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The pathogenesis of cholesterol gallstones is now recognized as a multifactorial process, including saturation of bile with cholesterol, destabilization of bile leading to cholesterol crystals and hypomotility permitting crystal growth, and agglomeration and retention of microstones which then grow to macroscopic gallstones. In the last 15 years meticulous research has demonstrated convincing evidence that many patients with cholesterol gallstone disease have a distinct defect in gall-bladder motor function that is induced by bile saturated with cholesterol.

Efficient fragmentation is the most important prerequisite for successful treatment of gallstones by extracorporeally induced shock waves. No data are available on the amount of energy necessary for stone disintegration and on the threshold energy below which no further fragmentation occurs. We therefore performed an in vitro investigation on human cholesterol gallstones to elucidate physical laws governing shock-wave lithotripsy. First, the focal pressure of the lithotripter was measured to calculate the energy traversing a stone. Second, 96 gallstones from 16 gall bladders were analysed with respect to physicochemical composition, radiological features and ultrasound before fragmentation was performed. Energy for stone disintegration was constant within each stone family but varied between 4.6 mL-1 and 36.8J mL-1 in different families. This energy correlated linearly with stone volume. None of the radiological and physicochemical factors revealed a clear-cut correlation of the different energies necessary for similar stone disintegration. The threshold energy differed between 0.26 mJ and 1.04 mJ per pulse. In conclusion, stone volume was the best parameter predicting stone fragmentation. However, in cholesterol stones with a similar composition the required energy per volume varies considerably together with the threshold energy. Radiological and ultrasound parameters appear to be of minor importance in explaining these differences.

Background & Aims: Excessive deoxycholic acid (DCA) in the bile acid pool with cholesterol supersaturation of bile is prevalent in patients with cholesterol gallstones (CGs). This study examined whether this is caused by enhanced conversion of cholic acid (CA) to DCA by intestinal bacteria., Methods: Ten patients with CGs with DCA excess (DCA/CA pool ratio, > 1.5) and 10 patients with low DCA (ratio, < 1.0) were compared for CA and DCA kinetics, ileal absorption of 75-Se-homotaurocholic acid (75-SeHCAT), and CA-7 alpha-dehydroxylation activity of the fecal microflora; the effects of ampicillin treatment on DCA excess were studied in 7 patients., Results: Patients with DCA excess and low DCA differed (P < 0.01) in the pool size of CA (mean, 5.8 vs. 34) and DCA (28 vs. 11 mumol/kg) and DCA input (8.8 vs. 3.5 mumol.kg-1.day-1. Whereas 75-SeHCAT excretion was similar, CA-7 alpha-dehydroxylation activity and levels of fecal 7 alpha-dehydroxylation bacteria were 3-fold and 1000-fold higher (P < 0.01) in patients with DCA excess, respectively. Ampicillin treatment decreased (P < 0.02) CA-7 alpha-dehydroxylation activity and DCA pool size, expanded the CA pool to normal size, and lowered cholesterol saturation of bile., Conclusions: Increased CA-7 alpha-dehydroxylation activity of the intestinal microflora may be an important factor for CG formation or growth in these patients.

In animal models of gallstone disease inflammatory alterations of the gallbladder mucosa are regularly found before the first appearance of cholesterol monohydrate crystals in bile. At sites of inflammation granulocytes generate reactive oxygen metabolites (ROM). The aim of our study was to investigate whether ROM may influence the cholesterol monohydrate crystal formation in supersaturated model bile. Superoxide anions (O2-), hydrogen peroxide (H2O2), and hydroxyl radicals (.OH) were generated by the interaction of Fe(3+)-EDTA with ascorbic acid (Asc). The influence of ROM on cholesterol crystal formation was studied by measurement of the nucleation time. To check whether lipid peroxidation was induced by the ROM generation, production of malondialdehyde equivalents was measured in bile with the thiobarbituric assay. Furthermore, the lipid pattern of bile after ROM exposure was analyzed by thin layer chromatography. Addition of Fe(3+)-EDTA/Asc to model bile markedly decreased the cholesterol nucleation time (NT) (p < 0.01), caused a significant increase in malonidialdehyde equivalents (p < 0.001) and induced the generation of 4-hydroxy-2,3-trans-nonenal (4-HNE). In an attempt to identify a specific oxygen metabolite responsible for the alterations in bile, the effects of various oxygen radical scavengers were tested. Desferal, which prevents -OH generation by chelation of ferrous iron, completely protected bile against Fe(3+)-EDTA/Asc-induced decrease in NT (p < 0.001), increase in lipid peroxidation (p < 0.001) and generation of 4-HNE. Our results indicate that formation of cholesterol crystals in model bile is enhanced by ROM. Hydroxyl radical induced lipid peroxidation appears to be the mechanism responsible for the crystallisation promoting activity of ROM.

