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Koutoukidis D, Jebb S, Tomlinson J, Mozes F, Pavlides M, Lacharie M, Saffioti F, Aveyard P, Cobbold J. Severe Dietary Energy Restriction for Compensated Cirrhosis Due to Metabolic Dysfunction-Associated Steatotic Liver Disease: A Randomised Controlled Trial. J Cachexia Sarcopenia Muscle 2025; 16:e13783. [PMID: 40275677 PMCID: PMC12022231 DOI: 10.1002/jcsm.13783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 02/07/2025] [Accepted: 03/03/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Compensated cirrhosis due to metabolic dysfunction-associated steatotic liver disease (CC-MASLD) increases morbidity and mortality risk but has no aetiology-specific treatment. We investigated the safety and efficacy signals of severe energy restriction. METHODS In this randomised controlled trial, adults with CC-MASLD and obesity in a tertiary hepatology centre were randomised 2:1 to receive one-to-one remote dietetic support with a low-energy (880 kcal/day, 80 g protein/day) total diet replacement programme for 12 weeks and stepped food reintroduction for another 12 weeks or standard of care (SoC). Given the exploratory nature of the study, three pre-defined co-primary outcomes were used to assess safety and efficacy signals: severe increases in liver biochemistry, changes in iron-corrected T1, and changes in liver stiffness on magnetic resonance elastography. Changes in liver steatosis on magnetic resonance imaging, physical performance based on the physical performance test and liver frailty index, and changes in fat-free mass were secondary outcomes. Magnetic resonance outcomes were assessed blind. RESULTS Between February 2022 and September 2023, 17 participants (36% female, median [IQR] age 58 [7.5] years) were randomised to SoC (n = 6) or intervention (n = 11). The trial stopped earlier than planned due to slow recruitment rate. 91% and 94% of participants completed the intervention and attended the 24-week follow-up, respectively. Compared with the SoC, the between-group weight change in the intervention was -11.9 kg (95% CI: -17.2, -6.6, p < 0.001) at 24 weeks. Liver biochemistry markers (alanine transaminase, aspartate transaminase, and total bilirubin) were stable in everyone throughout the trial. Iron-corrected T1 and steatosis significantly reduced (-149.9 ms [95% CI -258.1, -41.7, p = 0.01] and -6% [95% CI -11.3, -0.6, p = 0.03], respectively). There were no between-group differences in changes in liver stiffness (0.2 kPa [95% CI -1.1, 1.6]), the physical performance test (1.5 points [95% CI -1.9 to 4.9], p = 0.70) or the liver frailty index (0 [95% CI -0.6 to 0.6], p = 0.97). Compared with SoC, absolute fat-free mass reduced (-3.2 kg [95% CI -6 to -0.3], p = 0.04) but relative fat-free mass as percentage of total body weight increased (5.4% [95% CI 0.5 to 10.3], p = 0.046). No participant met the pre-defined safety criteria for enhanced observation or intervention discontinuation. There was no between-group differences in changes in cardiovascular markers and no evidence of hepatic decompensation or serious adverse events. CONCLUSIONS Severe energy restriction appears a safe option to achieve significant weight loss and reduce liver fat without adverse effects in people with CC-MASLD. A larger study is needed to confirm these findings. CLINICAL TRIAL REGISTRATION ISRCTN13053035, prospectively registered, overall study status: closed.
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Affiliation(s)
- Dimitrios A. Koutoukidis
- Nuffield Department of Primary Care Health SciencesUniversity of OxfordOxfordUK
- NIHR Oxford Biomedical Research CentreOxfordUK
| | - Susan A. Jebb
- Nuffield Department of Primary Care Health SciencesUniversity of OxfordOxfordUK
- NIHR Oxford Biomedical Research CentreOxfordUK
| | - Jeremy W. Tomlinson
- NIHR Oxford Biomedical Research CentreOxfordUK
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of MedicineUniversity of OxfordOxfordUK
| | - Ferenc E. Mozes
- Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of MedicineUniversity of OxfordOxfordUK
| | - Michael Pavlides
- Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of MedicineUniversity of OxfordOxfordUK
- Department of Gastroenterology and HepatologyJohn Radcliffe Hospital, Oxford University Hospitals NHS Foundation TrustOxfordUK
| | - Miriam Lacharie
- Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of MedicineUniversity of OxfordOxfordUK
| | - Francesca Saffioti
- Department of Gastroenterology and HepatologyJohn Radcliffe Hospital, Oxford University Hospitals NHS Foundation TrustOxfordUK
| | - Paul Aveyard
- Nuffield Department of Primary Care Health SciencesUniversity of OxfordOxfordUK
- NIHR Oxford Biomedical Research CentreOxfordUK
| | - Jeremy F. Cobbold
- NIHR Oxford Biomedical Research CentreOxfordUK
- Department of Gastroenterology and HepatologyJohn Radcliffe Hospital, Oxford University Hospitals NHS Foundation TrustOxfordUK
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Panganiban J, Kehar M, Ibrahim SH, Hartmann P, Sood S, Hassan S, Ramirez CM, Kohli R, Censani M, Mauney E, Cuda S, Karjoo S. Metabolic dysfunction-associated steatotic liver disease (MASLD) in children with obesity: An Obesity Medicine Association (OMA) and expert joint perspective 2025. OBESITY PILLARS 2025; 14:100164. [PMID: 40230708 PMCID: PMC11995806 DOI: 10.1016/j.obpill.2025.100164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 04/16/2025]
Abstract
Introduction This Obesity Medicine Association (OMA) Expert Joint Perspective examines steatotic liver disease (SLD), which is composed of metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH) in children with obesity. The prevalence of obesity is increasing, rates have tripled since 1963 from 5 % to now 19 % of US children affected in 2018. MASLD, is the most common liver disease seen in children, can be a precursor to the development of Type 2 Diabetes (T2DM) and is the primary reason for liver transplant listing in young adults. We must be vigilant in prevention and treatment of MASLD in childhood to prevent further progression. Methods This joint clinical perspective is based upon scientific evidence, peer and clinical expertise. The medical literature was reviewed via PubMed search and appropriate articles were included in this review. This work was formulated from the collaboration of eight hepatologists/gastroenterologists with MASLD expertise and two physicians from the OMA. Results The authors who are experts in the field, determined sentinel questions often asked by clinicians regarding MASLD in children with obesity. They created a consensus and clinical guideline for clinicians on the screening, diagnosis, and treatment of MASLD associated with obesity in children. Conclusions Obesity and the comorbidity of MASLD is increasing in children, and this is a medical problem that needs to be addressed urgently. It is well known that children with metabolic associated chronic disease often continue to have these chronic diseases as adults, which leads to reduced life expectancy, quality of life, and increasing healthcare needs and financial burden. The authors of this paper recommend healthy weight reduction not only through lifestyle modification but through obesity pharmacotherapy and bariatric surgery. Therefore, this guidance reviews available therapies to achieve healthy weight reduction and reverse MASLD to prevent progressive liver fibrosis, and metabolic disease.
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Affiliation(s)
| | - Mohit Kehar
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Canada
| | - Samar H. Ibrahim
- Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Phillipp Hartmann
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Division of Gastroenterology, Hepatology & Nutrition, Rady Children’s Hospital San Diego, San Diego, CA, USA
| | - Shilpa Sood
- Division of Pediatric Gastroenterology, Boston Children's Health Physicians, New York Medical College, Valhalla, NY, USA
| | - Sara Hassan
- University of Texas Southwestern, Dallas, TX, United States
| | | | - Rohit Kohli
- Children's Hospital Los Angeles, CA, United States
| | - Marisa Censani
- Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, United States
| | - Erin Mauney
- Tufts Medical Center, Boston, MA, United States
| | - Suzanne Cuda
- Alamo City Healthy Kids and Families, San Antonio, TX, United States
| | - Sara Karjoo
- Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States
- University of South Florida, Tampa, FL, United States
- Florida State University, Tallahassee, FL, United States
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Li R, Su K, Wu T, Xu L, Song W, Sun D, Zeng T, Chen J, Xin H, Li Y, Zang M, Hu M. Genome-wide enhancer-gene regulatory maps of liver reveal novel regulatory mechanisms underlying NAFLD pathogenesis. BMC Genomics 2025; 26:493. [PMID: 40375105 DOI: 10.1186/s12864-025-11668-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Accepted: 05/02/2025] [Indexed: 05/18/2025] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) represents the most widespread liver disease globally, ranging from non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH) to fibrosis/cirrhosis, with potential progression to hepatocellular carcinoma (HCC). Genome-wide association studies (GWASs) have identified several single nucleotide polymorphisms (SNPs) associated with NAFLD. However, numerous GWAS signals associated with NAFLD locate in non-coding regions, posing a challenge for interpreting their functional annotation. RESULTS In this study, we utilized the Activity-by-Contact (ABC) model to construct the enhancer-gene maps of liver by integrating epigenomic data from 15 liver tissues and cell lines. We constructed the most comprehensive genome-wide regulatory maps of the liver, identifying 543,486 enhancer-gene connections, including 267,857 enhancers and 16,872 target genes. Enrichment analyses revealed that the ABC SNPs are significantly enriched in active chromatin regions and active chromatin state. By combining the ABC regulatory maps and NAFLD GWAS data, we systematically identified ABC SNPs associated with NAFLD risk. Through the functional annotations, such as pathway enrichment and drug-gene interaction analyses, we identified 6 genes (GGT1, ACTG1, SPP1, EPHA2, PROZ and SHMT1) as candidate NAFLD genes, with SHMT1 previously reported. Among the SNPs connected to the candidate genes, the ABC SNP rs2017869 (odds ratio [OR] for the C allele = 1.10, 95% CI = 1.04-1.16, P = 5.97 × 10- 4) had the highest ABC score. According to the ABC maps, rs2017869 links to GGT1, and several drugs targeting this gene, such as liothyronine, showed potential benefits to patients with NAFLD. Furthermore, we identified that another novel gene, EPHA2, may play a crucial role in NAFLD by regulating the GGT levels. CONCLUSIONS Our study provides the most comprehensive ABC regulatory maps of the liver to date. This resource offers a valuable reference for identifying regulatory variants and prioritizing susceptibility genes of liver diseases, such as NAFLD.
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Affiliation(s)
- Ruofan Li
- Medical School of Chinese People's Liberation Army (PLA), 28 Fuxing Road, 100853, Beijing, China
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Kaiyan Su
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, 1,838 North Guangzhou Ave, Guangzhou, Guangdong, 510515, China
| | - Tianzhun Wu
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, 530021, China
| | - Li Xu
- Department of Hepatopancreatobiliary Surgery, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Wenyu Song
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China
| | - Dandan Sun
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Tao Zeng
- Medical School of Chinese People's Liberation Army (PLA), 28 Fuxing Road, 100853, Beijing, China
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Jinzhang Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, 1,838 North Guangzhou Ave, Guangzhou, Guangdong, 510515, China.
| | - Haibei Xin
- Department of Hepatobiliary Surgery, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
| | - Yuanfeng Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China.
| | - Mengya Zang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, 1,838 North Guangzhou Ave, Guangzhou, Guangdong, 510515, China.
| | - Minggen Hu
- Medical School of Chinese People's Liberation Army (PLA), 28 Fuxing Road, 100853, Beijing, China.
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853, China.
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Carbone F, Després JP, Ioannidis JPA, Neeland IJ, Garruti G, Busetto L, Liberale L, Ministrini S, Vilahur G, Schindler TH, Macedo MP, Di Ciaula A, Krawczyk M, Geier A, Baffy G, Faienza MF, Farella I, Santoro N, Frühbeck G, Yárnoz-Esquiroz P, Gómez-Ambrosi J, Chávez-Manzanera E, Vázquez-Velázquez V, Oppert JM, Kiortsis DN, Sbraccia P, Zoccali C, Portincasa P, Montecucco F. Bridging the gap in obesity research: A consensus statement from the European Society for Clinical Investigation. Eur J Clin Invest 2025:e70059. [PMID: 40371883 DOI: 10.1111/eci.70059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/12/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Most forms of obesity are associated with chronic diseases that remain a global public health challenge. AIMS Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation. MATERIALS AND METHODS This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood. RESULTS The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies. DISCUSSION The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity. CONCLUSION This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.
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Affiliation(s)
- Federico Carbone
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
| | - Jean-Pierre Després
- Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, Québec, Canada
- VITAM - Centre de Recherche en santé Durable, Centre intégré Universitaire de santé et de Services Sociaux de la Capitale-Nationale, Québec, Québec, Canada
| | - John P A Ioannidis
- Department of Medicine, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
- Department of Epidemiology and Population Health, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
- Department of Biomedical Science, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
| | - Ian J Neeland
- Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Cardiovascular Disease, Harrington Heart and Vascular Institute, Cleveland, Ohio, USA
| | - Gabriella Garruti
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Luca Busetto
- Department of Medicine, University of Padua, Padua, Italy
| | - Luca Liberale
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
| | - Stefano Ministrini
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
- Cardiology Department, Luzerner Kantonspital, Lucerne, Switzerland
| | - Gemma Vilahur
- Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, IIB-Sant Pau, Barcelona, Spain
- CiberCV, Institute Carlos III, Madrid, Spain
| | - Thomas H Schindler
- Washington University in St. Louis, Mallinckrodt Institute of Radiology, Division of Nuclear Medicine, Cardiovascular Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Maria Paula Macedo
- APDP - Diabetes Portugal, Education and Research Center, Lisbon, Portugal
- iNOVA4Health, NOVA Medical School | Faculdade de Ciências Médicas, NMS | FCM, Universidade Nova de Lisboa, Lisbon, Portugal
| | - Agostino Di Ciaula
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Marcin Krawczyk
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Andreas Geier
- Interdisciplinary Amyloidosis Center of Northern Bavaria, University Hospital of Würzburg, Würzburg, Germany
- Department of Internal Medicine II, Hepatology, University Hospital of Würzburg, Würzburg, Germany
| | - Gyorgy Baffy
- Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts, USA
| | - Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Ilaria Farella
- Department of Medicine and Surgery, LUM University, Casamassima, Italy
| | - Nicola Santoro
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Medicine and Health Sciences, "V. Tiberio" University of Molise, Campobasso, Italy
| | - Gema Frühbeck
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Yárnoz-Esquiroz
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Gómez-Ambrosi
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Emma Chávez-Manzanera
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - Jean-Michel Oppert
- Department of Nutrition, Pitié-Salpêtrière Hospital (AP-HP), Human Nutrition Research Center Ile-de-France (CRNH IdF), Sorbonne University, Paris, France
| | - Dimitrios N Kiortsis
- Atherothrombosis Research Centre, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Paolo Sbraccia
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Carmine Zoccali
- Renal Research Institute, New York, New York, USA
- Institute of Molecular Biology and Genetics (Biogem), Ariano Irpino, Italy
- Associazione Ipertensione Nefrologia Trapianto Renale (IPNET), c/o Nefrologia, Grande Ospedale Metropolitano, Reggio Calabria, Italy
| | - Piero Portincasa
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Fabrizio Montecucco
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
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5
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Younossi ZM, Razavi H, Sherman M, Allen AM, Anstee QM, Cusi K, Friedman SL, Lawitz E, Lazarus JV, Schuppan D, Romero-Gómez M, Schattenberg JM, Vos MB, Wong VWS, Ratziu V, Hompesch M, Sanyal AJ, Loomba R. Addressing the High and Rising Global Burden of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Steatohepatitis (MASH): From the Growing Prevalence to Payors' Perspective. Aliment Pharmacol Ther 2025; 61:1467-1478. [PMID: 39967239 DOI: 10.1111/apt.70020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/10/2024] [Accepted: 01/29/2025] [Indexed: 02/20/2025]
Abstract
BACKGROUND The continuum of metabolic syndrome encompasses a spectrum of dysfunctions impacting obesity-linked insulin resistance, glucose homeostasis, lipid metabolism and pro-inflammatory immune responses. The global prevalence of metabolic diseases, including diabetes, chronic liver disease, cardiometabolic disease and kidney disease, has surged in recent decades, contributing significantly to population mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is a leading cause of liver disease worldwide. MASLD poses a significant global health challenge with its rising prevalence, placing a substantial burden on healthcare systems, impacts patient well-being and incurs significant economic costs. Addressing MASLD requires a comprehensive understanding of its interconnected factors, including its prevalence, healthcare burden and economic implications. Lack of awareness, imprecise non-invasive diagnostic methods and ineffective preventive interventions are core components of the MASLD-related problem. AIM The aim of this article was to summarise the global burden of MASLD from the payer's perspective. METHODS We carried out a review of the global comprehensive burden of MASLD. These topics led to discussions and insights by an expert panel during the 7th Metabolic Continuum Roundtable meeting, which took place in November 2023. This meeting focused on the burden, patient-reported outcomes and health economics, from payor and societal perspectives, and aimed to identify opportunities for improving patient care, optimise resource allocation and mitigate the overall impact on individuals and society related to MASLD. During the roundtable, an emphasis emerged on the need for greater awareness and strategic deployment of diagnostic, therapeutic and preventative measures to address MASLD effectively. CONCLUSION The global burden of MASLD is high and growing. Prioritising the prevention of metabolic dysregulation and timely therapeutic interventions can yield a holistic strategy to combat MASLD, its progression and potentially lower disease costs. TRIAL REGISTRATION NCT06309992.
