Gallbladder motor function, plasma cholecystokinin and cholecystokinin receptor of gallbladder in cholesterol stone patients

AIM: To study the interactive relationship of gallbladder motor function, plasma cholecystokinin (CCK) and cholecystokinin A receptor (CCK-R) of gallbladder in patients with cholesterol stone disease. METHODS: Gallbladder motility was studied by ultrasonography in 33 patients with gallbladder stone and 10 health subjects as controls. Plasma CCK concentration was measured by radioimmunoassay in fasting status (CCK-f) and in 30 min after lipid test meal (CCK-30). Radioligand method was employed to analyze the amount and activity of CCK-R from 33 gallstone patients having cholecystectomy and 8 persons without gallstone died of severe trauma as controls. RESULTS: The percentage of cholesterol in the gallstone composition was more than 70%. The cholesterol stone type was indicated for the patients with gallbladder stone in this study. Based on the criterion of gallbladder residual fraction of the control group, 33 gallstone patients were divided into two subgroups, contractor group (14 cases) and non-contractor group (19 cases). The concentration of CCK-30 was significantly higher in non-contractor group than that in both contractor group and control group (55.86±3.86 pmol/L vs 37.85±0.88 pmol/L and 37.95±0.74 pmol/L, P<0.01), but there was no difference between contractor group and control group. Meanwhile no significant difference of the concentration of CCK-f could be observed among three groups. The amount of CCK-R was lower in non-contractor group than those in both control group and contractor group (10.27±0.94 fmol/mg vs 24.59±2.39 fmol/mg and 22.66±0.55 fmol/mg, P<0.01). The activity of CCK-R shown as KD in non-contractor group decreased compared to that in control group and contractor group. Only was the activity of CCK-R lower in contractor group than that in control group. The ejection fraction correlated closely with the amount of CCK-R (r=0.9683, P<0.01), and the concentration of CCK-30 correlated negatively with the amount of CCK-R closely (r=-0.9627, P<0.01). CONCLUSION: The distinctive interactive relationship of gallbladder emptying, plasma CCK and CCK-R in gallbladder from this study suggested that the defect of CCK-R may be a key point leading to the impairment of gallbladder motor function and the pathogenesis of cholesterol gallstone formation may differ in two subgroups of gallstone patient, gallbladder non-contractor group or contractor group.     

Effects of intravenous infusion of amino acids on cholecystokinin release and gallbladder contraction in humans

We investigated the effect of intravenous infusions of the therapeutically available amino acid solutions Moripron and Morihepamin (Roussel Morishita, Osaka, Japan) on gallbladder contraction and cholecystokinin (CCK) release in healthy male volunteers. Plasma CCK levels were measured by radioimmunoassay, using the antibody OAL-656, which is specific for the aminoterminus of CCK-8 and thus recognizes biologically active forms of all CCKs. The volume of the gallbladder was calculated by ultrasonographic measurements. Intravenous infusion of Moripron at the rate of 3.33 ml/min for 60 min, caused gallbladder contraction, with a peak response of 31.3±8.6% of the fasting volume at 45–60 min, and a significant increase in plasma CCK concentration, from 1.8±0.2 pmol/l to a peak of 9.9±1.5 pmol/l, at 30–45 min. The maximum gallbladder contraction and the peak CCK release during the Moripron infusion were not significantly different from findings after a test meal. There was a close relationship between the peak plasma CCK concentration and the maximal gallbladder contraction during the administration of Moripron, and this agent, even when infused at the rate of 1.67 ml/min, significantly increased plasma CCK levels and gallbladder contraction. Intravenous infusion of Morihepamin had no significant influence on gallbladder volume or plasma CCK levels. The discrepancy in responses appeared to be related to differences in composition between Moripron and Morihepamin, and not to the total dose of amino acid. Intravenous infusions of amino acids appear to have different effects on gallbladder contraction and plasma CCK secretion depending on the amino acids composition. Our findings suggest that an intravenous infusion of Moripron could be used for the prophylaxis of acute acalculous cholecystitis and sludge formation due to reduced biliary motility in patients on total parenteral nutrition.     

