ࡱ> PRO 0'bjbjqq D>ee-#####7778oD7 @ B B B B B B $m"%f #f ##{ xxx##@ x@ xx:,05 37: ,  0  %X%%#<xf f P( % :  HYPERLINK "http://www.medscape.com/viewarticle/569180_3" http://www.medscape.com/viewarticle/569180_3 The Medical Management of Primary Sclerosing Cholangitis: High-Dose UDCA HYPERLINK "javascript:newshowcontent('active','authordisclosures');"Authors and Disclosures HYPERLINK "http://www.medscape.com/viewarticle/569180"Abstract and Introduction HYPERLINK "http://www.medscape.com/viewarticle/569180_2"Ursodeoxycholic Acid High-Dose UDCA HYPERLINK "http://www.medscape.com/viewarticle/569180_4"UDCA Combined With Other Therapies HYPERLINK "http://www.medscape.com/viewarticle/569180_5"Other Therapies HYPERLINK "http://www.medscape.com/viewarticle/569180_6"Symptomatic Management of PSC HYPERLINK "http://www.medscape.com/viewarticle/569180_7"Conclusion HYPERLINK "javascript:newshowcontent('active','references');"References High-Dose UDCA Although UDCA was reported to improve liver enzyme levels in patients with PSC, the clinical benefits with respect to its effect on liver histology, symptoms, and radiologic appearance were not as clear. Therefore, it was hypothesized that higher doses of UDCA might be needed to see a beneficial effect on disease progression and survival. In this context, Harnois and colleagues HYPERLINK "javascript:newshowcontent('active','references');" [22] assessed the tolerability and effectiveness of high-dose UDCA (25-30 mg/kg/day) in a pilot study that enrolled 30 patients with PSC who were treated for 1 year. Changes in the Mayo risk score at 1 year of treatment and projected survival at 4 years of treatment were then compared with the results from the randomized, placebo-controlled trial conducted by Lindor HYPERLINK "javascript:newshowcontent('active','references');" [19] that examined the efficacy of 13 to 15 mg/kg/day of UDCA vs placebo. The higher-dose UDCA was well tolerated, was associated with improvement in liver biochemistries, and of particular interest, resulted in a significant improvement in the Mayo risk score after 1 year of treatment, which translated into a significant improvement in 4-year survival.HYPERLINK "javascript:newshowcontent('active','references');"[21] Compared with the findings from Lindor's study, the study by Harnois and coworkers found that the projected mortality rate was significantly higher among patients treated with placebo compared with patients who received high-dose UDCA (25-30 mg/kg/day), but no significant difference was found in the mortality rate between placebo and UDCA 13 to 15 mg/kg/day.HYPERLINK "javascript:newshowcontent('active','references');"[22] Despite the finding that UDCA dosed at 25 to 30 mg/kg/day had a positive effect in this study, Rost and colleagues HYPERLINK "javascript:newshowcontent('active','references');" [23] subsequently showed that biliary enrichment of UDCA actually reaches a plateau at 22 to 25 mg/kg/day, suggesting that such a high dose of UDCA (ie, 25-30 mg/kg/day) may not be needed regardless of whether it is well tolerated. These encouraging results with high-dose UDCA were also seen in a 2-year double-blind, placebo-controlled study conducted by Mitchell and colleagues HYPERLINK "javascript:newshowcontent('active','references');" [24] in which 26 patients with PSC were randomized to 20 mg/kg/day of UDCA or placebo. Similar to what was done in van Hoogstraten's study, cholangiography and liver biopsy were performed at study entry and after 2 years. Mitchell and coworkers found that while symptoms did not significantly improve with high-dose (20 mg/kg/day) UDCA, there was significant improvement in liver function tests (alkaline phosphatase, GGT) compared with placebo, and high-dose UDCA was well tolerated. However, of particular note, there was a significant reduction in liver fibrosis as assessed by staging, and in progression of cholangiographic appearance, in the high-dose UDCA group compared with placebo. In 2005, Olsson and colleagues HYPERLINK "javascript:newshowcontent('active','references');" [25] conducted