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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 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] [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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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. [PMID: 39967239 DOI: 10.1111/apt.70020] [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: 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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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] [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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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:S1590-8658(25)00201-4. [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] [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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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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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 2025:00041552-990000000-00214. [PMID: 39882643 DOI: 10.1097/mnh.0000000000001062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [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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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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10
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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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11
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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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12
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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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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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14
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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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15
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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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16
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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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17
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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] [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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18
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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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19
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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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20
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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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21
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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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22
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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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23
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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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24
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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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25
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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 2024. [PMID: 39548715 DOI: 10.1111/liv.16159] [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: 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 Medicine, University of Southampton, Southampton, UK
- National Institute for Health and Care Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service Foundation Trust, Southampton, UK
| | - Theresa J Hydes
- Department of Cardiovascular and Metabolic Medicine, 3rd Floor Clinical Sciences Centre, Institute of Life Course and Medical Sciences, Liverpool University Hospitals NHS Foundation Trust, University of Liverpool, Longmoor Lane, Liverpool, UK
- University Hospital Aintree, Liverpool University Hospital NHS Foundation Trust, Liverpool, UK
| | - Declan McDonnell
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
- National Institute for Health and Care Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service Foundation Trust, Southampton, UK
- HPB Unit, University Hospital Southampton, Southampton, UK
| | - Ryan M Buchanan
- Primary Care and Population Sciences Faculty of Medicine, University of Southampton, Southampton, UK
| | - Eleonora Scorletti
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
- National Institute for Health and Care Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service Foundation Trust, Southampton, UK
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Giovanni Targher
- Metabolic Diseases Research Unit, IRCCS Sacro Cuore-Don Calabria Hospital, Negrar di Valpolicella, Italy
- Department of Medicine, University of Verona Faculty of Medicine and Surgery, Verona, Italy
| | - Christopher D Byrne
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
- National Institute for Health and Care Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service Foundation Trust, Southampton, UK
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26
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Barberá A, White TM, Arora AK, Henry L, Lazarus JV, Younossi ZM. Patient-Reported Outcomes in Metabolic Dysfunction-Associated Steatotic Liver Disease. Semin Liver Dis 2024. [PMID: 39374917 DOI: 10.1055/a-2435-2091] [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] [Indexed: 10/09/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and can progress to serious complications, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Predisposing risk factors for MASH include obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. Patients with MASH often experience significant impairments in their health-related quality of life and other patient-reported outcomes (PROs), particularly in physical functioning domains, fatigue, and vitality. Incorporating PROs offers valuable insights into patients' perspectives on their symptoms, treatment efficacy, and overall well-being, thereby guiding more holistic and patient-centered care strategies. This review aims to investigate the utilization of patient-reported outcome measures (PROMs) in the context of MASLD and MASH care, identify which PROMs are employed, and summarize the outcomes reported.
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Affiliation(s)
- Aurora Barberá
- The Global NASH Council, Washington, District of Columbia
- Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain
| | - Trenton M White
- Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain
| | - Anish K Arora
- Department of Family and Community Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Linda Henry
- The Global NASH Council, Washington, District of Columbia
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia
| | - Jeffrey V Lazarus
- The Global NASH Council, Washington, District of Columbia
- Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain
- CUNY Graduate School of Public Health and Health Policy, New York City, New York
| | - Zobair M Younossi
- The Global NASH Council, Washington, District of Columbia
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia
- Center for Outcomes Research in Liver Disease (CORLD), Washington, District of Columbia
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Llamoza-Torres CJ, Fuentes-Pardo M, Ramos-Molina B. Metabolic dysfunction-associated steatotic liver disease: a key factor in hepatocellular carcinoma therapy response. METABOLISM AND TARGET ORGAN DAMAGE 2024; 4. [DOI: 10.20517/mtod.2024.64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The conceptual evolution of non-alcoholic fatty liver disease (NAFLD) to what, since 2023, is called metabolic dysfunction-associated steatotic liver disease (MASLD) not only represents a change in the classification and definition of the disease but also reflects a broader understanding of this heterogeneous condition, which still with many aspects to refine. Although the definition of NAFLD can be interchanged to a high percentage with the new MASLD concept in different aspects, MASLD has been proposed as a relevant factor that influences the response to new immunotherapeutic treatments in the management of MASLD-related hepatocellular carcinoma (HCC), compared to HCC of other etiologies. This indicates that the etiology of HCC plays a relevant role in the prognosis, highlighting the urgency of evaluating treatment regimens for this subgroup of patients in upcoming clinical trials. A better understanding of the pathophysiology of MASLD generates strategies that not only aid in its management but also provide strategies to directly intervene in the carcinogenesis of HCC.
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Abdel-Samiee M, Ibrahim ES, Kohla M, Abdelsameea E, Salama M. Regression of hepatic fibrosis after pharmacological therapy for nonalcoholic steatohepatitis. World J Gastrointest Pharmacol Ther 2024; 15:97381. [PMID: 39534523 PMCID: PMC11551621 DOI: 10.4292/wjgpt.v15.i6.97381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/28/2024] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
The global incidence of nonalcoholic fatty liver disease (NAFLD) is escalating considerably. NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis, which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix, leading to fibrosis. Hepatocyte ballooning is a key catalyst for fibrosis progression, potentially advancing to cirrhosis and its decompensated state. Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD; therefore, those with substantial fibrosis require timely intervention. Although liver biopsy is the most reliable method for fibrosis detection, it is associated with certain risks and limitations, particularly in routine screening. Consequently, various noninvasive diagnostic techniques have been introduced. This review examines the increasing prevalence of NAFLD, evaluates the noninvasive diagnostic techniques for fibrosis, and assesses their efficacy in staging the disease. In addition, it critically appraises current and emerging antifibrotic therapies, focusing on their mechanisms, efficacy, and potential in reversing fibrosis. This review underscores the urgent need for effective therapeutic strategies, given the dire consequences of advanced fibrosis.
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Affiliation(s)
- Mohamed Abdel-Samiee
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Essam Salah Ibrahim
- Department of Medicine, RCSI Medical University of Bahrain, Adliya 15503, Bahrain
| | - Mohamed Kohla
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Eman Abdelsameea
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Mohsen Salama
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
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29
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Kong Q, Gao Q, Li W, Chen Z. Effect of tenofovir versus entecavir on the long-term prognosis in hepatocellular carcinoma patients with concurrent metabolic dysfunction-associated steatotic liver disease and hepatitis B. Asian J Surg 2024; 47:4725-4734. [PMID: 39289060 DOI: 10.1016/j.asjsur.2024.03.147] [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: 12/22/2023] [Revised: 03/08/2024] [Accepted: 03/22/2024] [Indexed: 09/19/2024] Open
Abstract
BACKGROUND Currently, there remains ongoing controversy about the selection of postoperative antiviral drugs for hepatocellular carcinoma (HCC) patients with concurrent metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatitis B virus (HBV) infection (HPMH) who underwent hepatectomy. METHOD A multivariate Cox proportional hazards model and a propensity score matching (PSM) analysis were implemented to ensure equal baseline characteristics. The Kaplan‒Meier survival curves were employed for prognosis comparison between the two groups. RESULTS This study included 225 HPMH who all received post-hepatectomy antiviral therapy; with 107 in the tenofovir disoproxil fumarate (TDF) group and 118 in the entecavir (ETV) group. In the entire cohort, according to the multivariate analysis, patients in the TDF group showed better recurrence-free survival (RFS) (HR = 0.78; 95% CI, 0.55-0.95; p = 0.030) and overall survival (OS) (HR = 0.52; 95% CI, 0.30-0.97; p = 0.021) than those in the ETV group. After executing a PSM analysis, Kaplan‒Meier survival curve analysis disclosed significant differences for both RFS and OS between the two groups (p = 0.03 and p = 0.01, respectively). CONCLUSIONS In summary, our study suggests a more significant association of TDF in improving RFS and OS than ETV in HPMH who underwent hepatectomy through multivariate and PSM analysis. These findings indicate that the choice of antiviral drugs in HPHM holds crucial significance in guiding patient long-term prognosis.
