Browsing by Author "Loomba, Rohit"

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    A multisociety Delphi consensus statement on new fatty liver disease nomenclature
    (2023) Rinella, Mary E.; Lazarus, Jeffrey V.; Ratziu, Vlad; Francque, Sven M.; Sanyal, Arun J.; Kanwal, Fasiha; Romero, Diana; Abdelmalek, Manal F.; Anstee, Quentin M.; Pablo Arab, Juan; Arrese, Marco; Bataller, Ramon; Beuers, Ulrich; Boursier, Jerome; Bugianesi, Elisabetta; Byrne, Christopher D.; Castro Narro, Graciela E.; Chowdhury, Abhijit; Cortez-Pinto, Helena; Cryer, Donna R.; Cusi, Kenneth; El-Kassas, Mohamed; Klein, Samuel; Eskridge, Wayne; Fan, Jiangao; Gawrieh, Samer; Guy, Cynthia D.; Harrison, Stephen A.; Kim, Seung Up; Koot, Bart G.; Korenjak, Marko; Kowdley, Kris V.; Lacaille, Florence; Loomba, Rohit; Mitchell-Thain, Robert; Morgan, Timothy R.; Powell, Elisabeth E.; Roden, Michael; Romero-Gomez, Manuel; Silva, Marcelo; Singh, Shivaram Prasad; Sookoian, Silvia C.; Spearman, C. Wendy; Tiniakos, Dina; Valenti, Luca; Vos, Miriam B.; Wong, Vincent Wai-Sun; Xanthakos, Stavra; Yilmaz, Yusuf; Younossi, Zobair; Hobbs, Ansley; Villota-Rivas, Marcela; Newsome, Philip N.
    The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.
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    A multisociety Delphi consensus statement on new fatty liver disease nomenclature
    (2023) Rinella, Mary E.; Lazarus, Jeffrey V.; Ratziu, Vlad; Francque, Sven M.; Sanyal, Arun J.; Kanwal, Fasiha; Romero, Diana; Abdelmalek, Manal F.; Anstee, Quentin M.; Arab, Juan Pablo; Arrese, Marco; Bataller, Ramon; Beuers, Ulrich; Boursier, Jerome; Bugianesi, Elisabetta; Byrne, Christopher D.; Narro, Graciela E. Castro; Chowdhury, Abhijit; Cortez-Pinto, Helena; Cryer, Donna R.; Cusi, Kenneth; El-Kassas, Mohamed; Klein, Samuel; Eskridge, Wayne; Fan, Jiangao; Gawrieh, Samer; Guy, Cynthia D.; Harrison, Stephen A.; Kim, Seung Up; Koot, Bart G.; Korenjak, Marko; Howdley, Kris V.; Lacaille, Florence; Loomba, Rohit; Mitchell-Thain, Robert; Morgan, Timothy R.; Powell, Elisabeth E.; Roden, Michael; Romero-Gomez, Manuel; Silva, Marcelo; Singh, Shivaram Prasad; Sookbian, Silvia C.; Spearman, C. Wendy; Tiniakos, Dina; Valenti, Luca; Vos, Miriam B.; Wong, Vincent Wai-Sun; Xanthakos, Stavra; Yilmaz, Yusuf; Younossi, Zobair; Hobbs, Ansley; Villota-Rivas, Marcela; Newsome, Philip N.
    The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steato-hepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/ wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification.(c) 2023 American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and Fundacion Clinica Medica Sur, A.C. Published by Wolters Kluwer/Elsevier B.V/ Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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    A Precision Medicine Guided Approach to the Utilization of Biomarkers in MASLD
    (2024) Thakral, Nimish; Desalegn, Hailemichael; Diaz Piga, Luis Antonio; Cabrera, Daniel; Loomba, Rohit; Arrese Jiménez, Marco Antonio; Arab Verdugo, Juan Pablo
    The new nomenclature of metabolic dysfunction-associated steatotic liver disease (MASLD) emphasizes a positive diagnosis based on cardiometabolic risk factors. This definition is not only less stigmatizing but also allows for subclassification and stratification, thereby addressing the heterogeneity of what was historically referred to as nonalcoholic fatty liver disease. The heterogeneity within this spectrum is influenced by several factors which include but are not limited to demographic/dietary factors, the amount of alcohol use and drinking patterns, metabolic status, gut microbiome, genetic predisposition together with epigenetic factors. The net effect of this dynamic and intricate system-level interaction is reflected in the phenotypic presentation of MASLD. Therefore, the application of precision medicine in this scenario aims at complex phenotyping with consequent individual risk prediction, development of individualized preventive strategies, and improvements in the clinical trial designs. In this review, we aim to highlight the importance of precision medicine approaches in MASLD, including the use of novel biomarkers of disease, and its subsequent utilization in future study designs.
