Ursodeoxycholic acid reduces lipid peroxidation and mucin secretagogue activity in gallbladder bile of patients with cholesterol gallstones.

BACKGROUND: Recently it has been postulated that gallbladder mucin hypersecretion observed in the pathogenesis of cholesterol gallstone disease may be induced by biliary lipid peroxidation. Ursodeoxycholic acid treatment reduces mucin concentration and the formation of cholesterol crystals in the gallbladder bile of patients with cholesterol gallstones and this effect might be mediated by a decrease of biliary lipid peroxidation. MATERIAL AND METHODS: In a double-blind, placebo-controlled trial patients with symptomatic cholesterol gallstones received either ursodeoxycholic acid (750 mg daily) (n = 10) or placebo (n = 12) 10-12 days prior to cholecystectomy. As a marker for lipid peroxidation malondialdehyde was measured in bile together with mucin concentration. In addition, the mucin secretagogue activity of the individual bile samples was assessed in cultured dog gallbladder epithelial cells. RESULTS: Ursodeoxycholic acid therapy resulted in a significant reduction of lipid peroxidation in bile as determined by the biliary malondialdehyde concentration (1.36 +/- 0.28 vs. 2.05 +/- 0.38 micromol L(-1); P < 0.005) and the malondialdehyde (micromol L(-1))/total bile acid (mmol L(-1)) ratio (0.02 +/- 0.005 vs. 0.06 +/- 0.01; P < 0.001). Furthermore, a decrease in mucin concentrations (0.7 +/- 0.3 vs. 1.3 +/- 0.5 mg mL(-1); P < 0.005) and of the mucin secretagogue activity of gallbladder bile (0.9 +/- 0.2 vs. 2.2 +/- 0.3 times control; P < 0.001) was observed. CONCLUSIONS: The reduction of lipid peroxidation and mucin secretagogue activity of gallbladder bile induced by ursodeoxycholic acid treatment may contribute to the beneficial effects of this drug on gallbladder bile composition and symptoms in cholesterol gallstone patients.

Lipid peroxidation and mucin secretagogue activity in bile of gallstone patients.

BACKGROUND: Chronic inflammation of the gallbladder wall and mucin hypersecretion are considered to be important factors in the pathogenesis of cholesterol gallstone disease. The aim of the study was to compare mucin concentration and mucin secretagogue activity with lipid peroxidation in gallbladder bile of patients with cholesterol or pigment stones. MATERIAL AND METHODS: We studied mucin concentration and, as a marker of lipid peroxidation, malondialdehyde concentration in 11 rapid (1 to 3 days) and eight non-nucleating (> 21 days) gallbladder biles of patients with cholesterol or pigment stones. Furthermore, the mucin secretagogue activity of rapid and non-nucleating gallbladder biles, as well as 1-5 micromol L(-1) malondialdehyde on cultured gallbladder epithelial cells, was determined. RESULTS: Our data show an increased malondialdehyde (7.2 +/- 1.8 vs. 3.8 +/- 0.5 micromol L(-1), P = 0.01) and mucin concentration (0.9 +/- 0.09 vs. 0.41 +/- 0.03 mg mL(-1), P = 0.01) and an increased mucin secretagogue activity (2.0 +/- 0.5 vs. 1.1 +/- 0.3 mucin secretion/control, P = 0.04) and cholesterol saturation index (1.2 +/- 0.1 vs. 08 +/- 0.1, P = 0.04) in rapid as compared to non-nucleating gallbladder biles. Malondialdehyde stimulated mucin secretion of cultured gallbladder epithelial cells in a concentration dependent manner. CONCLUSIONS: Our results support a promoting effect of gallbladder mucin hypersecretion by lipid peroxidation leading to rapid formation of cholesterol crystals in gallbladder bile. These findings suggest that besides hypersecretion of cholesterol in bile, chronic inflammation of the gallbladder wall is implicated in the pathogenesis of cholesterol gallstone disease.

Human biliary mucin binds to E-selectin: a possible role in modulation of inflammation.

