Link
https://www.journal-of-hepatology.eu/article/S0168-8278(23)00418-X/fulltext
Abstract
The principal limitations of the terms nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition.
Methods
A modified Delphi process was led by three large pan-national liver associations. 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.
Results
A total of 236 panellists from 56 countries participated in four online surveys and two hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83% and 78%, respectively. 74% of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms ‘non-alcoholic’ and ‘fatty’ were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease (SLD) was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least one of five cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic SLD. A new category, outside pure MASLD, termed MetALD was selected to describe those with MASLD who consume greater amounts of alcohol per week (140 to 350 g/week and 210 to 420 g/week for females and males respectively).
Conclusions
The new nomenclature and diagnostic criteria are widely supported, non-stigmatising and can improve awareness and patient identification.
Keywords
Fatty liver disease
NAFLD
NASH
nomenclature
Delphi
MASLD
MetALD
steatohepatitis
steatotic liver disease
alcohol
type 2 diabetes
cardiometabolic
nonalcoholic
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Introduction
Unified global approaches to nomenclature and disease definition are critical for increasing disease awareness, driving policy change, identifying those at risk, facilitating diagnosis and access to care. Language can create or exacerbate stigma, marginalise segments of the affected population and, ultimately, contribute to health inequalities. It has been known for many years that being overweight or obese is associated with hepatic steatosis, hepatocyte injury and liver inflammation and fibrosis. This was formally recognized by the term “nonalcoholic steatohepatitis” in 1980 by Jurgen Ludwig. [1] Subsequently, the term nonalcoholic fatty liver disease (NAFLD) was used to describe the histological spectrum of steatosis to steatohepatitis with its subtypes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The histological classification was further expanded upon by various scoring systems categorising steatosis, disease activity and fibrosis.[2, 3, 4] This framework has served as the anchor for our current understanding of the disease, data on the burden of disease, and efforts to develop treatment for the condition.
While the nomenclature is widely used, it has always been appreciated that the term “nonalcoholic” did not accurately capture what the aetiology of the disease was, and notably, the term ‘fatty’ has been considered to be stigmatising by some. Furthermore, there are individuals with risk factors for NAFLD, such as type 2 diabetes, who consume more alcohol than the relatively strict thresholds used to define the nonalcoholic nature of the disease that are not adequately recognised by existing nomenclature, are excluded from trials and consideration for treatments.[5] Indeed, there is a recognition now that there are overlapping biological processes which may contribute to both NAFLD and alcohol-related liver disease (ALD). All of these factors have led to growing dissatisfaction with the current nomenclature. This was summarised in a paper by Eslam et al in 2020 and led to the proposal to use the term metabolic dysfunction associated fatty liver disease (MAFLD), which includes patients with a fatty liver regardless of the amount and pattern of alcohol intake under this terminology.[6, 7] While MAFLD was accepted by some, concerns were raised about the mixing of aetiologies, continued use of the term ‘fatty’ considered stigmatising by many, restricting the population to those with 2 metabolic risk factors and allowance of more liberal alcohol use, thus impacting our understanding of natural history.[8, 9, 10] One area of particular concern was the potential negative impact of changes in diagnostic criteria for the disease in terms of biomarker and therapeutic development.[7, 9, 10].
These concerns led to a multi-stakeholder effort under the auspices of the American Association for Study of Liver Disease (AASLD) and the European Association for Study of the Liver (EASL) in collaboration with the Asociación Latinoamericana para el Estudio del Hígado (ALEH) with engagement of academic professionals from around the world including hepatologists, gastroenterologists, paediatricians, endocrinologists, hepatopathologists and public health and obesity experts along with colleagues from industry, regulatory agencies and patient advocacy organisations to resolve these concerns and develop a consensus on a change in nomenclature and the diagnostic criteria for the condition. This manuscript summarises the methodology, including a multi-step Delphi process, the results of the process and provides the consensus recommendations endorsed by societies, patient advocacy groups, journals and industry for adoption by all stakeholders.
Methods
Panel Generation and Statement Development
The panel for this Delphi study was generated through an iterative, inclusive process involving diverse liver organisations around the world (Table 1). The Steering Committee (n=36) was composed of two co-chairs (MER, PNN), representing AASLD and EASL, respectively and 34 other members nominated by their respective associations with a view to ensuring broad geographic representation.
Table 1Delphi Panel Characteristics (N=225).
