Therapy of gallstone disease: What it was, what it is, what it will be

Cholesterol gallstone disease is a common clinical condition influenced by genetic factors,increasing age,female gender,and metabolic factors.Although laparoscopic cholecystectomy is currently considered the gold standard in treating patients with symptomatic gallstones,new perspectives regarding medical therapy of cholelithiasis are currently under discussion,also taking into account the pathogenesis of gallstones,the natural history of the disease and the analysis of the overall costs of therapy.A careful selection of patients may lead to successful nonsurgical therapy in symptomatic subjects with a functioning gallbladder harboring small radiolucent stones.The classical oral litholysis by ursodeoxycholic acid has been recently paralleled by new experimental observations,suggesting that cholesterol-lowering agents which inhibit cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe),or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis,might be proposed as additional approaches for treating cholesterol gallstones.In this review we discuss old,recent and future perspectives on medical treatment of cholesterol cholelithiasis.     

High rate of complicated idiopathic gallstone disease in pediatric patients of a North American tertiary care center

AIM： To assess spectrum and etiology of gallstones and biliary sludge in the pediatric population of a North American tertiary care centre. METHODS： Retrospective review of abdominal ultrasounds recorded at Saint Justine Hospital over a period of 24 mo （8/2003 to 8/2005） in patients 〈 19 years of age. Patients 〈 2 years of age were analyzed separately. RESULTS： The presence of gallstones was noted in 127 patients. In 107 it was a new diagnosis, in 48/105 （45.7%） patients 〉 2 years of age idiopathic gallstone disease was found. These 48 patients represent 2.1% of the population who required ultrasound for abdominal pain. Complicated gallstone disease occurred in 28/48 with idiopathic disease, mainly adolescent girls. Patients with hemolytic disorders, cystic fibrosis, oncologic diseases or kidney transplantation and gallstones were asymptomatic and stones were detected during routine abdominal ultrasound. Twenty two patients 〈 2 years of age not consulting for abdominal pain had gallstone disease of diverse etiology. Biliary sludge was seen in 84 patients, 78.5% on total parenteral nutrition. In 4 patients, sludge progressed to gallstones. CONCLUSION： Idiopathic gallstone disease and its rate of complication are more frequent in our cohort than expected from previous studies. Adolescent girls with abdominal pain and idiopathic gallstones require special attention for complicated disease course.     

Can pigment gallstones be induced by biliary stricture and prevented by medicine in Guinea pigs？

AIM: To determine the relationship between biliary stricture and pigment gallstone formation, and the prevention of pigment gallstones with medicine. METHODS: One hundred and eighteen male guinea pigs were randomly divided into four groups: stricture group (S, n = 30) underwent partial ligation of common bile duct, and fed on regular chow; S plus medicine group (S+M, n = 27) underwent the same operation but fed on medicinal chow (0.3 g chenodeoxycholic acid, 0.5 g glucurolactone, and 0.5 g aspirin were mixed up in 1.2 kg regular chow); medicinal control group (C+M, n = 30) was free of operation, and fed on medicinal chow; and control group (C, n = 31) was free of operation and fed on regular chow. One week later, laparotomy was performed, and the bile of gallbladder was collected, measured, and cultured. RESULTS: Gallstones were identif ied. Pigment gallstones were induced by biliary stricture in 95% (22/23) of S group. In the S+M group, the incidence of gallstone was reduced to 55% (11/20, vs S group, P < 0.01). The changes of indirect bilirubin and ionized calcium in the bile were consistent with gallstone incidences. CONCLUSION: Biliary stricture can cause pigment gallstone formation in guinea pigs, and the medicines used can lower the incidence of gallstones. The bilirubin and ionized calcium play important roles in pigment gallstone formation.     

