Clinical and Molecular Hepatology

"NAFLD"

Editorials

Rethinking Lean Metabolic Dysfunction-Associated Steatotic Liver Disease: Unrecognized Risk in Lean Populations: Donghee Kim, Anoushka Shenoy, Aijaz Ahmed; Received January 13, 2026 Accepted January 17, 2026 Published online January 27, 2026; DOI: https://doi.org/10.3350/cmh.2026.0056 [Accepted]

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Reconciling Definitions, Phenotypes and Outcomes in Lean MASLD: Editorial on “Normal-weight MASLD: reclassification, characteristics, and adverse liver outcomes across diverse populations”: Shanshan Wu; Received January 2, 2026 Accepted January 17, 2026 Published online January 27, 2026; DOI: https://doi.org/10.3350/cmh.2026.0004 [Accepted]

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Correspondence

Steatotic liver disease

The burden of steatotic liver disease before and during the COVID-19 pandemic: Correspondence to editorial on “Current burden of steatotic liver disease and fibrosis among adults in the United States, 2017-2023”: Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Rohit Loomba, Aijaz Ahmed; Clin Mol Hepatol 2025;31(2):e183-e185.
Published online February 17, 2025; DOI: https://doi.org/10.3350/cmh.2025.0152

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Reply to correspondence on “Current burden of steatotic liver disease and fibrosis among adults in the United States, 2017-2023”
Jeayeon Park, Su Jong Yu
Clinical and Molecular Hepatology.2025; 31(2): e221. CrossRef
Neonatal liver-derived FTH1-enriched extracellular vesicles attenuate ferroptosis and ameliorate MASLD pathogenesis
Xin Zeng, Wei Jiang, Tian Wu, Lan Li, Fudong Fu, Han Yao, Dongbo Wu
Free Radical Biology and Medicine.2025; 240: 693. CrossRef
Liver-Related COVID-19 Consequences: Dynamics of Liver Health in 2.5 Years
Ieva Vanaga, Oksana Kolesova, Aleksandrs Kolesovs, Maija Radzina, Davis Simanis Putrins, Jelena Egle, Sniedze Laivacuma, Jelena Storozenko, Ludmila Viksna
Journal of Clinical Medicine.2025; 14(21): 7604. CrossRef
Prevalence of MASLD and fibrosis assessed by transient elastography in U.S. adolescents: insights from NHANES 2017-2023
Jialin Wu, Junlong Huang, Shiyu Cao, Yang Lyu, Peiyao Yu, Tiejun Feng, Bonan Chen, Fuda Xie, Ge Zhang, Kangmin Zhuang, Aimin Li, Ka Fai To, Wei Kang
Diabetology & Metabolic Syndrome.2025;[Epub] CrossRef

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Letters to the Editor

Current burden of MASLD, MetALD, and hepatic fibrosis among US adults with prediabetes and diabetes, 2017–2023: Donghee Kim, Rohit Loomba, Aijaz Ahmed; Clin Mol Hepatol 2025;31(3):e235-e238.
Published online December 30, 2024; DOI: https://doi.org/10.3350/cmh.2024.1150

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Providing holistic care for patients with metabolic dysfunction‐associated steatotic liver disease/metabolic dysfunction‐associated steatohepatitis: Key aspects of clinical assessment and how to develop individualised care plans for surveillance and inter
Lanlan Chen, Paul Horn, Frank Tacke
Diabetes, Obesity and Metabolism.2026;[Epub] CrossRef
Association of gut microbiota dietary index with metabolic dysfunction-associated steatotic liver disease: the mediating roles of inflammation and body mass index
Yu Pu, Zongbiao Tan, Yanrui Wu, Suqi Zeng, Haodong He, Jixiang Zhang, Weiguo Dong
Frontiers in Nutrition.2025;[Epub] CrossRef
Advances in identifying risk factors of metabolic dysfunction-associated alcohol-related liver disease
Rui-Qi Ye, Yi-Fan Chen, Chang Ma, Xi Cheng, Wei Guo, Sha Li
Biomedicine & Pharmacotherapy.2025; 188: 118191. CrossRef
Disproportionately rising mortality rates of alcohol-associated acute Pancreatitis: Analysis from centers for Disease Control and prevention database (2011–2020)
Pojsakorn Danpanichkul, Yanfang Pang, Donghee Kim, Thanida Auttapracha, Shu-Yen Chan, Do Han Kim, Thanawin Pramotedham, Kanita Mankan, Chanokporn Puchongmart, Juan Pablo Arab, Luis Antonio Diaz, Jorge D. Machicado, Michael B. Wallace, Karn Wijarnpreecha
Pancreatology.2025; 25(4): 508. CrossRef
A Comparison of the Predictive Value of 12 Body Composition Markers for Metabolic Dysfunction-Associated Steatotic Liver Disease, At-Risk Metabolic Dysfunction-Associated Steatohepatitis, and Increased Liver Stiffness in a General Population Setting
Laurens A. van Kleef, Maurice Michel, Mesut Savas, Jesse Pustjens, Roel van de Laar, Edith Koehler, Elisabeth F.C. van Rossum, Harry L.A. Janssen, Jörn M. Schattenberg, Willem P. Brouwer
American Journal of Gastroenterology.2025;[Epub] CrossRef
Extrahepatic manifestation of metabolic dysfunction-associated steatotic liver disease
Anoushka Shenoy, Aijaz Ahmed, Donghee Kim
Metabolism and Target Organ Damage.2025;[Epub] CrossRef
Organokine-Mediated Crosstalk: A Systems Biology Perspective on the Pathogenesis of MASLD—A Narrative Review
Sandra Maria Barbalho, Lucas Fornari Laurindo, Vitor Engracia Valenti, Nahum Méndez-Sánchez, Mariana M. Ramírez-Mejía, Ricardo de Alvares Goulart
International Journal of Molecular Sciences.2025; 26(23): 11547. CrossRef
Editorial: Understanding How Social Determinants of Health Impact Mortality in MASLD—Insights From a National Analysis. Authors' Reply
Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, Rohit Loomba, Aijaz Ahmed
Alimentary Pharmacology & Therapeutics.2025;[Epub] CrossRef

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Steatotic liver disease

The fibrosis-4 index for advanced liver fibrosis in NAFLD with T2DM: Half a loaf is better than no bread: Zeyu Wang, Dong Wan, Meidong Xu, Yong Jiang; Clin Mol Hepatol 2025;31(1):e25-e26.
Published online December 10, 2024; DOI: https://doi.org/10.3350/cmh.2024.0993

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Age serves as the silent architect of FIB-4’s precision in unveiling advanced hepatic fibrosis in MASLD with T2DM: Correspondence to letter to the editor on “Diagnostic accuracy of the fibrosis-4 index for advanced liver fibrosis in nonalcoholic fatty liv
Ji Won Han, Dae Won Jun
Clinical and Molecular Hepatology.2025; 31(2): e152. CrossRef

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Review

Steatotic liver disease

Long-term outcomes and risk modifiers of metabolic dysfunction-associated steatotic liver disease between lean and non-lean populations: Pojsakorn Danpanichkul, Kanokphong Suparan, Vitchapong Prasitsumrit, Aijaz Ahmed, Karn Wijarnpreecha, Donghee Kim; Clin Mol Hepatol 2025;31(1):74-89.
Published online October 23, 2024; DOI: https://doi.org/10.3350/cmh.2024.0631

One-third of adults across the globe exhibit metabolic dysfunction-associated steatotic liver disease (MASLD)―formerly known as nonalcoholic fatty liver disease (NAFLD). To date, MASLD is the fastest-growing etiology of chronic liver disease and hepatocellular carcinoma (HCC). Besides the population with obesity, MASLD can also be found in lean populations, accounting for 13% of the global population, especially Asians. Notably, individuals with lean MASLD face equal or higher overall mortality rates compared to their non-lean counterparts. Risk modifiers encompass advanced age, hepatic fibrosis, and type 2 diabetes mellitus (T2DM). Moreover, the population with lean MASLD is associated with an increased risk of HCC, while their non-lean counterparts are more prone to cardiovascular outcomes and T2DM. Existing evidence indicates a similar risk of liver-related events and extrahepatic cancer between the two groups. However, MASLD-related genetic variants, such as PNPLA3 and TM6SF2, did not significantly affect mortality between the two populations. Still, underreporting alcohol consumption and regional representation limits the study’s comprehensiveness. Longitudinal studies and mechanistic explorations are needed to understand differences in lean versus non-lean MASLD populations. This review highlights the need for awareness and tailored interventions in managing MASLD, considering lean individuals’ unique risks.

