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Metabolic Dysfunction-Associated Fatty Liver Disease and Diabetes Mellitus are two prevalent metabolic disorders that often coexist and synergistically contribute to the progression of each other. Several pathophysiological pathways are involved in the association, including insulin resistance, inflammation, and lipotoxicity, providing a foundation for understanding the complex interrelationships between these conditions. The presence of MASLD has a significant impact on diabetes risk and the development of microvascular and macrovascular complications, and diabetes significantly contributes to an increased risk of liver fibrosis progression in MASLD and the development of hepatocellular carcinoma. Moreover, both pathologies have a synergistic effect on cardiovascular events and mortality. Therapeutic interventions targeting MASLD and diabetes are discussed, considering lifestyle modifications, pharmacological agents, and emerging treatment modalities. The review also addresses the challenges in managing these comorbidities, such as the need for personalized approaches and the potential impact on cardiovascular health. The insights gleaned from this analysis can inform clinicians, researchers, and policymakers in developing integrated strategies for preventing, diagnosing, and managing these metabolic disorders., Competing Interests: Conflicts of interest None., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Background: It is unclear what biopsychosocial factors influence the impact of NAFLD on health-related quality of life (HRQoL), and if these factors are equally important predictors between different nationalities., Methods: HRQoL (CLDQ) was measured in both Southern European (Spain, n = 513) and Northern European (United Kingdom -UK-, n = 224) cohorts of patients with NAFLD in this cross-sectional study. For each cohort, participant data were recorded on histological grade of steatohepatitis, stage of fibrosis and biopsychosocial variables. Regression analysis was used to explore which of these variables predicted HRQoL. Moderated mediation models were conducted using SPSS PROCESS v3.5 macro., Results: Participants with severe fibrosis reported more fatigue, systemic symptoms and worry, and lower HRQoL than those with none/mild fibrosis, regardless of place of origin. In addition, body mass index (BMI) and gender were found to be significant predictors of HRQoL in both Spanish and UK participants. Female gender was associated with worse emotional function, higher BMI and more fatigue, which predicted lower participants' HRQoL. UK participants showed more systemic symptoms and worry than Spanish participants, regardless of liver severity. The negative effects of gender on HRQoL through emotional function, BMI and fatigue were reported to a greater degree in UK than in Spanish participants., Conclusions: UK participants showed a greater impairment in HRQoL as compared to Spanish participants. Higher fibrosis stage predicted lower HRQoL, mainly in the Spanish cohort. Factors such as female gender or higher BMI contributed to the impact on HRQoL in both cohorts of patients and should be considered in future multinational intervention studies in NAFLD., Competing Interests: The authors have read the journal’s policy and have the following potential competing interests: The Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium is funded by the Innovative Medicines Initiative (IMI2) Program of the EU which receives funding from the European Federation of Pharmaceutical Industries and Associations (EFPIA). There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Funuyet-Salas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To better understand drivers of disease progression in non-alcoholic steatohepatitis (NASH), we assessed clinical and sociodemographic markers of fibrosis progression in adults with NASH., Patients and Methods: Physician-reported patient demographics and clinical characteristics were utilised from the real-world Global Assessment of the Impact of NASH (GAIN) study. Factors associated with likelihood of fibrosis progression since NASH diagnosis were identified using a logistic regression model., Results: Overall, 2349 patients in Europe from the GAIN study were included; mean age was 54.6 years and 41% were women. Significant covariates included age, years since diagnosis, employment status, fibrosis stage at diagnosis, type 2 diabetes mellitus, hypertension, liver transplant and liver biopsy at diagnosis. Risk of progression was 1.16 (95% confidence interval 1.12-1.20; p<0.001) times higher for each additional year since NASH diagnosis and 5.43 (2.68-11.37; p<0.001) times higher when physicians proposed a liver transplant at diagnosis. Compared with full-time employed patients, risk of progression was 1.77 (1.19-2.60; p=0.004) times higher for unemployed patients and 3.16 (1.30-7.63; p=0.010) times higher for those unable to work due to NASH., Conclusions: Disease duration, NASH severity and presence of other metabolic comorbidities could help to assess risk of progression in patients with NASH., (Copyright © 2023 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death., Design: We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate., Results: Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65)., Conclusions: This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD., Competing Interests: Competing interests: LM is supported by Investigator Driven Grants: Gilead, Intercept, Siemens Healthineers. Advisor/Consultancy: Alfa-Sigma, Boehringer-Ingelheim, BMS, Echosens, Galmed, Gilead Sciences, IBSA, Intercept, MEDA, MyGenomics, Merck Sharp & Dohme, Novartis, Pfizer, ProLon, Promethera, Resalis, Rottapharm-Madaus, Siemens Healthineers, Synageva. HH’s institutions have received research funding from Astra Zeneca, EchoSens, Gilead, Intercept, MSD, Novo Nordisk and Pfizer. He has served as consultant or on advisory boards for Astra Zeneca, Bristol Myers-Squibb, MSD and Novo Nordisk and has been part of hepatic events adjudication committees for Boehringer Ingelheim, KOWA and GW Pharma., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To describe in detail the epidemiology, diagnosis, clinical management, treatment options, impact on quality of life and unmet needs of patients with advanced liver fibrosis (F3-F4) associated with non-alcoholic steatohepatitis (NASH) in Spain., Methodology: Delphi study of two rounds of consultation rounds with 41 expert hepatologists from 16 autonomous communities to collect their experience in clinical practice., Results: The estimated prevalence of adult patients diagnosed with F3-F4 fibrosis associated with NASH in Spain is 0.019% (95% confidence interval [CI]: 0.019-0.020%). Approximately 7,588 adults with this condition are currently diagnosed and managed in the Digestive System Services of Spanish hospitals, and around 1,881 new patients are diagnosed each year. Management is multidisciplinary and includes the specialties of Digestive System, Endocrinology and Internal Medicine, considering the frequently associated metabolic comorbidities (obesity, type 2 diabetes mellitus or dysmetabolic iron overload). Despite a clear impact on quality of life, this it is not routinely evaluated in clinical practice. The most widely used non-invasive diagnostic techniques are transitional elastography and liver fibrosis index 4 (FIB-4). The absence of effective and safe treatments appears as the main unmet need for the management of these patients., Conclusions: This study provides a representation of the current situation of patients diagnosed with F3-F4 fibrosis associated with NASH in Spain, increasing the evidence available and contributing to informed decision-making by professionals and the health system., (Copyright © 2023 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background & Aims: Patients with fatty liver disease may experience stigma from the disease or comorbidities. In this cross-sectional study, we aimed to understand stigma among patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and healthcare providers., Methods: Members of the Global NASH Council created two surveys about experiences/attitudes toward NAFLD and related diagnostic terms: a 68-item patient and a 41-item provider survey., Results: Surveys were completed by 1,976 patients with NAFLD across 23 countries (51% Middle East/North Africa [MENA], 19% Europe, 17% USA, 8% Southeast Asia, 5% South Asia) and 825 healthcare providers (67% gastroenterologists/hepatologists) across 25 countries (39% MENA, 28% Southeast Asia, 22% USA, 6% South Asia, 3% Europe). Of all patients, 48% ever disclosed having NAFLD/NASH to family/friends; the most commonly used term was "fatty liver" (88% at least sometimes); "metabolic disease" or "MAFLD" were rarely used (never by >84%). Regarding various perceptions of diagnostic terms by patients, there were no substantial differences between "NAFLD", "fatty liver disease (FLD)", "NASH", or "MAFLD". The most popular response was being neither comfortable nor uncomfortable with either term (56%-71%), with slightly greater discomfort with "FLD" among the US and South Asian patients (47-52% uncomfortable). Although 26% of patients reported stigma related to overweight/obesity, only 8% reported a history of stigmatization or discrimination due to NAFLD. Among providers, 38% believed that the term "fatty" was stigmatizing, while 34% believed that "nonalcoholic" was stigmatizing, more commonly in MENA (43%); 42% providers (gastroenterologists/hepatologists 45% vs. 37% other specialties, p = 0.03) believed that the name change to metabolic dysfunction-associated steatotic liver disease (or MASLD) might reduce stigma. Regarding the new nomenclature, the percentage of providers reporting "steatotic liver disease" as stigmatizing was low (14%)., Conclusions: The perception of NAFLD stigma varies among patients, providers, geographic locations and sub-specialties., Impact and Implications: Over the past decades, efforts have been made to change the nomenclature of nonalcoholic fatty liver disease (NAFLD) to better align with its underlying pathogenetic pathways and remove any potential stigma associated with the name. Given the paucity of data related to stigma in NAFLD, we undertook this global comprehensive survey to assess stigma in NAFLD among patients and providers from around the world. We found there is a disconnect between physicians and patients related to stigma and related nomenclature. With this knowledge, educational programs can be developed to better target stigma in NAFLD among all stakeholders and to provide a better opportunity for the new nomenclature to address the issues of stigma., Competing Interests: Conflict of interest ZMY: research funding or consultation fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cymabay, GlaxoSmithKline, Intercept, Novo Nordisk, Siemens, Madrigal, Merck; VWSW: served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, Visirna, speaker for Abbott, AbbVie, Gilead Sciences, Novo Nordisk, Unilab, received a research grant from Gilead Sciences, co-founder of Illuminatio Medical Technology Limited; AMA: grant funding from NIH, Novo Nordisk, Target Pharma, consulting/advisory board for Novo Nordisk; JMS: consultant for Astra Zeneca, Apollo Endosurgery, Bayer, Boehringer Ingelheim, BMS, Gilead Sciences, GSK, Intercept Pharmaceuticals, Ipsen, Inventiva Pharma, Madrigal, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Siemens Healthineers, receives research funding from Gilead Sciences, Boehringer Ingelheim, Siemens Healthcare GmbH, has stock options of AGED diagnostics, Hepta Bio, received speaker honorarium from Boehringer Ingelheim, Echosens, MedPublico GmbH, Novo Nordisk, Madrigal Pharmaceuticals, Histoindex, MedPublico GmbH; CWS: speaker bureau fees from Gilead Sciences, Abbott; RL: receives funding support from NCATS, NIDDK, NHLBI, serves as a consultant to Aardvark Therapeutics, Altimmune, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Takeda, Terns Pharmaceuticals and Viking Therapeutics. In addition, his institution received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes, Terns Pharmaceuticals, co-founder of LipoNexus Inc; PC: received research grants by MSD and Intercept. Other coauthors report no conflicts of interest related to this study. