A multisociety Delphi consensus statement on new fatty liver disease nomenclature

Abstract

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

Conflict of interest statement

Manal F. Abdelmalek consults, advises, and received grants from Bristol Myers Squibb, Hanmi, Intercept, Inventiva, and Madrigal. She consults and advises 89Bio, Merck, NGM Bio, Novo Nordisk, Sonic Incytes, and Theratechnologies. She is on the speakers’ bureau for the Chronic Liver Disease Foundation, Clinical Care Options, Fishawack, Medscape, and Terra Firma. She received grants from Allergan, Boehringer Ingelheim, Celgene, Durect, Enanta, Enyo, Galmed, Genentech, Gilead, Novo Nordisk, Poxel, Target NASH, and Viking. Quentin M. Anstee, on behalf of Newcastle University, consults for Alimentiv, Akero, AstraZeneca, Axcella, 89Bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, GENFIT, Genentech, Gilead, GSK, Hanmi, HistoIndex, Intercept, Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Pharmanest, Prosciento, Poxel, RTI, Resolution Therapeutics, Ridgeline Therapeutics, Roche, Shionogi, and Terns. He is on the speakers’ bureau for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare. He received grants from AstraZeneca, Boehringer Ingelheim, and Intercept. He holds intellectual property rights with Elsevier, Ltd. Ramon Bataller is on the speakers’ bureau for Abbvie and Gilead. Ulrich Beuers consults for CSL Behring. He is on the speakers’ bureau for Abacus and Zambon. Elisabetta Bugianesi advises Boehringer Ingelheim, MSD, and Novo Nordisk. Helena Cortez-Pinto consults and received grants from Novo Nordisk and Roche. She received grants from Eisai, Gilead, GMP-Orphan, and Intercept. Kenneth Cusi Consults for Aligos, Arrowhead, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Covance, Lilly, Madrigal, Myovant, Novo Nordisk, Prosciento, Sagimet, and Siemens. He received grants from Echosens, Inventiva, LabCorp, Nordic Biosciences, and Target NASH. Sven M. Francque consults and received grants from Astellas, Falk, GENFIT, Gilead, Glympse Bio, Janssen, Inventiva, Merck, Pfizer, and Roche. He consults for AbbVie, Actelion, Aelin Therapeutics, Allergan, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Coherus, CSL Behring, Echosens, Eisai, ENYO, Galapagos, Galmed, Genetech, Intercept, Julius Clinical, Madrigal, Medimmune, NGM Bio, Novartis, Novo Nordisk, and Promethera. Samer Gawrieh consults for Pfizer and TransMedics. He received grants from LiverIncytes, Viking, and Zydus. Manuel Romero-Gómez advises and received grants from Novo Nordisk and Siemens. He advises AbbVie, Alpha-sigma, Allergan, AstraZeneca, Axcella, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Intercept, Inventia, Kaleido, MSD, Pfizer, Prosciento, Rubió, Shionogi, Sobi, and Zydus. He received grants from Echosens and Theratechnologies. Cynthia D. Guy consults for 89Bio, CymaBay, HistoIndex, Madrigal, and NGM. Stephen Harrison consults, advises, is involved with trials, received grants, and owns stock in Akero, Galectin, GENFIT, Hepion, and NGM Bio. He consults, advises, is involved with trials, and received grants from Axcella, Gilead, Intercept, Madrigal, and Poxel. He consults, advises, received grants, and owns stock in NorthSea Therapeutics. He consults, advises, and is involved with trials for Terns. He consults, advises, and received grants from HighTide, Novartis, Novo Nordisk, and Sagimet. He consults, advises, and owns stock in HistoIndex, Metacrine, and Sonic Incytes. He consults, received grants, and owns stock in Cirius. He consults, is involved with trials, and received grants from ENYO and Viking. He is involved with trials and received grants from Genentech. He consults and is involved with trials for Ionis. He consults and received grants from CiVi, CymaBay, Galmed, and Pfizer. He consults and owns stock in Hepta Bio. He consults and advises for Altimmune, Echosens North America, Foresite Labs, and Medpace. He advises and owns stock in ChronWell. He consults for AgomAb, Alentis, Aligos Therapeutics, Alimentiv, Blade, Bluejay, Boston Pharmaceuticals, Boxer Capital, Can-Fite BioPharma, the Chronic Liver Disease Foundation (CLDF), CohBar, Corcept, Fibronostics, Fortress Biotech, Galecto, Gelesis, GSK, GNS