Cholesterol-lowering effect of ursodeoxycholic acid in patients with primary biliary cirrhosis. Chenodeoxycholic acid and ursodeoxycholic acid effects in endogenous hypertriglyceridemias. A controlled double-blind trial. Effect of ursodeoxycholic acid on serum lipids of patients with primary biliary cirrhosis. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. Effects of additional administration of colchicine in ursodeoxycholic acid-treated patients with primary biliary cirrhosis: a prospective randomized study. Ursodeoxycholic acid for symptomatic primary biliary cirrhosis. Preliminary analysis of a double-blind multicenter trial. Italian Multicenter Group for the Study of UDCA in PBC. A randomized double-blind study of the short-time treatment of obese patients with nonalcoholic fatty liver disease with ursodeoxycholic acid. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo-controlled trial. Failure of ursodeoxycholic acid to prevent acute cellular rejection after liver transplantation. Ursodeoxycholic acid treatment lowers the serum level of antibodies against pyruvate dehydrogenase and influences their inhibitory capacity for the enzyme complex in patients with primary biliary cirrhosis Ursodeoxycholic acid as adjunctive therapy for problematic type 1 autoimmune hepatitis: a randomized placebo-controlled treatment trial. The effect of diet on bile acid kinetics and biliary lipid secretion in gallstone patients treated with ursodeoxycholic acid. DISSOLUTION OF CHOLESTEROL GALLSTONES BY URSODEOXYCHOLIC ACID Comparative efficacy and side effects of ursodeoxycholic and chenodeoxycholic acids in dissolving gallstones. A double-blind controlled study. Effects of ursodeoxycholic acid and aspirin on the formation of lithogenic bile and gallstones during loss of weight. Weight reduction and ursodeoxycholic acid in subjects with nonalcoholic fatty liver disease. A double-blind, placebo-controlled trial. Effect of high and low doses of ursodeoxycholic acid on gallstone dissolution in humans. Prophylaxis against Gallstone Formation with Ursodeoxycholic Acid in Patients Participating in a Very-Low-Calorie Diet Program Ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Interim analysis of a double-blind multicentre randomized trial. The UDCA-PBC Study Group. A randomised placebo‐controlled trial of ursodeoxycholic acid and S‐adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy Serum plant sterols and biliary cholesterol secretion in humans: studies with ursodeoxycholic acid.
We have previously shown in a 2-yr controlled trial that hypercholesterolemia , frequent in primary biliary cirrhosis , is lowered by ursodeoxycholic acid ( 13 to 15 mg daily ) . To further investigate this effect , we analyzed the influence of long-term ursodeoxycholic acid administration on serum lipids , lipoproteins and bile acids . The study involved a subgroup of 33 noncirrhotic patients ( 17 received ursodeoxycholic acid and 16 received a placebo ) analyzed at inclusion and after 2 yr . The total serum cholesterol concentration was markedly reduced in the  ursodeoxycholic acid-treated  patients in comparison with the controls ( mean + /- S.E.M. = 7.49 + /- 0.42 mmol/L and 7.07 + /- 0.23 mmol/L at entry and 4.44 + /- 0.40 mmol/L and 6.89 + /- 0.27 mmol/L at 2 yr in the ursodeoxycholic acid and placebo groups , respectively ; p < 0.02 ) . Quantitatively , this decrease was mainly caused by a fall in low-density-lipoprotein cholesterol , but very low density-lipoprotein cholesterol levels also fell significantly . High-density-lipoprotein cholesterol levels remained stable in both groups , but the high-density-lipoprotein2/high-density-lipoprotein3 cholesterol ratio fell significantly during ursodeoxycholic acid treatment . No significant change occurred in total triglyceride or total phospholipid levels . In the treated group , the proportion of ursodeoxycholic acid  increased ( up to 60 % of total circulating bile acids ) , whereas that of cholic and chenodeoxycholic acids  fell significantly . In conclusion , the cholesterol-lowering effect of ursodeoxycholic acid could be related to an improvement of cholestasis , modifications in cholesterol metabolism or both . Changes in endogenous bile acid composition induced by ursodeoxycholic acid might be the common denominator of these two mechanisms A double-blind controlled trial was carried out to compare the effects of chenodeoxycholic acid ( CDCA ) , ursodeoxycholic acid ( UDCA ) , and placebo on cholesterol and triglyceride levels in patients with endogenous hypertriglyceridemias . The dose of both bile acids was four 150-mg capsules day . Total serum cholesterol levels did not show appreciable changes with any of the treatments . HDL cholesterol was significantly increased after CDCA but not after UDCA or placebo . CDCA feeding was associated with a significant decrease in serum triglyceride levels , whereas the other treatments failed to show an effect . It is concluded that UDCA does not affect serum lipid levels , whereas CDCA lowers serum triglycerides and may be useful in the treatment of endogenous hypertriglyceridemia OBJECTIVE To study the effects of ursodeoxycholic