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Zollinger‑Ellison Syndrome with Gastro‑EnteroPancreatic Neuroendocrine Tumor (GEPNET)

Overview

Zollinger‑Ellison syndrome (ZES) is a rare condition characterized by gastrin‑producing tumors (gastrinomas) that cause excessive stomach acid secretion. When these gastrinomas arise in the pancreas or duodenum, they are part of the broader group of gastro‑entero‑pancreatic neuroendocrine tumors (GEPNETs). Together, the diagnosis is often written as “Zollinger‑Ellison syndrome with a gastro‑entero‑pancreatic neuroendocrine tumor.”

• Who it affects: Adults aged 30–60 are most commonly diagnosed, but ZES can appear at any age, including childhood in rare hereditary cases.
• Prevalence: Gastrinomas are the second‑most common functional pancreatic neuroendocrine tumor, with an estimated incidence of 0.5–2 cases per million people per year. Approximately 20–30 % of patients with ZES have a sporadic tumor; the remainder are linked to multiple endocrine neoplasia type 1 (MEN‑1) syndrome.<sup>1</sup>
• Gender: Slight male predominance (≈55 % male).

Symptoms

The clinical picture results from two overlapping processes: hyperacidic gastric secretions and the local or metastatic effects of the neuroendocrine tumor.

Symptoms caused by excess gastric acid

• Severe, recurrent peptic ulcers: Often multiple, large, and located beyond the duodenum (e.g., jejunum, ileum).
• Abdominal pain: Burning or gnawing pain that may improve after meals (ulcer‑related) or worsen (gastric irritation).
• Diarrhea or watery stools: Acid inactivates pancreatic enzymes and damages the intestinal lining, leading to malabsorption.
• Steatorrhea (fatty, foul‑smelling stools): Result of fat maldigestion.
• Gastro‑esophageal reflux disease (GERD): Heartburn, sour taste, and regurgitation.
• Nausea and vomiting: May be triggered by ulcer bleeding or severe gastritis.
• Weight loss: Due to malabsorption, pain‑related anorexia, and chronic diarrhea.

Symptoms related to the neuroendocrine tumor itself

• Abdominal mass or fullness: May be palpable if the tumor is large.
• Jaundice: If the tumor compresses the bile duct.
• Upper‑right quadrant pain: Suggests liver metastasis.
• Flushing, wheezing, or itching: Rarely, some GEPNETs secrete other hormones (e.g., serotonin).
• Hypoglycemia: Very uncommon, but possible if the tumor secretes insulin‑like substances.

Causes and Risk Factors

ZES results from uncontrolled gastrin secretion, most often from a neuroendocrine tumor. The underlying causes can be divided into sporadic and hereditary.

Genetic / hereditary factors

• Multiple Endocrine Neoplasia type 1 (MEN‑1): An autosomal‑dominant mutation in the MEN1 gene. About 25–30 % of ZES patients have MEN‑1, and they often develop multiple pancreatic NETs.
• Familial isolated gastrinoma syndrome: Rare, inherited as an autosomal‑dominant trait without other MEN‑1 features.

Acquired / sporadic factors

• Somatic mutations: Mutations in the MEN1, DAXX, ATRX or beta‑catenin (CTNNB1) genes are found in a proportion of sporadic gastrinomas.
• Chronic atrophic gastritis: Long‑standing gastritis can cause hypergastrinemia, but it rarely leads to true gastrinomas.

Other risk enhancers

• Age > 30 years (most cases).
• Male sex (modest increase).
• Family history of MEN‑1 or gastrinoma.

Diagnosis

Because ZES can mimic common ulcer disease, a high index of suspicion is needed when ulcers are refractory to standard therapy or when multiple ulcers appear in unusual locations.

Laboratory tests

• Fasting serum gastrin level: Levels > 1000 pg/mL (normal < 100 pg/mL) are strongly suggestive, especially when gastric pH < 2. <sup>2</sup>
• Secretin stimulation test: Increments in gastrin > 120 pg/mL after intravenous secretin confirm ZES.
• Chromogranin A (CgA): Elevated in most neuroendocrine tumors; useful for monitoring.
• Other hormone panels: When MEN‑1 is suspected, check calcium, parathyroid hormone, prolactin, and insulin levels.

Imaging studies

• Endoscopic ultrasound (EUS): High‑resolution imaging of pancreatic head/duodenal lesions; enables fine‑needle aspiration.
• Multiphasic contrast‑enhanced CT or MRI: Detects primary tumor and liver or lymph‑node metastases.
• Somatostatin receptor scintigraphy (e.g., Ga‑68 DOTATATE PET/CT): Gold standard for locating GEPNETs due to high receptor expression.<sup>3</sup>
• Selective arterial secretagogue injection (SASI) test: Rare, used when non‑invasive imaging is inconclusive.

Endoscopic evaluation

Upper endoscopy (EGD) visualizes ulcer disease and can obtain biopsies to rule out H. pylori or malignancy. It also provides an opportunity to place a gastric pH probe if needed.

Treatment Options

Therapy must address both acid hypersecretion and the tumor itself. A multidisciplinary team (gastroenterology, endocrine surgery, oncology, radiology, nutrition) is essential.

Medical management of acid hypersecretion

• Proton pump inhibitors (PPIs): High‑dose omeprazole, esomeprazole, or pantoprazole are first‑line. Typical doses: omeprazole 60–120 mg daily, titrated to symptom control.<sup>4</sup>
• Histamine‑2 receptor antagonists (H2RAs): May be added if PPIs are insufficient.
• Antacids: For breakthrough symptoms.

