deoxycholic-acid and Cholelithiasis

Recent epidemiological studies have suggested that hyperinsulinaemia may be a central factor in the pathogenesis of cholesterol gallstones, explaining a probable link with physical inactivity as well as abdominal adiposity. There is also increasing evidence for the hypothesis that enrichment of bile with DCA. 'the colonic bile acid', leads to enrichment of bile with cholesterol. Biliary DCA can be raised and lowered by slowing down and speeding up colonic transit, respectively. Slow transit is characteristic of non-obese British women with gallstones and of non-obese peasants in a gallstone-prone mountain community. High biliary DCA predicts recurrence of gallstones and so does laxative usage, a pointer to constipation and therefore to slow transit. In some studies, at least, a high fibre intake is protective against gallstones. Much else besides fibre influences colonic function. Future studies of gallstone aetiology should include measurements of colonic function. Measures that speed up colonic transit should be tested for their ability to prevent gallstone formation in high-risk individuals.

Topics: Adult; Body Mass Index; Cholelithiasis; Deoxycholic Acid; Epidemiologic Studies; Female; Gastrointestinal Transit; Humans; Male; Obesity; Risk Factors

The aim of this article is to review selected aspects of the pathogenesis of cholesterol-rich, gall-bladder stones (GBS)--with emphasis on recent developments in biliary cholesterol saturation, cholesterol microcrystal nucleation, statis within the gall-bladder and, particularly, on the roles of intestinal transit and altered deoxycholic acid (DCA) metabolism, in GBS development. In biliary cholesterol secretion, transport and saturation, recent developments include evidence in humans and animals, that bile lipid secretion is under genetic control. Thus in mice the md-2 gene, and in humans the MDR-3 gene, encodes for a canalicular protein that acts as a 'flippase' transporting phospholipids from the inner to the outer hemi-leaflet of the canalicular membrane. In the absence of this gene, there is virtually no phospholipid or cholesterol secretion into bile. Furthermore, when inbred strains of mice that have 'lith genes' are fed a lithogenic diet, they become susceptible to high rates of GBS formation. The precipitation/nucleation of cholesterol microcrystals from supersaturated bile remains a critical step in gallstone formation. methods of studying this phenomenon have now been refined from the original 'nucleation time' to measurement of cholesterol appearance/detection times, and crystal growth assays. Furthermore, the results of recent studies indicate that, in addition to classical Rhomboid-shape monohydrate crystals, cholesterol can also crystallize, transiently, as needle-, spiral- and tubule-shaped crystals of anhydrous cholesterol. A lengthy list of promoters, and a shorter list of inhibitors, has now been defined. There are many situations where GB stasis in humans is associated with an increased risk of gallstone formation--including iatrogenic stone formation in acromegalic patients treated chronically with octreotide (OT). As well as GB stasis, however, OT-treated patients all have 'bad' bile which is supersaturated with cholesterol, has excess cholesterol in vesicles, rapid microcrystal mulceation times and a two-fold increase in the percentage DCA in bile. This increase in the proportion of DCA seems to be due to OT-induced prolongation of large bowel transit time (LBTT). Thus LBTT is linearly related to (i) the percentage of DCA in serum; (ii) the DCA pool size; and (III) the DCA input or 'synthesis' rate. Furthermore, the intestinal prokinetic, cisapride, counters the adverse effects of OT on intestinal transit, and 'normalizes' the perce

Topics: Acromegaly; Animals; Bile Acids and Salts; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Gallbladder; Gastrointestinal Transit; Humans; Mice

Current evidence suggests that impaired intestinal motility may facilitate gallstone formation by influencing biliary deoxycholate levels or by modulating interdigestive gall bladder motility (fig 2), although a primary intestinal defect in gallstone pathogenesis has not yet been demonstrated. In the cold war period, most interesting events, from a political point of view, occurred at the border between capitalist and communist systems, near the iron curtain. Similarly, the gall bladder and biliary tract can be viewed as the border between liver and intestinal tract, where many interesting things occur with profound impact on both systems. Combined efforts by researchers in the field of hepatology and gastrointestinal motility should brake down the Berlin wall of ignorance of one of the most common diseases in the Western world.

Topics: Animals; Cholelithiasis; Cholesterol; Deoxycholic Acid; Gallbladder Emptying; Gastrointestinal Motility; Humans; Intestines; Postprandial Period

The primum movens in cholesterol gallstone formation is hepatic cholesterol hypersecretion and chronic supersaturation of bile. From this event a cascade of contributing factors can be differentiated: (i) Motility defects with impaired gallbladder contractility and gallbladder stasis, but also with small and large intestinal hypomotility. (ii) Multiple biochemical defects in gallbladder bile with increased biliary proteins, increased deoxycholic acid and rapid crystallization of biliary cholesterol from supersaturated unstable vesicles. There is considerable evidence that slow intestinal and colonic transit can increase the deoxycholic acid pool size and biliary cholesterol saturation. Changes in intestinal transit influence the anaerobic bacterial enzymatic biotransformation of conjugated cholate to more hydrophobic deoxycholate. This leads to biliary cholesterol hypersecretion and gallstone formation. Prokinetic drugs or administration of lactulose or fiber products like bran can change the slow intestinal transit favourably with subsequent reduction in deoxycholic acid formation and cholesterol saturation of bile. Whether these applications are indeed of value in the long-term prevention of gallstone disease, however, is doubtful, since fiber-rich diet in prevention of gallstone recurrence after complete gallstone dissolution was not successful.

Topics: Bile; Cholelithiasis; Cholesterol; Deoxycholic Acid; Dietary Fiber; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Lactulose

Topics: Bile Duct Diseases; Cholelithiasis; Deoxycholic Acid; Humans; Lithotripsy

Topics: Cholelithiasis; Deoxycholic Acid; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Topics: Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Non-surgical treatment of cholesterol gallstones is possible with oral chemolitholysis employing chenodeoxycholic acid (CDA) and/or ursodeoxycholic acid (UDA), oral chemolitholysis following ESWL and direct dissolution with methyl tert-butyl ether (MTBE). Oral chemolitholysis takes a long time (6-24 months), is suitable only for small stones (up to 1.5 cm) and has a success rate of 60-70%. Prior ESWL shortens the duration of oral treatment moderately and can be employed with larger (up to 3 cm) stones; it is, however, quite expensive. The new method of direct chemolysis of gallstones is rapid, very cheap, and effective (approx. 95% success rate), but is an invasive procedure. If previous results obtained with MTBE are confirmed, it could become a therapeutic alternative to cholecystectomy in the case of very large and multiple stones.

Topics: Administration, Oral; Chenodeoxycholic Acid; Cholelithiasis; Combined Modality Therapy; Deoxycholic Acid; Humans; Lithotripsy; Ursodeoxycholic Acid

The rationale, safety, and efficacy of cholesterol gallstone dissolution by orally administered ursodiol, chenodiol, or a combination of the two agents are summarized herein. Bile must be supersaturated in cholesterol for gallstones to form, and desaturation of bile by orally administered bile acids induces gradual stone dissolution. The mechanism of action of the two agents differs, but both cause a decreased input of cholesterol into the metabolic pool. Ursodiol is free of side effects, and the combination with chenodiol is equally efficacious and also has few side effects. Chenodiol, although an effective desaturation agent, causes diarrhea, mild reversible hepatic injury, and a small increase in the plasma cholesterol level. Extracorporeal shock-wave lithotripsy decreases gallstone size markedly and thereby increases the speed of dissolution by orally administered bile acids. Medical therapy with oral bile acids is appropriate for patients who present with small cholesterol stones and for patients with larger cholesterol gallstones who cannot or will not have surgery. Oral bile acids may also be valuable in the treatment of gallstone recurrence before it has become symptomatic or to prevent recurrence after prior successful dissolution of recurrent stones.

Topics: Administration, Oral; Chenodeoxycholic Acid; Cholecystography; Cholelithiasis; Cholesterol; Deoxycholic Acid; Drug Therapy, Combination; Gallbladder; History, 20th Century; Humans; Ursodeoxycholic Acid

The combination of dissolution and shockwave treatment for cholesterol stones is successful in 80% of the patients. The indication is strictly limited to cholesterol stones of between ten and thirty millimeters in diameter, or three stones of similar mass. In 80% of common duct stones which cannot be removed by endoscopy, shockwave treatment is a successful adjuvant procedure. It is estimated that recurrent stones will occur in 50% of the cases after five years. As long as the problem of recurrent stones persists, the group of stone carriers suitable for conservative treatment cannot be definitevely defined.

Topics: Chenodeoxycholic Acid; Cholelithiasis; Combined Modality Therapy; Deoxycholic Acid; Humans; Lithotripsy; Ursodeoxycholic Acid

Extracorporeal shock wave lithotripsy (ESWL) of gallstones is a new and experimental treatment. Recent data seem to indicate that the use of ursodeoxycholic acid (UDCA) after ESWL may optimize the results of the shock wave treatment. Most of the published data on the clinical use of such therapy emanate from two studies conducted in West Germany in approximately 300 patients. These subjects received combination therapy with UDCA and chenodeoxycholic acid (CDCA) before and after ESWL. The stone fragments gradually disappeared by 18 months after lithotripsy. No adverse effects attributable to the UDCA-CDCA treatment were noted. Several considerations support the view that adjuvant chemical dissolution therapy will be necessary for best results with ESWL, including compatibility of the rate of stone dissolution postlithotripsy with that of chemical dissolution rather than mechanical ejection; the common presence of cholesterol-supersaturated bile in gallstone patients, promoting reconglomeration of fragments; and decreased contractility of the gallbladder, which may improve after successful cholelitholytic therapy with UDCA. Placebo-controlled studies on the use of UDCA with ESWL are currently being conducted.

Topics: Chenodeoxycholic Acid; Cholelithiasis; Clinical Trials as Topic; Deoxycholic Acid; Germany, West; Humans; Lithotripsy; Ursodeoxycholic Acid

Topics: Administration, Oral; Chenodeoxycholic Acid; Cholelithiasis; Combined Modality Therapy; Deoxycholic Acid; Forecasting; Humans; Lithotripsy; Ursodeoxycholic Acid

Ursodiol, a naturally occurring bile acid, has gained Food and Drug Administration approval for the dissolution of cholesterol gallstones. Ursodiol inhibits hepatic cholesterol synthesis and secretion. Lithocholic acid, a potentially hepatotoxic metabolite of ursodiol and chenodiol, may accumulate to a lesser extent with ursodiol than with chenodiol. Enterohepatic recirculation of ursodiol and its metabolites occurs and is essential to the dissolution of cholesterol gallstones. Complete dissolution has been achieved in 17 percent of patients with noncalcified, radiolucent, floating, cholesterol gallstones. Recurrence of cholesterol gallstones may occur in over one-half of initial responders. Diarrhea reported in up to 50 percent of the patients on chenodiol has been reported in only 4 percent of patients treated with ursodiol. Increased mean aspartate aminotransferase levels to more than twice the pretreatment level seen with chenodiol therapy have not been reported with ursodiol. Reportedly fewer adverse reactions may give ursodiol a major advantage over chenodiol in hospital formulary considerations.

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Topics: Bile Duct Diseases; Caprylates; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Ethers; Glycerides; Humans; Lithotripsy; Methyl Ethers; Solvents; Ursodeoxycholic Acid

Topics: Adult; Aged; Bile; Cholelithiasis; Deoxycholic Acid; Female; Humans; Male; Middle Aged

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Lithotripsy; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Gallbladder; Humans; Ursodeoxycholic Acid

Topics: Animals; Bile; Cholelithiasis; Cholesterol; Deoxycholic Acid; Dietary Fiber; Epidemiologic Methods; Humans

Orally administered UDCA dramatically reduces the secretion of cholesterol into the bile. During UDCA therapy cholesterol balance is maintained by a reduction in both the relative and absolute absorption of cholesterol and, perhaps, by a combined moderate enhancement of bile acid synthesis and a suppression of cholesterol production. The percentage of UDCA in the bile is limited by the inability of UDCA to suppress bile acid synthesis from cholesterol and by the conversion of UDCA to CDCA by the intestinal bacteria.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Topics: Animals; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Ursodeoxycholic acid is the 7 beta-hydroxy epimer of chenodeoxycholic acid and is normally present in only trace amounts in the bile. Oral administration of pharmacological doses markedly decreases biliary cholesterol saturation. Complete or partial dissolution of radiolucent gallstones located in a functioning gallbladder occurred in about 40 to 55% of patients treated with ursodeoxycholic acid in controlled studies of 6 months duration. Patients showing partial gallstone dissolution at that time are likely to continue improving possibly to complete gallstone dissolution with continued therapy. The success rate with ursodeoxycholic acid may be increased top about 80% if more stringent patient selection criteria are applied to include only those with non-calcified floating cholesterol stones of less than 10 to 15 mm diameter. Those with calcified stones or stones greater than 15 mm diameter or unlikely to respond to ursodeoxycholic acid therapy. The optimal dose in published studies was about 8 to 10 mg/kg/day, which is about half to two-thirds the dose of chenodeoxycholic acid (15 mg/kg/day) achieving approximately equivalent results. Ursodeoxycholic acid appears to be remarkably well tolerated, with diarrhoea occurring in only a very small proportion of patients. While surgery is clearly the preferred treatment in many patients with symptomatic gallstones, in a carefully selected subgroup of such patients gallstone dissolution therapy with ursodeoxycholic acid offers an important and worthwhile alternative.

Topics: Animals; Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Humans; Kinetics; Lipids; Liver; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Intestinal Absorption; Liver; Ursodeoxycholic Acid

Topics: Bile; Bile Acids and Salts; Biological Transport; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Drug Administration Schedule; Humans; Hydroxymethylglutaryl CoA Reductases; Intestinal Absorption; Liver; Triglycerides; Ursodeoxycholic Acid

Topics: Anticholesteremic Agents; Bile; Bile Duct Diseases; Cholelithiasis; Cholesterol; Deoxycholic Acid; Drug Evaluation; Humans; Ursodeoxycholic Acid

Although data must be gleaned from international studies representing a broad range of dosage, duration of therapy, and details reported, sufficient evidence exists to state that UDCA is approximately as effective as CDCA in dissolving gallstones. Complete stone dissolution can be expected in a majority of well-selected patients treated with 10 to 15 mg/kg/day. Additional data on potential toxicity are needed, but current evidence suggests that this is very low. Treatment will be required for 1 to 2 years in most patients. Recurrence is emerging as an important aspect which needs a solution. Clearly, stone dissolution therapy is the treatment of choice in patients with a high operative risk and stones with radiologic characteristics suggesting a high probability of success. The proper place of this management modality in the therapy of the remaining majority of patients with gallstones will require careful assessment of potential benefit in each individual patient, the known risks, and the potential of as yet unrecognized long-term toxicity.

Topics: Animals; Bile; Bile Acids and Salts; Biological Availability; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholesterol, Dietary; Clinical Trials as Topic; Deoxycholic Acid; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Pregnancy; Recurrence; Rodentia; Ursodeoxycholic Acid

Topics: Animals; Calcinosis; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Colonic Neoplasms; Cost-Benefit Analysis; Deoxycholic Acid; Diarrhea; Female; Humans; Liver; Macaca mulatta; Male; Transaminases; Ursodeoxycholic Acid

Topics: Animals; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Gallstones; Humans; Intestines; Liver; Recurrence; Ursodeoxycholic Acid

Topics: Animals; Caprylates; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Glycerides; Humans; Ursodeoxycholic Acid

Topics: Animals; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Gallstone disease constitutes a major health problem in the western world, despite a successful form of surgical therapy, cholecystectomy. The past decade has witnessed considerable advances in our understanding of the physiochemical changes in bile that lead to cholesterol gallstone formation. This knowledge has resulted in a rational basis for identifying agents that could dissolve gallstones and for defining conditions that predispose to gallstone formation which might be eliminated or treated prophylactically. This review examines the concepts of gallstone formation and indicates the current status of medical therapy.

Topics: Adult; Bile; Chenodeoxycholic Acid; Cholecystectomy; Cholelithiasis; Deoxycholic Acid; Female; Humans; Pigments, Biological; Ursodeoxycholic Acid

Cholesterol gallstone formation occurs in three stages. First, the bile must be saturated with cholesterol, thereby allowing cholesterol crystals to form. Then, nucleation and growth of the gallstone can occur, although little is known about these latter two stages. Therapy for dissolution of gallstones is directed at desaturating the bile. Chenodeoxycholic acid (CDCA), the most extensively tested agent, is successful in dissolving 60 per cent of radiolucent gallstones; however, long-term safety remains to be demonstrated. Ursodeoxycholic acid (UDCA), the 7 beta epimer of CDCA, is a promising agent for cholesterol gallstone dissolution, but it, other potential agents, and dietary manipulations require more extensive study. An important problem, the prevention of recurrence of gallstones after dissolution, also needs resolution. Medical dissolution probably will be applicable as an alternative to cholecystectomy for most patients with radiolucent gallstones, but the specific relative indications remain to be determined. A variety of modalities, both medical and surgical, are being used for the treatment of retained or reformed bile duct stones. These include T-tube infusions, oral CDCA, and extraction either through the T-tube tract or after endoscopic papillotomy. Further studies, including controlled trials, are necessary to determine the relative indications for these methods.

Topics: Animals; Bile; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Contraceptives, Oral, Synthetic; Deoxycholic Acid; Diarrhea; Enterohepatic Circulation; Estrogens; Female; Gallstones; Humans; Liver; Male; Phosphatidylcholines; Pregnancy; Recurrence; Risk

Topics: Bile Acids and Salts; Biliary Tract Diseases; Celiac Disease; Chenodeoxycholic Acid; Cholelithiasis; Cholestasis; Cholic Acids; Colonic Neoplasms; Deoxycholic Acid; Diarrhea; Humans; Intestinal Diseases; Intestine, Small; Lipid Metabolism; Lithocholic Acid; Liver; Liver Circulation; Malabsorption Syndromes; Portal System

A multicompartmental model describing the enterohepatic circulation of conjugated bile acids in man under steady-state conditions is proposed. The model encompasses conjugation; deconjugation and reconjugation; dehydroxylation; sulfation, desulfation and resulfation; dehydrogenation; and stereoselective rehydrogenation. A dynamic description of the enterohepatic circulation and a brief description of bile acid functions in health and dysfunctions in disease are also discussed.

Topics: Bile; Bile Acids and Salts; Binding Sites; Cholelithiasis; Cholesterol; Cholic Acids; Circadian Rhythm; Deoxycholic Acid; Enterohepatic Circulation; Feces; Glycine; Humans; Lithocholic Acid; Models, Biological; Phospholipids

Topics: Bile Acids and Salts; Biliary Tract Diseases; Blind Loop Syndrome; Celiac Disease; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Diarrhea; Glycine; Humans; Intestinal Absorption; Intestinal Obstruction; Lithocholic Acid; Liver; Liver Circulation; Oxalates; Stomach Ulcer; Taurine

Octreotide inhibits gall bladder emptying and prolongs intestinal transit. This leads to increases in the proportion of deoxycholic acid in, and cholesterol saturation of, gall bladder bile, factors that contribute to the pathogenesis of octreotide induced gall stones.. To see if an intestinal prokinetic, cisapride, could overcome these adverse effects of octreotide and if so, be considered as a candidate prophylactic drug for preventing iatrogenic gall bladder stones.. A randomised, double blind, placebo controlled, crossover design was used to examine the effects of cisapride (10 mg four times daily) on gall bladder emptying, mouth to caecum and large bowel transit times, and the proportions of deoxycholic acid and other bile acids, in fasting serum from: (i) control subjects (n=6), (ii) acromegalic patients not treated with octreotide (n=6), (iii) acromegalics on long term octreotide (n=8), and (iv) patients with constipation (n=8).. Cisapride had no prokinetic effect on the gall bladder. In fact, it significantly increased both fasting and postprandial gall bladder volumes. However, it shortened mouth to caecum (from 176 (13) to 113 (11) minutes; p<0.001) and large bowel (from 50 (3.0) to 31 (3.4) h; p<0.001) transit times. It also reduced the proportion of deoxycholic acid in serum from 26 (2.3) to 15 (1.8)% (p<0.001), with a reciprocal increase in the proportion of cholic acid from 40 (3.5) to 51 (3.8)% (p<0.01). There were significant linear relationships between large bowel transit time and the proportions of deoxycholic acid (r=0.81; p<0.001) and cholic acid (r=-0.53; p<0.001) in fasting serum. INTERPRETATION/SUMMARY: Cisapride failed to overcome the adverse effects of octreotide on gall bladder emptying but it countered octreotide induced prolongation of small and large bowel transit. Therefore, if changes in intestinal transit contribute to the development of octreotide induced gall bladder stones, enterokinetics such as cisapride may prevent their formation.

Topics: Acromegaly; Adult; Cholelithiasis; Cholic Acid; Cisapride; Constipation; Cross-Over Studies; Deoxycholic Acid; Double-Blind Method; Female; Gallbladder Emptying; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Male; Middle Aged; Octreotide; Prospective Studies; Regression Analysis

Hillebrant C-G, Nyberg B, Angelin B, Axelson M, Björkhem I, Rudling M, Einarsson C (Huddinge University Hospital and Karolinska Hospital, Karolinska Institute, Stockholm, Sweden). Deoxycholic acid treatment in patients with cholesterol gallstones: failure to detect a suppression of cholesterol 7alpha-hydroxylase activity. J Intern Med 1999; 246: 399-407.. Based on animal studies, hydrophobic bile acids have been postulated to be particularly strong inhibitors of bile acid synthesis. The present study was undertaken to characterize in humans the effects of one of the most hydrophobic of the common bile acids, deoxycholic acid (DCA), on the transcriptional regulation and activity of the cholesterol 7alpha-hydroxylase, on hepatic cholesterol metabolism and on biliary lipid metabolism and plasma lipids. DESIGN, SUBJECTS AND SETTINGS: Thirteen patients with cholesterol gallstone disease were treated with DCA (750 mg day-1) for 3 weeks prior to cholecystectomy. Blood samples were collected before and during treatment. At operation, a liver biopsy and gallbladder bile were obtained. Twenty-eight untreated gallstone patients undergoing cholecystectomy served as controls. The study was carried out at a university hospital.. Deoxycholic acid comprised 72 +/- 6% (mean +/- SEM) of total biliary bile acids in DCA-treated patients (n = 8), and 21 +/- 2% in the controls (n = 16; P < 0.001). Cholesterol saturation of gallbladder bile averaged 102% in both treated (n = 7) and untreated (n = 16) patients. Cholesterol 7alpha-hydroxylase and HMG CoA reductase activities and mRNA levels were not different between DCA-treated and untreated gallstone patients. The LDL receptor mRNA levels were similar in both groups of patients. Plasma levels of total cholesterol were lowered by 10% upon DCA treatment (P < 0.05).. Treatment with DCA did not significantly affect mRNA levels and activity of hepatic cholesterol 7alpha-hydroxylase or HMG CoA reductase in patients with cholesterol gallstones. There was no effect on the saturation of gallbladder bile, Thus, the present study could not verify that the hydrophobicity of the bile acid pool is a major factor regulating human hepatic cholesterol 7alpha-hydroxylase activity.

Topics: Adult; Aged; Bile; Cholelithiasis; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Deoxycholic Acid; Detergents; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Liver; Male; Middle Aged; RNA, Messenger

The aims of the project were to study the effects of bile acid therapy on the fragmentation rate of cholesterol gallbladder stones by extracorporeal shock wave lithotripsy (ESWL) and on the clearance of fragments after ESWL. One hundred and two patients with biliary pain, between one and five radiolucent gallbladder stones, and a gallbladder with a patent cystic duct were randomized to three weeks of double-blind treatment with bile acids (ursodeoxycholic acid 500 mg and chenodeoxycholic acid 500 mg per day) or placebo before ESWL. After successful fragmentation by ESWL (largest fragment (< or = 5 mm) the patients were re-randomized to six months double-blind therapy with bile acids or placebo. The endpoint of pre-ESWL bile acid/placebo therapy was the proportion of patients having a successful fragmentation after < or = 3 sessions of ESWL. After post-ESWL bile acid/placebo therapy success was defined as a gallbladder cleared of fragments. Ninety-nine patients carried out three weeks of pre-ESWL treatment. There was no statistically significant difference in fragmentation rate between the two groups. After six months of post-ESWL therapy, 12 of 49 patients (24%) receiving bile acids had cleared the fragments from their gallbladder compared to 5 out of 50 patients (10%) who received placebo (p = 0.10). There was no significant difference in the occurrence of pain between the two groups. In conclusion, ESWL with or without adjuvant bile acid does not seem to be an attractive therapy for patients with uncomplicated symptomatic gallstone disease.

Topics: Adolescent; Adult; Aged; Bile Acids and Salts; Cholelithiasis; Deoxycholic Acid; Double-Blind Method; Female; Humans; Lithotripsy; Male; Middle Aged; Ursodeoxycholic Acid

Out of 34 patients enrolled and randomized, 31 completed the 6 months study period. Fifteen were treated with TUDCA, and 16 with UDCA. Dosage for both drugs was 10 mg/kg body weight daily. Superiprisingly, TUDCA was not found to be more active than UDCA in dissolving, totally or partially, the gallbladder stones; indeed, total dissolution was more frequent in the UDCA group. Since the two groups were similar as to number and size of the stones, the better results with UDCA cannot be attributed to the characteristics of the calculosis but must be ascribed to the molecule used. Both drugs induced an improvement in dyspeptic symptoms, but from this point of view, too, UCDA was more effective than TUDCA (p < 0.01). Finally, tolerability was also significantly better for UDCA, although TUDCA was altogether acceptable.

Topics: Adolescent; Adult; Aged; Cholecystectomy; Cholelithiasis; Deoxycholic Acid; Drug Evaluation; Female; Humans; Male; Middle Aged; Single-Blind Method; Solubility; Taurochenodeoxycholic Acid

Our aim was to examine the relationship between biliary deoxycholate and arachidonate in obese patients and the relationship of deoxycholate and arachidonate to the stimulation of biliary mucous glycoprotein among obese patients predisposed to cholesterol gallstones. Thirty-four obese patients predisposed to cholesterol gallstones by a weight-reducing diet (520 kcal/day) received placebo, ursodiol (1200 mg/day), or aspirin (1300 mg/day). Duodenal bile was collected prior to beginning the diet and at four weeks. There was no correlation between deoxycholate and arachidonate among the 34 patients before beginning the diet. With placebo, deoxycholate decreased while arachidonate and glycoprotein increased. With ursodiol, deoxycholate decreased while arachidonate decreased and glycoprotein did not change. With aspirin, there was no change in deoxycholate but a decrease in arachidonate and no change in glycoprotein. Our data do not support a role for biliary deoxycholate in the regulation of biliary arachidonate. Our data do support a role for arachidonate, but not deoxycholate, in the regulation of biliary glycoprotein during the formation of cholesterol gallstones.

Topics: Arachidonic Acid; Arachidonic Acids; Aspirin; Cholelithiasis; Cholesterol; Deoxycholic Acid; Dinoprostone; Double-Blind Method; Glycoproteins; Humans; Obesity; Ursodeoxycholic Acid; Weight Loss

Chenodeoxycholic acid (CDC) and ursodeoxycholic acid (UDC) have distinct physicochemical and metabolic properties which, being complementary, should favor more rapid removal of cholesterol from gallstones when both bile acids are administered together. To see if the combination is more effective and well tolerated, we have compared 5 mg/kg of CDC plus 5 mg/kg of UDC with a 10-mg/kg dose of UDC alone in 120 patients with radiolucent, sonographically confirmed gallstones and characteristics favoring complete dissolution. Ursodeoxycholic acid was chosen as the reference because it dissolves stones faster and is better tolerated than CDC. To minimize the influence of stone size, the major determinant of dissolution, patients were divided, on admission, into two groups according to the maximum stone diameter: 50 had stones less than or equal to 5 mm, 70 had stones greater than 5 mm but less than 15 mm. The effects of treatment on stone dissolution evaluated by cholecystography and ultrasonography at 6, 12, and 24 mo, were analyzed by the actuarial life-table method. In the group with smaller stones, significantly more patients had obtained complete dissolution after treatment with the combination (52%) than after treatment with UDC alone (24%) at 6 mo. After longer periods, results were still better with the combination, although the differences from UDC alone became smaller. In the patients with larger stones, rates of complete and partial dissolutions were higher after treatment with the combination (51% vs. 24% with UDC) at 6 mo and again the differences had become smaller after longer treatment. Although not statistically significant, stone calcification occurred more often with UDC (7 cases) than with the combination (1 case). We conclude that CDC plus UDC is preferable to UDC alone because it dissolves stones more quickly, with a lower incidence of stone calcification, and may result in reduced cost of treatment.

Topics: Bile; Chenodeoxycholic Acid; Cholelithiasis; Clinical Trials as Topic; Deoxycholic Acid; Drug Therapy, Combination; Female; Humans; Lipid Metabolism; Male; Middle Aged; Random Allocation; Ursodeoxycholic Acid

A prospective multicenter trial was performed to evaluate the use of external shockwave lithotripsy (ESL) and adjuvant medical therapy for the treatment of gallstones. A Medstone STS lithotripter was used together with ursodiol. Two hundred twenty-three patients were treated under general anesthesia (75%) or with intravenous analgesia (25%). Initial treatments were on an inpatient basis, but as centers gained experience, outpatient treatments became more common. Stone fragmentation and clearance were greatest in patients with solitary gallstones less than 2 cm in diameter. In this group of patients, stone fragmentation occurred in 97% of patients, and the cumulative stone-free rates at three and six months were 54% and 90%, respectively. These results indicate that fragmentation of gallstones can be achieved by a dry shock-wave lithotripter and that stone clearance is induced more rapidly by external shock-wave lithotripsy and adjuvant ursodiol therapy than by ursodiol therapy alone.

Topics: Adult; Aged; Cholelithiasis; Clinical Trials as Topic; Combined Modality Therapy; Deoxycholic Acid; Female; Humans; Lithotripsy; Male; Middle Aged; Multicenter Studies as Topic; Prospective Studies; Radiography; Ursodeoxycholic Acid

The balance between the synthesis of cholesterol and bile acids in the liver is a key factor in the formation of gallstones. Patients with cholesterol gallstones have been shown to have higher rates of hepatic cholesterol synthesis and lower rates of bile acid synthesis than control subjects, as measured by the activity of the respective rate-controlling enzymes. Treatment with ursodiol reduced the high levels of hydroxymethylglutaryl coenzyme. A reductase in gallstone patients treated for approximately one year. Such treatment did not appear to inhibit endogenous synthesis of bile acids. Ursodiol is distinct from chenodeoxycholic acid in that no significant abnormalities of liver function have been reported during its use. Bacterial 7-dehydroxylation is more active for chenodeoxycholic acid than ursodiol; thus less lithocholic acid is formed with ursodiol. Patients receiving the highest dose of ursodiol often have been shown to have the lowest percentage of lithocholic acid in the bile. During treatment with ursodiol for dissolution of gallstones, symptoms of biliary distress began to improve after three to six weeks. Gallstones will recur in about 50% of patients, but no consensus exists on management of patients after dissolution of their stones. Overall, ursodiol is a safe and effective litholytic agent.