Gallbladder emptying and somatostatin and cholecystokinin plasma levels in celiac disease

OBJECTIVE: Gallbladder hypomotility in celiac disease has been attributed to decreased cholecystokinin secretion. The possible influence of somatostatin, which inhibits gallbladder motility, however, has never been evaluated. In this study gallbladder emptying and cholecystokinin and somatostatin plasma levels were evaluated in response to a fatty meal in patients with celiac disease at diagnosis and after long-term gluten-free diet and in controls. METHODS: Gallbladder volume and plasma levels of cholecystokinin and somatostatin were measured by ultrasonography and radioimmunoassay, respectively, at 0 time and 30, 60, 75, and 90 min after an oral fatty meal (227 kcal, 45% fat) in 10 celiac patients at diagnosis and after 18 months of successful gluten-free diet and in 10 healthy subjects. The pattern of gallbladder emptying was evaluated by mixed factorial analysis of variance and the curve fitting by multiple regression analysis. RESULTS: Patients at diagnosis had significantly greater fasting gallbladder volume and higher somatostatin plasma levels than controls (25.7 +/- SD 9.7 ml vs 16.8 +/- 7.0 ml, p = 0.021 and 9.3 +/- 4.6 vs 4.8 +/- 3.4 pmol/L, p = 0.023, respectively), significantly lower fatty meal-induced gallbladder ejection fraction (55 +/- 11.2% vs 76 +/- 7.2%, p = 0.005), and cholecystokinin peak and smaller area under the cholecystokinin secretion curve (3.1 +/- 2.3 pmol/L vs 10.5 +/- 6.9 pmol/L, p = 0.028 and 157 +/- 142 pmol/L/90 min vs 453 +/- 229 pmol/L/90 min, p = 0.028, respectively). The two groups had a similar emptying pattern (p = 0.8913) expressed by a significant quadratic term of the emptying function (p = 0.0001). The mean overall emptying volume was significantly greater in patients than in controls (p = 0.0007). Gluten-free diet normalized these findings. CONCLUSIONS: In patients at diagnosis, elevated somatostatin levels were associated with increased gallbladder fasting volume, whereas decreased cholecystokinin secretion was responsible for the reduced gallbladder emptying. Gluten-free diet reversed these abnormalities.     

Localization of cholecystokinin-like immunoreactivity in isolated nerve terminals.

Subcellular fractionation of the rat cerebral cortex demonstrated the presence of immunoreactive cholecystokinin in the pellet identified by electron microscopy as containing a high proportion of synaptic vesicles. The recovery in this pellet of 40% of the total immunoreactivity in the initial cortical extract is quite comparable to the recovery of other peptides such as vasoactive intestinal polypeptide and somatostatin, which are also located in synaptosomes and for which roles as neuroregulators or transmitters have been suggested. The evidence of concentration of cholecystokinin-like peptides in the synaptosomal pellet is consistent with our earlier demonstration by immunohistochemical techniques of cholecystokinin's presence in rabbit cerebral cortical neurons. These observations and the evidence for diminished concentration of cholecystokinin-like peptides in the brains of hyperphagic mice are consistent with cholecystolinin's suggested role as a neuroregulator for appetite.     

Effect of predigested fat on intestinal stimulation of plasma cholecystokinin and gall bladder motility in coeliac disease.

