Y. Chrétien

Genetic factors of susceptibility and of severity in primary biliary cirrhosis

BACKGROUND/AIMS In primary biliary cirrhosis (PBC), pathogenesis is influenced by genetic factors that remain poorly elucidated up to now. We investigated the impact of sequence diversity in candidate genes involved in immunity (CTLA-4 and TNFalpha), in bile formation (10 hepatobiliary transporter genes) and in the adaptative response to cholestasis (three nuclear receptor genes) on the susceptibility and severity of PBC. METHODS A total of 42 Ht SNPs were identified and compared in 258 PBC patients and two independent groups of 286 and 269 healthy controls. All participants were white continental individuals with French ancestry. RESULTS Ht SNPs of CTLA-4 and TNFalpha genes were significantly associated with susceptibility to PBC. The progression rate of liver disease under ursodeoxycholic acid (UDCA) therapy was significantly linked to SNPs of TNFalpha and SLC4A2/anion exchanger 2 (AE2) genes. A multivariate Cox regression analysis including clinical and biochemical parameters showed that SLC4A2/AE2 variant was an independent prognostic factor. CONCLUSIONS These data point to a primary role of genes encoding regulators of the immune system in the susceptibility to PBC. They also demonstrate that allelic variations in TNFalpha and SLC4A2/AE2 have a significant impact on the evolutive profile of PBC under UDCA therapy.

Triple therapy with ursodeoxycholic acid, budesonide and mycophenolate mofetil in patients with features of severe primary biliary cirrhosis not responding to ursodeoxycholic acid alone

BACKGROUND/AIMS To assess the benefit of the UDCA-budesonide combination in association with mycophenolate mofetil (MMF) in patients with primary biliary cirrhosis (PBC) at high risk of developing cirrhosis or liver failure. METHODS Inclusion criteria for this three-year open study were: 1) suboptimal biochemical response to one-year UDCA therapy at 13-15 mg/kg/d; 2) significant interface hepatitis without cirrhosis at liver biopsy. Treatment regimen included UDCA (13-15 mg/kg/d), budesonide (6 mg/d) and MMF (1.5 g/d). All patients underwent a control biopsy at three years. RESULTS Fifteen patients fulfilled the inclusion criteria. Six patients (41%) normalized biochemistries and seven (47%) had a partial but significant biochemical response, as defined by a serum bilirubin less than 17 micromol/L, alanine aminotransferase less than 70 UI/L and alkaline phosphatase less than 250 UI/L. Histological activity and fibrosis were markedly improved. Side effects were minimal or absent. CONCLUSIONS Triple therapy with UDCA, budesonide and MMF may provide benefit in non-cirrhotic PBC patients with features of severe disease not responding to UDCA.

Diet-Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice: Debray, EL MOURABIT, et al.

The most typical expression of cystic fibrosis (CF)–related liver disease is a cholangiopathy that can progress to cirrhosis. We aimed to determine the potential impact of environmental and genetic factors on the development of CF‐related cholangiopathy in mice. Cystic fibrosis transmembrane conductance regulator (Cftr)−/− mice and Cftr+/+ littermates in a congenic C57BL/6J background were fed a high medium‐chain triglyceride (MCT) diet. Liver histopathology, fecal microbiota, intestinal inflammation and barrier function, bile acid homeostasis, and liver transcriptome were analyzed in 3‐month‐old males. Subsequently, MCT diet was changed for chow with polyethylene glycol (PEG) and the genetic background for a mixed C57BL/6J;129/Ola background (resulting from three backcrosses), to test their effect on phenotype. C57BL/6J Cftr−/− mice on an MCT diet developed cholangiopathy features that were associated with dysbiosis, primarily Escherichia coli enrichment, and low‐grade intestinal inflammation. Compared with Cftr+/+ littermates, they displayed increased intestinal permeability and a lack of secondary bile acids together with a low expression of ileal bile acid transporters. Dietary‐induced (chow with PEG) changes in gut microbiota composition largely prevented the development of cholangiopathy in Cftr−/− mice. Regardless of Cftr status, mice in a mixed C57BL/6J;129/Ola background developed fatty liver under an MCT diet. The Cftr−/− mice in the mixed background showed no cholangiopathy, which was not explained by a difference in gut microbiota or intestinal permeability, compared with congenic mice. Transcriptomic analysis of the liver revealed differential expression, notably of immune‐related genes, in mice of the congenic versus mixed background. In conclusion, our findings suggest that CFTR deficiency causes abnormal intestinal permeability, which, combined with diet‐induced dysbiosis and immune‐related genetic susceptibility, promotes CF‐related cholangiopathy.

Loss of ezrin in human intrahepatic cholangiocarcinoma is associated with ectopic expression of E-cadherin.

Ezrin connects proteins from the plasma membrane to the subcortical cytoskeleton, and contributes to epithelial integrity by interacting with the cell–cell adhesion molecule E‐cadherin. In the liver, ezrin is restricted to cholangiocytes, where it regulates biliary secretory functions. During carcinogenesis, ezrin expression is impaired and associated with enhancement of cell migratory activity in cancer cells; therefore, we aimed to analyse ezrin in cholangiocarcinogenesis.