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    Advancing the global public health agenda for NAFLD: a consensus statement
    (2022) Lazarus, Jeffrey, V; Mark, Henry E.; Anstee, Quentin M.; Arab, Juan Pablo; Batterham, Rachel L.; Castera, Laurent; Cortez-Pinto, Helena; Crespo, Javier; Cusi, Kenneth; Dirac, M. Ashworth; Francque, Sven; George, Jacob; Hagstrom, Hannes; Huang, Terry T-K; Ismail, Mona H.; Kautz, Achim; Sarin, Shiv Kumar; Loomba, Rohit; Miller, Veronica; Newsome, Philip N.; Ninburg, Michael; Ocama, Ponsiano; Ratziu, Vlad; Rinella, Mary; Romero, Diana; Romero-Gomez, Manuel; Schattenberg, Jorn M.; Tsochatzis, Emmanuel A.; Valenti, Luca; Wong, Vincent Wai-Sun; Yilmaz, Yusuf; Younossi, Zobair M.; Zelber-Sagi, Shira
    Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease that affects approximately one-quarter of the global adult population, causing a substantial burden of ill health with wide-ranging social and economic implications. It is a multisystem disease and is considered the hepatic component of metabolic syndrome. Unlike other highly prevalent conditions, NAFLD has received little attention from the global public health community. Health system and public health responses to NAFLD have been weak and fragmented, and, despite its pervasiveness, NAFLD is largely unknown outside hepatology and gastroenterology. There is only a nascent global public health movement addressing NAFLD, and the disease is absent from nearly all national and international strategies and policies for non-communicable diseases, including obesity. In this global Delphi study, a multidisciplinary group of experts developed consensus statements and recommendations, which a larger group of collaborators reviewed over three rounds until consensus was achieved. The resulting consensus statements and recommendations address a broad range of topics - from epidemiology, awareness, care and treatment to public health policies and leadership - that have general relevance for policy-makers, health-care practitioners, civil society groups, research institutions and affected populations. These recommendations should provide a strong foundation for a comprehensive public health response to NAFLD.
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    Clinical trial design, biomarkers and end points in metabolic and alcohol-related liver disease
    (2025) Díaz Piga, Luis Antonio; Thiele, Maja; Louvet, Alexandre; Lee, Brian P.; Ajmera, Veeral; Tavaglione, Federica; Hsu, Cynthia L.; Huang, Daniel Q.; Pose, Elisa; Bataller, Ramon; McClain, Craig; Mellinger, Jessica; Tincopa, Monica; Mitchell, Mack C.; Ratziu, Vlad; Rinella, Mary E.; Sarin, Shiv K.; Shah, Vijay H.; Szabo, Gyongyi; Wong, Vincent Wai-Sun; Bansal, Meena B.; Leggio, Lorenzo; Kamath, Patrick S.; Krag, Aleksander; Sanyal, Arun J.; Arrese, Marco; Arab Verdugo, Juan Pablo; Anstee, Quentin M.; Mathurin, Philippe; Loomba, Rohit
    Metabolic and alcohol-related liver disease (MetALD) is a newly defined entity within the spectrum of steatotic liver disease, characterized by the interplay of cardiometabolic risk factors and alcohol consumption. The evolving epidemiology and complex pathophysiology of MetALD present unique challenges and opportunities for clinical trial design. Inclusion criteria should require simultaneous evidence of metabolic dysfunction (at least two cardiometabolic features) and verified quantifiable alcohol exposure recorded over the preceding 3–6 months. Traditional histological end points are limited by invasiveness, sampling error and interpretative variability. Thus, imaging modalities, serum-based fibrosis biomarkers and quantitative measures of alcohol intake are gaining relevance as non-invasive, reproducible and patient-centric end points aiming to improve trial feasibility. Furthermore, incorporating alcohol biomarkers, stratifying patients by metabolic risk factor burden, and using adaptive designs of trials might enhance the precision and generalizability of MetALD clinical trials. Although uncertainties remain regarding optimal patient selection criteria, event rates and the dynamic interplay between metabolic dysfunction and alcohol intake, ongoing research efforts aim to refine diagnostic criteria, standardize methodologies and validate novel end points. These advances will ultimately accelerate drug development, improve trial efficiency and foster interventions to treat MetALD.