acid ( UDCA ) on lipid levels in patients with primary biliary cirrhosis ( PBC ) . DESIGN A r and omized , placebo-controlled prospect i ve trial of UDCA was conducted in 177 well-characterized patients with PBC . MATERIAL AND METHODS The two treatment groups ( placebo and UDCA ) were matched at entry with respect to age , sex , histologic stage of PBC , biochemical values , and serum lipid levels . Serum cholesterol , high-density lipoprotein cholesterol , and triglyceride levels were measured at entry , 1 year , and 2 years . RESULTS The decrease in total cholesterol level at 1 and 2 years in the UDCA-treated group was significant in comparison with that in the placebo group . Serum high-density lipoprotein cholesterol and triglyceride levels , however , were unchanged . No severe side effects from UDCA were noted . The changes in serum cholesterol levels at 2 years were directly and strongly correlated with changes in serum bilirubin concentrations ( r = 0.70 ; P < 0.001 ) and inversely correlated with initial serum cholesterol levels ( r = -0.86 ; P < 0.00001 ) . CONCLUSION The cholesterol-lowering effect of UDCA could be related to amelioration of the underlying liver disease or to a direct effect of the drug on the metabolism of cholesterol in patients with hypercholesterolemia BACKGROUND & AIMS There is no medical treatment of proven benefit for primary sclerosing cholangitis . This study aim ed at study ing the effect of a higher dose of ursodeoxycholic acid than previously used on survival , symptoms , biochemistry , and quality of life in this disease . METHODS A r and omized placebo-controlled study was performed in tertiary and secondary gastroenterology units . A total of 219 patients were r and omized to 17 to 23 mg/kg body weight per day of ursodeoxycholic acid ( n = 110 ) or placebo ( n = 109 ) for 5 years . Follow-up data are available from 97 patients r and omized to ursodeoxycholic acid  and for 101 r and omized to placebo .  Quality of life was assessed by using the Medical Outcomes Study 36-item Short-Form Health Survey . RESULTS The combined end point " death or liver transplantation " occurred in 7 of 97 ( 7.2 % ) patients in the ursodeoxycholic acid group vs 11 of 101 ( 10.9 % ) patients in the placebo group ( P = .368 ; 95 % confidence interval , -12.2 % to 4.7 % ) . The occurrence of liver transplantation as a single end point showed a similar positive trend for ursodeoxycholic acid treatment ( 5/97 [ 5.2 % ] vs 8/101 [ 7.9 % ] ; 95 % confidence interval , -10.4 % to 4.6 % ) . Three ursodeoxycholic acid and 4 placebo patients died from cholangiocarcinoma , and 1 placebo patient died from liver failure . Alkaline phosphatase and alanine aminotransferase tended to decrease during the first 6 months . There were no differences between the 2 groups in symptoms or quality of life . Analyses of serum ursodeoxycholic acid concentration gave no evidence that noncompliance may have influenced the results . CONCLUSIONS This study found no statistically significant beneficial effect of a higher dose of ursodeoxycholic acid than previously used on survival or prevention of cholangiocarcinoma in primary sclerosing cholangitis BACKGROUND / AIMS Intense pruritus and the risk of stillbirths and premature deliveries justify the search for an effective pharmacologic treatment of intrahepatic cholestasis of pregnancy . This study was design ed to test the efficacy of ursodeoxycholic acid in maternal pruritus , the biochemical abnormalities and the outcome of pregnancy , in patients with intrahepatic cholestasis of pregnancy of early onset . METHODS Pregnant patients hospitalized in a secondary case-referral center with intense pruritus and abnormal serum levels of bile salts and aminotransferases , detected before week 33 of pregnancy , were r and omly assigned to receive ursodeoxycholic acid , 1 g per day orally , or an identical placebo , until delivery , in a double-blind study . A 3-week trial period was chosen to compare drug and placebo effects . The follow-up was extended for 3 months after delivery . RESULTS Twenty-four patients entered the trial ; eight had deliveries before 2 weeks of treatment and one dropped out . The study was then completed in 15 patients : eight received ursodeoxycholic acid and seven placebo . No adverse effects were detected in the mothers or in their babies . After 3 weeks of treatment , patients receiving ursodeoxycholic acid ( mean daily dose 16 mg/kg body weight ) had a significant improvement in pruritus ( p<0.02 ) , in serum bilirubin ( 0.36+/-0.19 mg/dl ( mean+/-SD ) versus 0.95+/-0.48 in patients receiving placebo , p<0.01 ) , in aspartate aminotransferase ( 52+/-42 IU/l vs 98+/-44 , p<0.05 ) and in alanine aminotransferase ( 54+/-50 IU/l vs 229+/-154 , p<0.01 ) ; serum total bile salts also tended to be lower in patients receiving ursodeoxycholic acid ( 26.3+/-33.7 micromol/l vs 55.0+/-44.8 , p N.S. ) . Deliveries occurred at or near term in all mothers who received ursodeoxycholic acid ( mean week of pregnancy : 38 ) , while they occurred before week 36 of pregnancy in five patients who received placebo , including one stillbirth . All babies