Correlation of serum aspartate aminotransferase level to platelet count ratio index with non-alcoholic fatty liver disease activity score

In case of non-alcoholic fatty liver disease, the ratio of serum aspartate  aminotransferase (AST) level to platelet count index has been proposed as a non-invasive and readily available tool for the assessment of non-alcoholic steatohepatitis. The study was conducted on 50  non-alcoholic fatty liver disease patient (25  non-alcoholic steatohepatitis and 25 simple steatosis). The mean (± SD) serum AST level in the non-alcoholic steatohepatitis group  was 55.2 ± 30.1 IU/L whereas in simple steatosis group it was 33.6 ± 20.0 IU/L. The mean platelet count in the non-alcoholic steatohepatitis group was 303.1 ± 68.7 x 109 /L whereas in the simple steatosis group it was 327.8 ± 66.8 x 109/L. The mean AST platelet ratio index (APRI) score in non-alcoholic steatohepatitis group was 0.5 ± 0.3 and in the simple steatosis group it was 0.3 ± 0.2. In conclusion, the APRI  was  significantly higher in the non-alcoholic steatohepatitis group than the simple steatosis group

Outcomes and potential surrogate markers for future clinical trials of non-alcoholic steatohepatitis cirrhosis

Non-alcoholic steatohepatitis has emerged as a major public health problem, and the burden of non-alcoholic steatohepatitis cirrhosis is projected to increase by 64%-156% by 2030. The threat is aggravated by the fact that are currently no approved drugs for the treatment of non-alcoholic steatohepatitis. In this paper, we review the main challenges to drug development in patients with non-alcoholic steatohepatitis cirrhosis, and describe the opportunities brought by the advances in the understanding of the clinical and pathophysiological nuances of cirrhosis. The design of therapeutic regimens for non-alcoholic steatohepatitis cirrhosis will vary according to the specific cirrhosis substage (compensated vs decompensated), and the specific mechanistic basis of therapy, targeted either at improving aetiology-specific pathways and/or at more general aetiology-agnostic processes. The understanding of the probabilistic expectations for the whole range of potential outcomes, rooted at different mechanistic drivers at each specific substage, will be essential in order to choose adequate estimands and therapeutic strategies for clinical trials and individual patients with non-alcoholic steatohepatitis cirrhosis. Finally, we provide a summary of the main pitfalls and uncertainties in the design of clinical trials for non-alcoholic steatohepatitis cirrhosis and discuss potential biomarkers for use in trials and practice for these patient

Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice

While gap junctions mediate intercellular communication and support liver homeostasis, connexin hemichannels are preferentially opened by pathological stimuli, including inflammation and oxidative stress. The latter are essential features of non-alcoholic steatohepatitis. In this study, it was investigated whether connexin32 and connexin43 hemichannels play a role in non-alcoholic steatohepatitis. Mice were fed a choline-deficient high-fat diet or normal diet for 8 weeks. Thereafter, TAT-Gap24 or TAT-Gap19, specific inhibitors of hemichannels composed of connexin32 and connexin43, respectively, were administered for 2 weeks. Subsequently, histopathological examination was carried out and various indicators of inflammation, liver damage and oxidative stress were tested. In addition, whole transcriptome microarray analysis of liver tissue was performed. Channel specificity of TAT-Gap24 and TAT-Gap19 was examined in vitro by fluorescence recovery after photobleaching analysis and measurement of extracellular release of adenosine triphosphate. TAT-Gap24 and TAT-Gap19 were shown to be hemichannel-specific in cultured primary hepatocytes. Diet-fed animals treated with TAT-Gap24 or TAT-Gap19 displayed decreased amounts of liver lipids and inflammatory markers, and augmented levels of superoxide dismutase, which was supported by the microarray results. These findings show the involvement of connexin32 and connexin43 hemichannels in non-alcoholic steatohepatitis and, simultaneously, suggest a role as potential drug targets in non-alcoholic steatohepatitis