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The worldwide prevalence of non-alcoholic steatohepatitis (NASH) is increasing, causing a significant medical burden, but no approved therapeutics are currently available. NASH drug development requires histological analysis of liver biopsies by expert pathologists for trial enrolment and efficacy assessment, which can be hindered by multiple issues including sample heterogeneity, inter-reader and intra-reader variability, and ordinal scoring systems. Consequently, there is a high unmet need for accurate, reproducible, quantitative, and automated methods to assist pathologists with histological analysis to improve the precision around treatment and efficacy assessment. Digital pathology (DP) workflows in combination with artificial intelligence (AI) have been established in other areas of medicine and are being actively investigated in NASH to assist pathologists in the evaluation and scoring of NASH histology. DP/AI models can be used to automatically detect, localise, quantify, and score histological parameters and have the potential to reduce the impact of scoring variability in NASH clinical trials. This narrative review provides an overview of DP/AI tools in development for NASH, highlights key regulatory considerations, and discusses how these advances may impact the future of NASH clinical management and drug development. This should be a high priority in the NASH field, particularly to improve the development of safe and effective therapeutics., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or at-risk metabolic dysfunction-associated steatohepatitis (MASH) is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH., Methods: We included derivation (n = 790) and validation (n = 565) cohorts from international tertiary centers. Patients underwent laboratory assessment and liver biopsy for metabolic dysfunction-associated steatotic liver disease. Based on 12 lipids, body mass index, aspartate aminotransferase, and alanine aminotransferase, the MASEF score was developed to identify at-risk MASH and compared to the FibroScan-AST (FAST) score. We further compared the performance of a FIB-4 + MASEF algorithm to that of FIB-4 + liver stiffness measurements (LSM) by vibration-controlled transient elastography (VCTE)., Results: The diagnostic performance of the MASEF score showed an area under the receiver-operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of 0.76 (95% CI 0.72-0.79), 0.69, 0.74, 0.53, and 0.85 in the derivation cohort, and 0.79 (95% CI 0.75-0.83), 0.78, 0.65, 0.48, and 0.88 in the validation cohort, while FibroScan-AST performance in the validation cohort was 0.74 (95% CI 0.68-0.79; p = 0.064), 0.58, 0.79, 0.67, and 0.73, respectively. FIB-4+MASEF showed similar overall performance compared with FIB-4 + LSM by VCTE ( p = 0.69) to identify at-risk MASH., Conclusion: MASEF is a promising diagnostic tool for the assessment of at-risk MASH. It could be used alternatively to LSM by VCTE in the algorithm that is currently recommended by several guidance publications., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification., Competing Interests: Declaration of interests Manal F. Abdelmalek consults, advises, and received grants from Bristol Myers Squibb, Hanmi, Intercept, Inventiva, and Madrigal. She consults and advises 89Bio, Merck, NGM Bio, Novo Nordisk, Sonic Incytes, and Theratechnologies. She is on the speakers’ bureau for the Chronic Liver Disease Foundation, Clinical Care Options, Fishawack, Medscape, and Terra Firma. She received grants from Allergan, Boehringer Ingelheim, Celgene, Durect, Enanta, Enyo, Galmed, Genentech, Gilead, Novo Nordisk, Poxel, Target NASH, and Viking. Quentin M. Anstee, on behalf of Newcastle University, consults for Alimentiv, Akero, AstraZeneca, Axcella, 89Bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, GENFIT, Genentech, Gilead, GSK, Hanmi, HistoIndex, Intercept, Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Pharmanest, Prosciento, Poxel, RTI, Resolution Therapeutics, Ridgeline Therapeutics, Roche, Shionogi, and Terns. He is on the speakers’ bureau for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare. He received grants from AstraZeneca, Boehringer Ingelheim, and Intercept. He holds intellectual property rights with Elsevier, Ltd. Ramon Bataller is on the speakers’ bureau for Abbvie and Gilead. Ulrich Beuers consults for CSL Behring. He is on the speakers’ bureau for Abacus and Zambon. Elisabetta Bugianesi advises Boehringer Ingelheim, MSD, and Novo Nordisk. Helena Cortez-Pinto consults and received grants from Novo Nordisk and Roche. She received grants from Eisai, Gilead, GMP-Orphan, and Intercept. Kenneth Cusi Consults for Aligos, Arrowhead, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Covance, Lilly, Madrigal, Myovant, Novo Nordisk, Prosciento, Sagimet, and Siemens. He received grants from Echosens, Inventiva, LabCorp, Nordic Biosciences, and Target NASH. Sven M. Francque consults and received grants from Astellas, Falk, GENFIT, Gilead, Glympse Bio, Janssen, Inventiva, Merck, Pfizer, and Roche. He consults for AbbVie., Actelion, Aelin Therapeutics, Allergan, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Coherus, CSL Behring, Echosens, Eisai, ENYO, Galapagos, Galmed, Genetech, Intercept, Julius Clinical, Madrigal, Medimmune, NGM Bio, Novartis, Novo Nordisk, and Promethera. Samer Gawrieh consults for Pfizer and TransMedics. He received grants from LiverIncytes, Viking, and Zydus. Manuel Romero-Gómez advises and received grants from Novo Nordisk and Siemens. He advises AbbVie., Alpha-sigma, Allergan, AstraZeneca, Axcella, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Intercept, Inventia, Kaleido, MSD, Pfizer, Prosciento, Rubió, Shionogi, Sobi, and Zydus. He received grants from Echosens and Theratechnologies. Cynthia D. Guy consults for 89Bio, CymaBay, HistoIndex, Madrigal, and NGM. Stephen Harrison consults, advises, is involved with trials, received grants, and owns stock in Akero, Galectin, GENFIT, Hepion, and NGM Bio. He consults, advises, is involved with trials, and received grants from Axcella, Gilead, Intercept, Madrigal, and Poxel. He consults, advises, received grants, and owns stock in NorthSea Therapeutics. He consults, advises, and is involved with trials for Terns. He consults, advises, and received grants from HighTide, Novartis, Novo Nordisk, and Sagimet. He consults, advises, and owns stock in HistoIndex, Metacrine, and Sonic Incytes. He consults, received grants, and owns stock in Cirius. He consults, is involved with trials, and received grants from ENYO and Viking. He is involved with trials and received grants from Genentech. He consults and is involved with trials for Ionis. He consults and received grants from CiVi, CymaBay, Galmed, and Pfizer. He consults and owns stock in Hepta Bio. He consults and advises for Altimmune, Echosens North America, Foresite Labs, and Medpace. He advises and owns stock in ChronWell. He consults for AgomAb, Alentis, Aligos Therapeutics, Alimentiv, Blade, Bluejay, Boston Pharmaceuticals, Boxer Capital, CanFite BioPharma, the Chronic Liver Disease Foundation (CLDF), CohBar, Corcept, Fibronostics, Fortress Biotech, Galecto, Gelesis, GSK, GNS Healthcare, GRI Bio, Hepagene, Indalo, Inipharm, Innovate Biopharmaceuticals, Kowa Research Institute, Merck, MGGM, NeuroBo, Nutrasource, Perspectum, Piper Sandler, Prometic (now Liminal BioSciences), Ridgeline Therapeutics, Silverback, and Zafgen (now Larimar). He advises Arrowhead BVF Partners, Humana, and Pathai. He received grants from Bristol Myers Squibb, Conatus, Immuron, and Second Genome. Samuel Klein advises Alnylam, Altimmune, and Merck. Kris V. Kowdley advises, is on the speakers’ bureau, and received grants from Gilead and Intercept. He advises, received grants, and owns stock in Inipharm. He advises and received grants from 89bio, CymaBay, GENFIT, Ipsen, Madrigal, Mirum, NGM Bio, Pfizer, Pliant, and Zeds. He advises Enact, HighTide, and Protagonist. He is on the speakers’ bureau for AbbVie. He received grants from Boston Pharmaceuticals, Corcept, GSK, Hanmi, Janssen, Novo Nordisk, Terns, and Viking. Jeffrey V. Lazarus consults for Novavax. He received grants from AbbVie, Gilead, MSD, and Roche Diagnostics. Rohit Loomba consults and received grants from Arrowhead, AstraZeneca, Bristol Myers Squibb, Galmed, Gilead, Intercept, Inventiva, Ionis, Janssen, Lilly, Madrigal, Merck, NGM Bio, Novo Nordisk, Pfizer, and Terns. He consults and owns stock in 89Bio and Sagimet. Consults for Altimmune, Anylam, Amgen, CohBar, Glympse Bio, HighTide, Inipharm, Metacrine, Novartis, Regeneron, Theratechnologies, and Viking. He received grants from Boehringer Ingelheim, Galectin Therapeutics, Hanmi, and Sonic Incytes. He cofounded and owns stock in LipoNexus. Phillip N. Newsome consults, advises, is on the speakers’ bureau, and received grants from Novo Nordisk. He consults and advises Boehringer Ingelheim, Bristol Myers Squibb, Gilead, GSK, Intercept, Madrigal, Pfizer, Poxel, and Sun Pharma. He is on the speakers’ bureau for AiCME. Elizabeth E. Powell advises and received grants from Novo Nordisk. Vlad Ratziu consults and received grants from Intercept. He consults for Boehringer Ingelheim, Eny, Madrigal, NorthSea, Novo Nordisk, E. Poxel, and Sagimet. He received grants from Gilead. Mary E. Rinella consults for Boehringer Ingelheim, CytoDyn, GSK, Novo Nordisk, HistoIndex, Intercept, Madrigal, NGM Bio, and Sonic Incytes. Michael Roden consults and received grants from Boehringer Ingelheim and Novo Nordisk. He consults for Lilly. He is on the speakers’ bureau for AstraZeneca. Arun J. Sanyal consults and advises Avant Santé and AstraZeneca. He consults and received grants from Akero, Bristol Myers Squibb, Intercept, Lilly, Madrigal, and Novo Nordisk. He consults and owns stock in Rivus. He consults for AGED Diagnostics, Albireo, Alnylam, Altimmune, Boehringer Ingelhiem, 89Bio, Echosense, Genentech, Gilead, GSK, HistoIndex, Malinckrodt, Merck, NGM Bio, Novartis, PathAI, Pfizer, Poxel, Regeneron, Salix, Siemens, Surrozen, Takeda, Terns, and Zydus. He owns stock in Durect, Exhalenz, GENFIT, Indalo, Inversago, and Tiziana. He received royalties from Elsevier and Wolters Kluwer. Marcelo Silva consults, advises, and received grants from Zydus. He received grants from Inventiva and MSD. Dina Tiniakos consults for Clinnovate Health, ICON, Ionis, Inventiva, Merck, and Verily. Luca Valenti consults and received grants from Gilead. He consults for AstraZeneca, Boehringer Ingelheim, MSD, Novo Nordisk, Pfizer, and Resalis Therapeutics. Miriam B. Vos consults and advises Thiogenesis. She consults and received grants from Target Real World Evidence. She consults and owns stock in Intercept. She consults for Albireo, Boehringer Ingelheim, Lilly, Novo Nordisk, and Takeda. She received grants from Bristol Myers Squibb, Quest, and Sonic Incytes. Vincent Wai-Sun Wong consults and received grants from Gilead. He consults for AbbVie, Boehringer Ingelheim, Echosens, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet, and TARGET PharmaSolutions. He owns stock in Illuminatio Medical Technology. Yusuf Yilmaz consults for Zydus. He advises Novo Nordisk. He is on the speakers’ bureau for Echosens. Zobair Younossi consults for Bristol Myers Squibb, Gilead, Intercept, Madrigal, Merck, Novartis, Novo Nordisk, Quest, Siemens, and Terns. The remaining authors have no conflicts to report., (Copyright © 2023 Mary E. Rinella, Jeffrey V. Lazarus, Vlad Ratziu, Sven M. Francque, Arun J. Sanyal, Fasiha Kanwal, Diana Romero, Manal F. Abdelmalek, Quentin M. Anstee, Juan Pablo Arab, Marco Arrese, Ramon Bataller, Ulrich Beuers, Jerome Boursier, Elisabetta Bugianesi, Christopher D. Byrne, Graciela E. Castro Narro, Abhijit Chowdhury, Helena Cortez-Pinto, Donna Cryer, Kenneth Cusi, Mohamed El-Kassas, Samuel Klein, Wayne Eskridge, Jiangao Fan, Samer Gawrieh, Cynthia D. Guy, Stephen A. Harrison, Seung Up Kim, Bart Koot, Marko Korenjak, Kris Kowdley, Florence Lacaille, Rohit Loomba, Robert Mitchell-Thain, Timothy R. Morgan, Elisabeth Powell, Michael Roden, Manuel Romero-Gómez, Marcelo Silva, Shivaram Prasad Singh, Silvia C. Sookoian, C. Wendy Spearman, Dina Tiniakos, Luca Valenti, Miriam B. Vos, Vincent Wai-Sun Wong, Stavra Xanthakos, Yusuf Yilmaz, Zobair Younossi, Ansley Hobbs, Marcela Villota-Rivas, Philip N. Newsome (senior), NAFLD Nomenclature consensus group. Published by Elsevier España, S.L.U. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD), which affects approximately 25% of the global population, is an urgent health issue leading to various metabolic comorbidities. Circular RNAs (circRNAs), covalently closed RNA molecules, are characterized by ubiquity, diversity, stability, and conservatism. Indeed, they participate in various biological processes via distinct mechanisms that could modify the natural history of NAFLD. In this review, we briefly introduce the biogenesis, characteristics, and biological functions of circRNAs. Furthermore, we summarize circRNAs expression profiles in NAFLD by intersecting seven sequencing data sets and describe the cellular roles of circRNAs and their potential advantages as biomarkers of NAFLD. In addition, we emphatically discuss the exosomal non-coding RNA sorting mechanisms and possible functions in recipient cells. Finally, we extensively discuss the potential application of targeting disease-related circRNAs and competing endogenous RNA networks through gain-of-function and loss-of-function approaches in targeted therapy of NAFLD.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification., (Copyright © 2023 Mary E. Rinella, Jeffrey V. Lazarus, Vlad Ratziu, Sven M. Francque, Arun J. Sanyal, Fasiha Kanwal, Diana Romero, Manal F. Abdelmalek, Quentin M. Anstee, Juan Pablo Arab, Marco Arrese, Ramon Bataller, Ulrich Beuers, Jerome Boursier, Elisabetta Bugianesi, Christopher Byrne, Graciela E. Castro Narro, Abhijit Chowdhury, Helena Cortez-Pinto, Donna Cryer, Kenneth Cusi, Mohamed El-Kassas, Samuel Klein, Wayne Eskridge, Jiangao Fan, Samer Gawrieh, Cynthia D. Guy, Stephen A. Harrison, Seung Up Kim, Bart Koot, Marko Korenjak, Kris Kowdley, Florence Lacaille, Rohit Loomba, Robert Mitchell-Thain, Timothy R. Morgan, Elisabeth Powell, Michael Roden, Manuel Romero-Gómez, Marcelo Silva, Shivaram Prasad Singh, Silvia C. Sookoian, C. Wendy Spearman, Dina Tiniakos, Luca Valenti, Miriam B. Vos, Vincent Wai-Sun Wong, Stavra Xanthakos, Yusuf Yilmaz, Zobair Younossi, Ansley Hobbs, Marcela Villota-Rivas, Philip N. Newsome, NAFLD Nomenclature consensus group. Published by Elsevier B.V. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) represents a global public health burden. Despite the increase in its prevalence, the disease has not received sufficient attention compared to the associated diseases such as diabetes mellitus and obesity. In 2020 it was proposed to rename NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in order to recognize the metabolic risk factors and the complex pathophysiological mechanisms associated with its development. Furthermore, along with the implementation of the proposed diagnostic criteria, the aim is to address the whole clinical spectrum of the disease, regardless of BMI and the presence of other hepatic comorbidities. As would it be expected with such a paradigm shift, differing viewpoints have emerged regarding the benefits and disadvantages of renaming fatty liver disease. The following review aims to describe the way to the MAFLD from a historical, pathophysiological and clinical perspective in order to highlight why MAFLD is the approach to follow., Competing Interests: Declaration of interests None., (Copyright © 2023. Published by Elsevier España, S.L.U.)

