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Background: Accelerated nucleation, supersaturation of bile, and biliary stasis are known to be key factors in cholesterol gallstone formation. The mechanisms through which these factors interact to form stones are still incompletely understood. Among the proteins now known to be present in bile are several components of the fibrinolytic system: tissue plasminogen activator, urokinase-like plasminogen activator, and plasminogen activator inhibitors 1 and 2. The concentrations of plasminogen activator inhibitors 1 and 2 in gallbladder bile are increased in patients with gallstones. The aim of this study was to determine whether these fibrinolytic system proteins act as pro-nucleating agents for cholesterol gallstone formation., Methods: Nucleation assays were done on gallbladder bile from eight cholesterol stone patients and eight control patients. The effects of tissue plasminogen activator, urokinase-like plasminogen activator, and plasminogen activator inhibitors I and 2 on cholesterol crystal appearance time (CCAT) were tested, by direct observation using polarizing microscopy, after measurement of biliary lipids and calculation of cholesterol saturation indices., Results: There was no significant difference in cholesterol saturation indices between bile that nucleated and bile that did not (mean, 2.0 +/- 1.5 versus 1.8 +/- 0.5). When all samples in which nucleation occurred were compared, tissue plasminogen activator significantly shortened CCAT median from 4.75 days (range, 2-21) to 3.5 days (2.5-18) (P < 0.05). This was similar to the effect of fibronectin (3.75 days; range, 2-20), a known pro-nucleator used as a nucleation accelerating control (P < 0.05). None of the other fibrinolytic system proteins significantly accelerated CCAT., Conclusions: The results of this study suggest that tissue plasminogen activator may act as a pro-nucleating agent for cholesterol gallstone formation in gallbladder bile.

Background: This study sought to determine whether there is a positive correlation between gallbladder emptying, biliary pain, and in vitro contractility., Methods: Ultrasound measurements were carried out on 25 gallstone patients. The response of gallbladder strips to 1.75*10(-11) to 5.25*10(-7) M cholecystokinin-8 was recorded. In a second study 23 patients filled in pain questionnaires, and in vitro studies were again carried out., Results: Of five patients with no gallbladder emptying, four had in vitro contraction. Overall, a significant, positive linear correlation was found (P < 0.0001). In the second study in vitro contractility showed a positive linear correlation with pain., Conclusion: Gallbladder emptying correlates with contractility. However, since most 'non-contractors' can contract, we suggest the term 'non-emptying' or 'emptying' to describe gallbladder dynamics. The positive correlation between pain and contractility suggests that biliary pain has a muscular component.

To investigate the effects of cholecystectomy on gastric motor function, 13 patients with symptomatic gallstones were studied before and 8-12 months after surgery. Twelve healthy subjects entered the study as control group. The cutaneous electrogastrography and ultrasound examination of gastric emptying were simultaneously performed at pre- and post-prandial states. The dominant gastric frequency and its coefficient of variation were not affected by surgery. After cholecystectomy, an increase in normal 3 cpm wave percentage and a decrease in power ratio were found (P < 0.05 and P < 0.01, respectively). Gastric emptying recorded after cholecystectomy was faster than before surgery (306.9 +/- 15.9 min vs 336.9 +/- 11.8 min, respectively; P < 0.05). Such changes were associated with the relief of symptoms, and the comparison between patients and controls showed a normalization of the gastric electrical activity and gastric emptying after surgery. In conclusion, in symptomatic patients, gallstones are associated with motor dysfunctions, and cholecystectomy seems to induce a normalization of gastrointestinal motility.

The primum movens in cholesterol gallstone formation is hepatic cholesterol hypersecretion and chronic supersaturation of bile. A cascade of events will then include: (i) multiple biochemical defects: increased total biliary proteins (and qualitative shift to cholesterol crystallization-promoting factors), increased proportions of hydrophobic bile salts, increased mucin secretion, and rapid nucleation/crystallization of cholesterol from cholesterol-enriched biliary vesicles; (ii) multiple motility defects: impaired gallbladder contractility in vitro and gallbladder stasis in vivo, delayed intestinal transit. A genetic predisposition (together with environmental factors) might also be important. Therapy should be offered to patients with symptomatic gallstones. Cholecystectomy remains the only radical therapy for cholelithiasis. For a subgroup of patients with symptomatic, uncomplicated cholesterol stones who are unwilling to undergo surgery, or who have a significant surgical risk, alternative non-invasive therapies include: (i) oral litholysis of small stones by bile salts, (ii) fragmentation of 1-3 medium-sized stones by extracorporeal shock-wave lithotripsy, and (iii) topical dissolution of multiple stones by methyl tertbutyl ether. A major disadvantage of all non-surgical therapies, however, is the 50% recurrence rate of stones at 5 years. A number of prokinetic agents can improve gallbladder and/or intestine transit, two important contributing factors in gallstone disease. In selected patients, administration of these agents might enhance the clearance of cholesterol crystals/gallstones or might impede/delay gallstone formation and recurrence.

