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Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

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Date added: 11/01/2018
Date modified: 11/01/2018
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NAFLD is one of the most important causes of liver disease worldwide and will probably emerge as the leading cause of end-stage liver disease in the coming decades, with the disease affecting both adults and children. The epidemiology and demographic characteristics of NAFLD vary worldwide, usually parallel to the prevalence of obesity, but a substantial proportion of patients are lean. The large number of patients with NAFLD with potential for progressive liver disease creates challenges for screening, as the diagnosis of NASH necessitates invasive liver biopsy. Furthermore, individuals with NAFLD have a high frequency of metabolic comorbidities and could place a growing strain on health-care systems from their need for management. While awaiting the development effective therapies, this disease warrants the attention of primary care physicians, specialists and health policy makers.

Genome-scale study reveals reduced metabolic adaptability in patients with NAFLD Genome-scale study reveals reduced metabolic adaptability in patients with NAFLD

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Date added: 02/20/2016
Date modified: 11/07/2016
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Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD.

Genetics of alcoholic liver disease Genetics of alcoholic liver disease

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Date added: 05/22/2016
Date modified: 05/22/2016
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Excess alcohol consumption with consequent alcoholic liver disease (ALD) is a common cause of liver dysfunction and liver-related mortality worldwide. However, although the majority of heavy drinkers will develop steatosis, only a minority progress to advanced liver disease and cirrhosis. Thus, ALD is a complex disease where subtle inter-patient genetic variations and environmental factors interact to determine disease progression. One genome-wide association study specifically addressing genetic modifiers of ALD has been published. However, most of our understanding is based on studies conducted on nonalcoholic fatty liver disease. Translation of candidates from these studies into ALD has established a role for variants in genes including PNPLA3 and potentially TM6SF2 across the disease spectrum from steatosis, through cirrhosis to hepatocellular carcinoma. Here the authors review the current status of the field with a particular focus on recent advances.

Genetic Factors that Affect Risk of Alcoholic and Non-Alcoholic Fatty Liver Disease Genetic Factors that Affect Risk of Alcoholic and Non-Alcoholic Fatty Liver Disease

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Date added: 03/05/2017
Date modified: 03/05/2017
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Genome-wide association studies and candidate gene studies have informed our understanding of factors contributing to the well-recognized interindividual variation in the progression and outcomes of alcoholic liver disease and nonalcoholic fatty liver disease. We discuss the mounting evidence for shared modifiers and common pathophysiological processes that contribute to development of both diseases. We discuss the functions of proteins encoded by risk variants of genes including patatin-like phospholipase domain-containing 3 and transmembrane 6 superfamily member 2, as well as epigenetic factors that contribute to the pathogenesis of alcoholic liver disease and nonalcoholic fatty liver disease. We also discuss important areas of future genetic research and their potential to affect clinical management of patients.

Fibrosis and alcohol-related liver disease Fibrosis and alcohol-related liver disease

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Date added: 08/10/2019
Date modified: 08/10/2019
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Histological fibrosis stage is one of the most important prognostic factors in compensated and decompensated alcohol-related liver disease (ALD). Morphological assessment of fibrosis is useful for patient stratification, enabling individualised management, and for evaluation of treatment effects in clinical studies. In contrast to most chronic liver diseases where fibrosis is portal-based, fatty liver disease (FLD) of alcoholic or non-alcoholic aetiology (NAFLD) is associated with a centrilobular pattern of injury which leads to perivenular fibrosis and/or pericellular fibrosis. Progression of FLD drives expansive pericellular fibrosis, linking vascular structures and paving the way for the development of cirrhosis. At the cirrhotic stage, ongoing tissue damage leads to increasing fibrosis severity due to parenchymal loss and proliferation of fibrous scars. Histologic fibrosis staging systems have been devised, based on topography and the extent of fibrosis, for most chronic liver diseases. The utility of histological staging is reflected in different risks associated with individual fibrosis stages which cannot be reliably distinguished by non-invasive fibrosis assessment. In contrast to NAFLD, ALD-specific staging systems that enable the standardised prognostication required for clinical management and trials are lacking. Although morphological similarities between NAFLD and ALD exist, differences in clinical and histological features may substantially limit the utility of established NAFLD-specific staging systems for prognostication in ALD. This review summarises morphological features of fibrosis in ALD and compares them to other chronic liver diseases, particularly NAFLD. ALD-related fibrosis is examined in the context of pathogenetic mechanisms of fibrosis progression, regression and clinical settings that need to be considered in future prognostically relevant ALD staging approaches.

Fibrogenesis assessed by serological type III collagen formation identifies patients with progressiv Fibrogenesis assessed by serological type III collagen formation identifies patients with progressiv

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Date added: 11/07/2016
Date modified: 11/07/2016
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Elevated Pro-C3 levels are indicative of active fibrogenesis and structural progression of fibrosis and can potentially identify patients most likely to benefit from anti-metabolic and potential anti-fibrotic treatments. Serum Pro-C3 may facilitate patient selection and could help to speed up anti-fibrotic drug development and validation.

Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism: Implications in NAFLD Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism: Implications in NAFLD

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Date added: 10/11/2015
Date modified: 11/07/2016
Filesize: 2.47 MB
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The term non-alcoholic fatty liver disease (NAFLD) covers a pathologic spectrum from lipid accumulation alone (simple steatosis) to steatosis with associated inflammation and fibrosis (non-alcoholic steatohepatitis [NASH]). Non-alcoholic steatohepatitis can progress to cirrhosis and potentially to hepatocellular carcinoma. Although a genetic predisposition has been highlighted, NAFLD is strongly associated with an unhealthy lifestyle and hypercaloric diet in the context of obesity and metabolic disease. The dysregulation of specific pathways (insulin signalling, mitochondrial function, fatty acid, and lipoprotein metabolism) have been linked to steatosis, but elucidating the molecular events determining evolution of the disease still requires further research before it can be translated into specific personalized interventional strategies. In this review, the authors focus on the early events of the pathophysiology of NASH, dissecting the metabolic and nutritional pathways involving fatty acids and glucose sensors that can modulate lipid accumulation in the liver, but also condition the progression to cirrhosis and hepatocellular carcinoma.

Emerging anti-fibrotic therapies in the treatment of non-alcoholic steatohepatitis Emerging anti-fibrotic therapies in the treatment of non-alcoholic steatohepatitis

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Date added: 03/05/2017
Date modified: 03/05/2017
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Background

Non-alcoholic fatty liver disease (NAFLD) can lead to non-alcoholic steatohepatitis (NASH) and cirrhosis. Fibrosis predicts worse outcomes and mortality. New treatments targeting fibrosis are being investigated to reverse disease progression.

Aim

To review the new pipeline therapeutic agents targeting fibrosis in NASH patients, with particular focus on clinical trials in which reversing fibrosis and portal hypertension are the primary outcomes.

Methods

The literature was searched in PubMed between January 2000 and January 2016 using search terms non-alcoholic fatty liver disease and NASH, with filters of ‘English language’. We focused on fibrosis improvement as the key outcome. We also searched the ClinicalTrials.gov for promising agents that target fibrosis in NASH patients.

Results

Significant advances have been made on approaches targeting fibrosis in NASH patients. Many therapeutic agents are already in development, some of which have shown promising results in preclinical and phase I studies. Novel therapies have entered phase II and III studies targeting fibrosis reversal and/or improvement in portal hypertension. Innovative studies have also started looking into combining these agents, aiming at different mechanisms to maximise therapeutic outcomes. We found five clinical trials in phase II and one in phase III focusing on fibrosis in NASH patients as key outcomes. One of the phase II trials is using combination therapy to target fibrosis.

Conclusions

Ongoing research studies are already investigating new pathways aimed at reversing fibrosis in NASH patients. Novel therapeutic agents are in development and are expected to offer unique options to NASH patients with advanced fibrosis.

Determinants of fibrosis progression and regression in NASH Determinants of fibrosis progression and regression in NASH

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Date added: 11/02/2018
Date modified: 11/02/2018
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Cirrhosis has become the major liver-related clinical endpoint in non-alcoholic steatohepatitis (NASH). However, progression to cirrhosis is less predictable in NASH than in other chronic liver diseases. This is due to the complex and multifactorial aetiology of NASH, which is determined by lifestyle and nutrition, multiple genetic and epigenetic factors, and a prominent role of hepatic and extrahepatic comorbidities. Thus, modest changes in these cofactors can also induce fibrosis regression, at least in patients with precirrhotic liver disease. Fibrogenesis in NASH correlates with, but is indirectly coupled to, classical inflammation, since fibrosis progression is driven by repetitive periods of repair. While hepatocyte lipoapoptosis is a key driving force of fibrosis progression, activated hepatic stellate cells, myofibroblasts, cholangiocytes, macrophages and components of the pathological extracellular matrix are major fibrogenic effectors and thus pharmacological targets for therapies aimed at inhibition of fibrosis progression or induction of fibrosis reversal. The advent of novel, highly sensitive and specific serum biomarkers and imaging methods to assess the dynamics of liver fibrosis in NASH will improve detection, stratification and follow-up of patients with progressive NASH . These non-invasive tools will also promote the clinical development of antifibrotic drugs, by permitting the design of lean proof-ofconcept studies, and enabling development of a personalised antifibrotic therapy for patients with rapid fibrosis progression or advanced disease.

Definitions of Normal Liver Fat and the Association of Insulin Sensitivity with Acquired and Genetic Definitions of Normal Liver Fat and the Association of Insulin Sensitivity with Acquired and Genetic

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Date added: 01/10/2017
Date modified: 01/10/2017
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Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disease ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) and fibrosis. “Obese/Metabolic NAFLD” is closely associated with obesity and insulin resistance and therefore predisposes to type 2 diabetes and cardiovascular disease. NAFLD can also be caused by common genetic variants, the patatin-like phospholipase domain-containing 3 (PNPLA3) or the transmembrane 6 superfamily member 2 (TM6SF2). Since NAFL, irrespective of its cause, can progress to NASH and liver fibrosis, its definition is of interest. We reviewed the literature to identify data on definition of normal liver fat using liver histology and different imaging tools, and analyzed whether NAFLD caused by the gene variants is associated with insulin resistance. Histologically, normal liver fat content in liver biopsies is most commonly defined as macroscopic steatosis in less than 5% of hepatocytes. In the population-based Dallas Heart Study, the upper 95th percentile of liver fat measured by proton magnetic spectroscopy (1H-MRS) in healthy subjects was 5.6%, which corresponds to approximately 15% histological liver fat. When measured by magnetic resonance imaging (MRI)-based techniques such as the proton density fat fraction (PDFF), 5% macroscopic steatosis corresponds to a PDFF of 6% to 6.4%. In contrast to “Obese/metabolic NAFLD”, NAFLD caused by genetic variants is not associated with insulin resistance. This implies that NAFLD is heterogeneous and that “Obese/Metabolic NAFLD” but not NAFLD due to the PNPLA3 or TM6SF2 genetic variants predisposes to type 2 diabetes and cardiovascular disease.