N %
Professional characteristics
Primary sector of employment
Civil society 7 3
Private 21 9
Public 34 15
Academic 158 70
Other 4 2
Primary field/area of work
Clinical research 118 54
Healthcare provider 61 28
Non-clinical research 13 6
Patient/policy advocacy 18 9
Other 7 4
Primary area of specialty/expertisea (among healthcare providers, clinical and non-clinical researchers)
Gastroenterology 7 4
Endocrinology 13 7
Hepatology 151 82
Other 13 8
Years working in the field post-training
0-12 53 29
13-24 69 37
25-36 51 27
37-48 13 7
% of work in NAFLD-related clinical care, research or both
0-25 26 12
26-50 61 27
51-75 68 30
76-100 44 19
Number of articles (co)authored on topic of NAFLD
<6 32 17
6-20 42 22
21-50 39 21
50 74 40
Liver organization associated with (N invited)
AASLD (72) 60 27
ALEH (30) 27 12
APASL, AMAGE, INASL, SAASL, TASL (41) 29 13
EASL (70) 66 29
GI and endocrinological societies (21) 15 7
Pathology societies (4) 3 1
Patient organization (29) 24 11
Personal Characteristics
Gender
Woman 88 40
Man 135 60
Non-binary or gender diverse 0 0
Prefer not to say 0 0
Country where born (N=59)b
High income 163 73
Low and middle income 61 27
Country where currently working (N=54)b
High income 183 82
Low and middle income 41 18
Notes: Ns for different characteristics vary due to missing data; percentages may not sum to 100 due to rounding. With respect to respondent area of expertise 184 of 192 participating healthcare providers and researchers responded to the request to provide their area of expertise.
Abbreviations: AASLD, American Association for the Study of Liver Disease; 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; NAFLD, non-alcoholic fatty liver disease; SAASL, South Asian Association for Study of the Liver; TASL, Taiwan Association for the Study of the Liver.
a 24 panelists indicated that in their clinical practice or liver-focused research, they routinely care for or focus on liver disease patients who are under 18 years old. Note that numbers represent those that engaged in the process, rather than those who were invited to join the process, but did not respond.
b N of total countries represented.
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The consensus process used a modified Delphi method [11, 12, 13] to incorporate input from the literature and a diverse group of content experts, practitioners, and patient advocates. The steering committee identified 5 areas deemed fundamental to the consideration of a revised nomenclature, namely: 1. What are issues with current nomenclature, and can they be addressed? 2. What is the importance of steatohepatitis in disease definition and endpoints? 3. How should the role of alcohol be accounted for? 4. How might name change impact disease awareness, clinical trials and regulatory approval pathways? and 5. Can an alternative name reduce heterogeneity and allow for future advances? Between late 2021 and early 2022, the steering committee was divided into six working groups, each with a designated lead (SMF, MER, PNN, AJS, VR, FK), responsible for reviews of the literature to inform development of draft statements for their assigned topic area: patient-centred perspective (SMF); pros and cons of the current nomenclature (MER); defining fatty liver disease in the setting of metabolic dysfunction (PNN); disease heterogeneity (AJS); histopathology (VR); and how to manage the role of alcohol in dual aetiology (FK). The preliminary draft statements were compiled and shared with the larger steering committee for review, and the feedback was incorporated into a revised set of draft consensus statements (Supplementary Table 1).
Pan-national societies were asked to nominate additional experts and other stakeholders including patient advocacy organisations to be invited (n=267) to participate in the Delphi panel (Figure 1). Nominating societies were instructed to select individuals actively engaged in NAFLD research or clinical practice of patients with NAFLD. Consensus was defined a priori as a supermajority (67%) vote. To increase geographic diversity in the Delphi panel, an additional 30 experts were invited to participate in R2. The characteristics, including demographics, professional expertise, and geographic representation, of Delphi panel participants (n=224) are summarised in Table 1 and Supplementary Table 2.
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Figure 1Summary of the Delphi Process.
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Data Collection
The Delphi process comprised six components of online data collection (via the Qualtrics platform) and in-person discussions, including a first round (R1) survey (7 Apr-9 May 2022); a second round (R2) survey (15-27 June 2022 plus additional panellists 8 Sept-16 Oct); a large-group nomenclature consensus meeting (Chicago, IL, USA, July 2022); a third round (R3) survey (17-27 Oct 2022); a second convening (AASLD annual meeting, Washington, DC, USA, Nov 2022) involving both steering committee and larger panel discussions; and, a fourth round (R4) survey (2 Dec 2022-22 Jan 2023) (Figure 1). Draft consensus statements contained predominantly 4-point Likert-type response categories related to agreement/disagreement (e.g. agree/somewhat agree/somewhat disagree/disagree), support/opposition, etc., and 3-point responses (e.g., increase, no change, decrease). All statements included a ‘not qualified to respond’ option to accommodate the diverse expertise represented in the panel. In addition, in line with established Delphi processes, [11, 12, 13] text boxes appeared after panellists entered responses to each statement so they could provide comments and suggest edits, if desired. These were reviewed and used to modify statements in subsequent survey rounds.
