Selective arterial secretin injection test for localization of gastrinoma

We have already shown that gastrinomas release gastrin when stimulated with secretin in vitro. In order to ascertain whether this is true in vivo and whether the reaction is clinically useful in the localization of gastrinomas, secretin was injected into a feeding artery of the gastrinoma in four patients, and blood samples were taken from a peripheral artery (PA) and the hepatic vein (HV) for determination of immunoreactive gastrin (IRG) and immunoreactive insulin (IRI) levels. When secretin was injected into a feeding artery of the gastrinoma, IRG rose within 40 seconds in the HV and within 60 seconds in the PA. When secretin was injected into a nonfeeder, IRG did not rise for 2 min in the PA. This test was performed to two of the postgastrectomized patients and a patient with hypergastrinemia due to atrophic gastritis. In these patients, IRG in the hepatic vein did not rise for two minutes. It was concluded that secretin directly stimulates gastrinomas to release gastrin in vivo and that the selective arterial secretin injection test is helpful in determining the location of the gastrinoma.     

Secretin,a stimulus for duodenal and pancreatic “gastrin” release: Possible pathogenetic significance in Zollinger-Ellison (ZE) syndrome

Ex vivo hemoperfused pancreaticoduodenal preparations from dogs have been used to study intraluminal and circulatory patterns of release of immunoreactive gastrin under basal conditions and after secretin stimulation. Bidirectional release of immunoreactive gastrin was maximal at 3 U/min secretin infusion, and release into pancreatic and duodenal juice exceeded that into portal venous blood. Molecular sieving chromatography of peptides with gastrin-like immunoreactivity recovered from duodenal and pancreatic juice indicated a single species of a molecular size equivalent to CCK⁸ and smaller than minigastrin (G-14). The exact identity has not been defined. This study demonstrates that secretin stimulates release of gastrin-like peptides into blood and lumen of extra-antral gastrin-producing tissues in the dog. Unidirectional gastrin release patterns from gastrinoma tissue may explain the paradoxical increase in plasma gastrin levels in response to secretin in patients with gastrinomas (Zollinger-Ellison syndrome).     

Failure of secretin to stimulate gastrin release and adenylate cyclase activity in gastrinoma in vitro

It has been hypothesized that secretin may act directly on gastrinoma through the adenylate cyclase system to cause stimulation of gastrin release. We studied gastrinoma cells in vitro to determine whether secretin would stimulate gastrin release directly and whether the gastrinoma cell membrane had a functional secretin receptor adenylate cyclase system. Fresh tumor was prepared in cell suspensions containing 1.5 X 10(6) viable cells and incubated for 2 hours with either 2 mM CaCl2 alone (control) or 2 mM CaCL2 and 0.025 U/ml secretin. The gastrin content of the cells in each incubation chamber and the medium were determined by radioimmunoassay and results were expressed as mean gastrin pg/microgram protein +/- SD. Under basal conditions the cellular gastrin content was 39.9 +/- 6.4 (control) compared with 16.7 +/- 2.1 (secretin). After 2 hours of incubation, cellular gastrin content increased in both groups: 68.5 +/- 11.9 (control) to 68.3 +/- 5.5 (secretin). However, the percent of gastrin released into the medium during incubation decreased by one half in both groups (control 37.3% +/- 4.0% to 22.2% +/- 3.0%; secretin 42.8% +/- 7.0% to 18.9% +/- 1.8%). Adenylate cyclase activity was assessed by measuring cAMP generation in fresh-frozen gastrinoma and cultured gastrinoma cell membranes. Isoproterenol (10(-5) M), PGE1 (10(-4) M), and GppNHp (guanine nucleotide) (10(-5) M) caused fivefold to 25-fold increases in cAMP generation. Secretin did not stimulate adenylate cyclase activity above basal (21.73 +/- 4.07 and 2.29 +/- 1.2 pmol cAMP/mg protein/min) for frozen and cultured gastrinoma, respectively. Secretin failed to stimulate gastrin release and adenylate cyclase in vitro. This suggests that secretin-stimulated gastrin release in vivo may not be due to a direct effect of secretin on the gastrinoma.     

