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A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement

Published:April 08, 2020DOI:https://doi.org/10.1016/j.jhep.2020.03.039

      Summary

      The exclusion of other chronic liver diseases including “excess” alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, given our current understanding of the pathogenesis of MAFLD and its rising prevalence, “positive criteria” to diagnose the disease are required. In this work, a panel of international experts from 22 countries propose a new definition for the diagnosis of MAFLD that is both comprehensive and simple, and is independent of other liver diseases. The criteria are based on evidence of hepatic steatosis, in addition to one of the following three criteria, namely overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. We propose that disease assessment and stratification of severity should extend beyond a simple dichotomous classification to steatohepatitis vs. non-steatohepatitis. The group also suggests a set of criteria to define MAFLD-associated cirrhosis and proposes a conceptual framework to consider other causes of fatty liver disease. Finally, we bring clarity to the distinction between diagnostic criteria and inclusion criteria for research studies and clinical trials. Reaching consensus on the criteria for MAFLD will help unify the terminology (e.g. for ICD-coding), enhance the legitimacy of clinical practice and clinical trials, improve clinical care and move the clinical and scientific field of liver research forward.

      Keywords

      Introduction

      Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly named non-alcoholic fatty liver disease (NAFLD), affects about a quarter of the world's adult population, poses a major health and economic burden to all societies
      • Eslam M.
      • Sanyal A.J.
      • George J.
      MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.
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      • Hardy T.
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      • Eslam M.
      • et al.
      Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
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      Liver diseases in the Asia-Pacific region: a Lancet Gastroenterology & hepatology Commission.
      and yet has no approved pharmacotherapy. The high prevalence of this disease has been fuelled by the rapid rise in levels of sedentary behaviour, low levels of physical activity, excess calorie intake relative to expenditure in nutritionally imbalanced and unhealthy diets.
      • Inoue Y.
      • Qin B.
      • Poti J.
      • Sokol R.
      • Gordon-Larsen P.
      Epidemiology of obesity in adults: latest trends.
      In parallel, the prevalence of poor metabolic health in adults from affluent countries is high, even in normal weight individuals.
      • Stefan N.
      • Schick F.
      • Haring H.U.
      Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans.
      ,
      • Araujo J.
      • Cai J.
      • Stevens J.
      Prevalence of optimal metabolic health in American adults: national health and nutrition examination survey 2009-2016.
      In this context of high risk and prevalence, the lack of clear nomenclature for liver disease not due to alcohol use disorder, alongside the absence of defined clinical criteria for a “positive” diagnosis of this disease, constitute urgent unmet needs in the field.
      To tackle this challenge, an international panel of experts have detailed the rationale for an update of the nomenclature and metabolic dysfunction-associated fatty liver disease, MAFLD, has been proposed as a more appropriate term to describe the liver disease associated with known metabolic dysfunction.
      • Eslam M.
      • Sanyal A.J.
      • George J.
      MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.
      ,
      • Eslam M.
      • Sanyal A.J.
      • George J.
      Toward more accurate nomenclature for fatty liver diseases.
      MAFLD, as with the previous term NAFLD, represents the hepatic manifestation of a multisystem disorder, which is heterogeneous in its underlying causes, presentation, course and outcomes.
      • Byrne C.D.
      • Targher G.
      NAFLD: a multisystem disease.
      However, given its complex pathophysiology, it is unlikely that a single diagnostic test will become available so new diagnostic criteria will need to be developed to define MAFLD, as was the case for the metabolic syndrome, which notably has multiple definitions.
      • Stefan N.
      • Schick F.
      • Haring H.U.
      Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans.
      ,
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      • et al.
      Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III).
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      • Izzo Jr., J.
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      • et al.
      The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.
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      • et al.
      Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement.
      • Alberti K.
      • Eckel R.H.
      • Grundy S.M.
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      • Cleeman J.I.
      • Donato K.A.
      • et al.
      Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; American heart association; world heart federation; international atherosclerosis society; and international association for the study of obesity.
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • Casey D.E.
      • Collins K.J.
      • Himmelfarb C.D.
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      • Association A.D.
      2. Classification and diagnosis of diabetes: standards of medical care in diabetes—2018.
      Until now the exclusion of other chronic liver diseases, including “excess” alcohol intake, was necessary for the diagnosis of MAFLD. As the pathogenic process leading to MAFLD is now better understood and is seen to originate from an underlying state of systemic metabolic dysfunction, MAFLD is perceived as a standalone disease which warrants a positive diagnosis, rather than a “none”-disease rubric. Moreover, the rising prevalence of MAFLD makes its coexistence with other chronic liver diseases quite possible, further negating a diagnosis based on exclusion of concomitant diseases. It is therefore our belief that this disease needs to be defined by its own set of positive criteria, rather than by exclusion criteria.
      Hence, in this work we propose a comprehensive, yet simple, set of criteria for the diagnosis of MAFLD that are independent of the amount of alcohol consumed and can be applied to patients in any clinical setting. We also bring clarity to the diagnostic criteria, which are distinct from inclusion criteria for research studies and clinical trials. The long-term impact will be to promote wider discussion, help clinicians in routine clinical care, allow comparison of different studies, assist regulatory agencies and other stakeholders in case definition for clinical trials, and facilitate documentation in the ICD systems and diagnosis-related groups. The inclusion and endpoints of clinical trials that have been the focus of multiple other initiatives will likely evolve as acceptance of the new nomenclature and definition progresses.
      • Siddiqui M.S.
      • Harrison S.A.
      • Abdelmalek M.F.
      • Anstee Q.M.
      • Bedossa P.
      • Castera L.
      • et al.
      Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science.

      Criteria for a diagnosis of MAFLD

      Presently the definition of NAFLD as reported in most guidelines and recent publications is based on the presence of steatosis in >5% of hepatocytes in the absence of significant ongoing or recent alcohol consumption and other known causes of liver disease.
      • Siddiqui M.S.
      • Harrison S.A.
      • Abdelmalek M.F.
      • Anstee Q.M.
      • Bedossa P.
      • Castera L.
      • et al.
      Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science.
      European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity
      EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.
      • Wong V.W.
      • Chan W.K.
      • Chitturi S.
      • Chawla Y.
      • Dan Y.Y.
      • Duseja A.
      • et al.
      Asia-pacific working party on non-alcoholic fatty liver disease guidelines 2017-Part 1: definition, risk factors and assessment.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Charlton M.
      • Cusi K.
      • Rinella M.
      • et al.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Herein we propose a set of new “positive” criteria for the diagnosis of MAFLD regardless of alcohol consumption or other concomitant liver diseases.