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    Clinical Trial to Assess the Safety and Tolerability of Anti-IL 23 Monoclonal Antibody Guselkumab in Patients With Alcohol-Associated Liver Disease
    (2025) Díaz Piga, Luis Antonio; Morris, Sheldon; Dave, Shravan; Kim, Susy M.; Sarik, Wathnita; Richards, Lisa; Madamba, Egbert; Bettencourt, Ricki; Fulinara, Christian; Pham, Thuy; Miller, Grant; Carvalho-Gontijo Weber, Raquel; Momper, Jeremiah D.; He, Feng; Jain, Sonia; Jamieson, Catriona; Kisseleva, Tatiana; Brenner, David; Loomba, Rohit
    BackgroundThere are no FDA-approved therapies for alcohol-associated liver disease (ALD). Preclinical studies indicate that blocking IL-23/IL-17 signalling may reverse liver injury. Guselkumab, an IL-23-specific antibody approved for psoriasis, may be beneficial for ALD. AimsWe aimed to assess the safety and tolerability of guselkumab in patients with ALD. MethodsThis phase-1 dose-escalation study included patients with >= 2 DSM-5 criteria for alcohol use disorder, significant steatosis (MRI-PDFF >= 8%) and MRE < 3.63 kPa (to exclude advanced disease). Guselkumab was given subcutaneously on Days 1 and 29 in 30, 70 or 100 mg dose cohorts. Primary endpoints were adverse events (AEs) and dose-limiting toxicity. ResultsWe enrolled 13 patients (three 30 mg, three 70 mg, and seven 100 mg). Eleven completed the study and two early discontinued in the 100 mg group. Of them, 77% were men, and the median age was 53 [IQR 49-61] years. The median MRI-PDFF and MRE were 18.4% [IQR 8.4%-34.0%] and 2.5 [2.2-2.6] kPa, respectively. The most frequent AEs were hyperuricemia (13%, mild only) and elevated lipase (11%, mild and moderate). There were no serious adverse events or significant variations in liver enzymes. There was a suppression of peripheral interleukin (IL)-17, IL-23, IL-1b and TNF-alpha in the 70 and 100 mg groups, and a significant decrease in alcohol consumption over time (AUDIT-C: 6 [3-7] vs. 5 [1-6], p = 0.023). Conclusions Guselkumab is safe in doses up to 100 mg and may reduce inflammation markers in ALD. These findings support further phase 2 studies to evaluate the efficacy of guselkumab in ALD, particularly in patients with severe phenotypes.
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    Disparities in steatosis prevalence in the United States by Race or Ethnicity according to the 2023 criteria
    (2024) Díaz, Luis Antonio; Lazarus, Jeffrey V.; Fuentes López, Eduardo; Idalsoaga Ferrer, Francisco Javier; Ayares Campos, Gustavo Ignacio; Desaleng, Hailemichael; Danpanichkul, Pojsakorn; Cotter, Thomas G.; Dunn, Winston; Barrera Martínez, Francisco; Wijarnpreecha, Karn; Noureddin, Mazen; Alkhouri, Naim; Singal, Ashwani K.; Wong, Robert J.; Younossi, Zobair M.; Rinella, Mary E.; Kamath, Patrick S.; Bataller, Ramon; Loomba, Rohit; Arrese Jiménez, Marco; Arab Verdugo, Juan Pablo
    © The Author(s) 2024.Introduction: The 2023 nomenclature defined criteria for steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD), alcohol-associated liver disease (ALD), and the overlapping MASLD/ALD (MetALD). We aimed to assess racial and ethnic disparities in the SLD prevalence among United States (US) adults based on this new nomenclature. Methods: We undertook a cross-sectional study employing the 2017–2018 National Health and Nutrition Examination Survey (NHANES) database. We identified SLD according to a controlled attenuation parameter ≥288 dB/m, liver stiffness ≥7.2 kPa, or elevated aminotransferase levels. Alcohol use thresholds were established according to the updated SLD definition. We estimated prevalences using the complex design of the NHANES survey. Multivariable logistic regressions with complex design weights were employed. Results: A total of 5532 individuals are included. The mean age is 45.4 years, and 50.9% are women. The adjusted estimated prevalence of MASLD is 42.4% (95% CI: 41.1–43.8%), MetALD 1.7% (95% CI: 1.3–2.0%), and ALD 0.6% (95% CI: 0.3–0.8%). Hispanics exhibit a higher prevalence of SLD, but there are no significant differences in advanced fibrosis prevalence due to SLD among racial/ethnic groups. In MASLD, men, individuals aged 40–64 and ≥65 years, Hispanics, those with health insurance, higher BMI, diabetes, hypertension, hypertriglyceridemia, and low high-density lipoprotein (HDL) cholesterol or use of lipid-lowering agents are independently associated with a higher risk, while Blacks have the lowest risk. In MetALD, men and higher BMI are independently associated with a higher risk of MetALD in adjusted multivariable analysis. In ALD, the adjusted multivariable analysis shows that only health insurance is independently associated with a lower ALD risk. Conclusions: MASLD prevalence is high in the US, especially in men, older individuals, and Hispanics. MetALD and ALD prevalence was substantial but could be underestimated.
