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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
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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.

Mouse models of nonalcoholic steatohepatitis towards optimization of their relevance to human NASH Mouse models of nonalcoholic steatohepatitis towards optimization of their relevance to human NASH

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Date added: 12/23/2019
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Nonalcoholic steatohepatitis (NASH) arises from a variable interplay between environmental factors and genetic determinants that cannot be completely replicated in animals. Notwithstanding, preclinical models are needed to understand NASH pathophysiology and test mechanism‐based therapies. Among several mouse models of NASH, some exhibit the key pathophysiologic as well as histopathologic criteria for human NASH, whereas others may be useful to address specific questions. Models based on overnutrition with adipose restriction/inflammation and metabolic complications, particularly insulin resistance, may be most useful to investigate critical etiopathogenic factors. In‐depth pathologic description is required for all models. Some models demonstrate hepatocyte ballooning, which can be confused with microvesicular steatosis, whereas demonstration of an inflammatory infiltrate and pattern of liver fibrosis compatible with human NASH is desirable in models used for pharmacologic testing. When mice with specific genetic strains or mutations that cause overeating consume a diet enriched with fat, modest amounts of cholesterol, and/or simple sugars (“Western diet”), they readily develop obesity with liver disease similar to human NASH, including significant fibrosis. Purely dietary models, such as high‐fat/high‐cholesterol, Western diet, and choline‐deficient, amino acid–defined, are similarly promising. We share concern about using models without weight gain, adipose pathology, or insulin resistance/hyperinsulinemia and with inadequate documentation of liver pathology. NASH‐related fibrosis is a key endpoint in trials of possible therapies. When studied for this purpose, NASH models should be reproducible and show steatohepatitis (ideally with ballooning) and at least focal bridging fibrosis, while metabolic factors/disordered lipid partitioning should contribute to etiopathogenesis. Because murine models are increasingly used to explore pharmacologic therapies for NASH, we propose a minimum set of requirements that investigators, drug companies, and journals should consider to optimize their translational value.

The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

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Date added: 12/23/2019
Date modified: 12/23/2019
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Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH) are becoming the leading cause of liver-related morbidity and mortality worldwide, and a primary indication for liver transplantation. The pathophysiology of NASH is multifactorial and not yet completely understood; however, innate immunity is a major contributing factor in which liver-resident macrophages (Kupffer cells) and recruited macrophages play a central part in disease progression. In this Review, we assess the evidence for macrophage involvement in the development of steatosis, inflammation and fibrosis in NASH. In this process, not only the polarization of liver macrophages towards a pro-inflammatory phenotype is important, but adipose tissue macrophages, especially in the visceral compartment, also contribute to disease severity and insulin resistance. Macrophage activation is mediated by factors such as endotoxins and translocated bacteria owing to increased intestinal permeability, factors released from damaged or lipoapoptotic hepatocytes, as well as alterations in gut microbiota and defined nutritional components, including certain free fatty acids, cholesterol and their metabolites. Reflecting the important role of macrophages in NASH, we also review studies investigating drugs that target macrophage recruitment to the liver, macrophage polarization and their inflammatory effects as potential treatment options for patients with NASH.

Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance

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Date added: 11/01/2018
Date modified: 11/01/2018
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Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD-NO and 15 NAFLD-Ob) and 20 CTs without obesity, by gas chromatography–mass
spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep-IR; Hep-IR 5 endogenous glucose production 3 insulin), and the new glutamate–serine–glycine (GSG) index (glutamate/[serine 1 glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD-Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD-NO subjects compared to CTs. Glutamate, tyrosine, and the GSG-index were correlated with Hep-IR. The GSG-index correlated with liver enzymes, in particular, gamma-glutamyltransferase (R 5 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG-index, while only the new GSG-index was able to discriminate fibrosis F3-4 from F0-2 in this cohort.

Conclusion: Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG-index is a possible marker of severity of liver disease independent of body mass index.

Lipidomes in health and disease: Analytical strategies and considerations Lipidomes in health and disease: Analytical strategies and considerations

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Date added: 12/23/2019
Date modified: 12/23/2019
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Lipidomics is a rapidly-growing field which focuses on global characterization of lipids at molecular and systems levels. As small changes in the concentrations of lipids may have important physiological consequences, much attention in the field has recently been paid to more accurate quantitation and identification of lipids. Community-wide efforts have been initiated, aiming to develop best practices for lipidomic analyses and reporting of lipidomic data. Nevertheless, current approaches for comprehensive analysis of lipidomes have some inherent challenges and limitations. Additionally, there is, currently, limited knowledge concerning the impacts of various external and internal exposures on lipid levels. In this review, we discuss the recent progress in lipidomics analysis, with a primary focus on analytical approaches, as well as on the different sources of variation in quantifying lipid levels, both technical and biological.

Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance

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Date added: 01/09/2017
Date modified: 01/10/2017
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Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL) cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD). Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA) as compared to monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance.

Liver fibrosis: Direct antifibrotic agents and targeted therapies Liver fibrosis: Direct antifibrotic agents and targeted therapies

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Date added: 12/31/2018
Date modified: 12/31/2018
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Liver fibrosis and in particular cirrhosis are the major causes of morbidity and mortality of patients with chronic liver disease. Their prevention or reversal have become major endpoints in clinical trials with novel liver specific drugs. Remarkable progress has been made with therapies that efficiently address the cause of the underlying liver disease, as in chronic hepatitis B and C. Highly effective antiviral therapy can prevent progression or even induce reversal in the majority of patients, but such treatment remains elusive for the majority of liver patients with advanced alcoholic or nonalcoholic steatohepatitis, genetic or autoimmune liver diseases. Moreover, drugs that would speed up fibrosis reversal are needed for patients with cirrhosis, since even with effective causal therapy reversal is slow or the disease may further progress. Therefore, highly efficient and specific antifibrotic agents are needed that can address advanced fibrosis, i.e., the detrimental downstream result of all chronic liver diseases. This review discusses targeted antifibrotic therapies that address molecules and mechanisms that are central to fibrogenesis or fibrolysis, including strategies that allow targeting of activated hepatic stellate cells and myofibroblasts and other fibrogenic effector cells. Focus is on collagen synthesis, integrins and cells and mechanisms specific including specific downregulation of TGFbeta signaling, major extracellular matrix (ECM) components, ECM-crosslinking, and ECM-receptors such as integrins and discoidin domain receptors, ECM-crosslinking and methods for targeted delivery of small interfering RNA, antisense oligonucleotides and small molecules to increase potency and reduce side effects. With an increased understanding of the biology of the ECM and liver fibrosis and an improved preclinical validation, the translation of these approaches to the clinic is currently ongoing. Application to patients with liver fibrosis and a personalized treatment is tightly linked to the development of non-invasive biomarkers of fibrosis, fibrogenesis and fibrolysis.

Should we undertake surveillance for HCC in patients with NAFLD? Should we undertake surveillance for HCC in patients with NAFLD?

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Date added: 11/02/2018
Date modified: 11/02/2018
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The pandemic of obesity and its related complications is rapidly changing the epidemiology of many types of cancer, including hepatocellular carcinoma (HCC). Non-alcoholic fatty liver disease (NAFLD) is becoming a major cause of HCC, with a steadily rising trend compared to viral or alcohol-induced chronic hepatitis. The much greater prevalence of the underlying liver disease in the general population and the chance of HCC occurrence in non-cirrhotic liver are the most worrisome aspects of HCC in NAFLD. Effective screening programmes are currently hampered by limited knowledge of the pathways of carcinogenesis and a lack of tools able to stratify the risk of HCC in the NAFLD population. Hence, poor surveillance has prevented the development of an adequate treatment for NAFLD-related HCC. Systemic and hepatic molecular mechanisms involved in hepatocarcinogenesis, as well as potential early markers of HCC are being extensively investigated. This review describes the current clinical impact of HCC in NAFLD and discusses the most important unmet needs for its effective management.

The bidirectional impacts of alcohol consumption and the metabolic syndrome: cofactors for prog... The bidirectional impacts of alcohol consumption and the metabolic syndrome: cofactors for prog...

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Date added: 11/02/2018
Date modified: 11/02/2018
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"The bidirectional impacts of alcohol consumption and the metabolic syndrome: cofactors for progressive fatty liver disease"

Current medical practice artificially dichotomises a diagnosis of fatty liver disease into one of two common forms: alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Together, these account for the majority of chronic liver diseases worldwide. In recent years, there has been a dramatic increase in the prevalence of obesity and metabolic syndrome within the general population. These factors now coexist with alcohol consumption in a substantial proportion of the population. Each exposure sensitises the liver to the injurious effects of the other; an interaction that drives and potentially accelerates the genesis of liver disease. We review the epidemiological evidence and scientific literature that considers how alcohol consumption interacts with components of the metabolic syndrome to exert synergistic or supra-additive effects on the development and progression of liver disease, before discussing how these interactions may be addressed in clinical practice.

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.