E-selectin, expressed on endothelial cells, mediates adhesion of leukocytes and tumor cells to endothelium. CA19-9 (sialyl-Lewis(a)) and sialyl-Lewis(x) are specific ligands for E-selectin. We have recently shown that mucin-rich culture media from human gallbladder epithelial cells contains CA19-9. In this study, we have tested whether human biliary mucin binds to E-selectin. The ability of mucins to inhibit the adhesion of HL-60 cells to immobilized E-selectin was taken as an index for E-selectin binding. Gallbladder bile, hepatic bile, and culture medium from human gallbladder epithelial cells completely inhibited the adhesion of HL-60 cells to E-selectin. The mucin-rich fractions of human bile exhibited strong inhibition, whereas mucin-free fractions had little effect. In contrast to human bile samples, CA19-9-free medium from cultured dog gallbladder epithelial cells failed to inhibit HL-60 binding. Furthermore, after CA19-9 immunoaffinity chromatography, which selectively extracted CA19-9 from bile, bile samples showed poor inhibition of HL-60 adhesion to immobilized E-selectin. A good correlation was observed between E-selectin binding and CA 19-9 concentrations in bile. Our results show that human bile has E-selectin binding activity that is mediated by the CA19-9 side chain of biliary mucin.

Reduced myocardial cellular damage and lipid peroxidation in off-pump versus conventional coronary artery bypass grafting.

BACKGROUND: The development of new surgical devices and techniques allows off pump coronary artery bypass grafting (OPCAB) without the use of CPB and cardioplegia. This study tested whether OPCAB reduces myocardial cell damage, lipid peroxidation and systemic endothelin release when compared to conventional coronary artery bypass grafting. METHODS: Twenty-six patients were assigned to either the OPCAB procedure using a suction device and regular sternotomy (n = 13) or were treated conventionally using extracorporeal circulation, blood cardioplegia and hypothermic arrest (29-31 degrees C; n = 13). Troponin I and creatine kinase - MB were determined for cardiac specific cell damage. Myocardial and systemic malondialdhyde levels were measured to account for oxyradical mediated lipid peroxidation. Systemic big-endothelin levels were determined as a marker for endothelial cell activation. RESULTS: A significant reduction of the cardiac specific cell damage was observed in the OPCAB group vs. the CABG group over time in the absence of acute myocardial ischemia or infarction. In addition, systemic and myocardial lipid peroxidation as measured by the malondialdehyde (MDA) levels were lower in the OPCAB group when compared to CABG. Finally, plasma levels of big-Endothelin (big-ET) significantly rose in the CABG but not in the OPCAB group. CONCLUSIONS: The data of the present study indicate that OPCAB revascularization without the use of CPB and cardioplegic arrest reduces myocardial cell damage and lipid peroxidation. It is also associated with a reduced activation of the potent vasoconstrictor peptide endothelin. All of this may contribute to improved myocardial function and faster postoperative recovery from surgical revascularization procedures, particularly in critically ill patients.

Detection of colonic dysplasia by light-induced fluorescence endoscopy: a pilot study.

Light-induced fluorescence endoscopy (LIFE) has been shown to differentiate between normal mucosa and dysplastic lesions, and dysplastic lesions of the colon occult to routine white-light colonoscopy may thus be visualized by LIFE. We compared the sensitivity and specificity of LIFE to routine white-light colonoscopy in patients with colonic dysplasia. In a pilot study 20 patients with colonic adenoma, inflammatory bowel disease, or with a history of colon cancer were screened for colonic dysplasia during routine colonoscopy. Forty-two sites of mucosal abnormalities regarded as suspicious for dysplasia during white-light colonoscopy were additionally examined with a prototype LIFE system. Biopsies were taken from all 42 colonic sites. The LIFE images were classified as positive or negative for dysplasia. Sensitivity and specificity were calculated by correlating positive and negative findings to the histopathological results. Histopathology detected 21 adenomas with low-grade dysplasia and one with high-grade dysplasia. All dysplastic lesions were found by routine white-light endoscopy. The specificity of conventional white-light endoscopy was 80%. Of the 22 dysplastic lesions 20 were detected by LIFE (sensitivity 91%). The specificity of LIFE was 90% (two false-positive results). LIFE combined with conventional endoscopy may thus improve the detection of colonic dysplasia.