Citations

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Dietary vitamin E intake in metabolic dysfunction–associated steatotic liver disease and all-cause/cause-specific mortality
Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, Aijaz Ahmed
European Journal of Gastroenterology & Hepatology.2026; 38(1): 63. CrossRef
The Influence of Metabolic Dysfunction-Associated Steatotic Liver Disease and Body Mass Index on the Incidence of Alzheimer Disease: A Nationwide Cohort Study
Tae Seop Lim, Seok Jong Chung, Jimin Jeon, Ja Kyung Kim, Jinkwon Kim
Gut and Liver.2026; 20(1): 107. CrossRef
Contemporary trends in extrahepatic mortality of chronic liver disease in the United States from 2014 to 2023
Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, Aijaz Ahmed
Clinical and Molecular Hepatology.2026; 32(1): e24. CrossRef
Association of Metabolic Dysfunction–Associated Steatotic Liver Disease With Features of Cerebral Small‐Vessel Disease on Magnetic Resonance Images: A Large Cross‐Sectional Study
Yaqin Wang, Kui Chen, Changfa Wang, Zhongyang Hu, Xiaoling Zhu, Lei Liu
Journal of the American Heart Association.2026;[Epub] CrossRef
Phthalates exposure, biological aging, and increased risks of insulin resistance, prediabetes, and diabetes in adults with metabolic dysfunction-associated steatotic liver disease
Yueru Yang, Shuhui Wan, Linling Yu, Wei Liu, Jiahao Song, Da Shi, Yongfang Zhang, Weihong Chen, Weihong Qiu, Bin Wang
Diabetes & Metabolism.2025; 51(1): 101602. CrossRef
Increased MASH-associated liver cancer in younger demographics
Pojsakorn Danpanichkul, Yanfang Pang, Kanokphong Suparan, Thanida Auttapracha, Supapitch Sirimangklanurak, Abdelrahman M. Attia, Chanattha Thimphitthaya, Michelle Shi Ni Law, Zhenning Yu, Mostafa A. Soliman, Natchaya Polpichai, Chanakarn Kanitthamniyom, D
Hepatology Communications.2025;[Epub] CrossRef
Alcohol–Related Liver Disease, Followed by Metabolic Dysfunction–Associated Steatotic Liver Disease, Emerges as the Fastest‐Growing Aetiologies for Primary Liver Cancer in the United States
Pojsakorn Danpanichkul, Kwanjit Duangsonk, Markos Kalligeros, Michael B. Fallon, Chawinthorn Vuthithammee, Chun Wei Pan, Preenapun Saokhieo, William Derrick, Yanfang Pang, Vincent L. Chen, Donghee Kim, Amit G. Singal, Ju Dong Yang, Karn Wijarnpreecha
Alimentary Pharmacology & Therapeutics.2025; 61(6): 959. CrossRef
Current Burden of Lean Metabolic Dysfunction‐Associated Steatotic Liver Disease Among US Adults, 2017–2023
Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Rohit Loomba, Aijaz Ahmed
Alimentary Pharmacology & Therapeutics.2025; 61(5): 891. CrossRef
Comparative application of MAFLD and MASLD diagnostic criteria on NAFLD patients: insights from a single-center cohort
Maha Elsabaawy, Madiha Naguib, Ahmed Abuamer, Ahmed Shaban
Clinical and Experimental Medicine.2025;[Epub] CrossRef
Advanced lung cancer inflammation index: a key predictor of hepatic steatosis and fibrosis severity
Yajie Liu, Ruilin Wang
BMC Gastroenterology.2025;[Epub] CrossRef
Association of High‐Sensitivity Troponins in Metabolic Dysfunction‐Associated Steatotic Liver Disease With All‐Cause and Cause‐Specific Mortality
Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Aijaz Ahmed
Alimentary Pharmacology & Therapeutics.2025; 61(11): 1785. CrossRef
Addressing the burden of steatotic liver disease: The role of transient elastography: Correspondence to editorial on “Current burden of steatotic liver disease and fibrosis among adults in the United States, 2017-2023”
Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Rohit Loomba, Aijaz Ahmed
Clinical and Molecular Hepatology.2025; 31(2): e180. CrossRef
Current burden of steatotic liver disease and fibrosis among adults in the United States, 2017–2023
Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Rohit Loomba, Aijaz Ahmed
Clinical and Molecular Hepatology.2025; 31(2): 382. CrossRef
Liver cirrhosis in metabolic dysfunction-associated steatohepatitis
Donghyun Ko, Do Han Kim, Pojsakorn Danpanichkul, Masahito Nakano, Chitchai Rattananukrom, Karn Wijarnpreecha, Cheng Han Ng, Mark D Muthiah
Gastroenterology Report.2025;[Epub] CrossRef
Advances in identifying risk factors of metabolic dysfunction-associated alcohol-related liver disease
Rui-Qi Ye, Yi-Fan Chen, Chang Ma, Xi Cheng, Wei Guo, Sha Li
Biomedicine & Pharmacotherapy.2025; 188: 118191. CrossRef
Increased Mortality Among Lean Versus Non‐Lean Adults With MASLD: A Multicenter Study
Leith Ghani, Majd B. Aboona, Claire S. Faulkner, Pooja Rangan, Moises Nevah Rubin, Ma Ai Thanda Han, Michael B. Fallon, Vincent L. Chen, Karn Wijarnpreecha
Journal of Gastroenterology and Hepatology.2025; 40(8): 1919. CrossRef
Evolving Public Attention to Steatotic Liver Disease: A 20‐Year Analysis (2004–2024)
Pojsakorn Danpanichkul, Charat Thongprayoon, Kanokphong Suparan, Donghee Kim, Ornpailin Wanichthanaolan, Phuuwadith Wattanachayakul, Yanfang Pang, Mark D. Muthiah, Anand V. Kulkarni, Ju Dong Yang, Apichat Kaewdech, Wisit Cheungpasitporn, Karn Wijarnpreech
Journal of Gastroenterology and Hepatology.2025; 40(8): 2053. CrossRef
Meta‐Analysis: Effects of Steatotic Liver Disease‐Associated Genetic Risk Alleles on Longitudinal Outcomes
Matthew Kubina, Vitchapong Prasitsumrit, Jarell Tan, Joo Wei Ethan Quek, Dhiraj Peddu, Ankit Mishra, Pojsakorn Danpanichkul, Jake P. Mann, Eric Trépo, Stephan Buch, Daniel Q. Huang, Cheng Han Ng, Mark D. Muthiah, Yu Jun Wong, Karn Wijarnpreecha, Vincent L
Alimentary Pharmacology & Therapeutics.2025; 62(3): 244. CrossRef
Metabolic Impact of Alcohol Consumption in MASLD: Understanding MetALD and Beyond
Eva Juárez-Hernández, Montserrat Berrospe-Alfaro, Misael Uribe, Iván López-Mendez
Journal of Clinical and Experimental Hepatology.2025; 15(6): 103114. CrossRef
Current burden of MASLD, MetALD, and hepatic fibrosis among US adults with prediabetes and diabetes, 2017–2023
Donghee Kim, Rohit Loomba, Aijaz Ahmed
Clinical and Molecular Hepatology.2025; 31(3): e235. CrossRef
Predicting the risk of lean non-alcoholic fatty liver disease based on interpretable machine models in a Chinese T2DM population
Shixue Bao, Qiankai Jin, Tieqiao Wang, Yushan Mao, Guoqing Huang
Frontiers in Endocrinology.2025;[Epub] CrossRef
Effect of varenicline on major adverse liver outcomes in alcohol‐associated liver disease: An exploratory analysis
Pojsakorn Danpanichkul, Yanfang Pang, Donghee Kim, Thanathip Suenghataiphorn, Donghyun Ko, Andrew F. Ibrahim, Vitchapong Prasitsumrit, Kwanjit Duangsonk, Mazen Noureddin, Karn Wijarnpreecha, Suthat Liangpunsakul
Alcohol, Clinical and Experimental Research.2025; 49(11): 2451. CrossRef
Paradoxical association between steatotic liver disease and favorable hepatic outcomes in HCV patients with SVRs
Ming-Ling Chang, Jur-Shan Cheng, Jennifer Tai, Wei-Ting Chen, Sien-Sing Yang, Cheng-Hsun Chiu, Rong-Nan Chien, Chia-Lin Hsu, Shang-Jung Wu, Cathy SJ Fann
Hepatology International.2025; 19(6): 1347. CrossRef
Extrahepatic manifestation of metabolic dysfunction-associated steatotic liver disease
Anoushka Shenoy, Aijaz Ahmed, Donghee Kim
Metabolism and Target Organ Damage.2025;[Epub] CrossRef
Obesity-Driven Metabolic Disorders: The Interplay of Inflammation and Mitochondrial Dysfunction
Wooyoung Choi, Gun Ha Woo, Tae-Hwan Kwon, Jae-Han Jeon
International Journal of Molecular Sciences.2025; 26(19): 9715. CrossRef
Social Determinants of Health in Metabolic Dysfunction‐Associated Steatotic Liver Disease and All‐Cause/Cause‐Specific Mortality
Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, Rohit Loomba, Aijaz Ahmed
Alimentary Pharmacology & Therapeutics.2025;[Epub] CrossRef
Long-term prognosis of lean MASLD: evidence from three population-based prospective cohorts
Zhenyu Huo, Yijun Chen, Yating Huang, Zhirong Yang, Yujun Long, Qian Zhang, Shuohua Chen, Guodong Wang, Shengtao Zhu, Dianjianyi Sun, Canqing Yu, Jun Lv, Liming Li, Ming-Hua Zheng, Shouling Wu, Yuanjie Pang, Shanshan Wu
Gut.2025; : gutjnl-2025-336127. CrossRef
Metabolic dysfunction-associated steatotic liver disease: Prevalence and progression in lean patients
Gerard Stupecki, Emilia Kowalczyk, Agnieszka Ciba-Stemplewska, Magdalena Dolecka-Ślusarczyk, Iwona Gorczyca-Głowacka
Polish Annals of Medicine.2025; : 1. CrossRef
Increasing Prevalence of Steatotic Liver Disease in a Japanese Health Checkup Population, 2004–2022
Yuki Nakahata, Takao Miwa, Akihiro Obora, Takao Kojima, Nobuaki Yagi, Masahito Shimizu
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Frontiers in Gastroenterology.2025;[Epub] CrossRef
Role of ChREBP–PPARα–FGF21 Axis in Metabolic Dysfunction of MASLD
Karina Mireya Palacios Girón, Zamira Helena Hernandez Nazara, Montserrat Maldonado-González, Erika Martínez-López, Martha P. Sánchez Muñoz, Carlos Alfredo Bautista López, Ma. Soledad Aldana Aguiñaga, Jose Alfredo Dominguez-Rosales, Belinda Vargas-Guerrero
International Journal of Molecular Sciences.2025; 26(23): 11425. CrossRef
Implication of the Androgen Receptor in Muscle–Liver Crosstalk: An Overlooked Mechanistic Link in Lean-MASLD
Eleni Myrto Trifylli, Christiana Charalambous, Nikolaos Spiliotopoulos, Nikolaos Papadopoulos, Anastasia Oikonomou, Spilios Manolakopoulos, Melanie Deutsch
Livers.2025; 5(4): 65. CrossRef
Intestinal NLRP3 Deficiency Exacerbates MASLD in Male Mice via Reduced Butyrate Production
Li Chen, Jing Li, Hao Yu Jia, Chun Liu, Shan Shan Li, Feng Shang Zhu, Chang Qing Yang
Journal of Digestive Diseases.2025;[Epub] CrossRef
Poor Sensitivity of the Fatty Liver Index Among Lean Individuals
Mohammed Rifat Shaik, Yaron Rotman
American Journal of Gastroenterology.2025;[Epub] CrossRef
PNPLA3 as a driver of steatotic liver disease: navigating from pathobiology to the clinics via epidemiology
Ralf Weiskirchen, Amedeo Lonardo
Journal of Translational Genetics and Genomics.2024; 8(4): 355. CrossRef

