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Background & Aims: Sirtuin 5, encoded by the SIRT5 gene, is a NAD + -dependent deacylase that modulates mitochondrial metabolic processes through post-translational modifications. In this study, we aimed to examine the impact of the SIRT5 rs12216101 T>G non-coding single nucleotide polymorphism on disease severity in patients with non-alcoholic fatty liver disease (NAFLD)., Methods: The rs12216101 variant was genotyped in 2,606 consecutive European patients with biopsy-proven NAFLD. Transcriptomic analysis, expression of mitochondrial complexes and oxidative stress levels were measured in liver samples from a subset of bariatric patients. Effects of SIRT5 pharmacological inhibition were evaluated in HepG2 cells exposed to excess free fatty acids. Mitochondrial energetics in vitro were investigated by high-performance liquid chromatography., Results: In the whole cohort, the frequency distribution of SIRT5 rs12216101 TT, TG and GG genotypes was 47.0%, 42.3% and 10.7%, respectively. At multivariate logistic regression analysis adjusted for sex, age >50 years, diabetes, and PNPLA3 rs738409 status, the SIRT5 rs12216101 T>G variant was associated with the presence of non-alcoholic steatohepatitis (odds ratio 1.20, 95% CI 1.03-1.40) and F2-F4 fibrosis (odds ratio 1.18; 95% CI 1.00-1.37). Transcriptomic analysis showed that the SIRT5 rs12216101 T>G variant was associated with upregulation of transcripts involved in mitochondrial metabolic pathways, including the oxidative phosphorylation system. In patients carrying the G allele, western blot analysis confirmed an upregulation of oxidative phosphorylation complexes III, IV, V and consistently higher levels of reactive oxygen species, reactive nitrogen species and malondialdehyde, and lower ATP levels. Administration of a pharmacological SIRT5 inhibitor preserved mitochondrial energetic homeostasis in HepG2 cells, as evidenced by restored ATP/ADP, NAD+/NADH, NADP+/NADPH ratios and glutathione levels., Conclusions: The SIRT5 rs12216101 T>G variant, heightening SIRT5 activity, is associated with liver damage, mitochondrial dysfunction, and oxidative stress in patients with NAFLD., Impact and Implications: In this study we discovered that the SIRT5 rs12216101 T>G variant is associated with higher disease severity in patients with non-alcoholic fatty liver disease (NAFLD). This risk variant leads to a SIRT5 gain-of-function, enhancing mitochondrial oxidative phosphorylation and thus leading to oxidative stress. SIRT5 may represent a novel disease modulator in NAFLD., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721., Competing Interests: Declaration of Competing Interest FEM, SA, KW, JC, MA, EMG, SF, MRG, JC, IFL, RA, RSG, JMP, JB, VR, MW, SP, MA, RF, LM, ET, ME, PL, ATH, GP, HYJ, KP and PMB declare no conflicts of interest. MP is a shareholder in Perspectum Ltd. EMT is a shareholder in Perspectum Ltd. SA is currently employed by Boehringer Ingelheim (but was not during his participation in the project). GPA has served as a consultant and an advisory board member for Pfizer Inc., Inventiva Pharma, GlaxoSmithKline and KaNDy Therapeutics; he has been a consultant to BerGenBio ASA, Median Technologies, FRACTYL, Amryt Pharmaceuticals and AstraZeneca; and has given presentations on behalf of Roche Diagnostics and Medscape all through the University of Nottingham contract. CA declares the following potential conflicts of interest: Hologic: Support of study and expert; Guerbet: Member of board, PI of study; Siemens: Expert. EB has served as a consultant or advisory board member for Boehringer Ingelheim, Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer, ProSciento; and a speaker for Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer. She has also received a research grant from Gilead Sciences for fatty liver research. AG served as a speaker and consultant for AbbVie, Alexion, AstraZeneca, Bayer, BMS, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Sequana; received research funding from Intercept, Falk, Novartis. JMS reports consultancy for BMS, Boehringer Ingelheim, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Novartis, Pfizer, Roche, Sanofi; received research funding from Gilead Sciences and was on the speaker's bureau for Falk Foundation MSD Sharp & Dohme GmbH. MJS and PH are employed by Antaros Medical AB, Mölndal, Sweden. ES is employed by Perspectum Ltd., Oxford, UK. RB is a shareholder and employed (CEO) by Perspectum Ltd., Oxford, UK. KP and MK are employed by Resoundant Inc., Rochester, MN, USA. RLE and the Mayo Clinic have intellectual property rights and a financial interest in magnetic resonance elastography technology. AT is employed by ADVANZPHARMA, Capital House, 1st Floor, 85 King William Street, London, EC4N 7BL, United Kingdom. HC is employed by Boehringer Ingelheim Pharma GmbH & Co. MM is employed by Novartis AG, Basel, Switzerland. CY is employed by Pfizer Inc., Lake Mary, FL, USA. TT was employed by Pfizer at the time of her involvement with the project. QMA is coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multistakeholder consortium includes industry partners. QMA has received research grant funding from AstraZeneca, Boehringer Ingelheim, and Intercept Pharmaceuticals, Inc.; has served as a consultant on behalf of Newcastle University for Alimentiv, Akero, AstraZeneca, Axcella, 89bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, Genfit, Genentech, Gilead, GSK, Hanmi, HistoIndex, Intercept Pharmaceuticals, Inc., Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Poxel, Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI, Shionogi, and Terns; has served as a speaker for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare; and receives royalties from Elsevier Ltd. SN is a shareholder in Perspectum Ltd. SAH has research grants from Akero, Altimmune, Axcella-Cirius, CiVi Biopharma, Cymabay, Galectin, 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, Echosens, Enyo, Foresite Labs, Galectin, Genfit, Gilead Sciences, Hepion, HIghtide, HistoIndex, Intercept, Kowa, Madrigal, Metacrine, NeuroBo, NGM, Northsea, Novartis, Novo Nordisk, Poxel, Perspectum, Sagimet, Terns, and Viking., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The aims of this study were to quantify the histological improvement and its risk factors in patients with NASH enrolled in the placebo arms of randomized controlled trials (RCTs), and to indirectly compare the effect of several investigational drugs for NASH on validated histological outcomes., Data Synthesis: A comprehensive search was conducted to detect phase 2 and 3 RCTs comparing pharmacological interventions in patients with NASH. According to Food and Drug Administration (FDA) recommendations, primary outcomes included: 1) NASH resolution without worsening of fibrosis; 2) At least 1-point reduction in fibrosis without worsening of NASH. Meta-analysis and meta-regressions were conducted on placebo arms, while network meta-analysis was performed on intervention arms. A total of 15 RCTs met the eligibility criteria. The meta-analysis on placebo arms showed a pooled estimate rate of 17% (95%C.I. 12%-23%;I 2  = 86%; p < 0.01) for NASH resolution without worsening of fibrosis and of 21% (95%C.I. 13%-31%;I 2  = 84%; p < 0.01) for ≥1stage improvement of fibrosis