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Affiliation(s)
- Qingyan Kong
- Division of Hepatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Qianqian Gao
- Division of Hepatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Wenjie Li
- Division of Hepatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Zheyu Chen
- Division of Hepatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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Ezz-Eldin YM, Ewees MG, Azouz AA, Khalaf MM. Investigating the tamoxifen/high-fat diet synergy: a promising paradigm for nonalcoholic steatohepatitis induction in a rat model. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:9067-9079. [PMID: 38884676 PMCID: PMC11522070 DOI: 10.1007/s00210-024-03192-7] [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: 04/05/2024] [Accepted: 05/27/2024] [Indexed: 06/18/2024]
Abstract
Non-alcoholic steatohepatitis (NASH) is a severe liver condition characterized by excessive fat deposition, ballooning, and lobular inflammation. This investigation was conducted to estimate the capability of concomitant tamoxifen administration (TAM) with a high fat diet (HFD) to induce a reliable NASH model that mimics human NASH features. Rats were administered TAM (25 mg/kg/day p.o.) and consumed HFD for 5 weeks. A time-course investigation was conducted to determine the optimal time for NASH development. Liver function indices, hepatic lipid profile factors, oxidative stress biomarkers, and inflammatory mediators were estimated. Additionally, macroscopic and microscopic changes were examined. Compared with the time-matched control group receiving vehicle alone, TAM/HFD significantly impaired liver function indices represented as marked elevation in ALT, AST, and ALP serum levels. TAM/HFD significantly increased lipid profile factors including high TG and TC hepatic levels. Additionally, TAM/HFD remarkably raised hepatic levels of TNF-α and IL-17 and significantly decreased IL-10. The combination also increases the oxidative status evidenced by high content of MDA as well as low activity of GPx and SOD. Accordingly, the combination of TAM and HFD for 5 weeks collaboratively promotes NASH development by initiating compromised hepatocyte functionality, elevated lipid levels, oxidative stress, and liver inflammation.
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Affiliation(s)
- Yousra M Ezz-Eldin
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt.
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
| | - Mohamed G Ewees
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
| | - Amany A Azouz
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Marwa M Khalaf
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
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Jia Y, Zhou Y, Lei Y, Zeng R, Wan Z, Li D, Zhao Q, Liao X. Independent and joint relationships of cardiorespiratory fitness and body mass index with liver fat content. Diabetes Obes Metab 2024; 26:5087-5096. [PMID: 39164872 DOI: 10.1111/dom.15847] [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: 05/17/2024] [Revised: 07/07/2024] [Accepted: 07/16/2024] [Indexed: 08/22/2024]
Abstract
AIMS To investigate the relationship between cardiorespiratory fitness (CRF) and liver fat content (LFC) in community-based participants and highlight their relationship in people with different body mass indices (BMIs). MATERIALS AND METHODS Using UK Biobank data, CRF was estimated with bicycle ergometer fitness testing and was evaluated based on physical work capacity at 75% maximum heart rate (PWC75%). LFC was quantified through liver proton density fat fraction (PDFF) on magnetic resonance imaging. Multivariate linear regression models were used to analyse the associations of CRF and BMI with absolute reduction and percentage change in PDFF (%). RESULTS In total, 5765 participants with a mean age of 55.57 years and a median (range) follow-up of 10.7 (4.0-17.7) years were included. Compared with the lowest PWC75% tertile, the absolute reduction and percentage change in PDFF in the highest PWC75% tertile were -0.450 (95% confidence interval [CI] -0.699 to -0.192) and -4.152 (95% CI -6.044 to -2.104), respectively. These associations were independent of BMI, and individuals with obesity and normal weight had the largest absolute reduction and percentage change in LFC, respectively (p for interaction <0.001). Joint analysis showed that PWC75% and BMI had a negative dose-response relationship with PDFF. These associations were consistent in different sex and age subgroups (p for interaction >0.05). CONCLUSIONS There was a significant negative association between CRF and LFC, and this association was independent of BMI. The results of this study strongly recommend improving CRF to mitigate LFC.
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Affiliation(s)
- Yu Jia
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yiheng Zhou
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Lei
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Zeng
- Department of Cardiology, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Zhi Wan
- Department of Emergency Medicine, Disaster Medical Center, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Dongze Li
- Department of Emergency Medicine, Disaster Medical Center, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Qian Zhao
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoyang Liao
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
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Volniansky A, Lefebvre TL, Kulbay M, Fan B, Aslan E, Vu KN, Montagnon E, Nguyen BN, Sebastiani G, Giard JM, Sylvestre MP, Gilbert G, Cloutier G, Tang A. Inter-visit and inter-reader reproducibility of multi-parametric diffusion-weighted MR imaging in longitudinally imaged patients with metabolic dysfunction-associated fatty liver disease and healthy volunteers. Magn Reson Imaging 2024; 113:110223. [PMID: 39181478 DOI: 10.1016/j.mri.2024.110223] [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: 05/18/2024] [Revised: 07/31/2024] [Accepted: 08/21/2024] [Indexed: 08/27/2024]
Abstract
BACKGROUND Despite the widespread use of diffusion-weighted imaging (DWI) in metabolic dysfunction-associated fatty liver disease (MAFLD), MRI acquisition and quantification techniques vary in the literature suggesting the need for established and reproducible protocols. The goal of this study was to assess inter-visit and inter-reader reproducibility of DWI- and IVIM-derived parameters in patients with MAFLD and healthy volunteers using extensive sampling of the "fast" compartment, non-rigid registration, and exclusion voxels with poor fit quality. METHODS From June 2019 to April 2023, 31 subjects (20 patients with biopsy-proven MAFLD and 11 healthy volunteers) were included in this IRB-approved study. Subjects underwent MRI examinations twice within 40 days. 3.0 T DWI was acquired using a respiratory-triggered spin-echo diffusion-weighted echo-planar imaging sequence (b-values of 0, 10, 20, 30, 40, 50, 100, 200, 400, 800 s/mm2). DWI series were co-registered prior to voxel-wise non-linear regression of the IVIM model and voxels with poor fit quality were excluded (normalized root mean squared error ≥ 0.05). IVIM parameters (perfusion fraction, f; diffusion coefficient, D; and pseudo-diffusion coefficient, D*), and apparent diffusion coefficients (ADC) were computed from manual segmentation of the right liver lobe performed by two analysts on two MRI examinations. RESULTS All results are reported for f, D, D*, and ADC respectively. For inter-reader agreement on the first visit, ICC were of 0.985, 0.994, 0.986, and 0.993 respectively. For intra-reader agreement of analyst 1 assessed on both imaging examinations, ICC between visits were of 0.805, 0.759, 0.511, and 0.850 respectively. For inter-reader agreement on the first visit, mean bias and 95 % limits of agreement were (0.00 ± 0.03), (-0.01 ± 0.03) × 10-3 mm2/s, (0.70 ± 10.40) × 10-3 mm2/s, and (-0.02 ± 0.04) × 10-3 mm2/s respectively. For intra-reader agreement of analyst 1, mean bias and 95 % limits of agreement were (0.01 ± 0.09) × 10-3 mm2/s, (-0.01 ± 0.21) × 10-3 mm2/s, (-13.37 ± 56.19) × 10-3 mm2/s, and (-0.01 ± 0.16) × 10-3 mm2/s respectively. Except for parameter D* that was associated with between-subjects parameter variability (P = 0.009), there was no significant variability between subjects, examinations, or readers. CONCLUSION With our approach, IVIM parameters f, D, D*, and ADC provided excellent inter-reader agreement and good to very good inter-visit or intra-reader agreement, thus showing the reproducibility of IVIM-DWI of the liver in MAFLD patients and volunteers.
