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Background: Nucleating and antinucleating factors play an important role in the pathogenesis of cholesterol crystal nucleation., Patients and Methods: In 88 gallstone patients (59 female, 29 male) bile was examined for total biliary protein and glycoprotein concentration, nucleation time and cholesterol saturation index. Gallstone density was measured by in vivo computed tomography., Results: Total biliary protein concentration was positively correlated with the number of gallstones (r = 0.84, p < 0.01) and higher in radiologically detectable isodense gallstones as compared to non-isodense stones (p < 0.01). A negative correlation between total biliary protein concentration, glycoprotein concentration and nucleation time was observed (r = -0.45, p < 0.01 and r = -0.49, p < 0.05). Nucleation time was significantly shorter in the case of multiple versus solitary stones (2.6 +/- 1.3 versus 8.5 +/- 3.0 days, p < 0.01). Cholesterol saturation index and biliary cholesterol concentration were similar in both cases, however a negative correlation between cholesterol saturation index and stone density (r = -0.79, p < 0.01) was found. No correlation was found between cholesterol saturation index and nucleation time (r = -0.04, p > 0.1), independent of gallstone number. None of the examined parameters was related to sex, age, weight or gallbladder function., Conclusions: Multiple gallbladder stones seem to be associated with shorter nucleation time and higher biliary concentrations of total protein and glycoprotein than solitary stones.

Background: Biliary lipids and nucleation time are increasingly of importance in the understanding of the cholesterol nucleation process in gallstone patients., Methods: Biliary lipids, total lipid concentration (TLC), cholesterol saturation index (CSI) and nucleation time (NT) were studied in 221 bile samples from patients with solitary (n = 120) and multiple (n = 101) gallbladder stones., Results: Biliary cholesterol concentration and CSI did not differ between patients with solitary or multiple stones; however, it was positively correlated with the CSI (r = 0.93; p < 0.01). We found a negative correlation between CSI and TLC (r = -0.77 for solitary stones and r = -0.79 for multiple stones; p < 0.01). Furthermore, levels of total bile acids and phospholipids were similar in cases with solitary and multiple gallbladder stones. TLC did not correlate with single or multiple stones, whereas NT was determined to be negatively correlated with the number of gallstones (r = -0.39; p < 0.01). Patients with solitary stones had a significantly (p < 0.01) longer NT than those with multiple gallbladder stones (7.5 +/- 4.2 days versus 2.3 +/- 1.5 days)., Conclusions: Our findings suggest that there exists a nucleation-promoting activity, which seems to be more pronounced in patients with multiple gallbladder stones than in those with solitary stones, indicating a major risk factor for the higher recurrence rate seen in these patients.

Objective: The objective of this study was to determine the effect of ursodeoxycholic acid (UDCA), 1000 mg/day, on nucleation time and cholesterol saturation index (CSI) in human gallbladder bile., Methods and Results: In 48 patients with cholesterol gallbladder stones undergoing extracorporeal shockwave lithotripsy, bile samples exhibited a significant longer median nucleation time in the case of solitary stones (7.9 +/- 5.1 days) than in patients with multiple stones (1.7 +/- 1.0 days; p < 0.0001). Stone number and nucleation time were correlated inversely (r = -0.79). UDCA led to a significant prolongation of nucleation time (solitary stones 17.9 +/- 5.8 days, multiple stones 18.0 +/- 5.7 days; p < 0.01) with a concomitant disappearance of cholesterol liquid crystals and cholesterol monohydrate crystals in gallbladder bile. Initially, there was no difference in the CSI between patients with solitary stones or multiple gallbladder stones (1.4 +/- 0.3 vs. 1.4 +/- 0.4, respectively). UDCA caused a significant decrease in CSI by 64.3% (p < 0.01)., Conclusions: We conclude that UDCA prolongs the nucleation time by decreasing the cholesterol saturation index, as well as by diminishing cholesterol liquid crystals and cholesterol monohydrate crystals in gallbladder bile from patients with cholesterol gallstones. Second, recurrent stones essentially occur in patients with multiple cholesterol gallstones, reflected by a concomitant short nucleation time.

The daily administration of fish oil, containing 1.5 g omega-3-fatty acids causes a significant decrease in nucleation time (12.1 +/-7.3 vs. 2.0 +/- 1.2 days, p less than 0.001), as well as in biliary cholesterol saturation and biliary cholesterol composition in 13 healthy subjects. The nucleation time, cholesterol saturation index and biliary lipids showed no significant differences in 11 cholesterol gallstone patients after a six-week treatment period with omega-3-fatty acids. Taurocholate percentage increased significantly in the gallstone group (10.4 +/- 3.9 vs 13.5 +/- 1.7%, p less than 0.05). The levels of the other bile acids remained unchanged during the treatment period. Therefore, the incidence of gallstones might be increased after treatment with fish oil, containing omega-3-fatty acids.