Topics: Bile Acids and Salts; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Liver; Male; Recurrence; Time Factors; Ursodeoxycholic Acid

Topics: Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Humans; Recurrence; Ursodeoxycholic Acid

Ursodeoxycholic acid (ursodiol) is a naturally occurring bile acid that constitutes about 1-2% of the bile acids in human bile. Although well known for more than 20 years in Japan as a treatment for biliary distress and dyspepsia, ursodiol has been tested as a gallstone-dissolving agent only since 1976. Successful dissolution occurs in 30-80% of subjects with radiolucent gallstones, depending on the size and number of the stones. Calcified or pigment stones do not respond to this treatment. The current theory of the pathogenesis of gallstones is that lithogenic bile, which is supersaturated with cholesterol, is secreted by the liver and is not produced in the gallbladder. Thus, although stones form in the gallbladder, defective hepatic cholesterol and bile acid metabolism are responsible for the abnormal bile. Gallstone-prone individuals show increased hepatocholesterol formation and reduced bile acid synthesis. As the micellar solubility limit in bile is exceeded, cholesterol microcrystals precipitate. Four factors account for ursodiol's effectiveness in gallstone dissolution: (a) biliary cholesterol secretion is diminished markedly during therapy; (b) hepatic bile acid synthesis is not inhibited by ursodiol; (c) the 7 beta-hydroxy group of ursodiol resists bacterial dehydroxylation, which lowers the amount of lithocholic acid formed and the cholestasis and liver damage it can cause; and (d) ursodiol is virtually free of side effects and toxicity; less than 1% of subjects experience transient diarrhea, which does not require discontinuation of treatment, and liver function tests remain normal. In about 50% of subjects, stones may recur within 84 months, and can be retreated with ursodiol.

Topics: Bile; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Humans; Liver; Recurrence; Ursodeoxycholic Acid

Extracorporeal shock wave lithotripsy (ESWL) of gallstones is a new and experimental treatment. Recent data seem to indicate that the use of ursodeoxycholic acid (UDCA) after ESWL may optimize the results of the shock wave treatment. Most of the published data on the clinical use of such therapy emanate from two studies conducted in West Germany in approximately 300 patients. These subjects received combination therapy with UDCA and chenodeoxycholic acid (CDCA) before and after ESWL. The stone fragments gradually disappeared by 18 months after lithotripsy. No adverse effects attributable to the UDCA-CDCA treatment were noted. Several considerations support the view that adjuvant chemical dissolution therapy will be necessary for best results with ESWL, including compatibility of the rate of stone dissolution postlithotripsy with that of chemical dissolution rather than mechanical ejection; the common presence of cholesterol-supersaturated bile in gallstone patients, promoting reconglomeration of fragments; and decreased contractility of the gallbladder, which may improve after successful cholelitholytic therapy with UDCA. Placebo-controlled studies on the use of UDCA with ESWL are currently being conducted.

Topics: Chenodeoxycholic Acid; Cholelithiasis; Clinical Trials as Topic; Deoxycholic Acid; Germany, West; Humans; Lithotripsy; Ursodeoxycholic Acid

We attempted to determine whether the administration of aspirin or ursodeoxycholic acid during loss of weight could prevent the development of lithogenic changes in bile and the formation of gallstones. Sixty-eight obese subjects without gallstones who were entered in a program (520 kcal per day) to lose weight were randomly assigned to receive ursodeoxycholic acid (1200 mg per day), aspirin (1300 mg per day), or placebo in double-blind fashion for up to 16 weeks. At entry, at four weeks of treatment, and at three weeks after the completion of treatment, the subjects underwent ultrasonography to detect gallstones and duodenal drainage of bile to detect cholesterol crystals and to determine the bile saturation index and glycoprotein concentration. No gallstones or cholesterol crystals formed in the patients treated with ursodeoxycholic acid. Among the patients given placebo, gallstones formed in five (P less than 0.05 vs. ursodeoxycholic acid) and cholesterol crystals in six (P less than 0.001 vs. ursodeoxycholic acid); among those given aspirin, gallstones formed in two and cholesterol crystals in one (no significant difference from ursodeoxycholic acid treatment). By the fourth week, the bile saturation index increased in the placebo group (from 1.07 +/- 0.26 to 1.29 +/- 0.27; P less than 0.001), decreased in the ursodeoxycholic acid group (from 1.11 +/- 0.34 to 0.91 +/- 0.24; P less than 0.001), and did not change significantly in the aspirin group. The concentration of glycoprotein in bile increased in the placebo group (27.9 +/- 14.5 percent; P less than 0.001) but did not change significantly in the groups treated with ursodeoxycholic acid or aspirin. We conclude that ursodeoxycholic acid prevents lithogenic changes in bile and the formation of gallstones in obese subjects during loss of weight.

Topics: Adult; Aspirin; Bile; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Double-Blind Method; Female; Glycoproteins; Humans; Male; Ursodeoxycholic Acid; Weight Loss

In a controlled prospective double blind trial patients with cholesterol gall bladder stones are treated with ursodeoxy-cholic acid (group A: UDCA 11.1 mg/kg per day; n = 16) and Ursomenth respectively (group B: a mixture of UDCA/menthol: 4.75 mg/kg per day each; n = 17). With same stone number and size (10-12 mm) there is a complete dissolution rate in group A of 38%, and of 53% in group B within 15-16.9 months. The response rate (complete + partial dissolution) amounted to 75% and 76% respectively. In group A there is one case of stone calcification, in group B none. Both preparations are free of unwanted effects. This suggests that the cyclic monoterpene menthol enhances the effect of UDCA and is of comparable effect to a mixture of six different terpenes used in former times.

Topics: Adult; Aged; Cholelithiasis; Clinical Trials as Topic; Deoxycholic Acid; Double-Blind Method; Drug Combinations; Female; Humans; Male; Menthol; Middle Aged; Prospective Studies; Ursodeoxycholic Acid

Topics: Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Effects of specific dietary alterations in patients with radiolucent gallstones treated with ursodeoxycholic acid (UDCA, 750 mg at bedtime) were investigated. Patients were allocated randomly to one of four diets: standard (500 mg cholesterol/day), low-cholesterol (250 mg/day), added-bran (30 g/day), or substituted medium-chain triglycerides (MCT) oil (20% of fat). Dietary intake and good compliance were verified by computerized analysis of dietary diaries. Bile-acid kinetics (26 patients) or secretion of biliary lipids (23 other patients) were determined at enrollment and at 6 and 9 mo, respectively, during treatment. Although MCT further decreased the UDCA-induced decrease in the synthesis of chenodeoxycholic acid, it did not lessen desaturation of bile. Otherwise, compared to the standard diet, no experimental diet significantly altered the UDCA-induced increase of the pools of total bile acids and UDCA or the UDCA-induced decrease in synthesis of bile acids and in biliary secretion or saturation of cholesterol. If these dietary manipulations facilitate dissolution of gallstones by UDCA, they do so by other mechanisms.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Cholesterol, Dietary; Deoxycholic Acid; Dietary Fiber; Female; Glycine; Humans; Kinetics; Lipid Metabolism; Male; Middle Aged; Phospholipids; Taurine; Triglycerides; Ursodeoxycholic Acid

Topics: Adult; Aged; Cholecystography; Cholelithiasis; Cholesterol, Dietary; Combined Modality Therapy; Deoxycholic Acid; Dietary Fiber; Female; Humans; Male; Middle Aged; Prospective Studies; Random Allocation; Triglycerides; Ultrasonography; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Clinical Trials as Topic; Deoxycholic Acid; Drug Evaluation; Humans; Solubility; Ursodeoxycholic Acid

Chenodiol therapy appears especially appropriate only for the small group of patients who have floating radiolucent gallstones, are over 60 years of age, and have increased surgical risk factors. Such patients may benefit from a trial of Chenodiol therapy at a dose of 15 mg/kg of body weight and experience both fewer symptoms and reduced need for medically indicated cholecystectomy. Other patients should be evaluated on an individual basis, with consideration given to simple observation for silent gallstones, and to direct intervention if bile duct obstruction occurs. When therapy is chosen, periodic laboratory assessment is indicated and treatment should be continued 3 months beyond apparent dissolution or for 16 months if there is no change in gallstone size. Periodic assessment at annual intervals after dissolution is also indicated because of frequent gallstone recurrence. Where both Chenodiol and UDCA are available, physicians have generally preferred UDCA because of its absence of bile acid diarrhea and liver enzyme changes, even though clinical efficacy is the same.

Topics: Aged; Chemistry, Clinical; Chenodeoxycholic Acid; Cholelithiasis; Clinical Trials as Topic; Deoxycholic Acid; Drug Evaluation; Humans; Middle Aged; Solubility; Ursodeoxycholic Acid

The bioavailability of ursodeoxycholic acid (UDCA), a cholesterolic gallstone dissolving agent, has been analysed in seven healthy human volunteers. After absorption of a capsule containing a 500 mg dose, the time course of plasma concentrations of the drug presented a double peak profile over a 240 min period. In order to explain this result, a second group of five subjects bearing a four-way jejunal catheter fitted with an occluding balloon, received an oral dose of 250, 500 or 750 mg of the drug. Simultaneous analyses of plasma UDCA concentrations and jejunal UDCA contents were carried out. UDCA is poorly soluble in the gastro-duodeno-jejunal contents of fasted subjects since 21-50% of the ingested doses were recovered in solid form. The profile of plasma concentration paralleled the amount of soluble UDCA present in intestinal lumen. When jejunal contents were infused below the balloon a second plasma peak appeared in cases corresponding to ingestion of higher doses of UDCA. In conclusion, pharmacological doses of UDCA are not readily soluble in the stomach and intestine of a healthy fasting man. In consequence, the bioavailability of the drug varies with its progressive solubilization in the gastrointestinal tract. The present results suggest that repeated daily doses of UDCA should improve its bioavailability in treated gallstone patients.

Topics: Adult; Biological Availability; Cholelithiasis; Cholesterol; Deoxycholic Acid; Feces; Female; Humans; Intestinal Absorption; Jejunum; Kinetics; Male; Solubility; Ursodeoxycholic Acid

The correlation between biliary and serum levels of ursodeoxycholic and chenodeoxycholic acids was studied in a double-blind controlled manner in 39 patients before and during treatment with ursodeoxycholic acid, 800 mg/day; ursodeoxycholic acid, 400 mg/day; chenodeoxycholic acid, 750 mg/day; chenodeoxycholic acid, 375 mg/day; and placebo, respectively. On a total of 74 occasions, fasting duodenal bile and venous blood samples were obtained simultaneously. Biliary bile acid composition was determined by gas-liquid chromatography and serum ursodeoxycholic and chenodeoxycholic acid concentrations by radioimmunoassays. There was a much closer correlation between the biliary and serum levels of ursodeoxycholic acid (r = 0.8184, P less than 0.001) than between those of chenodeoxycholic acid (r = 0.4707, P less than 0.01). In contrast to serum chenodeoxycholic, which showed many overlaps between pre- and posttreatment values, serum ursodeoxycholic acid proved to be a very sensitive, specific, and convenient means of predicting the presence of increased levels of ursodeoxycholic acid in the enterohepatic cycle.

Topics: Bile; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Ursodeoxycholic Acid

Ursodeoxycholic acid is the 7 beta-hydroxy epimer of chenodeoxycholic acid and is normally present in only trace amounts in the bile. Oral administration of pharmacological doses markedly decreases biliary cholesterol saturation. Complete or partial dissolution of radiolucent gallstones located in a functioning gallbladder occurred in about 40 to 55% of patients treated with ursodeoxycholic acid in controlled studies of 6 months duration. Patients showing partial gallstone dissolution at that time are likely to continue improving possibly to complete gallstone dissolution with continued therapy. The success rate with ursodeoxycholic acid may be increased top about 80% if more stringent patient selection criteria are applied to include only those with non-calcified floating cholesterol stones of less than 10 to 15 mm diameter. Those with calcified stones or stones greater than 15 mm diameter or unlikely to respond to ursodeoxycholic acid therapy. The optimal dose in published studies was about 8 to 10 mg/kg/day, which is about half to two-thirds the dose of chenodeoxycholic acid (15 mg/kg/day) achieving approximately equivalent results. Ursodeoxycholic acid appears to be remarkably well tolerated, with diarrhoea occurring in only a very small proportion of patients. While surgery is clearly the preferred treatment in many patients with symptomatic gallstones, in a carefully selected subgroup of such patients gallstone dissolution therapy with ursodeoxycholic acid offers an important and worthwhile alternative.

Topics: Animals; Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Humans; Kinetics; Lipids; Liver; Ursodeoxycholic Acid

The National Cooperative Gallstone Study was a double-masked trial conducted to determine the efficacy and safety of chenodeoxycholic acid (chenodiol) for dissolution of cholesterol gallstones. Patients with radiolucent gallstones were randomly allocated to either a high dose (750 mg/d, n = 305) or low dose (375 mg/d, n = 306) of chenodiol or placebo (n = 305) administered for 2 yr. Specimens of gallbladder bile were obtained for biliary lipid analysis on 50% of all white obtained for biliary lipid analysis on 50% of all white patients at base line and after 3-mo therapy, on 45% at 12 mo, and on 36% at 24 mo. Among these specimens, 20% were inadequate for analysis. For analysis of data, available values during therapy were averaged up to time of dissolution, study exit, or study termination. In the high-dose group, percent chenodiol (molar percent of all bile acids) increased markedly and remained high during the 2 yr of follow-up. Also, molar percent cholesterol decreased significantly and remained low during the 2 yr of follow-up. In the low-dose group, percent chenodiol increased and remained significantly increased. Percent cholesterol saturation decreased at 3 mo, but at 24 mo it was not different from that in the placebo group, suggesting a physiological adaptation to the low dose by 2 yr. 79% of patients on high dose had greater than 70% chenodiol. Among these, half showed unsaturated bile (less than 100% cholesterol saturation) while the remainder were supersaturated; in the former group with unsaturated bile, 23% had complete dissolution and 51% had partial (greater than 50% reduction in stone size) or complete dissolution. In contrast, those with over 70% chenodiol and supersaturated bile had only 5% complete dissolution. Thus, development of unsaturated bile was a major factor associated with gallstone dissolution. The data also indicate that values for percent cholesterol saturation were a better predictor of gallstone dissolution than molar percent chenodiol, although a high percent chenodiol usually was required to obtain unsaturation.

Topics: Bile; Body Weight; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Lipid Metabolism; Lithocholic Acid; Male

Measurements of biliary lipid secretion rates were performed in 10 patients with radiolucent gallstones before and after 4 wk of administration of chenodeoxycholic acid and ursodeoxycholic acid (1 g/day) in a randomized crossover study. The results of both bile acid feeding periods were similar in many respects: expansion of the bile acid pool, increase in bile acid and phospholipid secretion, reduction in cholesterol output, and decrease in percent saturation of hepatic bile, which was more pronounced with ursodeoxycholic than chenodeoxycholic acid therapy. Despite these similarities, the mechanisms by which these two litholytic bile acids induced these changes were quite different. Ursodeoxycholic acid, in contrast to chenodeoxycholic acid, only partially suppresses bile acid synthesis. During chenodeoxycholic acid feeding, the ratio of phospholipids to bile acids increased from 0.264 to 0.307 (p less than 0.05), indicating an increased coupling of phospholipids by chenodeoxycholic acid, whereas ursodeoxycholic acid did not alter this ratio. The molar ratio of cholesterol to bile acid during the chenodeoxycholic- and ursodeoxycholic-acid periods decreased significantly from 0.073 to 0.058 and 0.041, respectively. However, this ratio during the ursodeoxycholic-acid period was unchanged when the amount of ursodeoxycholic acid was subtracted from total bile acid (0.069), indicating that UDCA has little, if any, effect on the mobilization of hepatic cholesterol into bile.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Humans; Lipid Metabolism; Male; Middle Aged; Secretory Rate; Ursodeoxycholic Acid

Twenty-eight patients with radiolucent biliary duct stones without cholangitis and jaundice were randomly allocated into two treatment groups receiving ursodeoxycholic acid 12 mg/kg (group A) or placebo (group B) in three daily doses for 24 months. In group A stones disappeared completely in seven patients and partially in one; placebo administration had no effect on stone size and three patients of group B (only one of group A) went to surgery for complications. Ursodeoxycholic acid treatment did not adversely affect liver function tests, and alkaline phosphatase decreased. Abdominal and biliary colics also became less frequent in the first six months of therapy in group A, but not in the placebo group. The bile was supersaturated with cholesterol in both groups, but decreased significantly only in patients receiving ursodeoxycholic acid even though the lithogenic index remained high. Cholesterol saturation of bile does not seem to be the only factor determining the dissolution of biliary duct stones which sometimes contain cholesterol as the main component.

Topics: Adolescent; Adult; Aged; Bile; Bile Acids and Salts; Bile Duct Diseases; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Double-Blind Method; Female; Humans; Male; Middle Aged; Random Allocation; Ursodeoxycholic Acid

In the context of a cooperative clinical trial carried out in the Cantons of Basel and Vaud, Switzerland, the litholytic effect of ursodeoxycholic acid (Ursochol) in a daily dose of 9 mg/kg was investigated in 42 patients with radiotransparent gallstones. The litholytic effect was evident in 22 (73%) of the 30 patients followed up for a maximum period of 1 year. Complete dissolution of gallstones was obtained in 40% of cases. In addition, ursodeoxycholic acid significantly reduced (p less than 0,001) the dyspeptic-painful symptoms and the number of biliary colics. Tolerance was excellent. In particular, no cases of diarrhea were observed.

Topics: Adult; Aged; Cholelithiasis; Clinical Trials as Topic; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Radiography; Ursodeoxycholic Acid

Although data must be gleaned from international studies representing a broad range of dosage, duration of therapy, and details reported, sufficient evidence exists to state that UDCA is approximately as effective as CDCA in dissolving gallstones. Complete stone dissolution can be expected in a majority of well-selected patients treated with 10 to 15 mg/kg/day. Additional data on potential toxicity are needed, but current evidence suggests that this is very low. Treatment will be required for 1 to 2 years in most patients. Recurrence is emerging as an important aspect which needs a solution. Clearly, stone dissolution therapy is the treatment of choice in patients with a high operative risk and stones with radiologic characteristics suggesting a high probability of success. The proper place of this management modality in the therapy of the remaining majority of patients with gallstones will require careful assessment of potential benefit in each individual patient, the known risks, and the potential of as yet unrecognized long-term toxicity.

Topics: Animals; Bile; Bile Acids and Salts; Biological Availability; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholesterol, Dietary; Clinical Trials as Topic; Deoxycholic Acid; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Pregnancy; Recurrence; Rodentia; Ursodeoxycholic Acid

In a double-blind controlled study of ursodeoxycholic acid (400 and 800 mg/day) and chenodeoxycholic acid (375 and 750 mg/day), in comparison with placebo, ursodeoxycholic acid was significantly more effective than chenodeoxycholic acid in dissolving gallstones after 12 mo of treatment. Although there continued to be better dissolution during ursodeoxycholic acid treatment (dissolution complete in 30% and partial in another 30% of the patients) than during chenodeoxycholic acid treatment (dissolution complete in 7% and partial in 40%) at 24 mo, this difference between the treatment groups was no longer statistically significant. The incidence of floating stones was significantly higher in the patients who dissolved their stones than in those who did not (p less than 0.001). The three failures of dissolution of floating stones during bile acid treatment were associated with chenodeoxycholic acid therapy--two of them with the 750-mg and the third with the 375-mg doses. Gallstone dissolution with ursodeoxycholic acid occurred in spite of a rise in biliary cholesterol saturation, which was consistent with a nonmicellar mechanism of cholelitholysis. Furthermore, more than threefold serum elevations of L-alanine aminotransferase were observed only during chenodeoxycholic acid therapy. They occurred in 2 patients treated with 375 and 750 mg/day, respectively. The enzyme levels normalized after discontinuation of chenodeoxycholic acid and have remained normal for 13 and 8 mo, respectively, after the institution of treatment with 800 mg/day of ursodeoxycholic acid. There was no correlation between the liver tests and biliary levels of lithocholic acid. Of all the symptoms studied, only constipation showed changes that approached statistical significance (p = 0.0681). There was a significant improvement of constipation in the combined chenodeoxycholic acid groups when they were compared with the combined ursodeoxycholic acid groups. The total bile acid pool expanded significantly in both the chenodeoxycholic acid and in the 800-mg ursodeoxycholic acid treatment groups. The marked increases of biliary ursodeoxycholic acid and chenodeoxycholic acid, respectively, indicated compliance with the treatment in all but 1 bile acid-treated patient. Neither serum triglycerides nor serum cholesterol showed significant changes in any of the treatment groups. The study shows that ursodeoxycholic acid dissolves gallstones faster and with fewer side effects than chenodeoxycholic

Topics: Alanine Transaminase; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Clinical Trials as Topic; Constipation; Deoxycholic Acid; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Placebos; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Double-Blind Method; Humans; Random Allocation; Solubility; Ursodeoxycholic Acid

We measured intestinal absorption of cholesterol by a plasma isotope ratio method and determined biliary bile acid and lipid composition of fasting gallbladder bile in 5 gallstone patients before therapy and during two randomized treatment periods with chenodeoxycholic or ursodeoxycholic acid (13 mg/kg . day). During chenodeoxycholic acid ingestion, biliary bile acids were composed predominantly (84%) of conjugates of chenodeoxycholic acid. During ursodeoxycholic acid administration, conjugates of ursodeoxycholic acid constituted half the bile acid pool (49%). Fasting gallbladder bile was supersaturated in cholesterol before treatment, but became unsaturated during administration of both chenodeoxycholic and ursodeoxycholic acids. In spite of these marked changes in biliary bile acid and lipid composition, cholesterol absorption was not significantly different before (45.4 +/- 4.3%, mean +/- SEM) or after chenodeoxycholic (42.7 +/- 5.1%) or ursodeoxycholic (46.8 +/- 3.7%) acid ingestion. We conclude that chenodeoxycholic and ursodeoxycholic acids unsaturate bile in cholesterol and dissolve gallstones by a mechanism other than the suppression of intestinal absorption of cholesterol.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Intestinal Absorption; Lipids; Male; Middle Aged; Random Allocation; Ursodeoxycholic Acid

Topics: Adult; Aged; Cholelithiasis; Clinical Trials as Topic; Deoxycholic Acid; Double-Blind Method; Dyspepsia; Female; Humans; Male; Middle Aged; Pain; Ursodeoxycholic Acid

Topics: Adult; Calcinosis; Cholelithiasis; Deoxycholic Acid; Female; Follow-Up Studies; Humans; Male; Middle Aged; Radiography; Ursodeoxycholic Acid

The effect of administration of primary and secondary bile acids on absorption of cholesterol was investigated in 15 volunteers. Eight Caucasians with radiolucent gallstones were studied before and after administration of chenodeoxycholic acid (all eight) and cholic acid (eight before, six after treatment) for 3 months, and seven healthy subjects were studied before and five were studied after administration of deoxycholic acid for 6 weeks. The hourly absorption of [3H]cholesterol was measured for 24 hours in a 20-cm duodenal segment by use of an intestinal perfusion technique. Fasting serum cholesterol and triglyceride levels were also measured before and after administration of bile acid. In patients with gallstones, absorption of cholesterol in the duodenum, expressed as the mean (+/- SEM) percentage of [3H]cholesterol absorbed hourly for 24 hours, was not significantly different after administration of chenodeoxycholic (22.5 +/- 4.4%) or cholic (25.6 +/- 5.9%) acid when compared with the pretreatment value (21.1 +/- 4.3%). Moreover, administration of chenodeoxycholic and cholic acid did not affect serum lipid levels. In contrast, administration of deoxycholic acid to healthy volunteers suppressed [3H]cholesterol absorption (13.2 +/- 3.2%) compared with that of the pretreatment period (26.5 +/- 3.8%) and decreased serum cholesterol levels by 15%. Our results suggest that chenodeoxycholic acid decreases the concentration of cholesterol in bile and dissolves gallstones by a mechanism other than inhibition of absorption of cholesterol. The data also indicate that the hypocholesterolemic effect of deoxycholic acid is due to the inhibition of intestinal absorption of cholesterol.

Topics: Adult; Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Clinical Trials as Topic; Deoxycholic Acid; Female; Humans; Intestinal Absorption; Male; Perfusion; Triglycerides

A double-blind clinical trial comparing ursodesoxycholic acid and chenodesoxycholic acid in patients with cholesterol stones in the gall-bladder showed that ursodesoxycholic acid was superior to the older drug not so much in percentage of biliary calculi dissolved but in dosage reduction (50%) and improved clinical and biological tolerance.

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Double-Blind Method; Humans; Ursodeoxycholic Acid

Topics: Animals; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Gallstones; Humans; Intestines; Liver; Recurrence; Ursodeoxycholic Acid

Ursodeoxycholic acid, 250 to 300, 500 to 600, or 900 to 1000 mg/d, was given orally for 6 to 38 months to 53 patients with cholesterol gallstones and functioning gallbladders. Forty-two patients had greater than 50% reduction in gallstone volume, number, or both, without apparent dose dependence and 27 of these patients had complete gallstone dissolution. Results of laboratory studies including liver function tests were not affected adversely and biliary lithocholic acid concentration did not increase during therapy. Most biliary symptoms seemed to disappear within 3 months and no patient developed diarrhea. Large diameter and increased number of gallstones were found to hinder dissolution. The percentage of biliary ursodeoxycholic acid increased with increasing dose and reached a maximum of 50% to 60% of total bile acids at a dose of about 10 to 12 mg/kg body weight. d. Biliary lithogenic index was reduced significantly during treatment with ursodeoxycholic acid, 500 to 600 and 900 to 1000 mg/d. Thus, ursodeoxycholic acid appears to be a safe and effective alternative to surgery in selected patients with gallstones.

Topics: Bile Acids and Salts; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Diarrhea; Dose-Response Relationship, Drug; Female; Humans; Lithocholic Acid; Liver; Male; Middle Aged; Random Allocation; Time Factors; Ursodeoxycholic Acid

In order to compare the effects on gallstone dissolution of three different doses of UDCA (4, 8 and 12 mg/kg/day), a controlled trial was carried out with seventy-one patients. The dissolution rate was higher in the group treated with the highest dose. Stone size was the major factor affecting the outcome of treatment, with a significantly higher success rate in patients with gallstones less than 10 mm than with stones greater than 10 mm.

Topics: Adult; Aged; Bile; Cholelithiasis; Cholesterol; Deoxycholic Acid; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Radiography; Time Factors; Ursodeoxycholic Acid

The effect on serum lipoprotein concentrations of chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) was examined in eight normolipemic patients with radiolucent gallstones during constant liquid formula infusion into the duodenum. Every patient received each bile acid (1000 mg/day) during two consecutive randomized 4-week periods. During treatment with CDCA but not UDCA, the serum triglycerides decreased by an average of 26%. Mean HDL cholesterol decreased by 46% during CDCA therapy and remained unchanged during UDCA administration. Simultaneous measurements of biliary lipid secretion showed a significant negative correlation between HDL cholesterol concentration and hepatic secretion of CDCA (r = -0.652) and a positive correlation between the LDL cholesterol/HDL cholesterol ratio and hepatic secretion of CDCA (r = 0.840). Despite their close chemical relationships and similar effects on biliary lipids, CDCA and UDCA differ markedly in their effects on serum lipoproteins. Because of this and minor side effects, UDCA seems to be a safer agent than CDCA for cholesterol gallstone dissolution.

Topics: Adult; Aged; Biliary Tract; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Lipoproteins; Male; Middle Aged; Triglycerides; Ursodeoxycholic Acid

Topics: Calcinosis; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Topics: Adult; Aged; Bile; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Drug Synergism; Female; Glycine max; Humans; Male; Middle Aged; Plant Extracts; Ursodeoxycholic Acid

Patients with radiolucent gallstones (diameter less than 1.5 cm) and functioning gallbladder were treated for 6-12 months with CDCA (38 patients, 12-15 mg/kg/day) or UDCA (78 patients randomly allocated to receive 5-6 or 10-12 mg/kg/day). Complete dissolutions and partial plus complete dissolutions were respectively 26 and 58% for CDCA, 14 and 58% for UDCA at the lower dose, and 29 and 71% for UDCA at the higher dose. Statistical analysis did not show any significant difference between the three different treatments. In patients with stones of 4-10 mm diameter treated with UDCA, complete dissolution occurred at the lower dose in 0 of 14 cases while complete dissolutions occurred at the higher dose in 5 of 18 cases, suggesting that the latter dose may be more effective (0.05 less than P less than 0.1). A highly significant correlation was demonstrated between gallstone size and number of dissolutions with both doses of UDCA. No side effects were observed with UDCA, while with CDCA diarrhea occurred in 28% and a transient increase in SGOT in a single patient. 1 patient on UDCA required emergency cholecystectomy for acute cholecystitis. Dyspeptic and/or pain symptom-atology improved in 65 and 85% of the patients treated with CDCA and UDCA, respectively. No variations in the blood lipids were observed.

Topics: Adult; Aged; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Random Allocation; Triglycerides; Ursodeoxycholic Acid

The cholelitholytic action of ursodeoxycholic acid (UDCA) was investigated by a double-blind clinical trial. The trial started with 151 subjects all confirmed by radiographic examination as having radiolucent gallstones in a functioning gallbladder. The subjects were divided into three groups receiving 600 mg/day of UDCA, 150 mg/day of UDCA, and placebo (lactose) per day, respectively. Seventy-nine cases were classed as dropouts or were excluded due to incomplete follow-up or inadequate patient selection, and the data on the remaining 72 cases were analyzed. After 6--12 mo of treatment, dissolution of decrease in size or number of stones occurred in 10 of the 29 cases in the 600 mg/day group (34.5%), 4 of 23 cases in the 150 mg/day group (17.4%), and 1 of 20 cases in the control group (5.0%). For those cases with noncalcified, less than 15 mm in diameter, and floating stones, efficacy increased to 83.3% in the 600 mg/day group. Lithogenic index of bile defined by Thomas and Hofmann became unsaturated after treatment in the 600 mg/day group. Neither diarrhea nor hepatic toxicity was noted. The results indicate that UDCA is a safe and effective litholytic agent.

