|
1
|
Gbadamosi SO, Evans KA, Brady BL, Hoovler A. Noninvasive tests and diagnostic pathways to MASH diagnosis in the United States: a retrospective observational study. J Med Econ 2025; 28:314-322. [PMID: 39963742 DOI: 10.1080/13696998.2025.2468582] [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: 12/20/2024] [Revised: 02/13/2025] [Accepted: 02/14/2025] [Indexed: 03/03/2025]
Abstract
AIM Although liver biopsy is considered the most reliable diagnostic tool for metabolic dysfunction-associated steatohepatitis (MASH), it is invasive and can be costly. Clinicians are increasingly relying on routine biomarkers and other noninvasive tests (NITs) for diagnosis. We examined real-world diagnostic pathways for patients newly diagnosed with MASH with a primary focus on NITs. MATERIALS AND METHODS This retrospective, observational study analyzed healthcare claims data (Merative MarketScan Commercial and Medicare Databases) from patients in the United States newly diagnosed with MASH from October 1, 2016, to March 31, 2023. Patients ≥18 years old with ≥12 months of continuous enrollment with medical and pharmacy benefits prior to diagnosis were included. Diagnostic pathways leading up to MASH diagnosis, including NITs (blood-based and imaging-based tests) and liver biopsies were assessed. Prevalence of comorbid conditions, MASH-associated medication use, and the diagnosing physician specialty were also examined. RESULTS A total of 18,396 patients were included in the analysis. Routine laboratory tests (alanine aminotransferase [ALT], albumin, aspartate aminotransferase [AST], cholesterol, complete blood count, and hemoglobin A1c) were performed among ≥70% of patients prior to MASH diagnosis, including 89% of patients with a liver enzyme test (ALT and/or AST). More than 75% of patients had necessary laboratory tests to calculate AST to platelet ratio index (APRI) and fibrosis-4 index (FIB-4) scores. The most common imaging performed was ultrasound (62%); liver biopsy was only performed in 10% of patients. There was a high prevalence of cardio metabolic risk factors such as hyperlipidemia (66%), hypertension (62%), obesity (58%), type 2 diabetes (40%), and cardiovascular disease (21%). Nearly half of the patients (49%) were diagnosed by a primary care physician. LIMITATIONS AND CONCLUSIONS This study highlights real-world diagnostic pathways among patients newly diagnosed with MASH, supporting previous findings that liver biopsies are infrequently used in favor of noninvasive methods.
Collapse
|
|
2
|
Giammarino A, Shah N, Ghani M, Ali H, Satapathy SK. Diagnostic Accuracy of Noninvasive Scores for Fibrotic MASH in a Cohort of Biopsy-proven MASLD Patients With Predominantly High BMI in the Primary Care Setting. J Clin Exp Hepatol 2025; 15:102556. [PMID: 40337254 PMCID: PMC12053704 DOI: 10.1016/j.jceh.2025.102556] [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: 04/09/2024] [Accepted: 03/20/2025] [Indexed: 05/03/2025] Open
Abstract
Background Currently, the Fibrosis-4 (FIB-4) and nonalcoholic fatty liver disease fibrosis score (NFS) are used to predict fibrosis and steatosis in patients with or at risk for metabolic dysfunction-associated steatotic liver disease (MASLD). More recently, the fibrotic nonalcoholic steatohepatitis (NASH) index (FNI) and steatosis-associated fibrosis estimator (SAFE) have been created. We have compared the accuracy of these noninvasive scoring systems in MASLD patients. Methods This is a retrospective analysis of 244 biopsy-proven MASLD patients from a tertiary health care system. Score performances were determined by calculating the area under the receiver operating characteristic (AUROC) curve with 95% confidence intervals, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). Results About 25 (10.3%) patients had fibrotic metabolic dysfunction-associated steatohepatitis (MASH). The FNI score was best at predicting fibrotic MASH with an AUROC of 0.78, while NFS was the worst at predicting fibrotic NASH with an AUROC of 0.60. In the entire cohort, FNI of 0.33, FIB-4 of 2.67, SAFE >100, and NFS >0.675 had PPVs of 17%, 31%, 17%, and 16%, respectively, and NPVs of 97%, 92%, 96%, and 91%, respectively. Specificity was greatest for FIB4 at 92% and NFS at 86%, whereas the sensitivity was greatest for FNI and SAFE scores at 88% and 80%, respectively. Conclusion FNI and SAFE scores have superior diagnostic accuracy for fibrotic MASH compared to other scoring systems. While liver biopsy remains the gold standard diagnostic method, noninvasive scores like FNI, and SAFE scores can be used in everyday clinical practice to assess for fibrotic MASH.
Collapse
Affiliation(s)
- Alexa Giammarino
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Gastroenterology and Transplant Hepatology, New Hyde Park, NY, 11040, USA
| | - Nairuti Shah
- NYU Langone Hospital - Long Island Department of Medicine, Mineola, NY, 11501, USA
| | - Maham Ghani
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Gastroenterology and Transplant Hepatology, New Hyde Park, NY, 11040, USA
| | - Hassam Ali
- Department of Gastroenterology, Hepatology & Nutrition, ECU Health Medical Center/Brody School of Medicine, Greenville, NC, 27834, USA
| | - Sanjaya K. Satapathy
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Gastroenterology and Transplant Hepatology, New Hyde Park, NY, 11040, USA
| |
Collapse
|
|
3
|
Ma N, Bansal MB, Chu J, Woodward M, Branch AD. Heavy metals are liver fibrosis risk factors in people without traditional liver disease etiologies. J Environ Sci (China) 2025; 155:329-342. [PMID: 40246469 PMCID: PMC12007413 DOI: 10.1016/j.jes.2024.08.027] [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: 02/06/2024] [Revised: 08/20/2024] [Accepted: 08/21/2024] [Indexed: 04/19/2025]
Abstract
Liver fibrosis is an important predictor of mortality. Liver disease case definitions changed in 2023. These definitions include an easily over-looked group with no traditional etiology (NTE) of liver disease and no steatosis. We analyzed heavy metals and cardiometabolic risk factors (CMRFs) as fibrosis risk factors in the NTE group and in people with another newly-defined condition, metabolic dysfunction-associated steatotic liver disease (MASLD). Two National Health and Nutrition Examination Survey (NHANES) datasets were analyzed. In NHANES III (1988-1994), fibrosis and steatosis were defined by Fibrosis-4 scores and ultrasound, respectively, in 12,208 adults. In NHANES 2017-2020, fibrosis and steatosis were defined by transient elastography and the controlled attenuation parameter (CAP) in 5525 adults. Fibrosis risk factors varied over time and by race/ethnicity. In the earlier dataset, NTE-fibrosis had a positive, non-significant, association with high blood levels of lead (Pb). MASLD-fibrosis was associated with Pb (OR = 2.5, 95 % CI, 1.4-4.4) and not with CMRFs in non-Hispanic Blacks but was associated with CMRFs in non-Hispanic Whites. Heavy metal exposures fell between the two time periods. In the later dataset, NTE-fibrosis was associated with Pb (OR = 4.2, 95 % CI, 2.6-6.8) and cadmium (OR = 1.8, 95 % CI, 1.1-3.0) in the total population, but not with most CMRFs. MASLD-fibrosis was strongly-significantly associated with CMRFs in every racial/ethnic group except non-Hispanic Blacks in whom CMRFs were only weakly associated with MASLD-fibrosis. Heavy metal pollution, which disproportionately impacts minoritized populations, decreased over time, but remained strongly associated with liver fibrosis in people lacking traditional etiological factors for liver disease.
Collapse
Affiliation(s)
- Ning Ma
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, 10029, USA
| | - Meena B Bansal
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, 10029, USA
| | - Jaime Chu
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, 10029, USA
| | - Mark Woodward
- The George Institute for Global Health, School of Public Health, Imperial College London, London, W12 7RZ, UK; The George Institute for Global Health, University of New South Wales, Sydney, 2000, Australia
| | - Andrea D Branch
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, 10029, USA.
| |
Collapse
|
|
4
|
Tsuchiyose E, Salimi A, Magee C, Khalili M. Culturally tailored steatotic liver disease management: Latino and Asian community partner perspectives and recommendations. Hepatol Commun 2025; 9:e0749. [PMID: 40489763 DOI: 10.1097/hc9.0000000000000749] [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: 02/13/2025] [Accepted: 05/08/2025] [Indexed: 06/11/2025] Open
Abstract
BACKGROUND Lifestyle modification is the mainstay of treatment for steatotic liver disease (SLD), and recommendations for behavior change require cultural tailoring to enhance their relevance for minority populations. This study aimed to explore community partner perspectives on barriers and facilitators to lifestyle modification and identify ways to improve cultural sensitivity for SLD management. METHODS We conducted semi-structured interviews with 20 community partners (public health professionals, community leaders, and health care workers) from Latino (n=9) and Asian (n=11) communities in San Francisco. Interviews explored community knowledge of SLD, perceived barriers and facilitators to lifestyle changes, and feedback on current education materials. Data were analyzed using thematic analysis. RESULTS Across 4 levels of influence (societal, community, interpersonal, and individual), 9 shared barriers and 6 shared facilitators emerged. Barriers included poverty, misinformation, social influences, time constraints, and limited nutrition and SLD knowledge, while facilitators included free outdoor spaces, food assistance programs, healthy cultural habits, and family. The Asian community uniquely cited safety concerns for outdoor activities and preference for Eastern medicine, while the Latino community expressed childcare constraints as barriers. We gathered 9 recommendations to improve the cultural sensitivity of lifestyle modification guidance, including working within traditional dietary frameworks, adapting exercise to activities of daily life, and embracing harm reduction for alcohol cessation. CONCLUSIONS Culturally tailored interventions may improve the relevance and sustainability of SLD lifestyle modification recommendations in Latino and Asian communities. Recommendations for interventions include harnessing community-based support, embracing cultural dietary modifications, and promoting feasible physical activity to enhance engagement in these populations.
Collapse
Affiliation(s)
- Erika Tsuchiyose
- Tufts University School of Medicine, Boston, Massachusetts, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, Zuckerberg San Francisco General, San Francisco, California, USA
| | - Aidin Salimi
- Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Catherine Magee
- Department of Medicine, Division of Gastroenterology and Hepatology, Zuckerberg San Francisco General, San Francisco, California, USA
| | - Mandana Khalili
- Department of Medicine, Division of Gastroenterology and Hepatology, Zuckerberg San Francisco General, San Francisco, California, USA
- Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| |
Collapse
|
|
5
|
Gao G, Zhang X, Wang Z, Xu J, Wang J, Liu T, Xie Z. Multiscale insights into cornuside's effects on NAFLD: A cross-disciplinary integrating bioinformatics, computational chemistry, and machine learning. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156809. [PMID: 40344848 DOI: 10.1016/j.phymed.2025.156809] [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: 10/31/2024] [Revised: 04/07/2025] [Accepted: 04/25/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a complex metabolic disorder involving intertwined signaling pathways, posing challenges for targeted therapeutic interventions. Cornus Fructus (CF), a traditional medicinal herb, holds potential for NAFLD treatment, with cornuside (COR) identified as its primary active component. METHODS This study employed a cross-disciplinary approach, integrating bioinformatics, computational chemistry, and machine learning to uncover COR's therapeutic mechanisms with precision and depth. RESULTS Using bioinformatics-driven analysis, 27 core targets were identified, revealing that COR modulated critical metabolic and inflammatory pathways. COR mitigated insulin resistance by regulating the AKT/GSK3β axis, enhanced cholesterol metabolism through LXR signaling, promoted fatty acid oxidation via PPARα activation, and suppressed inflammation by inhibiting NF-κB signaling. These results highlighted COR's ability to orchestrate multi-pathway regulation essential for restoring metabolic homeostasis in NAFLD. Molecular docking and molecular dynamics (MD) simulations provided atomistic insights, demonstrating COR's stable and high-affinity interactions with key targets. Additionally, machine learning algorithms enhanced target identification and pathway prediction, improving the precision and efficiency of the discovery process. CONCLUSION This study offered multi-scale mechanistic insights into COR's therapeutic effects on NAFLD, bridging experimental pharmacology and computational methods. The integration of bioinformatics, molecular simulation, and machine learning established a comprehensive framework for drug discovery, positioning COR as a promising candidate for NAFLD therapy and guiding future development of precision interventions.
Collapse
Affiliation(s)
- Gai Gao
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan Province, Henan University of Chinese Medicine, Zhengzhou 450046, China; School of Pharmacy, Minzu University of China, Beijing 100081, China
| | - Xiaowei Zhang
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan Province, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Zhenzhen Wang
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan Province, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Jiangyan Xu
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan Province, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Jinghui Wang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China.
| | - Tongxiang Liu
- School of Pharmacy, Minzu University of China, Beijing 100081, China.
| | - Zhishen Xie
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan Province, Henan University of Chinese Medicine, Zhengzhou 450046, China.
| |
Collapse
|
|
6
|
van Kleef LA, Pustjens J, Janssen HLA, Brouwer WP. Diagnostic Accuracy of the LiverRisk Score to Detect Increased Liver Stiffness Among a United States General Population and Subgroups. J Clin Exp Hepatol 2025; 15:102512. [PMID: 40093506 PMCID: PMC11908561 DOI: 10.1016/j.jceh.2025.102512] [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: 12/11/2024] [Accepted: 02/02/2025] [Indexed: 03/19/2025] Open
Abstract
Background The LiverRisk score (LRS) has recently been proposed to predict liver fibrosis and future development of liver-related outcomes in the general population. Here, we performed an external validation of this score. Methods We used data from National Health and Nutrition Examination Survey 2017-2020, a United States population-based cohort to assess the diagnostic accuracy of the LRS to detect a liver stiffness measurement (LSM) ≥8 and ≥12 kPa. Performance was tested among the entire general population and clinically relevant subgroups. Results The cohort comprised 7,025 participants (aged 49 [33-63], 49% male), and 9.7% had an LSM ≥8 and 3.2% had an LSM ≥12 kPa. The area under the receiver characteristic operator curve (AUC) in the overall population was 0.73 (95% confidence interval [CI] :0.71-0.75) and 0.78 (95% CI: 0.74-0.81) to detect an LSM ≥8 and ≥ 12 kPa, respectively, significantly outperforming the fibrosis 4 index (FIB-4) but not the nonalcoholic fatty liver disease fibrosis score, steatosis-associated fibrosis estimator (SAFE), or metabolic dysfunction-associated fibrosis 5 (MAF-5). Performance was consistent among most subgroups, but AUC levels to detect an LSM ≥8 kPa decreased to <0.70 among participants aged 18-40 or 60-80 years, blacks, and individuals with diabetes or liver steatosis. The LRS categorized 80.5% as very low risk, 17.7% as low risk, and 1.8% as at risk, prevalence of an LSM ≥8 in these groups was 6.3%, 20.8%, and 50.5%, respectively. The sensitivity to detect an LSM ≥8 kPa was 47.3% in the overall population (but dropped to 21.3% for individuals aged 18-40 years) despite applying the lowest cut-off, which should yield the highest sensitivity. Conclusion The LRS score is a promising new tool to predict liver fibrosis; however, its diagnostic accuracy attenuates especially among patients aged 18-40 or 60-80 years. The overall sensitivity was only 47.3% at the lowest LRS cut-off. Further studies assessing cost-benefit ratios according to the LRS compared to FIB-4 and other risk scores such as MAF-5 and SAFE are required to determine its usefulness in referral strategies.