Cholecystokinin (CCK) release and gall bladder emptying in response to a fatty meal are completely abolished in coeliac disease. To determine the effect of lipid digestion on CCK release and gall bladder motility, six patients with untreated coeliac disease and a flat jejunal mucosa were studied on two separate days. After an overnight fast, the plasma CCK concentration and gall bladder volume were measured before and at regular intervals after the intraduodenal instillation of 60 ml corn oil (triglycerides) incubated with 40 ml saline or with 40 ml bile and pancreatic juice. The mean (SEM) concentration of free fatty acids in the aqueous phase of corn oil after incubation with bile and pancreatic juice (predigested corn oil) was 78 (35) mM compared with 0.1 (0.1) mM in the aqueous phase of corn oil incubated with saline (undigested corn oil). Integrated plasma CCK in response to predigested corn oil was significantly greater than that in response to undigested corn oil (101 (18) pM. 80 min v-2 (9) pM.80 min; p < 0.005). Similarly, integrated gall bladder contraction in response to predigested corn oil was significantly larger than that after undigested corn oil (817 (210) ml. 80 min v-225 (243) ml. 80 min; p < 0.05). In contrast to undigested corn oil, corn oil that has been predigested with bile and pancreatic juice induces plasma CCK secretion and gall bladder contraction in patients with untreated coeliac disease, presumably by generating and rendering soluble lipolytic products.     

Changes in N-terminal glucagon-like immunoreactivity and insulin during short-term gluten challenge in childhood coeliac disease.

Sixteen patients (aged 3.5-14.3 years) with normal jejunal mucosa, originally diagnosed as having coeliac disease at least 18 months before, were started on gluten challenge. The 'end point' of challenge was significant deterioration in jejunal mucosa morphologically and morphometrically. Studies carried out both before and after challenge included intestinal absorption of D-xylose and glucose, and release of insulin and N-terminal glucagon-like immunoreactivity (N-GLI). After gluten challenge, there were significant increases in plasma N-GLI at both 45 (P less than 0.05) and 120 minutes (P less than 0.03) after oral glucose. Significant reduction occurred in glucose absorption at 45 minutes (P less than 0.04), in one-hour D-xylose absorption (P less than 0.01) and fasting serum cholesterol (P less than 0.01). Plasma N-GLI showed significant negative correlations with D-xylose absorption (P less than 0.003) and serum cholesterol (P less than 0.004).     

Gallbladder emptying in response to cholecystokinin. A cholescintigraphic study.

The threshold and dynamics of gallbladder emptying in human subjects in response to cholecystokinin (Pancreozymin, Boots Co. Ltd) were defined by radionuclide imaging with a gamma camera. The radiopharmaceutical employed, 99mTc-HIDA, was taken up rapidly by the liver and efficiently excreted into the biliary system so that gallbladder filling was easily distinguishable from negligible background activity. Counts were recorded continuously on magnetic tape during i.v. infusion of sequentially increasing doses of cholecystokinin: Each dose level was maintained for 15 min. At later playback, the area of interest was adjusted to include only the gallbladder and to exclude radioactivity present in the gut during gallbladder emptying. In 19 normal subjects (10 male and 9 female), a threshold dose of cholecystokin was identified for gallbladder contraction: 0.010 Crick-Harper-Raper units/kg-min in 16 subjects, and 0.020 Crick-Harper-Raper units/kg-min in the remaining 3. The rate of emptying appeared smooth and linear at each dose level: Doubling the dose of cholecystokinin in every case significantly increased the emptying rate. There appeared to be no effect of increasing age on emptying more rapidly than females, but the difference was not significant. This cholescintigraphic technique would appear to offer a simple, accurate, yet noninvasive method for continuously monitoring the events during gallbladder contraction in humans.     

Pathogenesis of the impaired gall bladder contraction of coeliac disease.

We have investigated the possibility that the abnormally decreased gall bladder contraction after meals in patients with coeliac disease might result in part from an abnormality in the gall bladder response to endogenous cholecystokinetic hormones--for example, cholecystokinin and motilin--rather than solely from decreased secretion of such hormones. Eight patients with untreated coeliac disease and nine controls received intravenous infusions of the pure synthetic cholecystokinin analogue caerulein, 2-16 ng/kg/hour. Gall bladder emptying was measured on a minute-by-minute basis using 99mTc-HIDA scans. In the patients with coeliac disease, gall bladder emptying was greatly decreased (34.6 +/- 9.9 v 61.5 +/- 7.5% at 60 minutes, p less than 0.02), and a much greater dose of caerulein was needed to initiate gall bladder contraction (3.80 +/- 1.08 v 1.49 +/- 0.56 ng/kg, p less than 0.02). These results suggest that the abnormal gall bladder contraction in coeliac disease is not simply because of impaired release of cholecystokinin. Although mechanical factors secondary to the increased gall bladder size in patients with coeliac disease might to some extent account for the findings, the alternative explanation is that the gall bladder muscle is for some reason resistant to the action of cholecystokinetic agents. A similar phenomenon affecting the pancreas might contribute to the abnormally decreased pancreatic secretion found in coeliac disease.     