Topics: Bile; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Diarrhea; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Liver Function Tests; Male; Middle Aged; Phospholipids; Time Factors; Ursodeoxycholic Acid

The present status of the use of cholelitholytic agents in Japan is presented. Open and double-blind studies of chenodeoxycholic acid and ursodeoxycholic acid are compared with respect to their efficacy and safety. Although the in vitro solubilization of cholesterol with ursodeoxycholic acid seems to be less than with chenodeoxycholic acid, the higher dose of ursodeoxycholic acid which can be used because of the lack of side effects such as diarrhea and elevation of transaminases and a lower lithogenic index of bile obtainable favors ursodeoxycholic acid as an oral cholelitholytic agent at the moment.

Topics: Adult; Aged; Chenodeoxycholic Acid; Cholelithiasis; Clinical Trials as Topic; Deoxycholic Acid; Double-Blind Method; Humans; Japan; Middle Aged; Ursodeoxycholic Acid

The effect of ursodesoxycholic acid (UDCA) on dyspeptic symptoms and pain in cholelithiasis and biliary dyskinesia has been investigated in a double blind trial. The results obtained in 661 patients investigated after 7 and 14 days of treatment show a significantly superior effect of UDCA compared with placebo.

Topics: Biliary Dyskinesia; Cholelithiasis; Clinical Trials as Topic; Deoxycholic Acid; Double-Blind Method; Dyspepsia; Female; Humans; Male; Placebos; Ursodeoxycholic Acid

Topics: Adult; Aged; Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acids; Deoxycholic Acid; Dose-Response Relationship, Drug; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Lithocholic Acid; Male; Microsomes, Liver; Middle Aged; Random Allocation; Ursodeoxycholic Acid

Topics: Bile Acids and Salts; Cholelithiasis; Cholesterol; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 7; Deoxycholic Acid; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Liver; Male; Middle Aged; Steroid Hydroxylases

Obese subjects are prone to supersaturated bile, which is maintained or increased during weight loss. In this report, two related studies were carried out on obese subjects to investigate effects of bile acid feeding on biliary lipid metabolism before and during weight reduction. In one study, chenodeoxycholic acid (CDCA), 750 mg/day, was given to 12 obese subjects during weight maintenance (1st mo) and during weight reduction (2nd mo). In the second study, effects of two bile acid preparations, CDCA and Bilron (containing mostly cholic acid and deoxycholic acid), randomly administered, were compared in another 12 obese subjects undergoing weight reduction. The results show that obese subjects had large pools of bile acids during weight maintenance which decreased on caloric restriction (1,000 kcal/day). CDCA increased pool size only modestly during weight maintenance, from 3,536 +/- 1,267 (SD) mg to 4,735 +/- 1,434 mg. Both CDCA and Bilron markedly reexpanded the contracted pool of bile acids in obese subjects on weight reduction. However, significantly reduced saturation of bile occurred only in those on CDCA and weight reductions, whereas supersaturation was unaltered when weight was maintained constant in these patients, or when Bilron was given. No significant side effects were noted during bile acid feeding for any of the subjects. Thus, CDCA given to obese subjects on weight reduction will reduce bile saturation and could protect against gallstones.

Topics: Adult; Bile; Bile Acids and Salts; Body Weight; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Diet, Reducing; Humans; Lipid Metabolism; Male; Middle Aged; Obesity; Triglycerides

Topics: Aged; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Female; gamma-Glutamyltransferase; Humans; Lipid Metabolism; Male; Middle Aged; Phospholipids

44 patients with radiolucent gallstones in gallbladders visible on cholecystography were randomly alloted to three treatment groups: ursodeoxycholic acid (600 mg/day), ursodeoxycholic acid (150 mg/day), a placebo. At the end of six months' treatment, cholecystograms of all the patients were interpreted by radiologists who were not aware of the treatment. Dissolution of gallstones occurred in 8 (26%) of the 31 patients treated with ursodeoxycholic acid, but not in the placebo group. Ursodeoxycholic acid had no hepatotoxicity, as assessed by standard liver-function tests. These results indicate that ursodeoxycholic acid, the 7beta epimer of chenodeoxycholic acid, is effective in the dissolution of cholesterol gallstones.

Topics: Adult; Aged; Alkaline Phosphatase; Aspartate Aminotransferases; Bile; Cholelithiasis; Cholesterol; Deoxycholic Acid; Drug Evaluation; Female; Follow-Up Studies; Humans; Liver Function Tests; Male; Middle Aged; Placebos; Triglycerides

Bile acid kinetics were measured by isotope dilution, and hourly outputs of bile acid, cholesterol, and phospholipid were quantified by duodenal perfusion over 24 hr including three liquid meals and an overnight fast in 6 gallstone patients during a pretreatment period and two randomized treatment periods with chenodeoxycholic (chenic) acid or cholic acid. During chenic acid ingestion, bile contained predominantly chenyl conjugates. During cholic acid ingestion, bile was composed of about equal amounts of cholyl and deoxycholyl conjugates; chenyl conjugates decreased markedly due in part to a 50% decrease in chenic acid synthesis. Total bile acid pool size doubled in half the patients receiving either bile acid and was not different during treatment with chenic or cholic acid. Compared to cholic acid, chenic acid caused decreased cholesterol output with no difference in bile acid or phospholipid output. Therefore, bile unsaturated with cholesterol entered the duodenum for more hours per day during chenic acid ingestion than during the cholic or pretreatment periods. There was no relationship among bile acid pool size, bile acid output, and hours per day of supersaturated bile; there was an inverse relationship between total pool size and recycling frequency such that bile acid output remained stable over a wide range of pool sizes. Fasting-state gallbladder bile was supersaturated during the cholic and pretreatment periods, but became unsaturated during chenic acid ingestion. However, hours per day of supersaturated bile could not be reliably predicted from the degree of saturation of fasting-state gallbladder bile (r = 0.62). The efficacy of chenic acid and the lack of efficacy of cholic acid for gallstone dissolution appear related to their different specific effects on biliary cholesterol secretion and not to any effect on bile acid and phospholipid secretion or bile acid pool size.

Topics: Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Fasting; Female; Humans; Kinetics; Lipid Metabolism; Lithocholic Acid; Male

The occurrence of cholesterol crystals was studied in 20 consecutive gallstone patients with functioning gallbladders. The frequency with which crystals were found rose sharply with the number of stones. Gallbladder bile was found more often to contain cholesterol crystals than hepatic bile of the same individual. Such crystals were absent in T tube drain bile from 10 consecutive choledochostomy patients, studied after the reestablishment of the enterohepatic circulation for at least five days. In gallstone patients in whom the gallbladder was visualized at cholecystography the hepatic bile contained cholesterol crystals more often than in patients with gallbladders not so visualized. In the latter patients the crystals tended to disappear after prolonged fasting. Bile analysis showed hepatic bile of patients with non-functioning gallbladders to be less lithogenic than bile in cases with functioning gallbladders. In the former group bile contained relatively more chenodeoxycholic acid than in the latter. The composition of bile with cholesterol crystals did not differ significantly from that of bile without crystals. In the final analysis it is important to identify possible factors responsible for the precipitation of cholesterol from supersaturated bile.

Topics: Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Chromatography; Chromatography, Gas; Crystallization; Deoxycholic Acid; Fasting; Gallbladder; Humans; Lithocholic Acid; Liver

Little information is available on the pathogenesis of cholesterol microlithiasis, and it is not clear if biliary lipid composition in these patients is similar to changes seen in cholesterol gall stone patients.. To measure biliary lipid composition in patients with cholesterol microlithiasis.. Eleven patients with cholesterol microlithiasis, 20 cholesterol gall stone patients, and 17 healthy controls.. Duodenal bile was collected in the fasting state during ceruletide infusion. Biliary cholesterol, phospholipids, and total bile acids were analysed by enzymatic assays, and conjugated bile acids by high pressure liquid chromatography.. Patients with microlithiasis had a cholesterol saturation index significantly higher than controls (mean value 1.30 (95% confidence interval 1.05-1.54) v 0.90 (0.72-1.08)) but similar to gall stone patients (1.51 (1.40-1.63)). This was due to a significant decrease in per cent phospholipid (10.0% (7.1-12.8)) compared with controls (21.4% (18.1-24.6)) and gall stone patients (24.9% (20.5-29.3)). Per cent cholesterol was similar in patients with microlithiasis and controls (5.3% (4.5-6.1) and 5.6 % (4.3-6.8), respectively) but was significantly increased in gall stone patients (10.9% (9.3-12.4)). Bile acid composition in patients with microlithiasis was similar to controls whereas in gall stone patients deoxycholic acid was significantly increased: 27.3% (24.8-29.7) v 19.0% (15.7-22.2) in controls and 20.6% (14.9-26.2) in patients with microlithiasis.. Patients with cholesterol microlithiasis have biliary cholesterol supersaturation, similarly to cholesterol gall stone patients. Whereas in the latter this is due to increased per cent cholesterol, in patients with microlithiasis this is caused by phospholipid deficiency, with normal per cent cholesterol and normal biliary bile acid composition.

Topics: Adult; Aged; Bile; Case-Control Studies; Ceruletide; Cholelithiasis; Cholesterol; Chromatography, High Pressure Liquid; Deoxycholic Acid; Female; Humans; Linear Models; Lipids; Male; Middle Aged; Phospholipids

Prolonged large bowel transit time and an associated increase in the proportion of deoxycholic acid (DCA) in serum and bile have been implicated in the development of cholesterol-rich gallstones and colon cancer. Prolongation of intestinal transit also increases intracolonic pH that, we hypothesized, should favor the solubilization and absorption of newly formed DCA within the colon. To test this hypothesis, we performed in vitro studies on homogenized cecal aspirates (obtained at colonoscopy) that were incubated anaerobically with [14C]cholic acid for 16 h after which the pH was adjusted to between 4.0 and 7.0 in 0.5-pH unit steps. The resultant reaction mixtures were centrifuged to separate the supernatant from the precipitate, and the specific activity of [14C]DCA was quantitated in both phases. As the pH in the aspirates was manipulated from 4.0 to 7.0, the proportion of newly formed, labeled DCA increased in the supernatant and fell in the precipitate, particularly at a hydrogen ion concentration of <100 x 10(-7) (equivalent to pH 5.0-7.0). These results show that the solubility of DCA in colonic contents increases with increasing pH. If solubility is rate limiting, this should lead to increased absorption that, in turn, would explain why the proportion of DCA in serum and bile increases with the prolongation of large bowel transit time.

Topics: Cecum; Centrifugation; Chemical Precipitation; Cholelithiasis; Colorectal Neoplasms; Deoxycholic Acid; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Solubility; Suction

Octreotide treatment of acromegalic patients induces cholesterol gallstone formation, in part by impairing cholecystokinin release and gall-bladder contraction. However, there are few data on the effect of octreotide on biliary arachidonic acid-rich phospholipids or mucin glycoprotein, factors which also influence cholesterol gallstone formation.. In acromegalic patients studied before and during 3 months of octreotide treatment, we measured mucin glycoprotein concentrations and the molecular species of phosphatidylcholine, and related the results to the cholesterol saturation and percentage of deoxycholic acid in gall-bladder bile.. The relative proportions of the major arachidonic acid-rich phosphatidylcholine species, PC 16:0-20:4 and PC 18:0-20:4, increased significantly during octreotide treatment. These changes were associated with a rise in the cholesterol saturation index and a non-significant twofold increase in mucin glycoprotein concentration. There were significant correlations between PC 16:0-20:4 and the cholesterol saturation index, percentage of vesicular cholesterol and percentage of deoxycholic acid in gall-bladder bile.. In acromegalic patients, octreotide increases the proportions of arachidonic acid-rich phospholipids, with associated rises in: (a) the cholesterol saturation index and percentage of vesicular cholesterol, and (b) the percentage of deoxycholic acid in gall-bladder bile-changes similar to those found in patients with cholesterol-rich gall-bladder stones.

Topics: Acromegaly; Adult; Arachidonic Acids; Case-Control Studies; Cholelithiasis; Deoxycholic Acid; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Mucins; Octreotide; Phosphatidylcholines; Phospholipids

Deoxycholic acid (DCA), implicated in the pathogenesis of gall stones and colorectal cancer, is mainly formed by bacterial deconjugation (cholylglycine hydrolase (CGH)) and 7 alpha-dehydroxylation (7 alpha-dehydroxylase (7 alpha-DH)) of conjugated cholic acid (CA) in the caecum/proximal colon. Despite this, most previous studies of CGH and 7 alpha-DH have been in faeces rather than in caecal contents. In bacteria, CA increases 7 alpha-DH activity by substrate-enzyme induction but little is known about CA concentrations or CA/7 alpha-DH induction in the human colon.. Therefore, in fresh "faeces", and in caecal aspirates obtained during colonoscopy from 20 patients, we: (i) compared the activities of CGH and 7 alpha-DH, (ii) measured 7 alpha-DH in patients with "low" and "high" percentages of DCA in fasting serum (less than and greater than the median), (iii) studied CA concentrations in the right and left halves of the colon, and examined the relationships between (iv) 7 alpha-DH activity and CA concentration in caecal samples (evidence of substrate-enzyme induction), and (v) 7 alpha-DH and per cent DCA in serum.. Although mean CGH activity in the proximal colon (18.3 (SEM 4.40) x10(-2) U/mg protein) was comparable with that in "faeces" (16.0 (4.10) x10(- 2) U/mg protein), mean 7 alpha-DH in the caecum (8.54 (1.08) x10(-4) U/mg protein) was higher (p<0.05) than that in the left colon (5.72 (0.85) x10(-4) U/mg protein). At both sites, 7 alpha-DH was significantly greater in the "high" than in the "low" serum DCA subgroups. CA concentrations in the right colon (0.94 (0.08) micromol/ml) were higher than those in the left (0.09 (0.03) micromol/ml; p<0.001) while in the caecum (but not in the faeces) there was a weak (r=0.58) but significant (p<0.005) linear relationship between 7 alpha-DH and CA concentration. At both sites, 7 alpha-DH was linearly related (p<0.005) to per cent DCA in serum. INTERPRETATION/SUMMARY: These results: (i) confirm that there are marked regional differences in bile acid metabolism between the right and left halves of the colon, (ii) suggest that caecal and faecal 7 alpha-DH influence per cent DCA in serum (and, by inference, in bile), and (iii) show that the substrate CA induces the enzyme 7 alpha-DH in the caecum.

Topics: Aged; Amidohydrolases; Cecum; Cholelithiasis; Cholic Acid; Deoxycholic Acid; Feces; Female; Gastrointestinal Contents; Humans; Hydroxysteroid Dehydrogenases; Male; Middle Aged; Oxidoreductases; Steroid Hydroxylases

The development of cholesterol gallstones, in some patients, has been associated with increased proportions of deoxycholic acid in the bile acid pool. Deoxycholic acid is a microbial product of cholic acid 7alpha-dehydroxylation in the intestines. The levels and activities of bile acid 7alpha-dehydroxylating bacteria have been reported to be increased in gallstone patients. The aim of the current study was to isolate 7alpha-dehydroxylating bacteria from gallstone patients and determine if these individuals are colonized by similar bacterial species.. The levels of 7alpha-dehydroxylating bacteria in fecal samples were determined by fecal dilutions in 24 gallstone patients and 10 controls. 7alpha-Dehydroxylating bacteria were isolated by a non-selective streak plate technique and 7alpha-dehydroxylation activity was determined by measuring the conversion of [14C]-cholic acid to [14C]-deoxycholic acid using thin-layer chromatography.. Gallstone patients had >42-fold (p<0.01) higher levels of 7alpha-dehydroxylating bacteria than patients who had not developed gallstones. Eighteen strains of 7alpha-dehydroxylating bacteria were isolated from eight gallstone patients. Attempts to isolate 7alpha-dehydroxylating bacteria from ten control patients were unsuccessful using identical isolation techniques. Surprisingly, all strains of bacteria isolated from gallstone patients appear to belong to the genus Clostridium.. Gallstone patients have higher levels of 7alpha-dehydroxylating fecal bacteria and appear to harbor only members of the genus Clostridium with this activity.

Topics: Adult; Aged; Bacterial Typing Techniques; Blotting, Southern; Cholelithiasis; Cholesterol; Cholic Acid; Cholic Acids; Chromatography, Thin Layer; Clostridium; Colony Count, Microbial; Deoxycholic Acid; DNA, Bacterial; Eubacterium; Feces; Female; Humans; Male; Middle Aged; Steroid Hydroxylases

Many patients with cholesterol gallbladder stones (GBS) have a high percentage of deoxycholic acid (DCA) in gallbladder bile (all of which are in the conjugated form), probably as a result of prolonged large bowel transit times (LBTT). However, whether the prolonged LBTT increases DCA formation, solubilization, or absorption (or all 3) is not known.. In 40 subjects (20 with GBS; age range, 24-74 years), we measured LBTT using radiopaque markers, and intestinal luminal pH by radiotelemetry. We also measured quantitative anaerobic bacteriology and the activities of 2 bile acid-metabolizing enzymes in fresh cecal aspirates obtained during clinically indicated unprepared colonoscopy, and related these results to the percentage of DCA in fasting serum measured by gas chromatography-mass spectrometry.. Compared with controls, GBS patients had longer LBTT (mean 23.1 +/- SEM 2.8 h vs. 36.5 +/- 3.3 h; P < 0.01); more total (2.7 +/- 0.6 x 10(9) vs. 5.9 +/- 1.5 x 10(9) cfu/mL) and Gram-positive (9.5 +/- 3.1 x 10(8) vs. 18.0 +/- 4.1 x 10(8) cfu/mL; P < 0.05) anaerobes; and greater 7alpha-dehydroxylating (7alpha-DH) activity (3.39 +/- 0.59 vs. 10.37 +/- 1.15 x 10(-4) U/mg protein) in the cecal aspirates. They also had higher intracolonic pH values (P < 0.02) and increased percentages of DCA in fasting serum (13.4% +/- 1.52% vs. 21.8% +/- 2. 19%; P < 0.005). Results of univariate and multivariate analyses confirmed that LBTT was critical in determining the percentage of DCA in serum and showed that 7alpha-DH activity and apparent distal colonic pH were also significant independent variables.. Slow colonic transit (more time), increased Gram-positive anaerobes (more bacteria), and greater 7alpha-DH activity (more enzyme) favor enhanced DCA formation; transit-induced increases in distal colonic luminal pH favor enhanced DCA solubilization/bioavailability; and increases in LBTT (more time) again favor DCA absorption.

Topics: Adult; Aged; Amidohydrolases; Bacteria, Anaerobic; Bile Acids and Salts; Cholelithiasis; Cholesterol; Colon; Deoxycholic Acid; Fasting; Gastrointestinal Transit; Humans; Hydrogen-Ion Concentration; Hydroxysteroid Dehydrogenases; Intestine, Large; Middle Aged; Oxidoreductases; Steroid Hydroxylases

Four main disturbances have been attributed to cholesterol gallstone disease: hypersecretion of cholesterol from the liver with cholesterol supersaturation in bile; disturbed motility with defective absorption and secretion by the gallbladder; increased crystallisation of cholesterol in the gallbladder bile; and slow intestinal transit with increased amount of deoxycholic acid in the bile acid pool. We aimed to evaluate the biliary lipid composition in a large series of gallstone patients, with emphasis on the amount of deoxycholic acid and with respect to number of stones, compared to gallstone free subjects.. Bile was sampled during operations through puncture of the gallbladder from 145 cholesterol gallstone patients, 23 patients with pigment stones and 87 gallstone free patients undergoing cholecystectomy. Biliary lipid composition, cholesterol saturation, bile acid composition, nucleation time and cholesterol crystals were analysed.. The patients with cholesterol gallstones showed higher molar percentage of cholesterol, lower total biliary lipid concentration, higher cholesterol saturation, shorter nucleation time and higher proportion of crystals in bile than the other groups. The nucleation time was significantly shorter in multiple cholesterol gallstone patients, but this was not due to higher cholesterol saturation. Male cholesterol gallstone patients showed higher cholesterol levels, lower total biliary lipid concentration, and higher cholesterol saturation in bile than female patients. There was no difference in biliary content of deoxycholic acid, but significantly lower content of cholic acid in gallstone patients compared to gallstone free patients.. We conclude that deoxycholic acid does not contribute to gallstone formation in cholesterol gallstone patients. The short nucleation time in patients with multiple cholesterol stones is not due to higher cholesterol saturation.

Topics: Adolescent; Adult; Aged; Bile; Bile Acids and Salts; Body Mass Index; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Female; Humans; Lipids; Male; Middle Aged

Treatment of acromegaly with octreotide increases the proportion of deoxycholic acid in, and the cholesterol saturation of, bile and induces the formation of gallstones. Prolongation of intestinal transit has been proposed as the mechanism for the increase in the proportion of deoxycholic acid in bile.. To study the effects of octreotide on intestinal transit in acromegalic patients during octreotide treatment, and to examine the relation between intestinal transit and bile acid composition in fasting serum.. Mouth to caecum and large bowel transit times, and the proportion of deoxycholic acid in fasting serum were measured in non-acromegalic controls, acromegalic patients untreated with octreotide, acromegalics on long term octreotide, and patients with simple constipation. Intestinal transit and the proportion of deoxycholic acid were compared in acromegalic patients before and during octreotide.. Acromegalics untreated with octreotide had longer mouth to caecum and large bowel transit times than controls. Intestinal transit was further prolonged by chronic octreotide treatment. There were significant linear relations between large bowel transit time and the proportion of deoxycholic acid in the total, conjugated, and unconjugated fractions of fasting serum.. These data support the hypothesis that, by prolonging large bowel transit, octreotide increases the proportion of deoxycholic acid in fasting serum (and, by implication, in bile) and thereby the risk of gallstone formation.

Topics: Acromegaly; Adult; Aged; Bile Acids and Salts; Cholelithiasis; Deoxycholic Acid; Drug Administration Schedule; Fasting; Female; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Intestine, Large; Male; Middle Aged; Octreotide; Risk Factors

The influence of deoxycholic acid (DCA) on the factors in gallbladder bile responsible for cholesterol gallstone disease has been a controversial subject of discussion. This might be partially due to patient selection or inappropriate methods. Therefore, we investigated the relationship between the percentage of DCA and lithogenic factors in the gallbladder bile of patients with cholesterol gallstones and with normal or moderately impaired gallbladder contractility. Patients with pigment stones served as a control group. The percentage of DCA in the gallbladder bile of 20 patients with cholesterol stones (23.2%+/-6.5%; mean+/-SD) was comparable to the DCA percentage in the gallbladder bile of 11 patients with pigment stones (26.5%+/-8.5%). No correlation was seen between the DCA percentage of total bile acids and the crystal observation time, cholesterol saturation index (CSI), total protein value, mucin level, and amount of cholesterol in vesicles or crystals in the total group of patients or in the subgroups with cholesterol or pigment stones, respectively. The lack of correlation between DCA percentage and CSI was determined in native bile (r = 0.048) as well as in crystal-free bile after ultracentrifugation (r = 0.107). Our findings demonstrate that in patients with gallstones, the percentage of DCA in gallbladder bile is not related to any of the known biliary factors associated with cholesterol gallstone disease. We conclude that in patients with normal or moderately impaired gallbladder function, an elevated DCA level in the gallbladder bile is of minor pathophysiologic significance for the formation of cholesterol gallstones.

Topics: Adult; Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Female; Humans; Lipids; Male; Middle Aged; Mucins; Phospholipids; Pigments, Biological; Ultracentrifugation

Our aim was to establish whether small intestine transit time is defective in subjects with cholesterol gallstones.. We enrolled 10 patients (eight women, two men; mean age, 48.7 yr; mean body mass index [BMI], 22.4 Kg/m2) with recently diagnosed cholelithiasis, with no liver pathology, who were not taking any drugs, and 11 comparable healthy volunteers (eight women, three men; mean age, 46.2 yr; mean BMI, 22.7 Kg/m2), who served as controls. All subjects underwent orocecal (by starch breath test technique and serum assays of salazopyrin), oroileal (by serum assays of tauroursodeoxycholic acid), and duodenoileal (by serum assays of taurocholic acid) transit times; cholesterol saturation index; and bile acid composition and gallbladder motility studies (by ultrasound). For serum assays, blood samples were collected over a period of 7 h. Gallbladder motility and orocecal transit time were evaluated simultaneously.. All four means of assessing transit time gave longer times in cholesterol gallstone patients than in controls: orocecal transit time (salazopyrin) = 366 +/- 13 vs 258 +/- 16 min, p < 0.0005; orocecal transit time (starch breath test) = 415 +/- 139 vs 290 +/- 15 min, p < 0.01; duodenoileal transit time: 272 +/- 23 vs 205 +/- 23 min, p < 0.03; and oroileal transit time: 308 +/- 18 vs 230 +/- 19 min, p < 0.009. Cholesterol gallstone patients showed an increase in percent molar biliary deoxycholic acid (30% +/- 4.5% vs 16% +/- 1.3%, p < 0.02) and a decrease in percent molar cholic acid 32% +/- 2.2% vs 40% +/- 1.3%, p < 0.03) and chenodeoxycholic acid (34% +/- 3% vs 41% +/- 1.8%, p < 0.03), compared with controls; patients also had greater percent molar biliary cholesterol. A linear relationship (r2 = 0.6324, p = 0.0012) between biliary deoxycholic acid and small bowel transit time was found. Residual gallbladder volumes were larger in cholesterol gallstone patients (11.38 +/- 1.27 vs 7.55 +/- 0.39 ml, p < 0.04), whereas basal gallbladder volumes, although higher, did not reach statistical significance (24.25 +/- 2.41 vs 19.98 +/- 1.63 ml; p = ns).. This study confirms that patients with cholesterol gallstones have delayed small bowel transit, defective gallbladder motor function, and increased biliary deoxycholic acid. Delayed small bowel transit may contribute to supersaturation of bile with cholesterol by increasing deoxycholic acid production.

Topics: Bile; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Gastrointestinal Transit; Humans; Male; Middle Aged

Plasma levels of the cholesterol precursor 7-dehydrocholesterol (7-DHC) were compared with activities of the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase assayed in liver biopsies from patients undergoing cholecystectomy. Some patients were treated with cholestyramine, deoxycholic acid or chenodeoxycholic acid prior to surgery in order to alter the activity of the enzyme. The median level of 7-DHC and the activity of HMG-CoA reductase in the untreated group were 55 ng/ml and 98 pmol/min/mg protein, respectively. The sterol levels and enzyme activities were increased in patients treated with cholestyramine (85 ng/ml and 439 pmol/min/mg protein) and deoxycholic acid (86 ng/ml and 173 pmol/min/mg protein) and decreased in patients treated with chenodeoxycholic acid (38 ng/ml and 51 pmol/min/mg protein). There was a strong positive correlation (rs=0.75, P<0.0005) between the plasma levels of 7-DHC and the activities of hepatic HMG-CoA reductase in these patients. This correlation was further improved when the plasma levels of 7-DHC were expressed relative to those of cholesterol (rs=0.90, P<0.0001). The results show that the level of 7-DHC in plasma reflects the activity of HMG-CoA reductase in the liver.

Topics: Adult; Aged; Anticholesteremic Agents; Biopsy; Chenodeoxycholic Acid; Cholecystectomy; Cholelithiasis; Cholesterol; Cholestyramine Resin; Dehydrocholesterols; Deoxycholic Acid; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Liver; Male; Middle Aged

Cholesterol crystallization in a dilute, bile salt-rich model bile is a multiphase process in which early filamentous crystals gradually transform to classical cholesterol monohydrate plates. The pertinence of similar transformations in more complex model systems or native bile is, however, unclear. The aim of the present study was to characterize and monitor cholesterol crystallization in a model bile of physiological relevance.. A supersaturated model bile was prepared with a lipid composition (18 mM cholesterol, 37 mM lecithin, 120 mM taurocholate) that was derived from analyzing 10 gallbladder biles from cholesterol gallstone patients. Cholesterol crystallization was followed by light and electron microscopy, and sequential density gradient analysis of cholesterol-containing precipitates.. During cholesterol crystallization a reproducible sequence of events was recorded. First (T<18 h), cholesterol-rich vesicular and multilamellar structures (density 1.005-1.015 g/ml) were observed. Later, (T>60 h) filamentous, helical, tubular (density 1.015-1.04 g/ml) and plate-like (density 1.04-1.06 g/ml) cholesterol crystals appeared. The concentration of crystals increased gradually, while bilayer structures became desaturated with cholesterol and disappeared, and early crystal forms were replaced by plates. Eventually (T>25 days) only classical plate-like cholesterol monohydrate crystals were present. Exposure of cholesterol-containing precipitates to micellar (100 mM) deoxycholate dissolved the bilayer structures but not the crystals.. These data demonstrate that cholesterol crystallization in a physiologically relevant model bile is a multiphase process consisting of a sequence of transitions from vesicular and multilamellar structures to early crystal forms and to classical plate-like cholesterol monohydrate crystals. These transitions are associated with increasing density and decreasing phospholipid content of cholesterol precipitates. We suggest that time-lapse density gradient ultracentrifugation is a useful method for investigating and quantitating the process of cholesterol crystallization and factors that influence this process in bile.

Topics: Animals; Bile; Centrifugation, Density Gradient; Cholagogues and Choleretics; Cholelithiasis; Cholesterol; Chromatography, Gel; Crystallization; Deoxycholic Acid; Egg Yolk; Kinetics; Microscopy, Electron; Models, Biological

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.. 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.. 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.. Increased CA-7 alpha-dehydroxylation activity of the intestinal microflora may be an important factor for CG formation or growth in these patients.