without worsening of NASH. Phase 3 (vs Phase 2)RCTs, older age and higher AST levels were significantly associated with progression of liver disease by univariate meta-regression. At network meta-analysis, Semaglutide (P-score 0.906), Pioglitazione alone (score 0.890) and plus Vitamin E (0.826) had the highest probability of being ranked the most effective intervention for NASH resolution without worsening of fibrosis, while Aldafermin (0.776), Lanifibranor (0.773) and Obeticholic acid (0.771) had the highest probability to achieve ≥1 stage of fibrosis improvement without worsening of NASH., Conclusion: This study confirms the heterogeneity of histological progression of untreated patients with NASH and provides evidence to stratify patients according to identified risk factors in future RCTs of combination therapies. PROSPERO CRD42021287205., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants., Methods: We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n = 301) and examined the enrichment of likely pathogenic rare variants vs. the general population. This was followed by validation at the gene level., Results: In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; odds ratio [OR] 5.26, 95% CI 2.1-12.6; p = 0.003) of autophagy-related 7 (ATG7), which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9; 95% CI 1.9-612; p = 0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30; 95% CI 1.1-7.5 and OR 12.30, 95% CI 2.6-36, respectively; p <0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T>C) was also associated with severe NAFLD in the clinical cohort (OR 1.7; 95% CI 1.2-2.5; p = 0.003), predisposed to hepatocellular ballooning (p = 0.007) evolving to fibrosis in the Liver biopsy cohort (n = 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p <0.001), with a larger effect in severely obese individuals in whom it was linked to hepatocellular carcinoma (p = 0.009). ATG7 protein localized to periportal hepatocytes, particularly in the presence of ballooning. In the Liver Transcriptomic cohort (n = 125), ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers., Conclusions: We identified rare and low-frequency ATG7 loss-of-function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation., Lay Summary: We found that rare mutations in a gene called autophagy-related 7 (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. These mutations cause an alteration in protein function and impairment of self-renewal of cellular content, leading to liver damage and inflammation., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest relevant to the present study. LV has received speaking fees from MSD, Gilead, AlfaSigma and AbbVie, served as a consultant for Gilead, Pfizer, AstraZeneca, Novo Nordisk, Intercept, Diatech Pharmacogenetics and Ionis Pharmaceuticals, and received research grants from Gilead. SR has served as a consultant for AstraZeneca, Celgene, Sanofi, Amgen, Akcea Therapeutics, Camp4, AMbys, Medacorp and Pfizer in the past 5 years, and received research grants from AstraZeneca, Sanofi and Amgen. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

Background and Aim: Direct Acting Antivirals(DAAs) achieve the highest rate of sustained viral response(SVR) in patients with genotype-1b(G1b) Hepatitis C virus(HCV) infection. Reducing treatment duration can simplify the management and improve adherence of therapy., Patients and Methods: The study evaluates the efficacy of 8 weeks of elbasvir/grazoprevir regimen in 75 treatment-naïve(TN), G1b patients with mild-moderate fibrosis(Liver Stiffness by Fibroscan® <9.0 kPa). Viral load(VL) has been evaluated by Roche TaqMan RT-PCR(LLOQ<15 IU/ml)., Results: Mean age was 61.0 ± 14.2 years, 44% were male, mean LS by Fibroscan® was 6.1 ± 1.8 kPa. Twenty-eight patients(37.3%) had an HOMA>2.5. Two patients were excluded from analysis(one dropped out and the other one had diagnosed genotype 2c at genotyping by sequencing performed after relapse). At 8 weeks(EOT), 71 out of 73 patients(97.3%) had undetectable HCV-RNA, while in two cases HCV-RNA was detectable but with VL<15 IU/ml. Both of them achieved SVR. Two G1b patients relapsed at 12 weeks of follow-up, both with baseline VL>800,000 IU/ml and HOMA score 1.3 and 3.8 respectively. Both had undetectable HCV VL at 4th week and at the EOT. Modified intention-to-treat SVR12 for G1b patients was 71/73(97.3%)., Conclusion: In naïve, genotype-1b HCV-infected patients with mild/moderate liver fibrosis, short course of 8 weeks of EBR/GZR appears to achieve high efficacy regardless of features of insulin resistance., Competing Interests: Declaration of Competing Interest VC: Travel Grant, Speaking, and Participation to Advisory Boards for: AbbVie, Gilead Sciences and Intercept. Grant and research support: MSD SP: Travel Grant, Speaking, and Participation to Advisory Boards for: AbbVie, Gilead Sciences and Intercept. VDM received research support from Abbvie, Gilead, Intercept and Merck/MSD and served on the advisory boards of Abbvie, Gilead and MSD/Merck. FCS: Research grants, travel grant, lecturing fees, advisory boards, scientific consultancy for Abbvie, Gilead Sciences, Janssen, MSD, ViiV AC: Research grants, lecturing fees, advisory boards, scientific consultancy for Abbvie, Gilead Sciences, BMS, MSD, Intercept. The other authors have no disclosures to declare., (Copyright © 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: The LISTEN trial (ClinicalTrial.gov accession: NCT01950884) is a phase IV 52 weeks double blind parallel randomized controlled trial that evaluated the effect of ezetimibe plus lifestyle and dietary intervention (eze) vs. lifestyle and dietary intervention alone (placebo) on progression and complications of non-alcoholic steatohepatitis (NASH) evaluated by liver histology., Methods and Results: Forty patients with NASH ascertained by histology were randomly allocated on the two study groups and subjected to a follow-up of 52 weeks, when they underwent a second liver biopsy. Main composite end point (EP) was based on the histological improvement in the severity of NASH. Thirty patients completed the study, Eze treatment was not able to improve the primary EP in comparison with placebo, with and odds ratio of 1.029 (0.18-6.38), p = 0.974. Treatment emergent adverse events registered during the study were not more prevalent in the treatment arm., Conclusions: ezetimibe administered on top of lifestyle and dietary modification failed to improve the histology of NASH in comparison with lifestyle and dietary modification alone., Trial Accession Number: ClinicalTrial.gov: NCT01950884., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood., Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1 -/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank., Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients., Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD., Lay Summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice., Competing Interests: Conflict of interest The authors have no potential conflicts (financial, professional or personal) directly relevant to the manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain., Methods: The most common NSS (NFS, FIB-4, BARD, APRI) and the Hepamet fibrosis score (HFS) were assessed in 1,173 European patients with NAFLD from tertiary centres. Performance