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  • Peptic ulcer disease, abdominal pain, and diarrhea are common presentations.
  • Patients have marked gastric acid secretion arising from a gastrin-secreting non–β islet cell tumor.
  • Multiple endocrine neoplasia syndrome type 1 (MEN 1) is present in ~20–25% of patients.
  • Serum gastrin concentration >1000 pg/mL in combination with acidic stomach pH <2.0 is diagnostic.
  • Up to 40% of patients have elevated serum gastrin levels that are <500 pg/mL and warrant a secretin test.
  • Significant hypergastrinemia can occur with proton pump inhibitor use, Helicobacter pylori infection, or chronic atrophic gastritis and hypochlorhydria.

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 0.5 to 4 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 3:2. The diagnosis of ZES is typically delayed by at least 5–7 years. Although the majority of gastrinomas develop as a sporadic tumor, approximately 20–25% of ZES patients have gastrinomas as part of the inherited multiple endocrine neoplasia syndrome type 1 (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.

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 proton pump inhibitors (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 enzymes (leading to malabsorption and steatorrhea), damages enterocytes, and causes primary bile acids to become insoluble. 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.

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