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

Abstract

Summary. 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 lowshear 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. Since mucus glycoproteins are major determinants of bile viscosity, an alteration in mucin macromolecular composition may conceivably cause the indomethacin-induced decrease in biliary viscosity and explain the beneficial effects of nonsteroidal anti-inflammatory drugs in gallstone disease. This view is based on the observation that in a number of animal models mucus hypersecretion is observed before crystal formation [11], and that in the prairie dog aspirin inhibits both cholesterol crystal formation and mucus secretion [10]. Recent studies on prairie dog gallbladder explants [15], however, failed to show an effect of aspirin on mucus secretion in concentrations which effectively inhibit prostaglandin synthesis. Furthermore, the relevance of the data collected in animal experiments for cholesterol gallstone disease in man is unclear. Studies in gallstone patients suggest that under aspirin treatment gallstone formation is reduced both during weight loss [2] and after successful litholytic therapy [7]. A recent prospective study by Rhodes et al [16] showed that in gallstone patients aspirin decreases mucus synthesis without a reduction in the mucus concentration of bile.The present study was designed to define the effect of oral indomethacin on lithogenicity of bile in patients with cholesterol gallstone disease. To seek a better understanding of the mechanisms involved in the action of NSAIDs in gallstone disease a detailed analysis of bile was performed, includi...

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