No 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

No effective medical therapy is currently available for primary sclerosing cholangitis (PSC). Ursodeoxycholic acid (UDCA) improves liver enzymes, but its effect on liver histology is controversial. Metronidazole (MTZ) prevents PSC-like liver damage in animal models and reduces intestinal permeability. We recruited 80 patients with PSC into a randomized placebo-controlled study to evaluate the effect of UDCA and MTZ (UDCA/MTZ) compared with UDCA/placebo on the progression of PSC. Patients (41 UDCA/placebo and 39 UDCA/ MTZ) were followed every third month. Assessment of liver function test, histological stage and grade, and cholangiography (via ERCP) at baseline showed no differences between the groups. After 36 months, serum aminotransferases ␥-glutamyltransferase, and alkaline phosphatase (ALP) decreased markedly in both groups, serum ALP more significantly in the UDCA/MTZ group (؊337 ؎ 54 U/L, P < .05) compared with the UDCA/placebo group. The New Mayo Risk Score decreased markedly only in the UDCA/MTZ group (؊0.50 ؎ 0.13, P < .01). The number of patients with improvement of stage (P < .05) and grade (P < .05) was higher in the combination group. ERCP findings showed no progression or improvement in 77% and 68% of patients on UDCA/MTZ and UDCA/placebo, respectively. In conclusion, combining MTZ with UDCA in PSC improved serum ALP levels and New Mayo Risk Score, but no statistically significant effect on disease progression as assessed via liver histology or ERCP was seen. Long-term studies using a higher dose of UDCA combined with MTZ in larger patient populations are indicated. (HEPATOLOGY 2004;40:1379 -1386

SUMMARY Background/aimTo evaluate the safety of budesonide in primary biliary cirrhosis.

Background-It has been suggested that phospholipase A2 (PLA2) has an essential role in the pathogenesis of inflammatory bowel diseases.