Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors

Abstract

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.

Diagnosis of Zollinger–Ellison Syndrome in the Era of Ppis, Faulty Gastrin Assays, Sensitive Imaging and Limited Access to Acid Secretory Testing

“…When ZES is suspected, the initial study almost always performed is a determination of a fasting serum gastrin concentration (FSG) [12, 13, 42, 45–48] (Table 1). This is a highly sensitive test for ZES (97–100%) [42] when properly performed, with a sensitivity >99% in the NIH studies [42].…”

“…PPIs have a much longer duration of action than histamine H 2 -receptor antagonists (the effects last up to one week or more after stopping therapy). Furthermore, because of their extended potency at suppressing acid secretion, PPIs cause hypergastrinemia in 80–100% of non-ZES patients, in ranges that overlap with most ZES patients [45, 48, 60, 65, 67–70, 103–105]. Therefore, to differentiate the source of the hypergastrinemia (appropriate due to drug induced acid suppression or inappropriate as in ZES), almost all guidelines, recommended PPIs be stopped for at least a week prior to gastric analysis.…”

Italian Association of Clinical Endocrinologists (AME) position statement: a stepwise clinical approach to the diagnosis of gastroenteropancreatic neuroendocrine neoplasms

“…Multiple ulcers or ulcers in unusual locations are a less frequent presenting feature than in the past [8, 84, 85, 87, 202, 204–208]. With the widespread use of gastric antisecretory drugs, particularly PPIs and H2RAs, symptoms may be masked.…”

“…Under these conditions, FSG >1,000 pg/mL means a certain diagnosis of ZES. On the contrary, a gastric pH >2.0 virtually excludes ZES [84]. In subjects under chronic therapy with PPIs these drugs have to be withdrawn for at least 1 week [84, 216], although the optimal wash-out time for PPIs should be longer (4 weeks).…”

“…On the contrary, a gastric pH >2.0 virtually excludes ZES [84]. In subjects under chronic therapy with PPIs these drugs have to be withdrawn for at least 1 week [84, 216], although the optimal wash-out time for PPIs should be longer (4 weeks). H2RAs exert a less pronounced suppression of gastric acid output than PPIs [217, 218].…”