Ursodeoxycholic acid exerts no beneficial effect in patients with symptomatic gallstones awaiting cholecystectomy.

Ursodeoxycholic acid (UDCA) and impaired gallbladder motility purportedly reduce biliary pain and acute cholecystitis in patients with gallstones. However, the effect of UDCA in this setting has not been studied prospectively. This issue is important, as in several countries (including the Netherlands) scheduling problems result in long waiting periods for elective cholecystectomy. We conducted a randomized, double-blind, placebo-controlled trial on effects of UDCA in 177 highly symptomatic patients with gallstones scheduled for cholecystectomy. Patients were stratified for colic number in the preceding year (<3: 32 patients; > or =3: 145 patients). Baseline postprandial gallbladder motility was measured by ultrasound in 126 consenting patients. Twenty-three patients (26%) receiving UDCA and 29 (33%) receiving placebo remained colic-free during the waiting period (89 +/- 4; median [range]: 75[4-365] days) before cholecystectomy (P = .3). Number of colics, non-severe biliary pain, and analgesics intake were comparable. A low number of prior colics was associated with a higher likelihood of remaining colic-free (59% vs. 23%, P < .001), without effects on the risk of complications. In patients evaluated for gallbladder motility, 57% were weak and 43% were strong contractors (minimal gallbladder volume > respectively < or = 6 mL). Likelihood to remain colic-free was comparable in strong and weak contractors (31% vs. 33%). In weak contractors, UDCA decreased likelihood to remain colic-free (21% vs. 47%, P = .02). In the placebo group, 3 preoperative and 2 post-cholecystectomy complications occurred. In contrast, all 4 complications in the UDCA group occurred after cholecystectomy. In conclusion, UDCA does not reduce biliary symptoms in highly symptomatic patients. Early cholecystectomy is warranted in patients with symptomatic gallstones.

Drugs affecting biliary lipid secretion and gallbladder motility: their potential role in gallstone treatment and prevention.

Gallstone disease in the Western world has an estimated prevalence of 10-15% and more than 75% are cholesterol-enriched gallstones. Defective gallbladder motility has been identified as an important pathogenic factor for cholesterol gallstone disease. Various agents may enhance or impair postprandial gallbladder motility, and their effects on interdigestive gallbladder and intestinal motility should also be taken into account. Patients in high-risk situations for gallstone disease, and those chronically treated with drugs inhibiting gallbladder motility (e.g. somatostatin analogues) may benefit from improving gallbladder motility with prokinetic agents. Whether such a strategy can really prevent gallstone formation is still unknown, long-term studies are lacking so far. The efficacy of bile acid therapy with UDCA for gallstone dissolution or for prevention in high risk patients is limited and hampered by high recurrence rates. The efficacy of UDCA in prevention of colics or gallstone related complications in symptomatic patients with gallbladder stones with contraindications for operation or on the waiting list should be explored further, since several retrospective studies showed favourable outcomes with this strategy.

Pharmacological manipulation of biliary water and lipids: potential consequences for prevention of acute biliary pancreatitis.

Acute biliary pancreatitis, caused by macroscopic cholesterol gallstones or microlithiasis, is often a severe disease with considerable morbidity and mortality. Formation of cholesterol gallstones and microlithiasis is caused by cholesterol crystallization from cholesterol supersaturated gallbladder bile. Particularly patients with fast and extensive crystallization, due to highly concentrated bile, low biliary phospholipid contents and gallbladder mucin hypersecretion seem at risk for pancreatitis. Patients who suffered from acute biliary pancreatitis should undergo cholecystectomy as secondary prevention strategy. For patients at high surgical risk, endoscopic sphincterotomy may be an appropriate alternative. Pharmacological manipulation of biliary lipids by the hydrophilic bile salt ursodeoxycholic acid is reserved for patients with recurrent pancreatitis despite previous cholecystectomy or sphincterotomy, or with contraindications to surgical and endoscopic treatment. Maintenance therapy with ursodeoxycholic acid is however a very effective secondary prevention strategy. Potentially, secondary prevention of acute biliary pancreatitis could also be achieved through decreasing biliary mucin contents by UDCA, NSAIDs or N-acetylcystein, or through achieving bile dilution (currently not feasible).

Small gallstones, preserved gallbladder motility, and fast crystallization are associated with pancreatitis.