       Suggestion

      The proposed criteria for a positive diagnosis of MAFLD are based on histological (biopsy), imaging or blood biomarker evidence of fat accumulation in the liver (hepatic steatosis) in addition to one of the following three criteria, namely overweight/obesity, presence of type 2 diabetes mellitus (T2DM), or evidence of metabolic dysregulation. The latter is defined by the presence of at least two metabolic risk abnormalities, listed in Box 1. A flowchart for the proposed diagnostic criteria is depicted in Fig. 1.
      Criteria defining metabolic risk factors.
      Tabled 1
      ∗The AHA/NHLBI guidelines for metabolic syndrome recognise an increased risk for cardiovascular disease and diabetes at waist-circumference thresholds of ≥94 cm in men and ≥80 cm in women and identify these as optional cut points for Caucasian individuals or populations with increased insulin resistance (13). HbA1c, glycated haemoglobin; MAFLD, metabolic dysfunction-associated fatty liver disease.
      Figure thumbnail gr1
      Fig. 1Flowchart for the proposed “positive” diagnostic criteria for MAFLD.
      For detection of steatosis, ultrasound is the most widely used first-line diagnostic modality and is recommended. It should be noted that ultrasound has limited sensitivity, it does not reliably detect steatosis of <20%, and its performance is suboptimal in individuals with body mass index (BMI) >40 kg/m2. Measurement of controlled attenuation parameter (or similar) using vibration-controlled transient elastography (FibroScan) is increasingly undertaken in routine clinical practice, with a reported area under the area under the receiver-operating-characteristic curve of 0.87 for steatosis, using biopsy as the reference standard.
      • Eddowes P.J.
      • Sasso M.
      • Allison M.
      • Tsochatzis E.
      • Anstee Q.M.
      • Sheridan D.
      • et al.
      Accuracy of FibroScan controlled attenuation parameter and liver Stiffness Measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease.
      CT or MRI can be used to diagnose moderate and severe steatosis if available. Magnetic resonance spectroscopy (MRS) provides a quantitative estimation of liver fat, but it is expensive, has limited availability, and requires special software. Therefore, MRI-derived proton density fat fraction which is in close agreement with MRS but is more practical is generally preferred in clinical trials.
      • Caussy C.
      • Reeder S.B.
      • Sirlin C.B.
      • Loomba R.
      Noninvasive, quantitative assessment of liver fat by MRI-PDFF as an endpoint in NASH trials.
      Pending appropriate validation from future research, serum biomarkers of steatosis could replace imaging methods. However, currently, this would only be appropriate for large epidemiological studies with markers such as fatty liver index (FLI), given the available data on the diagnostic and prognostic performance of FLI.
      • Siddiqui M.S.
      • Harrison S.A.
      • Abdelmalek M.F.
      • Anstee Q.M.
      • Bedossa P.
      • Castera L.
      • et al.
      Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science.
      European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity
      EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.
      • Wong V.W.
      • Chan W.K.
      • Chitturi S.
      • Chawla Y.
      • Dan Y.Y.
      • Duseja A.
      • et al.
      Asia-pacific working party on non-alcoholic fatty liver disease guidelines 2017-Part 1: definition, risk factors and assessment.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • Charlton M.
      • Cusi K.
      • Rinella M.
      • et al.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.