born alive had birth weights adequate for gestational age and they were thriving normally 3 months after delivery . CONCLUSIONS Ursodeoxycholic acid is effective and safe in patients with intrahepatic cholestasis of pregnancy of early onset , attenuating pruritus and correcting some biochemical abnormalities in the mothers . Relevant aspects of fetal outcome were also improved in patients receiving ursodeoxycholic acid compared to placebo BACKGROUND / AIMS Although ursodeoxycholic acid is effective for the treatment of primary biliary cirrhosis , some patients do not respond to this treatment . The objective of the present study was to investigate the effects of additional administration of colchicine in  ursodeoxycholic acid-treated patients with primary biliary cirrhosis . METHODS Twenty-two patients with primary biliary cirrhosis treated with ursodeoxycholic acid ( 600 mg/day ) for 30 months were r and omly assigned to two groups : group 1 , colchicine ( 1 mg/day ) and ursodeoxycholic acid ( n = 10 ) ; group 2 , ursodeoxycholic acid alone ( n = 12 ) . RESULTS In group 1 , there were significant decreases in mean serum levels of alkaline phosphatase , total bilirubin , gamma-glutamyltranspeptidase , alanine aminotransferase , aspartate aminotransferase , and IgM , and these changes were more remarkable in those who responded poorly to ursodeoxycholic acid . In contrast , there were no significant changes in those values in group 2 . CONCLUSIONS Additional administration of colchicine to ursodeoxycholic acid may be beneficial for patients with primary biliary cirrhosis , especially those who respond poorly to ursodeoxycholic acid .  It is necessary , however , to further confirm the efficacy of colchicine by examining histological changes and following the patients for longer periods The administration of ursodeoxycholic acid , a hydrophilic bile acid not hepatotoxic to humans , has been suggested for treatment of primary biliary cirrhosis to improve cholestasis and reduce hepatocellular damage . Efficacy of treatment has been studied mainly in patients with asymptomatic or early-stage disease . In January 1988 , to establish the efficacy and safety of ursodeoxycholic acid in a population with more severe disease , we started a multicenter , double-blind , placebo-controlled trial in patients with symptomatic disease , that is , with pruritus or serum bilirubin exceeding 2 mg/dl . Forty-four patients were assigned to ursodeoxycholic acid , 500 mg daily ( corresponding to about 8.7 mg/kg body weight in these patients ) , and 44 to a placebo . As planned at the beginning of the study , a preliminary analysis was performed when all patients had been followed for at least 6 months ( 33 patients up to 12 months ) . Pruritus , self-evaluated by the patients , and cholestyramine consumption , as recorded in a diary , decreased significantly ( p < 0.01 ) in both groups . In patients who initially had abnormal levels , serum bilirubin decreased significantly ( p < 0.05 ) in the ursodeoxycholic acid group compared to placebo . After 6 months the following were also significantly better in the ursodeoxycholic acid than in the placebo group : a composite weighted biochemical index taking into account the changes in serum bilirubin , alkaline phosphatase , gamma-GT and AST ( p < 0.001 ) ; serum prealbumin ( p < 0.05 ) ; IgG ( p < 0.01 ) and IgM ( p < 0.01 ) levels . ( ABSTRACT TRUNCATED AT 250 WORDS In order to determine the effect of ursodeoxycholic acid on nonalcoholic fatty liver disease , 30 patients with body mass indices higher than 25 , serum levels of alanine aminotransferase ( ALT ) , aspartate aminotransferase ( AST ) or gamma-glutamyltransferase ( gamma-GT ) at least more than 1.5 times the upper limit of normality , and hepatic steatosis demonstrated by ultrasonography were r and omized into two groups of 15 patients to receive placebo or 10 mg kg-1 day-1 ursodeoxycholic acid for three months . Abdominal computed tomography was performed to quantify hepatic fat content , which was significantly correlated with histological grading of steatosis ( r s = -0.83 , P < 0.01 ) . Patient body mass index remained stable for both groups throughout the study , but a significant reduction in mean ( + /- SEM ) serum levels of ALT , AST and gamma-GT was observed only in the treated group ( ALT = 81.2 + /- 9.7 , 44.8 + /- 7.7 , 48.1 + /- 7.7 and 52.2 + /- 6.3 IU/l at the beginning and after the first , second and third months , respectively , N = 14 , P < 0.05 ) . For the placebo group ALT values were 66.4 + /- 9.8 , 54.5 + /- 7 , 60 + /- 7.6 and 43.7 5 IU/l , respectively . No alterations in hepatic lipid content were observed in these patients by computed tomography examination ( 50.2 + /- 4.2 Hounsfield units ( HU ) at the beginning versus 51.1 + /- 4.1 HU at the third month ) . These results show that ursodeoxycholic acid is able to reduce serum levels of hepatic enzymes in patients with nonalcoholic fatty liver disease , but this effect is not related to modifications in liver fat content BACKGROUND & AIMS Treatment of intrahepatic cholestasis of pregnancy with ursodeoxycholic acid appears promising , but data are