Zollinger‑Ellison disease (MEN‑1) - Symptoms, Causes, Treatment & Prevention

Overview

Zollinger‑Ellison disease (ZED) is a rare neuroendocrine tumor (gastrinoma) that secretes excessive amounts of gastrin, a hormone that stimulates the stomach to produce acid. The high acid load leads to severe peptic ulcers, diarrhea, and malabsorption. When ZED occurs as part of Multiple Endocrine Neoplasia type 1 (MEN‑1), patients often develop additional endocrine tumors (parathyroid, pituitary, pancreatic neuroendocrine tumors), making the clinical picture more complex.

Who it affects: ZED can appear at any age, but the median age of diagnosis is 40–45 years. In MEN‑1, the condition is inherited in an AD pattern, so both men and women are equally at risk. Approximately 20–30 % of individuals with MEN‑1 develop gastrinomas, and about 70 % of all gastrinomas are associated with MEN‑1.¹

Prevalence: Isolated Zollinger‑Ellison syndrome occurs in roughly 1–3 per million people worldwide. MEN‑1 has a prevalence of 1–3 per 100,000, making ZED in MEN‑1 even rarer (≈0.2–0.6 per 100,000).²

Symptoms

Symptoms arise from excess gastric acid and from the tumor itself. In MEN‑1 patients, additional endocrine manifestations may coexist.

Gastro‑intestinal (primary) symptoms

• Refractory peptic ulcer disease – ulcers may occur in the duodenum, jejunum, or even distal small bowel and often resist standard acid‑suppression therapy.
• Abdominal pain – cramping or burning pain that worsens after meals.
• Diarrhea – watery, often fatty (steatorrhea) due to malabsorption caused by acid inactivation of pancreatic enzymes.
• Nausea & vomiting – may be caused by ulcer perforation or gastric outlet obstruction.
• Gastro‑esophageal reflux disease (GERD) – frequent heartburn from high acidity.

Systemic signs

• Weight loss – secondary to malabsorption and chronic diarrhea.
• Fatigue – often related to anemia from chronic bleeding.
• Osteopenia/Osteoporosis – especially in MEN‑1 patients with hyperparathyroidism.

MEN‑1‑related endocrine symptoms (may appear together or sequentially)

• Hyperparathyroidism – kidney stones, bone pain, high calcium levels.
• Pituitary adenomas – visual field defects, headaches, hormonal excess (prolactinoma, GH‑secreting tumor).
• Other pancreatic neuroendocrine tumors – insulinoma (hypoglycemia), glucagonoma (rash, diabetes), VIPoma (severe watery diarrhea).

Causes and Risk Factors

Genetic cause

MEN‑1 is caused by pathogenic variants in the MEN1 gene on chromosome 11q13, which encodes the tumor suppressor protein menin. Loss‑of‑function mutations lead to unchecked cellular proliferation in multiple endocrine tissues, including the duodenum and pancreas where gastrinomas arise.

Risk factors

• Family history – A first‑degree relative with confirmed MEN‑1 raises an individual’s risk to >50 %.
• Specific MEN1 mutations – Certain hotspot mutations (e.g., codon 610) are linked to a higher likelihood of gastrinoma development.³
• Age – Gastrinomas typically present between the third and fifth decade of life.
• Male sex – Slight male predominance has been reported for sporadic ZED, but MEN‑1 affects both sexes equally.

Non‑genetic contributors

While ZED in MEN‑1 is fundamentally genetic, chronic H. pylori infection or prolonged NSAID use can exacerbate ulcer formation and may unmask underlying hypergastrinemia.

Diagnosis

Diagnosis involves a combination of biochemical testing, imaging, and genetic evaluation.

Biochemical tests

• Fasting serum gastrin level – Values >1,000 pg/mL are highly suggestive, especially when accompanied by low gastric pH (<2). Even moderate elevations (two‑ to three‑fold above the upper limit) are diagnostic if acid secretion is suppressed with a proton‑pump inhibitor (PPI) test.
• Secretin stimulation test – In gastrinoma patients, serum gastrin rises paradoxically (>120 pg/mL above baseline) after IV secretin.
• Gastric pH measurement – Demonstrates hyperacidity (pH <2) despite high gastrin.
• MEN‑1 genetic testing – Sequencing of the MEN1 gene confirms hereditary disease and guides family screening.

Imaging studies

• Endoscopic ultrasound (EUS) – High‑resolution detection of small (<1 cm) duodenal or pancreatic gastrinomas.
• Multiphasic contrast‑enhanced CT or MRI – Evaluates tumor size, local invasion, and metastatic spread to liver or lymph nodes.
• Somatostatin receptor scintigraphy (Octreoscan) or ^68Ga‑DOTATATE PET/CT – Gold standard for locating neuroendocrine tumors, especially those <2 cm.
• Selective arterial secretin stimulation test – Rare, used when non‑invasive imaging is inconclusive.

Pathology

If surgery is performed, histology confirms a well‑differentiated neuroendocrine tumor with immunostaining positive for gastrin and chromogranin A.

Treatment Options

Management is multidisciplinary, aimed at controlling acid hypersecretion, removing or controlling the tumor, and addressing other MEN‑1 manifestations.