Competing Interests: Competing interests: We have read and understood BMJ policy on the declaration of interests and have the following interests to declare: MR-G declares consulting for Abbvie, Alpha-sigma, Allergan, Astra-Zeneca, Axcella, BMS, Boehringer-Ingelheim, Gilead, Intercept, Inventia, Kaleido, MSD, Novo-Nordisk, Pfizer, Prosciento, Rubió, Siemens, Shionogi, Sobi, Zydus. Research grants: Gilead, Intercept, Siemens, Theratechnologies. BS declares consulting for Abbvie, Celgene, Gilead, Roche, and Novo; filed patents on the treatment of covid-19, diabetes, and inflammatory diseases. SZ-S has given a one time presentation for and received support for attending a meeting from AbbVie, and a one time consultation fee from Siemens, outside of the submitted work.

Background and Aims: Management of NAFLD involves noninvasive prediction of fibrosis, which is a surrogate for patient outcomes. We aimed to develop and validate a model predictive of liver-related events (LREs) of decompensation and/or HCC and compare its accuracy with fibrosis models., Approach and Results: Patients with NAFLD from Australia and Spain who were followed for up to 28 years formed derivation (n = 584) and validation (n = 477) cohorts. Competing risk regression and information criteria were used for model development. Accuracy was compared with fibrosis models using time-dependent AUC analysis. During follow-up, LREs occurred in 52 (9%) and 11 (2.3%) patients in derivation and validation cohorts, respectively. Age, type 2 diabetes, albumin, bilirubin, platelet count, and international normalized ratio were independent predictors of LRE and were combined into a model [NAFLD outcomes score (NOS)]. The NOS model calibrated well [calibration slope, 0.99 (derivation), 0.98 (validation)] with excellent overall performance [integrated Brier score, 0.07 (derivation) and 0.01 (validation)]. A cutoff ≥1.3 identified subjects at a higher risk of LRE, (sub-HR 24.6, p < 0.001, 5-year cumulative incidence 38% vs 1.0%, respectively). The predictive accuracy at 5 and 10 years was excellent in both derivation (time-dependent AUC,0.92 and 0.90, respectively) and validation cohorts (time-dependent AUC,0.80 and 0.82, respectively). The NOS was more accurate than the fibrosis-4 or NAFLD fibrosis score for predicting LREs at 5 and 10 years ( p < 0.001)., Conclusions: The NOS model consists of readily available measures and has greater accuracy in predicting outcomes in patients with NAFLD than existing fibrosis models., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background & Aims: This study assessed the effects of the glucagon-like peptide-1 (GLP-1)/glucagon receptor co-agonist efinopegdutide relative to the selective GLP-1 receptor agonist semaglutide on liver fat content (LFC) in patients with non-alcoholic fatty liver disease (NAFLD)., Methods: This was a phase IIa, randomized, active-comparator-controlled, parallel-group, open-label study. A magnetic resonance imaging-estimated proton density fat fraction assessment was performed to determine LFC at screening and Week 24. Participants with an LFC of ≥10% at screening were randomized 1:1 to efinopegdutide 10 mg or semaglutide 1 mg, both administered subcutaneously once weekly for 24 weeks. Participants were stratified according to the concurrent diagnosis of type 2 diabetes mellitus (T2DM). Both drugs were titrated to the target dose over an 8-week time period. The primary efficacy endpoint was relative reduction from baseline in LFC (%) after 24 weeks of treatment., Results: Among 145 randomized participants (efinopegdutide n = 72, semaglutide n = 73), 33.1% had T2DM. At baseline, mean BMI was 34.3 kg/m 2 and mean LFC was 20.3%. The least squares (LS) mean relative reduction from baseline in LFC at Week 24 was significantly (p <0.001) greater with efinopegdutide (72.7% [90% CI 66.8-78.7]) than with semaglutide (42.3% [90% CI 36.5-48.1]). Both treatment groups had an LS mean percent reduction from baseline in body weight at Week 24 (efinopegdutide 8.5% vs. semaglutide 7.1%; p = 0.085). Slightly higher incidences of adverse events and drug-related adverse events were observed in the efinopegdutide group compared with the semaglutide group, primarily related to an imbalance in gastrointestinal adverse events., Conclusions: In patients with NAFLD, treatment with efinopegdutide 10 mg weekly led to a significantly greater reduction in LFC than semaglutide 1 mg weekly., Clinical Trial Number: EudraCT: 2020-005136-30; NCT: 04944992., Impact and Implications: Currently, there are no approved therapies for non-alcoholic steatohepatitis (NASH). The weight loss associated with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to decrease hepatic inflammation in patients with NASH. In addition to reducing liver fat content (LFC) indirectly through weight loss, glucagon receptor agonism may also reduce LFC by acting on the liver directly to stimulate fatty acid oxidation and reduce lipogenesis. This study demonstrated that treatment of patients with non-alcoholic fatty liver disease with the GLP-1/glucagon receptor co-agonist efinopegdutide (10 mg weekly) led to a significantly greater reduction in LFC compared to treatment with the GLP-1 receptor agonist semaglutide (1 mg weekly), suggesting that efinopegdutide may be an effective treatment for NASH., (Copyright © 2023 Manuel Romero-Gómez, Eric Lawitz, R. Ravi Shankar, Eirum Chaudhri, Jie Liu, Raymond L.H. Lam, Keith D. Kaufman, Samuel S. Engel, MK-6024 P001 Study Group. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Extracellular vesicles (EVs) have emerged as a potential source of circulating biomarkers in liver disease. We evaluated circulating AV+ EpCAM+ CD133+ EVs as a potential biomarker of the transition from simple steatosis to steatohepatitis., Methods: EpCAM and CD133 liver proteins and EpCAM+ CD133+ EVs levels were analysed in 31 C57BL/6J mice fed with a chow or high fat, high cholesterol and carbohydrates diet (HFHCC) for 52 weeks. The hepatic origin of MVs was addressed using AlbCrexmT/mG mice fed a Western (WD) or Dual diet for 23 weeks. Besides, we assessed plasma MVs in 130 biopsy-proven NAFLD patients., Results: Hepatic expression of EpCAM and CD133 and EpCAM+ CD133+ EVs increased during disease progression in HFHCC mice. GFP+ MVs were higher in AlbCrexmT/mG mice fed a WD (5.2% vs 12.1%) or a Dual diet (0.5% vs 7.3%). Most GFP+ MVs were also positive for EpCAM and CD133 (98.3% and 92.9% respectively), suggesting their hepatic origin. In 71 biopsy-proven NAFLD patients, EpCAM+ CD133+ EVs were significantly higher in those with steatohepatitis compare to those with simple steatosis (286.4 ± 61.9 vs 758.4 ± 82.3; p < 0.001). Patients with ballooning 367 ± 40.6 vs 532.0 ± 45.1; p = 0.01 and lobular inflammation (321.1 ± 74.1 vs 721.4 ± 80.1; p = 0.001), showed higher levels of these EVs. These findings were replicated in an independent cohort., Conclusions: Circulating levels of EpCAM+ CD133+ MVs in clinical and experimental NAFLD were increased in the presence of steatohepatitis, showing high potential as a non-invasive biomarker for the evaluation and management of these patients., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background & Aims: We conducted an individual patient data meta-analysis to establish stiffness cut-off values for magnetic resonance elastography (MRE) in staging liver fibrosis and to assess potential confounding factors., Methods: A systematic review of the literature identified studies reporting MRE data in patients with NAFLD. Data were obtained from the corresponding authors. The pooled diagnostic cut-off value for the various fibrosis stages was determined in a two-stage meta-analysis. Multilevel modelling methods were used to analyse potential confounding factors influencing the diagnostic accuracy of MRE in staging liver fibrosis., Results: Eight independent cohorts comprising 798 patients were included in the meta-analysis. The area under the receiver operating characteristic curve (AUROC) for MRE in detecting significant fibrosis was 0.92 (sensitivity, 79%; specificity, 89%). For advanced fibrosis, the AUROC was 0.92 (sensitivity, 87%; specificity, 88%). For cirrhosis, the AUROC was 0.94 (sensitivity, 88%, specificity, 89%). Cut-offs were defined to explore concordance between MRE and histopathology: ≥F2, 3.14 kPa (pretest probability, 39.4%); ≥F3, 3.53 kPa (pretest probability, 24.1%); and F4, 4.45 kPa (pretest probability, 8.7%). In generalized linear mixed model analysis, histological steatohepatitis with higher inflammatory activity (odds ratio 2.448, 95% CI 1.180-5.079, p <0.05) and high gamma-glutamyl transferase (GGT) concentration (>120U/L) (odds ratio 3.388, 95% CI 1.577-7.278, p <0.01] were significantly associated with elevated liver stiffness, and thus affecting accuracy in staging early fibrosis (F0-F1). Steatosis, as measured by magnetic resonance imaging proton density fat fraction, and body mass index(BMI) were not confounders., Conclusions: MRE has excellent diagnostic performance for significant, advanced fibrosis and cirrhosis in patients with NAFLD. Elevated inflammatory activity and GGT level may lead to overestimation of early liver fibrosis, but anthropometric measures such as BMI or the degree of steatosis do not., Impact and Implications: This individual patient data meta-analysis of eight international cohorts, including 798 patients, demonstrated that MRE achieves excellent diagnostic accuracy for significant, advanced fibrosis and cirrhosis in patients with NAFLD. Cut-off values (significant fibrosis, 3.14 kPa; advanced fibrosis, 3.53 kPa; and cirrhosis, 4.45 kPa) were established. Elevated inflammatory activity and gamma-glutamyltransferase level may affect the diagnostic accuracy of MRE, leading to overestimation of liver fibrosis in early stages. We observed no impact of diabetes, obesity, or any other metabolic disorder on the diagnostic accuracy of MRE., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Bile acid diarrhoea (BAD) is debilitating yet treatable, but it remains underdiagnosed due to challenging diagnostics. We developed a blood test-based method to guide BAD diagnosis., Design: We included serum from 50 treatment-naive patients with BAD diagnosed by gold standard 75 selenium homotaurocholic acid test, 56 feature-matched controls and 37 patients with non-alcoholic fatty liver disease (NAFLD). Metabolomes were generated using mass spectrometry covering 1295 metabolites and compared between groups. Machine learning was used to develop a BAD Diagnostic Score (BDS)., Results: Metabolomes of patients with BAD significantly differed from controls and NAFLD. We detected 70 metabolites with a discriminatory performance in the discovery set with an area under receiver-operating curve metric above 0.80. Logistic regression modelling using concentrations of decanoylcarnitine, cholesterol ester (22:5), eicosatrienoic acid, L-alpha-lysophosphatidylinositol (18:0) and phosphatidylethanolamine (O-16:0/18:1) distinguished BAD from controls with a sensitivity of 0.78 (95% CI 0.64 to 0.89) and a specificity of 0.93 (95% CI 0.83 to 0.98). The model was independent of covariates (age, sex, body mass index) and distinguished BAD from NAFLD irrespective of fibrosis stage. BDS outperformed other blood test-based tests (7-alpha-hydroxy-4-cholesten-3-one and fibroblast growth factor 19) currently under development., Conclusions: BDS derived from serum metabolites in a single-blood sample showed robust identification of patients with BAD with superior specificity and sensitivity compared with current blood test-based diagnostics., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Non-alcoholic steatohepatitis (NASH) can adversely affect health-related quality of life (HRQoL)., Aims: This double-blind, placebo-controlled, phase 2 trial aimed to report the effects of the glucagon-like peptide-1 receptor agonist, semaglutide, on HRQoL in patients with NASH as a secondary endpoint., Methods: Adults with biopsy-proven NASH and stage 1-3 fibrosis were randomised (3:3:3:1:1:1) to once-daily subcutaneous semaglutide 0.1, 0.2 or 0.4 mg, or placebo, for 72 weeks. Patients were invited to complete the Short Form-36 version 2.0 questionnaire at weeks 0, 28, 52 and 72., Results: Between January 2017 and September 2018, 320 patients were enrolled. At 72 weeks, semaglutide was associated with significant improvements in physical component summary (PCS) score (estimated treatment difference [ETD] 4.26; 95% confidence interval [CI]: 1.96-6.55; p = 0.0003); bodily pain (ETD 5.07; 95% CI: 2.15-7.99; p = 0.0007); physical functioning (ETD 3.51; 95% CI: 1.16-5.86; p = 0.0034); role limitations due to physical health problems (ETD 2.80; 95% CI: 0.28-5.33; p = 0.0294); social functioning (ETD 3.16; 95% CI: 0.53-5.78; p = 0.0183) and vitality (ETD 4.47; 95% CI: 1.63-7.32; p = 0.0021). There was no significant difference in the mental component summary score (ETD 1.02; 95% CI: -1.59 to 3.62; p = 0.4441). After 72 weeks, improvements in PCS scores were significantly greater in patients (pooled semaglutide and placebo) with NASH resolution than without (p = 0.014)., Conclusions: Treatment with semaglutide is associated with improvements in the physical components of HRQoL in patients with biopsy-proven NASH and fibrosis compared with placebo., Clinicaltrials: gov: NCT02970942., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

