Effect of truncal vagotomy on functional and morphological changes produced by duodenogastric reflux

The effects of truncal vagotomy on the functional and morphological changes produced by duodenogastric reflux have been studied in the dog. Duodenogastric reflux caused progressive damage to gastric mucosa, hypersecretion of acid to pentagastrin, and a hypergastrinemic response to a standard meal. Truncal vagotomy barely altered the mucosal changes produced by reflux, but it did prevent antral gland hyperplasia and reduced the acid gastrin secretory responses. These findings are clinically reassuring in that vagotomy effectively prevented the hypersecretory state produced by duodenogastric reflux.     

Effect of enkephalin and naloxone on gastric acid and serum gastrin and pancreatic polypeptide concentrations in humans.

The effects of a synthetic enkephalin analogue with prolonged opioid activity, D-ala-2-enkephalin (ala-enk) and naloxone given alone or in combination, on vagally, pentagastrin- and histamine-induced gastric secretion and plasma hormonal responses to vagal stimulation have been studied in healthy subjects. D-ala-2-enkephalin reduced basal gastric acid and pepsin secretion, and caused a dose-dependent inhibition of gastric secretory responses to modified sham-feeding and pentagastrin but not to histamine. It increased serum gastrin concentration and suppressed plasma pancreatic polypeptide response to modified sham-feeding. Naloxone alone at lower dose levels did not affect gastric secretion and plasma hormonal concentrations but at higher doses it reduced both basal and modified sham-feeding-induced secretion. When combined with ala-enk it reversed in part gastric secretory and plasma hormonal changes induced by this peptide during modified sham-feeding and pentagastrin stimulation. These results indicate that (1) stable enkaphalin analogue inhibits basal and vagally or pentagastrin-induced gastric secretion, and affects plasma hormonal response to vagal stimulation, at least in part, via activation of opioid receptors and (2) endogenous opioid substances may be involved in the stimulation of gastric secretion in man.     

Gastric and extragastric gastrin release in normal subjects in duodenal ulcer patients, and in patients with partial gastrectomy (Billroth I).

In 10 normal subjects, in 32 patients with duodenal ulcer (DU), and in 11 patients with partial gastrectomy (Billroth I), serum gastrin rose significantly after an oral and intraduodenal test meal. The highest increases were observed in DU patients after the oral as well as after the intraduodenal test meal. After the intraduodenal test meal in 4 normal subjects and in 17 DU patients an increase of gastric acid secretion and serum gastrin was measured. In basal state, after an intraduodenal or an oral test meal, DU patients with normal gastric acid secretory capacity had higher serum gastrin concentrations than DU patients with gastric hypersecretion. There was a good correlation between peak serum gastrin levels after the oral and after the intraduodenal test meal. From these data it is concluded: (1) Intraduodenal application of a test meal results in release of gastrin from extragastric sites. (2) Extragastric gastrin is biologically active. (3) DU patients are able to release more antral and more extragastric gastrin in response to a test meal. Further studies, however, are necessary to show the significance of these findings in the pathogenesis of peptic ulcer disease.     

Gastric secretory function in patients with chronic renal failure undergoing maintenance hemodialysis

Gastric secretion was evaluated in 9 male patients with chronic renal failure on maintenance hemodialysis. Five secreted low or normal quantities of acid and 4 exhibited hypersecretion, 2 of whom had associated peptic ulcer disease. Serum gastrin responses to a protein meal were comparable to control subjects. Calcium infusion in two basal hypersecretors depressed acid secretion. The only statistically significant correlation observed was between basal acid output and serum levels of parathormone. These studies suggest that while acid secretory abnormalities vary in patients with chronic renal failure on hemodialysis, there is no apparent sensitivity of the gastrin-secreting cells to protein or calcium ion which might account for acid hypersecretion. Secondary hyperparathyroidism may influence the occurrence of acid secretory abnormalities.     

Psychosensory initiation of gastric secretion in dogs. Inter-relation of vagal component, gastrin, histamine and somatostatin

The effects of vagal stimulation on gastric secretion and on blood gastrin, histamine and somatostatin release have been assessed in three esophagostomized dogs equipped with gastric fistula and Heidenhain pouch. The animals were submitted to sham feeding of variable duration (from 2.5 to 12.5 min) and composition. In response to standard composition of the sham feeding, acid and pepsin responses were observed in the gastric fistula only; they were closely related to the sham feeding duration. Integrated histamine responses were also closely related to sham feeding duration and were correlated with acid or pepsin responses. Gastrin was released by sham feeding induced-vagal stimulation, but there were no relationship between gastrin and secretory responses. Somatostatin release decreased as duration of sham feeding stimulation increased and correlated negatively with acid or pepsin responses. Modified standard sham feeding, by adding either lipids or glucids resulted in the same gastric and hormonal responses as standard sham feeding. It appears that 1 degree) vagal stimulation resulting in the psychosensorial receptors stimulation can be quantified, 2 degrees) histamine reduces somatostatin release and could represent a non cholinergic vagal mediator, capable of controlling somatostatin release in the cephalic phase of gastric secretion.     

