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Journal of Hepatology Jul 2020The exclusion of other chronic liver diseases including "excess" alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated... (Review)
Review
The exclusion of other chronic liver diseases including "excess" alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, given our current understanding of the pathogenesis of MAFLD and its rising prevalence, "positive criteria" to diagnose the disease are required. In this work, a panel of international experts from 22 countries propose a new definition for the diagnosis of MAFLD that is both comprehensive and simple, and is independent of other liver diseases. The criteria are based on evidence of hepatic steatosis, in addition to one of the following three criteria, namely overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. We propose that disease assessment and stratification of severity should extend beyond a simple dichotomous classification to steatohepatitis vs. non-steatohepatitis. The group also suggests a set of criteria to define MAFLD-associated cirrhosis and proposes a conceptual framework to consider other causes of fatty liver disease. Finally, we bring clarity to the distinction between diagnostic criteria and inclusion criteria for research studies and clinical trials. Reaching consensus on the criteria for MAFLD will help unify the terminology (e.g. for ICD-coding), enhance the legitimacy of clinical practice and clinical trials, improve clinical care and move the clinical and scientific field of liver research forward.
Topics: Causality; Consensus; Diabetes Mellitus, Type 2; Disease Progression; Fatty Liver; Humans; Liver Cirrhosis; Metabolic Diseases; Obesity; Terminology as Topic
PubMed: 32278004
DOI: 10.1016/j.jhep.2020.03.039 -
Drug Metabolism Reviews May 2017Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a "three-hit" process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 has been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may result in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters. Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 is more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 is up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major DMEs and transporters. We also discuss the potential mechanisms underlying these alterations.
Topics: Animals; Humans; Non-alcoholic Fatty Liver Disease; Pharmacokinetics
PubMed: 28303724
DOI: 10.1080/03602532.2017.1293683 -
BMC Medicine Feb 2017Non-alcoholic fatty liver disease has emerged a major challenge because of it prevalence, difficulties in diagnosis, complex pathogenesis, and lack of approved... (Review)
Review
Non-alcoholic fatty liver disease has emerged a major challenge because of it prevalence, difficulties in diagnosis, complex pathogenesis, and lack of approved therapies. As the burden of hepatitis C abates over the next decade, non-alcoholic fatty liver disease will become the major form of chronic liver disease in adults and children and could become the leading indication for liver transplantation. This overview briefly summarizes the most recent data on the pathophysiology, diagnosis, and treatment of non-alcoholic fatty liver disease. Ongoing clinical trials are focused on an array of disease mechanisms and reviewed here are how these treatments fit into the current paradigm of substrate overload lipotoxic liver injury. Many of the approaches are directed at downstream events such as inflammation, injury and fibrogenesis. Addressing more proximal processes such as dysfunctional satiety mechanisms and inappropriately parsimonious energy dissipation are potential therapeutic opportunities that if successfully understood and exploited would not only address fatty liver disease but also the other components of the metabolic syndrome such as obesity, diabetes and dyslipidemia.
Topics: Adult; Child; Humans; Non-alcoholic Fatty Liver Disease
PubMed: 28241825
DOI: 10.1186/s12916-017-0806-8 -
Gastroenterology Clinics of North... Dec 2016Nonalcoholic fatty liver disease (NAFLD) is an important cause of morbidity and mortality worldwide and is rapidly becoming the leading cause of end-stage liver disease... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is an important cause of morbidity and mortality worldwide and is rapidly becoming the leading cause of end-stage liver disease and liver transplant. With a prevalence of 30% in the United States, it has reached epidemic proportions. The clinical syndrome of NAFLD spans from bland steatosis to steatohepatitis, which can progress to fibrosis and cirrhosis. The pathogenesis includes the roles of hormones, nutritional and intestinal dysbiosis, insulin resistance, lipotoxicity, hepatic inflammation, and genes. Noninvasive testing and liver biopsy indications are reviewed. Approved and investigational therapies for NAFLD and nonalcoholic steatohepatitis are outlined in this article.
