Histologic Features and Clinical Outcomes of Lean Metabolic Dysfunction–Associated Steatotic Liver Disease

Importance Although metabolic dysfunction–associated steatotic liver disease (MASLD) is traditionally associated with obesity, it is increasingly recognized in individuals with normal weight (ie, lean MASLD). Objective To characterize the clinical, histologic, and prognostic features of lean MASLD, and evaluate the performance of noninvasive tests for advanced fibrosis. Design, Setting, and Participants Multinational, retrospective observational study of adults with biopsy-confirmed MASLD from 41 countries from the Global MASLD project. Exposures Lean vs overweight/obese MASLD, defined by body mass index (BMI) and waist circumference. Main Outcomes and Measures Primary outcomes were all-cause mortality and clinical events (hepatocellular carcinoma, hepatic decompensation, liver transplant, death), intermediate outcomes included histologic fibrosis severity, and tests included the Fibrosis-4 (FIB-4) score and liver stiffness measurement (LSM) by transient elastography. Results Among 18 326 patients (mean [SD] age, 50.9 [13.1] years; 8714 [47.6%] male), 6.7% were lean by BMI. Among 12 202 patients with waist circumference available, 6.0% were lean by waist circumference (κ = 0.41). Lean MASLD was most prevalent in Asia (11.3% by BMI, 11.7% by waist circumference). Compared with overweight/obese MASLD, lean MASLD had lower prevalence of type 2 diabetes (38.2% vs 48.3%; difference, −10.2% [95% CI, −13.0% to −7.4%]), advanced fibrosis (29.3% vs 37.2%; difference, −7.8% [95% CI, −10.5% to −5.2%]), and Non-Alcoholic Fatty Liver Disease Activity Scores (mean [SD], 3.96 [1.81] vs 4.41 [1.68]; difference, −0.44 [95% CI, −0.56 to −0.33]). The FIB-4 demonstrated lower accuracy for predicting advanced fibrosis (F3-F4) in lean vs overweight/obese MASLD (area under the curve, 0.76 [95% CI, 0.73-0.79] vs 0.79 [95% CI, 0.78-0.80]; difference, −0.03 [95% CI, −0.06 to 0.00]), while LSM had higher accuracy (area under the curve, 0.87 [95% CI, 0.84-0.90] vs 0.83 [95% CI, 0.82-0.84]; difference, 0.04 [95% CI, 0.01-0.07]). Unadjusted rates per 100 person-years in lean vs overweight/obese MASLD were 1.08 vs 0.91 for all-cause mortality and 1.51 vs 1.43 for clinical events, respectively; lean status was not independently associated with all-cause mortality (adjusted hazard ratio [aHR], 0.90 [95% CI, 0.69-1.16]) or clinical events (aHR, 0.94 [95% CI, 0.76-1.17]). Advanced fibrosis (F3-F4) was associated with all-cause mortality (1.46 vs 0.77 per 100 person-years; aHR, 2.10 [95% CI, 1.71-2.57]) and clinical events (3.21 vs 0.89 per 100 person-years; aHR, 3.41 [95% CI, 2.90-4.03]). Conclusions and Relevance Lean MASLD represents a distinct phenotype with milder histologic disease but similar clinical outcomes compared with overweight/obese MASLD. Fibrosis severity, rather than body composition, was associated with prognosis and LSM was reliable in lean individuals.

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Journal
JAMA
Published
2026-09-30
DOI
https://doi.org/10.1001/jama.2026.18491
Primary Topic
Liver Disease Diagnosis and Treatment
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article
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article

Histologic Features and Clinical Outcomes of Lean Metabolic Dysfunction–Associated Steatotic Liver Disease

Sombat Treeprasertsuk, Gulnara Aghayeva, Atsushi Nakajima, George Boon‐Bee Goh et al.
JAMA
Liver Disease Diagnosis and Treatment
article

Histologic Features and Clinical Outcomes of Lean Metabolic Dysfunction–Associated Steatotic Liver Disease

