CHAPTER 17
Zollinger–Ellison syndrome

Robert T. Jensen¹ and David C. Metz²

¹ National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

² Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Zollinger–Ellison syndrome (ZES) is a clinical syndrome characterized by symptoms due to excess gastric acid secretion (severe peptic ulcer disease [PUD], diarrhea, gastroesophageal reflux disease [GERD]) caused by the autonomous release of gastrin from a neuroendocrine tumor (NET; also called a gastrinoma, islet cell tumor, non‐β cell islet cell tumor). Patients with ZES have two important therapeutic considerations: treatment of the acid hypersecretion and treatment of the gastrinoma per se. These are both required because the gastric acid hypersecretion, if untreated, leads to increased morbidity and mortality due to complications of refractory PUD/GERD. Treatment of the gastrinoma is needed because 60–90% are malignant. ZES can occur either sporadically (not inherited; 75%) or as part of the multiple endocrine neoplasia type 1 syndrome (MEN1; 25%), an autosomal dominant disorder. These two forms need to be distinguished because they differ in many treatment options.

ZES is much less frequent than idiopathic PUD but can be suspected by the presence of severe PUD, family history of endocrinopathies with PUD, PUD with diarrhea or the presence of prominent gastric folds on upper gastrointestinal endoscopy (UGI) (Figure 17.1c,d) (due to trophic action of gastrin). This finding differs from small or lack of gastric folds on upper gastrointestinal endoscopy, characteristically seen in patients with atrophic gastritis (Figure 17.1b) (a frequent cause of hypergastrinemia, like ZES) compared to normal gastric folds (Figure 17.1a). The trophic action of gastrin on the gastric endocrine cells can lead to the development of gastric carcinoids in patients with ZES with MEN1 (MEN1/ZES) (arrows Figure 17.1d). ZES in MEN1/ZES patients characteristically occurs at an earlier age than in patients with sporadic ZES (Figure 17.1e).

Once the diagnosis is suspected, a fasting serum gastrin level (FSG) is usually the initial study because 99–100% of ZES patients have an elevated level. However, the most common cause of hypergastrinemia is not ZES, but is due to physiological hypergastrinemia secondary to achlor /hypochlorhydria seen in atrophic gastritis, pernicious anemia, or due to the use of potent acid suppressants such as proton pump inhibitors (PPIs; e.g., omeprazole). To distinguish ZES, measurement of gastric pH is required because ZES patients have gastric acid hypersecretion both in their basal acid output and maximal acid outputs (Figure 17.2b), and have inappropriately elevated FSG levels because in normal subjects acid physiologically suppresses gastrin release. An elevated FSG in the presence of a gastric pH <2 is strongly suggestive of ZES; however, in patients with FSG <10‐fold elevated, additional studies for diagnosis are required, including performing a secretin provocative test and assessing FSG levels (positive >120 pg/mL increase in FSG) (Figure 17.2a). In the past, a calcium infusion test (positive >395 pg/mL increase in FSG) (Figure 17.2a) or no/minimal increase in FSG with meal testing (Figure 17.2a) were used, but these are rarely used currently.

After establishing the diagnosis, controlling the gastric acid hypersecretion (usually with PPIs), assessment for the presence of MEN1, and tumor localization studies to determine the location of the primary and extent of disease (cross‐sectional imaging [computed tomography, magnetic resonance imaging], somatosatin receptor scintigraphy [Octreoscan or ⁶⁸Ga‐labeled somatostatin analogs with computed tomography/positron emission tomography scanning]) are recommended. For patients with sporadic disease, surgical exploration by a surgeon familiar with pancreatic neuroendocrine tumors (pNETs) should be undertaken in those patients with resectable disease and no medical contraindications to surgery. This is recommended because 50–60% of patients with sporadic ZES can be cured immediately postoperatively and 30–40% at >10 years (Figure 17.3a). In contrast, patients with MEN1/ZES are rarely cured (Figure 17.3a) without aggressive resections such as a Whipple procedure, which are not recommended, and thus routinely do not undergo surgery for resection of abdominal pNETs unless it is >1.5–2 cm in diameter on imaging studies. In sporadic ZES, 70–85% of gastrinomas occur in the duodenum not the pancreas, and in MEN1/ZES 85–100% are found in the duodenum. Duodenal gastrinomas can be small (2–10 mm) and thus it is important to perform a duodenotomy with careful search of the duodenum at surgery, to achieve an optimal cure rate (Figure 17.3b).