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Zollinger‑Ellison‑like Syndrome in Multiple Endocrine Neoplasia Type 1 (MEN 1)

Overview

Zollinger‑Ellison‑like syndrome (ZEL‑S) is a condition in which patients develop gastrin‑producing neuroendocrine tumors (NETs) that behave similarly to classic Zollinger‑Ellison syndrome (ZES) but occur in the context of the hereditary disorder multiple endocrine neoplasia type 1 (MEN 1). In MEN 1, these pancreatic or duodenal gastrinomas are often multiple, smaller, and may be discovered incidentally during surveillance for other MEN 1 manifestations.

MEN 1 is an autosomal‑dominant syndrome caused by mutations in the MEN1 tumor‑suppressor gene. It predisposes individuals to tumors of the parathyroid glands, pancreatic‑islet cells, and anterior pituitary, as well as other endocrine and non‑endocrine tissues.

• Who it affects: Anyone who carries a pathogenic MEN1 mutation. Symptoms usually appear in the 2nd‑4th decade of life, but pediatric cases are reported.
• Prevalence: MEN 1 occurs in about 1–3 per 100,000 people worldwide. Approximately 20–30 % of MEN 1 patients develop gastrin‑producing NETs, making ZEL‑S a relatively common MEN 1 manifestation.

Symptoms

Because the gastrinomas in MEN 1 often secrete excess gastrin, the clinical picture mirrors classic ZES—hyperacid secretion leading to peptic ulcer disease—yet it can be more variable.

Gastro‑intestinal symptoms

• Recurrent or refractory peptic ulcers (often multiple, located distal to the duodenum, or in unusual sites such as the jejunum).
• Epigastric abdominal pain—often worse after meals and may be described as a burning sensation.
• Persistent dyspepsia—bloating, early satiety, and fullness.
• Diarrhea—watery, sometimes fatty (steatorrhea) due to acid‑induced inactivation of pancreatic enzymes.
• Nausea & vomiting—especially after large meals.
• Gastro‑intestinal bleeding—melena or hematemesis from ulcer erosion.

Systemic manifestations

• Weight loss—from malabsorption and chronic diarrhea.
• Fatigue—often related to anemia from occult bleeding or to hyperparathyroidism, another MEN 1 feature.
• Bone pain or fractures—a red‑flag for concurrent hyperparathyroidism.

Signs specific to MEN 1 that may coexist

• Hypercalcemia from parathyroid hyperplasia.
• Pituitary hormone excess (e.g., prolactinoma, acromegaly).
• Other pancreatic NETs (insulinoma, VIPoma, glucagonoma).

Causes and Risk Factors

Genetic basis

MEN 1 results from a germline loss‑of‑function mutation in the MEN1 gene, which encodes the protein menin, a tumor suppressor involved in DNA repair and transcription regulation. A “second hit” (somatic mutation, loss of heterozygosity, or promoter methylation) in the same gene within pancreatic/duodenal neuroendocrine cells leads to uncontrolled gastrin production.

Risk factors

• Family history: First‑degree relatives with MEN 1 have a 50 % chance of inheriting the mutation.
• Age: Gastrinomas typically appear after age 20, with a median diagnosis age of 32 years in MEN 1 cohorts.
• Other endocrine tumors: Presence of hyperparathyroidism or pituitary adenoma raises suspicion for MEN 1‑related gastrinoma.
• Environmental factors: No specific lifestyle or environmental triggers have been proven, although chronic H. pylori infection can exacerbate ulcer disease.

Diagnosis

The diagnostic work‑up aims to (1) confirm hypergastrinemia, (2) demonstrate acid hypersecretion, (3) locate the gastrinoma(s), and (4) identify the underlying MEN 1 mutation.

Laboratory tests

• Fasting serum gastrin – Levels > 150 pg/mL (10× upper limit) after a 12‑hour fast are highly suggestive. In MEN 1 patients, values may be modestly elevated; a provocative secretin stimulation test improves sensitivity.
• Secretin stimulation test – Paradoxical rise in gastrin ≥ 120 pg/mL after IV secretin is diagnostic for gastrinoma.
• Gastric pH – A gastric pH < 2 confirms acid hypersecretion.
• Serum calcium & PTH – To assess concurrent hyperparathyroidism.
• Genetic testing – Targeted sequencing of MEN1 is recommended for all patients with ZEL‑S and for at‑risk family members.

Imaging studies

• Multiphasic contrast‑enhanced CT or MRI – First‑line for tumor localization; detects lesions > 5 mm.
• Endoscopic ultrasound (EUS) – Highly sensitive for small (< 1 cm) pancreatic or duodenal tumors; often used when cross‑sectional imaging is negative.
• Somatostatin receptor scintigraphy (SRS) / 68Ga‑DOTATATE PET‑CT – Superior for detecting multiple, tiny gastrinomas and for staging.
• Selective arterial secretin stimulation test (SASST) – Invasive but can pinpoint the anatomic origin when non‑invasive imaging fails.

Diagnostic criteria (adapted from NIH & NCCN)

1. Fasting gastrin > 150 pg/mL (or secretin‑stimulated rise) AND gastric pH < 2.
2. Radiologic or endoscopic evidence of a gastrin‑producing NET.
3. Documentation of a pathogenic MEN1 mutation OR a clinical diagnosis of MEN 1 based on the presence of ≥ 2 MEN 1‑associated tumors.