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    Global epidemiology of alcohol-related liver disease, liver cancer, and alcohol use disorder, 2000–2021
    (2025) Danpanichkul, Pojsakorn; Díaz Piga, Luis Antonio; Suparan, Kanokphong; Tothanarungroj, Primrose; Sirimangklanurak, Supapitch; Auttapracha, Thanida; Blaney, Hanna L.; Sukphutanan, Banthoon; Pang, Yanfang; Kongarin, Siwanart; Idalsoaga, Francisco; Fuentes-López, Eduardo; Leggio, Lorenzo; Noureddin, Mazen; White, Trenton M.; Louvet, Alexandre; Mathurin, Philippe; Loomba, Rohit; Kamath, Patrick S.; Rehm, Jürgen; Lazarus, Jeffrey V.; Wijarnpreecha, Karn; Arab Verdugo, Juan Pablo
    Background/Aims Alcohol represents a leading burden of disease worldwide, including alcohol use disorder (AUD) and alcohol-related liver disease (ALD). We aim to assess the global burden of AUD, ALD, and alcohol-attributable primary liver cancer between 2000–2021. Methods We registered the global and regional trends of AUD, ALD, and alcohol-related liver cancer using data from the Global Burden of Disease 2021 Study, the largest and most up-to-date global epidemiology database. We estimated the annual percent change (APC) and its 95% confidence interval (CI) to assess changes in age-standardized rates over time. Results In 2021, there were 111.12 million cases of AUD, 3.02 million cases of ALD, and 132,030 cases of alcohol-attributable primary liver cancer. Between 2000 and 2021, there was a 14.66% increase in AUD, a 38.68% increase in ALD, and a 94.12% increase in alcohol-attributable primary liver cancer prevalence. While the age-standardized prevalence rate for liver cancer from alcohol increased (APC 0.59%; 95% confidence interval [CI] 0.52 to 0.67%) over these years, it decreased for ALD (APC –0.71%; 95% CI –0.75 to –0.67%) and AUD (APC –0.90%; 95% CI –0.94 to –0.86%). There was significant variation by region, socioeconomic development level, and sex. During the last years (2019–2021), the prevalence, incidence, and death of ALD increased to a greater extent in females. Conclusions Given the high burden of AUD, ALD, and alcohol-attributable primary liver cancer, urgent measures are needed to prevent them at both global and national levels.
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    Global survey of stigma among physicians and patients with nonalcoholic fatty liver disease
    (2024) Younossi, Zobair M.; Alqahtani, Saleh A.; Alswat, Khalid; Yilmaz, Yusuf; Keklikkiran, Caglayan; Funuyet-Salas, Jesus; Romero-Gomez, Manuel; Fan, Jian-Gao; Zheng, Ming-Hua; El-Kassas, Mohamed; Castera, Laurent; Liu, Chun-Jen; Wong, Vincent Wai-Sun; Zelber-Sagi, Shira; Allen, Alina M.; Lam, Brian; Treeprasertsuk, Sombat; Hameed, Saeed; Takahashi, Hirokazu; Kawaguchi, Takumi; Schattenberg, Joern M.; Duseja, Ajay; Newsome, Phil N.; Francque, Sven; Spearman, C. Wendy; Fernandez, Marlen I. Castellanos; Burra, Patrizia; Roberts, Stuart K.; Chan, Wah-Kheong; Arrese, Marco; Silva, Marcelo; Rinella, Mary; Singal, Ashwani K.; Gordon, Stuart; Fuchs, Michael; Alkhouri, Naim; Cusi, Kenneth; Loomba, Rohit; Ranagan, Jane; Eskridge, Wayne; Kautz, Achim; Ong, Janus P.; Kugelmas, Marcelo; Eguchi, Yuichiro; Diago, Moises; Yu, Ming-Lung; Gerber, Lynn; Fornaresio, Lisa; Nader, Fatema; Henry, Linda; Racila, Andrei; Golabi, Pegah; Stepanova, Maria; Carrieri, Patrizia; Lazarus, Jeffrey, V
    Background & Aims: Patients with fatty liver disease may experience stigma from the disease or comorbidities. In this cross-sectional study, we aimed to understand stigma among patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and healthcare providers. Methods: Members of the Global NASH Council created two surveys about experiences/attitudes toward NAFLD and related diagnostic terms: a 68-item patient and a 41-item provider survey. Results: Surveys were completed by 1,976 patients with NAFLD across 23 countries (51% Middle East/North Africa [MENA], 19% Europe, 17% USA, 8% Southeast Asia, 5% South Asia) and 825 healthcare providers (67% gastroenterologists/hepatologists) across 25 countries (39% MENA, 28% Southeast Asia, 22% USA, 6% South Asia, 3% Europe). Of all patients, 48% ever disclosed having NAFLD/NASH to family/friends; the most commonly used term was "fatty liver" (88% at least sometimes); "metabolic disease" or "MAFLD" were rarely used (never by >84%). Regarding various perceptions of diagnostic terms by patients, there were no substantial differences between "NAFLD", "fatty liver disease (FLD)", "NASH", or "MAFLD". The most popular response was being neither comfortable nor uncomfortable with either term (56%-71%), with slightly greater discomfort with "FLD" among the US and South Asian patients (47-52% uncomfortable). Although 26% of patients reported stigma related to overweight/obesity, only 8% reported a history of stigmatization or discrimination due to NAFLD. Among providers, 38% believed that the term "fatty" was stigmatizing, while 34% believed that "nonalcoholic" was stigmatizing, more commonly in MENA (43%); 42% providers (gastroenterologists/hepatologists 45% vs. 37% other specialties, p = 0.03) believed that the name change to metabolic dysfunction-associated steatotic liver disease (or MASLD) might reduce stigma. Regarding the new nomenclature, the percentage of providers reporting "steatotic liver disease" as stigmatizing was low (14%). Conclusions: The perception of NAFLD stigma varies among patients, providers, geographic locations and sub-specialties. (c) 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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    High inherited risk predicts age-associated increases in fibrosis in patients with MASLD
