A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis

Combes, Burton; Carithers, Robert L.; Maddrey, Willis C.; Lin, Danyu; McDonald, Mary F.; Wheeler, Donald E.; Eigenbrodt, Edwin H.; Muñoz, Santiago J.; Rubin, Raphael; García–Tsao, Guadalupe; Bonner, Gregory F.; West, A. Brian; Boyer, James L.; Luketic, Velimir A.; Shiffman, Mitchell L.; Mills, A. Scott; Peters, Marion G.; White, H.M.; Zetterman, Rowen K.; Rossi, Stephen S.; Hofmann, Alan F.; Markin, Rodney S.

doi:10.1002/hep.1840220311

Cited by 96 publications

(125 citation statements)

References 8 publications

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“…UDCA has been shown to improve liver function tests, liver histology, and survival in primary biliary cirrhosis, [1][2][3][4][5][6] and similar effects have been observed in other cholestatic diseases. [7][8][9][10][11][12][23][24][25] The mechanism of action of UDCA in hepatobiliary diseases is still not completely understood.…”

Section: Discussionmentioning

confidence: 61%

“…In primary biliary cirrhosis, UDCA treatment slows progression of the disease and improves survival. [1][2][3][4][5][6] In primary sclerosing cholangitis (PSC), UDCA improves laboratory parameters, [7][8][9][10][11][12] and its effect on the outcome is currently being evaluated. There is evidence 11,12 that high doses (Ն20 mg/kg/d) of UDCA may be more effective than average doses (15 mg/kg/d).…”

mentioning

confidence: 99%

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Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

et al. 2004

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Ursodeoxycholic acid (UDCA) has beneficial effects in cholestatic liver diseases. In primary sclerosing cholangitis (PSC), there is evidence that high doses (؎20 mg/kg) of UDCA may be more effective than average doses. Biliary enrichment of UDCA at such high doses may represent the decisive factor for its beneficial effect. Up to now it is not clear how high-dose UDCA correlates with its biliary enrichment and whether bacterial degradation of large amounts of UDCA may lead to an increased bacterial formation of more toxic hydrophobic bile acids. We determined the biliary bile acid composition in 56 patients with PSC including 30 patients with repeat bile samples treated with various doses of UDCA. At a UDCA dose of 10 -13 mg/kg/d (n ‫؍‬ 18) biliary UDCA represented 43.1% ؉ 0.3% (mean ؉ SD) of total bile acids; at a UDCA dose of 14 -17 mg/kg (n ‫؍‬ 14), its biliary content increased to 46.9% ؉ 0.3%, at 18 -21 mg/kg (n ‫؍‬ 34) to 55.9% ؉ 0.2%, at 22-25 mg/kg (n ‫؍‬ 12) to 58.6% ؉ 2.3%, and at 26 -32 mg/kg (n ‫؍‬ 8) to 57.7% ؉ 0.4%. During UDCA treatment, the biliary content of all other bile acids was unchanged or decreased. In conclusion, biliary enrichment of UDCA increases with increasing dose and reaches a plateau at 22-25 mg/kg. There was no increase of toxic hydrophobic bile acids. If biliary enrichment of UDCA represents the decisive factor for its clinical effect, it seems likely that UDCA doses of up to 22-25 mg/kg may be more effective than lower doses. (HEPATOLOGY 2004;40:693-698.)

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Section: Discussionmentioning

confidence: 61%

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confidence: 99%

Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

et al. 2004

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“…63 However, the combined analysis of the other 3 large studies does not suggest that this is the case. 64 In fact, the greatest benefit is seen in those with the most severe disease, because predictably, more events were observed in patients with severe rather than with mild disease.…”

Section: Ursodeoxycholic Acid Therapymentioning

confidence: 96%

“…60 There have been many randomized controlled trials of UDCA in PBC and all included both asymptomatic and symptomatic patients. There have been 4 large trials, 32,[61][62][63] and the raw data from 3 of these trials have been combined as each used the same formulation of UDCA in the same dose, i.e., 13 to 15 mg/kg/d. 64 The analysis of these data collected from 548 patients shows that UDCA therapy leads to a significant increase in survival after up to 4 years of therapy, as judged by time to liver transplantation.…”