Comparison of four provocative tests for the diagnosis of gastrinoma.

In an attempt to determine the best provocative test for the diagnosis of gastrinoma, ten normal subjects, 13 patients with known gastrinoma, and one patient with presumed gastrinoma were administered four regimens: (1) rapid calcium infusion (2 mg Ca++/kg/min), (2) secretin (2 clinical units (CU)/kg/bolus), (3) long calcium infusion (12 mg Ca++/kg/3 h) and (4) a combination test consisting of a rapid calcium infusion followed immediately by secretin. Blood was drawn for serum gastrin levels before and following infusion of the test agents. The administration of rapid calcium followed by secretin provoked the greatest increases in serum gastrin above basal levels in both normals (29%) and patients (362%). Peak gastrin levels in patients were similar following the long calcium infusion (341%) but were less following the rapid calcium infusion alone (124%) and secretin alone (207%). There were no false-positive or false-negative tests with the calcium plus secretin when the criterion for diagnosis was either a 50% increase or a 200 pg/ml increase above the basal gastrin level. The distinct advantages (short test period, low patient morbidity, and relatively great potency) of the calcium plus secretin test make it an attractive alternative to other previously described provocative tests for the diagnosis of gastrinoma.     

Effect of sepsis or cytokine administration on release of gut peptides.

The effect of sepsis on plasma levels of various gut peptides was studied in rats. Sepsis was induced by cecal ligation and puncture (CLP); control animals underwent sham operation. Sixteen hours after CLP or sham operation, portal and systemic blood was drawn, and plasma levels of gastrin, vasoactive intestinal peptide (VIP), secretin, peptide YY (PYY), gastrin-releasing peptide (GRP), and substance P were determined by radioimmunoassay. Plasma levels of gastrin, VIP, PYY, and secretin were elevated in septic rats compared with nonseptic animals, with the highest levels noted in portal blood. There was no effect of sepsis on GRP or substance P levels. In other experiments, human recombinant interleukin 1 alpha (IL-1 alpha) or recombinant tumor necrosis factor alpha (TNF alpha) was injected intraperitoneally (300 micrograms/kg body weight in 3 divided doses over 16 hours). There was no change in plasma levels of gut peptides after IL-1 alpha injection. TNF alpha induced elevation of PYY levels in portal plasma with no change in other gut peptide levels. The results suggest that sepsis stimulates release of certain gut peptides and that TNF, but not IL-1, may be partly responsible for this response. The mechanism of the release of gut peptides and its significance in the pathophysiologic changes induced by sepsis remain to be determined.     

Hypergastrinemia after vagotomy is not associated with decreased gastric somatostatin

Although hypergastrinemia occurs after vagotomy, the mechanisms responsible are not understood. Somatostatin (SRIF) is a peptide that inhibits gastrin release, is present within the gastric fundus and antrum, and is under vagal control. In this study we have investigated the hypothesis that hypergastrinemia is associated with a decrease in gastric SRIF. We examined tissue levels of SRIF in gastric mucosa and muscle wall in rabbits undergoing vagotomy and pyloroplasty compared with sham-operated controls. We also compared the release of SRIF from gastric glands in response to vasoactive intestinal peptide and calcitonin gene-related peptide. Vagotomy resulted in an increase in gastrin compared with controls in both antrum (1062 +/- 176 pmol/gm vs 484 +/- 48 pmol/gm) and plasma (236 +/- 72 pmol/L vs 29 +/- 4 pmol/L; p less than 0.05). This was accompanied by an increase in the number of gastrin cells (25 +/- 4 vs 9 +/- 3; p less than 0.05). No significant differences were observed in gastric SRIF levels in either the fundus or antrum (p greater than 0.5). In addition, there were no differences in the release of SRIF from gastric glands of vagotomized animals compared with controls in response to vasoactive intestinal peptide and calcitonin gene-related peptide (p greater than 0.5). These data suggest that the elevations in plasma and antral gastrin levels after vagotomy are not a result of alterations in gastric SRIF.     

