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Anna Mae Diehl - One of the best experts on this subject based on the ideXlab platform.
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Similarities and differences in the pathogenesis of alcoholic and nonalcoholic Steatohepatitis.
Seminars in liver disease, 2009Co-Authors: Wing-kin Syn, Vanessa Teaberry, Steve S. Choi, Anna Mae DiehlAbstract:Subpopulations of individuals with alcohol-induced fatty livers and nonalcoholic steatosis develop Steatohepatitis. Steatohepatitis is defined histologically: increased numbers of injured and dying hepatocytes distinguish this condition from simple steatosis. The increased hepatocyte death is generally accompanied by hepatic accumulation of inflammatory cells and sometimes increases in myofibroblastic cells, leading to hepatic fibrosis and eventually, cirrhosis. The purpose of this review is to summarize similarities and differences in the pathogenesis of Steatohepatitis in alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD).
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Cytokines and the pathogenesis of non-alcoholic Steatohepatitis
Gut, 2005Co-Authors: Anna Mae Diehl, H Z Lin, Shiqi YangAbstract:Histopathological characteristics distinguish Steatohepatitis from other causes of chronic liver injury. For years, the main cause of Steatohepatitis was thought to be excessive consumption of alcohol. Increasingly, Steatohepatitis is being diagnosed in individuals who deny alcohol abuse. Arbitrarily, “non-alcoholic” Steatohepatitis (NASH) is subcategorised into “primary” and “secondary” NASH.1 Primary NASH refers to Steatohepatitis that is associated with the dysmetabolic syndrome (that is, obesity, type 2 diabetes, dyslipidaemia).2 Primary NASH is thought to be the predominant form of NASH, afflicting at least as many individuals in the USA as chronic hepatitis C. Secondary NASH refers to Steatohepatitis that accompanies other syndromes (for example, lipodystrophy) or that is caused by certain drugs (for example, amiodarone).3 Accumulating evidence suggests that common mechanisms may mediate the pathogenesis of alcohol induced Steatohepatitis and primary NASH.4 Although unproven, it is likely that primary and secondary NASH also share common pathogenic mechanisms. ### Obesity Obesity, especially visceral adiposity, is a major risk factor for NASH in humans.5 Even if they do not have an elevated body mass index, patients with NASH are very likely to be insulin resistant.2 Basic research on fat cell (adipocyte) biology provides some clues about why obesity, insulin resistance, and NASH may be interrelated. Obesity increases adipose tissue mass. It has long been known that adipose tissue is a source of free fatty acids that are delivered to the liver and a depot for triglycerides that are synthesised by hepatocytes and released into the blood. Only recently however has the neuroendocrine role of adipose tissue been appreciated. Fat produces hormones, such as leptin, resistin, and adiponectin, that regulate metabolism in other tissues, as well as fat itself. Fat is also a source of neurotransmitters, such as noradrenaline and angiotensin II. In addition, because adipocytes produce immunomodulatory cytokines, such as …
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Animal models of Steatohepatitis.
Best practice & research. Clinical gastroenterology, 2002Co-Authors: Ayman Koteish, Anna Mae DiehlAbstract:Abstract Animal models of hepatic steatosis and Steatohepatitis have improved our understanding of the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Three models, genetically obese ob/ob mice, lipoatrophic mice and normal rats fed choline-deficient, methionine-restricted diets, have been particularly informative. All support the multiple ‘hit’ hypothesis for NAFLD pathogenesis that suggests that fatty livers are unusually vulnerable to oxidants and develop Steatohepatitis when secondary insults generate sufficient oxidants to cause liver cell death and inflammation. Steatohepatitis, in turn, increases sensitivity to other insults that induce hepatic fibrosis, promoting the evolution of cirrhosis. Early during NAFLD pathogenesis, inhibitor kappa kinase beta (IKKβ), an enzyme that induces tumour necrosis factor alpha (TNFα) and other proinflammatory cytokines, is activated and this causes insulin resistance. Inhibition of IKKβ or TNFα improves insulin sensitivity, steatosis and Steatohepatitis in animals, suggesting novel strategies to prevent and treat early NAFLD in humans.
B. Fromenty - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial dysfunction induced by xenobiotics Involvement in steatosis and Steatohepatitis
2019Co-Authors: K. Begriche, J. Massart, B. FromentyAbstract:Many xenobiotics are able to induce liver steatosis, also referred to as fatty liver. This liver lesion is benign, but it can progress in the long term to Steatohepatitis characterized by necroinflammation and fibrosis. The occurrence of Steatohepatitis is a major issue because it can evolve toward extensive fibrosis, cirrhosis, and even hepatocellular carcinoma. It has been acknowledged that mitochondrial dysfunction is a major mechanism whereby xenobiotics can induce steatosis and Steatohepatitis. Inhibition of mitochondrial fatty acid oxidation is responsible for fat accretion, and impairment of the respiratory chain activity can favor the progression of steatosis to Steatohepatitis via reduced ATP levels and reactive oxygen species overproduction. There also is increasing evidence that some steatogenic xenobiotics can worsen nonalcoholic fatty liver disease (NAFLD), a large spectrum of liver lesions occurring in the context of obesity and type 2 diabetes. These xenobiotics can either aggravate the intrahepatic accumulation of fat or accelerate the progression of fatty liver to nonalcoholic Steatohepatitis. Mitochondrial dysfunction is deemed to be one important mechanism involved in NAFLD worsening. © 2019 Elsevier Inc. All rights reserved.