Healthcare, GRI Bio, Hepagene, Indalo, Inipharm, Innovate Biopharmaceuticals, Kowa Research Institute, Merck, MGGM, NeuroBo, Nutrasource, Perspectum, Piper Sandler, Prometic (now Liminal BioSciences), Ridgeline Therapeutics, Silverback, and Zafgen (now Larimar). He advises Arrowhead BVF Partners, Humana, and Pathai. He received grants from Bristol Myers Squibb, Conatus, Immuron, and Second Genome. Samuel Klein advises Alnylam, Altimmune, and Merck. Kris V. Kowdley advises, is on the speakers’ bureau, and received grants from Gilead and Intercept. He advises, received grants, and owns stock in Inipharm. He advises and received grants from 89bio, CymaBay, GENFIT, Ipsen, Madrigal, Mirum, NGM Bio, Pfizer, Pliant, and Zeds. He advises Enact, HighTide, and Protagonist. He is on the speakers’ bureau for AbbVie. He received grants from Boston Pharmaceuticals, Corcept, GSK, Hanmi, Janssen, Novo Nordisk, Terns, and Viking. Jeffrey V. Lazarus consults for Novavax. He received grants from AbbVie, Gilead, MSD, and Roche Diagnostics. Rohit Loomba consults and received grants from Arrowhead, AstraZeneca, Bristol Myers Squibb, Galmed, Gilead, Intercept, Inventiva, Ionis, Janssen, Lilly, Madrigal, Merck, NGM Bio, Novo Nordisk, Pfizer, and Terns. He consults and owns stock in 89Bio and Sagimet. Consults for Altimmune, Anylam, Amgen, CohBar, Glympse Bio, HighTide, Inipharm, Metacrine, Novartis, Regeneron, Theratechnologies, and Viking. He received grants from Boehringer Ingelheim, Galectin Therapeutics, Hanmi, and Sonic Incytes. He cofounded and owns stock in LipoNexus. Phillip N. Newsome consults, advises, is on the speakers’ bureau, and received grants from Novo Nordisk. He consults and advises Boehringer Ingelheim, Bristol Myers Squibb, Gilead, GSK, Intercept, Madrigal, Pfizer, Poxel, and Sun Pharma. He is on the speakers’ bureau for AiCME. Elizabeth E. Powell advises and received grants from Novo Nordisk. Vlad Ratziu consults and received grants from Intercept. He consults for Boehringer Ingelheim, Eny, Madrigal, NorthSea, Novo Nordisk, E. Poxel, and Sagimet. He received grants from Gilead. Mary E. Rinella consults for Boehringer Ingelheim, CytoDyn, GSK, Novo Nordisk, HistoIndex, Intercept, Madrigal, NGM Bio, and Sonic Incytes. Michael Roden consults and received grants from Boehringer Ingelheim and Novo Nordisk. He consults for Lilly. He is on the speakers’ bureau for AstraZeneca. Arun J. Sanyal consults and advises Avant Santé and AstraZeneca. He consults and received grants from Akero, Bristol Myers Squibb, Intercept, Lilly, Madrigal, and Novo Nordisk. He consults and owns stock in Rivus. He consults for AGED Diagnostics, Albireo, Alnylam, Altimmune, Boehringer Ingelhiem, 89Bio, Echosense, Genentech, Gilead, GSK, HistoIndex, Malinckrodt, Merck, NGM Bio, Novartis, PathAI, Pfizer, Poxel, Regeneron, Salix, Siemens, Surrozen, Takeda, Terns, and Zydus. He owns stock in Durect, Exhalenz, GENFIT, Indalo, Inversago, and Tiziana. He received royalties from Elsevier and Wolters Kluwer. Marcelo Silva consults, advises, and received grants from Zydus. He received grants from Inventiva and MSD. Dina Tiniakos consults for Clinnovate Health, ICON, Ionis, Inventiva, Merck, and Verily. Luca Valenti consults and received grants from Gilead. He consults for AstraZeneca, Boehringer Ingelheim, MSD, Novo Nordisk, Pfizer, and Resalis Therapeutics. Miriam B. Vos consults and advises Thiogenesis. She consults and received grants from Target Real World Evidence. She consults and owns stock in Intercept. She consults for Albireo, Boehringer Ingelheim, Lilly, Novo Nordisk, and Takeda. She received grants from Bristol Myers Squibb, Quest, and Sonic Incytes. Vincent Wai-Sun Wong consults and received grants from Gilead. He consults for AbbVie, Boehringer Ingelheim, Echosens, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet, and TARGET PharmaSolutions. He owns stock in Illuminatio Medical Technology. Yusuf Yilmaz consults for Zydus. He advises Novo Nordisk. He is on the speakers’ bureau for Echosens. Zobair Younossi consults for Bristol Myers Squibb, Gilead, Intercept, Madrigal, Merck, Novartis, Novo Nordisk, Quest, Siemens, and Terns. The remaining authors have no conflicts to report.