Some biliary proteins (pronucleators) seem to be essential factors for cholesterol crystal formation and crystal growth in bile. A recent study suggests that fibronectin is such a pronucleator in bile. Fibronectin also seems to closely interact with intestinal mucin. Since biliary mucin plays an important role in gallstone formation, such an interaction in bile may be of relevance in cholesterol gallstone formation. To more clearly elucidate the role of fibronectin in cholesterol gallstone disease, we measured the concentration of fibronectin in native bile of cholesterol gallstone patients and checked its influence on the cholesterol nucleation time of model bile. We further looked for a molecular interaction between biliary fibronectin and gallbladder mucin. We found that fibronectin is present in gallbladder bile of gallstone patients in low concentrations (2.6 +/- 1.2 micrograms/ml). Bile fibronectin did not interact with gallbladder mucin. Moreover, in a wide range of concentrations fibronectin had no influence on the nucleation time of model bile. We conclude that fibronectin does not seem to play a major role in cholesterol gallstone disease.

Background/aims: Supersaturation of bile with cholesterol, rapid nucleation of cholesterol crystals, and/or incomplete emptying of the gallbladder are believed to be required for gallstone formation. The importance of these factors for the recurrence of gallbladder stones was studied., Methods: Twenty patients, untreated after successful shock wave therapy, were studied in a matched case-control design for bile acid turnover, composition of duodenal bile, and gallbladder emptying. In 10 of them, gallstones had recurred within 12 +/- 2 months (X +/- SEM); the other 10 had been free of stones since 22 +/- 3 months., Results: In each group, duodenal bile was supersaturated with cholesterol in 8 of 10 patients and showed abnormal nucleation time of cholesterol crystals in half of the patients. Patients with recurrent stones had smaller pool sizes of cholic acid (-43%) and enhanced conversion of cholic acid to deoxycholic acid. The odds for stone recurrence were ninefold increased in the presence of excessive deoxycholic acid (exceeding cholic acid) in the bile acid pool or incomplete emptying of the gallbladder (residual volume > 5 mL) in response to cholecystokinin. The odds ratio was over 20-fold increased when incomplete emptying of the gallbladder coincided with supersaturated bile or with excessive deoxycholic acid., Conclusions: Enhanced conversion of cholic acid to deoxycholic acid and incomplete emptying of the gallbladder could be important cofactors for the recurrence of gallstones.