       Rationale

      Although there is no general consensus on the criteria to define “metabolic health” that indicates a high or low risk of cardiometabolic disease, a number of guidelines have evidence-based recommendations for risk assessment. The criteria for defining “metabolic health” status are commonly based on the metabolic syndrome definition proposed by the Adult Treatment Panel III.
      • Stefan N.
      • Schick F.
      • Haring H.U.
      Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans.
      ,
      • Cleeman J.I.
      • Grundy S.M.
      • Becker D.
      • Clark L.T.
      • Cooper R.S.
      • Denke M.A.
      • et al.
      Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III).
      • Black H.
      • Cushman W.
      • Green L.
      • Izzo Jr., J.
      • Jones D.
      • Materson B.
      • et al.
      The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.
      • Grundy S.M.
      • Cleeman J.I.
      • Daniels S.R.
      • Donato K.A.
      • Eckel R.H.
      • Franklin B.A.
      • et al.
      Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement.
      • Alberti K.
      • Eckel R.H.
      • Grundy S.M.
      • Zimmet P.Z.
      • Cleeman J.I.
      • Donato K.A.
      • et al.
      Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; American heart association; world heart federation; international atherosclerosis society; and international association for the study of obesity.
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • Casey D.E.
      • Collins K.J.
      • Himmelfarb C.D.
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      • Association A.D.
      2. Classification and diagnosis of diabetes: standards of medical care in diabetes—2018.
      The rationale for excess body weight as one of the three criteria for defining MAFLD (Fig. 1) stems from the fact that it has strong pathological link to MAFLD and is a critical determinant of adverse clinical outcomes. A recent meta-analysis of 239 prospective studies that controlled for multiple confounding factors demonstrated that both overweight and obesity are associated with higher all-cause mortality compared to a normal body weight (defined as a BMI of 18.5–<25.0 kg/m2 in Caucasian individuals).
      • Di Angelantonio E.
      • Bhupathiraju S.N.
      • Wormser D.
      • Gao P.
      • Kaptoge S.
      • de Gonzalez A.B.
      • et al.
      Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents.
      Although obesity can be classified as metabolically healthy obesity (MHO) and metabolically unhealthy obesity
      • Shea J.L.
      • Randell E.W.
      • Sun G.A.
      The prevalence of metabolically healthy obese subjects defined by BMI and dual-energy X-Ray absorptiometry.
      ,
      • Munoz-Garach A.
      • Cornejo-Pareja I.
      • Tinahones F.J.
      Does metabolically healthy obesity exist?.
      with purported differential impacts on the risk of cardiovascular outcomes, large-scale cohort studies do not support the notion that individuals with MHO, at least as currently defined, are protected from the development of cardiometabolic complications.
      • Eckel N.
      • Li Y.
      • Kuxhaus O.
      • Stefan N.
      • Hu F.B.
      • Schulze M.B.
      Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30 year follow-up from a prospective cohort study.
      • Caleyachetty R.
      • Thomas G.N.
      • Toulis K.A.
      • Mohammed N.
      • Gokhale K.M.
      • Balachandran K.
      • et al.
      Metabolically healthy obese and incident cardiovascular disease events among 3.5 Million men and women.
      • Lassale C.
      • Tzoulaki I.
      • Moons K.G.M.
      • Sweeting M.
      • Boer J.
      • Johnson L.
      • et al.
      Separate and combined associations of obesity and metabolic health with coronary heart disease: a pan-European case-cohort analysis.
      Similarly, a recent report demonstrated that individuals with MHO and MAFLD remain at high risk of developing significant hepatic fibrosis.
      • Ampuero J.
      • Aller R.
      • Gallego-Duran R.
      • Banales J.M.
      • Crespo J.
      • Garcia-Monzon C.
      • et al.
      The effects of metabolic status on non-alcoholic fatty liver disease-related outcomes, beyond the presence of obesity.
      Thus, the presence of both excess weight and metabolic dysfunction have independent effects on the risk of MAFLD and cardiometabolic outcomes. As MAFLD is commonly seen in clinical practice in association with overweight/obesity, this criterion would identify most patients in routine care (as opposed to those in clinical research and cohort studies). Similarly, an intimate association between MAFLD and T2DM has been demonstrated; >70% of patients with T2DM have MAFLD.
      • Williams C.D.
      • Stengel J.
      • Asike M.I.
      • Torres D.M.
      • Shaw J.
      • Contreras M.
      • et al.
      Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
      ,
      • Arrese M.
      • Barrera F.
      • Triantafilo N.
      • Arab J.P.
      Concurrent nonalcoholic fatty liver disease and type 2 diabetes: diagnostic and therapeutic considerations.
      This criterion can also be applied in clinical practice (Fig. 1).
      In addition, the presence of steatosis with at least two metabolic risk abnormalities mentioned in Box 1 and Fig. 1 should be a criterion to diagnose MAFLD in non-overweight/obese individuals. Lean individuals likewise are not protected from the development of MAFLD
      • Younossi Z.
      • Anstee Q.M.
      • Marietti M.
      • Hardy T.
      • Henry L.
      • Eslam M.
      • et al.
      Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
      ,
      • Inoue Y.
      • Qin B.
      • Poti J.
      • Sokol R.
      • Gordon-Larsen P.
      Epidemiology of obesity in adults: latest trends.
      ,
      • Chen F.
      • Esmaili S.
      • Rogers G.
      • Bugianesi E.
      • Petta S.
      • Marchesini G.
      • et al.
      Lean NAFLD: a distinct entity shaped by differential metabolic adaptation.
      and it is recognised that 6–20% of patients with MAFLD are neither overweight nor obese.
      • Younossi Z.
      • Anstee Q.M.
      • Marietti M.
      • Hardy T.
      • Henry L.
      • Eslam M.
      • et al.
      Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
      ,
      • Chen F.
      • Esmaili S.
      • Rogers G.
      • Bugianesi E.
      • Petta S.
      • Marchesini G.
      • et al.
      Lean NAFLD: a distinct entity shaped by differential metabolic adaptation.
      Indeed, in a recent study of 1,000 liver biopsies in patients with MAFLD, the histological severity of disease in patients with a BMI <23 kg/m2 was no different to that in those with a BMI >25 kg/m2.
      • Rastogi A.
      • Shasthry S.M.
      • Agarwal A.
      • Bihari C.
      • Jain P.
      • Jindal A.
      • et al.
      Non-alcoholic fatty liver disease - histological scoring systems: a large cohort single-center, evaluation study.
      There is also growing evidence that the importance of metabolic health extends beyond what is reflected by definitions of obesity. It has for instance been demonstrated that regardless of BMI, metabolically unhealthy individuals have higher cardiovascular disease risk than their metabolically healthy counterparts.
      • Lassale C.
      • Tzoulaki I.
      • Moons K.G.M.
      • Sweeting M.
      • Boer J.
      • Johnson L.
      • et al.
      Separate and combined associations of obesity and metabolic health with coronary heart disease: a pan-European case-cohort analysis.
      It should be noted that metabolically unhealthy lean patients may have greater ectopic fat accumulation, predominately in a visceral distribution.
      • Stefan N.
      • Schick F.
      • Haring H.U.
      Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans.
      Consistently, metabolically unhealthy non-obese patients with MAFLD are at greater risk of liver damage and cardiovascular risk compared to metabolically healthy individuals.
      • Ampuero J.
      • Aller R.
      • Gallego-Duran R.
      • Banales J.M.
      • Crespo J.
      • Garcia-Monzon C.
      • et al.
      The effects of metabolic status on non-alcoholic fatty liver disease-related outcomes, beyond the presence of obesity.
      To complicate matters further, metabolic health is a dynamic state across the life span and determinants for the conversion from metabolically healthy to unhealthy phenotypes need to be considered.
      • Cho Y.K.
      • Kang Y.M.
      • Yoo J.H.
      • Lee J.
      • Park J.Y.
      • Lee W.J.
      • et al.
      Implications of the dynamic nature of metabolic health status and obesity on risk of incident cardiovascular events and mortality: a nationwide population-based cohort study.
      Some studies suggest that liver fat accumulation is a very sensitive and early indicator of metabolic dysfunction.
      • Bril F.
      • Barb D.
      • Portillo-Sanchez P.
      • Biernacki D.
      • Lomonaco R.
      • Suman A.
      • et al.
      Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease.
      ,
      • Rotman Y.
      • Neuschwander-Tetri B.A.
      Liver fat accumulation as a barometer of insulin responsiveness again points to adipose tissue as the culprit.
      Thus, the proposed criteria would be able to capture the whole phenotypical spectrum from metabolically unhealthy normal weight to metabolically unhealthy obesity.

      MAFLD: a single overarching term

       Suggestion

      MAFLD should be the single overarching term used to describe the disease. Disease severity would be best described by the grade of activity and the stage of fibrosis. This is similar to what is accepted for other chronic liver diseases and recognises that MAFLD activity grade is a continuum.
      • McPherson S.
      • Hardy T.
      • Henderson E.
      • Burt A.D.
      • Day C.P.
      • Anstee Q.M.
      Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: Implications for prognosis and clinical management.
      This should replace the current dichotomous stratification into steatohepatitis and non-steatohepatitis which has limitations that are discussed below.