Crohn＇s disease in one mixed-race population in Brazil

AIM To evaluate the classification and severity of Crohn's disease in different racial groups.METHODS Patients with Crohn's disease from the outpatient clinic of the University Hospital Prof. Edgard Santos were enrolled in the study. This hospital is a reference centre for inflammatory bowel disease. Race was determined using self-identification. The Vienna's classification was applied for all subjects. The severity of Crohn's disease was determined according to the number of surgical procedures, hospital admissions in the last year and treatment with steroids and immunosuppressors. Statistical analysis was calculated using t test for means, χ2 or F for proportions. A P value ＜ 0.05 was considered to be significant.RESULTS Sixty-five patients were enrolled. Non-white patients were more frequently diagnosed with Crohn's disease in the age less than 40 years than white patients. The behaviour of disease was similar in both groups with a high frequency of the penetrating form.There was a tendency for non-white patients to have a greater frequency of hospital admissions in the last year compared to white subjects. Non-whites also had a higher rate of colonic and upper gastrointestinal involvement, and were also more frequently on treatment with immunossupressors than white patients although this difference was not statistically significant.CONCLUSION Non-white patients with Crohn's disease had an earlier diagnosis and appeared to have had a more severe disease presentation than white patients.     

Crohn''''s disease in one mixed-race population in Brazil

AIM: To evaluate the classification and severity of Crohn's disease in different racial groups.METHODS: Patients with Crohn's disease from the outpatient clinic of the University Hospital Prof. Edgard Santos were enrolled in the study. This hospital is a reference centre for inflammatory bowel disease. Race was determined using self-identification. The Vienna's classification was applied for all subjects. The severity of Crohn's disease was determined according to the number of surgical procedures, hospital admissions in the last year and treatment with steroids and immunosuppressors. Statistical analysis was calculated using t test for means, χ2 or F for proportions. A P value < 0.05 was considered to be significant.RESULTS: Sixty-five patients were enrolled. Non-white patients were more frequently diagnosed with Crohn's disease in the age less than 40 years than white patients. The behaviour of disease was similar in both groups with a high frequency of the penetrating form. There was a tendency for non-white patients to have a greater frequency of hospital admissions in the last year compared to white subjects. Non-whites also had a higher rate of colonic and upper gastrointestinal involvement, and were also more frequently on treatment with immunossupressors than white patients although this difference was not statistically significant.CONCLUSION: Non-white patients with Crohn's diseasehad an earlier diagnosis and appeared to have had a more severe disease presentation than white patients.     

Determination of chemical composition of gall bladder stones:Basis for treatment strategies in patients from Yaounde,Cameroon

AIM:Gallstone disease is increasing in sub-saharan Africa (SSA).In the west,the majority of stones can be dissolved with bilesalts,since the major component is cholesterol.This medicaltherapy is expensive and not readily accessible to poorpopulations of SSA.It was therefore necessary to analyze thechemical composition of biliary stones in a group of patients,so as to make the case for introducing bile salt therapy in SSA.METHODS:All patients with symptomatic gallstoneswere recruited in the study.All stones removed duringcholecystectomy were sent to Houston for x-ray diffractionanalysis.Data on age,sex,serum cholesterol,and thepercentage by weight of cholesterol,calcium carbonate,andamorphous material in each stone was entered into a pre-established proforma.Frequencies of the major componentsof the stones were determined.RESULTS:Sixteen women and ten men aged between 27and 73 (mean 44.9) years provided stones for the study.The majority of patients (65.38%) had stones with less than25% of cholesterol.Amorphous material made up more than50% and 100% of stones from 16 (61.53%) and 9 (34.61%)patients respectively.CONCLUSION:Cholesterol is present in small amounts ina minority of gallstones in Yaounde.Dissolution of gallstoneswith bile salts is unlikely to be successful.     