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Original Article

Steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease exhibits sex-specific microbial heterogeneity within intestinal compartments: Carlos Jose Pirola, Maria Silvina Landa, Mariano Schuman, Silvia Inés García, Adrian Salatino, Silvia Sookoian; Clin Mol Hepatol 2025;31(1):179-195.
Published online October 11, 2024; DOI: https://doi.org/10.3350/cmh.2024.0359

Background/Aims
Evidence suggests that the gastrointestinal microbiome plays a significant role in the biology of metabolic dysfunction-associated steatotic liver disease (MASLD). However, it remains unclear whether disparities in the gut microbiome across intestinal tissular compartments between the sexes lead to MASLD pathogenesis.
Methods
Sex-specific analyses of microbiome composition in two anatomically distinct regions of the gut, the small intestine and colon, were performed using an experimental model of MASLD. The study involved male and female spontaneously hypertensive rats and the Wistar-Kyoto control rat strain, which were fed either a standard chow diet or a high-fat diet for 12 weeks to induce MASLD (12 rats per group). High-throughput 16S sequencing was used for microbiome analysis.
Result
s: There were significant differences in the overall microbiome composition of male and female rats with MASLD, including variations in topographical gut regions. The beta diversity of the jejunal and colon microbiomes was higher in female rats than in male rats (PERMANOVA p-value=0.001). Sex-specific analysis and discriminant features using LEfSe showed considerable variation in bacterial abundance, along with distinct functional properties, in the jejunum and colon of animals with MASLD. Significantly elevated levels of lipopolysaccharide and protein expression of Toll-like receptor 4 were observed in the livers of male rats with MASLD compared with their female counterparts.
Conclusions
This study uncovered sexual dimorphism in the gut microbiome of MASLD and identified microbial heterogeneity within intestinal compartments. Insights into sex-specific variations in gut microbiome composition could facilitate customised treatment strategies.

Citations

Citations to this article as recorded by

New Definition, New Point of View: Sex and Gender Interpretation of MASLD—Interpretation of Guidelines and Review of the Literature
Massimo De Luca, Rita Verdoliva, Anna Lombardi, Antonio Giorgio
Gastroenterology Insights.2026; 17(1): 7. CrossRef
MASLD: Prevalence, Mechanisms, and Sex-Based Therapies in Postmenopausal Women
Ilaria Milani, Marianna Chinucci, Frida Leonetti, Danila Capoccia
Biomedicines.2025; 13(4): 855. CrossRef
Characteristics of serum bile acid profiles among individuals with metabolic dysfunction-associated steatotic liver disease
Sheng Lyu, Jiani Yang, Xin Xin, Qinmei Sun, Beiyu Cai, Xin Wang, Ziming An, Jian Sun, Yiyang Hu, Lei Shi, Qin Feng, Xiaojun Gou
BMC Gastroenterology.2025;[Epub] CrossRef
Gut-Liver Axis: The Role of Intestinal Microbiota and Their Metabolites in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease
Chao Cui, Shuai Gao, Jingfei Shi, Kai Wang
Gut and Liver.2025; 19(4): 479. CrossRef
Triglyceride-glucose-waist circumference index: A powerful tool for metabolic dysfunction-associated steatotic liver disease
Bryan Adrian Priego-Parra, Berenice M Román-Calleja, Rocio Gallego-Duran, Jordi Gracia-Sancho, Jose Antonio Velarde Ruiz-Velasco, Jose Maria Remes-Troche
World Journal of Hepatology.2025;[Epub] CrossRef
Sex and gender differences in metabolic dysfunction-associated liver disease
Rishitha Penmetsa, Sasha Kapil, Lisa B. VanWagner
Indian Journal of Gastroenterology.2025;[Epub] CrossRef
Animal models of lean metabolic dysfunction-associated steatotic liver disease (MASLD): bridging pathogenesis and novel drug discovery
Stavros P. Papadakos, Chara Georgiadou, Eva Kassi, Rallia-Iliana Velliou, Antonios Chatzigeorgiou
Expert Opinion on Drug Discovery.2025; 20(12): 1683. CrossRef

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Letter to the Editor

Steatotic liver disease

Sex-specific associations of metabolic dysfunction-associated steatotic liver disease with cardiovascular outcomes: Meng-Yuan Miao, Jie-Qiong Lyu, Wei Jiang, Zhong-Yue Liu, Guo-Chong Chen; Clin Mol Hepatol 2025;31(1):e35-e38.
Published online September 20, 2024; DOI: https://doi.org/10.3350/cmh.2024.0719

Citations

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Sex‐Specific Impact of Metabolic Dysfunction‐Associated Fatty Liver Disease on Incident Cardiovascular Diseases and Mortality
Mahsa Abbaszadeh, Farhad Hosseinpanah, Maryam Tohidi, Sahar Karimpour Reyhan, Maryam Mahdavi, Majid Valizadeh
Endocrinology, Diabetes & Metabolism.2025;[Epub] CrossRef
Implication of the Androgen Receptor in Muscle–Liver Crosstalk: An Overlooked Mechanistic Link in Lean-MASLD
Eleni Myrto Trifylli, Christiana Charalambous, Nikolaos Spiliotopoulos, Nikolaos Papadopoulos, Anastasia Oikonomou, Spilios Manolakopoulos, Melanie Deutsch
Livers.2025; 5(4): 65. CrossRef

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Correspondence

Steatotic liver disease

Correspondence to editorial on “Differences in liver and mortality outcomes of non-alcoholic fatty liver disease by race and ethnicity: A longitudinal real-world study”: Vy H. Nguyen, Mindie H. Nguyen; Clin Mol Hepatol 2024;30(4):1000-1001.
Published online August 5, 2024; DOI: https://doi.org/10.3350/cmh.2024.0611