Establishment of a human gastrinoma in nude mice

We report the first establishment and characterization of functioning gastrinoma from a human being transplanted into nude mice. Tissue was obtained at operation from a gastrinoma liver metastasis from a patient with the Zollinger-Ellison syndrome. The tumor was implanted subcutaneously in five athymic nude mice. Serum gastrin was measured by means of radioimmunoassay in specimens of mouse blood taken before and 5 minutes after intraperitoneal injection of secretin (100 micrograms/kg). In a second experiment serum gastrin was measured 30 minutes after injection of somatostatin analogue, SMS 201-995 (300 micrograms/kg). Studies were also done in 10 control mice. At passage, the fundus of each tumor-bearing mouse was weighed and examined microscopically. The gastrinoma (tumor line, PT) has been maintained for 34 months through four passages with a tumor doubling time of 37 to 45 days. The histology is similar to the original tumor. Immunocytochemistry showed that PT contained gastrin. In two mice metastasis developed 9 months after implantation. Gastrin levels in mice bearing PT have ranged from 216 to 12,000 pg/ml. Gastrin levels of control mice ranged from 0 to 63 pg/ml. Secretin increased gastrin levels in three of five mice tested and decreased gastrin levels in two mice. Repeat secretin tests showed identical results. SMS 201-995 decreased gastrin levels from basal values. Fundic weight of mice bearing PT (397 +/- 93 mg) was significantly greater than control fundic weight (180 +/- 26 mg). Gastrinomas growing in nude mice produce physiologically active gastrin as shown by elevated serum gastrin levels and by hyperplasia of the stomach. Two distinct subpopulations of gastrinoma cells respond differently to secretin. This model should provide important information on mechanisms of growth control and on gastrin release by gastrinomas in human beings.     

In vitro release of gastrin from isolated perfused antrum

In an in vitro preparation, isolated rat antra were perfused with different releasing agents in oxygenated Krebs-Ringer's A solution. Upon perfusion with 50 mM acetylcholine (+0.1 mM eserine), the mean gastrin levels in the effluent increased within 2 minutes to 4 times the basal level, while there was a smaller secondary release after 20 minutes. During perfusion with 50 mM glycine and 10 mM or 30 mM calcium chloride in Krebs-Ringer's A solution, gastrin levels in the effluent increased within 4 minutes to twice the basal level, without a secondary release of gastrin. Perfusion with eserine alone or with Krebs-Ringer's A solution failed to release gastrin.     

Effect of vagal stimulation on pancreatic secretion and on blood levels of gastrin, cholecystokinin, secretin, vasoactive intestinal peptide, and somatostatin.

We investigated in dogs the effect of graded frequencies of electrical vagal stimulation (1.5, 3, 6, and 12 cps) on pancreatic exocrine secretion and on portal blood levels of gastrin, secretin, cholecystokinin (CCK), vasoactive intestinal peptide (VIP), and somatostatin (STS). Stimuli of all four frequencies, each with a duration of 5 minutes, were applied with a secretin background of 0.25 CU/kg-hr, and one stimulatory period of 12 cps was applied without a secretin background. With secretin, a significant, frequency-dependent increase of volume and of pancreatic protein secretion occurred from 3 to 12 cps. Gastrin values increased significantly at all frequencies. VIP and STS increased significantly with 3, 6, and 12 cps. Maximal responses for gastrin, VIP, and STS were observed with 6 cps. Peak values for gastrin and VIP were found during stimulation, whereas STS peaked after the end of the stimulatory period. The integrated responses of gastrin and STS showed significant correlation (P less than 0.01). The results suggest that vagally induced pancreatic response is only partially mediated by gastrin and perhaps VIP, and that endogenous gastrin may be one of the releasing factors for somatostatin. Plasma levels of CCK and secretin did not change after electrical stimulation, which provides direct evidence that their release is unlikely to be under vagal control, and that CCK does not mediate the protein secretion obtained after electrical stimulation of the vagus.     

The early diagnosis of gastrinoma.