Analysis Plan
The survey question and textbox data in the Delphi study required quantitative and qualitative analysis. For the survey question, responses were generated and frequencies for all response categories were recoded to the 4-point response statements to dichotomous construction (e.g., agree + somewhat agree vs. somewhat disagree + disagree) to determine if the level of consensus with individual statements reached the minimum super-majority (i.e. >67%) cut-off, which was agreed upon a priori. For each statement, those selecting ‘not qualified to respond’ were removed from the denominator to calculate statement frequencies from the relevant sample. The qualitative data collected from the text boxes were reviewed individually by the co-chairs and working group leaders and then discussed in a series of meetings following each survey round to inform decisions regarding statement modification, deletion and/or addition.
For the final decision on both acronym and definition, an external expert committee, comprising content experts from hepatology, endocrinology, paediatrics and patient advocacy representatives, was created and led by two members of the Steering Committee (VR, AJS). The committee was established to represent diversity in terms of expertise and geography, with members chosen based on a prior substantial high-impact publication record in the field. It was composed of 21 members (including 15 who were not part of the Steering Committee) and included 4 endocrinologists and 5 paediatric hepatologists. The external committee discussed and recommended the final name and acronym from the top three choices that emerged from the final Delphi round. Additionally, based on the output from the Delphi process up to this point, the external committee refined the definition, including metabolic parameters for both adult and paediatric disease. The proposal from this external committee was discussed and approved by the broader NAFLD Nomenclature Steering Committee, and then presented to societies’ leadership (AASLD, EASL and ALEH) for additional commentary and approval.
Results
Delphi Panel Characteristics
Invitation to participate on the Delphi panel included seven societies or organisation types, with 29% from EASL, 27% from AASLD, 13% from APASL, 12% from ALEH, 7% from other societies, and 11% from patient advocacy organisations. We collected descriptive information from all Delphi panel participants including demographic and professional data (Table 1). The panel was geographically and demographically diverse; panellists from over 50 countries participated with regard to both country of birth (n=59 countries) and country where currently working (n=54 countries). Among the panellists, 40% identified themselves as female and 60% as male. Seventy of the panellists were from the academic sector, with smaller proportions from the public (15%), private (9%), and civil society (3%) sectors. The two largest fields/areas of work were clinical research (54%) and clinical care (28%), with hepatology (82%) accounting for an overwhelming majority of the areas of specialisation. There was substantial NAFLD-related expertise among panellists with 76% indicating they spend 26-100% of their work time in NAFLD-related clinical care, research, or both, and 61% reporting having authored >21 and 40% had >50 publications on the topic of NAFLD (Figure 2).
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Figure 2NAFLD-Related Professional Characteristics of Delphi Panelists.
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Response rates and panel participation
The R1 survey consisted of 37 statements within three domains: (1) Nomenclature and distinctions among disease elements (e.g., diagnostic criteria, prognosis, treatment); (2) Other factors possibly influencing consideration of additional or alternative terms; (3) Name/term preferences (Supplementary Table 1). Of 236 invited experts in R1, 206 participated and rated these statements (Response rate [RR] = 87%). They also provided 870 comments, which were reviewed and incorporated as additional statements and a new paediatric focused domain into the second round of consensus statements, with a total of 54 statements. Of the 236 panellists invited for R2, 195 participated in R2 (overall participation, 195+30, RR=83%), providing 1,370 comments. Comments were organised thematically by their content and reviewed by the leads who then proposed modifications to statements if appropriate, eliminated statements if redundant or as suggested by comments, or carried the statements forward to the next round. To minimise survey fatigue, statements thought to be repetitive or ambiguous were removed from the following round. Additionally, statements covering areas of high consensus were not carried forward to R3. Revised statements were shared with the full Steering Committee before proceeding with the next round. For example, in R3, statement revision resulted in 44 statements; there were 187 participants (of 226 invited, RR=83%) who provided an additional 268 comments.
After R2, all Delphi panellists were invited to an in-person (hybrid, i.e. with remote access) 1.5-day nomenclature consensus conference co-hosted by AASLD and EASL in Chicago, IL, USA July 8-9, 2022 for in-depth discussion of the extensive feedback generated from the first two rounds of data collection. This convening provided valuable guidance from a broader group that included the steering committee as well as the broader group of survey panellists to inform statement revision for the third round. The second in-person convening occurred at the annual AASLD conference on 6th November 2022 in Washington DC, USA with two fora for consideration and discussion of the third Delphi round – a closed meeting of the steering committee (n=34 in attendance) followed by a large-group session open to all 2022 AASLD participants including all Delphi panellists. These discussions provided further clarity on the key elements to include in the final round of the nomenclature consensus process.
Based on this feedback, the R4 survey took panellists through a series of four questions that allowed them to select their first and second choices pertaining to terminology preference, whether the term metabolic should be included in the name, the preferred nomenclature (based on their prior choices), and whether or not diagnostic criteria should be revised. Of 224 invited panellists, 174 participated (RR=78%) and provided 28 comments in a final open-ended textbox (Supplementary Fig. 1).