    (2025) Díaz, Luis Antonio; Alazawi, William; Agrawal, Saaket; Arab, Juan Pablo; Arrese, Marco; Idalsoaga, Francisco; Barreyro, Fernando Javier; Gadano, Adrián; Marciano, Sebastián; Martínez Morales, Jorge; Villela Nogueira, Cristiane; Leite, Nathalie; Alves Couto, Claudia; Theodoro, Rafael; Dias Monteiro, Mísia Joyner de Sousa; Oliveira, Claudia P.; Pessoa, Mario G.; Reis Alvares-da-Silva, Mario; Madamba, Egbert; Bettencourt, Ricki; Richards, Lisa M.; Majithia, Amit R.; Khera, Amit V.; Loomba, Rohit; Ajmera, Veeral
    Background & AimsLimited data have prevented routine genetic testing from being integrated into clinical practice in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to quantify the effect of genetic variants on changes in fibrosis severity per decade in MASLD.MethodsThis cross-sectional study included prospectively recruited adults with MASLD aged 18–70 who underwent magnetic resonance elastography (MRE) and genotyping for PNPLA3, TM6SF2, MBOAT7, GCKR, and HSD17B13. A genetic risk score (GRS) was calculated as the sum of established risk alleles in PNPLA3 minus protective variants in HSD17B13 (0=low risk, 1=high risk). We also estimated the polygenic risk score-hepatic fat content (PRS-HFC) and the adjusted version (PRS-5). The primary endpoint was the age-related change in liver stiffness measurement (LSM) on MRE by GRS. Findings were validated using an external cohort from Latin America.ResultsAmong 570 participants, the median age was 57 [49–64] years, 56.8% were women, and 34.2% were Hispanic. Median MRE was 2.4 [2.1–3.0] kPa, and 51% had high GRS. High GRS was independently associated with increased LSM (β=0.28 kPa, 95%CI:0.12–0.44, p=0.001) per 10-year age increase, while the low GRS group showed no significant difference. Similar findings were observed using PRS-HFC and PRS-5. PNPLA3 genotype alone also predicted higher LSM (C/G: β=0.32 kPa, 95%CI:0.02–0.61, p=0.034; G/G: β=0.87 kPa, 95%CI:0.52–1.22, p<0.0001) and G/G genotype was associated with significantly higher LSM by age 44, which was consistent in the validation population.ConclusionGRS, PRS-HFC, PRS-5, and PNPLA3 genotypes alone are associated with greater fibrosis per decade, resulting in divergent disease trajectories starting in midlife. Assessing genetic risk in MASLD will identify high-risk patients who require more frequent monitoring."
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    Inherited Genetic Risk of Liver Fibrosis in Lean Versus Nonlean Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD)
    (John Wiley & Sons Ltd., 2025) Tesfai, Kaleb; Díaz Piga, Luis Antonio; Arab, Juan Pablo; Arrese, Marco; Idalsoaga, Francisco; Ayares, Gustavo; Agrawal, Saaket; Barreyro, Fernando Javier; Gadano, Adrian; Marciano, Sebastián; Martínez Morales, Jorge; Villela‐Nogueira, Cristiane; Leite, Nathalie; Salles, Gil; Regina Cardoso, Claudia; Alves Couto, Claudia; Theodoro, Rafael; Monteiro. Mísia Joyner de Sousa Dias; Oliveira, Claudia P.; Pessoa, Mario G.; Alvares‐da‐Silva, Mario Reis; Huang, Daniel Q.; Madamba, Egbert; Singh, Seema; Lokanadham, Snigdha; Bettencourt, Ricki; Richards, Lisa M.; Khera, Amit V.; Loomba, Rohit; Ajmera, Veeral
    Introduction Previous studies have revealed conflicting results regarding liver fibrosis risk in lean metabolic dysfunction–associated steatotic liver disease (MASLD). We aimed to compare the risk of significant fibrosis in lean versus nonlean MASLD and identify fibrosis-associated factors in lean MASLD. Methods The study was a cross-sectional analysis of prospectively enrolled adults with MASLD. Individuals with lean MASLD were age- and sex-matched with nonlean MASLD. Fibrosis assessment included vibration-controlled transient elastography, magnetic resonance elastography and liver biopsy. A genetic risk score (GRS), summating the effect alleles of PNPLA3 and TM6SF2 minus the protective HSD17B13 genotype, was estimated to consider inherited genetic risk across BMI categories. Results were validated in an external Latin American cohort.ResultsThe mean ( SD) age of 312 included participants with MASLD was 58.3  11.6 years and 69.2% were female. 44 (14.1%) individuals were lean, 90 (28.9%) were overweight, 90 (28.9%) had class I obesity and 88 (28.1%) had class II or greater obesity. The prevalence of significant fibrosis was 27.3% in lean and 31.1% in nonlean (p = 0.653). Individuals with a high GRS had a higher prevalence of significant fibrosis compared to patients with low GRS (36.5% vs. 25.2%, p = 0.043) and the prevalence of significant fibrosis was similar in lean and nonlean patients with high GRS (31.3% vs. 37.1%, p = 0.645). The Latin American cohort exhibited similar results. Conclusions The prevalence of significant fibrosis and the effect of GRS were similar in lean and nonlean MASLD, highlighting that lean MASLD patients may have a comparable risk to overweight and obese MASLD.
