Summary
A gastrinoma (i.e., Zollinger-Ellison syndrome) is a gastrin-secreting neuroendocrine tumor and is most often located in the duodenum and pancreas. Most gastrinomas occur sporadically, but some are associated with other endocrine neoplasias (e.g., pituitary adenomas, parathyroid adenomas, insulinomas). More than half of all gastrinomas are malignant. Gastrinomas release high levels of gastrin, which stimulates the production of gastric acid. Patients typically present with recurrent, therapy-resistant peptic ulcer disease and diarrhea. Diagnosis is confirmed by findings of a fasting gastric pH ≤ 2 and fasting serum gastrin (FSG) > 1000 pg/mL. In case of diagnostic uncertainty after initial testing, a secretin stimulation test is obtained. The primary objectives of management are controlling acid hypersecretion and managing the malignant tumor. Proton pump inhibitors (PPIs) are the preferred therapy to control acid secretion. Surgical tumor resection is indicated in patients with localized disease. Chemotherapy and radiation may be considered in advanced disease.
Epidemiology
References:[1]
Epidemiological data refers to the US, unless otherwise specified.
Etiology
- Gastrinomas are assumed to arise from endocrine cells of the gut (mostly the duodenum) or the pancreas.
- Most gastrinomas occur sporadically (∼ 75% of cases). [2]
- Some gastrinomas occur in association with multiple endocrine neoplasia type 1 (MEN 1) (∼ 25% of cases). [2]
References:[3][4][5]
Pathophysiology
- Gastrinomas are neuroendocrine tumors of the GI tract that secrete gastrin.
-
Hypergastrinemia → stimulation of parietal cells → gastric acid hypersecretion, which leads to:
- Peptic ulcer disease
- Inactivation of pancreatic enzymes → diarrhea, steatorrhea → malabsorption
- ∼ 60% of gastrinomas are malignant (but slow-growing) [6]
Other causes of hypergastrinemia include PPI use, H. pylori infection, atrophic gastritis, chronic renal failure, vagotomy, gastric outlet obstruction, retained antrum syndrome, and extensive small bowel resection. [7]
References:[1][5][8]
Clinical features
Most patients manifest with recurrent, therapy-resistant peptic ulcer disease.
- Abdominal pain
- Diarrhea and steatorrhea
- Dyspeptic symptoms (e.g., heartburn)
- Upper gastrointestinal bleeding
- Weight loss
- Possible symptoms of other endocrine neoplasias (see multiple endocrine neoplasias for more information).
References:[1][8]
Diagnosis
Approach [9][10][11]
- Consider gastrinoma in patients with recurrent, therapy-resistant PUD, GERD, abdominal pain, and/or diarrhea.
- Obtain FSG and gastric pH levels in all patients.
- If initial studies are inconclusive, order a secretin stimulation test or measure basal gastric acid output.
- After diagnostic confirmation:
- Assess for underlying MEN 1 syndrome and other related conditions.
- Obtain EGD and abdominal imaging to localize the gastrinoma and assess for metastases.
To reduce the risk of severe complications of acid hypersecretion and peptic ulcer disease, avoid abruptly stopping PPIs when adequate coverage with H2RAs and/or antacids is unavailable. [12]
Laboratory studies [7][10]
Confirmatory studies
Consider stopping acid suppression medications prior to testing, if safe to do so. [11]
-
Fasting serum gastrin (FSG) and gastric pH (initial studies) ; [12]
- FSG > 1000 pg/mL and gastric pH < 2: gastrinoma is confirmed. [10]
- FSG 101–1000 pg/mL and gastric pH < 2; : inconclusive result; perform a secretin stimulation test [10]
- Gastric pH ≥ 2: gastrinoma is unlikely [7]
-
Secretin stimulation test
- Indication: inconclusive results of initial studies
- Mechanism [12]
- Findings
- ↑ Serum gastrin by > 120 pg/mL over baseline FSG confirms gastrinoma [9][12]
- False positives may occur due to secondary hypergastrinemia (e.g., H. pylori infection, chronic PPI use). [13]
-
Basal acid output [9]
- Indication: secretin stimulation test is unavailable or unreliable (e.g., due to PPI use)
- Findings: Basal acid output > 15 mEq/h suggests gastrinoma [9]
When it is safe to do so, stop acid suppression medications prior to performing confirmatory studies (PPIs: ≥ 1 week before; H2 receptor blockers (H2RAs): ≥ 24 hours before). [11]
Follow-up studies
If gastrinoma is confirmed, consider the following studies in consultation with a specialist (e.g., gastroenterology, endocrinology).
- Assessment for MEN 1, e.g.: [9][14]
- ↑ Calcium and parathyroid hormone levels: primary hyperparathyroidism
- ↑ Prolactin level: prolactinoma
- Mutation of the MEN1 gene on genetic testing
- Assessment for other hormonal syndromes (e.g., diagnostics for Cushing syndrome) [9]
- H. pylori stool antigen test
Up to 50% of all patients with gastrinoma have concomitant H. pylori infection; H. pylori infection can also cause a false positive on secretin stimulation test. [9][12]
Tumor localization [9]
Esophagogastroduodenoscopy (EGD) [12]
- Indication: all patients with confirmed gastrinoma
- Goals
-
Findings [9]
- Single duodenal ulcers (most common) or multiple ulcers in atypical locations (e.g., distal duodenum, jejunum)
- Thick gastric folds
The presence of multiple ulcers in atypical locations (e.g., the jejunum) should raise suspicion of gastrinoma. [15]
Imaging [9]
Obtain cross sectional imaging and either PET/CT or scintigraphy in all patients with confirmed gastrinoma.
-
Modalities
- CT or MRI abdomen with contrast
- Gallium PET/CT scan (preferred) or somatostatin receptor scintigraphy (octreotide scan) [10]
- Endoscopic ultrasonography (EUS) if PET/CT is not used [10]
- Findings [7]
Most gastrinomas are found in an area called the gastrinoma triangle. The superior vertex of the gastrinoma triangle is formed by the junction of the bile and cystic ducts, the medial vertex by the neck of the pancreas, and the inferior vertex by the third portion of the duodenum. [9]
Treatment
Gastrinomas are primarily managed by specialists (e.g., gastroenterology, oncology, surgery).
Pharmacological therapy [10]
-
Acid suppression medications: indicated for all patients with gastrinoma
- First-line: PPIs (e.g., omeprazole ) [9]
- Second-line: H2RBs (e.g., famotidine )
- Somatostatin analog: (e.g., octreotide): consider in advanced disease [7][9]
PPIs are preferred because of their long half-life. H2RAs should not be used for initial therapy because of very high and frequent dosing requirements (i.e., every 4–6 hours). [9]
Surgery [10]
- Exploration laparotomy: all patients with sporadic gastrinomas to identify tumors not seen on imaging
- Resection considered for:
- Liver transplant: considered for patients with metastases confined to the liver [7]
Anticancer therapy [9][10]
Consider the following therapies in patients with advanced or refractory disease.
- Chemotherapy (e.g., streptozocin, 5-fluorouracil, doxorubicin)
- Radiation (e.g., peptide receptor-targeted radiotherapy)
- Liver-directed therapy (e.g., chemoembolization) in patients with metastases primarily in the liver
Monitoring [9]
Consider the following for patients with active nonmetastatic disease.
- Biochemical studies: every 3–12 months (i.e., levels of gastrin, calcium, PTH, vitamin B12)
- Cross sectional imaging: annually
- Somatostatin receptor scintigraphy: at least every 3 years