Tabibian, James H.

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)

Abstract Increasing evidence points to the contribution of the intestinal microbiome as a potentially key determinant in the initiation and/or progression of hepatobiliary disease. While current understanding of this dynamic is incomplete, exciting insights are continually being made and more are expected given the developments in molecular and high‐throughput omics techniques. In this brief review, we provide a practical and updated synopsis of the interaction of the intestinal microbiome with the liver and its downstream impact on the initiation, progression and complications of hepatobiliary disease.

Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, fibroinflammatory cholangiopathy. The role of the microbiota in PSC etiopathogenesis may be fundamentally important, yet remains obscure. We tested the hypothesis that germ‐free (GF) mutltidrug resistance 2 knockout (mdr2 −/− ) mice develop a distinct PSC phenotype, compared to conventionally housed (CV) mdr2 −/− mice. Mdr2 −/− mice (n = 12) were rederived as GF by embryo transfer, maintained in isolators, and sacrificed at 60 days in parallel with age‐matched CV mdr2 −/− mice. Serum biochemistries, gallbladder bile acids, and liver sections were examined. Histological findings were validated morphometrically, biochemically, and by immunofluorescence microscopy (IFM). Cholangiocyte senescence was assessed by p16 INK4a in situ hybridization in liver tissue and by senescence‐associated β‐galactosidase staining in a culture‐based model of insult‐induced senescence. Serum biochemistries, including alkaline phosphatase, aspartate aminotransferase, and bilirubin, were significantly higher in GF mdr2 −/− ( P < 0.01). Primary bile acids were similar, whereas secondary bile acids were absent, in GF mdr2 −/− mice. Fibrosis, ductular reaction, and ductopenia were significantly more severe histopathologically in GF mdr2 −/− mice ( P < 0.01) and were confirmed by hepatic morphometry, hydroxyproline assay, and IFM. Cholangiocyte senescence was significantly increased in GF mdr2 −/− mice and abrogated in vitro by ursodeoxycholic acid (UDCA) treatment. Conclusions : GF mdr2 −/− mice exhibit exacerbated biochemical and histological features of PSC and increased cholangiocyte senescence, a characteristic and potential mediator of progressive biliary disease. UDCA, a commensal microbial metabolite, abrogates senescence in vitro . These findings demonstrate the importance of the commensal microbiota and its metabolites in protecting against biliary injury and suggest avenues for future studies of biomarkers and therapeutic interventions in PSC. (H epatology 2016;63:185–196)

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