NASH: Non-Alcoholic Steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease which refers to the presence of hepatic steatosis without significant intake of alcohol. Non-alcoholic fatty liver disease develops in a variety of forms from reversible simple steatosis to non-alcoholic steatohepatitis (NASH), which if left unchecked can progress to liver fibrosis, cirrhosis and even develop into hepatocellular carcinoma (Mells et al., 2014). NAFLD is thought to be nonthreatening, but with progression over several years could lead to NASH. A strong link between obesity and NASH has been shown. In addition to obesity, insulin resistance (type II diabetes mellitus), and hyperlipidemia all common components of metabolic syndrome, is frequently associated with NAFLD (Nseiri, Mograbi, & Ghali, 2012). If NAFLD goes undetected and progresses, steatohepatitis a serious inflammation of the liver can occur. Steatosis is a term used to describe any condition that allows fat to deposit within the interstitial spaces of an organ. Steatohepatitis comes in two forms. alcohol-related and non-alcoholic related. The distinction of hepatic steatosis lays in excessive alcohol consumption verses little to no alcohol consumption

Imbalance of the Humoral Component of the Immune System as a Basis for the Progression of Non-Alcoholic Fatty Liver Disease in Patients with Obesity and Concomitant Biliary Tract Pathology

The objective of the research was to study the features of the indicators of the humoral component of the immune system depending on the body mass index in patients with non-alcoholic hepatic steatosis, non-alcoholic steatohepatitis, concomitant obesity and biliary tract pathology.Material and methods. 200 patients with non-alcoholic fatty liver disease, concomitant obesity and biliary tract pathology including 100 patients with non-alcoholic hepatic steatosis and 100 with non-alcoholic steatohepatitis were examined. 70 out of 100 patients with non-alcoholic steatohepatitis had the minimum level of alanine transaminase activity and 30 patients had a moderate alanine transaminase activity. The control group included 30 apparently healthy persons. The body mass index was determined using the Quetelet formula. All the patients with non-alcoholic hepatic steatosis and non-alcoholic steatohepatitis were divided into three groups depending on the increase in the body mass index and the presence of biliary tract pathology. The humoral immune system state was evaluated by the levels of immunoglobulins A, M and G and the content of circulating immune complexes. Results. In patients with non-alcoholic hepatic steatosis and non-alcoholic steatohepatitis, concomitant obesity and biliary tract pathology, there were observed abnormalities in the humoral component of the immune system with possible increase in the levels of major immunoglobulin classes as well as in the content of circulating immune complexes being more pronounced in patients with non-alcoholic steatohepatitis compared to patients with non-alcoholic hepatic steatosis (p<0.05) and apparently healthy persons (p<0.001). The increase in the body mass index led to a significant increase in the levels of Ig A, M, G and the activation of circulating immune complexes.More significant changes in humoral indices were observed in patients with chronic non-calculous and calculous cholecystitis in the presence of inflammatory biliary tract changes during the exacerbation of the pathology compared to patients who underwent cholecystectomy on the background of the aggravation of postcholecystectomy syndrome.Conclusions. The obtained data indicated that one of the elements in the pathogenesis of non-alcoholic fatty liver disease with concomitant obesity and biliary tract pathology is a significant change in the indicators of humoral immunity, namely the increase in the levels of Ig (A, M, G) and circulating immune complexes which depend on the clinical form (non-alcoholic hepatic steatosis or non-alcoholic steatohepatitis), increase in the body mass index and the presence of biliary tract comorbidity

Rapid development of non-alcoholic steatohepatitis in Psammomys obesus (Israeli sand rat)

Background and Aims: A major impediment to establishing new treatments for non-alcoholic steatohepatitis is the lack of suitable animal models that accurately mimic the biochemical and metabolic characteristics of the disease. The aim of this study was to explore a unique polygenic animal model of metabolic disease as a model of non-alcoholic steatohepatitis by determining the effects of 2% dietary cholesterol supplementation on metabolic and liver endpoints in Psammomys obesus (Israeli sand rat). Methods: P. obesus were provided ad libitum access to either a standard rodent diet (20% kcal/fat) or a standard rodent diet supplemented with 2% cholesterol (w/w) for 4 weeks. Histological sections of liver from animals on both diets were examined for key features of non-alcoholic steatohepatitis. The expression levels of key genes involved in hepatic lipid metabolism were measured by real-time PCR. Results: P. obesus fed a cholesterol-supplemented diet exhibited profound hepatomegaly and steatosis, and higher plasma transaminase levels. Histological analysis identified extensive steatosis, inflammation, hepatocyte injury and fibrosis. Hepatic gene expression profiling revealed decreased expression of genes involved in delivery and uptake of lipids, and fatty acid and triglyceride synthesis, and increased expression of genes involved in very low density lipoprotein cholesterol synthesis, triglyceride and cholesterol export. Conclusions: P. obesus rapidly develop non-alcoholic steatohepatitis when fed a cholesterol-supplemented diet that appears to be histologically and mechanistically similar to patients. © 2014 Spolding et al

