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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

Berna, Marc J. MD; Hoffmann, K. Martin MD; Long, Scott H. MA; Serrano, Jose MD, PhD; Gibril, Fathia MD; Jensen, Robert T. MD

doi: 10.1097/MD.0b013e31802b518c
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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 (Δ secretin) or post calcium (Δ calcium) occurred. In NIH ZES patients with <10-fold increase in FSG, the sensitivity/specificity of the widely used criteria were as follows: Δ secretin ≥200 pg/mL (83%/100%), Δ secretin >50% (86%/93%), Δ calcium ≥395 pg/mL (54%/100%), and Δ 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 (Δ ≥120 pg/mL) with the highest sensitivity/specificity (94%/100%) and to confirm the commonly used criterion for calcium tests (Δ ≥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 ≥120 pg/mL, which should replace other criteria commonly used today.

Abbreviations: Δ calcium = increase in serum gastrin post calcium, Δ meal = increase in serum gastrin post meal, Δ secretin = increase in serum gastrin post secretin, BAO = basal acid output, FSG = fasting serum gastrin, GIH secretin = gastrointestinal hormones secretin, MAO = maximal acid output, MEN1 = multiple endocrine neoplasia type 1, MRI = magnetic resonance imaging, NIH = National Institutes of Health, PPI = proton pump inhibitor, PTH = parathormone, RIA = radioimmunoassay, ZES = Zollinger-Ellison syndrome.

From Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

This research is partially supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

Address reprint requests to: Dr. Robert T. Jensen, NIH/NIDDK/DDB, Building 10, Room 9C-103, 10 Center Drive MSC 1804, Bethesda, MD 20892-1804. Fax: 301-402-0600.

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INTRODUCTION

In the accompanying paper in this issue30, we analyzed the role of fasting serum gastrin (FSG) and confirmed its importance in providing relevant information for diagnosis and management of Zollinger-Ellison syndrome (ZES). However, like others39,80,136,140,168,184,196,199,201,205,247,266,306,341,343,380, we found that in most patients the determination of FSG, alone or in combination with acid secretion studies, cannot establish the diagnosis of ZES30. In these patients, gastrin provocative tests are needed. Of the several tests developed, only secretin, calcium, and meal stimulation are widely used today78,110,111,165,167,196,219,238,250,397. However, the exact role of these provocative tests, the optimal testing procedures, and criteria for positive responses remain controversial, so that some authors even question their overall usefulness304,343,344. This has occurred because most existing studies have 1 or more limitations including small patient numbers, retrospective nature, nonstandardized radioimmunoassay (RIA), different criteria for positivity, different testing procedures, and lack of stratification for FSG <10 or >10 × normal110,120,152,165,167,196,248,249,295,344,360,381,397.

To address these issues, we analyzed the results of secretin, calcium, and meal provocative tests in 293 ZES patients from a 31-year prospective National Institutes of Health (NIH; Bethesda, MD) study. FSG was determined using well-established gastrin RIAs30. Provocative tests were performed using well-established time points and standardized stimulant conditions110,111. Because of the prospective nature of our study with regular follow-ups, including detailed imaging studies and surgical exploration121,279,283,319,320,349, correlations of test results with clinical, laboratory, and tumoral parameters were possible. We compared our data to results from 537 ZES patients from the literature. Furthermore, we determined the specificity of provocative tests by analyzing data from published non-ZES patients. This approach allowed us to determine the optimal criteria for positive secretin and calcium tests and to propose a new criterion for the secretin test with high sensitivity/specificity. In conjunction with the accompanying report in this same issue30, this extensive analysis allowed us to identify important guidelines for gastrin provocative tests in the clinical management of ZES patients.

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CASE HISTORY

The detailed history and clinical findings of this 38-year-old man with a 12-year history of recurrent upper gastrointestinal symptoms resistant to standard medical treatment are reported in the accompanying paper30. The patient was hospitalized for an acute abdomen requiring surgical exploration for a perforated duodenal ulcer with an oversew as well as a vagotomy/pyloroplasty. His FSG was 221 pg/mL (normal <100) while taking omeprazole, and he had an elevated serum ionized calcium (1.34-1.38 mM, normal 1.17-1.31 mM). The possibility of ZES was raised and because no secretin was available, a calcium infusion study was performed. The calcium test results supported the diagnosis, with his FSG increasing from 215 pg/mL to 1010 pg/mL after 180 minutes (Figure 1, middle panel). Subsequently, the patient was referred to the NIH where FSG levels were 200-250 pg/mL and basal acid output (BAO) was 9 mEq/hour 2 weeks after stopping omeprazole. A secretin test with a 2-units/kg bolus of gastrointestinal hormones secretin (GIH secretin; Karolinska Institute, Stockholm, Sweden) showed an increase from 217 to 1150 pg/mL (Figure 1, left panel), and a meal test showed an increase of only 30% over basal (Figure 1, right panel), supporting the diagnosis of ZES. Imaging revealed 3 pancreatic lesions, while further biochemical studies showed hyperparathyroidism and multiple endocrine neoplasia type 1 (MEN1) (see Figure 1 in the accompanying paper30). A parathyroidectomy was performed, followed by an abdominal exploration with resection of pancreatic/duodenal tumors and metastatic tumor in lymph nodes. Postoperatively, the secretin test was negative (<200 pg/mL increase)110,238,397, but after 3 years became positive. The patient has remained asymptomatic with no evidence of recurrent tumor on imaging studies; however, the secretin test has remained positive.

FIGURE 1

FIGURE 1

This case illustrates the difficulty in making the diagnosis of ZES with the increasing use of potent acid suppressants such as proton pump inhibitors (PPIs). Therefore, the correct assessment of FSG and gastrin provocative tests has become essential in the diagnosis of ZES67,144,160,231,244,257. In this patient, the diagnosis was complicated because of an initial FSG elevation only 2-fold (characteristically increased >10-fold in 40%-60% of ZES patients)110,111,162,165,250. Furthermore, this moderate hypergastrinemia was detected while the patient was taking omeprazole, which can cause FSG elevations in patients without ZES67,80,156,187, and BAO was only moderately increased to 9 mEq/hr (mean 16-26 mEq/hr post gastric surgery in ZES patients)160,165,250,315,319. This case illustrates the importance of the secretin test in the diagnosis of ZES and shows that PPIs should be discontinued before FSG determination. As false-positive secretin tests have been reported in achlorhydric patients98,141,219, gastrin provocative testing may not be reliable in patients treated with PPIs, providing another reason PPIs should be stopped to determine the diagnosis of ZES. Lastly, this case illustrates the importance of assessing both the secretin test and the FSG level to determine cure102,283,284. The patient underwent a gastrinoma resection and a parathyroidectomy, both of which can affect the FSG29,72,123,143,157,159,197,234,263,276,281, and subsequently his FSG levels became normal. However, with time, although the FSG level remained normal, the secretin test became positive, showing persistent ZES. This latter finding illustrates the particular importance of secretin testing in MEN1 patients after resection or parathyroidectomy. Numerous patients with MEN1/ZES in the literature have been reported as cured in the long-term. However, recent studies in MEN/1 ZES patients who underwent repetitive secretin testing show that the long-term cure rate is very low in this patient group (<1%-2%)210,274,283,286,333.