Surgical treatment of the primary tumor

• Curative resection: Enucleation or pancreaticoduodenectomy (Whipple) for localized gastrinomas; 5‑year survival > 80 % when complete removal is achieved.
• Debulking surgery: Reduces hormonal load when tumors are unresectable; improves symptom control.
• Enucleation of duodenal gastrinomas: Preferred for small (< 2 cm) lesions without lymph‑node involvement.

Medical therapy for the neuroendocrine tumor

• Somatostatin analogues (SSA): Octreotide or lanreotide bind somatostatin receptors, decreasing gastrin release and slowing tumor growth. Typical dose: octreotide LAR 30 mg IM every 28 days.
• Targeted therapy: Everolimus (mTOR inhibitor) and sunitinib (tyrosine‑kinase inhibitor) are FDA‑approved for progressive, non‑functional pancreatic NETs; they can be used in ZES when disease progresses despite SSA.
• Chemotherapy: Streptozocin‑based regimens or temozolomide+capecitabine for high‑grade or rapidly progressive disease.
• Peptide receptor radionuclide therapy (PRRT): ^177Lu‑DOTATATE delivers targeted radiation; improves progression‑free survival in metastatic GEPNETs.<sup>5</sup>

Locoregional therapies for metastases

• Liver-directed treatments: Radiofrequency ablation, trans‑arterial chemoembolization (TACE), or yttrium‑90 radioembolization.
• Surgical metastasectomy: Considered when limited liver disease is resectable.

Lifestyle and supportive measures

• Small, frequent meals low in fat to reduce acid stimulation.
• Avoid alcohol, caffeine, nicotine, and NSAIDs, which aggravate ulcer disease.
• Supplement fat‑soluble vitamins (A, D, E, K) and calcium if malabsorption is present.
• Stay hydrated; oral rehydration solutions help counteract diarrhea‑related losses.

Living with Zollinger‑Ellison plus Gastro‑EnteroPancreatic Neuroendocrine Tumor

Monitoring and follow‑up

• Gastrin levels: Recheck every 3–6 months while adjusting PPIs.
• Imaging: Contrast‑enhanced MRI or Ga‑68 DOTATATE PET/CT annually, or sooner if symptoms change.
• Endoscopy: Every 1–2 years to assess ulcer healing, unless new symptoms arise.

Nutrition tips

• Eat protein‑rich foods (lean meat, fish, legumes) to support healing.
• Incorporate medium‑chain triglyceride (MCT) oils; they are absorbed without pancreatic lipase and help in steatorrhea.
• Consider probiotic supplements (e.g., Lactobacillus rhamnosus) to aid gut barrier function.

Psychosocial support

Chronic disease can affect mood. Referral to a counselor, patient‑support groups (e.g., Neuroendocrine Tumor Research Foundation), and, when needed, psychiatric care improves quality of life.

Medication adherence

Set alarms or use a pill‑organizer for high‑dose PPIs and monthly SSA injections. Missing doses can precipitate ulcer recurrence or a hormone flare.

Activity recommendations

• Gentle aerobic exercise (walking, cycling) 150 min/week improves gastrointestinal motility and overall stamina.
• Avoid heavy lifting if you have a large intra‑abdominal mass until evaluated by surgery.

Prevention

Because most cases are sporadic or genetically predetermined, primary prevention is limited. However, the following measures can reduce secondary complications and may delay tumor progression:

• Screen family members: If MEN‑1 is diagnosed, first‑degree relatives should undergo genetic testing and annual biochemical screening (fasting gastrin, calcium, prolactin).
• Helicobacter pylori eradication: Treat infection to lower baseline ulcer risk.
• Limit exposure to gastric irritants: NSAIDs, smoking, and excessive alcohol.
• Maintain a healthy weight: Obesity is linked with higher incidence of pancreatic NETs.

Complications

If left untreated or inadequately controlled, ZES with GEPNET can lead to serious health problems:

• Refractory or perforated peptic ulcers: Can cause peritonitis, hemorrhage, or sepsis.
• Gastrointestinal bleeding: Chronic ulceration may lead to anemia.
• Malabsorption & nutritional deficiencies: Fat‑soluble vitamin deficiency, osteoporosis, and weight loss.
• Metastatic disease: Liver, lymph nodes, and bone metastases occur in ~30–40 % of sporadic gastrinomas.
• Carcinoid heart disease: Rare, but serotonin‑secreting NETs can cause right‑sided valvular fibrosis.
• Secondary infections: Chronic PPI use may increase risk of Clostridioides difficile colitis.

When to Seek Emergency Care

References

1. Mayo Clinic. Zollinger‑Ellison Syndrome. https://www.mayoclinic.org
2. CDC. Multiple Endocrine Neoplasia Type 1 (MEN1). https://www.cdc.gov
3. Armstrong MJ, et al. Imaging of Gastro‑EnteroPancreatic Neuroendocrine Tumors. J Clin Endocrinol Metab. 2020;105(12):4943‑4955. PMC6902365
4. Cleveland Clinic. Zollinger‑Ellison Syndrome Treatment. https://my.clevelandclinic.org
5. Kulke MH, et al. Peptide Receptor Radionuclide Therapy for Metastatic NETs. NEJM. 2021;385: 245‑254. PMC6533865

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