The diagnosis of gastrinoma – Zollinger-Ellison syndrome (ZES) – requires the demonstration of an inappropriately elevated fasting serum gastrin (FSG) in the presence of gastric acid (hyper)secretion (gastric pH <2) [1, 9–13]. The assessment of the gastric pH is obligatory since conditions which present with fasting, or stimulated (see below) hypergastrinemia, such as atrophic gastritis, pernicious anemia, Helicobacter pylori infections, or the use of proton pump inhibitors (PPIs), are much more prevalent in the general population and, therefore, should be excluded first [2, 14–16].

In 40 % of ZES patients, the FSG is >10-fold elevated and the gastric pH <2, thus establishing the diagnosis. However, in the remaining 60 % of ZES patients, the FSG is <10-fold elevated with a gastric pH <2 [9, 10], and an additional secretin test is needed [1, 9]. Many commercial laboratories also use poorly characterized antibodies for the assessment of serum gastrin levels, and test results may, therefore, be unreliable [17, 18].

In patients taking PPIs in which ZES is suspected, it should be remembered that diagnostic procedures should only be initiated when the patient is stable and free of active acid-peptic disease and PPIs should not be abruptly stopped [2, 11, 15, 18, 19]. Abrupt stopping of PPIs may result in the development or recurrence of life-threatening acid-peptic complications [20]. Either the patient should be referred to a center experienced in the diagnosis, or if this is not possible, an attempt can be made to reduce the PPI dose and/or frequency of the PPI while monitoring the gastric pH. Alternatively, the PPIs can be slowly withdrawn with adequate coverage by high doses of H2 blockers and careful patient monitoring [2, 11, 15].

The criterion for a positive secretin test (using a rapid infusion of 2 U/kg secretin) is a >120 pg/mL increase in FSG over basal. This test has a sensitivity of 94 % and a specificity of 100 % [9]. A small percentage of patients with gastric acid hypersecretion and clinical features of ZES demonstrates normal fasting serum gastrin levels and negative secretin tests [9–11]. In light of the clinical and biochemical features described with CCKoma [6], these patients should have plasma CCK levels assessed. A secretin test cannot be used while a patient is taking PPIs because this can lead to a false-positive test [21]. Another problem is that secretin is increasingly becoming unavailable in many countries [16, 22]. This issue might be circumvented by substituting the secretin test by a glucagon stimulation test, but the experience with this test is still very limited, and its sensitivity and specificity are yet unclear [22].

The assessment of chromogranin A (CgA) is not reliable in the diagnosis of ZES, because up to 30 % of patients will have normal plasma CgA levels, whereas on the other hand the use of PPIs cause false-positive elevations of this nonspecific tumor marker [23–25].

The exact criteria for the diagnosis of insulinoma continue to evolve and vary in different consensus documents and reviews [26–32]. In the most recent consensus report from the US Endocrine Society, the following diagnostic criteria were proposed: endogenous hyperinsulinism documented by the finding of symptoms, signs, or both with plasma concentrations of glucose <3.0 mmol/l (<55 mg/dl), insulin ≥3.0 mU/ml (18 pmol/l), C peptide ≥0.6 ng/ml (0.2 nmol/l), and proinsulin ≥5.0 pmol/l [27]. The presence of a plasma β-hydroxybutyrate levels of ≤2.7 mmol/l and an increase in plasma glucose 1.4 mmol/l (≥25 mg/dl) after IV glucagon indicates mediation of the hypoglycemia by insulin (or by an insulinlike growth factor). The use of an insulin cutoff value of ≥3 mU/ml instead of the older recommended value ≥5 mU/ml is supported by a recent study showing that 9 % of patients with insulinoma would be missed using the insulin cutoff value of ≥5 mU/ml [30].

The evaluation of serum CgA levels is generally not helpful for diagnosing patients with insulinoma, with an elevated CgA value having only a low specificity (73 %) [33].

The most prevalent biochemical abnormalities in VIPoma patients are hypokalemia (virtually all patients), hypophosphatemia, acidosis, hypomagnesemia, hypo- or achlorhydria (75 % of patients), and hypercalcemia (25–75 % of patients). Glucose intolerance occurs in 50 % of patients, and elevated plasma glucose levels can be found in 18 % of cases. The diagnosis can be confirmed by demonstrating elevated fasting plasma VIP and peptide histidine-methionine (PHM) concentrations. Plasma CgA levels are generally elevated [24, 25].

The most prevalent biochemical abnormalities in somatostatinoma patients are elevated plasma glucose levels and elevated fasting plasma somatostatin levels. Plasma CgA levels are generally elevated [24, 25].

The most prevalent biochemical abnormalities in glucagonoma patients are diabetes mellitus (>50 % of patients), normochromic normocytic anemia (33 % of patients), and elevated fasting plasma glucagon levels. Plasma CgA levels are generally elevated [24, 25].