(Zollinger-Ellison Syndrome; Z-E Syndrome)
(See also Overview of Pancreatic Endocrine Tumors.)
Gastrinomas are a type of pancreatic endocrine tumor that arises from islet cells but can also arise from the gastrin-producing cells in duodenum and, much less rarely, other sites in the body. Gastrinomas occur in the pancreas or duodenal wall 80 to 90% of the time. The remainder occur in the splenic hilum, mesentery, stomach, lymph node, or ovary. About 50% of patients have multiple tumors. Gastrinomas usually are small (< 1 cm in diameter) and grow slowly. About 50% are malignant. About 40 to 60% of patients with gastrinoma have multiple endocrine neoplasia.
Zollinger-Ellison syndrome typically manifests as aggressive peptic ulcer disease, with ulcers occurring in atypical locations (up to 25% are located distal to the duodenal bulb). However, as many as 25% of patients do not have an ulcer at diagnosis. Typical ulcer symptoms and complications (eg, perforation, bleeding, obstruction) can occur. Diarrhea is the initial symptom in 25 to 40% of patients.
Gastrinoma is suspected by history, particularly when symptoms are refractory to standard acid suppressant therapy.
Serum gastrin level is the most reliable test. All patients have levels > 150 pg/mL (> 72.15 pmol/L); markedly elevated levels of > 1000 pg/mL (> 480 pmol/L) in a patient with compatible clinical features and gastric acid hypersecretion of > 15 mEq/hour establish the diagnosis. However, moderate hypergastrinemia can occur with hypochlorhydric states (eg, pernicious anemia, chronic gastritis, use of proton pump inhibitors), in renal insufficiency with decreased clearance of gastrins, in massive intestinal resection, and in pheochromocytoma.
A secretin provocative test may be useful in patients with gastrin levels < 1000 pg/mL (< 480 pmol/L). An IV bolus of secretin 2 mcg/kg is given with serial measurements of serum gastrin (10 minutes and 1 minute before, and 2, 5, 10, 15, 20, and 30 minutes after injection). The characteristic response in gastrinoma is an increase in gastrin levels, the opposite of what occurs in patients with antral G-cell hyperplasia or typical peptic ulcer disease. Patients also should be evaluated for Helicobacter pylori infection, which commonly results in peptic ulceration and moderate excess gastrin secretion.
Once the diagnosis of gastrinoma has been established, the tumor or tumors must be localized. The first test is abdominal CT or somatostatin receptor scintigraphy, which may identify the primary tumor and metastatic disease. PET or selective arteriography with magnification and subtraction is also helpful. If no signs of metastases are present and the primary is uncertain, endoscopic ultrasonography should be done. Selective arterial secretin injection is an alternative.
Proton pump inhibitors are the drugs of choice (eg, omeprazole or esomeprazole 40 mg orally 2 times a day). The dose may be decreased gradually once symptoms resolve and acid output declines. A maintenance dose is needed; patients need to take these drugs indefinitely unless they undergo surgery.
Octreotide injections, 100 to 500 mcg subcutaneously twice a day to 3 times a day, may also decrease gastric acid production and may be palliative in patients not responding well to proton pump inhibitors. A long-acting form of octreotide (20 to 30 mg IM once a month) can be used.
Surgical removal should be attempted in patients without apparent metastases. At surgery, duodenotomy and intraoperative endoscopic transillumination or ultrasonography help localize tumors. Surgical cure is possible in 20% of patients if the gastrinoma is not part of a multiple endocrine neoplasia syndrome.
In patients with metastatic disease, streptozocin in combination with 5-fluorouracil or doxorubicin is the preferred chemotherapy for islet cell tumors. It may reduce tumor mass (in 50 to 60%) and serum gastrin levels and is a useful adjunct to omeprazole. Newer chemotherapies under investigation for insulinoma include temozolomide-based regimens, everolimus, or sunitinib. Patients with metastatic disease are not cured by chemotherapy.
Most gastrinomas manifest with peptic ulcer symptoms, but some patients present with diarrhea.
About half of patients have multiple gastrinomas and about half have multiple endocrine neoplasia syndrome; half of gastrinomas are malignant.
Serum gastrin levels are usually diagnostic, but patients with borderline elevated levels may need a secretin provocative test.
Tumors can usually be localized with CT, somatostatin receptor scintigraphy, or positron emission tomography (PET).
Acid secretion is suppressed with a proton pump inhibitor, sometimes also with octreotide, pending surgical removal.