NAFLD is a multisystem condition and the leading cause of chronic liver disease globally. There are no approved NAFLD-specific dugs. To advance in the prevention and treatment of NAFLD, there is a clear need to better understand the pathophysiology and genetic and environmental risk factors, identify subphenotypes, and develop personalized and precision medicine. In this review, we discuss the main NAFLD research priorities, with a particular focus on socioeconomic factors, interindividual variations, limitations of current NAFLD clinical trials, multidisciplinary models of care, and novel approaches in the management of patients with NAFLD., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: to evaluate the performance of magnetic resonance elastography (MRE) to stage liver fibrosis in patients with histologically confirmed nonalcoholic fatty liver disease (NAFLD) and to assess the impact of potential confounding factors in MRE diagnostic accuracy. The secondary objective was to compare MRE with other non-invasive methods for staging fibrosis such as transient elastography (TE) and non-invasive scores (APRI and FIB-4)., Methods: sixty-five histologically confirmed NAFLD patients were prospectively enrolled at the Hospital Universitario Virgen del Rocío (Seville, Spain). Liver stiffness was measured by MRE, TE and non-invasive scores (APRI and FIB-4). Fibrosis was assessed by liver biopsy using the steatosis, activity and fibrosis (SAF) score. Patients were classified into three groups according to the consistency between MRE and histopathological findings: underestimation, concordance and overestimation groups. Areas under the ROC curve (AUROC) and diagnostic performance were evaluated., Results: the area under the ROC curve (AUROC) of MRE in advanced fibrosis (≥ F3) was 0.90 (0.82-0.97), while TE AUROC was 0.82 (0.72-0.93) (p = 0.22) and lower for the non-invasive test (FIB-4 0.67 and APRI 0.62). Inflammatory activity, steatosis grade and higher levels of liver biochemistry appeared to overestimate MRE results in the univariate analysis, but only gamma-glutamyl transferase (GGT) was statistically significant in the multivariate analysis (p < 0.01). Age, sex, body mass index (BMI), weight, diabetes mellitus (DM), high blood pressure (HBP), platelets or lipidic profile did not affect MRE accuracy., Conclusions: MRE is an effective and non-invasive method for detecting and staging liver fibrosis in NAFLD patients. MRE is more accurate than TE and allows the study of liver anatomy. Histological inflammation and surrogate biomarkers of inflammation can overestimate liver stiffness, but only GGT was statistically significant in the multivariate analysis. Important features of NAFLD patients such as obesity, DM, or lipidic profile did not affect MRE accuracy.

