Non-alcoholic Steatohepatitis Pathogenesis, Diagnosis, and Treatment.
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ABSTRACT:
SUBMITTER: Zhu B
PROVIDER: S-EPMC8452937 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
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Non-alcoholic Steatohepatitis Pathogenesis, Diagnosis, and Treatment.
Zhu Bo B Chan Siu-Lung SL Li Jack J Li Kathryn K Wu Hao H Cui Kui K Chen Hong H
Frontiers in cardiovascular medicine 20210907
There has been a rise in the prevalence of non-alcohol fatty liver disease (NAFLD) due to the popularity of western diets and sedentary lifestyles. One quarter of NAFLD patients is diagnosed with non-alcoholic steatohepatitis (NASH), with histological evidence not only of fat accumulation in hepatocytes but also of liver cell injury and death due to long-term inflammation. Severe NASH patients have increased risks of cirrhosis and liver cancer. In this review, we discuss the pathogenesis and cur ...[more]
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Project description:The initial presentation of non-alcoholic steatohepatitis (NASH) is hepatic steatosis. The dysfunction of lipid metabolism within hepatocytes caused by genetic factors, diet, and insulin resistance causes lipid accumulation. Lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress would further contribute to hepatocyte injury and death, leading to inflammation and immune dysfunction in the liver. During the healing process, the accumulation of an excessive amount of fibrosis might occur while healing. During the development of NASH and liver fibrosis, the gut-liver axis, adipose-liver axis, and renin-angiotensin system (RAS) may be dysregulated and impaired. Translocation of bacteria or its end-products entering the liver could activate hepatocytes, Kupffer cells, and hepatic stellate cells, exacerbating hepatic steatosis, inflammation, and fibrosis. Bile acids regulate glucose and lipid metabolism through Farnesoid X receptors in the liver and intestine. Increased adipose tissue-derived non-esterified fatty acids would aggravate hepatic steatosis. Increased leptin also plays a role in hepatic fibrogenesis, and decreased adiponectin may contribute to hepatic insulin resistance. Moreover, dysregulation of peroxisome proliferator-activated receptors in the liver, adipose, and muscle tissues may impair lipid metabolism. In addition, the RAS may contribute to hepatic fatty acid metabolism, inflammation, and fibrosis. The treatment includes lifestyle modification, pharmacological therapy, and non-pharmacological therapy. Currently, weight reduction by lifestyle modification or surgery is the most effective therapy. However, vitamin E, pioglitazone, and obeticholic acid have also been suggested. In this review, we will introduce some new clinical trials and experimental therapies for the treatment of NASH and related fibrosis.
| S-EPMC9845678 | biostudies-literature
Project description:Multiple parallel hits, including genetic differences, insulin resistance and intestinal microbiota, account for the progression of non-alcoholic steatohepatitis (NASH). Multiple hits induce adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level that subsequently induce hepatic steatosis, inflammation and fibrosis, among which oxidative stress is considered a key contributor to progression from simple fatty liver to NASH. Although several clinical trials have shown that anti-oxidative therapy can effectively control hepatitis activities in the short term, the long-term effect remains obscure. Several trials of long-term anti-oxidant protocols aimed at treating cerebrovascular diseases or cancer development have failed to produce a benefit. This might be explained by the non-selective anti-oxidative properties of these drugs. Molecular hydrogen is an effective antioxidant that reduces only cytotoxic reactive oxygen species (ROS) and several diseases associated with oxidative stress are sensitive to hydrogen. The progress of NASH to hepatocellular carcinoma can be controlled using hydrogen-rich water. Thus, targeting mitochondrial oxidative stress might be a good candidate for NASH treatment. Long term clinical intervention is needed to control this complex lifestyle-related disease.
| S-EPMC3821639 | biostudies-literature
Project description:BackgroundNon-alcoholic steatoheaptitis (NASH), the critical stage of non-alcoholic fatty liver disease (NAFLD), is of chronic progression and can develop cirrhosis even hepatocellular carcinoma (HCC). However, non-invasive biomarkers for NASH diagnosis remain poorly applied in clinical practice. Our study aims at testing the accuracy of the combination of cytokeratin-18 M30 fragment (CK-18-M30), fibroblast growth factor 21 (FGF-21), interleukin 1 receptor antagonist (IL-1Ra), pigment epithelium-derived factor (PEDF) and osteoprotegerin (OPG) in diagnosing NAFLD and NASH.Methods179 patients with biopsy-proven NAFLD were enrolled as training group, 91 age- and gender-matched healthy subjects were recruited at the same time as controls. 63 other NAFLD patients were separately collected as validation group. 45 alcoholic fatty liver disease (AFLD) patients, 50 hepatitis B virus (HBV) patients, 52 hepatitis C virus (HCV) patients were also included. Serum biomarker levels were measured by enzyme-linked immunosorbent assay.ResultsSerum levels of CK-18-M30, FGF-21, IL-1Ra and PEDF increased, while OPG decreased in a stepwise fashion in controls, non-NASH NAFLD patients and NASH patients (P < 0.01). The area under receiver-operating characteristics curve to diagnose NASH was 0.86 for CK-18-M30, 0.89 for FGF-21, 0.89 for IL-1Ra, 0.89 for PEDF and 0.89 for OPG. CK-18-M30 had 70% negative predictive value (NPV) and 79% positive predictive value (PPV) to diagnose NASH. A 5-step approach measuring CK-18-M30 followed by FGF21, IL-1Ra, PEDF and OPG gradually improved the NPV to 76% and PPV to 85%, which reached 80% and 76% respectively in the validation cohort.ConclusionCompared to single biomarker, stepwise combination of CK-18-M30, FGF-21, IL-1Ra, PEDF and OPG can further improve the accuracy in diagnosing NASH.