Collapse
Affiliation(s)
- Laurens A van Kleef
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Jesse Pustjens
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Canada
| | - Willem P Brouwer
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| |
Collapse
|
|
7
|
Trifylli EM, Angelakis A, Kriebardis AG, Papadopoulos N, Fortis SP, Pantazatou V, Koskinas J, Kranidioti H, Koustas E, Sarantis P, Manolakopoulos S, Deutsch M. Extracellular vesicles as biomarkers for metabolic dysfunction-associated steatotic liver disease staging using explainable artificial intelligence. World J Gastroenterol 2025; 31:106937. [DOI: 10.3748/wjg.v31.i22.106937] [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: 03/10/2025] [Revised: 04/18/2025] [Accepted: 05/22/2025] [Indexed: 06/12/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease globally. Current diagnostic methods, such as liver biopsies, are invasive and have limitations, highlighting the need for non-invasive alternatives.
AIM To investigate extracellular vesicles (EVs) as potential biomarkers for diagnosing and staging steatosis in patients with MASLD using machine learning (ML) and explainable artificial intelligence (XAI).
METHODS In this single-center observational study, 798 patients with metabolic dysfunction were enrolled. Of these, 194 met the eligibility criteria, and 76 successfully completed all study procedures. Transient elastography was used for steatosis and fibrosis staging, and circulating plasma EV characteristics were analyzed through nanoparticle tracking. Twenty ML models were developed: Six to differentiate non-steatosis (S0) from steatosis (S1-S3); and fourteen to identify severe steatosis (S3). Models utilized EV features (size and concentration), clinical (advanced fibrosis and presence of type 2 diabetes mellitus), and anthropomorphic (sex, age, height, weight, body mass index) data. Their performance was assessed using receiver operating characteristic (ROC)-area under the curve (AUC), specificity, and sensitivity, while correlation and XAI analysis were also conducted.
RESULTS The CatBoost C1a model achieved an ROC-AUC of 0.71/0.86 (train/test) on average across ten random five-fold cross-validations, using EV features alone to distinguish S0 from S1-S3. The CatBoost C2h-21 model achieved an ROC-AUC of 0.81/1.00 (train/test) on average across ten random three-fold cross-validations, using engineered features including EVs, clinical features like diabetes and advanced fibrosis, and anthropomorphic data like body mass index and weight for identifying severe steatosis (S3). Key predictors included EV mean size and concentration. Correlation, XAI, and SHapley Additive exPlanations analysis revealed non-linear feature relationships with steatosis stages.
CONCLUSION The EV-based ML models demonstrated that the mean size and concentration of circulating plasma EVs constituted key predictors for distinguishing the absence of significant steatosis (S0) in patients with metabolic dysfunction, while the combination of EV, clinical, and anthropomorphic features improved the diagnostic accuracy for the identification of severe steatosis. The algorithmic approach using ML and XAI captured non-linear patterns between disease features and provided interpretable MASLD staging insights. However, further large multicenter studies, comparisons, and validation with histopathology and advanced imaging methods are needed.
Collapse
Affiliation(s)
- Eleni Myrto Trifylli
- Gastrointestinal-Liver Unit, The 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, General Hospital of Athens “Hippocratio,” Athens 11521, Greece
- Laboratory of Reliability and Quality Control in Laboratory Hematology, Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica, Egaleo 12243, Attikí, Greece
| | - Athanasios Angelakis
- Department of Epidemiology and Data Science, Amsterdam University Medical Center, Amsterdam 1105, Netherlands
- Department of Methodology, Digital Health, Amsterdam Public Health Research Institute, Amsterdam 1105, Netherlands
- Data Science Center, University of Amsterdam, Amsterdam 1098, Netherlands
| | - Anastasios G Kriebardis
- Laboratory of Reliability and Quality Control in Laboratory Hematology, Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica, Egaleo 12243, Attikí, Greece
| | - Nikolaos Papadopoulos
- The Second Department of Internal Medicine, 401 General Army Hospital of Athens, Athens 11525, Greece
| | - Sotirios P Fortis
- Laboratory of Reliability and Quality Control in Laboratory Hematology, Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica, Egaleo 12243, Attikí, Greece
| | - Vasiliki Pantazatou
- Laboratory of Reliability and Quality Control in Laboratory Hematology, Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica, Egaleo 12243, Attikí, Greece
| | - John Koskinas
- Gastrointestinal-Liver Unit, The 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, General Hospital of Athens “Hippocratio,” Athens 11521, Greece
| | - Hariklia Kranidioti
- Gastrointestinal-Liver Unit, The 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, General Hospital of Athens “Hippocratio,” Athens 11521, Greece
| | - Evangelos Koustas
- Department of Oncology, General Hospital Evangelismos, Athens 10676, Greece
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Spilios Manolakopoulos
- Gastrointestinal-Liver Unit, The 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, General Hospital of Athens “Hippocratio,” Athens 11521, Greece
| | - Melanie Deutsch
- Gastrointestinal-Liver Unit, The 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, General Hospital of Athens “Hippocratio,” Athens 11521, Greece
| |
Collapse
|
|
8
|
Simeone PG, Costantino S, Liani R, Tripaldi R, Di Castelnuovo A, Tartaro A, Mengozzi A, Cosentino F, Cipollone F, Consoli A, Paneni F, Santilli F. Interleukin-1β in circulating mononuclear cells predicts steatotic liver disease improvement after weight loss in subjects with obesity and prediabetes or type 2 diabetes. Cardiovasc Diabetol 2025; 24:247. [PMID: 40514652 DOI: 10.1186/s12933-025-02706-8] [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: 02/07/2025] [Accepted: 03/24/2025] [Indexed: 06/16/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cardiovascular risk (CV) factor. Interleukin-1β (IL-1β), a cytokine involved in the pathogenesis of obesity-associated inflammation and type 2 diabetes (T2D), promotes hepatic steatosis. The Canakinumab Anti-inflammatory Thrombosis Outcome (CANTOS) trial showed that the inhibition of the IL-1β pathway was associated with a reduction of CV events in high-risk patients. The present study was designed to determine: (i) whether an equal degree of weight loss by liraglutide or lifestyle changes has a different impact on MASLD extent and IL-1β expression in peripheral blood mononuclear cells from obese subjects with prediabetes or early T2D; (ii) whether baseline IL-1β levels may predict the extent of weight loss and related metabolic changes. METHODS Thirty-two obese subjects with prediabetes (n = 16) or newly diagnosed T2D (n = 16), were randomized to the glucagon-like peptide receptor agonist (GLP1-RA) liraglutide or lifestyle counselling until achieving a comparable weight loss. Visceral adipose tissue (VAT) and gene expression of IL-1β in peripheral blood mononuclear cells were assessed by magnetic resonance and real time PCR, respectively. RESULTS At baseline, IL-1β was positively correlated to body mass index (BMI), fasting plasma glucose, HbA1c, VAT, MASLD extent, platelet count, chemerin and interleukin-1 receptor antagonist (IL1-RA). After achievement of the weight loss target in the two groups, a significant but comparable reduction of IL-1β (p for difference = 0.56) was observed in both arms, in parallel with a comparable improvement in glycaemic control, C reactive protein (CRP), BMI and MASLD. Furthermore, basal IL-1β levels independently predicted the extent of MASLD decrease (p = 0.030); subjects in the highest tertile showed a median decrease of - 8.0 (95% CI - 12.3 to - 4.8) compared with - 23.0 (95% CI - 39.5 to - 16.3) in the lowest tertile. CONCLUSION In patients with obesity with initial impairment of glucose metabolism successful weight loss is associated with a reduction of both IL-1β levels and MASLD degree. Of interest, basal levels of IL-1β predict the extent of MASLD improvement, regardless of the intervention. Our results may set the stage for ad-hoc studies investigating the usefulness of baseline IL-1β a level as a drug-response biomarker.
Collapse
Affiliation(s)
- Paola Giustina Simeone
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, 66100, Chieti, Italy
| | - Sarah Costantino
- Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Rossella Liani
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, 66100, Chieti, Italy
| | - Romina Tripaldi
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, 66100, Chieti, Italy
| | | | - Armando Tartaro
- Department of Neuroscience & Imaging, University of Chieti, Chieti, Italy
| | - Alessandro Mengozzi
- Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesco Cosentino
- Cardiology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, 171 76, Stockholm, Sweden
| | - Francesco Cipollone
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, 66100, Chieti, Italy
| | - Agostino Consoli
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, 66100, Chieti, Italy
| | - Francesco Paneni
- Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Francesca Santilli
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, 66100, Chieti, Italy.
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, 66100, Chieti, Italy.
| |
Collapse
|
|
9
|
Li L, Gao W, Yao F, Li J, Sang W, Zhang R. Innovative nanomedicine approaches for the management of nonalcoholic fatty liver disease. J Control Release 2025; 382:113680. [PMID: 40180250 DOI: 10.1016/j.jconrel.2025.113680] [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: 01/24/2025] [Revised: 03/17/2025] [Accepted: 03/31/2025] [Indexed: 04/05/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder globally. The prevalence of NAFLD in the general population is estimated to be 25-30 %, making it the most common chronic liver condition in China as well as worldwide. Given the escalating disease burden and the scarcity of effective therapeutic interventions, there is a pressing unmet clinical need. Consequently, the development of novel pharmaceuticals has emerged as a pivotal research focus in recent years. Moreover, the advent of nano-delivery technology offers innovative solutions for NAFLD drug therapy. This paper presents a comprehensive examination of the pathogenesis and therapeutic targets of NAFLD. It critically reviews the latest advancements in nanomedicine research pertinent to NAFLD treatment. The review synthesizes a broad range of research findings to bridge the gap between current knowledge and emerging therapeutic strategies, and aims to inform and guide future research directions in NAFLD management.
Collapse
Affiliation(s)
- Limeng Li
- School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China
| | - Weiqi Gao
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan 030032, China; Shanxi Academy of Advanced Research and Innovation (SAARl), Taiyuan, 030032, China
| | - Fengyang Yao
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, China
| | - Jiayi Li
- School of Forensic Medicine, Shanxi Medical University, Taiyuan 030001, China
| | - Wei Sang
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, China; Institute of Medical Technology, Shanxi Medical University, Taiyuan 030001, China.
| | - Ruiping Zhang
- The Radiology Department of Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University, Taiyuan 030001, China.
| |
Collapse
|
|
10
|
Wu D, Liu J, Guo Z, Wang L, Yao Z, Wu Q, Lu Y, Lv W. Natural bioactive compounds reprogram bile acid metabolism in MAFLD: Multi-target mechanisms and therapeutic implications. Int Immunopharmacol 2025; 157:114708. [PMID: 40306110 DOI: 10.1016/j.intimp.2025.114708] [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: 03/05/2025] [Revised: 04/20/2025] [Accepted: 04/20/2025] [Indexed: 05/02/2025]
Abstract
Metabolic-associated fatty liver disease (MAFLD) has become an increasingly prevalent liver disorder worldwide, being closely associated with obesity, metabolic syndrome, and insulin resistance. Bile acids (BAs), beyond their traditional role in lipid digestion, play a pivotal part in regulating lipid and glucose metabolism as well as inflammatory responses. Recent investigations have recognized BAs as key factors in the onset and progression of MAFLD, mainly via their interactions with nuclear receptors such as the farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor (TGR5). Additionally, active compounds derived from traditional Chinese medicine (TCM) have shown promising potential in the treatment of MAFLD. This study systematically reviews and analyzes the molecular mechanisms and recent progress in the application of TCM active ingredients for MAFLD treatment, with a focus on their regulation of BAs. These active ingredients, including saponins, flavonoids, polysaccharides, and sterols, exert therapeutic effects through diverse mechanisms, such as modulating BA synthesis and mediating receptor-signaling pathways, and are expected to restore metabolic homeostasis.
Collapse
Affiliation(s)
- Dongjie Wu
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Jing Liu
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ziwei Guo
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Liang Wang
- Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Ziang Yao
- Department of Traditional Chinese Medicine, Peking University People's Hospital, Beijing 100044, China
| | - Qingjuan Wu
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
| | - Yanping Lu
- Department of Hepatology, Shenzhen Bao'an District Traditional Chinese Medicine Hospital, Shenzhen 518100, China.
| | - Wenliang Lv
- Department of Infection, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
| |
Collapse
|
|
11
|
Sanyal AJ, Newsome PN, Kliers I, Østergaard LH, Long MT, Kjær MS, Cali AMG, Bugianesi E, Rinella ME, Roden M, Ratziu V, ESSENCE Study Group. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med 2025; 392:2089-2099. [PMID: 40305708 DOI: 10.1056/nejmoa2413258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Collaborators] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/02/2025]
Abstract
BACKGROUND Semaglutide, a glucagon-like peptide-1 receptor agonist, is a candidate for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). METHODS In this ongoing phase 3, multicenter, randomized, double-blind, placebo-controlled trial, we assigned 1197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 in a 2:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. The results of a planned interim analysis conducted at week 72 involving the first 800 patients are reported here (part 1). The primary end points for part 1 were the resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis. RESULTS Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% confidence interval [CI], 21.1 to 36.2; P<0.001). A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the patients in the semaglutide group and in 22.4% of those in the placebo group (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001). Results for the three secondary outcomes that were included in the plan to adjust for multiple testing were as follows: combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% of the patients in the semaglutide group and in 16.1% of those in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2 to 22.8; P<0.001). The mean change in body weight was -10.5% with semaglutide and -2.0% with placebo (estimated difference, -8.5 percentage points; 95% CI, -9.6 to -7.4; P<0.001). Mean changes in bodily pain scores did not differ significantly between the two groups. Gastrointestinal adverse events were more common in the semaglutide group. CONCLUSIONS In patients with MASH and moderate or advanced liver fibrosis, once-weekly semaglutide at a dose of 2.4 mg improved liver histologic results. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT04822181.).
