Norberto C. Chávez‐Tapia

Liver fibrosis represents a health problem with significant morbidity and mortality that affects 100 million people worldwide. It is a final pathway to several chronic liver diseases and is characterized by excess collagen and accumulation of extracellular matrix in response to chronic hepatocellular damage. Clinical and experimental data suggest that oxidative stress (OS) mediates the progression of fibrosis, and that OS-related molecules may act as mediators of molecular and cellular events implicated in liver fibrosis. The generation of reactive oxygen species (ROS) plays an important role in producing liver damage and initiating hepatic fibrogenesis. OS disrupts lipids, proteins and DNA, induces necrosis and apoptosis of hepatocytes and amplifies the inflammatory response. ROS also stimulate the production of profibrogenic mediators from Kupffer cells and circulating inflammatory cells and directly activate hepatic stellate cells, resulting in the initiation of fibrosis. Advances in understanding the mechanisms involved in fibrosis have identified new molecular targets with therapeutic potential for more targeted and personalized control of this disease. This review will highlight recent concepts in OS, antioxidants and the molecular pathways involved in hepatic fibrosis.

BACKGROUND: Bacterial infections are a frequent complication in patients with cirrhosis and upper gastrointestinal bleeding. Antibiotic prophylaxis seems to decrease the incidence of bacterial infections. Oral antibiotics, active against enteric bacteria, have been commonly used as antibiotic prophylaxis in patients with cirrhosis and upper gastrointestinal bleeding. This is an update of a Cochrane review first published in 2002. OBJECTIVES: To assess the benefits and harms of antibiotic prophylaxis in cirrhotic patients with upper gastrointestinal bleeding. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index EXPANDED until June 2010. In addition, we handsearched the references of all identified studies. SELECTION CRITERIA: Randomised clinical trials comparing different types of antibiotic prophylaxis with no intervention, placebo, or another antibiotic to prevent bacterial infections in cirrhotic patients with upper gastrointestinal bleeding. DATA COLLECTION AND ANALYSIS: Three authors independently assessed trial quality, risk of bias, and extracted data. We contacted study authors for additional information. Association measures were relative risk (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes. MAIN RESULTS: Twelve trials (1241 patients) evaluated antibiotic prophylaxis compared with placebo or no antibiotic prophylaxis. All trials were at risk of bias. Antibiotic prophylaxis compared with no intervention or placebo was associated with beneficial effects on mortality (RR 0.79, 95% CI 0.63 to 0.98), mortality from bacterial infections (RR 0.43, 95% CI 0.19 to 0.97), bacterial infections (RR 0.36, 95% CI 0.27 to 0.49), rebleeding (RR 0.53, 95% CI 0.38 to 0.74), days of hospitalisation (MD -1.91, 95% CI -3.80 to -0.02), bacteraemia (RR 0.25, 95% CI 0.15 to 0.40), pneumonia (RR 0.45, 95% CI 0.27 to 0.75), spontaneous bacterial peritonitis (RR 0.29, 95% CI 0.15 to 0.57), and urinary tract infections (RR 0.23, 95% CI 0.12 to 0.41). No serious adverse events were reported. The trials showed no significant heterogeneity of effects. Another five trials (650 patients) compared different antibiotic regimens. Data could not be combined as each trial used different antibiotic regimen. None of the examined antibiotic regimen was superior to the control regimen regarding mortality or bacterial infections. AUTHORS' CONCLUSIONS: Prophylactic antibiotic use in patients with cirrhosis and upper gastrointestinal bleeding significantly reduced bacterial infections, and seems to have reduced all-cause mortality, bacterial infection mortality, rebleeding events, and hospitalisation length. These benefits were observed independently of the type of antibiotic used; thus, no specific antibiotic can be preferred. Therefore, antibiotic selection should be made considering local conditions such as bacterial resistance profile and treatment cost.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is increasingly recognised as a condition associated with overweight or obesity that may progress to end-stage liver disease. NAFLD histology resembles alcohol-induced liver injury, but occurs in patients with no history of alcohol abuse. NAFLD has a broad spectrum of clinical and histological manifestations, ranging from simple fatty liver to hepatic steatosis with inflammation, advanced fibrosis, and cirrhosis. The inflammatory stage is known as non-alcoholic steatohepatitis (NASH). Recent reports indicate that weight loss induced by bariatric procedures could be beneficial for NASH treatment. OBJECTIVES: To assess the benefits and harms of bariatric surgery for NASH in obese patients. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded to October 2009. SELECTION CRITERIA: All randomised clinical trials evaluating any bariatric procedure versus no intervention, placebo (sham procedure), or other interventions in patients with NASH regardless of publication status, number of patients randomised, language, or blinding. Quasi-randomised clinical studies were to be considered for the review if no randomised clinical trials were identified. If included, their bias towards positive findings was to be considered. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate, and we planned to analyse the data by intention-to-treat. MAIN RESULTS: We could not find any randomised clinical trials or quasi-randomised clinical studies that fulfilled the inclusion criteria. Our search resulted in twenty-one prospective or retrospective cohort studies, in which improvement on steatosis or inflammation scores was reported. However, four studies also described some deterioration in the degree of fibrosis. AUTHORS' CONCLUSIONS: The lack of randomised clinical trials and quasi-randomised clinical studies precludes us to assess the benefits and harms of bariatric surgery as a therapeutic approach for patients with NASH. Limitations of all other studies with inferior design did not allow us to draw any unbiased conclusion on bariatric surgery for treatment of NASH.