for fibrosis risk stratification and for the prediction of long-term hepatic/extrahepatic events, hepatocarcinoma (HCC) and overall mortality were evaluated in terms of AUC and Harrell's c-index. For longitudinal data, NSS-based Cox proportional hazard models were trained on the whole cohort with repeated 5-fold cross-validation, sampling for testing from the 607 patients with all NSS available., Results: Cross-sectional analysis revealed HFS as the best performer for the identification of significant (F0-1 vs. F2-4, AUC = 0.758) and advanced (F0-2 vs. F3-4, AUC = 0.805) fibrosis, while NFS and FIB-4 showed the best performance for detecting histological cirrhosis (range AUCs 0.85-0.88). Considering longitudinal data (follow-up between 62 and 110 months), NFS and FIB-4 were the best at predicting liver-related events (c-indices>0.7), NFS for HCC (c-index = 0.9 on average), and FIB-4 and HFS for overall mortality (c-indices >0.8). All NSS showed limited performance (c-indices <0.7) for extrahepatic events., Conclusions: Overall, NFS, HFS and FIB-4 outperformed APRI and BARD for both cross-sectional identification of fibrosis and prediction of long-term outcomes, confirming that they are useful tools for the clinical management of patients with NAFLD at increased risk of fibrosis and liver-related complications or death., Lay Summary: Non-invasive scoring systems are increasingly being used in patients with non-alcoholic fatty liver disease to identify those at risk of advanced fibrosis and hence clinical complications. Herein, we compared various non-invasive scoring systems and identified those that were best at identifying risk, as well as those that were best for the prediction of long-term outcomes, such as liver-related events, liver cancer and death., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Chronic hepatitis C (CHC) is associated with hepatic steatosis, related to both a direct viral action and metabolic features. Vice-versa data on hepatic steatosis after viral eradication by direct-acting antiviral agents (DAA) are undefined although the presence of metabolic alterations could strongly influence the occurrence of steatosis as in NAFLD. The controlled attenuation parameter (CAP) (FibroscanⓇ) allows the qualitative and quantitative evaluation of fatty liver., Aim: to evaluate in patients with CHC whether hepatic steatosis diagnosed by CAP modifies after DAAs-induced sustained virologic response (SVR)., Methods: Data were collected the day of DAAs therapy starting and six months after SVR. CAP ≥ 248 dB/m defined the presence of steatosis., Results: 794 CHC SVR patients referring to 2 Italian Units were enrolled. Mean age was 64 ± 16 ys, 50% males, BMI 25.4 ± 4 kg/m 2 , genotype type-1 in 73%, type-3 in 8%. Prevalence of hepatic steatosis at baseline was 32% by US and 46% by CAP. De novo steatosis developed in 125 (29%), resolution in 122 (30%). At multivariate analysis de novo steatosis was independently associated with male sex (OR 1.7, CI 95% 1.09-2.67; p = 0.02) and baseline BMI (for unit increase OR 1.19, CI 95%1.11-1.29; p < 0.001). Baseline BMI (for unit increase OR 0.47, CI 95% 0.25-0.89; p = 0.02) and triglycerides (for unit increase OR 0.93, CI 95% 0.87-0.99; p = 0.03) prevented steatosis resolution after therapy., Conclusions: after SVR de novo steatosis and resolution of baseline steatosis are closely related to the presence of metabolic comorbidities., Competing Interests: Declaration of Competing Interest The Authors disclose no conflict of interests., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: Beyond type 2 diabetes, even a condition of prediabetes is associated with an increased cardiovascular (CV) risk, and HCV infection coexistence represents an exacerbating factor. CV prognosis improvement in prediabetes represents a challenge, due to the increasing prevalence of this metabolic condition worldwide. Hence, we aimed to prospectively assess how direct acting antivirals (DAAs) could affect major cardiovascular events (MACE) in a prediabetic HCV positive cohort., Methods and Results: In this prospective multicenter study, we enrolled HCV patients with overt prediabetes. We compared a subgroup of patients treated with DAAs with untreated prediabetic controls. We recorded all CV events occurred during an overall median follow-up of 24 months (IQR 19-34). 770 HCV positive prediabetic patients were enrolled, 398 untreated controls and 372 DAAs treated patients. Overall, the CV events annual incidence was much higher among prediabetic treated patients (1.77 vs. 0.62, p < 0.001), and HCV clearance demonstrated to significantly reduce CV events (RR: 0.411, 95%CI 0.148-1.143; p < 0.001), with an estimated NNT for one additional patient to benefit of 52.1. Moreover, an independent association between a lower rate of CV events and HCV clearance after DAAs was observed (OR 4.67; 95%CI 0.44-53.95; p = 0.016)., Conclusions: HCV eradication by DAAs allows a significant reduction of MACEs in the prediabetic population, and therefore represents a primary objective, regardless of the severity of liver disease and CV risk factors., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Liver and kidney are strictly connected in a reciprocal manner, in both the physiological and pathological condition. The Italian Association for the Study of Liver, in collaboration with the Italian Society of Nephrology, with this position paper aims to provide an up-to-date overview on the principal relationships between these two important organs. A panel of well-recognized international expert hepatologists and nephrologists identified five relevant topics: 1) The diagnosis of kidney damage in patients with chronic liver disease; 2) Acute kidney injury in liver cirrhosis; 3) Association between chronic liver disease and chronic kidney disease; 4) Kidney damage according to different etiology of liver disease; 5) Polycystic kidney and liver disease. The discussion process started with a review of the literature relating to each of the five major topics and clinical questions and related statements were subsequently formulated. The quality of evidence and strength of recommendations were graded according to the GRADE system. The statements presented here highlight the importance of strong collaboration between hepatologists and nephrologists for the management of critically ill patients, such as those with combined liver and kidney impairment., Competing Interests: Declaration of Competing Interest Maria Cristina Morelli: has served on advisory boards for Abbvie, Gilead sciences, Shionogi srl. Carlo Alessandria: reports personal fees from Alfasigma, outside the submitted work. Sherrie Bhoori: has served as speaker bureau for Boston Scientific, Eisai, Ipsen, Kedrion. Salvatore Petta: has served as Advisor and/or Speaker for AbbVie, Gilead, Intercept and Pfyze.r Patrizia Burra: has served as Advisor and/or Speaker for Kedrion, Biotest and Chiesi Farmaceutici. Maria Rendina, Ilaria Lenci, Piergiorgio Messa, Loreto Gesualdo, Francesco Paolo Russo Luisa Pasulo, Gaetano La Manna, Luigi Biancone: none to disclose., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The vaccination campaign against Sars-CoV-2 commenced in Italy at the end of December 2020. The first ones to receive the immunization against the virus were the health workers and the residents of nursing homes, following which the vaccine would be available for the entire population, beginning with the most vulnerable individuals. SARS-CoV2 vaccines have been demonstrated to be safe for the general population, although no data for patients with liver diseases or those having undergone liver transplantation are available so far. The present position statement AISF is an attempt to suggest, based on the published data on the impact of Sars-Cov-2 infection in patients with chronic liver disease, a possible priority for vaccination for this category of patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification., Methods: We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5)., Results: In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10 -13 ). