C.B.H.W. Lamers

Atrophic Gastritis and Helicobacter pylori Infection in Patients with Reflux Esophagitis Treated with Omeprazole or Fundoplication

BACKGROUND Helicobacter pylori infection plays an important part in the development of atrophic gastritis and intestinal metaplasia, conditions that predispose patients gastric cancer. Profound suppression of gastric acid is associated with increased severity of gastritis caused by H. pylori, but it is not known whether acid suppression increases the risk of atrophic gastritis. METHODS We studied patients from two separate cohorts who were being treated for reflux esophagitis: 72 patients treated with fundoplication in Sweden and 105 treated with omeprazole (20 to 40 mg once daily) in the Netherlands. In both cohorts, the patients were followed for an average of five years (range, three to eight). After fundoplication, the patients did not receive acid-suppressive therapy. The presence of H. pylori was assessed at the first visit by histologic evaluation in the fundoplication group and by histologic and serologic evaluation in the omeprazole group. The patients were not treated for H. pylori infection. Before treatment and during follow-up, the patients underwent repeated gastroscopy, with biopsy sampling for histologic evaluation. RESULTS Among the patients treated with fundoplication, atrophic gastritis did not develop in any of the 31 who were infected with H. pylori at base line or the 41 who were not infected; 1 patient infected with H. pylori had atrophic gastritis before treatment that persisted after treatment. Among the patients treated with omeprazole, none of whom had atrophic gastritis at base line, atrophic gastritis developed in 18 of the 59 infected with H. pylori(P<0.001) and 2 of the 46 who were not infected (P=0.62). CONCLUSIONS Patients with reflux esophagitis and H. pylori infection who are treated with omeprazole are at increased risk of atrophic gastritis.

Effect of a low dose of intraduodenal fat on satiety in humans: studies using the type A cholecystokinin receptor antagonist loxiglumide.

Satiation, the process that brings eating to an end, and satiety, the state of inhibition over further eating, may be influenced by cholecystokinin (CCK). In animal and human studies, it has been shown that infusion of exogenous CCK decreases food intake, but the doses given may well have led to supraphysiological plasma concentrations. This study was done to discover if a low dose of intraduodenal fat releasing physiological amounts of endogenous cholecystokinin exerts satiation or satiety effects, or both and if these effects could be inhibited by the CCK receptor antagonist loxiglumide. In 10 healthy lean volunteers (5 F, 5 M, mean age 26) three tests were performed in a randomised blind fashion. Intralipid 20% (6 g/h) (experiments A and C) or saline (experiment B) were given intraduodenally from 1030 until 1300. The subjects received saline (experiments A and B) or loxiglumide (experiment C) a specific CCK-receptor antagonist (10 mg/kg/h) intravenously from 0930 until 1300. At 1200 a meal was served. At regular time intervals hunger feelings were measured using visual analogue scales and food selection lists and plasma CCK was measured by radioimmunoassay. Food intake (mean (SEM)) during intraduodenal fat (206(35)g) was lower than in the control study (269(37)g, p = 0.09). Loxiglumide largely prevented the inhibitory effect of intraduodenal fat on food intake (245(30)g). From 1030 until the meal at 1200 there was a significant satiating effect of intraduodenal fat compared with the control and loxiglumide experiments according to the food selection lists, which was because of the satiating effect for the fat rich items (p<0.05). Also feelings of fullness were significantly higher during intraduodenal fat than in the control or loxiglumide experiments (p<0.05). During intraduodenal fat there was a significant increase of plasma CCK from 2.4(0.3) to 4.8(0.4) pM (p<0.001). Loxiglumide led to an exaggerated CCK release to a peak concentration of 16(2.4) pM before the meal. This study shows that in humans low dose intraduodenal fat increases satiety and satiation, mainly through the effect of CCK.

