Special SectionA new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement
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[1], [2], [3] 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.4 In parallel, the prevalence of poor metabolic health in adults from affluent countries is high, even in normal weight individuals.5,6 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.1,7 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.8 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.5,[9], [10], [11], [12], [13], [14] 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.15
Section snippets
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.[15], [16], [17], [18] Herein we propose a set of new “positive” criteria for the diagnosis of MAFLD regardless of alcohol consumption or other concomitant liver diseases.
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.35 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
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
Suggestion
Exclusion of alcohol-associated fatty liver disease (ALD) based on current criteria for alcohol use disorder,46 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 disease47 (Box 3).
Rationale
With the dramatic rise in
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,
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
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
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
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.
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