Topics: Adult; Bile Acids and Salts; Cholelithiasis; Cholesterol; Deoxycholic Acid; Feces; Female; Gram-Positive Bacteria; Humans; Hydroxylation; Male; Middle Aged

Little is known about the effects of biliary deoxycholic acid on the partitioning of biliary cholesterol between vesicles and micelles and on the rate of nucleation of cholesterol microcrystals, key steps in gallstone formation. Therefore, 43 samples of fresh gallbladder bile were obtained from a heterogeneous group of patients with and without stones. Univariate and multivariate analyses were then applied to determine the inter-relationships between biliary cholesterol saturation, total lipid concentration, and bile acid species and (1) the distribution of biliary cholesterol between vesicles and micelles and (2) the cholesterol microcrystal nucleation time. The percentage of deoxycholic acid in bile was shown to be linearly related to the cholesterol saturation index (r = .54; P < .001), the vesicular cholesterol:phospholipid molar ratio (r = .53; P < .001), and the molar concentration of cholesterol in the vesicles (r = .59; P < .001). The mean proportion of biliary deoxycholic acid conjugates was also greater in patients with rapid nucleation times (23.4 +/- SEM 1.1%) than in those with slow nucleation times (17.3 +/- 1.9%; P < .05). As total bile lipid concentration increased, the proportion of total biliary cholesterol in vesicles decreased (r = .53; P < .001), whereas the molar concentration of vesicular cholesterol increased (r = .42, P < .01). The cholesterol saturation indices, total bile lipid concentration, and proportion of biliary deoxycholate were independent determinants of the molar concentration of cholesterol in vesicles. We conclude that relative increases in the percentage of deoxycholic acid and in bile lipid concentration, favor the partitioning of cholesterol into vesicles. In turn, this leads to an increase in the vesicular cholesterol:phospholipid molar ratio and thus to a decrease in the cholesterol microcrystal nucleation time.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Centrifugation, Density Gradient; Chemical Phenomena; Chemistry, Physical; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Female; Gallbladder; Humans; Lipid Metabolism; Male; Micelles; Middle Aged; Multivariate Analysis; Solubility

Patients with cholesterol gallstone disease have a reduced pool of bile acids. Overly sensitive feedback inhibition of bile acid synthesis has been postulated to explain this size reduction. To test this hypothesis, hepatic bile acid concentration and the activity of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme for bile acid biosynthesis, were determined in ten patients with cholesterol gallstones and ten patients without gallstones. The bile acids present in liver tissue are the sum of those returning to liver and those newly synthesized in liver. If an overly sensitive feedback inhibition truly existed in our gallstone patients, a decreased concentration of hepatic bile acids would have been expected. However, patients with cholesterol gallstones had significantly higher total (143.3 +/- 25.5 vs 64.5 +/- 10.8 nmol/g liver, P < 0.01), chenodeoxycholic (64.1 +/- 9.9 vs 29.8 +/- 5.4, P < 0.01), deoxycholic (22.8 +/- 10.9 vs 2.0 +/- 0.7, P < 0.05), and ursodeoxycholic acid (6.2 +/- 1.4 vs 1.5 +/- 0.6, P < 0.01) concentrations than patients without gallstones. The activity of cholesterol 7 alpha-hydroxylase did not differ significantly between the two groups. Impaired hepatic transport or secretion of bile acids is strongly suspected in cholesterol gallstone patients. The findings of the present study showed no evidence of overly sensitive feedback inhibition of bile acid synthesis in cholesterol gallstone patients. Bile acid pool size may be affected by the inappropriate increase of hepatic bile acids rather than by overly sensitive feedback inhibition.

Topics: Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Deoxycholic Acid; Female; Humans; Liver; Male; Middle Aged; Ursodeoxycholic Acid

A total of 100 nonobese and normolipidemic subjects (29 control subjects, 49 patients with cholesterol stones [CSs], and 22 patients with brown pigment stones) were studied to elucidate the pathogenetic contributions of deoxycholate (DC) to supersaturated bile formation with special reference to de novo syntheses of cholesterol and bile acids in the liver. A higher proportion of DC was observed in gallbladder bile from patients with CSs (CSs; 21.7 +/- 1.4%, mean +/- SEM, vs. control subjects; 10.2 +/- 0.9%). Cholesterol saturation in bile was elevated parallel to the increase of DC (r = .48; P = .0002), irrespective of the existence of stones. In a comparison between the 52 subjects with increased DC in bile (> 10% of biliary bile acids) and the 20 subjects without the increase (< 10%), the molar percentage of cholesterol in bile was significantly higher in the former (9.4 +/- 0.5%) than in the latter (6.7 +/- 0.4%) (P < .001). Consistent with the decrease in steady-state level of low-density lipoprotein (LDL) receptor-messenger RNA (mRNA), the catalytic activity and mRNA level of microsomal hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for de novo cholesterol synthesis, were significantly lower in the former (2.9 +/- 0.3 pmol/min/mg protein) than in the latter (5.1 +/- 0.6) (P < .0001). Biliary molar percentage of bile acids was significantly lower in the former (69.8 +/- 1.1%) than in the latter (75.2 +/- 1.5%) (P < .01). However, contrary to expectations, the catalytic activity and mRNA level of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme for bile acid synthesis, were significantly higher in the former (5.8 +/- 0.4 pmol/min/mg protein) than in the latter (3.7 +/- 0.6) (P < .01). The magnitude of the impaired gallbladder emptying (control subjects; 78.4 +/- 4% vs. CSs; 58 +/- 3%; P < .0005) together with the prolonged small intestinal transit (control subjects; 126 +/- 9 minutes vs. CSs; 198 +/- 9 minutes; P < .01) correlated significantly with the increased percentage of DC in bile. It is concluded that in cholesterol gallstone disease an increase of DC in bile, linked to an impaired gallbladder emptying together with a prolonged small intestinal transit, may play a significant role in downregulating de novo cholesterol synthesis but not bile acid synthesis in the liver.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adult; Aged; Base Sequence; Bile; Bile Acids and Salts; Blood; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Gallbladder; Gastrointestinal Transit; Humans; Intestine, Small; Lipid Metabolism; Liver; Male; Middle Aged; Molecular Sequence Data; Oligonucleotide Probes

Because an increase in biliary deoxycholate levels seems to be a risk factor for cholesterol gallstone formation, we determined the relationship between deoxycholate levels and levels of the pronucleating protein, immunoglobulin G (Ig) in human gallbladder bile. Patients with cholesterol gallstones had a higher concentration of biliary IgG compared with a pigmented stone group and control patients. This was associated with the simultaneous presence of two conditions in the cholesterol stone group, supersaturated bile and a high deoxycholate/cholate ratio. The other patient groups met only one of the two conditions. Next, animal studies were performed to determine if model biles mimicking the two conditions could affect IgG secretion by the gallbladder. Gallbladders were exposed in vivo and then in an Ussing chamber to model biles. The voltage clamp technique was used to monitor functional integrity of the preparation. Three different model biles were tested: (1) taurodeoxycholate (TDC), 80%; taurocholate (TC), 20%; and cholesterol saturation index (CSI), 1.2; (2) TDC, 20%; TC, 80%; and CSI, 1.2; and (3) TDC, 80%; TC, 20%; and CSI, 0.6. IgG concentrations became significantly higher in group 1 than in the other two groups. The concentration of mucous glycoprotein was also significantly greater in group 1 when compared with group 2. Plasma cells were increased in number in mucosal and submucosal layers in group 1. We conclude that cholesterol supersaturated model bile with high content of TDC induces gallbladder epithelial alterations, which increase the luminal concentration of IgG and mucous glycoprotein.

Topics: Animals; Bile; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Glycoproteins; Humans; Immunoglobulin G; Osmolar Concentration; Pigmentation; Reference Values; Swine; Taurocholic Acid; Taurodeoxycholic Acid

The relations between the concentration of deoxycholic acid (DCA), the cholesterol saturation index, and the nucleation time in gall bladder bile were measured to determine the role of DCA in bile in the pathogenesis of cholesterol gall stone disease. Bile was obtained from patients with cholesterol gall stones (n = 30), subjects without gall stones (n = 35), and patients with pigment gall stones (n = 9). Three of 30 cholesterol gall stone patients and 10 of 35 gall stone free subjects were treated with antibiotics by mouth to decrease the concentration of bile DCA and determine the effect of DCA on biliary lithogenecity. Both the percentage and concentration of DCA in bile were similar in patients with and without cholesterol gall stones despite significant differences in their cholesterol saturation indices and nucleation times. Neither the percentage nor the concentration of DCA in bile correlated with either the cholesterol saturation index or the nucleation time. Analysis of subgroups with matching cholesterol saturation indices showed no correlation between the proportion of DCA in the bile and the cholesterol nucleation time. The proportion of DCA in bile was decreased by antibiotic treatment, but this had no effect on the cholesterol saturation index or nucleation time. These results suggest that DCA in bile is not responsible for biliary cholesterol saturation or cholesterol nucleation time.

Topics: Aged; Anti-Bacterial Agents; Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Gallbladder; Humans; Middle Aged; Phospholipids; Time Factors

Changes in biliary lipid composition, pH, ionised calcium, total and unconjugated bilirubin, and cholesterol nucleation time of gall bladder bile samples were examined in six patients who had undergone subtotal or total colectomy between five months and seven years previously, and values were compared with those in control patients with no gall stones. The colectomy group mainly comprised patients with ulcerative colitis and familial adenomatosis coli, in whom only a short length of the terminal ileum (mean (SEM) 2.25 (0.57) cm) had been resected. The reconstruction procedures were ileoanal anastomosis in two patients, terminal ileostomy in two, ileorectal anastomosis in one, and J shaped ileal pouch-anal anastomosis in one patient. The distributions of age, sex, and relative body weight were similar in the two groups. The gall bladder bile was lithogenic in the post colectomy group--these patients had a significantly increased cholesterol saturation index (p < 0.01) and rapid cholesterol nucleation time (p < 0.05) compared with the control group. A significant increase in the molar percentage of cholesterol and a decrease in that of total bile acid associated with significantly decreased secondary bile acids (p < 0.05) were observed in the post colectomy group. Gall stones formed in two of six patients after colectomy were cholesterol stones containing more than 80% cholesterol by dry weight. Total and unconjugated bilirubin, pH, and ionised calcium values were similar in the two groups. The results indicate that after total or subtotal colectomy the composition of gall bladder bile increases the risk of cholesterol gall stone formation.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Bilirubin; Calcium; Cholelithiasis; Cholesterol; Cholic Acids; Colectomy; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Postoperative Complications; Time Factors

Treatment of acromegaly with octreotide inhibits cholecystokinin release and gallbladder contraction and induces gallbladder stones. However, little is known about the effects of octreotide on bile composition.. Fresh gallbladder bile was obtained from three groups: (1) 11 nonacromegalic patients with cholesterol gallstones, (2) 6 acromegalic patients with octreotide-associated stones (treatment, 300-600 micrograms/day for 3-66 months), and (3) 8 acromogalic patients with no stones before octreotide treatment, 5 of whom were reexamined after 3-24 months of therapy.. Compared with stone-free acromegalic patients untreated with octreotide, bile from patients with cholesterol stones and from acromegalic patients with octreotide-associated stones had greater saturation indices (mean +/- SEM) (1.52 +/- 0.17 and 1.32 +/- 0.14 vs. 0.90 +/- 0.05, respectively; P < 0.01); more cholesterol in vesicles (61.2% +/- 4.5% and 67.7% +/- 7.2% vs. 37.7% +/- 3.5%; P < 0.009); more unstable vesicles (cholesterol/phospholipid ratios, 0.97 +/- 0.12 and 0.81 +/- 0.16 vs. 0.52 +/- 0.05; P < 0.02); more rapid nucleation (< 5 and < 5 days vs. > 18 days; P < 0.003); and more deoxycholic acid (22.8% +/- 2.4% and 23.6% +/- 4.8% vs. 13.9% +/- 1.4%; P < 0.05). In the paired studies, the saturation indices increased from 0.89 +/- 0.07 before octreotide treatment to 1.12 +/- 0.03 during octreotide treatment (P < 0.02), as did the percentage of deoxycholic acid from 13.3% +/- 2.1% to 24.9% +/- 2.7% (P < 0.03).. Acromegalic patients with octreotide-associated gallstones and stone-free acromegalic patients treated with octreotide have similar changes in bile composition to those in patients with "conventional" cholesterol gallstone disease.

Topics: Acromegaly; Adult; Aged; Bile; Chemical Phenomena; Chemistry, Physical; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Octreotide; Phospholipids

Topics: Acromegaly; Cholelithiasis; Deoxycholic Acid; Female; Gastrointestinal Transit; Humans; Octreotide

The metabolism and time-courses of urinary and fecal excretions of murideoxycholic acid (MDCA; 3 alpha,6 beta-dihydroxy-5 beta-cholanoic acid), a 6 beta-hydroxylated bile acid, was investigated in man. The study was carried out in two groups of subjects. Six cholecystectomized patients fitted with a cystic duct drain ingested 100 mg of a tracer dose of 3H-MDCA. Time-course of radioactivity in plasma was then followed for an 8-h period. Biliary, urinary and fecal excretions of radioactivity were measured for a 5-day period and excreted MDCA metabolites were identified. Five lithiasic patients with intact enterohepatic circulation ingested 500 mg of the same tracer dose of 3H-MDCA. Radioactivity in plasma was followed for a 49-h period and urinary and fecal excretions of radioactivity were measured daily for 7 days. In the first group, the excretion of the radioactivity by the three routes (bile+urine+feces) reached 97.8 +/- 1.5% of the ingested dose but dropped to 75 +/- 8.3% (urine+feces) in patients in the second group. In cholecystectomized patients, the estimation of intestinal MDCA absorption was dependent on cystic duct drain flow rate and gave values ranging from 20% to 87%. The biological half-life of MDCA in lithiasic patients averaged 3.4 +/- 0.7 days. Radioactivity appeared in the plasma in the first hour and reached a maximum 6 and 3 h after the beginning of the experiment in group I and II respectively. In the second group, another peak of radioactivity in plasma was observed just after breakfast.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Bile; Biotransformation; Cholecystectomy; Cholelithiasis; Deoxycholic Acid; Feces; Female; Humans; Kinetics; Male; Middle Aged; Tritium

The role of biliary deoxycholate as an endogenous carcinogen and the possible association between cholelithiasis and the subsequent development of carcinoma of the gall bladder is unclear. This paper describes biliary bile acid analysis performed on three groups of patients, 10 with cholelithiasis, 10 with carcinoma of the gall bladder and 10 control patients. This is the first report of bile acid changes in carcinoma of the gall bladder. In these 30 patients the total bile acids concentration was highly variable (11.44-53.68 mg/ml). The mean ratio of primary to secondary bile acids was 3.5:1. This ratio was, however, significantly higher in cholelithiasis than in the control group (5.34:1; P < 0.001); patients with carcinoma of the gall bladder had significantly higher secondary bile acids (1:1; P < 0.001). This is due to a marked increase in the secondary bile acids and indicates that raised biliary deoxycholate concentrations are present in patients with carcinoma of the gall bladder and therefore may well be a factor in carcinogenesis.

Topics: Bile Acids and Salts; Carcinoma; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acid; Cholic Acids; Deoxycholic Acid; Gallbladder Neoplasms; Humans; Lithocholic Acid

It has been previously reported that patients with cholesterol gallstones have increased biliary deoxycholate and arachidonate content as compared with normal subjects without gallstones. Increased biliary deoxycholate and arachidonate content might be a primary factor in the pathogenesis of cholesterol gallstones or merely an epiphenomenon due to the presence of gallstones. We therefore compared biliary bile acid composition in 46 patients with cholesterol gallstones and 22 patients with pigment stones. In addition, biliary phospholipid fatty acid composition was determined in 44 of these patients (30 cholesterol and 14 pigment stone patients). No significant differences were detected. In particular, the percentage deoxycholic acid (mean +/- SD: 20.3 +/- 8.8% and 21.5 +/- 10.9% respectively) and the percentage arachidonic acid (4.4 +/- 2.0% and 4.5 +/- 2.2%, respectively) were very similar. A significant correlation between age and biliary cholesterol saturation index was found only for the group of patients with pigment stones (R = 0.52, p less than 0.02). In conclusion, the present study does not support a primary role for increased biliary deoxycholic acid or arachidonic acid in the pathogenesis of cholesterol gallstones.

Topics: Arachidonic Acid; Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Deoxycholic Acid; Fatty Acids; Female; Humans; Male; Phospholipids; Pigments, Biological

Biliary lipid composition, cholesterol saturation, and bile acid pattern were determined in fasting duodenal bile of 10 patients (four men and six women, mean age 41 years) with Crohn's disease and a history of ileal resection (mean 64 cm). The data were compared with corresponding values in a group of healthy subjects. None of the patients with Crohn's disease had supersaturated bile. Cholesterol saturation was significantly lower in the patients with Crohn's disease than in the healthy subjects. The molar percentage of cholesterol was also lower among the patients but there was no significant difference. The molar percentages of phospholipids and bile acids were normal. Bile acid composition in the patients with ileal resection was characterised by a significant decrease in the deoxycholic acid fraction and a pronounced increase in the ursodeoxycholic acid fraction compared with the healthy subjects. The surprisingly high percentage of ursodeoxycholic acid may contribute to the low degree of cholesterol saturation in bile. Based on these results patients with Crohn's disease should not have an increased risk of cholesterol gall stone formation.

Topics: Adult; Age Factors; Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Crohn Disease; Deoxycholic Acid; Female; Humans; Ileum; Lipids; Male; Middle Aged; Risk Factors; Ursodeoxycholic Acid

The effect of two hydrophilic bile acids, murideoxycholic acid (3 alpha,6 beta-dihydroxy-5 beta-cholanoic acid) and ursodeoxycholic acid, on cholesterol and bile acid metabolism and hepatic pathology and gallstone composition was studied in the prairie dog. Cholesterol gallstones were induced by feeding a diet containing 1.2% cholesterol for 75 days. The animals were divided into six groups, and gallstone regression was studied as follows: groups 2 and 5, chow plus 0.2% cholesterol; groups 3 and 6, chow plus 0.2% cholesterol plus 0.15% ursodeoxycholic acid; groups 4 and 7, chow plus 0.2% cholesterol plus 0.15% murideoxycholic acid. Animals in groups 2 to 4 were killed after an additional 6 wk; animals in groups 5 to 7 were killed after an additional 12 wk. Gallstone dissolution did not occur in any group. The gallstones in groups 2, 3, 5 and 6 were typical cholesterol aggregates, as determined by polarized light microscopy and Fourier transform infrared spectrometry. The gallstones of the murideoxycholic acid group were large, solitary, dark stones that appeared radiopaque under 22 kVp x-ray examination. Scanning electron microscopy showed that in these stones the cholesterol crystals had been replaced by an amorphous material, both within the stone and on the stone surface. Chemical analysis indicated that at the end of 12 wk the calcium/sodium salt of the taurine conjugate of murideoxycholic acid (murideoxycholyl taurine) comprised 70% of the stones; protein, cholesterol and small amounts of other bile salts were also present. In vitro studies confirmed the insolubility of the sodium and calcium salts of murideoxycholyl taurine. These studies indicate that the hydrophilic bile acids, murideoxycholic acid and ursodeoxycholic acid, did not achieve gallstone dissolution under the conditions used. In the animals fed murideoxycholic acid, an insoluble calcium salt of murideoxycholyl taurine replaced cholesterol as the major constituent of gallbladder stones. This is the first example of an insoluble dihydroxy taurine-conjugated bile acid; administration of the unconjugated bile acid induced precipitation of a kind of gallstone not previously reported. The final result was transformation of cholesterol stones to bile salt stones.

Topics: Animals; Bile Acids and Salts; Chemical Phenomena; Chemistry, Physical; Cholelithiasis; Cholesterol; Deoxycholic Acid; Diet; Liver; Male; Microscopy, Electron, Scanning; Sciuridae; Ursodeoxycholic Acid

Infection of the biliferous system in patients with cholelithiasis was shown to be the most frequent when the levels of cholic acid in bile were low. Physiological concentrations of cholic and deoxycholic acids have antimicrobial activity against organisms not adapted to the presence in bile. Outer drainage of the bile ducts was accompanied by an increase in the levels of cholic acid when at the background of outer decompression bacteria were eliminated from the biliferous system. In vitro studies revealed a synergistic antibacterial effect of cholic and deoxycholic acid combinations with cefazolin.

Topics: Bile; Cefazolin; Cholelithiasis; Cholic Acids; Culture Media; Deoxycholic Acid; Drug Synergism; Enterobacteriaceae; Gentamicins; Humans; In Vitro Techniques; Pseudomonas aeruginosa; Staphylococcus aureus

Topics: Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans

Topics: Bile; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans

It has been previously suggested that treatment with ursodeoxycholic acid leads to decreased gallbladder emptying. The proposed mechanism is decreased release of cholecystokinin through negative feedback control by an increased amount of intraduodenal bile acids. In the present study we examined cholecystokinin release and gallbladder contraction after oral administration of a commercial fatty meal (Sorbitract; Dagra, Diemen, The Netherlands) using ultrasonography in eight normal subjects and eight gallstone patients before and after 1 and 4 weeks of treatment with ursodeoxycholic acid (10 mg kg-1.day-1). Fasting gallbladder volume increased in 15 of 16 subjects during treatment (P less than 0.01). Minimal volume did not change. Therefore, both absolute and relative gallbladder emptying increased during therapy. Maximal decrement of gallbladder volume in milliliters and percentage as well as integrated gallbladder contraction during 90 minutes in milliliters and percentage were significantly increased after 1 and 4 weeks of treatment with ursodeoxycholic acid when compared with data before therapy. Gallstone patients tended to have larger fasting and residual gallbladder volumes than normal subjects, whereas parameters for the amount of bile expelled (maximal decrement of gallbladder volume and integrated gallbladder contraction in milliliters and percentage) did not differ. Release of cholecystokinin did not change during treatment and did not differ significantly between patients and normal subjects. Mean relative percentage of ursodeoxycholic acid in bile during treatment in 13 subjects consenting to have duodenal intubation was 47% (range 31%-60%). Changes of fasting gallbladder volume after institution of bile acid treatment correlated significantly (r = 0.74, P less than 0.01) with changes of cholesterol saturation index but not with relative percentage of ursodeoxycholic acid in bile. This study indicates that gallbladder emptying does not decrease during treatment with ursodeoxycholic acid. Moreover, there is no evidence of decreased cholecystokinin release.

Topics: Adult; Aged; Bile; Cholecystokinin; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Gallbladder; Humans; Male; Middle Aged; Muscle Contraction; Reference Values; Ultrasonography; Ursodeoxycholic Acid

Cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) which are extracted with CH3OH from Bezoar can be separated on HPTLC silica gel plate (made in China) with isooctane-n-butyl acetate-acetic acid (4:2:1), and the three bile acids were determined by TLC densitometry.

Topics: Animals; Bile Acids and Salts; Cattle; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acid; Cholic Acids; Chromatography, Thin Layer; Densitometry; Deoxycholic Acid; Materia Medica

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Recurrence; Ursodeoxycholic Acid

The aim of the present study is to examine the efficacy of 6-hydroxy substituted bile acids on the prevention of cholesterol gallstones in a new hamster model of cholesterol cholelithiasis. Male golden Syrian hamsters were fed a nutritionally adequate semipurified lithogenic diet consisting of casein, cornstarch, soluble starch, butterfat, corn oil, and cellulose plus 0.3% cholesterol. Six different bile acids were added to this diet at the 0.05% level: chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid, murideoxycholic acid, 6 beta-methyl-hyodeoxycholic acid, and 6 alpha-methyl-murideoxycholic acid. At the end of the 6-wk feeding period, the control group receiving the lithogenic diet had a 55% incidence of gallstones. It was found that all bile acids had inhibited the formation of cholesterol gallstones; complete prevention of gallstones was observed with all 4 3,6-dihydroxy bile acids, whereas chenodeoxycholic acid and ursodeoxycholic acid were somewhat less effective (80% and 75% prevention, respectively). The accumulation of cholesterol in serum and liver induced by the lithogenic diet was inhibited to some extent by all of the bile acids; hyodeoxycholic acid, murideoxycholic acid, and 6 beta-methyl hyodeoxycholic acid were most effective in this respect. The administered bile acids tended to predominate in bile in the case of chenodeoxycholic acid, hyodeoxycholic acid, and 6 beta-methyl-hyodeoxycholic acid. In contrast, ursodeoxycholic acid seemed to be converted to chenodeoxycholic acid and murideoxycholic acid to hyodeoxycholic acid. Only 4% of the 6-methyl analogue of murideoxycholic acid, 6 alpha-methyl-murideoxycholic acid, was recovered in gallbladder bile. These experiments show that the new hamster model of cholesterol cholelithiasis is suitable for gallstone-prevention studies. It was not possible to draw definite conclusions concerning the mechanism of action of the administered bile acids on the basis of cholesterol saturation or the presence of liquid crystals. The detailed mechanism of gallstone prevention by hydrophilic bile acids in this model remains to be elucidated.

Topics: Animals; Cholelithiasis; Cholesterol; Cricetinae; Deoxycholic Acid; Male; Mesocricetus; Structure-Activity Relationship; Ursodeoxycholic Acid

Urinary bile acids from 20 patients treated with chenodeoxycholate, 18 treated with ursodeoxycholate, 15 treated with rifampicin and 8 patients with advanced cirrhosis were analyzed by gas-liquid chromatography and gas-liquid chromatography-mass spectrometry. Occurrence rates and amounts of three so-called unusual trihydroxy bile acids, hyocholate, ursocholate and omega-muricholate, were increased in patients treated with chenodeoxycholate, ursodeoxycholate or rifampicin and decreased in cirrhotic patients as compared with those in untreated healthy adults. These data suggest that chenodeoxycholate and ursodeoxycholate are hydroxylated to produce unusual trihydroxy bile acids in bile acid-loaded humans and that this metabolism may be related to the induction of hepatic microsomal enzymes by rifampicin. In contrast, the hydroxylation of chenodeoxycholate and ursodeoxycholate may be impaired by severe hepatic damage. Because the urine is a secretory pathway for internal bile acids, the occurrence of unusual trihydroxy bile acids in the urine may be used as an indicator of hepatic ability to metabolize "hydrophobic" dihydroxy bile acids to their secretory forms.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Chromatography, Gas; Deoxycholic Acid; Gas Chromatography-Mass Spectrometry; Humans; Hydroxy Acids; Liver Cirrhosis; Rifampin; Ursodeoxycholic Acid

We have carried out overnight measurements of hepatic secretion rate and duodenal output of biliary lipids using a duodenal perfusion technique. We correlated these measurements with the fasting state mass of biliary lipids within the gall bladder on the following morning using a combined nasoduodenal intubation and isotope scanning technique. We studied six gall stone subjects before and during treatment with ursodeoxycholic acid 675 mg/day. Lipid mass within the gall bladder correlated with the corresponding overnight hepatic secretion rate for all three biliary lipids. During ursodeoxycholic acid treatment, there was an increase in gall bladder bile acid mass without significant change in cholesterol or phospholipid mass. We conclude that the mass of individual biliary lipids within the fasting gall bladder is influenced by overnight hepatic biliary lipid secretion rate; and that the effect of ursodeoxycholic acid (675 mg/day) on cholesterol saturation index of fasting gall bladder bile is mediated via an increase in bile acid mass rather than through a decrease in cholesterol mass within the gall bladder.

Topics: Aged; Bile Acids and Salts; Bile Ducts; Cholelithiasis; Cholesterol; Deoxycholic Acid; Duodenum; Female; Gallbladder; Humans; Male; Middle Aged; Phospholipids; Ursodeoxycholic Acid

Topics: Administration, Oral; Adult; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Ethers; Female; Humans; Methyl Ethers; Solvents; Ursodeoxycholic Acid

Topics: Bile Acids and Salts; Cholelithiasis; Deoxycholic Acid; Follow-Up Studies; Humans; Recurrence; Solubility; Ursodeoxycholic Acid

The rate of decrease of gallstone diameter appeared to be linear with oral bile acid treatment time, as estimated by inspection of graphic data of individual patient serial oral cholecystograms. A theoretical basis for this model was derived. The hypothesis of diameter decrease proportional to treatment time was tested with data from 223 patients with radiolucent gallbladder stones up to 20 mm in diameter treated with 7-8 or 14-15 mg.kg-1.day-1 of either ursodiol or chenodiol for 1 year, followed up after 3, 6, and 12 months of treatment. Linearity of individual sets of data points was tested by mathematical and statistical methods, including polynomial curve fitting, linear regression analysis, quadratic vs. linear analyses of covariance, and prediction of 12-month stone size by linear extrapolation from diameters at 0 and 6 months. Most patients (greater than 70%) had rates of gallstone diameter decrease that were almost linear with treatment time, independently of different dissolution rates on a given regimen. Additional treatment time needed may be estimated from cholecystograms or ultrasonograms performed before treatment and after several months.

Topics: Chenodeoxycholic Acid; Cholecystography; Cholelithiasis; Deoxycholic Acid; Humans; Kinetics; Models, Biological; Time Factors; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid

Liver function has been assessed on the basis of radioimmunoassays of the primary conjugated cholic acid, cholylglycine, in the blood sera of cholelithiasis patients treated with cheno- and ursodeoxycholic acid drugs for a long time. The findings indicate that the blood serum cholylglycine levels may be regarded, among other things, as a prognostic criterion of the efficacy of cholelithiasis therapy with bile acid preparations for litholysis.

Topics: Adult; Aged; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Glycocholic Acid; Humans; Male; Middle Aged; Ursodeoxycholic Acid

The object of this study was to determine the effects of ursodeoxycholic acid administration on metastability in human gallbladder bile, as reflected by nucleation time. Bile samples from 10 patients with cholesterol gallstones who underwent preoperative ursodeoxycholic acid treatment exhibited a significantly longer median nucleation time (16 days) than those from 11 patients with cholesterol gallstones who received no preoperative treatment (4 days) (p less than 0.01). On the other hand, the median nucleation times of bile samples from 15 patients with noncholesterol gallstones and 24 patients without gallstones were 15 and 14 days, respectively. In addition, 3 mo of treatment with ursodeoxycholic acid significantly elevated the serum concentration of the antinucleating factor apolipoprotein A-I, from 133.3 +/- 12.3 to 148.6 +/- 13.2 mg/dl (p less than 0.05). These findings suggest that ursodeoxycholic acid retards cholesterol crystal nucleation, thereby inhibiting cholesterol gallstone formation. It is also possible that serum apolipoprotein A-I plays a role in this process.

