Zollinger-Ellison syndrome (ORPHA:913)
Zollinger-Ellison syndrome (ZES) is characterized by severe peptic disease (ulcers/esophageal disease) caused by hypergastrinemia secondary to a gastrinoma resulting in increased gastric acid secretion.
Epidemiology
Annual incidence is estimated at 1-2 cases per million. The condition is slightly more common in females than males (sex ratio of 1.3:1).
Clinical description
ZES is usually diagnosed in the fifth decade of life. Abdominal pain (typically in the upper abdomen) and diarrhea are the most frequent manifestations. Heartburn is often present (44% of cases). Other signs include nausea, vomiting, malabsorption, and weight loss. Some patients present with ulcer complications (gastrointestinal bleeding, perforation and penetration).
Etiology
ZES is caused by a gastrin-secreting tumor (gastrinoma), usually located in the duodenum (50-85% of cases), pancreas, abdominal lymph nodes or, in rare cases, ectopic locations (heart, ovary, liver etc.). ZES can be sporadic (75% of cases) or associated with multiple endocrine neoplasia type 1 (MEN1; see this term), which is transmitted in an autosomal dominant manner. MEN1 is caused by mutations in the MEN1 gene (11q13) encoding menin, a protein which binds and regulates the activity of numerous transcription factors.
Diagnostic methods
Diagnosis of ZES is first suspected on the basis of the clinical manifestations. Elevated fasting serum gastrin (FSG) levels are almost invariably present. FSG levels 10 times higher than normal and a gastric pH of <2 confirm the diagnosis. If the FSG level is elevated less than 10 fold and the gastric pH is <2, secretin stimulation (abnormal: increase >120 pg/ML) and basal acid (abnormal: >15 mEq/hr-basal) tests need to be done. Imaging studies (somatostatin receptor scintigraphy, CT scan, abdominal or endoscopic ultrasound) are required to localize the gastrinoma. Esophagogastroduodenoscopy may be indicated to detect duodenal ulcerations.
Differential diagnosis
Differential diagnoses include other causes of increased acid output and elevated FSG levels: Helicobacter pylori infections, retained gastric antrum, gastric outlet obstruction, renal failure, antral G cell syndromes, idiopathic gastroesophageal reflux or peptic ulcer disease, and physiological causes of hypergastrinemia (atrophic gastritis, pernicious anemia, or use of potent antisecretory drugs).
Antenatal diagnosis
Antenatal genetic testing may allow prenatal diagnosis of MEN1 but not gastrinomas.
Genetic counseling
Genetic counseling should be offered to ZES patients with MEN1.
Management and treatment
Gastric acid hypersecretion must be controlled both in the short- and long-term. Oral H(+)-K(+)-ATPase inhibitors (proton-pump inhibitors; PPIs) are now the drugs of choice because of their long duration of action and potency (administered in once- or twice-a-day doses). Intravenous PPIs are effective when oral drugs cannot be taken. Histamine H2-receptor antagonists can also be effective but frequent high doses are needed by many patients. Management also includes treatment directed at the tumor itself as 60-90% of tumors are malignant. For localized disease in non-MEN1 patients, surgery is recommended. For advanced metastatic disease, numerous antitumor therapies are used including chemotherapy, biotherapy (somatostatin/interferon analogues), embolization of hepatic metastases and aggressive surgery. A number of newer treatments (including somatostatin receptor-mediated radiotherapy, novel chemotherapeutic agents and growth factor/tyrosine kinase inhibitors) are under investigation.
Prognosis
In the absence of liver metastases, the prognosis is favorable (10-year survival rate of 90-100%). Patients with liver metastases (65-75% of patients) have a 10-year survival rate of 20-40%. Patients with MEN1 are rarely cured surgically due to the presence of multiple tumors and lymph node metastases, however, only 15% pursue an aggressive course and 10 year survival is 80-98%.

                            Last update: 
                            May 2009


                            - Expert reviewer(s): 
                             Robert JENSEN