Normal weight and central obesity as predictors of increased all-cause mortality in metabolic dysfunction associated steatotic liver disease

A multisociety Delphi consensus statement on new fatty liver disease nomenclatureJournal of HepatologyVol. 79Issue 6PreviewThe principal limitations of the terms NAFLD and 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. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. Full-Text PDF Open Access As the most common cause of liver disease worldwide, non-alcoholic fatty liver disease (NAFLD) poses a huge burden on healthcare.[1]Le M.H. Le D.M. Baez T.C. et al.Global incidence of non-alcoholic fatty liver disease: a systematic review and meta-analysis of 63 studies and 1,201,807 persons.J Hepatol. 2023; 79: 287-295Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Due to the potential stigma associated with this term and its inability to accurately capture the etiology of steatosis, a new nomenclature for fatty liver disease has recently been proposed.[2]Rinella M.E. Lazarus J.V. Ratziu V. et al.A multisociety Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol. 2023; 79: 1542-1556Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar Metabolic dysfunction-associated steatotic liver disease (MASLD) was introduced as a new term to replace NAFLD. Obesity plays a key role in fatty liver, and many predictive and diagnostic models for fatty liver, including the identification of MASLD, take obesity into account.[2]Rinella M.E. Lazarus J.V. Ratziu V. et al.A multisociety Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol. 2023; 79: 1542-1556Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar However, approximately 20% of patients with NAFLD have normal BMI, defined as lean NAFLD.[3]Ye Q. Zou B. Yeo Y.H. 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 Aug; 5: 739-752Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar Several recent studies suggest that lean NAFLD may have worse clinical outcomes, but the evidence is conflicting.4Nabi O. Lapidus N. Boursier J. et al.Lean individuals with NAFLD have more severe liver disease and poorer clinical outcomes (NASH-CO Study).Hepatology. 2023; 78: 272-283Crossref PubMed Scopus (13) Google Scholar, 5Younes R. Govaere O. Petta S. 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. 2022; 71: 382-390Crossref PubMed Scopus (105) Google Scholar, 6Tan E.X.X. Muthiah M.D. Ng C.H. et al.Editorial: clinical outcomes in lean NAFLD-the devil is in the details.Aliment Pharmacol Ther. 2023; 57: 1040-1041Crossref PubMed Scopus (1) Google Scholar Finding signatures that are strongly associated with poor clinical outcomes is essential for developing effective healthcare interventions and targets. Therefore, under the new nomenclature and diagnostic framework, we investigated the longitudinal associations between BMI and all-cause mortality for different steatotic liver disease (SLD) subtypes in a nationally representative sample of US adults.[7]CDC/NCHSAnalytic and reporting guidelines: the Third national Health and nutrition examination survey, NHANES III (1988-94). National Center for Health Statistics Centers for Disease Control and Prevention, Hyattsville, MD, USA1996 OctoberGoogle Scholar In addition, we examined waist-to-hip ratio (WHR) and waist circumference (WC) to investigate the performance of fat distribution in predicting mortality risk. A total of 13,856 participants aged 20-74 years from the Third National Health and Nutrition Examination Survey 1988-1994 (NHANES III) who underwent eligible liver ultrasound examinations were enrolled.[7]CDC/NCHSAnalytic and reporting guidelines: the Third national Health and nutrition examination survey, NHANES III (1988-94). National Center for Health Statistics Centers for Disease Control and Prevention, Hyattsville, MD, USA1996 OctoberGoogle Scholar To be nationally representative, the NHANES III was based on a complex survey design; therefore, all of our analyses used the recommended sample weights. The National Death Index mortality follow-up data through 31 December 2019 was linked to NHANES III for analysis.[8]National Center for Health Statistics Division of Analysis and Epidemiology NHANES III public-use linked mortality files.2019https://www.cdc.gov/nchs/data-linkage/mortality-public.htmGoogle Scholar The diagnosis of SLD was based on any degree of hepatic steatosis indicated by ultrasound. SLD was further classified as MASLD (≥1 cardiometabolic risk factor(s) and no other cause of SLD), metabolic dysfunction and alcohol associated/related liver disease (MetALD, meeting the criteria for MASLD except for increased alcohol intake), and other SLD (such as HBV/HCV infections, excessive alcohol consumption, cryptogenic).