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Review

Steatotic liver disease

Precision medicine and nucleotide-based therapeutics to treat steatotic liver disease: Andrea Caddeo, Stefano Romeo; Clin Mol Hepatol 2025;31(Suppl):S76-S93.
Published online August 5, 2024; DOI: https://doi.org/10.3350/cmh.2024.0438

Abstract
PDF

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex multifactorial disease and becoming the leading cause of liver-related morbidity and mortality. MASLD spans from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), that may progress to cirrhosis and hepatocellular carcinoma (HCC). Genetic, metabolic, and environmental factors strongly contribute to the heterogeneity of MASLD. Lifestyle intervention and weight loss represent a viable treatment for MASLD. Moreover, Resmetirom, a thyroid hormone beta receptor agonist, has recently been approved for MASLD treatment. However, most individuals treated did not respond to this therapeutic, suggesting the need for a more tailored approach to treat MASLD. Oligonucleotide-based therapies, namely small-interfering RNA (siRNA) and antisense oligonucleotide (ASO), have been recently developed to tackle MASLD by reducing the expression of genes influencing MASH progression, such as PNPLA3 and HSD17B13. Here, we review the latest progress made in the synthesis and development of oligonucleotide-based agents targeting genetic determinants of MASH.

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Original Article

Steatotic liver disease

Diagnostic accuracy of the Fibrosis-4 index for advanced liver fibrosis in nonalcoholic fatty liver disease with type 2 diabetes: A systematic review and meta-analysis: Ji Won Han, Hee Yeon Kim, Jung Hwan Yu, Mi Na Kim, Young Eun Chon, Ji Hyun An, Young-Joo Jin, Miyoung Choi, Seung Up Kim, Han Ah Lee, Dae Won Jun; Clin Mol Hepatol 2024;30(Suppl):S147-S158.
Published online July 25, 2024; DOI: https://doi.org/10.3350/cmh.2024.0330

Background/Aims
The Fibrosis-4 index (FIB-4) is a noninvasive test widely used to rule out advanced liver fibrosis (AF) in patients with nonalcoholic fatty liver disease (NAFLD). However, its diagnostic accuracy in NAFLD patients with type 2 diabetes mellitus (T2DM) is controversial due to the high prevalence of AF in this population.
Methods
Research focusing on the diagnostic accuracy of FIB-4 for liver fibrosis as validated by liver histology in NAFLD patients with T2DM was included, and 12 studies (n=5,624) were finally included in the meta-analysis. Sensitivity, specificity, hierarchical summary receiver operating characteristic (HSROC), positive predictive values (PPVs), and negative predictive values (NPVs) at low cutoffs (1.3–1.67) and high cutoffs (2.67–3.25) for ruling in and out AF were calculated.
Result
s: At low cutoffs, the meta-analysis revealed a sensitivity of 0.74, specificity of 0.62, and HSROC of 0.75. At high cutoffs, the analysis showed a sensitivity of 0.33, specificity of 0.92, and HSROC of 0.85, suggesting FIB-4 as useful for identifying or excluding AF. In subgroup analyses, high mean age and F3 prevalence were associated with lower sensitivity. The calculated NPV and PPV were 0.82 and 0.49 at low cutoffs, whereas the NPV was 0.28 and the PPV was 0.70 at high cutoffs. There were insufficient estimated NPVs <0.90 at a hypothesized prevalence of AF >30% at an FIB-4 cutoff range of 1.3–1.67.
Conclusions
Collectively, FIB-4 has moderate diagnostic accuracy for identifying or excluding AF in NAFLD patients with T2DM, but more evidence must be accumulated due to the limited number of currently reported studies and their heterogeneity.

Citations

Citations to this article as recorded by

Two-step clinical care pathway to predict MASLD-related advanced fibrosis and long-term outcomes in type 2 diabetes
Yuping Chen, Bingtian Dong, Xinrui Jin, Chuan Liu, Ming-Hua Zheng, Xiao Liang, Yameng Sun, Hye Won Lee, Huapeng Lin, Emmanuel Tsochatzis, Salvatore Petta, Elisabetta Bugianesi, Masato Yoneda, Hannes Hagström, Jérôme Boursier, José Luis Calleja, George Boo
Gut.2026; : gutjnl-2025-337506. CrossRef
Part 2: CAR Metabolic Dysfunction-Associated Steatotic Liver Disease Working Group Recommendations for Risk Stratifying Patients With MASLD
Mitchell P. Wilson, Gavin Low, Abdel-Aziz Shaheen, Andreu F. Costa, An Tang, Emily Pang, Silvia Chang, Alexandra Medellin, Jérémy Dana, Noam Millo, Ania Kielar, Li Xin Zhang, Toni Whitaker, Mark Swain, Victoria Leung, Daisy Fung, Casey Hurrell, Christophe
Canadian Association of Radiologists Journal.2026; 77(1): 73. CrossRef
Prognostic value of the FIB-4 index in patients with myocardial infarction with non-obstructive coronary arteries
Wei Zhang, Yuqi Chen, Liu Zhu, Siliang Peng, Mengchao Jin, Jiayu Yin
International Journal of Cardiology.2026; 445: 134045. CrossRef
Reply to: “A machine learning model to predict liver-related outcomes after the functional cure of chronic hepatitis B: Is cirrhosis driving the performance?”
Moon Haeng Hur, Jeong-Hoon Lee
Journal of Hepatology.2025; 82(3): e143. CrossRef
The fibrosis-4 index for advanced liver fibrosis in NAFLD with T2DM: Half a loaf is better than no bread
Zeyu Wang, Dong Wan, Meidong Xu, Yong Jiang
Clinical and Molecular Hepatology.2025; 31(1): e25. CrossRef
Non-Invasive Liver Fibrosis Test Using Shear Wave Elastography
Ji Won Han
The Korean Journal of Medicine.2025; 100(1): 26. CrossRef
Age serves as the silent architect of FIB-4’s precision in unveiling advanced hepatic fibrosis in MASLD with T2DM: Correspondence to letter to the editor on “Diagnostic accuracy of the fibrosis-4 index for advanced liver fibrosis in nonalcoholic fatty liv
Ji Won Han, Dae Won Jun
Clinical and Molecular Hepatology.2025; 31(2): e152. CrossRef
Targeting endoplasmic reticulum proteostasis in liver fibrosis: From signaling mechanisms to therapeutic opportunities
Yawei Kong, Zhengyang Chen, Zhentian Nie, Wei Chen
Pharmacological Research.2025; 217: 107823. CrossRef
Comparison of FIB-4, APRI and AST/ALT ratio with FibroScan in patients with NAFLD and type 2 diabetes: a single-center study from Bangladesh
Muhammad Shah Alam, Syeda Tanzina Kalam, Monirul Islam Khan, Jabed Ahmed, Rahul Saha, A. B. M. Kamrul-Hasan
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Xi-Shuang Chen, Hui-Zhen Liu, Fang Huang, Jian Meng, Jing-Xian Fang, Yu Han, Hui-Ming Zou, Qing Gu, Xue Hu, Qian-Wen Ma, Yue-Xia Han, Sui-Jun Wang
Frontiers in Endocrinology.2025;[Epub] CrossRef
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Forns index and fatty liver index, but not FIB-4, are associated with indices of glycaemia, pre-diabetes and type 2 diabetes: analysis of The Maastricht Study
Leen Heyens, Hanna Kenjic, Pieter Dagnelie, Casper Schalkwijk, Coen Stehouwer, Steven Meex, Jeroen Kooman, Otto Bekers, Marleen van Greevenbroek, Hans Savelberg, Geert Robaeys, Bastiaan de Galan, Annemarie Koster, Martien van Dongen, Simone Eussen, Ger Ko
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Letter to the Editor

Steatotic liver disease

Metabolic-associated fatty liver disease is less effective in predicting mortality than non-alcoholic fatty liver disease and metabolic dysfunction-associated steatotic liver disease: Letter to the editor on “Prognosis of biopsy-confirmed metabolic dysfunction-associated steatotic liver disease: A sub-analysis of the CLIONE study”: Yixuan Zhu, Xiaoyan Ma, Wenjing Ni, Yee Hui Yeo, Junping Shi, Jie Li; Clin Mol Hepatol 2024;30(4):974-977.
Published online July 4, 2024; DOI: https://doi.org/10.3350/cmh.2024.0417

Citations

Citations to this article as recorded by

MAFLD or MASLD: Which better represents the prognosis of the steatotic liver population: Letter to the editor on “Evolutionary changes in metabolic dysfunction-associated steatotic liver disease and risk of hepatocellular carcinoma: A nationwide cohort st
Ying Wang, Shengfeng Wang, Xiude Fan, Jiajun Zhao, Yongfeng Song
Clinical and Molecular Hepatology.2025; 31(2): e128. CrossRef

