Gastrin determinations in symptomatic patients before and after standard ulcer operations.

Whereas 67 patients with duodenal ulcer had fasting and 30-minute postprandial mean serum gastrin levels not substantially different from 32 normal subjects, they had substantially higher fasting and histamine-stimulated gastric acid secretion. The increased acid secretion found in patients with duodenal ulcer is not caused by increased serum gastrin levels. Ten patients with recurrent ulcer, after incomplete vagotomy and gastric resection, had high gastric acid secretion and normal serum gastrin levels. Three patients with recurrent ulcer following complete vagotomy and gastric resection, but with retained antrum, had both high gastric acid secretion and high fasting and postprandial secrum gastrin levels. Three patients with Zollinger-Ellison tumors had even higher basal acid outputs and serum gastrin levels. The combination of basic gastric acid secretory studies and serum gastrin determinations may identify three causes of recurrent ulcer: incomplete vagotomy, retained antrum, and Zollinger-Ellison tumor.     

The role of neurotensin in human gallbladder motility.

Gallbladder contraction in response to a fatty meal is thought to be caused by release of cholecystokinin (CCK). We have previously demonstrated a close correlation between circulating concentrations of CCK and contraction of the gallbladder in normal humans and in gallstone patients. Recent studies in animals, however, have shown that other potentially cholecystokinetic hormonal agents are released by a fatty meal, which suggests that other hormones may be involved in postprandial gallbladder contraction. Neurotensin, a 13-amino acid peptide, is released by fat; we have shown it to cause gallbladder contraction in dogs. In the present study, we measured release of neurotensin in seven normal adult volunteers. We determined the effects of infused neurotensin (4 pmol/kg-min) on gallbladder contractility, measured by ultrasonography in 10 adult volunteers, and we evaluated release of neurotensin in eight patients with gallstones. After ingestion of fat, we found significant release of neurotensin in normal volunteers from a mean basal concentration of 15.9 +/- 3.5 pg/ml to a maximum of 34.7 +/- 0.2 pg/ml. In the gallstone patients after fat ingestion, neurotensin rose from a basal of 16.8 +/- 3.1 pg/ml to a maximum of 53.4 +/- 28.1 pg/ml, which was a significantly greater release than in controls. Intravenous infusion of neurotensin produced dilatation of the gallbladder (from a mean basal volume of 13.7 +/- 2.3 cc to 20.0 +/- 1.8 cc). Neurotensin causes relaxation of the gallbladder in humans and, by contributing to stasis, may be involved in the formation of gallstones.     

Release of radioimmunologic cholecystokinin in human subjects

After the development of reliable, highly sensitive, specific radioimmunologic methods for measuring physiologic CCK concentrations in human plasma, we have been able to study the importance of CCK in the postprandial activation of pancreatic enzyme secretion. In man, food causes a threefold increase in the basal plasma CCK concentration with a peak at about 60 minutes. The highest CCK concentrations are observed after intraduodenal fat infusion. Selective proximal vagotomy results in a significant increase in basal CCK concentrations in duodenal ulcer patients without altering the postprandial CCK output. After gastric resection (Billroth I or Billroth II) an initial greater postprandial CCK output is observed. In patients with chronic pancreatic insufficiency without enzyme substitution, basal plasma CCK concentrations and the early postprandial CCK output were elevated which indicated a feedback mechanism between pancreatic enzyme secretion and CCK release from the mucosa of the upper small intestine.     

Plasma cholecystokinin response to a liquid fat meal in vagotomized patients.

Since previous studies have suggested that in patients with truncal vagotomy (TV) the plasma cholecystokinin (CCK) secretion in response to nutrients is impaired, we have measured the plasma CCK response to a liquid fat meal (250 ml 20% Intralipid) in six patients with TV and pyloroplasty. We have compared the results with those obtained in eight normal subjects, six patients with duodenal ulcer, and eight patients with highly selective vagotomy (HSV). Plasma CCK concentrations were measured by a sensitive and specific radioimmunoassay employing antibody T204 directed against the sulphated tyrosine region of CCK. Basal plasma CCK concentrations were not significantly different among the four groups studied (2.1 +/- 0.4 pmol/l in normal subjects, 2.8 +/- 0.5 pmol/l in duodenal ulcer patients, 3.1 +/- 0.5 pmol/l in patients with TV, and 2.7 +/- 0.5 pmol/l in patients with HSV). The increments in plasma CCK after ingestion of the fat meal in patients with TV (15.7 +/- 3.1 pmol/l) and HSV (14.9 +/- 1.6 pmol/l) were significantly higher (p less than 0.01) than those in normal subjects (4.8 +/- 0.9 pmol/l) and in patients with duodenal ulcer (5.5 +/- 0.6 pmol/l). Similarly, the integrated plasma CCK secretions in patients with TV (554 +/- 139 pmol/l, 120 min) and in patients with HSV (876 +/- 132 pmol/l, 120 min) were significantly increased (p less than 0.05) compared to those in normal subjects (187 +/- 29 pmol/l, 120 min) and in patients with duodenal ulcer (264 +/- 35 pmol/l, 120 min). It is concluded that patients with TV and HSV show an increased plasma CCK secretion in response to a liquid test meal.     

