Advances in Liver Disease

Digestive Disease Week (DDW) 2014

William F. Balistreri, MD


June 19, 2014

In This Article

Primary Sclerosing Cholangitis

The pathogenesis of primary sclerosing cholangitis (PSC) is unknown; however, the intriguing link with inflammatory bowel disease (IBD) presents a unique research challenge and opportunity.

Rossen and colleagues[20] characterized the intestinal mucosal microbiota in patients with PSC and reported that the mucosal-adherent microbiota at the ileocecal level showed significantly reduced richness. At the genus-like level, the relative abundance of uncultured Clostridiales was significantly lower than in patients with IBD and in healthy controls. The reduced amounts of these specific microbes in biopsies from patients with PSC may indicate a compromised gut, because this group of Firmicutes correlates significantly with health.

The gut-liver axis is considered to play an important role in the pathogenesis of PSC; therefore, Jones and colleagues[21] hypothesized that the type of IBD may determine the disease course of PSC. They found that Crohn disease and PSC were often diagnosed simultaneously, whereas the diagnosis of ulcerative colitis preceded detection of abnormal liver enzyme levels. Compared with ulcerative colitis, concomitant Crohn disease predisposed to extrahepatic bile duct injury and a greater degree of cholestasis. How disease pathogenesis and treatment of colitis are linked to short- and long-term outcomes in patients with both PSC and IBD, especially progression of bile duct epithelial injury and biliary fibrosis, requires further investigation.


Predicting liver and IBD outcomes in patients with PSC is challenging. Immunoglobulin G4 (IgG4)-positive patients with PSC have higher alkaline phosphatase levels, a shorter time to liver transplantation, and reduced colectomy-free survival compared with IgG4-negative patients with PSC.

Peerani and colleagues[22] presented a model for prognostic assessment in which a serum IgG4 cut-off value > 70 mg/dL predicted which patients with PSC will require liver transplantation. These findings need to be validated in a prospective cohort of patients.

Cancer Risk

Coexisting PSC is associated with an increased risk for colorectal cancer in patients with IBD. However, whether PSC is associated with an increased risk for extraintestinal cancers in an IBD cohort is unclear.

Ananthakrishnan and colleagues[23] documented that patients with both IBD and PSC had a significantly increased overall risk for cancer compared with patients without PSC. Specifically, there was an excess risk for digestive tract cancer, pancreatic cancer, colorectal cancer, and cholangiocarcinoma, but not for other solid-organ or hematologic malignancies. Patients with IBD and PSC had higher mortality compared with patients with IBD alone. The presence of chromosomal polysomy, detected with fluorescence in situ hybridization on cytologic specimens obtained by brush cytology, is strongly suggestive of cholangiocarcinoma.

Eaton and colleagues[24] determined that in patients with PSC, multifocal polysomy (MFP) is an independent predictor of the development of CCA. They suggest that patients with MFP should be followed closely for cancer development. These findings reinforce the importance of performing brush cytology of all suspicious bile duct lesions in patients with PSC to determine whether MFP is present.


de Vries and colleagues[25] reported that normalization of alkaline phosphatase levels within 1 year after diagnosis (which occurred in 30% of their cohort) was associated with long-term, event-free survival. Alkaline phosphatase levels may prove to be an important factor in prognostic modelling in PSC.


Tabibian and colleagues[26] investigated the safety and efficacy of oral rifaximin (550 mg twice a day for 12 weeks) as therapy for PSC. Oral rifaximin, at least at this dose and duration, was ineffective -- a recurring theme for most agents studied for this disorder. Nevertheless, additional studies are needed to determine whether other antimicrobial agents or strategies can exert therapeutic effects in PSC, and these studies should focus on the antimicrobial spectrum of a particular agent and its impact on the endogenous microflora.


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