Bile acid malabsorption as a cause of chronic diarrhea: diagnostic value of 7alpha-hydroxy-4-cholesten-3-one in serum.

To evaluate the usefulness of 7a-hydroxy-4-cholesten-3-one (HCO) serum concentrations as a diagnostic marker of bile acid malabsorption, we determined the reference range of HCO in 106 normal subjects (age 40.2+/-16.8 years; 55 women, 51 men) and conducted a utility study in 23 patients with chronic diarrhea of unknown origin (age 49.4+/-15.3 years, 13 women, 10 men). The diagnosis of bile acid malabsorption was made on the basis of a decreased retention of [75Se]homocholyltaurine after oral application (75SeHCAT test). HCO (reference range: 6-48 ng/ml) and the 75SeHCAT test yielded the same results in 19/23 (83%) patients. Bile acid malabsorption was identified by an increase of HCO in serum with a sensitivity of 90% and a specificity of 79%. Analysis of HCO in serum may serve as a novel, simple, and sensitive method for the detection of bile acid malabsorption in patients with chronic diarrhea of unknown origin.

Effect of bile acids on lipid peroxidation: the role of iron.

The toxic effect of hydrophobic bile acids is claimed to be in part mediated by lipid peroxidation. Conversely, antioxidant properties of tauroursodeoxycholic acid (TUDC), a hydrophilic bile acid, have been suggested as a possible mechanism by which TUDC confers its beneficial effect in a variety of diseases. We have investigated the effect of taurodeoxycholic acid (TDC), a hydrophobic bile acid and TUDC on lipid peroxidation using a pure lipid system both in the presence and absence of iron ions. Neither TDC nor TUDC showed any effect on spontaneous lipid peroxidation of phosphatidylcholine liposomes or sodium arachidonate solution. This lack of effect excludes the possibility of direct prooxidant or antioxidant properties for TDC and TUDC. Addition of ferrous ions (0.1 mM) to the lipid system brought about a linear increase in lipid peroxidation with time. The presence of TDC caused an increase in the rate and extent of iron-stimulated lipid peroxidation. The propensity of bile acids to increase iron-induced lipid peroxidation was related to hydrophobicity of the individual bile acids, with the highest effect observed with taurolithocholic acid, whereas TUDC did not have any influence. The TDC-induced increase in the iron-stimulated lipid peroxidation was concentration dependent. Addition of TUDC (10 mM) completely abolished the effect of TDC (2 mM) on iron-induced lipid peroxidation. This finding suggests that TUDC does not function as an antioxidant per se but may prevent lipid peroxidation caused by TDC. In conclusion, only in the presence of iron ions, hydrophobic bile acids may enhance lipid peroxidation. TUDC has no antioxidant activity per se but may counter the TDC-induced increase in iron-stimulated lipid peroxidation.

[Chronic inflammatory bowel diseases. Pathophysiology and drug therapy]. / Chronisch-entzündliche Darmerkrankungen. Pathophysiologie und medikamentöse Therapie.

Recent studies indicate that the normal intestinal flora, an exaggerated reaction of the intestinal immune system and a decreased epithelial barrier function of the gut play an important role in the pathogenesis of Crohn's disease and ulcerative colitis. The medical therapy of inflammatory bowel disease aims to correct these alterations. Aminosalicylates, corticosteroids, immunosuppressants and antibiotics are the four main groups of substances which are currently used for the therapy of inflammatory bowel diseases. Slow release formulation allow specific targeting of 5-aminosalicylic acid to the inflamed sections of the gut; with budesonid a corticosteroid therapy with minimal systemic side effects is possible. Future therapeutic options include specific immuno-modulatory therapy with cytokines or cytokine antibodies. Maintenance therapy may, conceivably, be performed with probiotics or antioxidants. Therefore, despite continued uncertainty about the cause of inflammatory bowel diseases, recent advances nourish the hope for further improvement of the control of disease activity and a better quality of life for patients with inflammatory bowel diseases.

[MRI of the small intestine with rapid MRI sequences in Crohn disease after enteroclysis with oral iron particles]. / Dünndarm-MRT mit schnellen MR-Sequenzen bei Morbus Crohn nach Enteroklysma mit oralen Eisenpartikeln.