       Rationale

      There is no doubt that the transition from steatosis to steatohepatitis is a cardinal feature for the progressive liver disease that leads to cirrhosis and cancer. For instance, progression from steatosis alone or steatosis with mild inflammation to bridging fibrosis has been shown to occur concurrently with the transition through steatohepatitis.
      • Pais R.
      • Charlotte F.
      • Fedchuk L.
      • Bedossa P.
      • Lebray P.
      • Poynard T.
      • et al.
      A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver.
      Beyond this qualitative association, several longitudinal studies, both natural history-based and interventional, have demonstrated a semiquantitative relationship between disease activity (grade of steatohepatitis) and changes in fibrosis. Increases in activity grade, as measured by the commonly used histological NAFLD activity score (NAS), which grades steatosis in addition to inflammation and liver cell injury, were shown to be associated with fibrosis progression, while reduction of activity grade was associated with fibrosis regression despite the persistence of steatohepatitis.
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Wong V.W.S.
      • Castellanos M.
      • Aller-de la Fuente R.
      • Metwally M.
      • et al.
      Fibrosis severity as a determinant of cause-specific mortality in patients with Advanced nonalcoholic fatty liver disease: a multi-national cohort study.
      • Adams L.A.
      • Lymp J.F.
      • St Sauver J.
      • Sanderson S.O.
      • Lindor K.D.
      • Feldstein A.
      • et al.
      The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
      • Kleiner D.E.
      • Brunt E.M.
      • Wilson L.A.
      • Behling C.
      • Guy C.
      • Contos M.
      • et al.
      Association of histologic disease activity with progression of nonalcoholic fatty liver disease.
      • Brunt E.M.
      • Kleiner D.E.
      • Wilson L.A.
      • Sanyal A.J.
      • Neuschwander-Tetri B.A.
      • Steatohepatitis N.
      Improvements in histologic features and diagnosis associated with improvement in fibrosis in nonalcoholic steatohepatitis: results from the nonalcoholic steatohepatitis clinical research network treatment trials.
      Pharmacological interventions and long-term observational natural history studies have shown the same directionality between activity grade, hepatic inflammatory changes and fibrosis progression/regression.
      • Kleiner D.E.
      • Brunt E.M.
      • Wilson L.A.
      • Behling C.
      • Guy C.
      • Contos M.
      • et al.
      Association of histologic disease activity with progression of nonalcoholic fatty liver disease.
      ,

      Ratziu V, Harrison SA, Francque S, Bedossa P, Anstee QM, Ben S, et al. ALT as a non-invasive biomarker of histological response to pharmacotherapy in NASH patients: insights from the elafibranor GOLDEN505 trial. 67th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2016; 2016: Newcastle University.

      The aforementioned findings suggest that a dichotomous classification to non-alcoholic steatohepatitis (NASH) or not-NASH may not capture the full spectrum of the disease course in response to changes in the underlying metabolic dysfunction or to pharmacological interventions. Therefore we propose that rather than a dichotomous classification (steatosis vs. steatohepatitis) the disease process in MAFLD is best described by the grade of activity and the stage of fibrosis.
      • Dufour J.F.
      Time to abandon NASH?.
      From a clinical and pathological concept, this suggestion should result in improved case identification, while subclassification may capture histological changes in disease status with relevant impacts on the disease course. Ultimately, future non-invasive tests capturing both disease activity and fibrosis stage should aim at making disease categorisation possible; liver biopsy should be reserved for complicated cases, where it may be needed to rule out other forms of liver disease, or to further characterise the disease process, as the pathology score represents not only “amount” but also location and parenchymal alteration, e.g. vascular alterations.

      MAFLD cirrhosis—no longer cryptogenic cirrhosis

       Suggestion

      We propose that patients with cirrhosis, with low or undetectable levels of steatosis, who meet the proposed diagnostic criteria for MAFLD should be considered under the umbrella of MAFLD, as MAFLD-related cirrhosis. The term “cryptogenic cirrhosis” in this group should be avoided.
      The proposed diagnostic criteria for MAFLD-related cirrhosis are patients with cirrhosis in the absence of typical histological signs suggestive of steatohepatitis who meet at least one of the following criteria: past or present evidence of metabolic risk factors that meet the criteria to diagnose MAFLD, as described above (Box 1) with at least one of the following i) documentation of MAFLD on a previous liver biopsy, ii) historical documentation of steatosis by hepatic imaging (Box 2). Notably, a history of past alcohol intake should be considered as patients may have a dual disease aetiology with alcohol use disorder, as detailed below.
      Criteria for a diagnosis of MAFLD-related cirrhosis.
      Tabled 1
      ∗History of past alcohol intake should be considered as patients may have a dual disease aetiology with alcohol use disorder. MAFLD, metabolic dysfunction-associated fatty liver disease.

       Rationale

      Growing evidences suggests that “cryptogenic cirrhosis” and “MAFLD cirrhosis” are two distinct entities that have different liver-related outcomes and should not be lumped together.
      • Thuluvath P.J.
      • Kantsevoy S.
      • Thuluvath A.J.
      • Savva Y.
      Is cryptogenic cirrhosis different from NASH cirrhosis?.
      • Caldwell S.
      • Marchesini G.
      Cryptogenic vs. NASH-cirrhosis: the rose exists well before its name….
      • Younossi Z.
      • Stepanova M.
      • Sanyal A.J.
      • Harrison S.A.
      • Ratziu V.
      • Abdelmalek M.F.
      • et al.
      The conundrum of cryptogenic cirrhosis: adverse outcomes without treatment options.
      In some patients with cirrhosis from fatty liver disease, steatosis may be absent. However, these patients should be considered as part of the spectrum of MAFLD as they have the same risk factors for liver disease as patients with typical MAFLD-related cirrhosis and therefore likely the same pathogenic drivers of metabolic dysfunction. Most likely, these patients are simply diagnosed at a later stage when typical histological signs of steatosis, inflammation and hepatocyte injury have vanished.