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    MetALD: New Perspectives on an Old Overlooked Disease
    (WILEY, 2025) Ayares, Gustavo; Díaz, Luis Antonio; Idalsoaga, Francisco; Alkhouri, Naim; Noureddin, Mazen; Bataller, Ramon; Loomba, Rohit; Arab, Juan Pablo; Arrese, Marco
    Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are the major contributors to the liver disease burden globally. The rise in these conditions is linked to obesity, type 2 diabetes, metabolic syndrome and increased alcohol consumption. MASLD and ALD share risk factors, pathophysiology and histological features but differ in their thresholds for alcohol use, and the ALD definition does not require the presence of metabolic dysfunction. A recent multi-society consensus overhauled the nomenclature of liver steatosis and introduced the term MetALD to describe patients with metabolic dysfunction who drink more than those with MASLD and less than those with ALD. This new terminology aims to enhance the understanding and management of liver disease but poses challenges, such as the need to accurately measure alcohol consumption in research and clinical practice settings. Recent studies show that MetALD has significant implications for patient management, as it is associated with increased mortality risks and more severe liver outcomes compared to MASLD alone. MetALD patients face increased risks of liver disease progression, cancer and cardiovascular disease. The diagnosis of MetALD involves the adequate quantification of alcohol use through standardised questionnaires and/or biomarkers as well as proper assessment of liver disease stage and progression risk using non-invasive tools including serologic markers, imaging, elastography techniques and genetic testing. Effective management requires addressing both metabolic and alcohol-related factors to improve outcomes. This review intends to provide a comprehensive overview of MetALD, covering pathogenesis, potential diagnostic approaches, management strategies and emerging therapies.
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    Noninvasive pathway for stratifying fibrosis in suspected metabolic dysfunction and alcohol-associated liver disease (MetALD)
    (2025) Diaz Piga, Luis Antonio; Tavaglione, Federica; Mittal, Nikita; Bettencourt, Ricki; Amangurbanova, Maral; Johnson, Amy; Marti-Aguado, David; Tincopa, Monica; Loomba, Ria; Khan-Riches, Asma; Madamba, Egbert; Siddiqi, Harris; Richards, Lisa; Sirlin, Claude B.; Ajmera, Veeral; Loomba, Rohit
    Background: Metabolic dysfunction and alcohol-associated liver disease (MetALD) may increase liver fibrosis progression, but data on screening are scarce. We aimed to assess the performance of noninvasive tests (NITs) for detecting significant fibrosis in individuals with suspected MetALD.Methods: This is a cross-sectional study of prospectively enrolled adults identified as overweight or obese. We included adults with suspected MetALD defined by ≥1 of 5 cardiometabolic criteria and self-reported alcohol use within MetALD ranges or lower self-reported alcohol use but with phosphatidylethanol (PEth) levels ≥25 ng/mL. Clinical assessment included contemporaneous magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE). Significant fibrosis was defined as MRE ≥3.14 kPa (or VCTE ≥7.6 kPa if MRE was missing). Analyses included AUROCs.Results: Among 617 individuals screened, we identified 97 (15.7%) with suspected MetALD. The mean age was 50.6±12.8 years, 67% were men, the mean body mass index was 31.4±6.5 kg/m2, 12.4% had diabetes, and 8% had significant fibrosis. Fibrosis-4 ≥1.3 demonstrated good performance for significant fibrosis (AUROC: 0.78, 95% CI: 0.58–0.98, sensitivity 80%, specificity 76%, positive predictive value 17%, and negative predictive value 98%). VCTE ≥8 kPa also had good performance (AUROC: 0.85, 95% CI: 0.66–1.00, sensitivity 80%, specificity 91%, positive predictive value 36%, and negative predictive value 99%). A stepwise approach using fibrosis-4 followed by VCTE yielded a low false negative rate (2% misclassified as low risk).Conclusions: A clinical care algorithm utilizing a stepwise approach with fibrosis-4 and VCTE shows adequate performance in detecting significant fibrosis in individuals with suspected MetALD.