PURPOSE: To evaluate the efficacy of breathhold MRI following enteroclysis with addition of oral magnetic particles to study the extension, detection of stenoses and extraluminal manifestations in Crohn's disease. MATERIAL AND METHODS: 18 patients with Crohn's disease and potential of surgical intervention were studied with enteroclysis with addition of oral magnetic particles. T1-/T2-weighted breathhold MRI w/o spectral fat suppression w/o i.v. Gd-DTPA was applied. RESULTS: Typical findings were marked bowel wall thickening with strong contrast enhancement. 95.8% of affected small bowel segments and 94.7% of stenoses were correctly detected by MRI. All four fistulas were detected and important extraluminal findings were seen in 6/18 patients. Additionally, one ileoileal and two ileosigmoidal adhesions, two extraluminal abscesses and affection of the right ureter were delineated. CONCLUSION: MRI in Crohn's disease offers the potential to avoid radiation exposure in this relatively young patient group. Important additional findings relevant to indication of surgery are seen in approximately one third of cases. The replacement of transduodenal intubation by oral contrast application remains to be further studied.

Biliary mucin secreted by cultured human gallbladder epithelial cells carries the epitope of CA 19-9.

Serum CA 19-9 is increased in patients with different gastrointestinal malignancies. Unfortunately, CA 19-9 is also detected in high concentrations in normal bile causing unspecific serum elevations during inflammatory disease of the biliary tract and cholestasis. In order to identify the source of CA 19-9 in bile, the capacity of cultured human gallbladder epithelial cells (HGBEC) to secrete CA 19-9 was investigated. Cells were harvested from gallbladders removed by cholecystectomy and cultured for up to 14 days in collagen I coated 24-well culture dishes. CA 19-9 was measured in the culture medium by a solid-phase CA 19-9 EIA (Boehringer). In addition, culture medium was separated by Sepharose 4B-Cl, Concanavalin-A (Con-A) and CA 19-9 affinity chromatography. Significant CA 19-9 activity was measured in the culture medium after a 24 hour incubation period. Following separation of the culture medium by Sepharose 4B-Cl and Con-A affinity chromatography, 90% of the CA 19-9 activity was recovered in the exclusion volume (> 2000 kDa) from which 90% were identified as Con-A negative. A close correlation was found between CA 19-9 and concentrations of mucin purified from human gallbladder bile. Furthermore, CA 19-9 affinity chromatography selectively extracted mucins from the culture medium of HGBEC. Finally, addition of the mucin secretagogue bethanechol (6 mM) to the culture medium increased CA 19-9 activity in the medium. In conclusion, normal HGBEC secrete mucins carrying the epitope of CA 19-9. During inflammatory biliary disease unspecific elevation of CA 19-9 in serum may reflect both inflammatory hypersecretion and leakage of biliary mucins into serum.

Sedimentation of biliary sludge: effect on composition of gallbladder bile from patients with cholesterol, mixed, or pigment stones.

BACKGROUND: Ultracentrifugation of bile has been used extensively to remove insoluble material such as sludge from bile before further studies of cholesterol nucleation. Although it has been recognized that this procedure may affect the composition of gallbladder bile, it has not been studied systematically in different gallstone populations. Therefore, we investigated the concentration of biliary lipids, protein, mucin, and bilirubin before and after ultracentrifugation. METHODS: Gallbladder bile samples were aspirated during laparoscopic surgery from 66 patients (35 with cholesterol, 16 with mixed, and 15 with pigment stones). RESULTS: Whereas the concentrations of bile acids, phospholipids, protein, and bilirubin in gallbladder bile did not change significantly after ultracentrifugation, cholesterol (20.6 +/- 1.6 to 14.8 +/- 1.2 mmol/l) and mucin concentrations (0.99 +/- 0.2 to 0.67 +/- 0.1 mg/ml) and the cholesterol saturation index (1.68 +/- 0.12 to 1.31 +/- 0.10) decreased significantly in gallbladder bile from patients with cholesterol stones. CONCLUSIONS: Sedimentation of biliary sludge may profoundly affect the composition of gallbladder bile, which has to be considered in studies of cholesterol saturation and nucleation. The cholesterol concentration difference between native and ultracentrifuged bile reflects the insoluble crystalline fraction of cholesterol and may be useful for quantitation of the mass of cholesterol crystals in gallstone-associated bile samples.