Role of antral histamine and gastrin in gastric acid secretion: experimental facts and hypotheses

Histamine isolated from the gastric antral mucosa probably potentiates the secretory activity of gastrin by suppression of the inhibitory effect of somatostatin on gastrin. In dogs with gastric fistula and Heindenhain pouch, acid secretion was obtained in response to exogenous gastrin, antral histamine or various combinations of both stimulants. Acid output was expressed by graphic representation: the administered doses of gastrin and antral histamine were reported respectively, on the X and Y axis, the acid output values were plotted on the intersection of the stimulant dosages used, and curves of equal acid outputs were drawn. This representation was used to approach the physiological and physiopathological mechanisms of gastric secretion, considering that gastrin and antral histamine could be the main parameters. It also seems possible that an histaminic factor could be involved in secretion processes. Excess or lack of one of the other stimulants could be responsible for an increased or a decreased secretory response: these facts can be related to the curves of high acid output or low acid output observed in the animal. Thus, histamine, especially of antral origin, might be an important component of the secretion mechanism, by modulation of gastrin activity; both substances could be the main mediators of somatostatin-induced inhibition.     

Regulation of somatostatin secretion by gastrin- and acid-dependent mechanisms.

The regulation of gastric somatostatin is linked to changes in gastric acidity, with a number of studies showing a good correlation between somatostatin secretion and gastrin-stimulated luminal acidity. However, gastrin may also have direct effects on somatostatin secretion independent of the concurrent acid status. We have examined the relative contribution of gastrin itself vs. gastric acid on the increase in somatostatin secretion observed after gastrin administration. Pentagastrin administered to conscious sheep for 2 h caused a 10- to 12-fold increase in both portal venous and peripheral jugular venous plasma somatostatin levels. This was associated with a decrease in gastric pH from 3.5 to 1.7. When the sheep were pretreated with the proton pump inhibitor omeprazole to prevent any change in gastric acidity, pentagastrin caused a similar increase in plasma somatostatin. The increase in somatostatin could also be produced by gastrin-17 infusions. Thus, these studies demonstrate that in the conscious animal gastrin can stimulate somatostatin independent of changes in gastric acidity. It is proposed that there is a negative feedback between somatostatin and gastrin, which may modulate the acid secretory response to gastrin.     

Sex hormones, and acid gastric secretion induced with carbachol, histamine, and gastrin

This study confirms previous reports that satisfactory gastric acid secretory responses to intravenous administration of histamine, carbachol, and gastrin can be obtained.Bilateral castration of the male rats significantly reduced acid gastric secretory responses to carbachol but not to histamine.Overiectomized rats treated with 17B-oestradiol (short-term treatment) showed a statistically significant reduction in gastric acid secretion induced with all the secretagogues, but the results when rats were treated with testosterone were inconsistent. In animals given gastrin or histamine gastric acid secretion was reduced and was of statistical significance with gastrin (0.02 < p < 0.05) but not with histamine (0.05 < p > 0.1).It is concluded that a high oestrogen blood level is capable of inhibiting effectively acid gastric secretion in both sexes except that a higher level of blood oestrogen is required in the male. The results showed further that of all the sex hormones used, only oestrogen had a significant effect on gastric acid secretion.     

Effect of pentagastrin on small bowel structure and function in the rat.

Since chronic pentagastrin stimulates pancreatic and proximal duodenal growth (15), we studied jejunal structure and function following subcutaneous pentagastrin (2 mg-100 g-1 day-1). After 15 days, macroscopic enlargement was confined to the proximal duodenum with a significant increase in wet weight (from 231 +/- SEM 6 to 308 +/- 13 mg) but there was no significant difference in wet and defatted dry intestinal weights, histological measurements of villous height and mucosal thickness or in glucose absorption per unit length of distal duodenum and proximal jejunum. Since chronic pentagastrin causes parietal cell hyperplasia and hypersecretion of gastric acid, the results suggest that the adaptive changes seen in the jejunum after ileectomy are neither mediated by gastrin nor by factors present in gastric secretions.     

