Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), represents one of the most prevalent chronic liver conditions worldwide, affecting an estimated 30% of the global population and serving as a leading cause of cirrhosis, hepatocellular carcinoma and liver-related mortality [
1]. The recent consensus-driven renaming from NAFLD to MASLD, formalized in 2023 by an international panel of experts, marks a pivotal shift toward a more pathophysiologically grounded framework that centers on underlying metabolic dysfunction [
2]. Within this evolving landscape, the distinction between lean (normal-weight) and non-lean (overweight/obese) MASLD has emerged as a clinically urgent issue. While obesity is a well-established risk factor, nearly 2–20% of MASLD cases occur in individuals with normal body mass index (BMI), a phenotype that challenges conventional assumptions about disease severity, natural history and management [
3,
4]. Whether lean MASLD is a milder or more aggressive phenotype remains critical for risk stratification and clinical guidance.
In this context, Song et al. [
5] provided a timely and comprehensive multi-cohort analysis that directly addresses these uncertainties. By comparing community- and hospital-based cohorts across ethnicities, the study offers critical insights into the reclassification of lean individuals under the NAFLD-to-MASLD transition, differences in cardiometabolic and fibrotic profiles between lean and non-lean MASLD, and their long-term outcomes on liver-related events (LREs) and all-cause mortality.
One of the key findings is the substantial discrepancy between NAFLD and MASLD definitions in community settings. The authors reported that 9.0% to 26.7% of lean NAFLD in community-based cohorts lacked any cardiometabolic risk factor (CMRF), thus failing to meet the current MASLD criteria [
5]. In contrast, hospital-based cohorts showed near-perfect alignment between NAFLD and MASLD definitions [
5]. This divergence highlights a critical challenge of the MASLD framework. While it strengthens biological plausibility by linking steatosis to metabolic dysfunction, it may inadvertently exclude a subset of lean individuals with idiopathic or genetically driven hepatic steatosis who remain at significant risk for progressive liver disease. As demonstrated in prior evidence, lean NAFLD patients may harbor high-risk genetic variants (e.g.,
PNPLA3 rs738409 GG,
TM6SF2 rs58542926 CC) and exhibit accelerated fibrosis despite metabolically “healthy” profiles [
6-
8]. Supporting this, a French community-based cohort found a more than 2-fold higher prevalence of advanced fibrosis in lean NAFLD patients (3.7% vs. 1.7% in non-lean NAFLD) [
6]. These findings suggest the current MASLD criteria may require refinement in lean individuals by incorporating alternative markers of metabolic dysfunction (i.e., visceral adiposity, insulin resistance indices, polygenic risk scores) even in the absence of conventional CMRFs.
Song et al. [
5] also revealed that lean and non-lean MASLD patients had a similar number of CMRFs except for CMRF 1 (i.e., overweight). Notably, despite having a lower BMI and lower waist circumference, 44.7% to 51.2% of lean MASLD still met ethnicity-specific waist circumference (WC) thresholds for abdominal obesity. This paradox underscores that adiposity in lean MASLD is not absent but rather redistributed. These findings strongly support the concept that lean MASLD represents a distinct metabolic phenotype, characterized by excess visceral and ectopic fat deposition, heightened insulin resistance and disproportionate metabolic risk relative to BMI [
9].
Regarding fibrosis, the authors found that lean MASLD was linked to less advanced fibrosis in community-based cohorts, whereas fibrosis severity was comparable between lean and non-lean patients in hospital-based cohorts [
5]. This discrepancy highlights the heterogeneity of MASLD shaped by the interplay of metabolic, genetic and environmental determinants. In community-based cohorts, lean MASLD typically manifests in individuals with relatively preserved metabolic health, including a better insulin sensitivity and lower systemic inflammation, thereby conferring a generally attenuated risk of progressive fibrogenesis. In this setting, BMI may serve as a reasonable, albeit imperfect, proxy for overall metabolic burden. Conversely, hospital-based cohorts are enriched for patients referred due to biochemical abnormalities, imaging findings suggestive of steatohepatitis or established cardiometabolic comorbidities. Within this selected population, lean MASLD individuals are disproportionately represented by those with metabolically unhealthy normal weight phenotypes, strong genetic susceptibility, sarcopenia or alternative drivers of liver injury such as gut dysbiosis or environmental exposures. Consequently, once lean MASLD reaches a threshold warranting specialist evaluation, its histologic severity converges with that of non-lean MASLD. These findings have significant implications for risk stratification and clinical-decision making for MASLD. In primary care, lean MASLD may justify less intensive monitoring, whereas in secondary or tertiary care, all MASLD patients, regardless of BMI, should undergo standardized non-invasive fibrosis evaluation (i.e., fibrosis score 4 [FIB-4] followed by vibration-controlled transient elastography).
In terms of long-term adverse liver outcomes, the authors reported similar risk of LREs between lean and non-lean MASLD in their hospital-based cohort [
5]. While the authors appropriately acknowledged that the potential selection bias, driven by comparable baseline fibrosis severity in the referred MASLD participants, may partly explain this null finding, a more fundamental concern lay in the study’s severely limited statistical power. Based on the parameters provided in Table 3 and Supplementary Table 8 of original article by Song et al. [
5], only 2.5% of statistical power was achieved to detect a clinically meaningful difference in LRE incidence, rendering the result highly susceptible to a type II error. Meanwhile, the median follow-up duration was just 4.6 years in this cohort, which was likely insufficient to capture an adequate number of LREs. From a pathophysiological perspective, the progression from established fibrosis to decompensation, hepatocellular carcinoma or liver-related mortality typically evolves over a longer time horizon, often exceeding 5–10 years, particularly in cohorts enriched for early-to-intermediate fibrosis stages. Consequently, the observed lack of association should be interpreted not as evidence of equivalence, but as inconclusive due to inadequate event accrual and follow-up duration. By contrast, the recent multi-cohort study incorporating three long-term cohorts from both Asian and European populations (2,501 incident within a median of 14 years of follow-up), demonstrated that lean MASLD exhibited a significantly 2.14-fold higher risk of LREs compared to non-lean MASLD [
10].