Topics: Adult; Aged; Aged, 80 and over; Apolipoprotein A-I; Apolipoproteins A; Bile; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Lipoproteins, HDL; Middle Aged; Preoperative Care; Ursodeoxycholic Acid

Topics: Animals; Cholelithiasis; Cholesterol; Cricetinae; Deoxycholic Acid; Drug Therapy, Combination; Esters; Gabexate; Guanidines; Mesocricetus; Solubility; Triglycerides; Trypsin Inhibitors; Ursodeoxycholic Acid

Topics: Animals; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Ursodeoxycholic acid (ursodiol) has been shown to be an effective oral agent for dissolution of gallstones that also has a favorable safety profile. In the selection of patients as candidates for this treatment, stone characteristics and the functional status of the gallbladder are the two most important criteria. Small, primarily cholesterol stones (radiolucent on plain film) are the most suitable for oral dissolution therapy. In addition, a functioning gallbladder (as evidenced by visualization on oral cholecystogram) is required to concentrate the ursodiol-enriched bile and effect stone dissolution. Ursodiol should not be used during pregnancy, in women likely to become pregnant, or in severe acute or chronic intrahepatic cholestasis. Acute cholestasis and common bile duct obstruction also preclude this treatment. Screening tests include basic laboratory tests of liver function, sonographic evaluation of the gallbladder and biliary tree, plain film of the abdomen, and oral cholecystogram. Since few patients meet all the selection criteria ideally, the decision to undertake treatment with ursodiol must be based on the entire clinical profile and on the patient's willingness to accept the predicted likelihood of success.

Topics: Age Factors; Body Weight; Cholelithiasis; Cholesterol; Deoxycholic Acid; Gallbladder; Humans; Ursodeoxycholic Acid

A method for the quantitative determination of three main bile acids, cholic acid (CA), ursodesoxycholic acid (UDCA) and chenodesoxycholic acid (CDCA), in bear gall, drainage from bear gall and bear gallstone is described. Experimental conditions: TLC Scanner CS-910, fluorescence scanning, lambda ex 470 nm and lambda em 550 nm for CA; lambda ex 380 nm and lambda em 450 nm for UDCA and CDCA. The results showed that the contents of UDCA and CDCA in bear gall drainage were higher than those in bear gall. The method is simple, rapid and sensitive. The reproducibility is good. The average recovery is 98.4%, CV is 1.4%.

Topics: Animals; Bile Acids and Salts; Carnivora; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acids; Chromatography, Thin Layer; Deoxycholic Acid; Drainage; Gallbladder; Ursidae; Ursodeoxycholic Acid

Twenty-four patients with radiolucent gall stones were treated with cholelitholytic bile acids. Complete gall-stone dissolution was achieved in 8 patients (33%) and partial dissolution in 3 patients (13%). Therapy was never successful for large gall stones (greater than 15 mm). Even in the group of patients with very small stones (less than or equal to 5 mm) complete dissolution was obtained in only 47% of cases. Patients with atypical abdominal complaints or without symptoms never developed biliary pain or colic nor did their symptoms improve during therapy. On the contrary, 3 of 6 patients with previous biliary pain or colic had to be operated because of recurrence during therapy.

Topics: Adult; Aged; Aged, 80 and over; Chenodeoxycholic Acid; Cholecystography; Cholelithiasis; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Ultrasonography; Ursodeoxycholic Acid

Topics: Cholelithiasis; Deoxycholic Acid; Diet, Reducing; Gallbladder; Glycoproteins; Humans; Ursodeoxycholic Acid

Topics: Cholelithiasis; Cholesterol; Deoxycholic Acid; Drug Therapy, Combination; Esters; Gabexate; Guanidines; Humans; Trypsin Inhibitors; Ursodeoxycholic Acid

Extracorporeal shock-wave cholelithotripsy was carried out in 135 symptomatic patients with radiolucent gallstones, followed by oral bile acid dissolution to assess the resultant stone disappearance rates. Fragmentation was satisfactory (all fragments less than 5 mm in diameter) in 34 patients (25%) after a single session of lithotripsy, and in 65 (48%) after multiple sessions. The overall satisfactory fragmentation rate was significantly higher in patients with single stones less than or equal to 20 mm in diameter when compared with those with larger solitary stones (71% vs. 38%, p less than 0.05), as it also was in all subjects with solitary stones when compared with those with multiple stones (60% vs. 34%, p less than 0.05). After 6, 9, and 12 mo of oral bile acid treatment, the stone-free rates were significantly higher in patients with satisfactory than in those with partial fragmentation (55% vs. 0%, 80% vs. 29%, and 90% vs. 33%, respectively; p less than 0.05). Only 1 of the 7 patients who had previously undergone endoscopic sphincterotomy for concomitant choledocholithiasis was free of stones after 1 yr of dissolution. During dissolution therapy, of the 102 patients in whom fragmentation had occurred, 1 (1%) developed mild acute pancreatitis, 23 (23%) suffered attacks of biliary colic, and 6 (6%) required cholecystectomy. We conclude that the result of fragmentation appears to be a major determinant of the success and rapidity of subsequent oral bile acid dissolution, and that when satisfactory, it allows for complete stone disappearance in most patients within the following year. A comparison of the present results with those of previous original studies suggests that to achieve such satisfactory fragmentation, patients should be selected on the basis of their stone characteristics, which optimally should present as solitary gallbladder calculi less than 20 mm in diameter. Furthermore, real-time ultrasonographic monitoring should be used during lithotripsy with a transducer centered along the shock-wave axis. Despite the innocuousness of the shock waves, the incidence of fragment migration and its possible complications, in our experience, emphasizes the need to restrict at present this nonoperative approach to the treatment of symptomatic gallstone disease.

Topics: Adult; Aged; Chenodeoxycholic Acid; Cholelithiasis; Combined Modality Therapy; Deoxycholic Acid; Female; Follow-Up Studies; Humans; Lithotripsy; Male; Middle Aged; Time Factors; Ursodeoxycholic Acid

Recurrence is a major problem in the medical treatment of gallstones but its extent is still uncertain. The aim of this study was to determine the magnitude of this event and to assess the effectiveness of a postdissolution treatment in preventing it. We evaluated the long-term recurrence rate after 96 confirmed dissolutions observed in 86 subjects (71 women, 15 men) over a 12-yr follow-up period. A low-dose postdissolution treatment (ursodeoxycholic acid, 300 mg/day) was administered to 36 subjects, whereas in the remaining 60 cases no postdissolution treatment was given. By actuarial life-table analysis, the cumulative proportion of gallstone recurrence was 12.5% at the first year, rising to 61% at the 11th year. Postdissolution treatment was effective in reducing the frequency of gallstone recurrence (p = 0.0067), but this was mainly related to its effect on younger subjects (less than or equal to 50 yr old). In older subjects the recurrence rate was unaffected by treatment. The probability of gallstone recurrence was significantly higher in subjects with multiple stones before dissolution treatment than in those who had had solitary stones (p = 0.0091). No other factor predictive of gallstone recurrence could be identified.

Topics: Actuarial Analysis; Adult; Aged; Cholelithiasis; Deoxycholic Acid; Female; Follow-Up Studies; Humans; Male; Middle Aged; Recurrence; Risk Factors; Time Factors; Ursodeoxycholic Acid

Fourteen patients with radiolucent gallstones proved by oral cholecystography (OC) and ultrasonography were treated with daily doses of 600 mg of ursodeoxycholic acid (UDCA) for one year. Among them, 2 patients had complete dissolution of gallstones and another one had partial dissolution. The success rate was 21.4% (3/14). Of the remaining 11 patients who failed to respond to UDCA treatment, calcifications of varied degrees were demonstrated in every gallstone by computed tomography (CT). None of these 14 patients had statistically significant changes in serum lipids, liver function tests and hemograms during the course of treatment and only one (7.1%) patient had transient diarrhea. It was concluded that UDCA was effective and safe for medical dissolution of non-calcified gallstones. However, the underestimation of the calcification of gallstones by OC precluded successful medical dissolution by UDCA. Therefore, meticulous selection of non-calcified gallstones by CT rather than OC as candidates for dissolution may improve the success rate.

Topics: Adult; Aged; Calcinosis; Cholelithiasis; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Ursodeoxycholic Acid

Nucleation time (NT) and growth time (GT) were measured in gallbladder bile of patients with cholesterol gallstones. NT was significantly shortened (NT less than 10 days) in pure cholesterol stones but was moderately shortened (11 less than or equal to NT less than or equal to 21) in mixed and combination stones. GT also was accelerated (GT less than 7 days) in cholesterol stones. NT was shortened in increased biliary total protein, but on the contrary, was shortened in decreased apo A-I. NT of bile by UDCA therapy but not CDCA was extended. This suggests that increased apo A-I during UDCA therapy might imply extension of NT. The strong negative correlation between GT and CSI of bile suggests that CSI plays an important role in crystal growth.

Topics: Aged; Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Time Factors; Ursodeoxycholic Acid

Topics: Administration, Oral; Cholelithiasis; Deoxycholic Acid; Family Practice; Humans; Prognosis; Ursodeoxycholic Acid

General Surgeons and physicians for internal medicine were asked for their results of dissolution-therapy of gallstones. 405 physicians were asked, 283 (69.9%) answered; 33.6% of these had some experience with the dissolution therapy. Data from 100 patients could be gathered completely: from 72 women (mean age 48 years) and from 27 men (mean age 53 years). The age-distribution resembled those of surgical gallstone-patients. In 27 cases the dissolution was successful (mean duration of therapy 49.6 weeks), in 25 cases there was a partial success (mean duration of therapy 54.8 weeks), and in 48 cases the dissolution-therapy failed (mean duration of therapy 55.5 weeks). In 60 cases therapy was stopped, but only 25 of these patients underwent cholecystectomy. In summary there is some evidence, that many collegues are sceptical against dissolution of gallstones, that the preoperative diagnostic procedure is ineffective, that the results of dissolution therapy in a common praxis is not as effective as in controlled studies, that dissolution therapy mainly is forced in patients at a normal risk--and not in high-risk patients, that only few patients are ready to take the pills longer than 1 year, and that in the case of stopping the therapy not all patients undergo consequently cholecystectomy.

Topics: Adult; Aged; Aged, 80 and over; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Ursodeoxycholic Acid

Oral dissolution treatment with chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) is indicated in the case of cholesterol gallstones. However, three conditions must be satisfied for treatment to be effective: 1) the stones must be radiolucent; 2) the gallbladder must be functioning, i.e. opacified by oral cholecystography; 3) the stones must be smaller than 15 mm in diameter. Most authors consider that treatment is only justified when the stones are symptomatic. On the basis of these criteria, it has been estimated that about 20% of patients with gallstones presenting to gastroenterologists could be suitable for treatment. The mean percentage of efficacy is of the order of 50 to 60% at 18 months to 2 years. This percentage may be as high as 70-80% in the case of floating stones smaller than 1 cm. At the optimal dose (15 mg/kg/day), CDCA may induce diarrhoea and raised transaminases. Its prolonged administration can induce hepatic lesions. UDCA (7-10 mg/kg/day) generally does not have any side effect. The combination of CDCA/UDCA at the dose of 7-8 mg/kg/day of each agent may be more effective. After stopping treatment, a recurrence is observed in about 50% of cases within 5 years. Regular ultrasonographic follow-up (annually, for example) is therefore necessary to treat recurrences in time. Because of the criteria of efficacy and its adverse effects, oral dissolution treatment is only indicated in a very limited number of patients. However, it constitutes an essential complement to extracorporeal lithotripsy, which may represent its principal indication at the present time.

Topics: Administration, Oral; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Recurrence; Ursodeoxycholic Acid

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.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Drug Administration Schedule; Female; Gallbladder; Humans; Lipid Metabolism; Male; Middle Aged; Time Factors; Ursodeoxycholic Acid

After endoscopic retrograde sphincterotomy, patients with an intact gallbladder are at risk for developing symptoms or complications of gallbladder stones. Medical dissolution of such stones would be desirable, especially in elderly patients with an increased surgical risk. However, sphincterotomy alters emptying dynamics of the gallbladder and markedly reduces bile salt pool size, effects that may alter response to chenodeoxycholic acid or ursodeoxycholic acid treatment. Studying two groups of 5 patients with an intact gallbladder after endoscopic retrograde sphincterotomy, we found that 15 mg/kg.day of chenodeoxycholic acid increased the mean (+/- SEM) biliary percentage of chenodeoxycholic acid from 35.5% +/- 4.0% to 88.8% +/- 1.9% (p less than 0.01) and decreased the mean saturation index of gallbladder bile from 1.02 +/- 0.22 to 0.55 +/- 0.08 (p less than 0.05). Ursodeoxycholic acid (10 mg/kg.day) increased the mean biliary percentage of ursodeoxycholic acid from 5.6% +/- 1.5% to 44.7% +/- 5.8% (p less than 0.01) and decreased the mean saturation index of gallbladder bile from 1.04 +/- 0.25 to 0.57 +/- 0.03 (p less than 0.05). A long-term trial of bile acid treatment in sphincterotomy patients with stones in an intact gallbladder is needed.

Topics: Aged; Aged, 80 and over; Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Gallbladder; Humans; Middle Aged; Sphincterotomy, Transduodenal; Ursodeoxycholic Acid

Topics: Bile; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Humans; Time Factors; Ursodeoxycholic Acid

Topics: Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

In view of the low solubility of calcium deoxycholate and the possible induction of cholesterol precipitation in the gallbladder by calcium insoluble salts, we find it of interest to study the precipitation of calcium deoxycholate and its dependence on other bile components. The findings of these studies were as follows: (i) Precipitation of calcium deoxycholate from mixtures of calcium chloride and monomeric deoxycholate (at concentrations below the critical micelle concentration (CMC] is very slow even at relatively high CaCl2 concentrations (more than 20 days at 50 mM CaCl2). (ii) At higher deoxycholic acid (DOC) concentrations, precipitation of micellar DOC is faster and requires much lower calcium chloride concentrations. For any given calcium concentration, the rate of precipitation is maximal at an optimal DOC concentration. In solutions containing 150 mM NaCl, the maximal rate of precipitation occurs at about 10 mM DOC, almost independent of Ca2+ concentration. At lower ionic strength (10 mM NaCl), the optimal DOC concentration is 30 mM. These observations suggest that the most important factors in determining the rate of Ca(DOC)2 precipitation are (a) the ratio between calcium ions bound to the surface of a DOC micelle, and the [DOC] (the Ca2+/DOC binding ratio) and (b) the concentration of DOC micelles. (iii) In the presence of conjugated deoxycholates, the crystallization of calcium deoxycholate is inhibited. Phosphatidylcholine has a similar, although smaller, inhibitory effect. Upon precipitation of calcium deoxycholate from a mixed micellar system containing sodium deoxycholate, phosphatidylcholine and cholesterol, the latter two components spontaneously form vesicles. The anti-nucleating effect of PC and conjugated bile salts is explained in terms of "poisoning" of the crystallization process. In view of the latter results we conclude that under normal conditions calcium deoxycholate is not likely to precipitate in the gallbladder.

Topics: Bile Acids and Salts; Calcium; Chemical Precipitation; Cholelithiasis; Deoxycholic Acid; Humans; Phosphatidylcholines; Solubility

The aim of this study was to determine the effect of chronic ursodeoxycholic acid administration on coupling of bile acids with cholesterol and phospholipid in hepatic bile, and on cholesterol absorption in the duodenum. A range of bile acid secretion rates was obtained during an evening meal and an overnight fast. Duodenal perfusion of polyethylene glycol as a nonabsorbable recovery marker and of [3H]cholesterol and [14C]lecithin as absorbable recovery markers was combined with continuous intravenous infusion of indocyanine green as a hepatic bile marker. Six subjects with gallstones were studied before and during chronic administration of ursodeoxycholic acid (675 mg/day). Duplicate pretreatment studies revealed good reproducibility for biliary lipid coupling and cholesterol absorption. During ursodeoxycholic acid administration there was a significant alteration not only in bile acid/cholesterol coupling (p less than 0.001), but also in bile acid/phospholipid coupling (p less than 0.001). Mean cholesterol absorption decreased from 25% to 15% (p less than 0.001) during ursodeoxycholic acid administration. These effects of chronic ursodeoxycholic acid administration on biliary lipid coupling are similar to those reported for acute administration, and are thus consistent with an effect caused by bile acid lipid-solubilizing capacity.

Topics: Aged; Bile Acids and Salts; Cholelithiasis; Cholesterol; Deoxycholic Acid; Duodenum; Eating; Fasting; Female; Humans; Intestinal Absorption; Male; Middle Aged; Phospholipids; Ursodeoxycholic Acid

Topics: Adult; Aged; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Drug Evaluation; Female; Humans; Liver; Male; Middle Aged; Pigments, Biological; Proteins; Selenomethionine; Ursodeoxycholic Acid

Impaired gallbladder emptying has been associated with gallstone disease but any effect on or from bile acid therapy for gallstone dissolution is unknown. We evaluated gallbladder filling and emptying with low-dose cholecystokinin infusion (0.02 U/kg.h) by computer-assisted cholescintigraphy in 52 controls versus 31 gallstone patients: 17 treated with 12-15 mg/kg.day of chenodeoxycholic acid and 14 with 8-10 mg/kg.day of ursodeoxycholic acid. Thirteen of 31 patients with complete dissolution had four scans: before, after 3 mo of therapy, after stone dissolution, and after discontinuation of bile acids. The 18 failures had three scans: before and after 3 and 15-18 mo of therapy. Before therapy, the 31 gallstone patients had significantly impaired gallbladder emptying compared with controls, but filling was not decreased. Bile acids significantly decreased emptying in both treatment groups after 3 mo of therapy. In the dissolution group, emptying improved once the stones had dissolved and increased further upon discontinuing the bile acids. In the failures, impaired emptying persisted for up to 15-18 mo. Gallbladder filling in the 31 gallstone patients was also significantly decreased after 3 mo of bile acid therapy, particularly in the failure patients, 5 of whom exhibited zero filling. No differences were detected between ursodeoxycholic acid and chenodeoxycholic acid for either gallbladder function or efficiency of dissolution. Thus, bile acid therapy impairs gallbladder filling and emptying in gallstone patients. Gallstone dissolution improves emptying, which is further enhanced when bile acids are discontinued.

Topics: Adult; Aged; Aged, 80 and over; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Gallbladder; Humans; Male; Middle Aged; Radionuclide Imaging; Ursodeoxycholic Acid

One hundred patients with radiolucent gall stones less than or equal to 1.5 cm in functioning gall bladders have received oral bile acid dissolution therapy since 1975. Complete data are available on 93 who have received at least six months' treatment. The complete dissolution rate in appropriately selected patients who complied with and tolerated an adequate course of treatment was 55%. By life table analysis the recurrence rates were 13% at one year, 21% at two years, 31% at three years, and 43% at four years. Thereafter the recurrence rate levelled out, being 49% at 11 years. Redissolution was achieved in all seven patients who had a second course of therapy, but was usually followed by re-recurrence. Patients whose gall stones recurred did not differ significantly from those who remained stone free with respect to age, sex, body weight, or time required for dissolution.

Topics: Adult; Aged; Aged, 80 and over; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prognosis; Recurrence; Ursodeoxycholic Acid

Topics: Adult; Cholecystography; Cholelithiasis; Cystic Fibrosis; Deoxycholic Acid; Female; Humans; Male; Ursodeoxycholic Acid

Between September 1986 and April 1987, extracorporeal shock-wave lithotripsy, supplemented by oral chemolitholysis, was undertaken on 157 patients with symptoms of gallstones. Partial or complete stone fragmentation was achieved in 148 (94.3%). Freedom from stones was maintained under continuous chemolysis treatment for an average observation period of 8.5 weeks in 31 (19.7%). Considerable fragment reduction was obtained in 97 (61.8%), of whom 26 (16.6%) were demonstrated to have only minimal stone residues. Insufficient fragmentation and (or) no response to litholysis occurred in 29 (18.5%). These preliminary results suggest that, if there are moderately sized (less than 25 mm) and only a few (1-3) noncalcified cholesterol stones, these two methods in combination promise to be an effective alternative to cholecystectomy.

Topics: Adult; Aged; Cholelithiasis; Combined Modality Therapy; Deoxycholic Acid; Humans; Lithotripsy; Middle Aged; Ultrasonography

Topics: Bile Duct Diseases; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Topics: Adult; Aged; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Monoterpenes; Prospective Studies; Terpenes; Ursodeoxycholic Acid

The buoyancy of gallstones was observed by taking anterior-posterior scout X-ray films of two patients standing during endoscopic retrograde cholangiography. In case 1, the large and small gallstones differed in buoyancy, and ursodeoxycholic acid treatment dissolved the floating small stones while failing to dissolve the nonfloating large stone. In case 2, both the large and small stones floated and are being dissolved by ursodeoxycholic acid treatment. Since floating or nonfloating and the plane of flotation depend on the specific gravity of the gallstone, the above findings suggest that a gallstone with a low specific gravity is more readily dissolved than one with a high specific gravity. The present method of estimating the buoyancy of gallstones was therefore considered extremely useful in selecting patients for medical litholytic treatment.

Topics: Cholangiopancreatography, Endoscopic Retrograde; Cholecystography; Cholelithiasis; Deoxycholic Acid; Female; Humans; Middle Aged; Posture; Pregnancy; Specific Gravity; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Bile acids and cholesterol metabolites may play a role in large bowel carcinogenesis. Currently, the bile acids chenodeoxycholic (CDCA) and ursodeoxycholic acid (UDCA) are being used for dissolution of cholesterol gallstones in surgical high-risk patients. The effect of prolonged exogenous bile acid intake on rectal epithelial cell proliferation, as a marker for preneoplasia, was evaluated in 19 patients selected for treatment. They were divided into two groups: nine patients received CDCA, 15 mg/kg/day for a mean duration of 11.0 months, while 11 patients received UDCA, 10 mg/kg/day for a mean duration of 9.2 months. Rectal biopsies taken before treatment and at one, three, six, and 12 months of treatment were analyzed and evaluated by three proliferative parameters including labeling index (LI), distribution of labeled cells, and total cells per crypt column. No significant alterations in epithelial cell proliferation were observed among patients treated with UDCA or CDCA with the exception of the number of cells per crypt column which, in the latter instance, deviated only slightly from the predicted values. The lack of major persistent alterations in the proliferative behavior of rectal epithelial cells does not justify any change in the selection of patients for gallstone therapy, but cannot exclude the potentially deleterious long-term effects of bile acid treatment.

Topics: Autoradiography; Biopsy; Cell Division; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Drug Evaluation; Epithelium; Humans; Precancerous Conditions; Rectal Neoplasms; Rectum; Time Factors; Ursodeoxycholic Acid

Topics: Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Topics: Administration, Oral; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Drug Therapy, Combination; Humans; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Ethers; Humans; Lithotripsy; Methyl Ethers; Ursodeoxycholic Acid

Topics: Adult; Aged; Bilirubin; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Solubility; Spectrum Analysis; Ultrasonography; Ursodeoxycholic Acid

The sonographic patterns of artificially produced pure cholesterol and pigment gallstones were evaluated in vitro. Cholesterol calculi exhibited a smooth echo with a relatively high beam penetration, whereas pigment calculi showed a sickle-like surface echo without beam penetration. Clinical evaluation of these criteria in 107 patients was based on correlating preoperative sonographic diagnosis with postoperative microchemical analysis of the calculi. Although small, smooth cholesterol calculi were detected via ultrasound with an accuracy of more than 90 percent, pigment calculi could not be separated and identified with satisfactory precision.

Topics: Adult; Aged; Bilirubin; Calcium; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Gallbladder; Humans; Male; Middle Aged; Ultrasonography; Ursodeoxycholic Acid

It has been reported that lactulose can reduce biliary secondary bile acid (deoxycholate) composition and by this action can decrease biliary cholesterol saturation in patients with supersaturated bile. We tried to confirm this by feeding 60 g of lactulose per day during a period of 12 weeks to 8 healthy females with colonic adenomatous polyps and slightly elevated biliary cholesterol saturation. Although a 38% reduction of biliary deoxycholate was noted--38% after 4 weeks, and 32% after 12 weeks of lactulose feeding (P less than 0.01)--at the expense of a rise in both primary bile acids, cholate and chenodeoxycholate, no significant change in biliary cholesterol saturation was found after 4 nor after 12 weeks of lactulose feeding. These results do not support the concept that colonic bacterial metabolites of bile acids play a major role in the production of supersaturated bile and cholesterol gallstone formation.

Topics: Bile; Cholelithiasis; Cholesterol; Colonic Polyps; Deoxycholic Acid; Disaccharides; Female; Humans; Lactulose; Middle Aged; Time Factors

Topics: Animals; Bilirubin; Cattle; Cattle Diseases; Cholelithiasis; Cholesterol; Cholic Acids; Chromatography, Thin Layer; Deoxycholic Acid; Medicine, Chinese Traditional; Medicine, East Asian Traditional

There is considerable evidence that the level of deoxycholic acid in the bile influences biliary cholesterol saturation. Deoxycholic acid is formed in the colon and absorbed slowly. Hence changes in colonic transit rate might influence biliary deoxycholic acid and the cholesterol saturation of bile. When 14 constipated subjects took standardised senna tablets for six weeks in a dose sufficient to lower mean whole gut transit time from 134 to 54 hours, deoxycholic acid as a proportion of biliary bile acids fell from 25.9 +/- 8.6 to 17.2 +/- 8.3% (p less than 0.0001) and deoxycholic acid pool measured by isotope dilution fell from 0.64 +/- 0.34 to 0.45 +/- 0.29 g (p less than 0.0001). In those subjects (n = 8) whose bile was initially supersaturated with cholesterol, the saturation index fell from 1.40 +/- 0.22 to 1.20 +/- 0.19 (p = 0.02). Conversely, when 12 normal volunteers took loperamide capsules sufficient to cause symptomatic constipation and to prolong mean transit-time from 48 to 103 hours, the deoxycholic acid pool increased from 0.40 +/- 0.24 to 0.57 +/- 0.17 g (p = 0.008). The percentage deoxycholic acid did not alter significantly, because the estimated total bile acid pool expanded (from 1.98 +/- 0.61 to 2.81 +/- 0.48 g; p less than 0.001), presumably because of loperamide slowing down small bowel transit. Despite this expansion of the bile acid pool, loperamide increased the cholesterol saturation index from 1.10 +/- 0.31 to 1.20 +/- 0.32 (p = 0.01). Changes in colonic transit rate alter the size of the deoxycholic acid pool and bile cholesterol saturation. These findings suggest that constipation or slow colonic transit might increase the chance of supersaturated bile and hence of gall stones.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Constipation; Deoxycholic Acid; Female; Gastrointestinal Motility; Humans; Intestinal Absorption; Kinetics; Male; Middle Aged; Time Factors

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.

Topics: Bile; Calcium Carbonate; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Microscopy, Polarization; Prognosis; Ursodeoxycholic Acid

Sixteen patients with radiolucent gallstones were treated with a combination of chenodeoxycholic and ursodeoxycholic acids for an average of 19 months. Liver tests remained normal in all patients. In nine of 15 patients (60%), in whom the gallbladder visualized during an oral cholecystogram, gallstones dissolved after one year, in eight of them, partially, and in the remaining one, completely. After two years, partial dissolution became complete in three patients, and partial dissolution occurred in 1 additional patient. Changes in lithogenic index and bile acid pool size were statistically not significant. Biliary content of chenodeoxycholic acid increased significantly from 25.7 +/- 3.53 to 45.2 +/- 3.31 (mean +/- SE)% and that of ursodeoxycholic acid from 2.6 +/- 0.52 to 34.6 +/- 2.45%. There were no discernible changes in serum triglycerides, total cholesterol, and HDL cholesterol. The findings suggest that the chenodeoxycholic-ursodeoxycholic acid combination provides a safe and efficacious treatment for some cholesterol gallstones.

Topics: Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Drug Therapy, Combination; Female; Humans; Lipids; Male; Time Factors; Ursodeoxycholic Acid

Gallstone formation and dissolution were studied in a prairie dog model of cholesterol (CH) cholelithiasis. Gallstones were induced in 49 prairie dogs by feeding 1.2% CH in a nutritionally adequate semisynthetic diet for 6 wk (period 1). At 6 wk, gallstones had developed in all animals examined. The diets were modified by reducing the amounts of CH to 0.4, 0.2, 0.1 and 0.0% (diets 1-4); hyodeoxycholic acid (HDA; 30 mg/kg/day) was added to these diets (diets 5-8). All animals were fed the modified experimental diets for an additional 8 wk (period 2). At week 14, spontaneous gallstone dissolution had not occurred, even in the groups given no added dietary CH during period 2 (group 4). Addition of HDA to the diet tended to reduce the incidence of biliary CH crystals and the size and number of CH gallstones. Biliary CH remained elevated and the lithogenic indices in all groups were found to be greater than 1.0 at the end of the experiment. Liver and plasma CH levels tended to be lower in the groups fed HDA. In these groups, HDA and 6 beta HDA became the major biliary bile acids. This study demonstrates that HDA achieved partial dissolution of gallstones in bile supersaturated with CH.

Topics: Animals; Cholelithiasis; Cholesterol, Dietary; Deoxycholic Acid; Diet; Disease Models, Animal; Male; Sciuridae

The aim of the present study was to establish whether the oral administration of bile acids with different hydrophilic properties affects the amount of phosphatidylcholine as well as the pattern of PC molecular species secreted in bile. We studied the biliary output of total and individual PC species in cholecystectomized T-tube patients, with a total biliary outflow, after oral administration of 750 mg of ursodeoxycholate (3 patients) or deoxycholate (3 patients). The latter experiments were repeated after 3 days of taurine supplementation (1500 mg daily) in order to increase, by means of the tauro-conjugation, the hydrophilicity of the secreted BA. A linear function was observed, during all the studies, between BA and PC biliary secretion, but the amount of PC secreted per mole of BA was higher for the less hydrophilic BA, such as deoxycholate, than for the more hydrophilic ursodeoxycholate or during deoxycholate plus taurine experiments. With regard to the pattern of PC molecular species, we observed no changes after administration of ursodeoxycholate. An increase in the secretion of the major polyenoic species (i.e., 16:0-18:2 and 16:0-20:4), with respect to the secretion of the monoenoic, was revealed during deoxycholate experiments. Conversely, during the deoxycholate plus taurine experiments, the secretion of the major monoenoic PC species (i.e., 16:0-18:1) increased more than that of the polyenoic species. We suggest that the observed modifications of the pattern of PC molecular species, secreted in bile, represent the result of a physicochemical effect of BA on liver membranes.