Biliary microbiota and mucin 4 impact the calcification of cholesterol gallstones

Background:Cholesterol gallstones account for over 80% of gallstones,and the pathogenesis of gallstone formation involves genetic and environmental factors.However,data on the evolution of cholesterol gallstones with various densities are limited.This study aimed to determine the roles of microbiota and mucins on the formation of calcified cholesterol gallstones in patients with cholelithiasis.Methods:Paired gallbladder tissues and bile specimens were obtained from cholelithiasis patients who were categorized into the isodense group and calcified group according to the density of gallstones.The relative abundance of microbiota in gallbladder tissues was detected.Immunohistochemistry and enzyme-linked immunosorbent assay were performed to detect the expression levels of MUC1,MUC2,MUC3 a,MUC3 b,MUC4,MUC5 ac and MUC5 b in gallbladder tissues and bile.The correlation of microbiota abundance with MUC4 expression was evaluated by linear regression.Results:A total of 23 patients with gallbladder stones were included.The density of gallstones in the isodense group was significantly lower than that of the calcified group(34.20 ± 1.50 vs.109.40 ± 3.84 HU,P 0.0 0 01).Compared to the isodense group,the calcified group showed a higher abundance of gram-positive bacteria at the fundus,in the body and neck of gallbladder tissues.The concentrations of MUC1,MUC2,MUC3 a,MUC3 b,MUC5 ac and MUC5 b in the epithelial cells of gallbladder tissues showed no difference between the two groups,while the concentrations of MUC4 were significantly higher in the calcified group than that in the isodense group at the fundus(15.49 ± 0.69 vs.10.23 ± 0.54 ng/m L,P 0.05),in the body(14.54 ± 0.94 vs.11.87 ± 0.85 ng/m L,P 0.05) as well as in the neck(14.77 ± 1.04 vs.10.85 ± 0.72 ng/m L,P 0.05) of gallbladder tissues.Moreover,the abundance of bacteria was positively correlated with the expression of MUC4(r = 0.569,P 0.05) in the calcified group.Conclusions:This study showed the potential clinical relevance among biliary microbiota,mucins and calcified gallstones in patients with gallstones.Gram-positive microbiota and MUC4 may be positively associated with the calcification of cholesterol gallstones.     

ABCB4 mutations underlie hormonal cholestasis but not pediatric idiopathic gallstones

AIM:To investigate the contribution of ABCB4 mutations to pediatric idiopathic gallstone disease and the potential of hormonal contraceptives to prompt clinical manifestations of multidrug resistance protein 3 deficiency.METHODS:Mutational analysis of ABCB4,screening for copy number variations by multiplex ligation-dependent probe amplification,genotyping for low expression allele c.1331T>C of ABCB11 and genotyping for variation c.55G>C in ABCG8 previously associated with cholesterol gallstones in adults was performed in 35 pediatric subjects with idiopathic gallstones who fulfilled the clinical criteria for low phospholipid-associated cholelithiasis syndrome(LPAC,OMIM#600803)and in 5young females with suspected LPAC and their families(5 probands,15 additional family members).The probands came to medical attention for contraceptiveassociated intrahepatic cholestasis.RESULTS:A possibly pathogenic variant of ABCB4was found only in one of the 35 pediatric subjects with idiopathic cholesterol gallstones whereas 15 members of the studied 5 LPAC kindreds were confirmed and another one was highly suspected to carry predictably pathogenic mutations in ABCB4.Among these 16,however,none developed gallstones in childhood.In 5index patients,all young females carrying at least one pathogenic mutation in one allele of ABCB4,manifestation of LPAC as intrahepatic cholestasis with elevated serum activity of gamma-glutamyltransferase was induced by hormonal contraceptives.Variants ABCB11c.1331T>C and ABCG8 c.55G>C were not significantly overrepresented in the 35 examined patients with suspect LPAC.CONCLUSION:Clinical criteria for LPAC syndrome caused by mutations in ABCB4 cannot be applied topediatric patients with idiopathic gallstones.Sexual immaturity even prevents manifestation of LPAC.     

Cholecystectomy is independently associated with nonalcoholic fatty liver disease in an Asian population