Data informing nomenclature considerations (R1-R4+)
Supplementary Table 1 shows the evolution of survey statements across survey rounds 1-3 and the degree of agreement in each round. Statements were modified for clarity, changed or removed based on review of open text comments, and output from face-to-face meetings. The main conclusions emerging by survey rounds are summarised in Figure 3. In the 4th Delphi round only 4 questions were asked to clarify remaining points of disagreement (Figure 4, Supplementary Fig. 1).
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Figure 3Overview of main findings by Delphi round.
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Figure 4NAFLD Nomenclature Result: Round 4 (Summary).
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Desire for a name change and the role of stigma
During round 1, a supermajority of respondents (74%) felt that the current names NAFLD and NASH were sufficiently flawed to consider a name change (Supplementary Table 1). The terms ‘nonalcoholic’ and ‘fatty’ were deemed to be stigmatising by 61% and 66% of respondents, respectively. A nomenclature that describes the underlying cause of the disease was preferred by 89% of respondents. While there were concerns over the precise meaning of ‘metabolic’ and to what extent this term was understood by clinicians, a super-majority felt that having ‘metabolic disease or dysfunction’ in the name would help patients better understand their disease (72%) and help healthcare professionals better explain or understand the disease (80%). Only a simple majority (56%) felt the terminology of ‘metabolic dysregulation’ to be a clearly defined clinical entity, although a supermajority (86%) felt that it highlighted a central aspect of disease pathophysiology.
Considerations regarding structure and composition of a new name
When given the choice of whether to select an ‘umbrella’ term encompassing different disease subcategories, 78% of respondents preferred the idea of an overarching term to encompass the replacement term for NAFLD, ALD and other conditions resulting in hepatic steatosis. Potential overarching terms were informed by survey rounds 2 and 3 and included fatty liver disease, steatotic liver disease, and lipogenic liver disease. Panellists were instructed to rank order their preference, as first, second and third choice. Fatty liver disease, steatotic liver disease, and lipogenic liver disease garnered 46%, 48% and 7% of first choice selections, respectively. When considering the combination of 1st and 2nd choice votes, steatotic liver disease was chosen by 95% of respondents. Sixty-eight % of the panellists preferred the use of a literal name (such as steatotic liver disease) as opposed to using a numerical subtype (such as type 1, type 2, etc.) as part of the new nomenclature. In round 4, 67% of respondents felt that the term ‘metabolic’ should be included in the revised nomenclature for the alternative name for NAFLD, as a subtype under the overarching term of steatotic liver disease chosen in R3 (Figure 5). Respondents were also asked whether a cardiometabolic risk factor should be added to the current definition and a simple majority were in favour of adding a metabolic qualifier to the definition.
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Figure 5Steatotic Liver Disease sub-classification.
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Considerations for disease definition
Respondents were asked their opinion regarding the concept of steatohepatitis as an important entity, and 95% of respondents felt the presence of steatohepatitis had prognostic implications and should remain an important distinction. Additionally, given the role of ‘resolution of steatohepatitis’ as one of the two European Medicines Agency (EMA) and US Food and Drug Administration (FDA) approvable endpoints, 93% felt it should remain for both clinical practice and trial endpoints.[14, 15] The current definition of NAFLD excludes consumption of >20g/30g of alcohol per day in females and males, respectively, with a more liberal approach to concomitant alcohol use proposed in the original MAFLD definition.[5, 7] To establish the permissibility of greater alcohol consumption, several questions were asked to better understand the impact of alcohol on the natural history of the disease and also how to characterise various levels of alcohol use in the definition. A supermajority felt that consumption of 30g-60g of alcohol daily in the setting of NAFLD alters the natural history of disease (95%) and may alter response to therapeutic interventions (90%). Furthermore, 90% felt that individuals with steatosis related to metabolic risk factors who consume more than minimal alcohol (30g-60g daily) represented an important group that should be considered in a different disease category and studied independently.
Perceived impact of name and/or definition change on disease awareness, development of biomarkers or clinical trials
When considering the potential impact of a change in name, definition or both, fifty-six percent felt that a change in nomenclature would positively impact disease awareness. In assessing the impact of a change in name only on the interpretation of existing and emerging clinical trial results, 18%, 72% and 11% (Supplementary Table 1; R3, Statement 27) felt it would hinder, have no impact and enhance, respectively. When a similar question was asked about the impact on regulatory approval of biomarkers if the name but not the definition changes, 12%, 63% and 25% felt it would accelerate, have no impact or delay approval respectively. In the event of both a name and definition change, 60% of respondents were concerned this could hinder the interpretation of existing and emerging clinical trial results that used the currently accepted definition of NAFLD, whereas 20% felt it would enhance and 20% thought there would be no impact. A simple majority (59%) felt that a change in disease definition would likely delay regulatory approval of biomarkers (R3 – S24) whereas 63% felt a change in name only would have no effect. Of note these questions did not discuss the proposed change to the definition.