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Affiliation(s)
- Zobair M Younossi
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
- The Global NASH Council, Washington, DC, USA
| | - Homie Razavi
- Center for Disease Analysis Foundation, Lafayette, Colorado, USA
| | - Michael Sherman
- RA Capital Management, L.P., Boston, Massachusetts, USA
- Department of Population Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Alina M Allen
- Division of Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota, USA
| | - Quentin M Anstee
- Faculty of Medical Sciences, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes & Metabolism, University of Florida, Gainesville, Florida, USA
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Eric Lawitz
- Texas Liver Institute, University of Texas Health San Antonio, San Antonio, Texas, USA
| | - Jeffrey V Lazarus
- Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain
- City University of New York Graduate School of Public Health and Health Policy (CUNY SPH), New York, New York, USA
| | - Detlef Schuppan
- Mainz University, Mainz, Germany
- Germany & Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Manuel Romero-Gómez
- Department of Medicine, UCM Digestive Diseases, Virgen del Rocío University Hospital, Institute of Biomedicine of Seville (HUVR/CSIC/US), CIBEREHD, ISCIII, University of Seville, Seville, Spain
| | - Jörn M Schattenberg
- Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Miriam B Vos
- Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Vincent Wai-Sun Wong
- State Key Laboratory of Digestive Disease, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Vlad Ratziu
- Sorbonne Université and Pitié-Salpêtrière Hospital Paris, Paris, France
| | | | - Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology at UC San Diego, MASLD Research Center California, La Jolla, California, USA
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6
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Steixner-Kumar AA, Santacruz D, Geiger T, Rust W, Böttner D, Krenkel O, Bahrami E, Okafo G, Barth TF, Haenle M, Kratzer W, Schlingeloff P, Schmidberger J, Neubauer H, Dick A, Werner M, Simon E. Single-cell landscape of peripheral immune cells in MASLD/MASH. Hepatol Commun 2025; 9:e0643. [PMID: 40257301 PMCID: PMC12014121 DOI: 10.1097/hc9.0000000000000643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 11/30/2024] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) progresses to metabolic dysfunction-associated steatohepatitis (MASH) and is a major cause of liver cirrhosis. Although liver inflammation is the hallmark feature of MASH versus MASLD, the involvement of the peripheral immune cell compartments in disease progression is poorly understood, and single-cell profiles of peripheral immune cells in MASLD/MASH are not known. METHODS Patients with MASLD/MASH and healthy volunteers have been prospectively enrolled in a cross-sectional study. Patients have been histologically stratified and further characterized by liver bulk RNA sequencing (RNA-Seq). Peripheral immune cells from patients and control blood samples have been comprehensively profiled using bulk and single RNA-Seq. RESULTS Twenty-two patients with fibrosis stage less than F3 have been histologically stratified into patients with low, medium, and high disease activity scores (NAFLD activity score [NAS]). In contrast to fibrosis, the NAS group correlated with noninvasive imaging readouts and blood biomarkers of liver damage and inflammation (ALT, AST). The prevalence of type 2 diabetes and obesity increased with the NAS stage. Bulk RNA-seq profiling of patient liver biopsies revealed gene signatures that were positively and negatively associated with NAS. Known marker genes for liver fibrosis where upregulated on RNA level. Blood bulk RNA-seq showed only moderate differences in patients versus healthy controls. In contrast, single-cell analysis of white blood cells revealed multiple alterations of immune (sub-)populations, including an increased abundance of immature B cells and myeloid suppressor cells in patients with MASLD/MASH as compared to healthy controls. CONCLUSIONS The study gives new insights into the pathophysiology of MASLD/MASH already manifesting relatively early in peripheral immune cell compartments. This opens new avenues for the development of new biomarker diagnostics and disease therapies.
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Affiliation(s)
- Agnes Anna Steixner-Kumar
- Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | - Diana Santacruz
- Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | - Tobias Geiger
- Department of Cardiometabolic Research, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | - Werner Rust
- Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | - Dennis Böttner
- Department of Cardiometabolic Research, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | - Oliver Krenkel
- Department of Cardiometabolic Research, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | - Ehsan Bahrami
- Department of Cardiometabolic Research, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | - George Okafo
- Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | | | - Mark Haenle
- Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
| | - Wolfgang Kratzer
- Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
| | | | | | - Heike Neubauer
- Department of Cardiometabolic Research, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | - Alec Dick
- Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | - Markus Werner
- Department of Cardiometabolic Research, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | - Eric Simon
- Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
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7
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Dai Q, Ain Q, Seth N, Rooney M, Zipprich A. Liver sinusoidal endothelial cells: Friend or foe in metabolic dysfunction- associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis. Dig Liver Dis 2025; 57:493-503. [PMID: 39904692 DOI: 10.1016/j.dld.2025.01.189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/27/2024] [Accepted: 01/15/2025] [Indexed: 02/06/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the predominant liver disease and is becoming the paramount contributor to end-stage liver disease and liver-related deaths. Liver sinusoidal endothelial cells (LSECs) located between the hepatic parenchyma and blood from viscera and gastrointestinal tract are the gatekeepers for the hepatic microenvironment and normal function. In normal physiological conditions, LSECs govern the substance exchange between hepatic parenchyma and blood through dynamic regulation of fenestration and maintain the quiescent state of Kupffer cells (KCs) and hepatic stellate cells. In MASLD, lipotoxicity, insulin resistance, gastrointestinal microbiota dysbiosis, and mechanical compression caused by fat-laden hepatocytes result in LSECs capillarization and dysfunction. The altered LSECs progressively shift from healer to injurer, exacerbating liver inflammation and advancing liver fibrosis. This review focuses on the deteriorative roles of LSECs and related molecular mechanisms involved in MASLD and their contribution to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis development and progression. Furthermore, in this review, we propose that targeting LSECs dysfunction is a prospective therapeutic strategy to restore the physiological function of LSECs and mitigate MASLD progression.
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Affiliation(s)
- Qingqing Dai
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, 07747, Jena, Thuringia, Germany
| | - Quratul Ain
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, 07747, Jena, Thuringia, Germany
| | - Navodita Seth
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, 07747, Jena, Thuringia, Germany
| | - Michael Rooney
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, 07747, Jena, Thuringia, Germany
| | - Alexander Zipprich
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, 07747, Jena, Thuringia, Germany.
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8
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Cunneely OP, Roberts A, Fargue S, Knight J, Assimos DG, Wood KD. Metabolic dysfunction associated steatotic liver and kidney stones: what is going on? Curr Opin Nephrol Hypertens 2025; 34:247-253. [PMID: 39882643 DOI: 10.1097/mnh.0000000000001062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
PURPOSE OF REVIEW Metabolic dysfunction associated steatotic liver disease (MASLD) is increasing throughout the world, affecting nearly one in three individuals. Kidney stone disease, which is also increasing, is associated with MASLD. Common risk factors for both, including obesity, diabetes, dyslipidemia, hypertension, and metabolic syndrome, are likely drivers of this association. We present here a review of the associations and possible interconnections between these two common disease processes. RECENT FINDINGS Epidemiological studies are discordant regarding the impact of sex on this association and on the impact of MASLD on incident stone risk. The nature of kidney stones is rarely taken into account.A favorable milieu for uric acid kidney stone formation may be created by a lower urine pH resulting from defective ammonium production associated with insulin resistance, common in MASLD.Endogenous oxalate synthesis, a major risk factor for calcium oxalate kidney stones, may be increased in MASLD via decline in the activity of enzymes involved in the detoxification of glyoxylate, the immediate precursor of oxalate. SUMMARY The nature of kidney stones associated with MASLD and factors driving this association remain to be elucidated. Potential mechanisms identified underlying this include an increase in the risk factors for both uric acid and calcium oxalate kidney stones.
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Affiliation(s)
- Owen P Cunneely
- Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama, USA
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9
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Riechelmann-Casarin L, Valente LC, Otton R, Barbisan LF, Romualdo GR. Are glyphosate or glyphosate-based herbicides linked to metabolic dysfunction-associated steatotic liver disease (MASLD)? The weight of current evidence. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2025; 116:104705. [PMID: 40311787 DOI: 10.1016/j.etap.2025.104705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 04/16/2025] [Accepted: 04/27/2025] [Indexed: 05/03/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects around 30 % of the world's population, increasing its prevalence by 50 % in the last three decades. MASLD pathogenesis is considered multiaxial, involving disturbances in the liver, adipose tissue (AT), and gut microbiome. In parallel with MASLD increasing trends, the total herbicide use has nearly tripled over the last three decades. Glyphosate (GLY) is the most used herbicide worldwide (825 mi kg/year). The intensive use of GLY-based herbicides (GBH) - largely driven by the adoption of glyphosate-tolerant genetically modified crops over the past two decades - has led to environmental (soil and water) and food contamination, resulting in continuous human exposure. Emerging (pre)clinical data highlights the significant implications of this herbicide on MASLD, marking a critical research area. Thus, this narrative review paper aimed at gathering and evaluating all epidemiological and (pre)clinical data on the implications of GLY or GBH on MASLD outcomes. Our work encompassed literature published between 2008-2025. Human urinary GLY levels are associated with different MASLD outcomes (steatosis risk, advanced fibrosis, increased transaminases) and comorbidities (higher risk for metabolic syndrome, diabetes, obesity and cardiovascular diseases) (6 studies). In vitro data indicate that GBH/GLY cause oxidative stress, genomic instability, apoptosis, and membrane disruption in hepatocytes, while promoting apoptosis and lipid peroxidation in (pre)adipocytes and cytokine production in monocytes (15 studies). In rodent studies (21 studies), GLY/GBH - in doses based on human exposure/toxicological limits - induces inflammatory and oxidative responses in the liver and AT, while causing dysbiosis and metabolic alterations in the gut microbiome axis. In the light of populational-, cell- and animal-based evidence, GLY/GBH disturbs key axis of MASLD pathogenesis and is hypothesized to be associated with its clinical outcomes.
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Affiliation(s)
- Luana Riechelmann-Casarin
- São Paulo State University (UNESP), Experimental Research Unit (UNIPEX), Botucatu Medical School, Brazil
| | - Leticia Cardoso Valente
- São Paulo State University (UNESP), Experimental Research Unit (UNIPEX), Botucatu Medical School, Brazil
| | - Rosemari Otton
- Interdisciplinary Post-graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | - Luís Fernando Barbisan
- São Paulo State University (UNESP), Department of Structural and Functional Biology, Botucatu Biosciences Institute, Brazil
| | - Guilherme Ribeiro Romualdo
- São Paulo State University (UNESP), Experimental Research Unit (UNIPEX), Botucatu Medical School, Brazil.
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Sánchez-Varela N, Cinza-Sanjurjo S, Danif-Ferreira T, Medina Araujo LI, Mosteiro Miguéns DG, Rey-Aldana D, Portela-Romero M. Diagnosis and Monitoring of Metabolic Dysfunction Associated with Fatty Liver Disease in Primary Care Patients with Risk Factors-EsteatoGal Study. J Clin Med 2025; 14:3089. [PMID: 40364120 PMCID: PMC12072284 DOI: 10.3390/jcm14093089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/23/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025] Open
Abstract
Objective: The objective of this study was to calculate the epidemiological impact of metabolic dysfunction associated with fatty liver disease (MAFLD) and hepatic fibrosis in primary care (PC). Secondarily, we assessed the correlation between serological markers (FIB-4, ELF test), abdominal ultrasound, and transient elastography in the early detection of MAFLD. Methods: An observational prospective study was designed to determine the prevalence of MAFLD and to assess the correlation between complementary tests. Patients were recruited from five health centres. Eligible participants were adults aged between 18 and 70 years with at least one metabolic risk factor, including being overweight (BMI 25-29.9 kg/m2) or obese (BMI > 30 kg/m2), or diagnosed with type 2 diabetes mellitus (T2DM), dyslipidemia, or metabolic syndrome. The prevalence of MAFLD was calculated. Correlations between diagnostic tests were evaluated using Pearson's correlation coefficient. Results: A total of 98 patients was included. Using CAP (controlled attenuation parameter) measurements, the prevalence of MAFLD was found to be 67.7%, and the prevalence of hepatic fibrosis was 6.5%. The correlation between conventional ultrasound and CAP from FibroScan® for the diagnosis of MAFLD was low and not statistically significant (0.160 [95% CI: -0.100; 0.400], p = 0.226). In contrast, the diagnosis of hepatic fibrosis using FibroScan® in PC showed a high correlation with diagnoses performed in gastroenterology department (0.942 [95% CI: 0.844; 0.979], p < 0.001). The correlation with biochemical markers was low and not statistically significant for both FIB-4 (0.125 [95% CI: -0.129; 0.363], p = 0.334) and the ELF test (0.159 [95% CI: -0.111; 0.407], p = 0.246). Conclusions: Two out of three patients with metabolic risk factors were diagnosed with MAFLD, while hepatic fibrosis diagnoses were uncommon. These results reinforce the validity of using FibroScan® in PC.
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Affiliation(s)
- Nerea Sánchez-Varela
- Centro de Salud Concepción Arenal, Área Sanitaria Integrada Santiago de Compostela, 15701 Santiago de Compostela, A Coruña, Spain; (N.S.-V.); (L.I.M.A.); (D.G.M.M.)
| | - Sergio Cinza-Sanjurjo
- Centro de Salud Milladoiro, Área Sanitaria Integrada Santiago de Compostela, 15895 O Milladoiro, A Coruña, Spain
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), 15706 Santiago de Compostela, A Coruña, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Madrid, Spain
- Departamento de Medicina, Universidad de Santiago de Compostela (USC), 15782 Santiago de Compostela, A Coruña, Spain
| | - Tatiana Danif-Ferreira
- Centro de Salud A Estrada, Área Sanitaria Integrada Santiago de Compostela, 36680 A Estrada, Pontevedra, Spain;
| | - Liseth I. Medina Araujo
- Centro de Salud Concepción Arenal, Área Sanitaria Integrada Santiago de Compostela, 15701 Santiago de Compostela, A Coruña, Spain; (N.S.-V.); (L.I.M.A.); (D.G.M.M.)
| | - Diego G. Mosteiro Miguéns
- Centro de Salud Concepción Arenal, Área Sanitaria Integrada Santiago de Compostela, 15701 Santiago de Compostela, A Coruña, Spain; (N.S.-V.); (L.I.M.A.); (D.G.M.M.)
| | - Daniel Rey-Aldana
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), 15706 Santiago de Compostela, A Coruña, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Madrid, Spain
- Departamento de Medicina, Universidad de Santiago de Compostela (USC), 15782 Santiago de Compostela, A Coruña, Spain
- Centro de Salud A Estrada, Área Sanitaria Integrada Santiago de Compostela, 36680 A Estrada, Pontevedra, Spain;
| | - Manuel Portela-Romero
- Centro de Salud Concepción Arenal, Área Sanitaria Integrada Santiago de Compostela, 15701 Santiago de Compostela, A Coruña, Spain; (N.S.-V.); (L.I.M.A.); (D.G.M.M.)
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), 15706 Santiago de Compostela, A Coruña, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Madrid, Spain
- Departamento de Medicina, Universidad de Santiago de Compostela (USC), 15782 Santiago de Compostela, A Coruña, Spain
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11
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Ding Y, Xu W, Feng Y, Shi B, Wang W. Prognostic Value of the Magnesium Depletion Score for Mortality Outcomes Among NAFLD Patients. INT J VITAM NUTR RES 2025; 95:33514. [PMID: 40298158 DOI: 10.31083/ijvnr33514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 03/06/2025] [Accepted: 03/14/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND The magnesium depletion score (MDS), a novel clinical score, incorporates alcohol consumption, kidney disease, use of diuretics and proton pump inhibitors (PPIs) to assess magnesium levels. However, the prognostic significance of the MDS individuals with nonalcoholic fatty liver disease (NAFLD) remains uncertain. This research aimed to explore the relationship between the MDS and mortality outcomes in NAFLD patients, including all-cause mortality, cancer mortality, and cardiovascular disease (CVD) mortality. METHOD Data acquired on 16,394 NAFLD patients from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018 were analyzed in this cohort study. Mortality outcomes were assessed using the linked National Death Index, which included all-cause mortality, cancer mortality, and CVD mortality. Cox proportional hazards models were used to determine the hazard ratios (HRs) for mortality outcomes related to the MDS. Subgroup analyses were also performed to explore the potential modifying influences of different demographic and clinical characteristics. RESULT An elevated MDS was associated with significantly higher risks of all-cause mortality (HR 1.22; 95% CI, 1.15-1.30), cancer mortality (HR 1.15; 95% CI, 1.03-1.28), and CVD mortality (HR 1.33; 95% CI, 1.18-1.51). While these associations remained consistent in many subgroups, factors such as gender, education level, and alcohol consumption influenced the link between the MDS and mortality. CONCLUSION The MDS is as an innovative and feasible prognostic indicator for mortality among NAFLD patients. Incorporating the MDS into clinical practice could improve risk stratification and inform targeted interventions aimed at diminishing the risk of mortality linked to magnesium deficiency within this group.