Collapse
Affiliation(s)
- Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond
| | - Philip N Newsome
- Roger Williams Institute of Liver Studies, Faculty of Life Sciences and Medicine, King's College London, Foundation for Liver Research and King's College Hospital, London
- College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | | | | | | | | | | | | | - Mary E Rinella
- Division of Gastroenterology, Hepatology, and Nutrition, University of Chicago, Chicago
| | - Michael Roden
- Department of Endocrinology and Diabetology, Faculty of Medicine, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, Munich-Neuherberg, Germany
| | - Vlad Ratziu
- Sorbonne Université, Institute for Cardiometabolism and Nutrition, Hôpital Pitié-Salpêtrière, INSERM Unité Mixte de Recherche Scientifique 1138 Centre de Recherche des Cordeliers, Paris
| | | |
Collapse
Collaborators
Anurag Maheshwari, Elliot Shin, Eric Lawitz, Cyrus Desouza, Stephanie Pointer, Mohammad Siddiqui, Julio Rosenstock, Grisell Ortiz-Lasanta, Gary Reiss, Eugene Schiff, Rohit Loomba, Don Lazas, Michael Fuchs, Christopher Still, Manal Abdelmalek, Tawfik Chami, Don Rockey, Johanna Hollweg, Donald Gardner, Bhaktasharan Patel, Anita Kohli, Ann Moore, Fadi Deeb, Zeid Kayali, Reem Ghalib, Ildiko Lingvay, Douglas Denham, Amir Hassan, Christopher Bowlus, James Maher, Shekhar Challa, Meena Bansal, Steven Fern, Bradley Freilich, Sonal Kumar, Rajalakshmi Iyer, Idalia Acosta, Jatinder Pruthi, Humberto Aguilar, Adam Deising, Na Li, William Bowman, Ira Jacobson, Lenore DePagter, Aasim Sheikh, Vishweshwar Ranga, Elif Oral, Naomi Gerber, Eva-Maria Heurich, Alonzo Williams, Harish Thakkar, Liana Billings, Kenolisa Onwueme, Vishal Bhagat, Chakradhar Reddy, Glenn Freed, Tuan Pham, Joseph Lim, Shahriar Sedghi, Deepak Venkat, Scott Wilson, Brian Borg, Matthew Myers, Bilal Hameed, Yaneicy Gonzalez Rojas, Jonathan Stine, Miguel Rebollar, Miguel Rodriguez, Pankaj Patel, Michael Steinbook, Maya Balakrishnan, Ethan Weinberg, Adolfo Cueli, Sujit Janardhan, Virginia Clark, Michelle Mallitz, Mordechai Rabinovitz, Dina Halegoua-DeMarzio, Natasha Ballard, Saeid Goshtasbi, Murtaza Mussaji, Arpan Mohanty, Apurva Modi, Michael Brown, Carl Wallach, Parvez Mantry, Huy Trinh, Robert Barish, Manuel Sanchez, Mitchell Shiffman, Louis Wilson, Francisco Pasquel, Alina Allen, Steven Zacks, David Victor, Naim Alkhouri, Michael Ryan, Winston Dunn, Angel Vento, Mousab Tabbaa, Mary Rinella, Anjali Morey, Rashmee Patil, Edward Mena, Guy Neff, John Hemmersmeier, Manuel Rodriguez, Naveen Gara, Karen Simon, Jude Acloque, Adil Fatakia, Conar Fitton, Esteban Olivera, Zubair Farooqui, Rosemary Laird, Kiran Rao, Susan Neese, Broderick Eaton, Daniel Gaudet, Magdy Elkhashab, Melanie Beaton, Giada Sebastiani, Magnus McLeod, Susan Greenbloom, Mark Swain, Andre Carpentier, Yves Robitaille, Adrian Gadano, Margarita Anders, Fernando Bessone, Gabriel Soteras, Maria Puente, Luis Colombato, Diego Aizenberg, Alejandra Mabel Camino, Alma Ladrón de Guevara Cetina, Rafael Aguirre Rivero, Axel Mena Quintero, Efrain Montaño Gonzalez, Diego Barraza Ortiz, Rita da Silva, Claudia de Oliveira, Cristiane Nogueira, Roberto José Filho, Giovanni Silva, Daniela Antunes, Mario Reis Alvares-da-Silva, Rodrigo Rocco, Larissa Sargentini, Heiner Wedemeyer, Anita Pathil-Warth, Jörn Schattenberg, Ingolf Schiefke, Jens Marquardt, Johannes Wiegand, Münevver Demir, Wolf-Peter Hofmann, George Abouda, Kosh Agarwal, Guru Aithal, William Alazawi, Quentin Anstee, Matthew Armstrong, Andrew Austin, Francesca Saffioti, Ben Hudson, Thinzar Min, Pinelopi Manousou, Michael Miller, Richard Parker, Janisha Patel, Harpal Randeva, Sanjeev Sharma, David Sheridan, Emmanouil Tsochatzis, Daniel Abeles, Juan Turnes, Javier Ampuero Herrojo, Isabel Conde, Rocío Aller de la Fuente, Jose Luis Calleja, Maria Teresa Arias Loste, Juan Manuel Pericàs, Moises Diago Madrid, Vlad Ratziu, Laurent Castera, Stanislas Pol, Albert Tran, Lawrence Serfaty, Philippe Mathurin, Cyrielle Caussy, Jérôme Boursier, Juliette Foucher, Marianne Maynard-Muet, Antonio Picardi, Gaetano Serviddio, Francesco Andreozzi, Salvatore Petta, Loris Pironi, Anna Fracanzani, Elisabetta Bugianesi, Luca Miele, Alessandra Mangia, Fabio Marra, Piotr Napora, Ewa Janczewska, Pawel Rajewski, Ewa Krecipro-Nizinska, Katarzyna Wawrzyniec-Lis, Jakub Klapaczynski, Adriana Ilavska, Katarina Cerna, Jozef Lacka, Sylvia Drazilova, Peter Posypanka, Elena Topalova-Zheleva, Lyudmila Mateva, Rozalina Balabanska, Diana Petrova, Stoyan Handzhiev, Veselin Kolchakov, Dimitar Dimitrov, Ivica Grgurevic, Silvija Canecki Varzic, Radan Bruha, Karel Dvorak, Vaclav Hejda, Nebojsa Lalic, Katarina Lalic, Dusica Vrinic Kalem, Edita Stokic, Irina Brcerevic, Liliana Gheorghe, Anca Trifan, Carmen Preda, Claudia Cimpoeru, Andra Suceveanu, Bogdan Pintea, Bogdan Procopet, Olga Orasan, Magdalena Morosanu, Ciprian Constantin, George Papatheodoridis, Grigorios Kaltsas, Alexandra Alexopoulou, Emmanouil Sinakos, Ioannis Goulis, Dimitrios Christodoulou, Triantafyllos Didangelos, Helena Cortez-Pinto, Jose Presa Ramos, Filipe Andrade, Joana Magalhães, Tarcísio Araújo, Rosa Jorge, Cristina Fonseca, Carla Rolanda, Adriano Cardoso, Guilherme Macedo, Mariana Monteiro, Ana Silva, Luís Maia, Manuel Pereira, Lise Lotte Gluud, Henning Grønbæk, Aleksander Krag, Frank Schiødt, Anja Geerts, Sven Francque, Yves Horsmans, Christophe Moreno, Mathieu Struyve, Christophe Van Steenkiste, O Holleboom, Lars Penne, Robert Roomer, Bernhard Ludvik, Vanessa Stadlbauer-Köllner, Evelyn Fließer-Görzer, Håvard Midgard, Svein Oskar Frigstad, John Ryan, Suzanne Norris, Stefan Bilz, Annalisa Berzigotti, Nicolas Goossens, Beat Muellhaupt, Thomas Zueger, George Bee Goh, Rahul Kumar, Yock Young Dan, Yusuf Yilmaz, Kamil Ozdil, Filiz Akyuz, Murat Kiyici, Metin Basaranoglu, Hatice Balaban, Meral Akdogan Kayhan, Saadettin Hulagu, Fehmi Ates, Ulus Akarca, Ramazan Idilman, Hilmi Sumbul, Eli Zuckerman, Gadi Lalazar, Ehud Zigmond, Helena Katchman, Rifaat Safadi, Marius Braun, Assy Nimer, Zhanna Kobalava, Yulia Samoilova, Tatyana Lysenko, Marina Sergeeva-Kondrachenko, Elena Frolova, Andrey Peskov, Svetlana Zyangirova, Leylya Gaysina, Irina Dvoryashina, Lidia Belousova, Igor Bakulin, Polina Ermakova, Tatiana Sveklina, Elizaveta Antonova, Marina Mayevskaya, Natalia Voloshina, Sindeep Bhana, Nazeer Chopdat, Matthys Basson, Bilal Bobat, Naayil Rajabally, Soritha Coetzer, Jacob George, Martin Weltman, Marno Ryan, Marie Sinclair, Leon Adams, Damian Harding, Oyekoya Ayonrinde, Scott Davison, John Bate, Natalie Funakoshi, Akash Shukla, Shrikant Mukewar, Sandeep Gupta, Mukesh Kalla, Samir Shah, Shiv Sarin, Shalimar, Rajiv Mehta, Kiran Singh, Mukesh Jain, Ajay Duseja, Vandana Midha, Bailuru Tantry, Dharmesh Kapoor, Paturi Rao, Narendra Choudhary, Rakesh Sahay, Parshottam Koradia, Wah Kheong Chan, Soek Siam Tan, Yeong Yeh Lee, Won Kim, Ji Hoon Kim, Won Young Tak, Hyung Joon Kim, Byoung Kuk Jang, Moon Young Kim, SangGyune Kim, Jun Yong Park, Jung Gil Park, Kojiro Mori, Norihisa Nishimura, Atsushi Naganuma, Tsuguru Hayashi, Taku Nakamasu, Shigetoshi Fujiyama, Yoshito Itoh, Hirofumi Kogure, Kazuhito Kawata, Takuya Nagano, Teruki Miyake, Tsunamasa Watanabe, Masataka Seike, Masanori Kawaguchi, Nami Mori, Masataka Tsuge, Michihiro Nonaka, Taku Sanada, Miwa Kawanaka, Takuma Nakatsuka, Jun Arai, Keizo Anzai, Hirayuki Enomoto, Shiro Takami, Masaru Baba, Hideki Fujii, Seiichi Mawatari, Norio Akuta, Toshihide Shima, Takuya Genda, Hayato Hikita, Nobuharu Tamaki, Tomomi Kogiso, Eishiro Mizukoshi, Kenichi Ikejima, Masato Yoneda, Naoki Hiramatsu, Hideki Hayashi, Yuichi Koshiyama, Atsushi Ishino, Jidong Jia, Lai Wei, Jing Zhang, Huiying Rao, Wen Xie, Jie Xu, Qing Xie, Yuemin Nan, Junqi Niu, Xuan An, Youwen Tan, Yongjian Zhou, Yimin Mao, Hong Deng, Jinlin Hou, Tao Han, Lixian Wu, Yongning Xin, Xuebing Yan, Minghua Zheng, Liang Xu, Guojun Li, Guoxin Hu, Guan Yujuan, Hong Wang, Wenjia Liu, Bihui Zhong, Zhang Zheng, Bai Lang, Sikui Wang, Yanbo Zhen, Xiaoping Wu, Chun-Jen Liu, Yi-Hsiang Huang, Jui-Ting Hu, Chi-Yi Chen, Pin-Nan Cheng, Ming-Lung Yu, Chun-Chao Chang, Cheng-Yuan Peng, Chia-Chi Wang, Arun Sanyal, Phillip Newsome, Michael Roden, Anna M G Cali, Jørgen Calí Eskildsen, Adel Belloum, Michelle T Long,
Collapse
|
|
12
|
Zargar AH, Bhansali A, Majumdar A, Maheshwari A, Bhattacharyya A, Dasgupta A, Saboo BD, Sethi BK, Sanyal D, Seshadri KG, Deshpande NR, Kapoor N, Lakhani OJ, Talwalkar PG, Kalra P, Mehrotra RN, Sahay RK, Shukla R, Kant S, Das S, Agarwal SC, Phatak SR, G S, Joshi SR, Shaikh SS, Aravind SR, Goswami S, Ghosh S, Panikar VK, Mohan V. Management of metabolic dysfunction-associated steatotic liver disease (MASLD)-An expert consensus statement from Indian diabetologists' perspective. Diabetes Obes Metab 2025; 27 Suppl 4:3-20. [PMID: 40457532 DOI: 10.1111/dom.16496] [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: 01/17/2025] [Revised: 05/12/2025] [Accepted: 05/17/2025] [Indexed: 06/11/2025]
Abstract
In India, the increasing prevalence of diabetes and obesity poses a significant threat towards a surge in the incidence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). Concomitant with the evolving guidelines, there is a need to direct and spread awareness among practicing diabetologists to identify and screen high-risk individuals for MASLD for timely management. Its asymptomatic nature and the evolving guidelines on diagnosis have hindered the precise estimates of MASLD in the high-risk group of individuals in a clinical setting. Therefore, an expert panel of diabetologists from India convened to review, discuss and document the approach towards screening, diagnosis and management of MASLD. Serum biomarkers, simple non-invasive tools and imaging techniques could direct the risk stratification of the patients. Early lifestyle interventions including weight loss and exercise are beneficial. The pharmacological landscape of drugs directed to insulin resistance, lipid metabolism, oxidative stress, inflammation, apoptosis and fibrogenesis pathways for the management of MASLD is expanding. In summary, the consensus statements are expected to serve as a useful guide in the screening and management of MASLD in the region and to direct a well-planned study design that could enhance the scientific value of these statements.
Collapse
Affiliation(s)
| | - Anil Bhansali
- Gini Health, Mohali, India
- Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Anirban Majumdar
- KPC Medical College, Kolkata, India
- The University of Newcastle, Newcastle, New South Wales, Australia
| | - Anuj Maheshwari
- Hind Institute of Medical Sciences, Sitapur, India
- Sri Hari Kamal Diabetes Care & Research Centre, Lucknow, India
| | | | - Arundhati Dasgupta
- Department of Endocrinology, Rudraksh Superspeciality Care Hospital, Siliguri, India
| | | | | | - Debmalya Sanyal
- The University of Newcastle, Newcastle, New South Wales, Australia
- Department of Endocrinology, KPC Medical College, Kolkata, India
- NH Rabindranath Tagore Hospital, Kolkata, India
| | | | | | - Nitin Kapoor
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, India
- Non-Communicable Disease Unit, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | | | | | - Pramila Kalra
- Department of Endocrinology, Ramaiah Medical College & Memorial Hospital, Bengaluru, India
| | | | - Rakesh Kumar Sahay
- Department of Endocrinology, Osmania Medical College & Osmania General Hospital, Hyderabad, India
| | - Rishi Shukla
- Department of Endocrinology, Regency Health, Kanpur, Uttar Pradesh, India
- Centre for Diabetes and Endocrine Diseases, Kanpur, India
| | - Saket Kant
- Max Super-Speciality, Shalimar Bagh and Balaji Action Medical and Cancer Institute, Delhi, India
| | - Sambit Das
- Department of Endocrinology, Kalinga Institute of Medical Sciences, Kalinga Institute of Industrial Technology University, Bhubaneswar, India
| | - Sanjay Chunilal Agarwal
- Dr Sanjay Agarwal's Aegle Clinic for Diabetes Care, Pune, India
- Department of Internal Medicine, Ruby Hall Clinic, Pune, India
- Diabetes & Medicine, Jehangir Hospital and Apollo Group of Hospitals, Pune, India
| | | | - Shanmugasundar G
- Magna Centres for Diabetes, Obesity and Endocrinology, Chennai, India
| | | | | | | | - Soumik Goswami
- Department of Endocrinology, NRS Medical College, Kolkata, India
| | - Sujoy Ghosh
- Department of Endocrinology, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Vijay Kumar Panikar
- Department of Endocrinology and Diabetes, Lilavati Hospital and Research Centre, Mumbai, India
- Dr. Panikar's Speciality Care Centres, Mumbai, India
| | - Viswanathan Mohan
- Madras Diabetes Research Foundation (ICMR-Collaborating Centre of Excellence) & Dr. Mohan's Diabetes Specialities Centre (IDF Centre of Excellence in Diabetes Care), Chennai, India
| |
Collapse
|
|
13
|
Holst JJ, Rosenkilde MM. Oxyntomodulin - past, present and future. Peptides 2025; 188:171393. [PMID: 40187415 DOI: 10.1016/j.peptides.2025.171393] [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: 02/17/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 04/07/2025]
Abstract
Almost since its discovery, glucagon was suspected to be formed in the gastrointestinal tract, and the L-cells were shown to contain glucagon-like immunoreactivity. This was due to the presence of two peptides that both contained the full glucagon sequence:glicentin of 69 amino acids and oxyntomodulin of 37 amino acids. While glicentin is a part of the glucagon precursor, proglucagon, and probably is inactive, oxyntomodulin, a fragment of glicentin, interacts although weakly with the glucagon as well as the GLP-1 receptor. However, in agreement with these activities, oxyntomodulin inhibited appetite and food intake in humans and inspired development of long acting, potent glucagon-GLP-1 co-agonists. Several such co-agonists are currently in clinical development and show promise because they combine GLP-1 like activities with those of glucagon agonism: additive weight loss and a stimulation of hepatic lipid metabolism with unique effectiveness on hepatic steatosis. They may therefore be effective in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD).
Collapse
Affiliation(s)
- Jens Juul Holst
- The NovoNordisk Foundation Center for Basic Metabolic Research, Denmark; Department of Biomedical Sciences, the Panum institute, University of Copenhagen, Denmark.
