Pathophysiological mechanisms involved in non-alcoholic steatohepatitis and novel potential therapeutic targets

Non-alcoholic fatty liver disease (NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as non-alcoholic fatty liver (NAFL) or simple steatosis, and non-alcoholic steatohepatitis (NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms, such as, insulin resistance (IR), lipotoxicity, inflammation, oxidative stress, and recently the gut-liver axis interaction has been described. Incretin-based therapies could play a role in the treatment of NAFLD. Glucagon-like peptide-1 (GLP-1) is an intestinal mucosa-derived hormone which is secreted into the bloodstream in response to nutrient ingestion; it favors glucose-stimulated insulin secretion, inhibition of postprandial glucagon secretion and delayed gastric emptying. It also promotes weight loss and is involved in lipid metabolism. Once secreted, GLP-1 is quickly degraded by dipeptidyl peptidase-4 (DPP-4). Therefore, DPP-4 inhibitors are able to extend the activity of GLP-1. Currently, GLP-1 agonists and DPP-4 inhibitors represent attractive options for the treatment of NAFLD and NASH. The modulation of lipid and glucose metabolism through nuclear receptors, such as the farsenoid X receptor, also constitutes an attractive therapeutic target. Obeticholic acid is a potent activator of the farnesoid X nuclear receptor and reduces liver fat content and fibrosis in animal models. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid with immunomodulatory, anti-inflammatory, antiapoptotic, antioxidant and anti-fibrotic properties. UDCA can improve IR and modulate lipid metabolism through its interaction with nuclear receptors such as, TGR5, farnesoid X receptor-α, or the small heterodimeric partner. Finally, pharmacologic modulation of the gut microbiota could have a role in the therapy of NAFLD and NASH. Probiotics prevent bacterial translocation and epithelial invasion, inhibit mucosal adherence by bacteria, and stimulate host immunity. In animal models, probiotics prevent obesity, decrease transaminase levels, and improve IR and liver histology in NASH.     

Mean platelet volume as a novel predictor of systemic inflammatory response in cirrhotic patients with culture-negative neutrocytic ascites

AIM: To identify a mean platelet volume (MPV) cutoff value which should be able to predict the presence of bacterial infection.METHODS: An observational, analytic, retrospective study. We evaluated medical records of cirrhotic patients who were hospitalized from January 2012 to January 2014 at the Gastroenterology Department of “Hospital General de México Dr. Eduardo Liceaga”, we included 51 cirrhotic patients with ascites fluid infection (AFI), and 50 non-infected cirrhotic patients as control group. Receiver operator characteristic curves were used to identify the best cutoff value of several parameters from hematic cytometry, including MPV, to predict the presence of ascites fluid infection.RESULTS: Of the 51 cases with AFI, 48 patients (94.1%) had culture-negative neutrocytic ascites (CNNA), 2 (3.9%) had bacterial ascites, and one (2%) had spontaneous bacterial peritonitis. Infected patients had greater count of leucocytes and polymorphonuclear cells, greater levels of MPV and cardiac frequency (P < 0.0001), and lower mean arterial pressure compared with non-infected patients (P = 0.009). Leucocytes, polymorphonuclear count, MPV and cardiac frequency resulted to be good or very good predictive variables of presence of AFI in cirrhotic patients (area under the receiving operating characteristic > 0.80). A cutoff MPV value of 8.3 fl was the best to discriminate between cirrhotic patients with AFI and those without infection.CONCLUSION: Our results support that MPV can be an useful predictor of systemic inflammatory response syndrome in cirrhotic patients with AFI, particularly CNNA.     

Metadoxine improves the three- and six-month survival rates in patients with severe alcoholic hepatitis

AIM:To evaluate the impact of metadoxine(MTD) on the 3- and 6-mo survival of patients with severe alcoholic hepatitis(AH).METHODS:This study was an open-label clinical trial,performed at the"Hospital General de México,Dr.Eduardo Liceaga".We randomized 135 patients who met the criteria for severe AH into the following groups:35 patients received prednisone(PDN)40 mg/d,35patients received PDN+MTD 500 mg three times daily,33 patients received pentoxifylline(PTX)400 mg three times daily,and 32 patients received PTX+MTD 500 mg three times daily.The duration of the treatment for all of the groups was 30 d.RESULTS:In the groups treated with the MTD,thesurvival rate was higher at 3 mo(PTX+MTD 59.4%vs PTX 33.3%,P=0.04;PDN+MTD 68.6%vs PDN20%,P=0.0001)and at 6 mo(PTX+MTD 50%vs PTX18.2%,P=0.01;PDN+MTD 48.6%vs PDN 20%,P=0.003)than in the groups not treated with MTD.A relapse in alcohol intake was the primary independent factor predicting mortality at 6 mo.The patients receiving MTD maintained greater abstinence than those who did not receive it(74.5%vs 59.4%,P=0.02).CONCLUSION:MTD improves the 3-and 6-mo survival rates in patients with severe AH.Alcohol abstinence is a key factor for survival in these patients.The patients who received the combination therapy with MTD were more likely to maintain abstinence than those who received monotherapy with either PDN or PTX.