LEAN MASLD: METABOLIC HETEROGENEITY AND IMPLICATIONS FOR DISEASE PROGRESSION
DOI:
https://doi.org/10.31435/ijitss.3(51).2026.6122Keywords:
Lean MASLD, MASLD, Metabolic Heterogeneity, Liver Fibrosis, PNPLA3, Visceral AdiposityAbstract
One of the most widespread liver diseases in the world is metabolic dysfunction-associated steatotic liver disease (MASLD), known until recently as non-alcoholic fatty liver disease (NAFLD). Its prevalence is estimated at 25% in the global population. MASLD is defined as a clinical condition characterized by excessive fat accumulation in the liver in the presence of at least one cardiometabolic risk factor. Although obesity plays a significant role in the pathomechanism of MASLD, it is estimated that approximately 10-20% of MASLD cases occur in individuals with a BMI <25 kg/m² (<23 kg/m² in the Asian population). As studies show, individuals with lean MASLD have a higher risk of liver fibrosis and overall mortality.
The aim of this study is a critical review of the current literature regarding the Lean MASLD phenotype, with particular emphasis on its metabolic heterogeneity. The work analyzes unique pathophysiological mechanisms, such as genetic predispositions and adipose tissue distribution disorders, and evaluates their impact on the risk of progression to advanced fibrosis and hepatocellular carcinoma. This work constitutes a literature review, focusing on clinical and cohort studies as well as review papers concerning the pathogenesis, diagnostics, and clinical course of liver steatosis in individuals with a normal BMI.
The literature analysis indicates a significant role of genetic variants, mainly the PNPLA3 polymorphism (I148M), which predisposes lean individuals to disease progression independently of metabolic factors. It has been shown that despite a normal BMI, these patients are often characterized by visceral adipose tissue dysfunction and an altered gut microbiota profile. Metabolic heterogeneity is manifested by the existence of a subgroup of patients with a "metabolically healthy" profile, in whom cardiovascular risk may be lower, but the risk of progression of liver lesions remains significant. The following work emphasizes that Lean MASLD is not a milder form of liver steatosis, and its diagnostics require going beyond the standard BMI measurement. It is necessary to implement personalized monitoring strategies, taking into account the genetic profile and metabolic assessment, to prevent long-term complications in this specific group of patients.
References
Rinella ME, et al. A multisociety Delphi consensus statement on new nomenclature for steatotic liver disease. J Hepatol. 2023;78(6):1966–1986. https://doi.org/10.1097/HEP.0000000000000520
Ye Q, 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(8):739-752. https://doi.org/10.1016/S2468-1253(20)30077-7
Sato-Espinoza K, Chotiprasidhi P, Huaman MR, Díaz-Ferrer J. Update in lean metabolic dysfunction-associated steatotic liver disease. World J Gastroenterol. 2024;16(3):452–464. https://doi.org/10.4254/wjh.v16.i3.452
Eslam M, et al. A new definition for metabolic dysfunction-associated fatty liver disease. J Hepatol. 2020;73(1):202-209. https://doi.org/10.1016/j.jhep.2020.03.039
Marjot T, Armstrong MJ, Stine JG. Skeletal muscle and MASLD: Mechanistic and clinical insights. Hepatol Commun. 2025;9(6):e0711. https://doi.org/10.1097/HC9.0000000000000711
Babu AF. Metabolic signatures in lean MASLD: Current insights and future directions. Metabolites. 2025;15(9):583. https://doi.org/10.3390/metabo15090583
Wang Z, Tan W, Yu Z, et al. Central obesity measured by weight-adjusted waist index is associated with lean MASLD. Clin Res Hepatol Gastroenterol. 2026;50(5):102822. https://doi.org/10.1016/j.clinre.2026.102822
Aron-Wisnewsky J, et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol. 2020 May;17(5):279-297. https://doi.org/10.1038/s41575-020-0269-9
Chowdhary R, Goyal MK, Vuthaluru AR, et al. Hepatic outcomes in lean versus nonlean metabolic dysfunction-associated steatotic liver disease: Propensity-matched cohort study. Hepatol Res. 2026. https://doi.org/10.1111/hepr.70158
Hagström H, Nasr P, Ekstedt M, et al. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long-term follow-up study. Hepatol Commun. 2017;2(1):48-57. https://doi.org/10.1002/hep4.1124
Lazarus JV, Mark HE, Anstee QM, et al. Advancing the global public health agenda for NAFLD: a consensus statement. Nat Rev Gastroenterol Hepatol. 2022;19(1):60-78. https://doi.org/10.1038/s41575-021-00523-4
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Julia Popielska, Sabina Zima, Bartosz Stawarski, Anna Jędral, Alicja Miścior, Jagoda Kucharczyk, Marlena Gajczak, Katarzyna Łukasiewicz, Klaudia Kuzdak, Keli Jabłońska
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