Despite the increasing awareness of gastrinoma and its lethal peptic ulcer sequelae, the diagnosis is often initially missed or made as a terminal event. The authors screened all patients with peptic ulcer symptoms serious enough to warrant hospital admission or those associated with diarrhea, nephrolithiasis, hypercalcemia, or pituitary abnormality. In a one-year period (1979-1980) nine (of 14 suspected) new gastrinoma patients were identified using a sensitive and specific gastrin radioimmunoassay in combination with provocative tests including IV secretin, calcium, and food. Conventional upper GI series, CAT scan, arteriography, and endoscopy provided no additional information other than to confirm the presence of ulcer disease. Basal plasma gastrin levels were more than 200 pmol L-1 in only three of the nine (normal fasting plasma gastrin levels are less than 25 pmol L-1). Three patients presented with acute¿ulcer perforation, and the diagnosis of gastrinoma was suspected because of multiple ulcers and pancreatic masses. In three other patients, previous duodenal ulcer surgery had failed. One patient with dyspepsia, high basal plasma gastrin, negative secretin and calcium infusion studies, and a positive meal test was diagnosed as having G-cell hyperplasia; this was confirmed by biopsy and antral gastrin extraction. Antrectomy alone resulted in cure. In all patients tested, a positive calcium infusion or secretin bolus (greater than 100% rise over basal) strongly suggested the diagnosis of gastrinoma, which was confirmed at surgery. In the acute perforations, initial management with omental patch and cimetidine therapy allowed survival of two patients, while emergency total gastrectomy in the third resulted in death due to esophagojejunal leak. Elective patients were treated with cimetidine initially for at least two weeks before total gastrectomy. In this group there were no operative mortalities, and postoperative morbidity was minimal. This series illustrates three important points: (1) careful screening of an ulcer population using gastrin radioimmunoassay and provocative tests has enabled a high yield of gastrinomas while conventional investigations are of minimal values; (2) a high index of suspicion in appropriate cases is necessary; and (3) total gastrectomy performed under elective circumstances is safe and allows the patients to resume a normal and healthy life without the sequelae of aggressive peptic ulceration or daily drug administration.     

Lack of effect of parathyroidectomy or calcium channel blockade on serum gastrin concentration and gastric acid secretion in a patient with hyperparathyroidism and Zollinger-Ellison syndrome

Management of patients with multiple endocrine neoplasia type I (Wermer's syndrome) who have concurrent hypercalcemia and hypergastrinemia is controversial. The usual therapeutic approach has been to perform parathyroidectomy first before surgery for ulcer disease in an effort to decrease serum calcium concentration and presumably remove one of the stimuli for both gastrin and gastric acid secretion. We present the history of a 48-year-old man with primary hyperparathyroidism and Zollinger-Ellison syndrome who underwent acid secretory studies and secretin stimulation tests before and after parathyroidectomy. We also studied the effect of calcium channel blockade on gastrin and gastric acid secretion, since calcium influx into endocrine cells, such as the gastrinoma cell, is thought to be critical in hormone secretion. Although parathyroidectomy reduced serum calcium and parathormone levels to normal, basal serum gastrin concentration and basal acid output remained unchanged. The peak rise in serum gastrin concentration after secretin injection was less after parathyroidectomy than before parathyroidectomy but was still abnormal. During administration of verapamil, a calcium channel antagonist, no change was seen in the serum gastrin concentration, secretin test response, or acid secretion. Basal acid output was 45.4 mmol/hr before parathyroidectomy or verapamil and 54.0 and 50.4 mmol/hr after parathyroidectomy or verapamil, respectively. In contrast, a small but significant decrease (p less than 0.05) in serum parathormone concentration occurred during treatment with verapamil, an observation that to the best of our knowledge has not been previously reported in humans.     