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Mitochondrial Dysfunction Induced by Xenobiotics: Involvement in Steatosis and Steatohepatitis
Mitochondria in Obesity and Type 2 Diabetes, 2019Co-Authors: K. Begriche, J. Massart, B. FromentyAbstract:Abstract Many xenobiotics are able to induce liver steatosis, also referred to as fatty liver. This liver lesion is benign, but it can progress in the long term to Steatohepatitis characterized by necroinflammation and fibrosis. The occurrence of Steatohepatitis is a major issue because it can evolve toward extensive fibrosis, cirrhosis, and even hepatocellular carcinoma. It has been acknowledged that mitochondrial dysfunction is a major mechanism whereby xenobiotics can induce steatosis and Steatohepatitis. Inhibition of mitochondrial fatty acid oxidation is responsible for fat accretion, and impairment of the respiratory chain activity can favor the progression of steatosis to Steatohepatitis via reduced ATP levels and reactive oxygen species overproduction. There also is increasing evidence that some steatogenic xenobiotics can worsen nonalcoholic fatty liver disease (NAFLD), a large spectrum of liver lesions occurring in the context of obesity and type 2 diabetes. These xenobiotics can either aggravate the intrahepatic accumulation of fat or accelerate the progression of fatty liver to nonalcoholic Steatohepatitis. Mitochondrial dysfunction is deemed to be one important mechanism involved in NAFLD worsening.
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Mitochondrial injury in Steatohepatitis
European journal of gastroenterology & hepatology, 2004Co-Authors: Dominique Pessayre, B. Fromenty, Abdellah MansouriAbstract:Rich diet and lack of exercise are causing a surge in obesity, insulin resistance and steatosis, which can evolve into Steatohepatitis. Patients with non-alcoholic Steatohepatitis have increased lipid peroxidation, increased tumour necrosis factor-α (TNF-α) and increased mitochondrial β-oxidation ra
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Nonalcoholic steatosis and Steatohepatitis. V. Mitochondrial dysfunction in Steatohepatitis.
American journal of physiology. Gastrointestinal and liver physiology, 2002Co-Authors: Dominique Pessayre, Abdellah Mansouri, B. FromentyAbstract:Rich diet and lack of exercise are causing a surge in the prevalence of obesity and hepatic steatosis, which causes “primary” Steatohepatitis in some patients. Ultrastructural mitochondrial lesions, decreased activity of respiratory chain complexes, and impaired ability to synthesize ATP are observed in these patients. Reactive oxygen species (ROS) may increase tumor necrosis factor-α (TNF-α) production and also oxidize fat deposits. TNF-α and lipid peroxidation products impair the flow of electrons along the respiratory chain, causing overreduction of respiratory chain components and enhanced mitochondrial ROS formation. Steatohepatitis can also be due to alcohol, drugs, or other causes that either directly increase ROS formation or first impair respiration, which secondarily increases ROS formation. Higher ROS formation in secondary Steatohepatitis could cause more lipid peroxidation, cytokine induction, and fibrogenesis than in primary Steatohepatitis.
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Mitochondria in Steatohepatitis.
Seminars in liver disease, 2001Co-Authors: Dominique Pessayre, B. Fromenty, Alain Berson, Abdellah MansouriAbstract:For the first time in history, populations in affluent countries may concomitantly indulge in rich food and physical idleness. Various combinations of obesity, diabetes, and hypertriglyceridemia, with insulin resistance as the common feature, cause hepatic steatosis, which can trigger necroinflammation and fibrosis. Patients with "primary" Steatohepatitis exhibit ultrastructural mitochondrial lesions, decreased activity of respiratory chain complexes, and have impaired ability to resynthesize ATP after a fructose challenge. Mitochondria play a major role in fat oxidation and energy production but also leak reactive oxygen species (ROS) and are the main cellular source of ROS. In patients with steatosis, mitochondrial ROS may oxidize hepatic fat deposits, as suggested in animal models. Lipid peroxidation products impair the flow of electrons along the respiratory chain, which may cause overreduction of respiratory chain components, further increasing mitochondrial ROS formation and lipid peroxidation. Another vicious circle could involve ROS-induced depletion of antioxidants, impairing ROS inactivation. Blood vitamin E is decreased in some obese children with Steatohepatitis, and serum transaminases improve after vitamin E supplementation. Steatohepatitis is also caused by alcohol abuse, drugs, and other causes. In "secondary" Steatohepatitis, mitochondrial ROS formation is further increased as the causative disease itself directly increases ROS or first impairs respiration, which secondarily increases mitochondrial ROS formation. This "second hit" could cause more lipid peroxidation, cytokine induction, Fas ligand induction, and fibrogenesis than in primary Steatohepatitis.