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Correspondence

Steatotic liver disease

In response to: Steatotic liver disease-know your enemies: Michael H. Le, Linda Henry, Mindie H. Nguyen; Clin Mol Hepatol 2024;30(2):284-286.
Published online February 19, 2024; DOI: https://doi.org/10.3350/cmh.2024.0108

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Original Article

Steatotic liver disease

Global incidence of adverse clinical events in non-alcoholic fatty liver disease: A systematic review and meta-analysis: Michael H. Le, David M. Le, Thomas C. Baez, Hansen Dang, Vy H. Nguyen, KeeSeok Lee, Christopher D. Stave, Takanori Ito, Yuankai Wu, Yee Hui Yeo, Fanpu Ji, Ramsey Cheung, Mindie H. Nguyen; Clin Mol Hepatol 2024;30(2):235-246.
Published online January 26, 2024; DOI: https://doi.org/10.3350/cmh.2023.0485

Background/Aims
Nonalcoholic fatty liver disease (NAFLD) is associated with a multitude of adverse outcomes. We aimed to estimate the pooled incidence of NAFLD-related adverse events.
Methods
We performed a systematic review and meta-analysis of cohort studies of adults with NAFLD to evaluate the pooled incidence of adverse events.
Result
s: 19,406 articles were screened, 409 full-text articles reviewed, and 79 eligible studies (1,377,466 persons) were included. Mean age was 51.47 years and body mass index 28.90 kg/m². Baseline comorbidities included metabolic syndrome (41.73%), cardiovascular disease (CVD) (16.83%), cirrhosis (21.97%), and nonalcoholic steatohepatitis (NASH) (58.85%). Incidence rate per 1,000 person-years for mortality included: all-cause (14.6), CVD-related (4.53), non-liver cancer-related (4.53), and liver-related (3.10). Incidence for liver-related events included overall (24.3), fibrosis progression (49.0), cirrhosis (10.9), liver transplant (12.0), and hepatocellular carcinoma (HCC) (3.39). Incidence for non-liver events included metabolic syndrome (25.4), hypertension (25.8), dyslipidemia (26.4), diabetes (19.0), CVD (24.77), renal impairment (30.3), depression/anxiety (29.1), and non-liver cancer (10.5). Biopsy-proven NASH had higher incidence of HCC (P=0.043) compared to non-NASH. Higher rates of CVD and mortality were observed in North America and Europe, hypertension and non-liver cancer in North America, and HCC in Western Pacific/Southeast Asia (P<0.05). No significant differences were observed by sex. Time-period analyses showed decreasing rates of cardiovascular and non-liver cancer mortality and increasing rates of decompensated cirrhosis (P<0.05).
Conclusions
People with NAFLD have high incidence of liver and non-liver adverse clinical events, varying by NASH, geographic region, and time-period, but not sex.

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Letter to the Editor

Steatotic liver disease

Letter regarding “Waiting for the changes after the adoption of steatotic liver disease”: Kuo Chao Yew, Sunny H. Wong, Vincent Wai-Sun Wong, Hazel H. Oon; Clin Mol Hepatol 2024;30(1):118-120.
Published online November 14, 2023; DOI: https://doi.org/10.3350/cmh.2023.0472

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Editorial

Steatotic liver disease

From nonalcoholic steatohepatitis, metabolic dysfunction-associated fatty liver disease, to steatotic liver disease: Updates of nomenclature and impact on clinical trials: Ming-Lun Yeh, Ming-Lung Yu; Clin Mol Hepatol 2023;29(4):969-972.
Published online September 18, 2023; DOI: https://doi.org/10.3350/cmh.2023.0359

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Letter to the Editor

Steatotic liver disease

Letter regarding “Risk factors in nonalcoholic fatty liver disease”: Abhijit Pratap, Umesh More, Pradnya Phalak, Anita Deshmukh; Clin Mol Hepatol 2023;29(4):1046-1047.
Published online August 22, 2023; DOI: https://doi.org/10.3350/cmh.2023.0268

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Correspondence on Letter regarding “Risk factors in nonalcoholic fatty liver disease”
Eileen L. Yoon, Dae Won Jun
Clinical and Molecular Hepatology.2023; 29(4): 1050. CrossRef

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Editorials

Viral hepatitis

The latest evidence on the impact of fatty liver on liver-related outcomes and mortality in chronic hepatitis B: Xianhua Mao, Lung Yi Mak, Wai-Kay Seto; Clin Mol Hepatol 2023;29(3):690-692.
Published online May 30, 2023; DOI: https://doi.org/10.3350/cmh.2023.0173

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Zhenqiu Liu, Yanfeng Jiang, Chen Suo, Huangbo Yuan, Ziyu Yuan, Tiejun Zhang, Li Jin, Xingdong Chen
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Development of a simple metabolic score to predict liver fibrosis risk in chronic hepatitis B patients: A retrospective cross-sectional study
Li Liu, Peng Ye, Qiuping Gu, Ling Zeng, Lijuan Liang, Yingfeng Wei
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Hepatitis B Virus and microRNAs: A Bioinformatics Approach
Verdiana Zulian, Giulia Fiscon, Paola Paci, Anna Rosa Garbuglia
International Journal of Molecular Sciences.2023; 24(24): 17224. CrossRef

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Steatotic liver disease

Non-invasive imaging biomarkers for liver steatosis in non-alcoholic fatty liver disease: present and future: Lynna Alnimer, Mazen Noureddin; Clin Mol Hepatol 2023;29(2):394-397.
Published online April 1, 2023; DOI: https://doi.org/10.3350/cmh.2023.0104

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Collagen fibers quantification for liver fibrosis assessment using linear dichroism photoacoustic microscopy
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Steatotic liver disease

Screening strategies for non-alcoholic fatty liver disease: a holistic approach is needed: Philipp Kasper, Münevver Demir, Hans-Michael Steffen; Clin Mol Hepatol 2023;29(2):390-393.
Published online March 20, 2023; DOI: https://doi.org/10.3350/cmh.2023.0059

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GH Replacement Therapy Is Associated with Ameliorations in Body Composition and Fatty Liver Index in Patients with Adult-Onset Isolated GH Deficiency
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Keishi Ichikawa, Spencer Hansen, Venkat S. Manubolu, Leili Pourafkari, Hooman Fazlalizadeh, Jairo Aldana-Bitar, Lisa B. VanWagner, Srikanth Krishnan, Matthew J. Budoff
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Teodora Biciusca, Sorina Ionelia Stan, Mara Amalia Balteanu, Ramona Cioboata, Alice Elena Ghenea, Suzana Danoiu, Ana-Maria Bumbea, Viorel Biciusca
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Original Article

Hepatic neoplasm

Factors associated with unrecognized cirrhosis in patients with hepatocellular carcinoma: Yi-Te Lee, Mohammad A. Karim, Hye Chung Kum, Sulki Park, Nicole E. Rich, Mazen Noureddin, Amit G. Singal, Ju Dong Yang; Clin Mol Hepatol 2023;29(2):453-464.
Published online February 1, 2023; DOI: https://doi.org/10.3350/cmh.2022.0450

Background/Aims
Cirrhosis is the most important risk factor of hepatocellular carcinoma (HCC), and patients with cirrhosis are recommended to receive semiannual surveillance for early HCC detection. However, early cirrhosis is often asymptomatic and can go undiagnosed for years, leading to underuse of HCC surveillance in clinical practice. We characterized the frequency and associated factors of unrecognized cirrhosis in a national sample of patients with HCC from the United States.
Methods
HCC patients aged 68 years and older, diagnosed during 2011 to 2015 were included from the SEERMedicare Linked Database. If cirrhosis was diagnosed within 6 months immediately preceding HCC diagnosis or after HCC diagnosis, cases were categorized as unrecognized cirrhosis. Factors associated with unrecognized cirrhosis were identified using logistic regression analyses. Factors associated with overall survival were evaluated using Cox regression analyses.
Result
s: Among 5,098 HCC patients, 74.8% patients had cirrhosis. Among those with cirrhosis, 57.4% had unrecognized cirrhosis, with the highest proportion (76.3%) among those with NAFLD-related HCC. Male sex (aOR: 2.12, 95% CI: 1.83–2.46), non-Hispanic Black race (aOR: 1.93, 95% CI: 1.45–2.57), and NAFLD etiology (aOR: 4.46, 95% CI: 3.68–5.41) were associated with having unrecognized cirrhosis. Among NAFLD-related HCC patients, male sex (aOR: 2.32, 95% CI: 1.71–3.14) was associated with unrecognized cirrhosis. Unrecognized cirrhosis was independently associated with worse overall survival (aHR: 1.17, 95% CI: 1.08–1.27) compared to recognized cirrhosis.
Conclusions
Unrecognized cirrhosis is common in NAFLD-related HCC, particularly among male and Black patients, highlighting these groups as important intervention targets to improve HCC surveillance uptake and outcomes.

