Metabolic Health and Outcomes in Fatty Liver: Does a Name Change Matter?

Fatty liver is present in an extraordinary number of people, with a recent meta-analysis estimating 32% of the world’s population had nonalcoholic fatty liver disease (NAFLD).1Riazi K. Azhari H. Charette J.H. et al.The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis.Lancet Gastroenterol Hepatol. 2022; 7: 851-861Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar The global prevalence reaches 39% when using the definition of metabolic-associated fatty liver disease (MAFLD), which requires the presence of excess adiposity, diabetes, or metabolic dysfunction, but is not exclusonary of other causes of liver disease (eg, excess alcohol).2Chan K.E. Koh T.J.L. Tang A.S.P. et al.Global prevalence and clinical characteristics of metabolic-associated fatty liver disease: a meta-analysis and systematic review of 10 739 607 individuals.J Clin Endocrinol Metab. 2022; 107: 2691-2700Crossref PubMed Scopus (61) Google Scholar NAFLD and MAFLD exist as a spectrum of disease from a histologic and metabolic perspective. The spectrum of histologic abnormalities portends the risk of outcomes; subjects with fatty liver but without significant liver injury or fibrosis typically have favorable outcomes with a low risk of progression to cirrhosis and its complications.3Taylor R.S. Taylor R.J. Bayliss S. et al.Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.Gastroenterology. 2020; 158: 1611-1625Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar In contrast, patients with steatohepatitis and fibrosis are more likely to develop liver-related morbidity and thus we spend a significant amount of energy trying to identify these patients so we can counsel, monitor, and treat them accordingly. The recently devised definition of MAFLD highlights the metabolic spectrum in fatty liver, from lean patients with metabolic syndrome features, overweight or obese individuals (with or without metabolic syndrome features), and those with overt type 2 diabetes. Subsequently, there has been renewed attention in examining the heterogeneity of metabolic dysfunction and how this may impact outcomes in patients with MAFLD. In the current edition of Clinical Gastroenterology and Hepatology, Chan et al4Chan K.E. Ng C.H. Fu C.E. et al.The spectrum and impact of metabolic dysfunction in MAFLD: a longitudinal cohort analysis of 32,683 overweight and obese individuals.Clin Gastroenterol Hepatol. 2023; 21: 2560-2569Abstract Full Text Full Text PDF Scopus (6) Google Scholar compare the health outcomes in overweight or obese individuals (defined by body mass index) in the Nationeal Health and Nutrition Examination Survey cohort over a 2-decade period according to the presence of MAFLD and metabolic health. Using the Fatty Liver Index (FLI) or the US-FLI to diagnose hepatic steatosis, two-thirds of the 32,683 individuals within the cohort were defined as having MAFLD. Of the subjects with MAFLD, 93% were classified as metabolically unhealthy MAFLD (MU-MAFLD), defined by the presence of diabetes or 2 or more features of the metabolic syndrome (central obesity, fasting glycemia, hypertension, hypertriglyceridemia, or low high-density lipoprotein-cholesterol). Metabolically healthy MAFLD (MH-MAFLD) subjects were overweight or obese, but did not have diabetes or more than 1 associated metabolic feature. Over approximately 8 years of follow-up, MU-NAFLD was associated with a 24% higher all-cause mortality risk compared with overweight or obese individuals without MAFLD. In contrast, MH-MAFLD had a similar risk compared with non-MAFLD patients. Not surprisingly, MU-MAFLD also had a 38% higher risk of a major adverse cardiovascular event, 20% increased risk of cardiovascular death, and a 24% increase in risk of cancer-related death. Within the group of MU-MAFLD subjects, those with diabetes as opposed to 2 or more metabolic abnormalities without diabetes, had greater risk of major adverse cardiac events, cardiovascular, cancer, and overall mortality. In contrast, the risk of major adverse cardiac events, cardiac, cancer, or all-cause mortality in MH-MAFLD subjects remained similar to the non-MAFLD control population overall. In parallel with this gradient of morbidity and mortality risk, the odds of advanced liver fibrosis (assessed by vibration controlled transient elastography) was 4-fold higher in MU-MAFLD patients compared to non-MAFLD patients, but was not increased in MH-MAFLD patients. This interesting study has several strengths, namely the large number of subjects who are broadly representative of the US population, and the examination of “hard” mortality outcomes, which are most relevant to our patients. It is pertinent to mention some limitations regarding the use of the FLI and US-FLI to diagnose fatty liver. These algorithms use measures of adiposity (body mass index, waist circumference) and serum triglyceride (FLI), or insulin and glucose levels (US-FLI) to predict fatty liver. This subsequently makes it difficult to discern the association of fatty liver with outcomes independently of these factors, which was 1 of the underlying aims of this study. The use of these algorithms may have also impacted the diagnosis of fatty liver within subgroups, with MH-MAFLD comprising only 7% of the MAFLD population which is lower when compared to a large Korean study using ultrasound which reported a prevalence of 27% across the full BMI spectrum.5Park H. Yoon E.L. Kim M. Cho S. Nah E.H. Jun D.W. Nomenclature Dilemma of Metabolic Associated Fatty Liver Disease (MAFLD): Considerable Proportions of MAFLD Are Metabolic Healthy.Clin Gastroenterol Hepatol. 