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The natural history of pruritus in primary biliary cirrhosis (PBC) remains poorly defined. The aim of this investigation was to evaluate outcomes of pruritus in clinical trials for ursodeoxycholic acid (UDCA). In a UDCA-placebo trial begun in 1988 (n = 180), a 55% prevalence rate for pruritus was observed. Serum alkaline phosphatase level and Mayo risk score were independent risk factors for pruritus (P < 0.0001). Among placebo-treated patients (n = 91), the annual risks for development or improvement/resolution of pruritus were 27% and 23%, respectively. For UDCA-treated patients (n = 89), a trend toward improvement in pruritus was observed after 1 year compared to placebo (30% vs. 23%, P = 0.08) but not at 2 or 3 years. In a 3-dose UDCA trial begun in 1995 (n = 155), the overall prevalence of pruritus was significantly lower at 37% when compared to UDCA-placebo participants (P < 0.001). Baseline serum alkaline phosphatase level and Mayo risk score were again independent risk factors for pruritus (P < 0.0001). Among 13 (3.9%) patients with refractory pruritus, symptom resolution (n = 5) or improvement (n = 8) was associated with the use of oral rifampin (300 or 600 mg daily). Two patients treated with rifampin developed biochemical evidence for hepatotoxicity necessitating drug withdrawal. Although less prevalent among recently diagnosed individuals, more than one third of PBC patients develop pruritus. No significant risk reduction in developing pruritus with UDCA therapy was observed compared to placebo-treated patients. The long-term administration of rifampin for refractory pruritus is associated with occasional hepatotoxicity.

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Most adenocarcinomas of the esophagogastic junction arise in the background of intestinal metaplasia, sometimes in an endoscopically visible Barrett's esophagus, more often in small areas of intestinal metaplasia of the cardia. In cases of adenocarcinoma, the intestinal metaplasia resembled that found in Barrett's esophagus, and was not associated with H. pylori.

We have previously demonstrated that after bile duct ligation hepatocytes express Bcl-2, although the mechanisms regulating Bcl-2 expression were not identified. Our aim was to determine if biliary constituents induce hepatocellular expression of Bcl-2 by a cyclooxygenase-2 (COX-2)-dependent mechanism. We used the choledocho-venous fistula (CVF) rat model for these studies and inhibited COX-2 by feeding the animals nimesulide, a selective inhibitor of COX-2 activity. Serum bile acids were 70-fold greater in CVF animals compared with controls, although liver histology and serum alanine aminotransferase values remained normal for the duration of the study. Neither Bcl-2 nor COX-2 was detected in sham-operated animals. However, Bcl-2 was expressed in hepatocytes but not in other liver cells in the CVF animals. In contrast, COX-2 protein was identified in Kupffer cells but not in hepatocytes of CVF animals. Hepatic Bcl-2 protein expression was fourfold lower in the livers from nimesulide-treated CVF rats. In conclusion, high circulating concentrations of biliary constituents are associated with stimulation of de novo hepatocyte expression of Bcl-2 and Kupffer cell expression of COX-2. These data suggest Kupffer cell-derived prostanoids may regulate Bcl-2 expression in the hepatocyte.

Primary sclerosing cholangitis (PSC) remains a rare but potentially devastating chronic, cholestatic liver disease. PSC causes obstruction of intra- and/or extra-hepatic bile ducts by inflammation and fibrosis, leading to biliary obstruction, cirrhosis and portal hypertension with all associated sequelae. The most dreaded consequence of PSC is cholangiocarcinoma, occurring in 10-20% of patients with PSC, and with population-based estimates of a 398-fold increased risk of cholangiocarcinoma in patients with PSC compared to the general population. We use the 4-D approach to endoscopic evaluation and management of PSC based on currently available evidence. After laboratory testing with liver chemistries and high-quality cross-sectional imaging with MRCP, the first D is Dominant stricture diagnosis and evaluation. Second, Dilation of strictures found during ERCP is performed using balloon dilation to as many segments as possible. Third, Dysplasia and cholangiocarcinoma diagnosis is performed by separated brushings for conventional cytology and fluorescence in situ hybridization (FISH), and consideration for direct cholangioscopy with SpyGlass™. Fourt and finally, Dosing of antibiotics is critical to prevent peri-procedural cholangitis. The aim of this review article is to explore endoscopic tools and techniques for the diagnosis and management of PSC and provide a practical approach for clinicians.

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