Paediatric perspective
There was a high degree of consensus among the paediatric panellists when considering statements/questions pertaining to the paediatric population. Only paediatricians answered the paediatrics specific questions, and the main themes addressed the role of stigma, use of the term ‘metabolic’ and the histological definition of the disease. In children and adolescents, 60% felt that use of the term ‘nonalcoholic’ was stigmatising for parents and/or paediatric patients, with 55% finding this to be the case with the term ‘fatty’. When asked if the current definition of NASH is less useful in children and adolescents due to a lower frequency of hepatocyte ballooning, 95% agreed that a reassessment of the definitions of steatohepatitis in the paediatric setting would be beneficial. In considering incorporation of the term ‘metabolic’ into the nomenclature, 90% estimated that this term may be confusing in the paediatric context since inborn errors of metabolism are referred to as ‘metabolic liver disease’.
Proposed new nomenclature for NAFLD, NASH and NAFLD with increased alcohol consumption
When considering different subcategories under the overarching term of SLD, 67% of respondents preferred the NAFLD replacement term to include the word ‘metabolic’. The top 3 acronyms, metabolic dysfunction-associated steatotic liver disease (MASLD), MetSLD, or metabolic steatotic liver disease (MSLD) were 30%, 30% and 22%, respectively (Figure 4). In total, 75% of respondents of the external expert committee chose metabolic dysfunction-associated steatotic liver disease (MASLD) as the replacement term for NAFLD and 88% metabolic dysfunction-associated steatohepatitis (MASH) as the replacement term for NASH. The acronym MetALD was chosen by 28% and MAASLD by 33% to represent a separate group of patients with MASLD that consume 140-350 g/week for females and 210-420 g/week for males. MetALD was chosen to avoid the possible confusion or perception associated with the acronym AASLD within MAASLD that may link the acronym to a specific professional association. Within MetALD there is a continuum where conceptually the condition can be seen to be MASLD or ALD predominant. This may vary over time within a given individual.
Proposed modifications to current definition
The strong epidemiological and pathogenic link between NAFLD, metabolic dysfunction and insulin resistance, informed a view in the external expert committee that the diagnosis be based on affirmative rather than exclusionary criteria such as nonalcoholic. There was near universal agreement that the criteria be defined sufficiently broadly to identify both individuals with obesity and cardiometabolic risk factors in the context of regional/ethnic differences. Simple, readily available and easily measurable parameters were also deemed necessary for this set of criteria to be broadly applied in clinical practice and in various clinical settings. Finally, the diagnostic criteria were selected to align with cardiometabolic risk factors believed to be associated with insulin resistance and already well-established and validated in the context of cardiovascular disease. [16] It was agreed that patients with steatosis and any one of the cardiometabolic criteria outlined in Figure 6 would be considered to have MASLD. Of note, making a diagnosis of MASLD does not imply that other causes of SLD do not need to be considered, which is particularly relevant in children where it is imperative to exclude other causes of hepatic steatosis prior to applying the MASLD diagnostic criteria to ensure that dual pathology is not missed.[17].
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Figure 6MASLD diagnostic criteria.
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Switching from a definition based on the exclusion of any other liver disease (i. e. NAFLD) to a definition based on specific, primarily cardiometabolic risk factors (i. e. MASLD) has potential limitations. Firstly, the key metabolic dysfunction underlying MASLD is insulin resistance, and the selected metabolic risk factors do not equally predict insulin resistance, as for example diastolic blood pressure and HDL-C are only weakly associated with insulin resistance.[18] Secondly, insulin resistance and steatosis may be present in the absence of any cardiometabolic risk factors, especially in younger adults in the primary care setting. Thus, patients with steatosis without overt cardiometabolic risk factors or other discernible cause are labelled as cryptogenic. If there is uncertainty and the clinician strongly suspects metabolic dysfunction despite the absence of CMRF then the term possible MASLD can be considered pending additional testing (e.g., HOMA-IR, OGTT) although this should be left to the discretion of the clinical team. Such cases and also cryptogenic cases that subsequently manifest CMRF can be rebadged as MASLD.
Role of alcohol in disease definitions
With respect to alcohol intake, the overwhelming consensus was to continue to limit alcohol intake (as previously limited for NAFLD) in the context of steatosis. The purpose of this process was to focus on NAFLD, not alcohol-related liver disease, but it was seen as relevant to comment on situations where these was overlap. We therefore created a separate category outside of pure MASLD, namely MetALD, with alcohol intake greater than that allowed for NAFLD/MASLD. Within the group of patients with MetALD, there may be individuals where MASLD is the perceived dominant driver and others where ALD is the perceived dominant driver, and indeed this may change over time. (Figure 5).