Sombat Treeprasertsuk, Gulnara Aghayeva, Atsushi Nakajima, George Boon‐Bee Goh, Stuart Keith Roberts, Laurent Castéra, Leyla de Avila, Shahinul Alam, Luis Antonio Díaz, Fariba Ahmadizar, Cyrielle Caussy, Elisabetta Bugianesi, Nicole J. Asal, Diana Barb, Johan Vessby, Paloma Carrillo, Jérôme Boursier, Rosa Lombardi, Salvatore Petta, Carrieri Patrizia, Μargarita Papatheodoridi, Lucia Carulli, FAHD AL-MULLA, Zobair M. Younossi, Ashwani Kumar Singal, Michael Betel, Pietro Lampertico, Ming-Hua Zheng, Khalid M. AlNaamani, Saleh Alqahtani, Anna Fracanzani, Shenoy Kotacherry Trivikrama, Juan Pablo Arab, Meena Bansal, Winston Dunn, Hannes Hagstrom, Khalid Alswat, Ahmed Cordie, Wah Kheong Chan, Adrian Gadano, Patrizia Burra, Brian Pearlman, Nicola Pugliese, Abdulrahman Al-Hussaini, Takashi Kobayashi, George Papatheodoridis, Mohamed El-Kassas, Cristiane Villela-Nogueira, Ming-Lung Yu, Fernando Bril, Naim Alkhouri, Arun Valsan, Saleh A. Alqahtani, Maria Stepanova, Jorge Arnold, Sven Francque, Marco Arrese, Roberta D’Ambrosio, Paul N Brennan, Narendra Singh Choudhary, Giada Sebastiani, Shalimar, Mohamed Abu-Farha, Nadege Gunn, Jose Luis Calleja Panero, Francesco Paolo Russo, Alessio Aghemo, A.G. (Onno) Holleboom, Faisal Abaalkhail, Takumi Kawaguchi, Emmanuel Tsochatzis, Rita Basu, Satoru Kakizaki, Graciela Castro-Narro, Hussain Abdulrahman Al-Omar, Mehmet Agirbasli, Marlen Ivon Castellanos Fernandez, Quentin M Anstee, Hamad Al-Ibrahim, Manal Abdelmalek, Vincent Wai-Sun Wong, Jian-Gao Fan, Zobair Younossi, Yusuf Yilmaz, Neeraj Bhala, Elamin Ibrahim Abdelgadir, Javier Crespo, Ajay Duseja, Didac Mauricio, Khalid Al-Naamani, Mario Guimaraes Pessoa, Marco Arrese Jimenez, Claudia P. Oliveira, Seung Up Kim, Alina Allen, Mattias Ekstedt
article en

Abstract

Importance Although metabolic dysfunction–associated steatotic liver disease (MASLD) is traditionally associated with obesity, it is increasingly recognized in individuals with normal weight (ie, lean MASLD). Objective To characterize the clinical, histologic, and prognostic features of lean MASLD, and evaluate the performance of noninvasive tests for advanced fibrosis. Design, Setting, and Participants Multinational, retrospective observational study of adults with biopsy-confirmed MASLD from 41 countries from the Global MASLD project. Exposures Lean vs overweight/obese MASLD, defined by body mass index (BMI) and waist circumference. Main Outcomes and Measures Primary outcomes were all-cause mortality and clinical events (hepatocellular carcinoma, hepatic decompensation, liver transplant, death), intermediate outcomes included histologic fibrosis severity, and tests included the Fibrosis-4 (FIB-4) score and liver stiffness measurement (LSM) by transient elastography. Results Among 18 326 patients (mean [SD] age, 50.9 [13.1] years; 8714 [47.6%] male), 6.7% were lean by BMI. Among 12 202 patients with waist circumference available, 6.0% were lean by waist circumference (κ = 0.41). Lean MASLD was most prevalent in Asia (11.3% by BMI, 11.7% by waist circumference). Compared with overweight/obese MASLD, lean MASLD had lower prevalence of type 2 diabetes (38.2% vs 48.3%; difference, −10.2% [95% CI, −13.0% to −7.4%]), advanced fibrosis (29.3% vs 37.2%; difference, −7.8% [95% CI, −10.5% to −5.2%]), and Non-Alcoholic Fatty Liver Disease Activity Scores (mean [SD], 3.96 [1.81] vs 4.41 [1.68]; difference, −0.44 [95% CI, −0.56 to −0.33]). The FIB-4 demonstrated lower accuracy for predicting advanced fibrosis (F3-F4) in lean vs overweight/obese MASLD (area under the curve, 0.76 [95% CI, 0.73-0.79] vs 0.79 [95% CI, 0.78-0.80]; difference, −0.03 [95% CI, −0.06 to 0.00]), while LSM had higher accuracy (area under the curve, 0.87 [95% CI, 0.84-0.90] vs 0.83 [95% CI, 0.82-0.84]; difference, 0.04 [95% CI, 0.01-0.07]). Unadjusted rates per 100 person-years in lean vs overweight/obese MASLD were 1.08 vs 0.91 for all-cause mortality and 1.51 vs 1.43 for clinical events, respectively; lean status was not independently associated with all-cause mortality (adjusted hazard ratio [aHR], 0.90 [95% CI, 0.69-1.16]) or clinical events (aHR, 0.94 [95% CI, 0.76-1.17]). Advanced fibrosis (F3-F4) was associated with all-cause mortality (1.46 vs 0.77 per 100 person-years; aHR, 2.10 [95% CI, 1.71-2.57]) and clinical events (3.21 vs 0.89 per 100 person-years; aHR, 3.41 [95% CI, 2.90-4.03]). Conclusions and Relevance Lean MASLD represents a distinct phenotype with milder histologic disease but similar clinical outcomes compared with overweight/obese MASLD. Fibrosis severity, rather than body composition, was associated with prognosis and LSM was reliable in lean individuals.

