Zollinger-Ellison Syndrome

Zollinger-Ellison Syndrome

ZES is caused by the uncontrolled secretion of abnormal amounts of gastrin by a duodenal or pancreatic neuroendocrine tumor (i.e., gastrinoma). Most cases (80%) are sporadic, but 20% are inherited. The inherited or familial form of gastrinoma is associated with multiple endocrine neoplasia type 1 (MEN1), which consists of parathyroid, pituitary, and pancreatic (or duodenal) tumors. Gastrinoma is the most common pancreatic tumor in patients with MEN I. Patients with MEN I usually have multiple gastrinoma tumors, and surgical cure is unusual. Sporadic gastrinomas are more often solitary and amenable to surgical cure. Currently, about 50 to 60% of gastrinomas are malignant, with lymph node, liver, or other distant metastases at operation. Five-year survival in patients presenting with metastatic disease is approximately 40%. The larger the primary gastrinoma, the higher the likelihood of metastatic disease. More than 90% of patients with sporadically, completely resected gastrinoma will be cured.

The most common symptoms of ZES are epigastric pain, GERD, and diarrhea. More than 90% of patients with gastrinoma have peptic ulcer. Most ulcers are in the typical location (proximal duodenum), but atypical ulcer location (distal duodenum, jejunum, or multiple ulcers) should prompt an evaluation for gastrinoma. Gastrinoma also should be considered in the differential diagnosis of recurrent or refractory peptic ulcer, secretory diarrhea, gastric rugal hypertrophy, esophagitis with stricture, bleeding or perforated ulcer, familial ulcer, peptic ulcer with hypercalcemia, and gastric carcinoid. The majority of patients with ZES have been symptomatic for several years before definitive diagnosis and, in general, patients with ZES and MEN1 are diagnosed in their 20s and 30s, while those with sporadic ZES more typically are diagnosed in their 40s and 50s.

ZES is an important part of the differential diagnosis of hypergastrinemia. All patients with gastrinoma have an elevated gastrin level, and hypergastrinemia in the presence of elevated BAO strongly suggests gastrinoma. Patients with gastrinoma usually have a BAO >15 mEq/h or >5 mEq/h if they have had a previous procedure for peptic ulcer. Acid secretory medications should be held for several days before gastrin measurement, because acid suppression may falsely elevate gastrin levels. Causes of hypergastrinemia can be divided into those associated with hyperacidity and those associated with hypoacidity . The diagnosis of ZES is confirmed by the secretin stimulation test. An IV bolus of secretin (2 U/kg) is given and gastrin levels are checked before and after injection. An increase in serum gastrin of 200 pg/mL or greater suggests the presence of gastrinoma. Patients with gastrinoma should have serum calcium and parathyroid hormone levels determined to rule out MEN1 and, if present, parathyroidectomy should be considered before resection of gastrinoma.

Eighty percent of primary tumors are found in the gastrinoma triangle, and many tumors are small (<1 cm), making preoperative localization difficult. Transabdominal ultrasound is quite specific, but not very sensitive. CT will detect most lesions >2 cm in size and MRI is comparable. EUS is more sensitive than these other noninvasive imaging tests, but it still misses many of the smaller lesions, and may confuse normal lymph nodes for gastrinomas. Currently, the preoperative imaging study of choice for gastrinoma is somatostatin receptor scintigraphy (the octreotide scan). When the pretest probability of gastrinoma is high, the sensitivity and specificity of this modality approach 100%. Gastrinoma cells contain type 2 somatostatin receptors that bind the indium-labeled somatostatin analogue (octreotide) with high affinity, making imaging with a gamma camera possible. Currently, angiographic localization studies are infrequently performed for gastrinoma. Both diagnostic angiography and transhepatic selective venous sampling of the portal system have been supplanted by selective secretin infusion, which helps to localize the tumor as inside or outside the gastrinoma triangle.

In this test, an arterial catheter is selectively placed in a named vessel supplying the pancreas (e.g., gastroduodenal or splenic), and a venous catheter is placed in a hepatic vein. Secretin is injected into the visceral artery and gastrin is sampled in the hepatic vein. A significant elevation in hepatic venous gastrin indicates that the tumor is supplied by the injected artery. This test should be performed if pancreaticoduodenectomy is contemplated. Probably the most important means of locating gastrinomas is intraoperative exploration.

All patients with sporadic (nonfamilial) gastrinoma should be considered for surgical resection and possible cure. The lesions should be located in 90% of patients, and the large majority is cured by extirpation of the gastrinoma(s). A thorough intraoperative exploration of the gastrinoma triangle and pancreas is essential, but other sites (i.e., liver, stomach, small bowel, mesentery, and pelvis) should be evaluated as part of a thorough intra-abdominal evaluation to find the primary tumor, which is usually solitary. The duodenum and pancreas should be extensively mobilized and intraoperative ultrasound should be used. Intraoperative EGD with transillumination should be considered. If the tumor cannot be located, generous longitudinal duodenotomy with inspection and palpation of the duodenal wall should be considered. Lymph nodes from the portal, peripancreatic, and celiac drainage basins should be sampled. Ablation or resection of hepatic metastases should be considered.

The management of gastrinoma in patients with MEN1 is controversial because the patients are rarely cured by operation, and the tumors tend to be small and multiple. If the tumor can be imaged preoperatively, operation by an experienced gastrinoma surgeon is reasonable.

Acid hypersecretion in patients with gastrinoma can always be managed with high-dose PPIs. Highly selective vagotomy may make management easier in some patients and should be considered in those with surgically untreatable or unresectable gastrinoma. Gastrectomy for ZES is no longer indicated.

Reference: Schwartz's principles surgery 9th edition