Criteria for the glucagon provocative test in the diagnosis of gastrinoma
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- Shibata, C., Kakyo, M., Kinouchi, M. et al. Surg Today (2013) 43: 1281. doi:10.1007/s00595-012-0334-2
The glucagon provocative test is useful for the diagnosis of gastrinoma. The aim of this study was to determine the criteria for the glucagon provocative test.
This study reviewed 8 patients that underwent the glucagon provocative test preoperatively and in whom the diagnosis was confirmed as gastrinoma histologically. The glucagon provocative test was performed by administering glucagon (20 μg/kg) intravenously, followed by 20 μg/kg h for the next 30 min, and plasma gastrin levels were measured 3 and 1 min before and 3, 5, 7, 10, 15, 20, and 30 min after the administration of glucagon. This study evaluated the peak value of plasma gastrin and the time required to reach the peak.
Two of the 8 patients had multiple endocrine neoplasm type 1. The basal plasma gastrin levels ranged from 524 to 10,300 pg/ml. The time required to reach the peak was 3–10 min for all patients. The increase in the peak from the basal value was 235–8,920 pg/ml, and the percentage of increase was 38–337 %.
These results suggest that a diagnosis of gastrinoma should thus be made when plasma gastrin levels peak within 10 min after glucagon administration, with an increase of greater than 200 pg/ml and greater than 35 % of the basal value.
Gastrinomas in patients with Zollinger-Ellison syndrome are often very small (<1 cm) and difficult to localize. There are various causes of hypergastrinemia including the use of proton pump inhibitors and histamine-2 receptor antagonists, and chronic gastritis associated with chronic Helicobacter pylori infection ; therefore, it is important to distinguish between gastrinoma and other causes of hypergastrinemia. Although plasma gastrin levels decrease after intravenous injection of secretin in normal subjects, the plasma gastrin levels increase paradoxically in patients with gastrinoma . The secretin provocative test, which utilizes this phenomenon of ‘paradoxical increase’, is a well-established diagnostic test for gastrinoma [3, 4]. It is, however, of concern that secretin is difficult to obtain not only in this country but also in other countries , and calcium is regarded as a candidate for an alternative secretagogue to secretin . A previous report showed the glucagon provocative test to be useful in the diagnosis of gastrinoma in 3 patients, because a paradoxical increase in plasma gastrin levels was also seen after intravenous glucagon administration . The diagnostic criteria for the glucagon provocative test, however, could not be determined because the study did not include a sufficient number of patients. It is also possible that some patients with gastrinoma do not respond to intravenous glucagon. Increased experience with patients with gastrinoma demonstrated the need to determine the diagnostic criteria for the glucagon provocative test.
Patients and methods
The study reviewed the medical records of 8 patients with a plasma gastrin concentration above the normal range and that underwent resection with a preoperative diagnosis of gastrinoma. All of the patients had a neuroendocrine tumor (NET) that was stained positive for gastrin by immunohistochemistry in the histological examination. The glucagon provocative test was performed before the operation in all of these patients. The study analyzed the age, sex, past history, operation performed, primary sites of gastrinoma, and the results of the glucagon provocative test. The glucagon provocative test was performed by injecting 20 μg/kg glucagon (Glucagon-G Novo, Eisai Co., Ltd., Tokyo, Japan) into a subcutaneous vein in the forearm followed by an infusion at 20 μg/kg h for 30 min. Blood samples were drawn from the contralateral cubital vein at 3 and 1 min before and 3, 5, 7, 10, 15, 20, and 30 min after the administration of glucagon. Plasma gastrin levels were estimated with a specific radioimmunoassay (SRL Inc., Tokyo, Japan). The following parameters of plasma gastrin levels were evaluated: (1) the average of values 3 and 1 min before glucagon administration as the basal value (pg/ml), (2) the time required to reach the peak (peak time), (3) peak (pg/ml), (4) the increase of peak (pg/ml) calculated by subtracting basal value from the peak, and (5) the percentage of increase in the peak calculated as the increase of peak/mean basal value × 100. The correlation between the basal value, peak, and increase of peak was analyzed using Pearson’s correlation coefficient and p values less than 0.05 were considered to be significant.