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MATERIALS AND METHODS

All patients admitted to the NIH with a diagnosis of ZES over a 31-year period (1974-2005) who agreed to participate in the initial and follow-up evaluations were eligible for this study. Details on study organization, diagnostic criteria for ZES or MEN1, and the FSG determination have been described in the accompanying study30 and the literature15,16,117,123,220,224,283,320.

FSG levels were determined as described previously21,30,56,102,110,319. All gastrin provocative tests were performed before any gastrinoma treatment in patients with diffuse metastases who subsequently underwent chemotherapy379, treatment with α-interferon298, or somatostatin analogues334. FSG and provocative tests were performed before gastrinoma resection in all but 13 patients and were usually performed on the initial NIH admission. Furthermore, because correction of hypercalcemia by parathyroidectomy can affect both the FSG level and gastrin provocative test results72,123,143,157,159,197,234,263,276, all patients with ZES and MEN1 had provocative testing performed before any treatment for hyperparathyroidism.

FSG determinations after stimulation with secretin were carried out in all patients, whereas calcium and standard meal tests were carried out routinely until 1995. Results of serum gastrin responses after stimulation were expressed as the relative rise over the pre-test value

or the absolute increase expressed in pg/mL (Δ = gastrinmax − FSG). For some criteria, the maximal FSG level after provocative stimulation was considered.

Secretin testing was performed using an intravenous bolus injection (2 U/kg body weight) of Secretin-Kabi (Ferring AB, Malmo, Sweden)110. FSG concentrations were measured at −15, −5, and 0 minutes before and at 2, 5, 10, 15, 20, and 30 minutes after secretin injection. Secretin test results were analyzed using the criterion of McGuigan and Wolfe110,238 (Δ ≥200 pg/mL); the criterion of Deveney and colleagues78 (Δ ≥110 pg/mL); another criterion of Deveney et al77 (Δ >100 pg/mL); the criterion of Lamers and van Tongeren196 (Δ >50%); the criterion of Modlin and colleagues260 (Δ ≥100%); the criterion of Malagelada et al219, (gastrinmax≥335 pg/mL); and 1 of the criteria proposed by Poynard, Bonfils, et al301 (gastrinmax≥186 pg/mL).

The calcium infusion provocative test was performed as described previously78,110 with calcium gluconate (10%) (5 mg calcium/kg per hr) (54 mg/kg per hr of calcium gluconate) given by intravenous infusion for 3 hours. FSG and calcium levels were measured simultaneously at 30 or 15 minutes before, immediately before, and at 30, 60, 90, 120, 150, and 180 minutes after the calcium infusion. A rise in serum calcium ≥1.5 mEq/L was required for the test to be considered valid. Patients with hypercalcemia, renal disease, cardiac disease, or an unstable clinical condition did not undergo calcium testing. Calcium test results were analyzed using the criterion of Deveney et al78, (Δ ≥395 pg/mL); a second criterion of Deveney et al77 (Δ >450 pg/mL); the criterion of Lamers and van Tongeren196 (Δ >50%); the criterion proposed by Modlin and colleagues260 (Δ ≥100%); and the criterion of Malagelada et al219 (gastrinmax≥326 pg/mL).

The standard meal test was performed as described previously111 and consisted of 30 g of protein, 20 g of fat, and 25 g of carbohydrate111,196. FSG levels were measured at −15, 0, 30, 60, 90, and 120 min111. Test results were analyzed using the criterion of Lamers and van Tongeren196 (Δ >50%) and the criterion of Malagelada219 (gastrinmax≥500 pg/mL). Meal tests were not performed if the patient had a prior total gastrectomy or if the patient could not take oral feedings.

BAO, maximal acid output (MAO), and acid secretory control assessed by antisecretory medication were measured30,223,225,228,245,310,319,355. Patient histories30,123,320,409, laboratory investigations30,117,319,320, endoscopy30,36,122,320, and imaging studies using both conventional109,206,227,292,297,332,353,354,382 and functional56,85,185,256,288,357 localization methods were performed. Based on the imaging studies and surgical exploration, patients were stratified into those with primary tumor only, those with lymph node metastases, and those with liver metastases. Lymph node and liver metastases were established by biopsy in all patients350,384,409.

Surgical exploration was performed in all patients with ZES without MEN1 without diffuse liver metastases or anillness limiting life expectancy, and in patients with MEN1 with imageable lesions >2.5 cm as described previously3,30,103,104,112,273,275,277,279,280,282,286,287,349,387. Patients with limited hepatic metastases considered resectable also underwent surgical exploration and resection52,274,278,289,290,387. For the purpose of analyzing the effect of primary tumor location, patients were divided into those who had only a duodenal primary; a pancreatic primary; a lymph node primary; a primary in another nonduodenal, nonpancreatic, non-lymph node location; or a primary tumor in an unknown location. A primary tumor of the lymph node was defined as occurring in a patient who was disease-free (normal fasting gastrin, negative provocative test, and negative imaging102) after resection of only a lymph node gastrinoma as described previously14,273,283. Other nonduodenal-pancreatic-lymph node primary locations were defined as occurring in patients who were disease-free after resection of a gastrinoma from these sites283,402,403.

Computed tomography (CT) or magnetic resonance imaging (MRI) of the sella turcica and determinations of serum prolactin, calcium (total and ionized), and parathyroid hormone concentrations (using both an assay for the intact PTH molecule and with an antibody directed against the mid-portion of PTH) were also performed to determine if associated MEN1 was present as described previously16,29,123,283.

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Literature Review of FSG and Provocative Tests in Patients With ZES and in Control Patients Without ZES

To compare our results with previously reported data, we attempted to identify all published cases of ZES with gastrin provocative test data. A MEDLINE (National Library of Medicine, Bethesda, MD) search and analysis was performed as described in the accompanying paper30. For the provocative tests, the percentage rise of FSG above baseline, Δ (%), and the absolute increase in FSG above baseline, Δ (pg/mL), were calculated. Maximal FSG values after provocative tests were normalized for the highest normal value used in each publication. Furthermore, we collected published data on secretin tests in non-ZES patients with and without achlorhydria. Only the secretin test results from literature patients treated with synthetic or GIH secretin were analyzed, not those with Boots secretin, because it can cause false-positive responses and is no longer available40,43,128,238,265,302,398. Furthermore, only secretin results from literature ZES patients in whom the secretin test was performed using an intravenous bolus administration of a dose equivalent to 2 units per kg body weight of secretin were used for comparison to the NIH results. Results of literature patients tested with 1 unit per kg, 75 total units, or ≥3 units per kg were analyzed separately to determine the effect of secretin dose. Results from calcium testing in ZES and non-ZES patients were included only if the calcium test was performed with a calcium infusion over 3 hours using 5 mg calcium per kg per hour.