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Affiliation(s)
- Anton Volniansky
- Department of Radiology, Radiation Oncology and Nuclear Medicine, Université de Montréal, Montréal, Canada; Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
| | - Thierry L Lefebvre
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada; Department of Physics, University of Cambridge, Cambridge, United Kingdom; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
| | - Merve Kulbay
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada; Department of Ophthalmology & Visual Sciences, McGill University, Montréal, Canada.
| | - Boyan Fan
- Department of Radiology, Radiation Oncology and Nuclear Medicine, Université de Montréal, Montréal, Canada; Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
| | - Emre Aslan
- Department of Radiology, Radiation Oncology and Nuclear Medicine, Université de Montréal, Montréal, Canada; Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
| | - Kim-Nhien Vu
- Department of Radiology, Radiation Oncology and Nuclear Medicine, Université de Montréal, Montréal, Canada.
| | - Emmanuel Montagnon
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Bich Ngoc Nguyen
- Service of Pathology, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Canada.
| | - Giada Sebastiani
- Department of Medicine, Division of Gastroenterology and Hepatology, McGill University Health Centre (MUHC), Montréal, Canada.
| | - Jeanne-Marie Giard
- Department of Medicine, Division of Hepatology and Liver Transplantation, Université de Montréal, Montréal, Canada
| | - Marie-Pierre Sylvestre
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada; Department of Social and Preventive Medicine, École de santé publique de l'Université de Montréal (ESPUM), Montréal, Canada.
| | - Guillaume Gilbert
- Department of Radiology, Radiation Oncology and Nuclear Medicine, Université de Montréal, Montréal, Canada; MR Clinical Science, Philips Healthcare Canada, Mississauga, Canada.
| | - Guy Cloutier
- Department of Radiology, Radiation Oncology and Nuclear Medicine, Université de Montréal, Montréal, Canada; Institute of Biomedical Engineering, Université de Montréal, Montréal, Canada; Laboratory of Biorheology and Medical Ultrasonics (LBUM), Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
| | - An Tang
- Department of Radiology, Radiation Oncology and Nuclear Medicine, Université de Montréal, Montréal, Canada; Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada; Institute of Biomedical Engineering, Université de Montréal, Montréal, Canada.
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Reyes-Avendaño I, Villaseñor-Altamirano AB, Reyes-Jimenez E, Velazquez-Enriquez JM, Baltiérrez-Hoyos R, Piña-Vázquez C, Muriel P, Villa-Treviño S, Arellanes-Robledo J, Vásquez-Garzón VR. Identification of key markers for the stages of nonalcoholic fatty liver disease: An integrated bioinformatics analysis and experimental validation. Dig Liver Dis 2024; 56:1887-1896. [PMID: 38824040 DOI: 10.1016/j.dld.2024.05.010] [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: 08/16/2023] [Revised: 03/14/2024] [Accepted: 05/08/2024] [Indexed: 06/03/2024]
Abstract
BACKGROUND The identification of biomarkers for the early diagnosis of nonalcoholic fatty liver disease (NAFLD) is urgently needed. Here, we aimed to identify NAFLD biomarkers in the early stages of steatosis (SS) and nonalcoholic steatohepatitis (NASH) based on differential gene expression from bioinformatics data. METHODS A meta-analysis was performed from transcriptomic databases retrieved from public repositories containing data from biopsies of patients at various stages of NAFLD development. The status of the selected molecules was validated in the serum of patients with NAFLD by ELISA. RESULTS We identified 121 differentially expressed genes (DEGs) associated with SS and 402 associated with NASH. Gene Ontology (GO) enrichment revealed that the altered genes were primarily associated with dysfunction of primary cellular processes, and pathway analyses were mainly related to cholesterol metabolism. We identified ACSS2, PCSK9, and CYP7A1 as candidate biomarkers for SS and ANGPTL3, CD36, CYP51A1, FASN, FAS, FDFT1, and LSS as candidate biomarkers for NASH. CONCLUSIONS By experimental validation of bioinformatics data from patients with NAFLD, we identified promising biomarkers for detecting SS and NASH that might be useful for screening and diagnosing early NAFLD stages in humans.
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Affiliation(s)
- Itayetzi Reyes-Avendaño
- Laboratorio de Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua 68020, Oaxaca, Mexico
| | - Ana Beatriz Villaseñor-Altamirano
- International Laboratory for Human Genome Research, Laboratorio Internacional de Investigación sobre el Genoma Humano (LIIGH), Universidad Nacional Autónoma de México (UNAM), 3001 Boulevard Juriquilla 76230, Querétaro, Mexico
| | - Edilburga Reyes-Jimenez
- Laboratorio de Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua 68020, Oaxaca, Mexico
| | - Juan Manuel Velazquez-Enriquez
- Laboratorio de Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua 68020, Oaxaca, Mexico
| | - Rafael Baltiérrez-Hoyos
- Laboratorio de Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua 68020, Oaxaca, Mexico; CONAHCYT-Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua 68020, Oaxaca, Mexico
| | - Carolina Piña-Vázquez
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
| | - Pablo Muriel
- Laboratorio de Hepatología Experimental, Departamento de Farmacología, Cinvestav-IPN, 07360 Ciudad de México, Mexico
| | - Saul Villa-Treviño
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
| | - Jaime Arellanes-Robledo
- CONAHCYT-Instituto Nacional de Medicina Genómica, Laboratorio de Enfermedades Hepáticas, Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Alcaldía Tlalpan 14610 Ciudad de México, Mexico
| | - Verónica Rocío Vásquez-Garzón
- Laboratorio de Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua 68020, Oaxaca, Mexico; CONAHCYT-Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua 68020, Oaxaca, Mexico.
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Wu Y, Zhou J, Zhang J, Li H. Cytokeratin 18 in nonalcoholic fatty liver disease: value and application. Expert Rev Mol Diagn 2024; 24:1009-1022. [PMID: 39387822 DOI: 10.1080/14737159.2024.2413941] [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: 02/07/2024] [Accepted: 10/04/2024] [Indexed: 10/15/2024]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is a common metabolism-related disease worldwide. Although studies have shown that some medications may be effective for treating NAFLD, they do not satisfy the medical requirements, and lifestyle changes are the most basic strategy. Thus, early detection of NAFLD and timely lifestyle interventions are highly important. AREAS COVERED The traditional diagnostic methods for NAFLD are limited by accuracy, cost, and security issues. Cytokeratin 18 (CK18), which is a marker of apoptosis and overall cell death, is an excellent biomarker for NAFLD. Liver fat accumulation in NAFLD triggers the activation of caspases, which increases the CK18 cleavage and its release into the blood. CK18 can help diagnose different stages of NAFLD, especially the nonalcoholic steatohepatitis (NASH) stage. In evaluating the efficacy of the NAFLD treatment and predicting the risk of NAFLD-related diseases, CK18 plays a significant role. EXPERT OPINION CK18 can non-invasively monitor the pathological conditions of NAFLD patients and provide new hope for the early diagnosis of NAFLD. Adding CK18 to the NAFLD diagnostic criteria that are widely used in clinical settings may be efficient for the detection of NAFLD and early effective intervention.