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    Placebo Rates in Metabolic Dysfunction-associated Steatohepatitis Clinical Trials: A Systematic Review and Meta-analysis
    (2025) Idalsoaga Ferrer, Francisco Javier; Diaz Piga, Luis Antonio; Alghsoon, Saleh; Lawendy, Bishoy; Sharma,Neha; Desalegn, Hailemichael; Yuan, Yuhong; Ha, My; Le, Jessica; MacDonald, John K.; Arrese, Marco; Loomba, Rohit; Jairath, Vipul; Khan, Mohammad Qasim; Arab, Juan Pablo
    Background: High placebo response rates complicate drug development in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials. We performed a meta-analysis to quantify placebo response and assess influencing factors.Methods: MEDLINE, Embase, and CENTRAL were searched from inception to May 7, 2025 for placebo-controlled trials of pharmacological interventions for MASH. Placebo response rates were pooled by random-effects model and meta-regression was used to evaluate the effects of patient and trial design factors on the primary outcomes.Results: One-hundred and twenty-seven studies (6,880 participants) were included. For the primary outcome, the pooled proportion of non-cirrhotic placebo patients achieving MASH resolution without worsening of fibrosis was 11% (95% CI: 8% to 14%). Meta-regression did not identify any significant patient or trial characteristics associated with placebo response. For the second primary outcome, the proportion of cirrhotic placebo patients whose Model for End-stage Liver Disease score increased from below 12 to ≥15 was 4% (95% CI 1% to 13%). Regarding secondary outcomes, 12% (95% CI: 8% to 18%) of placebo patients achieved normal alanine aminotransferase levels, and 22% (95% CI: 18% to 27%) showed an absolute reduction of 5% in hepatic fat content. Additionally, 19% of placebo patients (95% CI: 16% to 22%) achieved a relative reduction of 30% in fat content, while 2% (95% CI: 0.7% to 3%) progressed to cirrhosis.Conclusion: Placebo response rates among patients with MASH are generally elevated yet vary considerably depending on the outcome measured. This study provides valuable insights to enhance the design of future MASH trials.
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    Real-world evidence on non-invasive tests and associated cut-offs used to assess fibrosis in routine clinical practice
    (2023) Lazarus, Jeffrey, V; Castera, Laurent; Mark, Henry E.; Allen, Alina M.; Adams, Leon A.; Anstee, Quentin M.; Arrese, Marco; Alqahtani, Saleh A.; Bugianesi, Elisabetta; Colombo, Massimo; Cusi, Kenneth; Hagstrom, Hannes; Loomba, Rohit; Romero-Gomez, Manuel; Schattenberg, Jorn M.; Thiele, Maja; Valenti, Luca; Wong, Vincent Wai-Sun; Yilmaz, Yusuf; Younossi, Zobair M.; Francque, Sven M.; Tsochatzis, Emmanuel A.
    Background & Aims: Non-invasive tests (NITs) offer a practical solution for advanced fibrosis identification in non-alcoholic fatty liver disease (NAFLD). Despite increasing implementation, their use is not standardised, which can lead to inconsistent interpretation and risk stratification. We aimed to assess the types of NITs and the corresponding cut-offs used in a range of healthcare settings. Methods: A survey was distributed to a convenience sample of liver health experts who participated in a global NAFLD consensus statement. Respondents provided information on the NITs used in their clinic with the corresponding cut-offs and those used in established care pathways in their areas.Results: There were 35 respondents from 24 countries, 89% of whom practised in tertiary level settings. A total of 14 different NITs were used, and each respondent reported using at least one (median = 3). Of the respondents, 80% reported using FIB-4 and liver stiffness by vibration-controlled transient elastography (Fibroscan & REG;), followed by the NAFLD fibrosis score (49%). For FIB-4, 71% of respondents used a low cut-off of <1.3 (range <1.0 to <1.45) and 21% reported using age-specific cut-offs. For Fibroscan & REG;, 21% of respondents used a single liver stiffness cut-off: 8 kPa in 50%, while the rest used 7.2 kPa, 7.8 kPa and 8.7 kPa. Among the 63% of respondents who used lower and upper liver stiffness cut-offs, there were variations in both values (<5 to <10 kPa and >7.5 to >20 kPa, respectively).Conclusions: The cut-offs used for the same NITs for NAFLD risk stratification vary between clinicians. As cut-offs impact test performance, these findings underscore the heterogeneity in risk-assessment and support the importance of establishing consistent guidelines on the standardised use of NITs in NAFLD management. Lay summary: Owing to the high prevalence of non-alcoholic fatty liver disease (NAFLD) in the general population it is important to identify those who have more advanced stages of liver fibrosis, so that they can be properly treated. Non-invasive tests (NITs) provide a practical way to assess fibrosis risk in patients. However, we found that the cut-offs used for the same NITs vary between clinicians. As cut-offs impact test performance, these findings highlight the importance of establishing consistent guidelines on the standardised use of NITs to optimise clinical management of NAFLD.& COPY; 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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    Safety and Tolerability of Injectable Extended‐Release Naltrexone for the Management of Alcohol Use Disorder in Advanced Alcohol‐Associated Liver Disease
    (John Wiley & Sons Ltd., 2025) Díaz Piga, Luis Antonio; Collier, Summer; Yin, Jeffrey; Loomba, Rohit
    Background: Pharmacologic treatment of alcohol use disorder (AUD) in patients with advanced alcohol-associated liver dis-ease (ALD) remains underutilised due to concerns regarding hepatotoxicity. Injectable extended-release naltrexone (XR-NTX)may offer a safer alternative by avoiding first-pass hepatic metabolism, but data on its safety and effectiveness in patients withadvanced ALD are limited.Aim: To describe the clinical experience with XR-NTX in individuals with advanced ALD, evaluating its safety, tolerability andimpact on liver function and alcohol use.Methods: Retrospective case series of adults with ALD who received at least one dose of XR-NTX 380 mg IM at a tertiary carecentre between 2023 and March 2025. Clinical data and laboratory tests were extracted from electronic health records over aminimum follow-up of 12 weeks. Safety was assessed based on adverse events and liver biochemistry. Alcohol use was evaluatedusing phosphatidylethanol (PEth) levels.Results: Fourteen individuals with ALD were included (2 had F3 and 9 cirrhosis Child A–B). The median age was 51 [44–65]years, 64% were male, and median follow-up was 127 days. Four patients (29%) experienced mild adverse effects (injection sitepain, nausea and vomiting, fatigue and sexual side effects); none had hepatotoxicity or hepatic decompensation. No significantchanges in liver function tests or MELD/Child-Pugh scores were observed during the follow-up period. Eight participants (57%)had a decrease in alcohol consumption, with a non-significant decline in PEth levels.
