Review Article: Strategies to Determine Whether Hypergastrinaemia Is Due to Zollinger-Ellison Syndrome Rather Than a More Common Benign Cause

S.V.M. Murugesan; A. Varro; D.M. Pritchard

Disclosures

Aliment Pharmacol Ther. 2009;29(10):1055-1068. 

In This Article

Investigations Which May Help Determine the Cause of Mild-to-moderate Hypergastrinaemia

As discussed above, in some cases, the cause of hypergastrinaemia is relatively easily confirmed by taking a careful clinical history and by performing relatively straightforward initial investigations. However, many patients who have relatively minor symptoms (particularly those taking acid suppressing medication) will be found to have mild-to-moderate hypergastrinaemia and the investigating clinician frequently needs to determine whether or not they have ZES. One possible strategy for the further investigation of such patients involves conducting imaging studies. However, as these are sometimes negative (particularly when gastrinomas are small) and do have some associated risks, (particularly from the radiation dose and endoscopy), alternative less invasive strategies should also be considered. Several stimulation tests have been developed to attempt to differentiate between tumorous and nontumorous causes of hypergastrinaemia.[57] These include the secretin, calcium, meal and glucagon stimulation tests (Figure 3). We therefore sought to review the evidence for the use of these tests in clinical practice.

Figure 3.

Suggested algorithm for the investigation of hypergastrinaemia.

Secretin Stimulation Test

Secretin is normally secreted by duodenal S-cells in response to a low luminal pH following food-stimulated acid secretion. Its primary action is to cause the release of bicarbonate rich pancreatic juice from pancreatic acinar cells, thus neutralizing the acidic juice delivered from the stomach. This results not only in a negative feedback inhibition of further secretin secretion, but also decreases antral gastrin secretion. Secretin receptors are also found on the surface of other neuroendocrine cells including gastrinoma cells and secretin stimulation causes these cells to release stored gastrin. This forms the basis of the secretin stimulation test for diagnosing ZES. The results of secretin stimulation tests have been shown to correlate with the amount of secretin-receptor mRNA expressed by a gastrinoma.[77] Isenberg et al. first demonstrated that secretin does not stimulate normal antral G cells to release gastrin, but does stimulate gastrinoma cells to release this hormone. In their initial report, the authors quoted a > 90% specificity and sensitivity for the diagnosis of ZES when they documented a rise of > 200 pg/mL in serum gastrin concentration following secretin administration.[78]

Frucht et al. found that the sensitivity of the secretin test was 93% (CI, 76% to 99%) when the increase in gastrin was > 110 pg/mL and 85% (CI, 66% to 96%) when the increase was > 200 pg/mL.[3] 75% of patients demonstrated a significant increase in serum gastrin by 5 min, 95% by 10 min and 100% by 15 min, but only 6% showed elevated serum gastrin concentrations at 2 min. These authors therefore defined a test as being positive when there was a rise in serum gastrin concentration by > 200 pg/mL 15 min following an intravenous bolus of 2 U/kg of secretin administered in 10 mLs of 0.9% NaCl.

The secretin stimulation test has also been shown to be a valuable predictor of recurrence of gastrinoma following surgery.[79] The use of this test has recently been re-evaluated in a large patient cohort. In 293 patients with ZES who underwent gastrin stimulation testing, Berna et al. reported that serum gastrin concentrations increased in 97-99% of patients following secretin or calcium stimulation.[80] In this cohort, the sensitivity of the secretin stimulation test was 83% and the specificity 100% when the serum gastrin concentration increased by > 200 pg/mL above baseline concentrations following secretin administration (the conventional criterion for a positive secretin test). If the criterion of a rise in serum gastrin concentration by > 50% was used to define a positive test instead, the sensitivity of the test was reduced at 86% and the specificity was also decreased at 93%. However, if the criterion for a positive secretin stimulation test was considered to be a rise in serum gastrin concentration > 120 pg/mL from baseline, the authors showed an increase in the sensitivity (94%) without loss of specificity (100%). These authors have therefore suggested replacing the current criterion for a positive secretin stimulation test (namely an increase in serum gastrin concentration > 200 pg/mL post secretin) with an increase of > 120 pg/mL in serum gastrin concentration (Table 2). In comparison with other stimulation tests, these authors also confirmed the role of secretin stimulation test as the first line provocation test in this clinical situation. Secretin stimulation along with rapid gastrin radioimmunossay has also been successfully performed intraoperatively to confirm complete removal of gastrinoma tissue.[81]

