High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial

Abstract

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.

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

“…(Strength -1, Quality -B) 22. Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis (Strength -1, Quality -C) Ursodeoxycholic acid (UDCA), Omega-3 fatty acids, and Miscellaneous Agents Several studies 126,[137][138][139][140] investigated UDCA (conventional and high doses) to improve aminotransferases and steatosis in patients with NAFLD and liver histology in patients with NASH. All but one study 139 have been proof-of-concept studies with small numbers of participants and/or surrogate endpoints.…”

Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials

“…Seven RCTs (639 participants, 21% diabetic; three RCTs with post-treatment histology, five RCTs with a low risk of bias) evaluated UDCA in NAFLD (ESM Table 5) [82][83][84][85][86][87][88].…”

EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease

“…Vitamin E may be used in non-cirrhotic non-diabetic NASH patients but further studies are needed before firm recommendations can be made. Ursodeoxycholic acid (UDCA) has been investigated in several RCTs, at different doses and for up to 2 years, but only showed some biochemical but no histological improvements [83,87,96].…”