MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease

Fatty liver associated with metabolic dysfunction is common, affects a quarter of the population, and has no approved drug therapy. Although pharmacotherapies are in development, response rates appear modest. The heterogeneous pathogenesis of metabolic fatty liver diseases and inaccuracies in terminology and definitions necessitate a reappraisal of nomenclature to inform clinical trial design and drug development. A group of experts sought to integrate current understanding of patient heterogeneity captured under the acronym nonalcoholic fatty liver disease (NAFLD) and provide suggestions on terminology that more accurately reflects pathogenesis and can help in patient stratification for management. Experts reached consensus that NAFLD does not reflect current knowledge, and metabolic (dysfunction) associated fatty liver disease "MAFLD" was suggested as a more appropriate overarching term. This opens the door for efforts from the research community to update the nomenclature and subphenotype the disease to accelerate the translational path to new treatments. Fatty liver associated with metabolic dysfunction is common, affects a quarter of the population, and has no approved drug therapy. Although pharmacotherapies are in development, response rates appear modest. The heterogeneous pathogenesis of metabolic fatty liver diseases and inaccuracies in terminology and definitions necessitate a reappraisal of nomenclature to inform clinical trial design and drug development. A group of experts sought to integrate current understanding of patient heterogeneity captured under the acronym nonalcoholic fatty liver disease (NAFLD) and provide suggestions on terminology that more accurately reflects pathogenesis and can help in patient stratification for management. Experts reached consensus that NAFLD does not reflect current knowledge, and metabolic (dysfunction) associated fatty liver disease "MAFLD" was suggested as a more appropriate overarching term. This opens the door for efforts from the research community to update the nomenclature and subphenotype the disease to accelerate the translational path to new treatments. Arun J. SanyalView Large Image Figure ViewerDownload Hi-res image Download (PPT)Jacob GeorgeView Large Image Figure ViewerDownload Hi-res image Download (PPT) Since the term nonalcoholic fatty liver disease (NAFLD) was coined by Ludwig and colleagues1Ludwig J. Viggiano T.R. McGill D.B. et al.Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.Mayo Clin Proc. 1980; 55: 434-438PubMed Google Scholar in 1980 to describe fatty liver disease arising in the absence of significant alcohol intake, the nomenclature and criteria for a diagnosis has not been revisited. Yet, this disease has risen in prevalence, with a major impact on clinical and economic burden to society, such that nearly 1 billion people globally are affected.2Younossi Z. Anstee Q.M. Marietti M. et al.Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.Nat Rev Gastroenterol Hepatol. 2018; 15: 11-20Crossref PubMed Scopus (531) Google Scholar Of concern, NAFLD is increasingly recognized and diagnosed in children and adolescents,3Wiegand S. Keller K.M. Robl M. et al.Obese boys at increased risk for nonalcoholic liver disease: evaluation of 16 390 overweight or obese children and adolescents.Int J Obes (Lond). 2010; 34: 1468-1474Crossref PubMed Scopus (71) Google Scholar and this, when paired with the intimately associated hepatic as well as cardiovascular and oncological sequlae,4Jepsen P. Vilstrup H. Mellemkjaer L. et al.Prognosis of patients with a diagnosis of fatty liver - A registry-based cohort study.Hepatogastroenterology. 2003; 50: 2101-2104PubMed Google Scholar,5Sorensen H.T. Mellemkjaer L. Jepsen P. et al.Risk of cancer in patients hospitalized with fatty liver - A Danish cohort study.J Clin Gastroenterol. 2003; 36: 356-359Crossref PubMed Scopus (0) Google Scholar places an enormous burden on individuals, families, and health care systems.6Younossi Z. Tacke F. Arrese M. et al.Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.Hepatology. 2019; 69: 2672-2682Crossref PubMed Scopus (80) Google Scholar The estimated annual medical costs directly attributable to NAFLD exceed €35 billion in 4 large European countries (United Kingdom, France, Germany, and Italy) and $100 billion in the United States.7Younossi Z.M. Blissett D. Blissett R. et al.The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe.Hepatology. 