Prognosis of MAFLD vs. NAFLD and implications for a nomenclature change

See Article, pages 1284–1291 See Article, pages 1284–1291 In 2020, 32 hepatologists from Europe, South America, North Africa and the Asia-Pacific region published a consensus statement proposing to rename non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease or metabolic-associated fatty liver disease (MAFLD), along with a new definition.[1]Eslam M. Newsome P.N. Sarin S.K. Anstee Q.M. Targher G. Romero-Gomez M. et al.A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement.J Hepatol. 2020; 73: 202-209Abstract Full Text Full Text PDF PubMed Scopus (764) Google Scholar Two articles in this issue of the Journal of Hepatology add to the ongoing debate on the new nomenclature.[2]Nan Y. An J. Bao J. Chen H. Chen Y. Ding H. et al.The Chinese Society of Hepatology position statement on the redefinition of fatty liver disease.J Hepatol. 2021; 75: 454-461Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,[3]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75: 1284-1291Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar In 1836, Thomas Addison first described fatty degeneration of the liver in patients who consumed excessive alcohol.[4]Addison T. Observations on fatty degeneration of the liver.Guys Hosp Rep. 1836; 1: 485Google Scholar It was not until the late 1970s that people became aware of a similar pathology in patients with the metabolic syndrome who consumed little or no alcohol. In 1980, Ludwig and colleagues coined the term non-alcoholic steatohepatitis (NASH),[5]Ludwig J. Viggiano T.R. McGill D.B. Oh B.J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.Mayo Clin Proc. 1980; 55: 434-438PubMed Google Scholar which has been widely adopted in the subsequent 40 years. Nowadays, NAFLD is used as the umbrella term encompassing the spectrum of disease ranging from non-alcoholic fatty liver or simple steatosis to NASH, with the latter associated with faster fibrosis progression and a higher risk of liver-related complications.[6]Singh S. Allen A.M. Wang Z. Prokop L.J. Murad M.H. Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.Clin Gastroenterol Hepatol. 2015; 13 (643-654 e641-649; quiz e639-640)Abstract Full Text Full Text PDF Scopus (728) Google Scholar Although the hepatology community is familiar with these terminologies, there are notable deficiencies in the original nomenclature.[7]Wai-Sun Wong V. Kanwal F. On the proposed definition of metabolic-associated fatty liver disease.Clin Gastroenterol Hepatol. 2021; 19: 865-870Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar The term NAFLD does not highlight insulin resistance and metabolic disorders as the major underlying cause of fatty liver development. The “non-” prefix is sometimes used in medicine to describe a minor condition and distinguish it from a more important disorder. In the case of NAFLD – the most common cause of chronic liver disease affecting an estimated quarter of the global adult population – this is a largely unhelpful construction that also contributes to trivialising the condition. By excluding other liver diseases, the negative diagnostic criteria also reinforce the problem of stating what NAFLD is not, but not what it is. Several professional organisations have endorsed a call to adopt MAFLD as the accepted term. In 2020, the Asian Pacific Association for the Study of the Liver became the first to publish guidelines on the management of MAFLD.[8]Eslam M. Sarin S.K. Wong V.W. Fan J.G. Kawaguchi T. Ahn S.H. et al.The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease.Hepatol Int. 2020; 14: 889-919Crossref PubMed Scopus (144) Google Scholar In this issue, Nan and colleagues publish the Chinese Society of Hepatology position statement on the redefinition of fatty liver disease.[2]Nan Y. An J. Bao J. Chen H. Chen Y. Ding H. et al.The Chinese Society of Hepatology position statement on the redefinition of fatty liver disease.J Hepatol. 2021; 75: 454-461Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar The key statements, based on the voting results of 76 experts in hepatology, gastroenterology, infectious diseases and pathology, include: i) endorsement of the new term MAFLD; ii) official Chinese translation of MAFLD as 代谢相关脂肪性肝病; iii) positive criteria to define MAFLD; and iv) abandoning the terms “NASH”, “cryptogenic cirrhosis” and “secondary” fatty liver. Although the Chinese Society of Hepatology collected opinions from 76 experts, with a high level of agreement, the respondents were mostly academic researchers and might not be representative of clinicians working across different settings. While we respect each professional society’s way of communication and data collection, ultimately, something as substantial as a name change is also an awareness-raising exercise. The Society needs to engage its members and other stakeholders and clearly explain not only their decision but also the reasons, implications and process undertaken to change the name. Nan and colleagues stated primary care, care continuum and holistic management as some of the key reasons for supporting the name change.[2]Nan Y. An J. Bao J. Chen H. Chen Y. Ding H. et al.The Chinese Society of Hepatology position statement on the redefinition of fatty liver disease.J Hepatol. 