Nicholas F. LaRusso

Magnetic resonance cholangiography in patients with biliary disease: its role in primary sclerosing cholangitis

BACKGROUND/AIM Magnetic resonance cholangiography (MRC) is a non-invasive diagnostic procedure whose role in the management of patients with primary sclerosing cholangitis (PSC) is unclear. The aim of this study was to determine the usefulness of MRC in the evaluation of the biliary tree in patients with suspected biliary disease, and in particular, PSC. METHODS MRC and invasive cholangiography (ERCP or PTC) were both performed in 73 patients, (33 male, 40 female, mean age 56 years) with clinical and/or biochemical evidence of cholestasis. Images were interpreted by two radiologists unaware of the results of other studies. RESULTS Forty-two patients (58%) had benign biliary disease, including 23 patients (32%) with PSC; 9 patients (12%) had malignant biliary disease; and 22 patients (30%) had a normal biliary tree. Diagnostic quality images were obtained in 73/73 (100%) of MRC, and in 70/73 (96%) of invasive cholangiography (68 ERCPs, 2 PTCs) procedures. Using ERCP/PTC findings as the reference standard, MRC had an accuracy greater than 90% in the diagnosis of normal bile ducts, biliary dilatation, biliary obstruction, bile duct stones, and PSC. Using the final diagnosis, MRC had an overall diagnostic accuracy of 90% in the detection of biliary disease compared to 97% for invasive cholangiography. Additional diagnostic/therapeutic interventions were performed during ERCP in 73% of patients with PSC and in 43% of patients without PSC (p=0.02). CONCLUSIONS MRC has excellent diagnostic accuracy in the presence of biliary disease. Because of its noninvasive nature, MRC may have advantages over invasive cholangiography when diagnosis is the major goal of the procedure.

Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis

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 p16INK4a 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. (Hepatology 2016;63:185–196)

Defining the relationship between autoimmune disease and primary sclerosing cholangitis

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