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Unlike for advanced liver fibrosis, the practical rules for the early non-invasive diagnosis of cirrhosis in NAFLD remain not well defined. Here, we report the derivation and validation of a stepwise diagnostic algorithm in 1568 patients with NAFLD and liver biopsy coming from four independent cohorts. The study algorithm, using first the elastography-based tests Agile3+ and Agile4 and then the specialized blood tests FibroMeter V3G and CirrhoMeter V3G , provides stratification in four groups, the last of which is enriched in cirrhosis (71% prevalence in the validation set). A risk prediction chart is also derived to allow estimation of the individual probability of cirrhosis. The predicted risk shows excellent calibration in the validation set, and mean difference with perfect prediction is only -2.9%. These tools improve the personalized non-invasive diagnosis of cirrhosis in NAFLD., (© 2023. Springer Nature Limited.)

Background & Aims: Previous studies on the prognostic significance of non-invasive liver fibrosis tests in non-alcoholic fatty liver disease (NAFLD) lack direct comparison to liver biopsy. We aimed to evaluate the prognostic accuracy of fibrosis-4 (FIB4) and vibration-controlled transient elastography (VCTE), compared to liver biopsy, for the prediction of liver-related events (LREs) in NAFLD., Methods: A total of 1,057 patients with NAFLD and baseline FIB4 and VCTE were included in a multicenter cohort. Of these patients, 594 also had a baseline liver biopsy. The main study outcome during follow-up was occurrence of LREs, a composite endpoint combining cirrhosis complications and/or hepatocellular carcinoma. Discriminative ability was evaluated using Harrell's C-index., Results: FIB4 and VCTE showed good accuracy for the prediction of LREs, with Harrell's C-indexes >0.80 (0.817 [0.768-0.866] vs. 0.878 [0.835-0.921], respectively, p = 0.059). In the biopsy subgroup, Harrell's C-indexes of histological fibrosis staging and VCTE were not significantly different (0.932 [0.910-0.955] vs. 0.881 [0.832-0.931], respectively, p = 0.164), while both significantly outperformed FIB4 for the prediction of LREs. FIB4 and VCTE were independent predictors of LREs in the whole study cohort. The stepwise FIB4-VCTE algorithm accurately stratified the risk of LREs: compared to patients with "FIB4 <1.30", those with "FIB4 ≥1.30 then VCTE <8.0 kPa" had similar risk of LREs (adjusted hazard ratio [aHR] 1.3; 95% CI 0.3-6.8), whereas the risk of LREs significantly increased in patients with "FIB4 ≥1.30 then VCTE 8.0-12.0 kPa" (aHR 3.8; 95% CI 1.3-10.9), and even more for those with "FIB4 ≥1.30 then VCTE >12.0 kPa" (aHR 12.4; 95% CI 5.1-30.2)., Conclusion: VCTE and FIB4 accurately stratify patients with NAFLD based on their risk of LREs. These non-invasive tests are alternatives to liver biopsy for the identification of patients in need of specialized management., Lay Summary: The amount of fibrosis in the liver is closely associated with the risk of liver-related complications in non-alcoholic fatty liver disease (NAFLD). Liver biopsy currently remains the reference standard for the evaluation of fibrosis, but its application is limited by its invasiveness. Therefore, we evaluated the ability of non-invasive liver fibrosis tests to predict liver-related complications in NAFLD. Our results show that the blood test FIB4 and transient elastography stratify the risk of liver-related complications in NAFLD, and that transient elastography has similar prognostic accuracy as liver biopsy. These results support the use of non-invasive liver fibrosis tests instead of liver biopsy for the management of patients with NAFLD., Competing Interests: Conflict of interest Jerome Boursier: Board advisory for Bristol-Myers, Echosens, Intercept. Research grants to his institution from EchoSens, Intercept, Inventiva, Siemens. Speaker fees from Gilead, Intercept, Lilly, Siemens. Hannes Hagström: Board advisory for Bristol-Myers Squibb and Gilead. Research grants to his institution from Astra Zeneca, Pfizer, Gilead, MSD, EchoSens, Intercept. Mattias Ekstedt: Member of advisory board for AMRA Medical. Research grants to his institution from Intercept, Astra Zeneca and Gilead. Speaker fees from Olink. Manuel Romero-Gomez: Research grants to his institution from Intercept. Speaker and consulting fees from Intercept. Other authors have no conflict of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Though lifestyle interventions can reverse disease progression in people with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), unawareness about disease severity might compromise behavioural changes. Data from this first international cross-sectional survey of individuals with NAFLD/NASH were used to identify correlates of both unawareness about fibrosis stage and its association with adherence to lifestyle adjustments., Methods: Adults with NAFLD/NASH registered on the platform Carenity were invited to participate in an online 20-min, six-section survey in Canada, France, Germany, Italy, Spain and the United Kingdom to describe their experience with NAFLD/NASH and its care (N = 1411). Weighted binary and multinomial logistic regressions were performed to estimate the