Norberto C. Chávez-Tapia

Role of Oxidative Stress and Molecular Changes in Liver Fibrosis: A Review

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.

Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease

BackgroundIn vitro exposure of liver cells to high concentrations of free fatty acids (FFA) results in fat overload which promotes inflammatory and fibrogenic response similar to those observed in patients with Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH). Since the mechanisms of this event have not been fully characterized, we aimed to analyze the fibrogenic stimuli in a new in vitro model of NASH.MethodsHuH7 cells were cultured for 24 h in an enriched medium containing bovine serum albumin and increasing concentrations of palmitic and oleic acid at a molar ratio of 1:2 (palmitic and oleic acid, respectively). Cytotoxic effect, apoptosis, oxidative stress, and production of inflammatory and fibrogenic cytokines were measured.ResultsFFA induces a significant increment in the intracellular content of lipid droplets. The gene expression of interleukin-6, interleukin-8 and tumor necrosis factor alpha was significantly increased. The protein level of interleukin-8 was also increased. Intracellular lipid accumulation was associated to a significant up-regulation in the gene expression of transforming growth factor beta 1, alpha 2 macroglobulin, vascular endothelial growth factor A, connective tissue growth factor, insulin-like growth factor 2, thrombospondin 1. Flow cytometry analysis demonstrated a significant increment of early apoptosis and production of reactive oxygen species.ConclusionsThe exposure of hepatocytes to fatty acids elicits inflammation, increase of oxidative stress, apoptosis and production of fibrogenic cytokines. These data support a primary role of FFA in the pathogenesis of NAFLD and NASH.

Strong Association between Gallstones and Cardiovascular Disease

BACKGROUND AND AIM:Obesity is closely associated with the increased morbidity and mortality of many common diseases in the Western world, including coronary heart disease (CHD) and gallstone diseases (GD). We have investigated the association between GD and CHD in a cross-sectional study.METHODS AND RESULTS:Subjects who had gallstones visible by ultrasound were considered as cases and subjects negative for gallstones were classified as controls. Positive CHD was defined when the stress test was positive. Body mass index (BMI), waist circumference, blood pressure, serum lipid concentrations, and insulin resistance were measured. The association was estimated by odds ratios using logistic regression models adjusted for confounders. Four hundred and seventy-three subjects (292 males and 181 females) were included, comprising 354 controls and 119 cases. Subjects with GD had higher prevalence of CHD (15.96%) than controls (4.52%) (p < 0.0001). In univariate unconditional logistic regression analysis CHD, BMI ≥ 30 kg/m2, waist circumference, high blood pressure, and HOMA-IR > 2.5 were the most important risk factors for GD. In multivariate analysis (adjusted for age and gender, and BMI) the risk for GD in subjects with CHD was higher (OR 2.84, 95% CI: 1.33–6.07, p < 0.007).CONCLUSIONS:Subjects with CHD have an increased risk to have GD, both diseases are strongly associated and the main characteristics of these subjects are those frequently involved as part of the metabolic syndrome.

Eosinophilic Gastroenteritis: A Review

Eosinophilic gastroenteritis is a rare benign disease characterized by tissue eosinophilic infiltration that may involve several digestive tract layers. Also known as allergic, or eosinophilic allergic, gastroenteropathy, it usually involves the stomach and small intestine: rarely the colon. It may or may not be accompanied by higher counts of eosinophils in the peripheral blood. The main clinical manifestations depend on the site affected. It has been classified according to clinical and pathological features, and the symptoms depend on the patient’s immunological response to several cytokines released by eosinophils. Because of lack of understanding of the etiology and triggering factors, treatment is based mainly on corticosteroids; although other drugs acting on the immune system have been tested, the results are not always satisfactory. This review focuses on the epidemiology, pathophysiology, clinical features, and treatment of this hitherto under-diagnosed disease.

Prevalence of Hepatitis C Virus Infection among Hemodialysis Patients at a Tertiary-Care Hospital in Mexico City, Mexico

ABSTRACT We determined the prevalence of hepatitis C virus (HCV) in hemodialysis patients by antibody testing and HCV RNA determination by PCR. A total of 149 patients with kidney failure with replacement therapy were tested. The prevalence of anti-HCV was 6.7% (10 of 149 patients), and viremia was detectable in 8 of 149 (5%) patients. Three of 149 patients (2%) were anti-HCV negative with detectable HCV RNA.

