Current targets for Primary Sclerosing cholangitis

Primary Sclerosing Cholangitis(PSC) is a chronic liver disease characterized by inflammation of the biliary epithelia progressively leading to fibrosis and biliary strictures formation and in the advanced disease to liver cirrhosis and cholangiocarcinoma occurrence. To date, PSC eziology is not fully understood leading to a lack in effective therapies able to reduce disease progression. The present review aims to discuss the current concepts about PSC pathogenesis and provides an updating of the therapeutical approaches against such chronic biliary disease

The significance of genetics for cholangiocarcinoma development

Cholangiocarcinoma (CCA) is a rare malignancy of the liver, arising from bile ducts. The incidence is increasing worldwide, but the prognosis has remained dismal and virtually unchanged in the past 30 years. Although several risk factors have been associated with the development of this cancer, none of them are normally identified in most patients. Diagnosis in advanced stages of the disease and limited therapeutic options contribute to poor survival rates. The recent analysis of genetic and epigenetic alterations occurring in CCA has shed new light in the understanding of the molecular mechanisms leading to the malignant transformation of biliary cells. Further studies in this direction may foster new diagnostic, prognostic and therapeutic approaches. This review provides a global overview of recent advances in CCA and describes the most important genetic mutations and epigenetic alterations so far reported in CCA

Efficacy and costs of Direct Acting Antivirals (DAAS) for the treatment of HCV Iinfection amnog HCV-monoinfected and HIV/HCV co-infected patients in real-life setting

BACKGROUND Although several studies analyzing the effectiveness of DAAs have showed no differences between HCV-monoinfected and HIV/HCV-coinfected patients,data in real-life setting are still limited. PURPOSE To compare efficacy and costs of DAAs in HCV-monoinfected and HIV/HCV-coinfected subjects. METHODS A database of HCV-monoinfected and HIV/HCV-coinfected adults who started HCV therapy between January 2015 and July 2016 was created in order to collect the following data:sustained virological response to DAAs therapy at week 12(SVR12) and at week 24(SVR24) after treatment initiation, treatment regimen, and overall cost of anti-HCV regimens.Patients were treated as follows: sofosbuvir/ribavirin ± peg-INF (n=37), sofosbuvir/daclatasvir(n=72), sofosburiv/ledipasvir(n=68), sofosburiv/simeprevir(n=77), simeprevir/peg-interferon(n=13) or ombitasvir/paritaprevir/ritonavir/dasabuvir(n=14). Overall, ribavirin was used in combination with DAAs in 67% of patients. RESULTS The study enrolled 281 subjects(81% monoinfected and 19% co-infected), treated for 12(54% of monoinfected and 50% of co-infected) or 24 weeks(46% of monoinfected and 50% of co-infected). Two hundred and twenty nine patients had cirrhosis or high degree fibrosis (≥F3) at the beginning of DAAs (79% of HCV-monoinfected and 91% of HIV/HCV co-infected);other 23 subjects(all but one HCV-monoinfected) were treated after liver transplantation. Two hundreds and ten (93%) HCV-monoinfected patients completed the treatment; 96% achieved SVR12 and 97% reached SVR24. The most prescribed regimens were 12-week sofosburiv/simeprevir(27%) or sofosburiv/ledipasvir(17%), and 24-week sofosbuvir/daclatasvir(17%). The average cost of a complete HCV-treatment in monoinfected population was € 49.633 per patient. Among the 47 HIV/HCV-coinfected patients(87%) who completed the treatment, 94% achieved SVR12 and 96% obtained SVR24;12-week sofosburiv/simeprevir was prescribed to 24% of them, whereas the most frequent 24-week treatments were sofosburiv/daclatasvir and sofosburiv/ledipasvir(20% each). The average cost of a complete HCV-treatment in coinfected population was € 53.573 per patient. CONCLUSION This study confirms the high effectiveness of DAAs in the treatment of HCV infection in real life setting, both in HCV-monoinfected and HIV/HCV-coinfected patients. The average cost of single treatment was also similar between the two groups

HCC Development Is Associated to Peripheral Insulin Resistance in a Mouse Model of NASH

NAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC), even in the absence of cirrhosis, that makes NAFLD of such clinical importance. Aim: we aimed to create a mouse model reproducing the pathological spectrum of NAFLD and to investigate the role of possible co-factors in promoting HCC. Methods: mice were treated with a choline-deficient L-amino-acid-defined-diet (CDAA) or its control (CSAA diet) and subjected to a low-dose i.p. injection of CCl4 or vehicle. Insulin resistance was measured by the euglycemic-hyperinsulinemic clamp method. Steatosis, fibrosis and HCC were evaluated by histological and molecular analysis. Results: CDAA-treated mice showed peripheral insulin resistance at 1 month. At 1-3 months, extensive steatosis and fibrosis were observed in CDAA and CDAA+CCl4 groups. At 6 months, equal increase in steatosis and fibrosis was observed between the two groups, together with the appearance of tumor. At 9 months of treatment, the 100% of CDAA+CCl4 treated mice revealed tumor versus 40% of CDAA mice. Insulin-like Growth Factor-2 (IGF-2) and Osteopontin (SPP-1) were increased in CDAA mice versus CSAA. Furthermore, Immunostaining for p-AKT, p-c-Myc and Glypican-3 revealed increased positivity in the tumors. Conclusions: the CDAA model promotes the development of HCC from NAFLD-NASH in the presence of insulin resistance but in the absence of cirrhosis. Since this condition is increasingly recognized in humans, our study provides a model that may help understanding mechanisms of carcinogenesis in NAFLD

Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD.

Abstract Non-Alcoholic Fatty Liver Disease (NAFLD) represents the most common form of chronic liver injury and can progress to cirrhosis and hepatocellular carcinoma. A “multi-hit” theory, involving high fat diet and signals from the gut-liver axis, has been hypothesized. The role of the NLRP3-inflammasome, which senses dangerous signals, is controversial. Nlrp3−/− and wild-type mice were fed a Western-lifestyle diet with fructose in drinking water (HFHC) or a chow diet. Nlrp3−/−-HFHC showed higher hepatic expression of PPAR γ2 (that regulates lipid uptake and storage) and triglyceride content, histological score of liver injury and greater adipose tissue inflammation. In Nlrp3−/−-HFHC, dysregulation of gut immune response with impaired antimicrobial peptides expression, increased intestinal permeability and the occurrence of a dysbiotic microbiota led to bacterial translocation, associated with higher hepatic expression of TLR4 (an LPS receptor) and TLR9 (a receptor for double-stranded bacterial DNA). After antibiotic treatment, gram-negative species and bacterial translocation were reduced, and adverse effects restored both in liver and adipose tissue. In conclusion, the combination of a Western-lifestyle diet with innate immune dysfunction leads to NAFLD progression, mediated at least in part by dysbiosis and bacterial translocation, thus identifying new specific targets for NAFLD therapy

Fibronectin type III domain-containing protein 5 rs3480 A>G polymorphism, irisin, and liver fibrosis in patients with Nonalcoholic fatty liver disease

Contrasting data have been reported on the role of irisin, a novel myokine encoded by the FNDC5 gene, in NAFLD pathogenesis. We tested in patients with suspected NASH the association of FNDC5 variants, hepatic expression and circulating irisin with liver damage(F2-F4 fibrosis as main outcome). We also investigated whether irisin modulates hepatocellular fat accumulation and stellate cell activation in experimental models