Reactive oxygen metabolites promote cholesterol crystal formation in model bile: role of lipid peroxidation.

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.

Quantification of mucin in human gallbladder bile: a fast, specific, and reproducible method.

It is generally accepted that gallbladder mucin (GBM) plays an important role in the pathogenesis of cholesterol gallstone (ChG) disease. However, it remains unclear whether ChG patients have higher GBM concentrations than controls. Discrepant findings regarding biliary mucin concentrations may be due to methodological problems with the assays commonly used. The methods currently used to quantitate mucin in bile have not been systematically evaluated. To establish a reliable method for mucin quantification in bile, we evaluated three mucin assays: the classic Pearson-PAS (periodic acid Schiff) assay, a direct fluorometric assay, and a new PAS or fluorometric assay with the following modifications of the Pearson assay: preincubation of bile samples with TBS containing KSCN and sodium taurocholate and micellation of biliary lipids during gel chromatographic fractionation using 25 mM sodium taurocholate in the elution buffer. SDS-PAGE and monoclonal anti-human-GBM (GBM59) were used to identify mucin. Highly specific and reproducible mucin isolation was achieved with the modified method. We found considerable loss of mucin during the different purification steps in the Pearson method. The direct fluorometric assay showed unspecific fluorometric signal with low molecular constituents of bile. Our experiments showed that human-GBM can be accurately measured after a simple modified chromatographic fractionation followed by a PAS or fluorometric assay.

Simvastatin added to ursodeoxycholic acid does not enhance disappearance of gallstone fragments after shock wave therapy.

Inhibitors of the HMG-CoA reductase have been shown to further reduce the biliary cholesterol saturation in patients treated with oral bile acids for cholesterol gallbladder stones. It was the aim of our study to evaluate the efficacy of simvastatin in addition to ursodeoxycholic acid in the dissolution of gallstone fragments after shock wave lithotripsy and adjuvant bile acid dissolution therapy. Eighteen patients with a single radiolucent gallbladder stone and a serum cholesterol of more than 250 mg/dl were randomly assigned to receive either ursodeoxycholic acid alone (750 mg per day, group A, n = 9) or in combination with simvastatin (20 mg per day, group B, n = 9) for the dissolution of the gallstone fragments generated by extracorporeal shock wave lithotripsy. The two groups were well matched regarding their baseline characteristics. At the primary end point of the study 6 months after lithotripsy, there was no difference between the groups in the rate of gallstone disappearance with 4 of 9 patients being stone free in each group. As evaluated by life table analysis, even further follow-up showed no significant difference between the groups (P = 0.8). In group B, serum cholesterol levels decreased by 22% at 3 months (P = 0.01 vs. baseline) and by 24% at six months (P = 0.02) during treatment while no significant change was observed in group A. With both regiments, no adverse effects were observed. While simvastatin added to ursodeoxycholic acid resulted in a decrease of elevated serum cholesterol levels in gallstone patients, it did not enhance stone disappearance after shock wave lithotripsy and adjuvant bile acid dissolution therapy.

Gallbladder emptying determines early gallstone clearance after shock-wave lithotripsy.