Modulatory effect of glucose, amino acids, and secretin on CCK-8-induced somatostatin and pancreatic polypeptide release in dogs

Protein- and fat-rich test meals elicit a strong stimulatory effect on postprandial somatostatin (SLI) and pancreatic polypeptide (PP) release, whereas carbohydrate-rich meals rather attenuate the response of both hormones. Since there is evidence that intestinal hormones might contribute to the postprandial SLI and PP response, it was the aim of the present study to determine in dogs the effect of low-dose cholecystokinin octapeptide (CCK-8) on basal hormone levels and also during a background infusion of amino acids or glucose. In a group of six conscious dogs, sulfated CCK-8 was infused intravenously (i.v.) via a hindleg vein at stepwise increasing infusion rates of 10, 30, and 50 pmol X kg-1 X h. The infusion of CCK was applied during a background infusion of saline (2 ml/min), glucose (0.2 g/min), or an amino acid mixture (8.5%, 2 ml/min). CCK-8 had no effect on plasma insulin and glucagon levels under all experimental conditions. Plasma SLI levels were significantly stimulated by all doses of CCK. This stimulatory effect was similar during background infusions of either saline, glucose, or amino acids, respectively. Pancreatic polypeptide (PP) levels rose 200-300 pg/ml during CCK plus saline. This was slightly attenuated by glucose. During CCK plus amino acids, the PP response was augmented to 600-800 pg/ml. Since secretin is also released after the ingestion of a meal and intraduodenal acidification is a potent stimulus not only of secretin but also of gastric and pancreatic SLI release, the effect of secretin was examined additionally.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of gastrin release and gastric secretion by calcitonin in patients with peptic ulcer

We studied the effect of an intravenous infusion of calcitonin (2 MRCU/kg) on gastric secretion and serum gastrin and serum calcium levels in eight normal subjects, six patients with duodenal ulcer disease, three patients with primary hyperparathyroidism, six patients with histologically proved Zollinger-Ellison syndrome, and three patients with the Zollinger-Ellison syndrome and hyperparathyroidism. Gastric secretion was greatly inhibited in all groups of patients. Serum calcium was significantly diminished only in patients with hypercalcemia. Serum gastrin levels were depressed in all patients with elevated basal gastrin levels (DU, HPT, Z-E, and ZE + HPT). In normal subjects calcitonin inhibited strongly the serum gastrin response to food. These findings suggest that calcitonin may have a regulatory function in the release or catabolism of the hormone gastrin.     

Plasma gastrin and cholecystokinin response after pylorus-preserving pancreatoduodenectomy with Billroth-I type of reconstruction.

Plasma gastrin and cholecystokinin (CCK) responses were measured after a pancreatoduodenectomy (PD) using the Billroth-I type reconstruction combined with distal partial gastrectomy (standard PD) and combined with preservation of the pylorus and the duodenal bulb (PPPD). Six unoperated patients, 4 men and 2 women, were studied as control subjects. Basal plasma levels of gastrin were significantly higher in controls than in patients who had a standard PD (p less than 0.05) and gastrin responses to a meal were also blunted in these patients. In contrast basal and postprandial levels of gastrin after PPPD were significantly higher than these found in patients with standard PD (p less than 0.05). Postprandial gastrin response after PPPD were similar in pattern to these found in controls. Integrated gastrin release after PPPD was less than that of the control but was significantly greater than that in patients with standard PD. Basal plasma levels of CCK in the patients after the standard PD were significantly lower than in controls and significantly higher postprandial levels of CCK were found after PPPD compared to standard PD (p less than 0.05). However integrated CCK from 0 to 120 minutes were not significantly different between PPPD and standard PD groups. Based on these observations concerning hormonal release of gastrin and CCK, preservation of the stomach and the duodenal bulb appears to be a more physiologic reconstructive procedure than the standard PD. In addition the operation probably has more beneficial effect on the injured pancreas in time.     