limited so far . The aim of this r and omized study was to evaluate the efficacy and safety of ursodeoxycholic acid in comparison with cholestyramine . METHODS Eighty-four symptomatic patients with intrahepatic cholestasis of pregnancy were r and omized to receive either ursodeoxycholic acid , 8 - 10 mg/kg body weight daily ( n = 42 ) , or cholestyramine , 8 g daily ( n = 42 ) , for 14 days . The primary end point was a reduction of pruritus by more than 50 % after 14 days of treatment as evaluated by a pruritus score . Secondary end points were outcome of pregnancy , reduction of serum aminotransferase activities and serum bile acid levels , and drug safety . Intention-to-treat analysis was applied . RESULTS Pruritus was more effectively reduced by ursodeoxycholic acid than cholestyramine ( 66.6 % vs 19.0 % , respectively ; P < .005 ) . Babies were delivered significantly closer to term by patients treated with ursodeoxycholic acid than those treated with cholestyramine ( 38.7 + /- 1.7 vs 37.4 + /- 1.5 weeks , respectively , P < .05 ) . Serum alanine and aspartate aminotransferase activities were markedly reduced by 78.5 % and 73.8 % , respectively , after ursodeoxycholic acid , but by only 21.4 % , each , after cholestyramine therapy ( P < .01 vs ursodeoxycholic acid ) . Endogenous serum bile acid levels decreased by 59.5 % and 19.0 % , respectively ( P < .02 ) . Ursodeoxycholic acid , but not cholestyramine was free of adverse effects . CONCLUSIONS Ursodeoxycholic acid is safe and more effective than cholestyramine in intrahepatic cholestasis of pregnancy The efficacy and safety of ursodeoxycholic acid for the treatment of primary sclerosing cholangitis were evaluated in a prospect i ve , r and omized , double-blind , placebo-controlled trial . Fourteen patients with primary sclerosing cholangitis documented by cholestatic serum enzyme pattern , liver histological appearance and endoscopic retro grade cholangiography were included in the trial . Six patients received ursodeoxycholic acid ( 13 to 15 mg/kg body wt/day ) , and eight patients received placebo . Two patients had to be withdrawn from the study , one because of UDCA-related diarrhea and the other because of worsening of the disease during placebo treatment . Patients in the ursodeoxycholic acid group improved significantly during 1 yr of treatment with respect to serum levels of bilirubin ( median = -50 % ) , alkaline phosphatase ( median = -67 % ) , gamma-glutamyltransferase ( median = -53 % ) , AST ( median = -54 % ) and ALT ( median = -36 % ) compared with the placebo group , but not with respect to serum levels of hydrophobic bile acids . During ursodeoxycholic acid treatment , histopathological features also improved significantly , as evaluated by multiparametric score . Expression of human leukocyte antigen class I molecules appeared to be markedly reduced on liver cells after ursodeoxycholic acid treatment . We conclude that ursodeoxycholic acid is beneficial in reducing disease activity in patients with primary sclerosing cholangitis BACKGROUND / AIMS Acute rejection is still a major problem after liver transplantation .  Ursodeoxycholic acid has beneficial effects in cholestasis by reducing the expression of major histocompatibility complex antigens . METHODS We have performed a double-blind r and omised study comparing ursodeoxycholic acid with placebo for the prevention of acute cellular rejection after liver transplantation . Twenty-six patients received ursodeoxycholic acid 600 mg per day and 24 patients received placebo  for 2 months . RESULTS Neither rejection incidence nor rejection severity was significantly different in the two groups ( p > 0.90 ) . CONCLUSIONS We conclude that adjuvant ursodeoxycholic acid administration does not prevent rejection after liver transplantation A two-year r and omized , double-blind , placebo-controlled clinical trial used paired serum sample s from 122 patients with primary biliary cirrhosis to compare the effect of ursodeoxycholic acid and colchicine on their immune parameters . IgG antibodies to pyruvate dehydrogenase , the major autoantigen in primary biliary cirrhosis , were determined by enzyme-linked immunosorbent assay and immunoblot ; enzyme inhibition assay against pyruvate dehydrogenase was used to test the changes of the functional reactivity of the serum autoantibodies . Treatment with ursodeoxycholic acid decreased both the level of IgG antibodies to pyruvate dehydrogenase ( P<0.01 ) and the inhibitory titer of the sera for pyruvate dehydrogenase ( P<0.01 ) . Treatment with colchicine or placebo showed no statistically significant changes in either the antibody levels or the inhibitory titers .  Ursodeoxycholic acid thus alters the immune parameters of patients with primary biliary cirrhosis . The mechanism of these changes needs further investigation To evaluate the efficacy of ursodeoxycholic acid as adjunctive therapy in type 1 autoimmune hepatitis , 37 patients who had experienced treatment failure , repeated relapse , or incomplete response were r and omized to ursodeoxycholic acid ( 13 - 15 mg/kg daily ) or placebo for 6 months in addition to their usual corticosteroid schedule . Serum aspartate transaminase ( 70 % vs. 31 % , P = .04 ) and alkaline phosphatase ( 47 % vs. 7 % , P = .02 ) levels improved more commonly in the 21 patients r and omized to ursodeoxycholic acid .  