Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features

Abstract

In two-thirds of patients with Zollinger-Ellison syndrome (ZES), fasting serum gastrin (FSG) levels overlap with values seen in other conditions. In these patients, gastrin provocative tests are needed to establish the diagnosis of ZES. Whereas numerous gastrin provocative tests have been proposed, only the secretin, calcium, and meal tests are widely used today. Many studies have analyzed gastrin provocative test results in ZES, but they are limited by small patient numbers and methodologic differences. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of gastrin provocative tests in 293 patients with ZES and compare these data with those from 537 ZES and 462 non-ZES patients from the literature. In 97%-99% of gastrinoma patients, an increase in serum gastrin post secretin (Delta secretin) or post calcium (Delta calcium) occurred. In NIH ZES patients with <10-fold increase in FSG, the sensitivity/specificity of the widely used criteria were as follows: Delta secretin > or =200 pg/mL (83%/100%), Delta secretin >50% (86%/93%), Delta calcium > or =395 pg/mL (54%/100%), and Delta calcium >50% (78%/83%). A systematic analysis of the sensitivity and specificity of other possible criteria for a positive secretin or calcium test allowed us to identify a new criterion for secretin testing (Delta > or =120 pg/mL) with the highest sensitivity/specificity (94%/100%) and to confirm the commonly used criterion for calcium tests (Delta > or =395 pg/mL) (62%/100%). This analysis further showed that the secretin test was more sensitive than the calcium test (94% vs. 62%). Our results suggest that secretin stimulation should be used as the first-line provocative test because of its greater sensitivity and simplicity and lack of side effects. In ZES patients with a negative secretin test, 38%-50% have a positive calcium test. Therefore the calcium test should be considered in patients with a strong clinical suspicion of ZES but a negative secretin test. Furthermore, we found that some clinical (diarrhea, duration of medical treatment), laboratory (basal acid output), and tumoral (size, extent) characteristics correlate with the serum gastrin increase post secretin and post calcium. However, using the proposed criteria, the result of these provocative tests (that is, positive or negative) is minimally influenced by these factors, so secretin and calcium provocative tests are reliable in patients with different clinical, laboratory, and tumor characteristics. A systematic analysis of meal testing showed that 54%-77% of ZES patients have a <50% postprandial serum gastrin increase. However, 9%-20% of ZES patients had a >100% increase post meal, causing significant overlap with antral syndromes. Furthermore, we could not confirm the usefulness of meal tests for localization of duodenal gastrinomas. We conclude that the secretin test is a crucial element in the diagnosis of most ZES patients, the calcium test may be useful in selected patients, but the meal test is not helpful in the management of ZES. For secretin testing, the criterion with the highest sensitivity and specificity is an increase of > or =120 pg/mL, which should replace other criteria commonly used today.

Figure 1.

Secretin, calcium and meal gastrin provocative test results from the ZES patient in the case presentation. Left Panel. Secretin (2 units/kg IV bolus) was given at zero time and serum gastrin was measured at −5,0,2,5,10,15,20 and 30 min post secretin injection. This ZES patient shows the rapid increase in serum gastrin post secretin characteristic of patients with ZES ^,,,,,. Middle panel. A calcium infusion of 5 mg/kg/hr was started at 0 time and give for 3 hours as indicated by the solid bar. Serum gastrin levels were measured at −30,0,60,120,150 and 180 min after the infusion was begun. This ZES patient shows the characteristic slow rise in serum gastrin characteristic of patients with ZES ^,,,,. Right panel. A standard meal was given at 0 time and serum gastrin measured at −15, 0 30,60,90 and 120 min post meal. This ZES patient shows less than a 50% increase in serum gastrin post meal which is reported to be characteristic of patients with ZES and in contrast to patients with antral G cell hyperplasia/hyperfunction which have an exaggerated response (i.e.>100% increase) ^,,,,

Figure 2.

Correlation between fasting serum gastrin and secretin, calcium and meal provocative test results in ZES patients. Data from 280 NIH patients and 355 from the literature are shown. The correlation between the fasting serum gastrin level expressed as a fold increase and the absolute change in serum gastrin concentration after secretin injection (upper panels) or calcium infusion (middle panels) as well as the relative change in serum gastrin concentration after a standard meal (lower panels). Each point represents data from one patient. Indicated are the regression line and the correlation coefficient (r) using a least-squares analysis. Literature data are from publications listed in Table 2.

Figure 3.

Effect of the magnitude of basal hyperchlorhydria or primary tumor size on provocative test results after stimulation with secretin, calcium or a standard meal. Indicated is the median value of the absolute (secretin, calcium) serum gastrin increase after stimulation in ZES patients from NIH and from the literature. The meal results are expressed as the median percentage gastrin increase over the pretreatment value. Literature data are from publications listed in Table 2. Insufficient data on primary tumor size in patients in the literature was found to allow comparison of this variable in literature patients. Only patients without previous gastric acid-reducing surgery were included in the analysis of the effect of BAO and only patients without liver metastases were included in the analysis of the effect of primary tumor size. Numbers in parenthesis refer to number of patients with the indicated variable.

Figure 4.

Correlation between tumor size and secretin test results in ZES patients. The top panels show the correlation between the size of the largest tumor found at surgery or by imaging and the absolute change in serum gastrin after secretin injection (Δ secretin) in ZES patients from the NIH with and without liver metastases. The Δ secretin is expressed as the log of the change is serum gastrin with secretin. The middle and bottom panels show correlations of primary tumor size in ZES patients from NIH and from the literature with the Δ secretin. Each point represents data from one patient. Indicated are the regression line and the correlation coefficient (r) using a least-squares analysis. Literature data are from publications listed in Table 2. Tumor size is expressed as cm in diameter.

Figure 5.

Correlation between secretin, calcium and meal provocative test results in ZES patients from the NIH (n=223) and the literature (n=71). Represented is the correlation between the absolute changes in serum gastrin concentration after secretin injection (Δ secretin) or calcium infusion (Δ calcium) (upper panels); the correlation between Δ secretin and the relative change in serum gastrin concentration after a standard test meal (Δ meal)(middle panels) and the correlation between Δ calcium and Δ meal (bottom panels). Each point represents data from one patient. Indicated are the regression line and the correlation coefficient (r) using a least-squares analysis. Literature data are from publications listed in Table 2.