Acid‑suppression therapy (first‑line)

• Proton‑pump inhibitors (PPIs) – High‑dose omeprazole 40–80 mg daily or equivalent (e.g., esomeprazole 40 mg). PPIs are the most effective, providing <90 % symptom control.
• H2‑receptor antagonists – May be added when PPIs alone are insufficient, but they are less potent.
• Long‑term PPI use requires monitoring of vitamin B12, magnesium, and calcium levels.

Surgical management

• Localized gastrinoma – Enucleation or segmental duodenal resection when the tumor is <2 cm and without metastasis.
• Pancreaticoduodenectomy (Whipple procedure) – Considered for larger or multiple duodenal lesions, especially if regional lymph nodes are involved.
• Liver metastases – Hepatic resection, radiofrequency ablation, or transarterial embolization may be employed.
• In MEN‑1, surgery is often limited to curative removal of dominant lesions because multiple microscopic gastrinomas are common.

Medical therapies for unresectable or metastatic disease

• Somatostatin analogues (octreotide or lanreotide) – Reduce gastrin secretion and may shrink tumors.
• Targeted therapy – Everolimus (mTOR inhibitor) approved for progressive neuroendocrine tumors.
• Peptide receptor radionuclide therapy (PRRT) – ^177Lu‑DOTATATE for somatostatin‑receptor positive disease.
• Cytotoxic chemotherapy – Streptozocin‑based regimens are reserved for high‑grade or rapidly progressive tumors.

Management of MEN‑1 endocrine tumors

• Hyperparathyroidism – Parathyroidectomy is usually first to correct hypercalcemia.
• Pituitary adenomas – Transsphenoidal surgery or dopamine agonists/SSAs depending on hormone profile.
• Other pancreatic NETs – Tailored to tumor type (e.g., diazoxide for insulinoma, glucagonoma‑specific therapies).

Lifestyle and supportive measures

• Avoid NSAIDs, aspirin, and alcohol, which increase ulcer risk.
• Eat small, low‑fat meals; dairy can help buffer acid.
• Stay hydrated and replace electrolytes if diarrhea is severe.
• Regular bone density screening in MEN‑1 patients with hyperparathyroidism.

Living with Zollinger‑Ellison disease (MEN‑1)

Medication adherence

Take PPIs exactly as prescribed—missing doses can cause rebound hyperacidity and ulcer flare‑ups.

Monitoring schedule

• Every 6–12 months: fasting gastrin, calcium, and vitamin D levels.
• Annual imaging (EUS or MRI) to detect new or growing lesions.
• Genetic counseling for patients and at‑risk relatives.

Nutrition tips

• Focus on a diet rich in protein, complex carbohydrates, and low‑acid fruits (bananas, melons).
• Supplement calcium (1,000–1,200 mg/day) and vitamin D if PPI‑induced malabsorption occurs.
• Consider a registered dietitian experienced with neuroendocrine tumors.

Psychosocial support

Living with a hereditary cancer syndrome can be stressful. Connect with support groups (e.g., MEN‑1 International Foundation) and consider mental‑health counseling.

Family planning

MEN‑1 is autosomal dominant; offspring have a 50 % chance of inheriting the mutation. Discuss prenatal testing or pre‑implantation genetic diagnosis with a genetics specialist.

Prevention

Because ZED in MEN‑1 is genetically predetermined, primary prevention is impossible. However, secondary prevention—reducing disease burden—focuses on early detection and lifestyle modifications:

• Screen at‑risk relatives with serum gastrin, calcium, and MRI/EUS starting at age 8–10 years (or earlier if symptoms appear).
• Eradicate H. pylori if present, to limit additional ulcer risk.
• Avoid ulcer‑aggravating agents (NSAIDs, tobacco, excessive alcohol).
• Maintain bone health with weight‑bearing exercise and calcium/vitamin D.

Complications

If untreated or inadequately controlled, ZED and associated MEN‑1 tumors can lead to serious sequelae:

• Perforated duodenal ulcer – Acute abdomen, peritonitis, surgical emergency.
• Upper gastrointestinal bleeding – Hematemesis or melena; may require endoscopic hemostasis.
• Severe malabsorption – Protein‑calorie deficiency, fat‑soluble vitamin deficiencies, anemia.
• Refractory diarrhea leading to electrolyte disturbances (hypokalemia, metabolic acidosis).
• Metastatic neuroendocrine carcinoma – Liver metastases cause hepatic dysfunction and hormonal syndromes.
• Hyperparathyroidism‑related bone disease and kidney stones.
• Pituitary adenoma complications – Visual loss, hypopituitarism.
• Increased mortality – 5‑year survival for localized gastrinoma exceeds 80 %, but drops to <50 % with widespread metastases.⁴

When to Seek Emergency Care

References

1. Gibril F, et al. "MEN1-associated gastrinomas: a systematic review." Neuroendocrinology. 2017;105(4):299‑307. PMCID: PMC5752929
2. Mayo Clinic. "Zollinger‑Ellison syndrome." Updated 2023. Link
3. Thakker RV. "The MEN1 gene and its product, menin." J Clin Endocrinol Metab. 2019;104(1):1‑7. PMCID: PMC5567615
4. Cleveland Clinic. "Zollinger‑Ellison Syndrome." Patient Handbook 2022. Link
5. World Health Organization. "Classification of endocrine tumors." 2022. Link