Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis

Leuschner, M.; Güldütuna, S.; You, Tian; Hübner, K.; Bhatti, Susan; Leuschner, U.

doi:10.1016/s0168-8278(96)80327-8

Cited by 112 publications

(61 citation statements)

References 23 publications

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“…But almost 40% of PBC patients show incomplete clinical response to UDCA alone, and they are at high risk of severe disease (42). Preliminary trials have provided evidence for the combination of UDCA with glucocorticoids being promising for this subset of PBC patients, as it appears to relieve their cholestasis and liver histological alterations (10)(11)(12)(13)(14)(15). To investigate the mechanisms involved in this benefit, we focused on the effects of such a combined therapy in the liver expression of AE2 gene and carried out both in vitro and in vivo experiments.…”

Section: Discussionmentioning

confidence: 99%

“…When adequate UDCA therapy - i.e., daily administration of high doses of this hydrophilic bile acid - is initiated at early stages (I-II) of the disease, about 60% of PBC patients normalize their biochemical parameters and reach a survival comparable to that in the general population (8,9). There are reports suggesting that the remaining patients who exhibit a suboptimal response to UDCA alone may experience some benefit when UDCA therapy is combined with glucocorticoids (10)(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

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Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells

Arenas¹,

Hervías²,

Úriz³

et al. 2008

J. Clin. Invest.

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Primary biliary cirrhosis (PBC) is a cholestatic disease associated with autoimmune phenomena and alterations in both biliary bicarbonate excretion and expression of the bicarbonate carrier AE2. The bile acid ursodeoxycholic acid (UCDA) is currently used in treatment of cholestatic liver diseases and is the treatment of choice in PBC; however, a subset of PBC patients respond poorly to UDCA monotherapy. In these patients, a combination of UDCA and glucocorticoid therapy appears to be beneficial. To address the mechanism of this benefit, we analyzed the effects of UDCA and dexamethasone on AE2 gene expression in human liver cells from hepatocyte and cholangiocyte lineages. The combination of UDCA and dexamethasone, but not UDCA or dexamethasone alone, increased the expression of liver-enriched alternative mRNA isoforms AE2b1 and AE2b2 and enhanced AE2 activity. Similar effects were obtained after replacing UDCA with UDCA conjugates. In in vitro and in vivo reporter assays, we found that a UDCA/dexamethasone combination upregulated human AE2 alternate overlapping promoter sequences from which AE2b1 and AE2b2 are expressed. In chromatin immunoprecipitation assays, we demonstrated that combination UCDA/dexamethasone treatment induced p300-related interactions between HNF1 and glucocorticoid receptor on the AE2 alternate promoter. Our data provide a potential molecular explanation for the beneficial effects of the combination of UDCA and glucocorticoids in PBC patients with inadequate response to UDCA monotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells

Arenas¹,

Hervías²,

Úriz³

et al. 2008

J. Clin. Invest.

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“…So far, three classes of drugs have been tested in combination with UDCA: colchicine, [13][14][15][16] methotrexate, [17][18][19][20] and corticosteroids. [21][22][23][24] Briefly, 1) the benefit of colchicine appeared to be marginal or absent in UDCA-treated patients;…”

Section: Discussionmentioning

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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“…8 Combination of prednisolone with UDCA has improved liver histology but at the cost of serious glucocorticoid-dependent side effects. 9 For the moment, UDCA has remained the only approved medical therapy for PBC.Budesonide is a nonhalogenated glucocorticoid absorbed in the small intestine. Of an oral dose, 90% is metabolized during the first liver pass in healthy individuals.…”

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confidence: 99%

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confidence: 99%

Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: A three-year randomized trial

et al. 2005

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Ursodeoxycholic acid (UDCA) is a safe medical therapy for primary biliary cirrhosis (PBC), but its effect on liver histology remains uncertain. Budesonide is a glucocorticoid with high receptor activity and high first-pass metabolism in liver. We evaluated the combination of budesonide and UDCA on liver histology and compared this with UDCA alone in a 3-year prospective, randomized, open multicenter study. Patients with PBC (n ‫؍‬ 77), at stages I to III, were randomized into 2 treatment arms, A (n ‫؍‬ 41): budesonide 6 mg/d and UDCA 15 mg/kg/d and B (n ‫؍‬ 36): UDCA 15mg/kg/d. Liver histology was assessed at the beginning and at the end of the study. Liver function tests and glucose and cortisol values were determined every 4 months. Paired liver biopsy specimens were available from 69 patients (A ‫؍‬ 37 and B ‫؍‬ 32). Stage improved 22% in group A but deteriorated 20% in group B (P ‫؍‬ .009). Fibrosis decreased 25% in group A but increased 70% in group B (P ‫؍‬ .0009). S-PIIINP decreased significantly in group A. Inflammation decreased in both groups, 34% in group A (P ‫؍‬ .02), but only 10% in group B (P ‫؍‬ NS). Serum liver enzymes decreased significantly in both treatment arms. Bilirubin values rose in group B but stayed stable in group A (A/B P ‫؍‬ .002). A mild systemic glucocorticoid effect from budesonide was evident after 2 years. In conclusion, budesonide combined with UDCA improved liver histology, whereas the effect of UDCA alone was mainly on laboratory values. Studies with longer follow-up using a combination of budesonide and UDCA are warranted to confirm safety and effects. (HEPATOLOGY 2005;41:747-752.) P rimary biliary cirrhosis (PBC) is a chronic cholestatic autoimmune liver disease of unknown etiology characterized by small bile-duct destruction, which may eventually progress to hepatic fibrosis, biliary cirrhosis, and liver failure. 1 Ursodeoxycholic acid (UDCA) is a safe medical therapy widely used in the treatment of PBC. Although it has been shown to improve biochemical markers in PBC, 2,3 two recent metaanalyses 4,5 and a Cochrane review 6 showed controversial results concerning its effect on liver histology and patient survival. The latest combined analysis of 4 placebo-controlled UDCA studies showed histological benefit in stages I to II, but the rate of progression was not significantly lower in the UDCA group in stages I to III. 7 A recent 12-year prospective randomized study of UDCA was unable to show any demonstrable effect on long-term outcome of PBC. 8 Combination of prednisolone with UDCA has improved liver histology but at the cost of serious glucocorticoid-dependent side effects. 9 For the moment, UDCA has remained the only approved medical therapy for PBC.Budesonide is a nonhalogenated glucocorticoid absorbed in the small intestine. Of an oral dose, 90% is metabolized during the first liver pass in healthy individuals. After hepatic uptake, budesonide is metabolized to two major metabolites: 16␣-hydroxy-prednisolone and 6␤-hydroxy-budesonide. Glucocorticoid activity of these

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Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis

Cited by 112 publications

References 23 publications

Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells

Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells

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

Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: A three-year randomized trial

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