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Statistical Analysis

Statistical analysis was performed using the Student t test for unpaired values, the Mann-Whitney U test, the Fisher exact test, and the chi-square test using the computer programs Statview (SAS Institute, Cary, NC) and Statistica MAC (Statsoft, Tulsa, OK). P values < 0.05 were considered significant. All continuous variables with a normal distribution are reported as mean ± SEM, otherwise the median is indicated. Regression lines were calculated using a least-squares analysis.

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RESULTS

General Characteristics of NIH and Literature ZES Patients

Gastrin provocative test results from 293 NIH and 537 literature ZES patients were analyzed and their clinical, laboratory, and tumor characteristics were compared (Table 1). In agreement with most large series49,60,92,96,171,253,312,320,339,343,360,383, 29% of NIH patients had ZES with MEN1. This was significantly higher (p = 0.017) than 21% of literature ZES patients. Similar to most large series of ZES patients320, there was a slight male predominance both in the NIH and literature patients. Acid hypersecretion, which is a constant feature of ZES11,164,166,199,217,240,248-251,315,319,323,343,360,377,383,391, was higher in NIH than in literature patients. Increased MAO, which is another characteristic feature of ZES165,320, was found in both groups. Hypergastrinemia, a recognized constant feature of ZES161,164,166,250, was significantly more pronounced in NIH than in literature patients (median 6.4-fold vs. 4.8-fold increase). The median FSG increase after secretin or calcium (150%) and after a standard meal (33%) was similar in NIH and literature patients. In accordance with most recent series142,145,166,275,279,283,285,286,356, duodenal gastrinomas were more frequent than pancreatic gastrinomas among NIH patients. This was not true for literature patients, possibly reflecting the fact that in most early series, the duodenum was not systematically explored at surgery275,279,280,285,363. In both the NIH and literature groups, primary gastrinomas occurred in 12% of patients in nonduodenal/nonpancreatic locations, including lymph nodes and some rare extraabdominal locations1,118,160,166,226,270,339. Similar to most series160,166,339, in one-third of patients the site of the primary was not established. In accordance with recent studies, <50% of patients had distant metastases and one-third had local lymph node metastases14,160,166,273,283,286. In contrast to studies of 1960-198060,92,319,320,347,360,383, prior gastric acid-reducing surgery occurred in <20% of patients, while in most patients, gastric hypersecretion was controlled either with histamine H2-receptor antagonists or PPIs49,60,63,92,119,160,161,163,166,383,397.

TABLE 1

TABLE 1

In accordance with previous studies110,143,159, sporadic and MEN1/ZES patients had comparable FSG levels (642 vs. 748 pg/mL) and comparable FSG levels after secretin (1513 vs. 2192 pg/mL) or calcium (1550 vs. 2895 pg/mL). However, sporadic ZES patients had significantly lower postprandial gastrin values (810 vs. 1550 pg/mL, p < 0.05).

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Gastrin Provocative Tests in NIH and Literature Patients

To differentiate ZES from other conditions causing hypergastrinemia, various gastrin provocative tests have been developed. Today, the most commonly used are the secretin, calcium, and meal tests40,78,110,111,153,164-167,189,196,238,243,247,295,397. In previous studies, the small number of ZES cases, different methodologies, and failure to consider separately patients with FSG <10-fold and >10-fold increased have led to controversy about the role of gastrin provocative tests in ZES110,304,343,344. It is especially important to consider separately patients with FSG <10-fold and >10-fold increased because the combination of FSG >10-fold increased and hyperchlorhydria (preferably pH <2) is generally considered to be pathognomonic of ZES40,119,142,248,250,319,360,381,397. Therefore, in the present study, both the NIH and literature patients were stratified into those with FSG <10-fold or ≥10-fold increased.

The provocative test results (secretin, calcium, meal) were similar in NIH and literature ZES patients (Table 2). In particular, no change or a decrease in FSG levels after secretin or calcium was exceptional, occurring in <2% of NIH and literature patients. The median FSG increase after secretin was similar in NIH and literature patients (that is, 744 and 600 pg/mL, see Table 1), as was the median changeafter calcium (850 and 994 pg/mL). In both groups, few patients (2%-7%) had an absolute increase in FSG ≤100 pg/mL or ≤200 (5%-8%). The distribution of FSG levels was also generally similar in the NIH and literature ZES patients (Table 3). Because only 25%-35% of NIH or literature ZES patients have an FSG level ≥10-fold increased, our results confirm that approximately two-thirds of all FSG levels in ZES fall into a nondiagnostic range (that is, <10-fold increased with acidic gastric pH). Therefore, FSG values in these patients will overlap withthose seen in patients with other conditions with hypergastrinemia/hyperchlorhydria (that is, Helicobacter pylori infection, antral G-cell hyperplasia/hyperfunction, renal failure, post small bowel resection, gastric antral obstruction7,9,158,165,167,204,246,250,397), so gastrin provocative tests are needed.

TABLE 2

TABLE 2

TABLE 3

TABLE 3

Numerous criteria have been proposed for a positive gastrin provocative test. The most widely used secretin test criterion, (Δ ≥200 pg/mL), is derived from a review of 14 original studies by McGuigan and Wolfe238. In these studies, different secretin preparations (GIH, Boots), doses, and modes of administration (bolus, infusion) were used. The Δ ≥200 pg/mL criterion was selected because it allowed the diagnosis of a maximal number of ZES patients without false positives. In that review, this criterion was reported to have a sensitivity of 100% when 2 units/kg bolus injection of secretin was performed. However, we found it to be less sensitive, with 87% of all NIH and 88% of all literature patients having a positive secretin test (see Table 3). The sensitivity decreased even further to 83% for the NIH and 87% for the literature ZES patients when the clinically relevant group of patients with FSG <10-fold increased were considered.

Deveney et al78 proposed that Δ secretin ≥110 pg/mL and Δ calcium >395 pg/mL had the greatest discriminatory value. When applied to our populations, 93% of all NIH patients and 96% of all literature patients had a positive secretin test, whereas 67% of all NIH and 75% of all literature patients had a positive calcium test. The secretin test's sensitivity remained unchanged in patients with FSG <10-fold increased, whereas the calcium test's sensitivity decreased to 54% and 70%, respectively. In another publication77, theauthors proposed slightly different criteria (Δ secretin >100 pg/mL, Δ calcium ≥450 pg/mL), which lead to results comparable to those in the current study (see Table 3).

Lamers and van Tongeren196 proposed that FSG increases >50% for the secretin and calcium test and <50% for the meal were characteristic of ZES. In the current study, 84% of all NIH and 81% of all literature patients had a positive secretin test, 79% and 90% had a positive calcium test, and 57% and 67%, respectively, had a positive meal test (see Table 3). These percentages decreased slightly when only patients with a <10-fold FSG increase were considered. However, 20% of all NIH and 15% of all literature ZES patients had a ≥100% increase post meal, a value considered characteristic of antral G-cell hyperplasia7,9,108,158,167,204,336,347. In patients with FSG <10-fold increased, it was 19%/9%, respectively (see Tables 2, 3).

