Background: Ursodeoxycholic Acid (UDCA), at a dose of 13-15 mg/kg daily is the only recommended drug for patients with primary biliary cirrhosis (PBC). Recent meta-analysis point-out the need of a re-evaluation of the role of UDCA in PBC. One of the criticisms risen to UDCA therapy is the range of the dose (8-15 mg/Kg/day) since at this dosage UDCA doesn’t exceed 35-45 % of total biliary bile acids (BA). On the other hand, higher dosage (30 mg/Kg/day) of UDCA can produce up to 65-75% of biliary UDCA accumulation with a potentially higher activity for the higher enrichment of this poor detergent BA. The aim of our study is to evaluate the long-term effect (up to 12 years) of high dose UDCA on liver and bile biochemistry, and histology in a randomized open controlled study.

Methods: 40 non icteric PBC patients (I-II stage) have been randomized to receive high (H-UDCA;30 mg\Kg\day: 17 female and 3 male) or conventional UDCA dose (m-UDCA,15 mg\Kg\day: 18 female, and 2 males). Clinical and biochemical evaluations were performed twice per years. Liver biopsy was performed at baseline and after 6 years of treatment.

Results: Serum liver enzymes (ALT, AST, y-GT, ALP) and bilirubin significantly decreased in patients treated with H-UDCA compared to m-UDCA. Patients who normalized all the serum liver enzymes tests were defined “responders”, while patients who normalized only three parameters were defined “partial responders”. The other cases were considered “non-responder”. Among patients receiving H-UDCA, 85,7% were “responders” and 14,3% were “partial responders”. Instead, in the m-UDCA group, “responder”, “partial responder” and “non-responder” were respectively 23%, 35% and 42% (p<0.001). Biliary BA composition was significantly modified by the administration of both doses after 6 years of treatment. Total UDCA (glycol-UDCA + tauro-UDCA) become the predominant bile acids reaching value up to 70% in the H-UDCA group twice than the value reached in the m-UDCA group. UDCA and endogenous BA become almost conjugated with the glycine (G\T ratio 9-10) at both doses similarly to endogenous BA. Histological stage improved in 13 pts treated on H-UDCA dosage.

Conclusion: In PBC patients (stage I-II) high UDCA dosage seems to be more effective than conventional one on serum biochemistry and liver histology with a significant increased accumulation of UDCA in the enterohepatic circulation and bile suggesting that in early detection of the disease (stage I-II) high doses of UDCA might represent the ideal treatment without any major side effect. The extraordinary long-term result is represented by a steady state UDCA accumulation producing a less toxic and mild detergent bile facilitating the membrane cytotoxicity, recovery and patients improvement.