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Affiliation(s)
- Yue Ding
- Department of General Surgery, Tongji Hospital, School of Medicine, Tongji University, 200065 Shanghai, China
| | - Wei Xu
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, 200065 Shanghai, China
| | - Yuntao Feng
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, 200065 Shanghai, China
| | - Baomin Shi
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 200092 Shanghai, China
| | - Wei Wang
- Department of General Surgery, Shanghai Jiaotong University School of Medicine, Punan Branch of Renji Hospital, 200125 Shanghai, China
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Yu Y, Yang Y, Li Q, Yuan J, Zha Y. Predicting metabolic dysfunction associated steatotic liver disease using explainable machine learning methods. Sci Rep 2025; 15:12382. [PMID: 40216893 PMCID: PMC11992218 DOI: 10.1038/s41598-025-96478-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 03/28/2025] [Indexed: 04/14/2025] Open
Abstract
Early and accurate identification of patients at high risk of metabolic dysfunction-associated steatotic liver disease (MASLD) is critical to prevent and improve prognosis potentially. We aimed to develop and validate an explainable prediction model based on machine learning (ML) approaches for MASLD among the adult population. The national cross-sectional study collected data from the National Health and Nutrition Examination Survey from 2017 to 2020, consisting of 13,436 participants, who were randomly split into 70% training, 20% internal validation, and 10% external validation cohorts. MASLD was defined based on transient elastography and cardiometabolic risk factors. With 50 medical characteristics easily obtained, six ML algorithms were used to develop prediction models. Several evaluation parameters were used to compare the predictive performance, including the area under the receiver-operating-characteristic curve (AUC) and precision-recall (P-R) curve. The recursive feature elimination method was applied to select the optimal feature subset. The Shapley Additive exPlanations method offered global and local explanations for the model. The random forest (RF) model performed best in discriminative ability among 6 ML models, and the optimal 10-feature RF model was finally chosen. The final model could accurately predict MASLD in internal and external validation cohorts (AUC: 0.928, 0.918; area under P-R curve: 0.876, 0.863, respectively). The final model performed better than each of the traditional risk indicators for MASLD. An explainable 10-feature prediction model with excellent discrimination and calibration performance was successfully developed and validated for MASLD based on clinical data easily extracted using an RF algorithm.
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Affiliation(s)
- Yihao Yu
- Master of Finance, Australian National University, Canberra, Australia
| | - Yuqi Yang
- Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang, 550002, China
- NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Qian Li
- Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang, 550002, China
- NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Jing Yuan
- Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang, 550002, China
- NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Yan Zha
- Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang, 550002, China.
- NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People's Hospital, Guiyang, 550002, China.
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13
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Liu B, Jia Y, Gu Z, Li Y, Zhou Y, Cao Y. Periodontal diseases, potential mediators and development of liver fat content: a community-based large cohort. Front Med (Lausanne) 2025; 12:1563459. [PMID: 40270511 PMCID: PMC12014605 DOI: 10.3389/fmed.2025.1563459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/27/2025] [Indexed: 04/25/2025] Open
Abstract
Background A high level of liver fat content (LFC) is a key indicator of steatotic liver disease (SLD), reflecting its pathological essence. Periodontal disease (PD) recognized as a chronic inflammatory condition and cause a widespread adverse health impact. This study aims to investigate the relationship between PD and LFC development. Methods In the UK Biobank, PD were gathered through a digital questionnaire, including gum pain, gum bleed, or teeth loose. LFC was measured by Fatty Liver Index (>60 indicates SLD) in cross-sectional analysis and by magnetic resonance imaging (quantified by Proton Density Fat Fraction, PDFF) in longitudinal analysis. Multivariable logistic and linear regression models were conducted to investigate the association of PD and LFC. Results In cross-sectional analysis, 164,150 (37.4%) individuals were diagnosed with SLD, and PD showed a significant association with SLD (odds ratio: 1.104, 95% CI: 1.075-1.132). In prospective analysis, a total of 39,656 participants with a median follow-up of 10.3 years were included. PD showed an arithmetic mean difference of 0.091 in PDFF (95% CI: 0.047-0.139), with males exhibiting a stronger association than females (P for interaction <0.05). Significant mediating effects were observed for body mass index (19.58%), C-reactive protein (11.61%), blood glucose (6.70%), and healthy diet score (5.99%) between PD and PDFF (P for all <0.001). Conclusion There was a pronounced correlation between PD and LFC, with males predominantly driving this link. This correlation may be partially mediated by body fat, inflammation, dietary habit, and insulin resistance.
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Affiliation(s)
- Bofu Liu
- Department of Emergency Medicine and Laboratory of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Disaster Medical Center, Sichuan University, Chengdu, China
| | - Yu Jia
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhihan Gu
- Department of Emergency Medicine and Laboratory of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Disaster Medical Center, Sichuan University, Chengdu, China
| | - Yizhou Li
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center of Stomatology, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Yiheng Zhou
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yu Cao
- Department of Emergency Medicine and Laboratory of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Disaster Medical Center, Sichuan University, Chengdu, China
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Deng Y, Cui J, Jiang Y, Zhang J, Jiang J, Zhang Q, Hu Y. Exploring the Nutraceutical Potential of a Food-Medicine Compound for Metabolic-Associated Fatty Liver Disease via Lipidomics and Network Pharmacology. Foods 2025; 14:1257. [PMID: 40238509 PMCID: PMC11988326 DOI: 10.3390/foods14071257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 03/29/2025] [Accepted: 04/01/2025] [Indexed: 04/18/2025] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a prevalent global health issue closely tied to dietary habits, impacting a significant portion of the adult population. MAFLD is linked to various metabolic disorders, elevating risks of cirrhosis and hepatocellular carcinoma and severely impacting patients' quality of life. While therapeutic research has progressed, effective food-based interventions remain scarce. Natural products, rich in bioactive compounds and offering health benefits, have gained attention for their potential in managing MAFLD. This study employed network pharmacology and lipidomics to investigate the therapeutic effects of Food and Medicine Homology (FMH) on MAFLD using a high-fat-diet-induced HepG2 cell model. We identified 169 potential bioactive components from Radix Puerariae, Hericium erinaceus, Rhizoma Curcumae longae, Camellia oleifera, and Hoveniae Dulcis Semen, constructing a drug-component-target network that highlighted 34 key targets. The characteristic components of this FMH compound solution (HSD) were identified using UPLC-QTOF-MS/MS. In vitro, HSD significantly reduced intracellular lipid accumulation, decreased inflammatory markers, and mitigated hepatocyte damage. Lipidomics analysis revealed significant alterations in lipid metabolites, suggesting HSD's potential to modulate sphingolipid and glycerophospholipid metabolism, thus improving MAFLD outcomes. This research underscores the critical role of the FMH complex in modulating lipid metabolism and inflammatory pathways, offering valuable insights for developing FMH-based dietary supplements and functional foods to alleviate MAFLD. By leveraging the synergistic effects of natural compounds, our findings hold significant implications for innovative nutritional strategies in managing this prevalent metabolic disorder.
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Affiliation(s)
- Yuru Deng
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, China; dengyuru-@njtech.edu.cn (Y.D.); (J.Z.); (J.J.); (Y.H.)
| | - Jie Cui
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, China; dengyuru-@njtech.edu.cn (Y.D.); (J.Z.); (J.J.); (Y.H.)
- Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China;
| | - Yuxuan Jiang
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China;
| | - Jian Zhang
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, China; dengyuru-@njtech.edu.cn (Y.D.); (J.Z.); (J.J.); (Y.H.)
| | - Jinchi Jiang
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, China; dengyuru-@njtech.edu.cn (Y.D.); (J.Z.); (J.J.); (Y.H.)
| | - Quanbin Zhang
- Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China;
| | - Yonghong Hu
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, China; dengyuru-@njtech.edu.cn (Y.D.); (J.Z.); (J.J.); (Y.H.)
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China;
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Díaz Carnicero J, Saurí-Ferrer I, Redon J, Navarro J, Fernández G, Hurtado C, Ferreira K, Alvarez-Ortega C, Gómez A, Martos-Rodríguez CJ, Martí-Aguado D, Escudero D, Cedenilla M. Clinical and Economic Burden of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in a Spanish Mediterranean Region: A Population-Based Study. J Clin Med 2025; 14:2441. [PMID: 40217891 PMCID: PMC11989979 DOI: 10.3390/jcm14072441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/28/2025] [Accepted: 03/30/2025] [Indexed: 04/14/2025] Open
Abstract
Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent condition worldwide, with significant regional variability in prevalence estimates. This study aimed to determine the prevalence, demographic characteristics, and economic burden of MASLD, metabolic dysfunction-associated steatotic liver (MASL), and metabolic dysfunction-associated steatohepatitis (MASH) in the Valencian Community region of Spain. Methods: We conducted a retrospective analysis of electronic medical records from the Valencian public healthcare database of individuals aged over 24 years from 2012 to 2019. Results: Of the 3,411,069 individuals included in the database in 2019, 75,565 were diagnosed with MASLD, 74,065 with MASL, and 1504 with MASH based on the International Classification of Diseases (ICD), corresponding to a prevalence of 2.22%, 2.17%, and 0.04%, respectively. Among individuals with type 2 diabetes mellitus (T2DM) or obesity, the prevalence of MASLD was approximately three times and 2.5 times higher, respectively, compared to the overall population. The prevalence of MASLD, MASL, and MASH increased from 2012 to 2019 in all the populations studied. The highest risk of hospitalization was associated with liver-related causes, followed by all-cause hospitalization. The highest cost per subject in 2019 was observed in individuals with concomitant MASH and T2DM. Conclusions: Our findings indicate a rising prevalence of MASLD, MASL, and MASH, despite their potential underdiagnosis during the study period. The presence of MASLD or MASH was associated with high healthcare costs, particularly in patients with MASH and T2DM. Our results underline the need for more effective strategies to enhance disease awareness and improve resource allocation.
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Affiliation(s)
- Javier Díaz Carnicero
- Instituto de Investigación Sanitaria Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA), Hospital Clínico Universitario, 46010 Valencia, Spain; (J.D.C.); (I.S.-F.); (J.R.); (J.N.); (D.M.-A.)
| | - Inma Saurí-Ferrer
- Instituto de Investigación Sanitaria Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA), Hospital Clínico Universitario, 46010 Valencia, Spain; (J.D.C.); (I.S.-F.); (J.R.); (J.N.); (D.M.-A.)
| | - Josep Redon
- Instituto de Investigación Sanitaria Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA), Hospital Clínico Universitario, 46010 Valencia, Spain; (J.D.C.); (I.S.-F.); (J.R.); (J.N.); (D.M.-A.)
| | - Jorge Navarro
- Instituto de Investigación Sanitaria Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA), Hospital Clínico Universitario, 46010 Valencia, Spain; (J.D.C.); (I.S.-F.); (J.R.); (J.N.); (D.M.-A.)
| | - Gonzalo Fernández
- Value & Implementation, Global Medical & Scientific Affairs, MSD Spain, 28027 Madrid, Spain
| | - Carlos Hurtado
- Value & Implementation, Global Medical & Scientific Affairs, MSD Spain, 28027 Madrid, Spain
| | - Karine Ferreira
- Value & Implementation, Global Medical & Scientific Affairs, MSD Spain, 28027 Madrid, Spain
| | | | - Antón Gómez
- Value & Implementation, Global Medical & Scientific Affairs, MSD Spain, 28027 Madrid, Spain
| | | | - David Martí-Aguado
- Instituto de Investigación Sanitaria Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA), Hospital Clínico Universitario, 46010 Valencia, Spain; (J.D.C.); (I.S.-F.); (J.R.); (J.N.); (D.M.-A.)
- Gastroenterology and Hepatology, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain;
| | - Desamparados Escudero
- Gastroenterology and Hepatology, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain;
- Departamento de Medicina, Universidad de Valencia, 46010 Valencia, Spain
| | - Marta Cedenilla
- Value & Implementation, Global Medical & Scientific Affairs, MSD Spain, 28027 Madrid, Spain
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Karimi M, Akhgarjand C, Houjaghani H, Nejad MM, Sohrabpour AA, Poustchi H, Mohammadi H, Chamari M, Imani H. The Effect of Intermittent Fasting Diet in Comparison With Low-Calorie Diet on Inflammation, Lipid Profile, Glycemic Index, Liver Fibrosis in Patients With Metabolic-Associated Fatty Liver Disease (MAFLD): A Randomized Controlled Trial. Clin Ther 2025; 47:e9-e16. [PMID: 39915199 DOI: 10.1016/j.clinthera.2025.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 12/02/2024] [Accepted: 01/08/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND Metabolic-associated fatty liver disease (MAFLD) is a prevalent condition with significant health and economic burdens. Dietary interventions, such as intermittent fasting (IF) and low-calorie diets (LCD), have shown promise in managing MAFLD, but their comparative efficacy remains unclear. METHODS This 10-month, parallel, single-blind randomized controlled trial compared the effects of a 16:8 IF diet with an LCD on 52 patients with MAFLD. Anthropometric, biochemical, liver enzyme, steatosis, fibrosis, inflammatory, and oxidative status parameters were assessed before and after the interventions. RESULTS Both diets led to improvements in anthropometric measures and liver enzyme levels, with no significant differences between groups. However, the LCD group showed superior outcomes in reducing liver steatosis (-52.40 vs -44.63 dB/m; P < 0.001) and fibrosis (-0.74 vs -0.004 Kpa; P = 0.01) compared to the IF group. LCD also led to a significant decrease in serum triglycerides (-24.08 vs 11.22 mg/dL; P = 0.02), while neither intervention significantly affected inflammatory markers or oxidative status. CONCLUSION While both IF and LCD can be effective in managing MAFLD, LCD may offer additional benefits in terms of liver fat reduction and improvement in certain lipid parameters. These findings highlight the complexity of dietary interventions in MAFLD and the need for personalized approaches.
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Affiliation(s)
- Mehdi Karimi
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Camellia Akhgarjand
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Hirad Houjaghani
- Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Maryam Mofidi Nejad
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Mohammadi
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Chamari
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Imani
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
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17
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Cathcart J, Barrett R, Bowness JS, Mukhopadhya A, Lynch R, Dillon JF. Accuracy of Non-Invasive Imaging Techniques for the Diagnosis of MASH in Patients With MASLD: A Systematic Review. Liver Int 2025; 45:e16127. [PMID: 39400428 PMCID: PMC11891385 DOI: 10.1111/liv.16127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 09/14/2024] [Accepted: 09/27/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND AND AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health problem. The secondary stage in MASLD is steatohepatitis (MASH), the co-existence of steatosis and inflammation, a leading cause of progression to fibrosis and mortality. MASH resolution alone improves survival. Currently, MASH diagnosis is via liver biopsy. This study sought to evaluate the accuracy of imaging-based tests for MASH diagnosis, which offer a non-invasive method of diagnosis. METHODS Eight academic literature databases were searched and references of previous systematic reviews and included papers were checked for additional papers. Liver biopsy was used for reference standard. RESULTS We report on 69 imaging-based studies. There were 31 studies on MRI, 27 on ultrasound, five on CT, 13 on transient elastography, eight on controlled attenuation parameter (CAP) and two on scintigraphy. The pathological definition of MASH was inconsistent, making it difficult to compare studies. 55/69 studies (79.71%) were deemed high-risk of bias as they had no preset thresholds and no validation. The two largest groups of imaging papers were on MRI and ultrasound. AUROCs were up to 0.93 for MRE, 0.90 for MRI, 1.0 for magnetic resonance spectroscopy (MRS) and 0.94 for ultrasound-based studies. CONCLUSIONS Our study found that the most promising imaging tools are MRI techniques or ultrasound-based scores and confirmed there is potential to utilise these for MASH diagnosis. However, many publications are single studies without independent prospective validation. Without this, there is no clear imaging tool or score currently available that is reliably tested to diagnose MASH.