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.     

Urine acid output as a test of completeness of vagotomy

Peak acid output in response to sham feeding and changes in urine acid output 2 and 3 hours after a test meal have been measured in 20 normal volunteers, 17 asymptomatic patients after vagotomy, six patients with recurrent duodenal ulcer after vagotomy and ten normal subjects given a 48-h course of ranitidine, 150 mg 12-hourly. Gastric peak acid output in normal volunteers ranged from 6.9 to 22.1 mmol/h. All asymptomatic patients after vagotomy had a peak acid output less than 7 mmol/h, consistent with complete vagotomy. Five patients with recurrent ulcer had a peak acid output greater than 8 mmol/h, suggesting an incomplete vagotomy. Urine acid output after a test meal, expressed as the change from the basal rate of acid output, was always in a negative direction in normal subjects (fall in acid output = postprandial alkaline tide). This change was abolished in patients with complete vagotomy, in whom urine acid output increased after a meal. In five patients with incomplete vagotomy (and one other with recurrent ulcer and unknown vagal status) the urine acid output changed in a negative direction after a test meal. The relationship of urine acid output to gastric secretion was confirmed by the abolition of the postprandial alkaline tide in normal subjects given ranitidine. The results in patients with incomplete vagotomy did not overlap with those from patients with complete vagotomy. This suggests that this test could be used for the routine postoperative assessment of completeness of vagotomy.     

Gastric, pancreatic, and biliary secretion and the rate of gastric emptying after parietal cell vagotomy.

We compared the gastric, pancreatic, and biliary secretory responses to a liquid test meal and the rates of gastric emptying of liquid and solid test meals in six patients at least 1 year after parietal cell vagotomy with eight unoperated subjects, one with duodenal ulcer disease and seven normal control subjects. Parietal cell vagotomy decreased gastric acid secretion to one third of normal, but total trypsin and bile salt secretion during the first 150 postcibal minutes were normal. The liquid test meal emptied from the stomach faster after parietal cell vagotomy, the pattern of emptying being exponential in the vagotomy patients and linear in the normal subjects. The rate of gastric emptying of a liquid meal, although faster than normal, was less precipitous after parietal cell vagotomy than after truncal vagotomy plus drainage or subtotal gastrectomy, and trypsin and bile salt concentrations were not diluted to abnormal levels, as occurs after these other procedures. Furthermore, emptying and dispersion of solid food remained normal after parietal cell vagotomy. These findings probably explain, at least in part, the decreased incidence of postprandial dumping and diarrhea that accompanies parietal cell vagotomy compared with the other popular operations for duodenal ulcer.     

Release of cholecystokinin in man: correlation of blood levels with gallbladder contraction.

Although it is generally assumed that release of cholecystokinin (CCK) is the chief mechanism by which a fatty meal causes contraction of the gallbladder, measured release of CCK and gallbladder contraction have never been correlated. We have achieved this correlation in eight adult male volunteers, by means of a specific radioimmunoassay for CCK and by ultrasonographic imaging of the gallbladder. This study validates our CCK radioimmunoassay and correlates measured concentrations of CCK with changes in gallbladder size measured by ultrasonographic examination. Basal concentrations of CCK (82.6 +/- 10.4 pg/ml) rose significantly to a maximum of 411.1 +/- 79.9 pg/ml at 16 minutes after intraduodenal instillation of medium-chain triglyceride (Lipomul). Mean basal volume of the gallbladder was 34.6 cm3; maximum reduction of gallbladder volume (to one-third of original) was achieved at 18 minutes. Elevated CCK concentrations began to fall toward basal, and the gallbladder began to refill at 25 minutes. Results obtained after oral ingestion of Lipomul provide similar results. Linear regression analysis demonstrated excellent correlation between concentrations of CCK and gallbladder size during both contraction and relaxation phases. Future study of this correlation may be useful in patients with manifest dysfunction of the gallbladder, as well as in individuals known to be at risk of gallbladder disease.     