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10 -7 ). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10 -5 ) and without cirrhosis (p <0.05)., Conclusions: Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings., Lay Summary: By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest relevant to the present study. SR has served as a consultant for AstraZeneca, Celgene, Sanofi, Amgen, Akcea Therapeutics, Camp4, AMbys, Medacorp and Pfizer in the past 5 years, and received research grants from AstraZeneca, Sanofi and Amgen. LV has received speaking fees from MSD, Gilead, AlfaSigma and AbbVie, served as a consultant for Gilead, Pfizer, Astra Zeneca, Novo Nordisk, Intercept, Diatech Pharmacogenetics and Ionis Pharmaceuticals, and received research grants from Gilead. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS 'Liver Investigation: Testing Marker Utility in Steatohepatitis' consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aim: Increased intestinal permeability plays a key role in the pathogenesis of fat deposition in the liver. The aim of our study was to assess whether a single nucleotide polymorphism of protein tyrosine phosphatase non-receptor type 2 (PTPN2) (rs2542151 T→G), involved in intestinal permeability, may be associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM)., Methods and Results: We recruited a prospective cohort of NAFLD subjects and matched controls. Clinical data, PTPN2 genotype and laboratory data were collected for each patient. Results were stratified according to liver histology and diabetes. We enrolled 566 cases and 377 controls. PTPN2 genotype distribution did not significantly differ between patients and controls. In the entire population, patients with PTPN2 rs2542151 T→G (dominant model) have a higher prevalence of diabetes; 345 patients (60.9%) underwent liver biopsy: 198 (57.4%) had steatohepatitis and 75 (21.7%) had advanced fibrosis. At multiple logistic regression analysis PTPN2 rs2542151 T→G was associated with T2DM (OR 2.14, 95% CI 1.04-4.40, P = 0.03). Patients who underwent liver biopsy, rs2542151 T→G of PTPN2 was independently associated with severe steatosis (OR 2.00, 95% CI 1.17-3.43, p = 0.01) and severe fibrosis (OR 2.23, 95% CI 1.06-4.72, P = 0.03)., Conclusion: Our study shows that NAFLD patients with rs2542151 T→G of PTPN2 have a higher severity of fatty liver disease and a higher prevalence of T2DM. These results suggest that individual genetic susceptibility to intestinal permeability could play a role in liver disease progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interest., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Neurotensin (NTS), a 13-aminoacid peptide localized in central nervous system and gastrointestinal tract, is involved in lipid metabolism and promotes various cancers onset mainly by binding to neurotensin receptor 1 (NTSR1). Increased plasma levels of pro-NTS, the stable NTS precursor, have been associated with type 2 diabetes (T2D), cardiovascular diseases and metabolic associated fatty liver disease (MAFLD). We aimed to evaluate 1) the impact of NTS rs1800832 and NTSR1 rs6090453 genetic variants on liver damage in 1166 MAFLD European individuals, 2) the relation between NTS variant and circulating pro-NTS and 3) the hepatic NTS expression by RNAseq transcriptomic analysis in 125 bariatric patients., Results: The NTS rs1800832 G allele was associated with hepatic fibrosis (OR 1.27, 95% confidence interval (CI). 1.02-1.58; p = 0.03), even more in carriers of both NTS and NTSR1 G risk alleles (OR 1.17, 95% CI. 1.03-1.34; p = 0.01), with cirrhosis (OR 1.58, 95% CI. 1.07-2.34; p = 0.02) and HCC (OR 1.98, 95% CI. 1.24-3.2; p = 0.004). Pro-NTS circulating levels were correlated with T2D (p = 0.005), BMI, (p = 0.04), age (p = 0.0016), lobular inflammation (p = 0.0025), fibrosis>2 (p < 0.0001), cirrhosis (p = 0.0009) and HCC (p < 0.0001) and more so after stratification for the NTS G allele. Transcriptomic data showed that hepatic NTS expression correlated with that of fibrogenic genes (p < 0.05)., Conclusions: NTS rs1800832 variant is associated with advanced fibrosis and HCC in MAFLD patients likely affecting NTS protein activity. The rs6090453 NTSR1 gene variant synergizes with NTS rs1800832 mutation to promote liver damage. Prospective studies are necessary to confirm NTS role in liver disease progression., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The COVID-19 pandemic had a huge impact on national and regional health systems. The impact of SARS-CoV-2 on the quality of care for patients with liver disease is still unknown., Aims: The Italian Association for the Study of the Liver (AISF) conducted a survey to assess the impact of SARS-CoV-2 on hepatology units activities in Italy., Methods: A prospective web-based survey was proposed to all AISF active members. The survey was available online from April 8 2020, to May 3 2020, (lockdown phase in Italy)., Results: 194 AISF members answered the questionnaire, most of whom were specialists in Gastroenterology (41%) or Internal Medicine (28%), and worked in Northern Italy (51%). 26% of hepatology wards had been converted into COVID-19 wards, and 33% had bed reductions. All hepatological activities, including the management of patients with decompensated liver disease, liver transplant and HCC had been significantly reduced/stopped. The number of physicians answering that their practices had not been modified ranged between 0.6% (for chronic hepatitis) to 47% (for the execution of paracentesis). The recorded answers were consistent among different regions, and did not show any north-south gradient CONCLUSION: COVID-19 outbreak significantly impacted on hepatological clinical activity. This survey can serve as a basis to compare the impact of future measures aimed at delivering an acceptable level of liver care during a national pandemic or crisis., Competing Interests: Declaration of Competing Interest All Authors report no relevant conflicts of interests, (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD., Methods: The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance., Results: Case-control analysis identified signals showing p values ≤5 × 10 -8 at 4 locations (chromosome [chr] 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with 2 other signals with p <1 × 10 -7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits showed that the PNPLA3 signal (rs738409) had genome-wide significance for steatosis, fibrosis and NAFLD activity score and a new signal (PYGO1 rs62021874) had close to genome-wide significance for steatosis (p = 8.2 × 10 -8 ). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR single nucleotide polymorphism also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16, the genome-wide significance signals were replicated., Conclusions: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting that Wnt signalling pathways may be relevant in NAFLD pathogenesis., Lay Summary: Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may result in cirrhosis. To understand who is at risk of developing this disease and suffering liver damage, we undertook a genetic study to compare the genetic profiles of people suffering from fatty liver disease with genetic profiles seen in the general population. We found that particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individual's risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments., Competing Interests: Conflict of interest Quentin Anstee reports grants from European Commission during the conduct of the study; other from Acuitas Medical, grants, personal fees and other from Allergan/Tobira, other from E3Bio, other from Eli Lilly & Company Ltd, other from Galmed, grants, personal fees and other from Genfit SA, personal fees and other from Gilead, other from Grunthal, other from Imperial Innovations, grants and other from Intercept Pharma Europe Ltd, other from Inventiva, other from Janssen, personal fees from Kenes, other from MedImmune, other from NewGene, grants and other from Pfizer Ltd, other from Raptor Pharma, grants from GlaxoSmithKline, grants and other from Novartis Pharma AG, grants from AbbVie, personal fees from BMS, grants from GSK, other from NGMBio, other from Madrigal, other from Servier, outside the submitted work; Dina Tiniakos reports consultation fees from Intercept Pharmaceuticals Inc, Allergan, Cirius Therapeutics and an educational grant from Histoindex Pte Ltd; Guruprasad P. Aithal reports institutional consultancy income outside the scope of this study from GSK and Pfizer; Michael Allison reports consultancy/advisory with MedImmune/Astra Zeneca, E3Bio, honoraria from Intercept, Grant support from GSK, Takeda; Jean-Francois Dufour reports advisory committees with AbbVie, Bayer, BMS, Falk, Genfit, Genkyotex, Gilead Science, HepaRegenix, Intercept, Lilly, Merck, Novartis and speaking and teaching with Bayer, BMS, Intercept, Genfit, Gilead Science, Novartis; Pietro Invernizzi reports grants from Intercept, Gilead and Bruschettini; Mattias Ekstedt reports personal fees from AbbVie, AstraZeneca, Albireo, Diapharma, Gilead and non-financial support from Echosens (through LITMUS IMI project); Karine Clement has no personal honoraria but has consultancy and scientific collaboration activity for LNC therapeutics, Confotherapeutics and Danone Research; Jörn M. Schattenberg reports grants from Gilead and Boehringer Ingelheim and fees from Gilead, Boehringer Ingelheim, Galmed, Genfit, Intercept, Novartis, Pfizer and AbbVie outside the submitted work. All other authors report no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Nonalcoholic steatohepatitis (NASH) may progress to advanced liver disease (AdvLD). This study characterized comorbidities, healthcare resource utilization (HCRU) and associated costs among hospitalized patients with AdvLD due to NASH in Italy., Methods and Results: Adult nonalcoholic fatty liver disease (NAFLD)/NASH patients from 2011 to 2017 were identified from administrative databases of Italian local health units using ICD-9-CM codes. Development of compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC), or liver transplant (LT) was identified using first diagnosis date for each severity cohort (index-date). Patients progressing to multiple disease stages were included in >1 cohort. Patients were followed from index-date until the earliest of disease progression, end of coverage, death, or end of study. Within each cohort, per member per month values were annualized to calculate all-cause HCRU or costs(€) in 2017. Of the 9,729 hospitalized NAFLD/NASH patients identified, 97% were without AdvLD, 1.3% had CC, 3.1% DCC, 0.8% HCC, 0.1% LT. Comorbidity burden was high across all cohorts. Mean annual number of inpatient services was greater in patients with AdvLD than without AdvLD. Similar trends were observed in outpatient visits and pharmacy fills. Mean total annual costs increased with disease severity, driven primarily by inpatient services costs., Conclusion: NAFLD/NASH patients in Italy have high comorbidity burden. AdvLD patients had significantly higher costs. The higher prevalence of DCC compared to CC in this population may suggest challenges of effectively screening and identifying NAFLD/NASH patients. Early identification and effective management are needed to reduce risk of disease progression and subsequent HCRU and costs., Competing Interests: Declaration of Competing Interest This study was sponsored by Gilead Sciences, Inc., and executed by CliCon S.r.l on behalf of Gilead Sciences, Inc. The agreement signed by Clicon S.r.l. and Gilead does not create any entityship, joint venture or any similar relationship between parties. Clicon S.r.l. is an independent company. Neither CliCon S.r.l. nor any of their representatives are employees of Gilead for any purpose. SS, and LDE report no conflicts of interest in this work. JT and SS are employees of Gilead, Foster City, CA, USA. SP, MLP, and GM are consultants of Gilead Sciences, Inc. for this study., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Lysosomal storage diseases (LSDs) are a heterogeneous group of inherited disorders caused by loss-of-function mutations in genes encoding for lysosomal enzymes/proteins. The consequence is a progressive accumulation of substrates in these intracellular organelles, resulting in cellular and tissue damage. The overall incidence is about 1/8000 live births, but is likely underestimated. LSDs are chronic progressive multi-systemic disorders, generally presenting with visceromegaly, and involvement of the central nervous system, eyes, the skeleton, and the respiratory and cardiovascular systems. The age at onset and phenotypic expression are highly variable, according to the specific enzymatic defect and tissues involved, the residual activity, and the disease-causing genotype. Enzyme-replacement therapies and substrate-reduction therapies have recently become available, leading to the improvement in symptoms, disease progression and quality of life of affected individuals. Liver involvement and hepatosplenomegaly are frequent features of LSDs and a hallmark of adult-onset forms, frequently leading to medical attention. LSDs should therefore be considered in the differential diagnosis of liver disease with organomegaly. The present document will provide a short overview of adult-onset LSDs with hepatic involvement, highlighting the specificities and systemic manifestations of the ones most frequently encountered in clinical practice, which may hint at the correct diagnosis and the appropriate treatment., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: HCV is associated with an increased risk of cardiovascular events (CV). Whether HCV clearance by direct-acting antivirals (DAA) reduces incident CV disease is poorly understood. We investigate whether HCV eradication reduces CV