Hyperglycemia Modulates Gallbladder Motility and Small Intestinal Transit Time in Man

The aim of the present study was to investigate the effect of acute hyperglycemia on (1) the intestinal phase of gallbladder contraction induced by the intraduodenal administration of emulsified fat, and (2) the small intestinal transit time measured by the lactulose breath hydrogen test. Six healthy volunteers were studied in random order during normoglycemia and hyperglycemia (blood glucose levels 15 mmol/liter). Gallbladder volumes were measured with ultrasonography. Administration of 1 and 2 g/hr of fat resulted in significant reductions in gallbladder volumes from 24±2 cm3 to 11±1 cm3 (P<0.05) and 8±1 cm3 (P<0.05), respectively during normoglycemia, and from 24±2 cm3 to 21±2 cm3 (P<0.05) and 16±2 cm3, respectively (P<0.05) during hyperglycemia. Compared to normoglycemia, the gallbladder contraction was significantly (P<0.05) reduced during hyperglycemia. No significant differences in CCK secretion were observed between experiments. Small intestinal transit time during hyperglycemia (101±12 min) was significantly (P<0.05) prolonged compared to normoglycemia (57±12 min). During hyperglycemia, basal PP levels and PP secretion in response to intraduodenal fat were significantly (P<0.05) reduced compared to normoglycemia. It is concluded that (1) low doses of intraduodenal emulsified fat result in significant gallbladder contraction and CCK secretion, (2) acute hyperglycemia inhibits intraduodenal fat induced gallbladder contraction, (3) acute hyperglycemia does not affect the intraduodenal fat induced CCK secretion, (4) small intestinal transit is significantly prolonged during acute hyperglycemia, and (5) acute hyperglycemia inhibits basal and stimulated plasma PP secretion, suggesting impaired vagal-cholinergic tone during hyperglycemia.

Effect of hyperglycemia on gastrointestinal and gallbladder motility.

Gastrointestinal motor abnormalities occur frequently in patients with diabetes mellitus. The gastrointestinal motor dysfunction in these patients has been associated with the presence of autonomic neuropathy. Recently, however, several studies have shown that the gastrointestinal motor responses to various stimuli are impaired during acute hyperglycemia in both healthy subjects and diabetic patients. It has been demonstrated that acute hyperglycemia impairs esophageal peristalsis, reduces the lower esophageal sphincter pressure, delays gastric emptying, slows intestinal transit, and reduces the gallbladder contraction in response to various stimuli in healthy subjects. In diabetic patients gastric emptying and gallbladder contraction have been shown to be impaired during hyperglycemia. With regard to the mechanisms of action, it has been suggested that hyperglycemia may affect gastrointestinal function through vagal-cholinergic inhibition, by alterations in serum osmolality, or perhaps by alterations in gastrointestinal hormone secretion.

Effect of cholecystokinin on lower oesophageal sphincter pressure and transient lower oesophageal sphincter relaxations in humans.

The effect of cholecystokinin (CCK) on the lower oesophageal sphincter (LOS) pressure, frequency of transient LOS relaxations, and the number of reflux episodes was investigated in six healthy subjects. LOS pressure was recorded on four separate occasions during continuous intravenous infusion of either saline or CCK-33 in doses of 0.25, 0.5, or 1.0 Ivy Dog units per kg body weight per hour (IDU.kg-1.h-1) for 90 minutes. Plasma CCK concentrations did not change during saline infusion, but increased significantly from 2.5 (0.3) pmol/l to steady state levels of 4.0 (0.4) pmol/l, 6.1 (0.4) pmol/l, and 9.3 (0.9) pmol/l respectively starting from 30 minutes. LOS pressure did not change significantly during infusion of saline or of CCK-33 at doses of 0.25 or 0.5 IDU.kg-1.h-1. However, a significant (p < 0.05) reduction in LOS pressure to a minimum level of 12 (4) mm Hg at 30 minutes compared with basal level (18 (4) mm Hg) and compared with saline was observed during infusion of CCK-33 at a dose of 1.0 IDU.kg-1.h-1. In addition, oesophageal motility and pH were recorded simultaneously in these six subjects on two separate occasions one hour before (fasting) and three hours during administration of a gastric load (dextrose 5%, pH 3) combined with continuous intravenous infusion of saline or CCK-33 at a dose of 1.0 IDU,kg-1.h-1. Plasma CCK concentrations did not change during the gastric load combined with saline, but increased significantly to a steady state level of 10.8 (0.8) pmol/l during intravenous infusion of CCK. The number of transient LOS relaxations increased significantly in the first hour during administration of the gastric load compared with fasting levels, both during saline infusion (fasting: 1.7 (0.6)/h, 1st hour: 4.3 (1.2)/h) and during CCK infusion (fasting: 1.7 (0.5)/h, 1st hour: 3.8 (0.7)/h). In the second and third hours the number of transient LOS relaxations fell to fasting levels in both experiments. No significant differences were observed in the number and type of transient LOS relaxations, mechanism of gastro-oesophageal reflux, or duration of acid exposure between the two experiments. It is concluded that in healthy subjects infusion of CCK-33 in a dose of 1.0 IDU.kg-1.h-1 significantly reduces LOS pressure but does not affect the frequency of transient LOS relaxations or acid exposure time during a continuous liquid gastric load.