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, the Panum institute, University of Copenhagen, Denmark.
| |
Collapse
|
|
14
|
Li G, Wong VWS, Chan RSM, Sin DMC, Chu W, Wong V, Cheung C, Lam S, Lin H, Yeung S, Li TCM, Ho THY, Wong GLH, Yip TCF, Lui GCY. Lifestyle modification programme for people living with HIV with metabolic dysfunction-associated steatotic liver disease: a randomised controlled trial. Lancet HIV 2025; 12:e416-e427. [PMID: 40347962 DOI: 10.1016/s2352-3018(25)00032-3] [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] [Received: 11/26/2024] [Revised: 01/26/2025] [Accepted: 01/27/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease among people living with HIV, and preliminary evidence shows that lifestyle modification can reduce liver fat in people living with HIV with MASLD. We aimed to assess a dietitian-led lifestyle modification programme in inducing resolution of MASLD in this population. METHODS In this single-blind, randomised controlled trial at the Prince of Wales Hospital, Hong Kong, people living with HIV with fatty liver defined by intrahepatic triglyceride content ≥5% on proton magnetic resonance spectroscopy (1H-MRS) were enrolled if they were aged 18 years or older, were on antiretroviral therapy, and had HIV RNA of ≤50 copies per mL for 6 months or longer. Participants were randomly assigned (1:1) to either receive a dietitian-led lifestyle modification programme or standard care for 12 months. Randomisation was performed using computer-generated random numbers in blocks of 4 stratified by presence or absence of diabetes. The primary outcome, assessed in the intention-to-treat population, was resolution of MASLD, defined as intrahepatic triglyceride content less than 5% at month 12, measured by 1H-MRS. This trial was registered with ClinicalTrials.gov, NCT03913351, and is completed. FINDINGS From May 21, 2019, to March 22, 2022, 203 people were screened for eligibility, of whom 84 were randomly assigned to either the lifestyle modification programme (n=43) or standard care (n=41). 74 (88%) participants were male and ten (12%) were female. 78 participants completed all assessments during the 12-month intervention. In the intention-to-treat analysis, 12 (28%) participants in the intervention group and four (10%) in the control group had resolution of MASLD (p=0·040 adjusted for baseline diabetes status). No deaths were reported during the follow-up period. One serious adverse event (hospitalisation due to cellulitis) was reported in the control group. The occurrence of adverse events was similar in the intervention and control groups. The majority of adverse events were of mild severity, and none were considered to be related to study intervention. INTERPRETATION Our findings suggest that a lifestyle modification programme could be a routine behavioural strategy to improve a range of health outcomes in people living with HIV with MASLD. FUNDING Health and Medical Research Fund from the Health Bureau, Hong Kong Special Administrative Region. TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
Collapse
Affiliation(s)
- Guanlin Li
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Ruth Suk-Mei Chan
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Daisy Man-Ching Sin
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Winnie Chu
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Vivian Wong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Catherine Cheung
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Shirley Lam
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Huapeng Lin
- Department of Gastroenterology and Hepatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Center for Digestive Diseases Research and Clinical Translation of Shanghai Jiao Tong University, Shanghai, China
| | - Suey Yeung
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Timothy Chun-Man Li
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Tracy Hang-Yee Ho
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Grace Lai-Hung Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Grace Chung-Yan Lui
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; SH Ho Research Centre for Infectious Diseases, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
| |
Collapse
|
|
15
|
Kim JH, Lee Y, Nam CM, Kwon YJ, Lee JW. Impact of cardiometabolic risk factors for metabolic dysfunction-associated steatotic liver disease on mortality. Nutr Metab Cardiovasc Dis 2025; 35:103965. [PMID: 40187915 DOI: 10.1016/j.numecd.2025.103965] [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: 11/16/2024] [Revised: 02/14/2025] [Accepted: 02/25/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND AND AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) is a potential independent risk factor for cardiovascular disease (CVD)-associated and all-cause mortalities as they share common risk factors. We investigated the association between cardiometabolic risk factors for MASLD and CVD-associated and all-cause mortality risks in middle-aged and older Korean adults. METHODS AND RESULTS We used data from the Korean Genome and Epidemiology Study, a population-based prospective cohort study. Five cardiometabolic risk factors were assessed. MASLD was defined as liver steatosis with a fatty liver index (FLI) ≥60 and at least one cardiometabolic risk factor. The non-MASLD group included individuals with a FLI <60 or FLI ≥60 without cardiometabolic risk factors. The primary outcomes were CVD-associated and all-cause mortalities. Cox proportional hazard models were used to evaluate the association between cardiometabolic risk factors for MASLD and mortalities, adjusting for covariates. Multivariable Cox regression analysis revealed that the MASLD group had increased CVD-associated and all-cause mortality risks compared to the non-MASLD group. The presence of three or more and one or more cardiometabolic risk factors significantly increased the CVD-associated and all-cause mortality rate, respectively. The combination of hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and high glucose concentrations significantly increased both CVD-associated (hazard ratio [HR] 3.64; 95 % confidence interval [CI] 1.44-9.22; p = 0.006) and all-cause (HR 4.57; 95 % CI: 1.74-12.05; p = 0.002) mortality risks. CONCLUSION Cardiometabolic risk factors for MASLD are strongly associated with higher CVD-associated and all-cause mortality risks, highlighting the need to manage hypertriglyceridemia, low HDL-C, and high glucose concentrations.
Collapse
Affiliation(s)
- Jung-Hwan Kim
- Department of Family Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Yaeji Lee
- Department of Biostatistics and Computing, Yonsei University, Seoul, 03722, Republic of Korea
| | - Chung-Mo Nam
- Department of Health Informatics and Biostatistics, Graduate School of Public Health, Yonsei University, Seoul, 03722, Republic of Korea
| | - Yu-Jin Kwon
- Department of Family Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, 16995, Republic of Korea.
| | - Ji-Won Lee
- Department of Family Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Institute for Innovation in Digital Healthcare, Yonsei University, Seoul, 03722, Republic of Korea.
| |
Collapse
|
|
16
|
Nishimura T, Tada T, Akita T, Kondo R, Suzuki Y, Imajo K, Kokubu S, Abe T, Kuroda H, Hirooka M, Hiasa Y, Nogami A, Nakajima A, Ogawa S, Toyoda H, Oeda S, Takahashi H, Eguchi Y, Sugimoto K, Yano H, Tanaka J, Moriyasu F, Kage M, Kumada T, Iijima H. Diagnostic performance of attenuation imaging versus controlled attenuation parameter for hepatic steatosis with MRI-based proton density fat fraction as the reference standard: a prospective multicenter study. J Gastroenterol 2025; 60:727-737. [PMID: 39992415 PMCID: PMC12095409 DOI: 10.1007/s00535-025-02224-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/02/2025] [Indexed: 02/25/2025]
Abstract
BACKGROUND Attenuation Imaging (ATI) and controlled attenuation parameter (CAP) are non-invasive ultrasound-based methods for diagnosing hepatic steatosis. However, reports on the clinical usefulness of ATI are limited. We aimed to compare the ability of ATI and CAP to diagnose hepatic steatosis with magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) as the reference standard. METHODS We performed a prospective multicenter study of 562 patients with chronic liver disease who underwent ATI, CAP, and MRI-PDFF. Patients with skin-to-liver capsule distance (SCD) ≤ 25 mm underwent CAP with an M probe; those with SCD > 25 mm underwent CAP with an XL probe. MRI-PDFF was used as the reference standard: S0 corresponds to MRI-PDFF < 5.2%, S1 to 5.2% ≤ MRI-PDFF < 11.3%, S2 to 11.3% ≤ MRI-PDFF < 17.1%, and S3 to MRI-PDFF ≥ 17.1%. RESULTS The correlation coefficients for ATI and MRI-PDFF stratified by body mass index (< 30, ≥ 30 kg/m2), SCD (< 25, ≥ 25 mm), 2-dimensional share wave elastography (< 1.8 m/s), fibrosis-4 index (≤ 2.67), albumin-bilirubin score (< - 2.60) and type IV collagen 7 s (< 5.0 ng/ml) were significantly higher than those for CAP and MRI-PDFF. Areas under the receiver operating characteristics (95% CI) for ATI and CAP were 0.895 (0.869-0.922) and 0.845 (0.809-0.881) for ≥ S1 steatosis, 0.944 (0.926-0.963) and 0.881(0.852-0.910) for ≥ S2 steatosis, and 0.928 (95% CI 0.906-0.950) and 0.860 (95% CI 0.829-0.890) for S3 steatosis. ATI had higher diagnostic performance for all hepatic steatosis grades than CAP. CONCLUSIONS ATI is a more useful non-invasive method for diagnosing hepatic steatosis than CAP.
Collapse
Affiliation(s)
- Takashi Nishimura
- Division of Hepatobiliary and Pancreatic Disease, Department of Gastroenterology, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Japan
- Ultrasound Imaging Center, Hyogo Medical University Hospital, Nishinomiya, Japan
| | - Toshifumi Tada
- Department of Internal Medicine, Japanease Red Cross Himeji Hospital, Himeji, Japan
| | - Tomoyuki Akita
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Reiichiro Kondo
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Yasuaki Suzuki
- Department of Gastroenterology, Nayoro City General Hospital, Nayoro, Japan
| | - Kento Imajo
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Gastroenterology, Shin-Yurigaoka General Hospital, Kawasaki, Japan
| | - Shigehiro Kokubu
- Department of Gastroenterology, Shin-Yurigaoka General Hospital, Kawasaki, Japan
| | - Tamami Abe
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
| | - Hidekatsu Kuroda
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Asako Nogami
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Sadanobu Ogawa
- Department of Clinical Research, Ogaki Municipal Hospital, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Satoshi Oeda
- Liver Center, Saga Medical School, Saga University, Saga, Japan
- Department of Laboratory Medicine, Saga University Hospital, Saga, Japan
| | | | - Yuichiro Eguchi
- Liver Center, Saga Medical School, Saga University, Saga, Japan
| | - Katsutoshi Sugimoto
- Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Fuminori Moriyasu
- Department of Gastroenterology and Hepatology, International University of Health and Welfare, Sanno Hospital, Tokyo, Japan
| | - Masayoshi Kage
- Center for Innovative Cancer Therapy, Kurume University Research, Kurume, Japan
| | - Takashi Kumada
- Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Hiroko Iijima
- Division of Hepatobiliary and Pancreatic Disease, Department of Gastroenterology, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Japan.
- Ultrasound Imaging Center, Hyogo Medical University Hospital, Nishinomiya, Japan.
| |
Collapse
|
|
17
|
Marti-Aguado D, Carot-Sierra JM, Villalba-Ortiz A, Siddiqi H, Vallejo-Vigo RM, Lara-Romero C, Martín-Fernández M, Fernández-Patón M, Alfaro-Cervello C, Crespo A, Coello E, Merino-Murgui V, Madamba E, Benlloch S, Pérez-Rojas J, Puglia V, Ferrández A, Aguilera V, Monton C, Escudero-García D, Lluch P, Aller R, Loomba R, Romero-Gomez M, Marti-Bonmati L. Identification of Candidates for MASLD Treatment With Indeterminate Vibration-Controlled Transient Elastography. Clin Gastroenterol Hepatol 2025; 23:1183-1193.e5. [PMID: 39551253 DOI: 10.1016/j.cgh.2024.10.014] [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: 07/18/2024] [Revised: 09/15/2024] [Accepted: 10/09/2024] [Indexed: 11/19/2024]
Abstract
BACKGROUND AND AIMS A noteworthy proportion of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) have an indeterminate vibration-controlled transient elastography (VCTE). Among these patients, we aimed to identify candidates for MASLD treatment by diagnosing significant fibrosis. METHODS This was a real-world prospective study including a large dataset of MASLD patients with paired VCTE and liver biopsy from 6 centers. A total of 1196 patients were recruited and divided in training (3 centers, Spain), internal validation (2 centers, Spain), and external validation (1 center, United States) cohorts. In patients with indeterminate liver stiffness measurement (LSM) (8-12 kPa), a diagnostic algorithm was developed to identify significant fibrosis, defined as histological stage ≥F2. Statistical analysis was performed using Gaussian mixture model (GMM) and k-means unsupervised clusterization. RESULTS From the eligible population, 33%, 29%, and 31% had indeterminate VCTE in the training, internal and external validation samples, respectively. The controlled attenuation parameter allowed the differentiation of GMM clusters with a cutoff of 280 dB/m (area under the curve, 0.89; 95% confidence interval, 0.86-0.97). Within patients with <280 dB/m, a LSM between 8.0-9.0 kPa showed a 93% sensitivity and a 91% negative predictive value to exclude significant fibrosis. Among patients with ≥280 dB/m, a LSM between 10.3 and 12.0 kPa diagnosed significant fibrosis with a 91% specificity. Applying this algorithm to the validation cohorts, 36% of the indeterminate VCTE were reallocated. The reallocated high-risk group showed a prevalence of 86% significant fibrosis, opening the therapeutic window for MASLD patients. CONCLUSIONS To identify candidates for MASLD treatment among indeterminate VCTE, an algorithm-based on the sequential combination of LSM and controlled attenuation parameter thresholds can optimize the diagnosis of moderate-to-advanced fibrosis.
Collapse
Affiliation(s)
- David Marti-Aguado
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain; Biomedical Imaging Research Group (GIBI2(30)), La Fe Health Research Institute, Valencia, Spain; Imaging La Fe Node, Distributed Network for Biomedical Imaging Unique Scientific and Technical Infrastructures, Valencia, Spain.