Geoffrey C Farrell - One of the best experts on this subject based on the ideXlab platform.
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lipid peroxidation stellate cell activation and hepatic fibrogenesis in a rat model of chronic Steatohepatitis
Journal of Hepatology, 2003Co-Authors: Jacob George, Natasha Pera, Nghi Phung, Isabelle Leclercq, Jing Yun Hou, Geoffrey C FarrellAbstract:The MCD model of 'fibrosing Steatohepatitis' replicates the histologic features of human Steatohepatitis, and the sequence of steatosis, inflammatory cell injury and fibrogenesis. The temporal sequence is consistent with a concept for involvement of oxidative injury in inflammatory recruitment and pathogenesis of hepatic fibrogenesis.
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Drugs and Steatohepatitis
Seminars in Liver Disease, 2002Co-Authors: Geoffrey C FarrellAbstract:In addition to the usual associations with insulin resistance, type 2 diabetes, central obesity, and hypertriglyceridemia, nonalcoholic Steatohepatitis (NASH) has been associated with several drugs and toxins. However, drug-induced liver disease is a relatively uncommon cause of Steatohepatitis. The term drug-induced Steatohepatitis is preferred when the association appears to result from a direct toxic effect of the drug on the liver. For some agents implicated as causing cirrhosis or fatty liver disorders, the association may be coincidental because NASH is a common component of the insulin resistance (or metabolic) syndrome. In other instances, corticosteroids, tamoxifen, and estrogens may precipitate NASH in predisposed persons by exacerbating insulin resistance, central obesity, diabetes, and hypertriglyceridemia, and methotrexate may worsen hepatic fibrosis in NASH. Drug-induced Steatohepatitis is associated with prolonged therapy (more than 6 months) and possibly drug accumulation, which in the case of perhexiline maleate is favored by a genetic polymorphism of CYP2D6 that leads to slow perhexiline oxidation. The toxic mechanism appears to involve mitochondrial injury, which causes steatosis because of impaired beta-oxidation of fatty acids, and leads to generation of reactive oxygen species and ATP depletion. Thus, drug-induced Steatohepatitis may provide clues to injurious events in the more common metabolic forms of NASH. A clinical feature of some types of drug-induced Steatohepatitis is progression after discontinuation of the causative agent. It follows that early recognition of hepatotoxicity is crucial to prevent the development of severer forms of liver disease and improve the clinical outcome.
Sarah Safranek - One of the best experts on this subject based on the ideXlab platform.
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Metformin for Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis.
American family physician, 2019Co-Authors: Samira Farah, Thu Nguyen, Gary Kelsberg, Sarah SafranekAbstract:Metformin does not seem to be an effective treatment for nonalcoholic Steatohepatitis. There are no studies evaluating whether metformin improves long-term patient-oriented outcomes such as progression from NAFLD to nonalcoholic Steatohepatitis, cirrhosis, hepatocellular carcinoma, or death from liver failure.
Gagan Sood - One of the best experts on this subject based on the ideXlab platform.
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effect of bariatric surgery on nonalcoholic fatty liver disease systematic review and meta analysis
Clinical Gastroenterology and Hepatology, 2008Co-Authors: Rajasekhara R Mummadi, Krishna S Kasturi, Swapna Chennareddygari, Gagan SoodAbstract:Background & Aims Weight loss in overweight or obese individuals results in marked improvement or resolution of hypertension, diabetes mellitus, and hyperlipidemia. However, the overall effect of weight loss on nonalcoholic fatty liver disease (NAFLD) remains unclear. This systematic review and meta-analysis is an effort to explore the effect of weight loss after bariatric surgical procedures on NAFLD. Methods We performed an electronic literature search of published articles on bariatric surgery and liver histology since inception to September of 2007. Primary outcome measures were improvement and/or resolution in the 3 components of NAFLD (steatosis, Steatohepatitis, and fibrosis) after bariatric surgery–induced weight loss. A pooled proportion of patients with improvement or resolution was calculated for steatosis, Steatohepatitis, and fibrosis using a random effects model. Heterogeneity among the studies was assessed using the I 2 (inconsistency) statistic and subgroup analyses. Results A total of 15 studies (766 paired liver biopsies) were selected for final data extraction. The percentage reduction in mean body mass index after bariatric surgeries ranged from 19.11 to 41.76. The pooled proportion of patients with improvement or resolution in steatosis was 91.6% (95% confidence interval [CI], 82.4%–97.6%), in Steatohepatitis was 81.3% (95% CI, 61.9%–94.9%), in fibrosis was 65.5% (95% CI, 38.2%–88.1%), and for complete resolution of nonalcoholic Steatohepatitis was 69.5 (95% CI, 42.4%–90.8%). Conclusions Steatosis, Steatohepatitis, and fibrosis appear to improve or completely resolve in the majority of patients after bariatric surgery–induced weight loss.