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    The impact of stigma on quality of life and liver disease burden among patients with nonalcoholic fatty liver disease
    (2024) Younossi, Zobair M.; AlQahtani, Saleh A.; Funuyet-Salas, Jesus; Romero-Gomez, Manuel; Yilmaz, Yusuf; Keklikkiran, Caglayan; Alswat, Khalid; Yu, Ming-Lung; Liu, Chun-Jen; Fan, Jian-Gao; Zheng, Ming-Hua; Burra, Patrizia; Francque, Sven M.; Castera, Laurent; Schattenberg, Joern M.; Newsome, Philip N.; Allen, Alina M.; El-Kassas, Mohamed; Treeprasertsuk, Sombat; Hameed, Saeed; Wong, Vincent Wai-Sun; Zelber-Sagi, Shira; Takahashi, Hirokazu; Kawaguchi, Takumi; Fernandez, Marlen I. Castellanos; Duseja, Ajay; Arrese, Marco; Rinella, Mary; Singal, Ashwani K.; Gordon, Stuart C.; Fuchs, Michael; Eskridge, Wayne; Alkhouri, Naim; Cusi, Kenneth; Loomba, Rohit; Ranagan, Jane; Kautz, Achim; Ong, Janus P.; Kugelmas, Marcelo; Eguchi, Yuichiro; Diago, Moises; Gerber, Lynn; Lam, Brian; Fornaresio, Lisa; Nader, Fatema; Spearman, C. Wendy; Roberts, Stuart K.; Chan, Wah-Kheong; Silva, Marcelo; Racila, Andrei; Golabi, Pegah; Ananchuensook, Prooksa; Henry, Linda; Stepanova, Maria; Carrieri, Patrizia; Lazarus, Jeffrey, V
    Background & Aims: Patients with nonalcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD) face a multifaceted disease burden which includes impaired health-related quality of life (HRQL) and potential stigmatization. We aimed to assess the burden of liver disease in patients with NAFLD and the relationship between experience of stigma and HRQL. Methods: Members of the Global NASH Council created a survey about disease burden in NAFLD. Participants completed a 35-item questionnaire to assess liver disease burden (LDB) (seven domains), the 36-item CLDQ-NASH (six domains) survey to assess HRQL and reported their experience with stigmatization and discrimination. Results: A total of 2,117 patients with NAFLD from 24 countries completed the LDB survey (48% Middle East and North Africa, 18% Europe, 16% USA, 18% Asia) and 778 competed CLDQ-NASH. Of the study group, 9% reported stigma due to NAFLD and 26% due to obesity. Participants who reported stigmatization due to NAFLD had substantially lower CLDQ-NASH scores (all p <0.0001). In multivariate analyses, experience with stigmatization or discrimination due to NAFLD was the strongest independent predictor of lower HRQL scores (beta from -5% to -8% of score range size, p <0.02). Experience with stigmatization due to obesity was associated with lower Activity, Emotional Health, Fatigue, and Worry domain scores, and being uncomfortable with the term "fatty liver disease" with lower Emotional Health scores (all p <0.05). In addition to stigma, the greatest disease burden as assessed by LDB was related to patients' self-blame for their liver disease. Conclusions: Stigmatization of patients with NAFLD, whether it is caused by obesity or NAFLD, is strongly and independently associated with a substantial impairment of their HRQL. Self-blame is an important part of disease burden among patients with NAFLD. Impact and implications: Patients with nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), may experience impaired health-related quality of life and stigmatization. Using a specifically designed survey, we found that stigmatization of patients with NAFLD, whether it is caused by obesity or the liver disease per se, is strongly and independently associated with a substantial impairment of their quality of life. Physicians treating patients with NAFLD should be aware of the profound implications of stigma, the high prevalence of self-blame in the context of this disease burden, and that providers' perception may not adequately reflect patients' perspective and experience with the disease. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).