Novel Therapies for Cholestasis

The Liver Meeting 2017: American Association for the Study of Liver Diseases (AASLD)

William F. Balistreri, MD


December 13, 2017

Advances in Diagnosing Cholestasis

Magnetic resonance cholangiopancreatography (MRCP) is traditionally the primary method used to establish a diagnosis of primary sclerosing cholangitis (PSC); however, data defining its prognostic utility are limited.

Muir and colleagues[1] prospectively evaluated the association between the severity of biliary disease and disease progression, as assessed by MRCP, in 234 patients with PSC. Consensus reading of MRCP data by two radiologists was performed to characterize 18 hepatobiliary features, including the presence and severity of bile duct strictures and dilatation, intraductal stones, hepatic dysmorphy (eg, lobulated liver surface, atrophic lobe, caudate lobe hypertrophy), portal hypertension, and perihepatic lymph nodes. The associations between these features and PSC-related clinical events were determined using Cox regression, and an MRCP risk score was derived on the basis of factors with independent prognostic value.

Over a median follow-up period of 23 months, 20% of patients developed a PSC-related clinical event (ascending cholangitis, jaundice, cholangiocarcinoma, ascites, encephalopathy, variceal hemorrhage, or sepsis). In multivariate analysis, PSC-related events were associated with baseline hepatic dysmorphy, signs of portal hypertension, and perihepatic lymph nodes. On the basis of the model coefficients, an MRCP risk score assigning 1 point for each of these three variables was derived, which accurately predicted subsequent clinical events.

During follow-up, the risk for clinical events increased according to baseline MRCP risk score: no features, 6%; one variable, 14%; two variables, 30%; and three variables, 56%.

The prognostic utility of this simple MRCP risk score in patients with PSC-related disease warrants further validation.

Obeticholic Acid Therapy 

Currently, there are no approved therapies for patients with PSC.

Kowdley and colleagues[2] sought to test the safety and efficacy of obeticholic acid (OCA), a potent farnesoid X receptor agonist, for PSC. They conducted a randomized, double-blind, placebo-controlled, dose-finding, 24-week phase 2 study in which patients with PSC received one of three treatments: placebo, OCA 1.5 mg, or OCA 5 mg administered once daily for 12 weeks. After that period, patients tolerating OCA were titrated from 1.5 mg to 3 mg or from 5 mg to 10 mg.

The primary endpoint, a significant reduction in the serum alkaline phosphatase level, was achieved at week 24 in patients who received OCA (placebo: -27; OCA 1.5-3 mg: -105; OCA 5-10 mg: -110). Fibroblast growth factor 19 levels increased with OCA, but not with placebo, confirming farnesoid X receptor activation.

The adverse event rates were similar among treatments, with the exception of pruritus, which was increased during OCA administration in a dose-dependent manner.

Given the unmet medical need in patients with cholestatic diseases, further clinical evaluation is warranted.


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