Zollinger-Ellison Syndrome (ZES)

At a Glance

Clinical manifestations of Zollinger-Ellison syndrome (ZES), a syndrome caused by a gastrin-secreting neuroendocrine tumor (gastrinoma), result from high gastric acid output due to hypertrophy of parietal and histamine-secreting enterochromaffin-like (ECL) cells, as well as direct stimulation of parietal cells. More than 90% of patients develop peptic ulcers, but only a small number of patients with peptic ulcer disease have ZES. Abdominal pain (75%) and diarrhea (73%) are the most frequent initial presentations, followed by heartburn (44%), gastrointestinal bleeding (25%), and weight loss (17%). Gastrinoma should be suspected in patients with findings suggestive of acid hypersecretion (e.g., multiple refractory ulcers or refractory ulcers, or ulcer location distal to the duodenum), diarrhea, or a personal or family history of multiple endocrine neoplasia (MEN1).

Gastrinomas may be sporadic (60-90% of cases) or associated with MEN1 (25% of cases). Gastrinomas are found in the duodenum in more than 60% of patients with sporadic ZES and in more than 85% with MEN1-associated ZES. The second most common location is the pancreas (the “gastrinoma triangle”). Gastrinomas are usually single in sporadic and multiple in MEN1-associated cases. They are usually small (<1 cm) when found in the duodenum. Duodenal tumors are often malignant (60-90% of cases), but the degree of malignancy cannot be predicted by histological appearance. Pancreatic gastrinomas are more likely aggressive than duodenal tumors and may present with metastases to liver and/or bone. Metastatic disease is evident at the time of diagnosis in approximately one-third of patients; liver is the more common site.

Which Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Fasting serum gastrin, secretin stimulation test, and gastric acid secretion (basal acid output) studies have been used for diagnosis of ZES. The gastric acid secretion test is no longer used routinely.

Fasting serum gastrin should be performed in any patient suspected of having ZES. The combination of a fasting serum gastrin concentration higher than 1000 pg/mL (about 10 times the upper limit of normal) and an intragastric pH below 2.5 is virtually diagnostic of the disease. Measurement of gastric pH on a single specimen is important to exclude secondary hypergastrinemia due to achlorhydria. About two-thirds of patients with ZES have serum gastrin concentrations between 150 and 1000 pg/mL (mildly to moderately elevated). The secretin stimulation test should be used to evaluate these patients.

If fasting serum gastrin is not diagnostic, the secretin stimulation test should be used to differentiate patients with ZES from those with other causes of hypergastrinemia (G-cell hyperplasia, gastric outlet obstruction, antisecretory drug therapy, renal insufficiency, and massive small bowel resection). Secretin administration stimulates the release of gastrin from tumor cells (gastrinomas express secretin receptors) but not from normal gastric G-cells. Serial measurements are taken before (-5 and 0 minutes) and after (2,5,10,15, and 20 or 30 minutes) intravenous (IV) secretin administration.

Several criteria have been proposed to define a positive test. Two criteria commonly used are a rise of at least 200 pg/mL in serum gastrin and an increase over baseline of at least 50%. Antacid medications (H₂-blockers and proton pump inhibitors (PPI)) should be discontinued when feasible for at least 1 week prior to testing.

Gastric acid secretion studies are primarily of historical value; rarely, they may have an ancillary role in diagnosis.

Serum chromogranin A (CGA) is a non-specific marker for well-differentiated neuroendocrine tumors that does not distinguish the various tumor subtypes. CGA is usually elevated in patients with ZES, and the degree of increase tends to correlate with tumor volume, which may be useful for staging, prognosis, and monitoring. CGA can be increased in other conditions. Serum CGA is less sensitive and specific than fasting serum gastrin, but it may be used as a confirmatory test in difficult cases. CGA concentrations are usually normal or near normal in patients with high gastrin concentrations secondary to pernicious anemia and enterochromaffin-like cell (i.e., type I) carcinoid tumors. Falsely high values may be found in patients with renal insufficiency or severe malabsorption syndrome.

The calcium infusion study is considerably less sensitive and specific compared to the secretin stimulation test and is more difficult to perform. It is usually reserved for patients with gastric acid hypersecretion for whom there is strong clinical suspicion of gastrinoma despite a negative secretin stimulation test. The test is performed by infusing calcium gluconate and determining serum gastrin and calcium concentrations every 30 minutes. Infusion is associated with an increase in serum gastrin and calcium concentrations in patients with gastrinoma. Positive responses are usually observed between 120 and 180 minutes. A change of at least 395 pg/mL or 50% from baseline is a positive test.(Table 1)