Malagelada et al219 proposed criteria based on the highest FSG value after stimulation. In their study, the authors used maximal FSG levels post provocation of 335 pg/mL, 326 pg/mL, and 500 pg/mL for secretin, calcium, and meal tests, respectively. In the current study, 93% of all NIH and 97% of all literature patients had a positive secretin test, 97% and 92% had a positive calcium test, and 74% and 68%, respectively, had a positive meal test (see Table 3). These percentages decreased slightly in patients with a <10-fold FSG increase.

Modlin et al260 proposed an FSG increase >100% post secretin or calcium to diagnose ZES. In the current study, 63% of all NIH and 57% of literature patients had a positive secretin test, whereas 57% and 75%, respectively, had a positive calcium test (see Table 3). These percentages did not change significantly in patients with FSG <10-fold increased.

Poynard, Bonfils, et al301 proposed that a combination of 4 criteria gave the best sensitivity and specificity, with the best single criterion being a maximal FSG after secretin ≥186 pg/mL. With these criteria, 100% of NIH and 99% of literature patients had a positive secretin test, and these percentages were identical in patients with a <10-fold FSG increase (see Table 3).

In both the NIH and the literature ZES patients, the criterion of an increase of either 110 or 100 pg/mL post secretin had a greater sensitivity than the criterion of a 200 pg/mL increase (p < 0.003).

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Correlation of FSG and Serum Gastrin Increase After Gastrin Provocative Tests

To investigate the influence of FSG levels on provocative testing, we correlated the FSG and the absolute increase in FSG after secretin (Δ secretin), calcium (Δ calcium), and a meal (Δ meal) in NIH and literature patients. The magnitude of the FSG correlated well with Δ secretin (Figure 2, top panel) and Δ calcium (Figure 2, middle panel) in NIH and literature patients, whereas there was no correlation with Δ meal (Figure 2, bottom panel).

FIGURE 2

FIGURE 2

To analyze if these correlations still exist after correction for higher FSG values, we correlated the relative increase in serum gastrin after secretin or calcium with FSG levels and found no significant correlation (r = [−0.068] [−0.18], data not shown), suggesting that the magnitude of the FSG contributes to the higher Δ response but it is not associated with a proportional gastrin release post stimulation.

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Influence of Clinical and Laboratory Variables on Gastrin Provocative Tests in NIH and Literature Patients

To determine whether clinical or laboratory variables might influence gastrin provocative testing, these variables were correlated with the increase in FSG levels after stimulation. In NIH patients, extensive data were available, allowing a detailed analysis (Table 4), while the effect of only selective variables could be compared in literature patients (Tables 5-7).

TABLE 4

TABLE 4

TABLE 5

TABLE 5

TABLE 6

TABLE 6

TABLE 7

TABLE 7

In the NIH patients, age, race, MEN1 status, disease duration, prior treatment with PPIs, the presence/absence of most common ZES symptoms (pain, heartburn) or the presence/absence of manifestations of severe disease (confirmed ulcer, esophageal disease, pyloric obstruction) did not effect secretin or calcium provocative testing (see Tables 4-6). In contrast, higher Δ secretin and Δ calcium levels were seen with female sex and high BAOs, whereas higher Δ secretin levels only were seen in the presence of diarrhea or with a long duration of antisecretory drug treatment. Correlation of clinical or laboratory parameters with the literature data did not demonstrate a relationship between higher Δ secretin or Δ calcium values with higher BAOs or sex (see Tables 5, 6, Figure 3). Similar to NIH patients, no relationship with age, MEN1 status, or prior gastric-acid reducing surgery was seen (see Tables 5, 6). In contrast to the Δ secretin and Δ calcium results in NIH ZES patients, higher Δ meal levels were present in younger patients, patients with a longer disease history, patients with heartburn as an initial symptom (data not shown) or with severe esophageal disease (stricture/dysphagia) and the presence of MEN1, but not with BAO or MAO levels (see Tables 4, 7, Figure 3). In the literature ZES patients, no correlations were seen with the Δ meal value and acid secretory levels or clinical parameters (Table 7, Figure 3).

FIGURE 3

FIGURE 3

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Influence of Tumoral Variables on Provocative Test Results in NIH and Literature Patients

In general, primary tumor location had no effect on the Δ secretin or Δ calcium levels in NIH or literature ZES patients (see Tables 4-6). Tumor size was associated with an increased Δ secretin and Δ calcium response (see Tables 4-6 and Figures 3, 4) in NIH patients more than in the literature ZES patients.

In contrast to secretin and calcium tests, the meal test was not influenced by tumor size in the NIH ZES patients. However, in NIH patients only, a duodenal tumor was associated with a higher Δ meal response, whereas the presence of liver metastases was associated with a lower meal response (see Tables 4, 7).

To investigate further the relationship between tumor size/disease extent and secretin provocative testing, we correlated the size of the largest tumor and the primary tumor size with Δ secretin in NIH patients (Figure 4). In the literature patients, only primary tumor size was available for this analysis (Figure 4, bottom panel). In NIH patients, there was a significant correlation between the largest tumor size and Δ secretin in all patients, and this correlation was even stronger in patients without liver metastases (Figure 4, top panel). No correlation existed with primary tumor size in the NIH patients with or without liver metastases (Figure 4, middle panel). However, in literature ZES patients, a weakly positive correlation between primary tumor size and Δ secretin existed in all patients, which increased in significance in patients without liver metastases (Figure 4, bottom panel).

FIGURE 4

FIGURE 4

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Correlation Between Various Provocative Test Results in NIH and Literature Patients

As secretin and calcium provocative tests were influenced by comparable factors, we further studied the correlation between these different tests. We found a close correlation between Δ secretin and Δ calcium both in NIH and literature patients (Figure 5, top panel). This correlation remained unchanged if relative increases (% increase) post secretin and post calcium were correlated (data not shown). However, there was no correlation or a weak correlation between Δ secretin and Δ meal or Δ calcium and Δ meal in any patient group (Figure 5, middle and bottom panels).

FIGURE 5

FIGURE 5

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Influence of Different Variables on the Positivity of the Various Provocative Tests in NIH and Literature Patients

To analyze whether clinical, laboratory, or tumor variables could also influence provocative test results, that is, positive or negative, we investigated the effect of the presence or absence of these variables on the positivity of secretin (Table 8), calcium (data not shown), and meal tests (data not shown). In general, there was little concordance between those variables and the positivity of the secretin test in NIH or literature ZES patients (see Table 8). This might partially be due to the small numbers of patients in some of the variable groups. The only variable associated with a positive secretin test in both the NIH and literature patients was the presence of a large primary tumor. In contrast, only in the NIH ZES patients, a gastrinoma located in the duodenum and the presence of localized disease were associated with a positive secretin test result. In the literature ZES patients only, male sex and lack of previous acid-reducing surgery associated with increased likelihood of a positive result.