a randomized, placebo-controlled study involving 219 patients with PSC to assess the efficacy of higher-dose UDCA (17-23 mg/kg/day) vs placebo. The primary study endpoints were death (mainly from liver failure or cholangiocarcinoma) or liver transplantation. They found that the use of higher-dose UDCA significantly improved liver biochemistries -- however, there was no difference between the 2 groups in terms of quality of life or symptoms. Additionally, although the combined endpoint of death or liver transplantation improved in the UDCA group compared with placebo, it did not reach statistical significance. The study authors did see a trend toward improved survival without liver transplantation in the UDCA-treated patients, but they determined that the study was underpowered to truly exclude a significant effect on survival. Overall, the higher-dose UDCA was well tolerated, but results revealed no significant beneficial effects on survival or prevention of cholangiocarcinoma in PSC. A large randomized, controlled trial of high-dose UDCA in patients with PSC currently in progress at the Mayo Clinic will hopefully help to address this issue more definitively. Some studies have also shown a beneficial effect associated with the use of UDCA on the incidence of colonic neoplasia and cholangiocarcinoma in patients with PSC. PSC is associated with a 10% to 20% lifetime risk for the development of cholangiocarcinoma, and patients with ulcerative colitis and PSC are at a higher risk for colonic dysplasia and colon cancer (0.5% to 1% per year of disease).HYPERLINK "javascript:newshowcontent('active','references');"[1,2,26,27] Studies have demonstrated that UDCA use is associated with a lower prevalence of colonic neoplasia in patients with PSC and concomitant ulcerative colitis.HYPERLINK "javascript:newshowcontent('active','references');"[26-28] Indeed, an experimental study in rats found that treatment with UDCA reduced hepatocarcinogenesis.HYPERLINK "javascript:newshowcontent('active','references');"[29] In a recent study, Rudolph and colleaguesHYPERLINK "javascript:newshowcontent('active','references');"[30] sought to examine the influence of UDCA on the incidence of cholangiocarcinoma in patients with PSC. From 1987 to 2005, 150 patients with PSC but without cholangiocarcinoma at entry were included in the study. Subjects were treated with UDCA that was gradually increased in dosage throughout the study (to 18-21 mg/kg/day), as higher doses seemed to show beneficial effects. Liver biochemistries significantly improved during treatment. The annual incidence of cholangiocarcinoma was 0.49%, which decreased with time of treatment to a point such that after 8.3 years of treatment with UDCA, no other patients developed cholangiocarcinoma. Overall, data supporting the use of UDCA in patients with PSC are encouraging. Low-dose (8-15 mg/kg/day) and high-dose UDCA have demonstrated clinical benefits in patients with PSC. However, a consensus has not been reached regarding whether treatment with UDCA can halt disease progression in PSC. HYPERLINK "javascript:newshowcontent('active','T1');"Table 1 , HYPERLINK "javascript:newshowcontent('active','T2');"Table 2 and HYPERLINK "javascript:newshowcontent('active','T3');"Table 3 summarize the results of studies assessing the clinical effects of UDCA in PSC. Anthony Michaels, MD, Gastroenterology Fellow, Division of Gastroenterology, Hepatology, and Nutrition, University of Florida - Gainesville Authors' email: HYPERLINK "mailto:Anthony.michaels@medicine.ufl.edu"Anthony.michaels@medicine.ufl.edu Cynthia Levy, MD, Clinical Assistant Professor, Division of Gastroenterology, Hepatology, and Nutrition, University of Florida - Gainesville, Malcolm Randall VA Medical Center, Gainesville, Florida Authors' email: HYPERLINK "mailto:levyc@medicine.ufl.edu"levyc@medicine.ufl.edu Disclosure: Anthony Michaels, MD, has disclosed no relevant financial relationships. Disclosure: Cynthia Levy, MD, has disclosed no relevant financial relationships.      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