C. B. H. W. Lamers

Cephalic Stimulation of Gallbladder Contraction in Humans: Role of Cholecystokinin and the Cholinergic System

To determine the role of cholecystokinin and the cholinergic system in cephalic stimulation of gallbladder contraction and to compare the degree of gallbladder contraction by cephalic stimulation with postprandial gallbladder contraction, 8 healthy volunteers (4 males, 4 females, 20-65 years) underwent the following studies: sham feeding of an appetizing meal, sham feeding with intravenous atropine, and ingestion of the same meal. Gallbladder volume was measured by real-time ultrasonography and plasma cholecystokinin by a sensitive and specific radioimmunoassay using antibody T204. Gallbladder contraction in response to sham feeding, 30 +/- 4% (p = 0.0001 vs. basal), amounted to half of that seen after real feeding, 69 +/- 5% (p less than 0.0001 vs. basal). Significant dissociation between gallbladder response to sham feeding and real feeding was seen from 40 min (p less than 0.005-p = 0.0001). Atropine did not affect basal gallbladder volume but completely abolished gallbladder contraction in response to sham feeding. Neither sham feeding without nor sham feeding with atropine significantly affected plasma cholecystokinin levels. On the other hand, real feeding induced significant increases in plasma cholecystokinin from a basal level of 2.3 +/- 0.1 pM to a peak value of 5.9 +/- 0.4 pM at 40 min. It is concluded that an important cephalic phase of postprandial gallbladder contraction exists which is cholecystokinin-independent but dependent on a cholinergic mechanism.

Plasma cholecystokinin and gallbladder responses to intraduodenal fat in gallstone patients

Impaired gallbladder emptying is one of the various factors suggested to be involved in the pathogenesis of gallstones. The present study was undertaken to determine whether gallbladder emptying, endogenous cholecystokinin (CCK) secretion, or their interrelation is altered in patients with gallstones. After intraduodenal administration of 60 ml corn oil, plasma CCK concentration was measured by a sensitive and specific radioimmunoassay and gallbladder emptying by cholescintigraphy. Patients with gallstones (N=20) produced significantly less endogenous CCK (105±17 pmol/liter 60 min; P <0.001) than control subjects (191±11 pmol/liter 60 min, N=20); gallbladder emptying in the patients was significantly decreased at 5, 10, 40, 45, and 50 min but the reduction in gallbladder emptying did not reach statistical significance at 60 min (patients 44±8%, control subjects 60±4%). In addition, the gallbladder responsiveness to intravenous infusion of the synthetic CCK analog cerulein was investigated. Based on the results of gallbladder emptying in response to endogenous and exogenous CCK, four subgroups of gallstone patients were identified: (1) a group (N=7) with normal gallbladder sensitivity to CCK, (2) a group (N=6) with significantly increased gallbladder sensitivity to CCK, (3) a group (N=6) with impaired gallbladder emptying after corn oil due to a significantly reduced endogenous CCK secretion but with normal gallbladder sensitivity to CCK, and (4) one patient whose gallbladder was unresponsive to CCK and was found to have chronic cholecystitis at surgery.

Effects of Somatostatin on Human Satiety

Somatostatin (ST) inhibits gastrointestinal motility and exocrine and endocrine secretions. In animals, ST has been demonstrated to decrease food intake. We investigated, in a randomized double-blind investigation in 10 healthy humans, the effects of an intravenous ST infusion compared to saline on subjective hunger feelings. After 1 h, a low dose of fat was given intraduodenally to induce the release of endogenous upper-intestinal satiety factors. Ninety minutes later sandwiches were served and eaten until satiation. In the first hour, when no intraduodenal fat was given, there was a significant decrease in feelings of hunger with ST (p < 0.05). During the intraduodenal fat infusion this pattern reversed with a trend towards less satiety with ST. Food intake during intraduodenal fat infusion tended to be higher during ST (305 +/- 42 g) than during saline (205 +/- 36 g) although not significantly. In the 5 h after the experiment hunger feelings were significantly less after ST. In conclusion, we found evidence for a satiety effect of ST in humans which reversed towards less satiety when intraduodenal intralipid, which presumably produced endogenous satiety factors, was given. Postmeal satiety is higher after ST.

Effects of medium-chain and long-chain triglycerides on antroduodenal motility and small bowel transit time in man.