Effect of systemic gastric acid stimulation and intragastric pH changes on synchronous antral gastrin and somatostatin release in anesthetized,nonatropinized duodenal ulcer patients and controls

The synchronous changes in antral gastrin and somatostatin release in anesthetized, nonatropinized duodenal ulcer patients and control subjects were investigated by serial intraoperative blood sampling from the right gastroepiploic vein. The mean basal antral plasma gastrin and somatostatin concentrations of the two groups did not differ significantly. The significantly greater gastric acid secretory response to systemic gastric acid stimulation (pentagastrin stimulation) in duodenal ulcer patients compared with that of control subjects was not linked to any difference in antral somatostatin release pattern. The decrease in antral plasma gastrin release was significantly lower after acid instillation and the increase was significantly higher after alkali instillation in duodenal ulcer patients compared with those of controls, indicating an abnormal gastrin response to intragastric pH changes in duodenal ulcer patients, which was again not found to be coupled to any significant difference in antral somatostatin release. The results suggest that an abnormal somatostatin-mediated inhibition of gastrin release and/or gastric acid secretion does not exist in duodenal ulcer patients.     

Current concepts on physiological control of gastric acid secretion. Clinical applications.

Gastric acid secretion by the parietal cell is a single digestive process involving a continuous interplay between nervous and hormonal stimuli. Gastric acid hypersecretion and hypergastrinemia may represent pathologic disturbance of the normal "gastric phase" of acid secretion (excluded antrum syndrome) or abnormal gastrin secretion from a nongastric source as in the Zollinger-Ellison syndrome. Diagnosis of these two syndromes preoperatively is dependent on immunoassay for serum gastrin. A fall in serum gastrin level after the injection of secretin will distinguish the excluded antrum syndrome from the Zollinger-Ellison syndrome. Which hormone or hormones cause the acid hyposecretion of the watery diarrhea hypokalemia achlorhydria syndrome is still uncertain. Potential candidates include secretin, glucagon (alone or combined with gastrin), vasoactive intestinal peptide and gastric inhibitory polypeptide. Secretin has undergone trials as therapy in peptic ulcer whereas glucagon is under investigation for the treatment of acute pancreatitis because of its dual actions as (1) an enterogastrone and (2) an inhibitor of pancreatic secretion.     

Mechanisms of the inhibitory action of prostaglandins on meal-induced gastric secretion

In dogs with gastric fistula and Heidenhain pouch (HP), 15(S)-15-methyl prostaglandin E2 methyl ester (PG-S) infused intravenously in graded doses (0.5--2.0 microgram/kg/h) inhibited dose-dependently, meal-induced acid secretion both from the vagally innervated main stomach and from the HP. This inhibition was associated with a marked reduction in mucosal blood flow but without significant change in the ratio of aminopyrine concentration in the gastric juice and blood plasma, indicating that the reduction in gastric microcirculation was probably secondary to the inhibition of gastric secretion. In dogs with special cannulae that allowed complete separation of the stomach and the intestine, PG-S caused stronger inhibition of gastric acid and serum gastrin responses to gastric and intestinal meals after application directly to the gastric mucosa, than following duodenal administration. PG-S applied topically to the HP mucosa also suppressed direct chemical stimulation of the HP by L-histidine meal. We conclude that PG-S exerts its inhibitory action on gastric secretion both by local contact with the mucosa via suppression on gastrin release from the antral G-cells and by direct inhibition of the secretory activity of the oxyntic glands.     

Idiopathic gastric acid hypersecretion presenting as a diarrheal disorder and mimicking both Zollinger-Ellison syndrome and Crohn's disease

Many gastric acid hypersecretory states (basal acid output of greater than 15.0 mEq/h) exist for which the etiology is known, such as Zollinger-Ellison syndrome, systemic mastocytosis, antral exclusion, antral predominant Helicobacter pylori gastritis (antral G cell hyperplasia), chronic gastric outlet obstruction, short gut syndrome and basophilic leukemias. However, many hypersecretory patients have no identified etiology for their acid hypersecretion and are designated as idiopathic gastric acid hypersecretors with a basal acid output of greater than 10 mEq/h and a normal serum gastrin level. Because of the gastric acid hypersecretion these patients also commonly have an increased frequency of stools. Idiopathic gastric acid hypersecretion represents a known cause of gastric acid hypersecretion that is far more common than Zollinger-Ellison syndrome and it has a markedly different treatment regimen and natural history. We report a case of a patient with idiopathic gastric acid hypersecretion previously misdiagnosed as having Crohn's disease because of a presenting complaint of diarrhea and mimicking Zollinger-Ellison syndrome because her fasting serum gastrin level was elevated when incorrectly measured in the presence of antisecretory treatment.     