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Reviews

Steatotic liver disease

Liver transplantation for non-alcoholic fatty liver disease: indications and post-transplant management: Sara Battistella, Francesca D’Arcangelo, Marco Grasso, Alberto Zanetto, Martina Gambato, Giacomo Germani, Marco Senzolo, Francesco Paolo Russo, Patrizia Burra; Clin Mol Hepatol 2023;29(Suppl):S286-S301.
Published online December 28, 2022; DOI: https://doi.org/10.3350/cmh.2022.0392

Abstract
PDF

Non-alcoholic fatty liver disease (NAFLD) is currently the fastest growing indication to liver transplantation (LT) in Western Countries, both for end stage liver disease and hepatocellular carcinoma. NAFLD/non-alcoholic steatohepatitis (NASH) is often expression of a systemic metabolic syndrome; therefore, NAFLD/NASH patients require a multidisciplinary approach for a proper pre-surgical evaluation, which is important to achieve a post-transplant outcome comparable to that of other indications to LT. NAFLD/NASH patients are also at higher risk of post-transplant cardiovascular events, diabetes, dyslipidemia, obesity, renal impairment and recurrent NASH. Lifestyle modifications, included diet and physical activity, are key to improve survival and quality of life after transplantation. A tailored immunosuppressive regimen may be proposed in selected patients. Development of new drugs for the treatment of recurrent NASH is awaited.

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Steatotic liver disease

Bariatric surgery for non-alcoholic fatty liver disease: Indications and post-operative management: Anja Geerts, Sander Lefere; Clin Mol Hepatol 2023;29(Suppl):S276-S285.
Published online December 22, 2022; DOI: https://doi.org/10.3350/cmh.2022.0373

Abstract
PDF

The prevalence of obesity and metabolic consequences such as nonalcoholic fatty liver diseases (NAFLD) has become a crucial health problem. Lifestyle modifications, especially weight loss, effectively reduces liver injury in NAFLD patients. However, adherence to lifestyle changes is very low in the clinical setting. Bariatric surgery can improve metabolic components and cause long-term weight loss. Therefore, bariatric surgery could serve as an attractive treatment option for NAFLD patients. This review integrates data about the benefits of bariatric surgery on NAFLD but also describes the potential pitfalls.

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Steatotic liver disease

Eating, diet, and nutrition for the treatment of non-alcoholic fatty liver disease: Georg Semmler, Christian Datz, Michael Trauner; Clin Mol Hepatol 2023;29(Suppl):S244-S260.
Published online December 14, 2022; DOI: https://doi.org/10.3350/cmh.2022.0364

Abstract
PDF

Nutrition and dietary interventions are a central component in the pathophysiology, but also a cornerstone in the management of patients with non-alcoholic fatty liver disease (NAFLD). Summarizing our rapidly advancing understanding of how our diet influences our metabolism and focusing on specific effects on the liver, we provide a comprehensive overview of dietary concepts to counteract the increasing burden of NAFLD. Specifically, we emphasize the importance of dietary calorie restriction independently of the macronutrient composition together with adherence to a Mediterranean diet low in added fructose and processed meat that seems to exert favorable effects beyond calorie restriction. Also, we discuss intermittent fasting as a type of diet specifically tailored to decrease liver fat content and increase ketogenesis, awaiting future study results in NAFLD. Finally, personalized dietary recommendations could be powerful tools to increase the effectiveness of dietary interventions in patients with NAFLD considering the genetic background and the microbiome, among others.

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Steatotic liver disease

Interaction between sarcopenia and nonalcoholic fatty liver disease: Sae Kyung Joo, Won Kim; Clin Mol Hepatol 2023;29(Suppl):S68-S78.
Published online December 5, 2022; DOI: https://doi.org/10.3350/cmh.2022.0358

Abstract
PDF

Sarcopenia and nonalcoholic fatty liver disease (NAFLD) are common health problems related to aging. Despite the differences in their diagnostic methods, several cross-sectional and longitudinal studies have revealed the close link between sarcopenia and NAFLD. Sarcopenia and NAFLD are linked by several shared pathogenetic mechanisms, including insulin resistance, hormonal imbalance, systemic inflammation, myostatin and adiponectin dysregulation, nutritional deficiencies, and physical inactivity, thus implicating a bidirectional relationship between sarcopenia and NAFLD. However, there is not sufficient data to support a direct causal relationship between sarcopenia and NAFLD. Moreover, it is currently difficult to conclude whether sarcopenia is a risk factor for nonalcoholic steatohepatitis (NASH) or is a consequence of NASH. Therefore, this review intends to touch on the shared common mechanisms and the bidirectional relationship between sarcopenia and NAFLD.

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Steatotic liver disease

Screening strategy for non-alcoholic fatty liver disease: Saisai Zhang, Lung-Yi Mak, Man-Fung Yuen, Wai-Kay Seto; Clin Mol Hepatol 2023;29(Suppl):S103-S122.
Published online November 30, 2022; DOI: https://doi.org/10.3350/cmh.2022.0336

Abstract
PDF

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting approximately 25% of the general population worldwide, and is forecasted to increase global health burden in the 21st century. With the advancement of non-invasive tests for assessing and monitoring of steatosis and fibrosis, NAFLD screening is now feasible, and is increasingly highlighted in international guidelines related to hepatology, endocrinology, and pediatrics. Identifying high-risk populations (e.g., diabetes mellitus, obesity, metabolic syndrome) based on risk factors and metabolic characteristics for non-invasive screening is crucial and may aid in designing screening strategies to be more precise and effective. Many screening modalities are currently available, from serum-based methods to ultrasonography, transient elastography, and magnetic resonance imaging, although the diagnostic performance, cost, and accessibility of different methods may impact the actual implementation. A two-step assessment with serum-based fibrosis-4 index followed by imaging test vibration-controlled transient elastography can be an option to stratify the risk of liverrelated complications in NAFLD. There is a need for fibrosis surveillance, as well as investigating the cost-effectiveness of different screening algorithms and engaging primary care for first-stage triage screening.

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Steatotic liver disease

MAFLD: How is it different from NAFLD?: Cameron Gofton, Yadhavan Upendran, Ming-Hua Zheng, Jacob George; Clin Mol Hepatol 2023;29(Suppl):S17-S31.
Published online November 29, 2022; DOI: https://doi.org/10.3350/cmh.2022.0367

Abstract
PDF

“Metabolic dysfunction-associated fatty liver disease (MAFLD)” is the term suggested in 2020 to refer to fatty liver disease related to systemic metabolic dysregulation. The name change from nonalcoholic fatty liver disease (NAFLD) to MAFLD comes with a simple set of criteria to enable easy diagnosis at the bedside for the general medical community, including primary care physicians. Since the introduction of the term, there have been key areas in which the superiority of MAFLD over the traditional NAFLD terminology has been demonstrated, including for the risk of liver and extrahepatic mortality, disease associations, and for identifying high-risk individuals. Additionally, MAFLD has been adopted by a number of leading pan-national and national societies due to its concise diagnostic criterion, removal of the requirement to exclude concomitant liver diseases, and reduction in the stigma associated with this condition. The current article explores the differences between MAFLD and NAFLD diagnosis, areas of benefit, some potential limitations, and how the MAFLD terminology has opened up new fields of research.

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Steatotic liver disease

Noninvasive serum biomarkers for liver fibrosis in NAFLD: current and future: Tina Reinson, Ryan M. Buchanan, Christopher D. Byrne; Clin Mol Hepatol 2023;29(Suppl):S157-S170.
Published online November 22, 2022; DOI: https://doi.org/10.3350/cmh.2022.0348

In the last 20 years, noninvasive serum biomarkers to identify liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) have been developed, validated against liver biopsy (the gold standard for determining the presence of liver fibrosis) and made available for clinicians to use to identify ≥F3 liver fibrosis. The aim of this review is firstly to focus on the current use of widely available biomarkers and their performance for identifying ≥F3. Secondly, we discuss whether noninvasive biomarkers have a role in identifying F2, a stage of fibrosis that is now known to be a risk factor for cirrhosis and overall mortality. We also consider whether machine learning algorithms offer a better alternative for identifying individuals with ≥F2 fibrosis. Thirdly, we summarise the utility of noninvasive serum biomarkers for predicting liver related outcomes (e.g., ascites and hepatocellular carcinoma) and non-liver related outcomes (e.g., cardiovascular-related mortality and extra hepatic cancers). Finally, we examine whether serial measurement of biomarkers can be used to monitor liver disease, and whether the use of noninvasive biomarkers in drug trials for non-alcoholic steatohepatitis can accurately, compared to liver histology, monitor liver fibrosis progression/regression. We conclude by offering our perspective on the future of serum biomarkers for the detection and monitoring of liver fibrosis in NAFLD.