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Affiliation(s)
- Jennifer Cathcart
- Division of Molecular and Clinical MedicineUniversity of DundeeDundeeUK
- Gastroenterology DepartmentAberdeen Royal InfirmaryAberdeenUK
| | - Rachael Barrett
- Division of Molecular and Clinical MedicineUniversity of DundeeDundeeUK
| | - James S. Bowness
- University College London Hospitals NHS Foundation TrustLondonUK
- Department of Targeting InterventionUniversity College LondonLondonUK
| | | | - Ruairi Lynch
- Division of Molecular and Clinical MedicineUniversity of DundeeDundeeUK
| | - John F. Dillon
- Division of Molecular and Clinical MedicineUniversity of DundeeDundeeUK
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18
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Cheng YM, Wang SW, Wang C, Wang CC. Unmet needs of metabolic dysfunction - Associated "fatty or steatotic" liver disease. Tzu Chi Med J 2025; 37:152-156. [PMID: 40321956 PMCID: PMC12048125 DOI: 10.4103/tcmj.tcmj_232_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/28/2024] [Accepted: 12/10/2024] [Indexed: 05/08/2025] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), first named in 1980, is currently the most common chronic liver disease, imposing significant health, social, and economic burdens. However, it is defined as a diagnosis of exclusion, lacking a clear underlying cause in its diagnostic criteria. In 2020, metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed as a replacement for NAFLD, introducing additional criteria related to metabolic dysfunction. In 2023, metabolic dysfunction-associated steatotic liver disease (MASLD) was suggested to replace NAFLD, aiming to avoid the stigmatizing term "fatty" and incorporating cardiometabolic criteria for metabolic dysfunction. This divergence in nomenclature and diagnostic criteria between MAFLD and MASLD presents challenges to medical communication and progress. This review outlines the pros and cons of both terminologies, based on current research evidence, in the hope of fostering global consensus in the future.
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Affiliation(s)
- Yu-Ming Cheng
- Department of Gastroenterology and Hepatology, Tung’s Taichung MetroHarbor Hospital, Taichung, Taiwan
| | - Shao-Wen Wang
- Department of Education, Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare, New Taipei, Taiwan
| | - Ching Wang
- Department of Education, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
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19
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Chen VL, Kuppa A, Oliveri A, Chen Y, Ponnandy P, Patel PB, Palmer ND, Speliotes EK. Human genetics of metabolic dysfunction-associated steatotic liver disease: from variants to cause to precision treatment. J Clin Invest 2025; 135:e186424. [PMID: 40166930 PMCID: PMC11957700 DOI: 10.1172/jci186424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic disease and is a leading cause of advanced liver disease. We review here the genetic basis of MASLD. The genetic variants most consistently associated with hepatic steatosis implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, or mitochondrial/ER biology. The distinct mechanisms by which these variants promote hepatic steatosis result in distinct effects on cardiometabolic disease that may be best suited to precision medicine. Recent work on gene-environment interactions has shown that genetic risk is not fixed and may be exacerbated or attenuated by modifiable (diet, exercise, alcohol intake) and nonmodifiable environmental risk factors. Some steatosis-associated variants, notably those in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), are associated with risk of developing adverse liver-related outcomes and provide information beyond clinical risk stratification tools, especially in individuals at intermediate to high risk for disease. Future work to better characterize disease heterogeneity by combining genetics with clinical risk factors to holistically predict risk and develop therapies based on genetic risk is required.
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Affiliation(s)
- Vincent L. Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Annapurna Kuppa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Antonino Oliveri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Yanhua Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Prabhu Ponnandy
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Puja B. Patel
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Nicholette D. Palmer
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Elizabeth K. Speliotes
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
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20
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Li Z, Guo H, He H, Wang S, Pei S, Xie L. The relationship between smoking cessation history and significant liver fibrosis among the population with metabolic dysfunction-associated steatotic liver disease in the United States. PLoS One 2025; 20:e0320573. [PMID: 40168280 PMCID: PMC11960941 DOI: 10.1371/journal.pone.0320573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/19/2025] [Indexed: 04/03/2025] Open
Abstract
BACKGROUND Smoking was identified as a risk factor for the development of liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, the association between smoking cessation history and the development of liver fibrosis remains unclear. This study was intended to analyze the association between smoking cessation history and significant liver fibrosis in adult MASLD participants in the United States. METHODS This study utilized data from 2643 patients with MASLD from the National Health and Nutrition Examination Survey (NHANES). Significant liver fibrosis was detected based on transient elastography measurements. According to the smoking questionnaire data, patients were categorized as non-smokers, ex-smokers and current smokers. A multivariate logistic regression analysis, adjusted for weights, was performed to investigate the relationship between smoking cessation history and the presence of significant liver fibrosis in participants with MASLD. RESULTS A total of 2643 patients with MASLD were included in this study. Compared with non-smokers, ex-smokers had a slightly elevated risk of developing significant liver fibrosis (OR: 1.07, 95% CI: 1.02-1.13). Specifically, a positive correlation was observed between patients who quit smoking for < 20 years and significant liver fibrosis (OR: 1.07, 95% CI: 1.01-1.15). Furthermore, MASLD patients who started regularly smoking at an age of ≤ 20 years (OR: 1.09, 95% CI: 1.02-1.16) and had a smoking duration of ≥ 10 years before quitting (OR: 1.10, 95% CI: 1.02-1.18) were also highly correlated with an increased likelihood of developing significant liver fibrosis. CONCLUSIONS This study revealed that individuals with MASLD who have ceased smoking exhibit an elevated risk for significant liver fibrosis when compared to those who never smoked. It is highly emphasized that MASLD patients who quit smoking for < 20 years, started regularly smoking at an age of ≤ 20 years, and had a smoking duration of ≥ 10 years before quitting should be extremely vigilant regarding the risk of significant liver fibrosis.
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Affiliation(s)
- Zhongtao Li
- Department of General Surgery (Wenhua Road Campus), The Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Hepatobiliary Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, China
| | - Hao Guo
- Department of General Surgery (Wenhua Road Campus), The Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Hepatobiliary Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, China
| | - Hongyu He
- Department of General Surgery (Wenhua Road Campus), The Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Hepatobiliary Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, China
| | - Shu Wang
- Department of Urology Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Shufen Pei
- Department of Otolaryngology-Head and Neck Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Liang Xie
- Department of General Surgery (Wenhua Road Campus), The Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Hepatobiliary Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, China
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21
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Bilson J, Hydes TJ, McDonnell D, Buchanan RM, Scorletti E, Mantovani A, Targher G, Byrne CD. Impact of Metabolic Syndrome Traits on Kidney Disease Risk in Individuals with MASLD: A UK Biobank Study. Liver Int 2025; 45:e16159. [PMID: 39548715 PMCID: PMC11897864 DOI: 10.1111/liv.16159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 10/04/2024] [Accepted: 10/27/2024] [Indexed: 11/18/2024]
Abstract
BACKGROUND AND AIMS The impact of metabolic syndrome (MetS) traits on chronic kidney disease (CKD) risk in metabolic dysfunction-associated steatotic liver disease (MASLD) is unknown. We investigated the impact of type and number of MetS traits and liver fibrosis on prevalent CKD and incident end-stage renal disease (ESRD) risk in SLD. METHODS 234 488 UK Biobank participants' were analysed. Hepatic steatosis index (> 36 for SLD, < 30 for no SLD) and MRI-proton density fat fraction (≥ 5.56%) were used to identify SLD. MetS traits were identified using MASLD criteria. Advanced fibrosis (FIB-4 score > 2.67) was determined using FIB-4 scores. eGFR < 60 mL/min/1.73 m2 or albuminuria > 3 mg/mmol identified prevalent CKD. A validated algorithm identified incident ESRD. Binary logistic and Cox regressions were used to test associations with prevalent CKD ([adjusted odds ratios (ORs)]) and incident ESRD (adjusted hazard ratios [HRs]) respectively. RESULTS 102 410 participants (41.2%) had SLD. 64.4% had MetS. 1.3% had FIB-4 score > 2.67. With SLD and only one MetS trait, hypertension (OR 1.35, 95% CI 1.35-1.72) or type 2 diabetes (T2D) (OR 1.89, 95% CI 1.06-3.38) increased risk of prevalent CKD. MetS (≥ 3 traits) increased prevalent CKD risk (OR 1.94, 95% CI 1.75-2.15), which was further increased by advanced liver fibrosis (OR 4.29, 95% CI 3.36-5.47). CKD prevalence increased with increasing MetS traits. Over 13.6 years (median follow-up), MetS was associated with increased risk of developing ESRD (HR 1.70, 95% CI 1.19-2.43). CONCLUSIONS In MASLD, hypertension, and T2D, number of MetS traits and liver fibrosis increased risk of prevalent CKD and presence of MetS increased the risk of incident ESRD.
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Affiliation(s)
- Josh Bilson
- School of Human Development and Health, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
- National Institute for Health and Care Research Southampton Biomedical Research CentreUniversity of Southampton and University Hospital Southampton National Health Service Foundation TrustSouthamptonUK
| | - Theresa J. Hydes
- Department of Cardiovascular and Metabolic Medicine, 3rd Floor Clinical Sciences CentreInstitute of Life Course and Medical SciencesLiverpool University Hospitals NHS Foundation TrustUniversity of Liverpool, Longmoor LaneLiverpoolUK
- University Hospital Aintree, Liverpool University Hospital NHS Foundation TrustLiverpoolUK
| | - Declan McDonnell
- School of Human Development and Health, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
- National Institute for Health and Care Research Southampton Biomedical Research CentreUniversity of Southampton and University Hospital Southampton National Health Service Foundation TrustSouthamptonUK
- HPB Unit, University Hospital SouthamptonSouthamptonUK
| | - Ryan M. Buchanan
- Primary Care and Population Sciences Faculty of MedicineUniversity of SouthamptonSouthamptonUK
| | - Eleonora Scorletti
- School of Human Development and Health, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
- National Institute for Health and Care Research Southampton Biomedical Research CentreUniversity of Southampton and University Hospital Southampton National Health Service Foundation TrustSouthamptonUK
- Department of Genetics, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of MedicineUniversity and Azienda Ospedaliera Universitaria Integrata of VeronaVeronaItaly
| | - Giovanni Targher
- Metabolic Diseases Research UnitIRCCS Sacro Cuore—Don Calabria HospitalNegrar di ValpolicellaItaly
- Department of MedicineUniversity of Verona Faculty of Medicine and SurgeryVeronaItaly
| | - Christopher D. Byrne
- School of Human Development and Health, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
- National Institute for Health and Care Research Southampton Biomedical Research CentreUniversity of Southampton and University Hospital Southampton National Health Service Foundation TrustSouthamptonUK
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22
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Akeno Y, Maeda M, Murata F, Fukuda H. Metabolic dysfunction-associated fatty liver disease and risks of incident coronary artery disease and cerebrovascular disease: LIFE Study. Hepatol Res 2025. [PMID: 40317853 DOI: 10.1111/hepr.14185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 02/18/2025] [Accepted: 03/05/2025] [Indexed: 05/07/2025]
Abstract
AIM To estimate the risks of coronary artery and cerebrovascular diseases in metabolic dysfunction-associated fatty liver disease (MAFLD) using different fatty liver index (FLI) cut-off values in a Japanese population. METHODS We analyzed insurance claims and health checkup data from public medical insurance enrollees aged ≥40 years in seven Japanese municipalities who had undergone a health checkup between April 2015 and March 2022. The MAFLD cases were identified as hepatic steatosis (defined as FLI ≥60 or ≥37) with overweight/obesity, diabetes, or lean/normal weight with metabolic dysregulation. Cox proportional hazards models estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for MAFLD (reference: non-MAFLD) regarding incident coronary artery and cerebrovascular diseases. Covariates included age, sex, smoking habit, low-density lipoprotein cholesterol level, and statin use. RESULTS The study was undertaken using 163 834 individuals. The HRs of MAFLD for coronary artery disease were 1.44 (95% CI, 1.24-1.67) for FLI ≥ 60 and 1.49 (95% CI, 1.32-1.68) for FLI ≥ 37. The HRs of MAFLD for cerebrovascular disease were 1.58 (95% CI, 1.22-2.05) for FLI ≥ 60 and 1.41 (95% CI, 1.15-1.74) for FLI ≥ 37. In women, neither FLI cut-off was associated with coronary artery disease, and only FLI ≥ 60 was associated with cerebrovascular disease. CONCLUSIONS The MAFLD cases identified using the two FLI cut-off values were at higher risk for coronary artery and cerebrovascular diseases. Asian-specific FLI cut-offs may better identify hepatic steatosis in Japan than Western-specific cut-offs, but there is a need to consider sex differences when determining at-risk subgroups for targeted health interventions.
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Affiliation(s)
- Yurina Akeno
- Department of Health Care Administration and Management, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Megumi Maeda
- Department of Health Care Administration and Management, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Fumiko Murata
- Department of Health Care Administration and Management, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Haruhisa Fukuda
- Department of Health Care Administration and Management, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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23
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Allen MJ, Tulleners R, Brain D, O'Beirne J, Powell EE, Barnett A, Valery PC, Kularatna S, Hickman IJ. Implementation of a nurse-delivered, community-based liver screening and assessment program for people with metabolic dysfunction-associated steatotic liver disease (LOCATE-NAFLD trial). BMC Health Serv Res 2025; 25:421. [PMID: 40121480 PMCID: PMC11929169 DOI: 10.1186/s12913-025-12580-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 03/15/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND With the high burden of Metabolic dysfunction-associated steatotic liver disease (MASLD), (previously known as Non-Alcoholic Fatty Liver Disease - NAFLD) in the community, current models of care that require specialist review for disease risk stratification overwhelm hospital clinic capacity and create inefficiencies in care. The LOCal Assessment and Triage Evaluation of Non-Alcoholic Fatty Liver Disease (LOCATE-NAFLD) randomised trial compared usual care to a community-based nurse delivered liver risk assessment. This study evaluates the implementation strategy of the LOCATE model. METHODS The evaluation used mixed methods (quantitative trial data and qualitative framework analysis of semi-structured interviews) to explore the general practitioner (GP) and patient perspectives of acceptability (Acceptability Framework), and factors associated with reach, effectiveness, adoption, implementation, and maintenance (RE-AIM framework) of the LOCATE model of care. RESULTS The LOCATE model was considered highly acceptable by both patients and GPs. The model of care achieved appropriate reach across the participating health services, reaching high-risk patients faster than usual care and with predominantly positive patient experiences. A notable reduction in anxiety and stress was experienced in the intervention group due to the shorter waiting times between referral and assessment. There was an overall perception of confidence in nursing staff capability to perform the community-based screening and GPs indicated confidence in managing low-risk MASLD without the need for specialist review. Challenges to implementation, adoption and maintenance included variable prioritisation of liver disease assessment in complex cases, the need for further GP training in MASLD assessment and treatment pathways, available funding and referral pathways for community screening, and accessibility of effective diet and exercise professional support. CONCLUSION Nurse delivered community-based liver screening is highly acceptable to GPs and patients and has shown to be an effective mechanism to identify high risk patients. Adoption and maintenance of the model of care faces significant challenges related to affordable access to screening, prioritisation of liver disease in complex patient cohorts, and unresolved difficulties in prescribing effective strategies for sustained lifestyle intervention in the primary care setting. TRIAL REGISTRATION The trial was registered on 30 January 2020 and can be found via Australian New Zealand Clinical Trials Registry (ANZCTR) - ACTRN12620000158965.
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Affiliation(s)
- Michelle J Allen
- Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
| | - Ruth Tulleners
- Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - David Brain
- Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - James O'Beirne
- University of the Sunshine Coast, Maroochydore DC, QLD, Australia
- Sunshine Coast University Hospital, Birtinya, QLD, Australia
| | - Elizabeth E Powell
- Centre for Liver Disease Research, Translational Research Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, QLD, Australia
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Adrian Barnett
- Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | | | - Sanjeewa Kularatna
- Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
- Health Services and Systems Research, Duke - NUS Medical School, Singapore, Singapore
| | - Ingrid J Hickman
- Clinical Trials Capability, Centre for Clinical Research, The University of Queensland ULTRA Team, Herston, QLD, 4006, Australia
- Department of Nutrition and Dietetics, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
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Münte E, Hartmann P. The Role of Short-Chain Fatty Acids in Metabolic Dysfunction-Associated Steatotic Liver Disease and Other Metabolic Diseases. Biomolecules 2025; 15:469. [PMID: 40305160 PMCID: PMC12025087 DOI: 10.3390/biom15040469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/10/2025] [Accepted: 03/21/2025] [Indexed: 05/02/2025] Open
Abstract
With its increasing prevalence, metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a major global public health concern over the past few decades. Growing evidence has proposed the microbiota-derived metabolites short-chain fatty acids (SCFAs) as a potential factor in the pathophysiology of MASLD and related metabolic conditions, such as obesity and type 2 diabetes mellitus (T2DM). By influencing key pathways involved in energy homeostasis, insulin sensitivity, and inflammation, SCFAs play an important role in gut microbiota composition, intestinal barrier function, immune modulation, and direct metabolic signaling. Furthermore, recent animal and human studies on therapeutic strategies targeting SCFAs demonstrate their potential for treating these metabolic disorders.
