Zollinger-Ellison syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2] Mohamad Alkateb, MBBCh [3]

Overview

Development of Zollinger-Ellison syndrome is the result of increased levels of gastrin due to an existing gastrinoma in the duodenum or pancreas.

Pathogenesis

• Zollinger-Ellison syndrome is a disorder where increased levels of gastrin are produced, causing the stomach to produce excess hydrochloric acid. Often, the cause is a tumor (gastrinoma) of the duodenum or pancreas producing the hormone gastrin. Gastrin then causes an excessive production of acid which can lead to peptic ulcers (in almost 95% of patients).
• The gastrinoma tumor cells secrete excessive amounts of gastrin which leads to hyperplasia of the fundic parietal cells and increased basal gastric acid output. The excessive gastric acid output breaches the mucosal defenses of the gastric as well as the duodenal wall, causes ulceration, and inactivates pancreatic digestive enzymes with resultant fat malabsorption and diarrhea. Inhibition of absorption of sodium and water by the small intestine results in a secretory component of the diarrhea.
• Gastrin works on stomach parietal cells causing them to secrete more hydrogen ions into the stomach lumen. In addition, gastrin acts as a trophic factor for parietal cells, causing parietal cell hyperplasia. Thus, there is an increase in the number of acid secreting cells and each of these cells produces acid at a higher rate. The increase in acidity contributes to the development of peptic ulcers in the stomach and duodenum. High acid levels lead to multiple ulcers in the stomach and small bowel.
• The pathophysiology of ZES is related to the trophic action of gastrin on parietal cells of the gastric antrum and the resulting hypersecretory acid milleu.
• An overwhelming majority of patients with this disease consequently develop peptic ulcers, often large and multiple, frequently in distal duodenum and even proximal jejunum (an uncommon location for ulcers resulting from Helicobacter pylori or the use of nonsteroidal anti-inflammatory drugs).

Genetics

• Approximately 80% of the time, the primary causative lesion is thought to arise sporadically; in the remainder of recorded cases, this entity exists as part of MEN-1, an autosomal dominant disorder characterized by tumors of the pituitary, the parathyroid, and the pancreas.

Associated Conditions

• Multiple endocrine neoplasia type 1 (MEN 1)
• Gastrinoma
• Peptic ulcer disease

Gross Pathology

• Gross pathology reveals enlarged fundic mucosal folds with cerebriform pattern.

Microscopic Pathology

• Histologically, well-differentiated neuroendocrine tumor (NET) has a typical organoid arrangement of cells with nesting, trabecular, or gyriform patterns.
• The tumor cells are round with regular bland nuclei and produce large amounts of secretory granules with diffuse immunoexpression of neuroendocrine markers. In contrast, the poorly differentiated NET has atypical, sheet-like, diffuse and irregular nuclei, less cytoplasmic secretory granules, and limited biomarker immunoexpression.
• An important feature for the diagnosis of neuroendocrine tumors is immunostaining for chromogranin A and synaptophysin. Gastrin immunostaining can be used to differentiate from other neuroendocrine tumors. Gastrinomas express a high density of somatostatin receptors, thus making somatostatin scintigraphy an effective localizing tool.