Wim P.M. Hopman

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.

Fasting gallbladder volume, postprandial emptying and cholecystokinin release in gallstone patients and normal subjects

Since abnormal gallbladder emptying may be a contributing factor in the development of gallstone disease, we determined fasting gallbladder volume and postprandial contraction in 20 gallstone patients and 20 normal subjects with the aid of ultrasonography. Moreover, basal plasma cholecystokinin levels and postprandial cholecystokinin (CCK) release were determined. Gallstone patients were divided into strong contractors (13 pts) and weak contractors (below 95% confidence interval for AUC contraction in % during 90 min: 7 pts). Strong contractor patients had significantly larger mean fasting volumes than normal subjects (mean +/- S.E.: 34.9 +/- 6.1 ml and 18.9 +/- 1.6 ml, respectively). This was not true for weak contractor patients (mean fasting volume 23.2 +/- 3.2 ml). Both strong contractor and weak contractor patients had significantly higher mean residual volumes than normal subjects (17.0 +/- 4.1 ml, 18.0 +/- 2.9 ml, and 8.8 +/- 1.1 ml, respectively). Absolute gallbladder emptying was significantly higher for strong contractor patients than for normal subjects, but relative emptying was the same. Opposite patterns of CCK release occurred in gallstone patients and normal subjects. In normal subjects, more CCK release was associated with stronger gallbladder emptying. In contrast, weak contractor gallstone patients had significantly higher CCK release than strong contractor patients. (AUC CCK: 304 +/- 89 pmol/l x 90 min and 106 +/- 29 pmol/l x 90 min, respectively). The present study indicates that strong contractor gallstone patients may have large residual gallbladder volumes due to large starting volumes, whereas weak contractor patients may have large residual volumes due to impaired contraction. Subjects with large fasting and residual volumes may be at increased risk for gallstone disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of graded physiologic doses of cholecystokinin on gallbladder contraction measured by ultrasonography

This study was undertaken to determine in healthy humans the effect of graded physiologic doses of cholecystokinin (CCK) on gallbladder size as assessed by ultrasonography and to analyze the relations between the doses of CCK infused, the plasma CCK increments, the decreases in gallbladder volume, and the cumulative intraduodenal bilirubin output. Infusion of stepwise-increasing doses of CCK, ranging from 0.2 to 6.4 pmol/kg X h, induced dose-related increases in plasma CCK (r = 0.99; p less than 0.001), decreases in gallbladder volume (r = 0.99; p less than 0.001), and increases in intraduodenal bilirubin output (r = 0.96; p less than 0.01). There was a highly significant correlation between the decreases in gallbladder volume and the cumulative intraduodenal bilirubin outputs (r = 0.98; p less than 0.001). Infusion of 0.8 pmol/kg X h of CCK, resulting in an increase in plasma CCK of 1.3 +/- 0.5 pmol/L, was the threshold for stimulating gallbladder contraction as assessed by both ultrasonography and measurement of intraduodenal bilirubin output. It is concluded that ultrasonography is a sensitive method for the quantitation of gallbladder contraction and that physiologic plasma CCK concentrations do stimulate gallbladder contraction.

Plasma cholecystokinin response to oral fat in patients with Billroth I and Billroth II gastrectomy.