Background: In contrast to earlier beliefs, it is nowadays assumed that no relation exists between dyspeptic symptoms and the presence of gallstones. Although many studies indeed failed to show a relation, each has been too small to exclude it. The aim of this meta-analysis is to systematically review epidemiologic studies and to synthesize the data., Methods: Twenty-one controlled studies on the association between gallstones and dyspeptic symptoms were analyzed after critical appraisal with regard to selection bias, blinding, confounding, and data presentation. Most of them had reasonable validity. Inconsistencies between results of the studies could not be explained by differences in study design or validity. There was a slight indication of publication bias., Results: Upper abdominal pain was consistently associated with gallstones (pooled odds ratios, about 2.0), with no preference for the right side. The findings on biliary pain were inconsistent. The results exclude with reasonable certainty an association between gallstones and 'classical' dyspeptic symptoms such as flatulence, heartburn, and acid regurgitation, bloating, and belching. An exception was nausea and vomiting (odds ratio, 1.4). Unspecified food intolerance was related to gallstones, but fat intolerance was not., Conclusions: We conclude that it is not sensible to call dyspeptic symptoms 'gallstone dyspepsia', since component symptoms do not show a consistent relation with gallstones, and their diagnostic meaning over and above abdominal pain has not been evaluated.

Background: Risk factors for gallstones are not fully understood, especially in men. Obesity and other risk factors for gallstone disease were investigated in Japanese men based on gallbladder ultrasonography., Methods: Forty-one men with gallstones, 31 with postcholecystectomy state, and 2044 with a normal gallbladder were identified among 2228 men aged 49-55 years who received a retirement health examination at three hospitals of the Japan Self-Defense Forces between 1991 and 1992. Glucose tolerance was determined with a 75-g oral glucose tolerance test., Results: Body mass index was not associated with gallstones, although it was significantly, positively related to postcholecystectomy. Waist to hip circumference ratio tended to be weakly associated with gallstones. Diabetes mellitus was associated only with postcholecystectomy. Smoking, alcohol intake, and physical activity were not measurably related to either gallstones or postcholecystectomy., Conclusions: The present study failed to substantiate an association of gallstone risk with either obesity or any other risk factor. Further observation is needed in view of the limited study power.

Background: Impaired gallbladder emptying is a pathogenetic factor in gallstone formation. To test whether gallbladder motility can be improved by high-dose cholecystokinin (CCK), gallbladder emptying was measured sonographically in 21 patients with cholesterol gallstone disease and 6 healthy controls., Methods: The effects of CCK infusions of 0.06 IDU/kg.min (group A, n = 11) and 0.12 IDU/kg.min (group B, n = 10) were compared with the response to a standard CCK infusion (0.02 IDU/kg.min). Controls received CCK at all infusion rates., Results: The ejection fraction was smaller after CCK infusion of 0.06 IDU/kg.min than after the standard stimulus (group A, 52 +/- 10 versus 64 +/- 10%, p < 0.05; controls, 66 +/- 10 versus 91 +/- 3%, p < 0.05). After infusion of 0.12 IDU/kg.min CCK ejection fractions decreased even more (group B, 44 +/- 16 versus 65 +/- 12%, p < 0.05; controls, 54 +/- 12 versus 91 +/- 3%, p < 0.05). High-dose CCK infusions shortened the ejection period markedly, whereas the ejection rate remained unaltered., Conclusions: High-dose CCK does not improve gallbladder motility but blocks the ejection process early, leading to reduced gallbladder emptying in gallstone patients and healthy subjects.

Cholelithiasis affects 10-15% of the adult population in Western society, and about 75% of gallstones are of cholesterol type. Hepatic hypersecretion of cholesterol with the formation of instable cholesterol-rich vesicles in bile, an imbalance between nucleation-inhibiting and nucleation-promoting proteins with further aggregation of cholesterol crystals in a gallbladder with a motility defect (stasis), all play a role in the pathogenesis of cholesterol gallstones. Experimental animal models suggest that gallstone formation can be prevented by improving gallbladder emptying. Thus, a better understanding of the causes underlying the impaired gallbladder motor function in patients with gallstones might lead to the selection of therapeutic approaches for those individuals who are at increased risk for the formation or recurrence of gallstones. The present article focuses on current concepts and theories on the pathogenesis of cholesterol gallstones with emphasis on the gallbladder motility defect. Several treatment strategies for the correction of gallbladder hypomotility are also discussed.

Recent advances in our understanding of the natural history of gallstones and the introduction of new treatment options have dramatically altered the approach to gallstone management. Most patients with cholelithiasis are asymptomatic, and for them, expectant management is now recommended by many authorities. This approach may also be acceptable for some patients who have only occasional episodes of biliary colic. Laparoscopic cholecystectomy is preferred for patients who have had repeated episodes of biliary colic or acute cholecystitis and who are suitable operative candidates. Nonsurgical options include oral dissolution therapy with bile acids, extracorporeal shock wave lithotripsy, and contact dissolution with methyl tert-butyl ether. Each has significant limitations but may be considered for selected patients with symptomatic gallstones who are not candidates for general anesthesia or who refuse surgery. Future improvements in nonsurgical therapies may ultimately expand their use.

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.