      Dual aetiology: concomitant MAFLD with other liver diseases

       Suggestion

      Exclusion of alcohol-associated fatty liver disease (ALD) based on current criteria for alcohol use disorder,
      • Singal A.K.
      • Bataller R.
      • Ahn J.
      • Kamath P.S.
      • Shah V.H.
      ACG clinical guideline: alcoholic liver disease.
      viral infections (HIV, HBV or HCV), drug-induced liver injury, autoimmune hepatitis either at baseline or at follow-up is not a prerequisite for diagnosis. Patients who meet the criteria to diagnose MAFLD as described above and who also have one of these concomitant conditions should be defined as having dual (or more) aetiology fatty liver disease
      • Boyle M.
      • Masson S.
      • Anstee Q.M.
      The bidirectional impacts of alcohol consumption and the metabolic syndrome: Cofactors for progressive fatty liver disease.
      (Box 3).
      Dual aetiology fatty liver disease (concomitant MAFLD and other liver disease).
      Tabled 1
      ∗These thresholds are derived from quantities beyond which a person is at more risk for alcohol related liver disease and may be in excess of the quantity needed to modify disease progression in MAFLD. This requires further study. MAFLD, metabolic dysfunction-associated fatty liver disease.

       Rationale

      With the dramatic rise in the global prevalence of MAFLD, it can and frequently does coexist with other conditions such as viral hepatitis and ALD.
      • Brunt E.M.
      • Ramrakhiani S.
      • Cordes B.G.
      • Neuschwander-Tetri B.A.
      • Janney C.G.
      • Bacon B.R.
      • et al.
      Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease.
      • Sanchez-Munoz D.
      • Castellano-Megias V.M.
      • Romero-Gomez M.
      Histologic features of steatohepatitis in patients with a clinical diagnosis of autoimmune cholestasis.
      • Cotrim H.P.
      • Andrade Z.A.
      • Parana R.
      • Portugal M.
      • Lyra L.G.
      • Freitas L.A.
      Nonalcoholic steatohepatitis: a toxic liver disease in industrial workers.
      These individuals likely have a different natural history and response to therapy
      • De Luca-Johnson J.
      • Wangensteen K.J.
      • Hanson J.
      • Krawitt E.
      • Wilcox R.
      Natural history of patients presenting with autoimmune hepatitis and coincident nonalcoholic fatty liver disease.
      • Choi H.S.
      • Brouwer W.P.
      • Zanjir W.M.
      • de Man R.A.
      • Feld J.J.
      • Hansen B.E.
      • et al.
      Non-Alcoholic steatohepatitis is associated with liver-related outcomes and all-cause mortality in chronic hepatitis B.
      • Chiang D.J.
      • McCullough A.J.
      The impact of obesity and metabolic syndrome on alcoholic liver disease.
      than those with liver disease of a single aetiology. Moreover, the currently recommended cut-offs to define significant alcohol consumption, or the duration of alcohol withdrawal that constitutes abstinence, in those with suspected MAFLD are arbitrary.
      • Ajmera V.H.
      • Terrault N.A.
      • Harrison S.A.
      Is moderate alcohol use in nonalcoholic fatty liver disease good or bad? A critical review.
      Adding to the complexity, the low reliability of the current diagnostic methods, such as patient interviews and serum biomarkers, the fact that patients usually underestimate their alcohol consumption, and the lack of standardisation of terminology such as “social” and “binge” drinking
      • Ceballos N.
      • Babor T.F.
      Editor's corner: binge drinking and the evolving language of alcohol research.
      renders it hard to ascertain true alcohol consumption and its long-term impact on liver disease. We believe that the greatest benefit of a dual aetiology criterion compared with previous guidelines is that MAFLD will no longer be a diagnosis of exclusion. Instead, exclusion of significant alcohol intake through patient interviews will aid in diagnosis but will not be required, as dual aetiology fatty liver disease is possible and even frequent.
      • Boyle M.
      • Masson S.
      • Anstee Q.M.
      The bidirectional impacts of alcohol consumption and the metabolic syndrome: Cofactors for progressive fatty liver disease.

       Disease subphenotyping

      MAFLD may, in the future, be subclassified based on new knowledge that might indicate the predominant pathophysiological pathway that drives the development of a morphologically limited set of histological features (steatosis, ballooning, inflammation and fibrosis) but which leads to different clinical outcomes. Such subclassification will be particularly valuable for MAFLD given its substantial heterogeneity.
      • Cespiati A.
      • Youngson N.A.
      • Tourna A.
      • Valenti L.
      Genetics and epigenetics in the clinic: precision medicine in the management of fatty liver disease.
      • Eslam M.
      • George J.
      Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology.
      • Eslam M.
      • Valenti L.
      • Romeo S.
      Genetics and epigenetics of NAFLD and NASH: clinical impact.
      Thus, while we suggest the umbrella term MAFLD, it is in the knowledge that further subclassification will likely ensue. Subclassification for example may encompass the role of genetic variants such as patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), membrane bound O-acyltransferase domain-containing 7 (MBOA7) and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), and epigenetic or other modifiers of disease. This recognises the fact that MAFLD represents a complex disease trait that may be influenced by a range of independent modifiers that individually may be insufficient to cause disease, as recently reviewed.
      • Eslam M.
      • Sanyal A.J.
      • George J.
      MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.
      ,
      • Eslam M.
      • George J.
      Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology.
      A likely consequence of implementing the proposed diagnostic criteria for MAFLD will be to highlight a new category of fatty liver disease, including a relative minority of patients previously deemed as affected by NAFLD that is not MAFLD, and cannot be attributed to alcohol or other known causes.
      • Chen F.
      • Esmaili S.
      • Rogers G.
      • Bugianesi E.
      • Petta S.
      • Marchesini G.
      • et al.
      Lean NAFLD: a distinct entity shaped by differential metabolic adaptation.
      ,
      • Fracanzani A.L.
      • Petta S.
      • Lombardi R.
      • Pisano G.
      • Russello M.
      • Consonni D.
      • et al.
      Liver and cardiovascular damage in patients with lean nonalcoholic fatty liver disease, and association with visceral obesity.
      This may foster new discoveries into the causes, mechanisms, classification and treatment of fatty liver disease.

      Alternative causes of fatty liver disease

       Suggestion

      We suggest that the terms “primary” and “secondary” hepatic steatosis are avoided because all pathological processes are secondary. Instead, we propose use of “alternative causes” of fatty liver disease to describe the latter that includes conditions such as: medications (corticosteroids, valproic acid, tamoxifen, methotrexate, and amiodarone), coeliac disease, starvation, total parenteral nutrition, severe surgical weight loss or disorders of lipid metabolism (abetalipoproteinemia, hypobetalipoproteinemia, lysosomal acid lipase deficiency, familial combined hyperlipidaemia, lipodystrophy, Weber–Christian syndrome, glycogen storage disease, Wilson disease). These may be associated with metabolic dysfunction (MAFLD) or be present with other triggers of less frequent forms of fatty liver disease.