Hyperglycemia Reduces Gastric Secretory and Plasma Pancreatic Polypeptide Responses to Modified Sham Feeding in Humans

We have investigated the effect of acute stable hyperglycemia on gastric acid secretion and serum gastrin and pancreatic polypeptide (PP) release. Gastric acid output was measured under basal conditions and in response to modified sham feeding (MSF) in 7 healthy volunteers on two separate occasions: during normoglycemia (serum glucose 5 mmol/l) and during hyperglycemia (serum glucose 15 mmol/l). PP secretion was determined as an indirect measure of vagal-cholinergic tone. Basal acid output during hyperglycemia (4.7 +/- 1.0 mmol/h) was not significantly different from euglycemia (5.4 +/- 0.6 mmol/h), but MSF-stimulated acid output during hyperglycemia (14.7 +/- 3.3 mmol/90 min) was significantly (p < 0.05) reduced compared to euglycemia (24.7 +/- 3.2 mmol/90 min). Serum gastrin levels were not affected by MSF. During hyperglycemia, the integrated PP secretion in response to MSF (235 +/- 95 pmol/l.90 min) was significantly (p < 0.05) reduced compared to euglycemia (434 +/- 71 pmol/l.90 min). This study indicates that (1) serum glucose affects cephalic-stimulated gastric acid secretion, and (2) PP secretion after MSF is significantly reduced during hyperglycemia suggesting impaired vagal-cholinergic activity during hyperglycemia.

Effect of hyperglycaemia on gallbladder motility in Type 1 (insulin-dependent) diabetes mellitus

SummaryPatients with diabetes mellitus are at increased risk of developing gallstones. This has been attributed, among other factors, to alterations in gallbladder motility in the presence of autonomic neuropathy. Since high blood glucose concentrations impair gastric emptying in diabetic patients, we have investigated the effect of acute hyperglycaemia on gallbladder motility. Seven Type 1 (insulin-dependent) diabetic patients were studied twice during euglycaemia (blood glucose 5 mmol/l) and hyperglycaemia (blood glucose 15 mmol/l) using a clamp technique. In addition, seven healthy volunteers were studied during euglycaemia and hyperglycaemia. Gallbladder volumes, measured with ultrasonography, were studied before and during infusion of step-wise increasing doses of cholecystokinin-33, 0.25, 0.5 and 1.0 Ivy Dog Unit · kg−1 · h−1, each dose for 30 min. Mean basal gallbladder volumes were not significantly different in the four experiments. Administration of cholecystokinin resulted in significant (p<0.05) dose-dependent reductions in gallbladder volume in all experiments. During euglycaemia the gallbladder contraction in diabetic patients was not significantly different from the control subjects. During hyperglycaemia the gallbladder contraction in the diabetic patients was significantly (p<0.05) reduced compared to euglycaemia only during infusion of 0.25 Ivy Dog Unit · kg−1 · h−1 of cholecystokinin (19±6% vs 33±6%). Compared to euglycaemia, during hyperglycaemia the gallbladder contraction in the control subjects was significantly (p<0.05) reduced during infusion of 0.25, 0.5 and 1.0 Ivy Dog Unit · kg−1 · h−1 of cholecystokinin (14±4% vs 31±3%; 42±6% vs 65±5%; 74±4% vs 90±3%, respectively). It is concluded that during euglycaemia the gallbladder contraction in response to cholecystokinin in Type 1 diabetic patients is not significantly different from control subjects. During hyperglycaemia the gallbladder contraction in response to 0.25 Ivy Dog Unit · kg−1 · h−1 cholecystokinin, leading to cholecystokinin levels as observed after ingestion of a light meal, is significantly reduced in Type 1 diabetic patients.

Effect of acute hyperglycaemia on gall bladder contraction induced by cholecystokinin in humans.