Back in January 2022, an EASL-Lancet Commission on the impact of liver disorders in the European region commissioned by the WHO demonstrated that this condition is, actually, the second leading cause of loss of labor years in Europe after ischemic heart disease (1). This is a very relevant piece of information since this is something that is going to impact the new generations of Europeans unless a significant change is made in public health policies. Despite the advances made over the last few years in hepatitis C virus clearance-understood as a significant reduction of morbidity and mortality associated with Hepatitis B and C viruses-there are still challenges ahead to improve liver health due to the high use of alcohol, and the inseparable triad obesity / diabetes mellitus / metabolic associated fatty liver disease. Also, access to healthcare for several population groups at risk of presenting higher rates of liver disease has become a problem.

Objective: In retrospective studies, liver stiffness (LS) by vibration-controlled transient elastography (VCTE) is associated with the risk of liver decompensation in patients with non-alcoholic steatohepatitis (NASH), but prospective data in biopsy-confirmed cohorts with advanced fibrosis are limited. We aimed to establish thresholds for LS by VCTE that predict progression to cirrhosis among patients with bridging fibrosis and hepatic decompensation among patients with cirrhosis due to NASH., Design: We used data from four randomised placebo-controlled trials of selonsertib and simtuzumab in participants with advanced fibrosis (F3-F4). The trials were discontinued due to lack of efficacy. Liver fibrosis was staged centrally at baseline and week 48 (selonsertib study) or week 96 (simtuzumab study). Associations between LS by VCTE with disease progression were determined using Cox proportional hazards regression analysis., Results: Progression to cirrhosis occurred in 16% (103/664) of participants with bridging fibrosis and adjudicated liver-related events occurred in 4% (27/734) of participants with baseline cirrhosis. The optimal baseline LS thresholds were ≥16.6 kPa for predicting progression to cirrhosis, and ≥30.7 kPa for predicting liver-related events. Baseline LS ≥16.6 kPa (adjusted HR 3.99; 95% CI 2.66 to 5.98, p<0.0001) and a ≥5 kPa (and ≥20%) increase (adjusted HR 1.98; 95% CI 1.20 to 3.26, p=0.008) were independent predictors of progression to cirrhosis in participants with bridging fibrosis, while baseline LS ≥30.7 kPa (adjusted HR 10.13, 95% CI 4.38 to 23.41, p<0.0001) predicted liver-related events in participants with cirrhosis., Conclusion: The LS thresholds identified in this study may be useful for risk stratification of NASH patients with advanced fibrosis., Competing Interests: Competing interests: RL receives funding support from NIAAA (U01AA029019), NIEHS (5P42ES010337), NCATS (5UL1TR001442), NIDDK (U01DK130190, U01DK061734, R01DK106419, P30DK120515, R01DK121378, R01DK124318), NHLBI (P01HL147835), and DOD PRCRP (W81XWH-18-2-0026). RL serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition his institutions received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes and Terns Pharmaceuticals. Co-founder of LipoNexus Inc. DH receives funding support from Singapore Ministry of Health’s National Medical Research Council under its NMRC Research Training Fellowship (MOH-000595-01). In addition, he has served as an advisory board member for Eisai. MFA receives funding support from NIDDK (U01DK130177, U01DK061713, R01DK12137), NCI (UG1CA242643) and DOD (W81XWH2010514). MFA serves as a consultant/advisor to Bristol-Myer Squibb, CohBar, Inventiva, Madrigal, NGM Biopharmaceuticals, Novo Nordisk, Theratechnologies, 89 Bio, Somologics, and Hanmi Pharmaceuticals. In addition, her institutions received research grants from Allergan, Boehringer-Ingelheim, Bristol-Myers Squibb, Enyo, Enanta, Durect, Galectin Therapeutics, Gilead, Galmed, Intercept, Hanmi, Inventiva, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Poxel, TARGET PharmaSolutions, Celgene, Genentech. and Viking Pharmaceuticals. QMA is funded by the LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) consortium funded by the Innovative Medicines Initiative (IMI2) Program of the European Union under Grant Agreement 777377; this Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. He reports Research Grant Funding from Allergan/Tobira, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Glympse Bio, Intercept, Novartis Pharma AG, Pfizer Ltd; Consultancy from 89Bio, Abbvie/Allergan, Altimentiv, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Boehringer Ingelheim, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genentech, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Johnson & Johnson, Madrigal, MedImmune, Medpace, Merck, Metacrine, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, PathAI, Pfizer, Poxel, ProSciento, Raptor Pharma, Roche, Servier, Shionogi, Terns, The Medicines Company, Viking Therapeutics; Speaker fees from Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, Kenes, Medscape; and Royalties from Elsevier. DD, LM, CJ, AB, RSH, CC and RPM are employees and shareholders of Gilead Sciences. VW served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Inventiva, Merck, Novo Nordisk, Pfizer, ProSciento, Sagimet Biosciences, and TARGET PharmaSolutions; and a speaker for Abbott, AbbVie, Echosens, Gilead Sciences, Novo Nordisk. He has received a research grant from Gilead Sciences, and was a co-founder of Illuminatio Medical Technology Limited. JB was a consultant for Gilead Sciences, Actelion and Surrozen., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Extracellular vesicles (EVs) are membrane-derived vesicles released by a variety of cell types, including hepatocytes, hepatic stellate cells, and immune cells in normal and pathological conditions. Depending on their biogenesis, there is a complex repertoire of EVs that differ in size and origin. EVs can carry lipids, proteins, coding and non-coding RNAs, and mitochondrial DNA causing alterations to the recipient cells, functioning as intercellular mediators of cell-cell communication (auto-, para-, juxta-, or even endocrine). Nevertheless, many questions remain unanswered in relation to the function of EVs under physiological and pathological conditions. The development and optimization of methods for EV isolation are crucial for characterizing their biological functions, as well as their potential as a treatment option in the clinic. In this manuscript, we will comprehensively review the results from different studies that investigated the role of hepatic EVs during liver diseases, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, fibrosis, and hepatocellular carcinoma. In general, the identification of patients with early-stage liver disease leads to better therapeutic interventions and optimal management. Although more light needs to be shed on the mechanisms of EVs, their use for early diagnosis, follow-up, and prognosis has come into the focus of research as a high-potential source of 'liquid biopsies', since they can be found in almost all biological fluids. The use of EVs as new targets or nanovectors in drug delivery systems for liver disease therapy is also summarized.