| | - José Miguel Carot-Sierra
- Department of Applied Statistics, Operations Research and Quality, Universitat Politècnica de València, Valencia, Spain
| | - Aida Villalba-Ortiz
- Department of Applied Statistics, Operations Research and Quality, Universitat Politècnica de València, Valencia, Spain
| | - Harris Siddiqi
- MASLD Research Center, Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Rose Marie Vallejo-Vigo
- Digestive Diseases Department, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Virgen del Rocío University Hospital, Institute of Biomedicine of Seville, Department of Medicine, University of Seville, Seville, Spain
| | - Carmen Lara-Romero
- Digestive Diseases Department, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Virgen del Rocío University Hospital, Institute of Biomedicine of Seville, Department of Medicine, University of Seville, Seville, Spain
| | - Marta Martín-Fernández
- Department of Cell Biology, Genetics, Histology and Pharmacology, University of Valladolid, Valladolid, Spain; BioCritic, Group for Biomedical Research in Critical Care Medicine, Valladolid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
| | - Matías Fernández-Patón
- Biomedical Imaging Research Group (GIBI2(30)), La Fe Health Research Institute, Valencia, Spain; Imaging La Fe Node, Distributed Network for Biomedical Imaging Unique Scientific and Technical Infrastructures, Valencia, Spain
| | - Clara Alfaro-Cervello
- Pathology Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain; Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Ana Crespo
- Digestive Disease Department, Hospital Arnau de Vilanova, Valencia, Spain
| | - Elena Coello
- Digestive Disease Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Víctor Merino-Murgui
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain
| | - Egbert Madamba
- MASLD Research Center, Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Salvador Benlloch
- Digestive Disease Department, Hospital Arnau de Vilanova, Valencia, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - Judith Pérez-Rojas
- Pathology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Víctor Puglia
- Pathology Department, Hospital Arnau de Vilanova, Valencia, Spain
| | - Antonio Ferrández
- Pathology Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain; Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Victoria Aguilera
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Hepatology and Liver Transplantation Unit, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Cristina Monton
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain
| | - Desamparados Escudero-García
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain; Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Paloma Lluch
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain; Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Rocío Aller
- BioCritic, Group for Biomedical Research in Critical Care Medicine, Valladolid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Department of Medicine, Dermatology and Toxicology, Universidad de Valladolid, Valladolid, Spain; Gastroenterology Unit, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
| | - Rohit Loomba
- MASLD Research Center, Division of Gastroenterology, University of California San Diego, La Jolla, California; Division of Gastroenterology and Hepatology, University of California San Diego, La Jolla, California
| | - Manuel Romero-Gomez
- Digestive Diseases Department, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Virgen del Rocío University Hospital, Institute of Biomedicine of Seville, Department of Medicine, University of Seville, Seville, Spain; University of Seville, Seville, Spain
| | - Luis Marti-Bonmati
- Biomedical Imaging Research Group (GIBI2(30)), La Fe Health Research Institute, Valencia, Spain; Imaging La Fe Node, Distributed Network for Biomedical Imaging Unique Scientific and Technical Infrastructures, Valencia, Spain; Radiology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| |
Collapse
|
|
18
|
Chen VL, Morgan TR, Rotman Y, Patton HM, Cusi K, Kanwal F, Kim WR. Reply: AASLD Resmetirom Guidance. Hepatology 2025; 81:E164-E165. [PMID: 39951255 DOI: 10.1097/hep.0000000000001267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 01/28/2025] [Indexed: 05/20/2025]
Affiliation(s)
- Vincent L Chen
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Timothy R Morgan
- VA Long Beach Healthcare System, Long Beach, California, USA
- Department of Medicine, Division of Gastroenterology, University of California Irvine, Irvine, California, USA
| | - Yaron Rotman
- Liver and Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Heather M Patton
- VA San Diego Healthcare System, San Diego, California, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, San Diego, California, USA
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes, and Metabolism, University of Florida, Gainesville, Florida, USA
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- VA Health Services Research and Development Service, Center for Innovations in Quality, Effectiveness, and Safety, Houston, Texas, USA
- Michael E DeBakey VA Medical Center, Houston, Texas, USA
| | - W Ray Kim
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Phoenix, Arizona, USA
| |
Collapse
|
|
19
|
Abdollahi S, Lotfi AS, Saravani R, Taheri H. An association study of SERPINA1 gene polymorphisms with the risk of metabolic dysfunction-associated steatotic liver disease In an Iranian population: A preliminary case-control study. Biochem Biophys Rep 2025; 42:101974. [PMID: 40176953 PMCID: PMC11964567 DOI: 10.1016/j.bbrep.2025.101974] [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: 11/06/2024] [Revised: 03/02/2025] [Accepted: 03/06/2025] [Indexed: 04/05/2025] Open
Abstract
Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a type of fat accumulation in the liver that can lead to cirrhosis and chronic liver disease. MASLD is recognized as the most frequent of liver-associated deaths worldwide. The SERPINA1 gene encodes a serine protease protein that plays a pivotal role in the pathogenesis of liver deficiencies. In this study, we aimed to evaluate the genetic association between rs6647 (M1), rs709932 (M2), and rs1303 (M3) variants in the SERPINA1 gene and the risk of MASLD in an Iranian population. Methods In this case-control study, 120 patients affected by MASLD and 120 healthy subjects participated. The Nephelometry system measured serum levels of α1-antitrypsin (A1AT). Biochemical tests were conducted to assess serum levels of blood parameters using commercially available kits. DNA extraction was performed using the salting-out method, followed by the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method for genotyping. Statistical analysis was performed by SPSS v16.0. Results The findings showed that the rs6647 G allele significantly increased the risk of MASLD. The G allele in codominant, dominant, and over-dominant models caused an increase in the risk of MASLD. Additionally, the rs709932 T allele was more frequent among patients compared to healthy subjects and significantly enhanced the risk of MASLD. The T allele in the codominant and recessive models indicated a high risk for MASLD in our population. The G allele of rs1303 caused an enhancement in the mean serum levels of A1AT in the MASLD group. Conclusions Our results show an association between SERPINA1 gene variants and the risk of MASLD. The rs6647 (M1) and rs709932 (M2) variants of the SERPINA1 gene increased the risk of disorder in our population.
Collapse
Affiliation(s)
- Samira Abdollahi
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Abbas Sahebghadam Lotfi
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Ramin Saravani
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Clinical Biochemistry, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Hamed Taheri
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Internal Medicine, Ali-Ibn-Abitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, Iran
| |
Collapse
|
|
20
|
Hakim A, Lin KH, Schwantes-An TH, Abreu M, Tan J, Guo X, Yates KP, Lotta L, Verweij N, Loomba R, Kleiner DE, Schwimmer JB, Rotter JI, Chalasani NP. A comprehensive evaluation of candidate genetic polymorphisms in a large histologically characterized MASLD cohort using a novel framework. Hepatol Commun 2025; 9:e0728. [PMID: 40434633 PMCID: PMC12122170 DOI: 10.1097/hc9.0000000000000728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Accepted: 03/16/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND There is a substantial heritable component to metabolic dysfunction-associated steatotic liver disease (MASLD), and several genetic variants that promote MASLD development or associate with its severity have been reported. These associations vary in terms of their effect size and degree of replication. METHODS We developed a framework to classify previously identified MASLD genetic polymorphisms into 4 tiers based on effect size and extent of replication in the literature. We tested the association between "tier 1" single-nucleotide polymorphisms (OR ≥1.5, replicated in >2 independent studies) and biopsy measures of MASLD severity in a large, well-characterized histologic cohort of MASLD patients (n=3094). RESULTS Across 19 "tier 1" variants reflecting 11 genetic loci, only those in the PNPLA3-SAMM50-PARVB locus showed significant associations with biopsy-proven fibrosis severity and NAFLD activity score; the highest risk was for the rs738409 p.I148M variant in PNPLA3. A genetic risk score based on "tier 1" variants, as well as a previously developed genetic risk score based on variants in PNPLA3, TM6SF2, and HSD17B13, were both associated with fibrosis and NAFLD activity score, but these results were driven entirely by PNPLA3 rs738409. CONCLUSIONS Our study provides a framework to prioritize evaluation of genetic polymorphisms for future replication efforts and demonstrates that in a large case-only cohort, histologic severity of MASLD is only robustly associated with the presence of variation in PNPLA3 among known candidate genes. These findings may have implications for patient risk stratification based on the presence of PNPLA3 rs738409.
Collapse
Affiliation(s)
- Aaron Hakim
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Kung-Hung Lin
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Tae-Hwi Schwantes-An
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Marco Abreu
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jingyi Tan
- Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Xiuqing Guo
- Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Katherine P. Yates
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Luca Lotta
- Regeneron Genetics Center, Tarrytown, New York, USA
| | - Niek Verweij
- Regeneron Genetics Center, Tarrytown, New York, USA
| | - Rohit Loomba
- Department of Family Medicine and Public Health, Division of Epidemiology, University of California at San Diego, San Diego, California, USA
| | - David E. Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA
| | - Jeffrey B. Schwimmer
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California, San Diego School of Medicine, La Jolla, California, USA
| | - Jerome I. Rotter
- Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Naga P. Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| |
Collapse
|
|
21
|
Laine S, Sjöros T, Garthwaite T, Honka MJ, Löyttyniemi E, Norha J, Eskola O, Koivumäki M, Vähä-Ypyä H, Sievänen H, Vasankari T, Hirvonen J, Laitinen K, Houttu N, Kalliokoski KK, Saunavaara V, Knuuti J, Heinonen IHA. Effects of reducing sedentary behavior on liver insulin sensitivity, liver fat content, and liver enzyme levels: a six-month randomized controlled trial. Am J Physiol Endocrinol Metab 2025; 328:E756-E771. [PMID: 40244864 DOI: 10.1152/ajpendo.00446.2024] [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: 11/06/2024] [Revised: 11/26/2024] [Accepted: 03/31/2025] [Indexed: 04/19/2025]
Abstract
Metabolic syndrome increases the risk of developing noncommunicable diseases such as metabolic dysfunction-associated steatotic liver disease. The aim was to investigate the effects of sedentary behavior (SB) reduction on liver glucose uptake (LGU), endogenous glucose production (EGP), liver fat content (LFC), and liver enzyme levels [alanine aminotransferase (ALT), aspartate aminotransferase, and γ-glutamyltransferase]. Forty-four sedentary (daily SB time ≥ 10 h), physically inactive middle-aged adults with metabolic syndrome were randomized into intervention (INT; n = 23, 21 completed) and control (CON; n = 21, 19 completed) groups. For 6 mo, INT aimed to limit SB by 1 h/day, whereas CON aimed to maintain usual habits. SB and physical activity (PA) were measured continuously with hip-worn accelerometers. Before and at the end of the intervention, LGU was measured using positron emission tomography during the hyperinsulinemic-euglycemic clamp. EGP was calculated, and LFC was measured by magnetic resonance spectroscopy. INT reduced SB by 51 [95% confidence interval (CI): 22, 78] min/day and increased moderate-to-vigorous physical activity (MVPA) by 22 (95% CI: 12, 33) min/day, with no significant change in CON. Differences in liver health markers between the groups were not significant. However, according to the exploratory analyses among participants who successfully reduced SB, ALT decreased (-1.1 [95% CI: 0.93, 1.36] U/L) compared with the continuously sedentary participants (+0.8 [95% CI: 0.65, 1.05] U/L) (group × time, P = 0.006). To enhance liver health, reducing SB for longer durations and/or increasing the intensity of PA may be necessary. However, successfully reducing SB may lead to better levels of circulating ALT liver enzymes.NEW & NOTEWORTHY Aiming to reduce sedentary behavior (SB) by 1 h/day did not significantly influence liver health markers, suggesting that more substantial reductions or a different approach might be necessary to see improvements. However, achieving the desired behavioral change could lead to improvements in ALT levels. This study is the first to analyze how reducing SB and replacing it with nonguided physical activity impacts liver health in adults with metabolic syndrome, offering insights for future intervention strategies.
Collapse
Affiliation(s)
- Saara Laine
- Turku PET Centre, University of Turku, Åbo Akademi University, and Turku University Hospital, Turku, Finland
| | - Tanja Sjöros
- Turku PET Centre, University of Turku, Åbo Akademi University, and Turku University Hospital, Turku, Finland
| | - Taru Garthwaite
- Turku PET Centre, University of Turku, Åbo Akademi University, and Turku University Hospital, Turku, Finland
| | - Miikka-Juhani Honka
- Turku PET Centre, University of Turku, Åbo Akademi University, and Turku University Hospital, Turku, Finland
| | - Eliisa Löyttyniemi
- Department of Biostatistics, University of Turku and Turku University Hospital, Turku, Finland
| | - Jooa Norha
- Turku PET Centre, University of Turku, Åbo Akademi University, and Turku University Hospital, Turku, Finland
| | - Olli Eskola
- Turku PET Centre, University of Turku, Åbo Akademi University, and Turku University Hospital, Turku, Finland
| | - Mikko Koivumäki
- Turku PET Centre, University of Turku, Åbo Akademi University, and Turku University Hospital, Turku, Finland
| | - Henri Vähä-Ypyä
- The UKK Institute for Health Promotion Research, Tampere, Finland
| | - Harri Sievänen
- The UKK Institute for Health Promotion Research, Tampere, Finland
| | - Tommi Vasankari
- The UKK Institute for Health Promotion Research, Tampere, Finland
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Jussi Hirvonen
- Department of Radiology, University of Turku and Turku University Hospital, Turku, Finland
| | - Kirsi Laitinen
- Institute of Biomedicine and Nutrition and Food Research Center, University of Turku, Turku, Finland
| | - Noora Houttu
- Institute of Biomedicine and Nutrition and Food Research Center, University of Turku, Turku, Finland
| | - Kari K Kalliokoski
- Turku PET Centre, University of Turku, Åbo Akademi University, and Turku University Hospital, Turku, Finland
| | - Virva Saunavaara
- Turku PET Centre, University of Turku, Åbo Akademi University, and Turku University Hospital, Turku, Finland
- Division of Medical Imaging, Department of Medical Physics, Turku University Hospital, Turku, Finland
| | - Juhani Knuuti
- Turku PET Centre, University of Turku, Åbo Akademi University, and Turku University Hospital, Turku, Finland
| | - Ilkka H A Heinonen
- Turku PET Centre, University of Turku, Åbo Akademi University, and Turku University Hospital, Turku, Finland
| |
Collapse
|
|
22
|
Wu Y, Dong P, Wu Q, Zhang Y, Xu G, Pan C, Tong H. Insights into Clinical Trials for Drugs Targeting MASLD: Progress, Challenges, and Future Directions. Clin Pharmacol Ther 2025; 117:1614-1626. [PMID: 39953659 DOI: 10.1002/cpt.3606] [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: 11/04/2024] [Accepted: 01/29/2025] [Indexed: 02/17/2025]
Abstract
The transition in terminology from fatty liver disease to metabolic dysfunction-associated steatotic liver disease (MASLD) marks a considerable evolution in diagnostic standards. This new definition focuses on liver fat accumulation in the context of overweight/obesity, type 2 diabetes, or metabolic dysfunction, without requiring the exclusion of other concurrent liver diseases. The new definition also provides clear guidelines for defining alcohol consumption in relation to the disease. MASLD is currently acknowledged as the most widespread liver disorder globally, affecting ~25% of the population. Despite the extensive array of clinical trials conducted in recent years, the number of approved treatments for metabolic dysfunction-associated fatty liver disease is very limited. In the review critically evaluates the results of clinical trials of related drugs and assesses the future directions for drug development trials. The renaming of MASLD presents new challenges and opportunities for the design of clinical trials and the selection of target populations for drug development.
Collapse
Affiliation(s)
- Yu Wu
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Pu Dong
- Department of Infectious Diseases, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qifang Wu
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Ya Zhang
- Hepatology Diagnosis and Treatment Center & Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gang Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chenwei Pan
- Department of Infectious Diseases, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Precision General Practice and Health Management, Wenzhou, China
| | - Haibin Tong
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| |
Collapse
|
|
23
|
Caussy C, Vergès B, Leleu D, Duvillard L, Subtil F, Abichou-Klich A, Hervieu V, Milot L, Ségrestin B, Bin S, Rouland A, Delaunay D, Morcel P, Hadjadj S, Primot C, Petit JM, Charrière S, Moulin P, Levrero M, Cariou B, Disse E. Screening for Metabolic Dysfunction-Associated Steatotic Liver Disease-Related Advanced Fibrosis in Diabetology: A Prospective Multicenter Study. Diabetes Care 2025; 48:877-886. [PMID: 39887699 DOI: 10.2337/dc24-2075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 12/31/2024] [Indexed: 02/01/2025]
Abstract
OBJECTIVE Screening for advanced fibrosis (AF) resulting from metabolic dysfunction-associated steatotic liver disease (MASLD) is recommended in diabetology. This study aimed to compare the performance of noninvasive tests (NITs) with that of two-step algorithms for detecting patients at high risk of AF requiring referral to hepatologists. RESEARCH DESIGN AND METHODS We conducted a planned interim analysis of a prospective multicenter study including participants with type 2 diabetes and/or obesity and MASLD with comprehensive liver assessment comprising blood-based NITs, vibration-controlled transient elastography (VCTE), and two-dimensional shear-wave elastography (2D-SWE). AF risk stratification was determined by a composite criterion of liver biopsy, magnetic resonance elastography, or VCTE ≥12 kPa depending on availability. RESULTS Of 654 patients (87% with type 2 diabetes, 56% male, 74% with obesity), 17.6% had an intermediate/high risk of AF, and 9.3% had a high risk of AF. The area under the empirical receiver operating characteristic curves of NITs for detection of high risk of AF were as follows: fibrosis-4 index (FIB-4) score, 0.78 (95% CI 0.72-0.84); FibroMeter, 0.74 (0.66-0.83); FibroTest, 0.78 (0.72-0.85); Enhanced Liver Fibrosis (ELF) test, 0.82 (0.76-0.87); and SWE, 0.84 (0.78-0.89). Algorithms with FIB-4 score/VCTE showed good diagnostic performance for referral of patients at intermediate/high risk of AF to specialized care in hepatology. An alternative FIB-4 score/ELF test strategy showed a high negative predictive value (NPV; 88-89%) and a lower positive predictive value (PPV; 39-46%) at a threshold of 9.8. The FIB-4 score/2D-SWE strategy had an NPV of 91% and a PPV of 58-62%. The age-adapted FIB-4 score threshold resulted in lower NPVs and PPVs in all algorithms. CONCLUSIONS The FIB-4 score/VCTE algorithm showed excellent diagnostic performance, demonstrating its applicability for routine screening in diabetology. The ELF test using an adapted low threshold at 9.8 may be used as an alternative to VCTE.