Medium-chain triglycerides are known to inducediarrhea, possibly resulting from accelerated intestinaltransit. We performed antroduodenal manometry andlactulose hydrogen breath testing simultaneously in eight healthy subjects in order to determinethe effects of intraduodenally administered medium-chaintriglycerides (MCT) and long-chain triglycerides (LCT)on gastrointestinal motility and small bowel transit time. LCT (15 mmol/hr) induced a fedmotor pattern. In contrast, during MCT, in bothequimolar (15 mmol/hr; MCT-1) and equicaloric (30mmol/hr; MCT-2) amounts comparable to LCT,interdigestive motility was preserved but with a significantly (P <0.05) shorter MMC cycle length (MCT-1, 65 ± 7min; MCT-2, 53 ± 6 min) compared to control(saline infusion; 127 ± 14 min). Duodenocecaltransit time (DCTT) was significantly (P < 0.05) accelerated during administrationof MCT (MCT-1, 56 ± 6 min; MCT-2, 69 ± 9min) and was not affected by LCT (105 ± 13 min)when compared to control (101 ± 9 min). Inconclusion: MCT, in contrast to LCT, preserve interdigestive motility with a shorterMMC cycle length and accelerate DCTT.

Effect of Atropine on the Plasma Cholecystokinin Response to Intraduodenal Fat in Man

The present study was undertaken to determine whether atropine inhibits the plasma cholecystokinin (CCK) response to intraduodenal fat. Plasma CCK concentrations were measured by radioimmunoassay using two sequence-specific antibodies. Antibody 1703 bound to all COOH-terminal CCK peptides containing at least 14 amino acid residues, while antibody T204 was specific for the sulphated tyrosine region of CCK. Intraduodenal instillation of 60 ml corn oil in 6 normal subjects induced significant increases in plasma CCK. Intravenous administration of atropine (0.015 mg/kg as bolus followed by 0.005 mg/kg X h over 3 h) resulted in significant inhibition of plasma CCK concentrations at 10, 20 and 30 min (antibody 1703) and at 20 and 30 min (antibody T204 ) after instillation of fat. However, the peak increments in plasma CCK during atropine (8.6 +/- 1.9 pmol/l, antibody 1703; 5.4 +/- 1.1 pmol/l, antibody T204 ) were not different from those found without atropine (6.3 +/- 0.8 pmol/l, antibody 1703; 3.9 +/- 0.9 pmol/l, antibody T204 ). Similarly, the integrated plasma CCK secretion after intraduodenal fat was not significantly different when measured during atropine (461 +/- 119 pmol/l X 3 h, antibody 1703; 269 +/- 97 pmol/l X 3 h, antibody T204 ) and without atropine (428 +/- 62 pmol/l X 3 h, antibody 1703; 188 +/- 66 pmol/l X 3 h). It is concluded that administration of atropine delays but does not inhibit the CCK response to intraduodenal corn oil in man.

Gastrointestinal disturbances with obesity.

Steatosis and steatohepatitis are associated with obesity. Despite florid histological changes, patients with non-alcoholic steatohepatitis generally remain asymptomatic, and it usually runs a relatively benign course. An elevated insulin level may be important in the pathogenesis. There is a marked regression of fatty changes after weight reduction. In obese subjects the risk of developing gallstones is increased due to an increased saturation of gallbladder bile with cholesterol and possible gallbladder stasis. During weight reduction with very low calorie diets the incidence in gallstones increases probably because of an increased saturation of bile during the loss of weight. Ursodeoxycholic acid appears to be a promising prophylactic agent. Chenodeoxycholic acid is not useful for these subjects. There is controversy over whether obesity contributes to gastroesophageal reflux and gastric emptying disturbances. There are changes in gastrointestinal peptide plasma levels in obesity but it is not clear if this contributes to its development. The risk for high-risk colorectal adenomas and carcinomas is reported to be increased in obese males. Vertical banded gastroplasty and gastric bypass procedures are nowadays the surgical options for the treatment of obesity. Nutritional deficiencies, particularly of vitamin B12, folate and iron are common after gastric bypass and must be sought and treated. Dumping is another potential complication of this operation. If stenosis and gastric outlet obstruction develop endoscopic dilatation is a good therapeutic option.