Prophylactic Activated Recombinant Factor VII in Liver Resection and Liver Transplantation: Systematic Review and Meta-Analysis

Background and Aim Intraoperative blood loss is a frequent complication of hepatic resection and orthotopic liver transplantation. Recombinant activated coagulation factor VII (rFVIIa) is a coagulation protein that induces hemostasis by directly activating factor X. There is no clear information about the prophylactic value of rFVIIa in hepatobiliary surgery, specifically in liver resection and orthotopic liver transplantation. The aim of this study was to assess the effect of rFVIIa prophylaxis to prevent mortality and bleeding resulting from hepatobiliary surgery. Methods Relevant randomized trials were identified by searching The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index. Randomized clinical trials comparing different rFVIIa prophylactic schemas against placebo or no intervention to prevent bleeding in hepatobiliary surgery were included. Adults undergoing liver resection, partial hepatectomy, or orthotopic liver transplantation were included. Dichotomous data were analyzed calculating odds ratios (ORs) and 95% confidence intervals (CIs). Continuous data were analyzed calculating mean differences (MD) and 95% CIs. Results Four randomized controlled trials were included. There were no significant differences between rFVIIa and placebo for mortality (OR 0.96; 95% CI 0.35–2.62), red blood cell units (MD 0.32; 95% CI −0.08–0.72) or adverse events (OR 1.55; 95% CI 0.97–2.49). Conclusions The available information is limited, precluding the ability to draw conclusions regarding bleeding prophylaxis in hepatobiliary surgery using rFVIIa. Although an apparent lack of effect was observed in all outcomes studied, further research is needed.

Translational approaches: From fatty liver to non-alcoholic steatohepatitis

Over the past few decades, non-alcoholic fatty liver disease (NAFLD) has become one, if not the most common, cause of chronic liver disease affecting both adults and children. The increasing number of cases at an early age is the most worrying aspect of this pathology, since it provides more time for its evolution. The spectrum of this disease ranges from liver steatosis to steatohepatitis, fibrosis and in some cases, hepatocellular carcinoma. NAFLD may not always be considered a benign disease and hepatologists must be cautious in the presence of fatty liver. This should prompt the use of the available experimental models to understand better the pathogenesis and to develop a rational treatment of a disease that is dangerously increasing. In spite of the growing efforts, the pathogenesis of NAFLD is still poorly understood. In the present article we review the most relevant hypotheses and evidence that account for the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis. The available in vitro and in vivo experimental models of NASH are discussed and revised in terms of their validity in translational studies. These studies must be aimed at the discovery of the still unknown triggers or mediators that induce the progression of hepatic inflammation, apoptosis and fibrosis.

A systematic review and meta-analysis of the use of oral zinc in the treatment of hepatic encephalopathy

Background and aimBecause low serum zinc levels precipitate hepatic encephalopathy, zinc supplementation is considered a potential therapeutic option. The aim of this study was to assess the effects of oral zinc supplementation in the treatment of hepatic encephalopathy.MethodsFor this systematic review and meta-analysis, data sources included electronic databases (CENTRAL, MEDLINE, EMBASE) and manual searching. Randomized clinical trials of adult patients diagnosed with liver cirrhosis and hepatic encephalopathy were included. The types of interventions considered were any oral zinc supplementation versus no intervention, placebo, or other interventions for the management of hepatic encephalopathy. The data were analyzed by calculating the RR for each trial and expressing the uncertainty as 95% CI. Continuous data were analyzed by calculating the standard mean differences (SMD) between groups within each trial and their 95% CI. Statistical heterogeneity was defined as a P-value > 0.10 (χ2) or I2 > 25%.ResultsFour trials with a total of 233 patients were included. Oral zinc supplementation was associated with a significant improvement in performance on the number connection test (SMD –0.62; 95% CI –1.12 to –0.11) reported in three trials (n = 189), but not with encephalopathy recurrence reduction (RR 0.64; 95% CI 0.26 to 1.59) reported in two trials (n = 169). Other clinically significant outcomes (mortality, liver related morbidity, quality of life) were not reported.ConclusionOral zinc supplementation improved performance on the number connection test, but no evidence about other clinical or biochemical outcomes was available.

Acute-on-chronic liver failure: a review.

There is no universally accepted definition of acute-on-chronic liver failure; however, it is recognized as an entity characterized by decompensation from an underlying chronic liver disease associated with organ failure that conveys high short-term mortality, with alcoholism and infection being the most frequent precipitating events. The pathophysiology involves inflammatory processes associated with a trigger factor in susceptible individuals (related to altered immunity in the cirrhotic population). This review addresses the different definitions developed by leading research groups, epidemiological and pathophysiological aspects, and the latest treatments for this entity.

In Vitro Models for the Study of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease is regarded as the hepatic manifestation of metabolic syndrome and is an important and common cause of chronic liver disease with a potential to develop end-stage liver disease. While important advances in the pathophysiology have been achieved using genetically modified and diet-induced animal models, in-vitro models have been only recently proposed. These models include primary culture and immortalized cell lines. Here we critically review the characteristics of the in vitro models described, the advantages and limitations of the in vitro approach, and the results derived.