Topics: Combined Modality Therapy; Gastrointestinal Agents; Humans; Non-alcoholic Fatty Liver Disease; Risk Factors; Weight Reduction Programs
PubMed: 27837778
DOI: 10.1016/j.gtc.2016.07.003 -
Metabolism: Clinical and Experimental Aug 2016Nonalcoholic fatty liver disease (NAFLD) is the liver injury most often associated with disorders of insulin resistance, including obesity, diabetes and the metabolic... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is the liver injury most often associated with disorders of insulin resistance, including obesity, diabetes and the metabolic syndrome. The term encompasses several patterns of liver injury, including a relatively benign condition of steatosis without hepatocellular injury, nonalcoholic steatohepatitis (NASH), and a pattern of zone 1 steatosis, inflammation and fibrosis mainly observed in prepubertal children. Staging and grading systems have been developed to characterize the histological changes in NAFLD, mainly as a tool for clinical research. The histological features of NAFLD across these different manifestations and the scoring systems used to evaluate disease severity are discussed.
Topics: Biopsy; Fatty Liver; Humans; Liver; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease
PubMed: 26775559
DOI: 10.1016/j.metabol.2015.11.008 -
Science (New York, N.Y.) Jun 2011Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third of adults and an increasing number of children in developed countries. The... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third of adults and an increasing number of children in developed countries. The disease begins with the aberrant accumulation of triglyceride in the liver, which in some individuals elicits an inflammatory response that can progress to cirrhosis and liver cancer. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood, and therapeutic options are limited. Here, we discuss recent mechanistic insights into NAFLD, focusing primarily on those that have emerged from human genetic and metabolic studies.
Topics: Animals; Dietary Fats; Disease Models, Animal; Disease Progression; Fatty Liver; Female; Genetic Predisposition to Disease; Humans; Insulin Resistance; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Non-alcoholic Fatty Liver Disease; Obesity; Triglycerides
PubMed: 21700865
DOI: 10.1126/science.1204265 -
Nutrients Oct 2020Non-alcoholic fatty liver disease (NAFLD) is the first cause of chronic liver disease worldwide; it ranges from simple steatosis to steatohepatitis (NASH) and,... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is the first cause of chronic liver disease worldwide; it ranges from simple steatosis to steatohepatitis (NASH) and, potentially, cirrhosis and hepatocarcinoma. NAFLD is also an independent risk factor for type 2 diabetes, cardiovascular diseases, and mortality. As it is largely associated with insulin resistance and related disorders, NAFLD has been recently re-named as Metabolic dysfunction-Associated Fatty Liver Disease (MAFLD). At present, there are no approved pharmacological treatments for this condition. Vitamin D is a molecule with extensive anti-fibrotic, anti-inflammatory, and insulin-sensitizing properties, which have been proven also in hepatic cells and is involved in immune-metabolic pathways within the gut-adipose tissue-liver axis. Epidemiological data support a relationship hypovitaminosis D and the presence of NAFLD and steatohepatitis (NASH); however, results from vitamin D supplementation trials on liver outcomes are controversial. This narrative review provides an overview of the latest evidence on pathophysiological pathways connecting vitamin D to NAFLD, with emphasis on the effects of vitamin D treatment in MAFLD by a nonsystematic literature review of PubMed published clinical trials. This article conforms to the Scale for Assessment of Narrative Review Articles (SANRA) guidelines. Evidence so far available supports the hypothesis of potential benefits of vitamin D supplementation in selected populations of NAFLD patients, as those with shorter disease duration and mild to moderate liver damage.