Collapse
Affiliation(s)
- Cyrielle Caussy
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
- CarMeN Laboratory, INSERM U1060, INRA U1397, Institut National des Sciences Appliquées de Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France
- Institut d'Hépatologie de Lyon, Lyon, France
| | - Bruno Vergès
- Department of Endocrinology, Diabetes and Metabolic Disorders, INSERM Unit, Lipides, Nutrition, Cancer (LNC) UMR 1231, Dijon University Hospital, University of Burgundy, Dijon, France
| | - Damien Leleu
- Department of Biochemistry, INSERM Unit, LNC-UMR 1231, Dijon University Hospital, University of Burgundy, Dijon, France
| | - Laurence Duvillard
- Department of Biochemistry, INSERM Unit, LNC-UMR 1231, Dijon University Hospital, University of Burgundy, Dijon, France
| | - Fabien Subtil
- Hospices Civils de Lyon, Service de Biostatistique, Lyon, France
- UMR 5558, CNRS, Université Claude Bernard Lyon 1, Villeurbanne, France
| | - Amna Abichou-Klich
- Hospices Civils de Lyon, Service de Biostatistique, Lyon, France
- UMR 5558, CNRS, Université Claude Bernard Lyon 1, Villeurbanne, France
| | - Valérie Hervieu
- Biopathology of Tumors, Groupement Hospitalier Est (GHE) Hospital, Hospices Civils de Lyon, Bron, France
| | - Laurent Milot
- Service de Radiologie, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Bérénice Ségrestin
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
| | - Sylvie Bin
- Service Recherche et Epidémiologie Cliniques, Pôle de Santé Publique, Hospices Civils de Lyon, Lyon, France
| | - Alexia Rouland
- Department of Endocrinology, Diabetes and Metabolic Disorders, INSERM Unit, Lipides, Nutrition, Cancer (LNC) UMR 1231, Dijon University Hospital, University of Burgundy, Dijon, France
| | - Dominique Delaunay
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
| | - Pierre Morcel
- L'Institut du Thorax, INSERM, CNRS, CHU Nantes, Nantes Université, Nantes, France
| | - Samy Hadjadj
- L'Institut du Thorax, INSERM, CNRS, CHU Nantes, Nantes Université, Nantes, France
| | - Claire Primot
- L'Institut du Thorax, INSERM, CNRS, CHU Nantes, Nantes Université, Nantes, France
| | - Jean-Michel Petit
- Department of Endocrinology, Diabetes and Metabolic Disorders, INSERM Unit, Lipides, Nutrition, Cancer (LNC) UMR 1231, Dijon University Hospital, University of Burgundy, Dijon, France
| | - Sybil Charrière
- CarMeN Laboratory, INSERM U1060, INRA U1397, Institut National des Sciences Appliquées de Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France
- Fédération d'Endocrinologie, Diabète et Nutrition, Hôpital Cardiovasculaire, Hospices Civils de Lyon, Bron, France
| | - Philippe Moulin
- CarMeN Laboratory, INSERM U1060, INRA U1397, Institut National des Sciences Appliquées de Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France
- Fédération d'Endocrinologie, Diabète et Nutrition, Hôpital Cardiovasculaire, Hospices Civils de Lyon, Bron, France
| | - Massimo Levrero
- Institut d'Hépatologie de Lyon, Lyon, France
- Service d'Hépatologie, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
- INSERM U1350, UMR PaThLiv, Université Claude Bernard Lyon 1, Lyon, France
| | - Bertrand Cariou
- L'Institut du Thorax, INSERM, CNRS, CHU Nantes, Nantes Université, Nantes, France
| | - Emmanuel Disse
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
- CarMeN Laboratory, INSERM U1060, INRA U1397, Institut National des Sciences Appliquées de Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France
| |
Collapse
|
|
24
|
Barb D, Kalavalapalli S, Godinez Leiva E, Bril F, Huot-Marchand P, Dzen L, Rosenberg JT, Junien JL, Broqua P, Rocha AO, Lomonaco R, Abitbol JL, Cooreman MP, Cusi K. Pan-PPAR agonist lanifibranor improves insulin resistance and hepatic steatosis in patients with T2D and MASLD. J Hepatol 2025; 82:979-991. [PMID: 39824443 DOI: 10.1016/j.jhep.2024.12.045] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 01/20/2025]
Abstract
BACKGROUND & AIMS Lanifibranor is a pan-PPAR agonist that improves glucose/lipid metabolism and reverses steatohepatitis and fibrosis in adults with metabolic dysfunction-associated steatohepatitis (MASH). We tested its effect on insulin resistance (IR) at the level of different target tissues in relation to changes in intrahepatic triglyceride (IHTG) content. METHODS In this single-center phase II study, 38 patients with type 2 diabetes and MASLD were randomized 1:1 to receive lanifibranor 800 mg or placebo for 24 weeks. The primary endpoint was the change in IHTG (1H-MRS). The main prespecified secondary endpoint was the change in hepatic, muscle and adipose tissue insulin sensitivity using the gold-standard euglycemic hyperinsulinemic clamp technique to measure glucose turnover. Other secondary endpoints included changes in cardiometabolic parameters (i.e., HbA1c, lipid profile, adiponectin). RESULTS Lanifibranor significantly lowered IHTG compared to placebo (full analysis set [FAS] -44% vs. -12%, respectively; least squares mean difference -31%, 95% CI -51 to -12%; in completers -50% vs. -16%; both p <0.01). More patients in the lanifibranor group (vs. the placebo group) achieved a ≥30% IHTG reduction (FAS 65% vs. 22%; completers 79% vs. 29%; both p <0.01) and steatosis resolution (FAS 25% vs. 0%; p <0.05). Lanifibranor significantly improved hepatic and peripheral IR (i.e. fasting endogenous [primarily hepatic] glucose production, hepatic IR, and insulin-stimulated muscle glucose disposal or Rd). Secondary metabolic endpoints also improved (fasting glucose, insulin, HOMA-IR, HbA1c, HDL-C), and adiponectin increased 2.4-fold (all p <0.001). Lanifibranor caused modest weight gain (+2.7%). Adverse events were mild (gastrointestinal side effects, hemoglobin decrease) and drug-related treatment-emergent adverse events leading to study discontinuation were balanced between groups. CONCLUSIONS Lanifibranor significantly improves hepatic, muscle and adipose tissue IR. Lanifibranor treatment was safe and effective in reducing hepatic steatosis and cardiometabolic risk factors associated with metabolic dysfunction. IMPACT AND IMPLICATIONS No prior studies have evaluated the effect of lanifibranor on insulin sensitivity at the level of muscle, liver and adipose tissue and its relationship to changes in intrahepatic triglyceride (IHTG) content in insulin-resistant individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes. We observed a significant decrease in IHTG after 24 weeks of treatment (by ∼50%, p <0.001 vs. placebo) that was associated with a major improvement in hepatic and peripheral (Rd) insulin sensitivity, restoration of adipose tissue function and improvement in cardiometabolic risk factors. This study has important clinical implications because it offers proof-of-concept that targeting the key underlying metabolic defects in MASLD (i.e. insulin resistance, lipotoxicity and hyperglycemia) can restore cardiometabolic health. It offers a compelling rationale for lanifibranor treatment in individuals with MASLD, either alone or in combination with weight loss and other treatment strategies. CLINICALTRIALS GOV IDENTIFIER NCT03459079.
Collapse
Affiliation(s)
- Diana Barb
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida, USA
| | - Srilaxmi Kalavalapalli
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida, USA
| | - Eddison Godinez Leiva
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida, USA
| | - Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Lucile Dzen
- Inventiva Pharma, Daix, France, and New York, NY, USA
| | - Jens T Rosenberg
- Advanced Magnetic Resonance Imaging and Spectroscopy Facility, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA
| | | | - Pierre Broqua
- Inventiva Pharma, Daix, France, and New York, NY, USA
| | - Andrea Ortiz Rocha
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida, USA
| | - Romina Lomonaco
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida, USA
| | | | | | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida, USA.
| |
Collapse
|
|
25
|
Xu QY, Ren TY, Zhou YC, Xu J, Du LD, Hong DY, Zhang QR, Chu HK, Peng Z, Fan JG, Jiang L. Prevotella copri-produced 5-aminopentanoic acid promotes pediatric metabolic dysfunction-associated steatotic liver disease. Hepatobiliary Pancreat Dis Int 2025; 24:303-315. [PMID: 40057459 DOI: 10.1016/j.hbpd.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 02/24/2025] [Indexed: 05/03/2025]
Abstract
BACKGROUND Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the causative role and molecular mechanisms of P. copri in pediatric MASLD. METHODS C57BL/6 J mice aged 3 weeks were fed a high-fat diet (HFD) and orally administered with P. copri for 5 weeks. We assessed the key features of MASLD and the gut microbiota profile. By untargeted metabolomics on mouse fecal samples and the supernatant from P. copri culture, we identified P. copri-derived metabolite and tested its effects in vitro. RESULTS In HFD-fed mice, administration of P. copri significantly promoted liver steatosis. Genes associated with inflammation and fibrosis were significantly upregulated in the livers from the HFD + P. copri group compared with those in the livers from the HFD group. In addition, P. copri reduced gut microbial diversity, increased the proportion of Firmicutes and decreased Bacteroidota. Importantly, 5-aminopentanoic acid (5-AVA) was significantly enriched in both mouse feces from the HFD + P. copri group and the culture supernatant of P. copri. In vitro, 5-AVA aggravated palmitic acid-induced lipid accumulation in HepG2 cells and primary mouse hepatocytes. Mechanistically, P. copri-produced 5-AVA exacerbated hepatic steatosis by promoting lipogenesis and fatty acid uptake, while also reducing hepatic very-low-density lipoprotein export. CONCLUSIONS Our findings demonstrated that P. copri promotes liver steatosis in HFD-fed juvenile mice through its metabolite 5-AVA, suggesting its potential as a therapeutic target for the management of pediatric MASLD.
Collapse
Affiliation(s)
- Qing-Yang Xu
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Tian-Yi Ren
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yong-Chang Zhou
- Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Juan Xu
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Lan-Duoduo Du
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Dong-Yang Hong
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Qian-Ren Zhang
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Hui-Kuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhong Peng
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Lu Jiang
- Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China; Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
| |
Collapse
|
|
26
|
Zoncapè M, Tsochatzis EA. Liver Fibrosis Testing in Patients With Type 2 Diabetes: The Time Is Now. Diabetes Care 2025; 48:871-873. [PMID: 40392997 DOI: 10.2337/dci25-0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 05/22/2025]
Affiliation(s)
- Mirko Zoncapè
- Sheila Sherlock Liver Centre, Royal Free Hospital, London, U.K
- UCL Institute of Liver and Digestive Health, University College London, London, U.K
| | - Emmanuel A Tsochatzis
- Sheila Sherlock Liver Centre, Royal Free Hospital, London, U.K
- UCL Institute of Liver and Digestive Health, University College London, London, U.K
| |
Collapse
|
|
27
|
Zhong H, Liu C, Huang Z, Tan P, Chen H, Fu W. Crosstalk between Hepatic Stellate Cells and Hepatic Macrophages in Metabolic Dysfunction-Associated Steatohepatitis. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:1040-1056. [PMID: 40414682 DOI: 10.1016/j.ajpath.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/29/2025] [Accepted: 02/19/2025] [Indexed: 05/27/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease is the most prevalent liver condition worldwide. Its more severe manifestation, metabolic dysfunction-associated steatohepatitis (MASH), is accompanied by distinctive hepatocellular injury and inflammation with fibrosis. The involvement of chronic inflammation and accompanying immune cell activation in the maturation phases of MASH progression, mediated through hepatic stellate cells (HSCs), plays a central role. This review highlights the detailed molecular and cellular mechanisms of MASH, with special attention to the dynamic dialogue between HSCs and hepatic macrophages. This review will help narrow the existing gaps, with a summary of key roles HSCs and hepatic macrophages play within liver immunity to inflammation, discussing critical intercellular communication pathways as well as proposing new venues for research toward a better understanding of MASH pathobiology, which could pave ways toward breakthroughs in the clinical condition.
Collapse
Affiliation(s)
- Haoran Zhong
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Chen Liu
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zhiwei Huang
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Peng Tan
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hao Chen
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China; Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Biliary-Pancreatic Center, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
| | - Wenguang Fu
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China; Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Biliary-Pancreatic Center, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
| |
Collapse
|
|
28
|
Zelber-Sagi S, Schonmann Y, Weinstein G, Yeshua H. Liver Fibrosis Marker FIB-4 Is Associated With Hepatic and Extrahepatic Malignancy Risk in a Population-Based Cohort Study. Liver Int 2025; 45:e70139. [PMID: 40358032 DOI: 10.1111/liv.70139] [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: 01/14/2025] [Revised: 04/08/2025] [Accepted: 05/01/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND AND AIMS An association between Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and the development of extrahepatic malignancies has been demonstrated. However, the association of fibrosis with extrahepatic cancer is unclear. Our study aimed to test the long-term association between liver fibrosis marker and the incidence of hepatic and extrahepatic malignancies. METHODS A retrospective cohort study of a nationally representative sample, following 763 752 adult Clalit health services members without pre-existing liver-related diagnoses or malignancies for 14.67 years. The adjusted association between baseline liver Fibrosis-4 score (FIB-4; FIB-4 ≥ 2.67 indicated presumed advanced fibrosis), assessed from routine laboratory measurements, and incident cancer was assessed through multivariable Cox regression models. RESULTS The study included 763 752 people (mean age 54.3 ± 8.2 years, 43.9% males). Presumed advanced fibrosis was associated with a 16% greater risk for malignancy compared to the risk of those with no fibrosis (hazard ratio (HR) = 1.16; 95% CI, 1.10-1.22), adjusting for age, sex, ethnicity, socioeconomic status, peripherality index, baseline smoking, and obesity. The association of advanced fibrosis with malignancy was stronger when the age-specific FIB-4 cutoff was applied (HR = 1.40; 1.34-1.46) and in a subsample of subjects with MASLD diagnosis at baseline (HR = 1.43; 1.12-1.83). The association remained robust across sex, age, and ethnic groups. Both inconclusive fibrosis and fibrosis were strongly associated with malignancy of the liver or bile ducts [(HR = 1.41; 1.21-1.66) and (HR = 5.66; 4.19-7.64), respectively]. CONCLUSIONS Liver fibrosis score is independently associated with malignancy occurrence and certain types of malignancies, and may serve as an indicator of high-risk cancer in the general population.
