Prospective Clinical Trial of Rifaximin Therapy for Patients With Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease in which emerging data suggest that oral antibiotics may offer therapeutic effects. We enrolled patients with PSC in a 12-week, open-label pilot study to investigate the efficacy and safety of 550 mg of oral rifaximin twice daily. The primary end point was serum alkaline phosphatase (ALK) at 12 weeks. Secondary end points included (1) serum bilirubin, gamma-glutamyl transpeptidase, and Mayo PSC risk score; (2) fatigue impact scale, chronic liver disease questionnaire, and short form health survey (SF-36) scores; and (3) adverse effects (AEs). Analyses were performed with nonparametric tests. Sixteen patients were enrolled, among whom the median age was 40 years; 13 (81%) were male, 13 had inflammatory bowel disease, and baseline ALK was 342 IU/mL (interquartile range, 275-520 IU/mL). After 12 weeks of treatment, there were no significant changes in ALK (median increase of 0.9% to 345 IU/mL; P = 0.47) or any of the secondary biochemical end points (all P > 0.05). Similarly, there were no significant changes in fatigue impact scale, chronic liver disease questionnaire, or SF-36 scores (all P > 0.05). Three patients withdrew from the study due to AEs; 4 others reported mild AEs but completed the study. In conclusion, although some antibiotics may have promise in treating PSC, oral rifaximin, based on the results herein, seems inefficacious for this indication. Future studies are needed to understand how the antimicrobial spectra and other properties of antibiotics might determine their utility in treating PSC.

High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis.

OBJECTIVES: Some studies have suggested that ursodeoxycholic acid (UDCA) may have a chemopreventive effect on the development of colorectal neoplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We examined the effects of high-dose (28-30 mg/kg/day) UDCA on the development of colorectal neoplasia in patients with UC and PSC. METHODS: Patients with UC and PSC enrolled in a prior, multicenter randomized placebo-controlled trial of high-dose UDCA were evaluated for the development of colorectal neoplasia. Patients with UC and PSC who received UDCA were compared with those who received placebo. We reviewed the pathology and colonoscopy reports for the development of low-grade or high-grade dysplasia or colorectal cancer. RESULTS: Fifty-six subjects were followed for a total of 235 patient years. Baseline characteristics (including duration of PSC and UC, medications, patient age, family history of colorectal cancer, and smoking status) were similar for both the groups. Patients who received high-dose UDCA had a significantly higher risk of developing colorectal neoplasia (dysplasia and cancer) during the study compared with those who received placebo (hazard ratio: 4.44, 95% confidence interval: 1.30-20.10, P=0.02). CONCLUSIONS: Long-term use of high-dose UDCA is associated with an increased risk of colorectal neoplasia in patients with UC and PSC.

The predictors of the presence of varices in patients with primary sclerosing cholangitis.

UNLABELLED: The predictors for developing varices in patients with primary sclerosing cholangitis (PSC) have not been well studied prospectively. We sought to define the predictors for the presence of varices at baseline and for newly developing varices in patients with PSC. We used prospectively collected data from a multicenter randomized trial of high dose ursodeoxycholic acid for PSC. All 150 patients enrolled were reviewed for predictors of varices and we excluded 26 patients who had esophageal varices at baseline so that predictors of newly developing varices could be determined. Clinical examination, blood tests, and upper endoscopy were done before randomization, at 2 years and after 5 years. Liver biopsy was performed at entry and at 5 years. The median age (interquartile range) of patients was 45.9 years (35.8, 54.9). In a multivariable logistic regression, a higher Mayo risk score (> or =0.87) or a higher aspartate/alanine aminotransferase (AST/ALT) ratio (> or =1.12) were significantly associated with the presence of varices at initial endoscopy (odds ratio = 1.9 and 3.9). By the end of the study, 25 patients had new varices (20.2%). In a Cox model, after adjustment for baseline variables lower platelet count and higher total bilirubin at 2 years were significantly associated with the presence of new varices. The platelet count of 205 (x 10(9)/L) and the total bilirubin level of 1.7 mg/dL were the best cutoff values for the detection of new varices. CONCLUSION: A higher Mayo risk score and higher AST/ALT ratio were significantly associated with the presence of varices at initial endoscopy. Lower platelet count and higher total bilirubin at 2 years were significantly associated with an increased risk of developing new varices in patients with PSC.

High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis.

