Tabibian, James H

Primary sclerosing cholangitis (PSC) is a pathogenically complex, chronic, fibroinflammatory disorder of the bile ducts without known etiology or effective pharmacotherapy. Emerging in vitro and in vivo evidence support fundamental pathophysiologic mechanisms in PSC centered on enterohepatic circulation. To date, no studies have specifically interrogated the chemical footprint of enterohepatic circulation in PSC. Herein, we evaluated the metabolome and lipidome of portal venous blood and bile obtained at the time of liver transplantation in patients with PSC (n = 7) as compared to individuals with noncholestatic, end-stage liver disease (viral, metabolic, etc. (disease control, DC, n = 19)) and to nondisease controls (NC, living donors, n = 12). Global metabolomic and lipidomic profiling was performed on serum derived from portal venous blood (portal serum) and bile using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and differential mobility spectroscopy-mass spectroscopy (DMS-MS; complex lipid platform). The Mann–Whitney U test was used to identify metabolites that significantly differed between groups. Principal-component analysis (PCA) showed significant separation of both PSC and DC from NC for both portal serum and bile. Metabolite set enrichment analysis of portal serum and bile demonstrated that the liver-disease cohorts (PSC and DC) exhibited similar enrichment in several metabolite categories compared to NC. Interestingly, the bile in PSC was uniquely enriched for dipeptide and polyamine metabolites. Finally, analysis of patient-matched portal serum and biliary metabolome revealed that these biological fluids were more homogeneous in PSC than in DC or NC, suggesting aberrant bile formation and enterohepatic circulation. In summary, PSC and DC patients exhibited alterations in several metabolites in portal serum and bile, while PSC patients exhibited a unique bile metabolome. These specific alterations in PSC are amenable to hypothesis testing and, potentially, therapeutic pharmacologic manipulation.

Dominant strictures (DSs) of the biliary tree occur in approximately 50% of patients with primary sclerosing cholangitis (PSC) and may cause significant morbidity. Nevertheless, the definition and management of DSs lacks consensus. We aimed to better understand current perceptions and practices regarding PSC‐associated DSs. We conducted an anonymous, 23‐question, survey‐based study wherein electronic surveys were distributed to 131 faculty in the Division of Gastroenterology and Hepatology at the three Mayo Clinic campuses (Rochester, Scottsdale, and Jacksonville) as well as the affiliated practice network. Responses were aggregated and compared, where applicable, to practice guidelines of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver. A total of 54 faculty (41.2%) completed the survey, of whom 24 (44.4%) were hepatologists, 21 (38.9%) gastroenterologists, and 9 (16.7%) advanced endoscopists. One of the major study findings was that there was heterogeneity among participants' definition, evaluation, management, and follow‐up of DSs in PSC. The majority of participant responses were in accordance with societal practice guidelines, although considerable variation was noted. Conclusion: Despite the prevalence and morbidity of DSs in PSC, clinical perceptions and practices vary widely among hepatologists, gastroenterologists, and advanced endoscopists who manage these patients, even within a single health care system. Further studies are needed to address these variations, develop general and evidence‐based consensus, and increase adherence to societal guidelines. ( Hepatology Communications 2018;2:836‐844)

Primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma (CCA) and gallbladder carcinoma (GBCa). Surveillance for GBCa is recommended, but the clinical utility of surveillance for other hepatobiliary cancers (HBCa) in PSC, namely CCA and hepatocellular carcinoma (HCC), remains unclear. We aimed to determine whether surveillance is associated with better survival after diagnosis of HBCa in patients with PSC. Medical records of PSC patients seen at the Mayo Clinic Rochester from 1995 to 2015 were reviewed. Patients were included if they had ≥1 year of follow‐up and developed HBCa. Patients were categorized according to their surveillance status (abdominal imaging, carbohydrate antigen 19‐9, and alpha‐fetoprotein). The primary endpoints were HBCa recurrence, HBCa‐related death, and all‐cause mortality. Overall survival was assessed by the Kaplan‐Meier survival method; HBCa‐related survival was assessed using competing risk regression. Tests of significance were two‐tailed, and a P value <0.05 was considered statistically significant. From 1995 to 2015, a total of 79 of 830 PSC patients were diagnosed with HBCa. Cumulative follow‐up was 712 and 283 person‐years pre‐ and post‐HBCa diagnosis, respectively. Seventy‐eight percent of patients (54/79) developed CCA, 21% (17/79) HCC, 6% (5/79) GBCa, 3% (2/79) both CCA and HCC, and 1% (1/79) both HCC and GBCa. Fifty‐one percent (40/79) were under HBCa surveillance, and 49% (39/79) were not. Patients in the surveillance group had significantly higher 5‐year overall survival (68% versus 20%, respectively; P < 0.001) and significantly lower 5‐year probability of experiencing an HBCa‐related adverse event (32% versus 75%, respectively; P < 0.001) compared with the no‐surveillance group. Conclusion: This study demonstrates that HBCa surveillance significantly improves outcomes, including survival, in patients with PSC. (Hepatology 2018;67:2338‐2351).

Abstract Cholestatic liver diseases ( CLD s) encompass a variety of disorders of bile formation and/or flow which generally result in progressive hepatobiliary injury and ultimately end‐stage liver disease. Many patients with CLD are diagnosed between the ages of 20‐50 years, a particularly productive period of life professionally, biologically and in other respects; it is not surprising, thus, that CLD is often associated with impaired health‐related quality of life ( HRQOL ) and uncertainty regarding implications for and outcomes of pregnancy. Primary sclerosing cholangitis ( PSC ) and primary biliary cholangitis ( PBC ) are the most prominent CLD s, both having considerable morbidity and mortality and representing major indications for liver transplantation. These disorders, as a consequence of their complications (eg ascites, hepatic osteodystrophy), associated conditions (eg inflammatory bowel disease) and symptoms (eg pruritus and fatigue), can significantly impair an array of domains of HRQOL . Here we review these impactful clinical aspects of PSC and PBC as well as the topics of fertility and pregnancy.

Cholestatic liver diseases are conditions with impaired bile formation and/or flow due to genetic, immunologic, environmental, or other causes. Unless successfully treated, this can lead to chronic liver injury and end‐stage liver disease. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) embody the most prominent adult cholestatic liver diseases with regard to incidence, morbidity, and mortality. A considerable proportion of patients with PBC and PSC experience progressive liver disease and ultimately liver‐related death due to a paucity of effective pharmacotherapy; however, novel pharmacologic developments offer substantial promise in this regard. Here, we provide a brief review and update on current and emerging pharmacotherapies for PBC and PSC. (Hepatology Communications 2017;1:7–17)