2016; 64: 1577-1586Crossref PubMed Scopus (274) Google Scholar Although reducing disease burden through prevention seems obvious, this has not been achieved. Further, although pharmacotherapies are expected to become available in the near future, none to date has been approved. Thus far, several phase 2b and phase 3 studies either have fallen short of meeting current required histologic endpoints, or have done so with a modest margin. Muted efficacy of various compounds in development are in part a reflection of the imprecise definitions and the lack of precision medicine including consideration of heterogeneity of the disease. Despite these alarming data, the nomenclature of the disease and the criteria for diagnosis have not been updated to reflect our expanding knowledge. The heterogeneity of the population with NAFLD with respect to its primary drivers and coexisting disease modifiers, represent an important impediment to the discovery of highly effective drug treatments. The phenotypic manifestation of fatty liver diseases likely reflects the sum of the dynamic and complex systems-level interactions of these drivers; it follows that effective treatment requires that they be targeted with precision, based on a person's phenotype and genetic background.8Friedman S.L. Neuschwander-Tetri B.A. Rinella M. et al.Mechanisms of NAFLD development and therapeutic strategies.Nat Med. 2018; 24: 908-922Crossref PubMed Scopus (211) Google Scholar,9Eslam M. George J. Genetic insights for drug development in NAFLD.Trends Pharmacol Sci. 2019; 40: 506-516Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar However, trial recruitment is currently based on histologic grading and staging, and that is a problem because many pathways lead to the same histologic phenotype, without dissection of the predominant pathogenic pathways.10Buzzetti E. Pinzani M. Tsochatzis E.A. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD).Metabolism. 2016; 65: 1038-1048Abstract Full Text Full Text PDF PubMed Google Scholar,11Skoien R. Richardson M.M. Jonsson J.R. et al.Heterogeneity of fibrosis patterns in non-alcoholic fatty liver disease supports the presence of multiple fibrogenic pathways.Liver Int. 2013; 33: 624-632Crossref PubMed Scopus (24) Google Scholar Perhaps not surprisingly, the response rates to current investigational agents range from 20% to 40% with a difference from placebo of 10% to 20%.8Friedman S.L. Neuschwander-Tetri B.A. Rinella M. et al.Mechanisms of NAFLD development and therapeutic strategies.Nat Med. 2018; 24: 908-922Crossref PubMed Scopus (211) Google Scholar Thus, a "one size fits all approach" would seem inappropriate when dealing with a very heterogeneous liver disease. From the patient's perspective, the term "nonalcoholic fatty liver disease" not only trivializes the problem by including terms such as "non," but is also pejorative, as it introduces words such as "alcoholic," potentially placing the blame on patients as having caused their condition. It also implies that the treatment must entirely lie in the patient's hand. This has enormous implications on how industry and policy makers choose to allocate resources for tackling the syndrome, which clearly is a major cause of death. Lessons can be learned from cardiologists, diabetologists, neurologists, and oncologists who have successfully distanced the disease they are trying to treat from the underlying obesity, smoking, alcohol abuse, and drug abuse. Some of these factors have high genetic predisposition. In support of this idea, a meeting organized by the European Liver Patient's Association with the European Commission in 2018 suggested that a change in nomenclature was one of their key requirements. As a first step to tackle this challenge, revising the nomenclature and definitions of the disease is critical. Recently, concerns over the inaccuracies of the nomenclature of fatty liver disease have been raised by individual experts.12Dufour J.F. Time to Abandon NASH?.Hepatology. 2016; 63: 9-10Crossref PubMed Scopus (4) Google Scholar, 13Bellentani S. Tiribelli C. Is it time to change NAFLD and NASH nomenclature?.Lancet Gastroenterol Hepatol. 2017; 2: 547-548Abstract Full Text Full Text PDF PubMed Google Scholar, 14Loria P. Lonardo A. Carulli N. Should nonalcoholic fatty liver disease be renamed?.Dig Dis. 2005; 23: 72-82Crossref PubMed Scopus (0) Google Scholar In prior work, we called for a consensus to consider these aspects,15Eslam M. Sanyal A.J. George J. Toward more accurate nomenclature for fatty liver diseases.Gastroenterology. 