       Rationale

      The classification of steatosis into primary and secondary is misleading, anachronistic, and indeed does not consider that hepatic steatosis >5% is not physiological and must be secondary to dysfunction of multiple pathways regulating lipid entry, synthesis and oxidation, and excretion. The term “alternative causes” of hepatic steatosis recognises the existence of these less frequent causes of steatosis while acknowledging that MAFLD represents the overwhelming majority of cases of hepatic steatosis seen in clinical practice.

      The distinction between diagnostic criteria and inclusion criteria for clinical trials

      Diagnostic criteria for clinical purposes in any disease or syndrome are distinct from inclusion criteria for clinical studies or trials, at least regarding their intended purpose (Table S1). Diagnostic criteria generally are a set of symptoms, signs and tests used in routine clinical care to broadly reflect the features of a disease. The aim is to identify individuals with the condition as accurately as possible, in order to guide their management. By contrast, inclusion criteria for trials or studies are the main attributes of a study target population that the investigators will utilise to address their research question.
      • Hulley S.B.
      Designing Clinical Research.
      The differences between diagnostic and inclusion criteria will depend on a variety of factors, including the study or trial design, as well as drugs' specific mechanisms of action, but not necessarily on clinical features of patients presenting to the clinics. Thus, setting definitions for MAFLD based on “positive” criteria and the exclusion of patients with fatty liver unrelated to metabolic dysfunction (with fatty liver but not MAFLD) will render study cohorts more homogeneous, thereby increasing the likelihood of detecting a significant impact of clinical approaches targeting MAFLD.
      Every clinical trial poses a unique set of requirements/criteria (inclusions/exclusions) for participating individuals. In this context, the decision to include patients with dual aetiology (e.g., those with MAFLD and alcohol intake, irrespective of the amount of alcohol that is allowed, current or past alcohol consumption etc.) is dependent entirely on the clinical trial designer. In trials seeking to test the mechanism of action of a drug for example, more stringent inclusion criteria might be necessary. These considerations in no way detract from the conduct of the trial, nor does it affect the diagnostic criteria proposed for MAFLD. The analogous situation is evident in viral hepatitis in which patient recruitment for treatment trials required the presence of viraemia but also included various limits of alcohol intake or undertook analyses based on insulin resistance criteria.
      Multiple recent reports suggest that enrolling patients for MAFLD clinical trials is particularly challenging, with various pharmaceutical companies having to delay or scale back ongoing trials due to recruitment difficulties. However, rather than simply adding more sites, innovative strategies could help to expedite recruitment. Based on the conceptualised diagnostic criteria above and the reality of the real-world patient landscape, we need to consider a more pragmatic approach to target patients with MAFLD, potentially with a higher threshold of alcohol intake than currently used. Furthermore, with the very high prevalence of MAFLD and alcohol intake worldwide, the relatedness between any current study population and real-world populations is of concern. Indeed, hepatology faces unique challenges in discriminating between pure alcohol-associated and pure metabolic dysfunction-associated disorders with similar manifestations and overlapping features. Lessons can be learned from the viral hepatitis field, with direct-acting antivirals leading to revolutionary changes such that clinical trials moved to explore the benefit of therapy in HIV/HCV-coinfected patients and in subgroups with mixed cryoglobulinemia.

      Conclusion

      In this consensus, an international panel of experts propose clear and simple criteria for a diagnosis of MAFLD that shifts it from a disease of exclusion to one of inclusion. The diagnosis is based on recognition of underlying abnormalities in metabolic health with acceptance that MAFLD may commonly coexist with other conditions (Fig. 1). We believe that the proposed diagnostic criteria are novel and practical. Future research will involve an iterative process of clinical validation of the criteria in prospective studies, confirming the feasibility of the criteria to level the clinical trial recruitment field and most importantly, utility in routine clinical practice. We acknowledge that other initiatives are required to subphenotype patients with MAFLD, and fatty liver disease in general, in order to drive precision patient management and create effective pathways between primary care and liver clinics. Finally, reaching consensus on the criteria for MAFLD will also help unify the terminology (e.g. for ICD-coding), to enhance the legitimacy of clinical practice and clinical trials, to improve clinical care and to move the clinical and scientific field of hepatology forward.

       Abbreviations

      ALD, alcohol-associated fatty liver disease; BMI, body mass index; FLI, fatty liver index; HbA1c, glycated haemoglobin; MAFLD, metabolic dysfunction-associated fatty liver disease; MHO, metabolically healthy obesity; MRS, magnetic resonance spectroscopy; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis; T2DM, type 2 diabetes mellitus.

      Financial support

      ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant ( APP1053206 , APP1149976 ) and Project grants ( APP1107178 and APP1108422 ). PNN is supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham . The views expressed are those of the authors and not necessarily those of the NIHR, the Department of Health and Social Care or the NHS.

      Authors' contributions

      ME, PNM, SKS, QMS,GT, MRG, SZS, VWS, JFD, JS,TK, MA, LV, GS, CT, HYJ, JGF,HG, YY, HCP, CPO,PB, LA,MHZ,YF,WKC, NMS, SHA, LC, EB, VR, JG, contributed to conceptualisation and the writing of the manuscript.