Discussion
Identification of a new name and definition for the condition formerly known as nonalcoholic fatty liver disease has been a challenging process given the broad range of global stakeholders. It is imperative that any new proposal be sufficiently better than the existing nomenclature and that it enhances awareness, understanding of the disease and drug/biomarker development. This robust, representative, patient-centric Delphi process systematically addressed all the issues and views over the past years and through consensus has arrived at both a new name and a refined definition. By inclusion of patient advocacy groups throughout the entire process, the new nomenclature strives to accelerate disease awareness whilst minimising stigma associated with use of terms perceived as stigmatising by some patients and their caregivers.
Several important findings emerged from the nomenclature consensus process; there was clear support for a name change, use of an overarching term which could accommodate the evolution of disease understanding, and use of a metabolic descriptor in the new nomenclature. Both the overarching term of steatotic liver disease (SLD) and the more specific metabolic dysfunction-associated steatotic liver disease (MASLD) provide an affirmative non-stigmatising description of the condition rather than a diagnosis of exclusion. This is also seen in the definition, which requires the presence of at least one cardiometabolic risk factor in addition to hepatic steatosis. The proposed nomenclature is not intended to be static, but rather allows the flexibility for refinement as new evidence emerges about underlying pathophysiology and risk factors.
A key consideration is the preservation of existing data on natural history, biomarkers and clinical trials as part of these changes. To address the impact of the refined definition, an analysis of the LITMUS consortium European was performed, which demonstrated that 98% of the existing Registry cohort of patients with NAFLD would fulfill the new criteria for MASLD.[19] Conceptually patients with the previous definition (NAFLD) can now be seen to be completely covered by the categories of MASLD and possible MASLD. The introduction of a separate MetALD subcategory where metabolic and alcohol-related risk factors coexist sits outside MASLD/NAFLD and is an opportunity to generate new knowledge for this common group of patients. In addition, maintenance of the term, and clinical definition, of steatohepatitis ensures retention and validity of prior data from clinical trials and biomarker discovery studies of patients with NASH to be generalizable to individuals classified as MASLD or MASH under the new nomenclature, without impeding the efficiency of research.
The Delphi process utilised a super-majority threshold of ≥67% with two exceptions, the consideration of stigma and a binary question to retain or revise the current definition. Whilst recognizing that perceptions of stigma differ widely,[20, 21] especially across different languages and cultures, in this study it became clear that substantial proportions of the respondents deemed terms such as ‘fatty’ stigmatising, hence its exclusion as part of any new name. Although health care professionals may contend that patients have not reported this previously, this likely reflects in part a failure to ask the question in the first place and the power imbalance in the doctor-patient relationship. Moreover, a recent large study indicated that some health care professionals and patients considered the terms fatty and nonalcoholic to be pejorative and stigmatising.[21] The use of medical terminology such as steatosis may at one level be seen as over-medicalising the lexicon yet it affords patients the opportunity to disclose their condition to friends and colleagues without having to face prejudice and stigma that can be inherent to the word ‘fatty’.[21, 22] Efforts to increase disease awareness have had modest success, possibly impacted by the perception that care providers deem the term ‘fatty liver’ as describing an indolent condition. With therapeutics on the horizon, there is renewed energy to identify ‘at-risk’ patients, which in conjunction with new terminology may bolster awareness and sense of importance.
The overarching term of steatotic liver disease encompasses the spectrum of causes of hepatic steatosis, thus allowing precise classification once a specific aetiology has been identified. The new names also allow for further characterization of fibrotic severity, e.g. MASH with stage 3 fibrosis. Disease staging and severity are not altered by this process, although it is anticipated that in the near to medium term, disease staging will be achieved using non-invasive tests, which can be incorporated into further clarifications of disease stage. Thus, the current consensus process does not deviate from prior case definitions for steatohepatitis and disease stages.[23] The diagnosis of MASLD/MASH with advanced fibrosis cirrhosis, when steatosis may not be present, will be based upon existing agreed criteria for NASH cirrhosis.[23] This also applies to patients with MetALD and ALD with significant fibrosis who may not have steatosis, yet have SLD as part of the over-arching nomenclature, reflecting the mechanism of injury.