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Affiliation(s)
- Yuan Wu
- School of Medicine, The 2nd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Liver Disease Department of Integrative Medicine, Ningbo No. 2 Hospital, Ningbo, China
| | - Jing Zhou
- Liver Disease Department of Integrative Medicine, Ningbo No. 2 Hospital, Ningbo, China
| | - Jun Zhang
- Liver Disease Department of Integrative Medicine, Ningbo No. 2 Hospital, Ningbo, China
| | - Hongshan Li
- School of Medicine, The 2nd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Liver Disease Department of Integrative Medicine, Ningbo No. 2 Hospital, Ningbo, China
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Tajudin M, Hagström H, Rössner S. Successful Example of Implementing Screening of Liver Fibrosis in Specialist Diabetes Care. GASTRO HEP ADVANCES 2024; 4:100577. [PMID: 39902461 PMCID: PMC11788731 DOI: 10.1016/j.gastha.2024.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 10/18/2024] [Indexed: 02/05/2025]
Abstract
Background and Aims Patients with type 2 diabetes (T2D) constitute a risk group for presence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD). Yet, there are few published examples of collaborations between endocrinologists and hepatologists in caring for patients with T2D and MASLD. Here, we describe a pathway for screening of liver fibrosis in routine specialist diabetes care at a tertiary care hospital. Methods Patients with T2D seen at the Endocrinology department at Karolinska University Hospital, Stockholm, Sweden, during a structured intervention for T2D between October 2016 and September 2023 were eligible for inclusion. Liver stiffness measurements (LSM) and controlled attenuation parameter (CAP) as proxies for liver fibrosis and steatosis, respectively, were obtained utilizing vibration-controlled transient elastography (VCTE). An LSM cut-off to exclude advanced fibrosis was set to <8 kPa. Presence of MASLD was defined as a CAP value of CAP ≥ 294 dB/m. Results A total of 177 patients with a valid LSM were included. The median age was 60 years and 60% were women. The median LSM was 5.8 (interquartile range 4.6-8.1) kPa, and the median CAP was 306 (258-362) dB/m. In total, 27% had LSM ≥8 kPa and 11% had LSM ≥12 kPa. MASLD was present in 55%. The clinical score for aspartate aminotransferase, alanine aminotransferase, age, platelet count had a low sensitivity for identifying patients with VCTE measurements above 8 kPa (34%) and 12 kPa (37%). Conclusion This study provides an example of a productive partnership between endocrinologists and hepatologists using direct VCTE measurements, leading to the identification of a significant number of patients with presumed advanced fibrosis.
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Affiliation(s)
- Muna Tajudin
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Hannes Hagström
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Sophia Rössner
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Division of Endocrinology, Karolinska University Hospital, Stockholm, Sweden
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Akhgarjand C, Entezarian M, Samavat S, Tavakoli A, Anoushirvani A, Asghari G, Yusbashian E, Dehghan P, Mirmiran P, Imani H. The association of fructose and fiber consumption and physical activity with non-alcoholic fatty liver disease in children and adolescents: a cross-sectional study. BMC Nutr 2024; 10:140. [PMID: 39434194 PMCID: PMC11494766 DOI: 10.1186/s40795-024-00943-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 09/30/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is emerging as the most prevalent liver disease in overweight and obese children. While no cure exists, dietary and lifestyle modifications have been shown to improve the condition. This study investigates the relationship between fructose and fiber consumption, physical activity, and NAFLD in children. METHODS A cross-sectional study was conducted on 378 overweight and obese children aged 6-13 years. NAFLD diagnosis was confirmed via ultrasound, and dietary intake was assessed using a 147-item food frequency questionnaire (FFQ). Physical activity was evaluated using the Modifiable Activity Questionnaire (MAQ). Multivariable logistic regression models were applied to determine the associations. RESULTS After excluding 53 participants due to incomplete data, 325 were included in the final analysis. The mean age was 9.2 ± 1.7 years, and 35% had NAFLD. No significant association was found between fructose intake and NAFLD (OR: 0.67, 95% CI: 0.35-1.29, P = 0.221). However, higher intake of legume fiber (OR: 0.48, 95% CI: 0.26-0.90, P = 0.03) and nut fiber (OR: 0.52, 95% CI: 0.28-0.95, P = 0.04) was significantly associated with a reduced risk of NAFLD. Physical activity showed a trend towards reduced NAFLD risk but was not statistically significant after adjustments (OR: 0.53, 95% CI: 0.22-1.04, P = 0.07). CONCLUSIONS While fructose intake was not significantly linked to NAFLD in this population, fiber from legumes and nuts appeared protective. Further prospective studies are needed to confirm these findings and clarify the role of physical activity in NAFLD prevention.
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Affiliation(s)
- Camellia Akhgarjand
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdieh Entezarian
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Simin Samavat
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Aryan Tavakoli
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Aliarash Anoushirvani
- Firoozabadi Clinical Research Development Unit (FACRDU), Department of Pediatrics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Hemato-Oncology Ward, Firoozgar Hospital, Iran University of Medical Science, Tehran, Iran
| | - Golaleh Asghari
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Emad Yusbashian
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pooneh Dehghan
- Department of Imaging, Research Development Center, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parvin Mirmiran
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti 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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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 2024. [PMID: 39400428 DOI: 10.1111/liv.16127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [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 Medicine, University of Dundee, Dundee, UK
- Gastroenterology Department, Aberdeen Royal Infirmary, Aberdeen, UK
| | - Rachael Barrett
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK
| | - James S Bowness
- University College London Hospitals NHS Foundation Trust, London, UK
- Department of Targeting Intervention, University College London, London, UK
| | | | - Ruairi Lynch
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK
| | - John F Dillon
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK
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Dolapchiev LI, Gonzales KA, Cruz LR, Gagea M, Stevenson HL, Kwan SY, Beretta L. Gut Microbiome and Hepatic Transcriptomic Determinants of HCC Development in Mice with Metabolic Dysfunction-Associated Steatohepatitis. J Hepatocell Carcinoma 2024; 11:1891-1905. [PMID: 39372712 PMCID: PMC11456366 DOI: 10.2147/jhc.s485532] [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] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 09/18/2024] [Indexed: 10/08/2024] Open
Abstract
Purpose Hepatocellular carcinoma (HCC) related to metabolic dysfunction-associated steatotic liver disease (MASLD) is often diagnosed at a late stage, and its incidence is increasing. Predictive biomarkers are therefore needed to identify individuals at high risk of HCC. We aimed to characterize the gut microbiome and hepatic transcriptome associated with HCC development in female mice with hepatocyte-deletion of Pten (HepPten -). These mice present with large variations in HCC development, making them a powerful model for biomarker discovery. Methods & Results Sequencing of stool 16S and hepatic RNA was performed on a first set of mice. Among all liver histology parameters measured, the strongest association with microbiome composition changes was with the number of tumors detected at necropsy, followed by inflammation. The gut microbiome of mice with more than 2 tumors was enriched with Lachnospiraceae UCG and depleted of Palleniella intestinalis and Odoribacter. In contrast, hepatic transcriptomic changes were most strongly associated with tumor burden, followed by liver fibrosis. The 840 differentially expressed genes correlating with tumor burden were enriched in leukocyte extravasation and interleukin 10 receptor A (IL10RA) pathways. In addition, the abundance of Spp1-high epithelial cells is correlated with tumor burden. Association between tumor number and depletion of Palleniella intestinalis, and between tumor burden and circulating levels of C-X-C motif chemokine ligand 13 (CXCL13) and stem cell factor (SCF), was further validated in an independent set of mice. Conclusion We identified microbiome components contributing to liver carcinogenesis by inducing inflammation, and changes in hepatic gene expression and hepatic cells distribution that contribute to tumor growth. Such information can be highly valuable for the development of new prevention strategies as well as of new biomarkers for risk modeling in HCC.