Mean serum levels , however , were similar before and after the treatment period . The frequency of dose reduction or corticosteroid withdrawal was comparable in both groups ( 29 % versus 31 % , P > .9 ) , and clinical improvement ( 48 % vs. 44 % , P > .9 ) or its absence ( 52 % vs. 56 % , P > .9 ) occurred as commonly in patients receiving ursodeoxycholic acid or placebo . The modified histological activity score ( 3.5 + /- 0.8 vs. 3 . 5 + /- 0.9 ) and the modified fibrosis score ( 2.4 + /- 0.4 vs. 2.4 + /- 0.4 ) were similar before and after treatment with ursodeoxycholic acid and no different than after placebo therapy . We conclude that ursodeoxycholic acid can improve certain laboratory tests in problematic patients with type 1 autoimmune hepatitis when administered adjunctively for 6 months . Short-term therapy , however , does not facilitate reduction in the dose of corticosteroids or its withdrawal , affect clinical outcome , or reduce histological activity Effects of specific dietary alterations in patients with radiolucent gallstones treated with ursodeoxycholic acid ( UDCA , 750 mg at bedtime ) were investigated . Patients were allocated r and omly to one of four diets : st and ard ( 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 st and ard 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 44 patients with radiolucent gallstones in gallbladders visible on cholecystography were r and omly 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 st and ard liver-function tests . These results indicate that ursodeoxycholic acid , the 7beta epimer of chenodeoxycholic acid , is effective in the dissolution of cholesterol gallstones 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 exp and ed 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 acid . The results of the study are also consistent with the view that ursodeoxycholic acid is cholelitholytic at a lower dose than is chenodeoxycholic 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 r and omly 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 OBJECTIVE Nonalcoholic fatty liver disease is an increasingly recognized condition that may progress to end-stage liver disease . We investigated the effects of weight reduction and ursodeoxycholic acid administration in patients with this disease . RESEARCH METHODS AND PROCEDURES A double-blind , placebo-controlled trial . Twenty-seven women with a body mass index of > 30 kg/m2 and willing to participate in the diet plan for six weeks were studied were assigned to one of two treatment groups ( ursodeoxycholic acid , n = 14 : placebo n = 13 ) . Both groups received a normal diet ( 1,200 kcal/d ) plus 1200 mg/d of ursodeoxycholic acid or placebo .  Hepatic steatosis , was assessed by abdominal ultrasound . Fasting glucose , cholesterol , triglycerides , and aminotransferases levels were determined before and after treatment . RESULTS Body mass index decreases significantly from 34.2 + /- 4.2 kg/m2 and 33.3 + /- 1.6 kg/m2 to 31.8 + /- 4.5 kg/m2 and 30.6 + /- 2.6 kg/m2 in the ursodeoxycholic acid and placebo groups , p < 0.001 . The hepatic steatosis index decreased from 2.3 + /- 0.7 to 1.0 + /- 0.6 and 2.2 + /- 0.7 to 1.1 + /- 0.7 in the ursodeoxycholic acid and placebo groups , p<0.003 . Serum AST decreased significantly from 41.2 + /- 5.6 to 34.5 + /- 3.4 in the ursodeoxycholic acid group , p < 0.001 , and from 43.6 + /- 4.2 to 35.3 + /- 2.9 in the placebo group , p < 0.001 . Serum ALT decreased from 62.9 + /- 6.5 to 44.0 + /- 3.5 in the ursodeoxycholic acid group , p < 0.001 , and from 63.5 + /- 4.5 to 44.0 + /- 3.5 in the placebo group . We did not find any differences in all variables studied between groups . CONCLUSIONS The present study shows beneficial effect of weight reduction , producing improvements in biochemical and imaging markers of liver disease To test the effectiveness of ursodeoxycholic acid as a gallstone dissolving agent , doses of 250 mg/day and 1000 mg/day were administered for 1 year to two groups of 10 and 11 subjects each . Success was defined as a reduction in stone size and number of 50 % or more . Both groups of subjects were similar when comparing age , height , weight , gallstone size , and number although more men were enrolled in the high-dose treatment group . After 1 yr of high-dose ursodeoxycholic acid , successful treatment occurred in 70 % of subjects associated with a rise in biliary ursodeoxycholic acid  ( 1.7 to 51 % ) and a decline in the proportions of cholic acid ( 36 to 16 % ) , deoxycholic acid ( 19 to 10 % ) , chenodeoxycholic acid ( 41 to 23 % ) , and lithocholic acid ( 1.9 to 0.4 % ) . The mean cholesterol saturation index decreased from 1.5 to 0.7 and was accompanied by a 3.0-fold reduction in the activity of HMG CoA reductase ( 81 to 29 units ) in 2 subjects . With low-dose ursodeoxycholic acid , successful treatment occurred in 30 % of subjects accompanied by a rise in biliary ursodeoxycholic acid  to 29 % of total bile