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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.

From NASH to HCC: current concepts and future challenges From NASH to HCC: current concepts and future challenges

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Date added: 12/23/2019
Date modified: 12/23/2019
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Caloric excess and sedentary lifestyle have led to a global epidemic of obesity and metabolic syndrome. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), is estimated to affect up to one-third of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Owing to the high prevalence of NAFLD, especially in industrialized countries but also worldwide, and the consequent burden of progressive liver disease, there is mounting epidemiological evidence that NAFLD has rapidly become a leading aetiology underlying many cases of hepatocellular carcinoma (HCC). In this Review, we discuss NAFLD-associated HCC, including its epidemiology, the key features of the hepatic NAFLD microenvironment (for instance, adaptive and innate immune responses) that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities. The challenges and future directions of research will also be discussed, including clinically relevant biomarkers for early detection, treatment stratification and monitoring as well as approaches to therapies for both prevention and treatment in those at risk or presenting with NAFLD-associated HCC.

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.

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.

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.

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.

Glucose kinetics: an update and novel insights into its regulation by glucagon and GLP-1 Glucose kinetics: an update and novel insights into its regulation by glucagon and GLP-1

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Date added: 05/27/2018
Date modified: 05/27/2018
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Purpose of review
Glucagon and GLP-1 share the same origin (i.e., proglucagon); primarily GLP-1 is generated from intestinal L-cells and glucagon from pancreatic α-cell, but intestinal glucagon and pancreatic GLP-1 secretion is likely. Glucose kinetics are tightly regulated by pancreatic hormones insulin and glucagon, but other hormones, including glucagon-like peptide-1 (GLP-1), also play an important role. The purpose of this review is to describe the recent findings on the mechanisms by which these two hormones regulate glucose kinetics.

Recent findings
Recent findings showed new important mechanisms of action of glucagon and GLP-1 in the regulation of glucose metabolism. Knock out of glucagon receptors protects against hyperglycemia without causing hypoglycemia. GLP-1 not only stimulates insulin secretion, but it has also an independent effect on the liver and inhibits glucose production. Moreover, when coinfused with glucagon, GLP-1 limits the hyperglycemic effects. Both hormones have also central effects on gastric emptying (delayed), intestinal motility (reduced), and satiety (increased).

Summary
The implications of these findings are very important for the management of type 2 diabetes given that GLP-1 receptor agonist are currently approved for the treatment of hyperglycemia and glucagon receptor antagonists and GLP-1/glucagon dual agonists are under development.

Hypoxia-inducible factor 2α drives nonalcoholic fatty liver progression by triggering hepatocyte... Hypoxia-inducible factor 2α drives nonalcoholic fatty liver progression by triggering hepatocyte...

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Date added: 02/13/2019
Date modified: 02/13/2019
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"Hypoxia-inducible factor 2α drives nonalcoholic fatty liver progression by triggering hepatocyte release of histidine rich glycoprotein"

Mechanisms underlying progression of nonalcoholic fatty liver disease (NAFLD) are still incompletely characterized. Hypoxia and hypoxia‐inducible factors (HIFs) have been implicated in the pathogenesis of chronic liver diseases, but the actual role of HIF‐2α in the evolution of NAFLD has never been investigated in detail. In this study, we show that HIF‐2α is selectively overexpressed in the cytosol and the nuclei of hepatocytes in a very high percentage (>90%) of liver biopsies from a cohort of NAFLD patients at different stages of the disease evolution. Similar features were also observed in mice with steatohepatitis induced by feeding a methionine/choline‐deficient diet. Experiments performed in mice carrying hepatocyte‐specific deletion of HIF‐2α and related control littermates fed either a choline‐deficient L‐amino acid–defined or a methionine/choline‐deficient diet showed that HIF‐2α deletion ameliorated the evolution of NAFLD by decreasing parenchymal injury, fatty liver, lobular inflammation, and the development of liver fibrosis. The improvement in NAFLD progression in HIF‐2α‐deficient mice was related to a selective down‐regulation in the hepatocyte production of histidine‐rich glycoprotein (HRGP), recently proposed to sustain macrophage M1 polarization. In vitro experiments confirmed that the up‐regulation of hepatocyte HRGP expression was hypoxia‐dependent and HIF‐2α‐dependent. Finally, analyses performed on specimens from NAFLD patients indicated that HRGP was overexpressed in all patients showing hepatocyte nuclear staining for HIF‐2α and revealed a significant positive correlation between HIF‐2α and HRGP liver transcript levels in these patients. Conclusions: These results indicate that hepatocyte HIF‐2α activation is a key feature in both human and experimental NAFLD and significantly contributes to the disease progression through the up‐regulation of HRGP production.

Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers.. Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers..

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Date added: 06/02/2018
Date modified: 06/02/2018
Filesize: 256 Bytes
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"Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD"

Background:
Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2^EK/KK) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common ‘obese/metabolic’ NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids.

Methods:
Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs.

Results:
The TM6SF2^EK/KK and TM6SF2^EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2^EK/KK than the TM6SF2^EE group (p <0.05). Polyunsaturated fatty acids (PUFA) were deficient in liver and serum TGs and liver PCs but hepatic free fatty acids were relatively enriched in PUFA (p <0.05). Incorporation of PUFA into TGs and PCs in TM6SF2 knockdown hepatocytes was decreased (p <0.05). Hepatic expression of TM6SF2 was decreased in variant carriers, and was co-expressed with genes regulated by PUFAs.

Conclusions:
Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers.

Improvement of non‐invasive markers of NAFLD from an individualised, web‐based exercise program Improvement of non‐invasive markers of NAFLD from an individualised, web‐based exercise program

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Date added: 12/23/2019
Date modified: 12/23/2019
Filesize: 256 Bytes
Downloads: 1489

Background:
Lifestyle modifications remain the cornerstone of treatment in non‐alcoholic fatty liver disease (NAFLD). However, they requently fail related to the inability of patients to implement lasting changes.

Aims:
To evaluate the effects of a short, web‐based, individualised exercise program on non‐invasive markers of hepatic steatosis, inflammation and fibrosis.

Methods:
Patients with histologically confirmed NAFLD underwent an 8‐week, web‐based, individualised exercise program that contained bidirectional feedback.

Results:
Forty‐four patients entered the study and 41 completed the assigned training goal (93.2%). In the completer population, 8 weeks of individualised exercise increased the VO2peak by 12.2% compared to baseline (P < .001). ALT and AST decreased by 14.3% (P = .002) and 18.2% (P < .001) and remained at this level until follow‐up 12 weeks after the intervention. Markers of inflammation including hsCRP, ferritin, and M30 decreased. In parallel, gut microbiota exhibited increased metagenomic richness (P < .05) and at the taxonomic levels Bacteroidetes and Euryarchaeota increased whereas Actinobacteria phylum decreased. Surrogate scores of steatosis and fibrosis including the fatty liver index (FLI), FiB‐4, APRI and transient elastography showed significant reductions. In parallel, a marker of procollagen‐3 turnover (PRO‐C3) decreased while C4M2, reflecting type IV collagen, degradation increased suggesting beneficial hepatic fibrosis remodelling from exercise. Also, an enhancement in health‐related quality of life was reported.

Conclusion:
The current study underlines the plausibility and potential of an 8 week individualised web‐based exercise program in NAFLD.

Clinical trial number: NCT02526732