This study examined the effect of acute hyperglycaemia, induced by intravenous glucose, on gall bladder motility. Six healthy volunteers were studied in random order on three occasions during normoglycaemia and hyperglycaemia with blood glucose concentrations stabilised at 8 and 15 mmol/l. Gall bladder volumes, measured with ultrasonography, were studied before and during infusion of stepwise increasing doses of cholecystokinin (CCK-33; 0.25, 0.5, and 1.0 IDU.kg-1.h-1). Each dose was given for 30 minutes. Pancreatic polypeptide (PP) secretion was determined as an indirect measure of cholinergic tone. Infusion of CCK-33 resulted in significant dose dependent reductions in gall bladder volume in all three experiments. Compared with normoglycaemia the gall bladder contraction was significantly (p < 0.05) reduced during infusion of 0.25 and 0.5 IDU kg-1.h-1 CCK-33 in the 8 mmol/l hyperglycaemic experiment, and during infusion of 0.25, 0.5, and 1.0 IDU kg-1.h-1 CCK-33 in the 15 mmol hyperglycaemic experiment. During hyperglycaemia basal plasma PP concentrations and PP secretion in response to CCK-33 were significantly (p < 0.05) reduced. It is concluded that blood glucose concentrations affect gall bladder motility, that an acute hyperglycaemia at 8 and 15 mmol/l reduces the gall bladder responsiveness to CCK-33 in a dose dependent manner, and that hyperglycaemia reduces basal and CCK-33 stimulated plasma PP concentrations, suggesting impaired cholinergic activity during hyperglycaemia.

Gall bladder emptying in severe idiopathic constipation

BACKGROUND It has been suggested that slow transit constipation (STC) may be part of a panenteric motor disorder. AIM To evaluate motility of an upper gastrointestinal organ, the gall bladder, in 16 patients with STC and 20 healthy controls. METHODS Gall bladder emptying (ultrasonography) was studied in response to neural, cephalic-vagal stimulation with modified sham feeding (MSF) for 90 minutes and in response to hormonal stimulation with cholecystokinin (CCK, 0.5 IDU/kg/h) for 60 minutes. RESULTS Fasting gall bladder volume in patients with STC (17 (2) cm3) was significantly (p<0.01) reduced compared with that in controls (24 (2) cm3). Gall bladder emptying in response to MSF was significantly reduced in patients with STC expressed both as percentage emptying (11 (5)% versus 22 (3)%; p<0.05) and as absolute emptying (2.1 (0.7) cm3 versus 4.9 (0.7) cm3; p<0.02). However, percentage gall bladder emptying in response to CCK was not different between patients and controls (73 (4)% versus 67 (4)%) although the absolute reduction in gall bladder volume was significantly (p<0.05) smaller in patients (10.7 (1.1) cm3versus 15.3 (1.4) cm3). CONCLUSIONS Patients with slow transit constipation have smaller fasting gall bladder volumes, impaired gall bladder responses to vagal cholinergic stimulation, but normal gall bladder responses to hormonal stimulation with CCK. These results point to abnormalities in gastrointestinal motility proximal from the colon in slow transit constipation and more specifically, impaired neural responsiveness.

Effect of Intravenous Fat on Cholecystokinin Secretion and Gallbladder Motility in Man

During total parenteral nutrition (TPN) gallbladder bile stasis and hypomotility have been well documented. Little is known, however, about the effect of the separate components of TPN on gallbladder motor function. Inasmuch as fat, administered intraduodenally, is a potent stimulus of cholecystokinin (CCK) secretion and gallbladder contraction we have investigated whether intravenous (IV) fat affects gallbladder motility. Six healthy volunteers were studied on two separate occasions, during infusion of Intralipid 10%, 200 mL/h or saline infusion (control) for 3 hours, to evaluate the effect of IV infusion of fat on (1) plasma CCK concentration and gallbladder volume and (2) CCK-induced gallbladder emptying. Intravenous infusion of Intralipid resulted in significant increases in serum triglycerides from 0.9 +/- 0.1 to 5.1 +/- 1.3 mmol/L (at 90 min). During fat infusion no significant changes in plasma CCK and gallbladder volume were noted when compared with basal values or to the control experiment. During IV fat, concomitant infusion of 0.25, 0.5, and 1.0 Ivy dog unit (IDU) per kilogram per hour of CCK-33 resulted in a significant reduction in gallbladder volume from 26 +/- 6 cm3 (basal) to 15 +/- 4 cm3 (p less than .05), 6 +/- 2 cm3 (p less than .05) and 2.5 +/- 1 cm3 (p less than .05), respectively. No significant differences in CCK-induced gallbladder emptying were observed between IV fat and saline infusion (control). It is concluded that, in contrast to intraduodenal fat, IV infusion of fat does not affect (1) basal plasma CCK and gallbladder volume and (2) CCK-induced gallbladder contraction.