Objective: Our aim was to determine whether the association between active coping and depressive symptoms in patients with non-alcoholic fatty liver disease (NAFLD) was mediated by vitality, and whether diabetes and obesity could impact on this relationship. We also wanted to find out whether mental health and role-physical modulated the relationship between passive/avoidance coping and self-efficacy, and the role of liver fibrosis., Methods: Depressive symptoms (BDI-II), self-efficacy (GSE), coping (COPE-28) and quality of life (SF-12) were evaluated in 509 biopsy-proven NAFLD patients in this cross-sectional study. Mediation and moderated mediation models were conducted using the SPSS PROCESS v3.5 macro., Results: Vitality mediated the relationship between active coping and depressive symptoms (-2.254, CI = -2.792 to -1.765), with diabetes (-0.043, p = 0.017) and body mass index (BMI) (-0.005, p = 0.009) moderating the association. In addition, mental health (-6.435, CI = -8.399 to -4.542) and role-physical (-1.137, CI = -2.141 to -0.315) mediated the relationship between passive/avoidance coping and self-efficacy, with fibrosis stage (0.367, p < 0.001) moderating this association. Specifically, the presence of diabetes and significant fibrosis, and a higher BMI, were associated with greater negative impact on participant depressive symptoms or self-efficacy., Conclusion: A maladaptive coping style was associated with poorer vitality, mental health and role-physical in NAFLD patients, which along with the presence of metabolic comorbidity (diabetes and obesity) and significant fibrosis predicted more depressive symptoms or poorer self-efficacy in these patients. These results suggested incorporating emotional and cognitive evaluation and treatment in patients with NAFLD., Competing Interests: Declaration of Competing Interest The authors have no competing interests to report., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Diet could be both culprit and solution of NAFLD. Dietary modifications have been associated with histological features improvement in NAFLD. The Western diet was related to a greater risk of disease progression while the Mediterranean diet (MD) could promote regression of histological lesions. Modifications in the nutrient composition seems to have lesser impact on NAFLD than dietary modifications. An intrinsic interaction between nutrients in the diet support a specific effect not seen when added separately. Dietary modifications should focus on promoting weight loss but also look for patterns that are able to promote histological improvement. Although several micronutrients' deficit has been related to NAFLD progression, prescribing these micronutrients' supplementation did not reach a positive impact. However, an enriching diet with specific nutrients could be useful, like olive oil supplemented in MD. Geometry of nutrition defines a framework to better understand the interaction between nutrients, foods, and dietetic pattern in the model of diseases and how we could approach taking into consideration the interaction between meals and disease features. After analyzing baseline diet and histological lesions, we could calculate the distance to optimal diet and to promote changes in lifestyle to reach all these goals. A standard MD menu would be recommended., Competing Interests: M.R.-G. received consulting or speaker fee for: Abbvie, Alpha-sigma, Allergan, Astra-Zeneca, Axcella, BMS, Boehringer-Ingelheim, Gilead, Intercept, Inventia, Kaleido, MSD, Novo-Nordisk, Pfizer, Prosciento, Rubió, Siemens, Shionogi, Sobi, Zydus. Research Grants: Gilead, Intercept, Siemens.R.A. and F.M. have nothing to disclose., (Thieme. All rights reserved.)

Non-alcoholic steatohepatitis belongs to the spectrum of metabolic-associated fatty liver diseases characterized by steatosis linked to obesity, diabetes, metabolic syndrome, dyslipidemia and immune-mediated disorders. The main features of MAFLD include high prevalence, heterogeneity, complexity and dynamic disease. Pruritus and asthenia are the main clinical manifestation that impact on quality of life and patient-reported outcomes. Biochemical or imagen-based non-invasive test have been implemented in the diagnostic process. Liver biopsy remains as the gold standard. Therapeutic options included life-style intervention. Mediterranean hypocaloric Diet to lose weight, exercise to fight sarcopenia and alcohol abstinence. In non-responders, drug-therapy focusing on obesity, diabetes and fibrosis using sequentially or combined to promote steatosis, inflammation and fibrosis regression., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Introduction: Background: type 2 diabetes (T2D) is a risk factor for nonalcoholic fatty liver disease (NAFLD). Objective: to evaluate the prevalence of NAFLD in a cohort of patients with T2D. Methods: an observational, descriptive study performed between May 2018 and December 2019 at the Endocrinology and Nutrition Unit. The χ² test was performed for qualitative variables and a non-parametric test for the comparison of medians of quantitative variables. Steatosis degree was defined by the coefficient attenuated parameter (CAP): (S0: < 248 dB/m; S1: 248-268 dB/m; S2: 268-288 dB/m; S3: > 288 dB/m) or stiffness: F0-F1: < 8 kPa; F2: 8-10 kPa; F3: 10-15 kPa; F4: > 15 kPa, using transient elastography (TE) (FibroScan®). A univariate analysis was performed and subsequently a multivariate analysis with statistically significant variables used to study the predictive factors of intense steatosis and advanced fibrosis. Results: n = 104 patients with T2D; 84 (80.7 %) were obese. TE demonstrated advanced fibrosis in 20 % and intense steatosis (S3) in more than 50 %. Lower total bilirubin (OR: 0.028; 95 % CI: (0.002-0.337); p = 0.005) was found to be an independent factor for S3 steatosis in the multivariate analysis. BMI ((OR: 1.497; 95 % CI: (1.102-2.034); p = 0.01)) was a predictive factor for advanced fibrosis in a multivariate analysis. Conclusions: NAFLD-associated intense steatosis and NAFLD-associated fibrosis were commonly found in patients with T2DM and obesity. Diabetic patients should be screened for liver disease as one more target organ.

A common splice variant in HSD17B13 (rs72613567:TA) was recently found to be associated with a reduced risk of developing chronic liver disease in NAFLD patients and a reduced risk of progression to advanced fibrosis and cirrhosis. In this study, we aimed to evaluate the prognosis of cirrhotic patients harboring this variant. We performed a retrospective analysis on 483 prospectively recruited patients from four different hospitals in Spain, followed-up for at least 5 years. We collected clinical, demographic, and biochemical data, and we performed a genotyping analysis for common variants previously associated with liver disease risk (HSD17B13 rs72613567:TA and PNPLA3 rs738409). Patients homozygous for the TA allele showed a higher MELD score (p = 0.047), Child−Turcotte−Pugh score (p = 0.014), and INR levels (p = 0.046), as well as decreased albumin (p = 0.004) at baseline. After multivariate analysis, patients with the “protective” variant indeed had an increased risk of hepatic decompensation [aHR 2.37 (1.09−5.06); p = 0.029] and liver-related mortality [aHR 2.32 (1.20−4.46); p = 0.012]. Specifically, these patients had an increased risk of developing ascites (Log-R 11.6; p < 0.001), hepatic encephalopathy (Log-R 10.2; p < 0.01), and higher mortality (Log-R 14.1; p < 0.001) at 5 years of follow-up. Interactions with the etiology of the cirrhosis and with the variant rs738409 in PNPLA3 are also described. These findings suggest that the variant rs72613567:TA in HSD17B13 has no protective effect, but indeed increases the risk of decompensation and death in patients with advanced chronic liver disease.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem, but the prevalence of fibrosis associated with non-alcoholic steatohepatitis (NASH) is largely unknown in the general population. This study aimed to provide an updated estimation of the prevalence of NASH fibrosis in Spain., Methods: This was an observational, retrospective, cross-sectional, population-based study with merged data from two Spanish datasets: a large (N = 12 246) population-based cohort (ETHON), including transient elastography (TE) data, and a contemporary multi-centric biopsy-proven NASH cohort with paired TE data from tertiary centres (N = 501). Prevalence for each NASH fibrosis stage was estimated by crossing TE data from ETHON dataset with histology data from the biopsy-proven cohort., Results: From the patients with valid TE in ETHON dataset (N = 11 440), 5.61% (95% confidence interval [95% CI]: 2.53-11.97) had a liver stiffness measurement (LSM) ≥ 8 kPa. The proportion attributable to NAFLD (using clinical variables and Controlled Attenuation Parameter) was 57.3% and thus, the estimated prevalence of population with LSM ≥ 8 kPa because of NAFLD was 3.21% (95% CI 1.13-8.75). In the biopsy-proven NASH cohort, 389 patients had LSM ≥ 8 kPa. Among these, 37% did not have significant fibrosis (F2-4). The estimated prevalence of NASH F2-3 and cirrhosis in Spain's adult population were 1.33% (95% CI 0.29-5.98) and 0.70% (95% CI 0.10-4.95) respectively., Conclusions: These estimations provide an accurate picture of the current prevalence of NASH-related fibrosis in Spain and can serve as reference point for dimensioning the therapeutic efforts that will be required as NASH therapies become available., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: NAFLD clinical trials have shown suboptimal results, particularly for liver fibrosis, despite the robust preclinical drug development. We aimed to assess the histological response after the experimental treatment versus placebo by carrying out a meta-analysis of NAFLD clinical trials., Methods: After a systematic review of NAFLD clinical trials to May 2021, applying strict selection criteria, the following primary outcomes were observed: (a) NASH resolution, with no worsening of fibrosis when available; (b) fibrosis improvement  ≥ 1 stage, with no worsening of NAS when available; (c) worsening of NAS; (d) worsening of liver fibrosis  ≥ 1 stage, including the progression to cirrhosis on histopathology. Other histological, clinical, and biochemical outcomes were considered secondary endpoints. Heterogeneity was explored by subgroup and sensitivity analyses, and univariable meta-regression., Results: Twenty-seven randomized clinical trials were included. The pooled efficacy for NASH resolution receiving experimental therapy was 19% (95%CI 15-23; I 2 96.2%) compared with placebo 10% (95%CI 7-12; I 2 85.8%) (OR 1.66 (95%CI 1.24-2.21); I 2 57.8%), while it was 26% (95%CI 22-29); I 2 90%)) versus 18% (95%CI 15-21; I 2 59%)) for fibrosis improvement (OR 1.34 (95%CI 1.13-1.58); I 2 25.4%). For these outcomes, the therapy showed higher efficacy in trials longer than 48 weeks, with  < 60% of diabetic population, and when it targeted FXR, PPAR, and antidiabetic mechanisms, and with a NAS  < 5 for NASH resolution. Also, NASH (OR 0.57 (95%CI 0.39-0.84); I 2 67%) and fibrosis worsening (OR 0.65 (95%CI 0.46-0.92); I 2 61.9%) were prevented with the therapy., Conclusion: This meta-analysis provides information about the efficacy of the therapy versus placebo by comparing different and combined trial outcomes such as NASH resolution, fibrosis improvement, and NAS and fibrosis worsening. Changes in the experimental design and selection criteria of the clinical trials might be suitable to increase the efficacy., (© 2022. The Author(s).)

