Zollinger-Ellison Syndrome (ZES)

Definition, Etiology, PathogenesisTop

Zollinger-Ellison syndrome (ZES) is characterized by gastrin-secreting tumors (gastrinomas), which are most frequently located in the duodenum or pancreas, rarely in adjacent lymph nodes.

ZES is associated with refractory recurrent peptic ulcers due to hypergastrinemia and subsequent hyperplasia of parietal cells leading to hypersecretion of gastric acid. Diarrhea is a common sequela, caused by 3 mechanisms: high gastric acid secretion with inadequate intestinal reabsorption; inactivation of pancreatic digestive enzymes due to high-volume acid output and interference with bile acid–related emulsification, resulting in maldigestion and malabsorption; and inhibition of intestinal sodium and water reabsorption, causing secretory diarrhea.

In 80% of cases the tumors are sporadic. In 20% of cases they are associated with multiple endocrine neoplasia type 1 (MEN 1).

Most gastrinomas are well-differentiated neuroendocrine tumors. They predominantly secrete gastrin but may also secrete other neuroendocrine peptides, such as vasoactive intestinal peptide (VIP) and glucagon.

Clinical Features and Natural HistoryTop

Almost half of the patients have signs and symptoms consistent with the clinical picture of ZES. Common clinical features include persistent peptic ulcer disease (PUD), coexisting severe reflux esophagitis, diarrhea, steatorrhea, and weight loss. Acid hypersecretion–related structural complications such as strictures and perforation are seen, although uncommonly.

ZES-related PUD is often characterized as solitary ulcers sized <1 cm predominantly located in the first portion of the duodenum that are refractory to medical therapy and atypically recurrent in the absence of any other known causative variable. Ulcers may occur in unusual locations, including beyond the first or second duodenal segment.

The coexistence of pancreatic insulinoma, pituitary tumor, or hyperparathyroidism may be seen in the case of MEN 1.

Two-thirds of the tumors are malignant, but the rate of growth varies widely. They may metastasize, most frequently to the surrounding lymph nodes, liver, spleen, mediastinum, and bones. Duodenal gastrinomas are usually smaller, multifocal, and commonly associated with lymph node involvement. They are less likely to have metastasized to the liver at the time of diagnosis compared with pancreatic gastrinomas.

DiagnosisTop

ZES should be suspected in the setting of multiple, refractory, or atypically distal PUD, diarrhea, or MEN 1 history.

Diagnostic Tests

1. Laboratory tests:

1) Gastrin levels: The initial evaluation includes measurement of fasting serum gastrin concentration; a level ≥10 times the upper limit of normal with a gastric pH ≤2.0 confirms the diagnosis. Higher levels are more suggestive of pancreatic (as compared with duodenal) tumors, larger tumors, or metastatic disease.

2) Gastric pH: The initial evaluation includes measurement of gastric pH; low gastric pH with an elevated gastrin level is confirmatory. Elevated gastric pH despite high gastrin levels may be suggestive of etiologies that are related to secondary hypergastrinemia, such as those related to proton pump inhibitor (PPI) use.

3) Secretin stimulation test: In patients with gastrin or gastric pH levels that are not diagnostic, this test differentiates gastrinomas from other hypergastrinemia-related etiologies. Secretin stimulates gastrinoma cells, resulting in a dramatic serum gastrin rise in the setting of gastrinoma, compared with a normal response of G-cell inhibition. The test is conducted by administering a weight-based secretin dose and monitoring serum gastrin levels frequently within 20 minutes of administration. PPIs must be discontinued for a minimum of 3 weeks prior to testing to avoid false-positive results. The secretin stimulation test is considered positive if the gastrin level is >95 pmol/L (200 ng/L) in ≥1 sample. The test should be avoided in patients with active severe ZES symptoms.

4) Additional tests: Serum chromogranin (elevated), gastric acid secretion studies (basal acid output monitoring; this is not commonly performed due to technical difficulty).

5) Other related findings typical of MEN 1 syndrome (eg, hypercalcemia, parathyroid hormone, prolactin level) may be present.

2. Endoscopy: Hypertrophy of the gastric mucosal folds, ulcers in the upper gastrointestinal tract (~75% in the duodenal bulb), tumor localization.

3. Imaging studies: Somatostatin receptor scintigraphy (SRS) and endoscopic ultrasonography (EUS) (sensitivity, 80%; this permits fine-needle aspiration for histologic determination), ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and selective arteriography (sensitivity for pancreatic tumors, 75%-100%; sensitivity for duodenal tumors, 38%-63%; this is reserved for patients strongly suspected to have gastrinoma in the setting of negative imaging results).

4. Additional evaluation: Testing for inherited genetic syndromes (eg, MEN1, VHL, MUTYH, CHEK2, BRCA1, BRCA2).

Diagnostic Criteria

Diagnosis is based on the characteristic clinical features, typical laboratory findings, and location of the tumor confirmed using imaging studies.

Differential Diagnosis

PUD (particularly duodenal ulcers); other conditions associated with hypergastrinemia: pernicious anemia, proliferation of G cells in the prepyloric region (eg, atrophic gastritis, Helicobacter pylori infection, and patients after gastric resection with preserved prepyloric area [retained antrum syndrome]). If the diagnosis of ZES is confirmed or highly suspected, a diagnostic workup of MEN 1 syndrome should be conducted, as 20% to 25% of patients have MEN 1.

TreatmentTop

The goal of treatment is to heal peptic ulcers and remove the gastrin-secreting tumor(s), whenever possible. Medical therapy is the standard of care for most ZES patients with MEN 1 syndrome, whereas curative surgery is the standard for patients with sporadic disease and no metastatic spread.

1. Medical therapy: PPIs in higher doses, for example, omeprazole 60 mg daily, esomeprazole 120 mg daily, lansoprazole 45 mg daily, rabeprazole 60 mg daily, or pantoprazole 80 mg daily.

Somatostatin analogues may be used in patients with symptomatic metastatic gastrinomas, although response is variable.

2. Surgical treatment: Curative tumor resection. If location of the tumor was not established using imaging tests, exploratory laparotomy with careful inspection of the abdominal cavity should be performed. Approximately 50% of patients who have had a tumor successfully removed remain in good clinical condition for many years; the others require further anticancer treatment. Successful resection reduces the risk of morbidity associated with subsequent metastatic tumor spread.

For patients with resectable liver-isolated metastatic gastrinoma-related disease, surgical resection of hepatic metastases may be considered along with primary tumor resection. Where unresectable, bland embolization, embolization with chemotherapy, embolization with radiation therapy, or ablation may be considered.