Emmanouil Sinakos

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 (28–30u2009mg/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.

Bile acid changes after high-dose ursodeoxycholic acid treatment in primary sclerosing cholangitis: Relation to disease progression†

High‐dose (28‐30 mg/kg/day) ursodeoxycholic acid (UDCA) treatment improves serum liver tests in patients with primary sclerosing cholangitis (PSC) but does not improve survival and is associated with increased rates of serious adverse events. The mechanism for the latter undesired effect remains unclear. High‐dose UDCA could result in the production of hepatotoxic bile acids, such as lithocholic acid (LCA), because of limited small bowel absorption of UDCA and conversion of UDCA by bacteria in the colon. We determined the serum bile acid composition in 56 patients with PSC previously enrolled in a randomized, double‐blind controlled trial of high‐dose UDCA versus placebo. Samples for analysis were obtained at the baseline and at the end of treatment. The mean changes in the UDCA level (16.86 versus 0.05 μmol/L) and total bile acid level (17.21 versus −0.55 μmol/L) were significantly higher in the UDCA group (n = 29) versus the placebo group (n = 27) when pretreatment levels were compared (P < 0.0001). LCA was also markedly increased (0.22 versus 0.01 μmol/L) in the UDCA group compared to the placebo group (P = 0.001). No significant changes were detected for cholic acid, deoxycholic acid, or chenodeoxycholic acid. Patients (n = 9) in the UDCA group who reached clinical endpoints of disease progression (the development of cirrhosis, varices, liver transplantation, or death) tended to have greater increases in their posttreatment total bile acid levels (34.99 versus 9.21 μmol/L, P < 0.08) in comparison with those who did not. Conclusion: High‐dose UDCA treatment in PSC patients results in marked UDCA enrichment and significant expansion of the total serum bile acid pool, including LCA. HEPATOLOGY 2010

Many patients with primary sclerosing cholangitis and increased serum levels of carbohydrate antigen 19-9 do not have cholangiocarcinoma.

BACKGROUND & AIMSnPatients with primary sclerosing cholangitis (PSC) have an increased incidence of cholangiocarcinoma (CCA). Carbohydrate antigen 19-9 (CA 19-9) is the main serum marker used to diagnose CCA, although increased levels of CA 19-9 are also associated with other hepatic complications. We evaluated the long-term outcomes in patients with PSC and significant increases in levels of CA 19-9.nnnMETHODSnWe analyzed data from all Mayo Clinic patients with PSC and serum levels of CA 19-9 greater than 129 U/mL from 2000-2010 (n = 73). We reviewed patients records for CCA diagnosis, other malignancies, recurrent bacterial cholangitis, and persistent cholestasis.nnnRESULTSnThirty-seven percent of patients reviewed had no evidence of CCA after a median follow-up time of 30 months. The initial levels of CA 19-9 from patients without CCA were significantly lower than those from patients with CCA (286 vs 895 U/mL, P < .0001). At the start of the study, patients without CCA were more likely to have cirrhosis, compared with patients with CCA (48% vs 24%, P = .03), and lower levels of bilirubin (2 vs 6.8 mg/dL, P = .003), compared with patients with CCA. No factors known to affect CA 19-9 levels were identified in 33% of patients without CCA; endoscopic treatment and recurrent bacterial cholangitis were associated with levels of CA 19-9 in 26% and 22% of these patients, respectively.nnnCONCLUSIONSnThirty-seven percent of patients with PSC who have serum levels of CA 19-9 greater than 129 U/mL do not have CCA. Additional studies should be performed to determine the outcomes of these patients.

High dose ursodeoxycholic acid increases risk of adverse outcomes in patients with early stage primary sclerosing cholangitis

Aliment Pharmacol Ther 2011; 34: 1185–1192

Colon Neoplasms Develop Early in the Course of Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

BACKGROUND & AIMSnColon cancer surveillance guidelines for patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) suggest annual colonoscopy once the diagnosis of concomitant disease is made, but there is little evidence to support this recommendation. We conducted a retrospective review of patients with colonic neoplasms (colon cancer or dysplasia) to test this guidelines validity and determined when colonic neoplasms occurred in the population.nnnMETHODSnRecords were retrospectively reviewed from 54 patients with IBD, PSC, and colonic neoplasia for dates of diagnosis of IBD, PSC, and colon neoplasia and descriptive information about the colon neoplasms that developed.nnnRESULTSnThe occurrence of colon neoplasms within 2 years of diagnosis of IBD and PSC (21.5 per 100 patient years of follow-up) was similar to the occurrence within 8 to 10 years from diagnosis of IBD and PSC (20.4 per 100 patient years of follow-up). The colonic neoplasms that developed in this population were spread throughout the colon.nnnCONCLUSIONSnPatients with IBD and PSC have a risk of developing colonic neoplasms soon after the coexistence of the 2 diseases is discovered. This finding supports the current colon cancer surveillance guideline recommendations of yearly colonoscopies for this patient population, beginning at the time of diagnosis of PSC in patients with IBD or with the diagnosis of IBD in patients with PSC.