JAMA
Linköping University (SE), Kurume University (JP), Universidade Federal do Rio de Janeiro (BR), Uppsala University (SE), Amrita Institute of Medical Sciences and Research Centre (IN), Medanta The Medicity (IN), Karolinska University Hospital (SE), University of Louisville (US), Kaohsiung Medical University (TW), Chulalongkorn University (TH), Recep Tayyip Erdoğan University (TR), Pontificia Universidad Católica de Chile (CL), Chinese University of Hong Kong (HK), Shanghai Jiao Tong University (CN), Georgetown University (US), Virginia Commonwealth University (US), University of Milan (IT), Yonsei University (KR), Université Paris Cité (FR), Singapore General Hospital (SG), Wenzhou Medical University (CN), Hôpital Beaujon (FR), King Faisal Specialist Hospital & Research Centre (SA), The Royal Free Hospital (GB), XinHua Hospital (CN), McGill University Health Centre (CA), First Affiliated Hospital of Wenzhou Medical University (CN), Hospital de Sant Pau (ES), The Alfred Hospital (AU), King Saud University (SA), Hospital Italiano de Buenos Aires (AR), Kaohsiung Medical University Chung-Ho Memorial Hospital (TW), Amsterdam UMC Location University of Amsterdam (NL), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), University of Malaya (MY), University of California San Diego (US), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES), Monash Alfred Psychiatry Research centre (AU), Assistance Publique – Hôpitaux de Paris (FR), Marqués de Valdecilla University Hospital (ES), Hospices Civils de Lyon (FR), Antwerp University Hospital (BE), National Hospital Organization Takasaki Medical Center (JP), Instituto de Investigación Marqués de Valdecilla (ES), Hôpital Lyon Sud (FR), Laiko General Hospital of Athens (GR), Medanta The Medicity (IN), Center for Outcomes Research in Liver Diseases (US), University of Kansas Medical Center (US), Sree Gokulam Medical College and Research Foundation (IN), Global Health Council (US), Hamilton Medical Center (US), Instituto de Gastroenterología (CU), Velocity Clinical Research (United States) (US), Hospital Universitário Clementino Fraga Filho (BR), University of Palermo (AR), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Azienda Ospedale - Università Padova (IT), Amsterdam University Medical Centers (NL), IRCCS Humanitas Research Hospital (IT), Cairo University hospitals (EG), Institut de Recerca Sant Pau (ES), University College London (GB), Post Graduate Institute of Medical Education and Research (IN), All India Institute of Medical Sciences (IN), Helwan University (EG), Yokohama City University (JP), University of Palermo (IT)
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Liver Disease Diagnosis and Treatment
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