AIM: To investigate the relationship between gallstone disease and nonalcoholic fatty liver disease(NAFLD) in a large Asian population. METHODS: A cross-sectional study including 17612 subjects recruited from general health check-ups at the Seoul National University Hospital, Healthcare System Gangnam Center between January 2010 and December 2010 was conducted. NAFLD and gallstone disease were diagnosed based on typical ultrasonographic findings. Subjects who were positive for hepatitis B or C, or who had a history of heavy alcohol consumption( 30 g/d for men and 20 g/d for women) or another type of hepatitis were excluded. Gallstone disease was defined as either the presence of gallstones or previous cholecystectomy, and these two entities(gallstones and cholecystectomy) were analyzed separately. Clinical parameters including body mass index, waist circumference, hypertension, diabetes, smoking status, and regular physical activity were reviewed. Laboratory parameters, including serum levels of gamma-glutamyl transpeptidase, alanine aminotransferase, aspartate aminotransferase, fasting glucose, fasting insulin, total cholesterol, triglycerides, and high-density lipoprotein, were also reviewed.RESULTS: The mean age of the subjects was 48.5± 11.3 years, and 49.3% were male. Approximately 30.3% and 6.1% of the subjects had NAFLD and gallstone disease, respectively. The prevalence of gallstone disease(8.3% vs 5.1%, P 0.001), including both the presence of gallstones(5.5% vs 3.4%, P 0.001) and a history of cholecystectomy(2.8% vs 1.7%, P 0.001), was significantly increased in the NAFLD group. In the same manner, the prevalence of NAFLD increased with the presence of gallstone disease(41.3% vs 29.6%, P 0.001). Multivariate regression analysis showed that cholecystectomy was associated with NAFLD(OR = 1.35, 95%CI: 1.03-1.77, P = 0.028). However, gallstones were not associated with NAFLD(OR = 1.15, 95%CI: 0.95-1.39, P = 0.153). The independent association between cholecystectomy and NAFLD was still significant after additional adjustment for insulin resistance(OR = 1.45, 95%CI: 1.01-2.08, P = 0.045). CONCLUSION: This study shows that cholecystectomy, but not gallstones, is independently associated with NAFLD after adjustment for metabolic risk factors. These data suggest that cholecystectomy may be an independent risk factor for NAFLD.     

Incidence of gallstone disease in Italy：Results from a multicenter,population-based Italian study （the MICOL project）

AIM：To evaluate gallstone incidence and risk factors in a large population-based study. METHODS： Gallstone incidence and risk factors, were evaluated by structured questionnaire and physical examination, respectively, in 9611 of 11 109 （86.5%） subjects who were gallstone-free at the cross-sectional study. RESULTS： Six centers throughout Italy enrolled 9611 subjects （5477 males, 4134 females, aged 30-79 years）, 9517 of whom were included into analysis： 424 subjects （4.4%） had gallstones and 61 （0.6%） had been cholecystectomized yielding a cumulative incidence of 0.67% per year （0.66% in males, 0.81% in females）. Increasing age, a high body mass index （BMI）, a history of diabetes, peptic ulcer and angina, and low cholesterol and high triglyceride levels were identifi ed as risk factors in men while, in females, the only risk factors were increasing age and a high BMI.Increasing age and pain in the right hypocondrium in men and increasing age in females were identifi ed as predictors of gallstones. Pain in the epigastrium/ right hypocondrium was the only symptom related to gallstones; furthermore, some characteristics of pain （forcing to rest, not relieved by bowel movements） were significantly associated with gallstones. No correlation was found between gallstone characteristics and clinical manifestations, while increasing age in men and increasing age and BMI in females were predictors of pain. CONCLUSION：Increasing age and BMI represent true risk factors for gallstone disease （GD）; pain in the right hypocondrium and/or epigastrium is confi rmed as the only symptom related to gallstones.     

Enterohepatic cycling of bilirubin: a putative mechanism for pigment gallstone formation in ileal Crohn's disease.