Acid and Endocrine Responses to Meals Varying in pH in Normal and Duodenal Ulcer Subjects

Recent studies suggest that duodenal ulcers may develop because of increased drive to secrete acid and decreased effectiveness of feedback mechanisms that inhibit acid output. This study was designed to compare gastric acid, gastrin, gastric inhibitory peptide (GIP) and secretin responses to meals (varying in pH) in 12 normal subjects and nine duodenal ulcer patients. Acid secretion was measured by an intragastric titration method which allows actual measurement of acid response to food within the stomach (ten per cent amino acid meal (AAM) adjusted to various pH levels, 7-1.5). Blood samples were collected at each pH level for radioimmunoassay of gastrin, secretin and GIP. Gastric acid and gastrin responses to AAM were found to be significantly greater in duodenal ulcer patients than in normal subjects. In duodenal ulcer patients, acid response to AAM at pH 7 or 5.5 reached 82% of Histalog maximum. Decreasing the pH of the meal resulted in a stepwise reduction in both acid secretion and gastrin in normal subjects and duodenal ulcer patients. At pH 1.5, acid inhibition was complete, but gastrin inhibition was partial. Secretin increased significantly at pH 1.5; there was no difference in secretin release between the groups. Plasma GIP was highest at pH 7 in all individuals. Use of a marker substance showed 80% recovery of AAM at pH 7-4; below pH 4, recovery rose to about 90%. We conclude that gastric acid and gastrin release are pH-dependent in normal and duodenal ulcer subjects. Inhibition of gastric secretion by acidified meals is associated with a pH-dependent suppession of gastrin and GIP levels and elevation of plasma secretin. This study confirms increased acid and gastrin responses in duodenal ulcer patients but shows no evidence of defective feedback inhibition of gastric secretion and gastrin release.     

Observations on the effect of a somatostatin analog in the Zollinger-Ellison syndrome: implications for the treatment of apudomas

Somatostatin is known to inhibit hormone release and gastrointestinal secretion and hence may be useful in the treatment of amine precursor uptake, decarboxylase tumors. Clinical application has been limited by the short half-life, potency, and specificity of the natural hormone. Our study evaluated the effect of a synthetic analog of somatostatin, SMS 201-995 (Sandoz, Inc., E. Hanover, N.J.) on basal and stimulated gastrin release and gastric acid secretion in 10 patients with the Zollinger-Ellison syndrome. In experiment 1, H2-receptor antagonists were discontinued for 48 hours; SMS 201-995, 1 microgram/kg, was given subcutaneously; gastrin and SMS levels in plasma were determined by radioimmunoassay; and gastric secretion was measured and titrated at 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 18 hours. The mean +/- SEM baseline gastrin level (1526 +/- 733 pg/ml) was significantly inhibited for 16 hours (p less than 0.05, paired t test). Gastric secretion was neutralized for as long as 18 hours (p 0.05). In experiment 2, three patients received either a secretin (2 U/kg) or a calcium stimulation test (2 mg/kg) with or without pretreatment with SMS 201-995, 1 microgram/kg, subcutaneously. The mean +/- SEM interpreted change in gastrin (ng X 60 min/ml) without SMS 201-995, 36.8 +/- 11 (secretin), and 129 +/- 30 (calcium) were reduced with SMS 201-995 to -1.1 +/- 0.76 (secretin) and -29 +/- 28 (calcium) (p less than 0.05). In the Zollinger-Ellison syndrome, SMS 201-995 caused significant and long-lasting inhibition of both tumor gastrin release and gastric acid secretion, probably by direct action on both the gastrinoma and the stomach. SMS 201-995 blocks acid secretion and secretin- and calcium-stimulated gastrin release, indicating that SMS 201-995 inhibits peptide secretion by postreceptor mechanisms. SMS 201-995 will be useful in the palliative treatment of apudomas.     