Topics: Bile; Bile Acids and Salts; Cholecystectomy; Cholelithiasis; Deoxycholic Acid; Female; Humans; Middle Aged; Phosphatidylcholines; Solubility; Taurine; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Gallstones; Humans; Ursodeoxycholic Acid

Topics: Aged; Calcinosis; Cholelithiasis; Deoxycholic Acid; Female; Humans; Ursodeoxycholic Acid

Fatty acid esters (at the 7 position) of chenodeoxycholic (CDCA) and ursodeoxycholic (UDCA) acids have been tested for their effects on formation and dissolution of gallstones in hamsters. The free bile acids were fed at a level of 0.2% of the diet and esters were fed at equimolar levels. The earlier finding that CDCA does not affect gallstone formation in hamsters fed the Dam and Christensen diet were confirmed. The acetic, butyric and lauric acid esters of CDCA had a very slight inhibitory effect on lithogenesis but CDCA 7 oleate and linoleate completely inhibited gallstone formation. UDCA and its 7 oleate inhibited both formation and progression of gallstones. The observed effects are probably a function of the form of the bile acid and not of the esterifying acid. The observation that ethyl oleate has a slight litholytic effect suggests that the acid moiety of the ester may exert a slight influence.

Topics: Animals; Chenodeoxycholic Acid; Cholelithiasis; Cricetinae; Deoxycholic Acid; Esters; Mesocricetus; Oleic Acids; Ursodeoxycholic Acid

Topics: Adult; Age Factors; Aged; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Gallbladder; Humans; Intestinal Absorption; Lipid Metabolism; Liver; Male; Middle Aged; Sex Factors; Ursodeoxycholic Acid

The fasting concentrations of ursodeoxycholic acid were determined in peripheral and portal venous serum of untreated (n = 12) and ursodeoxycholic acid-treated (n = 7) patients undergoing cholecystectomy. The levels of ursodeoxycholic acid were also determined in peripheral venous serum of 9 healthy subjects before and during treatment with ursodeoxycholic acid. Ursodeoxycholic acid, as well as cholic, chenodeoxycholic, and deoxycholic acids, were analyzed by a highly specific method based on isotope dilution-mass spectrometry. The fasting peripheral venous serum concentration of total (unconjugated plus conjugated) ursodeoxycholic acid averaged 0.14 mumol/L in the untreated gallstone patients and 0.19 mumol/L in the healthy subjects. The corresponding value in portal venous serum was 0.44 mumol/L. Treatment with ursodeoxycholic acid raised the level of this bile acid about 25-fold in portal as well as in peripheral venous serum. The proportion of unconjugated ursodeoxycholic acid was 34% in portal and 49% in peripheral venous serum of treated subjects. The mean hepatic uptake of ursodeoxycholic acid was calculated to be about 60% both in untreated and treated subjects. This uptake was significantly lower than that of cholic acid (83%). The hepatic uptake of ursodeoxycholic acid also tended to be lower than that of chenodeoxycholic acid (68%). This was mainly due to a lower hepatic uptake of unconjugated ursodeoxycholic acid (34%) compared with unconjugated chenodeoxycholic acid (49%). The relatively low hepatic uptake of unconjugated ursodeoxycholic acid explains why serum levels of the administered bile acid are higher during treatment with ursodeoxycholic acid than during treatment with chenodeoxycholic acid. Our results also give evidence that the hepatic uptake of ursodeoxycholic acid cannot be saturated under physiologic conditions.

Topics: Adult; Aged; Bile Acids and Salts; Cholecystectomy; Cholelithiasis; Deoxycholic Acid; Fasting; Female; Humans; Liver; Male; Mass Spectrometry; Middle Aged; Portal Vein; Radioisotope Dilution Technique; Time Factors; Ursodeoxycholic Acid; Veins

Does ursodeoxycholic acid (UDC) production protect hibernating species of Ursidae against gallstone disease? Five wild bears (Ursis Americana) were studied. Older bears had more UDC than younger ones, suggesting UDC production is an acquired phenomena. Bile salt pools were 10 times larger than that of man and were characteristically conjugated with Taurine alone. The relative composition of the principal lipids in bear bile fell well within the range of cholesterol solubility. Cholesterol gallstones are not reported in Ursidae, probably because of the large bile acid pool and high UDC content.

Topics: Animals; Bile; Bile Acids and Salts; Carnivora; Cholelithiasis; Cholesterol; Chromatography, Gas; Deoxycholic Acid; Female; Gallbladder; Hibernation; Lipid Metabolism; Male; Phospholipids; Ursidae; Ursodeoxycholic Acid

Hyodeoxycholic acid and its isomer, 6 beta-hyodeoxycholic acid, when added to a lithogenic diet prevented the formation of cholesterol gallstones and crystals in prairie dogs. This beneficial effect occurred in the presence of bile supersaturated with cholesterol. Hyodeoxycholic acid abolished the feedback inhibition of hepatic hydroxymethylglutaryl coenzyme A reductase activity, the rate-limiting enzyme of cholesterol synthesis, and prevented elevations in serum and liver cholesterol observed in animals fed a 0.4 percent cholesterol diet. The gallbladder bile of the animals fed hyodeoxycholic acid and 6 beta-hyodeoxycholic acid contained abundant liquid crystals. This suggests that these bile acids prevented the transition of cholesterol from its liquid crystalline phase to solid crystals and stones.

Topics: Animals; Bile; Cholelithiasis; Cholesterol; Cholesterol, Dietary; Crystallization; Deoxycholic Acid; Diet; Disease Models, Animal; Female; Glycodeoxycholic Acid; Hydroxymethylglutaryl CoA Reductases; Liver; Male; Microsomes, Liver; Sciuridae

Dissolution of cholesterol stones in the gallbladder can give rise to insoluble sediment and pigment stones. Thus can lead to a change of the type of gallstones. We have observed such a development during a period of 4 years in 23.5% of a group of 51 patients, whose cholesterol stones originally had been dissolved. Formation of pigment stones can be prevented, if calcium sediments with a grain size below 3 mm are removed early and forcefully enough out of the gallbladder. The voiding function of the gallbladder must be intact for such treatment, and this has to be tested before appropriate drug therapy is choosen.

Topics: Aged; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Follow-Up Studies; Humans; Middle Aged; Ursodeoxycholic Acid

Chemical dissolution of cholesterol gallstones using ursodeoxycholic acid (UDCA) in six patients with histologically confirmed HBsAg-negative chronic active hepatitis was started after a minimum of one year of therapy with steroids, azathioprine, or chloroquine and a treatment-free period of 8-15 months. The treatment with UDCA lasted 3-20 months with a daily dose of 8-11 mg/kg. Four patients served as controls. A decrease in transaminases (P less than 0.05) occurred in all patients during the UDCA therapy. After completion of the treatment, the figures rose again, but did not return to the initial value. The stones dissolved in five patients. A second liver biopsy was carried out in two patients after UDCA therapy, and this showed no detectable deterioration. Four patients refused biopsy because the laboratory parameters had improved under UDCA. A stone recurred in one patient six months after the end of therapy; the others have remained free of stones for up to 24 months.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Follow-Up Studies; Glycocholic Acid; Hepatitis, Chronic; Humans; Male; Middle Aged; Time Factors; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Altered gallbladder motility could predispose to, or result from, gallstone formation and could also explain the alleged relief of biliary colic seen during bile acid therapy. Therefore, in 14 controls, 25 patients with radiolucent gallstones, and 14 patients with radiopaque gallstones, we used two techniques to measure gallbladder contraction--radionuclide imaging and real-time ultrasound--in response to one of two stimuli--a Lundh meal or intravenous cholecystokinin-octapeptide. Using the radionuclide technique, postprandial gallbladder emptying (t1/2) was prolonged (p less than 0.01) both in patients with radiopaque (26.7 +/- 3.1 min, mean +/- SEM) and radiolucent (21.7 +/- 3.1) gallstones when compared with controls (10.2 +/- 1.5). In patients with radiolucent stones, the t1/2 of gallbladder emptying became further prolonged (p less than 0.05) after 1 mo of therapy with 8-10 mg/kg body wt X day of ursodeoxycholic acid, to 32.1 +/- 4.4 min. A similar pattern of results was seen after cholecystokinin-octapeptide and also with real-time ultrasound. Thus, after both stimuli and using two independent techniques, gallbladder contraction was reduced in patients with gallstones. The slower and less complete gallbladder emptying with ursotherapy might explain the reduction in biliary colic noted during treatment.

Topics: Adult; Aged; Cholelithiasis; Deoxycholic Acid; Eating; Female; Gallbladder; Humans; Imino Acids; Infusions, Parenteral; Male; Middle Aged; Muscle Contraction; Radionuclide Imaging; Sincalide; Technetium; Technetium Tc 99m Lidofenin; Time Factors; Ultrasonography; Ursodeoxycholic Acid

Topics: Adult; Bile Acids and Salts; Cholelithiasis; Deoxycholic Acid; Female; Humans; Lipid Metabolism; Male; Middle Aged

Topics: Animals; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Hydrolysis; Intestinal Absorption; Lethal Dose 50; Male; Mice; Mice, Inbred Strains; Rats; Rats, Inbred Strains; Ursodeoxycholic Acid

Topics: Calcinosis; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Radiography; Ursodeoxycholic Acid

In spite of the great progress seen in the diagnostic and treating method for gallstone patients in this 10 years, the criteria of the operative indication for these patients have not been discussed for a long time. I wish to emphasize it is high time for us to examine a matter, since chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) have begun to be popular in Japanese medical field as an oral gallstone solubilizer. I have mentioned the different dissolving mechanism of cholesterol after the administration of CDCA or UDCA. Recently, residual gallstones are removed using the newly developed instruments, such as a duodenal fiberscope, a choledochal fiberscope, a specially designed basket catheter and a YAG laser knife. Direct gallstone solubilizer, however, is still useful for special cases where gallstones are difficult to be removed by mechanical means. In an attempt to give answer to this, we have developed and used clinically the mixed solution of d-limonene and middle chain monoglyceride for cholesterol gallstones and 90% dimethyl sulfoxide and chelating polyphosphate for bilirubin gallstones.

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cyclohexenes; Deoxycholic Acid; Dimethyl Sulfoxide; Humans; Limonene; Solubility; Terpenes; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Male; Ursodeoxycholic Acid

Biliary lipid composition and lithogenicity were studied in 40 patients after ileal resection of different extent. The lithogenic index increased in extended ileal resection and ileostomy groups. There was a significant positive correlation between the lithogenic index and the length of ileal resection (r = 0.65, p less than 0.001). Total bile acid concentration and the proportion of deoxycholic acid were decreased after ileal resections as compared to controls. Especially these changes were remarkable in the extended ileal resection and ileostomy groups (p less than 0.001). Nine out of 40 patients were restudied after one month of oral ursodeoxycholic acid administration (300mg/day). Ursodeoxycholic acid consistently reduced the lithogenicity by decreasing the proportion of cholesterol in bile. Ursodeoxycholic acid was useful reducing bile lithogenicity in patients whose bile was supersaturated after ileal resection.

Topics: Adult; Aged; Bile; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Ileostomy; Lipids; Male; Middle Aged; Ursodeoxycholic Acid

Topics: Animals; Chenodeoxycholic Acid; Cholecystectomy; Cholelithiasis; Cholesterol; Colonic Neoplasms; Deoxycholic Acid; Female; Humans; Male; Risk; Ursodeoxycholic Acid

The effect of various dietary additions such as cholesterol, beta-sitosterol, bile acids, and bile acid analogs on gallstone formation was studied in the hamster. Gallstones were formed in 50% of the animals fed a high glucose, fat-free diet. Administration of 0.2% cholesterol or 1% beta-sitosterol had no effect on the incidence of gallstones. Ursodeoxycholic acid (0.5%) and its analog ursodeoxy-oxazoline [2-(3 alpha, 7 beta-dihydroxy-24-nor-5 beta-cholanyl)-4,4-dimethyl-2- oxazoline] were ineffective in preventing gallstones. Hyodeoxycholic acid and hyodeoxy-oxazoline [2-(3 alpha,6 alpha-dihydroxy-24-nor-5 beta-cholanyl)-4,4-dimethyl-2- oxazoline] at the same dosage effectively prevented gallstones, while the trihydroxy bile acid, hyocholic acid, was not effective. Of all the dietary regimens tested, only hyodeoxycholic acid significantly lowered serum cholesterol. The lithogenic diet produced a five-fold increase in hepatic HMG-CoA reductase activity; this activity was not affected by dietary cholesterol or beta-sitosterol. Hyodeoxycholic acid and hyocholic acid feeding increased the reductase activity by an additional 50% while the other bile acids had no effect. beta-Sitosterol doubled the cholesterol 7 alpha-hydroxylase activity whereas hyodeoxy-oxazoline lowered it. Hyodeoxycholic acid-fed animals had significantly lower cholesterol absorption than the animals on the lithogenic diet alone. Biliary cholesterol content increased dramatically in the animals fed the lithogenic diet and was increased still further by ursodeoxycholic acid, hyodeoxycholic acid, and hyodeoxy-oxazoline. These data show that hyodeoxycholic acid and hyodeoxy-oxazoline do not prevent gallstones by inhibiting hepatic cholesterol synthesis or biliary cholesterol secretion.

Topics: Animals; Bile; Bile Acids and Salts; Cholanes; Cholelithiasis; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cholic Acids; Cricetinae; Deoxycholic Acid; Diet; Hydroxymethylglutaryl CoA Reductases; Liver; Male; Mesocricetus; Phospholipids; Sitosterols; Sterols; Ursodeoxycholic Acid

Topics: Bile; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Topics: Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

An unknown bile acid was found by gas-liquid chromatography in the serum of patients who were administered ursodeoxycholic acid for the treatment of cholesterol gallstones. Identification of the chemical structure of the unknown bile acid was performed by the use of gas-liquid chromatography-mass spectrometry. Mass spectrum analysis of the methyl ester trimethylsilyl ether of the bile acid showed explicitly that this is dihydroxy-5 beta-cholanoic acid, since peaks at m/e 460 and 370 characteristic of methyl ester trimethylsilyl ether of dihydroxy bile acid were clearly exhibited. Sites of the two hydroxyl groups on the steroid nucleus were determined to be at the 3- and 7-positions by conversion of the bile acid to the corresponding dioxo-cholanoic acid and by comparison of the gas-liquid chromatographic behavior with those of authentic dioxo bile acids. Four authentic 3,7-dihydroxy-5 beta-cholan-24-oic acids were chemically synthesized and retention times and mass spectra of their methyl ester trimethylsilyl ether derivatives compared precisely with that of the unknown bile acid. The results indicate that the unknown bile acid is 3 beta, 7 beta-dihydroxy-5 beta-cholan-24-oic acid. Preliminary experiments suggest that 3 beta, 7 beta-dihydroxy-5 beta-cholan-24-oic acid is absent as amino acid-conjugated forms in serum. It is also suggested that the bile acid is excreted into urine but not into bile.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Chromatography, Gas; Chromatography, Thin Layer; Deoxycholic Acid; Humans; Indicators and Reagents; Magnetic Resonance Spectroscopy; Mass Spectrometry; Stereoisomerism; Ursodeoxycholic Acid

Topics: Age Factors; Cholangitis; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

We have compared the kinetics and physical-chemical mechanisms of human cholesterol gallstone dissolution in simulated normal, chenodeoxycholate-rich, and ursodeoxycholate-rich " biles ." Owing to reduced micellar cholesterol solubilizing capacities, dissolution rates in ursodeoxycholate-rich biles were initially slower than in normal or chenodeoxycholate-rich biles . At later time points, dissolution rates in ursodeoxycholate-rich bile became accelerated; this was shown to be associated with the development of a lamellar liquid-crystalline phase that took place first on the stones' surfaces and was then followed by dispersion of liquid-crystalline vesicles into the micellar solution. As subsequent dissolution occurred in a two-phase system of micelles and liquid-crystalline vesicles, the quantity of cholesterol solubilized exceeded micellar saturation. In normal and chenodeoxycholate-rich biles , no phase changes were observed either on the surfaces of the stones or in the micellar solution, and the quantity of cholesterol solubilized was limited by micellar saturation. These results was limited by micellar saturation. These results are consistent with phase equilibria diagrams of the simulated bile systems and suggest that the predominant physical-chemical mechanism of in vivo gallstone dissolution with ursodeoxycholic acid is via liquid crystalline dispersion of cholesterol. In contrast, micellar dissolution of cholesterol is the only mechanism possible with chenodeoxycholic acid.

Topics: Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; In Vitro Techniques; Kinetics; Ursodeoxycholic Acid

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Lipoproteins; Ursodeoxycholic Acid

Squalene is an obligate intermediate of cholesterol synthesis and plasma squalene to cholesterol ratio correlates significantly with cholesterol synthesis rate in the liver. Sixteen nonobese patients with radiolucent gallstones were randomly allocated into two treatment groups receiving 15 mg/kg/day ursodeoxycholic acid (group A) or 15 mg/kg/day lactose (group B) administered three times daily for 30 days. In group A, biliary squalene to cholesterol ratio was significantly lowered (from 1.19 to 0.86, P less than 0.02), as was cholesterol saturation (from 1.39 to 0.95, P less than 0.001); levels of plasma very-low-density lipoprotein cholesterol (VLDL-C) (from 30 to 26 mg/dL) and plasma VLDL-triglyceride (VLDL-TG) (from 81 to 68 mg/dL) decreased significantly only in the group taking ursodeoxycholic acid. No variations of squalene concentrations and squalene to cholesterol ratio were observed in the plasma of both groups. Biliary cholesterol saturation during ursodeoxycholic acid administration correlated directly with squalene to cholesterol ratio in bile; reduction of these two parameters is accompanied by decreased VLDL-C levels.

Topics: Adult; Bile; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Lipid Metabolism; Lipids; Lipoproteins; Male; Middle Aged; Radiography; Random Allocation; Squalene; Ursodeoxycholic Acid

Prairie dogs of both sexes were fed a semisynthetic diet containing 0.35% cholesterol for a period of 8 weeks. This lithogenic diet induced cholesterol gallstones in ten "lithogenic control animals", five males and five females. Three animals maintained with a high glucose, fat-free diet did not develop gallstones although the cholesterol saturation of their bile approached unity. The formation of gallstones was prevented in four out of five males and all five females fed the lithogenic diet plus 0.1% hyodeoxycholic acid (30 mg per kg body weight per day). The biles of the prairie dogs receiving hyodeoxycholic acid were abnormally colored, cloudy, and highly saturated with cholesterol but contained neither cholesterol crystals nor gallstones (with the exception of one male). Feeding the relatively hydrophilic bile acid, hyodeoxycholic acid, was associated with an increase in hepatic microsomal HMG-CoA reductase activity. Cholesterol 7 alpha-hydroxylase, on the other hand, was inhibited by the administered bile acid. The dietary hyodeoxycholic acid was transformed, in part, to 3 alpha, 6 beta-dihydroxy-5-beta-cholanoic acid and hyocholic acid. It is concluded that hyodeoxycholic acid and its metabolites did not prevent the induced cholelithiasis by causing a decrease in the concentration of biliary cholesterol. Instead, this hydrophilic bile acid apparently increases the amount of cholesterol in the bile, probably in the form of a liquid crystalline mesophase. Hyodeoxycholic acid apparently prevents gallstones by preventing the nucleation and aggregation of cholesterol crystals. The lithogenic diet induced moderate to marked bile duct proliferation together with portal fibrosis and inflammatory infiltration. The addition of hyodeoxycholic acid to the lithogenic diet reduced all of the portal tract changes.

Topics: Animals; Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cholesterol, Dietary; Chromatography, Gas; Deoxycholic Acid; Feces; Female; Gas Chromatography-Mass Spectrometry; Hydroxymethylglutaryl CoA Reductases; Lipids; Liver; Male; Sciuridae

During the decade in which the medical dissolution of gall stones has become feasible several drugs have been introduced but only the two listed in the British National Formulary have been intensively evaluated and shown to be effective--chenodeoxycholic acid and the closely allied ursodeoxycholic acid. The dissolution of gall stones was last reviewed in the "BMF" in 1976, at which stage experience with chenodeoxycholic acid was limited. Since then the indications and potential for this bile acid in treating gall stones have become better understood, and data on the newly introduced ursodeoxycholic acid are being evaluated. Cholesterol, but not pigment, gall stones are amenable to oral dissolution treatment. This review will cover firstly, chenodeoxycholic acid, secondly, ursodeoxycholic acid, then a comparison of the two drugs, an assessment of the place of medical dissolution in the management of gall stones, and, finally, the dissolution of stones in the common bile duct.

Topics: Chenodeoxycholic Acid; Cholecystography; Cholelithiasis; Deoxycholic Acid; Gallstones; Humans; Recurrence; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Liver; Ursodeoxycholic Acid

Topics: Adult; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Humans; Lipids; Male; Middle Aged; Ursodeoxycholic Acid

A study was attempted to establish a screening method for detecting cholelitholytic ingredients from a wide variety of natural substances. Although mice were selected as a suitable pathological model of cholelithiasis to detect a small amount of the ingredients, all the conventional lithogenic diets caused unfavorable influence on the animals. Therefore, as the first step we formulated a new lithogenic diet consisting of butter, cholesterol, cholic acid, etc, which was adequate for mice. Subsequently, the pathological characteristics and persistence of cholelithiasis were examined in the animals; the changes in bile compositions including free and conjugated bile acids, cholesterol and phospholipids were observed before and at the onset of cholelithiasis. Following confirmation of the stone formation, a normal diet was substituted for the lithogenic diet to likewise assess the bile compositions 4 and 6 weeks later. An increasing tendency for deoxycholic acid, disappearance of chenodeoxycholic acid and decrease in ursodeoxycholic acid were seen under the condition of cholelithiasis. In addition, the cholic acid-glycine conjugate which should not exist in the normal state and the increase in free and tauring-conjugated cholic acid were noticed. The biliary cholesterol level in treated mice increased to about 4 times higher than that in untreated mice, while the biliary phospholipids and total bile acids levels increased to only about 1.5 and about 2 times the control levels, respectively. The incidence of stone formation rose sharply at an experimental period between 2 and 3 weeks after starting the lithogenic diet. Gallstones die not disappear even at the 6th week after substituting a normal diet for the lithogenic one. However, the cholic acid-glycine conjugate disappeared, and deoxycholic acid as well as chenodeoxycholic acid and ursodeoxycholic acid tended to recover to the normal levels in the bile.

Topics: Animals; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Male; Mice; Phospholipids; Ursodeoxycholic Acid

In a prospective dosage response study of 84 patients with radiolucent gall bladder stones treated with ursodeoxycholic acid (UDCA), a dose of 500 mg daily was as effective as 1,000 mg daily. Complete dissolution of stones was achieved in 9 of 31 patients (29%) treated for at least 6 months with the lower dose, and in 7 of 33 patients (21%) on the higher dose. 4 patients in each group continue on treatment having shown partial gall-stone dissolution. When the two dosage groups were considered together, small stones dissolved more readily than larger ones and, after allowance for stone size, success rates were equal in obese and non-obese patients. Treatment with UDCA was well tolerated and significant adverse effects were not encountered.

Topics: Adolescent; Adult; Aged; Cholelithiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Prospective Studies; Radiography; Ursodeoxycholic Acid

A radioimmunoassay for serum ursodeoxycholic conjugates using a 125iodine ligand has been developed. The bile acid was present in normal fasting serum (0.19 +/- SD 0.19 mumol/l, n = 24) and 2-hour post-prandial serum (0.8 +/- SD 0.8 mumol/l, n = 16). Gallstone patients undergoing oral ursodeoxycholic acid therapy had significantly higher post-prandial serum levels (21.5 +/- SD 14.0 mumol/l, n = 15) by radioimmunoassay. Gas liquid chromatography analysis indicated that in normal serum ursodeoxycholic acid was totally conjugated, whereas sera from gallstone patients contained a proportion as the free bile acid (10.2 +/- SD 8.1 mumol/l, n = 15). Following an oral dose of ursodeoxycholic acid, both unconjugated and conjugated forms of the bile acid appeared in the serum of healthy individuals.

Topics: Bile Acids and Salts; Cholelithiasis; Deoxycholic Acid; Fasting; Female; Humans; Iodine Radioisotopes; Isotope Labeling; Male; Radioimmunoassay; Ursodeoxycholic Acid

We studied liquid crystal formation in bile samples obtained from the patients with radiolucent gallstones who had been administered either ursodeoxycholic acid (UDCA) at a dose of 600 mg/day or chenodeoxycholic acid (CDCA) at 400 mg/day for one week preoperatively. The UDCA/total bile acids ratio was found to range from 50 to 60% and the CDCA/total bile acids ratio ranged from 70 to 80%. Cholesterol molar percent was 5 in UDCA-rich bile and 6 in CDCA-rich bile. Phospholipid molar percentage was about the same in both groups. Liquid crystal formation was confirmed only in the UDCA-rich bile samples but not in the CDCA-rich bile samples. This result suggests that cholesterol in the UDCA-rich bile samples is not solubilized by the bile salt and phospholipid mixed micelles but also consumed to form liquid crystals.

Topics: Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Crystallization; Deoxycholic Acid; Gallbladder; Humans; Ursodeoxycholic Acid

The present study was undertaken to characterize the effects of ursodeoxycholic acid on biliary lipid metabolism in man. Fifteen gallstone patients were treated with ursodeoxycholic acid at a daily dosage of 15 mg per kg body weight for about 4 weeks before cholecystectomy. At operation a liver biopsy, together with gallbladder and hepatic bile, were obtained. Eighteen untreated gallstone patients undergoing cholecystectomy served as controls. During treatment with ursodeoxycholic acid, hepatic bile became unsaturated with cholesterol in all patients investigated. The total biliary lipid concentration remained unchanged. The hepatic cholesterol concentration decreased by about 20%. No significant change in the microsomal HMG CoA reductase activity was observed (38.5 +/- 6.7 pmol . min-1 . mg protein-1 vs 38.3 +/- 4.7 pmol . min-1 . mg protein-1 in the controls; means +/- SEM). Plasma concentrations of total cholesterol were reduced by about 10%, and those of high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol by about 15%. Plasma triglyceride levels remained essentially unchanged during treatment. We conclude that, similar to chenodeoxycholic acid therapy, ursodeoxycholic acid treatment results in unsaturation of fasting hepatic bile. In contrast to the changes seen during chenodeoxycholic acid feeding, however, the unsaturation of hepatic bile during ursodeoxycholic acid treatment is not primarily related to a decreased hepatic HMG CoA reductase activity. Furthermore, while chenodeoxycholic acid tends to increase plasma LDL levels, such changes are not seen during ursodeoxycholic acid treatment.

Topics: Adult; Aged; Bile Acids and Salts; Biliary Tract; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Lipids; Lipoproteins; Male; Microsomes, Liver; Middle Aged; Ursodeoxycholic Acid

Topics: Adult; Cholelithiasis; Deoxycholic Acid; Female; Humans; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Drug Evaluation; Humans; Ursodeoxycholic Acid

51 patients with radiolucent gallstones of diameter less than or equal to 15 mm were treated for 6 months with a new form of ursodeoxycholic acid (UDCA) in a single dose of 450 mg at bedtime. This new form has 3 components with fractionate liberation. The rate of partial and complete dissolution after 6 months was 63.4%, reaching 85% for gallstones of less than 5 mm diameter. The results show that a single dose of 450 mg UDCA at bedtime is as effective as UDCA at mealtimes in the dissolution of radiolucent gallstones. Administration of the drug once a day should be more acceptable to patients.

Topics: Cholelithiasis; Delayed-Action Preparations; Deoxycholic Acid; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Radiography; Ursodeoxycholic Acid

Using compressed discs and microcrystals of cholesterol monohydrate, we evaluated the mechanisms and kinetics of dissolution in conjugated bile salt-lecithin solutions. In stirred conjugated ursodeoxycholate-lecithin and cheno-deoxycholate-lecithin solutions, dissolution of 10,000-psi discs was micellar and linear with time for 10 hours. The dissolution rate constants (k) decreased in proportion to the lecithin content and dissolution rates and k values were appreciably smaller in conjugated ursodeoxycholate-lecithin solutions. After dissolution for 5 to 10 days the discs incubated with ursodeoxycholate-lecithin systems became progressively transformed into macroscopic liquid crystals. Unstirred dissolution of 3,000-psi discs in "simulated" human bile containing physiological lecithin concentrations gave apparent k values that decreased in the following order: ursodeoxycholate-rich >/= chenodeoxycholate-rich > normal. In most cases the discs incubated with ursodeoxycholate-rich bile became covered with a microscopic liquid-crystalline layer. With 20-25 moles % lecithin, these layers eventually dispersed into the bulk solution as microscopic vesicles. During dissolution of microcrystalline cholesterol in conjugated ursodeoxycholate-lecithin systems, a bulk liquid-crystalline phase formed rapidly (within 12 hours) and the final cholesterol solubilities were greater than those in conjugated chenodeoxycholate-lecithin micellar systems. Prolonged incubation of cholesterol microcrystals with pure lecithin or lecithin plus bile salt liposomes did not reproduce these effects. Condensed ternary phase diagrams of conjugated ursodeoxycholate-lecithin-cholesterol systems established that cholesterol-rich liquid crystals constituted an equilibrium precipitate phase that coexisted with cholesterol monohydrate crystals and saturated micelles under physiological conditions. Similar phase dissolution-relationships were observed at physiological lecithin-bile salt ratios for a number of other hydrophilic bile salts (e.g., conjugated ursocholate, hyocholate, and hyodeoxycholate). In contrast, liquid crystals were not observed in conjugated chenodeoxycholate-lecithin-cholesterol systems except at high (nonphysiological) lecithin contents. Based on these and other results we present a molecular hypothesis for cholesterol monohydrate dissolution by any bile salt-lecithin system and postulate that enrichment of bile with highly hydrophilic bile salts will induce crystalline cho

Topics: Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Humans; Kinetics; Phosphatidylcholines; Solubility; Structure-Activity Relationship; Ursodeoxycholic Acid

Topics: Calcinosis; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Humans; Micelles; Solubility; Ursodeoxycholic Acid

Gallstone dissolution was observed on 60 occasions in 54 patients; in 6, recurrent stones were dissolved by a second course of medical treatment. When complete gallstone dissolution was confirmed (by two consecutive cholecystograms, 3 months apart) bile-acid treatment was stopped, and the patients were followed for up to 71/2 years with oral cholecystograms taken annually (or sooner if symptoms suggested early recurrence). Recurrence was detected 30 times after the 60 episode of gallstone dissolution (50%), in 25 of the 54 patients (46%), and in 25 of 46 patients who had had at least one post-dissolution X-ray before recurrence (54%). In 21 of these 25 patients (84%) the recurrence was observed within 2 years of treatment being stopped. There were no significant differences in clinical details and pre-treatment gallstone characteristics between the 25 gallstone-recurrent (at any time) and the 29 gallstone-free (at the time of study) patients, nor between a subgroup of patients in whom recurrent stones developed rapidly (less than or equal to 1 year) and a subgroup who remained gallstone-free for 3 years. It is concluded that long-term follow-up is advisable and that post-dissolution treatment will be necessary to prevent gallstone recurrence.