In a 24-month trial of a combination therapy with ursodeoxycholic acid and chenodeoxycholic acid complete dissolution of radiolucent gallstones was achieved in 15 of 55 patients (27.3%). A decrease of stone volume of greater than 35% was achieved in a further 28 patients (50.9%). In 12 patients (21.8%) inadequate compliance (3.6%), a nonfunctioning gallbladder (3.6%), absence of size decrease (10.9%), or acute cholecystitis (3.6%) required interruption of therapy. Determination of the cholesterol saturation index (CSI) did not facilitate patient selection, nor was there a statistically significant difference between responders and nonresponders to dissolution therapy. In the course of treatment the average CSI showed a statistically significant decrease from 1.54 +/- 0.12 to 0.82 +/- 0.06 (p less than 0.001). Patients in whom complete dissolution was achieved and those in whom no improvement was observed differed significantly in nucleation time (4.7 +/- 0.8 versus 15.0 +/- 2.2 days; p less than 0.001) and initial gallstone volume (274 +/- 78 versus 1045 +/- 180 mm3). The nucleation time increased statistically significantly during the therapy in the successfully treated group. The percentages of glycocholic acid (8.1 +/- 1.13 versus 4.1 +/- 0.55%; p less than 0.01), taurocholic acid (2.2 +/- 0.45 versus 0.8 +/- 0.23%; p less than 0.05), and glycodeoxycholic acid (4.9 +/- 0.70 versus 1.4 +/- 0.37%; p less than 0.001) were statistically significantly different after the treatment. There were no statistically significant differences between patients with complete and incomplete stone dissolution with regard to age, mean body weight, or laboratory variables.

In this study we examined the influence of different lipid lowering drugs (xantinolnicotinate (Xn), bezafibrate (Bf) and a combination of inositolnicotinate and clofibrate (In-Cl)) on the lipid and lipoprotein concentration in 61 hyperlipidemics of the types IIb, IV and V. Treatment with the 3 drugs showed a significant LDL-cholesterol decrease in type IIb and a LDL-cholesterol increase in the types IV and V. Concerning protective HDL lipoproteins an increase of HDL-cholesterol could be observed in all three types only by treatment with xantinolnicotinate and bezafibrate. Concomitantly in type V a type conversion to type IV could be observed under drug treatment regarding the chemical composition of the lipoprotein fractions VLDL, LDL and HDL.

The gallbladder bile of obese patients without gallstones is supersaturated with cholesterol. The cholesterol saturation index (CSI, LI) of 27 obese patients was 1.32 +/- 0.2. The CSI of 24 normal weight gallstone patients was determined with 1.16 +/- 0.37 and is therefore not significantly different from CSI of obese stone free individuals. The supersaturated bile from obese patients does not accelerated the nucleation of cholesterol crystals. The nucleation time of obese persons was statistically significant longer (16.0 +/- 3.0 days) than in gallstones patients (6.0 +/- 0.78 days) (p less than 0.001). In 50% of the patients with gallstones cholesterol monohydratcrystals were present in the native gallbladder bilde, whereas such crystals are found in only 3.7% of the obese group. Liquid crystals occurred more frequently and in larger number in the bile of the obese patients. The stone forming potency of gallbladder bile can be estimated better by the determination of nucleation time and cholesterol crystals occurrence than by the calculation of the saturation index (CSI).

The average incidence of gallstones in european countries is about 25%. Excessive secretion of cholesterol into the bile can predispose to saturation and gallstone-formation. Obesity, overnutrition, diets rich in refined carbohydrates, diets high in cholesterol intake and poor in dietary fibre, lipid lowering drugs, age and female sex hormones are recognized causing increased cholesterol secretion into the bile. These metabolic consequences may predispose to a higher incidence of cholesterol gallstone than in normal persons. Taking all the results of the literature together patients with gallstones should be encouraged to take a low cholesterol, low calorie, low refined carbohydrate and high polyunsaturated fat diet rich in bran und vegetable fibre. Obese patients should reduce their body weight. These dietary recommendations should be given for patients with gallstones during bile acid therapy and after successful dissolution in order to prevent gallstone recurrence.

Cholelithiasis is a civilization-related disease with multifactorial causation. The supersaturation of the bile with cholesterol is a deciding risk factor, which, however, does not lead to gallstone formation in each individual case. The connection between supersaturated bile and the formation of stone whose primary constituent is cholesterol, are the cholesterol-monohydrate crystals. Several risk factors lead to cholesterol supersaturation of the bile. Other risk factors induce or maintain the nucleation of the cholesterol crystals. In the following paper the nucleating and inhibiting factors and the pathophysiology of cholesterol gallstones will be discussed.