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Affiliation(s)
- Eliane Münte
- Department of Pediatrics, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
| | - Phillipp Hartmann
- Department of Pediatrics, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
- Division of Gastroenterology, Hepatology & Nutrition, Rady Children’s Hospital San Diego, San Diego, CA 92123, USA
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25
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Hernandez R, Garcia-Rodriguez NS, Arriaga MA, Perez R, Bala AA, Leandro AC, Diego VP, Almeida M, Parsons JG, Manusov EG, Galan JA. The hepatocellular model of fatty liver disease: from current imaging diagnostics to innovative proteomics technologies. Front Med (Lausanne) 2025; 12:1513598. [PMID: 40109726 PMCID: PMC11919916 DOI: 10.3389/fmed.2025.1513598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 02/06/2025] [Indexed: 03/22/2025] Open
Abstract
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a prevalent chronic liver condition characterized by lipid accumulation and inflammation, often progressing to severe liver damage. We aim to review the pathophysiology, diagnostics, and clinical care of MASLD, and review highlights of advances in proteomic technologies. Recent advances in proteomics technologies have improved the identification of novel biomarkers and therapeutic targets, offering insight into the molecular mechanisms underlying MASLD progression. We focus on the application of mass spectrometry-based proteomics including single cell proteomics, proteogenomics, extracellular vesicle (EV-omics), and exposomics for biomarker discovery, emphasizing the potential of blood-based panels for noninvasive diagnosis and personalized medicine. Future research directions are presented to develop targeted therapies and improve clinical outcomes for MASLD patients.
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Affiliation(s)
- Renee Hernandez
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Natasha S Garcia-Rodriguez
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Marco A Arriaga
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Ricardo Perez
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Auwal A Bala
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Ana C Leandro
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Vince P Diego
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Marcio Almeida
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Jason G Parsons
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Eron G Manusov
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Jacob A Galan
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
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Patterson WB, Young ND, Holzhausen EA, Lurmann F, Liang D, Walker DI, Jones DP, Liao J, Chen Z, Conti DV, Chatzi L, Goodrich JA, Alderete TL. Oxidative gaseous air pollutant exposure interacts with PNPLA3-I148M genotype to influence liver fat fraction and multi-omics profiles in young adults. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 368:125692. [PMID: 39864653 PMCID: PMC11859754 DOI: 10.1016/j.envpol.2025.125692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 12/10/2024] [Accepted: 01/13/2025] [Indexed: 01/28/2025]
Abstract
PNPLA3-I148M genotype is the strongest predictive single-nucleotide polymorphism for liver fat. We examine whether PNPLA3-I148M modifies associations between oxidative gaseous air pollutant exposure (Oxwt) with i) liver fat and ii) multi-omics profiles of miRNAs and metabolites linked to liver fat. Participants were 69 young adults (17-22 years) from the Meta-AIR cohort. Prior-month residential Oxwt exposure (redox-weighted oxidative capacity of nitrogen dioxide and ozone) was spatially interpolated from monitoring stations via inverse-distance-squared weighting. Liver fat fraction was assessed by MRI. Serum miRNAs and metabolites were assayed via NanoString nCounter and LC-HRMS, respectively. Multi-omics factor analysis (MOFA) was used to identify latent factors with shared variance across omics layers. Multivariable linear regression models adjusted for age, sex, body mass index, and genotype with liver fat or MOFA factors as an outcome and examined PNPLA3 (rs738409; CC/CG vs. GG) as a multiplicative interaction term. Overall, a standard deviation difference in Oxwt exposure was associated with 8.9% relative increase in liver fat (p = 0.04) and this relationship differed by PNPLA3 genotype (p-value for interaction term: pintx<0.001), whereby relative increases in liver fat for GG and CC/CG participants were 71.8% and 2.4%, respectively. There was no main effect of Oxwt on MOFA Factor 1 expression (p = 0.85), but there was an interaction with PNPLA3 genotype (pintx = 0.01), whereby marginal slopes were 0.211 and -0.017 for GG and CC/CG participants, respectively. MOFA Factor 1 in turn was associated with liver fat (p = 0.006). MOFA Factor 1 miRNAs targeted genes in Fatty Acid Biosynthesis and Metabolism and Lysine Degradation pathways. MOFA Factor 9 was also associated with liver fat and was comprised of branched-chain keto acid and amino acid metabolites. The effects of Oxwt exposure on liver fat is exacerbated in young adults with two PNPLA3 risk alleles, potentially through differential effects on miRNA and/or metabolite profiles.
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Affiliation(s)
- William B Patterson
- Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Nathan D Young
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Elizabeth A Holzhausen
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | | | - Donghai Liang
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Douglas I Walker
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Dean P Jones
- Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Jiawen Liao
- Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA
| | - Zhanghua Chen
- Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA
| | - David V Conti
- Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA
| | - Lida Chatzi
- Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA
| | - Jesse A Goodrich
- Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA
| | - Tanya L Alderete
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
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Qu H, Zhou L, Wang J, Tang D, Zhang Q, Shi J. Iron overload is closely associated with metabolic dysfunction-associated fatty liver disease in type 2 diabetes. Obesity (Silver Spring) 2025; 33:490-499. [PMID: 39915040 PMCID: PMC11897857 DOI: 10.1002/oby.24236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 11/22/2024] [Accepted: 12/03/2024] [Indexed: 03/14/2025]
Abstract
OBJECTIVE The relationship between iron metabolism disturbances and metabolic dysfunction-associated fatty liver disease (MAFLD) remains controversial. This study aimed to investigate the association of iron overload with MAFLD in patients with type 2 diabetes mellitus (T2DM). METHODS This study included 155 Chinese inpatients with T2DM. MAFLD was diagnosed and grouped using magnetic resonance imaging (MRI). MRI biomarkers such as proton density fat fraction and iron accumulation (R 2 * ) were measured. Their clinical characteristics were compared, and the association of iron metabolism markers with MAFLD in patients with T2DM was analyzed. RESULTS Iron metabolism markers, including MRI-R 2 * , ferritin, serum iron, hepcidin, and total iron-binding capacity, were overloaded in groups with MAFLD (p < 0.001 for trend). They were positively correlated with MAFLD and reflected the severity of MAFLD. The five markers of logistic regression analysis revealed an increased MAFLD risk (p < 0.001 for trend). The areas under the curve of five markers all exceeded 0.5, indicating certain predictive values for MAFLD. CONCLUSIONS MAFLD is associated with significant iron overload in Chinese patients with T2DM. Serum iron, ferritin, total iron-binding capacity, hepcidin, andR 2 * value are essential iron metabolism markers to evaluate and predict the progression of MAFLD in patients with T2DM.
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Affiliation(s)
- Huanjia Qu
- Department of EndocrinologyThe Affiliated Hospital of Hangzhou Normal UniversityHangzhouChina
| | - Lingling Zhou
- Department of EndocrinologyThe Affiliated Hospital of Hangzhou Normal UniversityHangzhouChina
| | - Jing Wang
- Department of EndocrinologyThe Affiliated Hospital of Hangzhou Normal UniversityHangzhouChina
| | - Dong Tang
- Department of RadiologyThe Affiliated Hospital of Hangzhou Normal UniversityHangzhouChina
| | - Qiuling Zhang
- Department of EndocrinologyThe Affiliated Hospital of Hangzhou Normal UniversityHangzhouChina
| | - Junping Shi
- Department of Metabolic Disease CenterThe Affiliated Hospital of Hangzhou Normal UniversityHangzhouChina
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Teimouri A, Ebrahimpour Z, Feizi A, Iraj B, Saffari E, Akbari M, Karimifar M. Pre-diabetes and cardiovascular risk factors in NAFLD patients: a retrospective comparative analysis. Front Endocrinol (Lausanne) 2025; 16:1416407. [PMID: 39991738 PMCID: PMC11842249 DOI: 10.3389/fendo.2025.1416407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 01/13/2025] [Indexed: 02/25/2025] Open
Abstract
Objectives Insulin resistance plays a critical role in the pathophysiology of diabetes mellitus and non-alcoholic fatty liver disease (NAFLD). Moreover, insulin resistance has a central role in atherogensis as the major leading cause of cardiovascular disease (CVD). The aim of the present study was to assess the frequency of pre-diabetes and evaluate the cardiometabolic risk factors among NAFLD patients, comparing those with pre-diabetes to those with normal glucose tolerance. Methods In the current retrospective case-control study, the data of 1031 NAFLD patients was retrieved. Based on blood glucose levels, 337 diabetics, 340 pre-diabetes, and, 354 normal glucose patients were diagnosed. After excluding diabetic NAFLD patients, 694 individuals were divided into two groups: normal glucose and pre-diabetes. Various variables, such as age, anthropometric measurements, hypertension, systolic and diastolic blood pressure, and lipid profiles, were extracted from patient files. Statistical analysis was conducted to assess cardiovascular risk factors in NAFLD patients. Results Higher age, female gender, higher BMI, triglyceride, waist and hip circumference and waist-to-hip ratio were found in pre-diabetic NAFLD individuals compared with normoglycemic ones (P-value<0.05). Multivariable age-, sex-, BMI- and smoking- adjusted logistic regression showed a predicting role of pre-diabetes and NAFLD concurrence with metabolic syndrome (P-value<0.001, OR:4.31, 95% CI: 2.95- 6.29), but not CVD (P-value=0.353, OR:1.37, 95% CI: 0.71- 2.61). Conclusion In this study, nearly one-third of NAFLD patients had pre-diabetes. The mean value of age, BMI, TG, waist and Hip circumference was significantly higher in pre-diabetic patients. The concurrence of pre-diabetes and NAFLD was a predicting factor for metabolic syndrome, but not CVD events.
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Affiliation(s)
- Azam Teimouri
- Isfahan Gastroenterology and Hepatology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Ebrahimpour
- Metabolic Liver Disease Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Awat Feizi
- Department of Biostatistics and Epidemiology, School of Public Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Bijan Iraj
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Elahe Saffari
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mojtaba Akbari
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mozhgan Karimifar
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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Wu X, Pan T, Fang Z, Hui T, Yu X, Liu C, Guo Z, Liu C. Identification of EGR1 as a Key Diagnostic Biomarker in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Through Machine Learning and Immune Analysis. J Inflamm Res 2025; 18:1639-1656. [PMID: 39925925 PMCID: PMC11806694 DOI: 10.2147/jir.s499396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 01/25/2025] [Indexed: 02/11/2025] Open
Abstract
Background Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), as a common chronic liver condition globally, is experiencing an increasing incidence rate which poses significant health risks. Despite this, the detailed mechanisms underlying the disease's onset and progression remain poorly understood. In this study, we aim to identify effective diagnostic biomarkers for MASLD using microarray data combined with machine learning techniques, which will aid in further understanding the pathogenesis of MASLD. Methods We collected six datasets from the Gene Expression Omnibus (GEO) database, using five of them as training sets and one as a validation set. We employed three machine learning methods-LASSO, SVM, and Random Forest (RF)-to identify hub genes associated with MASLD. These genes were further validated using the external dataset GSE164760. Additionally, functional enrichment analysis, immune infiltration analysis, and immune function analysis were conducted. A TF-miRNA-mRNA network was constructed, and single-cell RNA sequencing was used to determine the distribution of key genes within key cell clusters. Finally, the expression of the key genes was further validated using the palmitic acid-induced AML-12 cell line and the MCD mouse model. Results In this study, through differential gene expression (DEGs) analysis and machine learning techniques, we successfully identified 10 hub genes. Among these, the key gene EGR1 was validated and screened using an external dataset, with an area under the curve (AUC) of 0.882. Enrichment analyses and immune infiltration assessments revealed multiple pathways involving EGR1 in the pathogenesis and progression of MASLD, showing significant correlations with various immune cells. Furthermore, additional cellular experiments and animal model validations confirmed that the expression trends of EGR1 are highly consistent with our analytical findings. Conclusion Our research has confirmed EGR1 as a key gene in MASLD, providing novel insights into the disease's pathogenesis and identifying new therapeutic targets for its treatment.
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Affiliation(s)
- Xuanlin Wu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Tao Pan
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Zhihao Fang
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Titi Hui
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Xiaoxiao Yu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Changxu Liu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Zihao Guo
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Chang Liu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
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Liang B, Qiu X, Huang J, Lu Y, Shen H, Ma J, Chen Y. Nonlinear associations of the hs-CRP/HDL-C index with metabolic dysfunction-associated steatotic liver disease and advanced liver fibrosis in US adults: insights from NHANES 2017-2018. Sci Rep 2025; 15:4029. [PMID: 39900651 PMCID: PMC11791041 DOI: 10.1038/s41598-025-88685-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 01/30/2025] [Indexed: 02/05/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally widespread chronic liver condition that may progress to severe liver diseases, including advanced liver fibrosis. The high-sensitivity C-reactive protein-to-high-density lipoprotein cholesterol (hs-CRP/HDL-C) index may be a potential indicator for MASLD and advanced liver fibrosis, given its relevance to inflammation and plasma lipids. In this study, the hs-CRP/HDL-C index was investigated in relation to prevalent MASLD and advanced liver fibrosis. The study analyzed secondary data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 database. The hs-CRP/HDL-C index was calculated by the quotient of hs-CRP and HDL-C. Multiple logistic regression models, Cochran-Armitage trend tests, smooth curve fitting, threshold effect analyses, and stratified analyses were used to evaluate whether the hs-CRP/HDL-C index associated with MASLD and advanced liver fibrosis. The study cohort comprised 3684 participants, of whom 1268 (34.42%) were diagnosed with MASLD and 156 (12.28%) with advanced liver fibrosis. Logistic analyses adjusted for covariates revealed positive associations of the hs-CRP/HDL-C index with MASLD and advanced liver fibrosis, consistent across all subgroups. Smooth curve fitting and threshold effect analyses revealed nonlinear relationships of hs-CRP/HDL-C index with MASLD and advanced liver fibrosis, with inflection points at 0.8 for MASLD and 1.2 for advanced liver fibrosis. Additionally, significant interactions were observed between MASLD and covariates such as gender, smoking status, chronic kidney disease (CKD), and cancer. Similarly, the hs-CRP/HDL-C index exhibited positive correlations with advanced liver fibrosis across diverse subgroups, with notable interactions related to cancer. MASLD and advanced liver fibrosis were associated with hs-CRP/HDL-C index, indicating its potential utility as a clinical marker for these conditions.
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Affiliation(s)
- Bin Liang
- Department of Gastroenterology, Minzu Hospital of Guangxi Medical University, Nanning, China
| | - Xue Qiu
- Department of Cardiology, The first Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jiansheng Huang
- Department of Cardiology, The first Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yequan Lu
- Department of Respiratory, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Hairong Shen
- Department of Spleen and Gastrointestinal Endocrinology, Shenzhen Pingle Orthopedic Hospital, Pingshan District Traditional Chinese Medical Hospital), Shenzhen, China
| | - Jianchao Ma
- Department of Orthopedics, Minzu Hospital of Guangxi Medical University, No. 232, Mingxiu Dong Road, Nanning, China.
| | - Yongyu Chen
- Department of Hematology, Minzu Hospital of Guangxi Medical University, No. 232, Mingxiu Dong Road, Nanning, China.
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Xue J, Zhao L, Shao L, Zhang H, Feng Y, Shuai P. Higher risk of carotid plaque among lean individuals with non-alcoholic fatty liver disease: A retrospective study. PLoS One 2025; 20:e0316997. [PMID: 39899517 PMCID: PMC11790118 DOI: 10.1371/journal.pone.0316997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 12/19/2024] [Indexed: 02/05/2025] Open
Abstract
BACKGROUND Lean individual with non-alcoholic fatty liver disease (L-NAFLD) is a prominent area of research, yet its pathogenesis and association with other diseases such as atherosclerotic cardiovascular disease remain uncertain. OBJECT A retrospective study, investigate the association between non-alcoholic fatty liver disease (NAFLD) and carotid plaque (CP) in lean [body mass index (BMI) <24Kg/m2] and non-lean (BMI≥24Kg/m2) populations, as well as identify the related influence factors. METHOD 3,587 participants were eligible and categorized into 4 groups based on the presence with CP and BMI, binary logistic regression analysis was utilized alongside other statistical methods. RESULTS L-NAFLD participants had a 1.395-fold higher risk of CP compared to lean individuals without NAFLD. Age, gender, systolic blood pressure, low-density lipoprotein cholesterol, fasting blood glucose, and Fibrosis-4 index (FIB-4) were identified as independent risk factors with cutoff values lower than the normal upper limits. However, this association was not observed among non-lean participants, regardless of confounding factors adjustment. Moreover, the impact of FIB-4 on the association of NAFLD and CP was more significant in lean CP participants (OR = 1.360 for 1.30 ~ 2.67, and OR = 2.002 for >2.67~<3.48) than in non-lean CP ones. CONCLUSION The L-NAFLD population had a higher risk of CP, while lean CP individuals experienced more severe liver fibrosis. Implementing stricter management of risk factors may improve the health status of high-risk populations.