Supersaturation and rapid nucleation of cholesterol in bile are of key importance in the pathogenesis of cholesterol gallstones. While the effects of bile acids and phospholipids on cholesterol saturation of bile have been extensively studied, their influence on the cholesterol nucleation time has not been compared. We, therefore, investigated whether increases of bile acid or phospholipid concentrations in bile by in vitro supplementation affect the cholesterol nucleation time. Bile samples were obtained at surgery from patients with cholesterol gallstones. Prior to the nucleation assay the bile samples were divided into 0.5-ml aliquots and supplemented with 1.25, 2.5, 5.0, and 10.0 mumol/ml of different phosphatidylcholines (PC-dimyristoyl, PC-dipalmitoyl, PC-distearoyl, and extracted biliary PCs) or with 5.0, 10.0, and 20.0 mumol/ml of bile acids (glycine or taurine conjugates of cholic acid, deoxycholic acid, or chenodeoxycholic acid). The increase of phosphatidylcholine or bile acid concentration decreased the mean cholesterol saturation index to a similar extent (PC: 0.1-0.3; BA: 0.1-0.2). Supplementations of bile with increasing amounts of synthetic or biliary PCs caused a marked prolongation of the nucleation time in bile from 1.5 +/- 0.2 up to > or = 21 days or 2.5 +/- 0.7 up to > or = 21 days. Concurrently, biliary cholesterol was shifted from vesicles to mixed micelles and the cholesterol/phospholipid ratio of the remaining vesicles was progressively lowered. In contrast, the addition of bile acids to gallbladder bile did not affect the cholesterol nucleation time (2.2 +/- 0.3 days), the percentage of vesicular cholesterol, or the cholesterol/phospholipid ratio of vesicles and micelles.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary polyunsaturated fatty acids of the n-6 and the n-3 class show differing effects on serum lipids and hepatic lipoprotein metabolism, which could be induced by alterations in hepatocellular cholesterol balance. As both fatty acid classes exert parallel effects on lipoprotein uptake and synthesis of cholesterol in the liver, we studied whether they have differing effects on the excretory pathways for cholesterol. Male Syrian hamsters were fed for 3 weeks low-cholesterol diets supplemented (9% w/w) with either saturated (coconut fat), n-6 unsaturated (safflower oil) or n-3 unsaturated fatty acids (fish oil), which shifted the serum lipid levels. N-6 unsaturated fatty acids increased both the synthesis of cholic acid (+57%; P = 0.05) and, in fistula bile, the secretion of cholesterol (+37%; P < 0.05 vs. saturated fatty acids). By contrast, n-3 unsaturated fatty acids did not enhance synthesis of cholic acid or biliary secretion of cholesterol (-30%, NS). The fatty acid pattern of biliary phospholipids was modified according to the major unsaturated fatty acids in the diet. The alterations both in phospholipid fatty acid composition and in secretory ratio of cholesterol to phospholipids and bile acids persisted during controlled secretion of taurocholic acid at increasing rates. In conclusion, hepatic excretion of cholesterol is increased on dietary n-6 unsaturated fatty acids, and low on n-3 unsaturated fatty acids. These two dietary fatty acid classes change differently the fatty acid composition of biliary phospholipids and the secretory ratio of cholesterol to phospholipids and bile acids in bile.

Because fatty acid composition of biliary phospholipids influences cholesterol secretion into bile, we investigated whether replacement of n-1 monounsaturated or n-6 polyunsaturated fatty acids with n-3 polyunsaturated fatty acids in biliary phosphatidylcholines reduces supersaturation with cholesterol and prevents precipitation of cholesterol crystals in bile of gallstone patients. Seven patients with radiolucent gallstones in functioning gallbladders were studied before (control) and after 5 wk of dietary supplementation with marine fish oil (11.3 gm/day = 3.75 gm n-3 polyunsaturated fatty acids/day). Duodenal bile was collected for analysis during intravenous infusion of cholecystokinin. Gallbladder emptying in response to cholecystokinin was comparable before and during intake of n-3 polyunsaturated fatty acids. Intake of n-3 polyunsaturated fatty acids increased (p less than 0.001) the fractions of eicosapentaenoic and docosahexaenoic acids and decreased the fractions of linoleic (p less than 0.001) and arachidonic acids (p less than 0.02) in biliary phospholipids. Concomitantly, the molar ratio of cholesterol to phospholipids decreased (-19%; p less than 0.05). As a consequence, the cholesterol saturation index was reduced by -25% (p = 0.01), from 1.60 +/- 0.44 to 1.24 +/- 0.38. However, in vitro nucleation time of duodenal bile was not prolonged. The decrease in cholesterol saturation was not sufficient to prevent nucleation of cholesterol crystals in bile of gallstone patients. In conclusion, our data suggest that cholesterol saturation can be influenced by the fatty acid composition of the phosphatidylcholines secreted in bile.

The aim of the study was to evaluate the metabolism of individual bile acids in patients with cholesterol gallstone disease. Therefore, we determined pool size and turnover of deoxycholic (DCA), cholic (CA), and chenodeoxycholic acid (CDCA) in 23 female gallstone patients classified according to their gallbladder function and in 15 healthy female controls. Gallstone patients had normal hepatic bile acid synthesis, but, depending on gallbladder function, differed with respect to turnover and size of the bile acid pools: Patients with well-emptying gallbladder (group A, n = 9) had enhanced turnover and reduced pools of CA (-46%; P less than 0.01 vs. controls) and CDCA (-24%; P less than 0.05), but normal input and size of the DCA pool. With reduced gallbladder emptying (less than 50% of volume; group B, n = 6), turnover and pools of CA, CDCA, and DCA were similar as in controls. Patients with loss of gallbladder reservoir (group C, n = 8) had increased input (+100%; P less than 0.01) and pool size of DCA (+45%; P = 0.07) caused by rapid conversion of CA to DCA, while the pools of CA (-71%; P less than 0.001 vs. controls) and CDCA (-36%; P less than 0.05) were reduced by enhanced turnover. Thus, in patients with cholesterol gallstones, the pools of primary bile acids are diminished, unless gallbladder emptying is reduced. Furthermore, in a subgroup of gallstone patients, who had completely lost gallbladder function, the CA pool is largely replaced by DCA owing to rapid transfer of CA to the DCA pool. This probably contributes to supersaturation of bile with cholesterol.