The present study was undertaken to determine whether bypassing the duodenum in patients with Billroth II gastrectomy affects plasma cholecystokinin (CCK) release in response to ingestion of fat. Plasma CCK concentrations were measured by radioimmunoassay using two antibodies; antibody 1703 binds to all carboxl-terminal CCK-peptides containing at least 14 amino acid residues, while antibody T204 is specific for the sulphated tyrosine region of CCK. There were no significant differences among fasting plasma CCK concentrations in seven patients with Billroth II gastrectomy (1.3 ± 0.4 fmol/ml, antibody 1703; 2.6 ± 0.4 fmol/ml, antibody T204), six patients with Billroth I gastrectomy (0.6 ± 0.3 fmol/ml, antibody 1703; 2.9 ± 0.5 fmol/ml, antibody T204), and nine normal subjects (0.7 ± 0.1 fmol/ml, antibody 1703; 1.9 ± 0.3 fmol/ml, antibody T204). Ingestion of 250 ml 20% Intralipid induced similar increases in plasma CCK in patients with Billroth II gastrectomy (11.2 ± 2.0 fmol/ml, antibody 1703; 10.1 ± 2.4 fmol/ml, antibody T204) as in patients with Billroth I gastrectomy (11.8 ± 2.0 fmol/ml, antibody 1703; 8.4 ± 1.1 fmol/ml, antibody T204). However, the increments in plasma CCK in patients with gastrectomy (11.5 ± 1.4 fmol/ml, antibody 1703; 9.3 ± 1.4 fmol/ml, antibody T204) were significantly (p < 0.01) greater than those in normal subjects (4.7 ± 0.8 fmol/ml, antibody 1703; 4.1 ± 0.7 fmol/ml). Similarly, the integrated plasma CCK secretion in patients with Billroth II gastrectomy (510 ± 58 fmol/ml.120 min, antibody 1703; 458 ± 69 fmol/ml.120 min, antibody T204) and in patients with Billroth I gastrectomy (457 ± 143 fmol/ml.120 min, antibody 1703; 365 ± 61 fmol/ml.120 min, antibody T204) were significantly (p < 0.05) greater than in normal subjects (230 ± 49 fmol/ml.120 min, antibody 1703; 162 ± 24 fmol/ml.120 min, antibody T204). It is concluded that the plasma CCK response to oral fat is significantly greater in patients with partial gastrectomy than in normal subjects, and that patients with Billroth I and Billroth II gastrectomy have similar increases in plasma CCK after ingestion of fat.

Effect of ageing on postprandial conjugated and unconjugated serum bile acid levels in healthy subjects

Abstract. Colorectal cancer is a disease of elderly subjects. A decreased ileal absorption of bile acids in elderly subjects may lead to an increased exposure of the colonic mucosa to secondary bile acids. This may contribute to an enhanced risk of colorectal cancer. In this study fasting and postprandial conjugated and unconjugated serum levels of cholic, chenodeoxycho‐lic, and deoxycholic acid in 12 elderly and 12 younger subjects were investigated. Intestinal transit time, gallbladder emptying and jejunal bacterial flora were also studied in both age groups. Fasting levels of conjugated and unconjugated serum bile acids were similar in both age groups. Postprandial levels of all individual conjugated bile acids increased to a significantly higher extent in the younger subjects. Postprandial unconjugated serum bile acid levels did not differ significantly between both age groups, although unconjugated deoxycholic levels tended to increase to higher levels in the elderly. Results of jejunal bacterial counts, gallbladder emptying and intestinal transit time were similar in both groups. These data suggest that conjugated bile acids are reabsorbed less effectively in elderly subjects.

Plasma cholecystokinin concentrations in patients with pancreatic insufficiency measured by sequence-specific radioimmunoassays

It has been claimed that plasma cholecystokinin (CCK) concentrations are raised in patients with pancreatic insufficiency. We have measured plasma CCK concentrations in 32 patients with pancreatic insufficiency (22 alcoholic pancreatitis and 10 cystic fibrosis) and in 30 normal subjects by radioimmunoassays using antibodies with different specificties. Antibody 1703 binds to COOH-terminal forms of CCK containing at least 14 amino acid residues and does not cross-react with gastrins. Antibody T204 binds to all CCK-peptides containing the sulfated tyrosyl region and shows low cross-reactivity with sulfated gastrins but no binding to nonsulfated gastrins. Antibody 5135 binds to all COOH-terminal CCK-peptides and shows full cross-reactivity with gastrins. In patients with pancreatic insufficiency, plasma CCK concentrations (1.2±0.1 pmol/liter, antibody 1703; 2.0±0.2 pmol/liter, antibody T204; 12.5±1.4 pmol/liter, antibody 5135) were not significantly different from those in normal subjects (1.1±0.1 pmol/liter, antibody 1703; 2.2±0.3 pmol/liter, antibody T204; 10.5±0.9 pmol/liter, antibody 5135). Furthermore, plasma CCK concentrations in patients with pancreatic insufficiency due to alcoholic pancreatitis (1.2±0.1 pmol/liter, antibody 1703; 1.9±0.2 pmol/liter, antibody T204; 14.0 ±1.9 pmol/liter, antibody 5135) were not significantly different from those in patients with cystic fibrosis (1.2±0.2 pmol/liter, antibody 1703; 2.4±0.4 pmol/liter, antibody T204, 9.1 ±1.0 pmol/liter, antibody 5135). Cross-reactivity with gastrin accounted for almost all CCK-like-immunoreactivity measured with antibody 5135. Oral ingestion of 250 ml 20% Intralipid induced similar increases in plasma CCK in six patients with pancreatic insufficiency (4.3±1.5 pmol/liter, antibody 1703; 2.9±0.6 pmol/liter, antibody T204) as in seven normal subjects (5.0±0.9 pmol/liter, antibody 1703; 4.3±0.9 pmol/liter, antibody T204). It is concluded that CCK concentrations in fasting plasma are very low, that oral fat induces significant increases in plasma CCK, and that in patients with pancreatic insufficiency plasma CCK levels are not increased.

