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

Abstract

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

American association for the study of liver diseases endpoints conference: Design and endpoints for clinical trials in primary biliary cirrhosis

“…Published trials of medical therapy for PBC that have included assessment of interface hepatitis have confirmed the observation of Corpechot et al 24 that this lesion is refractory to reversal. 50,51 The French study further incorporated this histologic lesion into a Prognostic Score Index with equal value to elevated bilirubin and depressed albumin. Thus, inclusion of interface hepatitis would appear to be necessary in clinical trials.…”

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

“…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).…”

Brazilian society of hepatology recommendations for the diagnosis and management of autoimmune diseases of the liver

“…Compared to prednisolone, budesonide is 15-20 times more potent. Two randomized placebo-controlled trials compared UDCA/budesonide vs. UDCA/placebo in a total of 116 patients with PBC (159,160) . Both studies had a 2-year treatment duration.…”