What's in a name? New nomenclature for steatotic liver disease- to be or not to be?

A multi-society Delphi consensus statement on new fatty liver disease nomenclatureJournal of HepatologyPreviewThe principal limitations of the terms nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. Full-Text PDF Open Access “What's in a name? That which we call a rose by any other name would smell just as sweet.” This line from Shakespeare's “Romeo & Juliet,” while not intended for 21st-century hepatology, may aptly depict the ongoing conversation. Juliet's lament about Romeo's Montague lineage not impacting his intrinsic attributes takes a different dimension when applied to 'steatotic liver disease' (SLD). Here, the significance and connotations of its proper nomenclature surpass the mere nominal concern Juliet first voiced back in 1597. Just recently, the new nomenclature for SLD and ‘metabolic dysfunction-associated steatotic liver disease’ (MASLD) has been released in a Delphi consensus statement of 236 experts on SLD from 56 countries, being endorsed by all major international hepatology societies, as well as national societies. The adoption of the SLD designation marks a considerable stride in diminishing stigma and elevating comprehension of SLD among both clinicians and patients. This shift provides an explicit diagnosis, aiding in the refinement of patient interactions and perceptions. However, potential inherent limitations persist. Specifically, it should be noted that a mere 53% of panelists endorsed the modification of the current diagnostic criteria to the new ones. This vote underscores the intricate nature of this matter, while simultaneously highlighting the existence of contentious viewpoints within the field. Among them, we want to put a few to discussion:I.While the emphasize on hepatic steatosis as a pathophysiological hallmark in the pathogenesis of MASLD and ‘alcohol-related liver disease’ (ArLD) is important, it might miss the following patient populations:a.Patients with advanced fibrosis/cirrhosis in which hepatic steatosis is vanishing (‘burnt-out’ metabolic dysfunction-associated steatohepatitis [MASH]). In contrast to patients with only steatosis at an early stage, these patients presenting at a late stage of their disease are indeed at risk of complications related to MASLD.[1]Angulo P. Kleiner D.E. Dam-Larsen S. Adams LA Bjornsson ES Charatcharoenwitthaya P 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.e10Google Scholar,[2]Taylor R.S. Taylor R.J. Bayliss S. Hagström H Nasr P Schattenberg JM et al.Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.Gastroenterology. 2020; 158: 1611-1625.e12Google Scholar In the absence of steatosis, these patients even have worse outcomes.[3]Younossi Z. Stepanova M. Sanyal A.J. Harrison SA Ratziu V Abdelmalek MF et al.The conundrum of cryptogenic cirrhosis: adverse outcomes without treatment options.J Hepatol. 2018; 69: 1365-1370Google Scholar However, the new MASLD definition may specifically delay and complicate the correct diagnosis of this important patient population, which is also relevant to scientific studies.b.Patients with a strong/predominant genetic component that impairs hepatic mitochondrial function and amplifies the inflammatory driver of fibrogenesis in MASLD.[4]Luukkonen P.K. Qadri S. Ahlholm N. Porthan K Männistö V Sammalkorpi H et al.Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease.J Hepatol. 2022; : 76526-76535Google Scholar Especially lean patients with hepatic steatosis – previously termed ‘lean NAFLD’ – are not included in the current definition (if no other cardiometabolic risk factors are present). However, extensive evidence has shown that they might be especially vulnerable to adverse outcomes (potentially due to their genetic risk profile).[5]Ye Q. Zou B. Yeo Y.H. Li J Huang DQ Wu Y et al.Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis.Lancet Gastroenterol Hepatol. 2020; 5: 739-752Google Scholar,[6]Tang A. Ng C.H. Phang P.H. Chan KE Chin YH Fu CE et al.Comparative burden of metabolic dysfunction in lean NAFLD vs non-lean NAFLD - a systematic review and meta-analysis.Clin Gastroenterol Hepatol : official Clin Pract J Am Gastroenterological Assoc. 