Copyright © 2023 American Association for the Study of Liver Disease, European Association for the Study of the Liver (EASL), and Fundación Clínica Médica Sur, A.C. Published by Wolters Kluwer/Elsevier B.V/Elsevier España, S.L.U.

Figures

FIGURE 1

Summary of the Delphi process. The top section depicts the iterative sampling approach employed to generate a large, diverse Delphi panel (267 experts invited and 225 participated across the 4 rounds). The 2 co-chairs, from AASLD and EASL, respectively, convened representatives from several other large pan-national societies and patient advocacy organisations to form the Steering Committee. This group identified 6 topics/working groups that led the development of a preliminary set of consensus statements, which were reviewed by the larger steering committee and subsequently revised. The co-chairs elicited nominations for Delphi panel members from a diverse group of liver organisations. The bottom section depicts the 4 survey rounds (R1–R4) of data collection from the full Delphi panel, which involved panelists’ indicating their level of agreement/disagreement (ie, consensus) with statements in each survey round, as well as the ability to provide comments in open-ended text boxes. Draft consensus statements were revised based on panelists’ comments for subsequent rounds. Two large expert convenings were held following R2 and R3 to permit group discussion of issues raised from the survey data collection components of the Delphi methodology. Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALEH, Asociación Latinoamericana para el Estudio del Hígado (Latin American Association for the Study of the Liver); AMAGE, African Middle East Association of Gastroenterology; APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; GI, gastrointestinal; INASL,Indian National Association for the Study of the Liver; RR, response rate; SAASL, South Asian Association for the Study of the Liver; TASL, Taiwan Association for the Study of the Liver.

FIGURE 2

NAFLD-related professional characteristics of Delphi panelists. (A) Data represent the number of respondents (x-axis) and percentage (y-axis) of time spent in NAFLD-related clinical care, research, or both. Similarly, (B) depicts the number of respondents (x-axis) and percentage (y-axis) that have (co)authored articles on the topic of NAFLD.

FIGURE 3

Overview of main findings by Delphi round. The conclusions reached at the end of each Delphi round are depicted here. Results are shown at each corresponding Delphi round with respect to name change and definition, depicted in light green and orange, respectively. An independent subcommittee that comprised expert endocrinologists, hepatologists, paediatricians, and patients chose between the top 3 acronyms emerging from the fourth Delphi round and outlined the specifics of the definition to include cardiometabolic parameters, as dictated by the fourth Delphi round. Abbreviation: SLD, steatotic liver disease.