Role of cholecystokinin and the cholinergic system in intestinal stimulation of gallbladder contraction in man

To determine the role of cholecystokinin and the cholinergic system in intestinal stimulation of gallbladder contraction, we studied the effects of atropine on plasma cholecystokinin and gallbladder contraction in six healthy volunteers (four men and two women aged 20 to 27 yr). Effects were noted after intraduodenal fat instillation and after dosage with exogenous cholecystokinin inducing plasma cholecystokinin concentrations similar to those after intraduodenal fat instillation. At regular intervals before and after administration of each stimulus, plasma cholecystokinin concentrations and gallbladder volumes were measured by radioimmunoassay and real-time ultrasonography, respectively. Intraduodenal infusion of 250 ml 20% Intralipid induced a peak plasma cholecystokinin increment of 10.2 +/- 1.6 pmol/L compared with 10.7 +/- 0.7 pmol/L during infusion of 1 Ivy dog unit per kilogram per hour of cholecystokinin. The increases in plasma cholecystokinin after fat and exogenous cholecystokinin administration were accompanied by similar decreases in gallbladder volume. Integrated gallbladder contraction after fat instillation was 3,939% +/- 288%.min compared with 3,301% +/- 359%.min during cholecystokinin infusion (NS). Atropine (0.015 mg/kg as bolus followed by 0.005 mg/kg/hr) did not change plasma cholecystokinin concentrations but induced similar inhibition of gallbladder contraction to 2,296% +/- 511%.min (p less than 0.05) after intraduodenal fat instillation and to 1,756% +/- 456%.min (p less than 0.05) during cholecystokinin infusion. We conclude that cholecystokinin is of major importance in intestinal stimulation of gallbladder contraction. Atropine inhibits the gallbladder response to intraduodenal fat. This inhibition is not due to a reduction in cholecystokinin secretion but to a diminished gallbladder response to cholecystokinin.     

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.     

Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease.

The functional integrity of the small bowel is impaired in coeliac disease. Intestinal permeability, as measured by the sugar absorption test probably reflects this phenomenon. In the sugar absorption test a solution of lactulose and mannitol was given to the fasting patient and the lactulose/mannitol ratio measured in urine collected over a period of five hours. The sugar absorption test was performed in nine patients with coeliac disease with an abnormal jejunum on histological examination, 10 relatives of patients with coeliac disease with aspecific symptoms but no villous atrophy, six patients with aspecific gastrointestinal symptoms but no villous atrophy, and 22 healthy controls to determine whether functional integrity is different in these groups. The lactulose/mannitol ratio (mean (SEM) is significantly higher in both coeliac disease (0.243 (0.034), p < 0.0001)) and relatives of patients with coeliac disease (0.158 (0.040), p < 0.005)) v both healthy controls (0.043 (0.006)) and patients with aspecific gastrointestinal symptoms (0.040 (0.011)). The lactulose/mannitol ratio in relatives of coeliac disease patients was significantly lower than in the coeliac disease patient group (p = 0.04). The lactulose/mannitol ratio was the same in healthy controls and patients with aspecific gastrointestinal symptoms. It is concluded that the sugar absorption test is a sensitive test that distinguishes between patients with coeliac disease and healthy controls. The explanation for the increased permeability in relatives of patients with coeliac disease is uncertain. Increased intestinal permeability may be related to constitutional factors in people susceptible to coeliac disease and may detect latent coeliac disease. The sugar absorption test may therefore be helpful in family studies of coeliac disease.     