Formation of a fistula between the gallbladder and bowel may allow a gallstone to enter the intestinal tract. In the two cases described here, the colon was involved. The authors describe diagnosis and management of these cases and make treatment recommendations based on their experience.

Octreotide is increasingly being used in the treatment of acromegaly. It effectively suppresses growth hormone secretion but also has inhibitory effects on gastrointestinal regulatory peptides and induces gallbladder paresis, which may predispose to gallstone formation. In nine acromegalic patients receiving long-term octreotide treatment gallbladder emptying, assessed by 99Tc-EHIDA scintigraphy after a standard fatty meal, was significantly impaired (p less than 0.005) when compared with normal healthy control subjects. Asymptomatic gallstone formation occurred in one patient who had the most severely impaired gallbladder emptying. Between 24 and 96 h after cessation of octreotide, in six of seven patients studied, gallbladder emptying had not only recovered but demonstrated significant rebound hypermotility (p less than 0.005). This finding has important implications for the administration of long-term octreotide therapy and suggests that a drug-free period each week may enable evacuation of gallbladder contents and reduce the risk of gallstone formation.

In seven patients operated on with cholecystectomy for simple gallstones, sphincter of Oddi manometry was performed during surgery. The sphincter was localized as a zone with elevated base-line pressure and phasic contractile activity. Mean value of the amplitude was 90 mm Hg; wave duration, 4 sec; frequency, 5/min; and base-line pressure, 10 mm Hg. No activity was seen in the antrum or duodenum. The plotting of peak-to-peak intervals in a histogram showed that these were evenly distributed around 6 sec or at integrated multiples of this value. This indicates that the sphincter of Oddi is paced. The origin of the pacing is not yet established.

Antral distension in seven healthy subjects had the same inhibitory effect, approximately 20% inhibition, on gastric acid secretion stimulated by pentagastrin and betazole (Histalog). The plasma concentration of neurotensin in peripheral venous blood was unchanged during antral distension in healthy subjects. The plasma concentration of neurotensin in portal blood was also unchanged during antral distension in anaesthetized duodenal ulcer patients and in non-ulcer patients. The inhibition of pentagastrin-stimulated gastric acid secretion by balloon distension of the antrum was unchanged by preceding intramuscular injection of metoclopramide. The inhibitory effect of antral distension on gastric acid secretion in healthy subjects does not seem to be mediated by secretin, cholecystokinin, bulbogastrone, neurotensin, or a dopaminergic mechanism.

Electrical spike potentials and intrauminal pressure variations were recorded from the human duodenum and distal ileum before and after i.v. administration of 80 log Ivy units of cholecystokinin. In the duodenum, quantitative calculations of motility gave identical values before and after drug administration, and results were identical in patients before and after cholecystectomy as well as in hernia patients without upper gastrointestinal disease. A decrease in amplitude of the spike potentials was observed in the duodenum during the first few minutes after drug administration in all groups. Recordings from the distal ileum in ileostomy patients showed a significant increase in motility after CCK administration whereas the spike potential amplitude was unchanged.

It has earlier been suggested that cholecystectomy, by eliminating the reservoir function of the gallbladder, will induce reflux of bile to the stomach. In the present study 23 patients were studied for duodenogastric reflux of bile acid before and 3 months after cholecystectomy. At the test the gastric contents were continuously aspirated via a nasogastric tube, collected at 15-min intervals for 2 h in the fasting patient, and analyzed for volume and bile acid concentration. The results were compared with those in 14 control subjects. Significant duodenogastric reflux of bile acid (greater than 100 mumol/h) was seen more frequently in gallstone patients than in controls. This is explained by a high prevalence of bile acid reflux in patients with a reduced or absent opacification of the gallbladder at cholecystography. Cholecystectomy increased the prevalence of bile acid reflux in the patients with well-opacified gallbladders at cholecystography. The duodenogastric reflux of bile acid in patients with a poor filling of the gallbladder at cholecystography was not further enhanced by cholecystectomy. It is concluded that gallstone patients have an increased tendency to duodenogastric reflux of bile acid. This tendency is further enhanced by removal of a functioning gallbladder. The findings may explain some of the symptoms in patients with gallstones. The reflux may also be responsible for symptoms in the so-called postcholecystectomy syndrome.

The papillary function of cholelithiasis patients with and without juxtapapillary duodenal diverticulum (JPDD) was examined manometrically. The papillary function was evaluated on the basis of dP(0.5), the pressure difference between the resting pressure and the perfusion pressure. Patients with a dP(0.5) less than 5 cm H2O were considered to have papillary dysfunction. In cholecystolithiasis patients the incidence of papillary dysfunction was significantly greater in those with JPDD than in those without JPDD (p less than 0.05). However, there was no significant difference in dP(0.5) between those with and without JDPP because of the small number of patients involved. Also, in patients with choledocholithiasis there was no difference in the papillary function between those with and without JPDD. All who had JPDD showed papillary dysfunction. From our results, JPDD is suspected to have an important role in causing papillary dysfunction or loss of papillary muscle tone. This dysfunction may be closely connected with the formation of common bile duct stones.