Conversely, Song et al. [
5] reported a 31% higher risk of all-cause mortality among lean MASLD compared with their non-lean counterparts, which was in line with prior evidence [
10-
12]. The recent meta-analysis incorporating 21 cohort studies also demonstrated a 43% greater risk of all-cause mortality in lean MASLD [
11]. Meanwhile, the pooled analysis of three long-term prospective population-based cohorts also confirmed the 26% increased risk of deaths in lean MASLD [
10]. These findings collectively underscore the higher burden of extrahepatic comorbidities in lean MASLD, including cardiovascular disease (CVD) and chronic kidney disease (CKD) as suggested by the authors. In support, Huo et al. [
10] reported a 22% increased risk of CVD-related mortality in lean MASLD versus non-lean phenotype, particularly in MASLD with increased alcohol intake (MetALD) subtype. Likewise, Nabi et al. [
6], using data from a large community-based French cohort, found that lean NAFLD patients faced a 149% higher risk of CKD compared to non-lean individuals. A plausible mechanism is disproportionately severe insulin resistance in lean MASLD, despite preserved BMI, which may act as a systemic driver of both hepatic and systemic organ damage. Consequently, lean MASLD should be reconceptualized as a distinct, high-risk phenotype that warrants vigilant screening for cardiovascular disease, chronic kidney disease and other metabolic complications, akin to its non-lean counterpart.
In conclusion, lean MASLD represents a distinct and clinically significant phenotype that challenges the appropriateness of BMI alone as a surrogate for liver or systemic health. Although it may present with less advanced fibrosis in general population, lean MASLD exhibits comparable histologic severity in clinical cohorts and consistently poor long-term prognosis driven by disproportionate insulin resistance and ectopic fat accumulation. The current MASLD definition may fail to identify lean individuals who remain at substantial risk for progressive liver disease. Moving forward, precision phenotyping by integrating visceral adiposity, insulin sensitivity markers and polygenic risk may guide risk assessment and achieve better prognosis for patients with MASLD.
FOOTNOTES
-
Authors’ contribution
Conception or design of the work: S Wu. Data collection: S Wu. Data interpretation: S Wu. Drafting the article: S Wu. Critical revision of the article: S Wu. Final approval of the version: S Wu.
-
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 82570631).
-
Conflicts of Interest
The author has no conflicts to disclose.
Abbreviations
cardiometabolic risk factor
metabolic dysfunction-associated steatotic liver disease
MASLD with increased alcohol intake
non-alcoholic fatty liver disease
REFERENCES
- 1. Miao L, Targher G, Byrne CD, Cao YY, Zheng MH. Current status and future trends of the global burden of MASLD. Trends Endocrinol Metab 2024;35:697-707.
- 2. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol 2023;79:1542-1556.
- 3. Dey P. The emerging phenotype of nonalcoholic fatty liver disease in lean individuals: what’s different? Front Endocrinol (Lausanne) 2025;16:1693123.
- 4. Kim D, Danpanichkul P, Wijarnpreecha K, Cholankeril G, Loomba R, Ahmed A. Current burden of lean metabolic dysfunction-associated steatotic liver disease among US adults, 2017-2023. Aliment Pharmacol Ther 2025;61:891-894.
- 5. Song SJ, Yoon EL, Wong VW, Jo AJ, Wong GL, Lai JC, et al. Normal-weight metabolic dysfunction-associated steatotic liver disease: reclassification, characteristics, and adverse liver outcomes across diverse populations. Clin Mol Hepatol 2026;32:646-660.
- 6. Nabi O, Lapidus N, Boursier J, de Ledinghen V, Petit JM, Kab S, et al. Lean individuals with NAFLD have more severe liver disease and poorer clinical outcomes (NASH-CO study). Hepatology 2023;78:272-283.
- 7. Younes R, Govaere O, Petta S, Miele L, Tiniakos D, Burt A, 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;71:382-390.
- 8. Seko Y, Lin H, Wong VW, Okanoue T. Impact of PNPLA3 in lean individuals and in cryptogenic steatotic liver disease. Liver Int 2025;45:e16164.
- 9. Babu AF. Metabolic signatures in lean MASLD: current insights and future directions. Metabolites 2025;15:583.
- 10. Huo Z, Chen Y, Huang Y, Yang Z, Long Y, Zhang Q, et al. Long-term prognosis of lean MASLD: evidence from three population-based prospective cohorts. Gut 2026;75:772-785.
- 11. Danpanichkul P, Suparan K, Prasitsumrit V, Ahmed A, Wijarnpreecha K, Kim D. Long-term outcomes and risk modifiers of metabolic dysfunction-associated steatotic liver disease between lean and non-lean populations. Clin Mol Hepatol 2025;31:74-89.
- 12. Ghani L, Aboona MB, Faulkner CS, Rangan P, Rubin MN, Han MAT, et al. Increased mortality among lean versus non-lean adults with MASLD: a multicenter study. J Gastroenterol Hepatol 2025;40:1919-1925.
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