      Conflicts of interest

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

      Supplementary data

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      Linked Article

      • Letter regarding “A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement”
        Journal of HepatologyVol. 73Issue 6
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          We read with great interest the paper published in Journal of Hepatology by Eslam et al.,1 which we feel is particularly relevant to hepatologists who manage patients with non-alcoholic fatty liver disease (NAFLD), a disease now advocated to be redefined as metabolic dysfunction-associated fatty liver disease (MAFLD). With the rising prevalence of MAFLD, we increasingly encounter patients with heterogeneous clinical profiles – from simple excessive hepatic fat detected on imaging, to steatohepatitis or even cirrhosis.
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      • Blood biomarkers for the diagnosis of hepatic steatosis in metabolic dysfunction-associated fatty liver disease
        Journal of HepatologyVol. 73Issue 5
        • Preview
          Recently, Eslam et al.1 published an international expert consensus statement on a new definition of metabolic dysfunction-associated fatty liver disease (MAFLD) to replace non-alcoholic fatty liver disease (NAFLD). In this statement, new diagnostic criteria for MAFLD were proposed, in which hepatic steatosis (HS) detected either by imaging techniques, blood biomarkers/scores or by liver histology was the first step in the diagnostic flowchart. Serum biomarkers of HS such as fatty liver index2,3 (FLI, an algorithm based on body mass index, waist circumference, triglyceride level and gamma glutamyltransferase level) were mentioned in this statement, although their diagnostic cut-off values were not discussed.
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      • Capturing patient experience: A qualitative study of change from NAFLD to MAFLD real-time feedback
        Journal of HepatologyVol. 74Issue 5
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          We read with great interest the recent influential article by Eslam et al. suggesting the shift in nomenclature from non-alcoholic fatty liver diseases to metabolic dysfunction-associated fatty liver disease (MAFLD) and introducing, for the first time, positive diagnostic criteria;1,2 a proposal that seems to be gaining momentum.3–7
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      • Reply to: correspondence regarding “A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement”: Bringing evidence to the NAFLD-MAFLD debate
        Journal of HepatologyVol. 73Issue 6
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          We thank Mak et al.,1 and Zheng et al.,2 for their interest and comments on our work.3 Mak et al. suggest that the diagnostic criteria for metabolic dysfunction-associated fatty liver disease (MAFLD) are highly relevant to daily clinical practice. This is because of clear evidence of the high prevalence of MAFLD in patients with chronic hepatitis B (CHB) reported in their study using the new MAFLD criteria. Importantly, the new definition was superior to the old non-alcoholic fatty liver disease (NAFLD) criteria for identifying patients with more severe liver injury (steatosis, fibrosis and elevated liver enzymes).
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      • Non-alcoholic fatty liver disease: Not time for an obituary just yet!
        Journal of HepatologyVol. 74Issue 4
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          There has been a concerted effort to change the nomenclature of non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD), and one wonders if it is appropriate and timely to bid adieu to the good old term. Numerous reasons have been put forth to justify this, as outlined in a recently published statement proposing the change.1,2 However, there are considerable flaws in the proposal, and changing NAFLD to MAFLD is unlikely to move the field forward.
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      • Redefinition of fatty liver disease from NAFLD to MAFLD raised disease awareness: Mexican experience
        Journal of HepatologyVol. 75Issue 1
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          Non-alcoholic fatty liver disease (NAFLD) is defined as excess hepatic fat accumulation after the exclusion of heavy alcohol use or other secondary causes of steatosis. In 2018, it was estimated that NAFLD affects about the 25% of the world population, with the highest prevalence in South America (32%).1 Worryingly, it has been estimated that liver deaths related to NAFLD will increase by 178% by 2030,1 with no approved drug treatment to date. Thus, NALFD represents a burden to health and economic systems in all societies.
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      • Insights into contribution of genetic variants towards the susceptibility of MAFLD revealed by the NMR-based lipoprotein profiling
        Journal of HepatologyVol. 74Issue 4
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          A new definition of metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed by a panel of international experts from 22 countries.1 The diagnostic criteria for MAFLD are based on evidence of hepatic steatosis detected using imaging techniques, blood biomarkers/scores and/or liver histology, in addition to one of the following conditions: overweight/obesity, presence of type 2 diabetes, or evidence of metabolic dysregulation.1 Compared with the diagnostic criteria of non-alcoholic fatty liver disease (NAFLD),2 the definition of MAFLD excluded patients with fatty liver unrelated to metabolic dysfunction but included a large number of patients with concomitant metabolic fatty liver and other known liver diseases.
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      • Yet more evidence that MAFLD is more than a name change
        Journal of HepatologyVol. 74Issue 4
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          In their elegant study in 4,653 Chinese patients, Xia et al.1 provide robust evidence that the presence of metabolic dysfunction, including but not limited to adiposity, is a prerequisite for the deleterious impacts of the PNPLA3 rs738409 and TM6SF2 rs58542926 risk alleles on hepatic steatosis and lipoprotein profiles. They conclude that the MAFLD definition has dual advantages compared to the old NAFLD definition: i) it better captures the population who would benefit from an evaluation of genetic risks for fatty liver and ii) it overcomes the issue that the role of the variants was easy to neglect in those with alcoholic fatty liver disease/viral hepatitis etc., under the NAFLD definition.
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      • Clinical utility of the MAFLD definition
        Journal of HepatologyVol. 74Issue 4
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          There is currently robust discussion regarding the newly proposed metabolic dysfunction-associated fatty liver disease (MAFLD) definition.1 As compared to its predecessor – non-alcoholic fatty liver disease (NAFLD), MAFLD is a diagnosis of inclusion relying on a set of metabolic risk factors and the presence of hepatic steatosis.2–5 There is evidence in epidemiology studies of discrepancies between the two definitions.6–8 However, no studies have examined the two definitions in well-defined clinical cohorts.
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      • MAFLD: A holistic view to redefining fatty liver disease
        Journal of HepatologyVol. 74Issue 4
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          We thank Poniachik et al.,1 and Moreno et al.,2 for their interest in our work3,4 and acknowledging its multiple positive attributes. As they indicate, this includes the adoption of metabolic dysfunction-associated fatty liver disease (MAFLD) as an apt term reflecting the undisputed role of metabolic dysfunction in pathogenesis, and diagnostic criteria based on specific inclusions and not the absence of other diseases. The authors suggest that the consensus helps physicians to identify and treat all risk factors in those with chronic liver disease and through this, enables holistic care, clinical research and the development of public health prevention policies.
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      • MAFLD: A game changer redefining fatty liver disease for adults and children
        Journal of HepatologyVol. 74Issue 4
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          We thank Zheng et al.,1 Hegarty et al.,2 and Baffy3 for their interest in our work4,5 and acknowledging its multiple positive attributes.
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      • A new definition for non-alcoholic fatty liver disease