Acute pancreatitis is a severe complication of gallstones with considerable mortality. We sought to explore the potential risk factors for biliary pancreatitis. We compared postprandial gallbladder motility (via ultrasonography) and, after subsequent cholecystectomy, numbers, sizes, and types of gallstones; gallbladder bile composition; and cholesterol crystallization in 21 gallstone patients with previous pancreatitis and 30 patients with uncomplicated symptomatic gallstones. Gallbladder motility was stronger in pancreatitis patients than in patients with uncomplicated symptomatic gallstones (minimum postprandial gallbladder volumes: 5.8 +/- 1.0 vs. 8.1 +/- 0.7 mL; P = .005). Pancreatitis patients had more often sludge (41% vs. 13%; P = .03) and smaller and more gallstones than patients with symptomatic gallstones (smallest stone diameters: 2 +/- 1 vs. 8 +/- 2 mm; P = .001). Also, crystallization occurred much faster in the bile of pancreatitis patients (1.0 +/- 0.0 vs. 2.5 +/- 0.4 days; P < .001), possibly because of higher mucin concentrations (3.3 +/- 1.9 vs. 0.8 +/- 0.2 mg/mL; P = .04). No significant differences were found in types of gallstones, relative biliary lipid contents, cholesterol saturation indexes, bile salt species composition, phospholipid classes, total protein or immunoglobulin (G, M, and A), haptoglobin, and alpha-1 acid glycoprotein concentrations. In conclusion, patients with small gallbladder stones and/or preserved gallbladder motility are at increased risk of pancreatitis. The potential benefit of prophylactic cholecystectomy in this patient category has yet to be explored.

Effects of hydrophobic and hydrophilic bile salts on gallstone growth and dissolution in model biles.

UNLABELLED: Cholesterol crystallization is a prerequisite for gallstone formation and growth, whereas dissolution of crystallized cholesterol forms the basis of nonsurgical therapy. Crystallization has been studied in detail, but dissolution mechanisms and effects of gallstones are largely unknown. METHODS: We evaluated gallstone growth or dissolution, cholesterol crystallization and lipid distribution into various phases, in model biles with low or intermediate phospholipid contents (crystal-containing left two-phase or central three-phase zones), and with high phospholipid or low cholesterol contents (crystal-free right two-phase or bottom one-phase zones). RESULTS: In model biles with added gallstones plotting in left two-phase and central three-phase zones, gallstone masses increased, whereas crystallization in the aqueous phase was less than without gallstones (P<0.001). In biles plotting in the right two-phase zone, gallstone masses decreased, depending on bile salt hydrophobicity (TUDC>TC>TCDC: P<0.001). In biles plotting in the bottom one-phase zone containing TC or TCDC, gallstone masses increased. In contrast, gallstone masses decreased in case of TUDC with preferential distribution of cholesterol into emerging vesicles. CONCLUSIONS: Our findings suggest competition between gallstone surface and surrounding aqueous phase for precipitation of cholesterol in crystal-containing zones. Different gallstone dissolution mechanisms may exist for TUDC and TCDC.

Smooth muscle function and dysfunction in gallbladder disease.

The gallbladder epithelium and smooth muscle layer are exposed to concentrated biliary solutes, including cholesterol and potentially toxic hydrophobic bile salts, which are able to influence muscle contraction. Physiologically, gallbladder tone is regulated by spontaneous muscle activity, hormones, and neurotransmitters released into the muscle from intrinsic neurons and extrinsic sympathetic nerves. Methods to explore gallbladder smooth muscle function in vitro include cholecystokinin (CCK) receptor-binding studies and contractility studies. In human and animal models, studies have focused on cellular and molecular events in health and disease, and in vitro findings mirror in vivo events. The interplay between contraction and relaxation of the gallbladder muscularis leads in vivo to appropriate gallbladder emptying and refilling during fasting and postprandially. Defective smooth muscle contractility and/or relaxation are found in cholesterol stone-containing gallbladders, featuring a type of gallbladder leiomyopathy; defects of CCKA receptors and signal transduction may coexist with abnormal responses to oxidative stress and inflammatory mediators. Abnormal smooth musculature contractility, impaired gallbladder motility, and increased stasis are key factors in the pathogenesis of cholesterol gallstones.

Micturition is associated with phase III of the interdigestive migrating motor complex in man.

OBJECTIVES: In previous manometric studies, we observed that micturition was associated with phase III of the migrating motor complex. The present study aimed to objectify this possible relationship and to examine whether modulation of micturition frequency influences migrating motor complex phase III incidence. METHODS: In a retrospective study, ambulatory antroduodenal manometry and micturition data of 27 subjects were analyzed. In a prospective study, antroduodenal motility and micturition patterns were studied in five subjects who were subjected to an oral water load. Volunteers were either allowed to micturate ad libitum or instructed to postpone micturition. RESULTS: In the retrospective part of the study, a statistically significant association was found between phase III and micturition. Of all micturitions, 50% took place during or within 10 min from phase III. Also, in the prospective part of the study, phase III and micturition, as well as micturition urge, showed a significant association (p < 0.05). CONCLUSION: Micturition and phase III of the migrating motor complex are associated in time.

Effects of hydrophobic and hydrophilic bile salt mixtures on cholesterol crystallization in model biles.