events., Methods: In a prospective multicentre study, 2204 HCV patients (F0-F2:29.5%, F3-F4: 70.5%) were enrolled. Males were 48%, median age was 68 (59-74) years and BMI 25.9 (23.1-28); 24.7% were smokers, 18% had diabetes, 13.2% had cholesterol levels >200 mg/dl and 9.1% took statins, 44% had hypertension. During an overall median follow-up of 28 (24-39) months, incident CV events, such as ischemic heart disease (IHD) and ischemic cerebral stroke (ICS), were recorded. An overall of 2204 patients were evaluated as control group and 1668 patients after HCV elimination were followed as a case group. Factors associated with CV events were evaluated by uni- and multi-variate analyses., Results: Incident CV rates per 100 patient years in pre-treatment and untreated controls and treated cases were 1.12, 1.14 and 0.44 (p = 0.0001 vs. controls), respectively, and a decreased of relative risk (RR = 0.379; p = 0.0002) was observed. CV risk was 2.0-3.5 times lower then in controls (HR 3.671; 95%C.I.:1.871-7.201; p < 0.001). The calculated number of patients to be treated to get a benefit in a patient was 55.26. The annual incidence reduction of CV events was 0.68%. HCV clearance was independently associated with CV events reduction (OR, 4.716; 95% C.I.:1.832-12.138; p = 0.001)., Conclusions: HCV clearance by DAA reduces CV events (IHD and ICS) with both clinical and socio-economic benefits., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background & Aims: The effectiveness of direct-acting antivirals (DAAs) against hepatitis C virus (HCV), following successful treatment of early hepatocellular carcinoma (HCC), has been studied extensively. However, the benefit in terms of overall survival (OS) remains to be conclusively demonstrated. The aim of this study was to assess the impact of DAAs on OS, HCC recurrence, and hepatic decompensation., Methods: We prospectively enrolled 163 consecutive patients with HCV-related cirrhosis and a first diagnosis of early Barcelona Clinic Liver Cancer stage 0/A HCC, who had achieved a complete radiologic response after curative resection or ablation and were subsequently treated with DAAs. DAA-untreated patients from the ITA.LI.CA. cohort (n = 328) served as controls. After propensity score matching, outcomes of 102 DAA-treated (DAA group) and 102 DAA-untreated patients (No DAA group) were compared., Results: In the DAA group, 7/102 patients (6.9%) died, HCC recurred in 28/102 patients (27.5%) and hepatic decompensation occurred in 6/102 patients (5.9%), after a mean follow-up of 21.4 months. OS was significantly higher in the DAA group compared to the No DAA group (hazard ratio [HR] 0.39; 95% CI0.17-0.91; p = 0.03). HCC recurrence was not significantly different between the DAA and No DAA groups (HR0.70; 95% CI0.44-1.13; p = 0.15). A significant reduction in the rate of hepatic decompensation was observed in the DAA group compared with the No DAA group (HR0.32; 95% CI0.13-0.84; p = 0.02). In the DAA group, sustained virologic response was a significant predictor of OS (HR 0.02; 95% CI 0.00-0.19; p <0.001), HCC recurrence (HR 0.25; 95% CI 0.11-0.57; p <0.001) and hepatic decompensation (HR 0.12; 95% CI 0.02-0.38; p = 0.02)., Conclusions: In patients with HCV-related cirrhosis who had been successfully treated for early HCC, DAAs significantly improved OS compared with No DAA treatment., Lay Summary: We aimed to determine whether direct-acting antivirals (DAAs) significantly improve overall survival in patients with hepatitis C virus-related compensated cirrhosis and a first diagnosis of hepatocellular carcinoma (HCC) which has been successfully treated with curative resection or ablation. Using propensity-score matched patients, we found that DAAs improved overall survival and reduced the risk of hepatic decompensation. However, the risk of HCC recurrence was not significantly reduced., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Dyslipidemia and altered iron metabolism are typical features of nonalcoholic fatty liver disease (NAFLD). Proprotein convertase subtilisin/kexin type 7 ( PCSK7 ) gene variation has been associated with circulating lipids and liver damage during iron overload. The aim of this study was to examine the impact of the PCSK7 rs236918 variant on NAFLD-related traits in 1,801 individuals from the Liver Biopsy Cohort (LBC), 500,000 from the UK Biobank Cohort (UKBBC), and 4,580 from the Dallas Heart Study (DHS). The minor PCSK7 rs236918 C allele was associated with higher triglycerides, aminotransferases, and hepatic inflammation in the LBC ( P < 0.05) and with hypercholesterolemia and liver disease in the UKBBC. In the DHS, PCSK7 missense variants were associated with circulating lipids. PCSK7 was expressed in hepatocytes and its hepatic expression correlated with that of lipogenic genes ( P < 0.05). The rs236918 C allele was associated with upregulation of a new "intra-PCSK7" long noncoding RNA predicted to interact with the protein, higher hepatic and circulating PCSK7 protein ( P < 0.01), which correlated with triglycerides ( P = 0.04). In HepG2 cells, PCSK7 deletion reduced lipogenesis, fat accumulation, inflammation, transforming growth factor β pathway activation, and fibrogenesis. In conclusion, PCSK7 gene variation is associated with dyslipidemia and more severe liver disease in high risk individuals, likely by modulating PCSK7 expression/activity., (Copyright © 2019 Dongiovanni et al.)

Background & Aims: Interventions aimed at lifestyle changes are pivotal for the treatment of non-alcoholic fatty liver disease (NAFLD), and web-based programs might help remove barriers in both patients and therapists., Methods: In the period 2010-15, 716 consecutive NAFLD cases (mean age, 52; type 2 diabetes, 33%) were treated in our Department with structured programs. The usual protocol included motivational interviewing and a group-based intervention (GBI), chaired by physicians, dietitians and psychologists (five weekly meetings, n = 438). Individuals who could not attend GBI entered a web-based intervention (WBI, n = 278) derived from GBI, with interactive games, learning tests, motivational tests, and mail contacts with the center. The primary outcome was weight loss ≥10%; secondary outcomes were alanine aminotransferase within normal limits, changes in lifestyle, weight, alanine aminotransferase, and surrogate markers of steatosis and fibrosis., Results: GBI and WBI cohorts had similar body mass index (mean, 33 kg/m 2 ), with more males (67% vs. 45%), younger age, higher education, and more physical activity in the WBI group. The two-year attrition rate was higher in the WBI group. Healthy lifestyle changes were observed in both groups and body mass index decreased by almost two points;the 10% weight target was reached in 20% of WBI cases vs. 15% in GBI (not significant). In logistic regression analysis, after adjustment for confounders and attrition rates, WBI was not associated with a reduction of patients reaching short- and long-term 10% weight targets. Liver enzymes decreased in both groups, and normalized more frequently in WBI. Fatty liver index was reduced, whereas fibrosis remained stable (NAFLD fibrosis score) or similarly decreased (Fib-4)., Conclusion: WBI is not less effective than common lifestyle programs, as measured by significant clinical outcomes associated with improved