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Affiliation(s)
- Lillian I Dolapchiev
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Kristyn A Gonzales
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lorenzo R Cruz
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mihai Gagea
- Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Heather L Stevenson
- Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, USA
| | - Suet-Ying Kwan
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Baskaya F, Lemainque T, Klinkhammer B, Koletnik S, von Stillfried S, Talbot SR, Boor P, Schulz V, Lederle W, Kiessling F. Pathophysiologic Mapping of Chronic Liver Diseases With Longitudinal Multiparametric MRI in Animal Models. Invest Radiol 2024; 59:699-710. [PMID: 38598653 DOI: 10.1097/rli.0000000000001075] [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: 04/12/2024]
Abstract
OBJECTIVES Chronic liver diseases (CLDs) have diverse etiologies. To better classify CLDs, we explored the ability of longitudinal multiparametric MRI (magnetic resonance imaging) in depicting alterations in liver morphology, inflammation, and hepatocyte and macrophage activity in murine high-fat diet (HFD)- and carbon tetrachloride (CCl 4 )-induced CLD models. MATERIALS AND METHODS Mice were either untreated, fed an HFD for 24 weeks, or injected with CCl 4 for 8 weeks. Longitudinal multiparametric MRI was performed every 4 weeks using a 7 T MRI scanner, including T1/T2 relaxometry, morphological T1/T2-weighted imaging, and fat-selective imaging. Diffusion-weighted imaging was applied to assess fibrotic remodeling and T1-weighted and T2*-weighted dynamic contrast-enhanced MRI and dynamic susceptibility contrast MRI using gadoxetic acid and ferucarbotran to target hepatocytes and the mononuclear phagocyte system, respectively. Imaging data were associated with histopathological and serological analyses. Principal component analysis and clustering were used to reveal underlying disease patterns. RESULTS The MRI parameters significantly correlated with histologically confirmed steatosis, fibrosis, and liver damage, with varying importance. No single MRI parameter exclusively correlated with 1 pathophysiological feature, underscoring the necessity for using parameter patterns. Clustering revealed early-stage, model-specific patterns. Although the HFD model exhibited pronounced liver fat content and fibrosis, the CCl 4 model indicated reduced liver fat content and impaired hepatocyte and macrophage function. In both models, MRI biomarkers of inflammation were elevated. CONCLUSIONS Multiparametric MRI patterns can be assigned to pathophysiological processes and used for murine CLD classification and progression tracking. These MRI biomarker patterns can directly be explored clinically to improve early CLD detection and differentiation and to refine treatments.
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Affiliation(s)
- Ferhan Baskaya
- From the Institute for Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany (F.B., T.L., S.K., V.S., W.L., F.K.); Department for Diagnostic and Interventional Radiology, RWTH Aachen University, Aachen, Germany (T.L.); Institute of Pathology, RWTH Aachen University, Aachen, Germany (B.K., S.S., P.B.); and Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany (S.R.T.)
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Sharma A, Godina Leiva E, Kalavalapalli S, Lomonaco R, Marangi SA, Valdez Saenz E, Gonzalez MA, Ortiz Rocha A, Cuervo Pardo N, Rosenberg J, Bedossa P, Bril F, Barb D, Cusi K. Obesity increases the risk of hepatic fibrosis in young adults with type 2 diabetes mellitus: the need to screen. Obesity (Silver Spring) 2024; 32:1967-1974. [PMID: 39315409 DOI: 10.1002/oby.24130] [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: 04/29/2024] [Revised: 06/18/2024] [Accepted: 07/03/2024] [Indexed: 09/25/2024]
Abstract
OBJECTIVE The objective of this study was to determine the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in young compared with older adults. METHODS Individuals (n = 1420) with (63%) and without type 2 diabetes mellitus (T2D; 37%) who attended internal medicine clinics and did not have a known history of MASLD underwent laboratory evaluation and transient elastography to assess for hepatic steatosis and fibrosis. Magnetic resonance elastography and liver biopsy were recommended when indicated. RESULTS A total of 243 participants were ages <45 years, and 1177 were ages ≥45 years. Obesity, T2D, and metabolic syndrome were highly prevalent in young adults. Frequencies of steatosis and fibrosis were high in young adults (50.2% and 7.5% vs. older adults 52.7% and 9.9%, respectively) and were significantly higher in those with both obesity and T2D (71.1% and 15.7%, respectively; p < 0.01). In young adults, T2D and obesity were the strongest risk factors for hepatic fibrosis (odds ratios 4.33 [95% CI: 1.37-13.68] and 1.16 [95% CI: 1.07-1.25], respectively; p < 0.05). CONCLUSIONS There is a high prevalence of clinically significant hepatic fibrosis in young adults with cardiometabolic risk factors. Up to one in seven young adults with obesity and T2D had clinically significant hepatic fibrosis on elastography. This highlights the need to screen young adults with cardiometabolic risk factors for MASLD for early detection and intervention.
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Affiliation(s)
- Anu Sharma
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Eddison Godina Leiva
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Srilaxmi Kalavalapalli
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Romina Lomonaco
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Stephen A Marangi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Enrique Valdez Saenz
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Maria A Gonzalez
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Andrea Ortiz Rocha
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Nathaly Cuervo Pardo
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Jens Rosenberg
- Advanced Magnetic Resonance Imaging and Spectroscopy Facility, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA
| | - Pierre Bedossa
- Department of Pathology, Hôpital Beaujon AP-HP, Clichy, France
| | - Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Diana Barb
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
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Ktenopoulos N, Sagris M, Gerogianni M, Pamporis K, Apostolos A, Balampanis K, Tsioufis K, Toutouzas K, Tousoulis D. Non-Alcoholic Fatty Liver Disease and Coronary Artery Disease: A Bidirectional Association Based on Endothelial Dysfunction. Int J Mol Sci 2024; 25:10595. [PMID: 39408924 PMCID: PMC11477211 DOI: 10.3390/ijms251910595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 09/23/2024] [Accepted: 09/29/2024] [Indexed: 10/20/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is regarded as a liver manifestation of metabolic syndrome. It is linked to insulin resistance, obesity, and diabetes mellitus, all of which increase the risk of cardiovascular complications. Endothelial dysfunction (EnD) constitutes the main driver in the progression of atherosclerosis and coronary artery disease (CAD). Several pathophysiological alterations and molecular mechanisms are involved in the development of EnD in patients with NAFLD. Our aim is to examine the association of NAFLD and CAD with the parallel assessment of EnD, discussing the pathophysiological mechanisms and the genetic background that underpin this relationship. This review delves into the management of the condition, exploring potential clinical implications and available medical treatment options to facilitate the deployment of optimal treatment strategies for these patients.
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Affiliation(s)
- Nikolaos Ktenopoulos
- First Department of Cardiology, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.S.); (A.A.); (K.T.); (K.T.); (D.T.)
| | - Marios Sagris
- First Department of Cardiology, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.S.); (A.A.); (K.T.); (K.T.); (D.T.)
| | - Maria Gerogianni
- Endocrine Unit, 2nd Propaedeutic Department of Internal Medicine, School of Medicine, Research Institute and Diabetes Center, Attikon University Hospital, National and Kapodistrian University of Athens, 12641 Athens, Greece;
- Second Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Konstantinos Pamporis
- Department of Hygiene, Social-Preventive Medicine & Medical Statistics, Medical School, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece;
| | - Anastasios Apostolos
- First Department of Cardiology, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.S.); (A.A.); (K.T.); (K.T.); (D.T.)
| | - Konstantinos Balampanis
- Second Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Konstantinos Tsioufis
- First Department of Cardiology, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.S.); (A.A.); (K.T.); (K.T.); (D.T.)
| | - Konstantinos Toutouzas
- First Department of Cardiology, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.S.); (A.A.); (K.T.); (K.T.); (D.T.)
| | - Dimitris Tousoulis
- First Department of Cardiology, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.S.); (A.A.); (K.T.); (K.T.); (D.T.)
