Non-alcoholic fatty liver disease: Not time for an obituary just yet!

Abstract

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]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 (668) Google Scholar,[2]Eslam M. Sanyal A.J. George J. Neuschwander-Tetri B. Tiribelli C. Kleiner D.E. et al.MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.Gastroenterology. 2020; 158 (e1): 1999-2014Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar However, there are considerable flaws in the proposal, and changing NAFLD to MAFLD is unlikely to move the field forward.[2]Eslam M. Sanyal A.J. George J. Neuschwander-Tetri B. Tiribelli C. Kleiner D.E. et al.MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.Gastroenterology. 2020; 158 (e1): 1999-2014Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar We have serious misgivings on this matter. To begin with, the statement by the MAFLD consensus group that the term NAFLD was coined by Ludwig and colleagues[2]Eslam M. Sanyal A.J. George J. Neuschwander-Tetri B. Tiribelli C. Kleiner D.E. et al.MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.Gastroenterology. 2020; 158 (e1): 1999-2014Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar is factually incorrect. Although the histological features of NAFLD were first described decades ago, Klatskin and his colleagues, in 1979, were the first to use the term ‘non-alcoholic liver disease’.[3]Reuben A. Leave gourmandising.Hepatology. 2002; 36: 1303-1306Crossref PubMed Scopus (10) Google Scholar Later, while reporting similar findings, Ludwig and colleagues coined the term “non-alcoholic steatohepatitis (NASH)”. Although an association between metabolic syndrome (MS) and NAFLD has been established and NAFLD termed the hepatic manifestation of MS,[4]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.Hepatology. 2018; 67: 328-357Crossref PubMed Scopus (2317) Google Scholar this generalisation has since been questioned, since the complex heterogeneity of this entity precludes any single postulation to explain its pathogenesis. Besides, individuals with normal BMI also develop NAFLD, and studies in non-Caucasian populations have shown that a significant proportion of patients with NAFLD do not have insulin resistance (IR).[5]Singh S.P. Misra B. Kar S.K. Panigrahi M.K. Misra D. Bhuyan P. et al.Nonalcoholic fatty liver disease (NAFLD) without insulin resistance: is it different?.Clin Res Hepatol Gastroenterol. 2015; 39: 482-488Crossref PubMed Scopus (17) Google Scholar Further, even with elevated hepatic triacylglycerol and diacylglycerol content, hepatic IR has not been observed in murine models,[6]Monetti M. Levin M.C. Watt M.J. Sajan M.P. Marmor S. Hubbard B.K. et al.Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver.Cell Metab. 2007; 6: 69-78Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar and dissociation of hepatic steatosis from IR has also been noted in a subset of individuals.[7]Kantartzis K. Peter A. Machicao F. Machann J. Wagner S. Königsrainer I. et al.Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene.Diabetes. 2009; 58: 2616-2623Crossref PubMed Scopus (235) Google Scholar Importantly, in subjects with PNPLA3 polymorphisms,[8]Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (1982) Google Scholar steatosis occurs independently of IR and serum lipid concentration. Further, increased serum bile acid levels also seem to be independently associated with NASH in non-diabetics.[9]Li H. Ma J. Gu L. Jin L. Chen P. Zhang X. et al.Increased serum total bile acid is independently associated with non-alcoholic steatohepatitis in non-diabetes population.2020 Mayhttps://www.researchsquare.com/article/rs-27123/v1Crossref Google Scholar NAFLD is also associated with gut dysbiosis independent of BMI and IR.[10]Da Silva H.E. Teterina A. Comelli E.M. Taibi A. Arendt B.M. Fischer S.E. et al.Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance.Sci Rep. 2018; 8: 1466Crossref PubMed Scopus (115) Google Scholar Finally, “soft” drink consumption has also been linked to the development of fatty liver independent of obesity, diabetes and hyperlipidemia[11]Abid A. Taha O. Nseir W. Farah R. Grosovski M. Assy N. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome.J Hepatol. 2009; 51: 918-924Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar and last but not least, cigarette smoking too has been found to be an independent risk factor in NAFLD progression.[12]Jung H.-S. Chang Y. Kwon M.-J. Sung E. Yun K.E. Cho Y.K. et al.Smoking and the risk of non-alcoholic fatty liver disease: a cohort study.Am J Gastroenterol. 2019; 114: 453-463Crossref PubMed Scopus (28) Google Scholar Thus it is clear that pathogenesis of NAFLD is multifactorial and complex, involving multiple and divergent pathways. In Medicine, a change of name of any disease has significant implications for both medical professionals and patients.