Collapse
Affiliation(s)
- Shira Zelber-Sagi
- Faculty of Social Welfare and Health Sciences, School of Public Health, University of Haifa, Haifa, Israel
| | - Yochai Schonmann
- Department of Quality Measurements and Research, Clalit Health Services, Tel Aviv, Israel
- Department of Family Medicine, Clalit Health Services, Tel Aviv, Israel
| | - Galit Weinstein
- Faculty of Social Welfare and Health Sciences, School of Public Health, University of Haifa, Haifa, Israel
| | - Hanny Yeshua
- Department of Family Medicine, Clalit Health Services, Tel Aviv, Israel
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| |
Collapse
|
|
29
|
Díaz LA, Tavaglione F, Mittal N, Bettencourt R, Amangurbanova M, Johnson A, Marti-Aguado D, Tincopa M, Loomba R, Khan-Riches A, Madamba E, Siddiqi H, Richards L, Sirlin CB, Ajmera V, Loomba R. Noninvasive pathway for stratifying fibrosis in suspected metabolic dysfunction and alcohol-associated liver disease (MetALD). Hepatol Commun 2025; 9:e0718. [PMID: 40377491 PMCID: PMC12088636 DOI: 10.1097/hc9.0000000000000718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/13/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND Metabolic dysfunction and alcohol-associated liver disease (MetALD) may increase liver fibrosis progression, but data on screening are scarce. We aimed to assess the performance of noninvasive tests (NITs) for detecting significant fibrosis in individuals with suspected MetALD. METHODS This is a cross-sectional study of prospectively enrolled adults identified as overweight or obese. We included adults with suspected MetALD defined by ≥1 of 5 cardiometabolic criteria and self-reported alcohol use within MetALD ranges or lower self-reported alcohol use but with phosphatidylethanol (PEth) levels ≥25 ng/mL. Clinical assessment included contemporaneous magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE). Significant fibrosis was defined as MRE ≥3.14 kPa (or VCTE ≥7.6 kPa if MRE was missing). Analyses included AUROCs. RESULTS Among 617 individuals screened, we identified 97 (15.7%) with suspected MetALD. The mean age was 50.6±12.8 years, 67% were men, the mean body mass index was 31.4±6.5 kg/m2, 12.4% had diabetes, and 8% had significant fibrosis. Fibrosis-4 ≥1.3 demonstrated good performance for significant fibrosis (AUROC: 0.78, 95% CI: 0.58-0.98, sensitivity 80%, specificity 76%, positive predictive value 17%, and negative predictive value 98%). VCTE ≥8 kPa also had good performance (AUROC: 0.85, 95% CI: 0.66-1.00, sensitivity 80%, specificity 91%, positive predictive value 36%, and negative predictive value 99%). A stepwise approach using fibrosis-4 followed by VCTE yielded a low false negative rate (2% misclassified as low risk). CONCLUSIONS A clinical care algorithm utilizing a stepwise approach with fibrosis-4 and VCTE shows adequate performance in detecting significant fibrosis in individuals with suspected MetALD.
Collapse
Affiliation(s)
- Luis Antonio Díaz
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Federica Tavaglione
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Nikita Mittal
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Ricki Bettencourt
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Maral Amangurbanova
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Amy Johnson
- Liver Unit, Department of Medicine, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - David Marti-Aguado
- Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain
| | - Monica Tincopa
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Ria Loomba
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Asma Khan-Riches
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Egbert Madamba
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Harris Siddiqi
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Lisa Richards
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Claude B. Sirlin
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, California, USA
| | - Veeral Ajmera
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
| | - Rohit Loomba
- MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA
- School of Public Health, University of California at San Diego, La Jolla, California, USA
| |
Collapse
|
|
30
|
Panganiban J, Kehar M, Ibrahim SH, Hartmann P, Sood S, Hassan S, Ramirez CM, Kohli R, Censani M, Mauney E, Cuda S, Karjoo S. Metabolic dysfunction-associated steatotic liver disease (MASLD) in children with obesity: An Obesity Medicine Association (OMA) and expert joint perspective 2025. OBESITY PILLARS 2025; 14:100164. [PMID: 40230708 PMCID: PMC11995806 DOI: 10.1016/j.obpill.2025.100164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 04/16/2025]
Abstract
Introduction This Obesity Medicine Association (OMA) Expert Joint Perspective examines steatotic liver disease (SLD), which is composed of metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH) in children with obesity. The prevalence of obesity is increasing, rates have tripled since 1963 from 5 % to now 19 % of US children affected in 2018. MASLD, is the most common liver disease seen in children, can be a precursor to the development of Type 2 Diabetes (T2DM) and is the primary reason for liver transplant listing in young adults. We must be vigilant in prevention and treatment of MASLD in childhood to prevent further progression. Methods This joint clinical perspective is based upon scientific evidence, peer and clinical expertise. The medical literature was reviewed via PubMed search and appropriate articles were included in this review. This work was formulated from the collaboration of eight hepatologists/gastroenterologists with MASLD expertise and two physicians from the OMA. Results The authors who are experts in the field, determined sentinel questions often asked by clinicians regarding MASLD in children with obesity. They created a consensus and clinical guideline for clinicians on the screening, diagnosis, and treatment of MASLD associated with obesity in children. Conclusions Obesity and the comorbidity of MASLD is increasing in children, and this is a medical problem that needs to be addressed urgently. It is well known that children with metabolic associated chronic disease often continue to have these chronic diseases as adults, which leads to reduced life expectancy, quality of life, and increasing healthcare needs and financial burden. The authors of this paper recommend healthy weight reduction not only through lifestyle modification but through obesity pharmacotherapy and bariatric surgery. Therefore, this guidance reviews available therapies to achieve healthy weight reduction and reverse MASLD to prevent progressive liver fibrosis, and metabolic disease.
Collapse
Affiliation(s)
| | - Mohit Kehar
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Canada
| | - Samar H. Ibrahim
- Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Phillipp Hartmann
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Division of Gastroenterology, Hepatology & Nutrition, Rady Children’s Hospital San Diego, San Diego, CA, USA
| | - Shilpa Sood
- Division of Pediatric Gastroenterology, Boston Children's Health Physicians, New York Medical College, Valhalla, NY, USA
| | - Sara Hassan
- University of Texas Southwestern, Dallas, TX, United States
| | | | - Rohit Kohli
- Children's Hospital Los Angeles, CA, United States
| | - Marisa Censani
- Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, United States
| | - Erin Mauney
- Tufts Medical Center, Boston, MA, United States
| | - Suzanne Cuda
- Alamo City Healthy Kids and Families, San Antonio, TX, United States
| | - Sara Karjoo
- Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States
- University of South Florida, Tampa, FL, United States
- Florida State University, Tallahassee, FL, United States
| |
Collapse
|
|
31
|
Wu S, Anand N, Guo Z, Li M, Santiago Figueroa M, Jung L, Kelly S, Franses JW. Bridging Immune Evasion and Vascular Dynamics for Novel Therapeutic Frontiers in Hepatocellular Carcinoma. Cancers (Basel) 2025; 17:1860. [PMID: 40507341 PMCID: PMC12153674 DOI: 10.3390/cancers17111860] [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: 05/01/2025] [Revised: 05/30/2025] [Accepted: 05/30/2025] [Indexed: 06/16/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally, driven by chronic liver disease and a complex tumor microenvironment (TME). Recent advances in spatial omics, single-cell analyses, and AI-driven digital pathology have shed light on the intricate heterogeneity of HCC, highlighting key roles for immune suppression, angiogenesis, and fibrosis in tumor progression. This review synthesizes current epidemiological trends, noting a shift from viral hepatitis to metabolic syndrome as a primary etiology in Western populations, and elucidates how TME components-such as tumor-associated macrophages, cancer-associated fibroblasts, vascular endothelial cells, and immunosuppressive cytokines-contribute to resistance against conventional therapies. We detail the evolution of immunotherapeutic strategies from monotherapy to combination regimens, including dual immune checkpoint blockade and the integration of antiangiogenic agents. Emerging circulating and tissue-based biomarkers offer promise for enhanced patient stratification and real-time monitoring of treatment responses. Collectively, these innovations herald a paradigm shift toward TME-directed precision oncology in HCC, emphasizing the need for multi-targeted approaches to synergistically modulate interacting cellular constituents and ultimately improve clinical outcomes.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Joseph W. Franses
- Section of Hematology and Oncology, Department of Internal Medicine, University of Chicago, 900 E. 57th St., KCBD 7114, Chicago, IL 60637, USA; (S.W.); (N.A.); (Z.G.); (M.L.); (M.S.F.); (L.J.); (S.K.)
| |
Collapse
|
|
32
|
de Jong VD, Alings M, Bruha R, Cortez-Pinto H, Dedoussis GV, Doukas M, Francque S, Fournier-Poizat C, Gastaldelli A, Hankemeier T, Holleboom AG, Miele L, Moreno C, Muris JWM, Ratziu V, Romero-Gomez M, Schattenberg JM, Serfaty L, Stefan DC, Tushuizen ME, Verheij J, Willemse J, Franco OH, Grobbee DE, Castro Cabezas M, GRIPonMASH consortium. Global research initiative for patient screening on MASH (GRIPonMASH) protocol: rationale and design of a prospective multicentre study. BMJ Open 2025; 15:e092731. [PMID: 40447415 PMCID: PMC12164639 DOI: 10.1136/bmjopen-2024-092731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 05/12/2025] [Indexed: 06/16/2025] Open
Abstract
INTRODUCTION The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) may be as high as 38% in the adult population with potential serious complications, multiple comorbidities and a high socioeconomic burden. However, there is a general lack of awareness and knowledge about MASLD and its progressive stages (metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis). Therefore, MASLD is still far underdiagnosed. The 'Global Research Initiative for Patient Screening on MASH' (GRIPonMASH) consortium focuses on this unmet public health need. GRIPonMASH will help (primary) healthcare providers to implement a patient care pathway, as recommended by multiple scientific societies, to identify patients at risk of severe MASLD and to raise awareness. Furthermore, GRIPonMASH will contribute to a better understanding of the pathophysiology of MASLD and improved identification of diagnostic and prognostic markers to detect individuals at risk. METHODS This is a prospective multicentre observational study in which 10 000 high-risk patients (type 2 diabetes mellitus, obesity, metabolic syndrome or hypertension) will be screened in 10 European countries using at least two non-invasive tests (Fibrosis-4 index and FibroScan). Blood samples and liver biopsy material will be collected and biobanked, and multiomics analyses will be conducted. ETHICS AND DISSEMINATION The study will be conducted in compliance with this protocol and applicable national and international regulatory requirements. The study initiation package is submitted at the local level. The study protocol has been approved by local medical ethical committees in all 10 participating countries. Results will be made public and published in scientific, peer-reviewed, international journals and at international conferences. REGISTRATION DETAILS NCT05651724, registration date: 15 Dec 2022.
Collapse
Affiliation(s)
- Vivian D de Jong
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
- Julius Clinical BV, Zeist, The Netherlands
| | - Marco Alings
- Cardiology, Amphia Hospital, Breda, The Netherlands
| | - Radan Bruha
- General University Hospital and the First Faculty of Medicine, Charles University, Praha, Czech Republic
| | - Helena Cortez-Pinto
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - George V Dedoussis
- Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece
| | - Michail Doukas
- Pathology, Erasmus MC Universitair Medisch Centrum Rotterdam, Rotterdam, Zuid-Holland, The Netherlands
| | - Sven Francque
- Division of Gastroenterology and Hepatology, University Hospital Antwerp, Edegem, Belgium
| | | | - Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Thomas Hankemeier
- Leiden Academic Centre for Drug Research, Leiden University, Leiden, Zuid-Holland, The Netherlands
| | - Adriaan G Holleboom
- Department of Vascular Medicine and Internal Medicine, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands
| | - Luca Miele
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore - Campus di Roma, Roma, Lazio, Italy
- Liver Transplant Unit and Steatotic Liver Disease Clinic, Digestive Disease Center CEMAD, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Lazio, Italy
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hopital Erasme, Bruxelles, Belgium
| | - Jean W M Muris
- Family Medicine, Maastricht University, Maastricht, The Netherlands
| | - Vlad Ratziu
- ICAN - Institute for Cardiometabolism and Nutrition, Hôpital Pitié Salpêtrière, Sorbonne University, Paris, France
| | - Manuel Romero-Gomez
- UCM Digestive Diseases and SeLiver Group, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville (HUVR/CSIC/US), University of Seville, Sevilla, Andalucía, Spain
| | - Jörn M Schattenberg
- Department of Internal Medicine II, Saarland University Hospital, Homburg, Saarland, Germany
- Saarland University, Saarbrucken, Germany
| | | | | | - Maarten E Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
| | | | | | - Oscar H Franco
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Diederick E Grobbee
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
- Julius Clinical BV, Zeist, The Netherlands
| | - Manuel Castro Cabezas
- Julius Clinical BV, Zeist, The Netherlands
- Department of Internal Medicine, Franciscus Gasthuis en Vlietland, Rotterdam, Zuid-Holland, The Netherlands
- Endocrinology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | | |
Collapse
|
|
33
|
Kanda T, Sasaki-Tanaka R, Abe H, Kimura N, Yoshida T, Hayashi K, Sakamaki A, Yokoo T, Kamimura H, Tsuchiya A, Kamimura K, Terai S. Polygenic Risk Score for Metabolic Dysfunction-Associated Steatotic Liver Disease and Steatohepatitis: A Narrative Review. Int J Mol Sci 2025; 26:5164. [PMID: 40507973 PMCID: PMC12155528 DOI: 10.3390/ijms26115164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2025] [Revised: 05/18/2025] [Accepted: 05/26/2025] [Indexed: 06/16/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are spreading worldwide as the most critical causes of cirrhosis and hepatocellular carcinoma (HCC). Thus, improving the screening and managing strategies for patients with MASLD or MASH is necessary. A traditional non-systemic review provided this narrative. Genetic variations associated with the development of MASLD and MASH, such as PNPLA3, TM6SF2, GCKR, MBOAT7, MERTK, and HSD17B13, were initially reviewed. PNPLA3 genetic variants appeared to be strongly associated with the increased pathogenesis of MASLD, MASH, cirrhosis, and HCC. We also reviewed the useful polygenic risk score (PRS) for the development of MASLD, MASH, their related cirrhosis, and the occurrence of HCC. PRSs appeared to be better predictors of MASLD, MASH, the development of cirrhosis, and the occurrence of HCC in patients with MASLD or MASH than any single-nucleotide polymorphisms. RNA interference and antisense nucleotides against the genetic variations of PNPLA3 and HSD17B13 are also being developed. Multidisciplinary collaboration and cooperation involving hepatologists, geneticists, pharmacologists, and pathologists should resolve complicated problems in MASLD and MASH. This narrative review highlights the importance of the genetic susceptibility and PRS as predictive markers and personalized medicine for patients with MASLD or MASH in the future.
Collapse
Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Uonuma Kikan Hospital, Minamiuonuma 949-7302, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan (K.H.); (A.S.); (H.K.)
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan (K.H.); (A.S.); (H.K.)
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan (K.H.); (A.S.); (H.K.)
| | - Naruhiro Kimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan (K.H.); (A.S.); (H.K.)
| | - Tomoaki Yoshida
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan (K.H.); (A.S.); (H.K.)
| | - Kazunao Hayashi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan (K.H.); (A.S.); (H.K.)
| | - Akira Sakamaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan (K.H.); (A.S.); (H.K.)
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan (K.H.); (A.S.); (H.K.)
| | - Hiroteru Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan (K.H.); (A.S.); (H.K.)
| | - Atsunori Tsuchiya
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Chuo 409-3898, Japan;
| | - Kenya Kamimura
- Department of General Medicine, Niigata University School of Medicine, Niigata 951-9510, Japan;
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8520, Japan (K.H.); (A.S.); (H.K.)
| |
Collapse
|
|
34
|
Xuan Y, Wang B, Xie B, Cen Y, Yu S, Yao Q. Nonlinear relationship between serum high sensitivity C reactive protein to high density lipoprotein cholesterol ratio with non-alcoholic fatty liver disease. Sci Rep 2025; 15:18579. [PMID: 40425766 PMCID: PMC12116901 DOI: 10.1038/s41598-025-03528-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 05/21/2025] [Indexed: 05/29/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become an increasing public health concern. We examined the association between serum high-sensitivity C-reactive protein(hs-CRP)to high-density lipoprotein cholesterol (HDL-C) ratio (HCHR) and the prevalence of NAFLD, extent of hepatic steatosis and fibrosis in the general US population. This cross-sectional analysis included 4039 adult participants from the 2017 to 2018 National Health and Nutrition Examination Survey. Multivariable logistic regression and multivariable linear regression analyses were used to assess the association between HCHR levels and NAFLD, fatty liver degree, and liver fibrosis. Generalized additive models examined the nonlinear relationship between the HCHR and NAFLD. In the three models, HCHR was positively associated with NAFLD, model 1 (OR 1.315, 95% CI 1.273, 1.359), model 2 (OR 1.364, 95% CI 1.317, 1.412) and model 3 (OR 1.120, 95% CI 1.074, 1.168). Stratified analyses showed that the association was more prominent in women, those younger than 40 years, Mexican-Americans, and those with a 25-30 kg/m2 BMI. Nonlinear association analysis revealed a threshold effect between HCHR and NAFLD, with a threshold inflection point of 2.598. We also found a significant link between HCHR and liver steatosis and the risk of liver fibrosis. In the US adult population, the increased risk of NAFLD, liver fibrosis, and severity of hepatic steatosis are independently associated with increased HCHR, and the HCHR may serve as a potential marker for NAFLD and liver fibrosis.