Gastric emptying and postprandial symptoms after Billroth II resection

Gastric emptying was studied in 18 symptomatic and 16 asymptomatic patients after Billroth II (BII) resection (without vagotomy) and the possible relationships between emptying and postprandial symptoms in these patients were assessed. The BII patients were compared with 20 nonoperated patients who had duodenal ulcer disease and 16 healthy subjects. Gastric emptying of two test meals (a semisolid porridge meal and a solid pancake meal) was measured with a radionuclide technique. The major difference between the BII patients and control subjects and duodenal ulcer patients was an increased rate of emptying of the semisolid meal in the first 5 minutes after meal consumption. The percentage of the meal remaining in the stomach at 5 minutes after completion was significantly less in the symptomatic (45.3% +/- 4.3%) than in the asymptomatic BII patients (79.4% +/- 2.6%). A positive correlation was demonstrated between the initial emptying rate of semisolids and the intensity of postprandial nausea (p less than 0.01), vomiting (p less than 0.05), and vasomotor symptoms (p less than 0.001). The duration of the lag phase for solid and semisolid meals was shorter in BII patients than in healthy subjects but was as short in nonoperated duodenal ulcer patients. The duration of the lag phase for solid food in the BII patients correlated positively with the score for postprandial epigastric pain (p less than 0.001). The rate of emptying of the solid meal was lower in symptomatic BII patients (28.1% +/- 3.6% per hour) than in asymptomatic patients (47.8% +/- 7.2% per hour) and correlated with the severity of postprandial fullness and nausea. The emptying of the solid meal was inversely related to the initial emptying rate of the semisolid meal (p less than 0.05). Therefore, the results of this study support the assumption that many of the postprandial symptoms occurring after BII resection reflect alterations in gastric emptying. Some of the emptying abnormalities present after BII resection may be related to duodenal ulcer disease rather than to the surgical procedure.     

Inhibition of the stimulated exocrine pancreas by absorbed amino acids

Intravenous infusion of amino acids is known to inhibit the stimulated pancreas and it has been suggested that this may act as a feedback mechanism in pancreatic regulation. To investigate this, chronic pancreatic fistula dogs were studied to determine if postprandial levels of hyperaminoacidemia inhibit the stimulated pancreas. Duplicate dose-response experiments using exogenous cholecystokinin (CCK) and intraduodenal amino acids were performed with and without a simultaneous intravenous infusion of mixed amino acids, which simulated postprandial hyperaminoacidemia. Significant (P < 0.05), though minor, inhibition of pancreatic responses to both endogenous and exogenous CCK was noted with the simultaneous infusion of amino acids. It was concluded that, while amino acids may exert some inhibitory influence on pancreatic secretion after absorption, this is unlikely to be an important physiological mechanism.     

Effect of low-dose somatostatin infusion on pancreatic and gastric endocrine function in lean and obese nondiabetic human subjects

The present study was designed to compare, in lean and obese nondiabetic subjects, basal and postprandial levels of peripheral venous plasma insulin, glucagon, gastrin, pancreatic polypeptide (PP), glucose, triglycerides, and somatostatin-like immunoreactivity (SLI) during the infusion of synthetic somatostatin-14 or saline. Thirty-five minutes before the ingestion of the test meal, an infusion of synthetic somatostatin-14 was started at a rate of 0.5 ng/kg X min and was increased to 1.0 ng/kg X min 30 min after consumption of the meal and lasted for another 90 min. During the infusion of saline, basal peripheral vein levels of insulin, gastrin, and triglycerides were elevated in obese subjects, whereas basal plasma SLI levels were significantly lower compared with the lean controls. Basal glucagon and PP levels were similar in both groups. After the ingestion of the meal, augmented concentrations of insulin and gastrin were observed in the obese subjects, whereas postprandial SLI and PP levels were reduced. Chromatography of fasting plasma revealed all measurable SLI to be confined to the void volume fractions of a Bio-Gel P-10 column. The rise in SLI after the meal was due to an increase of SLI co-eluting with somatostatin-28 and somatostatin-14. During the infusion of somatostatin, only basal insulin levels were significantly lower in the obese subjects, whereas no change of any basal hormone level was observed in the lean group. During the infusion of somatostatin, SLI levels were elevated by 20-30 pg/ml in both groups compared with the saline controls. During the infusion rate of 0.5 ng/kg X min, only postprandial PP levels were reduced significantly in the obese group, while all the other parameters were unaffected in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated levels of fasting and glucose-stimulated pancreatic polypeptide in patients with duodenal ulcer

Mean fasting preoperative pancreatic polypeptide levels in a group of 18 patients with duodenal ulcer disease were 462 +/- 88 pg/ml, with 13 patients having markedly elevated levels (mean 600 +/- 106 pg/ml) and 5 patients having normal or minimally elevated levels (mean 112 +/- 32 pg/ml). Mean fasting postoperative pancreatic polypeptide levels significantly decreased to 136 +/- 36 pg/ml, with decreases occurring in 12 of 13 patients who had had markedly elevated preoperative values. Parietal cell vagotomy and truncal vagotomy produced significant reductions in both fasting pancreatic polypeptide levels and in the glucose-stimulated pancreatic polypeptide response during the first 60 minutes. There was no correlation between pancreatic polypeptide levels (fasting and stimulated) and duration of ulcer disease, indications for ulcer operation, type of operation, or age of patient. These results suggest that elevated fasting pancreatic polypeptide levels may indicate vagal hyperactivity in some patients with duodenal ulcer.     