Effects of somatostatin-14 and somatostatin-28 on plasma hormonal and gastric secretory responses to cephalic and gastrointestinal stimulation in man

This study was designed to determine the influence of cephalic and gastrointestinal meal stimulation on plasma levels of somatostatin-like immunoreactivity (SLI) and to compare plasma hormonal and gastric secretory effects of somatostatin-14 (SS-14) and its putative prohormone, somatostatin-28 (SS-28), in humans. Cephalic stimulation induced by modified sham feeding did not affect plasma SLI, whereas a gastric liver extract meal caused a significant increase in SLI. Infusion of SS-28 dose-dependently suppressed gastric acid, serum gastrin, and plasma pancreatic polypeptide (PP) responses to cephalic and gastrointestinal stimulation. SS-28 was equipotent with SS-14 as gastric inhibitor when compared on the basis of molar doses infused but was 4-10 times less potent on the basis of plasma SLI concentrations obtained. A lower and more physiological dose of SS-14 (75 pmol/kg-h) reduced gastric acid and PP responses but failed to affect the serum gastrin response to a meal; whereas a larger, pharmacological dose (500 pmol/kg-h) also suppressed serum gastrin responses. We conclude that meal releases SLI into the circulation and that SS-28 mimics the gastric secretory and plasma hormonal effects of SS-14 but is several times less potent than SS-14 in terms of circulating hormone levels.     

Reversible Basal Gastric Hypersecretion with Parathyroid Adenomas and Duodenal Ulcer

Summary: Profound hypersecretion of gastric acid, basally, was detected in a duodenal ulcer patient with familial primary hyperparathyroidism. Repeated fasting serum gastrin estimations were normal. Following surgical treatment of the hyperparathyroidism, there was a sustained fall in basal acid output from 34 to 4.5 mEq per hour. Two years later, an infusion of calcium intravenously re-produced dramatic gastric acid hyper-secretion, up to 64 mEq per hour, confirming the extreme hypersensitivity to mild hypercalcaemia. The infusion also provoked a rise in serum gastrin levels.
This study has demonstrated that pronounced basal acid hypersecretion with ulcer may occur in hyperparathyroidism in the absence of the Zollinger-Ellison syndrome. Thus, parathyroid adenomas do sometimes influence gastric secretion like a gastrin-producing tumour, or a retained excluded gastric antrum. This exaggerated response may be mediated by rises in serum gastrin, stimulated by calcium.     

Prostaglandins and vagal stimulation of gastric secretion in duodenal ulcer patients

The effects of a stable prostaglandin (PG) E2 analog (15-R-15 methyl PGE2) and aspirin, a potent inhibitor of cyclooxygenase, on modified sham-feeding (MSF)-stimulated gastric secretion and serum gastrin and pancreatic polypeptide (PP) levels were measured in patients with duodenal ulcer. PGE2 analog given orally significantly reduced gastric acid and pepsin secretion and suppressed serum PP but not gastrin responses to MSF. Suppression of PG generation in the gastric mucosa did not influence the secretory or hormonal responses to MSF. This study shows that endogenous PGs are not involved in the control of vagally stimulated gastric secretion, but exogenous PGE2 analog is an effective inhibitor of such secretion and merits clinical evaluation in the treatment of duodenal ulcer.     

Idiopathic gastric acid hypersecretion

Many patients with acid-peptic disease have idiopathic gastric acid hypersecretion defined as a basal acid output >10.0 meq/hr; however, a significant proportion have basal acid outputs >15.0 meq/hr, which is within the range found in Zollinger-Ellison syndrome. Although idiopathic gastric acid hypersecretion is more common than Zollinger-Ellison syndrome, it is important that these two disorders be differentiated because of differences in treatment and natural history. In the present study, we compared 124 patients with idiopathic gastric acid hypersecretion and 137 patients with Zollinger-Ellison syndrome. There were no significant differences with regard to age at diagnosis, history of upper gastrointestinal hemorrhage, nausea, vomiting, and family history of duodenal ulcer and other acid-peptic disease. However, significant differences were observed between patients with idiopathic gastric acid hypersecretion and patients with Zollinger-Ellison syndrome with regard to percentage of males: 77% compared to 64% (P=0.008), mean serum gastrin: 60 pg/ml compared to 3679 pg/ml (normal <100 pg/ml) (P<0.001), mean basal acid output: 15.4 meq/hr compared to 47.0 meq/hr (P<0.001), mean age at onset of symptoms: 33 years compared to 41 years (P<0.001), mean duration of symptoms before diagnosis: 11 years compared to five years (P<0.001), percentage with abdominal pain: 67% compared to 82% (P=0.00004), percentage with diarrhea: 12% compared to 75% (P<0.000001), percentage with pyrosis: 58% compared to 40% (P=0.003), percentage with duodenal ulcer: 53% compared to 74% (P<0.000001), and percentage with esophagitis: 31% compared to 42% (P=0.0004). The differences in clinical features could be attributed to difference in mean basal acid output, and/or differences in levels of basal acid output used for diagnosis of idiopathic gastric acid hypersecretion (basal acid output >10.0 meq/hr) and Zollinger-Ellison syndrome (basal acid output >15.0 meq/hr). When 45 patients with idiopathic gastric acid hypersecretion and 39 patients with Zollinger-Ellison syndrome with basal acid outputs 15.1–30.0 meq/hr were compared, the main significant differences were with regard to mean serum gastrin: 69 pg/ml compared to 655 pg/ml (P<0.001), percentage of male gender: 82% compared to 62% (P=0.03), and percentage with diarrhea: 16% compared to 64% (P=0.000005). These results indicate that in general patients with idiopathic gastric acid hypersecretion and patients with Zollinger-Ellison syndrome often have similar clinical features that can be difficult to distinguish. However, the increased frequency of diarrhea and female gender should lead to a strong suspicion of Zollinger-Ellison syndrome, which can be distinguished in almost every case by measurement of serum gastrin.     