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent, yet largely underappreciated liver condition which is closely associated with obesity and metabolic disease. Despite affecting an estimated 1 in 4 adults globally, NAFLD is largely absent on national and global health agendas., Methods: We collected data from 102 countries, accounting for 86% of the world population, on NAFLD policies, guidelines, civil society engagement, clinical management, and epidemiologic data. A preparedness index was developed by coding questions into 6 domains (policies, guidelines, civil awareness, epidemiology and data, NAFLD detection, and NAFLD care management) and categorising the responses as high, medium, and low; a multiple correspondence analysis was then applied., Results: The highest scoring countries were India (42.7) and the United Kingdom (40.0), with 32 countries (31%) scoring zero out of 100. For 5 of the domains a minority of countries were categorised as high-level while the majority were categorised as low-level. No country had a national or sub-national strategy for NAFLD and <2% of the different strategies for related conditions included any mention of NAFLD. National NAFLD clinical guidelines were present in only 32 countries., Conclusions: Although NAFLD is a pressing public health problem, no country was found to be well prepared to address it. There is a pressing need for strategies to address NAFLD at national and global levels., Lay Summary: Around a third of the countries scored a zero on the NAFLD policy preparedness index, with no country scoring over 50/100. Although NAFLD is a pressing public health problem, a comprehensive public health response is lacking in all 102 countries. Policies and strategies to address NAFLD at the national and global levels are urgently needed., Competing Interests: Conflict of interest HEM, MV-R, and AP report receiving consulting fees from the EASL International Liver Foundation related to this work. The EASL International Liver Foundation received grants from Intercept, Bristol-Myers-Squibb Company, Genfit, and MSD to support this study. The funders played no role in the conceptualisation, design, data collection, analysis, decision to publish, or preparation of the manuscript. All other authors declare no relevant completing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr -/-). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30 kg/m 2 ), diabetes mellitus and ALT were found to be risk factors whereas A-allele from CPS1 was a protective factor from liver fibrosis. CPS1 hepatic expression was diminished in parallel with the increase of fibrosis, and its levels reverted up to normality after changing diet in CDA-HFD mice. In conclusion, liver fibrosis and steatosis were associated with a reduction in both gene and protein expression patterns of mitochondrial urea cycle enzymes. A-allele from a variant on CPS1 may protect from fibrosis development. CPS1 expression is restored in a preclinical model when the main trigger of the liver damage disappears., (© 2022. The Author(s).)

Objective: The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD., Design: The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI) 2 ). Liver/non-liver-related events and survival free of transplantation were recorded during the follow-up, compared by log-rank testing and reported by adjusted HR., Results: Lean patients represented 14.4% of the cohort and were predominantly of Italian origin (89%). They had less severe histological disease (lean vs non-lean: non-alcoholic steatohepatitis 54.1% vs 71.2% p<0.001; advanced fibrosis 10.1% vs 25.2% p<0.001), lower prevalence of diabetes (9.2% vs 31.4%, p<0.001), but no significant differences in the prevalence of the PNPLA3 I148M variant (p=0.57). During a median follow-up of 94 months (>10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069)., Conclusions: Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and PNPLA3 genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds., Lay Summary: NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease that affects approximately one-quarter of the global adult population, causing a substantial burden of ill health with wide-ranging social and economic implications. It is a multisystem disease and is considered the hepatic component of metabolic syndrome. Unlike other highly prevalent conditions, NAFLD has received little attention from the global public health community. Health system and public health responses to NAFLD have been weak and fragmented, and, despite its pervasiveness, NAFLD is largely unknown outside hepatology and gastroenterology. There is only a nascent global public health movement addressing NAFLD, and the disease is absent from nearly all national and international strategies and policies for non-communicable diseases, including obesity. In this global Delphi study, a multidisciplinary group of experts developed consensus statements and recommendations, which a larger group of collaborators reviewed over three rounds until consensus was achieved. The resulting consensus statements and recommendations address a broad range of topics - from epidemiology, awareness, care and treatment to public health policies and leadership - that have general relevance for policy-makers, health-care practitioners, civil society groups, research institutions and affected populations. These recommendations should provide a strong foundation for a comprehensive public health response to NAFLD., (© 2021. Springer Nature Limited.)

Abstract: One fifth of patients with nonalcoholic fatty liver disease (NAFLD) may progress to nonalcoholic steatohepatitis (NASH), which can increase the risk of cirrhosis, cancer, and death. To date, reported predictors of NASH progression have been heterogeneous.We identified determinants of fibrosis progression in patients with NASH in the United States using physician-reported data from the real-world Global Assessment of the Impact of NASH (GAIN) study, including demographics and clinical characteristics, NASH diagnostic information, fibrosis stage, comorbidities, and treatment. We developed a logistic regression model to assess the likelihood of fibrosis progression since diagnosis, controlling for sociodemographic and clinical variables. An iterative nested model selection approach using likelihood ratio test determined the final model.A total of 989 patients from the GAIN US cohort were included; 46% were women, 58% had biopsy-proven NAFLD, and 74% had fibrosis stage F0-F2 at diagnosis. The final multivariable model included age, years since diagnosis, sex, employment status, smoking status, obesity, fibrosis stage, diagnostic biopsy, Vitamin E, and liver transplant proposed at diagnosis. Odds of progression were 17% higher (odds ratio, 1.17 [95% CI: 1.11-1.23]; P < .001) with each year since NASH diagnosis, 41% lower (0.59 [0.38-0.90]; P = .016) for women than men, 131% higher (2.31 [1.30-4.03]; P = .004) for smokers versus non-smokers, and 89% higher (1.89 [1.26-2.86]; P = .002) with obesity. Odds of progression were also higher with part-time, retired, unemployed, and unable to work due to NASH status versus full-time employment, and when a liver transplant was proposed at diagnosis.Disease duration and severity, obesity, smoking, and lack of full-time employment were significant determinants of fibrosis progression. These findings can support clinical and health-policy decisions to improve NASH management in the US., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Metabolic associated fatty liver disease (MAFLD) is the most prevalent form of liver disease worldwide, accounting for a high liver-related mortality and morbidity with extensive multi-organ involvement. This entity has displaced viral hepatitis as the main cause of severe forms of hepatic diseases, although the onset and transition of MAFLD stages still remains unclear. Nevertheless, innate and adaptive immune responses seem to play an essential role in the establishment and further progression of this disease. The immune system is responsible of safeguard and preserves organs and systems function, and might be altered under different stimuli. Thus, the liver suffers from metabolic and immune changes leading to different injuries and loss of function. It has been stablished that cell-cell crosstalk is a key process in the hepatic homeostasis maintenance. There is mounting evidence suggesting that MAFLD pathogenesis is determined by a complex interaction of environmental, genetic and host factors that leads to a full plethora of outcomes. Therefore, herein we will revisit and discuss the interplay between immune mechanisms and MAFLD, highlighting the potential role of immunological markers in an attempt to clarify its relationship., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gallego-Durán, Montero-Vallejo, Maya-Miles, Lucena, Martin, Ampuero and Romero-Gómez.)

Background: Non-alcoholic fatty liver disease (NAFLD) is affecting more people globally. Indeed, NAFLD is a spectrum of metabolic dysfunctions that can progress to hepatocellular carcinoma (NAFLD-HCC). This development can occur in a non-cirrhotic liver and thus, often lack clinical surveillance. The aim of this study was to develop non-invasive surveillance method for NAFLD-HCC., Methods: Using comprehensive ultra-high-performance liquid chromatography mass-spectrometry, we investigated 1,295 metabolites in serum from 249 patients. Area under the receiver operating characteristic curve was calculated for all detected metabolites and used to establish their diagnostic potential. Logistic regression analysis was used to establish the diagnostic score., Findings: We show that NAFLD-HCC is characterised by a complete rearrangement of the serum lipidome, which distinguishes NAFLD-HCC from non-cancerous individuals and other HCC patients. We used machine learning to build a diagnostic model for NAFLD-HCC. We quantified predictive metabolites and developed the NAFLD-HCC Diagnostic Score (NHDS), presenting superior diagnostic potential compared to alpha-fetoprotein (AFP). Patients' metabolic landscapes show a progressive depletion in unsaturated fatty acids and acylcarnitines during transformation. Upregulation of fatty acid transporters in NAFLD-HCC tumours contribute to fatty acid depletion in the serum., Interpretation: NAFLD-HCC patients can be efficiently distinguished by serum metabolic alterations from the healthy population and from HCC patients related to other aetiologies (alcohol and viral hepatitis). Our model can be used for non-invasive surveillance of individuals with metabolic syndrome(s), allowing for early detection of NAFLD-HCC. Therefore, serum metabolomics may provide valuable insight to monitor patients at risk, including morbidly obese, diabetics, and NAFLD patients., Funding: The funding sources for this study had no role in study design, data collection, data analyses, interpretation or writing of the report as it is presented herein., Competing Interests: Declaration of Competing Interest Drs. Alonso and Arretxe are employed by OWL Metabolomics (One Way Liver, S.L). Prof. Banales is a member of the scientific advisory board of OWL Metabolomics. Remaining authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH., Methods: In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The primary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis., Results: A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs. 33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, P = 0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo., Conclusions: In this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; NATIVE ClinicalTrials.gov number, NCT03008070.)., (Copyright © 2021 Massachusetts Medical Society.)

