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Gut-stimulated inflammasome activation drives progression of liver injury in NASH
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Abstracts / Digestive and Liver Disease 46S (2014) e136–e141
biochemical and clinical improvement during the 6 month followup and the second patient maintained a stable improvement for 12 months (Child-Pugh score from C-11 to B-8, MELD score from 21 to 16). Conclusions: The isolation procedure can be carried out under cGMP conditions and, the hBTSCs therapy resulted safe for the patients. http://dx.doi.org/10.1016/j.dld.2014.08.025 9 EFFICACY AND SAFETY OF LONG-TERM THERAPY WITH ENTECAVIR (ETV) OR TENOFOVIR (TDF) IN PATIENTS WITH HBV-RELATED CIRRHOSIS M. Fasano 1 , M. Ciarallo 1 , A. Giammario 1 , B. Caccianotti 1 , G. Angarano 2 , T. Santantonio 1 1
Clinic of Infectious Diseases, Univerisity of Foggia, Foggia, Italy 2 Clinic of Infectious Diseases, University of Bari, Bari, Italy
Background: In virological suppressed patients the goal of therapy is the prevention of liver disease progression, hepatic decompensation, HCC development and need for OLT. Aims: To assess the impact of long-term ETV or TDF therapy on the progression of HBV-related liver disease and verify the safety profile in cirrhotic patients. Patients and methods: 48 patients with HBV-related liver cirrhosis Child A, HBeAg-negative, treated with ETV (25 patients) or TDF (23 patients) for a median of 34 months (range 1–78) were enrolled. Nine patients had HBV/HDV coinfection. The patients were subjected to periodic monitoring of liver and kidney function, and surveillance for HCC. At the time of therapy initiation and every 2–3 years, patients performed esophagogastroduodenoscopy. In TDF patients, bone densitometry was performed at baseline and after 2 years. Results: All patients had virological response after 12 months of treatment. No patient had ascitic decompensation, except 3 HDV-positive patients. At baseline, in the TDF group, 9 patients had esophageal varices (6 = F1, F2 = 2, F3 = 1); at the end of FU, 5 remained stable, 2 improved and 2 worsened. In the ETV group, 3 patients had esophageal varices F1 that remained stable. At the time of TDF therapy initiation, 5 patients already had a HCC. During FU, 4/5 patients recurred and 3 of these died for HCC. A new diagnosis of HCC was reported in 6 cases (4 TDF, 2 ETV). ETV or TDF therapy was well tolerated, only 1 patient showed reduction eGFR <50 ml/min and reduced TDF dose. After at least 2 years of therapy, 19/23 TDF patients repeated MOC, which remained stable in 13 cases, worsened in 3 and improved in 3 cases. Conclusions: Antiviral treatment has a favorable impact on the natural history of HBV-related cirrhosis, while not reducing the risk of HCC. http://dx.doi.org/10.1016/j.dld.2014.08.026
10 GUT-STIMULATED INFLAMMASOME ACTIVATION DRIVES PROGRESSION OF LIVER INJURY IN NASH S. Gemini 1 , L. Agostinelli 1 , C. Rychlicki 1 , S. De Minicis 1 , M.G. Faraci 1 , C. Candelaresi 1 , S. Traini 1 , S. Saccomanno 1 , C. Pinto 1 , G. Surace 1 , F. Capretti 1 , M. Marzioni 1 , G. Svegliati Baroni 1,2 1 Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy 2 Obesity Center, Università Politecnica delle Marche, Ancona, Italy
Non-Alcoholic Fatty Liver Disease (NAFLD), the most common chronic liver disease, includes several pathological conditions, ranging from simple steatosis to Non-Alcoholic Steatohepatitis (NASH), that can lead to cirrhosis and hepatocellular carcinoma. Dietary habits influence gut microflora composition, promoting bacterial translocation, that in the liver elicit a pro-inflammatory and pro-fibrogenic response, potentially through a inflammasomemediated mechanism. To test the role of bacterial translocation on liver fibrogenesis and inflammation, we performed a microfloratransplantation experiment. Previously gut-sterilized mice were subjected to oral gavage of caecum content obtained from donor CTRL- or HFD-treated mice. Liver damage was enhanced in chimeric mice fed CTRL diet, but receiving the microbiota of HFD-treated mice. By activating inflammasome cascade, microflora contribute to increase inflammation and fibrogenesis. Inflammasome activation, was observed also in a NAFLD/NASH mouse model. Mice were treated with a choline-deficient, l-aminoacid-defined-diet (CDAA) and its control, CSAA-diet, for up to 9 months. In each group, half mice were also treated with a weekly low-dose i.p.-injection of CCl4 . We observed peripheral insulin-resistance at 1 month, followed by increased steatosis, fibrosis and infiltrating macrophages. Moreover, our model showed all the main features of HCC development, including early modifications of pro-carcinogenetic genes expression, increased hepatocyte proliferation, and tumor nodules formation. To better elucidate the role of inflammasome in liver injury, we fed mice with an high fat-high carbohydrate (HFHC) diet for 16 weeks. We observed hepatic fat accumulation, increased fibrogenic markers expression, and a substantial increase of the inflammatory response with an enhanced expression of inflammasome components. Antibiotic treatment significantly reduced steatosis, fibrosis and inflammation, confirming the role of gutderived endotoxins in NASH pathogenesis. This is further confirmed by in vitro experiments performed on activated mouse HSCs, where LPS increased the expression of inflammasome components and MCP-1, leading to a pro-inflammatory phenotype, that could drive the progression of liver injury. http://dx.doi.org/10.1016/j.dld.2014.08.027