effect of explanatory variables on unawareness of fibrosis stage and poor adherence to lifestyle changes respectively., Results: In the study group, 15.5% had obesity and 59.2% did not know their fibrosis stage. After multiple adjustments, individuals with a body mass index (BMI) ≥35 were over twice as likely to not know their fibrosis stage. People with a BMI >30 had a threefold higher risk of having poor adherence to lifestyle changes. Unawareness about fibrosis stage was also significantly associated with poor adherence to lifestyle adjustments., Conclusions: As fibrosis stage is becoming the main predictor of NAFLD progression, improving patient-provider communication-especially for people with obesity-about liver fibrosis stage, its associated risks and how to mitigate them, is needed. Training for healthcare professionals and promoting patient educational programmes to support behaviour changes should also be included in the liver health agenda., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background & Aims: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive fibrotic liver disease that can lead to cirrhosis. While liver biopsy is considered the reference standard for the histologic diagnosis of NASH and staging of fibrosis, its use in clinical practice is limited. Non-invasive tests (NITs) are increasingly being used to identify and stage liver fibrosis in patients with NASH, and several can assess liver-related outcomes. We report changes in various NITs in patients treated with obeticholic acid (OCA) or placebo in the phase III REGENERATE study., Methods: Patients with NASH and fibrosis stage F2 or F3 (n = 931) were randomized (1:1:1) to receive placebo, OCA 10 mg, or OCA 25 mg once daily. Various NITs based on clinical chemistry and/or imaging were evaluated at baseline and throughout the study., Results: Rapid, sustained reductions from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase levels, as well as in Fibrosis-4 (FIB-4), FibroTest, FibroMeter, and FibroScan-AST scores were observed in OCA-treated vs. placebo-treated patients. Reduction in liver stiffness by vibration-controlled transient elastography was observed in the OCA 25 mg group vs. the placebo group at Month 18. NIT changes were associated with shifts in histologic fibrosis stage. The greatest improvements were observed in patients with ≥1-stage fibrosis improvement; however, improvements in ALT, AST, FIB-4, and FibroTest were also observed in OCA-treated patients whose histologic fibrosis remained stable., Conclusions: Based on the REGENERATE Month 18 interim analysis, rapid and sustained improvements in various NITs were observed with OCA treatment. Dynamic changes in selected NITs separated histologic responders from non-responders. These results suggest that NITs may be useful in assessing histologic response to OCA therapy. CLINICALTRIALS., Gov Number: NCT02548351 LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive liver disease that can lead to cirrhosis. To diagnose and assess liver fibrosis (scarring) in patients with NASH, non-invasive tests (NITs) are increasingly being used rather than liver biopsy, which is invasive, expensive, and can be risky. In the REGENERATE study, which is evaluating the effects of obeticholic acid vs. placebo in patients with NASH, various NITs were also evaluated. This analysis shows that improvements in levels of certain blood components, as well as favorable results of ultrasound imaging and proprietary tests of liver function, were associated with improvements in liver fibrosis after treatment with obeticholic acid, suggesting that NITs may be useful alternatives to liver biopsy in assessing NASH patients' response to therapy., Competing Interests: Conflict of interest MR was a consultant over the past 36 months for Alnylam, Amgen, AMRA, BMS, Boehringer Ingelheim, Centara, Coherus, Enanta, Galecto, Intercept Pharmaceuticals, Inc., Madrigal, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Fractyl, Gelesis, Siemens, Thetis, Terns, Rivus, 3vbio (Sagimet), 89Bio, and Novartis. She currently has no active consulting contracts. J-FD reports advisory committee participation for AbbVie, Bayer, Bristol-Myers Squibb, Falk, Genfit, Genkyotex, Gilead Sciences, HepaRegeniX, Intercept Pharmaceuticals, Inc., Lilly, Merck, Novartis; speaking and teaching fees from Bayer, Bristol-Myers Squibb, Intercept Pharmaceuticals, Inc., Genfit, Gilead Sciences, Novartis, Roche. QMA reports support from Intercept Pharmaceuticals, Inc. in relation to the present study; research funds as Coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multi-stakeholder consortium includes industry partners, in addition, Allergan/Tobira, AstraZeneca, GlaxoSmithKline, Glympse Bio, Novartis Pharma AG, Pfizer Ltd; royalties or licenses from Elsevier Ltd; consulting fees from 89Bio, Allergan/Tobira, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genentech, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Madrigal, MedImmune, Medpace, Metacrine, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, PathAI, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Roche, Servier, Terns, The Medicines Company, Viking Therapeutics; honoraria from Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, Kenes, Medscape; member