BACKGROUND/AIMS: Disappearance of gallbladder stones after shock-wave lithotripsy combined with bile acid therapy depends on mechanical evacuation and dissolution of fragments. Many patients with gallstones have impaired gallbladder emptying and may show delayed stone clearance after lithotripsy. METHODS: The effect of gallbladder emptying on gallstone clearance after lithotripsy was prospectively studied in 57 patients with one radiolucent gallbladder stone < or = 20 mm. Gallbladder emptying was assessed sonographically before and after 2 weeks of ursodeoxycholic acid (UDCA) treatment. RESULTS: UDCA increased gallbladder fasting and residual volume and decreased ejection rate but did not affect ejection fraction. Patients with an ejection fraction > 60% achieved complete gallstone clearance after lithotripsy in a higher percentage than patients with smaller ejection fractions (1 month, 31% vs. 7%, P = 0.022; 2 months, 55% vs. 18%, P = 0.003; 3 months, 66% vs. 29%, P = 0.005). Patients who became stone-free within 1 month showed larger ejection fractions than patients with retained fragments (67% +/- 4% vs. 56% +/- 3% before UDCA, P = 0.032; 65% +/- 4% vs. 53% +/- 3% with UDCA, P = 0.017). Further, ejection rate during UDCA therapy was larger in patients with complete gallstone disappearance within 1 month than in patients with delayed fragment clearance (1.57%/min +/- 0.36%/min vs. 0.76%/min +/- 0.09%/min; P = 0.002). CONCLUSIONS: Gallbladder emptying is a major determinant of early gallstone clearance after lithotripsy.

Fibronectin in human gallbladder bile: cholesterol pronucleating and/or mucin "link" protein?

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.

Gallstone recurrence after shock-wave therapy.

BACKGROUND/AIMS: The long-term outcome of nonoperative gallstone therapy depends on both absence of stones and absence of biliary pain. The aim of the present study was to determine the rate of stone recurrence and the rate of symptoms within 5 years after successful shock wave lithotripsy combined with bile acid therapy. METHODS: One hundred consecutive patients (single stones, n = 89; 2 or 3 stones, n = 11) were followed up for a median of 4.3 years after stone disappearance and discontinuation of bile acids. RESULTS: Twenty-three of the 100 patients developed recurrent stones. Calculated by actuarial analysis, the recurrence rate was 7% +/- 3%, 11% +/- 3%, 13% +/- 4%, 20% +/- 5%, and 31% +/- 7% (mean +/- SD) at 1, 2, 3, 4, and 5 years, respectively. The recurrent stones were small (6 +/- 5 mm) and were associated with recurrent biliary pain in 14 (61%) of the 23 patients. Repeated shock wave lithotripsy and/or bile acid medication resulted in stone disappearance in only 10 of 20 patients with recurrence. CONCLUSIONS: The long-term rate of stone recurrence after lithotripsy of primarily solitary gallbladder calculi is lower than expected from post-bile acid dissolution trials. Recurrence of stones frequently is associated with recurrence of biliary pain.

Indomethacin decreases viscosity of gallbladder bile in patients with cholesterol gallstone disease.

There is experimental evidence that inhibition of cyclooxygenase with nonsteroidal anti-inflammatory drugs may decrease cholesterol gallstone formation and mitigate biliary pain in gallstone patients. The mechanisms by which NSAIDs exert these effect are unclear. In a prospective, controlled clinical trial we examined the effects of oral indomethacin on the composition of human gallbladder bile. The study included 28 patients with symptomatic cholesterol or mixed gallstones. Of these, 8 were treated with 3 x 25 mg indomethacin daily for 7 days prior to elective cholecystectomy while 20 received no treatment and served as controls. Bile and tissue samples from the gallbladder were obtained during cholecystectomy. Indomethacin tissue levels in the gallbladder mucosa, as assessed by HPLC, were 1.05 +/- 0.4 ng/mg wet weight, a concentration known to inhibit effectively cyclooxygenase activity. Nevertheless, no differences between the treated and untreated groups were found in the concentrations of biliary mucus glycoprotein (0.94 +/- 0.27 versus 0.93 +/- 0.32 mg/ml) or total protein (5.8 +/- 0.9 versus 6.4 +/- 1.3 mg/ml), cholesterol saturation (1.3 +/- 0.2 versus 1.5 +/- 0.2), or nucleation time (2.0 +/- 3.0 versus 1.5 +/- 2.0 days). However, biliary viscosity, measured using a low-shear rotation viscosimeter, was significantly lower in patients receiving indomethacin treatment (2.9 +/- 0.6 versus 5.6 +/- 1.2 mPa.s; P < 0.02). In conclusion, in man oral indomethacin decreases bile viscosity without alteration of bile lithogenicity or biliary mucus glycoprotein content.(ABSTRACT TRUNCATED AT 250 WORDS)