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The hormone gastrin plays two very important roles in gastrointestinal physiology. The first as a major factor in meal-stimulated gastric acid secretion and the second as a trophic hormone for epithelial and enterochromaffin cells. These roles are abnormally exaggerated under conditions of chronic hypergastrinemia (i.e., Zollinger-Ellison syndrome, pernicious anemia). More recently, the concern about the potential risk of chronic hypergastrinemia has risen because of the widespread use of proton pump inhibitors for maintenance therapy in reflux esophagitis.

Pathophysiology of Hypergastrinemia

The most frequent conditions of hypergastrinemia in man are the Zollinger-Ellison syndrome with autonomous gastrin hypersecretion by the tumour cell and reactive hypergastrinemia in type A autoimmune chronic atrophic gastritis with achlorhydria causing unrestrained gastrin release from the gastrin-producing antral G-cells. Both entities differ with respect to the pH in the gastric fluid, which is < 2 in patients with Zollinger-Ellison syndrome and neutral in type A gastritis. Other conditions with moderate hypergastrinemia as treatment with proton pump inhibitors, gastric outlet obstruction, previous vagotomy, chronic renal failure or short bowel syndrome are of minor clinical importance [2].

Because gastrin secretion by the G cells of the antral mucosa is inhibited by an acid pH in the gastric lumen, hypergastrinemia may be induced by any treatment that decreases gastric acidity. For example, the administration of H2-receptor antagonists causes an increase in plasma gastrin levels proportional to the dose [1].

Zollinger-Ellison Syndrome

The Zollinger-Ellison syndrome is characterized pathophysiologically by a significant hypergastrinemia derived from a gastrin-secreting neuroendocrine tumor with a primary location in the pancreas or duodenum. Chronic hypergastrinemia in turn triggers gastric acid hypersecretion yielding in chronic or recurrent or refractory peptic ulcer disease and/or chronic diarrhea. One half of patients with ZES will have distant metastases in the liver by the time the diagnosis is established and one half of all patients with ZES will experience chronic diarrhea as chief complaint rather than peptic ulcer-related symptoms and signs. Gastrinomas have been reported to either manifest sporadically or to occur in conjunction with the genetic background of the MEN-I syndrome. Diagnosis is based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. Upper gastrointestinal tract endoscopy will provide evidence for peptic ulcer disease in anatomical regions located aborally the duodenal bulb within the descending part of the duodenum or even farther distally within the jejunum. Peptic ulcers frequently occur in groups indicating some substantial acid hypersecretion. A gastric pH > 2 is mutually exclusive for ZES. Increased serum gastrin levels confirm the diagnosis biochemically. Gastrin secretion can be determined in the basal state or following stimulation with secretin or calcium. High sensitivity and specificity for the diagnosis of ZES is provided by determining the ratio of basal versus pentagastrin-stimulated gastric acid secretion: The ratio of BAO / MAO > 0.6 is highly specific for gastrinoma. To localize the gastrin-secreting tumor computer-assisted tomography, endoscopic ultrasound, and somatostatin receptor scintigraphy provide useful help but most recently, endoscopic ultrasound with high resolution transducers appear to improve preoperative site localization. If modern imaging techniques fail to elucidate the site of the tumor, intraoperative diaphany may help to detect gastrinomas within the duodenal wall. Definitive treatment will only be achieved by total surgical resection of the gastrin-producing tumor in the pancreas or duodenum including dissection of the regional lymph nodes. Control of symptoms will have to be achieved by administration of highly potent proton pump inhibitors in up to 2-3-fold increased standard doses to inhibit gastric acid hypersecretion. Elevation of gastric pH > 4 will be the therapeutic target to protect the mucosa of the upper gastrointestinal tract. Basal acid output should be reduced to less than 10 mEq H(+) per hour which requires administration of highly potent proton pump inhibitors with a recommended starting dose of 60 mg omeprazole equivalents per day [3].

Notes & References

[1] Freston JW. Omeprazole, hypergastrinemia, and gastric carcinoid tumors. Ann Intern Med. 1994;121:232-233.

[2] Arnold R. Diagnosis and differential diagnosis of hypergastrinemia. Wien Klin Wochenschr. 2007;119:564-569.

[3] Banasch M, Schmitz F. Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors. Wien Klin Wochenschr. 2007;119:573-578.

Credits & Notices

Authors-contributors to this page (listed alphabetically, last name, first & middle initial only, no institutional affiliations, no scientific titles):

Stawicki SP

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