2021; 75: 454-461Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar For historical reasons, Chinese patients are free to choose where to receive management. Many prefer tertiary centres and believe specialist care is the best. However, as the prevalence of fatty liver and disease awareness increase, such a model will become inefficient and unsustainable. Both clinicians and patients should understand the multi-system nature of fatty liver disease. Unless a patient has already developed advanced liver disease, primary care physicians are often best suited to coordinate the management. That said, it remains to be seen how much the name change can contribute to improved care models. It is important to note that the renaming debate is not without controversies. Two editorials in the Journal of Hepatology and Hepatology last year described potential issues requiring further discussion.[9]Ratziu V. Rinella M. Beuers U. Loomba R. Anstee Q.M. Harrison S. et al.The times they are a-changin' (for NAFLD as well).J Hepatol. 2020; 73: 1307-1309Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar,[10]Younossi Z.M. Rinella M.E. Sanyal A.J. Harrison S.A. Brunt E.M. Goodman Z. et al.From NAFLD to MAFLD: implications of a premature change in terminology.Hepatology. 2021; 73: 1194-1198Crossref PubMed Scopus (107) Google Scholar One key argument is that the change in nomenclature may be confusing and jeopardise existing efforts to promote disease awareness among patients, policymakers and non-hepatologists. However, an article by representatives of patient advocacy groups from North America, Europe and Asia-Pacific expressed support for the new term and highlighted the risk of stigmatisation related to the word “alcoholic” in the original name.[11]Shiha G. Korenjak M. Eskridge W. Casanovas T. Velez-Moller P. Hogstrom S. et al.Redefining fatty liver disease: an international patient perspective.Lancet Gastroenterol Hepatol. 2021; 6: 73-79Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar The second point is that the term “metabolic-associated” remains vague, as other liver diseases such as Wilson’s disease are arguably also metabolic in nature. Authors of the Hepatology editorial suggest that the change in terminology “is justified when more scientific, complete understanding of its pathogenesis, and/or risk stratification, and/or molecular phenotyping, and/or novel precision medicine-based therapeutic approaches are elucidated”. In our opinion, this may not be a reasonable requirement. Science is always advancing; how and when can we declare to have a complete understanding of the pathogenesis of a disease? Moreover, while molecular phenotyping has and will continue to teach us a lot about the pathogenesis and management of fatty liver disease, this will unlikely be adopted in routine clinical practice, especially in non-hepatology settings where most people living with NAFLD are seen. A simple terminology will more likely facilitate case identification and multidisciplinary models of care.[12]Lazarus J.V. Anstee Q.M. Hagstrom H. Cusi K. Cortez-Pinto H. Mark H.E. et al.Defining comprehensive models of care for NAFLD.Nat Rev Gastroenterol Hepatol. 2021 Jun 25; https://doi.org/10.1038/s41575-021-00477-7Crossref PubMed Scopus (16) Google Scholar The third argument surrounds issues related to drug development. There are concerns that the change in terminology and definition will affect both patient recruitment and endpoint assessment, particularly resolution of NASH with no worsening of liver fibrosis, which is currently a key histological endpoint for conditional drug approval.[13]Wong V.W. Chitturi S. Wong G.L. Yu J. Chan H.L. Farrell G.C. Pathogenesis and novel treatment options for non-alcoholic steatohepatitis.Lancet Gastroenterol Hepatol. 2016; 1: 56-67Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar Adopting the term MAFLD involves not only a change of name but also of disease definition.[1]Eslam M. Newsome P.N. Sarin S.K. Anstee Q.M. Targher G. Romero-Gomez M. et al.A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement.J Hepatol. 2020; 73: 202-209Abstract Full Text Full Text PDF PubMed Scopus (764) Google Scholar NAFLD is defined as the presence of hepatic steatosis in patients without excessive alcohol consumption, concomitant liver diseases or secondary causes of fatty liver. The presence of metabolic risk factors is not mandatory. In contrast, MAFLD is defined as the presence of hepatic steatosis together with one or more of the following: (1) overweight or obesity; (2) type 2 diabetes; or (3) two or more other metabolic risk abnormalities. As a result, some patients who were previously classified as having “lean” NAFLD (normal body mass index) may not fulfil the criteria of MAFLD. On the other hand, patients with hepatic steatosis who were previously classified as not having NAFLD due to alcohol consumption (≥30 g/day in men or ≥20 g/day in women), other liver diseases, or secondary causes of fatty liver may nevertheless be diagnosed with MAFLD. Data from population studies suggest that the majority of patients with fatty liver would fulfil the definitions of both MAFLD and NAFLD, but up to 10-25% may only meet the criteria of one of the conditions.