BACKGROUND & AIMS: Patients with ileal disease, bypass, or resection are at increased risk for developing gallstones. In ileectomized rats, bilirubin secretion rates into bile are elevated, most likely caused by increased colonic bile salt levels, which solubilize unconjugated bilirubin, prevent calcium complexing, and promote its absorption and enterohepatic cycling. The hypothesis that ileal disease or resection engenders the same pathophysiology in humans was tested. METHODS: Sterile gallbladder bile samples were obtained intraoperatively from 29 patients with Crohn's disease and 19 patients with ulcerative colitis. Bilirubin, total calcium, biliary lipids, beta-glucuronidase activities, and cholesterol saturation indices in bile were measured, and markers of hemolysis and ineffective erythropoiesis in blood were assessed. RESULTS: Bilirubin conjugates, unconjugated bilirubin, and total calcium levels were increased 3-10-fold in bile of patients with ileal disease and/or resection compared with patients with Crohn's colitis or ulcerative colitis. Biliary bilirubin concentrations correlated positively with the anatomic length and duration of ileal disease. Endogenous biliary beta-glucuronidase activities were comparable in all groups, and both the hemogram and serum vitamin B12 levels were normal. CONCLUSIONS: This study establishes that increased bilirubin levels in bile of patients with Crohn's disease are caused by lack of functional ileum, supporting the hypothesis that enterohepatic cycling of bilirubin occurs.     

Low-dose ursodeoxycholic acid prolongs cholesterol nucleation time in gallbladder bile of patients with cholesterol gallstones

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.     

Effects of colectomy on bile composition, cholesterol saturation and cholesterol crystal formation in humans

Total or subtotal colectomy is the surgical treatment of choice for patients with ulcerative colitis. Recently it has been reported that colectomy may lead to increased lithogenicity of bile, short nucleation time, cholesterol crystal formation, and gallstone disease. We examined whether colectomy in patients with ulcerative colitis leads to changes in bile composition that predisposes to cholesterol crystal formation and cholesterol gallstone disease. Ten consecutive patients who had previously undergone ileostomy and colectomy because of ulcerative colitis were admitted for ileal pouch surgery. At operation bile was obtained by puncture of the gallbladder. Controls were 35 patients undergoing cholecystectomy (23 for cholesterol gallstone disease and 12 for reasons other than gallstone disease). The gallbladder bile was analyzed for cholesterol crystals, bile acid, and biliary lipid composition, cholesterol saturation, and nucleation time. The colectomized patients had normal biliary lipid composition, normal cholesterol saturation, and normal nucleation time, in contrast to gallstone patients who displayed highly supersaturated bile with a short nucleation time. Thus patients with ileostomy after colectomy because of ulcerative colitis have normal cholesterol saturation and nucleation time of bile.     

Biliary lipid composition in patients with nonoperated Crohn's disease

Lipid composition of fasting duodenal bile was studied in 56 patients with nonoperated Crohn's disease, 21 normals matched for age and sex, 13 patients with cholesterol cholelithiasis, and 9 patients with ileal resections. Crohn's patients had a significantly higher mean saturation index, calculated according to Thomas (0.84±0.51) when compared to normal (0.63±0.25). Patients with ileocolonic Crohn's disease and patients with severe bile acid malabsorption, particularly, showed an increased incidence of cholesterol saturated bile. Saturation in patients with nonoperated Crohn's disease was not increased to the levels found in patients with ileal resection or cholesterol gallstones. Bile acid composition of gallbladder bile was characterized by a significant decrease of thedeoxycholate fractions in patients with Crohn's ileocolitis and colitis as well as in ileal resected patients. These qualitative changes of bile acid composition may influence cholesterol solubility. It is concluded that patients with nonoperated Crohn's disease may have an increased risk of developing cholesterol gallstones.     

Utility of biliary microscopy for the prediction of the chemical composition of gallstones and the outcome of dissolution therapy with ursodeoxycholic acid