Immune and Inflammatory Pathways in Non-Alcoholic Steatohepatitis (NASH). An update

Non-alcoholic steatohepatitis (NASH), also known as fatty liver disease (FLD), is a major public health problem. It is considered to be the hepatic manifestation of the metabolic syndrome. Chronic inflammation of the liver is an essential key in the progression from simple hepatic steatosis to steatohepatitis, the evolutionary stage of fatty liver disease. Moreover, the innate immune system plays a crucial role in the progression of hepatic inflammation. For this reason, it is of utmost importance to elucidate the connections between immune mechanisms, Toll-like receptor cytokine signalling, in order to find new effective treatments. Further studies are necessary to test theories presented in this paper. The elucidation of mechanisms underlying the progression of hepatic steatosis towards steatohepatitis is essential for the development of useful diagnosis and treatment for medical practice

Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH

Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM

The effect of 12 weeks regular physical activity and vitamin E in the treatment of non-alcoholic steatohepatitis: A pilot study

Background: Despite the prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH), there was no treatment has been proven to be effective in these common diseases. Although many studies have shown that lifestyle modifications such as increasing physical activities and exercise could be effective in the treatment of these common diseases, the optimal strategy was still not determined. According to the beneficial effects of antioxidant agents in the treatment of NASH, vitamin E has been used for this purpose by some clinicians. We designed this study for assessing beneficial effects of regular physical activity on the biochemical and imaging responses in patients with NASH and comparing this with vitamin E as an accepted treatment for NASH. Materials and Methods: This study was Randomized and single-blind clinical trials were carried out in Gonbad-e Kavus through which a total of 30 consecutive patients with the ultra sonographic diagnosis of non-alcoholic steatohepatitis (NASH)were enrolled and randomized to one of the three groups: Vitamin E 800 mg/day, regular physical activity, or both. Results: In all treatment groups improvement in liver transaminases level, serum lipids and ultrasonographic grading of fatty liver occurred after three months of treatment. When these decrement was compared between the treatment groups, there was no statistically significant difference in the value of improvement between the three groups (ANOVA: p>0.5). I.e. all three interventions improved the biochemical and ultrasonographic finding of fatty liver in the same way. Both groups with regular exercise had significant mean weight loss in comparison with the vitamin E group (a mean decrease of 3.0 kg in exercise group, 5.8 kg in subjects on regular exercise plus vitamin E and 0.2 kg in vitamin E group, ANOVA: p=0.04). Conclusion: There were no significant differences between exercise and vitamin E alone or in combination regarding the reduction in the level of liver enzymes and sonographic evidences of fatty liver although both resulted in significant improvements in biochemical endpoints. This implies that physical activity could be considered as effective as vitamin E in the improvement of biochemical and ultrasonographic presentations of NASH and the addition of Vitamin E does not offer any benefits. According to the findings of this pilot study a full-powered study with a control group should be designed. © 2015, Iranian Association of Gastroenterology and Hepatology. All rights reserved

Novel Molecular Mechanisms in the Development of Non-Alcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in adults and children worldwide. NAFLD has become a severe health issue and it can progress towards a more severe form of the disease, the non-alcoholic steatohepatitis (NASH). A combination of environmental factors, host genetics, and gut microbiota leads to excessive accumulation of lipids in the liver (steatosis), which may result in lipotoxicity and trigger hepatocyte cell death, liver inflammation, fibrosis, and pathological angiogenesis. NASH can further progress towards liver cirrhosis and cancer. Over the last few years, cell-derived extracellular vesicles (EVs) have been identified as effective cell-to-cell messengers that transfer several bioactive molecules in target cells, modulating the pathogenesis and progression of NASH. In this review, we focused on recently highlighted aspects of molecular pathogenesis of NASH, mediated by EVs via their bioactive components. The studies included in this review summarize the state of art regarding the role of EVs during the progression of NASH and bring novel insight about the potential use of EVs for diagnosis and therapeutic strategies for patients with this disease