[14]Lin S. Huang J. Wang M. Kumar R. Liu Y. Liu S. et al.Comparison of MAFLD and NAFLD diagnostic criteria in real world.Liver Int. 2020; 40: 2082-2089Crossref PubMed Scopus (157) Google Scholar,[15]Wai-Sun Wong V. Lai-Hung Wong G. Woo J. Abrigo J.M. Ka-Man Chan C. She-Ting Shu S. et al.Impact of the new definition of metabolic associated fatty liver disease on the epidemiology of the disease.Clin Gastroenterol Hepatol. 2020 Oct 31; (S1542-3565(20)31504-4) (Online ahead of print)https://doi.org/10.1016/j.cgh.2020.10.046Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Chronic hepatitis B remains endemic in China and many other Asian and sub-Saharan African countries. Therefore, the use of MAFLD to describe patients with dual pathology is practical and appealing. If a patient has concomitant chronic hepatitis B and autoimmune liver disease, for example, both conditions would in theory be carefully documented and managed. In contrast, concomitant fatty liver in patients with chronic hepatitis B is often ignored. With accumulating data supporting a contribution of fatty liver and metabolic risk factors to disease progression and liver-related complications in patients with chronic hepatitis B, the MAFLD definition may facilitate a more comprehensive approach for such patients. Another common argument for MAFLD being the better definition is that the MAFLD criteria are more useful in identifying patients with future adverse clinical events than the NAFLD criteria. In this issue of the Journal of Hepatology, Kim and colleagues analyse data of the third National Health and Nutrition Examination Survey 1988-1994 cohort in the United States to examine the prognostic implications of the new MAFLD criteria.[3]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75: 1284-1291Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar The study included 7,761 community patients aged 20-74. Similar to previous findings, among 2,702 patients with fatty liver diagnosed by abdominal ultrasonography, 2,044 (75.6%) fulfilled both the MAFLD and NAFLD definitions, 212 (7.8%) only had MAFLD, 394 (14.6%) only had NAFLD, and 52 (1.9%) did not meet either definition. Using individuals without fatty liver as the reference group, those who had both MAFLD and NAFLD had increased overall mortality at a median follow-up of 23 years (adjusted hazard ratio [aHR] 1.13; 95% CI 1.00-1.26 in the fully adjusted model), but the highest risk of mortality was observed in the group that fulfilled the MAFLD definition alone (aHR 1.66; 95% CI 1.19-2.32). In comparison, the group that only fulfilled the NAFLD definition did not have increased mortality (aHR 0.94; 95% CI 0.60-1.46). Neither definition correlated with cardiovascular mortality, and only the MAFLD alone group had increased cancer mortality (aHR 1.95; 95% CI 1.05-3.62). The study by Kim and colleagues provides important data from the United States and adds to the current literature demonstrating that the MAFLD definition enriches a cohort with more advanced liver disease, cardiovascular risk, renal disease and increased mortality.16Yamamura S. Eslam M. Kawaguchi T. Tsutsumi T. Nakano D. Yoshinaga S. et al.MAFLD identifies patients with significant hepatic fibrosis better than NAFLD.Liver Int. 2020; 40: 3018-3030Crossref PubMed Scopus (107) Google Scholar, 17Lee H. Lee Y.H. Kim S.U. Kim H.C. Metabolic dysfunction-associated fatty liver disease and incident cardiovascular disease risk: a nationwide cohort study.Clin Gastroenterol Hepatol. 2020 Dec 22; (S1542-3565(20)31717-1. https://doi.org/10.1016/j.cgh.2020.12.022. Online ahead of print)Abstract Full Text Full Text PDF Scopus (49) Google Scholar, 18Sun D.Q. Jin Y. Wang T.Y. Zheng K.I. Rios R.S. Zhang H.Y. et al.MAFLD and risk of CKD.Metabolism. 2021; 115: 154433Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Nevertheless, the question on the threshold to define a disease goes deeper than just showing an association with more adverse outcomes. For example, one can increase the cut-off of fasting plasma glucose to define diabetes mellitus (Fig. 1A). Although the new group would have a very high risk of complications, the definition misses those who will develop complications, albeit at a lower incidence. We also learn from the study by Kim and colleagues that patients with MAFLD had increased overall mortality (Fig. 1B).[3]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75: 1284-1291Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar If anything, patients who had MAFLD but not NAFLD (i.e. excluding those not fulfilling the metabolic criteria) had an even higher mortality rate. However, the group that we should pay particular attention to is patients who had NAFLD but not MAFLD because this is the group who may risk being undiagnosed and untreated under the new definition. In the current study, the overall, cardiovascular and cancer mortality of this group was no different from that of individuals without fatty liver. Although information on liver-related morbidity and mortality is not available, other studies have shown a very low prevalence of significant liver fibrosis in patients with NAFLD not fulfilling the MAFLD metabolic criteria.[15]Wai-Sun Wong V. Lai-Hung Wong G. Woo J. Abrigo J.M. Ka-Man Chan C. She-Ting Shu S. et al.Impact of the new definition of metabolic associated fatty liver disease on the epidemiology of the disease.Clin Gastroenterol Hepatol. 