Zollinger-Ellison Syndrome

Essentials of Diagnosis

• Peptic ulcer disease, may be severe and atypical

• Gastric acid hypersecretion

• Diarrhea common, relieved by nasogastric suction

• Most cases are sporadic; 25% with multiple endocrine neoplasia (MEN) type 1

General Considerations

• Caused by gastrin-secreting gut neuroendocrine tumors (gastrinomas), which result in hypergastrinemia and acid hypersecretion

• Gastrinomas cause < 1% of peptic ulcers

• Primary gastrinomas may arise in the pancreas (25%), duodenal wall (45%), lymph nodes (5–15%), or other locations (20%)

• Most gastrinomas are solitary or multifocal nodules that are potentially resectable; 25% are small multicentric gastrinomas associated with MEN 1 that are more difficult to resect

• Gastrinomas are malignant in less than two-thirds; one-third have already metastasized to the liver at initial presentation

• Screening for Zollinger-Ellison syndrome with fasting gastrin levels indicated for patients with

  • Ulcers refractory to standard therapies

  • Giant ulcers (> 2 cm)

  • Ulcers located distal to the duodenal bulb

  • Multiple duodenal ulcers

  • Frequent ulcer recurrences

  • Ulcers associated with diarrhea

  • Ulcers occurring after ulcer surgery

  • Ulcers with complications

  • Ulcers with hypercalcemia

  • Family history of ulcers

  • Ulcers not related to Helicobacter pylori or nonsteroidal anti-inflammatory drugs (NSAIDs)

Symptoms and Signs

• Peptic ulcers in > 90%, usually solitary and in proximal duodenal bulb, but may be multiple or in distal duodenum

• Isolated gastric ulcers do not occur

• Gastroesophageal reflux symptoms

• Diarrhea, steatorrhea, and weight loss secondary to pancreatic enzyme inactivation

Differential Diagnosis

• Peptic ulcer disease due to other cause, eg, NSAIDs, H pylori

• Gastroesophageal reflux disease, esophagitis, gastritis, pancreatitis, or cholecystitis

• Diarrhea due to other cause

• Other gut neuroendocrine tumor

  • Carcinoid

  • Insulinoma

  • VIPoma

  • Glucagonoma

  • Somatostatinoma

• Hypergastrinemia due to other cause

  • Pernicious anemia

  • Gastric outlet obstruction

  • Vagotomy

  • Chronic kidney disease

Laboratory Tests

• Fasting serum gastrin concentration increased (> 150 pg/mL [> 150 ng/L]) in patients not taking H₂-receptor antagonists for 24 h or proton pump inhibitor for 6 days

• Serum calcium, parathyroid hormone, prolactin, leutinizing hormone, follicle-stimulating hormone, and growth hormone level in all patients with Zollinger-Ellison syndrome to exclude MEN 1

• Gastric pH of > 3.0 implies hypochlorhydria and excludes gastrinoma

Imaging Studies

• CT and MRI scans

  • Commonly obtained to look for large hepatic metastases and primary lesions

  • However, they have low sensitivity for small lesions

• Somatostatin receptor scintigraphy (SRS) with SPECT has high sensitivity (> 80%) for detecting hepatic metastases, as well as primary tumors

• Endoscopic ultrasonography (EUS)

  • Indicated in patients with negative SRS

  • May be useful to detect small gastrinomas in the duodenal wall, pancreas, or peripancreatic lymph nodes

• Combination of SRS and EUS can localize > 90% of primary gastrinomas preoperatively

Diagnostic Procedures

• Secretin stimulation test distinguishes Zollinger-Ellison syndrome from other causes of hypergastrinemia

• Secretin, 2 units/kg intravenously, produces a rise in serum gastrin of > 200 pg/mL (200 ng/L) within 2–30 min in 85% of patients with gastrinoma

Medications

• Proton pump inhibitors (omeprazole, rabeprazole, pantoprazole, esomeprazole, or lansoprazole), 40–120 mg/day, titrated to achieve a basal acid output of < 10 mEq/h for metastatic disease

Surgery

• Primary resection of gastrinoma at laparotomy for localized disease

• Preoperative studies, duodenotomy with careful duodenal inspection, and intraoperative palpation and sonography allow successful localization and resection in the majority of cases

• Surgical resection of isolated hepatic metastases

Complications

• In patients with unresectable disease, complications of gastric acid hypersecretion can be prevented in almost all cases by sufficient doses of proton pump inhibitors

• Treatment options for metastatic disease include interferon, octreotide, combination therapy, and chemoembolization

Prognosis

• 15-year survival of patients without liver metastases at initial presentation is > 95%

• 10-year survival of patients with hepatic metastases is 30%

When to Refer

• All patients with Zollinger-Ellison syndrome should be referred to a gastrointestinal surgeon with expertise in evaluation and management