        Journal of HepatologyVol. 74Issue 4
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          We read with great interest the article "A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement" by Eslam et al. published recently in Journal of Hepatology.1 We believe that the true epidemic of non-alcoholic fatty liver disease (NAFLD), which currently affects more than 25% of the world's population, certainly requires attention and decisions at multiple levels to bring it under control .2 Consistent with its importance, it seems necessary to start naming it with an inclusive criteria and not negation as we have been doing until today.
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      • Change from NAFLD to MAFLD increases the awareness of fatty liver disease in primary care physicians and specialists
        Journal of HepatologyVol. 74Issue 5
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          The recent landmark articles by Eslam et al1,2 have attracted substantial attention from various stakeholders.3–9 although concerns have been raised that such a change may lead to confusion, particularly among non-hepatologists.10
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      • “Dual aetiology fatty liver disease”: A recently proposed term associated with potential pitfalls
        Journal of HepatologyVol. 74Issue 4
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          We read with interest the manuscript entitled “A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement”, by Mohammed Eslam, Philip N Newsome and colleagues.1
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      • Hypertension in NAFLD: An uncontrolled burden
        Journal of HepatologyVol. 74Issue 5
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          With great interest we have read the recent consensus statement of Eslam et al. suggesting the redefinition of non-alcoholic fatty liver disease (NAFLD) to metabolic (dysfunction)-associated fatty liver disease (MAFLD).1 One of the proposed metabolic abnormalities within the diagnostic criteria is an office blood pressure (OBP) ≥130/85 mmHg, or antihypertensive drug treatment.1
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      • The sub-Saharan Africa position statement on the redefinition of fatty liver disease: From NAFLD to MAFLD
        Journal of HepatologyVol. 74Issue 5
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          We read with great interest the landmark consensus on the redefinition of fatty liver disease by Eslam et al. This includes a shift in nomenclature from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) as a more apt term, as well as the adoption of a set of simple and pertinent “positive” criteria to diagnose the disease, independent of alcohol intake or other liver diseases.1,2 These twin proposals provide a major advance in the conceptualisation of fatty liver diseases, but given the variation between different health systems, reaching a broad and global consensus is imperative.
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      • NAFLD to MAFLD in adults but the saga continues in children: an opportunity to advocate change
        Journal of HepatologyVol. 74Issue 4
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          We welcome the attempt by an international group of experts to assign a positive diagnosis, in metabolic dysfunction-associated fatty liver disease (MAFLD), to a heterogenous condition captured under the acronym non-alcoholic fatty liver disease (NAFLD).1 The authors point out that the definition applies to adults but children with fatty liver require their own consideration.
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      • Population-specific cut-off points of fatty liver index for the diagnosis of hepatic steatosis
        Journal of HepatologyVol. 75Issue 3
        • Preview
          Recently, metabolic dysfunction-associated fatty liver disease (MAFLD)1 was proposed by an international panel of experts from 22 countries to replace non-alcoholic fatty liver disease (NAFLD). In this statement,1 positive diagnostic criteria for MAFLD were proposed. In the diagnostic flowchart, the diagnosis of hepatic steatosis (HS) was the first step. Of the 3 methods highlighted for the diagnosis of HS, liver biopsy is the gold standard but invasive, abdominal ultrasonography is currently the most widely used first-line imaging technique,2 and fatty liver index (FLI) is the only blood biomarker mentioned, but no specific cut-off points were given.
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      • Is the name ‘NAFLD’ too big to fail? Let’s keep it for ‘nutrition-associated fatty liver disease’
        Journal of HepatologyVol. 74Issue 4
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          Recently, a panel of international liver experts from 22 countries proposed revising the current classification of NAFLD and using ‘positive’ criteria to define the disease .1 This new conceptual framework emphasizes the pathogenesis rooted in metabolic dysregulation, favors disease continuity rather than viewing it as a dichotomy between steatosis and steatohepatitis, and aims to bring clarity to the diagnostic criteria independent of other liver diseases. To highlight the importance of this sweeping initiative, the group also proposed to rename NAFLD to MAFLD, which stands for metabolic dysfunction-associated fatty liver disease.
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      • MAFLD: Now is the time to capitalize on the momentum
        Journal of HepatologyVol. 74Issue 5
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          We thank Abdel Alem et al.,1 Kasper et al.2 Fouad et al.3 and Spearman et al.4 for their interest in our work.5,6 Abdel Alem et al.1 report an important qualitative study that shows a high level of dissatisfaction among patients with the old acronym “NAFLD” and their strong preference for a name change to “MAFLD”. This study in concert with a recent statement by >30 patient advocacy associations led by the European Liver Patients' Association (ELPA) and associations across different disciplines from diabetes to renal medicine and obesity medicine, highlights the increasing traction that MAFLD has received.
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      • Reply to: Correspondence on “A new definition for metabolic associated fatty liver disease: an international expert consensus statement”: MAFLD: Moving from a concept to practice
        Journal of HepatologyVol. 73Issue 5
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          We thank Xu et al.,1 and Huang et al.,2 for their interest and comments on our work.3 In a cohort of 35,335 individuals with metabolic dysfunction-associated fatty liver disease (MAFLD), Xu and co-workers demonstrated the high diagnostic ability of fatty liver index as a marker for hepatic steatosis in patients with MAFLD. This is particularly useful when access to ultrasonography is limited. Huang and colleagues reported on a cohort of 13,083 patients from the NHANES III (National Health and Nutrition Examination Surveys) database.
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      • MAFLD criteria overlooks a number of patients with severe steatosis: Is it clinically relevant?
        Journal of HepatologyVol. 73Issue 5
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          Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new concept proposed in 2020.1 Unlike non-alcoholic fatter liver disease (NAFLD),2 the diagnosis of MAFLD requires the presence any of the following 3 metabolic risks, including overweight/obesity, presence of diabetes mellitus, and evidence of metabolic dysregulation.1,3 However, there are patients that have hepatic steatosis but no metabolic risk, who thus do not meet the diagnostic criteria of MAFLD. The clinical features and the management of this specific group of patients remain unclear.
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      • Validation of Baveno VI and expanded Baveno VI criteria to identify high-risk varices in patients with MAFLD-related compensated cirrhosis
        Journal of HepatologyVol. 73Issue 6
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          Metabolic dysfunction-associated fatty liver disease (MAFLD), as a new entity, is a highly prevalent disease affecting more than one-quarter of the world's population, and is the leading cause of chronic liver disease in the United States and Europe.1,2 We read with interest the recent article by Eslam and Newsome et al.,1 in which they proposed a new definition for MAFLD-related cirrhosis. MAFLD-related cirrhosis is the result of multiple etiological factors and complex interactions between metabolic dysfunction, poor lifestyle habits and diet, imbalanced microbiota and genetic predisposition.
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