacement (potassium, magnesium) for chronic diarrhea.
• Pancreatic enzyme replacement if steatorrhea persists despite acid control.

5. Lifestyle & supportive measures

• Small, frequent meals; low‑fat diet to reduce duodenal irritation.
• Avoid NSAIDs, aspirin, and alcohol, which can worsen ulcer disease.
• Smoking cessation – smoking impairs ulcer healing.

Living with Zollinger‑Ellison Syndrome (gastrinoma)

Medication adherence

Take PPIs exactly as prescribed, usually twice daily. Carry an extra supply when traveling.

Monitoring

• Annual fasting gastrin level (or more often if symptoms change).
• Periodic endoscopy every 1–2 years to assess ulcer healing.
• Imaging (CT/MRI or DOTATATE PET) every 1–2 years to detect tumor recurrence or metastasis.

Nutrition

• Consume a balanced diet rich in complex carbs, lean protein, and vegetables.
• Consider a dietitian’s help for managing steatorrhea or weight loss.

Psychosocial support

Living with a chronic rare disease can be stressful. Connecting with patient groups (e.g., NETS) and mental‑health professionals improves quality of life.

Travel and emergencies

Carry a letter from your physician explaining the need for high‑dose PPIs and any injectable medications (e.g., octreotide). Keep a list of local hospitals familiar with neuroendocrine tumors.

Prevention

Because ZES is largely driven by genetic mutations or sporadic neuroendocrine tumor development, primary prevention is limited.

• Family screening – If a first‑degree relative has MEN‑1, genetic counseling and periodic gastrin testing are recommended.
• Avoid known ulcer‑aggravating agents (NSAIDs, excessive alcohol) to reduce secondary complications.
• Healthy lifestyle – Maintaining a healthy weight and avoiding smoking may lower the risk of neuroendocrine tumor progression, though evidence is indirect.

Complications

If untreated or poorly controlled, ZES can lead to serious health issues:

• Perforated peptic ulcer – Can cause peritonitis and requires emergency surgery.
• Severe gastrointestinal bleeding – May need endoscopic hemostasis or transfusion.
• Malabsorption & nutritional deficiencies – Anemia, osteoporosis, and protein‑energy wasting.
• Refractory ulcer disease – Chronic pain, scarring, and gastric outlet obstruction.
• Metastatic gastrinoma – Liver metastases occur in ~30–50 % of sporadic cases and up to 70 % in MEN‑1, decreasing survival.
• Neuroendocrine tumor-related hormonal syndromes – Rarely, gastrinomas secrete other peptides causing flushing or wheezing.

Five‑year survival for localized disease exceeds 80 % with modern therapy, but metastatic disease drops survival to 30‑50 %.^[5]

When to Seek Emergency Care

References

1. Mayo Clinic. Zollinger‑Ellison syndrome. https://www.mayoclinic.org. Accessed May 2026.
2. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). “Zollinger‑Ellison Syndrome.” https://www.niddk.nih.gov. Accessed May 2026.
3. Cleveland Clinic. “Management of Gastrinomas and Zollinger‑Ellison Syndrome.” https://my.clevelandclinic.org. 2023.
4. Anderson RB, et al. “Surgical outcomes in sporadic versus MEN‑1 associated gastrinomas.” *Ann Surg*. 2022;275(4):679‑687.
5. Wang J, et al. “Long‑term survival of patients with Zollinger‑Ellison syndrome: a population‑based study.” *J Clin Endocrinol Metab*. 2021;106(9):2735‑2743.