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Wang AL, Mishkit O, Mao H, Arivazhagan L, Dong T, Lee F, Bhattacharya A, Renfrew PD, Schmidt AM, Wadghiri YZ, Fisher EA, Montclare JK. Collagen-targeted protein nanomicelles for the imaging of non-alcoholic steatohepatitis. Acta Biomater 2024; 187:291-303. [PMID: 39236796 DOI: 10.1016/j.actbio.2024.08.052] [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: 05/08/2024] [Revised: 08/22/2024] [Accepted: 08/28/2024] [Indexed: 09/07/2024]
Abstract
In vivo molecular imaging tools hold immense potential to drive transformative breakthroughs by enabling researchers to visualize cellular and molecular interactions in real-time and/or at high resolution. These advancements will facilitate a deeper understanding of fundamental biological processes and their dysregulation in disease states. Here, we develop and characterize a self-assembling protein nanomicelle called collagen type I binding - thermoresponsive assembled protein (Col1-TRAP) that binds tightly to type I collagen in vitro with nanomolar affinity. For ex vivo visualization, Col1-TRAP is labeled with a near-infrared fluorescent dye (NIR-Col1-TRAP). Both Col1-TRAP and NIR-Col1-TRAP display approximately a 3.8-fold greater binding to type I collagen compared to TRAP when measured by surface plasmon resonance (SPR). We present a proof-of-concept study using NIR-Col1-TRAP to detect fibrotic type I collagen deposition ex vivo in the livers of mice with non-alcoholic steatohepatitis (NASH). We show that NIR-Col1-TRAP demonstrates significantly decreased plasma recirculation time as well as increased liver accumulation in the NASH mice compared to mice without disease over 4 hours. As a result, NIR-Col1-TRAP shows potential as an imaging probe for NASH with in vivo targeting performance after injection in mice. STATEMENT OF SIGNIFICANCE: Direct molecular imaging of fibrosis in NASH patients enables the diagnosis and monitoring of disease progression with greater specificity and resolution than do elastography-based methods or blood tests. In addition, protein-based imaging probes are more advantageous than alternatives due to their biodegradability and scalable biosynthesis. With the aid of computational modeling, we have designed a self-assembled protein micelle that binds to fibrillar and monomeric collagen in vitro. After the protein was labeled with near-infrared fluorescent dye, we injected the compound into mice fed on a NASH diet. NIR-Col1-TRAP clears from the serum faster in these mice compared to control mice, and accumulates significantly more in fibrotic livers.This work advances the development of targeted protein probes for in vivo fibrosis imaging.
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Affiliation(s)
- Andrew L Wang
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, Brooklyn, NY 11201, USA; Department of Biomedical Engineering, State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, NY 11203, USA
| | - Orin Mishkit
- Center for Advanced Imaging Innovation and Research (CAI2R), New York University Grossman School of Medicine, New York, NY 10016, USA; Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Heather Mao
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, Brooklyn, NY 11201, USA
| | - Lakshmi Arivazhagan
- Diabetes Research Group, Department of Medicine, New York University Grossman School of Medicine, USA
| | - Tony Dong
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, Brooklyn, NY 11201, USA
| | - Frances Lee
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, Brooklyn, NY 11201, USA
| | - Aparajita Bhattacharya
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, Brooklyn, NY 11201, USA; Department of Cell Biology, State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, NY 11203, USA
| | - P Douglas Renfrew
- Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY 10010, USA
| | - Ann Marie Schmidt
- Diabetes Research Group, Department of Medicine, New York University Grossman School of Medicine, USA
| | - Youssef Z Wadghiri
- Center for Advanced Imaging Innovation and Research (CAI2R), New York University Grossman School of Medicine, New York, NY 10016, USA; Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Edward A Fisher
- Leon H. Charney Division of Cardiology and Cardiovascular Research Center, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Jin Kim Montclare
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, Brooklyn, NY 11201, USA; Department of Biomedical Engineering, New York University Tandon School of Engineering, Brooklyn, NY 11201, USA; Department of Chemistry, New York University, New York, NY 10012, USA; Department of Biomaterials, New York University College of Dentistry, New York, NY 10010, USA.
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Akhverdyan N, Wieland A, Sullivan S, Lindsay M, Swartwood S, Arndt G, Kaizer LK, Jensen T. Changes in Transient Elastography with Glucagon-Like Peptide-1 Receptor Agonist Use in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Real-World Retrospective Analysis. Metab Syndr Relat Disord 2024; 22:608-618. [PMID: 38868900 DOI: 10.1089/met.2024.0115] [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] [Indexed: 06/14/2024] Open
Abstract
Introduction: Current guidelines recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD), especially in patients with comorbid diabetes and obesity. This study investigated the effects of GLP-1RAs on hepatic steatosis and fibrosis in patients with MASLD, as measured by changes in vibration-controlled transient elastography (VCTE) and other clinical parameters in a real-world clinical setting. Methods: We conducted a single-center, retrospective analysis of 96 patients with MASLD from a multidisciplinary care clinic who completed VCTE at baseline and follow-up within 6-24 months to compare changes in controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), as well as other metabolic markers, between GLP-1RA users and nonusers using two-sample t-tests and Wilcoxon rank-sum tests. We also assessed whether improvements in hepatic steatosis, defined as a change in CAP >38 dB/m as previously described in the literature, were associated with improvement in fibrosis. Results: GLP-1RA use resulted in significant improvements in weight (-8.1 kg vs. -3.5 kg, P = 0.009), body mass index (BMI) (-2.9 kg/m2 vs. -1.3 kg/m2, P = 0.012), alanine aminotransferase (-15.0 IU/L vs. -4.0 IU/L, P = 0.017), aspartate aminotransferase (-5.0 IU/L vs. -1.0 IU/L, P = 0.021), glycated hemoglobin (HbA1c) (-0.7% vs. 0.1%, P = 0.019), and CAP (-59.9 dB/m vs. -29.1 dB/m, P = 0.016). Responders also had significant improvements in weight (-9.2 kg vs. -1.9 kg, P < 0.001), BMI (-3.3 kg/m2 vs. -0.7 kg/m2, P < 0.001), diastolic blood pressure (-6.1 mmHg vs. -0.7 mmHg, P = 0.028), HbA1c (-0.8% vs. 0.3%, P < 0.001), and LSM (-1.5 kPa vs. 0.1 kPa, P < 0.001). Conclusions: Patients with MASLD treated with GLP-1RAs showed significant improvements in hepatic steatosis and multiple other metabolic parameters, with weight loss as the proposed mechanism for this liver improvement. In addition, change in CAP >38 dB/m was associated with improvements in LSM and other metabolic parameters, suggesting the clinical utility of VCTE in the surveillance of MASLD.
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Affiliation(s)
- Nazar Akhverdyan
- University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Amanda Wieland
- Division of Hepatology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Shelby Sullivan
- Division of Gastroenterology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Mark Lindsay
- Division of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Sheila Swartwood
- Division of Hepatology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Gretchen Arndt
- Division of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Laura Katherine Kaizer
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Thomas Jensen
- Division of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
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Fishman JC, Qian C, Kim Y, Rochon H, Szabo SM, Sun R, Charlton M. Cost burden of cirrhosis and liver disease progression in metabolic dysfunction-associated steatohepatitis: A US cohort study. J Manag Care Spec Pharm 2024; 30:929-941. [PMID: 38845444 PMCID: PMC11365567 DOI: 10.18553/jmcp.2024.24069] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/31/2024]
Abstract
BACKGROUND Metabolic dysfunction-associated steatohepatitis (MASH), formerly nonalcoholic steatohepatitis, is characterized by fat accumulation and inflammation of the liver and may result in progression to cirrhosis and liver-related events. OBJECTIVE To characterize the impact of cirrhosis and progression to liver-related events on costs and health care resource use (HCRU) among MASH patients in the United States. METHODS The study cohort included patients with diagnosed nonalcoholic steatohepatitis (International Classification of Diseases, Tenth Revision, Clinical Modification code K75.81) in Optum's deidentified Clinformatics Data Mart Database (October 2015 to December 2022) and were stratified by baseline cirrhosis status. Among those without cirrhosis at baseline, patients were further stratified by status of progression to cirrhosis during follow-up. Total HCRU and costs per-person per-year (PPPY) were estimated and compared descriptively between the cohorts. In addition, gamma generalized linear models were used to compare costs PPPY between those with vs without cirrhosis at baseline, as well as with vs without progression during follow-up, while adjusting for baseline patient and disease characteristics. Annual costs per person were also longitudinally modeled using gamma generalized linear mixed models to understand longitudinal changes in costs PPPY while accounting for time correlations within individual patients. Lastly, a series of sensitivity analyses were conducted to assess the impact of study design features and clinical variations of total costs PPPY. RESULTS A total of 28,576 adults were included, and 9,157 (32.0%) had baseline cirrhosis; of the 19,419 without baseline cirrhosis, a total of 4,235 (21.8%) progressed over follow-up. Mean (SD) HCRU and costs PPPY were higher among patients with cirrhosis ($110,403 [$226,037]) than without ($28,340 [$61,472]; P < 0.01) and among those with progression ($58,128 [$102,626]) than without ($20,031 [$39,740]; P < 0.01). Costs remained significantly greater when adjusted for covariates, with a risk ratio (95% CI) of 1.99 (1.89-2.09) when comparing with vs without baseline cirrhosis and 2.28 (2.15-2.42) when comparing with vs without progression over follow-up. Costs increased with each subsequent year, to 21% by year 6 among those with cirrhosis at baseline and 49% among those without baseline cirrhosis who progressed. CONCLUSIONS The financial burden of MASH is substantial and significantly greater among those with cirrhosis or disease progression. Although patients without cirrhosis incur lower burden, the increase over time is greater and associated with progression. Therapies that slow progression may help alleviate the financial burden, and strategies are needed to identify patients with MASH at risk of progressing to cirrhosis.