To learn whether microcrystalline solids in bile could predict gallstone composition, the findings determined by polarizing microscopy of gallbladder bile were related to stone type at cholecystectomy in 53 patients. Cholesterol crystals were present in 36 of 39 cholesterol stone bile and absent in 12 of 14 bile from non-cholesterol stones. Fifteen cholesterol stones (eight radiopaque) contained calcium carbonate, and characteristic vaterite microspheroliths were observed in 53% of their bile. In another study, crystals in basal duodenal bile were related to the outcome of gallstone dissolution treatment with ursodeoxycholic acid, 10 mg/kg X day. In 39 patients treated for 1 yr, efficacy (complete gallstone dissolution) was 41% overall and 52% in patients with stones less than or equal to 10 mm in diameter. In connection with the findings of biliary microscopy, efficacy was 93% in 14 patients with cholesterol crystals in bile, and 27% in 11 patients with microspheroliths in bile. Cholecystectomies in 9 patients with dissolution failure revealed 4 cases of non-cholesterol stones and 5 cases (including 3 with on-therapy calcification) of calcium carbonate-rich cholesterol stones with a surface/interior mineral ratio greater than 3. The results confirm that cholesterol crystals in bile are a sensitive measure of cholesterol gallstones. They also show that vaterite microspheroliths in bile indicate the presence of calcium carbonate in gallstones. Both findings suggest that biliary crystals reflect gallstone composition, and it is demonstrated that this information is useful in predicting the success or failure of cholelitholysis with ursodeoxycholic acid. Finally, the data show that radiologically undetectable stone calcification reduces the probability of dissolution, and that the calcified structures appearing in some stones during treatment are composed of calcium carbonate.     

Decreased protein concentration and improved metastability of bile induced by ursodeoxycholate

Previous studies demonstrated that higher biliary protein is associated with reduced metastability of bile. This study attempted to examine the induced effect of ursodeoxycholate on metastability of bile by measuring the nucleation time and biliary protein in cholesterol gallstone patients. Thirty-seven patients with functioning gallbladders were studied 10 control patients without gallstones and 27 with cholesterol gallstones. Ten of 27 cholesterol gallstone patients were treated with ursodeoxycholate (600 mg/ day) prior to surgery. Twelve of 17 untreated gallstone patients had cholesterol crystals in gallbladder bile while cholesterol crystals were absent in the ursodeoxycholate-treated gallstone patients and in the controls. Total protein concentration and cholesterol saturation index were significantly greater in the untreated gallstone patients with crystals than in those without crystals in bile. The treatment with ursodeoxycholate significantly decreased biliary protein concentration and cholesterol saturation index associated with the prolonged nucleation time. Cholesterol nucleation time correlated with biliary total protein concentration and cholesterol saturation index but not with total lipid concentration. It is concluded from the present study that ursodeoxycholate decreases biliary protein thereby partly increasing metastability of gallbladder bile.     

Decreased protein concentration and improved metastability of bile induced by ursodeoxycholate.

Previous studies demonstrated that higher biliary protein is associated with reduced metastability of bile. This study attempted to examine the induced effect of ursodeoxycholate on metastability of bile by measuring the nucleation time and biliary protein in cholesterol gallstone patients. Thirty-seven patients with functioning gallbladders were studied 10 control patients without gallstones and 27 with cholesterol gallstones. Ten of 27 cholesterol gallstone patients were treated with ursodeoxycholate (600 mg/day) prior to surgery. Twelve of 17 untreated gallstone patients had cholesterol crystals in gallbladder bile while cholesterol crystals were absent in the ursodeoxycholate-treated gallstone patients and in the controls. Total protein concentration and cholesterol saturation index were significantly greater in the untreated gallstone patients with crystals than in those without crystals in bile. The treatment with ursodeoxycholate significantly decreased biliary protein concentration and cholesterol saturation index associated with the prolonged nucleation time. Cholesterol nucleation time correlated with biliary total protein concentration and cholesterol saturation index but not with total lipid concentration. It is concluded from the present study that ursodeoxycholate decreases biliary protein thereby partly increasing metastability of gallbladder bile.     

Concanavalin A-binding cholesterol crystallization inhibiting and promoting activity in bile from patients with Crohn's disease compared to patients with ulcerative colitis.

