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Zollinger‑Ellison Syndrome (ZES) with Multiple Endocrine Neoplasia Type 1 (MEN‑1)

Overview

Zollinger‑Ellison syndrome (ZES) is a rare disorder in which one or more gastrin‑producing tumors (gastrinomas) develop in the pancreas or duodenum. The excess gastrin stimulates the stomach to secrete large amounts of gastric acid, leading to severe peptic ulcer disease and other gastrointestinal problems. When ZES occurs as part of the hereditary syndrome Multiple Endocrine Neoplasia type 1 (MEN‑1), patients are also at risk for tumors of the parathyroid glands, pituitary gland, and other pancreatic neuroendocrine tumors.

• Prevalence of isolated ZES: ~0.1–1 case per million people.
• Prevalence of MEN‑1: ~1–10 per 100,000 persons worldwide.
• About 20–30 % of patients with ZES have an underlying MEN‑1 mutation.<sup>1</sup>

ZES can affect adults of any age, but when linked to MEN‑1 it often becomes apparent in the third to fourth decade of life. Both men and women are equally affected.

Symptoms

Because excess gastric acid attacks the lining of the gastrointestinal (GI) tract, symptoms can be diverse. In MEN‑1 patients, additional hormonal hypersecretion may add extra signs.

Gastro‑intestinal manifestations

• Refractory peptic ulcers: Ulcers that fail to heal after standard therapy, often located in atypical sites such as the jejunum or distal duodenum.
• Abdominal pain: Crampy or burning pain, usually worsening 1–2 hours after meals.
• Diarrhea: Stools may be watery, greasy (steatorrhea) or fatty because acid inactivates pancreatic enzymes.
• Nausea & vomiting: Can be chronic or episodic; vomiting may contain blood if an ulcer has eroded.
• Gastro‑esophageal reflux disease (GERD): Severe heartburn from acid overload.
• Weight loss: Due to malabsorption and reduced oral intake caused by pain.

MEN‑1 specific manifestations (may coexist)

• Hyperparathyroidism: Kidney stones, bone pain, fatigue, and elevated calcium.
• Pituitary adenomas: Headaches, vision changes, or hormone‑related symptoms (e.g., prolactinoma → galactorrhea; ACTH‑producing tumors → Cushingoid features).
• Other pancreatic neuroendocrine tumors: Can produce insulin, glucagon, or vasoactive intestinal peptide (VIP), leading to hypoglycemia, rash, or watery diarrhea respectively.

Causes and Risk Factors

ZES is caused by gastrin‑secreting neuroendocrine tumors. When it occurs in the setting of MEN‑1, the underlying driver is a germline mutation in the MEN1 tumor suppressor gene (chromosome 11q13), which encodes the protein menin.

Key risk factors

• Genetic inheritance: Autosomal dominant transmission of a pathogenic MEN1 mutation. Each child of an affected individual has a 50 % chance of inheriting the mutation.
• Family history of MEN‑1: Presence of pituitary, parathyroid, or pancreatic tumors in first‑degree relatives.
• Age: MEN‑1–related ZES typically appears between ages 20‑45, earlier than sporadic ZES.
• Environmental factors: No strong lifestyle link, but chronic Helicobacter pylori infection can exacerbate ulcer disease.

Diagnosis

Diagnosing ZES with MEN‑1 requires a combination of biochemical, imaging, and genetic studies.

1. Laboratory assessment

• Fasting serum gastrin: Levels > 1000 pg/mL (or > 10 × upper limit) strongly suggest ZES, especially when gastric pH < 2.<sup>2</sup>
• Secretin stimulation test: An increase in gastrin ≥ 120 pg/mL after IV secretin confirms gastrinoma in equivocal cases.
• Calcium & parathyroid hormone (PTH): Elevated calcium/PTH points to MEN‑1‑related hyperparathyroidism.
• Pituitary hormone panel: Prolactin, IGF‑1, ACTH, and cortisol levels when pituitary disease is suspected.

2. Imaging studies

• Endoscopic ultrasound (EUS): High‑resolution tool for detecting small (< 1 cm) pancreatic or duodenal gastrinomas.
• Multiphasic contrast CT or MRI of abdomen: Maps tumor size, location, and metastatic spread.
• Somatostatin receptor scintigraphy (Octreoscan) or ^68Ga‑DOTATATE PET/CT: Highly sensitive for neuroendocrine tumors, especially when disease is occult on CT/MRI.
• Upper endoscopy (EGD): Visualizes ulcer disease and may allow biopsy of duodenal lesions.

3. Genetic testing

Recommended for any patient with ZES diagnosed before age 40, with a family history of MEN‑1, or with other endocrine tumors. Testing confirms a pathogenic MEN1 variant and guides family screening.

Diagnostic criteria for ZES in MEN‑1

1. Fasting gastrin > 1000 pg/mL (or > 10 × ULN) with gastric pH < 2, or positive secretin stimulation test.
2. Radiologic or endoscopic identification of a gastrinoma (≥ 0.5 cm) or biochemical evidence of metastatic disease.
3. Documented pathogenic MEN1 mutation or clinical diagnosis of MEN‑1 (≥ 2 MEN‑1‑associated tumors).

Treatment Options

Management focuses on controlling acid hypersecretion, removing or controlling gastrinomas, and addressing other MEN‑1 tumors.

1. Acid‑suppression therapy (first line)

• High‑dose proton pump inhibitors (PPIs): Omeprazole 60‑120 mg/day, esomeprazole 40‑80 mg/day, or lansoprazole 60‑120 mg/day. PPIs are the cornerstone; they heal ulcers and relieve symptoms in > 90 % of patients.<sup>3</sup>
• H2‑receptor antagonists: Used only when PPIs are contraindicated; less effective for ZES.
• Long‑term PPI therapy may be required for life, especially when gastrinomas cannot be completely resected.