of advisory board for Medpace (NorthSea Therapeutics). ZG has no conflicts to report. ZY reports consulting fees and research grants from Gilead Sciences, Intercept Pharmaceuticals, Inc., BMS, Novo Nordisk, Viking, Terns, Siemens, Quest, AbbVie, Madrigal, Merck, and Novartis. SAH reports consulting/advisory, stock ownership/equity from Akero, Galectin, Genfit, Madrigal, Metacrine, Histoindex and NGM Bio; grants from Axcella, Cirius, CymaBay, Galectin, Galmed, Genfit, Gilead, HighTide, Madrigal, NGM, Novartis, Novo Nordisk, Pfizer, and Second Genome; consulting/advisory for Alentis, Axcella, Bristol-Meyers Squibb, CiVi, CLDF, Corcept, Echosens, , Gilead, HighTide, Medpace, Novartis, Novo Nordisk, Perspectum, Prometric, Viking, Hepagene, Hepion, and Terns. RL reports research grants from Intercept Pharmaceuticals, Inc., Boehringer -Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead, Inventiva, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Pfizer, Siemens; consulting fees from Anylam/Regeneron, Amgen, Ar Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Inipharm, Intercept, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Sagimet, 89Bio, Viking Therapeutics; advisory committee participation for Intercept Pharmaceuticals, Inc.; co-founder of Liponexus, Inc. AJS is President of Sanyal Biotechnology; he reports stock options in Sanyal Bio, Exhalenz, Akarna, GenFit, Hemoshear, Durect, Indalo, Tiziana, Rivus; paid consultant to 89Bio, Albireo, Amgen, Ardelyx, Boehringer Ingelheim, Bird Rock, Bristol-Myers, Conatus, Covance, Echosens-Sandhill, ENYO, Genentech, General Electric, Genfit, Gilead, Hemoshear, HistoIndex, Inventiva, Janssen, Lilly, Madrigal, Mallinckrodt, Merck, NGM Bio, Nimbus, NorthSea, Novartis, Novo Nordisk, Owl, PathAI, Perspectum, Pfizer, Poxel, Prosciento, Regeneron, Rivus, Roche, Salix, Sanofi, Second Genome, Servier, Siemens, Takeda, Terns, Tiziana, Zydus; unpaid consultant to Immuron, Intercept Pharmaceuticals, Inc., Galectin, Sequana, Fractyl; Durect, Indalo, Allergan, Chemomab, Affimune, Teva, BASF, AMRA, Perspectum, Biocellvia; advisory board member for Immuron; royalties from Elsevier and UptoDate; grant support from Gilead, Mallinckrodt, Salix, Novartis, Galectin, Bristol-Myers, Sequana; receipt of equipment from Echosens-Sandhill; ongoing research collaboration with Echosens-Sandhill, Owl, Second Genome, Siemens; his institution has received grant support from Conatus, Gilead, Mallinckrodt, Boehringer Ingelheim, Novartis, Bristol-Myers, Merck, Lilly, Novo Nordisk, Fractyl, Madrigal, Inventiva, Covance; his institution has received fees from AstraZeneca. MB reports employment at and stock ownership in Intercept Pharmaceuticals, Inc. at the time of the study. AT reports employment at and stock ownership in Intercept Pharmaceuticals, Inc. MN reports employment at and stock ownership in Intercept Pharmaceuticals, Inc. at the time of the study. RS reports employment at and stock ownership in Intercept Pharmaceuticals, Inc. at the time of the study. TG reports employment at and stock ownership in Intercept Pharmaceuticals, Inc. at the time of the study. AV reports employment at Intercept Pharmaceuticals, Inc. at the time of the study. VR reports consulting fees from Galmed, Genfit, Madrigal, NGM, Bristol-Myers Squibb, Boehringer Ingelheim, Theratechnologies, Terns; advisory committee participation for Intercept Pharmaceuticals, Inc. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021. Published by Elsevier B.V.)

Background and Aims: Non-alcoholic steatohepatitis (NASH) is a chronic disease that can progress to end-stage liver disease (ESLD). A large proportion of early-stage NASH patients remain undiagnosed compared to those with advanced fibrosis, who are more likely to receive disease management interventions. This study estimated the disease burden and economic impact of diagnosed NASH in the adult population of France, Germany, Italy, Spain and the United Kingdom in 2018., Methods: The socioeconomic burden of diagnosed NASH was estimated using cost-of-illness methodology applying a prevalence approach to estimate the number of adults with NASH and the attributable economic and wellbeing costs. Given undiagnosed patients do not incur costs in the study, the probability of diagnosis is central to cost estimation. The analysis was based on a literature review, databases and consultation with clinical experts, economists and patient groups., Results: The proportion of adult NASH patients with a diagnosis ranged from 11.9% to 12.7% across countries, which increased to 38.8%-39.1% for advanced fibrosis (F3-F4 compensated cirrhosis). Total economic costs were €8548-19 546M. Of these, health system costs were €619-1292M. Total wellbeing costs were €41 536-90 379M. The majority of the undiagnosed population (87.3%-88.2% of total prevalence) was found to have early-stage NASH, which, left untreated, may progress to more resource consuming ESLD over time., Conclusions: This study found that the majority of economic and wellbeing costs of NASH are experienced in late disease stages. Earlier diagnosis and care of NASH patients could reduce future healthcare costs., (© 2021 The Authors. Liver International published by John Wiley & Sons Ltd.)