BACKGROUND/AIMS: Crohn's disease is a risk factor for gallstone formation. In contrast, patients with ulcerative colitis have an incidence of gallstone formation comparable to the general population. The reason for this difference is not known. The aim of this study was to elucidate the factors controlling cholesterol crystallization in gallbladder bile of Crohn's disease and ulcerative colitis patients. METHODS: Gallbladder bile was obtained by aspiration during bowel resections (26 Crohn's disease patients, 20 ulcerative colitis patients). Biliary lipid composition, crystal detection time and the effect of extraction of the concanavalin A-binding fraction on crystal formation were determined. RESULTS: Cholesterol crystals were present in seven of the 26 bile samples of Crohn's disease-patients and one of the 20 ulcerative colitis patients. Four of the bile samples of Crohn's disease patients were fast nucleating. None of the 20 ulcerative colitis patients had fast nucleating bile. Lipid composition, total lipid concentration and CSI were not significantly different between the two groups. In Crohn's disease patients extraction of concanavalin A-binding fraction decreased crystallization in 10 bile samples but accelerated crystallization in one bile sample. In eight bile samples from ulcerative colitis patients crystallization increased after concanavalin A-binding fraction extraction. CONCLUSIONS: Compared to ulcerative colitis patients, gallbladder bile of Crohn's disease patients showed increased cholesterol crystallization despite comparable lipid composition and cholesterol saturation index. This difference is caused by increased cholesterol crystallization-promoting activity. Bile from ulcerative colitis patients contains a Con A-binding factor which inhibits cholesterol crystallization.     

Combined Bile Acid Therapy is More Effective on Biliary Lipids and Dissolution Rates than Monotherapy After Gallstone Lithotripsy

Background: Accurate sampling to gallbladder bile for biliary analysis is essential for determining any potential difference between combined bile acid therapy and monotherapy in gallstone patients.
Methods: In 104 gallstone patients undergoing extracorporeal shock wave lithotripsy with following bile acid therapy [either chenodeoxycholic acid (500 mg/day) and ursodeoxycholic acid (500 mg/day), group I (n = 53), or ursodeoxycholic acid alone (1000 mg/day), group II (n = 51)], bile samples, obtained by direct fine needle puncture of the gallbladder, were investigated for biliary lipids, total biliary protein concentration, and nucleation time before and after 12 months of bile acid therapy.
Results: Initially, a negative correlation was found between nucleation time and number of gallstones and between total biliary protein concentration and nucleation lime ( r = -0.52 and r = -0.49 in group I vs r = -0.56 and r = -0.51 in group II, p < 0.01 in each group). The correlation between total biliary protein concentration and nucleation time was also found after 12 months of bile acid treatment ( r = -0.54 in group I vs r = -0.47 in group II, p < 0.01 in each group). In group I, the decrease in cholesterol saturation index, biliary cholesterol, cholic acid, deoxycholic acid, and total protein concentration was more pronounced than in group II ( p < 0.01). The same effect was found concerning the prolongation of nucleation time ( p < 0.01). Furthermore, dissolution rates were higher in group I compared with group II (80.4 vs 69.0%, p < 0.01).
Conclusion: In gallstone patients, combined therapy with urso- and che-nodeoxycholic acid is superior to either ursodeoxycholic acid alone or biliary parameters in bile samples obtained by direct line needle puncture of the gallbladder.     

Stabilization of biliary lipid particles by ursodeoxycholic acid

We evaluated the effect of ursodeoxycholic acid on the metastability of human bile as reflected by nucleation time and also assessed the mechanism of its action in an ultrastructural study. Ursodeoxycholic acid significantly prolonged the nucleation time of gallbladder bile from cholesterol gallstone patients without causing either drastic changes in the distribution of cholesterol between the nonmicellar and micellar fractions of bile or biliary choiesterol desaturation. Gel permeation chromatography resolved two distinct components of the nonmicellar fraction: vesicles and phospholipid lamellae (identified by electron microscopy). Nonmicellar cholesterol was predominantly carried by vesicles in the bile of untreated gallstone patients, whereas it was chiefly carried by phospholipid lamellae in patients treated with ursodeoxycholic acid. Furthermore, phospholipid lamellae from untreated gallstone patients showed rapid transformation and cholesterol microcrystal formation within seven days, whereas the lamellae from ursodeoxycholic acid-treated patients were stabilized and showed little change. On the other hand, biliary mucin concentration was reduced by the treatment with ursodeoxycholic acid. These findings suggest that ursodeoxycholic acid stabilizes phospholipid lamellae and consequently prolongs nucleation time. It is also possible that the reduction of biliary mucin plays a role in this process.