Patients with multiple cholesterol gallbladder stones have been found to be at a higher risk for the recurrence of gallstones after successful nonsurgical treatment than those with a solitary stone. Cholesterol gallstone recurrence, like primary gallstone formation, probably involves a triple defect with supersaturation, abnormally rapid nucleation of cholesterol in bile and altered gallbladder motor function. We investigated whether the increased recurrence rate of patients with multiple stones might be caused by more rapid nucleation. Therefore the time required for cholesterol monohydrate crystals to appear in ultracentrifuged bile of patients with solitary (n = 71) or multiple (n = 42) cholesterol gallstones was determined. The cholesterol nucleation time was significantly (p less than 0.01) longer in the bile from patients with solitary stones (less than 1 to 16 days, median = 2.0 days) than in the bile from patients with multiple stones (less than 1 to 8 days, median = 1.0 days). Moreover, 15 of 71 (21.1%) patients with solitary cholesterol stones but only 1 of 42 (2.4%) patients with multiple cholesterol stones showed a normal (greater than 4 days) nucleation time. However, no difference in the cholesterol saturation index was found between the bile samples from patients with solitary stones and the bile samples from patients with multiple stones (1.55 +/- 0.65 vs. 1.54 +/- 0.59, mean +/- S.D., respectively). The more rapid cholesterol nucleation in gallbladder bile may, therefore, be the major risk factor causing the higher percentage of stone recurrence in patients with multiple cholesterol stones as compared with patients with solitary cholesterol stones.

While it is generally accepted that cholesterol supersaturation of bile is of key importance in the rapid formation of cholesterol crystals, the role of total biliary protein and pH in the pathogenesis of cholesterol gallstones is less well understood. The relation of cholesterol saturation, total protein, and pH was studied in 73 gallbladder bile samples with and 35 gallbladder bile samples without cholesterol crystals. In samples containing crystals, a trend to higher values of cholesterol and to a higher cholesterol saturation index was observed. However, significantly (P = 0.02) higher concentrations of total protein were found in samples with crystals [0.80 +/- 0.40 g/dL (8.0 +/- 4.0 g/L)] than in samples without crystals [0.63 +/- 0.26 g/dL (6.3 +/- 2.6 g/L)]. Moreover, of 22 bile samples with total protein concentrations greater than 10.0 g/L, cholesterol crystals were detected in all but 2. Total lipids, bile acids, phospholipids, and pH values were not significantly different in the two groups of bile samples. It was concluded that high biliary protein concentrations are frequently associated with cholesterol crystals and may, therefore, be a possible risk factor in the pathogenesis of cholesterol gallstones.

The effect of endoscopic sphincterotomy on bile acid composition and cholesterol saturation of bile has been studied in cholecystectomized patients. Individual bile acids and biliary lipids were measured in hepatic bile of 13 cholecystectomized females aged 56.8 +/- 16.6 years more than 9 months (mean 16.7 +/- 8.8 months) after sphincterotomy and of 12 cholecystectomized females aged 59.3 +/- 11.5 years who served as controls. The sphincterotomy group exhibited a significantly (p less than 0.01) higher percentage of chenodeoxycholic acid in bile--39.2 +/- (SD) 7.7%--than the controls with cholecystectomy only (29.1 +/- 7.4%), but showed no differences in the proportion of cholic acid (32.4 +/- 6.2 vs. 33.6 +/- 7.8%). The percentages of the secondary bile acids, deoxycholic acid (25.0 +/- 8.8 vs. 32.3 +/- 8.3%), and lithocholic acid (1.7 +/- 0.8 vs. 2.6 +/- 2.3%) were lower, but these differences were not statistically significant. The biliary lipid composition in the sphincterotomy group was not different from that in the controls, resulting in a similar cholesterol saturation index in both groups (1.87 +/- 0.60 vs. 2.02 +/- 0.60 according to Carey and Small; 1.45 +/- 0.32 vs. 1.55 +/- 0.32 according to Hegardt and Dam). These findings do not demonstrate any alterations of the bile composition after sphincterotomy which may be expected to have undesirable effects on the biliary and/or gastrointestinal system.