[13]Young M.E. Norman G.R. Humphreys K.R. The role of medical language in changing public perceptions of illness.PLOS ONE. 2008; 3: e3875Crossref PubMed Scopus (33) Google Scholar The term ‘NAFLD’ aptly describes individuals who have fatty liver but neither consume significant amounts of alcohol nor had any other reason for fatty liver. Research in NAFLD to date has failed to pinpoint any factor as the sole cause for hepatic steatosis and NAFLD still encompasses a spectrum of disorders, metabolic syndrome being a part – maybe a major part – of that spectrum with a relatively barren treatment armamentarium. Will changing nomenclature address these concerns? We fear it might paradoxically misdirect therapeutics in the direction of MS alone which may ultimately turn out to be a red herring. The consensus group found multiple faults with the term NAFLD; these include: i) NAFLD is a disease of exclusion instead of being defined by inclusion, ii) NAFLD is a vastly heterogeneous entity and cannot be managed as one single condition and iii) patients with NAFLD do consume alcohol and the impact of alcohol, albeit in non-significant amounts, is under scrutiny. In Medicine, naming a disease through exclusion has been acceptable since time immemorial. Non-Hodgkin lymphoma encompasses vastly diverse malignancies and yet the terminology very effectively delineates those disorders from Hodgkin lymphoma. Regarding heterogeneity, it is not clear how a mere change of name would make the entity more homogeneous. If the word “metabolic” in MAFLD is meant as a reference to MS, it would be a rejection of much of the scientific evidence gathered on NAFLD pathogenesis. In contrast to the assertion of the proponents of MAFLD, who after splitting “nonalcoholic” into - ‘non’ and ‘alcoholic’, suggest that the word “non” trivializes the problem while the word “alcoholic” demeans the patient, we believe that the word ‘nonalcoholic’ does go a long way in destigmatizing the patient. The European Liver Patients Association (ELPA) is believed to have expressed displeasure with the term NAFLD to the European Commission in 2018, and suggested that a change in nomenclature was required.[2]Eslam M. Sanyal A.J. George J. Neuschwander-Tetri B. Tiribelli C. Kleiner D.E. et al.MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.Gastroenterology. 2020; 158 (e1): 1999-2014Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar The degree of assertion and the rationale for such a suggestion are unclear; it is also unclear whether the diverse pathogenesis of NAFLD – especially in non-Caucasians – was considered in the decision. Further, an opinion on the impact of non-significant alcohol intake on hepatic steatosis is also unclear as acknowledged in the consensus statement. Notably, metabolic abnormalities and BMI are well described risk factors for alcoholic liver disease too,[14]Louvet A. Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment.Nat Rev Gastroenterol Hepatol. 2015; 12: 231-242Crossref PubMed Scopus (434) Google Scholar but it is unclear why both conditions more or less related to alcohol should be brought under the umbrella of MAFLD. The change of nomenclature has also been argued against since NAFLD is treated by cardiologists, diabetologists and primary care providers in addition to hepatologists; a name change could create unnecessary clinical confusion and coding issues.[15]Hashimoto E. Tokushige K. Ludwig J. Diagnosis and classification of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: current concepts and remaining challenges.Hepatol Res. 2015; 45: 20-28Crossref PubMed Scopus (59) Google Scholar The heterogeneity of NAFLD and presence of multiple pathophysiological pathways inherent to its progression implies that the time is ripe to classify NAFLD in a novel way that takes into account the various pathophysiological processes. We wish to propose the ‘MEGA-D’ classification emphasising the ‘mega diversity’ or heterogeneity in NAFLD where NAFLD remains the umbrella entity with different subgroups under it (NAFLD-M: Metabolic syndrome associated NAFLD, NAFLD-E: Environmental Stressor Related NAFLD, NAFLD-G: Genetic Factor Associated NAFLD, NAFLD-A: Bile Acid Dysregulation Related NAFLD, NAFLD-D: Gut Dysbiosis Related NAFLD) representing separate pathways culminating in hepatic steatosis. We feel, instead of semantic juggling, collaborative efforts should be launched worldwide to better understand the vast heterogeneity in NAFLD across populations and ethnicities and explore its different pathophysiologic mechanisms, with the sole purpose of modifying disease progression, bolstering the treatment arsenal and curbing this epidemic. The study was supported by a grant from the Kalinga Gastroenterology Foundation , Cuttack, India. Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work: SPS, PA, KRK, HSC, GM, MER, KM, MLP, MAM, SHC, GPA, SSHGCF, SKS, AD, SKA, ASD, KLG. Drafting the work or revising it critically for important intellectual content: SPS, PA, KRK, HSC, GM, MER, KM, MLP, MAM, SHC, GPA, SSHGCF, SKS, AD, SKA, ASD, KLG. Final approval of the version to be published: SPS, PA, KRK, HSC, GM, MER, KM, MLP, MAM, SHC, GPA, SSHGCF, SKS, AD, SKA, ASD, KLG. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: SPS, PA. Authors declare they have no conflict of interest regarding the content of this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details. The following is/are the supplementary data to this article: Download .pdf (.34 MB) Help with pdf files Multimedia component 1 A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statementJournal of HepatologyVol. 73Issue 1PreviewThe 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. Full-Text PDF Yet more evidence that MAFLD is more than a name changeJournal of HepatologyVol. 74Issue 4PreviewIn 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. Full-Text PDF