What is Zollinger-Ellison syndrome, its symptoms, cause, and treatment?

Zollinger-Ellison Syndrome: Overview, Symptoms, Causes, and Treatment

Zollinger-Ellison syndrome (ZES) is a rare disorder characterized by gastrin-secreting neuroendocrine tumors (gastrinomas) that cause excessive gastric acid production, leading to severe peptic ulceration and diarrhea, with treatment primarily consisting of proton pump inhibitors for symptom control and surgical resection when possible for the underlying gastrinoma. 1

What is Zollinger-Ellison Syndrome?

Zollinger-Ellison syndrome is a clinical condition caused by gastrinomas, which are neuroendocrine tumors that secrete excessive amounts of the hormone gastrin. These tumors are most commonly located in the "gastrinoma triangle" which includes:

• Duodenum (most common location)
• Pancreas
• Extra-hepatic biliary system

The syndrome can occur sporadically (approximately 75% of cases) or as part of Multiple Endocrine Neoplasia type 1 (MEN1) syndrome (approximately 25% of cases). 2

Symptoms

The excessive gastrin production leads to several characteristic symptoms:

• Severe peptic ulceration: Often multiple, recurrent, and atypically located ulcers (including jejunal ulcers)
• Diarrhea: Occurs in approximately 50% of patients at diagnosis 1
• Abdominal pain: Present in about 70% of patients at diagnosis 1
• Gastroesophageal reflux disease (GERD): Common due to acid hypersecretion
• Weight loss: Due to malabsorption and chronic diarrhea
• Gastrointestinal bleeding: From ulcerations

The symptoms often persist for years before diagnosis, with an average delay of 5-7 years from symptom onset to diagnosis. 3

Cause

The primary cause of ZES is a gastrin-secreting neuroendocrine tumor (gastrinoma). These tumors can be:

1. Sporadic: Occurring without genetic predisposition (75% of cases)
2. Associated with MEN1: A hereditary condition caused by mutations in the MEN1 gene (25% of cases)

Gastrinomas have malignant potential, with metastases developing in approximately 60% of patients. The likelihood of metastasis correlates with the size of the primary tumor. 1

Diagnosis

Diagnosis of ZES involves several key steps:

1. Biochemical testing:

   • Fasting serum gastrin level >100 pg/mL (sensitivity 99%)
   • Gastrin level >1000 pg/mL with gastric pH <2 is diagnostic 2
   • Secretin stimulation test: Paradoxical rise in gastrin after secretin administration

2. Imaging studies:

   • CT/MRI scans (multiphase for liver metastases)
   • Somatostatin receptor scintigraphy (Octreoscan)
   • Endoscopic ultrasound (83% sensitivity for pancreatic gastrinomas) 2
   • Gallium-68 DOTATOC PET (current gold standard for localization)

3. Endoscopy:

   • Upper endoscopy to identify ulcerations
   • Endoscopic ultrasound for tumor localization

Treatment

Medical Management

1. Proton Pump Inhibitors (PPIs):

   • First-line therapy for controlling acid hypersecretion
   • Lansoprazole 60 mg daily is the FDA-approved starting dose 4
   • Dose can be adjusted based on individual response
   • Doses up to 90 mg twice daily may be needed in some patients
   • Daily doses greater than 120 mg should be administered in divided doses 4

2. Somatostatin Analogs (SSAs):

   • Octreotide or lanreotide for symptom control in patients with gastrinoma 1
   • May help control tumor growth in well-differentiated tumors 5

Surgical Management

1. Sporadic ZES:

   • Surgical exploration is recommended for potential curative resection in patients without unresectable metastatic disease 1, 6
   • Complete resection can result in 10-year survival of 90% 1

2. ZES with MEN1:

   • Surgical approach is more controversial
   • Evaluation and treatment of associated hyperparathyroidism is required 2

3. Metastatic Disease:

   • Debulking surgery may be considered for dominant symptomatic lesions 1
   • Liver-directed therapies for hepatic metastases

Prognosis

Prognosis depends on several factors:

• Complete resection results in 10-year survival of 90% for gastrinomas 1
• Survival is less favorable with larger primary tumors or metastatic disease
• With modern PPI therapy, mortality from acid hypersecretion complications is rare 7

Special Considerations

1. Monitoring:

   • Regular follow-up with gastrin levels and imaging studies
   • Adjustment of PPI dosage as needed

2. MEN1 Association:

   • All patients should be evaluated for other endocrine tumors 1
   • Genetic testing for MEN1 mutations should be considered

3. Medication Management:

   • PPIs should be continued long-term in most patients
   • If surgery is performed, PPIs may still be required post-operatively until gastrin levels normalize

The management of ZES has dramatically improved with the advent of PPIs, transforming what was once a condition requiring total gastrectomy into a manageable chronic disease with excellent long-term outcomes when properly treated.