histological outcomes in NAFLD. eHealth programs may effectively contribute to NAFLD control., Lay Summary: In patients with non-alcoholic fatty liver disease, participation in structured lifestyle programs may be jeopardized by job and time constraints. A web-based intervention may be better suited for young, busy patients, and for those living far from liver units. The study shows that, following a structured motivational approach, a web-based, interactive intervention coupled with six-month face-to-face meetings is not inferior to a standard group-based intervention with respect to weight loss, adherence to healthy diet and habitual physical activity, normalization of liver enzymes, and stable surrogate markers of fibrosis., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatitis C virus (HCV) infection is now considered a systemic disease due to the occurrence of extra-hepatic manifestations. Among these, the renal involvement is frequent. HCV infection, in fact, is strongly associated with proteinuria and chronic kidney disease (CKD) and negatively affects the prognosis of renal patients. In the last few years, availability of more specific and effective drugs against HCV has dramatically changed the clinical course of this disease. These drugs may provide further advantages in the CKD population as a whole by reducing progression of renal disease, mortality rate and by increasing the survival of graft in renal transplant recipients. The strict pathogenetic and prognostic link between HCV infection and CKD requires an ongoing relationship among the healthcare professionals involved in the treatment of both HCV infection and CKD. Therefore, Scientific Societies involved in the care of this high-risk population in Italy have organized a joint expert panel. The aim of the panel is to produce a position statement that can be used in daily clinical practice for the management of HCV infected patients across the whole spectrum of renal disease, from the conservative phase to renal replacement treatments (dialysis and transplantation). Sharing specific evidence-based expertise of different professional healthcare is the first step to obtain a common ground of knowledge on which to instate a model for multidisciplinary management of this high-risk population. Statements cover seven areas including epidemiology of CKD, HCV-induced glomerular damage, HCV-related renal risk, staging of liver disease in patients with CKD, prevention of transmission of HCV in hemodialysis units, treatment of HCV infection and management of HCV in kidney transplantation., (Copyright © 2018 Roberto Minutolo, Alessio Aghemo, Antonio Chirianni, Fabrizio Fabrizi, Loreto Gesualdo, Edoardo G. Giannini, Paolo Maggi, Vincenzo Montinaro, Ernesto Paoletti, Marcello Persico, Francesco Perticone, Salvatore Petta, Massimo Puoti, Giovanni Raimondo, Maria Rendina, Anna Linda Zignego, on behalf of the Italian Society of Nephrology (SIN), the Italian Association for the Study of the Liver (AISF), the Italian Society of Infectious and Tropical Disease (SIMIT), the Italian Society of Internal Medicine (SIMI). Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Baveno VI and expanded Baveno VI criteria can avoid the need for esophagogastroduodenoscopy (EGD) to screen for varices needing treatment (VNT) in a substantial proportion of compensated patients with viral and/or alcoholic cirrhosis. This multicenter, cross-sectional study aims to validate these criteria in patients with compensated cirrhosis due to non-alcoholic fatty liver disease (NAFLD), accounting for possible differences in liver stiffness measurement (LSM) values between M and XL probes., Methods: We assessed 790 patients with NAFLD-related compensated cirrhosis who had EGD within six months of a reliable LSM, measured by FibroScan® using M and/or XL probe. Baveno VI and expanded Baveno VI criteria were tested. The main variable used to optimize criteria was the percentage of endoscopies spared, keeping the risk of missing large VNT below a 5% threshold., Results: LSM was measured by both M and XL probes (training set) in 314 patients, while only M or XL probe (validation sets) were used to measure LSM in 338 and 138 patients, respectively. In the training set, use of Baveno VI and expanded Baveno VI criteria reduced the number of EGD by 33.3% and by 58%, with 0.9% and 3.8% of large esophageal varices missed, respectively. The best thresholds to rule-out VNT were identified as platelet count >110,000/mm 3 and LSM <30 kPa for M probe, and platelet count >110,000/mm 3 and LSM <25 kPa for XL probe (NAFLD cirrhosis criteria). Thus, usage of NAFLD cirrhosis criteria would have led to an absolute reduction in the number of EGD screened patients of 34.7% and 10.5% with respect to Baveno VI and expanded Baveno VI criteria, respectively., Conclusion: The new NAFLD cirrhosis criteria, established for the FibroScan probe, can reduce the use of EGD for screening of VNT in NAFLD cirrhosis by more than half, with a chance of missing VNT below 5%., Lay Summary: In non-alcoholic fatty liver disease-related compensated cirrhosis, the expanded Baveno VI criteria work better than the Baveno VI criteria for ruling out the presence of varices needing treatment, sparing unnecessary and invasive screening procedures. New diagnostic criteria for this patient group, based on liver stiffness measurement and platelet count, and optimized for the specific FibroScan ® probe used, work better than both Baveno VI and expanded Baveno VI criteria. The accuracy of all non-invasive scoring criteria was lower in non-obese patients., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data., Methods: A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections., Results: If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30%), between 2016-2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15-56%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population., Conclusions: NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden., Lay Summary: Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Recent studies suggest an association between hepatitis C virus (HCV) infection and cardiovascular damage, including carotid atherosclerosis, with a possible effect of HCV clearance on cardiovascular outcomes. We aimed to examine whether HCV eradication by direct-acting antiviral agents (DAA) improves carotid atherosclerosis in HCV-infected patients with advanced fibrosis/compensated cirrhosis., Materials and Methods: One hundred eighty-two consecutive patients with HCV and advanced fibrosis or compensated cirrhosis were evaluated. All patients underwent DAA-based antiviral therapy according to AISF/EASL guidelines. Intima-media thickness (IMT), carotid thickening (IMT ≥1 mm) and carotid plaques, defined as focal thickening of ≥1.5 mm at the level of the common carotid, were evaluated by ultrasonography (US) at baseline and 9-12 months after the end of therapy. Fifty-six percent of patients were male, mean age 63.1 ± 10.4 years, and 65.9% had compensated cirrhosis. One in five had diabetes, 14.3% were obese, 41.8% had arterial hypertension and 35.2% were smokers. At baseline, mean IMT was 0.94 ± 0.29 mm, 42.8% had IMT ≥1 mm, and 42.8% had carotid plaques., Results: All patients achieved a 12-week sustained virological response. IMT significantly