acids ; and a decline in deoxycholic acid ( 33 to 25 % ) , chenodeoxycholic acid ( 46 to 22 % ) , and lithocholic acid ( 4.0 to 2.4 % ) , while cholic acid ( 22 % ) did not change . The mean cholesterol saturation index fell from 1.9 to 1.2 . No untoward effects ( diarrhea or elevated serum transaminase levels ) were noted in either group . These results confirm that both high and low doses of ursodeoxycholic acid dissol ve gallstones in humans and were not associated with uncomfortable side effects . However , high doses of ursodeoxycholic acid were more effective and produced a greater reduction in the cholesterol saturation index , presumably by reducing hepatic cholesterol synthesis . Thus , the smallest effective dose of ursodeoxycholic acid probably lies between 250 mg and 1000 mg/day Gallstone disease is a major health problem throughout the Western world . Approximately 12 % of adults in the United States have gallstones [ 1 , 2 ] . Although most of these persons are asymptomatic [ 3 ] , more than 500 000 cholecystectomies are done yearly for treatment of symptomatic gallstones and associated complications [ 1 ] . Laparoscopic cholecystectomy has made it much easier to manage symptomatic patients , but the annual cost of caring for such patients exceeds $ 5 billion [ 1 ] . Preventing gallstones from forming is therefore an important goal . The development of cholesterol gallstones is associated with certain well-defined risk factors [ 1 , 4 - 6 ] . For most adults , the most important of these factors appear to be obesity and active weight reduction . Several studies have clearly shown that the risk for gallstones increases stepwise with increasing body weight [ 7 - 11 ] . The prevalence of gallstones is two- to threefold greater in persons who weigh as little as 20 % more than their ideal body weight and as much as eightfold greater in patients who exceed their ideal body weight by twofold or more [ 7 - 9 ] . The risk for developing gallstones during active weight reduction is also well accepted [ 9 - 17 ] . Ten percent to 25 % of persons having rapid weight reduction through very-low-calorie dieting develop gallstones [ 12 - 14 ] . In addition , 35 % of patients with morbid obesity develop gallstones as they lose weight after bariatric surgery [ 15 - 18 ] . Ursodeoxycholic acid is a bile salt that reduces cholesterol secretion into bile and improves biliary cholesterol solubility . It is used to dissolve cholesterol gallstones [ 19 - 22 ] . Its properties have led to the hypothesis that it could prevent the formation of cholesterol gallstones in certain high-risk population s. Two previous studies showed that ursodeoxycholic acid could reduce the incidence of gallstone formation in persons participating in a very-low-calorie diet program [ 12 ] and after bariatric surgery [ 18 ] . These preliminary reports inspired two multicenter , r and omized , double-blind , placebo-controlled trials to determine the optimum dose at which ursodeoxycholic acid could prevent gallstone formation in patients having rapid weight reduction . We evaluated approximately 1000 patients participating in a very-low-calorie liquid protein diet program .  A similar study [ 23 ] done in parallel with ours evaluated the effects of ursodeoxycholic acid during weight reduction in more than 300 patients having proximal gastric bypass surgery at 10 surgical weight loss centers . Taken together , these studies clearly show that the prophylactic use of ursodeoxycholic acid is highly effective for the prevention of gallstone formation in patients having rapid weight reduction . Methods Patients We recruited patients from 31 Health Management Re sources -affiliated diet centers throughout the United States that agreed to collaborate in this trial . All patients at these centers were informed of the risk for gallstone formation while dieting and were asked whether they would participate in a study to prevent gallstone formation . To be accepted into this trial , all patients had to 1 ) have a body mass index of 38 kg or more ; 2 ) be between 18 and 70 years of age ; 3 ) be willing to participate in the Health Management Re sources very-low-calorie diet plan for 16 weeks ; and 4 ) have normal serum potassium and calcium levels . Women of childbearing age had to have a negative serum pregnancy test result . Patients were excluded from the study if they had any one the following : 1 ) previous cholecystectomy ; 2 ) gallstones or gallbladder sludge on ultrasonogram ; 3 ) hypersensitivity to bile acids or eggs ; 4 ) a history of hypothyroidism or the Cushing syndrome ; 5 ) an eating disorder or other psychological problem that would interfere with participation in the diet program ; 6 ) use of oral bile salt preparations , aluminum-based antacids , or lithium ; 7 ) long-term use of nonsteroidal anti-inflammatory agents ( including aspirin ) or antihyperlipidemic agents [ including cholestyramine ] within 2 weeks of entering into the trial ; and 8) a total bilirubin level of more than 2.0 mg/dL , a serum creatinine level of more than 2.0 mg/dL , or an alanine aminotransferase level of more than 133 kat/L.  