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Affiliation(s)
| | | | - Yestle Kim
- Madrigal Pharmaceuticals, Inc., West Conshohocken, PA
| | | | | | - Rosie Sun
- Broadstreet HEOR, Vancouver, BC, Canada
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Chen LZ, Jing XB, Chen X, Xie YC, Chen Y, Cai XB. Non-Invasive Serum Markers of Non-Alcoholic Fatty Liver Disease Fibrosis: Potential Tools for Detecting Patients with Cardiovascular Disease. Rev Cardiovasc Med 2024; 25:344. [PMID: 39355605 PMCID: PMC11440407 DOI: 10.31083/j.rcm2509344] [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: 03/05/2024] [Revised: 05/23/2024] [Accepted: 05/28/2024] [Indexed: 10/03/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), one of the most common chronic liver diseases with a prevalence of 23%-25% globally, is an independent risk factor for cardiovascular diseases (CVDs). Growing evidence indicates that the development of NAFLD, ranging from non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), advanced fibrosis to cirrhosis, and even hepatocellular carcinoma, is at substantial risk for CVDs, which clinically contribute to increased cardiovascular morbidity and mortality. Non-invasive serum markers assessing liver fibrosis, such as fibrosis-4 (FIB-4) score, aspartate transaminase-to-platelet ratio index (APRI), and NAFLD fibrosis score (NFS), are expected to be useful tools for clinical management of patients with CVDs. This review aims to provide an overview of the evidence for the relationship between the progression of NAFLD and CVDs and the clinical application of non-invasive markers of liver fibrosis in managing patients with CVDs.
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Affiliation(s)
- Ling-Zi Chen
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, 515041 Shantou, Guangdong, China
| | - Xu-Bin Jing
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, 515041 Shantou, Guangdong, China
| | - Xiang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, 515041 Shantou, Guangdong, China
| | - Yan-Chun Xie
- Department of Endoscopy Center, Cancer Hospital of Shantou University Medical College, 515041 Shantou, Guangdong, China
| | - Yun Chen
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, 515041 Shantou, Guangdong, China
| | - Xian-Bin Cai
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, 515041 Shantou, Guangdong, China
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Khokhlov L, Siraw B, Ali M, Hussain F, Brown A, Shemisa K. Patients with atrial fibrillation and diabetes mellitus affected by nonalcoholic fatty liver disease have a greater risk of mortality and worse clinical outcomes. Cardiovasc Endocrinol Metab 2024; 13:e0307. [PMID: 38846627 PMCID: PMC11152824 DOI: 10.1097/xce.0000000000000307] [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: 12/10/2023] [Accepted: 05/13/2024] [Indexed: 06/09/2024]
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is associated with several adverse clinical outcomes. In this study, we assessed the association between NAFLD and several clinical outcome measures in patients with diabetes mellitus (DM) and atrial fibrillation (AF). Methods We queried the National Inpatient Sample (NIS) between 2016 and 2019 for adult patients who were hospitalized with DM and AF. NAFLD was the independent variable. The primary outcome was inpatient mortality. The secondary outcomes were cardiogenic shock, cardiac arrest, gastrointestinal bleeding (GIB), invasive mechanical ventilation, length of stay, and total hospital charges. A multivariable logistic regression model was used to estimate odds ratios with a 95% confidence interval (CI) and a P value of less than 0.05 was considered significant. Results There were 6 723 293 hospitalizations with AF and DM and 253 639 (3.7%) had NAFLD. NAFLD and non-NAFLD cohorts had a mean age of 70.4 vs. 73.8 years, respectively. Overall, 55.6% were male and 73.8% were White. NAFLD was found to be significantly associated with in-hospital mortality [adjusted odds ratio (AOR), 4.2; 95% CI, 4.08-4.32], cardiogenic shock (AOR, 4.78; 95% CI, 4.59-4.98), cardiac arrest (AOR, 3.43; 95% CI, 3.27-3.59), GIB (AOR, 1.92; 95% CI, 1.86-1.98), length of stay, and total hospital charges. Conclusion In patients with AF and DM patients, the presence of NAFLD was associated with significantly worse clinical outcomes and higher resource utilization. Adverse cardiovascular events were common as well as GIB. Screening and prevention strategies modifying the risk and disease severity of NAFLD are needed.
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Affiliation(s)
- Leonid Khokhlov
- Department of Internal Medicine, Good Samaritan Hospital, TriHealth, Cincinnati, Ohio
| | - Bekure Siraw
- Department of Internal Medicine, Ascension Saint Joseph Hospital, Chicago, Illinois
| | - Mehnaaz Ali
- Department of Internal Medicine, Good Samaritan Hospital, TriHealth, Cincinnati, Ohio
| | - Fatima Hussain
- Department of Internal Medicine, Good Samaritan Hospital, TriHealth, Cincinnati, Ohio
| | - Amanda Brown
- Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, USA
| | - Kamal Shemisa
- Department of Internal Medicine, Good Samaritan Hospital, TriHealth, Cincinnati, Ohio
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Drozdov I, Szubert B, Rowe IA, Kendall TJ, Fallowfield JA. Accurate prediction of all-cause mortality in patients with metabolic dysfunction-associated steatotic liver disease using electronic health records. Ann Hepatol 2024; 29:101528. [PMID: 38971372 DOI: 10.1016/j.aohep.2024.101528] [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: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 07/08/2024]
Abstract
INTRODUCTION AND OBJECTIVES Despite the huge clinical burden of MASLD, validated tools for early risk stratification are lacking, and heterogeneous disease expression and a highly variable rate of progression to clinical outcomes result in prognostic uncertainty. We aimed to investigate longitudinal electronic health record-based outcome prediction in MASLD using a state-of-the-art machine learning model. PATIENTS AND METHODS n = 940 patients with histologically-defined MASLD were used to develop a deep-learning model for all-cause mortality prediction. Patient timelines, spanning 12 years, were fully-annotated with demographic/clinical characteristics, ICD-9 and -10 codes, blood test results, prescribing data, and secondary care activity. A Transformer neural network (TNN) was trained to output concomitant probabilities of 12-, 24-, and 36-month all-cause mortality. In-sample performance was assessed using 5-fold cross-validation. Out-of-sample performance was assessed in an independent set of n = 528 MASLD patients. RESULTS In-sample model performance achieved AUROC curve 0.74-0.90 (95 % CI: 0.72-0.94), sensitivity 64 %-82 %, specificity 75 %-92 % and Positive Predictive Value (PPV) 94 %-98 %. Out-of-sample model validation had AUROC 0.70-0.86 (95 % CI: 0.67-0.90), sensitivity 69 %-70 %, specificity 96 %-97 % and PPV 75 %-77 %. Key predictive factors, identified using coefficients of determination, were age, presence of type 2 diabetes, and history of hospital admissions with length of stay >14 days. CONCLUSIONS A TNN, applied to routinely-collected longitudinal electronic health records, achieved good performance in prediction of 12-, 24-, and 36-month all-cause mortality in patients with MASLD. Extrapolation of our technique to population-level data will enable scalable and accurate risk stratification to identify people most likely to benefit from anticipatory health care and personalized interventions.
