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 done 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 ulcers with 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 result in marked gastric hypersecretion with serious consequences and patients 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, a gastric secretory study) 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, serum parathyroid hormone (PTH), prolactin, luteinizing hormone-follicle-stimulating hormone (LH-FSH), and growth hormone (GH) levels 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.