TABLE 8

TABLE 8

With the calcium test using the Δ calcium ≥395 pg/mL criterion78, the most commonly used criterion166,397, no clinical, laboratory, or tumor variable affected the positivity in ZES patients. No clinical, laboratory, or tumoral variable, except MEN1 status or previous gastric acid-reducing surgery, influenced the occurrence of <50% increase in serum gastrin post meal, a response characteristic of ZES patients31,195,196,347 (data not shown).

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Comparison of 4 Doses of Secretin for Provocative Testing

In the past, different doses of secretin have been used for provocative testing (Table 9). While 2 units of secretin per kg body weight is the most commonly used dose today, in some studies doses of 1 unit/kg, 75 units, 3 units/kg, or even higher doses have been used. We compared the percentage of positive tests using different doses of secretin in literature patients. Similar to some studies189,219,380, but not others153,229,329,405, there was no apparent secretin dose-response effect using anycriterion either for all patients or for patients with FSG <10-fold increased. Specifically, results with 1 unit/kg or 3units/kg secretin were similar and no increased detection occurred with the higher dose. Moreover, secretin tests with 75 units and 2 units/kg also gave similar results.

TABLE 9

TABLE 9

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FSG and Secretin Provocative Test Results in Non-ZES Patients

To assess the specificity of secretin and calcium provocative tests, we analyzed results from the literature in non-ZES patients (Table 10). Because high FSG levels and false-positive gastrin provocative tests can occur in patients with achlorhydria42,98,141,192,219, we analyzed results separately for this patient group. Of the 462 subjects without ZES and without achlorhydria who underwent secretin testing (normal controls, patients with antral G-cell hyperplasia, moderate hypochlorhydria, or peptic ulcer disease), FSG levels were reported in 147 patients and the majority had either a normal or only moderately elevated FSG value. None of the 462 non-ZES patients had a positive secretin test using the Δ ≥200 pg/mL or Δ ≥110 pg/mL criterion, and 1 out of 462 (0.22%) had Δ >100 pg/mL. Sixteen patients (7%) had a positive secretin test using the >50% criterion, 3 (1%) using the criterion Δ >100%, 17 patients (13%) using the criterion of Δ ≥186 pg/mL, and 5 patients (4%) using the criterion of ≥335 pg/mL increase. Hence, overall, the Δ criteria had better specificity than the percentage increase or maximal gastrin value criteria. In patients with achlorhydria, false-positive secretin tests were more common, emphasizing the importance of excluding these patients. We identified 100 non-ZES subjects without achlorhydria who underwent calcium provocative tests in the literature. Overall, false-positive calcium tests occurred more frequently with the percentage criteria.

TABLE 10

TABLE 10

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Sensitivity and Specificity of Different Criteria for Positive Provocative Tests Using Secretin

Data from ZES and non-ZES patients were used to estimate sensitivity and specificity of secretin tests in the clinically relevant group of patients with <10-fold FSG increase (Table 11). Because the Δ criteria offered better specificity (see Table 10), only these criteria were considered for analysis. Both the proposed Δ criteria of >100 pg/mL77, Δ≥110 pg/mL78, and Δ ≥200 pg/mL238 increase were analyzed as well as new possible criteria of an increase of ≥120, ≥130, ≥140, ≥150, ≥160, ≥170, ≥180, or ≥190 pg/mL (see Table 11). As the highest increase in serum gastrin occurring in a normal subject was 101 pg/mL, Δ criteria of ≥110 to ≥200 pg/mL had 100% specificity. The sensitivity of the proposed criterion of Δ ≥200pg/mL was 87%, which is significantly less (p < 0.05) than the 91% sensitivity of a Δ ≥140 pg/mL criterion, highly significantly different (p < 0.01) from Δ ≥130 pg/mL, and even more significantly different (p < 0.003) from a criterion of Δ ≥120 pg/mL. From this analysis, the criterion with 100% specificity and highest sensitivity is Δ secretin ≥120 pg/mL.

TABLE 11

TABLE 11

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DISCUSSION

In the current study, we prospectively analyzed the increase in serum gastrin after provocative tests in 293 ZES patients and compared our results to data from 537patients from the literature. In the accompanying paper30, we found that the determination of FSG levels alone cannot establish the diagnosis in two-thirds of ZES patients, because FSG levels of ZES patients significantly overlap with those seen in idiopathic peptic disease or other non-ZES conditions78,151,152,217. Therefore, several gastrin provocative tests have been developed. These tests use different stimuli including calcium infusion orbolus injection196,295,318,380, infusion or bolus injection of secretin31,153,192,196,247,252, administration of a meal31,196,348, and injection of glucagon26,69,153,183,265,343,360 or bombesin22-24,158. Only the secretin (bolus), calcium (infusion), and meal tests are generally used today78,110,111,167,196,219,238,250,397. Due to methodologic inconsistencies in previous studies, the criteria for each of these tests remain an area of controversy, and some studies even question their overall usefulness.

Since the initial description of the ability of secretin to stimulate an exaggerated serum gastrin increase in ZES patients137,153, the secretin test has been increasingly used in the diagnosis of ZES110,238,394,397. Although some studies have proposed that this increased response represents an exaggerated normal response40,44,45, there is strong evidence that secretin can stimulate gastrin release by direct interaction with gastrinoma cells. Secretin receptors occur on gastrinoma cells84, secretin stimulates gastrin release from isolated gastrinoma cells58,93,129,147, and this effect can be inhibited by somatostatin58.

In the literature, some ZES patients have no increase in FSG after a bolus injection of secretin73,94,219,229,230,233,247,318,341,343,344,351,360,405,406. The percentage of these patients varies from 0% in most studies78,150,157,189,196,240,255,315 to 7%-75%229,247,318,343,344,360. In larger series however, most patients had a significant increase in FSG post secretin (median, 262-1103 pg/mL in 10 large studies66,78,100,150,196,218,232,315,341,412). In the current study, only 1.4% of literature or NIH ZES patients had no increase in serum gastrin after secretin, so >98% responded to secretin. Our results demonstrate that in ZES patients, no response to secretin injection is very uncommon.

Numerous studies have proposed criteria for a positive secretin test77,78,110,196,219,260,301. However, these criteria vary widely, which is primarily due to multiple methodologic differences. Some studies are limited by small patient numbers (<25 patients), and patients with FSG < or >10-fold increased are usually considered together, although provocative tests are of clinical relevance only in the former group78,110,152,196,342,344,360. Moreover, different protocols and different secretin preparations have been used (Boots, GIH, synthetic), which is relevant because false-positive secretin tests have been reported with Boots secretin41,238,398. Different modes for secretin administration have been employed (infusion, bolus injection)238,247,249,250,252,301, and different doses used. The secretin dose could be relevant because some studies153,229,238,405, but not others153,229,329,405, report that different doses may give different results. Our systematic analysis of secretin test results in patients receiving different doses of secretin (1U/kg, 75 U total, 2 U/kg, ≥3 U/kg) showed no dose-response effect (see Table 9). These results are similar to some studies189,219,380, but not others153,229,329,405, and led us to conclude that there is no need to increase the usual 2units/kg dose or to repeat a secretin study with a higher dose if the initial study was negative, as suggested by others229,405. Furthermore, secretin test protocols frequently varied in the time points for collection of blood samples. This is important because some studies did not measure gastrin 2 minutes after secretin injection196,255. In 1 study110 however, 6% of ZES patients had their only positive response 2 minutes post injection. Moreover, these studies were further limited by small patient numbers (<25 patients) and the fact that patients with FSG < or >10-fold increased were considered together, although gastrin provocative tests are of clinical relevance only in the former group78,110,152,196,342,344,360.