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Affiliation(s)
- Jiangfeng Xue
- Department of Health Management, The People’s Hospital of Yubei District of Chongqing, Chongqing, China
| | - Lun Zhao
- Department of Digestive System Disease, The People’s Hospital of Yubei District of Chongqing, Chongqing, China
| | - Liang Shao
- Department of Sohome Health Management, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan Province, China
| | - Huiwang Zhang
- Department of Health Management, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan Province, China
| | - Yewei Feng
- Department of Health Management, The People’s Hospital of Yubei District of Chongqing, Chongqing, China
| | - Ping Shuai
- Department of Health Management, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan Province, China
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Xiao TG, Witek L, Bundy RA, Moses A, Obermiller CS, Schreiner AD, Dharod A, Russo MW, Rudnick SR. Identifying and Linking Patients At Risk for MASLD with Advanced Fibrosis to Care in Primary Care. J Gen Intern Med 2025; 40:629-636. [PMID: 39060786 PMCID: PMC11861828 DOI: 10.1007/s11606-024-08955-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024]
Abstract
BACKGROUND AND AIMS Severity of fibrosis is the driver of liver-related outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD), and non-invasive testing such as fibrosis-4 (FIB-4) score is utilized for risk stratification. We aimed to determine if primary care patients at risk for MASLD and advanced fibrosis were evaluated with subsequent testing. A secondary aim was to determine if at-risk patients with normal aminotransferases had advanced fibrosis. METHODS Primary care patients at increased risk for MASLD with advanced fibrosis (n = 91,914) were identified using previously established criteria. Patients with known alternative/concomitant etiology of liver disease or cirrhosis were excluded. The study cohort included patients with calculated FIB-4 score in 2020 (n = 52,006), and stratified into low, indeterminate, and high likelihood of advanced fibrosis. Among those at indeterminate/high risk, rates of subsequent testing were measured. RESULTS Risk stratification with FIB-4 characterized 77% (n = 40,026) as low risk, 17% (n = 8847) as indeterminate, and 6% (n = 3133) as high risk. Among indeterminate/high-risk patients (n = 11,980), 78.7% (n = 9433) had aminotransferases within normal limits, 0.95% (n = 114) had elastography, and 8.2% (n = 984) were referred for subspecialty evaluation. CONCLUSION In this cohort of primary care patients at risk for MASLD with fibrosis, the FIB-4 score identified a substantial proportion of indeterminate/high-risk patients, the majority of which had normal aminotransferase levels. Low rates of subsequent testing were observed. These data suggest that a majority of patients at increased risk for liver-related outcomes remain unrecognized and highlight opportunities to facilitate their identification.
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Affiliation(s)
- Ted G Xiao
- Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Lauren Witek
- Informatics and Analytics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Richa A Bundy
- Informatics and Analytics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Adam Moses
- Informatics and Analytics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Corey S Obermiller
- Informatics and Analytics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Andrew D Schreiner
- Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Ajay Dharod
- Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
- Informatics and Analytics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
- Department of Implementation Science, Division of Public Health Science, Wake Forest School of Medicine, Winston-Salem, NC, USA
- Wake Forest Center for Healthcare Innovation, Wake Forest School of Medicine, Winston-Salem, NC, USA
- Wake Forest Center for Biomedical Informatics, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Mark W Russo
- Division of Liver Diseases and Transplant, Atrium Health Carolina Medical Center, Charlotte, NC, USA
| | - Sean R Rudnick
- Section of Gastroenterology and Hepatology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
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Ionescu VA, Gheorghe G, Bacalbasa N, Diaconu CC. Metabolic Dysfunction-Associated Steatotic Liver Disease: Pathogenetic Links to Cardiovascular Risk. Biomolecules 2025; 15:163. [PMID: 40001466 PMCID: PMC11852489 DOI: 10.3390/biom15020163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/12/2025] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is correlated with an increased cardiovascular risk, independent of other traditional risk factors. The mechanisms underlying this pathogenic link are complex yet remain incompletely elucidated. Among these, the most significant are visceral adiposity, low-grade inflammation and oxidative stress, endothelial dysfunction, prothrombotic status, insulin resistance, dyslipidemia and postprandial hyperlipemia, gut dysbiosis, and genetic mutations. Cardiovascular diseases are the leading cause of death in patients with MASLD. These patients have an increased incidence of coronary artery disease, carotid artery disease, structural and functional cardiac abnormalities, and valvulopathies, as well as arrhythmias and cardiac conduction disorders. In this review, we present the latest data on the association between MASLD and cardiovascular risk, focusing on the pathogenic mechanisms that explain the correlation between these two pathologies. Given the high rates of cardiovascular morbidity and mortality among patients with MASLD, we consider it imperative to raise awareness of the risks associated with this condition within the general population. Further research is essential to clarify the mechanisms underlying the increased cardiovascular risk linked to MASLD. This understanding may facilitate the identification of new diagnostic and prognostic biomarkers for these patients, as well as novel therapeutic targets.
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Affiliation(s)
- Vlad Alexandru Ionescu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania;
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Gina Gheorghe
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania;
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Nicolae Bacalbasa
- Department of Visceral Surgery, Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania;
- Department of Surgery, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
| | - Camelia Cristina Diaconu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania;
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
- Academy of Romanian Scientists, 050085 Bucharest, Romania
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Pei Y, Goh GBB. Genetic Risk Factors for Metabolic Dysfunction-Associated Steatotic Liver Disease. Gut Liver 2025; 19:8-18. [PMID: 39774124 PMCID: PMC11736312 DOI: 10.5009/gnl240407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 01/11/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common cause of liver disease, and its burden on health systems worldwide continues to rise at an alarming rate. MASLD is a complex disease in which the interactions between susceptible genes and the environment influence the disease phenotype and severity. Advances in human genetics over the past few decades have provided new opportunities to improve our understanding of the multiple pathways involved in the pathogenesis of MASLD. Notably, the PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 single nucleotide polymorphisms have been demonstrated to be robustly associated with MASLD development and disease progression. These genetic variants play crucial roles in lipid droplet remodeling, secretion of hepatic very low-density lipoprotein and lipogenesis, and understanding the biology has brought new insights to this field. This review discusses the current body of knowledge regarding these genetic drivers and how they can lead to development of MASLD, the complex interplay with metabolic factors such as obesity, and how this information has translated clinically into the development of risk prediction models and possible treatment targets.
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Affiliation(s)
- Yiying Pei
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
- Medicine Academic Clinical Program, Duke-National University of Singapore (Duke-NUS) Medical School, Singapore
| | - George Boon-Bee Goh
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
- Medicine Academic Clinical Program, Duke-National University of Singapore (Duke-NUS) Medical School, Singapore
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Lee J, Han CI, Lee DY, Sung PS, Bae SH, Yang H. Performance of Noninvasive Indices for Discrimination of Metabolic Dysfunction-Associated Steatotic Liver Disease in Young Adults. Gut Liver 2025; 19:116-125. [PMID: 39639749 PMCID: PMC11736320 DOI: 10.5009/gnl240323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/11/2024] [Accepted: 09/24/2024] [Indexed: 12/07/2024] Open
Abstract
Background/Aims Although numerous noninvasive steatosis indices have been developed to assess hepatic steatosis, whether they can be applied to young adults in the evaluation of metabolic dysfunction-associated steatotic liver disease (MASLD) remains uncertain. Methods Data from patients under 35 years of age who visited the Liver Health Clinic at the Armed Forces Goyang Hospital between July 2022 and January 2024 were retrospectively collected. Steatosis was diagnosed on the basis of a controlled attenuation parameter score ≥250 dB/m. MASLD was defined as the presence of steatosis in patients with at least one cardiometabolic risk factor. Results Among the 1,382 study participants, 901 were diagnosed with MASLD. All eight indices for diagnosing steatosis differed significantly between the MASLD and non-MASLD groups (p<0.001). Regarding the predictive performance, the hepatic steatosis index (HSI), fatty liver index (FLI), Framingham steatosis index, Dallas steatosis index, Zhejiang University index, lipid accumulation product, visceral adiposity index, and triglyceride glucose-body mass index exhibited an area under the curve of 0.898, 0.907, 0.899, 0.893, 0.915, 0.869, 0.791, and 0.898, respectively. The cutoff values for the FLI and HSI were re-examined, indicating a need for alternative cutoff values for the HSI, with a rule-in value of 42 and a rule-out value of 36 in this population. Conclusions This study presents novel findings regarding the predictive performance of established steatosis markers in young adults. Alternative cutoff values for the HSI in this population have been proposed and warrant further validation.
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Affiliation(s)
- Jaejun Lee
- The Catholic University Liver Research Center, Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chang In Han
- Department of Internal Medicine, Armed Forces Goyang Hospital, Goyang, Korea
| | - Dong Yeup Lee
- Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Pil Soo Sung
- The Catholic University Liver Research Center, Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Si Hyun Bae
- The Catholic University Liver Research Center, Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyun Yang
- The Catholic University Liver Research Center, Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Obradović F, Vitello DJ, Hasjim BJ, Obayemi J, Polineni P, Gmeiner M, Koep E, Jain A, Crippa F, Duarte-Rojo A, Rohan VS, Kulik L, Doll JM, Banea T, McNatt GE, Zhao L, VanWagner LB, Manski CF, Ladner DP. Comparing the cost of cirrhosis to other common chronic diseases: A longitudinal study in a large national insurance database. Hepatology 2025:01515467-990000000-01133. [PMID: 39773884 DOI: 10.1097/hep.0000000000001206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 11/26/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND AND AIMS Cirrhosis prevalence is increasing, yet costs associated with its chronic, complex care are poorly understood. The aim was to characterize the costs of care for patients with cirrhosis and compare them to other chronic diseases such as heart failure (HF) and chronic obstructive pulmonary disease (COPD), for which the public health burden is better recognized. APPROACH AND RESULTS Patients enrolled in Medicare Advantage plans from a large national insurer between 2011 and 2020 with cirrhosis, HF, and COPD were identified by ICD-9/-10 codes. Costs (USD) of care were calculated per patient-month and included inpatient medical, emergency medical, pharmacy, and other costs. In all, 93,308 patients with cirrhosis, 355,520 patients with HF, and 318,949 patients with COPD were analyzed. Patients with cirrhosis, HF, and COPD had a mean (SD) age of 69.6 (9.5), 75.9 (9.7), and 72.9 (9.8) years, respectively. The most frequent etiologies were metabolic dysfunction-associated steatohepatitis (37.7%) and alcohol-associated cirrhosis (22.1%). The total monthly cost of care for patients with cirrhosis, HF, and COPD was $3032.00, $2491.60, and $1955.60 respectively. The cost for patients with cirrhosis exceeded that for HF by $540.40 (21.7% higher) and COPD by $1076.30 (55.0% higher). The monthly cost of care for decompensated cirrhosis was $3969.30, which was 59.3% ($1477.70) higher than for HF and 103.0% ($1,955.60) higher than for COPD. CONCLUSIONS The cost of care for cirrhosis is high, significantly higher than HF and COPD. Interventions directed at optimizing care to prevent progression to cirrhosis and decompensation are likely to alleviate this public health burden.
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Affiliation(s)
- Filip Obradović
- Department of Economics, Northwestern University, Evanston, Illinois, USA
| | - Dominic J Vitello
- Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center (CTC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Bima J Hasjim
- Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center (CTC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Joy Obayemi
- Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center (CTC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Praneet Polineni
- Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center (CTC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Michael Gmeiner
- Department of Economics, London School of Economics, London, UK
| | - Eleena Koep
- Center for Health Care Research, UnitedHealth Group, Eden Prairie, Minnesota, USA
| | - Aditya Jain
- Department of Economics, Northwestern University, Evanston, Illinois, USA
| | - Federico Crippa
- Department of Economics, Northwestern University, Evanston, Illinois, USA
| | - Andrés Duarte-Rojo
- Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center (CTC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern Medicine, Chicago, Illinois, USA
| | - Vinayak S Rohan
- Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center (CTC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Surgery, Division of Transplantation, Northwestern Medicine, Chicago, Illinois, USA
| | - Laura Kulik
- Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center (CTC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern Medicine, Chicago, Illinois, USA
| | - Julianna M Doll
- Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center (CTC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Therese Banea
- Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center (CTC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Gwen E McNatt
- Organ Transplant Center, University of Iowa Healthcare, Iowa City, Iowa, USA
| | - Lihui Zhao
- Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center (CTC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Lisa B VanWagner
- Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Charles F Manski
- Department of Economics, Northwestern University, Evanston, Illinois, USA
- Institute for Policy Research, Northwestern University, Evanston, Illinois, USA
| | - Daniela P Ladner
- Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center (CTC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Surgery, Division of Transplantation, Northwestern Medicine, Chicago, Illinois, USA
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Le P, Tatar M, Dasarathy S, Alkhouri N, Herman WH, Taksler GB, Deshpande A, Ye W, Adekunle OA, McCullough A, Rothberg MB. Estimated Burden of Metabolic Dysfunction-Associated Steatotic Liver Disease in US Adults, 2020 to 2050. JAMA Netw Open 2025; 8:e2454707. [PMID: 39821400 PMCID: PMC11742522 DOI: 10.1001/jamanetworkopen.2024.54707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 11/03/2024] [Indexed: 01/19/2025] Open
Abstract
Importance Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease and is projected to become the leading indication for liver transplant (LT) in the US. Understanding its clinical burden can help to identify opportunities for prevention and treatment. Objective To project the burden of MASLD in US adults from 2020 to 2050. Design, Setting, and Participants This decision analytical modeling study used an agent-based state transition model that simulates the natural history of MASLD progression among adults 18 years of age or older. Primary data sources for model inputs were the published literature. Exposure Natural history of MASLD. Main Outcomes and Measures Cases of MASLD, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, hepatocellular carcinoma (HCC), LT, and liver-related death. Results The model simulated 2 821 624 individuals (mean age. 35.8 years; 50.9% female). The model predicted a steady increase in the prevalence of MASLD from 33.7% (86.3 million people) in 2020 to 41.4% (121.9 million people) by 2050. Cases of MASH would increase from 14.9 million (5.8% of US adults) in 2020 to 23.2 million (7.9% of US adults) by 2050. The number of cases of MASH and clinically significant fibrosis (ie, F≥F2, centrilobular and periportal fibrosis or more severe disease) were estimated to increase from 6.7 million to 11.7 million. By 2046 to 2050, MASLD would cause 22 440 new cases of HCC and 6720 new cases of LT per year compared with 11 483 new cases of HCC and 1717 new cases of LT in 2020 to 2025. Liver-related mortality was estimated to increase from 30 500 deaths (1.0% of all-cause deaths in adults) in 2020 to 95 300 deaths (2.4%) in 2050. Conclusions and Relevance In this decision analytical modeling study, the model forecast a substantial increase in clinical burden of MASLD over the next 3 decades in the absence of effective treatments. These results suggest that health systems should plan for large increases in the number of HCC cases and in the need for LT.
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Affiliation(s)
- Phuc Le
- Center for Value-Based Care Research, Cleveland Clinic, Cleveland, Ohio
| | - Moosa Tatar
- Center for Value-Based Care Research, Cleveland Clinic, Cleveland, Ohio
- University of Houston School of Pharmacy, Houston, Texas
| | - Srinivasan Dasarathy
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, Ohio
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Naim Alkhouri
- Department of Hepatology, Arizona Liver Health, Tucson
| | - William H. Herman
- University of Michigan School of Public Health, Ann Arbor
- University of Michigan School of Medicine, Ann Arbor
| | - Glen B. Taksler
- Center for Value-Based Care Research, Cleveland Clinic, Cleveland, Ohio
| | | | - Wen Ye
- University of Michigan School of Public Health, Ann Arbor
| | | | - Arthur McCullough
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
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Abolfazli S, Butler AE, Jamialahmadi T, Sahebkar A. A Golden Shield: The Protective Role of Curcumin against Liver Fibrosis. Curr Med Chem 2025; 32:1987-2004. [PMID: 37605399 DOI: 10.2174/0929867331666230821095329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/28/2023] [Accepted: 07/13/2023] [Indexed: 08/23/2023]
Abstract
Several chronic liver injuries can result in liver fibrosis, a wound-healing response defined by an excessive buildup of diffuse extracellular matrix (ECM). Liver fibrosis may progress to liver cirrhosis, liver failure, or hepatocellular carcinoma. Many cellular routes are implicated in the fibrosis process; however, hepatic stellate cells appear to be the main cell type involved. Curcumin, a polyphenolic substance extracted from the Curcuma longa plant, has a diversity of pharmacologic impacts, including anti- inflammatory, antioxidant, antiproliferative and antiangiogenic actions. The anti-fibrotic property of curcumin is less clear, but curcumin's ability to influence inflammatory cytokines, inflammatory pathways, the expression of pro-apoptotic (up-regulated) and anti- apoptotic (down-regulated) proteins, and its ability to lower oxidative stress likely underlie its anti-fibrotic properties. In this review, we investigate and analyze the impact of curcumin on several disorders that lead to liver fibrosis, and discuss the therapeutic applications of curcumin for these disorders.