2019; 157: 590-593Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar and in this review, an international panel sought to integrate epidemiological knowledge about disease progression that includes steatosis and steatohepatitis associated with metabolic dysfunction, with information about risk prediction derived from genetic and phenotyping studies. We suggest a new nomenclature based on consensus voting by participants to describe the disease that will allow us to properly subphenotype and stratify patients, via the application of more precise genetic, anthropometric, and metabolic phenotyping approaches. In turn, detailed phenotyping will translate into individualized risk prediction and prevention strategies, and improvements in clinical trial design. Following discussions, an initial concept sheet was circulated to the panel of contributors. This revealed widespread agreement and consensus that it was time to revisit the nomenclature of metabolic fatty liver disease as a critical initial step for improved patient subphenotyping, clinical trials design, and ultimately, for personalization of medicine. Subsequently, a manuscript was drafted, circulated to the panel, and feedback incorporated over several rounds of revision. To reach consensus on a nomenclature, the Delphi method was adopted in 2 rounds. This method is a recommended iterative process for use in the health care setting as a reliable means to solicit and distil the judgments of experts and to determine consensus via a systematic progression of repeated rounds of voting.16Dalkey N.C. Studies in the Quality of Life; Delphi and Decision-Making. Lexington Books, Lexington, MA1972Google Scholar A "closed" electronic survey URL was sent to participants providing a unique link that could be used only once. Survey data were collected and managed using REDCap (Research Electronic Data Capture). In the first round of surveys members suggested 1 or more terms to describe metabolic fatty liver disease. In a second round (based on a summary of the experts' suggestions), participants were asked to vote on the suggested terminology. To ensure a robust and transparent process, anonymity of the participants was maintained. We now recognize that metabolic fatty liver disease is a phenotype with complex and disparate causes; the current terminology (NAFLD) represents an umbrella term for the multiple underlying subtypes.17Yki-Jarvinen H. Luukkonen P.K. Heterogeneity of non-alcoholic fatty liver disease.Liver Int. 2015; 35: 2498-2500Crossref PubMed Google Scholar,18Lonardo A. Ballestri S. Targher G. "Not all forms of NAFLD were created equal." Do metabolic syndrome-related NAFLD and PNPLA3-related NAFLD exert a variable impact on the risk of early carotid atherosclerosis?.Atherosclerosis. 2017; 257: 253-255Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar This is evidenced by the wide spectrum of disease severity and natural history, as well as the substantial interpatient variability across the spectrum. Although hepatic steatosis is highly prevalent, only a minority exhibit inflammatory injury at any time; more importantly, an individual can oscillate between steatosis and steatohepatitis even over a short timeframe.19Adams L.A. Lymp J.F. St Sauver J. et al.The natural history of nonalcoholic fatty liver disease: a population-based cohort study.Gastroenterology. 2005; 129: 113-121Abstract Full Text Full Text PDF PubMed Scopus (1874) Google Scholar In addition, although there is convincing evidence that liver-related complications (ie, cirrhosis and cancer) are more likely in those with steatohepatitis, progression is far from inevitable.19Adams L.A. Lymp J.F. St Sauver J. et al.The natural history of nonalcoholic fatty liver disease: a population-based cohort study.Gastroenterology. 2005; 129: 113-121Abstract Full Text Full Text PDF PubMed Scopus (1874) Google Scholar, 20Angulo P. Kleiner D.E. Dam-Larsen S. et al.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397.e10Abstract Full Text Full Text PDF PubMed Scopus (778) Google Scholar, 21Vilar-Gomez E. Calzadilla-Bertot L. Wong V.W.S. et al.Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.Gastroenterology. 2018; 155: 443-457.e17Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Further, there is growing evidence that hepatocellular carcinoma can develop in a fatty liver in the absence of cirrhosis.22Mittal S. El-Serag H.B. Sada Y.H. et al.Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2016; 14: 124-131.e1Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar Even among those with steatohepatitis, there appear to be individuals with apparent rapid-fibrosis progression and those with inherently slow-fibrosis progression.23Singh S. Allen A.M. Wang Z. et al.Fibrosis progression in nonalcoholic fatty liver versus nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.Gastroenterology. 2014; 146: S947-S948Abstract Full Text PDF Google Scholar Finally, disease evolution can be modified by exogenous interventions (for instance, lifestyle changes),24Vilar-Gomez E. Martinez-Perez Y. Calzadilla-Bertot L. et al.Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.Gastroenterology. 2015; 149: 367-378.e5Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar superimposed disease states (eg, type 2 diabetes mellitus),25Loomba R. Abraham M. Unalp A. et al.Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.Hepatology. 2012; 56: 943-951Crossref PubMed Scopus (204) Google Scholar inherited predisposition,26Pelusi S. Cespiati A. Rametta R. et al.Prevalence and risk factors of significant fibrosis in patients with nonalcoholic fatty liver without steatohepatitis.Clin Gastroenterol Hepatol. 2019; 17: 2310-2319.e6Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar and can even "spontaneously" regress, as has been demonstrated in placebo group participants in treatment trials and by observational dual-biopsy studies in secondary/tertiary care settings.23Singh S. Allen A.M. Wang Z. et al.Fibrosis progression in nonalcoholic fatty liver versus nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.Gastroenterology. 2014; 146: S947-S948Abstract Full Text PDF Google Scholar,27Han M.A.T. Altayar O. 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For example, given the rapidly escalating prevalence of metabolic fatty liver disease in children and young adolescents, we still do not understand if their natural history follows a different trajectory from those who develop disease in adulthood, middle age, or even old age.29Nobili V. Alisi A. Valenti L. et al.NAFLD in children: new genes, new diagnostic modalities and new drugs.Nat Rev Gastroenterol Hepatol. 2019; 16: 517-530Crossref PubMed Scopus (8) Google Scholar The heterogeneity in clinical presentation and disease course of fatty liver disease is likely influenced by multiple factors, including age, gender, hormonal status, ethnicity, diet, alcohol intake, smoking, genetic predisposition, the microbiota, and metabolic status. Thus, the final outcome will reflect the balance of these diverse inputs, each interacting with the other and modifying the ultimate manifestations and clinical course (Figure 1). It follows that effective treatment will require systematic dissection of the pathways involved and likely multifaceted and personalized treatments.30Mardinoglu A. Uhlen M. Boren J. Broad Views of non-alcoholic fatty liver disease.Cell Syst. 2018; 6: 7-9Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,31Pirola C.J. Sookoian S. Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity.World J Gastroenterol. 2018; 24: 1601-1615Crossref PubMed Scopus (1) Google Scholar A brief summary of current knowledge about factors contributing to NAFLD heterogeneity is provided below. NAFLD prevalence, the risk of hepatic and extrahepatic complications, and the likelihood of overall and disease-specific mortality increases with advancing age.19Adams L.A. Lymp J.F. St Sauver J. et al.The natural history of nonalcoholic fatty liver disease: a population-based cohort study.Gastroenterology. 2005; 129: 113-121Abstract Full Text Full Text PDF PubMed Scopus (1874) Google Scholar,21Vilar-Gomez E. Calzadilla-Bertot L. Wong V.W.S. et al.Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.Gastroenterology. 2018; 155: 443-457.e17Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar,32Ong J.P. Pitts A. Younossi Z.M. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease.J Hepatol. 2008; 49: 608-612Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar,33Frith J. Day C.P. Henderson E. et al.Non-alcoholic fatty liver disease in older people.Gerontology. 2009; 55: 607-613Crossref PubMed Scopus (107) Google Scholar With aging, substantial changes occur in the liver, including a decline in hepatic blood flow, hepatic volume, and liver function, a reduction in bile acid synthesis and alterations in cholesterol metabolism, as well as a reduction in mitochondrial number with subsequent increases in oxidative respiration.34Frith J. Jones D. Newton J.L. Chronic liver disease in an ageing population.Age Ageing. 