UNLABELLED: Previous controlled trials are inconclusive regarding the efficacy of ursodeoxycholic acid (UDCA) for treating primary sclerosing cholangitis (PSC). One hundred fifty adult patients with PSC were enrolled in a long-term, randomized, double-blind controlled trial of high-dose UDCA (28-30 mg/kg/day) versus placebo. Liver biopsy and cholangiography were performed before randomization and after 5 years. The primary outcome measures were development of cirrhosis, varices, cholangiocarcinoma, liver transplantation, or death. The study was terminated after 6 years due to futility. At enrollment, the UDCA (n = 76) and placebo (n = 74) groups were similar with respect to sex, age, duration of disease, serum aspartate aminotransferase and alkaline phosphatase levels, liver histology, and Mayo risk score. During therapy, aspartate aminotransferase and alkaline phosphatase levels decreased more in the UDCA group than the placebo group (P < 0.01), but improvements in liver tests were not associated with decreased endpoints. By the end of the study, 30 patients in the UDCA group (39%) versus 19 patients in the placebo group (26%) had reached one of the pre-established clinical endpoints. After adjustment for baseline stratification characteristics, the risk of a primary endpoint was 2.3 times greater for patients on UDCA than for those on placebo (P < 0.01) and 2.1 times greater for death, transplantation, or minimal listing criteria (P = 0.038). Serious adverse events were more common in the UDCA group than the placebo group (63% versus 37% [P < 0.01]). CONCLUSION: Long-term, high-dose UDCA therapy is associated with improvement in serum liver tests in PSC but does not improve survival and was associated with higher rates of serious adverse events.

A pilot trial of high-dose ursodeoxycholic acid in nonalcoholic steatohepatitis.

PURPOSE: Standard dose (13-15 mg/kg) ursodeoxycholic acid (UCDA) is ineffective in the treatment of nonalcoholic steatohepatitis (NASH), however, its immunomodulatory and hepatoprotective effects are dose related. Therefore, we examined the impact of high-dose (28-32 mg/kg) UCDA on aminotransaminase levels in a pilot study of patients with NASH. METHODS: Twelve patients with biopsy-proven NASH and elevated aminotransaminases were prescribed high-dose UCDA for 6 months. Liver function tests were monitored during and after treatment with the study endpoint defined as normalization of aminotransaminase levels. RESULTS: Normalization of aspartate aminotransaminase (AST) levels was observed in two (17%) patients, however, no patient normalized their alanine aminotransaminase (ALT) levels. A trend towards a minor reduction in median (range) ALT values from baseline to end of treatment was noted [124 (66-229) vs. 101 (53-188) IU/l, p = 0.07], whereas AST levels remained unchanged [85 (40-132) vs. 98 (28-147) IU/l, p = 0.83]. One patient discontinued treatment prematurely due to diarrhea. No significant change in fasting glucose, triglyceride or HDL cholesterol was observed with treatment. No significant change in ALT or AST levels was observed in the 6-month period after cessation of treatment. CONCLUSION: High-dose UCDA does not normalize aminotransaminase levels in patients with NASH. Other inexpensive well-tolerated agents for the treatment of NASH need to be investigated.

Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis.

Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC); however, marked variability in the incidence of CCA in PSC is reported. Furthermore, limited information exists on risk factors for the development of CCA in PSC. The aim of this study was to determine the incidence of CCA in patients with PSC and to evaluate baseline risk factors for the later development of CCA. From a previous study of the natural history of PSC, we identified 161 patients with PSC who did not have CCA at study entry. Patients were followed until a diagnosis of CCA was established, liver transplantation was performed, or death occurred. Patients were followed for a median of 11.5 yr (interquartile range 4.0-16.1 yr). Fifty-nine patients (36.6%) died, 50 patients (31.1%) underwent liver transplantation, and 11 patients (6.8%) developed CCA. The rate of CCA developing was approximately 0.6% per year. Compared to the incidence rates of CCA in the general population, the relative risk of CCA in PSC was significantly increased (RR = 1,560; 95%CI = 780, 2,793; p < 0.0001). On univariate analysis, a history of variceal bleeding (p < 0.001), proctocolectomy (p= 0.01), and lack of symptoms (p= 0.02) were significant risk factors for CCA with the Mayo Risk Score being marginally significant (p= 0.051). Multivariate analysis determined only variceal bleeding to be a significant risk factor for CCA (RR 24.2; 95%CI: 3.3-67.1). No association was found between the duration of PSC and the incidence of CCA. In conclusion, approximately 7% of PSC patients later developed CCA over a mean follow-up of 11.5 yr, which is dramatically higher than the rates in the general population. Variceal bleeding is a major risk factor for the later development of CCA.