[2]Rinella M.E. Lazarus J.V. Ratziu V. et al.A multisociety Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol. 2023; 79: 1542-1556Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar Increased alcohol intake was defined as 140-350 g/week for women and 210-420 g/week for men, while excessive alcohol intake was anything above this. BMI was categorized as normal (<25 kg/m2), overweight (25-29.9 kg/m2), and obese (≥30 kg/m2). WC and WHR were classified into low and high categories according to World Health Organization criteria. High WC was defined as ≥88 cm for women and ≥102 cm for men, and high WHR was defined as ≥0.85 for women and ≥0.90 for men, which is also the criteria for central obesity. Multivariable Cox proportional hazards models were used to assess the association between adiposity categories and mortality. Multivariable restricted cubic spline (RCS) models with four knots were utilized to investigate the dose-response pattern. For all models, we adjusted for demographics (age, sex, ethnicity, marital status), socioeconomics (education, income), lifestyle (physical activity, healthy eating index, smoking status), medical history (diabetes, hypertension, malignancy), and laboratory tests (FIB-4 index, triglycerides, HDL cholesterol, C-reactive protein). To determine the independent association of each adiposity measure with mortality, we additionally adjusted for WHR and WC in the BMI analyses, and for BMI in the WC and WHR analyses. Data analyses were performed between 1 August and 1 November 2023. Of the 13,856 participants who underwent liver ultrasound, 10,617 had complete information on body measures, mortality status, and covariates. Finally, 3,872 participants were identified as having SLD (MASLD: 3,195, MetALD: 198, other SLD: 479). During 26.17 years (IQR 19.33–28.02) of follow-up, 1,571 deaths occurred. After adjusting for potential confounders, the RCS model showed that BMI (p overall <0.001), WC (p overall <0.001), and WHR (p overall =0.002) were all significantly associated with all-cause mortality in MASLD (Fig. 1). The risk of mortality decreased with increasing BMI, reaching a minimum risk at around 30 kg/m2 and then remaining relatively flat. The mortality increased with the elevation of WC and WHR; however, a slight J-shaped pattern was present in WHR. The results of the multivariate Cox regression analysis were consistent with the RCS model. For MetALD and other SLD, the associations of WC and WHR with mortality were similar to those observed in the MASLD. However, most of them did not reach statistical significance, which may be due to the limited statistical power resulting from the insufficient sample size. The pattern of BMI-mortality association in MetALD was similar to that of MASLD, with BMI below 30 kg/m2 tending to have a higher risk, although not statistically significant. In other SLD, the opposite trend was observed, with higher BMI tending to increase mortality. The current results are consistent with previous findings that lean NAFLD is associated with worse clinical outcomes.[4]Nabi O. Lapidus N. Boursier J. et al.Lean individuals with NAFLD have more severe liver disease and poorer clinical outcomes (NASH-CO Study).Hepatology. 2023; 78: 272-283Crossref PubMed Scopus (13) Google Scholar Moreover, we reveal for the first time an independent association between central obesity and long-term mortality in MASLD, which highlights the need to consider weight and fat distribution together to identify high-risk individuals and set intervention targets. This study was supported by the Beijing Medical Award Foundation (No. YXJL-2023-0877-0184). The authors declare that they do not have any conflict of interest to disclose in terms of funding for this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details. Guarantor of the Article: Kai Liu and Junhong Chen Author contributions: KL conceived and supervised the research. CJ designed the study and performed data analysis. CJ and HZ interpreted the results and wrote the manuscript. All authors critically revised the manuscript and approved its final draft. The Third National Health and Nutrition Examination Survey (NHANES III) dataset are publicly available at the National Center for Health Statistics of the Center for Disease Control and Prevention (wwwn.cdc.gov/nchs/nhanes/nhanes3/default.aspx). All the remaining data are available within the article. The National Health and Nutrition Examination Survey were reviewed and approved by the National Center for Health Statistics ethics review board. Written informed consent was obtained from each patient included in the study. The following are the supplementary data to this article: Download .pdf (.44 MB) Help with pdf files Multimedia component 1