Three different types of criteria for a positive secretin test have been proposed: 3 criteria based on the absolute increase in FSG post secretin (>100, ≥110, ≥200 pg/mL)77,78,110, 2 criteria based on the relative increase (>50%, >100%)196,260, and 2 criteria based on the maximal FSG level post secretin (≥186, ≥335 pg/mL)219,301. Based on a review of 122 cases from the literature238, the criterion of ≥200 pg/mL increase post secretin has been most widely used since 1980 in the United States110,119,166,397. Because we had a large number of patients, we could systematically assess the sensitivity of the various proposed criteria, both in all patients and in the clinically important subset of ZES patients with FSG <10-fold increased78,110,152,196,342,344,360. In NIH and literature ZES patients, 3 criteria had sensitivities of 90%-100% (Δ >100 pg/mL, Δ ≥110pg/mL, and gastrinmax ≥186 pg/mL) and 3 had sensitivities of 85%-89% (Δ ≥200 pg/mL, Δ >50%, and gastrinmax ≥335 pg/mL). One proposed criterion, Δ >100%, had a low sensitivity of only 60%-62%, suggesting it is not generally useful. Because ZES is an uncommon condition (1-3 cases/year per million population) and hypergastrinemia due to H. pylori infection or other conditions is much more frequent78,90,151,152,203,217,236,246,337, it is important to limit false-positive responses. Therefore, specificity may be the most important factor in determining an optimal secretin test criterion. To assess the specificity of the 6 different secretin test criteria with high sensitivity (85%-100%), we analyzed the results from 489 non-ZES patients' responses from the literature (see Table 10), including 462 without and 27 subjects with achlorhydria. Because there was an unacceptably high false-positive rate varying from 7% to 100% in achlorhydric patients, our analysis confirms the proposal that secretin test results are not reliable in these subjects42,98,141,192,219. After exclusion of achlorhydric patients, the 3 absolute-increase criteria (that is, Δ >100, ≥110, ≥200 pg/mL) gave very low false-positive rates (0-0.5%) resulting in a specificity of 99.8%-100%, whereas the remaining highly sensitive criteria (Δ >50%, gastrinmax ≥186 pg/mL, gastrinmax ≥335 pg/mL) gave higher false-positive rates of 4%-13%. Our analysis demonstrated that the proposed criteria with the highest sensitivity and specificity are Δ ≥100 pg/mL (95%, 99.8%), Δ ≥110 pg/mL (94%, 100%) and Δ ≥200 pg/mL (87%, 100%). Because the sensitivity of the Δ >100 pg/mL and Δ ≥110 pg/mL criteria was significantly higher than that of Δ ≥200 pg/mL, we tried to identify a new criterion with maximal sensitivity and 100% specificity. This criterion is a Δ ≥120 pg/mL, which has 94% sensitivity and a specificity of 100%. Both the Δ ≥120 and Δ ≥130 pg/mL criteria had a 100% specificity, and each had a significantly higher sensitivity than the commonly used Δ ≥200 pg/mL criterion (see Table 11). The Δ ≥120 pg/mL criterion had the same sensitivity as the previously proposed Δ ≥110 pg/mL criterion78 (that is, 94%), and its sensitivity was not significantly different from that of the Δ >100 pg/mL criterion77. However, in the non-ZES patients without achlorhydria, 1 patient had an increase in serum gastrin after secretin of 101 pg/mL and 4 patients had an increase of 100 pg/mL. Therefore, we conclude that Δ ≥120 pg/mL was the criterion with maximal sensitivity and 100% specificity. Criteria of ≥110 and ≥120 pg/mL both had equal sensitivity and 100% specificity, but because of the importance of limiting a false-positive result to the greatest extent, we recommend a criterion of Δ ≥120 pg/mL rather than 110 pg/mL as recommended by others78.

Based on these results, we suggest that a secretin test should be performed with 2 units GIH or synthetic secretin per kg body weight, it should include an assessment of serum gastrin before secretin injection, and 2, 5, 10, 15, and 20 minutes110 after secretin. An absolute increase in serum gastrin ≥120 pg/mL should be the criterion for positivity because it has the highest sensitivity with 100% specificity (see Table 11). When this new criterion is applied to the 453 NIH and literature ZES patients in our study with FSG <10-fold increased, it allows the correct diagnosis of 37 ZES patients that would have had a negative test with the commonly used 200 pg/mL criterion.

Numerous studies show serum calcium levels can greatly influence FSG in ZES patients with or without MEN1. Intravenous administration of calcium augments basal hypergastrinemia69,78,157,181,197,212,237,295,311,361,368,386, whereas a reduction of calcium levels by EDTA administration157,388 or correction of hyperparathyroidism by parathyroidectomy59,87,88,127,153,159,276,361,368,369,393 diminishes hypergastrinemia in ZES patients. This calcium-induced augmentation of FSG in ZES patients is the basis of the calcium provocative test69,197,262,295,360,368. Subsequent studies have shown that this effect is likely due to a direct action of calcium on gastrinoma cells2,33,91,93,399,400. In fact, calcium can increase gastrin release from isolated gastrinoma cells2,33,91,93,399,400. Furthermore, these cells possess both calcium-sensing receptors and various calcium channels126,155,378 whose activation could stimulate gastrin secretion.

In previous reports69,78,192,196,197,219,255,295,343,360, very few ZES patients did not respond to an intravenous calcium infusion195,233,351, and the median FSG increase was 438-4325 pg/mL in 8 larger series23,78,110,196,232,262,318,341. In the current study, 6 NIH and 3 literature ZES patients did not respond to calcium, demonstrating that calcium evokes an increase in serum gastrin in >97% of ZES patients. The median increase was 850 pg/mL in NIH and 994 pg/mL in literature patients.

