Approach

The diagnosis is made once it is determined that the patient has an elevated level of fasting serum gastrin (FSG) in the absence of achlorhydria, and either a positive secretin test or histologically proven neuroendocrine tumor.[8]

Clinical evaluation

The signs and symptoms are due to hypersecretion of gastrin, and are generally vague and not specific to Zollinger-Ellison syndrome (ZES). The most common presenting symptoms are abdominal pain (70% to 100% of patients), diarrhea (37% to 73% of patients), and gastroesophageal reflux disease (44% of patients). Ten to twenty percent of patients present with diarrhea as their only symptom.[1][2]​​ Steatorrhea may also be a presenting feature due to inactivation of pancreatic enzymes by excess acid. Patients presenting with peptic ulcer disease refractory to medical therapy, associated with diarrhea and/or gastrointestinal bleeding in the absence of nonsteroidal anti-inflammatory drug use or Helicobacter pylori infection, should all be evaluated for ZES. Furthermore, the presence of multiple ulcers or ulcers in atypical locations, including the second part of the duodenum, should raise suspicion for ZES and prompt additional investigation.

Metastases occur most commonly to the liver, followed by bone, particularly the axial skeleton, leading to lower back pain.

Laboratory evaluation

Fasting serum gastrin and gastric pH

The diagnosis of ZES requires the demonstration of an inappropriately elevated FSG level in the presence of hypergastrinemia when gastric acid secretion is present.[15]

The evaluation of ZES begins with measuring FSG level, a very sensitive but nonspecific test. It is elevated in >99% of all patients with ZES.[15] In the absence of renal disease, an FSG level >1000 picograms/mL (greater than 10 times the upper limit of normal) is highly suggestive of ZES. Physicians should be aware of the variability in measurement among commercially available assay kits. Both falsely high and falsely low concentrations of gastrin have been demonstrated if the degree of hypergastrinemia is mild (50-400 picograms/mL). This can lead to unnecessary investigations in patients without ZES, or misdiagnosis and under-treatment of patients with ZES.[16][17]

A raised FSG alone is not adequate to make the diagnosis of ZES because of the many other possible causes of hypergastrinemia. Gastric pH should therefore be checked alongside FSG to exclude hypergastrinemia secondary to other causes, particularly appropriate hypergastrinemia due to hypochlorhydria or achlorhydria (caused by conditions such as atrophic gastritis, Helicobacter pylori infections, pernicious anemia, or proton-pump inhibitor [PPI] ingestion). Nasogastric tube aspiration has classically been used to estimate gastric pH, but it can be uncomfortable for patients and can underestimate gastric acid output.[18] Endoscopy can also be used to measure gastric acid levels, with one study indicating that acid output and concentration correlate well between endoscopically retrieved gastric contents and nasogastric tube retrieval. While endoscopic sampling was shown to overestimate total acid volume, it provided more reproducible results and offered greater patient tolerance than nasogastric tube placement.[19]

Interpretation of gastric pH results in the context of raised FSG:[15]

  • In the case of hypochlorhydria or achlorhydria, gastric pH will be >2. A pH of >2 effectively excludes the diagnosis of ZES.

  • If FSG levels are >1000 picograms/mL (i.e., >10-fold elevated) and gastric pH is <2, the diagnosis of ZES can be made (this applies to 40% of all patients with ZES).

  • If FSG is between 100 and 1000 picograms/mL (i.e., <10-fold elevated), as is the case in 60% of patients with ZES, and gastric pH is <2, additional testing is needed (see below).

Management of patients on PPI therapy during the workup for ZES

With the introduction of potent gastric acid antisecretory drugs, such as PPIs, over the past decade, it has become increasingly difficult to diagnose ZES. This is because PPIs have a prolonged duration of action (up to 1 week) and cause hypergastrinemia in 80% to 100% of all people without ZES, thus confounding the diagnosis.[15] The elevated FSG levels in these patients are due to negative feedback from decreased basal acid levels (i.e., appropriate hypergastrinemia).

In order to differentiate appropriate from inappropriate fasting hypergastrinemia, the FSG and gastric pH should ideally be repeated 1 week after discontinuation of PPI therapy.[8] However, guidelines recommend that PPI treatment should not be abruptly stopped in patients with overt clinical symptoms of gastrinoma and/or risks of complications (e.g., active ulcer disease) because of the potential for rapid development of severe acid-peptic problems.[15]​​​​ In practice, the diagnosis of ZES cannot easily be established without stopping PPI treatment. It is therefore recommended that if the diagnosis is unclear (FSG <10-fold increased, gastric pH <2, no tumor seen on imaging), the patient should be referred to a specialist center for further investigation. If this is not possible, PPI withdrawal should be cautiously performed (only in an asymptomatic patient in whom active acid-peptic disease or damage has been excluded by endoscopy), with adequate cover by H2 antagonists and careful patient monitoring.[15]

Additional testing

In patients with low gastric pH (<2) and elevated gastrin levels 100-1000 picograms/mL (i.e., <10-fold elevated), a secretin stimulation test should be performed. A calcium infusion test (involving intravenous infusion with calcium gluconate) can also be used because gastrin-secreting tumors express receptors for calcium.[20][21] The secretin test is, however, the most sensitive and specific test for diagnosis of ZES. A positive secretin test is characterized by a rise in FSG following the administration of intravenous secretin. Different cutoffs for a positive result have been proposed, including an absolute increase in gastrin concentration ≥120 picograms/mL or ≥200 picograms/mL, or a 50% increase in gastrin concentration.[18] However, data suggest that the criterion with the highest sensitivity and specificity is an increase of ≥120 picograms/mL, with sensitivity reported as 94% and specificity as 100%.[22] Secretin stimulates the release of gastrin by gastrinoma cells, with levels peaking by 10 minutes, whereas normal gastrin-secreting cells (gastric G cells) are inhibited by secretin. The secretin test should not be performed on patients taking PPIs because of the potential for false positives. PPIs should therefore be withdrawn at least 1 week before the test; as for the measurement of FSG and gastric pH levels, this should be done under the supervision of an experienced provider and only once active ulcer disease has been excluded. 