Intravenous administration of bombesin in man stimulates natural killer cell activity against tumour cells

Peptides from both the nervous and endocrine system have been shown to influence immune functions. This study describes the stimulatory effect of bombesin on natural killer cell activity of peripheral blood mononuclear cells. The stimulation of cytotoxicity by bombesin in vivo was much higher than found in vitro. In vitro studies with bombesin and gastrin revealed that the stimulatory effect of bombesin in vivo can for a major part be attributed to other stimulatory mediators which are released by BBS. These results indicate that neuropeptide release might rapidly interfere, both directly and indirectly, with natural killer activity of peripheral blood mononuclear cells.

Effect of zinc therapy on natural killer cell activity in inflammatory bowel disease

Disturbances in zinc metabolism have been documented in patients with inflammatory bowel disease. In this study we evaluated the effect of in vivo treatment with zinc on the in vitro natural killer cell activity in thirteen inflammatory bowel disease patients, with stable disease and mild–moderate disease activity, in a double‐blind randomized cross‐over trial. The results of our study show a long‐lasting effect of in vivo zinc administration, which decreased peripheral blood natural killer cell activity in inflammatory bowel disease.

Prospective Study of the Effect of the Belsey Mark-IV Fundoplication on Reflux Mechanisms

BACKGROUND Transient lower esophageal sphincter relaxations (TLESRs) are the major mechanism permitting gastroesophageal reflux (GER). Little information is available on how anti-reflux surgery affects reflux mechanisms, especially TLESRs. We evaluated the effects of partial fundoplication (Belsey Mark IV) on reflux mechanisms. METHODS Sixteen patients were prospectively studied before and after Belsey Mark-IV operation by endoscopy, 24-h esophageal pH-metry, and simultaneous recording of pH and lower esophageal sphincter (LES) characteristics by sleeve manometry. RESULTS The operation was successful in 14 of 16 patients (87%). Fasting and postprandial reflux decreased significantly (P < 0.01) after the operation. Partial fundoplication significantly (P < 0.05) decreased the number of TLESRs per hour in the fasting and postprandial period from 3.2+/-0.4 and 5.6+/-0.5 to 1.7+/-0.3 and 2.8+/-0.4, respectively. The percentage of TLESRs associated with reflux also decreased significantly (P < 0.05). Basal LES pressure increased from 14.7+/-2.1 mmHg to 17.9+/-2.6 mmHg (not significant). CONCLUSIONS Partial fundoplication controls GER through a reduction in the number of TLESRs and by decreasing the number of relaxations associated with reflux.

Gallbladder Motility in Response to Sham Feeding and Cholecystokinin in Lean and Obese Subjects

The risk of developing gallstones is increased in obese subjects. We have investigated whether gallbladder motility in obese subjects is different from that in lean control subjects. In 25 healthy non-diabetic obese subjects and 20 age- and sex-matched lean controls, fasting gallbladder volumes, gallbladder contraction in response to cephalic vagal cholinergic stimulation by modified sham feeding (MSF) and to hormonal stimulation with cholecystokinin (CCK) were studied. Gallbladder volumes were measured during a 30-min MSF period followed 1 h later by a 1-hour continuous i.v. infusion of 0.5 IDU/kg ideal weight of CCK-33. Fasting gallbladder volumes were significantly (p < 0.001) larger in obese (47 +/- 4 cm3) compared to lean subjects (24 +/- 2 cm3). Fasting gallbladder volume was correlated with body mass index (p < 0.01). Gallbladder contraction during MSF was significantly (p < 0.01) reduced in obese (12 +/- 2%) compared to lean subjects (22 +/- 3%). CCK infusion, leading to physiological post-prandial plasma CCK levels, induced a significantly (p < 0.001) greater absolute gallbladder contraction in obese (27 +/- 3 cm3) compared to lean subjects (15 +/- 1 cm3) but the percentage gallbladder contraction was in the same range (64 +/- 3% vs. 67 +/- 4%, respectively). In addition, residual gallbladder volumes after CCK infusion were significantly (p < 0.001) larger in obese (15 +/- 2 cm3) than in lean subjects (7 +/- 1 cm3). Two groups of obese subjects were identified: one with increased (>40 cm3) and one with normal (< or = 40 cm3) fasting gallbladder volumes. Only obese subjects with increased fasting volumes showed abnormal gallbladder motility.