The effect of a new potent choleretic drug (Febuprol) on lipid composition and cholesterol nucleation time in gallbladder bile was studied in 8 patients with cholesterol gallstones. Nine untreated patients with cholesterol cholecystolithiasis and functioning gallbladder served as controls. Under Febuprol treatment (3 X 100 mg for 6-10 days) mean concentrations of total bile acids (125.4 vs. 59.5 mmol/l), phospholipids (46.1 vs. 25.6 mmol/l) and total lipids (10.4 vs. 5.9 g/dl) were significantly higher (p less than 0.01) than in controls. No significant difference between both groups was calculated for the mean values of cholesterol (17.8 vs. 13.3 mmol/l), cholesterol saturation index (1.5 vs. 2.1) and cholesterol nucleation time (2.1 vs. 2.6 days). Our findings are compatible with a choleretic effect of Febuprol but no alteration of the rapid cholesterol crystallisation in gallbladder bile of patients with cholesterol gallstones was found.

Several investigators have reported an association between low serum cholesterol levels and an increased frequency of colorectal cancer. Because low cholesterol levels may be a result of an established cancer, we have investigated the relation between serum cholesterol levels and the frequency of colorectal adenomas, which are thought to be precursors of colon cancer. We prospectively studied 1083 consecutive patients who underwent colonoscopy (241 of whom were excluded because of malignant disease, chronic inflammatory bowel disease, familial polyposis, or partial colectomy). In the remaining 842 patients, analysis of covariance was performed to evaluate the contribution of serum cholesterol to the risk of colorectal adenoma. Serum cholesterol levels were significantly and positively associated with the frequency of colorectal adenoma in subjects of both sexes. After adjustment for age and body-mass index, this positive association remained significant between the top quintile and the lowest quintile for serum cholesterol, with regard to the total study group (odds ratio, 2.0; 95 percent confidence limits, 1.1 and 3.6) and men only (odds ratio, 2.2; 95 percent confidence limits, 1.0 and 4.8). We conclude that there is not an inverse correlation between serum cholesterol levels and the risk of colorectal adenomas; on the contrary, there appears to be a small positive association.

Ascitic fluid concentrations of cholesterol, triglycerides and phospholipids, were compared with ascitic fluid total protein in 40 patients with chronic liver disease, 51 patients with various neoplasms and 1 patient with cardiac failure. Seven patients with both chronic liver disease and malignancy were considered separately. The first 54 patients (23 cirrhotic and 31 with malignancy) were used to determine median values and ranges and to define the most suitable cutoff concentrations between both groups. Median values for cholesterol (75 mg per dl), phospholipids 0.79 mmole per liter), triglycerides (75 mg per dl) and protein (3.8 gm per dl) were higher in malignant ascites compared to ascitic fluid concentrations of cholesterol (20 mg per dl), phospholipids (0.33 mmole per liter), triglycerides (51 mg per dl) and protein (1.9 gm per dl) in patients with cirrhosis. The best discrimination values were 48 mg per dl for cholesterol, 0.6 mmole per liter for phospholipids, 65 mg per dl for triglycerides and 2.5 gm per dl for protein. Application of these cutoff points to 38 subsequent patients (17 cirrhotic, 1 with cardiac failure and 20 with malignancy) revealed an efficiency of 86.8% for cholesterol, 86.8% for phospholipids, 68.4% for triglycerides and 79.0% for protein. From the data of all 92 patients, an efficiency of 92.3% for cholesterol, 79.4% for phospholipids, 72.8% for triglycerides and 79.4% for protein was calculated. We conclude that ascitic fluid cholesterol determination offers an excellent, cost-effective discrimination of ascites due to cirrhosis vs. ascites caused by malignancies.

The cholesterol content of bile-duct stones from 40 patients after cholecystectomy was compared with 22 gall-bladder stones. There were 18 (82%) cholesterol-rich stones (cholesterol content more than 60% of dry weight) among gall-bladder stones, but only 12 (30%) among bile-duct stones. Eight bile-duct stones (20%) contained fibrous material, a further seven (18%) had a cholesterol-rich nucleus and cholesterol-poor outer layer. These findings indicate that residual fibres or small migrated gall-bladder stones can form the nidus for the growth of choledochal stones. The cholesterol content of bile-duct stones did not correlate with the age of the patient, time since cholecystectomy or cholesterol saturation of hepatic bile.