The glucagon test may be a suitable alternative to the secretin test for the diagnosis of ZES, but it is not routinely done in clinical practice.[23] However, the glucagon test may be considered as an alternative if secretin is not available.

Genetic testing for MEN1

Genetic testing for multiple endocrine neoplasia type 1 (MEN1) should be performed in a selected subgroup of patients, namely 1) in patients with two or more primary MEN1-associated endocrine tumors (e.g., parathyroid adenoma, enteropancreatic tumor, or pituitary adenoma) or hypercalcemia associated with an endocrine tumor; and 2) in patients showing MEN1-related features who have a first-degree relative with diagnosed MEN1.[18]

Imaging

Once a biochemical diagnosis of ZES has been confirmed, further evaluation should center on tumor localization via imaging in order to determine primary location, depth of invasion, and presence of metastatic disease.

Computed tomography (CT) or magnetic resonance imaging (MRI) scan

Imaging with abdominal (with or without pelvis) multiphasic CT or MRI scan with intravenous contrast is recommended; these remain the most widely used initial imaging modalities in patients with ZES, because of their widespread availability.[18][24] However, they have been shown to miss many small lesions <1 cm.[18] MRI has shown a higher sensitivity for the detection of liver metastases, compared with CT.[18]

Somatostatin receptor scintigraphy (SRS)

SRS has also been used to localize gastrinomas. It involves the administration of indium-radiolabeled octreotide, which binds selectively to somatostatin receptors found on gastrinoma cells.[18] Positive imaging not only provides information on overall tumor burden and location but also confirms the presence of somatostatin receptors, which can have therapeutic implications.[24][25]​​ It has shown reasonable sensitivity (77% to 78%) and high specificity (93% to 94%) for detection of the primary tumor and its metastases, although sensitivity decreases for small tumors (<1 cm).[26] Diagnostic accuracy of SRS can be improved by performing it in combination with single-photon emission CT (SRS-SPECT).[27] Studies have shown that this combination has higher sensitivity and specificity in primary tumor detection (78% to 88%, and 97%, respectively) compared with SRS alone.[28][29][30]

Gallium(Ga)-68 DOTATATE positron emission tomography (PET)

Ga-68 DOTATATE is a radiolabeled somatostatin analog. Studies have shown that Ga-68 DOTATATE PET has higher sensitivity and specificity (72% to 100% and 83% to 100%, respectively) in localizing the primary tumor, especially small tumors, compared with CT, MRI, and SRS.[31][32][33]​​ Gallium-68 DOTATATE PET scan should be included in the diagnostic pathway of all neuroendocrine tumors, including gastrinomas, in order to both identify the primary tumor and stage the disease.[18] Combining Ga-68-radiotracers with traditional CT scans (PET/CT) further enhances diagnostic accuracy compared with PET alone, showing sensitivity of 93% and specificity of 96% in primary tumor detection.[34] Ga-68 DOTATATE PET/CT was approved by the US Food and Drug Administration (FDA) in 2016.

Endoscopic ultrasound (EUS)

Because nearly one-half of gastrinomas occur in the duodenal wall and these tend to be small (<1 cm), EUS can be a useful imaging modality for their detection, due to its high sensitivity in detecting small tumors. EUS has also been shown to have high sensitivity and specificity for the detection of small pancreatic endocrine tumors. A further advantage of this technique is the possibility of performing fine needle aspiration/biopsy (FNA/B) to take cytologic/histologic samples to confirm the diagnosis of gastrinoma. EUS-FNA/B is now considered the primary sampling technique for pancreatic neuroendocrine tumors.[18] One study found that EUS-guided fine needle aspiration (FNA) is as sensitive as CT-guided FNA in diagnosing pancreatic neuroendocrine tumors; the authors reported that the main advantage of EUS-guided FNA was the diagnosis of smaller pancreatic neuroendocrine tumors in the head of the pancreas.[35]

When used as a screening modality in asymptomatic patients with MEN1, EUS has been reported to be more accurate than CT in the detection of smaller tumors. This has led experts to recommend it as an annual screening modality for all patients with MEN1, although evidence suggests that the growth rate of small pancreatic neuroendocrine tumors (i.e., <2 cm) is low and that EUS screening frequency can likely be extended.[36][37]

Esophagogastroduodenoscopy (EGD)

EGD is usually performed to determine the presence of gastric or duodenal ulcers in patients with abdominal pain. The presence of postbulbar duodenal ulcerations is suggestive of ZES.

Routine EGD with or without biopsy sampling is well established as a safe and effective procedure. Although several adverse events are associated with routine EGD, their overall incidence is low.[38]

Chest CT scan

Chest CT scan (with or without contrast) may be performed to check for lung metastases if clinically indicated.[24]

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