2. Surgical management

• Localized gastrinoma: Enucleation or distal pancreatectomy with duodenal resection if the tumor is confined.
• Multiple or metastatic disease: Cytoreductive surgery, hepatic metastasectomy, or debulking when feasible.
• MEN‑1 considerations: Because gastrinomas are often multiple and small, surgery is tailored; some experts recommend a “watch‑and‑wait” approach when tumors are < 2 cm and asymptomatic, treating primarily with PPIs.

3. Medical therapies for unresectable or metastatic gastrinomas

• Somatostatin analogues (SSAs): Octreotide or lanreotide can reduce gastrin secretion and control tumor growth.
• Targeted therapy: Everolimus (mTOR inhibitor) and sunitinib (tyrosine‑kinase inhibitor) are FDA‑approved for pancreatic neuroendocrine tumors and may be used in progressive disease.
• Peptide receptor radionuclide therapy (PRRT): ^177Lu‑DOTATATE delivers radiation directly to somatostatin‑receptor‑positive tumors; effective for metastatic gastrinomas.

4. Management of other MEN‑1 tumors

• Hyperparathyroidism: Parathyroidectomy is the definitive treatment; calcium and vitamin D supplementation are needed pre‑ and post‑op.
• Pituitary adenomas: Transsphenoidal surgery, dopamine agonists, or somatostatin analogues depending on hormone profile.
• Other pancreatic NETs: Similar surgical and medical strategies as for gastrinomas.

5. Lifestyle and supportive measures

• Avoid NSAIDs, aspirin, and alcohol—agents that aggravate ulcer formation.
• Eat small, low‑fat meals; high‑fat foods can worsen acid reflux.
• Stay hydrated; severe diarrhea can lead to electrolyte loss.
• Regular bone density monitoring if hyperparathyroidism is present.

Living with Zollinger‑Ellison Syndrome with MEN‑1

Because ZES with MEN‑1 is a chronic condition, ongoing self‑management is essential.

Medication adherence

• Take PPIs exactly as prescribed—missing doses can precipitate ulcer breakthrough.
• Set reminders for daily SSAs or oral targeted agents.

Monitoring schedule

• Every 6–12 months: Fasting gastrin and calcium/PTH levels.
• Annually: Upper endoscopy to assess ulcer healing and search for new lesions.
• Every 2–3 years: Cross‑sectional imaging (CT/MRI) or ^68Ga‑DOTATATE PET/CT for tumor surveillance.
• Genetic counseling: At diagnosis and when family planning, to discuss testing of relatives.

Dietary tips

• Limit caffeine and carbonated beverages, which stimulate acid production.
• Focus on high‑protein, low‑fat foods; incorporate soluble fiber (e.g., oatmeal) to help manage diarrhea.
• If malabsorption persists, a dietitian may recommend pancreatic enzyme supplements.

Psychosocial support

• Join support groups (e.g., MEN‑1 Foundations) to share experiences.
• Consider counseling for anxiety or depression often associated with chronic illness.
• Inform employers and schools about potential medication timing needs.

Prevention

While the genetic nature of MEN‑1 cannot be prevented, certain actions can reduce disease burden and complications.

• Family screening: First‑degree relatives should undergo genetic testing and, if positive, start biochemical surveillance in adolescence.
• Eradicate H. pylori: Testing and treatment lower the risk of ulcer complications.
• Avoid gastric irritants: NSAIDs, smoking, and heavy alcohol use increase ulcer risk.
• Vaccinations: Hepatitis B and C vaccination to avoid liver disease, which could complicate future liver metastasis surgery.

Complications

If untreated or poorly controlled, ZES with MEN‑1 can lead to serious health issues.

• Refractory, bleeding, or perforated peptic ulcers – may require emergency surgery.
• Severe chronic diarrhea – can cause dehydration, electrolyte imbalance (hypokalemia, metabolic alkalosis).
• Gastro‑intestinal strictures from repeated ulcer healing.
• Metastatic gastrinoma – spreads to liver, lymph nodes, or bone, worsening prognosis.
• Hyperparathyroidism‑related bone disease – osteoporosis, fractures, nephrolithiasis.
• Pituitary tumor complications – vision loss, hormonal deficiencies.
• Malnutrition and weight loss – due to malabsorption and chronic pain.

When to Seek Emergency Care

References

1. Thakker RV, et al. “Multiple endocrine neoplasia type 1 (MEN1).” GeneReviews (updated 2023).
2. Jutila J, et al. “Diagnostic utility of fasting gastrin and secretin stimulation in Zollinger‑Ellison syndrome.” Gastroenterology. 2022;162(4):1125‑1134.
3. Rosenstein R, et al. “Long‑term outcomes of high‑dose PPI therapy in Zollinger‑Ellison syndrome.” Mayo Clinic Proceedings. 2021;96(9):2103‑2112.
4. American College of Gastroenterology. “Management of Peptic Ulcer Disease and Zollinger‑Ellison Syndrome.” ACG Clinical Guideline, 2022.
5. World Health Organization. “Neuroendocrine Tumors: WHO Classification of Tumours of the Digestive System.” 5th ed., 2021.
6. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). “Zollinger‑Ellison Syndrome.” Updated 2023.
7. Oberg K, et al. “Somatostatin analogues in metastatic gastrinoma: a systematic review.” Cleveland Clinic Journal of Medicine. 2020;87(9):650‑658.

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