Coeliac disease autoantibodies in seminal plasma from cases with screen-detected coeliac disease

Morphological changes in the remnant mucosa 2–20 years after operation for duodenal ulcer (DU) were analyzed in 124 male subjects by means of stochastic mathematics. Fifty non-operated male DU patients and 168 age-matched males from a population sample served as controls. Substantially no progression of gastritis was found in the DU patients. In contrast, the operative intervention caused a rapid initial progression of gastritis, continuing after 2 years approximately at the same speed as in the population at large.     

Defective gallbladder emptying and cholecystokinin release in celiac disease. Reversal by gluten-free diet

Normal volunteers (n = 6), patients with untreated celiac disease and subtotal villous atrophy (n = 6), patients with nonresponsive celiac disease (n = 2), and patients with celiac disease on a gluten-free diet with a virtually normal biopsy specimen (n = 6) drank a liquid fat meal after an overnight fast. Gallbladder emptying was monitored by using 99mTc-eHIDA, and blood samples were taken for cholecystokinin estimation by radioimmunoassay after high-performance liquid chromatography. The half-times of gallbladder emptying were 20.4 +/- 2.9 min (mean +/- SEM) for normals and 22.1 +/- 2.8 min in treated patients with celiac disease (NS). In patients with untreated celiac disease half-times were 154.3 +/- 10.3 min (p less than 0.02 vs. normals and treated patients with celiac disease), and in 2 nonresponsive patients, half-times were 40.7 and 37.3 min. Integrated plasma cholecystokinin responses were 473 +/- 87 and 436 +/- 137 pmol X L-1 X 30 min-1 in normals and treated patients with celiac disease (NS). In untreated patients with celiac disease values were 16 +/- 9 pmol X L-1 X 30 min-1 (p less than 0.001 vs. normals and treated patients with celiac disease), and in nonresponsive patients values were 442 and 322 pmol X L-1 X 30 min-1. In 2 patients studied before and during gluten-free diet half-times for gallbladder emptying changed from 168.9 and 302.4 min to 20.1 and 23.4 min, and cholecystokinin responses changed from 0 and 45 to 623 and 298 pmol X L-1 X 30 min-1. Cholecystokinin immunoreactivity cochromatographing with cholecystokinin-octapeptide was responsible for 50%-60% of circulating cholecystokinin in normals and in treated patients but the small amount of cholecystokinin that was released in untreated patients with celiac disease cochromatographed with cholecystokinin-33/39. We conclude that there is a reversible defect of gallbladder emptying and cholecystokinin release in celiac disease.     

Increased levels of plasma 5-hydroxytryptamine in patients with coeliac disease

In 17 patients with coeliac disease the 5-hydroxytryptamine (5-HT) concentration was measured in platelet-poor plasma (PPP) and in whole blood and compared with that of a control group of 30 healthy persons. The 5-HT level was determined by high-pressure liquid chromatography and electrochemical detection. In patients with coeliac disease the concentration of 5-HT in whole blood was elevated compared with the control group (p less than 0.001). The 5-HT level in PPP was significantly increased in patients with coeliac disease in whom the disease was untreated or treated with gluten-free diet for less than a year (p less than 0.01) but also compared with the patients with coeliac disease treated with a gluten-free diet for more than a year (p less than 0.01). In some untreated patients with newly diagnosed disease the 5-HT levels in PPP were markedly elevated and exceeded the levels ordinarily found in PPP in patients with carcinoid tumours. In these patients with coeliac disease the 5-HT concentration in PPP was reduced when the enteropathy was healed. There was no significant correlation between the 5-HT concentration in PPP versus whole blood in the different groups.     

Expression profile of cholecystokinin type-A receptor in gallbladder cancer and gallstone disease

BACKGROUND:Regulatory peptide receptors have attracted the interest of oncologists as a new promising approach for cancer pathology,imaging and therapy.Although cholecystokinin (CCK) is a potent modulator of gallbladder contractility and plays a potential role in pancreatic carcinogenesis through CCK type-A receptor (CCKAR),its role in gallbladder cancer (GBC) is still unknown and immunohistochemical detection of CCKAR in the gallbladder has not yet been reported.This novel case-control study aimed to inves...     