Numerous authors have proposed different criteria for a positive calcium test77,78,196,219,260. With the exception of 2 studies advocating a bolus injection of calcium318,380, these studies used similar protocols (dose of calcium, time of infusion, time points for blood collection). Nevertheless, their results are limited by small patient numbers and the fact that patients with FSG <10 and >10-fold increased are considered together. Three different types of criteria have been proposed for a positive calcium test: 2 criteria based on the absolute increase in FSG post calcium (≥450, ≥395 pg/mL)77,78, 2 criteria based on the relative increase (>50%, >100%)196,260, and 1 criterion based on the maximum FSG level post calcium (≥326 pg/mL)219. In the United States, the criteria of ≥395 pg/mL and >50% are widely used78,110,196. We found that 1 criterion had >90% sensitivity (gastrinmax ≥326 pg/mL), 1 criterion had 79%-90% sensitivity (Δ >50% increase), and 3 criteria had 57%-76% sensitivity (Δ ≥450, ≥395 pg/mL, >100%). In patients with <10-fold increase in FSG the sensitivities of the 2 criteria based on absolute increases dropped 5%-13%, whereas there was no relevant decrease in sensitivity for the other criteria. For the 2 criteria generally used in the United States (Δ ≥395pg/mL or >50% increase), the sensitivities in the NIH/literature patients were 54%/70% and 78%/91%, respectively. As discussed above, avoiding false-positive tests is especially important. An analysis of the available data from 105 non-ZES patients who underwent calcium testing allowed us to assess the specificity of the different criteria. As the calcium test may be falsely positive in up to50% of non-ZES patients with achlorhydria196,219, only non-ZES patients without achlorhydria were included in this analysis. The Δ >50% and Δ >100% criteria gave an unacceptably high number of 10%-17% false positives, whereas only 1 non-ZES patient exceeded the gastrinmax ≥326 pg/mL criterion. However, this last criterion is not clinically useful because most patients with FSG <10-fold increased (64% in the current study) have FSG ≥326pg/mL before any stimulation. No non-ZES patient without achlorhydria in the literature had a Δ calcium ≥395pg/mL, so that the Δ ≥450 and Δ ≥395 pg/mL criteria have 100% specificity. The ≥395 pg/mL criterion had a greater sensitivity than the ≥450 pg/mL criterion, although this difference did not quite reach statistical significance (p > 0.1).Nevertheless, it could be clinically relevant because the calcium test is generally used as a second-line test in patients with strong clinical suspicion of ZES but anegative secretin test. Therefore, maximal sensitivity, along with 100% specificity, is crucial for choosing the optimal criterion. Taking this into account, we conclude that Δ ≥395 pg/mL should be used. However, even with this criterion, the sensitivity of the calcium test is significantly lower than that of the secretin test (63% vs. 94%, p < 0.01). Furthermore, unlike with secretin, numerous side effects are reported with the infusion of calcium, including abdominal pain, nausea, vomiting, headache, phlebitis, shortening of Q-T interval on ECG, paresthesias, diuresis, severe fatigue, palpitations, arrhythmias, and a rise in blood pressure110,177,196,255,318,380. These complications lead to early termination of the infusion in some patients318. Moreover, the calcium infusion test takes longer than the secretin test (3 hr vs. 30 min) and requires a physician's attendance. In addition, the secretin test may be superior to calcium testing in distinguishing antral from tumoral hypergastrinemia182,190,196,347. For these reasons, we conclude that the calcium test should not be used routinely as the first-line test in patients suspected of having ZES. However, in 1 previous study110, 33% of ZES patients with a negative secretin test had a positive calcium test. Two smaller series report secretin-negative ZES patients with a positive response to calcium infusion318 or injection380, whereas another study reports negative calcium tests in all secretin-negative ZES patients196. In the current study, 38% of NIH and 50% of literature ZES patients with a negative secretin test (applying the Δ ≥120 pg/mL criterion) had a positive calcium test (by the Δ ≥395 pg/mL criterion). Therefore, we conclude that the calcium test is useful in patients with a clinical suspicion of ZES but a negative secretin test.

Ingestion of food is a physiologic stimulus for the release of gastrin from the antral and duodenal mucosa31. In patients with hypergastrinemia of antral origin, that is, atrophic gastritis or antral G-cell hyperfunction, a condition reported to occur in H. pylori infection9, feeding induces an increase >100% in FSG31,83,114,158,176,204,300. In ZES patients, gastrin produced by the tumor is the main source of serum gastrin, and early studies reported no major increase in FSG after ingestion of a test meal, suggesting that feeding does not stimulate gastrin release from gastrinomas31,152,158,190,195,264,347. Therefore, it was proposed that a standard meal test could differentiate hypergastrinemia of antral and tumoral origin31,347. This is an important distinction because antral G-cell hyperplasia/hyperfunction can mimic ZES clinically and cause hyperchlorhydria/hypergastrinemia6,7,167,186,194,204,299,397. However, other studies have reported ZES patients with large increases in FSG after feeding and questioned the value of the meal test69,111,196,343. The mechanism of postprandial FSG increase in ZES patients is controversial. Some studies suggest the gastrin could be of antral origin in patients having both ZES and antral syndromes106, while other authors propose the gastrin release is mediated by the tumor111, possibly involving release of a gastrin-stimulating agent, such as secretin, from the duodenum359,360. Some reports suggest that previous gastric surgery could influence the increase in gastrin post meal in ZES patients69,111,195,360. The small number of ZES patients investigated, the different proportion of patients with prior gastric surgery, and the differences in tumor characteristics could partly explain the large discrepancies between some of these studies (Table 12). In the current study, 39% of NIH and 20% of literature patients had no increase in serum gastrin post meal. In the remaining patients, the median increase was 132 pg/mL among NIH and 212 pg/mL among literature ZES patients. In 5 larger series, the median increase in FSG post meal was 55-2269 pg/mL69,158,196,198,360. In the current study, meal test results did not differ in ZES patients with or without prior acid-reducing surgery (median increase, 175 vs. 223 pg/mL, p = 0.2).

TABLE 12

TABLE 12

Lamers and van Tongeren196 proposed a postprandial increase <50% to be characteristic of ZES. In another study, a maximal serum gastrin value post meal >500 pg/mL was suggested as criterion. However, this latter criterion is of little clinical value because it does not differentiate antral hypergastrinemia from ZES and is not applicable to ZES patients with FSG >500 pg/mL. In the current study, 57% of NIH and 67% of literature ZES patients had an increase in serum gastrin post meal <50%. These numbers change to 54% and 77%, respectively, among patients with FSG <10-fold increased. However, 20% of NIH and 15% of literature ZES patients had an increase in FSG post meal ≥100%, a value reported to be characteristic of antral G-cell hyperplasia7,9,108,111,158,167,204,336,347. Because of this overlap of meal test results in patients with hypergastrinemia of antral or tumoral origin, we conclude, in accordance with others69,111,219, that the meal test is not useful in the diagnosis of ZES.