FIGURE 4

NAFLD nomenclature results: round 4 (summary). Delphi round 4 consisted of 4 questions. All panelists responded to all questions irrespective of their response to the preceding question. These are the aggregate results for respondents on each question. The first question addressed whether a literal term to replace NAFLD was preferred over a numerical subtype (eg, types 1–3) and 68% preferred the literal term. The second was whether or not the term “metabolic” should be included in the name, and 67% felt it should. The third presented a choice of acronyms that had emerged as the top 4 in Delphi R3 and the top 3 (nearly equal in preference) were advanced to the expert panel for a final decision as there was no clear majority. The last question was binary and simply asked if the definition of the NAFLD replacement term should be retained or refined to include a cardiometabolic qualifier. Abbreviations: MAS, metabolic dysfunction associated steatosis; MASLD, metabolic dysfunction associated steatotic liver disease; MetSLD, metabolic dysfunction associated steatotic liver disease; MHS, metabolic hepatic steatosis; MSLD, metabolic steatotic liver disease.

FIGURE 5

Steatotic liver disease (SLD) subclassification. This depicts the schema for SLD and its subcategories. SLD, diagnosed histologically or by imaging, has many potential aetiologies. Metabolic dysfunction associated steatotic liver disease (MASLD), defined as the presence of hepatic steatosis in conjunction with one cardiometabolic risk factor (CMRF) and no other discernible cause, ALD, and an overlap of the 2 (MetALD), comprises the most common causes of SLD. Persons with MASLD and steatohepatitis will be designated as metabolic dysfunction associated steatohepatitis (MASH). Within the MetALD group, there exists a continuum across which the contribution of MASLD and ALD will vary. To align with current literature, limits have been set accordingly for weekly and daily consumption, understanding that the impact of varying levels of alcohol intake varies between individuals. Other causes of SLD need to be considered separately, as is already done in clinical practice, given their distinct pathophysiology. Multiple aetiologies of steatosis can coexist. If there is uncertainty and the clinician strongly suspects metabolic dysfunction despite the absence of CMRF, this may be early MASLD and prompt additional testing (eg, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and oral glucose tolerance tests). Those with no identifiable cause (cryptogenic SLD) may be recategorised in the future pending developments in our understanding of disease pathophysiology. Finally, the ability to provide an affirmative diagnosis allows for the coexistence of other forms of liver disease with MASLD, for example, MASLD + autoimmune hepatitis or viral hepatitis. *Weekly intake 140–30 g female, 210–420 g male (average daily 20–50 g female, 30–60 g male). **eg, Lysosomal acid lipase deficiency (LALD), Wilson disease, hypobetalipoproteinemia, inborn errors of metabolism. ***eg, HCV, malnutrition, celiac disease, human immunodeficiency virus (HIV).

FIGURE 6

MASLD diagnostic criteria. In the presence of hepatic steatosis, the finding of any CMRF would confer a diagnosis of MASLD if there are no other causes of hepatic steatosis. If additional drivers of steatosis are identified, then this is consistent with a combination aetiology. In the case of alcohol, this is termed MetALD or ALD, depending on extent of alcohol intake. In the absence of overt cardiometabolic criteria, other aetiologies must be excluded, and if none is identified, this is termed cryptogenic SLD although, depending on clinical judgment, it could also be deemed to be possible MASLD and, thus, would benefit from periodic reassessment on a case-by-case basis. In the setting of advanced fibrosis/cirrhosis, steatosis may be absent, requiring clinical judgment based on CMRFs and absence of other aetiologies. Abbreviations: ALD, alcohol-associated/related liver disease; BMI, body mass index; BP, blood pressure; CMRF, cardiometabolic risk factors; DILI, drug-induced liver disease; MetALD, metabolic dysfunction and alcohol associated steatotic liver disease; SLD, steatotic liver disease; WC, waist circumference.