Calcium Stimulation Test

The calcium provocation test is based on a principle similar to that of the secretin test, as calcium administration stimulates the release of stored gastrin from gastrinoma cells. Serum gastrin concentrations are measured at timed intervals during an intravenous infusion of 10% calcium gluconate (at a dose of 5 mg/kg body weight over 3 h). More than 80% of gastrinoma patients show an increase in serum gastrin of > 200 pg/mL within the third hour of calcium infusion.[82] Frucht et al. demonstrated that the sensitivity of the calcium stimulation test was 43% (CI, 23% to 66%) if the criterion of an increase in serum gastrin concentration of 395 pg/mL was used to define a positive test, whereas it was 74% (CI, 52% to 90%) if the criterion was changed to an increase of 50%. Patients usually demonstrated positive responses at 120 to 180 min. Interestingly, the calcium infusion test was positive in 33% of patients with a negative secretin test, suggesting that it may have a diagnostic role in such patients.[3]

Berna and colleagues in the same study mentioned above also reported that the sensitivity of the calcium stimulation tests was 54% and specificity 100% for an increase in serum gastrin concentrations > 395 pg/mL from baseline, whereas the sensitivity increased to 78%, but specificity fell to 83% if the criterion used for a positive test was an increase in serum gastrin concentration by 50% from baseline. These authors also found that approximately 38-50% of confirmed ZES patients who had a negative secretin test had a positive calcium stimulation test, again suggesting that the calcium stimulation test may have a role in patients with a strong clinical suspicion of ZES and a negative secretin stimulation test.[80]

Secretin and Calcium Stimulation Test (Combined)

In a single study of 34 patients with gastrinoma, Wada et al. found that the diagnosis could be made in 100% of cases by combining these two tests.[83] However, this approach is rarely undertaken in current clinical practice.

Meal Stimulation Test

The physiological response to a standard test meal (of two eggs and toast) is an increase in plasma gastrin of up to two to threefold.[84,85] Berson and Yalow demonstrated that patients with ZES demonstrate no or only a very minimal increase in serum gastrin concentration after ingestion of such a protein rich test meal, whereas patients with nontumorous causes of hypergastrinaemia show a more pronounced increase in serum gastrin following the same protein test meal.[85] In their recent study, Berna et al. found significant overlap of results from meal stimulation tests in patients with ZES and other antral syndromes and hence do not recommend the meal stimulation test for investigation of the cause of hypergastrinaemia.[80] It should also be noted that such meal stimulation tests may only help differentiate ZES patients from non-ZES patients in those who have not had previous gastric surgery. Evidence also suggests that the meal stimulation test is not useful for screening for the presence of pancreatic endocrine tumours in patients with MEN1.[86]

Glucagon Stimulation Test

Korman et al. demonstrated a rise in serum gastrin concentration following the administration of glucagon to patients with ZES, but a paradoxical fall in serum gastrin concentrations in patients with pernicious anaemia.[87] This finding was confirmed by Shibata et al.,[88] but the test has not been widely evaluated; however, further studies are required to determine the overall efficacy of the glucagon stimulation test.

Overall Role of Stimulation Tests

As outlined above, the secretin test is more sensitive, easier to perform (avoiding the need for an infusion), shorter in duration and has less associated side effects than the calcium stimulation test and is therefore usually the preferred initial stimulation test of choice. However, the calcium stimulation test probably does have some role to play in the investigation of patients with a negative secretin stimulation test in whom ZES is still strongly suspected. Although these tests are most often used to investigate patients with mild-to-moderate hypergastrinaemia, it should be noted that they are equally applicable to patients in whom the fasting serum gastrin concentration is greater than 1000 pg/mL. It is also important to note that these tests do not provide any information about the extent or location of a gastrinoma and do not help differentiate sporadic from MEN type-I associated gastrinomas.

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