2020 Oct 31; (S1542-3565(20)31504-4) (Online ahead of print)https://doi.org/10.1016/j.cgh.2020.10.046Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,[16]Yamamura S. Eslam M. Kawaguchi T. Tsutsumi T. Nakano D. Yoshinaga S. et al.MAFLD identifies patients with significant hepatic fibrosis better than NAFLD.Liver Int. 2020; 40: 3018-3030Crossref PubMed Scopus (107) Google Scholar Data on the risk of liver-related complications in lean patients with fatty liver are conflicting.[19]Leung J.C. Loong T.C. Wei J.L. Wong G.L. Chan A.W. Choi P.C. et al.Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients.Hepatology. 2017; 65: 54-64Crossref PubMed Scopus (157) Google Scholar,[20]Younes R. Govaere O. Petta S. Miele L. Tiniakos D. Burt A. et al.Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?.Gut. 2021 Feb 4; (gutjnl-2020-322564. https://doi.org/10.1136/gutjnl-2020-322564. Online ahead of print)Crossref PubMed Scopus (21) Google Scholar Further studies are warranted in light of the MAFLD criteria. The Chinese Society of Hepatology is the latest among several professional societies to endorse the name and definition of MAFLD while comparative data like the study by Kim and colleagues remain limited.[2]Nan Y. An J. Bao J. Chen H. Chen Y. Ding H. et al.The Chinese Society of Hepatology position statement on the redefinition of fatty liver disease.J Hepatol. 2021; 75: 454-461Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,[3]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75: 1284-1291Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar There has thus been a call for more discussion, evidence and wider representation. Currently, the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases have convened a nomenclature consensus workgroup including representatives from South America and Asia. The plan is to obtain opinion from not only hepatologists and gastroenterologists but also stakeholders including clinicians from other specialties, primary care physicians, patients and regulators. Hopefully, a well-accepted name and definition for this common liver disease will facilitate research and improve patient care in the years to come. The authors received no financial support to produce this manuscript. Both authors contributed to the literature review and the ideas in this editorial. They also drafted the manuscript and approved its final version. Vincent Wong served as a consultant or advisory board member for 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Echosens, Gilead Sciences, Inventiva, Merck, Novartis, Novo Nordisk, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions, and Terns; and a speaker for Abbott, AbbVie, Echosens, Gilead Sciences, and Novo Nordisk. He has received a research grant from Gilead Sciences, and is a co-founder of Illuminatio Medical Technology Limited. JVL reports grants and personal fees from AbbVie, Gilead Sciences and MSD; personal fees from CEPHEID, GSK, Genfit, Intercept, and Janssen, outside the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details. The following is the supplementary data to this article: Download .pdf (.15 MB) Help with pdf files Multimedia component 1 Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United StatesJournal of HepatologyVol. 75Issue 6PreviewRecently, international experts proposed redefining non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MAFLD), based on modified criteria. It is suspected that outcomes such as mortality may differ for these clinical entities. We studied the impact of MAFLD and NAFLD on all-cause and cause-specific mortality in US adults. Full-Text PDF The Chinese Society of Hepatology position statement on the redefinition of fatty liver diseaseJournal of HepatologyVol. 75Issue 2PreviewFatty liver disease associated with metabolic dysfunction is of increasing concern in mainland China, the world’s most populous country. The incidence of fatty liver disease is highest in China, surpassing the incidence in European countries and the USA. An international consensus panel recently published an influential report recommending a novel definition of fatty liver disease associated with metabolic dysfunction. This recommendation includes a switch in name from non-alcoholic fatty liver disease (NAFLD) to metabolic (dysfunction)-associated fatty liver disease (MAFLD) and adoption of a set of positive criteria for disease diagnosis that are independent of alcohol intake or other liver diseases. Full-Text PDF One not like the other: The weakness of the blood sugar-MAFLD analogyJournal of HepatologyVol. 76Issue 2PreviewWe read the articles by Dr. Nan and colleagues1 and Dr. Kim and colleagues2 as well as the comments by Drs. Wong and Lazarus3 with great interest. Dr. Nan et al.1 present the consensus of the Chinese Society of Hepatology’s endorsement of the proposal for the redefinition of fatty liver disease,4,5 joining multiple other liver societies, patient associations, and nurse leaders.6 Dr. Kim et al.2 provide another piece of evidence demonstrating that the MAFLD definition outperforms the previous NAFLD definition in identifying advanced liver disease, cardiovascular risk, renal disease, cancer, and increased mortality. Full-Text PDF