Background and Aims: Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH)., Methods: PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model., Results: We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs., Conclusions: When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking., Lay Summary: Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring., Competing Interests: Conflict of interest EAS, FEM, MHZ, YV, JAL, CKL, LAJY, NP, CHL, GPA and PMB have nothing to declare. ANAJ, SN and MP are shareholders of Perspectum Ltd. MRG reports grant funding from Gilead Sciences and Intercept; consultancy from Allergan, Gilead Science, Intercept, Medimmune, Shionogi, ProSciento, Kaleido, Siemens, Abbvie, Novo Nordisk, Genfit and Zydus. MJB and TAT are shareholders and employees of Pfizer. QMA is coordinator of the IMI2 LITMUS consortium and he reports research grant funding from Abbvie, Allergan/Tobira, AstraZeneca, GlaxoSmithKline, Glympse Bio, Novartis Pharma AG, Pfizer Ltd., Vertex; consultancy on behalf of Newcastle University for Abbott Laboratories, Acuitas Medical, Allergan/Tobira, Blade, BNN Cardio, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Imperial Innovations, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Kenes, Madrigal, MedImmune, Metacrine, NewGene, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Servier, Viking Therapeutics; and speaker fees from Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, MedScape. SAH has research grants from Akero, Axcella, Cirius, CiVi Biopharma, Cymabay, Galectin, Galmed, Genfit, Gilead Sciences, Hepion Pharmaceuticals, Hightide Therapeutics, Intercept, Madrigal, Metacrine, NGM Bio, Northsea Therapeutics, Novartis, Novo Nordisk, Poxel, Sagimet, Viking. He has received consulting fees from Akero, Altimmune, Alentis, Arrowhead, Axcella, Canfite, Cirius, CiVi, Cymabay, Echosens, Enyo, Fibronostics, Foresite Labs, Fortress Biotech, Galectin, Genfit, Gilead Sciences, Hepion, HIghtide, HistoIndex, Intercept, Kowa, Madrigal, Metacrine, NGM, Northsea, Novartis, Novo Nordisk, Poxel, Prometic, Ridgeline, Sagimet, Terns, and Viking. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease globally. Despite the increased demand placed on health-care systems, little attention has been given to the design and implementation of efficient and effective models of care for patients with NAFLD. In many health-care settings, no formal pathways exist and, where pathways are in place, they are often not standardized according to good practices. We systematically searched the peer-reviewed literature with the aim of identifying published examples of comprehensive models of care that answered four key questions: what services are provided? Where are they provided? Who is offering them? How are they coordinated and integrated within health-care systems? We identified seven models of care and synthesized the findings into eight recommendations nested within the 'what, where, who and how' of care models. These recommendations, aimed at policy-makers and practitioners designing and implementing models of care, can help to address the increasing need for the provision of good practice care for patients with NAFLD., (© 2021. Springer Nature Limited.)

Background and Aim: Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD)., Methods: Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years)., Results: Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non-NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these., Conclusions: The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death., (© 2021 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aim: There is debate among the hepatology community regarding the simple non-invasive scoring systems and histological scores (even it was developed for histological classification) in predicting clinical outcomes in patients with non-alcoholic fatty liver disease (NAFLD). This study aimed to determine whether the presence of simple non-invasive scoring systems and histological scores could predict all-cause mortality, liver-related mortality, and liver disease decompensation (liver failure, cirrhosis, hepatocellular carcinoma, or decompensated liver disease)., Methods: The pooled hazard ratio of prognostic factors and incidence rate per 1000 person-years in patients with NAFLD was calculated and further adjusted by two different models of handling the duplicated data., Results: A total of 19 longitudinal studies were included. Most simple non-invasive scoring systems (Fibrosis-4 Score, BARD, and aspartate aminotransferase-to-platelet ratio index ) and histological scores (NAFLD activity score, Brunt, and "steatosis, activity, and fibrosis" ) failed in predicting mortality, and only the NAFLD fibrosis score > 0.676 showed prognostic ability to all-cause mortality (four studies, 7564 patients, 118 352 person-years followed up, pooled hazard ratio 1.44, 95% confidence interval [CI] 1.05-1.96). The incidence rate per 1000 person-years of all-cause mortality, liver-related mortality, cardiovascular-related mortality, and liver disease decompensation resulted in a pooled incidence rate per 1000 person-years of 22.65 (14 studies, 95% CI 9.62-53.31), 3.19 (7 studies, 95% CI 1.14-8.93), 6.02 (6 studies, 95% CI 4.69-7.74), and 11.46 (4 studies, 95% CI 5.33-24.63), respectively., Conclusion: Non-alcoholic fatty liver disease fibrosis score showed promising prognostic value to all-cause mortality. Most present simple non-invasive scoring systems and histological scores failed to predict clinical outcomes., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: to establish the clinical and economic consequences (resource utilization and healthcare costs) of non-alcoholic fatty liver in the setting of the usual clinical practice in Spain., Patients and Methods: an observational, retrospective study was performed based on a review of the medical records of adult patients ≥ 18 years of age who sought medical care from 2017 to 2018. Patients were categorized into two groups according to fibrosis stage (estimation method: FIB-4): a) F0-F2; and b) F3-F4 (advanced fibrosis). Follow-up lasted one year. Primary endpoints included comorbidity, concomitant medication, resource utilization and costs. Results were analyzed using a multivariate approach with p < 0.05., Results: a total of 8,151 patients were recruited with a mean age of 61.1 years and 51.5 % were male. By group: a) mild fibrosis n = 7,127, 87.4 %; and b) advanced fibrosis n = 1,024, 12.6 % (6.8 % with liver cirrhosis). The most common comorbidities included 63 % dyslipidemia, 52 % obesity, 52 % hypertension and 35 % diabetes. The average number of drugs used was 2.1 per patient. Patients with advanced fibrosis (F3-F4) had a higher average number of concomitant medications (2.5 vs 2.1; p < 0.001) and a higher AST/ALT ratio (1.1 vs 0.8; p < 0.001). The average cost (patient-year) for subjects with advanced fibrosis, corrected for covariates, was higher (€1,812 vs €1,128, p < 0.001). Age, morbidity, concomitant medication, fibrosis stage and total costs were higher in patients with diabetes., Conclusions: patients with advanced fibrosis were associated with more comorbidity and concomitant medications, which resulted in higher healthcare costs for the National Health System.

The prevalence of non alcoholic fatty liver disease (NAFLD) has increased to 25% in the general population and could double by 2030. Liver fibrosis is the main indicator of morbidity and mortality and recent estimations suggest a substantial number of individuals with undiagnosed advanced liver disease. Strategies to monitor advanced fibrosis are essential for early detection, referral, diagnosis and treatment in primary care and endocrine units, where NAFLD and consequently liver fibrosis are more prevalent. Blood-based non-invasive methods could be used to stratify patients according to the risk of the progression of fibrosis and combined with imaging techniques to improve stratification. Powerful new diagnostic tools such as MRE and PDFF are emerging and might prevent the need for liver biopsy in the near future. The current therapeutic landscape of NAFLD is rapidly evolving with an increasing number of molecules that treat key factors involved in its progression, but that still have a limited or no ability to effectively reverse fibrosis. Management of this disease will probably require a combination of sequential and personalized treatments as a result of its complex and dynamic pathophysiology. Lifestyle interventions are still the most effective therapeutic option and should be better integrated into patient management together with specific programs of bariatric endoscopy/surgery for morbidly obese patients., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Nonalcoholic fatty liver disease (NAFLD) is a systemic, dynamic, heterogeneous, and multiaxis entity, the pathogenesis of which is still uncertain. The gut-liver axis is regulated and stabilized by a complex network encompassing a metabolic, immune, and neuroendocrine cross-talk between the gut, the microbiota, and the liver. Changes in the gut-liver axis affect the metabolism of lipids and carbohydrates in the hepatocytes, and they impact the balance of inflammatory mediators and cause metabolic deregulation, promoting NAFLD and its progression to nonalcoholic steatohepatitis. Moreover, the microbiota and its metabolites can play direct and indirect roles in gut barrier function and fibrosis development. In this review, we will highlight findings from the recent literature focusing on the gut-liver axis and its relation to NAFLD. Finally, we will discuss the impact of technical issues, design bias, and other limitations on current knowledge of the gut microbiota in the context of NAFLD., Competing Interests: Dr. Rescigno reports grants from Intercept Pharmaceuticals, during the conduct of the study; grants from Gelesis, grants from Kraft-Heinz, outside the submitted work. Dr. Romero-Gómez reports grants from Intercept, grants from Gilead Sciences, personal fees from Shionogi, personal fees from Alfa Wassermann, personal fees from Prosciento, personal fees from Kaleido, personal fees from Novo Nordisk, personal fees from MSD, personal fees from BMS, personal fees from Allergan, personal fees from Boehringer-Ingelheim, personal fees from Zydus, personal fees from Intercept Pharma, personal fees from Gilead Science, outside the submitted work., (Thieme. All rights reserved.)

Our aim was to analyze how type 2 diabetes and obesity influence quality of life (QoL) and coping in patients with nonalcoholic fatty liver disease (NAFLD), and which coping strategies predict diabetic or obese participants' QoL. QoL (SF-12, CLDQ-NAFLD) and coping strategies (COPE-28) were evaluated in 307 biopsy-proven NAFLD patients with absence or presence of diabetes or obesity. QoL was compared with normality tables for the general Spanish population. Interactive effects were found in physical functioning ( p = 0.008), role-physical ( p = 0.016) and activity ( p = 0.014). Diabetic patients reported worse scores when they were also obese and vice versa, that is, obese patients scored worse when they were also diabetic. Both diabetic and obese patients had lower QoL than those without metabolic pathology or the general population, and obese patients also reported more passive/avoidance coping. Active coping, positive reframing and acceptance predicted better QoL, while denial, self-blame, self-distraction, disengagement and religion predicted lower QoL. In conclusion, diabetes and obesity were associated with lower QoL in patients with NAFLD. Obesity was also associated with more passive/avoidance coping. Furthermore, passive/avoidance coping strategies predicted lower QoL than active, recommending modification of maladaptive coping strategies in future multidisciplinary NAFLD treatments.