UNLABELLED: The hydrophilic bile salt ursodeoxycholate is frequently used to dissolve cholesterol gallstones. We have now quantitated crystallization as a function of bile salt hydrophobicity, phospholipid content, cholesterol saturation and total lipid concentration (TLCo). METHODS: Crystallization in supersaturated model biles with low phospholipid contents (left two-phase-micelles and crystal-containing-zone) was assessed during 21 days by microscopy and chemical measurement of crystal mass. For model biles with higher phospholipid contents (central three-phase-micelles, vesicles and crystal-containing-zone), lipid distribution into various phases was determined by combined ultracentrifugation-filtration-dialysis methodology (Biochim. Biophys. Acta 1532 (2001) 15-27). RESULTS: In the left two-phase zone, crystal numbers and masses were highest in case of more hydrophilic bile salt composition (TUDC 100%>TC/TUDC 70%/30%>TC 100%>TC/TDC 70%/30%>TDC 100%) and decreased with increasing phospholipid contents, lower TLCo and lower cholesterol saturation index (CSI). In contrast, in the presence of vesicles (three-phase zone), crystallization decreased at increasing bile salt hydrophilicity, with concomitant increased vesicular cholesterol solubilization. CONCLUSIONS: Presence of vesicular phases is a prerequisite for inhibition of cholesterol crystallization by tauroursodeoxycholate.

Incorporation of cholesterol in sphingomyelin- phosphatidylcholine vesicles has profound effects on detergent-induced phase transitions.

Vesicle <--> micelle transitions are important phenomena during bile formation and intestinal lipid processing. The hepatocyte canalicular membrane outer leaflet contains appreciable amounts of phosphatidylcholine (PC) and sphingomyelin (SM), and both phospholipids are found in the human diet. Dietary SM enrichment inhibits intestinal cholesterol absorption. We therefore studied detergent-induced vesicle --> micelle transitions in SM-PC vesicles. Phase transitions were evaluated by spectrophotometry and cryotransmission electron microscopy (cryo-TEM) after addition of taurocholate (3-7 mM) to SM-PC vesicles (4 mM phospholipid, SM/PC 40%/60%, without or with 1.6 mM cholesterol). After addition of excess (5-7 mM) taurocholate, SM-PC vesicles were more sensitive to micellization than PC vesicles. As shown by sequential cryo-TEM, addition of equimolar (4 mM) taurocholate to SM-PC vesicles induced formation of open vesicles, then (at the absorbance peak) fusion of bilayer fragments into large open structures (around 200 nm diameter) coexisting with some multilamellar or fused vesicles and thread-like micelles and, finally, transformation into an uniform picture with long thread-like micelles. Incorporation of cholesterol in the SM/PC bilayer changed initial vesicular shape from spherical into ellipsoid and profoundly increased detergent resistance. Disk-like micelles and multilamellar vesicles, and then extremely large vesicular structures, were observed by sequential cryo-TEM under these circumstances, with persistently increased absorbance values by spectrophotometry. These findings may be relevant for bile formation and intestinal lipid processing. Inhibition of intestinal cholesterol absorption by dietary SM enrichment may relate to high resistance against bile salt-induced micellization of intestinal lipids in presence of the sphingolipid.

Quantitation of cholesterol crystallization from supersaturated model bile.

Cholesterol crystallization is an essential step in gallstone formation. Although spectrophotometry and nephelometry have been used for quantitation of crystallization, potential effects of crystal size and shape have not been evaluated. We determined crystallization in model biles [total lipid concentration 7.3 g/dl, egg yolk Phosphatidylcholine (EYPC)/(EYPC+taurocholate) molar ratio = 0.05, 0.15, or 0.30; cholesterol saturation index (CSI) = 1.2, 1.7, or 2.0; 37 degrees C] plotting in the central three-phase (micelles, vesicles, and crystals containing) zone or in the left two-phase (micelles and crystals containing) zone of the equilibrium ternary phase diagram. Extent of crystallization estimated by spectrophotometry and nephelometry was related to chemical determination of crystal mass and to crystal size or shape (by microscopy). With all methods, crystallization was less extensive when vesicles were present (central three-phase zone) and at lower CSIs. In the left two-phase zone, particularly at EYPC/(EYPC+taurocholate), ratio of 0.15, there were strong increases in spectrophotometric and nephelometric readings during the first days of incubation, but decreases at later stages, despite progressive increases in crystal mass by chemical measurement. Initially, there were large numbers of very small crystals (<10 microm) in these biles, which were subsequently replaced by large cholesterol monohydrate crystals. Decreasing sizes of harvested cholesterol monohydrate crystals by sonication increased spectrophotometric and nephelometric values despite identical crystal mass. When cholesterol crystal mass is assayed by indirect methods such as spectrophotometry or nephelometry, results are strongly influenced by crystal size.