Effect of chronic antacid ingestion on serum gastrin and gastric secretion

Basal gastrin and acid secretion, and histamine- and food-stimulated acid secretion were examined before and after 6 weeks of regular antacid consumption by 20 normal volunteers, in order to test the hypothesis that regular use of antacids produces gastrin cell hyperplasia, altered gastrin inhibition by acid, and gastric hypersecretion. We found no differences in fasting serum gastrin, basal or maximal histamine-stimulated acid, or acid output in response to a protein meal after consumption of commercial antacids with or without calcium carbonate. The results suggest that normal subjects do not acquire functional hyperactivity of the gastrin mechanism after a period of regular antacid use.     

Effect of small bowel bypass on serum gastrin levels and gastric acid secretion in man.

In animals massive resection of the small intestine is followed by increased gastric acid secretion and an increase in serum gastrin levels. Whether hypersecretion occurs in man after intestinal resections or intestinal bypass is unclear, but an increase in fasting gastrin levels has been reported after intestinal resection. In this series a significant increase in basal gastric acid secretion and fasting serum gastrin levels has been demonstrated after intestinal bypass. However, none of the patients developed peptic ulcer or clinical symptoms of hypersecretion after the bypass operation. Whether the increase in basal secretion and the serum gastrin concentration are interrelated or of any clinical importance is uncertain.     

Gastric acid and pancreatic polypeptide responses to modified sham feeding: indication of an increased basal vagal tone in a subgroup of duodenal ulcer patients.

The effect of sham feeding upon gastric acid secretion and pancreatic polypeptide release was investigated in 28 patients with duodenal ulcer in order to evaluate whether high basal vagal activity is the cause of basal acid hypersecretion in patients with duodenal ulcer and basal secretion higher than 30% of their peak acid output. The patients were divided into two groups based on the ratio of basal/pentagastrin stimulated peak acid output (BAO/PAO) was higher or lower than 0.30: group A n = 19 (BAO/PAO less than or equal to 0.30) and group B n = 9 (BAO/PAO greater than 0.30). Gastric acid response to sham feeding (SAO) was significantly higher than basal level in group A (SAO: 11.4 mEq/h (2.5-20.1) vs BAO: 5.2 mEq/h (0.8-22.9), p less than 0.01, median (range)) while in group B the acid secretion did not increase with sham feeding (SAO: 9.6 mEq/h (4.5-13.6) vs BAO: 8.8 mEq/h (6.3-13.8) ns, median (range)). A negative correlation (r= -0.6118226, p less than 0.01) was found between acid increase expressed as basal subtracted sham feeding response (SAO-BAO) and BAO/PAO ratio of the entire group of duodenal ulcer patients (n = 28) suggesting that the greater is basal acid secretory capacity the smaller is acid increase in response to residual vagal activation. Pancreatic polypeptide response to sham feeding was higher in group A than in group B but no correlation (r = 0.20, n = 28) nor individual covariation was found between acid and pancreatic polypeptide secretions during vagal stimulation. sham feeding did not change serum gastrin. It is concluded that an increased vagal stimulation seems to be the cause of basal hypersecretion in a subgroup of patients with duodenal ulcer. The lact of correlation between the pancreatic polypeptide and acid responses to vagal stimulation interferes with the reliability of pancreatic polypeptide as indicator of vagal tone on gastric parietal cells.