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Original Articles

Steatotic liver disease

Single-cell phenotypes of peripheral blood immune cells in early and late stages of non-alcoholic fatty liver disease: Kathryn Jane Waller, Hajar Saihi, Wenhao Li, James Hallimond Brindley, Anja De Jong, Wing-kin Syn, Conrad Bessant, William Alazawi; Clin Mol Hepatol 2023;29(2):417-432.
Published online November 21, 2022; DOI: https://doi.org/10.3350/cmh.2022.0205

Background/Aims
Immune and inflammatory cells respond to multiple pathological hits in the development of nonalcoholic steatohepatitis (NASH) and fibrosis. Relatively little is known about how their type and function change through the non-alcoholic fatty liver disease (NAFLD) spectrum. Here we used multi-dimensional mass cytometry and a tailored bioinformatic approach to study circulating immune cells sampled from healthy individuals and people with NAFLD.
Methods
Cytometry by time of flight using 36 metal-conjugated antibodies was applied to peripheral blood mononuclear cells (PBMCs) from biopsy-proven NASH fibrosis (late disease), steatosis (early disease), and healthy patients. Supervised and unsupervised analyses were used, findings confirmed, and mechanisms assessed using independent healthy and disease PBMC samples.
Result
s: Of 36 PBMC clusters, 21 changed between controls and disease samples. Significant differences were observed between diseases stages with changes in T cells and myeloid cells throughout disease and B cell changes in late stages. Semi-supervised gating and re-clustering showed that disease stages were associated with fewer monocytes with active signalling and more inactive NK cells; B and T cells bearing activation markers were reduced in late stages, while B cells bearing co-stimulatory molecules were increased. Functionally, disease states were associated with fewer activated mucosal-associated invariant T cells and reduced toll-like receptor-mediated cytokine production in late disease.
Conclusions
A range of innate and adaptive immune changes begin early in NAFLD, and disease stages are associated with a functionally less active phenotype compared to controls. Further study of the immune response in NAFLD spectrum may give insight into mechanisms of disease with potential clinical application.

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Viral hepatitis

Association between hepatic steatosis and the development of hepatocellular carcinoma in patients with chronic hepatitis B: Yun Bin Lee, Yeonjung Ha, Young Eun Chon, Mi Na Kim, Joo Ho Lee, Hana Park, Kwang-il Kim, Soo-Hwan Kim, Kyu Sung Rim, Seong Gyu Hwang; Clin Mol Hepatol 2019;25(1):52-64.
Published online October 23, 2018; DOI: https://doi.org/10.3350/cmh.2018.0040

Abstract
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Background/Aims
Nonalcoholic fatty liver disease (NAFLD) is becoming a worldwide epidemic, and is frequently found in patients with chronic hepatitis B (CHB). We investigated the impact of histologically proven hepatic steatosis on the risk for hepatocellular carcinoma (HCC) in CHB patients without excessive alcohol intake.
Methods
Consecutive CHB patients who underwent liver biopsy from January 2007 to December 2015 were included. The association between hepatic steatosis (≥ 5%) and subsequent HCC risk was analyzed. Inverse probability weighting (IPW) using the propensity score was applied to adjust for differences in patient characteristics, including metabolic factors.
Result
s: Fatty liver was histologically proven in 70 patients (21.8%) among a total of 321 patients. During the median (interquartile range) follow-up of 5.3 (2.9–8.3) years, 17 of 321 patients (5.3%) developed HCC: 8 of 70 patients (11.4%) with fatty liver and 9 of 251 patients (3.6%) without fatty liver. The five-year cumulative incidences of HCC among patients without and with fatty liver were 1.9% and 8.2%, respectively (P=0.004). Coexisting fatty liver was associated with a higher risk for HCC (adjusted hazards ratio [HR], 3.005; 95% confidence interval [CI], 1.122–8.051; P=0.03). After balancing with IPW, HCC incidences were not significantly different between the groups (P=0.19), and the association between fatty liver and HCC was not significant (adjusted HR, 1.709; 95% CI, 0.404–7.228; P=0.47).
Conclusions
Superimposed NAFLD was associated with a higher HCC risk in CHB patients. However, the association between steatosis per se and HCC risk was not evident after adjustment for metabolic factors.

Citations

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Review

Steatotic liver disease

NASH Therapy: omega 3 supplementation, vitamin E, insulin sensitizers and statin drugs: Stephen Caldwell; Clin Mol Hepatol 2017;23(2):103-108.
Published online May 10, 2017; DOI: https://doi.org/10.3350/cmh.2017.0103

Abstract
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Non-alcoholic steatohepatitis (NASH) is the more aggressive form of non-alcoholic fatty liver disease (NAFLD). NASH can progress to hepatic fibrosis, cirrhosis, portal hypertension and primary liver cancer. Therapy is evolving with a substantial number of trials of promising new agents now in progress. In this article however, we will examine data for several older forms of therapy which have been fairly extensively studied over the years: Polyunsaturated Fatty Acid (PUFA) supplements, vitamin E, insulin sensitizing agents with a focus on pioglitazone and statin agents. Early interest in PUFA derived from their potential benefit in cardio-metabolic disease and the close association of NAFLD/NASH with Metabolic Syndrome. Results have been variable although most studies show reduction of liver fat without other major effects and their effects are influenced by concomitant weight loss and underlying genetic factors. Vitamin E has had some efficacy in pediatric NASH but questionable efficacy in even mild NASH among adults. Pioglitazone has shown significant histological benefit in a number of trials but concern over side-effects (especially weight gain) have dampened enthusiasm. A newer insulin sensitizer, liraglutide, has also shown promise in a small randomized, controlled trial. Very limited data exists regarding the histological effects of the statins in NASH and these agents appear to be fairly neutral with neither clear cut benefit nor detriment. Their use is best guided by cardiovascular risks rather than liver histology.

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Original Articles

Steatotic liver disease

Serum bilirubin levels are inversely associated with nonalcoholic fatty liver disease: Min-Sun Kwak, Donghee Kim, Goh Eun Chung, Seung Joo Kang, Min Jung Park, Yoon Jun Kim, Jung-Hwan Yoon, Hyo-Suk Lee; Korean J Hepatol 2012;18(4):383-390.
Published online December 21, 2012; DOI: https://doi.org/10.3350/cmh.2012.18.4.383

Abstract
PDF

Background/Aims

Serum bilirubin exerts antioxidant and cytoprotective effects. In addition, elevated serum bilirubin levels are associated with a decreased risk of metabolic and cardiovascular diseases. However, few studies have evaluated whether serum bilirubin is associated with non-alcoholic fatty liver disease (NAFLD), which is closely associated with other metabolic diseases. The aim of this study was thus to elucidate the association between serum total bilirubin levels and NAFLD.

Methods

A cross-sectional study of 17,348 subjects undergoing a routine health check-up was conducted. Subjects positive for hepatitis B or hepatitis C virus, or with other hepatitis history were excluded. NAFLD was diagnosed on the basis of typical ultrasonographic findings and an alcohol consumption of less than 20 g/day.

Results

The mean age of the subjects was 49 years and 9,076 (52.3%) were men. The prevalence of NAFLD decreased steadily as the serum bilirubin level increased in both men and women (P<0.001 for both). Multivariate regression analysis adjusted for other metabolic risk factors showed that serum bilirubin level was inversely associated with the prevalence of NAFLD [odds ratio (OR)=0.88, 95% confidence interval (CI)=0.80-0.97]. Furthermore, there was an inverse, dose-dependent association between NAFLD and serum total bilirubin levels (OR=0.83, 95% CI=0.75-0.93 in the third quartile; OR=0.80, 95% CI=0.71-0.90 in the fourth quartile vs. lowest quartile, P for trend <0.001).

Conclusions

Serum bilirubin levels were found to be inversely associated with the prevalence of NAFLD independent of known metabolic risk factors. Serum bilirubin might be a protective marker for NAFLD.