Abstracts / Digestive and Liver Disease 46S (2014) e136–e141
biochemical and clinical improvement during the 6 month followup and the second patient maintained a stable improvement for 12 months (Child-Pugh score from C-11 to B-8, MELD score from 21 to 16). Conclusions: The isolation procedure can be carried out under cGMP conditions and, the hBTSCs therapy resulted safe for the patients. http://dx.doi.org/10.1016/j.dld.2014.08.025 9 EFFICACY AND SAFETY OF LONG-TERM THERAPY WITH ENTECAVIR (ETV) OR TENOFOVIR (TDF) IN PATIENTS WITH HBV-RELATED CIRRHOSIS M. Fasano 1 , M. Ciarallo 1 , A. Giammario 1 , B. Caccianotti 1 , G. Angarano 2 , T. Santantonio 1 1
Clinic of Infectious Diseases, Univerisity of Foggia, Foggia, Italy 2 Clinic of Infectious Diseases, University of Bari, Bari, Italy
Background: In virological suppressed patients the goal of therapy is the prevention of liver disease progression, hepatic decompensation, HCC development and need for OLT. Aims: To assess the impact of long-term ETV or TDF therapy on the progression of HBV-related liver disease and verify the safety profile in cirrhotic patients. Patients and methods: 48 patients with HBV-related liver cirrhosis Child A, HBeAg-negative, treated with ETV (25 patients) or TDF (23 patients) for a median of 34 months (range 1–78) were enrolled. Nine patients had HBV/HDV coinfection. The patients were subjected to periodic monitoring of liver and kidney function, and surveillance for HCC. At the time of therapy initiation and every 2–3 years, patients performed esophagogastroduodenoscopy. In TDF patients, bone densitometry was performed at baseline and after 2 years. Results: All patients had virological response after 12 months of treatment. No patient had ascitic decompensation, except 3 HDV-positive patients. At baseline, in the TDF group, 9 patients had esophageal varices (6 = F1, F2 = 2, F3 = 1); at the end of FU, 5 remained stable, 2 improved and 2 worsened. In the ETV group, 3 patients had esophageal varices F1 that remained stable. At the time of TDF therapy initiation, 5 patients already had a HCC. During FU, 4/5 patients recurred and 3 of these died for HCC. A new diagnosis of HCC was reported in 6 cases (4 TDF, 2 ETV). ETV or TDF therapy was well tolerated, only 1 patient showed reduction eGFR <50 ml/min and reduced TDF dose. After at least 2 years of therapy, 19/23 TDF patients repeated MOC, which remained stable in 13 cases, worsened in 3 and improved in 3 cases. Conclusions: Antiviral treatment has a favorable impact on the natural history of HBV-related cirrhosis, while not reducing the risk of HCC. http://dx.doi.org/10.1016/j.dld.2014.08.026
10 GUT-STIMULATED INFLAMMASOME ACTIVATION DRIVES PROGRESSION OF LIVER INJURY IN NASH S. Gemini 1 , L. Agostinelli 1 , C. Rychlicki 1 , S. De Minicis 1 , M.G. Faraci 1 , C. Candelaresi 1 , S. Traini 1 , S. Saccomanno 1 , C. Pinto 1 , G. Surace 1 , F. Capretti 1 , M. Marzioni 1 , G. Svegliati Baroni 1,2 1 Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy 2 Obesity Center, Università Politecnica delle Marche, Ancona, Italy
Non-Alcoholic Fatty Liver Disease (NAFLD), the most common chronic liver disease, includes several pathological conditions, ranging from simple steatosis to Non-Alcoholic Steatohepatitis (NASH), that can lead to cirrhosis and hepatocellular carcinoma. Dietary habits influence gut microflora composition, promoting bacterial translocation, that in the liver elicit a pro-inflammatory and pro-fibrogenic response, potentially through a inflammasomemediated mechanism. To test the role of bacterial translocation on liver fibrogenesis and inflammation, we performed a microfloratransplantation experiment. Previously gut-sterilized mice were subjected to oral gavage of caecum content obtained from donor CTRL- or HFD-treated mice. Liver damage was enhanced in chimeric mice fed CTRL diet, but receiving the microbiota of HFD-treated mice. By activating inflammasome cascade, microflora contribute to increase inflammation and fibrogenesis. Inflammasome activation, was observed also in a NAFLD/NASH mouse model. Mice were treated with a choline-deficient, l-aminoacid-defined-diet (CDAA) and its control, CSAA-diet, for up to 9 months. In each group, half mice were also treated with a weekly low-dose i.p.-injection of CCl4 . We observed peripheral insulin-resistance at 1 month, followed by increased steatosis, fibrosis and infiltrating macrophages. Moreover, our model showed all the main features of HCC development, including early modifications of pro-carcinogenetic genes expression, increased hepatocyte proliferation, and tumor nodules formation. To better elucidate the role of inflammasome in liver injury, we fed mice with an high fat-high carbohydrate (HFHC) diet for 16 weeks. We observed hepatic fat accumulation, increased fibrogenic markers expression, and a substantial increase of the inflammatory response with an enhanced expression of inflammasome components. Antibiotic treatment significantly reduced steatosis, fibrosis and inflammation, confirming the role of gutderived endotoxins in NASH pathogenesis. This is further confirmed by in vitro experiments performed on activated mouse HSCs, where LPS increased the expression of inflammasome components and MCP-1, leading to a pro-inflammatory phenotype, that could drive the progression of liver injury. http://dx.doi.org/10.1016/j.dld.2014.08.027