decreased from baseline to follow-up (0.94 ± 0.29 mm vs. 0.81 ± 0.27, p <0.001). Consistently, a significant reduction in the prevalence of patients with carotid thickening from baseline to follow-up was observed (42.8% vs. 17%, p <0.001), while no changes were reported for carotid plaques (42.8% vs. 47.8%, p = 0.34). These results were confirmed in subgroups of patients stratified for cardiovascular risk factors and liver disease severity., Conclusion: HCV eradication by DAA improves carotid atherosclerosis in patients with severe fibrosis with or without additional metabolic risk factors. The impact of this improvement in the atherosclerotic burden in terms of reduction of major cardiovascular outcomes is worth investigating in the long term., Lay Summary: Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with advanced fibrosis/compensated cirrhosis. The improvement in intima-media thickness and carotid thickening was confirmed after stratification for severity of liver disease and cardiovascular risk factors. Hepatitis C virus eradication by direct-acting antiviral agents also lead to improvement in glucose homeostasis and increased cholesterol levels., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Controlled attenuation parameter (CAP) can be performed together with liver stiffness measurement (LSM) by transient elastography (TE) and is often used to diagnose fatty liver. We aimed to define the validity criteria of CAP., Methods: CAP was measured by the M probe prior to liver biopsy in 754 consecutive patients with different liver diseases at three centers in Europe and Hong Kong (derivation cohort, n=340; validation cohort, n=414; 101 chronic hepatitis B, 154 chronic hepatitis C, 349 non-alcoholic fatty liver disease, 37 autoimmune hepatitis, 49 cholestatic liver disease, 64 others; 277 F3-4; age 52±14; body mass index 27.2±5.3kg/m 2 ). The primary outcome was the diagnosis of fatty liver, defined as steatosis involving ≥5% of hepatocytes., Results: The area under the receiver-operating characteristics curve (AUROC) for CAP diagnosis of fatty liver was 0.85 (95% CI 0.82-0.88). The interquartile range (IQR) of CAP had a negative correlation with CAP (r=-0.32, p<0.001), suggesting the IQR-to-median ratio of CAP would be an inappropriate validity parameter. In the derivation cohort, the IQR of CAP was associated with the accuracy of CAP (AUROC 0.86, 0.89 and 0.76 in patients with IQR of CAP <20 [15% of patients], 20-39 [51%], and ≥40dB/m [33%], respectively). Likewise, the AUROC of CAP in the validation cohort was 0.90 and 0.77 in patients with IQR of CAP <40 and ≥40dB/m, respectively (p=0.004). The accuracy of CAP in detecting grade 2 and 3 steatosis was lower among patients with body mass index ≥30kg/m 2 and F3-4 fibrosis., Conclusions: The validity of CAP for the diagnosis of fatty liver is lower if the IQR of CAP is ≥40dB/m. Lay summary: Controlled attenuation parameter (CAP) is measured by transient elastography (TE) for the detection of fatty liver. In this large study, using liver biopsy as a reference, we show that the variability of CAP measurements based on its interquartile range can reflect the accuracy of fatty liver diagnosis. In contrast, other clinical factors such as adiposity and liver enzyme levels do not affect the performance of CAP., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Assessment of long-term outcome is required in hepatitis C virus (HCV)-infected patients with cirrhosis, who have been successfully treated for Barcelona Clinic Liver Cancer (BCLC) stage A hepatocellular carcinoma (HCC). However, problems arise due to the lack of models accounting for early changes during follow-up. The aim of this study was to estimate the impact of early events (HCC recurrence or hepatic decompensation within 12months of complete radiological response) on 5-year overall survival (OS) in a large cohort of patients with HCV and cirrhosis, successfully treated HCC., Methods: A total of 328 consecutive Caucasian patients with HCV-related cirrhosis and BCLC stage 0/A HCC who had complete radiological response after curative resection or thermal ablation were prospectively recruited to this study. Primary endpoint of the study was 5-year OS. Independent baseline and time-dependent predictors of 5-year OS were identified by Cox model., Results: The observed 5-year survival rate was 44%. The observed HCC early recurrence and early hepatic decompensation rate were 21% and 10%, respectively. Early hepatic decompensation (Hazard Ratio [HR] 7.52; 95% confidence intervals (CI): 1.23-13.48) and HCC early recurrence as time-dependent covariates (HR 2.50; 95%CI: 1.23-5.05), presence of esophageal varices at baseline (HR 1.66; 95% CI: 1.02-2.70) and age (HR 1.04; 95% CI: 1.02-1.07) were significantly associated with the 5-year OS., Conclusion: Survival in HCV-infected patients with cirrhosis and successfully treated HCC is influenced by early hepatic decompensation. Our study indirectly suggests that direct-acting antiviral agents could improve OS of HCC patients through long-term preservation of liver function, resulting in a lower cirrhosis-related mortality and a greater change of receiving curative treatments., Lay Summary: Survival in hepatitis C virus (HCV) infected patients with cirrhosis and successfully treated hepatocellular carcinoma (HCC), is mainly influenced by early hepatic decompensation. HCV eradication after treatment with new direct-acting antiviral agents could improve overall survival of HCC patients through long-term preservation of liver function., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Chronic hepatitis C virus (HCV) infection is a major public health problem at a global level, causing an enormous burden of hepatic and extra-hepatic morbidity and mortality. Treatment of chronic HCV (CHC) has been revolutionized in the last few years by the introduction of highly effective and well tolerated direct acting antiviral agents (DAAs) able to achieve >90% rates of sustained virological response (SVR) in many groups of patients, including those previously excluded from interferon-based regimens. For such reason interferon-free regimens are now the treatments of choice for all patients. Successful anti-HCV treatment can stop liver disease progression and can solve the HCV-related extra hepatic manifestations, eventually reducing both liver-related and overall mortality. Together with the rapidly accumulating data about the evolution of treatment landscape, different guidelines from national and international Liver Scientific Societies have been published until today. However, these recommendations may not be applied worldwide as, due to high treatment costs, most of them identify as priority groups only patients with advanced liver disease. Moreover some types of patients pose clinical management problems for which even the guidelines do not always provide useful answers. With the aim of treatment optimization by filling some of the gaps of the current guidelines and addressing the remaining unmet needs in practice, a group of Italian experts, experienced on treatment of HCV infection, met in Stresa in February 2016. The summary of all the considerations arising from this two-day meeting and the final statements are reported in this position paper., (Copyright © 2016. Published by Elsevier Ltd.)