2022; Abstract Full Text Full Text PDF Scopus (8) Google Scholar With these caveats in mind, is this study informative as to the debate regarding the use of NAFLD versus MAFLD? It is clear that a heterogeneity of metabolic dysfunction exists among subjects with NAFLD and MAFLD, and that prognosis is worse in NAFLD and MAFLD patients with more severe metabolic dysfunction, such as with type 2 diabetes.6Vilar-Gomez E. Calzadilla-Bertot L. Wong V.W. et al.Type 2 diabetes and metformin use associate with outcomes of patients with nonalcoholic steatohepatitis-related, Child-Pugh A cirrhosis.Clin Gastroenterol Hepatol. 2021; 19: 136-145Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Similar to the findings of this study, a previous analysis of the National Health and Nutrition Examination Survey cohort found cardiovascular and all-cause mortality to be higher in NAFLD subjects with concomitant metabolic syndrome, whereas NAFLD subjects without the metabolic syndrome had outcomes that were similar to participants without liver disease.7Younossi Z.M. Otgonsuren M. Venkatesan C. et al.In patients with non-alcoholic fatty liver disease, metabolically abnormal individuals are at a higher risk for mortality while metabolically normal individuals are not.Metabolism. 2013; 62: 352-360Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Another notable point raised by the study is whether MH-MAFLD subjects truly represent an at-risk group that needs to be identified and managed given their similarity in mortality and cardiovascular disease outcomes with non-MAFLD subjects. As MAFLD subjects who were metabolically healthy were an average 16 years younger than the metabolically unhealthy MAFLD subjects, it is possible they were assessed earlier in their disease course without sufficient follow-up to reveal risk of complications. Unfortunately, over time, metabolically healthy obese individuals are at increased risk of becoming metabolically unhealthy, developing steatohepatitis and liver fibrosis, and thus it would be premature to dismiss these individuals as having no risk.8Smith G.I. Mittendorfer B. Klein S. Metabolically healthy obesity: facts and fantasies.J Clin Invest. 2019; 129: 3978-3989Crossref PubMed Scopus (275) Google Scholar, 9Kim Y. Chang Y. Cho Y.K. Ahn J. Shin H. Ryu S. Metabolically healthy versus unhealthy obesity and risk of fibrosis progression in non-alcoholic fatty liver disease.Liver Int. 2019; 39: 1884-1894Crossref PubMed Scopus (25) Google Scholar, 10Ampuero J. Aller R. Gallego-Duran R. Banales J.M. Crespo J. Garcia-Monzon C. et al.The effects of metabolic status on non-alcoholic fatty liver disease-related outcomes, beyond the presence of obesity.Aliment Pharmacol Ther. 2018; 48: 1260-1270Crossref PubMed Scopus (69) Google Scholar The new definition of MAFLD has brought renewed attention to the underlying causes of fatty liver. It is clearly important to assess the underlying metabolic factors in our patients because they predict prognosis with advanced metabolic dysfunction and diabetes identifying a more severe course. “Metabolically healthy” subjects with fatty liver are unlikely to develop significant morbidity in the short to medium term, however remain at risk of worsening metabolic and liver disease. As these may progress silently, they represent a cohort for management and monitoring which may be most efficiently performed within primary care. As our understanding of the heterogeneity in the pathogenesis and natural history of fatty liver disease increases, we will be able to define better which at-risk groups should be targeted for monitoring and treatment. The Spectrum and Impact of Metabolic Dysfunction in MAFLD: A Longitudinal Cohort Analysis of 32,683 Overweight and Obese IndividualsClinical Gastroenterology and HepatologyVol. 21Issue 10PreviewMetabolic associated fatty liver disease (MAFLD) was recently proposed as an alternative name change for better encapsulation of disease. However, there exists a spectrum of MAFLD where both metabolically healthy (MH) and metabolically unhealthy (MU) individuals are included. In view of limited evidence, we sought to examine the prevalence, clinical characteristics, and differences in outcomes of MH-MAFLD at the population level. Full-Text PDF