The proposed nomenclature also improves upon the prior “nonalcoholic” label and appropriately assigns a metabolic basis for this liver disease which was long recognized as “the hepatic manifestation of the metabolic syndrome”.[5] This important conceptual change has several practical consequences. First, when addressing patients, it allows for a coherent and straightforward explanation of the disease as it is intuitively easier to understand in the context of its underlying cardiometabolic abnormalities linked to insulin resistance and its association with the patient’s other conditions, rather than in the framework of a diagnosis of exclusion. This also helps to communicate to the patient the main therapeutic actions to be taken both from a liver and a holistic perspective. Secondly, we believe that using this classification will enhance disease awareness, since the alignment of the diagnostic criteria for MASLD with widely recognized phenotypic traits in diabetes and cardiovascular medicine will make it easier for the larger community of healthcare providers to identify individuals with this condition. There is a strong convergence between the metabolic set of criteria we propose for diagnosing MASLD and those proposed by Eslam et al. for MAFLD. [24] However, the current consensus approach decided to prioritise robust and easily accessible clinical criteria and biological measurements, and as such these criteria do not include direct measurements of insulin resistance (such as fasting insulin or HOMA-IR) because of their complexity, cost and variability between laboratories. However, in patients with hepatic steatosis in the absence of overt cardiometabolic risk factors, secondary testing for insulin resistance may be useful to identify those with possible MASLD. It is important to understand that the set of diagnostic criteria for MASLD are not intended to diagnose “metabolic syndrome” or predict the occurrence of cardiovascular outcomes. The cardiometabolic risk factors are intended to identify patients likely to have insulin resistance as the main cause of hepatic steatosis. There was consideration of providing differential weighting for the cardiometabolic risk factors such as type 2 diabetes although the literature is conflicting in that regard with some indicating no parameter is better than another at identifying hepatic steatosis.[25].
This process focusses on nomenclature and definition of NAFLD rather than a determination of what constitutes hepatic steatosis or assessment of disease severity. There is an extensive literature on the confirmation of hepatic steatosis [26, 27] which we did not seek to interrogate – often this is a pragmatic determination in clinical practice which is where this guidance starts. Moreover, this nomenclature process, in line with published guidance,[21, 28, 29] is not advocating for the routine use of tests to confirm hepatic steatosis although in reality most, if not all, patients will usually have imaging at some point. Finally, we recognise it is the evaluation of fibrosis either as part of screening strategies or individual clinical decisions, which is relevant for most clinical settings.[30] That remains unchanged after this process, other than the name (e.g. MASLD with advanced fibrosis).
Contrary to the initial proposal by Eslam et al, the Delphi process revealed that most experts consider that MetALD patients should be classified in a category distinct from MASLD, mainly because of the added pathogenic value of alcohol consumption and consequential prognostic implications. The condition MetALD provides an opportunity to better define the natural history for such patients and the development of biomarkers and therapies which are currently lacking for this group of patients.[31] ALD is a distinct liver disease (of which steatosis is one of the features) and thus categorised under the SLD umbrella. This should raise awareness of alcohol as a driver of steatosis and highlight the impact of excessive alcohol consumption (i.e., higher than 50-60 g daily in females and males, respectively) irrespective of their association with metabolic dysfunction. Studies have shown that even in excessive drinkers, obesity increases the prevalence of cirrhosis and glycaemic dysregulation increases fibrosis severity.[32, 33] Patterns of alcohol use must also be taken into consideration as bingeing (even within the total weekly ‘allowable limit’ for MASLD) can be detrimental. We also recognise that validated objective tools are not currently available to determine the relative contribution of MASLD and ALD in patients with MetALD and hence we rely on self-reported alcohol intake which can be inaccurate. In that regard this is a conceptual construct and might be better seen as a disease spectrum with different weights of different modifiable disease drivers (cardiometabolic factors and alcohol). This is also relevant for the distinction between patients with MetALD and those drinking more heavily that are termed as having ALD. Also the category of ALD without metabolic factors is relatively rare amongst patients with significant fibrosis but it was felt to represent part of the spectrum.
In addition to defining a distinct category for patients with MASLD and greater alcohol consumption (MetALD), the proposed nomenclature allows, by introducing the umbrella term of steatotic liver disease, for diagnostic subgroups of steatotic liver disease to be identified, namely those that are drug-related as well as others. The latter encompasses the many “secondary” causes of NAFLD, most of which are rare diseases, including monogenic diseases.[31] This is particularly relevant in children, in whom rare genetic metabolism defects can cause steatosis and must be considered.[17] Patients with steatosis without overt cardiometabolic risk factors or other discernible cause are labelled as cryptogenic, although depending on clinical judgement could also be deemed to have possible MASLD and would benefit from periodic reassessment on a case-by-case basis. Of note, genetic variants influencing the prevalence and/or severity of MASLD such as PNPLA3, TM6SF2 and HSD17B13, and other genetic risk variants that are common in the general population, were not considered a distinct nosological entity. This was because these variants are disease modifiers for both MASLD and ALD rather than causative factors, in contrast to rare variants responsible for monogenic diseases. The change in nomenclature in favour of a positive diagnosis based on the presence of cardiometabolic risk factors will also allow for a rational reclassification of most cases of the condition formerly known as “lean NASH” into the regular MASLD category, as long as currently defined metabolic risk factors are present. The “cryptogenic” category will, as mentioned, also accommodate the rare specific causes of steatotic liver disease unrelated to metabolic dysfunction, alcohol consumption, drug intake or other causes [34] while waiting for a precise identification of the causal agent by future research.