2023; 21: 1750-1760.e12Google ScholarII.Numerous studies have shown that fibrosis rather than steatosis per se is linked with morbidity and mortality in MASLD,1Angulo P. Kleiner D.E. Dam-Larsen S. Adams LA Bjornsson ES Charatcharoenwitthaya P 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.e10Google Scholar, 2Taylor R.S. Taylor R.J. Bayliss S. Hagström H Nasr P Schattenberg JM et al.Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.Gastroenterology. 2020; 158: 1611-1625.e12Google Scholar especially when it comes to cardiovascular events and extrahepatic malignancies being the predominant causes of death. Putting the focus on steatosis again has the following limitations:a.It attributes a ‘disease’ to millions of individuals that might never suffer from any consequences of hepatic steatosis. Among an increasing number of studies,[7]Semmler G. Wernly S. Bachmayer S. Leitner I Wernly B Egger M et al.Metabolic dysfunction-associated fatty liver disease (MAFLD)-Rather a bystander than a driver of mortality.J Clin Endocrinol Metab. 2021; 106: 2670-2677Google Scholar a recent pooled analysis from the Framingham Heart Study, the Coronary Artery Risk Development in Young Adults Study, and the Multi-ethnic Study of Atherosclerosis demonstrated that – after proper multivariable adjustment – the association of hepatic steatosis per se and cardiovascular outcomes vanished.[8]Ahmed H.S. Wang N. Carr J.J. Ding J Terry JG VanWagner LB et al.The association between hepatic steatosis and incident cardiovascular disease, cancer, and all-cause mortality in a US multicohort study.Hepatology (Baltimore, Md). 2023; 77: 2063-2072Google Scholarb.Despite placing the doctors’ and patients’ focus on steatosis, there is currently no tool available to sufficiently monitor changes in steatosis. Although controlled attenuation parameter (CAP), which has not been included in the definition of MASLD, would offer this potential, little data has evaluated its accuracy in longitudinal quantification of changes in hepatic steatosis.III.The current definition requires ‘imaging or biopsy’ to diagnose hepatic steatosis but does not include CAP (as one example of elastography methods to quantify hepatic steatosis) or non-invasive scores (such as the ‘fatty liver index’ [FLI]). Despite the limitations of CAP and FLI, one still has to consider the inter- and intra-observer variability of ultrasound,[9]Hernaez R. Lazo M. Bonekamp S. Kamel I Brancati FL Guallar E et al.Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis.Hepatology (Baltimore, Md). 2011; 54: 1082-1090Google Scholar and the low sensitivity to detect mild hepatic steatosis <10%.[10]Lee S.S. Park S.H. Kim H.J. Kim SY Kim MY Kim DY et al.Non-invasive assessment of hepatic steatosis: prospective comparison of the accuracy of imaging examinations.J Hepatol. 2010; 52: 579-585Google Scholar Here, the reliance on ultrasound alone might be especially controversial in obesity as accuracy for hepatic steatosis declines.IV.Criteria for metabolic dysfunction are very broad, requiring only one out of five cardiometabolic risk factors, and have not been validated to identify patients at risk for complications of MASLD. While they might identify 98% of patients enrolled in the European LITMUS study, it is unclear whether this broad definition improves risk stratification. Especially as numerous recent studies have identified insulin resistance as the main hallmark of SLD,[4]Luukkonen P.K. Qadri S. Ahlholm N. Porthan K Männistö V Sammalkorpi H et al.Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease.J Hepatol. 2022; : 76526-76535Google Scholar it could be considered at least as one criterion. In summary, the new nomenclature clearly represents a milestone in the understanding and management of patients with MASLD. Nevertheless, proposing the name ‘metabolic dysfunction-associated liver disease” (MALD) in line with ArLD under the umbrella term of SLD would be a potential alternative. In the end, time will tell whether the new MASLD nomenclature and criteria are meant to be, or not to be. No funding specific for this study was received. The authors declare that they have no conflicts of interest regarding the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details. Drafting of the manuscript (G.S., B.W., C.D.), critical revision of the manuscript for important intellectual content (G.S., B.W., C.D.). The following are the supplementary data to this article. Download .pdf (.8 MB) Help with pdf files Multimedia component 1