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Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common conditions with a rising burden. Yet there are significant management gaps between clinical guidelines and practice in patients with NAFLD and NASH. Further, there is no single global guiding strategy for the management of NAFLD and NASH. The American Gastroenterological Association, in collaboration with 7 professional associations, convened an international conference comprising 32 experts in gastroenterology, hepatology, endocrinology, and primary care providers from the United States, Europe, Asia, and Australia. Conference content was informed by the results of a national NASH Needs Assessment Survey. The participants reviewed and discussed published literature on global burden, screening, risk stratification, diagnosis, and management of individuals with NAFLD, including those with NASH. Participants identified promising approaches for clinical practice and prepared a comprehensive, unified strategy for primary care providers and relevant specialists encompassing the full spectrum of NAFLD/NASH care. They also identified specific high-yield targets for clinical research and called for a unified, international public health response to NAFLD and NASH. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common conditions with a rising burden. Yet there are significant management gaps between clinical guidelines and practice in patients with NAFLD and NASH. Further, there is no single global guiding strategy for the management of NAFLD and NASH. The American Gastroenterological Association, in collaboration with 7 professional associations, convened an international conference comprising 32 experts in gastroenterology, hepatology, endocrinology, and primary care providers from the United States, Europe, Asia, and Australia. Conference content was informed by the results of a national NASH Needs Assessment Survey. The participants reviewed and discussed published literature on global burden, screening, risk stratification, diagnosis, and management of individuals with NAFLD, including those with NASH. Participants identified promising approaches for clinical practice and prepared a comprehensive, unified strategy for primary care providers and relevant specialists encompassing the full spectrum of NAFLD/NASH care. They also identified specific high-yield targets for clinical research and called for a unified, international public health response to NAFLD and NASH., Competing Interests: Declaration of competing interest These authors disclose the following: Jay H. Shubrook has served as an advisor to Sanofi, Eli Lilly, Novo Nordisk, Bayer, and MannKind. Elisabetta Bugianesi has served as a consultant to Gilead, BMS, Boehringer, Intercept, and Innova. Zobair Younossi has received research funding from or served as a consultant for Gilead Sciences, Intercept, BMS, Novo Nordisk, Viking, Terns, Siemens, Shionogi, AbbVie, Madrigal, Merck, Abbott, Axcella, and Novartis. Yamini Natarajan has received grants from Gilead and Allergan. Mary E. Rinella has served as a consultant for Amgen, Alnylam, Allergan, BMS, Boehringer Ingelheim, Coherus, CymaBay, Enanta, Fibrogen, Fractyl, Galecto, Gelesis, Genentech, GENFIT, Gilead, Intercept, Lipocine, Madrigal, Merck, Metacrine, NGM Biopharmaceuticals, Novo Nordisk, Novartis, Pfizer, Sagimet, Siemens, Takeda, Terns, Thetis, Viking, 3vBio, 89Bio. Robert H. Eckel has served on advisory boards for Novo Nordisk, Provention Bio, Kaleido, and KOWA, and a scientific advisory committee for PROMINENT (CVOT). Stephen A. Harrison has served as advisory board/consultant for Akero, Altimmune, Arrowhead, Axcella, B. Riley, Boston Pharma, Cirius, Civi Biotherma, CLDF, Corcept, CymaBay, Echosens, Fibronostics, Foresite Labs, Fortress, Galectin, Gelesis, GENFIT, Gilead, Hepion, Hightide Bio, HistoIndex, Intercept, Inipharm, Ionis, Kowa, Madrigal, Medpace, Metacrine, Microba, NGM Bio, NorthSea, Novartis, Novo Nordisk, Piper Sandler, Poxel, Prometic, Ridgeline Therapeutics, Sagiment, Sonic Incytes, Terns, Theratech, Viking, 89 Bio; received grant/research support from Axcella, BMS, Cirius, Civi Biopharma, Conatus, CymaBay, Enyo, Galectin, Galmed, Genentech, GENFIT, Gilead, Hepion, Hightide Bio, Immuron, Intercept, Madrigal, NGM Bio, NorthSea, Novartis, Novo Nordisk, Pfizer, Sagimet, Second Genome, Tobira/Allergan, Viking; and has stock/shares (self-managed) in Akero, Cirius, Galectin, GENFIT, Hepion, HistoIndex, Metacrine, NGM Bio, and NorthSea. Christos Mantzoros reports grants, personal fees, and other from Coherus Biosciences, grants, personal fees and other from Novo Nordisk, personal fees and nonfinancial support from Ansh, Aegerion, PES, California Walnut Commission, and personal fees from GENFIT, Intercept, Regeneron, CardioMetabolic Health Conference and The Metabolic Institute of America, and Amgen. Samuel Klein is a shareholder of Aspire Bariatrics and has served as a consultant for Pfizer, Novo Nordisk, and Boehringer Ingelheim. Robert H. Eckel has received research funding from Gilead (2014–2015), Merck (2016–2018), and Wako (2014–2017). Kenneth Cusi has received research support as principal investigator for the University of Florida from Cirius, Echosens, Inventiva, Novartis, Novo Nordisk, Poxel, and Zydus, and is a consultant for Allergan, Astra-Zeneca, Axcella, BMS, Boehringer Ingelheim, Coherus, Eli Lilly, Genentech, Gilead, HighTide, Inventiva, Intercept, Ionis, Janssen, Pfizer, Poxel, Prosciento, Madrigal, Novo Nordisk, and Sanofi-Aventis. The remaining authors disclose no conflicts., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is a global public health concern. Its natural history, the development of nonalcoholic steatohepatitis (NASH) and fibrosis, is highly variable, prone to endogenous (e.g., genetics, microbiota) and exogenous (e.g., nutrition, alcohol, physical activity) disease modifiers, and can fluctuate over time. The complexity of its pathophysiology is reflected by the multitude of pharmacological targets in development. NASH clinical trials have provided valuable insight that is applicable to future trial design. Endpoints for NASH have evolved over the past decade and will continue to be refined. Currently accepted endpoints for conditional approval include resolution of NASH without worsening of fibrosis and/or improvement in fibrosis without worsening of NASH by standardized evaluation of paired liver histology. In pediatric NASH, practical obstacles, pubertal hormonal changes, and stringent safety requirements mandate adaptations in trial design. In adult patients with NASH-related cirrhosis, clinical events (e.g. decompensation, hepatocellular carcinoma, transplantation, death) are more prevalent and thereby are viable primary endpoints. Consideration of the natural fluctuation of disease, the clinical implication of the chosen primary endpoint, and factors that may affect placebo response will facilitate an accurate determination of efficacy of emerging therapeutics for NASH. Conclusion: The June 2018 American Association for the Study of Liver Diseases and European Association for the Study of the Liver joint workshop on NAFLD endpoints summarized important findings from ongoing and completed trials, defined the scientific evidence supporting distinct endpoints, and provided guidance for future trial design., (© 2019 by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver.)