Topics: Adipose Tissue; Clinical Trials as Topic; Dietary Supplements; Fatty Liver; Gastrointestinal Microbiome; Humans; Non-alcoholic Fatty Liver Disease; Receptors, Calcitriol; Vitamin D; Vitamin D Deficiency
PubMed: 33126575
DOI: 10.3390/nu12113302 -
Hepatology Communications Jan 2022The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related cirrhosis in the United States and globally highlights the need to better understand... (Review)
Review
The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related cirrhosis in the United States and globally highlights the need to better understand the mechanisms causing progression of hepatic steatosis to fibrosing steatohepatitis and cirrhosis in a small proportion of patients with NAFLD. Accumulating evidence suggests that lipotoxicity mediated by hepatic free cholesterol (FC) overload is a mechanistic driver for necroinflammation and fibrosis, characteristic of nonalcoholic steatohepatitis (NASH), in many animal models and also in some patients with NASH. Diet, lifestyle, obesity, key genetic polymorphisms, and hyperinsulinemia secondary to insulin resistance are pivotal drivers leading to aberrant cholesterol signaling, which leads to accumulation of FC within hepatocytes. FC overload in hepatocytes can lead to ER stress, mitochondrial dysfunction, development of toxic oxysterols, and cholesterol crystallization in lipid droplets, which in turn lead to hepatocyte apoptosis, necrosis, or pyroptosis. Activation of Kupffer cells and hepatic stellate cells by hepatocyte signaling and cholesterol loading contributes to this inflammation and leads to hepatic fibrosis. Cholesterol accumulation in hepatocytes can be readily prevented or reversed by statins. Observational studies suggest that use of statins in NASH not only decreases the substantially increased cardiovascular risk, but may ameliorate liver pathology. Conclusion: Hepatic FC loading may result in cholesterol-associated steatohepatitis and play an important role in the development and progression of NASH. Statins appear to provide significant benefit in preventing progression to NASH and NASH-cirrhosis. Randomized controlled trials are needed to demonstrate whether statins or statin/ezetimibe combination can effectively reverse steatohepatitis and liver fibrosis in patients with NASH.
Topics: Animals; Anticholesteremic Agents; Cholesterol; Cholesterol, Dietary; Ezetimibe; Fatty Liver; Homeostasis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Non-alcoholic Fatty Liver Disease; Risk Factors
PubMed: 34558856
DOI: 10.1002/hep4.1801 -
Digestive Diseases and Sciences May 2016Inflammation and hepatocyte injury and death are the hallmarks of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD),... (Review)
Review
Inflammation and hepatocyte injury and death are the hallmarks of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), which is a currently burgeoning public health problem. Innate immune activation is a key factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. Thus, identification of the underlying mechanisms by which immune cells in the liver recognize cell damage signals or the presence of pathogens or pathogen-derived factors that activate them is relevant from a therapeutic perspective. In this review, we present new insights into the factors promoting the inflammatory response in NASH including sterile cell death processes resulting from lipotoxicity in hepatocytes as well as into the altered gut-liver axis function, which involves translocation of bacterial products into portal circulation as a result of gut leakiness. We further delineate the key immune cell types involved and how they recognize both damage-associated molecular patterns or pathogen-associated molecular patterns through binding of surface-expressed pattern recognition receptors, which initiate signaling cascades leading to injury amplification. The relevance of modulating these inflammatory signaling pathways as potential novel therapeutic strategies for the treatment of NASH is summarized.
Topics: Cell Death; Fatty Liver; Humans; Immunity, Innate; Inflammation; Non-alcoholic Fatty Liver Disease
PubMed: 26841783
DOI: 10.1007/s10620-016-4049-x -
International Journal of Molecular... Jul 2021Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with a broad spectrum ranging from simple steatosis to advanced stage of... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with a broad spectrum ranging from simple steatosis to advanced stage of nonalcoholic steatohepatitis (NASH). Although there are many undergoing clinical trials for NAFLD treatment, there is no currently approved treatment. NAFLD accounts as a major causing factor for the development of hepatocellular carcinoma (HCC), and its incidence rises accompanying the prevalence of obesity and diabetes. Reprogramming of antidiabetic and anti-obesity medicine is a major treatment option for NAFLD and NASH. Liver inflammation and cellular death, with or without fibrosis account for the progression of NAFLD to NASH. Therefore, molecules and signaling pathways involved in hepatic inflammation, fibrosis, and cell death are critically important targets for the therapy of NAFLD and NASH. In addition, the avoidance of aberrant infiltration of inflammatory cytokines by treating with antagonists also provides a therapeutic option. Currently, there is an increasing number of pre-clinical and clinical trials undergoing to evaluate the effects of antidiabetic and anti-obesity drugs, antibiotics, pan-caspase inhibitors, / antagonists, and others on NAFLD, NASH, and liver fibrosis. Non-invasive serum diagnostic markers are developed for fulfilling the need of diagnostic testing in a large amount of NAFLD cases. Overall, a better understanding of the underlying mechanism of the pathogenesis of NAFLD is helpful to choose an optimized treatment.
Topics: Animals; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Fatty Liver; Humans; Non-alcoholic Fatty Liver Disease; Randomized Controlled Trials as Topic; Signal Transduction
PubMed: 34299189
DOI: 10.3390/ijms22147571