Diuretic therapy had to be discontinued at least 1 day before trial entry . A total of 1004 consecutive patients who met all entry criteria and agreed to participate were enrolled in the trial . The study was approved by the human investigations review committee at each of the participating centers and by the medical review boards of Health Management Re sources , Inc. , and Ciba-Geigy Pharmaceutical Company . Informed consent was obtained from all participants before study entry . Study Design If a patient met all entry criteria and agreed to participate in the study , a baseline ultrasonogram of the gallbladder was obtained and all exclusion criteria were review ed . If gallstones , gallbladder sludge , or both were identified , or if any other exclusion criteria were present , the patient was not entered into the trial . All other patients were entered into the study and r and omly assigned to receive either placebo , 300 mg of ursodeoxycholic acid once daily , 600 mg of ursodeoxycholic acid in two divided doses daily , or 1200 mg of ursodeoxycholic acid in two divided doses daily . Blocks of four patients at each of the 31 centers were used in the r and omization . Treatment groups were blinded using a double-dummy technique . All patients were provided with two coded medication bottles ( one for the morning and one for the evening ) ; each bottle contained either placebo or ursodeoxycholic acid in capsules that were identical in appearance . Patients were instructed to take two pills from the morning bottle and two pills from the evening bottle daily . Thus , each patient took two capsules twice daily . Each patient began taking coded medication on the first day that he or she began the Health Management Re sources diet plan and continued to take it throughout the entire 16-week program . The Health Management Re sources diet was a 520-kcal/d liquid protein diet containing 50 g of protein , 79 g of carbohydrate , and 1 to 3 g of fat ( depending on the particular preparation selected ) . All patients consumed this diet 3 to 5 times daily for 16 weeks and were instructed not to consume any other food . Supplements providing 100 % to 150 % of the U.S. recommended daily allowance of vitamins and minerals were supplied for each patient . Consumption of noncaloric fluids ( water and diet or club sodas ) was not limited . Each patient was evaluated biweekly throughout the study . At each visit , body weight and all adverse experiences that had occurred since the previous visit were recorded . Patients were instructed to return all medication bottles and unused medications to their study center . Compliance with study medication was assessed by pill count . Gallbladder ultrasonography was repeated after 8 weeks of dieting and after 16 weeks of dieting or termination from the trial , or both . Gallstones and gallbladder sludge were defined using st and ard and well-accepted criteria [ 24 ] . Radiologists from each of the 31 participating centers met and agreed to these criteria before the start of the study . Although the radiologists were aware that the patients were participants in this study , they were blinded to the particular group to which each patient had been assigned . The reading of the radiologist at each site was considered final , and these findings were not review ed by a single central radiologist . If a patient was found to have developed one or more gallstones , his or her participation in the trial was complete . No further weight loss data were collected from these patients as part of the trial . Gallbladder sludge was not considered a primary end point . Patients who developed sludge were informed of this and were continued in the trial . Bile Analysis Thirty-two patients from a single Health Management Re sources center ( Austin Diagnostic Center , Austin , Texas ) volunteered to participate in bile analysis . Each of these patients had endoscopy to obtain  bile  for analysis before starting the diet and at the completion of the trial . All patients had routine upper endoscopy while under conscious sedation ( midazolam , 2 mg to 4 mg ) in the morning , after an overnight fast . The tip of the endoscope was advanced into the second portion of the duodenum , and the ampulla of Vater was visualized . An intravenous dose of sincalide ( Kinevac , 0.02 to 0.06 g/kg ) was then administered to stimulate gallbladder contraction . As bile entered the duodenum , it was aspirated through the suction port of the endoscope and collected . Bile sample s were immediately centrifuged at 25 000 g for 30 minutes , and a sample of the sediment was examined for cholesterol crystals with a polarizing microscope ( magnification , 400 ) . The supernatant was frozen for later analysis by the primary investigator . All bile sample s were thawed and analyzed as a single batch . Total phospholipid levels were determined by the method of Bartlett [ 25 ] . Cholesterol was determined in whole bile after appropriate dilution with an assay kit ( Sigma Chemical Co. , St. Louis , Missouri ) . The bile salt composition of each bile sample was determined using reverse-phase , high-performance liquid chromatography in a Waters model 600 system ( Waters Chromatography , Milford , Massachusetts ) as described previously [ 26 ] . The percentage of total bile acids that were conjugates of ursodeoxycholic acid ( tauro-plus glyco- ) was assessed . The cholesterol saturation index of each bile sample was calculated from tables developed by Carey [ 27 ] using the computer program of Kuroki and colleagues [ 28 ] . Four patients did not have enough bile collected to allow paired analysis of cholesterol saturation and assessment of the percentage of ursodeoxycholic acid . Statistical Analysis The Ciba-Geigy Pharmaceutical Company was responsible for overseeing data collection and data analysis . Based on uncontrolled observations , we have proposed ursodeoxycholic acid ( UDCA ) as a novel therapeutic approach in primary biliary cirrhosis ( PBC ) . To confirm and extend our original findings , we have design ed a double-blind multicentre r and omized clinical trial . An interim analysis was planned at 6 months , involving all subjects included in the trial , with a final analysis at 2 years . The  UDCA-PBC trial began in June 1987 and will be completed in March 1990 . Seventy patients were r and omized to receive UDCA and 68 a placebo .  The two groups were well matched with respect to age , sex , duration and prevalence of symptoms and histologic severity ( 50 % of the UDCA group had stage III-IV disease vs. 37 % of the placebo group ) . During the first 6 months of follow-up , six patients withdrew from the trial . At 6 months , the proportion of patients with jaundice was significantly lower ( p less than 0.01 ) in UDCA recipients than in the placebo group . There was a similar decrease in the proportion of patients with pruritus and fatigue in both groups . The following laboratory test values were significantly lower in UDCA recipients than in the placebo group after 6 months of therapy : serum bilirubin , alkaline phosphatase , alanine aminotransferase ( ALAT ) , aspartate aminotransferase ( ASAT ) , gamma-glutamyltranspeptidase activities ( p less than 0.001 ) , cholesterol ( p less than 0.003 ) and IgM levels ( p less than 0.03 ) . The results of this interim analysis confirm and extend the biochemical data provided by our previous pilot study . However the final analysis of the trial is necessary for a definitive assessment of the safety and efficacy of UDCA therapy in PBC A r and omised placebo controlled study was performed in 32 women with intrdhepatic cholestasis of pregnancy . The population was divided into four groups : for 20 days each group was treated only with ursodeoxycholic acid , or S‐adenosylmethionine , or a combination of both drugs , or a placebo ( vitamin )  . Itching , st and ard liver function tests and serum total bile acids were measured before , during , and after treatment . Itching improved in all the women as well as the biochemical abnormalities . No side‐effects in the mother or in the infant were recorded during and after therapy . A combination of ursodeoxycholic acid and S‐adenosylmethionine is more effective than placebo and than either drug alone Ratios of cholestanol , campesterol , and sitosterol to cholesterol in serum are known to reflect cholesterol absorption efficiency . Here , a possible link between these ratios and biliary secretion rates of cholesterol was investigated . Biliary lipid secretion rates and serum sterols were determined in 13 patients with gallstones . Seven were treated with ursodeoxycholic acid ( UDCA ) ( 1,000 mg/d ) . Serum cholesterol and non-cholesterol sterols were also measured in a cross over study in 20 healthy volunteers , who received either placebo or UDCA ( 750 mg/d ) .  Biliary cholesterol secretion was significantly lower , whereas the non-cholesterol sterols and their ratio to cholesterol were higher in patients with gallstones treated with UDCA .  A highly significant negative linear correlation between the ratios of non-cholesterol sterols to cholesterol and biliary cholesterol secretion was observed . In volunteers , administration of UDCA for 4 weeks was followed by a significant increase in non-cholesterol sterols and their ratios . Even 4 weeks after discontinuing UDCA administration , campesterol and sitosterol were still significantly higher than pretreatment levels , which was also true for the campesterol-cholesterol ratio after 8 weeks . The results suggest that the ratios of cholestanol , campesterol , and sitosterol to cholesterol can be used as indicators of changes in biliary cholesterol secretion rates
In the subgroup of patients with primary biliary cirrhosis  , ursodeoxycholic acid  reduced total cholesterol ( WMD : − 29.86 mg/dL , 95 % CI : -47.39 , − 12.33 , p = 0.001 ) and LDL-C ( WMD : -37.27 mg/dL , 95 % CI : -54.16 , − 20.38 , p < 0.001 ) concentrations without affecting TG and HDL-C. Conclusion This meta- analysis suggests that ursodeoxycholic acid therapy might be associated with significant total cholesterol lowering particularly in patients with primary biliary cirrhosis
Objective The aim of this meta- analysis of r and omized placebo-controlled trials was to examine whether ursodeoxycholic acid treatment is an effective lipid-lowering agent .