2009; 38: 11-18Crossref PubMed Scopus (53) Google Scholar Cellular senescence has also been implicated.35Donati B. Telomeres V.L. NAFLD and chronic liver disease.Int J Mol Sci. 2016; 17: 383Crossref PubMed Scopus (0) Google Scholar,36Papatheodoridi A.M. Chrysavgis L. 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The metabolic syndrome: how definition impacts the prevalence and risk in US adults: 1999–2004 NHANES.Metab Syndr Relat Disord. 2007; 5: 331-342Crossref PubMed Scopus (0) Google Scholar Emerging evidence suggests that sarcopenia is associated with both NAFLD and NAFLD-related advanced fibrosis, even after adjusting for body mass index (BMI) and insulin resistance.39Lee Y.H. Jung K.S. Kim S.U. et al.Sarcopaenia is associated with NAFLD independently of obesity and insulin resistance: Nationwide surveys (KNHANES 2008–2011).J Hepatol. 2015; 63: 486-493Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar,40Lee Y.H. Kim S.U. Song K. et al.Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: nationwide surveys (KNHANES 2008–2011).Hepatology. 2016; 63: 776-786Crossref PubMed Scopus (74) Google Scholar Presumably, aging also captures greater exposure to the drivers, which result in steatohepatitis and fibrosis. Equally, as recently reviewed,41Lonardo A. Nascimbeni F. Ballestri S. et al.Sex differences in NAFLD: state of the art and identification of research gaps.Hepatology. 2019; 70: 1457-1469Crossref PubMed Scopus (17) Google Scholar there is substantial sexual dimorphism in many aspects of fatty liver disease with regard to risk factors, prevalence, fibrosis pattern, and disease outcomes. Generally, prevalence tends to be lower in women predominantly at earlier disease stages, whereas disease frequency increases in postmenopausal women.41Lonardo A. Nascimbeni F. Ballestri S. et al.Sex differences in NAFLD: state of the art and identification of research gaps.Hepatology. 2019; 70: 1457-1469Crossref PubMed Scopus (17) Google Scholar Similarly, fatty liver prevalence is lower in post-menarchal girls than in boys.42Anderson E.L. Howe L.D. Jones H.E. et al.The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis.PLoS One. 2015; 10e0140908Crossref PubMed Scopus (179) Google Scholar Among postmenopausal women, those not on hormone replacement therapy tend to have higher disease prevalence compared with those on hormone replacement therapy,43Clark J.M. Brancati F.L. Diehl A.M. Nonalcoholic fatty liver disease.Gastroenterology. 2002; 122: 1649-1657Abstract Full Text Full Text PDF PubMed Google Scholar and similarly, premenopausal women have less severe hepatic fibrosis and better survival compared with men and postmenopausal women.44Yang J.D. Abdelmalek M.F. Pang H. et al.Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis.Hepatology. 2014; 59: 1406-1414Crossref PubMed Scopus (96) Google Scholar,45Yang J.D. Suzuki A. The influence of menopause on the development of hepatic fibrosis in nonobese women with nonalcoholic fatty liver disease: reply.Hepatology. 2014; 60: 1792-1793Crossref PubMed Scopus (0) Google Scholar Consistently, a longer duration of estrogen deficiency associates with a higher likelihood of fibrosis among postmenopausal women with fatty liver disease.46Klair J.S. Yang J.D. Abdelmalek M.F. et al.A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease.Hepatology. 2016; 64: 85-91Crossref PubMed Scopus (66) Google Scholar By analogy, studies of diet-induced mouse models suggests that males develop more severe steatosis and liver histology compared with females.47Norheim F. Hui S.T. Kulahcioglu E. et al.Genetic and hormonal control of hepatic steatosis in female and male mice.J Lipid Res. 2017; 58: 178-187Crossref PubMed Scopus (17) Google Scholar,48Ganz M. Csak T. Szabo G. High fat diet feeding results in gender specific steatohepatitis and inflammasome activation.World J Gastroenterol. 2014; 20: 8525-8534Crossref PubMed Scopus (57) Google Scholar Although the mechanisms for these effects are not completely understood, sex differences in adiposity, metabolic risk factors, and body fat distribution (which tends to shift toward abdominal obesity after menopause), likely play a role.49Lovejoy J.C. Champagne C.M. de Jonge L. et al.Increased visceral fat and decreased energy expenditure during the menopausal transition.Int J Obes (Lond). 