Optimizing biochemical markers as endpoints for clinical trials in primary biliary cirrhosis

Biochemical tests have been recommended as endpoints for clinical trials in primary biliary cirrhosis (PBC) because the use of liver transplantation and death as endpoints in ursodeoxycholic acid (UDCA) therapeutic trials is unfeasible. The best inclusion criteria cut‐off values and cut‐off for demonstrating treatment success have not been defined.

Pathogenesis and management of pruritus in cholestatic liver disease

Patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy commonly complain of pruritus. The underlying pathogenesis remains obscure with several mediators possibly playing an important role; these include lysophosphatidic acid, bile salts, opioids, histamine and progesterone metabolites. We describe in this review novel insights into the pathogenesis and management of pruritus in patients with cholestasis.

Varices in early histological stage primary biliary cirrhosis

Background/Goals Esophageal varices (EV) in early histological stages of primary biliary cirrhosis (PBC) have been recognized but not well defined. We sought to determine the prevalence, clinical characteristics, and predictors of EV in early-stage PBC, as well as to evaluate the effectiveness of recent guidelines regarding EV screening in PBC patients. Study We retrospectively reviewed the charts of 325 PBC patients who had undergone complete evaluation before enrollment into 2 large clinical trials at the Mayo Clinic. Results Nineteen percent (62/325) of our patient population had EV on esophagogastroduodenoscopy; 6% (8/127) of early-stage PBC patients had EV. Ninety five percent of our PBC patients with varices met at least one of the following conditions: male sex, low albumin (<3.5 g/dL), elevated bilirubin level (≥1.2 mg/dL), and/or prolonged prothrombin time (≥12.9 s). The sensitivity and specificity of these variables in combination to predict the presence of varices were 95% and 55%, respectively. Serum bilirubin ≥1.2 mg/dL and albumin <3.5 were independent predictors of varices with hazard values of 5.4 and 3.5 respectively. Conclusions EV can occur in a minority of early-stage PBC patients. Various models may be used to identify PBC patients who are candidates for screening esophagogastroduodenoscopy for EV. Based on adequate performance and its simplicity, we propose that male sex, low albumin, elevated bilirubin, and/or prolonged prothrombin time be used as a model to noninvasively predict EV. Further validation is required.

Treatment options for primary sclerosing cholangitis

Primary sclerosing cholangitis is a cholestatic liver disease characterized by inflammation and fibrosis of intra-/extrahepatic bile ducts, leading to multifocal strictures. Primary sclerosing cholangitis exhibits a progressive course resulting in cirrhosis and the need for liver transplantation over a median period of 12 years. The disease is frequently associated with inflammatory bowel disease and carries an increased risk of colorectal cancer and cholangiocarcinoma. Despite extensive research, there is currently no effective medical treatment. Multiple drugs are shown to be ineffective in halting disease progression, including ursodeoxycholic acid, the most widely evaluated drug. High-dose ursodeoxycholic acid (28–30 mg/kg/day) was recently shown to increase the adverse events rate. Endoscopic or radiological dilatation of a ‘dominant’ stricture may lead to symptomatic and biochemical improvement. However, liver transplantation is the only life-prolonging treatment for patients with end-stage disease. Studies with promising drugs, such as antibiotics, antifibrotic agents and bile acid derivatives, are eagerly awaited.

Editorial: Bile Acid Profiles in Intrahepatic Cholestasis of Pregnancy: Is This the Solution to the Enigma of Intrahepatic Cholestasis of Pregnancy?

Intrahepatic cholestasis of pregnancy (ICP) is a rare pregnancy-related liver disease characterized by pruritus, abnormal liver function tests, and an increased risk of fetal complications. An increase in the levels of bile acids is considered to be the diagnostic hallmark of the disease. Ursodeoxycholic acid (UDCA) is currently the most effective therapy. Tribe et al. (this issue) hypothesized that measuring the longitudinal profiles of individual bile acids would provide further insight into the mechanisms of disease. They used a novel chromatography method, which allowed the simultaneous measurement of 15 serum bile acids between 16 weeks of pregnancy and 4 weeks post-partum. ICP was associated with a predominant rise in cholic acid conjugated with taurine and glycine from 24 weeks of pregnancy. UDCA treatment significantly reduced serum taurocholic and taurodeoxycholic acid concentrations. Finally, bile acid profiles were similar in normal pregnancy and pregnancy associated with pruritus gravidarum. The study by Tribe et al. (this issue) presents a significant contribution to the solution of this enigmatic disease by expanding our knowledge on the pathophysiology of ICP and proposing a convenient method for diagnosis and monitoring of this disorder.