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.

The diagnostic value of anti-mitochondrial antibodies, especially in primary biliary cirrhosis.

Anti-mitochondrial antibodies (AMA) are present in sera of approximately 90-95% of patients with primary biliary cirrhosis (PBC) and, thus, constitute one of the most important diagnostic criteria for this disease. The major mitochondrial autoantigens have been identified, cloned, and sequenced and the immunological features of AMA, including their antigen specificities and epitopes, have been well characterized. In clinical laboratories, indirect immunofluorescence (IIF) microscopy is routinely employed for the detection of AMA mainly because of technical simplicity and cost effectiveness. However, IIF lacks both specificity and sensitivity, and in up to 10% of patients diagnosed with PBC based on standard diagnostic criteria, AMA cannot be detected by IIF. In some of these patients, AMA aredetectable by more sensitive techniques, such as enzyme-linked immunosorbent assays (ELISAs) or SDS-PAGE followed by immunoblotting. Nonetheless, there are patients whose sea are negative for AMA by any of these methods despite clinical, biochemical, and histological findings that are diagnostic for PBC. Some have argued that AMA-positive and AMA-negative PBC represent two distinct entities, but recent evidence supports the view that they are clinically and biochemically quite similar. The situation is further complicated by the fact that AMA, even those recognizing the major PBC autoantigens, are also present in a variety of other liver diseases. In addition, patients exhibiting the clinical, histological, and biochemical features of both PBC and autoimmune hepatitis, the so-called 'overlap syndrome,' are not uncommon. In conclusion, AMA status, though invaluable in establishing and confirming the diagnosis of PBC in > or =90% of PBC patients, is not sufficient by itself to allow the differential diagnosis of liver diseases. The choice of therapeutic regimen should, therefore, be based on a combination of serological, biochemical and histological findings, rather than AMA status alone.