[2] High levels of gastrin in the blood (hypergastrinemia) trigger the parietal cells of the stomach to release excess gastric acid.

About one-half to two-thirds of single gastrinomas are malignant tumors that most commonly spread to the liver and to lymph nodes near the pancreas and small bowel.

The diagnosis is made through several laboratory tests and imaging studies:[13] In addition, the source of the increased gastrin production must be determined using MRI or somatostatin receptor scintigraphy.

[18] Diagnosis can sometimes be very difficult, especially considering patients who take a proton pump inhibitor (PPI) medication for gastric reflux, which constitute a large and increasing proportion of people who develop Zollinger-Ellison syndrome.

[21] Sporadic reports of unusual cases of peptic ulceration in the presence of pancreatic tumors occurred prior to 1955, but Robert M. Zollinger and Edwin H. Ellison, surgeons at Ohio State University, were the first to postulate a causal relationship between these findings.

The American Surgical Association meeting in Philadelphia in April 1955 heard the first public description of the syndrome, and Zollinger and Ellison subsequently published their findings in Annals of Surgery.