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Affiliation(s)
- Sajad Abolfazli
- Student Research Committee, School of Pharmacy, Mazandaran University of Medical Science, Sari, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland-Bahrain, Adliya, Bahrain
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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Castañé H, Jiménez-Franco A, Hernández-Aguilera A, Martínez-Navidad C, Cambra-Cortés V, Onoiu AI, Jiménez-Aguilar JM, París M, Hernández M, Parada D, Guilarte C, Zorzano A, Hernández-Alvarez MI, Camps J, Joven J. Multi-omics profiling reveals altered mitochondrial metabolism in adipose tissue from patients with metabolic dysfunction-associated steatohepatitis. EBioMedicine 2025; 111:105532. [PMID: 39731853 PMCID: PMC11743550 DOI: 10.1016/j.ebiom.2024.105532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 12/13/2024] [Accepted: 12/15/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form steatohepatitis (MASH) contribute to rising morbidity and mortality rates. The storage of fat in humans is closely associated with these diseases' progression. Thus, adipose tissue metabolic homeostasis could be key in both the onset and progression of MASH. METHODS We conducted a case-control observational research using a systems biology-based approach to analyse liver, abdominal subcutaneous adipose tissue (SAT), omental visceral adipose tissue (VAT), and blood of n = 100 patients undergoing bariatric surgery (NCT05554224). MASH was diagnosed through histologic assessment. Whole-slide image analysis, lipidomics, proteomics, and transcriptomics were performed on tissue samples. Lipidomics and proteomics profiles were determined on plasma samples. FINDINGS Liver transcriptomics, proteomics, and lipidomics revealed interconnected pathways associated with inflammation, mitochondrial dysfunction, and lipotoxicity in MASH. Paired adipose tissue biopsies had larger adipocyte areas in both fat depots in MASH. Enrichment analyses of proteomics and lipidomics data confirmed the association of liver lesions with mitochondrial dysfunction in VAT. Plasma lipidomics identified candidates with high diagnostic accuracy (AUC = 0.919, 95% CI 0.840-0.979) for screening MASH. INTERPRETATION Mitochondrial dysfunction is also present in VAT in patients with obesity-associated MASH. This may cause a disruption in the metabolic equilibrium of lipid processing and storage, which impacts the liver and accelerates detrimental adaptative responses. FUNDING The project leading to these results has received funding from 'la Caixa' Foundation (HR21-00430), and from the Instituto de Salud Carlos III (ISCIII) (PI21/00510) and co-funded by the European Union.
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Affiliation(s)
- Helena Castañé
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d'Investigació Sanitària Pere Virgili, Reus, Spain; Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira i Virgili, Reus, Spain.
| | - Andrea Jiménez-Franco
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d'Investigació Sanitària Pere Virgili, Reus, Spain; Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira i Virgili, Reus, Spain
| | | | - Cristian Martínez-Navidad
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d'Investigació Sanitària Pere Virgili, Reus, Spain
| | - Vicente Cambra-Cortés
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d'Investigació Sanitària Pere Virgili, Reus, Spain
| | - Alina-Iuliana Onoiu
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d'Investigació Sanitària Pere Virgili, Reus, Spain
| | - Juan Manuel Jiménez-Aguilar
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d'Investigació Sanitària Pere Virgili, Reus, Spain
| | - Marta París
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d'Investigació Sanitària Pere Virgili, Reus, Spain; Department of Surgery, Hospital Universitari de Sant Joan, Reus, Spain
| | - Mercè Hernández
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d'Investigació Sanitària Pere Virgili, Reus, Spain; Department of Surgery, Hospital Universitari de Sant Joan, Reus, Spain
| | - David Parada
- Department of Pathology, Hospital Universitari de Sant Joan, Reus, Spain
| | - Carmen Guilarte
- Department of Pathology, Hospital Universitari de Sant Joan, Reus, Spain
| | - Antonio Zorzano
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - María Isabel Hernández-Alvarez
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Institut de Biomedicina de la Universitat de Barcelona IBUB, Barcelona, Spain
| | - Jordi Camps
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d'Investigació Sanitària Pere Virgili, Reus, Spain; Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira i Virgili, Reus, Spain.
| | - Jorge Joven
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d'Investigació Sanitària Pere Virgili, Reus, Spain; Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira i Virgili, Reus, Spain; The Campus of International Excellence Southern Catalonia, Tarragona, Spain.
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DiStefano JK, Gerhard GS. A complement to epigenetics in metabolic dysfunction-associated steatotic liver disease: Editorial on "DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease". Clin Mol Hepatol 2025; 31:297-300. [PMID: 39188228 PMCID: PMC11791565 DOI: 10.3350/cmh.2024.0704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 08/27/2024] [Indexed: 08/28/2024] Open
Affiliation(s)
- Johanna K. DiStefano
- Metabolic Disease Research Unit, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Glenn S. Gerhard
- Lewis Katz School of Medicine, Temple University School of Medicine, Philadelphia, PA, USA
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Maharajan N, Vijayakumar KA, Cho GW. Therapeutic potential of the flavonoid compound Licochalcone D in metabolic dysfunction-associated steatotic liver disease. Biochem Biophys Res Commun 2025; 744:151216. [PMID: 39721362 DOI: 10.1016/j.bbrc.2024.151216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/21/2024] [Accepted: 12/18/2024] [Indexed: 12/28/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease associated with type 2 diabetes, which doubles the risk of developing this condition. Various flavonoid compounds have a positive effect on lipid metabolism, inflammation, and insulin resistance and can contribute to slowing down the progression of MASLD. In the current study, we investigated the biological effects of Licochalcone D (Lico D), a flavonoid, in a metabolic disease model. Oil Red O staining, quantitative real-time polymerase chain reaction, and western blotting were performed. For in vivo experiments, we used high-fat diet (60 %) plus low-dose streptozotocin (30 mg/kg; 5 days; intraperitoneal)-induced metabolic disease mouse model and evaluated lipid metabolism. We observed that Lico D reduced lipid accumulation and increased lipid metabolism both in vitro and in vivo. Additionally, we identified that the AMP-activated protein kinase and Sirtuin 1 pathways were activated in the mouse liver and hepatic steatosis cell model. In silico analysis revealed that Lico D passes the "Lipinski Rule of Five," which indicates drug-likeness properties. In conclusion, our findings highlight the role of Lico D in improving metabolic dysfunction-associated steatotic liver disease.
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Affiliation(s)
- Nagarajan Maharajan
- Department of Otorhinolaryngology - Head and Neck Surgery, University of Maryland School of Medicine, 21201, Baltimore, MD, USA.
| | - Karthikeyan A Vijayakumar
- Department of Biological Science, College of Natural Sciences, Chosun University, 309 Pilmun-daero, Dong-gu, 61452, Gwangju, South Korea; The Basic Science Institute of Chosun University, Chosun University, 61452, Gwangju, South Korea.
| | - Gwang-Won Cho
- Department of Biological Science, College of Natural Sciences, Chosun University, 309 Pilmun-daero, Dong-gu, 61452, Gwangju, South Korea; The Basic Science Institute of Chosun University, Chosun University, 61452, Gwangju, South Korea; Department of Integrative Biological Science, BK21 FOUR Education Research Group for Age-Associated Disorder Control Technology, Chosun University, 61452, Gwangju, South Korea.
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Cheng H, Wu J, Peng H, Li J, Liu Z, Wang X, Zhang K, Xie L. Epigenetic Modulation with 5-Aza-CdR Prevents Metabolic-Associated Fatty Liver Disease Promoted by Maternal Overnutrition. Nutrients 2024; 17:106. [PMID: 39796540 PMCID: PMC11722594 DOI: 10.3390/nu17010106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/03/2024] [Accepted: 12/12/2024] [Indexed: 01/13/2025] Open
Abstract
BACKGROUND/OBJECTIVES This study builds on previous findings from mouse models, which showed that maternal overnutrition induced by a high-fat diet (HFD) promotes metabolic-associated fatty liver disease (MAFLD) in offspring, linked to global DNA hypermethylation. We explored whether epigenetic modulation with 5-Aza-CdR, a DNA methylation inhibitor, could prevent MAFLD in offspring exposed to maternal overnutrition. METHODS The offspring mice from dams of maternal overnutrition were fed either a chow diet or a high-fat diet (HFD) for 10 weeks. These mice were randomly divided into two groups: HFD, and AZA + HFD. Mice assigned to the AZA group were given 5-Aza-CdR during the last three weeks. RESULTS Our findings show that 5-Aza-CdR treatment in HFD-fed offspring effectively countered weight gain, improved glucose regulation, and minimized hepatic fat buildup along with serum lipid imbalances. Additionally, it boosted AMPK signaling and raised PPAR-α expression, pointing to enhanced fatty acid oxidation. We also detected an increase in JNK signaling, affecting the gene expression associated with cell death and proliferation. Notably, treated mice displayed more hepatic inflammation than the HFD group alone, suggesting a complex, dual impact on MAFLD management. Significant apoptotic and inflammatory gene changes were identified, along with corresponding differentially methylated regions triggered by 5-Aza-CdR, marking potential therapeutic targets. CONCLUSIONS 5-Aza-CdR was shown to mitigate MAFLD features in offspring of maternal overnutrition by reversing DNA hypermethylation and improving metabolic pathways, though its dual impact on inflammation highlights the need for further research to optimize its therapeutic potential.
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Affiliation(s)
- Henghui Cheng
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (H.C.); (H.P.); (Z.L.); (X.W.)
| | - Jie Wu
- Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA; (J.W.); (J.L.)
| | - Hui Peng
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (H.C.); (H.P.); (Z.L.); (X.W.)
| | - Jiangyuan Li
- Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA; (J.W.); (J.L.)
- Department of Statistics, Texas A&M University, College Station, TX 77843, USA
| | - Zhimin Liu
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (H.C.); (H.P.); (Z.L.); (X.W.)
| | - Xian Wang
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (H.C.); (H.P.); (Z.L.); (X.W.)
| | - Ke Zhang
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (H.C.); (H.P.); (Z.L.); (X.W.)
- Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA; (J.W.); (J.L.)
| | - Linglin Xie
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (H.C.); (H.P.); (Z.L.); (X.W.)
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Lam R, Jain D, Deng Y, Acharya E, Lim JK. Advanced Liver Fibrosis Predicts Liver Outcomes in Biopsy-proven Metabolic Dysfunction-associated Steatotic Liver Disease: A U.S.-based Single-center Retrospective Cohort Study. J Clin Transl Hepatol 2024; 12:988-996. [PMID: 39649030 PMCID: PMC11622200 DOI: 10.14218/jcth.2024.00189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 09/25/2024] [Accepted: 09/29/2024] [Indexed: 12/10/2024] Open
Abstract
BACKGROUND AND AIMS Data regarding risk factors and long-term outcomes of U.S. patients with biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) are limited. This study aimed to investigate the role of clinical and histologic risk factors on long-term outcomes in patients with MASLD. METHODS A retrospective cohort study of 451 adults with biopsy-proven MASLD was conducted at a U.S. academic hospital from 2012 to 2020. An experienced pathologist evaluated the index liver biopsy. Patients with a prior liver transplant or alternative etiologies of chronic liver disease were excluded. The duration of the risk exposure was determined from the date of the index liver biopsy to an outcome event or the last follow-up examination. Outcome events of interest included incident liver-related events, liver decompensation, and all-cause mortality. RESULTS In the final cohort of 406 patients followed for a median of 3.7 years (interquartile range: 4.8 years), 35 patients died, 41 developed hepatic decompensation, and 70 experienced a liver-related event. Among histologic risk factors, stage 3 (adjusted Hazard ratio (aHR) 2.68, 95% confidence interval (CI) 1.18-6.11) and stage 4 (aHR 6.96, 95% CI 3.55-13.64) fibrosis were associated with incident liver-related events compared to stage 0-1 fibrosis. Stage 4 (aHR 8.46, 95% CI 3.26-21.99) fibrosis alone was associated with incident liver decompensation events compared to stage 0-1 fibrosis. Among clinical risk factors, hypertension (aHR 2.58, 95% CI 1.05-6.34) was associated with incident liver decompensation. CONCLUSIONS In a U.S. single-center cohort of patients with biopsy-proven MASLD, advanced fibrosis was the primary risk factor for incident liver decompensation and liver-related events.
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Affiliation(s)
- Robert Lam
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Dhanpat Jain
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Yanhong Deng
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | | | - Joseph K. Lim
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
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Zou C, Liu X, He M, Sun Y, Sang Y, Peng G, Ma Y, Geng H, Liang J. Insulin Resistance Mediates the Association Between Vitamin D and Non-Alcoholic Fatty Liver Disease. Int J Prev Med 2024; 15:77. [PMID: 39867257 PMCID: PMC11759225 DOI: 10.4103/ijpvm.ijpvm_221_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 11/14/2023] [Indexed: 01/28/2025] Open
Abstract
Background Vitamin D (VD) deficiency and insulin resistance (IR) increase the risk of non-alcoholic fatty liver disease (NAFLD), but few studies have explored the potential mechanisms by which IR mediates the association between VD and the pathogenesis of NAFLD at the genetic level using publicly available databases. Methods This is a cross-sectional study, and we utilized the National Health and Nutrition Examination Survey (NHANES) dataset, as well as data from GSE200765 obtained from the Gene Expression Omnibus (GEO) website. A total of 723 individuals who had completed liver ultrasound examination and the detection of VD levels were included in the final analysis. A gene expression dataset, GSE200765, was also downloaded from the GEO website, to explore the potential mechanism of VD and NAFLD. Results In the NHANES data, covariates significantly differed in four VD categories, and the controlled attenuation parameter (CAP), vibration-controlled transient elastography-liver stiffness measurement (VCTE-LSM), and IR were reduced with an increase in VD levels. Mediation analysis revealed that IR mediated the association between VD and both CAP and LSM, and the estimated mediation effects were 29.0% and 39.8%, respectively. Bioinformatics analysis showed that seven differentially expressed genes (DEGs) (solute carrier family 2 member 2 [SLC2A2], protein phosphatase 1 regulatory subunit 3E [PPP1R3E], CAMP responsive element binding protein 3-like 3 [CREB3L3], Interleukin-6 [IL-6], peroxisome proliferator-activated receptor gamma coactivator 1-alpha [PPARGC1A], nuclear factor kappa B inhibitor alpha [NFKBIA], and phosphoenolpyruvate carboxykinase 2 [PCK2]) were enriched in the IR pathway in comparison groups (VD group vs. lipid group), suggesting that VD improved NAFLD via changed IR. Conclusions VD deficiency and IR were the risk factors for NAFLD, and increased VD levels improved the status of NAFLD. The underlying mechanism may be that elevated VD levels reduced IR, which improved the expression of DEGs involved in the IR pathway.