Postprandial serum gastrin levels in patients with combined hypergastrinaemia and hyperchlorhydria.

We have determined the serum gastrin response to a standard test meal in 13 unoperated patients with combined fasting hypergastrinaemia (more than 150 ng/l) and basal hypersecretion of gastric acid (BAO more than 10 mmol/h). In 10 of 11 patients with proved of presumptive Zollinger-Ellison syndrome the peak postprandial rise in serum gastrin concentration was less than 50 per cent of basal value. The integrated gastrin response to feeding ranged from 71-9 to 211-8 mug/lX 150 min. In 2 patients with proved hypergastrinaemia of antral origin, however, serum gastrin rose to 223 per cent and 255 per cent respectively of basal value after ingestion of the meal. The integrated postprandial serum gastrin responses in these patients were 66-8 and 22-0 mug/lX 150 min. Two patiets with Zollinger-Ellison syndrome and total gastrectomy showed peak serum gastrin levels after feeding of 174 and 255 per cent of basal concentration. The integrated postprandial gastrin secretions were 365 and 366 mug/l X 150 min respectively. It is concluded that the serum gastrin response to feeding, when expressed as percentage change, may be helpful in the differential diagnosis of unoperated patients with fasting hypergastrinaemia and basal gastric acid hypersecretion.     

Parietal cell autoantibodies and hypergastrinemia in achlorhydria and the Zollinger-Ellison syndrome.

Parietal cell autoantibody (PCA), basal gastrin, and calcium-stimulated gastrin were measured in twenty patients with achlorhydria, in eight patients with the Zollinger-Ellison syndrome, and in fifty control subjects. In twelve patients with achlorhydria with a spared antrum, PCA was positive and basal gastrin was elevated. In contrast, eight achlorhydric patients with antral gastritis had negative PCA and significantly lower basal gastrin levels. Patients with the Zollinger-Ellison syndrome did not demonstrate positive PCA despite elevated levels of basal gastrin, nor was PCA present in normal controls. This study suggests that certain achlorhydric states are caused by an autoimmune response, particularly if antral function is spared.     

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.     

Duodenal but not gastric transection disturbs motility of the sphincter of Oddi in the dog

The aim of the present study was to elucidate the effect of gastric and duodenal transection on biliary manometry in anesthetized dogs. The basal biliary pressure and increase in pressure during saline perfusion at rates of 1.0 and 1.5 ml/min were studied in intact controls, during infusion of cholecystokinin (CCK) alone, and after gastric and duodenal transection. CCK dose-dependently lowered the basal pressure and the increase in pressure during perfusion. Gastric transection 1.5 cm proximal to the pylorus did not affect these parameters. In contrast, duodenal transection 1.0 cm distal to the pylorus significantly increased these parameters compared to all other groups. These observations suggest that the proximal duodenal transection, as performed during conventional distal gastrectomy, may contribute to the pathogenesis of postgastrectomy gallstone formation by altering motor function of the sphincter of Oddi.     

Antral gastrin cell hyperplasia in patients with peptic ulcer.

The total number of gastrin (G) cells in the stomach was determined by using a histologic counting method and planimetry in ulcerous and nonulcerous patients. The preoperative basal and postprandial serum gastrin values and the gastrin cell mass in the gastrectomy specimen could be compared in 16 surgical patients. There was a significant correlation between the integrated gastrin response to feeding and the total gastrin cell number in the stomach. No correlation was found between the basal serum gastrin level and the total gastrin cell count. A total gastrin cell number higher than 50 million was found in the stomach of three duodenal ulcer patients with preoperative postprandial hypergastrinemia as well as in one patient with normal serum gastrin values. Gastrin cell counts between 6 and 42 million were found in control stomachs and in patients with gastric ulcer. Preoperative feeding tests could be useful to select patients with an elevated antral G cell number.