2008; 32: 949-958Crossref PubMed Scopus (402) Google Scholar A recent study in mice from approximately 100 strains included in the hybrid mouse diversity panel demonstrated that multiple molecular pathways and gene networks implicated in lipid metabolism, insulin-signaling, and inflammation show sexual dimorphism.50Kurt Z. Barrere-Cain R. LaGuardia J. et al.Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease.Biol Sex Differ. 2018; 9: 46Crossref PubMed Scopus (5) Google Scholar Similarly, another study demonstrated sexual differences in liver gene expression of regulators of multiple metabolic pathways using a mice computational model. Notably, some such as peroxisome proliferator-activated receptor PPARα, farnesoid X receptor, and liver X receptor, which are highly gender dependent, are currently being investigated as therapeutic targets for steatohepatitis.51Tomas T.C. Urlep Z. Moskon M. et al.LiverSex computational model: sexual aspects in hepatic metabolism and abnormalities.Front Physiol. 2018; 9: 360Crossref PubMed Scopus (5) Google Scholar A further study demonstrated gender-related pathways contribute to steatosis and fibrosis in male and female mice (males mainly inflammation and females mainly alterations of redox state), despite similar endpoints.52Marin V. Rosso N. Dal Ben M. et al.An animal model for the juvenile non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.PLoS One. 2016; 11e0158817Crossref PubMed Scopus (14) Google Scholar Clearly, sex and menopausal status influence disease outcomes and require stratification as treatment responses can vary substantially. Population-based data show ethnic differences in the prevalence of fatty liver; a recent meta-analysis demonstrated both NAFLD prevalence and risk of nonalcoholic steatohepatitis (NASH) were highest in Hispanic individuals, intermediate in white individuals, and lowest in black individuals; however, fibrosis risk did not differ according to ethnicity.53Rich N.E. Oji S. Mufti A.R. et al.Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the United States: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2018; 16: 198-210.e2Abstract Full Text Full Text PDF PubMed Google Scholar Metabolic fatty liver disease is also rapidly increasing in Asian populations.54Zhou F. Zhou J. Wang W. et al.Unexpected rapid increase in the burden of nonalcoholic fatty liver disease in China From 2008 to 2018: a systematic review and meta-analysis.Hepatology. 2019; 70: 1119-1133Crossref PubMed Scopus (11) Google Scholar Previous studies have demonstrated that Asian individuals tend to accumulate liver fat at lower BMI compared with those of other races.55Weston S.R. Leyden W. Murphy R. et al.Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease.Hepatology. 2005; 41: 372-379Crossref PubMed Scopus (267) Google Scholar The course of disease also appears to be more severe in Asian compared with non-Asian individuals, and they tend to have more lobular inflammation and higher grades of ballooning compared with other ethnicities.56Mohanty S.R. Troy T.N. Huo D. et al.Influence of ethnicity on histological differences in non-alcoholic fatty liver disease.J Hepatol. 2009; 50: 797-804Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar,57Tabibian J.H. Lazo M. Durazo F.A. et al.Nonalcoholic fatty liver disease across ethno-racial groups: do Asian-American adults represent a new at-risk population?.J Gastroenterol Hepatol. 2011; 26: 501-509Crossref PubMed Scopus (11) Google Scholar Although data regarding fibrosis are scarce in the preceding studies, Asian individuals tended to have a higher risk of fibrosis, whereas African individuals were at lower risk compared with white individuals; this did not reach significance, perhaps due to sample size limitations.56Mohanty S.R. Troy T.N. Huo D. et al.Influence of ethnicity on histological differences in non-alcoholic fatty liver disease.J Hepatol. 2009; 50: 797-804Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar,57Tabibian J.H. Lazo M. Durazo F.A. et al.Nonalcoholic fatty liver disease across ethno-racial groups: do Asian-American adults represent a new at-risk population?.J Gastroenterol Hepatol. 2011; 26: 501-509Crossref PubMed Scopus (11) Google Scholar However, and notably, these biopsy-based studies might suffer from selection bias. For example, a community-based study in Hong Kong suggested that although NAFLD is detected in a quarter of the p