Histologic Features and Clinical Outcomes of Lean Metabolic Dysfunction–Associated Steatotic Liver Disease
Leyla de Avila, Khalid M. AlNaamani, Margarita Papatheodoridi, Salvatore Petta, Hannes Hagström, Seung Up Kim, Atsushi Nakajima, Javier Crespo, Laurent Castera, Naim Alkhouri, Ming-Hua Zheng, Sombat Treeprasertsuk, Shalimar, Emmanuel Tsochatzis, Shenoy Kotacherry Trivikrama, Jian-Gao Fan, Stuart K. Roberts, Khalid Alswat, Vincent Wai-Sun Wong, Yusuf Yilmaz, Winston Dunn, Sven Francque, Ahmed Cordie, Ming-Lung Yu, Mattias Ekstedt, George Boon-Bee Goh, Claudia P. Oliveira, Mario Guimaraes Pessoa, Wah Kheong Chan, Marlen Ivon Castellanos Fernandez, Ajay Duseja, Juan Pablo Arab, George Papatheodoridis, Giada Sebastiani, Cristiane Villela-Nogueira, Roberta D’Ambrosio, Pietro Lampertico, A. G. Holleboom, Arun Valsan, Mohamed El-Kassas, Takashi Kobayashi, Satoru Kakizaki, Cyrielle Caussy, Brian Pearlman, Nicola Pugliese, Johan Vessby, Narendra Singh Choudhary, Takumi Kawaguchi, Francesco Paolo Russo, Adrian Gadano, Luis Antonio Diaz, Ashwani K. Singal, Nadege Gunn, Didac Mauricio, Marco Arrese, Anna Fracanzani, Rosa Lombardi, Alessio Aghemo, Saleh A. Alqahtani, Maria Stepanova, Zobair M. Younossi, , Zobair Younossi, Faisal Abaalkhail, Elamin Ibrahim Abdelgadir, Manal Abdelmalek, Mohamed Abu-Farha, Gulnara Aghayeva, Mehmet Agirbasli, Fariba Ahmadizar, Shahinul Alam, Abdulrahman Al-Hussaini, Hamad Al-Ibrahim, Naim Alkhouri, Khalid Al-Naamani, Alina Allen, Fahd Al-Mulla, Hussain Abdulrahman Al-Omar, Saleh Alqahtani, Khalid Alswat, Quentin M Anstee, Juan Pablo Arab, Jorge Arnold, Marco Arrese Jimenez, Nicole J. Asal, Meena Bansal, Diana Barb, Rita Basu, Michael Betel, Neeraj Bhala, Jerome Boursier, Paul N Brennan, Fernando Bril, Elisabetta Bugianesi, Patrizia Burra, Jose Luis Calleja Panero, Patrizia Carrieri, Paloma Carrillo-Fernández, Lucia Carulli, Laurent Castera, Graciela Castro-Narro, Cyrielle Caussy, Wah Kheong Chan, Phunchai Charatcharoenwitthaya, Yogesh Chawla, Narendra Choudhary, Abhijit Chowdhury, Catherine Cioffi Cohen, Ahmed Cordie, Kathleen Corey, Javier Crespo, Lorenzo D’Antiga, Ruth De Bruyne, Nkos Dedes, Moises Diago, Luis Antonio Diaz, Bruce D. Dimmig, Amreen M. Dinani, Ajay Duseja, Yuichiro Eguchi, Mohamed El-Kassas, Abdel-Naser Elzouki, Ahad Eshraghian, Wayne Eskridge, Jian-Gao Fan, Marlen Fernandez, Anna L. Fracanzani, Sven Francque, Adrian Gadano, Julia Galhardo, Amalia Gastaldelli, Elena S George, Jacob George, Lynn Gerber, Hasmik Ghazinyan, Amit Goel, George Goh, Zachary D. Goodman, Stuart Gordon, Andrea A. Gossard, Isabel Graupera, Giovanni Guaraldi, Nadege Gunn, Saeed Hamid, Mohamad Hassanein, A.G. (Onno) Holleboom, Patrick M. Horne, Katharina Luise Hupa-Breier, Ramazan Idilman, Scott Isaacs, Mads Israelsen, Satoru Kakizaki, Mustafa Kanat, Achim Kautz, Takumi Kawaguchi, Shelley Keating, Caglayan Keklikkıran, James Kim, Seung Up Kim, Ali Kirik, Rohit Kohli, Alice Pik-Shan Kong, Alexander Krag, Mohammad Shafi Kuchay, Carina Kugelmas, Marcelo Kugelmas, Jimmy Che-To Lai, Brian Lam, Diane Langenbacher, Mei-Hsuan Lee, Laurentius Lesmana, Chun-Jen Liu, Rosa Lombardi, Rohit Loomba, Ellina Lytvyak, Paula Macedo, Giulio Marchesini, Didac Mauricio, Tagreed A Mazi, Nahum Mendez Sanchez, Juan M. Mendive, Luca Miele, Mark Dhinesh Muthiah, Atsushi Nakajima, Alexander Nersesov, João Marcello de Araujo Neto, Phil Newsome, Suzanne Norris, Mazen Noureddin, Janus Ong, Masafumi Ono, Ana Ostojic, Nazli Parast, Brian Pearlman, Elizabeth Pekas, Mário Guimarães Pessôa, Salvatore Petta, Claudia Pinto Marques Souza Oliveira, Carlos J. Pirola, Nicola Pugliese, Mary Rinella, Stuart Roberts, Michael Roden, Marina Idalia Rojo-López, Stefano Romeo, Manuel Romero Gomez, Akash Roy, Arun Sanyal, Jörn Schattenberg, Carolin Schneider, Jeffrey Schwimmer, Giada Sebastiani, Mai Sedki, Yuya Seko, Lawrence Serfaty, Najla Shamsi, Jay Shubrook, Gerald Shulman, Shivaram Prasad Singh, Silvia Sookoian, Wendy Spearman, Hilmi Erdem Sümbül, Yoshio Sumida, Hiroyuki Suzuki, Frank Tacke, Hirokazu Takahashi, Maja Sofie Thiele, Jeremy Tomlinson, Sombat Treeprasertsuk, Emmanouil Tsochatzis, Tsubasa Tsutsumi, Christian Tzeuton, Pietro Vajro, Luca Valenti, Umberto Vespasiani Gentilucci, Cristiane A. Villela-Nogueira, Miriam Benedicta Vos, Ali A. Weinstein, Robert Wilechansky, Vincent Wong, Yusuf Yilmaz, Ming-Lung Yu, Shira Zelber-Sagi, Ming-Hua Zheng, Prooksa Ananchuensook, Leena Kondarappassery Balakumaran, Brian Lam, Arathi Venu, Grazia Pennisi, Ying Shang, Wen-Yue Liu, Hye Won Lee, Paula Iruzubieta, Rida Nadeem, Felice Cinque, Mirko Zoncapé, Rui-Xu Yang, Sherlot Juan Song, Nicholas Dunn, Zouhir Gadi, Ming-Lun Yeh, Kevin Kim-Jun Teh, Sanjiv Mahadeva, Licet Gonzalez Fabian, Ahmed Almohsen, Nathalie Leite, Chencheng Xie, Ethan Friend, Maria Poca, Berenice Segrestin, Andrei RacilaImportance
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.