Despite the many strengths of this rigorous process, we acknowledge limitations. The individual statements changed between R1 and R3 (Supplementary Table 1) and there was variation in levels of agreement for individual statements although this reflects their evolution, as important issues arose that we needed to consider regarding the NAFLD nomenclature. Furthermore, the lack of uniform agreement on many topics reflects the diversity of opinions involved in the process. A priori, we chose a threshold of 67% (supermajority) to define consensus, which meant that some opinions, although held by a simple majority (more than 50% but less than 67%), did not influence the final decisions, with the exception of stigma and the decision to alter the disease definition. Nonetheless, we are confident that statements supported by a super majority were addressed and incorporated.
In conclusion, we believe this process, which has multi-stakeholder endorsement, provides a strong platform from which we can increase disease awareness, reduce stigma and accelerate drug and biomarker development for the benefit of patients with MASLD, MASH and MetALD.
Conflicts of Interest
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 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, GlaxoSmithKline, 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 Ingleheim, 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, GlaxoSmithKline, 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 for 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, GlaxoSmithKline, Hanmi, Janssen, Novo Nordisk, Terns, and Viking.
Jefferey 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 89 Bio 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 co-founded and owns stock in LipoNexus.
Phillip Newsome consults, advises, is on the speakers’ bureau, and received grants from Novo Nordisk. He consults and advises Boehringer Ingelheim, Bristol Myers Squibb, Gilead, GlaxoSmithKline, Intercept, Madrigal, Pfizer, Poxel, and Sun Pharma. He is on the speakers’ bureau for AiCME.
Elizabeth 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, Poxel, and Sagimet. He received grants from Gilead.
Mary E. Rinella consults for Boehringer Ingelheim, CytoDyn, GlaxoSmithKline, 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, GlaxoSmithKline, 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 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.
Acknowledgements
The authors would like to express their appreciation to the governing boards of the three lead societies AASLD, ALEH and EASL, and specifically society leadership, Norah Terrault (AASLD President 2023), Laurie DeLeve (AASLD President 2022), and W. Ray Kim (AASLD President-elect); Graciela Castro Narro (ALEH President); Thomas Berg (EASL Secretary General 2021-2023) and Aleksander Krag (EASL Secretary General 2023-2025). The authors would also like to thank Matthew D’Uva from AASLD for his tireless work and support of this project and recognize the contributions of all of the members of the NAFLD nomenclature consensus group who provided feedback, analysis, and recommendations over multiple Delphi rounds. (Table 2) We acknowledge the assistance of the EU – IMI2 funded LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) consortium for analysis of data derived from the European NAFLD Registry. Finally, the authors and methodology team would also like to thank Delfina Boudou and Trenton White (ISGlobal, Spain).
Appendix A. Supplementary data
The following are the supplementary data to this article:
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Supplementary Figure 1. NAFLD Nomenclature Result: Round 4 (Complete)
The fourth and final Delphi round to achieve consensus on a nomenclature was informed by the results from the previous three Delphi rounds (see Table 2) as well as feedback from multiple in-person convenings involving in-depth discussion among panel members. Thus, round 4 comprised a series of questions depicted in the flow chart above that enabled panel members to select both their preferred/first-choice nomenclature as well, as their preference should an option other than their first-choice garner majority support from the panel. The results of this process are presented in this figure.
Legend: Q displayed to all; Q displayed if person chose A/numerical in Q1; Q displayed if person chose B/literal in Q1; Q displayed if person chose A/incl ‘Metabolic’ in Q2b or Q2b1; Q displayed if person chose B/does not incl Metabolic in Q2b or Q2b1.
Abbreviations: NAFLD, non-alcoholic fatty liver disease; Q, question; SLD, steatotic liver disease; incl, include; *MetSLD, metabolic dysfunction-associated steatotic liver disease; *MSLD, metabolic dysfunction-associated steatotic liver disease; MAS, metabolic dysfunction-associated steatosis; MHS, metabolic dysfunction-associated hepatic steatosis; *MASLD, metabolic dysfunction-associated steatotic liver disease; VASLD, visceral adiposity-associated steatotic liver disease; LLD, lipotoxic liver disease; NASLD, nutrition-associated steatotic liver disease; IRSLD, insulin-resistance associated steatotic liver disease.
*Note: These names appear to be the same but each has distinct characteristics; refer to survey Q3a or Q3b1 for details.
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DOI: https://doi.org/10.1016/j.jhep.2023.06.003
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© 2023 American Association for the Study of Liver Diseases (AASLD), 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.