ZOLLINGER-ELLISON SYNDROME (ZES)

Screening Criteria Hypergastrinemia

This disorder refers to the triad of a non-beta islet cell tumor, a greatly increased production of gastric acid, and severe peptic ulcer disease. Often, the associated tumors cannot be located even with invasive procedures such as laparotomy. Therefore, the diagnosis is often established based on the presence of certain chemical criteria which include an excessive fasting serum gastrin level that does not increase postprandially, an exaggerated response in the fasting serum gastrin level following an intravenous bolus of secretin, and basal acid hypersecretion. This disorder afflicts 0.1 to 1.0% of patients with peptic ulcer disease. Although most cases of peptic ulcer disease may be linked to a more common etiology (NSAID abuse or Helicobacter pylori infection), the diagnosis of ZES should be suspected in patients with PUD who deny NSAID use, who are negative for H. pylori infection, who suffer aggressive PUD refractory to therapy, who have associated diarrhea or steatorrhea, or who display a solitary duodenal-bulb ulcer or large gastric mucosal folds on esophagogastroduodenoscopy (EGD). Approximately 20% of cases are associated with type 1 multiple endocrine neoplasia (MEN-1), and this diagnosis should be suspected when PUD is associated with hypercalcemia, nephrolithiasis or pituitary tumors with resultant acromegaly, hyperprolactinemia, or hypopituitarism. MEN-1 associated gastrinomas are more likely to be multicentric and located in the duodenum. Men are affected more frequently with ZES than are women and the mean age at presentation is 45 to 50 years old.

The associated tumors are termed gastrinomas because of their ability to secrete excessive amounts of gastrin. These tumors are malignant in 60 to 90% of all cases. Although the majority of gastrinomas are located in the pancreas, other common sites of the tumor include the wall of the stomach or duodenum, the mesentery, the spleen, the liver, the ovaries, and in the lymph nodes. Approximately 80% of these tumors are located in the gastrinoma triangle, which is bordered by the neck of the pancreas, the confluence of the cystic and common bile ducts, and the third part of the duodenum.

Symptoms include those related to PUD plus the presence of diarrhea, steatorrhea, or gastroesophageal reflux disease (GERD). Once the diagnosis is suspected, the workup should include measurement of fasting serum gastrin levels. Normally, the level is less than 100 pg/ml. The gastrin value in ZES is almost always elevated; however, the values are not always extreme. In 40% of cases the serum gastrin value is less than 500 pg/ml. An elevated gastrin value is not always consistent with a diagnosis of ZES as many other conditions are associated with hypergastrinemia. However, in patients with hypergastrinemia in excess of 1000 pg/ml and a gastric pH of less than 2, the diagnosis of ZES may be made. Another method to establish the diagnosis in the presence of hypergastrinemia is to measure the basal acid output over 1 hour. This is done by placing a nasogastric tube and then aspirating gastric contents in 15 ml aliquots. The diagnosis of ZES is made when the basal acid output is greater than 15 mEq/hour (greater than 5 mEq/hour in patients who are post gastric surgery) in patients with elevated gastrin levels. Another chemical method to establish the diagnosis is the secretin provocative test which is performed in the following manner:

1. Obtain baseline fasting serum gastrin levels at 0 and 15 minutes.

2. After the second fasting serum gastrin sample is drawn, administer secretin 2U/kg as an

intravenous bolus.

3. Obtain blood samples for determination of the serum gastrin level at 2, 5, 10, 15, 20, and 30 minutes after administering the bolus of secretin.

The test is considered diagnostic of ZES if there is a rise of the serum gastrin from the baseline values of more than 200 pg/ml after the administration of secretin. The test is 87 to 93% sensitive and false-positive findings may be noted in patients with achlorhydria or in patients who are post vagotomy. An important clinical note is that in patients with a chemical analysis as described above which is consistent with ZES and who are suspected to possibly have MEN-1, measurement of serum levels of calcium, prolactin, luteinizing hormone, follicle-stimulating hormone, and growth hormone is prudent.

Once the diagnosis is established chemically, the next step entails tumor localization. Abdominal CT imaging after the infusion of intravenous contrast is a good initial study to detect tumor and rule out metastatic spread; however, MRI studies provide a better means for assessing hepatic involvement. Radionuclide scanning with octreotide is based on the fact that the radiolabeled octreotide, an analogue of somatostatin, will bind to the excessive number of somatostatin receptors on the gastrinoma cells. This study is very efficient in determining the extent of metastatic spread of the tumor. Arteriography is a means (sensitivity of approximately 50%) of detecting primary gastrinomas. If all of the above measures are not successful in tumor localization, exploratory laparotomy and intraoperative palpation may be successful at detecting duodenal gastrinomas. Intraoperative endoscopy with transillumination and duodenotomy along the lateral duodenal wall has been reported to increase the diagnostic yield.

Therapy for ZES should attempt to achieve two main goals, one is to control the symptoms related to gastric hypersecretion and the other is to control the associated tumor. The first goal may be accomplished via the use of histamine 2 blockers or proton pump inhibitors. The second goal of the treatment plan for patients with ZES (tumor control) may be accomplished surgically if the tumor can be localized and if there is no associated metastases or concomitant MEN-1 syndrome. If the tumor cannot be localized or resected, then highly selective vagotomy may aid medical management in controlling symptoms. Patients with associated MEN-1 syndrome are not considered surgical candidates because the gastrinomas associated with this syndrome are usually multiple submucosal and extrapancreatic tumors that are not amenable to resection. Approximately 15% of cases with liver metastases have disease that is localized to a single lobe and may therefore be potentially curable by surgical means. If widespread metastasis (liver, lymph nodes, or bone) is present, the current chemotherapy regimen used includes streptozocin with doxorubicin; however, this form of chemotherapy has not met with great success.