BACKGROUND: Antibiotic prophylaxis seems to decrease the incidence of bacterial infections in patients with cirrhosis and upper gastrointestinal bleeding and is considered standard of care. However, there is no updated information regarding the effects of this intervention. AIM: To assess the benefits and harms of antibiotic prophylaxis in cirrhotic patients with gastrointestinal bleeding by performing a systematic review of randomised trials. METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE and Science Citation Index EXPANDED until June 2010. We statistically combined data calculating relative risk (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes. RESULTS: Twelve trials (1241 patients) evaluating antibiotic prophylaxis against placebo or no antibiotic prophylaxis were included. Antibiotic prophylaxis was associated with reduced mortality (RR 0.79, 95% CI 0.63-0.98), mortality from bacterial infections (RR 0.43, 95% CI 0.19-0.97), bacterial infections (RR 0.35, 95% CI 0.26-0.47), rebleeding (RR 0.53, 95% CI 0.38-0.74) and days of hospitalisation (MD -1.91, 95% CI -3.80-0.02). Trials analysing rebleeding rate and hospitalisation length are still scarce, thus, caution should be exerted when interpreting the results. CONCLUSIONS: Antibiotic prophylaxis in patients with cirrhosis and upper gastrointestinal bleeding significantly reduced bacterial infections, and reduce all-cause mortality, bacterial infection mortality, rebleeding events and hospitalisation length. Novel clinically significant outcomes were included in this meta-analysis. Some benefits are biased and the risks are not yet properly assessed, this encourages future research in this field.

Bile acids (BAs), the end products of cholesterol catabolism, are essential for the absorption of lipids and fat-soluble vitamins; but they have also emerged as novel signaling molecules that act as metabolic regulators. It has been well described that the enterohe-patic circulation, a nuclear (FXR) and a cytoplasmic (TGR5/M-BAR) receptor aid in controlling hepatic bile acid synthesis. Modulating bile acid synthesis greatly impacts in metabolism, because these receptors also are implicated in glucose, lipid, and energy expenditure. Recent studies had revealed the way these receptors participate in regulating gluconeogenesis, peripheral insulin sensitivity, glycogen synthesis, glucagon like peptide 1 (GLP-1) and insulin secretion. Nowadays, it is demonstrated that enhancing bile acid signaling in the intestine contributes to the metabolic benefits of bile acid sequestrants and bariatric surgery on glucose homeos-tasis. This paper discusses the role of bile acid as regulators of glucose metabolism and their potential as therapeutic targets for diabetes.