The high rate of stone recurrence represents a drawback of non-surgical therapy of cholesterol gallstone disease. Although most studies report that long-term bile acid treatment does not have protective effects, preliminary results suggest that low-dose ursodeoxycholic acid decreases the rate of gallstone recurrence in a subgroup of younger patients. To clarify the underlying mechanism we investigated whether low-dose ursodeoxycholic acid treatment influences biliary cholesterol saturation and/or nucleation time of cholesterol. Ten patients with cholesterol gallstones and functioning gallbladder received 250 mg ursodeoxycholic acid/day at bedtime 6-10 days prior to cholecystectomy. Eleven patients with cholesterol gallstones without treatment served as controls. Cholesterol crystals were present in the gallbladder bile of 7 out of the 10 patients receiving ursodeoxycholic acid and in all control biles. Ursodeoxycholic acid treatment significantly (P less than 0.02) decreased the cholesterol saturation index (mean +/- S.E.: 0.94 +/- 0.05 vs. 1.43 +/- 0.18) and led to an approximately 5-fold prolongation (P less than 0.005) of the cholesterol nucleation time (mean +/- S.E.: 12.0 +/- 2.4 vs. 2.3 +/- 0.7 days). We conclude that low-dose ursodeoxycholic acid might be effective in the prevention of post-dissolution gallstone recurrence by both decreasing cholesterol saturation and prolonging cholesterol nucleation time.

The mechanism of ethinylestradiol-induced biliary secretion of excess cholesterol, a potential causative factor of cholesterol gallstones, is not yet known. It might be related to altered bile acid metabolism, since the rate of cholesterol and phospholipid secreted into bile is thought to be influenced by the hydrophobicity of the bile acid species secreted. We therefore studied the effect of ethinylestradiol on bile acid metabolism and on secretory relationships between taurocholate and cholesterol/phospholipids in bile. Litter-matched Syrian female hamsters (80 to 100 gm body weight) were injected subcutaneously with either 0.2 ml per day corn oil (controls) or a pharmacologic dose of 5 mg per kg per day ethinylestradiol in corn oil (EE-hamsters; n = 6) for 5 days. On Day 6, bile was collected for 60 min (basal secretory rate) via a bile duct fistula after exclusion of the gallbladder. Then, a graded infusion of taurocholate was given for 110 to 130 min. Secretory rates (nmoles.min-1.-1 liver) for bile acids, cholesterol and phospholipids were determined and their mutual "linkage coefficients" (nmoles of secretory increment per 1 nmole of bile acid secreted) calculated by linear regression analysis. EE-hamsters had higher (p less than 0.02) basal secretory rates of cholesterol (0.71 +/- 0.21 vs. 0.45 +/- 0.10) and phospholipids (5.74 +/- 1.04 vs. 4.21 +/- 0.73) than controls at comparable bile flow and bile salt secretion rates. Cholic acid pool size and the fractional composition of bile acid species in bile were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to test whether shock wave fragmentation of human gallstones increases their dissolution rates in a bile acid-lecithin solution, we carried out in vitro experiments. Stones comparable in size, weight and cholesterol content (86%) from the same human gallbladder were disintegrated by shock waves. A glycoursodeoxycholic acid (GUDC)-lecithin solution served as solvent. After 10 days incubation in this solvent, intact stones had lost only 4% of their cholesterol. This value increased to 92% after disintegration of the stones by 300 shock wave discharges. Fragments with a size of less than 2 mm had lost 55% of their cholesterol after day 1 and 99% after day 10. A large stone fragment cleaved off by shock waves lost much more cholesterol (42% after 10 days) than an intact untreated stone (4% after 10 days) comparable in size, weight and cholesterol content. These data show that shock wave lithotripsy of cholesterol gallstones considerably accelerates their dissolution rate in a GUDC-lecithin solvent, the desirable fragment size being 2 mm or less. However, even large fragments may lose much more cholesterol than comparable intact stones as a result of changes in surface structure as documented by scanning electron microscopy. The experiments favor the concept of a combined treatment of gallbladder stones by extracorporeally generated shock waves and bile salt therapy.