| S-EPMC4486729 | biostudies-literature
Project description:This paper is based upon the "Charles Lieber Satellite Symposia" organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human immunodeficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible repair. We aim to (1) determine the immuno-pathology of alcohol-induced liver damage, (2) examine the role of genetics in the development of ASH, (3) propose diagnostic markers of ASH and NASH, (4) examine age differences, (5) develop common research tools to study alcohol-induced effects in clinical and pre-clinical studies, and (6) focus on factors that aggravate severity of organ-damage. The intention of these symposia is to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.
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Project description:While metabolic syndrome and alcohol consumption are the two main causes of chronic liver disease, one of the two conditions is often predominant, with the other acting as a cofactor of morbimortality. It has been shown that obesity and alcohol act synergistically to increase the risk of fibrosis progression, hepatic carcinogenesis and mortality, while genetic polymorphisms can strongly influence disease progression. Based on common pathogenic pathways, there are several potential targets that could be used to treat both diseases; based on the prevalence and incidence of these diseases, new therapies and clinical trials are needed urgently.
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Project description:Background and aimsNon-alcoholic fatty liver disease (NAFLD) is a usual chronic liver disease and lacks non-invasive biomarkers for the clinical diagnosis and prognosis. Extracellular vesicles (EVs), a group of heterogeneous small membrane-bound vesicles, carry proteins and nucleic acids as promising biomarkers for clinical applications, but it has not been well explored on their lipid compositions related to NAFLD studies. Here, we investigate the lipid molecular function of urinary EVs and their potential as biomarkers for non-alcoholic steatohepatitis (NASH) detection.MethodsThis work includes 43 patients with non-alcoholic fatty liver (NAFL) and 40 patients with NASH. The EVs of urine were isolated and purified using the EXODUS method. The EV lipidomics was performed by LC-MS/MS. We then systematically compare the EV lipidomic profiles of NAFL and NASH patients and reveal the lipid signatures of NASH with the assistance of machine learning.ResultsBy lipidomic profiling of urinary EVs, we identify 422 lipids mainly including sterol lipids, fatty acyl lipids, glycerides, glycerophospholipids, and sphingolipids. Via the machine learning and random forest modeling, we obtain a biomarker panel composed of 4 lipid molecules including FFA (18:0), LPC (22:6/0:0), FFA (18:1), and PI (16:0/18:1), that can distinguish NASH with an AUC of 92.3%. These lipid molecules are closely associated with the occurrence and development of NASH.ConclusionThe lack of non-invasive means for diagnosing NASH causes increasing morbidity. We investigate the NAFLD biomarkers from the insights of urinary EVs, and systematically compare the EV lipidomic profiles of NAFL and NASH, which holds the promise to expand the current knowledge of disease pathogenesis and evaluate their role as non-invasive biomarkers for NASH diagnosis and progression.
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Project description:Hepatocellular carcinoma(HCC) is the sixth most common cancer in the world and is usually caused by viral hepatitis (HBV and HCV), alcoholic, and non-alcoholic fatty liver disease(NAFLD). Viral hepatitis accounts for 80% of HCC cases worldwide. In addition, With the increasing incidence of metabolic diseases, NAFLD is now the most common liver disease and a major risk factor for HCC in most developed countries. This review mainly described the specificity and similarity between the pathogenesis of viral hepatitis(HBV and HCV)-induced HCC and NAFLD-induced HCC. In general, viral hepatitis promotes HCC development mainly through specific encoded viral proteins. HBV can also exert its tumor-promoting mechanism by integrating into the host chromosome, while HCV cannot. Viral hepatitis-related HCC and NASH-related HCC differ in terms of genetic factors, and epigenetic modifications (DNA methylation, histone modifications, and microRNA effects). In addition, both of them can lead to HCC progression through abnormal lipid metabolism, persistent inflammatory response, immune and intestinal microbiome dysregulation.
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