Citations

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Therapeutic application and construction of bilirubin incorporated nanoparticles
Qing Yao, Ruijie Chen, Vadivel Ganapathy, Longfa Kou
Journal of Controlled Release.2020; 328: 407. CrossRef
Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1
Terry D. Hinds, Justin F. Creeden, Darren M. Gordon, Adam C. Spegele, Steven L. Britton, Lauren G. Koch, David E. Stec
Antioxidants.2020; 9(9): 889. CrossRef
A Nomogram Model Based on Noninvasive Bioindicators to Predict 3‐Year Risk of Nonalcoholic Fatty Liver in Nonobese Mainland Chinese: A Prospective Cohort Study
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Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity
Valentina Ceccarelli, Ilaria Barchetta, Flavia Agata Cimini, Laura Bertoccini, Caterina Chiappetta, Danila Capoccia, Raffaella Carletti, Claudio Di Cristofano, Gianfranco Silecchia, Mario Fontana, Frida Leonetti, Andrea Lenzi, Marco Giorgio Baroni, Eugeni
International Journal of Molecular Sciences.2020; 21(23): 9091. CrossRef
Natural Product Heme Oxygenase Inducers as Treatment for Nonalcoholic Fatty Liver Disease
David E. Stec, Terry D. Hinds
International Journal of Molecular Sciences.2020; 21(24): 9493. CrossRef
Bilirubin Nanoparticles Reduce Diet-Induced Hepatic Steatosis, Improve Fat Utilization, and Increase Plasma β-Hydroxybutyrate
Terry D. Hinds, Justin F. Creeden, Darren M. Gordon, Donald F. Stec, Matthew C. Donald, David E. Stec
Frontiers in Pharmacology.2020;[Epub] CrossRef
Serum lactate levels are associated with serum alanine aminotransferase and total bilirubin levels in patients with type 2 diabetes mellitus: A cross-sectional study
Minori Ishitobi, Toshio Hosaka, Naru Morita, Ken Kondo, Toshitaka Murashima, Atsuko Kitahara, Kazuto Takahashi, Yoshikazu Sumitani, Toshiaki Tanaka, Toshihiko Yokoyama, Takuma Kondo, Hitoshi Ishida
Diabetes Research and Clinical Practice.2019; 149: 1. CrossRef
Reduced biliverdin reductase-A levels are associated with early alterations of insulin signaling in obesity
Flavia Agata Cimini, Andrea Arena, Ilaria Barchetta, Antonella Tramutola, Valentina Ceccarelli, Chiara Lanzillotta, Mario Fontana, Laura Bertoccini, Frida Leonetti, Danila Capoccia, Gianfranco Silecchia, Claudio Di Cristofano, Caterina Chiappetta, Fabio D
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Western Diet-Induced Metabolic Alterations Affect Circulating Markers of Liver Function before the Development of Steatosis
Daniela Gabbia, Marco Roverso, Maria Guido, Diana Sacchi, Michela Scaffidi, Maria Carrara, Genny Orso, Francesco Paolo Russo, Annarosa Floreani, Sara Bogialli, Sara De Martin
Nutrients.2019; 11(7): 1602. CrossRef
CRISPR Cas9-mediated deletion of biliverdin reductase A (BVRA) in mouse liver cells induces oxidative stress and lipid accumulation
Darren M. Gordon, Samuel O. Adeosun, Somtochukwu I. Ngwudike, Christopher D. Anderson, John E. Hall, Terry D. Hinds, David E. Stec
Archives of Biochemistry and Biophysics.2019; 672: 108072. CrossRef
Applying Non-Invasive Fibrosis Measurements in NAFLD/NASH: Progress to Date
Somaya Albhaisi, Arun J. Sanyal
Pharmaceutical Medicine.2019; 33(6): 451. CrossRef
Hepatoprotective Effects of a Ruthenium(II) Schiff Base Complex in Rats with Diet-Induced Prediabetes
Lindokuhle Patience Mabuza, Mlindeli Wilkinson Gamede, Sanam Maikoo, Irvin Noel Booysen, Phikelelani Siphosethu Nguban, Andile Khathi
Current Therapeutic Research.2019; 91: 66. CrossRef
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Ryoichi Fujiwara, Mathias Haag, Elke Schaeffeler, Anne T. Nies, Ulrich M. Zanger, Matthias Schwab
Hepatology.2018; 67(4): 1609. CrossRef
Bilirubin in the Liver–Gut Signaling Axis
Abdul-Rizaq Hamoud, Lauren Weaver, David E. Stec, Terry D. Hinds
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Biliverdin reductase and bilirubin in hepatic disease
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American Journal of Physiology-Gastrointestinal and Liver Physiology.2018; 314(6): G668. CrossRef
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Transplantation Reviews.2018; 32(4): 234. CrossRef
Loss of biliverdin reductase-A promotes lipid accumulation and lipotoxicity in mouse proximal tubule cells
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American Journal of Physiology-Renal Physiology.2018; 315(2): F323. CrossRef
Genetically Regulated Bilirubin and Risk of Non-alcoholic Fatty Liver Disease: A Mendelian Randomization Study
Lei Luo, Ping An, Xinyong Jia, Xiaobian Yue, Sujun Zheng, Shuang Liu, Yu Chen, Wei An, Cheryl A. Winkler, Zhongping Duan
Frontiers in Genetics.2018;[Epub] CrossRef
Relationship between serum bilirubin concentrations and diabetic nephropathy in Shanghai Han’s patients with type 1 diabetes mellitus
Xu Li, Lei Zhang, Haibing Chen, Kaifeng Guo, Haoyong Yu, Jian Zhou, Ming Li, Qing Li, Lianxi Li, Jun Yin, Fang Liu, Yuqian Bao, Junfeng Han, Weiping Jia
BMC Nephrology.2017;[Epub] CrossRef
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Journal of Gastroenterology and Hepatology.2013; 28(S4): 71. CrossRef

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The Prevalence of Metabolic Syndrome in Patients with Nonalcoholic Fatty Liver Disease: Ki Won Moon, M.D., Joung Muk Leem, M.D., Sang Seok Bae, M.D., Ki Man Lee, M.D., Seok Hyung Kim, M.D.*, Hee Bok Chae, M.D., Seon Mee Park, M.D. and Sei Jin Youn, M.D.; Korean J Hepatol 2004;10(3):197-206.

Abstract
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Background/Aims
Nonalcoholic fatty liver disease (NAFLD) is associated with dyslipidemia, obesity, and insulin resistance, which are the main features of metabolic syndrome. First, we examined the prevalence of metabolic syndrome among patients with NAFLD . We then compared the prevalence of metabolic syndrome in simple steatosis with that in nonalcoholic steatohepatitis (NASH). Finally, we sought to identify clinical factors associated with the stage of liver fibrosis. Methods: From November 2002 to March 2004, we enrolled consecutive 25 patients with NAFLD from patients visiting outpatient clinic. The 17 controls were healthy persons w ho visited our health promotion center. We compared the clinical and biochemical data of the NAFLD group with those of the control group. Using histologic findings, we divided NAFLD into simple steatosis and NASH. We then compared the clinical and biochemical data of the simple steatosis group with those of the NASH group. Results: Fourteen patients (14/25, 56%) had metabolic syndrome in the NAFLD group. There was no difference in the prevalence of metabolic syndrome between the simple steatosis (5/10, 50%) and the NASH group (9/15, 60%). We found significant differences in cardiovascular risk factors between the two groups, but homeostasis model assessment insulin resistance w as the only significantly different factor between the simple steatosis group and the NASH group. In addition, no difference in histological features was found between NASH with metabolic syndrome and without metabolic syndrome. Conclusions: A considerable number of patients with NAFLD had metabolic syndrome. There was a close correlation between NAFLD and metabolic syndrome. We could not find any cardiovascular risk factors that could predict a severe fibrosis. (Korean J Hepatol 2004;10:197-206)

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Review

Insulin Resistance in Non-Alcoholic Fatty Liver Disease: Jeong Hyun Park; Korean J Hepatol 2006;12(1):16-30.

Abstract
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Insulin resistance is the pathophysiological hallmark of various kinds of clinical diseases, including non- alcoholic fatty liver disease. Insulin resistance is the common characteristic of metabolic syndrome and its related features. Insulin resistance is a systemic disease that affects the nervous system, muscles, pancreas, kidney, heart and immune system, in addition to the liver. A complex interaction between genes and environment factors enhances insulin resistance and the phenotypic expression of NAFLD (non- alcoholic fatty liver disease) in individual patients. Advanced fibrotic liver disease is associated with many features of metabolic syndrome, and the risk of progressive liver disease should not be underestimated for the individuals suffering with metabolic disorders. Abnormalities of insulin signaling can cause the state of insulin resistance, but there is no clear cut scientific evidence that distorted insulin signaling is the primary pathophysiological defect. Increased adipose tissue mass can cause peripheral tissue insulin resistance via the changes of the adipocytokine secretory patterns. We discuss in this article the sequences of the insulin signaling cascades and the possible molecular targets of insulin resistance, the humoral “cross talk” between the distorted secretory patterns of the adipocytokines, and the peripheral tissue insulin resistance along with the pathophysiology of NAFLD. (Korean J Hepatol 2006;12:16-30)

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Liver Pathology

Nonalcoholic Steatohepatitis: So-Young Jin; Korean J Hepatol 2006;12(3):455-459.

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