Gastrin release from dispersed gastrinoma cells: effects of calcium and calcium ionophore (A23187)

Dispersed single-cell suspensions of human gastrinoma tissue were incubated for 15, 60, and 120 min in a calcium-containing medium, (0.1, 2, 10 mM) in calcium-free medium and in calcium-free medium containing the calcium ionophore A23187 (0.01, 1, and 100 micrograms/ml). Supernatant and pellet (intracellular) gastrin levels were determined by radioimmunoassay. Supernatant gastrin levels remained stable over 120 min in calcium chloride or calcium gluconate containing medium, while intracellular pellet gastrin approximately tripled during the same incubation period. Total gastrin (supernatant plus pellet) approximately doubled during the 2-hr incubation in calcium. However, calcium (0.1, 2, or 10 mM) failed to produce a dose-dependent rise in supernatant, pellet, or total gastrin when compared to calcium-free incubates. Contrary to the expected gastrin response to calcium, supernatant and pellet gastrin levels were higher in incubates in calcium-free medium than in calcium-containing incubates. A23187 (0.01 or 1 mcg/ml) in a calcium-free medium decrease supernatant gastrin while high dose ionophore (100 mcg/ml) increased supernatant gastrin. All doses of ionophore stimulated pellet and total gastrin levels. Thus, it appears that the clinical augmentation of gastrin levels, seen with calcium challenge in vivo may not be solely due to changes in serum calcium.     

Usefulness of selective arterial secretin injection test for localization of gastrinoma in the Zollinger-Ellison syndrome.

Secretin was injected into a feeding or nonfeeding artery of a gastrinoma and blood samples were taken from the hepatic vein (HV) or a peripheral artery (PA) to measure the changes of serum immunoreactive gastrin concentration (IRG). The IRG in the HV rose within 40 seconds and in the PA rose within 60 seconds after the injection of secretin into a feeding artery, but not after secretin was injected into a nonfeeder. These results indicated that secretin directly stimulates a gastrinoma to release gastrin in vivo. The selective arterial secretin injection test (SASI test) was applied in three patients in whom gastrinomas could not be located by computed tomography, ultrasonography, or arteriography, and functioning gastrinomas were located in all three patients. In one patient, malignant gastrinomas in the head of the pancreas and in the duodenum could be resected radically with the help of this test.     

Effect of secretin on gastrin release from gastrinoma cells in vitro

Secretin appears to have a direct effect on gastrinoma cells, which results in a paradoxic increase in the serum gastrin level in patients with the Zollinger-Ellison syndrome. To evaluate this effect, gastrinoma cells were challenged with secretin in acute cell dispersion or after 2 weeks in culture. Acutely dispersed cells were incubated for 15 minutes or 3 hours with and without secretin 10(-6) mol/L. (sec). There was no significant difference in gastrin release between control and sec groups in the two acute incubation periods. At 15 minutes the control value was 47 +/- 1 and the sec value was 54 +/- 1 ng/ml, while at 3 hours the control value was 59 +/- 1 and the sec value was 61 +/- 1 ng/ml. In the cell culture preparation, secretin stimulated gastrin release at all doses (control 463 +/- 85, SEC 10(-10) mol/L 603 +/- 37, sec 10(-8) mol/L 706 +/- 37, sec 10(-6) mol/L 798 +/- 48 pg/ml ([p less than 0.05, Student t test]). These results indicate that secretin stimulates gastrin release directly from cultured gastrinoma cells in a dose-dependent manner but does not stimulate gastrin release from acute cell dispersion. This might be attributed partly to the recovery of secretin receptors in the cultured cells.     

Human gastrin response to secretin after vagotomy.

The gastrin response to a liquid meal with and without secretin infusion was studied in nine patients undergoing selective or truncal vagotomy with pyloroplasty for duodenal ulcer disease. Fasting gastrin levels were significantly increased in eight of nine patients after vagotomy, but secretin infusion did not consistently suppress these basal gastrin levels either pre- or postoperatively. Infusion of secretin did significantly lower the integrated gastrin response to feeding both pre- and postoperatively in eight of nine patients. Vagotomy alone did not significantly alter the integrated gastrin response to feeding. This data gives evidence that secretin infusion remains a helpful diagnostic test, differentiating those patients with recurrent ulcer and elevated gastrin levels postvagotomy from those patients with occult Zollinger-Ellison syndrome.     