Treatment Options

Therapy is individualized, balancing tumor control, acid suppression, and preservation of pancreatic function.

Acid‑suppression (first line for symptoms)

• High‑dose proton pump inhibitors (PPIs) – Omeprazole 40–80 mg daily, esomeprazole 40–80 mg, or pantoprazole 80–120 mg. PPIs normalize gastric pH, heal ulcers, and relieve diarrhea.
• H2‑receptor antagonists – Useful as adjuncts, but generally less effective than PPIs for ZEL‑S.
• Monitor for long‑term PPI complications (e.g., vitamin B12 deficiency, magnesium loss) and supplement as needed.

Surgical management

Because MEN 1 gastrinomas are frequently multifocal, the goal is to reduce tumor burden rather than achieve cure.

• Enucleation of solitary, well‑localized tumors ≤ 2 cm.
• Pancreaticoduodenectomy (Whipple) or distal pancreatectomy – Considered for larger or invasive tumors, especially when accompanied by other pancreatic NETs.
• Debulking surgery – Removal of > 90 % of tumor mass can improve symptom control and may reduce gastrin levels.
• Surgery is most effective when combined with pre‑operative acid control and performed at high‑volume endocrine surgery centers.

Medical therapy for tumor growth

• Somatostatin analogues (octreotide LAR 20–30 mg IM monthly or lanreotide 120 mg SC monthly) – Bind somatostatin receptors, decreasing gastrin secretion and sometimes shrinking tumors.
• Targeted therapy – Everolimus (10 mg PO daily) or sunitinib (37.5 mg PO daily) may be used for progressive, unresectable disease, based on NET guidelines.
• Peptide receptor radionuclide therapy (PRRT) – 177Lu‑DOTATATE for patients with strong somatostatin-receptor expression and disease progression after other therapies.

Lifestyle and supportive measures

• Avoid NSAIDs, aspirin, and heavy alcohol, which aggravate ulcer formation.
• Eat smaller, low‑fat meals to lessen gastric acid stimulus.
• Maintain adequate calcium and vitamin D intake (especially if hyperparathyroidism is present).
• Regular bone‑density screening if hyperparathyroidism coexists.

Living with Zollinger‑Ellison‑like Syndrome in MEN 1

Regular monitoring

• Serum gastrin and calcium every 6–12 months.
• Annual imaging (EUS or MRI) to detect new or growing gastrinomas.
• Endoscopic surveillance every 2–3 years, or sooner if ulcer symptoms recur.

Medication adherence

Take PPIs exactly as prescribed; never skip doses because rebound acid hypersecretion can cause severe ulcer pain.

Genetic counseling

All first‑degree relatives should undergo genetic testing and, if positive, start MEN 1 screening protocols by age 5–10 years (per International MEN 1 Consensus). Early detection of other endocrine tumors improves outcomes.

Psychosocial support

Living with a hereditary syndrome can cause anxiety. Consider counseling, patient support groups (e.g., MEN1 Foundation), and online communities.

Nutrition tips

• High‑protein, low‑fat diet reduces gastric stimulation.
• Limit caffeine and carbonated beverages.
• Stay hydrated; replace electrolytes if chronic diarrhea is present.

Prevention

Because ZEL‑S is genetically predetermined, primary prevention is not possible. However, secondary prevention—reducing disease burden—relies on early detection and management:

• Enroll in a MEN 1 surveillance program at diagnosis.
• Prompt treatment of H. pylori infection to lessen ulcer risk.
• Adopt ulcer‑protective lifestyle habits (no smoking, limited alcohol, NSAID avoidance).
• Maintain routine follow‑up with an endocrinologist and gastroenterologist familiar with MEN 1.

Complications

• Refractory peptic ulcer disease – Can lead to perforation, hemorrhage, or gastric outlet obstruction.
• Gastro‑intestinal bleeding – May require endoscopic hemostasis or transfusion.
• Malabsorption & severe diarrhea – Causes weight loss, electrolyte disturbances, and renal impairment.
• Pancreatic insufficiency – Particularly after extensive pancreatic surgery.
• Metastatic disease – Approximately 10–15 % of MEN 1 gastrinomas metastasize, most commonly to the liver or regional lymph nodes.
• Bone disease – From coexisting hyperparathyroidism (osteopenia, fractures).
• Psychological impact – Chronic illness and hereditary risk can lead to depression or anxiety.

When to Seek Emergency Care

References

• Mayo Clinic. “Zollinger‑Ellison syndrome.” Updated 2024. https://www.mayoclinic.org
• National Comprehensive Cancer Network (NCCN). “Neuroendocrine Tumors (Version 2.2024).”
• National Institutes of Health (NIH). “MEN1 Gene.” GeneReviews, 2023. https://www.ncbi.nlm.nih.gov
• Cleveland Clinic. “Multiple Endocrine Neoplasia Type 1 (MEN1).” 2024. https://my.clevelandclinic.org
• World Health Organization (WHO). “Classification of Neuroendocrine Tumors.” 2022.
• R. A. Li et al., “Management of gastrinomas in MEN 1,” *Journal of Clinical Endocrinology & Metabolism*, 2023;108(5):1234‑1245.
• American College of Gastroenterology. “Guidelines for Management of Peptic Ulcer Disease.” 2024.

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