Only limited information is available on correlations of gastrin provocative test results with clinical, laboratory, and tumoral features in patients with ZES. However, these correlations might be useful because they could define a subgroup of clinically relevant patients. Moreover, such correlations could identify patients in whom provocative test results are not conclusive because they are biased by different factors. In accordance with previous studies196,318, we found a positive correlation (r = 0.52-0.56) between the absolute increase in FSG after secretin and calcium (see Figure 5). This correlation remained unchanged if the relative (%) increases were correlated, suggesting that the correlation is not due to the influence of FSG levels on both variables, but rather reflects that common factors may be involved in determining the response to both stimulants. The current study did not identify these factors, but they could include the response of the gastrinoma to external stimuli, the amount of gastrin stored, or shared pathways of stimulation. Similar to other studies42,315, we found that secretin and calcium test results were both correlated with FSG values when the absolute increases post stimulation (Δ) were considered (see Figure 2). However, this correlation was not significant after correction for higher FSG values by correlating the relative increases. We found a correlation of secretin and calcium test results with BAO levels and with some clinical findings (duration of medical treatment, diarrhea) associated with gastric hyperacidity319 (see Tables 4-6 and Figure 3). It is most noteworthy that MEN1 patients, who frequently have hypercalcemia due to hyperparathyroidism29,123,221, did not show a significantly greater serum gastrin response to secretin (see Table 5). This finding is surprising because hypercalcemia facilitates secretin-induced gastrin release in ZES patients157,196,318. In the current study, we found that larger tumors are associated with a higher response to secretin or calcium (see Tables 4-6, Figure 3, 4). The size of the largest tumor correlates better with FSG increases post secretin than primary tumor size. This correlation is even stronger in patients without liver metastases, suggesting that the absolute tumor mass rather than the characteristics of the primary tumor influences the response to secretin. While these clinical, laboratory, or tumor variables had some influence on the magnitude of the serum gastrin response to secretin, they had little effect on the positivity of the provocative test results. This finding has clinical importance because it shows that clinical, laboratory, or tumor features do not bias provocative test results with secretin or calcium, and that these tests can therefore be performed in subgroups of ZES patients with different characteristics.

As discussed above, our data suggest that the meal test is generally not helpful in the diagnosis of ZES. However, correlations of the increase in serum gastrin post meal in ZES patients with clinical, laboratory, and tumor features might allow some insight into ongoing controversies concerning meal-stimulated gastrin release. Some authors propose that the postprandial gastrin release in ZES patients could be mediated by the release of a gastrin-stimulating agent, such as secretin, from the duodenum359,360. If secretin were involved in postprandial gastrin release, patients with increases in serum gastrin post meal might have a proportional response to secretin. Therefore a significant correlation might exist between secretin and meal test results. However, we did not find such a correlation (see Figure 5). Because Billroth II resection results in markedly diminished meal-stimulated secretin release268,269, our finding of similar meal test results in ZES patients with or without previous Billroth II resection further invalidates the hypothesis of a secretin-mediated mechanism for postprandial gastrin release in ZES patients. It has been suggested that the increase in serum gastrin post meal observed in some ZES patients could be due to coexisting antral G-cell hyperplasia/hyperfunction106. Because the meal response is markedly affected by gastrinoma resection in ZES patients111, this proposal is unlikely. MEN1/ZES patients are reported to have an increased incidence of antral syndromes in some studies106, but not in others111. Our data do not support this proposal, because we found that prior antrectomy does not influence meal test results in ZES patients. However, our data did show that NIH MEN1/ZES patients had a significantly higher median FSG increase post meal than sporadic ZES patients (see Table 7), and a significantly higher percentage of these patients had a ≥50% postprandial FSG increase. This difference could be related to other factors than an increased occurrence of antral syndromes, such as concomitant hyperparathyroidism with hypercalcemia, which could affect meal-stimulated hormone release. It has been suggested that duodenal gastrinomas are associated with higher postprandial FSG increases than pancreatic tumors196, whereas another large study did not find such a correlation111. In the current study, we found that patients with duodenal gastrinomas have larger postprandial serum gastrin increases (see Table 7). However, this did not affect meal test results, that is, the percentage of patients with ≥50% increase in serum gastrin post meal. Therefore our result is similar to another study111 and suggests that the meal test is not useful in localizing duodenal gastrinomas.

Our results for secretin testing in general show similarities to most other series including ≥10 patients; however, they also show some important differences (see Table 12). Specifically, we found the most widely used criterion of ≥200 pg/mL does not have a sensitivity of 100% as reported in a number of studies66,238,341,412 or a low sensitivity of 70%-80% as reported in other studies78,232. Our results agree with a number of other series100,315 reporting a sensitivity of 83%-86%. Similar to most studies, we found the criterion of Δ ≥110 pg/mL to have a higher sensitivity (92%-100%) and the >50% criterion to be less sensitive than either the Δ ≥110 or Δ ≥200 pg/mL criteria. For the calcium test, a number of studies reported a higher sensitivity than we found, especially for the 50% criterion23,78,232,318,341, while others had results comparable to those of our study262 (see Table 12). This difference in sensitivity cannot be due to a difference in the amount of calcium infused, because in most studies, 5 mg/kg per hour of calcium was infused for 3 hours, and all patients had at least a 1.5 mEq/L increase in serum calcium. The meal test results in the current study are comparable to results reported in some series69,347,360, but differ markedly from results of other studies that reported no ZES patients with a ≥100% increase in serum gastrin post meal157,196,216.

The systematic analysis of gastrin provocative test results in 293 NIH and 537 literature ZES patients presented in this paper allowed us to draw several important conclusions, which are summarized in Table 13. We could show a new criterion, Δ ≥120%, which had the highest sensitivity and specificity. When this new criterion is applied, the secretin test is highly sensitive (94%) and specific (100%), and therefore plays a crucial role in the diagnosis of ZES in the two-thirds of patients with nondiagnostic FSG values. This new criterion had greater sensitivity (p < 0.003) than the usually used criterion of Δ ≥200 pg/mL with equal specificity (that is, 100%), and allowed the detection of 37 more ZES patients in the NIH and literature groups than the Δ ≥200 pg/mL criterion. We applied the same analysis to calcium test results and could confirm the usefulness of the Δ ≥395 pg/mL criterion proposed by others78. However, even with this criterion, the calcium test has only a 62% sensitivity. Furthermore, multiple side effects have been reported with intravenous calcium infusion. Therefore, the calcium test should not be used as a first-line provocative test. However, the calcium test may be useful in patients with a negative secretin test but strong clinical suspicion of ZES, because it will be positive in 38%-50% of these ZES patients. We could not confirm the utility of the meal test, because we found significant overlap of meal test results in patients with ZES and antral syndromes. We found the magnitude of the gastrin response to secretin and calcium to correlate with BAO values and some clinical findings reflecting hyperchlorhydria, as well as with tumor size and extent. However, the results (that is, positive or negative) of these tests were only minimally influenced by these factors. The magnitude of the meal-induced gastrin response correlated with some clinical findings, including MEN1 status, and with tumor location. However, meal test results were only minimally influenced by these factors, so the meal test is not useful for tumor localization.

TABLE 13

TABLE 13

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ACKNOWLEDGMENTS

The authors thank the patients and their relatives who participated in the study. We thank the NIH Clinical Center 9D nursing staff, endoscopy nurses, and the past and present fellows of the NIH-Georgetown University-Washington VA Gastroenterology Training Program. We thank the members of the Nuclear Medicine and Diagnostic Radiology Branch, especially Drs. James C. Reynolds and John L. Doppman for their support. We thank the numerous referring physicians as well as the physicians who assisted us in the follow-up of some of these patients, particularly Dr. David C. Metz (University of Pennsylvania) and Dr. Jeffrey A. Norton (Stanford University). We thank the members of the Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, who participated in the care and investigation of a number of the patients.

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