Zollinger-Ellison syndrome

ALSO KNOWN AS: Z-E syndrome, gastrinoma, ZES

RELATED CONDITIONS: Gastroesophageal reflux disease (GERD), peptic ulcer disease, multiple endocrine neoplasia syndrome I (MEN1)

DEFINITION: Zollinger-Ellison syndrome is a rare condition in which tumors called gastrinomas in the pancreas or duodenum of the small intestine produce abnormally high levels of the hormone gastrin. Gastrin overproduction induces excessive secretion of stomach acid, which erodes the inner linings of the stomach and upper small intestine.

Risk factors: Between 20 and 25 percent of Zollinger-Ellison syndrome cases occur in people with multiple endocrine neoplasia type 1 (MEN 1), an autosomal dominant genetic condition characterized by pituitary and pancreatic islet endocrine tumors and overactivity of the parathyroid glands.

Etiology and the disease process: The inner linings of the stomach and small intestine (mucous membranes) are composed of several different cell types that work together to digest food. One of these cell types, G cells, resides in the mucous membranes that line the stomach and upper small intestine (duodenum) and produces a protein hormone called gastrin that is released into the bloodstream. Gastrin directly stimulates another group of cells in the stomach mucosa called parietal cells to secrete hydrochloric acid. The production of acid by the parietal cells is the main reason for the highly acidic environment in the stomach. Gastrin also signals to a third group of cells in the lining of the stomach called enterochromaffin-like (ECL) cells, which produce histamine in response to gastrin. Histamine is a powerful parietal cell-signaling molecule that causes parietal cells to make even more hydrochloric acid, which helps purge the stomach of most microorganisms, denatures proteins in foodstuffs, and activates the stomach-specific enzyme pepsin, which is secreted by the chief cells, a fourth type of cell found in the stomach mucosa. Pepsin secretion by the chief cells is also stimulated by gastrin.

Gastrin secretion is stimulated by the stretching of the stomach, activity of the vagus nerve, presence of digested proteins in the stomach, or high blood calcium levels. The presence of large amounts of stomach acid and hormones made by lower portions of the gastrointestinal tract inhibits gastrin's release into the bloodstream.

Patients with Zollinger-Ellison syndrome have one or more, typically small tumors (gastrinomas) in the pancreas or duodenum that produce excessive quantities of gastrin. Because these tumors do not reside in the stomach, the usual mechanisms that down-regulate gastrin production are unavailable. Continuous production of high blood gastrin levels constantly stimulates the parietal cells to overproduce hydrochloric acid, which erodes the stomach and duodenal mucous membranes.

Patients with multiple endocrine neoplasia type 1 (MEN1) are at increased risk for Zollinger-Ellison syndrome. MEN1 is also known as Wermer syndrome and is inherited as an autosomal dominant genetic condition that maps to chromosome 11. Individuals with MEN1 also show a predisposition to develop pituitary, parathyroid, and pancreatic tumors.

Incidence: The international incidence of Zollinger-Ellison syndrome is approximately 0.5 to 3 cases per million patients per year.

Symptoms: The most common symptoms of Zollinger-Ellison syndrome are abdominal pain and diarrhea, usually experienced in combination, but not always. Other symptoms include heartburn, nausea, vomiting, loss of appetite, gastrointestinal bleeding, ulcers, and weight loss.

Screening and diagnosis: A blood test called a fasting serum gastrin test examines blood gastrin levels and is usually performed in combination with a gastric acid secretory test, which examines basic acid output (BAO). High blood gastrin levels and basic acid output are usually diagnostic for Zollinger-Ellison syndrome.

Gastrin provocative tests determine if gastrin production is subject to the normal control mechanisms. Typically, blood gastrin levels are measured before and after the patient, who has fasted all night, is injected with calcium or secretin, an inhibitor of gastrin production. Large jumps in blood gastrin concentrations (above 120 picograms per milliliter) are diagnostic for Zollinger-Ellison syndrome.

Imaging studies detect the actual tumor and determine its location, size, and whether it has undergone metastasis. The imaging method of choice is somatostatin receptor scintigraphy (SRS). Somatostatin binds to any gastrin-producing cell, and during SRS, a radioactively labeled somatostatin-like molecule is injected into the patient. This molecule homes to the tumor and labels it, allowing it to be viewed. Computed tomography (CT) and magnetic resonance imaging (MRI) scans are also used, as is upper gastrointestinal endoscopic ultrasound, which is more effective for detecting pancreatic gastrinomas. Esophagogastroduodenoscopy (EGD) is effective for visualizing the ulcerations present in the stomach and duodenum.

Treatment and therapy: Proton pump inhibitors are the drugs of choice to manage excessive acid production. These include omeprazole (Prilosec), lansoprazole (Prevacid), pantoprazole (Protonix), esomeprazole (Nexium), and rabeprazole (Aciphex). Somatostatin analogs are also used to reduce gastric acid and serum gastrin levels in patients with Zollinger-Ellison syndrome. In almost all cases, surgical removal of the tumors is highly recommended to prevent metastasis. In patients with mestases, chemotherapy, interferon, and octreotide can be tried, although their success rates are low. Liver translant may also be an option.

Prognosis, prevention, and outcomes: In patients without metastasis of the gastrinomas, prognosis is excellent. In these cases, the five-year survival rate is over 90 percent. MEN1 patients have a high frequency of recurrence. In those patients whose tumors have metastasized, the prognosis is rather poor; liver metastases are the primary cause of mortality in patients with Zollinger-Ellison syndrome.

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