Section: Ursodeoxycholic Acid Therapymentioning

confidence: 99%

Management of primary biliary cirrhosis

2000

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Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver, which predominantly affects women once over the age of 20 years. Most cases are diagnosed when asymptomatic (60%). The antimitochondrial antibody is present in serum in most, but not in all, patients with PBC. The disease generally progresses slowly but survival is less than an age-and gender-matched general population. The symptomatic patient may have fatigue, generalized pruritus, portal hypertension, osteoporosis, skin xanthomata, fat soluble vitamin deficiencies, and/or recurrent asymptomatic urinary tract infections. Many nonhepatic autoimmune diseases are found in association with PBC and may prompt initial presentation. To date, immunosuppressive therapy has not been shown to prolong survival in PBC. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been shown when given in a dose of 13 to 15 mg/kg daily for up to 4 years to delay the time to liver transplantation or death. This therapy also causes a significant improvement of all the biochemical markers of cholestasis but has no beneficial effects on any of the symptoms or associated disorders. Treatment with UDCA does not obviate the need for liver transplantation. Therapies to prevent complications arising from malabsorption, portal hypertension, and/or osteoporosis are required as well. Good control of pruritus can be achieved in most patients. PBC is diagnosed with increasing frequency, but the agent(s) responsible for this slowly progressive destruction of the interlobular bile ducts remains elusive and hence a specific therapy remains unavailable. (HEPATOLOGY 2000;31:1005-1013.) PREAMBLE

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“…[1][2][3][4] In addition, a combined analysis, pooling 548 patients involved in three large trials using a similar dose of UDCA, has demonstrated that 4-year UDCA therapy increases survival free of orthotopic liver transplantation (OLT). 5 In untreated patients with PBC, elevated levels of serum bilirubin level (SBL) have been consistently found to be an independent predictor of a poor prognosis.…”

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confidence: 99%

Clinical significance of serum bilirubin levels under ursodeoxycholic acid therapy in patients with primary biliary cirrhosis

Bonnand

et al. 1999

Hepatology

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We determined whether the normalization of serum bilirubin level (SBL) induced by ursodeoxycholic acid (UDCA) therapy was associated with an improved clinical outcome in patients with primary biliary cirrhosis (PBC). We estimated the prognostic values of SBL measured after 6 months of UDCA treatment for survival free of orthotopic liver transplantation (OLT). We used a database of 548 patients with PBC followed in three trials of UDCA. Among UDCA-treated patients, we compared survival free of OLT in patients with normalized SBL (I17 mol/L) with those who had persistently elevated SBL. Difference in survival was tested between UDCA-treated patients whose SBL normalized with treatment and placebo patients who had normal baseline SBL. We evaluated, in each treatment group, the prognostic value of 6-month SBL. Survival was estimated using the Kaplan-Meier method and compared by the Cox model. Survival free of OLT was significantly longer in patients who had normalized SBL (P F .0001; relative risk [RR]: 3.7, UDCA group). Survival free of OLT was not significantly different between UDCA patients with normalized SBL and placebo patients with a normal baseline SBL (P ‫؍‬ .69). For several cutoffs of 6-month SBL, RRs of OLT or death were similar in UDCA-treated and placebo patients: the RR of OLT or death associated with a 6-month SBL more than 30 mol/L was 6.0 for UDCA and 5.7 for placebo groups. In conclusion, normalization of SBL during therapy is associated with improved clinical outcome. SBL under UDCA therapy is a prognostic factor in PBC. SBL under UDCA therapy should be interpreted as in untreated patients. (HEPATOLOGY 1999;29:39-43.)

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A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis

Cited by 96 publications

References 8 publications

Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

Management of primary biliary cirrhosis

Clinical significance of serum bilirubin levels under ursodeoxycholic acid therapy in patients with primary biliary cirrhosis

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