Topics: Adult; Aged; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Follow-Up Studies; Humans; Male; Middle Aged; Recurrence; Sex Factors; Solubility; Time Factors; Ursodeoxycholic Acid

Today patients with gallstones are treated surgically, by means of drugs, or by endoscopy. However, only cholesterol stones can be dissolved with bile acids. Besides the cholesterol stones in the gallbladder, insoluble pigment stones or insoluble stones with a high inorganic calcium content will be found. In every patient, the solubility of the gallbladder stones must be established by mineralogical analysis. Sonography is very helpful in detecting gallbladder stones, but it is impossible to perform a mineralogical analysis with this method. Plain radiography is likewise insufficient. The only way to obtain a relatively accurate selection of patients with soluble gallstones is the performance of roentgenography after cholecystography. Cholecystography for mineralogical analysis must always follow detection of gallstones by sonography.

Topics: Chenodeoxycholic Acid; Cholecystography; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Three therapeutic strategies are possible in a patient with asymptomatic or mildly symptomatic cholesterol gallstones: Cholecystectomy, medical gallstone dissolution, and expectant attitude. The course of cholelithiasis under these three strategies was evaluated by three decision trees. The incidences of possible complications were taken from the literature. For every complication the costs of drugs, absenteeism, treatment as outpatient and inpatient were listed. The costs multiplied by the likelihood of the complication represent the expected costs of the complication under consideration. The sum of the costs due to the initial treatment and the expected costs of all possible complications corresponds with the expected average costs of a therapeutic strategy. It is 21 000,- DM with medical gallstone dissolution, 25 000,- DM with immediate cholecystectomy, and 27 000,- DM with expectant attitude, respectively. Gallstone dissolution becomes more expensive than cholecystectomy only when its efficacy drops below 40%. The data show that the costs are less important for the choice of the therapy in cholelithiasis. The advantage of the decision tree lies in the fact that it describes the history and the costs of a disease by figures. Thereby, disagreement on the effects of a therapy on the course of the disease can be analysed and discussed more distinctly.

Topics: Cholecystectomy; Cholelithiasis; Deoxycholic Acid; Female; Humans; Middle Aged; Recurrence; Ursodeoxycholic Acid

To elucidate the role of conjugated biliary bile acids in gallstone dissolution, the acids in bile were determined by high-performance liquid chromatography before and after the treatment with ursodeoxycholic acid for 3-26 months in patients with gallstone. The stone-dissolving effect of ursodeoxycholic acid was confirmed in 7 of 10 patients and the lithogenic index lowered significantly after the treatment. The compositions of cholate, chenodeoxycholate and ursodeoxycholate were about 33, 45 and 4%, respectively, in the control and pre-treatment groups. In the post-treatment group, a markedly low value was observed in primary bile acids both glycine-conjugates and taurine-conjugates, especially in cholate, with a significantly high value of ursodeoxycholate (p less than 0.001) of both conjugates. On the other hand, no difference was observed in the composition of deoxycholate with significantly low percentage of taurine-conjugates compared with that in the pre-treatment group. The ratio of glycine- to taurine-conjugated bile acids showed a significantly higher value in the post-treatment group than in the pre-treatment group (p less than 0.001) and the control group (p less than 0.005). The bile specimens were measured concomitantly by gas-liquid chromatography and the results were compared with those of high-performance liquid chromatography. The mean value of total bile acids, the ratio of cholate to chenodeoxycholate and the ratio of glycine- to taurine-conjugated bile acids obtained by the former analysis procedure represented about 57, 80 and 115% of those of the latter. It is concluded that the high G/T value seems to have a role in the dissolution mechanism.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Chromatography, Gas; Chromatography, High Pressure Liquid; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Ursodeoxycholic Acid

A dose-response study comparing ursodeoxycholic and chenodeoxycholic acid was carried out in six men with asymptomatic radiolucent gallstones present in well-visualizing gallbladders. The study tested the effects of a low (averaging 6 mg/kg/day) or medium dose (averaging 11 mg/kg/day) of each bile acid on the cholesterol saturation of bile as well as on bile acid metabolism, as inferred from biliary and fecal bile acid composition. Ursodeoxycholic acid, at low or medium doses, induced bile desaturation in most patients, whereas chenodeoxycholic acid did not. Despite the greater desaturation efficacy of ursodeoxycholic acid, biliary bile acids became less enriched with the administered bile acid during ursodeoxycholic acid treatment than during chenodeoxycholic acid treatment. Both bile acids were nearly completely 7-dehydroxylated to lithocholic acid by colonic bacteria, but biliary lithocholic increased only slightly (and similarly) with each bile acid. Fecal bile acid composition suggested that administered ursodeoxycholic acid suppressed endogenous bile acid synthesis much less than chenodeoxycholic acid. The results indicate that ursodeoxycholic acid and chenodeoxycholic acid have similar but not identical effects on bile acid metabolism, but that for a given dose, ursodeoxycholic acid is a more potent desaturating agent than chenodeoxycholic acid. The results suggest that cholesterol gallstone dissolution with ursodeoxycholic acid should occur with a dose of 8-10 mg/kg in most nonobese patients.

Topics: Aged; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Therapy, Combination; Feces; Humans; Male; Middle Aged; Ursodeoxycholic Acid

In two groups of gallstone patients ideally suited for medical treatment, the effect of six to 18 months' therapy was compared retrospectively in 52 given chenodeoxycholic acid (CDCA) and 46 given ursodeoxycholic acid (UDCA). The minimum dose (mg kg-1 day-1) required to desaturate bile consistently was 10.1 for UDCA and 14.3 for CDCA. In patients completing six months' treatment, 23 of 35 (66%) taking a mean of 7.7 (+/- SEM 0.5) mg UDCA and 34 of 42 (81%) taking 14.7 +/- 0.2 mg CDCA showed partial or complete dissolution of gallstones. The mean dose in the UDCA-treated patients, however, was artefactually lowered by previous dose-response studies: in those who had not taken multiple doses, the mean UDCA intake in the 'responders' at six months was 9.1 +/- 0.3 mg kg-1 day-1. At six months, more UDCA (five of 35 or 14.3%) than CDCA (four of 42 or 9.5%)-treated patients showed complete dissolution of gallstones, but, by one year, the situation was reversed, 20 of 41 (49%) CDCA-treated and eight of 30 (27%) UDCA-treated patients showing complete dissolution of gallstones. Cumulative efficacy at one year had risen to 76% for UDCA and 89% for CDCA. Both treatments reduced the frequency of dyspepsia and biliary colic; 37% of CDCA and 2.6% of UDCA-treated patients showed hypertransaminasaemia; diarrhoea developed in 60% of the CDCA group but in none of the UDCA group.

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Liver Function Tests; Male; Middle Aged; Retrospective Studies; Triglycerides; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Topics: Animals; Bile; Biotransformation; Cholelithiasis; Cholesterol; Cricetinae; Deoxycholic Acid; Humans; Intestinal Absorption; Kinetics; Liver; Mice; Rats; Solubility; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

Biliary lipid classes (bile acids, phospholipids, cholesterol) as well as individual biliary bile acids were measured in duodenal bile samples obtained before treatment from 284 white men and 264 white women participating in the National Cooperative Gallstone Study. The patients had radiolucent gallstones present in visualizing gallbladders. Calculated biliary cholesterol saturation was significantly higher in women (143 +/- 43, mean +/- SD, vs. 132 +/- 39 for men). Chenodeoxycholic acid was the major biliary bile acid in both sexes (40.0 +/- 9.9 in men; 38.8 +/- 9.3 in women, NS). Cholic acid was the second most common bile acid, constituting 32.9 +/- 8.8 in men and 31.8 +/- 8.9 in women (NS). When other demographic and clinical characteristics, including serum lipids, were related with biliary lipid composition, only percent ideal body weight correlated significantly. The partial correlation coefficient adjusted for percent ideal body weight indicated that the proportion of chenodeoxycholic acid correlated negatively with the mole fraction of cholesterol in bile in men, but not in women. Multiple regression analyses showed that bile saturation could not be predicted reliably from any clinical, chemical, or radiologic measurement in either sex. Published data for biliary lipid composition in individuals with biliary disease showed considerable overlap with the National Cooperative Gallstone Study data reported here, suggesting that cholesterol gallstone disease is not caused solely by increased biliary cholesterol saturation.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Body Weight; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Lipids; Male; Middle Aged; Phospholipids; Radiography; White People

The comparative rate of formation of lithocholic acid from chenodeoxycholic acid and its 7 beta epimer, ursodeoxycholic acid, was studied in human subjects and in a rhesus monkey. [24-14C]Chenodeoxycholic acid and [24-14C]ursodeoxycholic acid were incubated in vitro, under anaerobic conditions, in fecal samples from 7 control and 7 asymptomatic gallstone subjects. The incubations were carried out for 0, 0.5, 1, 4, and 12 h. In addition, the labeled precursors were instilled into the colon of 4 asymptomatic gallstone patients and a rhesus monkey in which a bile duct fistula had been created. Radioactive metabolites were analyzed by thin-layer chromatography in the in vitro fecal incubates and in the in vivo colonic aspirates, stool, and bile. The biotransformation of the unlabeled material was analyzed by gas-liquid chromatography in the in vitro incubates and in the in vivo fecal samples of the rhesus monkey. There was no statistical difference between chenodeoxycholic and ursodeoxycholic acids in their rate of biotransformation to lithocholic acid, when the total group of 14 subjects was compared. However, among these 14, a subgroup of 4 subjects (2 controls and 2 with gallstones) was identified in whom the rate of degradation to lithocholic acid was significantly faster for chenodeoxycholic than for ursodeoxycholic acid. Increases in the concentrations of the precursors led to a decrease in the rate, but not a change in the comparative pattern of lithocholic acid formation. At the lower concentrations, the conversion of both bile acids to lithocholic acid was almost complete after 12 h. In the in vivo studies, the formation of lithocholic acid from chenodeoxycholic and ursodeoxycholic acids was comparable both in the 4 human subjects and in the rhesus monkey. The results of this study indicate that, in most cases, the risk of liver damage from lithocholic acid formation should be similar for both epimers. However, there appears to be a small population in which this risk could be higher during chenodeoxycholic acid than during ursodeoxycholic acid treatment due to a more rapid formation of lithocholic acid.

Topics: Adult; Aged; Anaerobiosis; Animals; Biotransformation; Chenodeoxycholic Acid; Cholelithiasis; Colon; Deoxycholic Acid; Feces; Female; Humans; Lithocholic Acid; Macaca mulatta; Male; Middle Aged; Ursodeoxycholic Acid

22 patients with radiolucid stones and functioning gallbladder were grouped to establish ursodeoxycholic acid efficacy (i.e. gallstones dissolution) and innocuousness for gallbladder lithiasis. Methodological aspects were detailed, the dose determined (8 and 10 mg/k/d.) and the patients evaluated after a six months' treatment. 11 patients received "day-time" doses and the other 11 "overnight" dose. Only 7 subjects turned out to be evaluated for the study of biliary lipids, to the other 15 the development of their gallstones was followed up. Successful gallstone dissolution was achieved in 8 patients (53,3%), 2 reduced size and number. 5 out of these 8 patients received "day-time" doses and the other 3 "overnight" doses. From an attendance point of view, we do not consider biliary lipids study (bile cholesterol saturation rate) to be necessary.

Topics: Cholelithiasis; Cholesterol; Deoxycholic Acid; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Ursodeoxycholic Acid

Topics: Adolescent; Adult; Aged; Cholelithiasis; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Radiography; Recurrence; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Recurrence; Ursodeoxycholic Acid

In spite of many reports which suggested the efficacy of chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) on cholesterol gallstone dissolution, problems still remain to be solved, such as the ideal dosage and duration of treatment to obtain maximal benefit with minimal untoward effects. The author reports in this paper a comparative study on changes of bile acid level and lipid composition in blood and bile during the clinical course after initiation of CDCA and UDCA therapy in effectively and ineffectively responding groups of patients with cholesterol gallstones in the gallbladder.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Lipids; Liver; Male; Middle Aged; Phospholipids; Ursodeoxycholic Acid

Topics: Calcinosis; Calcium; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Solubility; Ursodeoxycholic Acid

Ten healthy middle-aged women volunteered for a study to test the effect of lactulose--a synthetic, non-absorbable disaccharide--on the colonic metabolism of bile acids and on bile lipid composition. Lactulose (60 g daily in eight cases, 39 g daily in two) was taken as a proprietary syrup for six weeks, and bile was collected by duodenal intubation before and immediately after six weeks. All subjects showed a fall in the percentage of the 7-alpha-dehydroxylated bile acid deoxycholic acid (mean 28.4 +/- SEM 3.7 to 15.6 +/- 2.4; p less than 0.002) and a rise in the percentage of the primary bile acid chenodeoxycholic acid (mean 33.2 +/- 42.9 +/- 2.9; p less than 0.001). The percentage of cholic acid rose in eight subjects but mean values did not differ significantly. Bile was initially super-saturated with cholesterol in most subjects and became less saturated with cholesterol in all but one (mean saturation index 1.40 +/- 0.11 to 1.19 +/- 0.07; p less these 0.005). These data support the theory colonic bacteria contribute to cholesterol gall-stone formation.

Topics: Bacteria; Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Colon; Deoxycholic Acid; Disaccharides; Female; Humans; Lactulose; Middle Aged

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Prognosis; Ursodeoxycholic Acid

Cheno- and ursodeoxycholic acid feeding are both efficient in conservative gallstone therapy. Urso decreases biliary cholesterol excretion even more than cheno. Glyco-urso becomes dose dependent the predominant bile acid conjugate in bile under urso feeding. We therefore studied the kinetics of cholesterol gallstone dissolution in aqueous solutions of 100 mM glyco-cheno, 100 mM glyco-urso, and mixtures of both consisting of 40 mM glyco-urso plus 60 mM glyco-cheno and 80 mM glyco-urso plus 20 mM glyco-cheno in vitro. The daily dissolution rates of cholesterol achieved by these solutions were for 100 mM glyco-cheno 0.87 +/- 0.1 mg (mean +/- SEM), for 40 mM glyco-urso plus 60 mM glyco-cheno 0.28 +/- 0.003 mg, for 80 mM glyco-urso plus 20 mM glyco-cheno 0.07 +/- 0.002 mg, and for 100 mM glyco-urso 0.07 +/- 0.03 mg. Correspondingly were the weight decreases of the gallstones by 100 mM glyco-cheno 1.2 +/- 0.1 mg/day, by 40 mM glyco-urso plus 60 mM glyco-cheno 0.3 +/- 0.01 mg/day, by 80 mM glyco-urso plus 20 mM glyco-cheno 0.11 +/- 0.02 mg/day, and by 100 mM glyco-urso 0.1 +/- 0.02 mg/day. Complete gallstone dissolution occurred during the observation time of 4 months only by 100 mM glyco-cheno in 12.8 +/- 3.3 weeks. Thus glyco-urso dissolves only little cholesterol and decreases the speed of cholesterol gallstone dissolution. It is concluded that high doses of urso in gallstone therapy which lead to great amounts of glyco-urso in bile may diminish gallstone dissolution rates.

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Drug Interactions; Glycine; Glycochenodeoxycholic Acid; Humans; Kinetics; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Diffusion; Glycine; Glycochenodeoxycholic Acid; In Vitro Techniques; Kinetics; Solubility; Taurine; Taurochenodeoxycholic Acid; Ursodeoxycholic Acid; Water; X-Ray Diffraction

The effect of cholic acid pool expansion on biliary lipid composition was investigated in 21 subjects with cholesterol gallstones. All subjects were fed cholic acid (15 mg/kg/day) and ampicillin (2 g/day) in order to depress the intestinal degradation of cholic to deoxycholic acid. Five additional subjects were given ampicillin alone. The treatment lasted 2-3 wk. Parameters investigated included biliary and plasma lipid, biliary bile acid composition, and total and individual bile acid pool size. In 11 of 21 subjects (group I) cholic acid pool expanded two-threefold, whereas deoxycholic acid pool increased only slightly. In this group mean saturation index fell from 1.32 +/- 0.27 (mean +/- SD) to 0.93 +/- 0.25 (p less than 0.001), and plasma cholesterol increased from 185 +/- 45 mg/dl before to 213 +/- 37 after treatment (p less than 0.01). In the remaining 10 subjects (group II) the increase of the deoxycholic acid pool for exceeded that of cholic acid, and in these subjects the saturation index rose from a mean value of 1.07 +/- 0.27 to 1.42 +/- 0.22 after treatment (p less than 0.01). In this group plasma cholesterol tended to decrease (from 213 +/- 57 to 197 +/- 51 after treatment). In the 5 subjects treated with ampicillin alone deoxycholic acid pool was greatly reduced, and the saturation index fell from 1.25 +/- 0.25 to 0.95 +/- 0.35. The results suggest that cholic acid pool expansion reduces bile cholesterol saturation, whereas the increase of deoxycholic acid pool tends to supersaturate the bile. It is concluded that a determinant of bile cholesterol saturation might be the detergent power of the bile acid pool.

Topics: Adult; Aged; Ampicillin; Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Humans; Lipids; Middle Aged

Topics: Adult; Aged; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; In Vitro Techniques; Micelles; Phosphatidylcholines; Solubility; Ursodeoxycholic Acid

Topics: Bile; Cholecystectomy; Cholelithiasis; Deoxycholic Acid; Dyspepsia; Humans; Periodicity; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Diarrhea; Female; Humans; Male; Ursodeoxycholic Acid

Topics: Animals; Bile Acids and Salts; Cholelithiasis; Cholesterol 7-alpha-Hydroxylase; Cholesterol, Dietary; Clofibrate; Deoxycholic Acid; Female; Hydroxymethylglutaryl CoA Reductases; Liver; Organ Size; Rats

26 patients (20 females and 6 males, mean age 40.5 years +/- SEM 2.20, mean weight 60.2 kg +/- 1.98) with radiolucent gallstones of diameter less than or equal to 10 mm were treated for 6 months with ursodeoxycholic acid (UDCA), a single dose of 600 mg at bedtime. The rate of partial + complete dissolutions was 85%, reaching 100% for gallstones of less than 4 mm diameter. No side effects were observed. In a similar series of patients treated with UDCA t.i.d. at mealtimes (10--12 mg/kg/day) a slightly lower dissolution rate was obtained but the difference was not statistically significant.

Topics: Adult; Chemical Phenomena; Chemistry, Physical; Cholelithiasis; Cholesterol; Deoxycholic Acid; Drug Administration Schedule; Female; Humans; Male; Solubility; Ursodeoxycholic Acid

Topics: Anticholesteremic Agents; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

To study further the role of hepatic cholesterol synthesis in patients with gallstones, the activity of the rate-limiting step in cholesterogenesis, hydroxymethyl glutaryl co-enzyme A reductase (HMGCoAR), was measured in operative wedge liver biopsies from ten patients with untreated cholesterol gallstones, six with pigment stones and ten controls. Hepatic HMGCoAR was also measured in six patients with cholesterol-rich gallstones treated for 1-24 months with 14.6-18.6 mg chenodeoxycholic acid (CDCA) kg-1 day-1, in two patients with radiolucent pigment stones treated with 17.3 and 17.7 mg CDCA kg-1 day-1 and in ten other patients with cholesterol-rich stones given 4.5-7.2 mg ursodeoxycholic acid kg-1 day-1 for 1-6 months. HMGCoAR activity was also related to the free and esterified cholesterol content of both hepatic homogenates and the microsomal fractions. Compared with the controls (HMGCoAR activity 14.6 +/- 1.6 (SEM) pmole mg microsomal protein-1 min-1), the mean activity in untreated cholesterol cholelithiasis was 32.2 +/- 2.0 (P < 0.001), but was near normal in patients with pigment stones (16.2 +/- 1.5). In cholesterol gallstone patients, chenodeoxycholic acid treatment reduced the mean enzyme activity by 51% compared with the untreated gallstone group (P < 0.001) and in smaller doses, ursodeoxycholic acid therapy lowered it by 40% (P < 0.001) but in the two patients with pigment stones, CDCA did not seem to affect HMGCoAR activity. Despite this four-fold variation in enzyme activity, there were no significant differences in mean free or esterified cholesterol concentrations in whole liver homogenates or in the microsomal fraction from any of the patient groups.

Topics: Adolescent; Adult; Aged; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Liver; Male; Microsomes, Liver; Middle Aged; Sterols; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Ursodeoxycholic Acid

We treated 30 patients with radiolucent gallstones with chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA) at daily dosages of 300 to 600 mg. Duration of treatment ranged from 5 to 16 months. Gallstone dissolution was noted in 23.3% of the group. CDCA was effective in 22.2%, and UDCA was effective in 25%. Treatment with these bile acids was usually effective when radiolucent stones smaller than 5 mm in diameter were found in the normally functioning gallbladder. Improvement of symptoms was noted in 60.9% of the patients who had symptoms related to biliary disease prior to the treatment. There was no definite evidence of hepatotoxicity due to these bile acids, although transient elevation of transaminase activity of unknown clinical significance was observed in 36.7% of the patients during the course of treatment. Five patients (16.7%) experienced diarrhea during treatment, but it was transient as long as the dose remained at 300 mg daily. Our experience with UDCA revealed comparative efficacy to that of CDCA, and side effects were rare. Long-term low-dose therapy with CDCA or UDCA seems to be an effective and safe treatment for radiolucent gallstones.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Humans; Liver Function Tests; Male; Middle Aged; Radiography; Time Factors; Ursodeoxycholic Acid

Topics: Adolescent; Adult; Aged; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acids; Chromatography, Gas; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Ursodeoxycholic Acid

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acids; Deoxycholic Acid; Gallbladder; Humans; Intestinal Absorption; Lipid Metabolism; Propantheline

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Liver; Ursodeoxycholic Acid

20 patients with radiolucent gallbladder stones were reviewed after 6 months' treatment with ursodeoxycholic acid (UDCA) at a dose of either 500 or 1,000 mg daily. Successful treatment could not be predicted from the patients' characteristics, nor from stone size or pre-treatment biliary lipid analysis. During treatment the bile in patients who responded to UDCA differed from bile in those who did not: mean cholesterol content was lower in responders (4.1 +/- 0.6 vs. 5.7 +/- 0.5 mol%, p less than 0.025) as was the lithogenic index (0.57 +/- 0.06 vs. 0.81 +/- 0.06, p less than 0.005) and the mean UDCA-corrected lithogenic index (0.79 +/- 0.10 vs. 1.04 +/- 0.07, p less than 0.05). However, the individual response could not be predicted from biliary lipid analysis during treatment.

Topics: Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Phospholipids; Ursodeoxycholic Acid

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Glycochenodeoxycholic Acid; Humans; Phosphatidylcholines; Solubility; Thermodynamics; Ursodeoxycholic Acid

The hepatotoxic potential of the cholelitholytic bile acids, chenodeoxycholic (chenic), and ursodeoxycholic acids, was compared in the rhesus monkey. A placebo-controlled treatment trial with 40 and 120 mg/kg/day doses of chenic acid and ursodeoxycholic acid, respectively, was conducted in 20 animals. Both chenic and ursodeoxycholic acids induced comparable abnormalities of liver function and structure. Liver biopsies, performed before and after 6 mo of treatment, showed the development of distinct light microscopic changes, including inflammation, fibrosis, and ductular proliferation in the portal fields as well as lobular rearrangement with formation of septa and regenerative nodules. Electron microscopy confirmed light microscopy, but showed no specific changes of cell organelles. Light microscopic examination of the kidneys, lungs, heart, intestine, and brain in 10 monkeys, which were sacrificed after 6 mo of controlled bile acid treatment, showed no abnormalities. Biliary lithocholic acid, all of which was unsulfated, increased several-fold to comparable levels in the bile acid-treated groups. Follow-up studies 6 mo after termination of bile acid treatment showed normalization of liver function tests and of bile acid composition as well as a considerable improvement of the histologic abnormalities. However, the restitution of normal liver structure was incomplete, with fibrosis and mild inflammation persisting in the portal fields. Our studies show that, in this primate species, chenic and ursodeoxycholic acids have comparable hepatotoxic effects, which are associated with similar increases of unsulfated lithocholic acid in bile.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Liver; Macaca mulatta; Male; Microscopy, Electron; Ursodeoxycholic Acid

Topics: Adult; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Humans; Liver; Male; Ursodeoxycholic Acid

The effects of four different doses of ursodeoxycholic acid (250, 500, 750, and 1000 mg daily) on biliary lipids were studied in 24 patients with radiolucent gallbladder stones. There was a significant increase in the proportion of ursodeoxycholic acid in bile after all doses, being greatest with 750 and 1000 mg daily. Unsulphated lithocholic acid was also increased in the bile after therapy, while the other major bile acids were reduced. The cholesterol content of bile was reduced by all doses, and this change was most marked after 1000 mg (from 10.9 +/- 1.4 to 5.6 +/- 0.5 mol%, P < 0.01). Biliary cholesterol saturation improved significantly only after 750 and 1000 mg daily.

Topics: Adolescent; Adult; Aged; Bile; Cholelithiasis; Cholesterol; Deoxycholic Acid; Dose-Response Relationship, Drug; Female; Humans; Lipids; Male; Middle Aged; Ursodeoxycholic Acid

Chenodeoxycholic acid (cheno) and ursodeoxycholic acid (urso) dissolve cholesterol gallstones in humans. In the present study conjugation of biliary bile acids with glycine and taurine and their effects on biliary cholesterol saturation were investigated during treatment with cheno, urso, and cheno-urso. Ten patients were included in this study, and every patient served as his own control. Each of the treatment periods lasted for 3 mo. During treatment with cheno or urso, daily doses of 11.9-15.6 mg/kg were administered, while during treatment with cheno-urso each bile acid was administered at one-half the dose. In the control period biliary bile acids consisted of 31.8 +/- 2.8% glycocheno, 10.9 +/- 1.2% taurocheno, 1.0 +/- 0.1% glycourso, and 0.3 +/- 0.1% taurourso. During the three treatment periods dihydroxy bile acids in bile and glycine conjugation of these dihydroxy bile acids increased significantly (P < 0.05). During treatment with urso the amounts of glycourso in bile were positively correlated to the dose of urso administered (P < 0.05). No correlation existed between urso dose and the amounts of taurourso in bile. Biliary cholesterol was 9.0 +/- 1.0 mol% in the control period and decreased during treatment with cheno, urso, and chenourso to 5.2 +/- 0.5, 3.7 +/- 0.3, and 3.8 +/- 0.3 mol%, respectively. Cholesterol saturation index corrected for the biliary content of glycourso and taurourso was 1.2 +/- 0.1 in the control period and decreased during treatment with cheno, urso, and cheno-urso to 0.8 +/- 0.1, 1.0 +/- 0.1 and 0.7 +/- 0.1, respectively. Thus urso treatment led to the lowest biliary content of cholesterol, but cheno-urso treatment led to significantly lower cholesterol saturation indices than urso treatment (P < 0.05).

Topics: Aged; Anticholesteremic Agents; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Drug Therapy, Combination; Female; Glycochenodeoxycholic Acid; Glycocholic Acid; Humans; Male; Middle Aged; Solubility; Taurochenodeoxycholic Acid; Taurocholic Acid; Ursodeoxycholic Acid

This paper describes seven patients with radiolucent gallstones in functioning gallbladders who did not respond to chenodeoxycholic acid (CDCA). Despite large doses (greater than or equal to 19 mg CDCA/kg/day), CDCA-rich bile (CDCA conjugates 70-97% of total biliary bile acids) and greater than or equal to one year's treatment, their fasting duodenal bile remained supersaturated with cholesterol and their gallstones did not dissolve. Five patients came to cholecystectomy, gallstone analysis and liver biopsy for measurement of hepatic cholesterogenesis (HMGCoAR activity). In three who stopped CDCA before surgery, the mean HMGCoAR (pmol/mg microsomal protein/min) of 50.2 was higher than in our untreated gallstone controls (32.2 +/- SEM 2.0; P less than 0.05). Two patients who took CDCA until surgery had a mean HMGCoAR of 33.5--more than twice that in CDCA-treated gallstone controls. These findings suggest that non-response to CDCA may be related to high or unsuppressed hepatic cholesterogenesis. In one patient who did not respond to CDCA, treatment with 19 mg ursodeoxycholic acid/kg/day did desaturate his bile.

Topics: Adult; Aged; Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Liver; Male; Middle Aged; Obesity; Solubility; Ursodeoxycholic Acid

Scanning electron microscope studies on cholesterol gallstones, which had been subjected to, but had not been completely dissolved by, chenodeoxycholate and deoxycholate salts, have indicated the presence of an insoluble organic matrix, probably a mucopolysaccharide. Solution of a gallstone in vitro is enhanced by the addition of heparin which dissolved this matrix, thus allowing complete dissolution of cholesterol in a gallstone.

Topics: Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Heparin; Humans; In Vitro Techniques; Microscopy, Electron, Scanning

Rabbits fed a diet containing 0.75% dihydrocholesterol for 7 days develop bile acid allodeoxycholic (ADCA) and deoxycholic acid (DCA) stones in the gallbladder. In this model, inflammatory changes in the gallbladder mucosa are often observed even before stones are formed. Within 3 days of the lithogenic diet, abnormalities of platelet function were detectable. Platelet aggregation upon addition of adenosine diphosphate (ADP) was impaired. At the same time the red cells became crenated and developed thorny spicules (echinocytes). This morphological changes was associated with intracellular dehydration and excessive loss of potassium. These changes coincided with a rise in serum ADCA and DCA and preceded a slow rise in serum cholesterol. In vitro incubation studies also suggested that the bile acids had probably caused membrane injury to the platelets and red cells. It is concluded that changes in the bile ADCA and DCA probably induce gallbladder epithelial injury in this model of experimental cholelithiasis.

Topics: Animals; Blood Coagulation; Cholelithiasis; Cholestanol; Cholesterol; Deoxycholic Acid; Epithelium; Erythrocyte Count; Erythrocytes; Female; Gallbladder; Male; Microscopy, Electron, Scanning; Osmolar Concentration; Platelet Aggregation; Potassium; Rabbits; Sodium

The effect of ursodeoxycholic acid (UDCA) on bile lipid composition and bile acid kinetics was evaluated in seven cholesterol gallstone patients following one month of UDCA administration (12 mg/kg/day). UDCA administration induces a significant reduction in the cholesterol saturation index (SI). After UDCA treatment, UDCA becomes the predominant biliary bile acid while chenodeoxycholic, cholic, and deoxycholic acid are significantly reduced. UDCA pool significantly increases, and chenodeoxycholic, cholic, and total bile acid pools significantly decrease. The reduction in bile lithogenicity during UDCA administration suggests that UDCA may be useful for cholesterol gallstone treatment in man.

