Zollinger-Ellison syndrome (ZES) is characterized by peptic ulcers, diarrhea, and marked gastric acid hypersecretion in association with a gastrin-secreting non–β islet cell endocrine tumor (gastrinoma). The reported incidence of gastrinomas ranges from 0.1 to 3 cases per million of the population per year. ZES is a rare cause of peptic ulcer disease and accounts for only 0.1–1% of ulcers. The mean age of onset of symptoms is 41 years, and slightly more males than females are affected, with a ratio of about 3:2. The diagnosis of ZES is typically delayed by at least 6–9 years. Although the majority of gastrinomas develop as a sporadic tumor, approximately 20–25% of ZES patients have gastrinomas as part of the inherited MEN 1. MEN 1 is an autosomal-dominant inherited syndrome characterized by pancreatic neuroendocrine tumors, pituitary tumors, and hyperparathyroidism, and is caused by mutations of the MEN 1 tumor suppressor gene on chromosome 11q13.

Patients with ZES most often present with symptoms arising from excessive gastric acid secretion. The unregulated gastrin production from the gastrinoma binds to CCK-2 receptors located on enterochromaffin-like (ECL) cells causing the release of histamine. Histamine then binds to H₂ receptors on parietal cells to stimulate the release of acid. In addition, gastrin also has trophic effects on gastric epithelial and ECL cells. Chronic hypergastrinemia increases parietal cell mass, which further augments acid hypersecretion. The enteroendocrine cells that make up the gastrinoma are well differentiated and round, with small nuclei and prominent nucleolus. They often contain neuroendocrine tumor markers, including chromogranin A, neurospecific enolase, and synaptophysin.

Gastrinomas are derived from the enteroendocrine cells that arise from the embryologic endoderm. Due to their origin, gastrinomas are considered to be neuroendocrine tumors (NETs). The World Health Organization further classifies NETs in different sites into poorly differentiated or well-differentiated endocrine tumors or carcinomas. Well-differentiated tumors are further divided into classes with different behavior depending on size, functionality, location, invasiveness, and proliferative indices. Accurate classification not only provides prognostic implications but also affects treatment. Most gastrinomas are well-differentiated pancreatic neuroendocrine tumors (pNETs) grade 1.

A. Symptoms and Signs

Abdominal pain and diarrhea are the most common symptoms experienced by ZES patients. Gastroesophageal reflux, nausea, weight loss, and bleeding are other typical symptoms. The widespread use of acid-suppressive medications such as PPIs may mask symptoms and delay diagnosis. Table 16–1 shows the frequency of these presenting symptoms in ZES patients. Diarrhea arises from the hypersecretion of acid, which inactivates pancreatic digestive enzymes (leading to malabsorption and steatorrhea), damages enterocytes, and causes primary bile acids to become insoluble. Over 70% of ZES patients have diarrhea which may be the only presenting symptom in 3–10% of cases. Nasogastric suctioning can alleviate the diarrhea. In advanced cases, patients experience symptoms directly from the growth of the gastrinoma. Patients with ZES and MEN 1 syndrome may also present with primary hyperparathyroidism as well as anterior pituitary tumors, and up to 37% develop gastric carcinoids.

The majority of ZES patients develop peptic ulcers, which can appear similar to ulcers associated with H pylori and nonsteroidal anti-inflammatory drug (NSAID) use. ZES patients often also have prominent gastric folds that can be seen on upper endoscopy. Only a small fraction present with a perforated ulcer or esophageal stricture. ZES should be suspected in patients who have had peptic ulcers in unusual locations (eg, second part of the duodenum and jejunum), patients with severe ulcers refractory to acid-suppressive medications, ulcer patients with hypercalcemia, and those with a personal history or family history of MEN 1 syndrome. Clinicians should also consider ZES among patients who present with the triad of abdominal pain, diarrhea, and weight loss as well as patients with prominent gastric folds on endoscopy. ZES may also be considered as a rare cause of ulcers in patients without H pylori infection who have not taken any aspirin or NSAIDs.