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Affiliation(s)
| | | | - Ian A Rowe
- Leeds Institute of Medical Research, University of Leeds, UK; Leeds Liver Unit, St James's University Hospital, Leeds Teaching Hospitals, UK
| | - Timothy J Kendall
- Edinburgh Pathology, University of Edinburgh, Edinburgh, UK; Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Jonathan A Fallowfield
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
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Ahamed F, Eppler N, Jones E, Zhang Y. Understanding Macrophage Complexity in Metabolic Dysfunction-Associated Steatotic Liver Disease: Transitioning from the M1/M2 Paradigm to Spatial Dynamics. LIVERS 2024; 4:455-478. [PMID: 39328386 PMCID: PMC11426415 DOI: 10.3390/livers4030033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses metabolic dysfunction-associated fatty liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), with MASH posing a risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The global prevalence of MASLD is estimated at approximately a quarter of the population, with significant healthcare costs and implications for liver transplantation. The pathogenesis of MASLD involves intrahepatic liver cells, extrahepatic components, and immunological aspects, particularly the involvement of macrophages. Hepatic macrophages are a crucial cellular component of the liver and play important roles in liver function, contributing significantly to tissue homeostasis and swift responses during pathophysiological conditions. Recent advancements in technology have revealed the remarkable heterogeneity and plasticity of hepatic macrophage populations and their activation states in MASLD, challenging traditional classification methods like the M1/M2 paradigm and highlighting the coexistence of harmful and beneficial macrophage phenotypes that are dynamically regulated during MASLD progression. This complexity underscores the importance of considering macrophage heterogeneity in therapeutic targeting strategies, including their distinct ontogeny and functional phenotypes. This review provides an overview of macrophage involvement in MASLD progression, combining traditional paradigms with recent insights from single-cell analysis and spatial dynamics. It also addresses unresolved questions and challenges in this area.
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Affiliation(s)
- Forkan Ahamed
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Natalie Eppler
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Elizabeth Jones
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
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Woolley JJ, Fishman J, Parrinello CM, O'Connell T. Cardiovascular risk in US adults with nonalcoholic steatohepatitis (NASH) vs. matched non-NASH controls, National Health and Nutrition Examination Survey, 2017-2020. PLoS One 2024; 19:e0309617. [PMID: 39190769 DOI: 10.1371/journal.pone.0309617] [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: 04/23/2024] [Accepted: 08/12/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND NASH is considered a contributor to atherosclerotic cardiovascular disease (ASCVD) risk; however, its contribution beyond traditional risk factors for CVD, particularly diabetes, is less clearly understood. This study aimed to quantify the cardiovascular-event risk associated with NASH, independent of diabetes status. METHODS A cross-sectional analysis was conducted using the 2017-2020 NHANES pre-pandemic cycle. NASH was defined based on presence of steatosis without other causes of liver disease, and FibroScan+AST score from vibration-controlled transient elastography (VCTE). Significant fibrosis (stages F2-F4) was identified by liver stiffness measurement from VCTE. Predicted primary CV-event risk was estimated using both the Pooled Cohort Equations (PCE) and the Framingham Risk Score (FRS). NASH patients were matched with non-NASH controls on age, sex, race/ethnicity, and diabetes status. Weighted logistic regression was conducted, modeling elevated predicted CV risk (binary) as the dependent variable and indicators for NASH / fibrosis stages as independent variables. RESULTS A sample of 125 NASH patients was matched with 2585 controls. NASH with significant fibrosis was associated with elevated predicted 10-year CV risk, although this association was only statistically significant in PCE analyses (odds ratio and 95% CI 2.34 [1.25, 4.36]). Analyses restricting to ages <65 years showed similar results, with associations of greater magnitude. CONCLUSION Independent of diabetes, a significant association was observed between NASH with significant liver fibrosis and predicted primary CV-event risk in US adults, particularly for those <65. These findings suggest the importance of accounting for NASH and liver-fibrosis stage in predicting CV-event risk.
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Affiliation(s)
| | - Jesse Fishman
- Formerly of Madrigal Pharmaceuticals, Conshohocken, Pennsylvania, United States of America
| | | | - Tom O'Connell
- Medicus Economics, Boston, Massachusetts, United States of America
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Favre-Bulle T, Moradpour D, Marques-Vidal P, Vaucher J. Trends in the burden of hospitalised patients with cirrhosis in Switzerland: a cross-sectional study of cirrhosis-related hospitalisations between 1998 and 2020. BMJ Open 2024; 14:e081822. [PMID: 39181561 PMCID: PMC11344505 DOI: 10.1136/bmjopen-2023-081822] [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: 11/07/2023] [Accepted: 08/05/2024] [Indexed: 08/27/2024] Open
Abstract
OBJECTIVE Liver cirrhosis is an increasing cause of morbidity and mortality worldwide with a heavy load on healthcare systems. We analysed the trends in hospitalisations for cirrhosis in Switzerland. DESIGN Cross-sectional study. SETTING Large nationwide inpatient database, years between 1998 and 2020. PARTICIPANTS Hospitalisations for cirrhosis of adult patients were selected. MAIN OUTCOMES AND MEASURES Hospitalisations with either a primary diagnosis of cirrhosis or a cirrhosis-related primary diagnosis with a mandatory presence of cirrhosis as a secondary diagnosis were considered following the 10th revision of the International Statistical Classification of Diseases and Related Health Problems codes. Trends in demographic and clinical characteristics, in-hospital mortality and length of stay were analysed. Causes and costs of cirrhosis-related hospitalisations were available from 2012 onwards. RESULTS Cirrhosis-related hospitalisations increased from 1631 in 1998 to 4052 in 2020. Of the patients, 68.7% were men. Alcohol-related liver disease was the leading cause, increasing from 44.1% (95% CI, 42.4% to 45.9%) in 2012 to 47.9% (95% CI, 46.4% to 49.5%) in 2020. Assessed by exclusion of other coded causes, non-alcoholic fatty liver disease was the second cause at 42.7% (95% CI, 41.2% to 44.3%) in 2020. Hepatitis C virus-related cirrhosis decreased from 12.3% (95% CI, 11.2% to 13.5%) in 2012 to 3.2% (95% CI, 2.7% to 3.8%) in 2020. Median length of stay decreased from 11 to 8 days. Hospitalisations with an intensive care unit stay increased from 9.8% (95% CI, 8.4% to 11.4%) to 15.6% (95% CI, 14.5% to 16.8%). In-hospital mortality decreased from 12.1% (95% CI, 10.5% to 13.8%) to 9.7% (95% CI, 8.8% to 10.7%). Total costs increased from 54.4 million US$ (51.4 million €) in 2012 to 92.6 million US$ (87.5 million €) in 2020. CONCLUSIONS Cirrhosis-related hospitalisations and related costs increased in Switzerland from 1998 to 2020 but in-hospital mortality decreased. Alcohol-related liver disease and non-alcoholic fatty liver disease were the most prevalent and preventable aetiologies of cirrhosis-related hospitalisations.
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Affiliation(s)
- Timothee Favre-Bulle
- Service of Internal Medicine, Etablissements Hospitaliers du Nord Vaudois, Yverdon-les-Bains, Switzerland
- Department of Medicine, University of Lausanne Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Darius Moradpour
- Department of Medicine, Service of Gastroenterology and Hepatology, University of Lausanne, Lausanne, Switzerland
| | | | - Julien Vaucher
- Department of Medicine, University of Lausanne, Lausanne, Switzerland
- Department of Medicine and Specialties, University of Fribourg, Fribourg, Switzerland
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