Topics: Adult; Bile; Bile Acids and Salts; Carbon Radioisotopes; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Drug Evaluation; Female; Humans; Hydrolysis; Lithocholic Acid; Male

During the last years bile acids have gained more and more clinical importance. They play a decisive part in intestinal fat resorption. Increased bile acid content in the colon will result in diarrhea. By determination of serum bile acids the liver function can be judged exactly. It seems probable that bile acids take part in the pathogenesis of gastritis gastric ulcer and colonic cancer. By administration of chenodeoxycholic acid and ursodeoxycholic acid dissolution of cholesterol stones within the gall bladder is possible.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Colonic Neoplasms; Deoxycholic Acid; Gastritis; Humans; Intestinal Absorption; Liver Diseases; Oxalates; Stomach Ulcer

Topics: Administration, Oral; Adult; Aged; Cholelithiasis; Deoxycholic Acid; Drug Evaluation; Female; Humans; Male; Middle Aged

Prior animal models of cholesterol gallstone formation have been criticized for their dissimilarity to the conditions of humans with gallstones. We present a new hamster model of cholesterol cholelithiasis that more closely approximates the human situation. Sixty female Golden Syrian hamsters (average weight 83.2 +/- 3.4 g) were allocated to six groups of 10 animals each. Groups were fed standard diet (containing 0.8 gm cholesterol/g of food) or increased cholesterol diet (containing 2.4 mg cholesterol/g of food), with or without ethinyl estradiol, 15 micrograms/kg/d. Two groups receiving both increased cholesterol and ethinyl estradiol also received either chenodeoxycholic acid or ursodeoxycholic acid, 20 mg/kg/d. The animsl were sacrificed at 12 wk. Cholesterol gallstones (78.3 +/- 5.0% cholesterol by weight) formed in 30% of the animals fed ethinyl estradiol, 50% of those fed increased cholesterol, and 90% of those fed the combination of both. Bile was saturated in all three groups, with the saturation index of the combination group (2.08 +/- 0.17) being the highest. In both groups receiving bile acid therapy, no gallstones were found, and the bile remained unsaturated. For the bile acid-fed groups, both hepatic HMG-CoAR and hepatic cholesterol 7 alpha-hydroxylase activities were reduced (P less than 0.01) when compared to the group fed standard diet and to the grou fed the combination. Thus, a new animal model of cholesterol gallstone formation has been developed in which chenodeoxycholic acid and ursodeoxycholic acid therapy prevented gallstone formation through mechanisms similar to those reported in cholesterol gallstone patients.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cholesterol, Dietary; Cricetinae; Deoxycholic Acid; Disease Models, Animal; Female; Hydroxymethylglutaryl CoA Reductases; Liver; Mesocricetus

Topics: Adult; Aged; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Humans; Hyperlipidemias; Male; Middle Aged; Ursodeoxycholic Acid

The last 10 years have witnessed an enormous amount of work on the medical dissolution of gallstones. Many compounds have been tested and one, chenodeoxycholic acid, is already available for clinical use in the UK. Others will certainly follow. Much remains to be learned of the mechanisms of action of these drugs and the safety of prolonged administration. Effective methods of preventing gallstone recurrence need to be devised. The practice of cholecystectomy is not yet threatened by medical dissolution of gallstones, but in selected patients medical treatment is now a viable alternative. A start has been made.

Topics: Bile; Butyrates; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Drug Combinations; Fluorenes; Humans; Oils, Volatile; Recurrence; Terpenes

Twelve non-obese patients with radiolucent gallstones were fed on a standard diet. After 10 days (period A), six patients received 15 mg/kg/day of ursodeoxycholic acid (UDCA) (group I) and the other six (group II) the same dose of chenodeoxycholic acid (CDCA) for 15 days (period B). An intravenous injection of 20 micro Ci of 14C-UDCA and of 14C-CDCA was given on the 11th day of period B to the patients of group I and II respectively. Stools were collected at the end of period A and B and one bile sample was collected on the 12th day of period B. The faecal bile acid loss was higher during chenotherapy (36.12 mumol/kg/day) than during ursotherapy (23.94 mumol/kg/day), as was the proportion of lithocholic acid (73% vs 43%) in the faeces. Decay constant rate of faecal radioactivity was 0.365 day-1 in group I and 0.642 in group II. The results indicate that faecal bile acid excretion and turnover rate are greater during CDCA than UDCA, while UDCA increases the bile acid pool size to an even greater extent than does CDCA (150.2 vs 94.9 mumol/kg). This is probably because the former is more slowly degraded to poorly reabsorbable compounds. In fact, the bile saturation index was 0.66 in group I and 1.05 in group II, even though biliary CDCA in the latter had risen to 69.6%.

Topics: Bile Acids and Salts; Carbon Radioisotopes; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Feces; Female; Humans; Lithocholic Acid; Male; Ursodeoxycholic Acid

Topics: Bile Acids and Salts; Cholecystectomy; Cholelithiasis; Cholestasis; Common Bile Duct; Deoxycholic Acid; Gallstones; Humans; Lithocholic Acid

Topics: Adult; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acids; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Radiography

The relation between colonic bacterial metabolites in bile and saturation of bile with cholesterol was investigated. Eleven healthy men ingested metronidazole (2 g daily) for 10 days to inhibit anaerobic bacterial activity. Bile composition was determined in fasting samples aspirated from the duodenum before metronidazole was given, at the end of 10 days on metronidazole, and a month after the drug was discontinued. Bile cholesterol saturation fell in ten of the eleven subjects from a mean of 1.00 to 0.83 and rose in all eleven after the drug was stopped. At the same time the proportion of deoxycholate in bile acid decreased from a mean of 24% to 7%, returning to 22% of the total a month after metronidazole had been stopped, and the proportion of chenodeoxycholate changed significantly from 33% to 46% and back to 33%. There was little change in cholate concentrations. Deoxycholate is formed exclusively by bacterial action in the colon. Its administration increases cholesterol saturation of bile, while chenodeoxycholate reduces it. These results suggest that colonic function is important in regulating bile composition. Dietary measures which reduce the return of newly formed deoxycholate from the colon to the bile reduce cholesterol saturation and so are likely to reduce the risk of gallstones.

Topics: Adult; Anticholesteremic Agents; Bacteroides; Bile; Cholelithiasis; Cholesterol; Colon; Deoxycholic Acid; Dietary Fiber; Humans; Male; Metronidazole; Middle Aged

Topics: Bile; Cholelithiasis; Colon; Deoxycholic Acid; Humans

During the last decade the non-surgical management of gallbladder stones has become possible. Oral chenodeoxycholic acid (CDCA) and more recently, ursodeoxycholic acid (UDCA), have proved to be safe and effective. For the treatment of bile duct stones, various methods including flushing, chemical dissolution and mechanical procedures are now available. A combination of these techniques can be used in a logical sequence and should enable the successful treatment of most patients with bile ducts stones.

Topics: Adult; Bile Ducts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Gallbladder; Humans; Male

A reduction in total bile acid pool size was noted in nine of ten dogs after the implantation of inert prosthetic gallstones. Sham cholecystotomy without implantation of a prosthesis also produced a small decrease in bile acid pool size but was significantly less than the decrease noted with prosthetic stones. Bile acid ratios--cholic acid, chenodeoxycholic acid and deoxycholic acid--did not change after implantation of prosthetic stones. These findings raise the possibility that the small total bile acid pool size noted in patients with cholesterol gallstones is a phenomenon secondary to the pathologic state of the gallbladder.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholecystectomy; Cholelithiasis; Cholic Acids; Deoxycholic Acid; Dogs; Female; Lithocholic Acid; Prostheses and Implants

Topics: Adult; Bile; Bile Acids and Salts; Cholelithiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Female; Humans; Lipids; Male; Middle Aged

In view of the excess prevalence of gallstones among women and the association of gallstones with diminished bile acid pool size, we measured bile acid pools in 27 male and 25 female healthy human volunteers. The average bile acid pool in the women was significantly smaller than in the men (2.25 +/- .12 g versus 2.88 +/- .16 g; p = 0.003). Chenodeoxycholic acid pool size, computed from bile acid composition data available in 43 of these subjects, was also smaller in women than men (0.94 +/- 0.06 versus 1.22 +/- 0.07 g; p = 0.004). Age, race, and body size bore no statistically significant relationship to bile acid pool size. Biliary cholesterol saturation was positively correlated with weight and obesity and showed a significant inverse correlation with chenodeoxycholic acid pool size, but not with total bile acid pool size. These findings suggest a possible mechanism for the higher prevalence of gallstones among women.

Topics: Adolescent; Adult; Arizona; Bile Acids and Salts; Body Height; Body Weight; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acids; Deoxycholic Acid; Female; Humans; Indians, North American; Male; Sex Factors; White People

Twenty-three patients with gallstones were treated with two dosage levels of ursodeoxycholic acid, 600 mg/day and 150 mg/day. Two to three months after the treatment, the molar percentage of cholesterol in bile significantly decreased (from 7.4 to 4.5 mole % in the 600 mg group and from 7.6 to 4.0 mole % in the 150 mg group), so that bile became unsaturated in most patients in both treatment groups. However, there was no significant difference between the two groups. Biliary ursodeoxycholate increased in proportion to dose, and the sum of ursodeoxycholic acid plus chenodeoxycholic acid in biliary bile acids was over 70%. The was no significant increase in the proportion of lithocholate in bile. The major fecal bile acid of patients receiving ursodeoxycholic acid was lithocholic acid. Serum bile acid concentration rose slightly after 3 months of ursodeoxycholic acid treatment, and the major circulating bile acid became ursodeoxycholic acid. Ursodeoxycholic acid is well absorbed from intestine, undergoes little biotransformation during hepatic passage, and is 7-dehydroxylated by colonic bacteria. The litholytic activity of ursodeoxycholic acid was demonstrated in two patients receiving 450 mg and 150 mg, respectively, of the bile acid per day.

Topics: Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Lipid Metabolism; Lithocholic Acid; Middle Aged; Phospholipids

Topics: Calcium; Chemical and Drug Induced Liver Injury; Chenodeoxycholic Acid; Cholangitis; Cholecystectomy; Cholecystitis; Cholelithiasis; Cholestasis; Cholesterol; Deoxycholic Acid; Humans

Topics: Chenodeoxycholic Acid; Cholelithiasis; Costs and Cost Analysis; Deoxycholic Acid; Humans; Recurrence; Time Factors

Topics: Bile; Bile Acids and Salts; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans

Topics: Adult; Bile Acids and Salts; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Male; Middle Aged

Topics: Animals; Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Ethinyl Estradiol; Female; Haplorhini; Humans; Kinetics; Norethindrone; Papio; Pregnancy; Pregnancy, Animal

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cricetinae; Deoxycholic Acid; Female; Humans

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans

Ursodeoxycholic acid (UDCA), 7beta hydroxy epimer of chenodeoxycholic acid (CDCA), has been used as a choleretica for 20 years in Japan. Recent report showing increased excretion of UDCA in bile after CDCA administration may suggest the possibility that UDCA has similar effects to CDCA on bile cholesterol unsaturation and on gallstone dissolution. The present paper describes the clinical usefulness of UDCA for gallstone patients during the past two years. Seventy-four gallstone patients with functioning gall-bladders, 19 men and 55 women with a mean age of 48 years, have been treated for 6 months or more. UDCA, supplied in tablets (Ursosan), was given 450 mg per day. The disappearance or the reduction of stone size or number, or both (dissolution effect) was recognized in 32 out of 74 patients (43%). In case of radiolucent stones, the overall effective rate was estimated for 24 of 46 patients (52%). There may be no significant difference in dissolution effect between CDCA and UDCA treatment, however, the merit of UDCA treatment seems to have its few side effects.

Topics: Adult; Aged; Cholelithiasis; Deoxycholic Acid; Female; Humans; Male; Middle Aged

With the introduction of medical treatment (chenodeoxycholic acid therapy) of cholesterol gallstones, the prediction of the gallstone type, cholesterol--non-cholesterol stones, (i.e. cholesterol predominating or not), has become important. In 24 consecutive patients admitted for surgery because of gallstones, the value of various criteria for differentiation between the two types of stones was assessed. It is concluded that the combined requirements of radiolucency of the stones and a cholesterol saturation index in duodenal bile above 1.00 constitutes a fairly reliable method for selection of patients for dissolution therapy with chenodeoxycholic acid.

Topics: Adult; Aged; Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Duodenum; Gallbladder; Humans; Middle Aged; Phospholipids

Rabbits fed a diet containing 40 per cent casein, 15 per cent oleic acid and 45 per cent laboratory pellets developed glycoallodeoxycholic acid and glycodeoxycholic acid gallstones. The oral administration of kanamycin prevented allo bile acid stone formation in the oleic acid fed rabbit without leading to cholesterol gallstone formation. Kanamycin reduced the concentration of allodeoxycholic acid in the bile of oleic acid fed rabbits from 16.6+/-4.1 per cent of total bile acids to 1.1+/-1.1 per cent, with a reciprocal increase in deoxycholic acid concentration. The allodeoxycholate concentration was far below that found in control bile samples, 10.2+/-2.3 per cent. If the effect of kanamycin on the bile composition is by its antibiotic action, this eliminates the importance of a hepatic contribution to allodeoxycholate stone formation.

Topics: Administration, Oral; Animals; Bile; Cholelithiasis; Cholesterol; Cholesterol, Dietary; Deoxycholic Acid; Female; Glycocholic Acid; Kanamycin; Liver; Male; Oleic Acids; Rabbits

Topics: Bile Acids and Salts; Chemical Phenomena; Chemistry; Cholelithiasis; Cholic Acids; Deoxycholic Acid; Heparin; Humans; In Vitro Techniques; Phosphatidylcholines

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Prospective Studies

Biliary cholesterol saturation has been correlated with disease variables that might effect bile acid loss in ileitis patients with (N = 9) or without (N = 8) intestinal resection having a defined prevalence of gallstones. In addition, cholesterol saturation was determined in ulcerative colitis patients (N = 7) and gallstone patients (N = 18) as well as in 5 normal controls. Biliary cholesterol saturation in ileitis patients both with and without resection was similar to that in gallstone patients yet the prevalence of gallstones was only 12%. Cholesterol saturation did not correlate with ileal resection nor the extent, duration, or activity of ileitis. Biliary cholesterol saturation was not different in ulcerative colitis patients from that in normal subjects. It is concluded that cholesterol saturation of bile alone does not account for the high prevalence of cholesterol gallstones that has been reported in ileitis patients.

Topics: Adult; Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Ileitis; Middle Aged

Topics: Bile; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acids; Deoxycholic Acid; Glycine max; Humans; Phosphatidylcholines; Phospholipids

Topics: Chemical Phenomena; Chemistry; Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Humans; Time Factors

When raw wheat bran was added to the diet of six subjects for 4-6 weeks, chenodeoxycholate (CDC) synthesis increased from 0.46 +/- 0.12 to 0.57 +/- 0.17 mmol/day pool increased from 1.72 +/- 0.47 to 2.19 +/- 0.74 mmol (rho less than 0.05). Deoxycholate (DC) pool size diminished from 1.20 +/- 0.29 to 0.80 +/- 0.16 mmol, but cholate synthesis and pool size were unaffected. Overall, the size of the bile salt pool did not change. In spite of this, when 10 patients with probable cholesterol gallstones took bran supplements for 4-6 weeks, their gallbladder bile aspirated from the duodenum became less saturated with cholesterol. The molar percentage of cholesterol fell from 10.1 +/- 3.1% to 8.6 +/- 2.7% (rho less than 0.01), and the saturation index of bile fell from 1.49 +/- 0.40 to 1.29 +/- 0.38 (rho less than 0.005). Bran probably operates primarily on the colon, reducing the formation or absorption of the bacterial metabolite DC, a substance which impairs CDC synthesis.

Topics: Adult; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Diet; Female; Humans; Kinetics; Lipid Metabolism; Male; Middle Aged; Seeds; Triticum

Postcholecystectomy biliary lipid composition and bile acid kinetics were studied in 24 women and 4 men. Hepatic bile was collected periodically for as long as 4 months without interrupting the enterohepatic circulation and without infecting the biliary system. In 23 patients with cholesterol gallstones, fasting biliary cholesterol made up 10.2% of total lipids in the steady state; in 5 patients with bilirubinate stones, saturation of fasting hepatic bile with cholesterol was lower (8.7% of total lipids). The percentage of deoxycholic acid after cholecystectomy was not higher than that of seven healthy, noncholecystectomized controls. Postcholecystectomy studies of diurnal variation of biliary lipids (7 patients) showed that postprandial hepatic bile had a significantly lower cholesterol saturation than fasting bile. Pool sizes of cholic and chenodeoxycholic acids were low (average 0.4 g/70 kg, each); total synthesis for both bile acids was normal (average 460 mg/day/70 kg), but fractional turnover rates of the two primary bile acids increased after cholecystectomy, probably due to more frequent recycling of the small bile acid pool.

Topics: Adolescent; Adult; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholecystectomy; Cholelithiasis; Cholesterol; Cholic Acids; Circadian Rhythm; Deoxycholic Acid; Eating; Fasting; Female; Gallbladder; Humans; Kinetics; Lipids; Liver; Male; Middle Aged; Phospholipids

Topics: Absorption; Arteriosclerosis; Bile Acids and Salts; Cellulose; Cholelithiasis; Cholesterol; Colonic Neoplasms; Constipation; Deoxycholic Acid; Dietary Fiber; Humans; Hypercholesterolemia; Intestinal Absorption; Lipid Metabolism; Lithocholic Acid; Pectins; Water

Relative concentrations of conjugated and sulfated bile acids in duodenal bile were measured in 5 patients before and during treatment with 0.50-0.75 g of chenodeoxycholic acid per day for 3-4 months. Lithocholic acid constituted 0.8-3.3% (mean 1.8%) of total conjugated and sulfated bile acids before and 0-5.4% (mean 2.6%) during treatment. Lithocholic acid was the predominant bile acid in the sulfate fraction in three patients and chenodeoxycholic acid in two. Sulfated bile acids constituted less than 1% of total bile acids and did not increase during treatment. Ursodeoxycholic acid, the other major metabolite of chenodeoxycholic acid, was found in higher amounts during therapy. The unsaturated bile acid 3beta-hydroxy-delta5-cholenic acid, which was found exclusively as its sulfate ester, showed a slight fall. The average G/T conjugation ratio rose from 2.2 to 4.5.

Topics: Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acids; Deoxycholic Acid; Female; Glycocholic Acid; Humans; Lithocholic Acid; Male; Time Factors

The cholesterol content of biliary lipids increased significantly when 16 healthy volunteers ingested deoxycholic acid (DC) for two weeks in a daily dose of 100-150 mg. Serum cholesterol also fell significantly to 88% of the baseline levels. Since DC is formed in the colon we suggest that populations in whom there is a high colonic absorption of bacterially metabolized cholate--that is, DC--have an increased predisposition to cholesterol gall stones.

Topics: Adult; Alkaline Phosphatase; Aspartate Aminotransferases; Bacteria; Bile; Bilirubin; Cholelithiasis; Cholesterol; Colon; Deoxycholic Acid; Female; Humans; Liver; Liver Function Tests; Male; Middle Aged; Triglycerides

In three healthy rhesus monkeys fed chenodeoxycholic (chenic) acid, there was no consistent increase in the total exchangeable cholesterol pool or input to the cholesterol pool. In three similar monkeys fed cholic acid, the total exchangeable pool increased in all animals and input to the cholesterol pool increased in two. Serum glutamic-pyruvic transaminase (SGPT) increased transiently in two animals in each group. Morphologic abnormalities (triaditis with atypical ductular proliferation) were noted in one animal; this animal was ingesting chenic acid but had normal liver test results at the time of biopsy. Biliary bile acids contained 8 to 14 percent lithocholic acid in the chenic acid group and 48 to 72 percent deoxycholic acid in the cholic acid group.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bile; Bile Acids and Salts; Biopsy; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Diet; Disease Models, Animal; Lithocholic Acid; Liver; Liver Function Tests; Macaca mulatta

Chenodeoxycholic acid is an important drug for the treatment of cholesterol cholelithiasis in man. Although no toxicity has been demostrated in man, liver lesions develop in rhesus monkeys treated with chenodeoxycholic acid. To elucidate the mechanism of toxicity, chenodeoxycholic acid. To elucidate the mechanism of toxicity, chenodeoxycholic acid was fed daily to three groups of 6 animals each at the following dose: 10, 40, and 100 mg per kg; 2 separate animals were not treated and served as controls. After 1 month, the animals were killed. During the treatment period, most blood tests (e.g., blood count, blood urea nitrogen, albumin, SGOT, lactate dehydrogenase) remained within normal limits, but there was a significant dose-related increase in serum leucine aminopeptidase levels. The percentage of lithochlic acid, the 7-dehydroxylated bacterial metabolite of chenodeoxycholic acid, rose from 1% in the control animal to almost 14% in the 100 mg per kg-treated group. Liver biopsies obtained before treatment and at necropsy showed no significant changes. Thus, exposure of the liver to increased amounts of lithocholic acid during chenodeoxycholic acid treatment might result in elevation of serum leucine aminopeptidase activity.

Topics: Animals; Bile; Body Weight; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Diarrhea; Dose-Response Relationship, Drug; Female; Leucyl Aminopeptidase; Lithocholic Acid; Liver; Macaca mulatta; Male; Phospholipids

Chenodeoxycholate was administered to 13 patients with cholesterol gallstones. During the treatment period the bile composition changed markedly. Chenodeoxycholate increased from 42.9% of the total bile salts before treatment to 79.3% after 8 weeks of treatments. Ursodeoxycholate increased from 2.3 to 12.6% and lithocholate from 1.1 to 3.3%. In contrast, cholate decreased from 40.3% of the total bile salts to 3.1% and deoxycholate decreased from 12.5 to 2.5%. Less than 5% of chenodeoxycholate, ursodeoxycholate, cholate and deoxycholate in bile were sulfate esters. In contrast, considerable amounts of lithocholate were sulfated. The sulfation of lithocholate increased from 32.8% of the total lithocholate before treatment to 73.9% after 8 weeks of treatment. Sulfated lithocholate is more rapidly eliminated in feces and urine than the nonsulfated compound. Furthermore, sulfated lithocholate is less toxic. Therefore, the increase in the sulfation of lithocholate observed in most of our patients represents a protective mechanism.

Topics: Aged; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Humans; Lithocholic Acid; Middle Aged; Time Factors

The essential role of the gallbladder in gallstone formation should not be underestimated, as cholesterol stones originate in the gallbladder. The possible significance of stratification of bile in the gallbladder has been studied using recently proposed lithogenic parameters, such as triangular co-ordinates, lithogenic index and cholesterol saturation index. Bile becomes less lithogenic as the concentrating process in the gallbladder progresses. The concentrating activity of the gallbladder seems to differ considerably for each bile constituent. Bile salts are most concentrated in the gallbladder, followed by phospholipids and cholesterol. The presence of a selective absorption process in the gallbladder is suggested. As the gallbladder diminishes the lithogenicity of bile during storage, its role probably lies in its ability to interrupt the enterohepatic circulation leading to the production of lithogenic bile as well as providing a recess to ensure continuous growth of stones.

Topics: Bile; Bile Acids and Salts; Bilirubin; Cholelithiasis; Cholesterol; Deoxycholic Acid; Humans; Liver

Topics: Chenodeoxycholic Acid; Cholelithiasis; Deoxycholic Acid; Female; Humans; Male

Topics: Aged; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Solubility; Time Factors

Topics: Bile Acids and Salts; Cellulose; Cholelithiasis; Cholic Acids; Chromatography, Thin Layer; Deoxycholic Acid; Diet; Feces; Humans; Intestinal Neoplasms; Intestine, Large; Nigeria; Taurocholic Acid

Topics: Animals; Bile; Bile Acids and Salts; Carbon Monoxide; Cholelithiasis; Chromatography, Gas; Chromatography, Thin Layer; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Deoxycholic Acid; Humans; Hydroxylation; In Vitro Techniques; Lithocholic Acid; Mass Spectrometry; Microsomes, Liver; Rats; Species Specificity

Kinetic studies of cholic and chenodeoxycholic acids were carried out in three patients by simultaneous intravenous administration of appropriate pairs of (3)H- and (14)C-labeled compounds. The results obtained indicated two sources of error: chemical impurity and loss of tritium by biological exchange. Precautions are listed for use of tritiated bile acids in studies of pool sizes and turnover rates.

Topics: Adult; Bile; Bile Acids and Salts; Carbon Radioisotopes; Chenodeoxycholic Acid; Cholecystectomy; Cholelithiasis; Cholic Acids; Deoxycholic Acid; Evaluation Studies as Topic; Female; Humans; Injections, Intravenous; Kinetics; Methods; Middle Aged; Tritium

Topics: Adult; Aged; Bile; Bile Acids and Salts; Carbon Radioisotopes; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acids; Chromatography, Thin Layer; Colon; Deoxycholic Acid; Female; Glycine; Humans; Injections; Intestinal Absorption; Male; Middle Aged; Taurine; Taurocholic Acid; Time Factors

Topics: Bile; Bile Acids and Salts; Bile Ducts, Intrahepatic; Chenodeoxycholic Acid; Cholecystectomy; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Gallbladder; Humans; Lithocholic Acid; Liver Circulation

Topics: Adult; Aged; Bacteria; Bile; Bile Acids and Salts; Biliary Tract; Biodegradation, Environmental; Chenodeoxycholic Acid; Cholecystectomy; Cholelithiasis; Cholesterol; Cholic Acids; Chromatography; Deoxycholic Acid; Female; Glycine; Humans; Hydroxylation; Keto Acids; Kinetics; Male; Middle Aged

Topics: Alkanes; Bile Acids and Salts; Cetylpyridinium; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Chromatography, Gas; Deoxycholic Acid; Drug Synergism; Drug Therapy, Combination; Heparin; Hexamethonium Compounds; Humans; Infusions, Parenteral; Intubation; Pyridinium Compounds; Sodium Chloride; Surface-Active Agents

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Glycocholic Acid; Heparin; Humans; Phosphatidylcholines; Taurocholic Acid

Topics: Aged; Cholelithiasis; Deoxycholic Acid; Female; Humans; Radiography; Retrospective Studies

Bile acid kinetics and biliary lipid composition were characterized in six women with gallstones before and after 6 mo of oral therapy with chenodeoxycholic acid, an agent that induces dissolution of cholesterol gallstones in man. Over a dosage range of 1-4 g/day, absorption varied from 0.8 to 2.3 g/day. The chenodeoxycholic acid pool expanded two-to sixfold, and bile became composed predominantly (> 90%) of chenodeoxycholic acid conjugated chiefly with glycine. Cholic acid and deoxycholic acid pools decreased markedly, so that the total bile acid pool expanded much less, about twofold on the average. Cholic acid synthesis decreased in five of the six patients, consistent with negative feedback inhibition of cholic acid synthesis by chenodeoxycholic acid. In four patients whose bile was above or close to saturation with cholesterol, the bile became unsaturated; in two patients, whose bile was unsaturated, it remained so. In five patients with radiolucent gallstones, chenodeoxycholic acid therapy was continued after completion of kinetic and composition measurements; the stones decreased in size or dissolved entirely during the subsequent 6 to 18 mo. Similar measurements of bile acid kinetics and biliary lipid composition were made before and after a 6-mo period without medication in a control group of six healthy women; no changes occurred.

Topics: Administration, Oral; Bile; Bile Acids and Salts; Carbon Radioisotopes; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Chromatography, Gas; Chromatography, Thin Layer; Deoxycholic Acid; Feces; Female; Humans; Lipids; Lithocholic Acid; Radioisotope Dilution Technique; Tritium

Topics: Acute Disease; Adolescent; Adult; Aged; Bile Acids and Salts; Cholelithiasis; Cholestasis; Chromatography, Gas; Chromatography, Ion Exchange; Deoxycholic Acid; Hepatitis A; Humans; Jaundice; Lithocholic Acid; Mass Spectrometry; Middle Aged

Topics: Administration, Oral; Animal Feed; Animals; Bile Acids and Salts; Body Weight; Cholelithiasis; Cholesterol; Cholic Acids; Cricetinae; Deoxycholic Acid; Disease Models, Animal; Fatty Acids; Female; Lithocholic Acid; Liver; Male; Organ Size; Sex Factors; Testis

Isotopic bile salt studies were carried out in eight middle-aged women with radiolucent galstones in functioning gallbladders and in 10 matched controls. In the gallstone patients the size of the bile salt pool was reduced by 37% to 1.79 g, but there was considerable overlap with the normal subjects. The cholate and chenodeoxycholate pools were reduced, but the deoxycholate pool was normal in size. There were changes in bile salt metabolism which resembled those found after cholecystectomy but were less marked. This suggests that in gallstone disease the storage capacity of the gallbladder is impaired. This may contribute to the small bile salt pool, but it is unlikely to be the sole or even the major cause.

Topics: Adult; Bile Acids and Salts; Carbon Radioisotopes; Chenodeoxycholic Acid; Cholecystectomy; Cholelithiasis; Cholic Acids; Deoxycholic Acid; Female; Gallbladder; Humans; Kinetics; Middle Aged; Taurocholic Acid

Topics: Bile Acids and Salts; Bilirubin; Calcium; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Esters; Humans; New Zealand; Phospholipids; Phosphorus; Potassium; Sodium

Topics: Adult; Animals; Bile; Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acids; Chromatography, Thin Layer; Deoxycholic Acid; Dogs; Duodenum; Evaluation Studies as Topic; Female; Guinea Pigs; Humans; Intestinal Secretions; Lithocholic Acid; Male; Methods; Microchemistry; Middle Aged; Species Specificity; Spectrometry, Fluorescence; Taurocholic Acid

Topics: Acetylcysteine; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acids; Deoxycholic Acid; Drug Combinations; Enzyme Therapy; Glycocholic Acid; Heparin; Humans; In Vitro Techniques; Pancreatin; Papain; Phosphatidylcholines; Taurocholic Acid; Trypsin

Topics: Animals; Bile; Bile Acids and Salts; Cholelithiasis; Chromatography, Gas; Deoxycholic Acid; Dietary Fats; Male; Oleic Acids; Rabbits