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Metabolic (dysfunction)-associated fatty liver disease in individuals of normal weight

Abstract

Metabolic (dysfunction)-associated fatty liver disease (MAFLD) affects up to a third of the global population; its burden has grown in parallel with rising rates of type 2 diabetes mellitus and obesity. MAFLD increases the risk of end-stage liver disease, hepatocellular carcinoma, death and liver transplantation and has extrahepatic consequences, including cardiometabolic disease and cancers. Although typically associated with obesity, there is accumulating evidence that not all people with overweight or obesity develop fatty liver disease. On the other hand, a considerable proportion of patients with MAFLD are of normal weight, indicating the importance of metabolic health in the pathogenesis of the disease regardless of body mass index. The clinical profile, natural history and pathophysiology of patients with so-called lean MAFLD are not well characterized. In this Review, we provide epidemiological data on this group of patients and consider overall metabolic health and metabolic adaptation as a framework to best explain the pathogenesis of MAFLD and its heterogeneity in individuals of normal weight and in those who are above normal weight. This framework provides a conceptual schema for interrogating the MAFLD phenotype in individuals of normal weight that can translate to novel approaches for diagnosis and patient care.

Key points

  • Lean metabolic (dysfunction)-associated fatty liver disease (MAFLD) is common, and these patients have a worse long-term outcome than patients without MAFLD.

  • MAFLD in patients of normal weight likely has a similar prognosis to that in patients with overweight or obesity.

  • Metabolic health is a major determinant of MAFLD pathogenesis in patients of normal weight.

  • Metabolic flexibility and adaptation have major roles in shaping the metabolic health of an individual and consequently the risk of MAFLD.

  • There are no specific guidelines for the management of patients of normal weight with MAFLD but lifestyle interventions remain a cornerstone of treatment.

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Fig. 1: The global prevalence of lean MAFLD.
Fig. 2: The clinical course of fatty liver disease in normal weight and obesity.
Fig. 3: The interaction of multiple factors influences the pathogenesis of MAFLD in individuals of normal weight.
Fig. 4: A proposed hypothesis for the role of metabolic adaptation in MAFLD.

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Acknowledgements

M.E. and J.G. are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; National Health and Medical Research Council of Australia (NHMRC) Program and Investigator Grants (AAP2008983, APP1053206, APP1196492) and Project and Ideas grants (APP2001692, APP1107178, and APP1108422). H.B.E.-S. is supported by grants RP190641 and NIH P30DK056338.

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Eslam, M., El-Serag, H.B., Francque, S. et al. Metabolic (dysfunction)-associated fatty liver disease in individuals of normal weight. Nat Rev Gastroenterol Hepatol 19, 638–651 (2022). https://doi.org/10.1038/s41575-022-00635-5

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