Evidence for nongastrin-mediated somatostatin inhibition of parietal cell function

Somatostatin (SRIF), a tetradecapeptide, has been reported to suppress gastrin release and hence inhibit acid secretion in vivo. This study was performed to determine whether SRIF has any direct effect on parietal cell (PC). Isolated gastric cells were prepared by collagenase digestion and calcium chelation of rabbit fundic mucosa. PC enrichment (75% +/- 5%) was accomplished by velocity sedimentation with an elutriator rotor. Acid, as assessed by the accumulation of 14C-aminopyrine (AP) and macromolecular (intrinsic factor [IF]) secretion were used as markers of PC function. Cells were stimulated with histamine (H) (10(-6) mol/L). SRIF (10(-10) to 10(-6) mol/L) significantly inhibited H-stimulated 14C-AP accumulation (p less than 0.05). Inhibition of H-stimulated IF release was less sensitive, occurring at 10(-8) and 10(-7) mol/L (p less than 0.05), and loss of inhibition was observed at 10(-6) mol/L (p less than 0.05). These results demonstrate a direct inhibitory action of SRIF on PC secretion. The difference in inhibitory effect on IF and proton secretion is consistent with the postulation that SRIF may function at more than one site within the PC.     

Postprandial plasma secretin response in Whipple-treated patients

We hypothesize that the presence of a few secretin-releasing cells sited in the upper jejunum may provoke a postprandial secretin response to meal loading in patients who have undergone the Whipple procedure. This procedure involves gastrectomy and total duodenectomy and requires gastrointestinal tract reconstruction by one of three methods: (i) choledocho-pancreatico-gastro alignment (PD-1), (ii) pancreatico-choledocho-gastro alignment (PD-2) (both these methods excluding the upper jejunum from the route of food passage), or (iii) gastro-pancreatico-choledocho alignment (PD-3), in which food passes through the upper jejunum. Fasting and postprandial plasma secretin and gastrin response were measured in 47 Whipple-treated patients, 16 given a PD-1, 15 given a PD-2, and 16 given a PD-3, and in 15 healthy controls. Plasma secretin response and integrated secretin release were higher, but not significantly, in the PD-3 group, and lower in all three Whipple-treated groups than in the control (P<0.05). Plasma gastrin concentration showed no significant increase in any of the three treated groups and was significantly lower than in the controls (P<0.05). The integrated gastrin release also did not differ among the treated groups and was lower than in the controls (P<0.05). Twenty-four-h monitoring showed that the gastric pH was neutral or alkaline in all three treated groups. The failure to prove our hypothesis may be due to the presence of too few secretin-releasing cells in the upper jejunum to respond to the meal loading and/or to the intragastric pH not being sufficiently acidic to stimulate those secretin-releasing cells present in the upper jejunum.     

The Zollinger-Ellison syndrome--23 years later.

The effects of recent diagnostic and therapeutic advances were assessed in 65 patients with the Zollinger-Ellison syndrome (ZES). Twenty-seven patients seen between 1955 and 1970 were compared with 38 patients seen between 1971 and 1977. The earlier patients had a higher incidence of virulent ulcer disease (56% vs. 24%), other endocrinopathies (48% vs. 13%), and malignant gastrinoma (44% vs. 25%). Earlier diagnosis is the result of liberal use of serum gastrin measurements and provocative tests for gastrin release (calcium and secretin), and an increased awareness of this syndrome. Because their basal gastrin values were in a range that overlapped ordinary ulcer disease, 47% of patients encountered in recent years required provocative testing with secretin for diagnosis. If the gastrin concentration falls to normal following resection of a gastrinoma, the tumor has probably been completely removed. In our patients, gastrin measurements after total gastrectomy had no prognostic significance in regards to clinical progression or regression of the neoplasm. Of 12 patients treated with cimetidine, nine experienced symptomatic improvement, and three did not. Resection of the gastrinoma should be attempted if the lesion is solitary and located in the body or tail of the pancreas, or if it is an isolated duodenal lesion. Otherwise, total gastrectomy remains the treatment of choice. In 38 patients, total gastrectomy with Roux-en-Y esophagojejunostomy was followed by 97% survival and minimal difficulties with nutrition or dumping.