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Affiliation(s)
- Caiyan Zou
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Affiliated Hospital of Southeast University, Xuzhou Clinical School of Nanjing Medical University, Xuzhou, Jiangsu, China
| | - Xuekui Liu
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Affiliated Hospital of Southeast University, Xuzhou Clinical School of Nanjing Medical University, Xuzhou, Jiangsu, China
- Department of Central Laboratory, Xuzhou Central Hospital, Xuzhou Institute of Medical Science, Jiangsu Province, China
| | - Maosheng He
- Department of Ultrasound, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Yan Sun
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Affiliated Hospital of Southeast University, Xuzhou Clinical School of Nanjing Medical University, Xuzhou, Jiangsu, China
| | - Yiquan Sang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Affiliated Hospital of Southeast University, Xuzhou Clinical School of Nanjing Medical University, Xuzhou, Jiangsu, China
| | - Gangshan Peng
- Department of Graduate School, Xuzhou Medical University, Xuzhou, China
| | - Yamei Ma
- Department of Bengbu Medical College, Bengbu, China
| | - Houfa Geng
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Affiliated Hospital of Southeast University, Xuzhou Clinical School of Nanjing Medical University, Xuzhou, Jiangsu, China
| | - Jun Liang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Affiliated Hospital of Southeast University, Xuzhou Clinical School of Nanjing Medical University, Xuzhou, Jiangsu, China
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Rahmanian M, Deravi N, Poudineh M, Poopak A, Mirmohammadali SN, Fekrvand S, Tadbir K, Ebrahimian S, Zargarzadeh N, Pirzadeh M, Abdi A, Firouzabadi FD, Mechanick JI. Prevalence of metabolic dysfunction–associated fatty liver disease among patients with diabetic kidney disease: a systematic review and meta-analysis. EGYPTIAN LIVER JOURNAL 2024; 14:87. [DOI: 10.1186/s43066-024-00393-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 11/08/2024] [Indexed: 01/03/2025] Open
Abstract
Abstract
Background
Mechanistic relationships between metabolic dysfunction–associated fatty liver disease (MAFLD) and chronic kidney disease are well characterized. Specifically, in type 2 diabetes (T2D), insulin resistance leads to MAFLD, and hyperglycemia leads to microvascular complications such as diabetic kidney disease (DKD). This systematic review and meta-analysis aims to describe the specific association between MAFLD and DKD for the first time.
Methods
PubMed, Web of Science, Google Scholar, and Scopus databases were searched up to February 2023 to identify relevant published articles. After screening the titles, abstracts, and full texts of the retrieved articles, cross-sectional studies and cohorts reporting on MAFLD in patients with DKD were identified and then analyzed.
Results
A total of 2615 articles were identified, of which 5 had sufficient data and fulfilled the eligibility criteria for meta-analysis. A total of 2345 patients with DKD were in the included studies. The prevalence rates of radiologically diagnosed MAFLD among patients with DKD ranged from 25 to 96%. The pooled prevalence rate of radiologically diagnosed MAFLD among patients with DKD was 0.55 (95% CI = 0.21–0.89, I2 = 99.79%, P-value < 0.01).
Conclusion
MAFLD is prevalent in patients with DKD. This finding emphasizes the need for aggressive case finding and then guideline-directed medical therapy of MAFLD, especially in patients with T2D and DKD to prevent further complications. Future studies should investigate mechanisms underpinning MAFLD and DKD in patients with T2D, especially in the context of cardiometabolic risk.
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Cui Y, Yang K, Guo C, Xia Z, Jiang B, Xue Y, Song B, Hu W, Zhang M, Wei Y, Zhang C, Zhang S, Fang J. Carbon monoxide as a negative feedback mechanism on HIF-1α in the progression of metabolic-associated fatty liver disease. Nitric Oxide 2024; 153:1-12. [PMID: 39369813 DOI: 10.1016/j.niox.2024.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 10/01/2024] [Accepted: 10/03/2024] [Indexed: 10/08/2024]
Abstract
Metabolic-associated fatty liver disease (MAFLD) encompasses various chronic liver conditions, yet lacks approved drugs. Hypoxia-inducible factor-1α (HIF-1α) is pivotal in MAFLD development. Our prior research highlighted the efficacy of the nano-designed carbon monoxide (CO) donor, targeting HIF-1α in a mouse hepatic steatosis model. Given heme oxygenase-1 (HO-1, a major downstream molecule of HIF-1α) as the primary source of intrinsic CO, we hypothesized that upregulation of HO-1/CO, responsive to HIF-1α, forms a negative feedback loop regulating MAFLD progression. In this study, we explored the potential negative feedback mechanism of CO on HIF-1α and its downstream effects on MAFLD advancement. HIF-1α emerges early in hepatic steatosis induced by a high-fat (HF) diet, triggering increased HO-1 and inflammation. SMA/CORM2 effectively suppresses HIF-1α and steatosis progression when administered within the initial week of HF diet initiation but loses impact later. In adipose tissues, concurrent metabolic dysfunction and inflammation with HIF-1α activation suggest adipose tissue expansion initiates HF-induced steatosis, triggering hypoxia and liver inflammation. Notably, in an in vitro study using mouse hepatocytes treated with fatty acids, downregulating HO-1 intensified HIF-1α induction at moderate fatty acid concentrations. However, this effect diminished at high concentrations. These results suggest the HIF-1α-HO-1-CO axis as a feedback loop under physiological and mild pathological conditions. Excessive HIF-1α upregulation in pathological conditions overwhelms the CO feedback loop. Additional CO application effectively suppresses HIF-1α and disease progression, indicating potential application for MAFLD control.
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Affiliation(s)
- Yingying Cui
- Peking University First Hospital Ningxia Women and Children's Hospital (Ningxia Hui Autonomous Region Maternal and Child Health Hospital), Yinchuan, 750000, China; Department of Toxicology, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China
| | - Kai Yang
- Department of Medical Technology, Anhui Medical College, No.632, Furong Road, Hefei, Anhui Province, China
| | - Chunyu Guo
- Department of Toxicology, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China
| | - Zhengmei Xia
- Department of Toxicology, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China
| | - Benchun Jiang
- Department of Gastricintestinal Surgery, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang, 110004, Liaoning, China
| | - Yanni Xue
- Department of Toxicology, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China
| | - Bingdong Song
- Department of Toxicology, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China
| | - Weirong Hu
- Department of Toxicology, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China
| | - Mingjie Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang, 110004, Liaoning, China
| | - Yanyan Wei
- Department of Infectious Disease, the First Affiliated Hospital of Anhui Medical University, No 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Cheng Zhang
- Department of Toxicology, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China
| | - Shichen Zhang
- Anhui Provincial Center for Maternal and Child Health Genetics, School of Public Health and Health Management, Anhui Medical College, No 632 Furong Road, Hefei, 230601, Anhui, China.
| | - Jun Fang
- Department of Toxicology, School of Public Health, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei, 230022, Anhui, China; Anhui Provincial Center for Maternal and Child Health Genetics, School of Public Health and Health Management, Anhui Medical College, No 632 Furong Road, Hefei, 230601, Anhui, China; Faculty of Pharmaceutical Sciences, Sojo University, Ikeda 4-22-1, Kumamoto, 860-0082, Japan.
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Ramachandran P, Brice M, Sutherland EF, Hoy AM, Papachristoforou E, Jia L, Turner F, Kendall TJ, Marwick JA, Carragher NO, Oro D, Feigh M, Leeming DJ, Nielsen MJ, Karsdal MA, Hartmann N, Erickson M, Adorini L, Roth JD, Fallowfield JA. Aberrant basement membrane production by HSCs in MASLD is attenuated by the bile acid analog INT-767. Hepatol Commun 2024; 8:e0574. [PMID: 39585303 PMCID: PMC11596521 DOI: 10.1097/hc9.0000000000000574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 09/07/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND The farnesoid X receptor (FXR) is a leading therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis. INT-767, a potent FXR agonist, has shown promise in preclinical models. We aimed to define the mechanisms of INT-767 activity in experimental MASH and dissect cellular and molecular targets of FXR agonism in human disease. METHODS Leptin-deficient ob/ob mice were fed a MASH-inducing diet for 15 weeks before the study started. After baseline liver biopsy and stratification, mice were allocated to INT-767 (10 mg/kg/d) or vehicle treatment for 8 weeks, either alongside an ongoing MASH diet (progression) or following conversion to normal chow (reversal). Effects on extracellular matrix remodeling were analyzed histologically and by RNA-sequencing. Serum fibrosis biomarkers were measured longitudinally. Human liver samples were investigated using bulk and single-cell RNA-sequencing, histology, and cell culture assays. RESULTS INT-767 treatment was antifibrotic during MASH progression but not reversal, attenuating the accumulation of type I collagen and basement membrane proteins (type IV collagen and laminin). Circulating levels of PRO-C4, a type IV collagen formation marker, were reduced by INT-767 treatment and correlated with fibrosis. Expression of basement membrane constituents also correlated with fibrosis severity and adverse clinical outcomes in human MASH. Single-cell RNA-sequencing analysis of mouse and human livers, and immunofluorescence staining colocalized FXR and basement membrane expression to myofibroblasts within the fibrotic niche. Treatment of culture-activated primary human HSCs with INT-767 decreased expression of basement membrane components. CONCLUSIONS These findings highlight the importance of basement membrane remodeling in MASH pathobiology and as a source of circulating biomarkers. Basement membrane deposition by activated HSCs is abrogated by INT-767 treatment and measurement of basement membrane molecules should be included when determining the therapeutic efficacy of FXR agonists.
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Affiliation(s)
- Prakash Ramachandran
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Madara Brice
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Elena F. Sutherland
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Anna M. Hoy
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Eleni Papachristoforou
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Li Jia
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Frances Turner
- Edinburgh Genomics, University of Edinburgh, Edinburgh, UK
| | - Timothy J. Kendall
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
- Edinburgh Pathology, University of Edinburgh, Edinburgh, UK
| | - John A. Marwick
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Neil O. Carragher
- Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | | | | | | | | | | | | | - Mary Erickson
- Intercept Pharmaceuticals Inc., San Diego, California, USA
| | | | | | - Jonathan A. Fallowfield
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
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Babu AF, Palomurto S, Kärjä V, Käkelä P, Lehtonen M, Hanhineva K, Pihlajamäki J, Männistö V. Metabolic signatures of metabolic dysfunction-associated steatotic liver disease in severely obese patients. Dig Liver Dis 2024; 56:2103-2110. [PMID: 38825414 DOI: 10.1016/j.dld.2024.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/02/2024] [Accepted: 05/13/2024] [Indexed: 06/04/2024]
Abstract
BACKROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Still, most patients with MASLD die from cardiovascular diseases indicating metabolic alterations related to both liver and cardiovascular pathology. AIMS AND METHODS The aim of this study was to assess biologic pathways behind MASLD progression from steatosis to metabolic dysfunction-associated steatohepatitis (MASH) using non-targeted liquid chromatography-mass spectrometry analysis in 106 severely obese individuals (78 women, mean age 47.7 7 ± 9.2 years, body mass index 41.8 ± 4.3 kg/m²) undergoing laparoscopic Roux-en-Y gastric bypass. RESULTS We identified several metabolites that are associated with MASLD progression. Most importantly, we observed a decrease of lysophosphatidylcholines LPC(18:2), LPC(18:3), and LPC(20:3) and increase of xanthine when comparing those with steatosis to those with MASH. We found that indole propionic acid and threonine were negatively correlated to fibrosis, but not with the metabolic disturbances associated with cardiovascular risk. Xanthine, ketoleucine, and tryptophan were positively correlated to lobular inflammation and ballooning but also with insulin resistance, and dyslipidemia, respectively. The results did not change when taking into account the most important genetic risk factors of MASLD. CONCLUSIONS Our findings suggest that there are several separate biological pathways, some of them independent of insulin resistance and dyslipidemia, associating with MASLD.
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Affiliation(s)
- Ambrin Farizah Babu
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70211 Kuopio, Finland; Afekta Technologies Ltd., Microkatu 1, 70210 Kuopio, Finland
| | - Saana Palomurto
- Department of Surgery, Kuopio University Hospital, 70210 Kuopio, Finland
| | - Vesa Kärjä
- Department of Pathology, Kuopio University Hospital, 70210 Kuopio, Finland
| | - Pirjo Käkelä
- Department of Surgery, Kuopio University Hospital, 70210 Kuopio, Finland
| | - Marko Lehtonen
- School of Pharmacy, Faculty of Health Science, University of Eastern Finland, 70211 Kuopio, Finland; LC-MS Metabolomics Center, Biocenter Kuopio, 70211 Kuopio, Finland
| | - Kati Hanhineva
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70211 Kuopio, Finland; Afekta Technologies Ltd., Microkatu 1, 70210 Kuopio, Finland; Department of Life Technologies, Food Sciences Unit, University of Turku, 20014 Turku, Finland
| | - Jussi Pihlajamäki
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70211 Kuopio, Finland; Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, 70210 Kuopio Finland
| | - Ville Männistö
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, 70210 Kuopio, Finland.
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Sualeheen A, Tan SY, Georgousopoulou E, Daly RM, Tierney AC, Roberts SK, George ES. Mediterranean diet for the management of metabolic dysfunction-associated steatotic liver disease in non-Mediterranean, Western countries: What's known and what's needed? NUTR BULL 2024; 49:444-462. [PMID: 39258424 DOI: 10.1111/nbu.12707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 08/14/2024] [Accepted: 08/14/2024] [Indexed: 09/12/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide, affecting 30% of the population in Western countries. MASLD is considered the hepatic manifestation of the metabolic syndrome, pathophysiologically underpinned by insulin resistance and frequently co-exists with hypertension, central obesity and dyslipidaemia. Currently, safe and effective pharmacotherapies for MASLD are limited, making weight loss with lifestyle changes the mainstay therapy. A Mediterranean diet (MedDiet) has emerged as an effective dietary pattern for preventing and managing MASLD, but most studies have been conducted in Mediterranean countries, necessitating further investigation into its benefits in Western populations. Additionally, the effect of holistic multimodal lifestyle interventions, including physical activity combined with the MedDiet, is not well established. Finally, MASLD's widespread prevalence and rapid growth require improved accessibility to interventions. Digital health delivery platforms, designed for remote access, could be a promising approach to providing timely support to individuals with MASLD. This narrative review summarises the current evidence related to the effects of the MedDiet in Western, multicultural populations with MASLD. This includes a detailed description of the composition, prescription and adherence to dietary interventions in terms of how they have been designed and applied. The evidence related to the role of physical activity or exercise interventions prescribed in combination with the MedDiet for MASLD will also be reviewed. Finally, recommendations for the design and delivery of dietary and physical activity or exercise interventions to inform the design of future randomised controlled trials to facilitate the optimal management of MASLD are outlined.
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Affiliation(s)
- Ayesha Sualeheen
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - Sze-Yen Tan
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - Ekavi Georgousopoulou
- Discipline of Nutrition and Dietetics, Faculty of Health, University of Canberra, Canberra, New South Wales, Australia
| | - Robin M Daly
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - Audrey C Tierney
- School of Allied Health, Centre for Implementation Research, Health Research Institute, University of Limerick, Limerick, Ireland
| | - Stuart K Roberts
- Department of Gastroenterology, Alfred Health, Prahran, Victoria, Australia
- Central Clinical School, Monash University, Clayton, Victoria, Australia
| | - Elena S George
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
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Khodadadi N, Sadeghi A, Poustchi H, Abbasi B, Nilghaz M, Melekoglu E, Yari Z, Hekmatdoost A. Effectiveness of flaxseed consumption and fasting mimicking diet on anthropometric measures, biochemical parameters, and hepatic features in patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): a randomized controlled clinical trial. Nutr Diabetes 2024; 14:93. [PMID: 39550356 PMCID: PMC11569120 DOI: 10.1038/s41387-024-00350-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 10/26/2024] [Accepted: 11/04/2024] [Indexed: 11/18/2024] Open
Abstract
BACKGROUND AND AIM Although benefits of flaxseed and fasting mimicking diet (FMD), each alone, have been shown in the management of metabolic dysfunction-associated steatotic liver disease (MASLD), the benefit of combining the two is not clear. This study aimed to investigate the effect of the combination of FMD and flaxseed supplementation on surrogate measures of MASLD. METHODS The present study was conducted as a randomized, parallel, open-label controlled clinical trial on a hundred patients with MASLD for 12 weeks. Eligible participants were assigned to four groups including control group (lifestyle modification recommendations); flaxseed group (30 g/day of flaxseed powder consumption); FMD group (16 h of fasting per day), and combination of FMD with flaxseed. Changes in anthropometric parameters, serum levels of lipids, glycemic measures, High-sensitivity C-reactive protein (hs-CRP), and liver enzymes, and hepatic steatosis and fibrosis by transient elastography were assessed. RESULTS Serum triglycerides, total cholesterol, fasting blood glucose and insulin, hs-CRP and liver enzymes decreased in all intervention groups. Hepatic steatosis score decreased in the intervention groups, but not significantly in comparison to the control group. Hepatic fibrosis score decreased significantly in the intervention groups compared to control. CONCLUSION Our data indicate that the combination of FMD with flaxseed consumption is not superior to either of the interventions alone in the management of MASLD.
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Affiliation(s)
- Navideh Khodadadi
- Department of Clinical Nutrition, National Nutrition and Food Technology Research Institute, School of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Sadeghi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Hossein Poustchi
- Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnood Abbasi
- Department of Nutrition, Electronic Health and Statistics Surveillance Research Center, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Maryam Nilghaz
- Department of Clinical Nutrition, National Nutrition and Food Technology Research Institute, School of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ebru Melekoglu
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Cukurova University, Adana, 01250, Turkey
| | - Zahra Yari
- Department of Nutrition Research, National Nutrition and Food Technology Research Institute, School of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition, National Nutrition and Food Technology Research Institute, School of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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