Zollinger-Ellison syndrome is a rare condition in which one or more tumors form in your pancreas or the upper part of your small intestine (duodenum). These tumors, called gastrinomas, secrete large amounts of the hormone gastrin, which result in hypergastrinemia and acid hypersecretion. Less than 1% of peptic ulcer disease is caused by gastrinomas. Primary gastrinomas may arise in the pancreas (25%), duodenal wall (45%), or lymph nodes (5–15%), and in other locations or of unknown primary (20%). Approximately 80% arise within the “gastrinoma triangle” bounded by the porta hepatis, the neck of the pancreas, and the third portion of the duodenum.
Most gastrinomas are solitary or multifocal nodules that are potentially resectable. Approximately 25% of patients have small multicentric gastrinomas associated with MEN 1 that are more difficult to resect. Over two-thirds of gastrinomas are malignant, and one-third have already metastasized to the liver at initial presentation.
Signs and symptoms
- Over 90% of patients with Zollinger-Ellison syndrome develop peptic ulcers.
In most cases, the symptoms are indistinguishable from other causes of peptic ulcer disease and therefore the syndrome may go undetected for years. Ulcers usually are solitary and located in the duodenal bulb, but they may be multiple or occur more distally in the duodenum. Isolated gastric ulcers do not occur.
- Gastroesophageal reflux symptoms occur often.
- Diarrhea occurs in one-third of patients, in some cases in the absence of peptic symptoms.
Gastric acid hypersecretion can cause direct intestinal mucosal injury and pancreatic enzyme inactivation, resulting in diarrhea, steatorrhea, and weight loss; nasogastric aspiration of stomach acid stops the diarrhea.
Screening for Zollinger-Ellison syndrome with fasting gastrin levels should be obtained in patients with ulcers that are refractory to standard therapies, giant ulcers (larger than 2 cm), ulcers located distal to the duodenal bulb, multiple duodenal ulcers, frequent ulcer recurrences, ulcers associated with diarrhea, ulcers occurring after ulcer surgery, and patients with ulcer complications. Ulcer patients with hypercalcemia or family histories of ulcers (suggesting MEN 1) should also be screened. Finally, patients with peptic ulcers who are H pylori–negative and who are not taking NSAIDs should be screened.
The most sensitive and specific method for identifying Zollinger-Ellison syndrome is demonstration of an increased fasting serum gastrin concentration (greater than 150 pg/ mL [150 ng/L]). If possible, levels should be obtained with patients not taking H2-receptor antagonists for 24 hours or proton pump inhibitors for 6 days; however, withdrawal of the proton pump inhibitor may be accompanied by massive gastric hypersecretion with serious consequences and should be closely monitored.
The median gastrin level is 500–700 pg/mL (500–700 ng/L), and 60% of patients have levels less than 1000 pg/mL (1000 ng/L). Hypochlorhydria with increased gastric pH is a much more common cause of hypergastrinemia than is gastrinoma. Therefore, a measurement of gastric pH (and, where available, gastric secretory studies) is performed in patients with fasting hypergastrinemia. Most patients have a basal acid output of over 15 mEq/h. A gastric pH of greater than 3.0 implies hypochlorhydria and excludes gastrinoma. In a patient with a serum gastrin level of greater than 1000 pg/mL (1000 ng/L) and acid hypersecretion, the diagnosis of Zollinger-Ellison syndrome is established. With lower gastrin levels (150–1000 pg/mL [150–1000 ng/L]) and acid secretion, a secretin stimulation test may be performed to distinguish Zollinger-Ellison syndrome from other causes of hypergastrinemia. Intravenous secretin (2 units/kg) produces a rise in serum gastrin of over 200 pg/mL (200 ng/L) within 2–30 minutes in 85% of patients with gastrinoma.
An elevated serum calcium suggests hyperparathyroidism and MEN 1 syndrome. In all patients with Zollinger-Ellison syndrome, a serum parathyroid hormone (PTH), prolactin, luteinizing hormone-follicle-stimulating hormone (LH-FSH), and growth hormone (GH) level should be obtained to exclude MEN 1.
Imaging studies are obtained in an attempt to determine whether there is metastatic disease and, if not, to identify the site of the primary tumor. CT and MRI scans are commonly obtained first to look for large hepatic metastases and primary lesions, but they have low sensitivity for small lesions.
Gastrinomas express somatostatin receptors that bind radiolabeled octreotide. Somatostatin receptor scintigraphy (SRS) with single photon emission computed tomography (SPECT) allows total body imaging for detection of primary gastrinomas in the pancreas and lymph nodes, primary gastrinomas in unusual locations, and metastatic gastrinomas (liver and bone). The 80% sensitivity for tumor detection of SRS exceeds all other imaging studies combined. If SRS is positive for tumor localization, further imaging studies are not necessary. In patients with negative SRS, endoscopic ultrasonography (EUS) may be useful to detect small gastrinomas in the duodenal wall, pancreas, or peripancreatic lymph nodes. With a combination of SRS and EUS, more than 90% of primary gastrinomas can be localized preoperatively.
Gastrinomas are one of several gut neuroendocrine tumors that have similar histopathologic features and arise either from the gut or pancreas. These include carcinoid, insulinoma, VIPoma, glucagonoma, and somatostatinoma. These tumors usually are differentiated by the gut peptides that they secrete; however, poorly differentiated neuroendocrine tumors may not secrete any hormones. Patients may present with symptoms caused by tumor metastases (jaundice, hepatomegaly) rather than functional symptoms. Once a diagnosis of a neuroendocrine tumor is established from the liver biopsy, the specific type of tumor can subsequently be determined. Both carcinoid and gastrinoma tumors may be detected incidentally during endoscopy after biopsy of a submucosal nodule and must be distinguished by subsequent studies.
Hypergastrinemia due to gastrinoma must be distinguished from other causes of hypergastrinemia. Atrophic gastritis with decreased acid secretion is detected by gastric secretory analysis. Other conditions associated with hypergastrinemia (eg, gastric outlet obstruction, vagotomy, chronic kidney disease) are associated with a negative secretin stimulation test.
The most important predictor of survival is the presence of hepatic metastases. In patients with multiple hepatic metastases, initial therapy should be directed at controlling hypersecretion. Oral proton pump inhibitors (omeprazole, esomeprazole, rabeprazole, pantoprazole, or lansoprazole) are given at a dose of 40–120 mg/day, titrated to achieve a basal acid output of less than 10 mEq/h. At this level, there is complete symptomatic relief and ulcer healing. Owing to the slow growth of these tumors, 30% of patients with hepatic metastases have a survival of 10 years.
Cure can be achieved only if the gastrinoma can be resected before hepatic metastatic spread has occurred. Lymph node metastases do not adversely affect prognosis. Laparotomy should be considered in all patients in whom preoperative studies fail to demonstrate hepatic or other distant metastases. A combination of preoperative studies, duodenotomy with careful duodenal inspection, and intraoperative palpation and sonography allows successful localization and resection in the majority of cases. The 15-year survival of patients who do not have liver metastases at initial presentation is over 95%. Surgery usually is not recommended in patients with MEN 1 due to the presence of multifocal tumors and long-term survival in the absence of surgery in most patients.