The glucagon provocative test was conducted in the same manner in several patients with an increased fasting plasma gastrin level but with no tumor detected by imaging modalities.
Summary of the 8 patients with gastrinomas
Basal value (pg/ml)
Peak time (min)
Increase in peak (pg/ml)
Resection of the gastric remnant with tumor
Enucleation of the tumor
SSPPDb + Partial hepatectomy
Duodenum, Pancreatic body
The effect of glucagon in increasing plasma gastrin levels has been reported previously in patients with gastrinoma [7, 8]. The plasma gastrin levels in all 8 patients histologically confirmed to have a diagnosis of gastrinoma increased rapidly in response to the administration of intravenous glucagon. An analysis of the time to reach the peak value, the increase in the peak value, and the percentage of increase over the basal value suggested that patients should be diagnosed to have a gastrinoma if an increase in plasma gastrin levels greater than 200 pg/ml and 35 % is observed within 10 min after the administration of glucagon. The secretin provocative test has been considered the most powerful tool in the differential diagnosis of gastrinoma, and a standard diagnostic criterion for this test is a post-administration increase in plasma gastrin levels of greater than 200 pg/ml in one study  and 110 pg/ml in another study . Berna et al.  suggested that the standard criterion for a positive secretin test should be an increase in plasma gastrin levels greater than 120 pg/ml rather than 200 pg/ml. These levels of plasma gastrin for the diagnosis of gastrinoma in the secretin test are comparable to those with the glucagon provocative test in the current series.
One study, however, reported that the plasma gastrin levels do not always increase in response to intravenous glucagon . It is possible that there are some patients with gastrinoma whose gastrin levels do not reach the diagnostic criteria according to the current study with the glucagon provocative test. In addition, some patients with a gastrinoma show a negative response to secretin.
The use of the glucagon provocative test may prove important in patients with gastrinoma to determine the completeness of resection during surgery and possibly in diagnosing a postoperative recurrence. The plasma gastrin levels do not increase in response to glucagon after the complete resection of gastrinomas . The criteria for plasma gastrin levels proposed in this study might also be applicable to these intraoperative and postoperative tests. The identification of a secretagogue for preoperative, intraoperative, and postoperative provocative testing could also be used with a selective arterial secretagogue injection (SASI) test, in which the regional localization of the gastrinoma could be determined by selective administration to various anatomic regions and evaluation of blood samples from the hepatic vein . A glucagon at a dose of 100 μg is an appropriate dose for SASI . The criteria for changes in the plasma gastrin levels during the SASI test with glucagon thus need to be determined in further studies.
Roy et al.  reported that the primary site of the gastrinoma could not be determined based on surgery and imaging modalities in 61 of 261 (23 %) patients. A patient with gastrinoma had a tumor that could not be localized by imaging modalities, but the feeding artery for the tumor was suggested to be a gastroduodenal artery by a SASI test with secretin. Secretin, however, has not been available since 2004 in this country . These facts indicate that an adequate secretagogue alternative to secretin is important in the diagnosis and localization of gastrinomas. Glucagon has an advantage in comparison to calcium, because glucagon induces a rapid and sharp increase of plasma gastrin levels. The term ‘paradoxical increase’ is applicable to the increase in plasma gastrin levels after glucagon administration in patients with gastrinoma, because the intravenous administration of glucagon decreases plasma gastrin levels in normal subjects . Secretin receptors present in gastrinomas and the expression of the total secretin receptor are correlated with the results of the secretin test [16, 17]. Therefore, the direct binding of secretin to secretin receptors on gastrinoma cells must be the mechanism by which secretin induces the ‘paradoxical increase.’ A similar mechanism could be considered for glucagon, and it is important to identify the glucagon receptors on gastrinoma cells by either immunohistochemistry or other methods.
The authors thank Dr. Michael G. Sarr, Department of Surgery, Mayo Clinic, MN, USA, for reviewing this manuscript.