Abnormalities of upper gut motility in patients with slow-transit constipation.

OBJECTIVE To further delineate motor activity of the upper gastrointestinal tract in patients with slow-transit constipation. DESIGN A prospective study comparing healthy volunteers with patients with a clinical diagnosis of slow-transit constipation. METHODS Eighteen patients with clinical diagnosis of slow-transit constipation and 10 healthy controls were included in the study. Fasting antroduodenal motility was measured by perfusion manometry for at least one complete cycle of the migrating motor complex or a maximum of 300 min. Oesophageal manometry, gastric emptying and orocaecal transit time measurements were also performed. RESULTS At least one complete cycle of the migrating motor complex was observed in all controls, but in only nine patients (P < 0.01 versus control). The migrating motor complex cycle was incomplete (n = 5) or phase 3 activity was absent (n = 4) in the other patients. The incidence of clustered contractions was significantly increased in slow-transit constipation (P = 0.05 versus controls). The area under the contraction curve during late phase 2 (1509+/-296 mmHg x s) in patients with a complete cycle was significantly smaller than that in controls (2997+/-614 mmHg x s; P = 0.05). Orocaecal transit time was not significantly different among patients and controls, but oesophageal motility was abnormal in five of 18 patients and gastric emptying was abnormal in eight of 15 patients. CONCLUSION Abnormalities of upper gut motility occur frequently in patients with slow-transit constipation. Interdigestive antroduodenal motility is characterized by (i) absence or prolonged duration of the migrating motor complex, (ii) an increased number of clustered contractions, or (iii) a decreased motility during late phase 2 of the migrating motor complex.

Release of peptide YY and inhibition of gastric acid secretion by long-chain and medium-chain triglycerides but not by sucrose polyester in men.

In the present study, we have investigated the effects of intraduodenal perfusion of long‐chain and medium‐chain triglycerides and of sucrose polyester on the release of peptide YY in healthy men.

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.

Basal and Fat-Stimulated Plasma Peptide YY Levels in Celiac Disease

The distal gut hormone peptide YY (PYY) mediates feedback inhibition of gastric acid secretion, gastrointestinal motility, and pancreatic enzyme output. To investigate the influence of maldigestion on PYY, we determined plasma PYY levels in patients with celiac disease under basal conditions and in response to intraduodenal fat. Basal PYY was increased in untreated celiac patients (N = 13) compared to patients on a gluten free diet (N = 9) [15.6 (11.8–27.0) pM vs 12.2 (10.1–13.1) pM; P < 0.05] and compared to control subjects (N = 15) [9.5 (8.3–10.4) pM; P < 0.001]. Integrated PYY in response to intraduodenally infused predigested fat (1071 ± 293 pM 80 min) was significantly (P < 0.05) greater than in response to undigested fat (322 ± 223 pM 80 min) in six untreated celiacs. Plasma concentrations of PYY and cholecystokinin were strongly correlated (r = 0.79; P < 0.001). We conclude that basal PYY levels in untreated celiac disease are elevated, that predigestion of fat enhances PYY release in these patients, and that PYY secretion is correlated with CCK release.