In uncontrolled clinical studies, ursodeoxycholic acid (UDCA) had a beneficial effect on nonalcoholic steatohepatitis (NASH). However, a large controlled trial using UDCA (13-15 mg/ kg/day) was unable to confirm these results. Accordingly, a randomized, placebo-controlled study was initiated with a high dose of UDCA (23-28 mg/kg/day). The allocation of patients and the evaluation of liver histology were performed according to a modified Brunt score and the nonalcoholic fatty liver disease activity score (NAS). With the modified Brunt score, 185 patients with histologically proven NASH were randomized [intention to treat (ITT)], and 147 were treated per protocol (PP). With the NAS, 137 patients were confirmed to have NASH, 48 had borderline NASH, and 1 did not have NASH. The treatment time was 18 months. At entry, the treatment groups were comparable. A second biopsy sample was obtained from 139 of 185 patients (NAS: 107/137). The primary criterion for evaluation was a change in the liver histology; the secondary criteria were single histological variables and liver biochemistry. Significant differences in the overall histology could not be detected between the two treatment groups with the modified Brunt score (P 5 0.881) or NAS (P 5 0.355). Only lobular inflammation improved significantly (P for the modified Brunt score 5 0.011, P for NAS 5 0.005). In subgroup analyses, significant improvements in lobular inflammation were also observed in males, younger patients up to 50 years of age, slightly overweight patients, and patients with hypertension and an increased histology score. The fibrosis score did not change (P for ITT 5 0.133, P for PP 5 0.140). With the exception of cglutamyl transferase, UDCA did not improve laboratory data. Conclusion: High-dose UDCA failed to improve the overall histology in patients with NASH in comparison with placebo.

Though hepatic mitochondrial function might be impaired in patients with NASH, total beta-oxidation of octanoic acid remains normal. Gender-specific metabolic modifications seem to account for significant differences of the cumulative (13)CO(2) recovery in women and men. This may have further consequences for the appraisal of (13)C breath tests which involve octanoic acid. Further trials focusing on the assessment of body composition and energy expenditure could contribute essential further information.