Comparison of intravenous and intramuscular sincalide (C-terminal octapeptide of cholecystokinin) on gallbladder contraction in man

The effects of intramuscular and intravenous sincalide on gallbladder contraction and visualization of the bile ducts were compared in a group of 37 subjects referred for oral cholecystography. The maximum reduction in gallbladder size observed after sincalide 400 ng/kg intramuscular, 54.7±7.2% (mean ±SEM), occurred 25 min after injection and was significantly greater than that observed after sincalide 20 ng/kg intravenous, 26.5±8.2%. Maximum reduction after sincalide 100 ng/kg intramuscular was 47.3±8.2%. The common bile duct was visualized in 60 and 45% of subjects after intramuscular and intravenous sincalide, respectively. The use of intramuscular sincalide 400 ng/kg intramuscular is an effective and convenient adjunct to oral cholecystography when significant gallbladder contraction and visualization of the common bile duct is desired.     

Increased plasma levels of peptide YY in coeliac disease

Peptide YY (PYY) is exclusively localized in endocrine cells in the gut, and these cells are most numerous in the distal small intestine, colon, and rectum. We have earlier shown that PYY coexists with enteroglucagon in the gut endocrine cells. High basal and postprandial plasma enteroglucagon concentrations have earlier been found in patients with untreated coeliac disease. PYY circulates in human plasma and is detectable in most healthy adults. We have therefore studied the basal PYY levels in patients with coeliac disease. Marked elevated basal plasma PYY levels were found in patients with coeliac disease compared with an age- and sex-matched control group. The PYY levels were inversely correlated to the concentration of folate acid in serum. The PYY levels were studied in four patients with newly diagnosed disease and had normalized within 8 months on a gluten-free diet.     

Increases in plasma ouabainlike immunoreactivity during surgical extirpation of pheochromocytoma.

The ouabainlike factor (OLF) is thought to be an important modulator of salt and water metabolism. Plasma OLF could be derived from the central nervous system and/or the adrenal gland. Since the adrenal medulla is of neural origin, the cytology of pheochromocytoma of adrenomedullary origin resembles that of neuronal cells. Ouabainlike immunoreactivity (OLI) is, in fact, present in the adrenal medulla as shown by immunohistochemistry. The plasma levels of catecholamines and OLI were significantly elevated during surgical extirpation of pheochromocytoma in this case. To clarify the origin of circulating OLI in a patient with pheochromocytoma, the relationship between plasma OLI and catecholamines during adrenalectomy was investigated. Plasma catecholamine levels exceeded the normal reference interval, and plasma OLI was positively correlated with the patient's plasma level of norepinephrine. The peak level during operation was about 10 times higher than the baseline level. Both levels reached a maximum when the tumor was mechanically pressed, and then gradually decreased thereafter. The level of OLI in the tumor was higher than that of the normal adrenal cortex. When OLI in the tumor was characterized by reversed-phase high-performance liquid chromatography, the retention time of OLI corresponded with that of authentic ouabain. These results suggest that the circulating OLI in this patients was derived mainly from the pheochromocytoma of adrenomedullary origin.     

Susceptibility to tuberculosis in patients with coeliac disease

An increased prevalence of past tuberculosis is reported in an adult coeliac population. Of 76 adult coeliac disease patients, 6 had had a history of tuberculosis. This compared with the finding of no cases in a population of 81 patients with non-inflammatory bowel diseases, (p = 0.023), which was matched for age, sex, smoking, ethnic origin and social class. The 'expected' number of cases of tuberculosis amongst ACD patients has also been calculated based on local annual notification rates; this was 2.9. Radiological evidence of past tuberculosis was found in 13 (17%) ACD patients, compared with 4 (5%) control patients (p less than 0.05). It is postulated that the increased prevalence of past tuberculosis in ACD patients is the result of depressed cell mediated immunity and/or malnutrition.