Collapse
Affiliation(s)
- Yanyan Xuan
- Department of Hospital Infection, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.
- Department of Hepatology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.
- Department of Geriatrics Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.
| | - Bujiang Wang
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Binhua Xie
- Department of Rheumatology Immunology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Yuanyuan Cen
- Department of Respiratory and Critical Care Medicine, Cixi Longshan Hospital, Ningbo, Zhejiang, China
| | - Songping Yu
- Department of Geriatrics Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Qi Yao
- Department of Geriatrics Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.
| |
Collapse
|
|
35
|
Shen L, Patel R, Negrete L, Shon A, Lemieux S, Liang T, Altmayer S, Jha P, Kamaya A. Qualitative assessment of hepatic steatosis on modern grayscale ultrasound: more accurate than previously thought? Abdom Radiol (NY) 2025:10.1007/s00261-025-05008-5. [PMID: 40423706 DOI: 10.1007/s00261-025-05008-5] [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: 04/14/2025] [Revised: 05/08/2025] [Accepted: 05/13/2025] [Indexed: 05/28/2025]
Abstract
OBJECTIVE To assess the diagnostic performance of standardized qualitative assessment of hepatic steatosis on grayscale ultrasound. METHODS This retrospective, single-center, multi-case, multi-reader study included 200 patients with ultrasound examinations of the liver. Three readers assessed hepatic steatosis based on a standardized system of 3 ultrasound features: presence of increased fine echoes, visualization of right hemidiaphragm, and visualization of portal triads, assigning a four-grade category (normal, mild, moderate, or severe). Magnetic resonance imaging proton density fat fraction (MRI-PDFF) was used as reference standard. Binary discrimination (normal vs. steatosis) was summarized with binary area under the curve (AUC), sensitivity, and specificity. Discrimination across four categories was performed with pairwise comparisons. Reader differences were tested with the Obuchowski-Rockette-Hillis model. Inter-reader agreement was calculated with Gwet's agreement coefficient (AC). RESULTS Of the 200 patients, 27% (54/200) had normal liver (MRI-PDFF < 5%), 35% (70/200) had mild steatosis (MRI-PDFF ≥ 5-17.4%), 15% (29/200) had moderate steatosis (MRI-PDFF > 17.4-22.1%), and 24% (47/200) had severe steatosis (MRI-PDFF > 22.1%). Median time interval between ultrasound and MRI exams was 4 days (IQR 1-28). Sensitivity, specific, and binary AUC for readers 1/2/3 were 90%/82%/94%, 65%/82%/54%, and 0.87/0.85/0.88 with no statistically significant difference between readers (p = 0.46). Four-class category analysis showed excellent performance of ultrasound to distinguish extreme categories (AUC > 0.95 for normal vs. severe). Inter-reader agreement was substantial (Gwet's AC 0.63) for steatosis category assignment and moderate to substantial (Gwet's AC 0.55-0.71) for ultrasound features. CONCLUSION Contrary to popular belief, qualitative ultrasound assessment of hepatic steatosis is accurate in detecting and grading steatosis when evaluation criteria are standardized.
Collapse
|
|
36
|
Ge Z, Wu Q, Lv C, He Q. The Roles of T Cells in the Development of Metabolic Dysfunction-Associated Steatohepatitis. Immunology 2025. [PMID: 40414629 DOI: 10.1111/imm.13943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 02/28/2025] [Accepted: 04/28/2025] [Indexed: 05/27/2025] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH), the progressed period of metabolic dysfunction-associated steatotic liver disease (MASLD), is a multifaceted liver disease characterised by inflammation and fibrosis that develops from simple steatosis, even contributing to hepatocellular carcinoma and death. MASH involves several immune cell-mediated inflammation and fibrosis, where T cells play a crucial role through the release of pro-inflammatory cytokines and pro-fibrotic factors. This review discusses the complex role of various T cell subsets in the pathogenesis of MASH and highlights the progress of ongoing clinical trials involving T cell-targeted MASH therapies.
Collapse
Affiliation(s)
- Zhifa Ge
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qingwei Wu
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chengyu Lv
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qifeng He
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| |
Collapse
|
|
37
|
Zhang C, Yang D, Suzuki H, Chen J, Wang J, Ye M, Zhou J, Zeng Q, Bai M, Lin MJ, Lee J, Zhu H, Hoshida Y, Zeng X. Hepatocyte-specific CLSTN3B ablation impairs lipid droplet maturation and alleviates diet-induced steatohepatitis in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.05.20.655199. [PMID: 40475430 PMCID: PMC12139921 DOI: 10.1101/2025.05.20.655199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/16/2025]
Abstract
Excessive lipid accumulation in hepatocytes, a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), can lead to progressive liver damage. Understanding the molecular mechanisms governing lipid storage in hepatocytes is essential for identifying therapeutic targets to halt MASLD progression. Here, we show a pivotal role for the protein calsyntenin 3β (CLSTN3B) in promoting lipid droplet (LD) maturation and lipid storage in hepatocytes. Previously characterized as an endoplasmic reticulum (ER)-LD contact protein that facilitates LD maturation in adipocytes, we now show that CLSTN3B expression is strongly induced in mouse hepatocytes by peroxisome proliferator-activated receptor gamma (PPARγ) in response to dietary caloric excess. Hepatocyte-specific deletion of CLSTN3B in mice significantly increases energy expenditure, reduces metabolic efficiency, and protects against diet-induced hepatic steatosis and fibrosis. Mechanistically, CLSTN3B deficiency causes reduced LD phospholipid coverage and increased lipase recruitment. This results in enhanced fatty acid oxidation driven by a futile cycle of lipolysis and re-esterification. Notably, human clinical data reveal a positive correlation between hepatic CLSTN3B expression and MASLD severity and progression, emphasizing its relevance to human disease. Together, our findings establish CLSTN3B as a key regulator of hepatocyte lipid storage and metabolic efficiency and highlight its potential as a therapeutic target in MASLD.
Collapse
Affiliation(s)
- Chuanhai Zhang
- Department of Physiology, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Dengbao Yang
- Department of Physiology, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Hiroyuki Suzuki
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jingxuan Chen
- Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center
| | - Jingjing Wang
- Children’s Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Children’s Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Mengchen Ye
- Xaira Therapeutics, Brisbane, CA, 94005, USA
| | - Jin Zhou
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Qiyu Zeng
- Children’s Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Children’s Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Meijuan Bai
- Department of Physiology, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Mei-Jung Lin
- Department of Physiology, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jeon Lee
- Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center
| | - Hao Zhu
- Children’s Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Children’s Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yujin Hoshida
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Xing Zeng
- Department of Physiology, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| |
Collapse
|
|
38
|
Capone F, Vacca A, Bidault G, Sarver D, Kaminska D, Strocchi S, Vidal-Puig A, Greco CM, Lusis AJ, Schiattarella GG. Decoding the Liver-Heart Axis in Cardiometabolic Diseases. Circ Res 2025; 136:1335-1362. [PMID: 40403112 DOI: 10.1161/circresaha.125.325492] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/24/2025]
Abstract
The liver and heart are closely interconnected organs, and their bidirectional interaction plays a central role in cardiometabolic disease. In this review, we summarize current evidence linking liver dysfunction-particularly metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and cirrhosis-with an increased risk of heart failure and other cardiovascular diseases. We discuss how these liver conditions contribute to cardiac remodeling, systemic inflammation, and hemodynamic stress and how cardiac dysfunction in turn impairs liver perfusion and promotes hepatic injury. Particular attention is given to the molecular mediators of liver-heart communication, including hepatokines and cardiokines, as well as the emerging role of advanced research methodologies, including omics integration, proximity labeling, and organ-on-chip platforms, that are redefining our understanding of interorgan cross talk. By integrating mechanistic insights with translational tools, this review aims to support the development of multiorgan therapeutic strategies for cardiometabolic disease.
Collapse
Affiliation(s)
- Federico Capone
- Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (F.C., A.V., S.S., G.G.S.)
- Department of Medicine, Unit of Internal Medicine III, Padua University Hospital, University of Padua, Padova, Italy (F.C.)
- Department of Biomedical Sciences, University of Padova, Italy (F.C.)
| | - Antonio Vacca
- Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (F.C., A.V., S.S., G.G.S.)
- Clinica Medica, Department of Medicine, University of Udine, Italy (A.V.)
| | - Guillaume Bidault
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, United Kingdom (G.B., A.V.-P.)
| | - Dylan Sarver
- Division of Cardiology, Department of Medicine (D.S., D.K., A.J.L.), University of California, Los Angeles
- Department of Microbiology, Immunology and Molecular Genetics (D.S., A.J.L.), University of California, Los Angeles
- Department of Human Genetics (D.S., A.J.L.), University of California, Los Angeles
| | - Dorota Kaminska
- Division of Cardiology, Department of Medicine (D.S., D.K., A.J.L.), University of California, Los Angeles
| | - Stefano Strocchi
- Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (F.C., A.V., S.S., G.G.S.)
- Max Rubner Center for Cardiovascular Metabolic Renal Research, Deutsches Herzzentrum der Charité, Charité-Universitätsmedizin Berlin, Germany (S.S., G.G.S.)
| | - Antonio Vidal-Puig
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, United Kingdom (G.B., A.V.-P.)
- Centro de Investigacion Principe Felipe, Valencia, Spain (A.V.-P.)
| | - Carolina M Greco
- Department of Biomedical Sciences, Humanitas University, Milan, Italy (C.M.G.)
- IRCCS Humanitas Research Hospital, Milan, Italy (C.M.G.)
| | - Aldons J Lusis
- Division of Cardiology, Department of Medicine (D.S., D.K., A.J.L.), University of California, Los Angeles
- Department of Microbiology, Immunology and Molecular Genetics (D.S., A.J.L.), University of California, Los Angeles
- Department of Human Genetics (D.S., A.J.L.), University of California, Los Angeles
| | - Gabriele G Schiattarella
- Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (F.C., A.V., S.S., G.G.S.)
- Max Rubner Center for Cardiovascular Metabolic Renal Research, Deutsches Herzzentrum der Charité, Charité-Universitätsmedizin Berlin, Germany (S.S., G.G.S.)
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany (G.G.S.)
- Friede Springer Cardiovascular Prevention Center at Charité-Universitätsmedizin Berlin, Germany (G.G.S.)
- Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine, Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy (G.G.S.)
| |
Collapse
|
|
39
|
Cuthbertson DJ, Kennedy OJ, Bilson J, Hydes TJ, Targher G, Glyn-Owen K, Buchanan R, Roderick P, Byrne CD. Impact of metabolic dysfunction severity in steatotic liver disease and its interaction with liver fibrosis on all-cause mortality and multiple hepatic and extra-hepatic outcomes. Metabolism 2025; 170:156306. [PMID: 40414560 DOI: 10.1016/j.metabol.2025.156306] [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: 03/19/2025] [Revised: 05/12/2025] [Accepted: 05/21/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND In metabolic dysfunction-associated steatotic liver disease (MASLD) and in MASLD with alcohol consumption (MetALD), we investigated the effect of severity of metabolic dysfunction on incident major adverse liver outcomes (MALO), major cardiovascular events (MACE), obesity-related cancers, and all-cause mortality (ACM). METHODS SLD was identified among 502,381 UK Biobank participants using the Hepatic Steatosis Index (HSI) (>36 vs.<30). Metabolic syndrome (MetS) traits and MetS (≥3 traits) using MASLD/MetALD criteria. Cox regression was used to estimate adjusted hazard ratios and 95%CIs [aHR(95%CIs)] of MASLD or MetALD plus 1 to 5 MetS traits with incident MALO, MACE, obesity-related cancers and 5-year/10-year incidence rates versus reference (no SLD/MetS traits). RESULTS Median follow-up was 148 to 149 months. Comparing MASLD with one versus five MetS traits, respectively, to the reference; for MALO, [aHRs (95%CIs)] were 2.27 (1.03-5.00) and 9.19 (4.98-16.95); for MetALD, aHRs were 1.65 (0.53-5.11) and 8.54 (3.65-19.95) respectively. For MACE, with MASLD; aHRs were 1.51 (1.19-1.92) and 4.81 (4.06-5.69) respectively; with MetALD, aHRs were 1.46 (1.00-2.13) and 4.64 (3.51-6.14) respectively. For obesity-related cancers; with MASLD, aHRs were 1.04 (0.87-1.23) and 1.46 (1.29-1.66) respectively; with MetALD, aHRs were 1.01 (0.79-1.29) and 1.51 (1.24-1.83) respectively. 5-year and 10-year incidence rates also increased progressively with increasing MetS traits. Combining SLD, MetS and high liver fibrosis risk (defined by FIB-4 ≥ 2.67) was strongly associated with MALO in both MASLD and MetALD (aHRs 27.48, (17.72-42.61); 43.36, 20.53-91.58 respectively). CONCLUSION In MASLD or MetALD, the numbers of MetS traits markedly influence risk and incidence of liver-related outcomes, MACE, obesity-related cancers and ACM.
Collapse
Affiliation(s)
- Daniel J Cuthbertson
- Department of Cardiovascular and Metabolic Medicine, University of Liverpool, Liverpool, Merseyside, UK; Metabolism & Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK; Liverpool Centre for Cardiovascular Sciences, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK.
| | - Oliver J Kennedy
- Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; Division of Cancer Sciences, The University of Manchester, Manchester M13 9PL, UK.
| | - Josh Bilson
- Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
| | - Theresa J Hydes
- Department of Cardiovascular and Metabolic Medicine, University of Liverpool, Liverpool, Merseyside, UK; Metabolism & Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK; Liverpool Centre for Cardiovascular Sciences, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK.
| | - Giovanni Targher
- Department of Medicine, University of Verona, Verona, Italy; Metabolic Diseases Research Unit, IRCCS Sacro Cuore - Don Calabria Hospital, Negrar di Valpolicella, VR, Italy.
| | - Kate Glyn-Owen
- Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
| | - Ryan Buchanan
- Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
| | - Paul Roderick
- Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
| | - 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.
| |
Collapse
|
|
40
|
Zhang Y, Luo PY, Tang YN, Wang J, Gao S, Fan YC, Wang K. Association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD): data from the NHANES III (1988-1994). Nutr Metab (Lond) 2025; 22:46. [PMID: 40399925 PMCID: PMC12093885 DOI: 10.1186/s12986-025-00942-z] [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: 11/01/2024] [Accepted: 05/12/2025] [Indexed: 05/23/2025] Open
Abstract
BACKGROUND The prognostic value of the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study aimed to evaluate the associations between the NHHR and all-cause and cause-specific mortality in patients with MASLD. METHODS Data for this study were obtained from the National Health and Nutrition Examination Survey (NHANES III and the National Death Index (NDI). The NHHR was calculated according to the formula. The results of mortality associated with the NDI were recorded as of December 31, 2019. We used a multivariate Cox proportional hazard model and restricted cubic spline (RCS) regression to assess the associations between the NHHR and all-cause and cause-specific mortality. In addition, subgroup analyses were performed to explore the relationships between the NHHR and all-cause and cause-specific mortality. RESULTS This study included 3155 patients with a definite diagnosis of MASLD. A total of 1,381 (43.8%) patients with MASLD died, and 1,774 (56.2%) survived. Multivariate Cox proportional hazards model analysis showed that NHHR was not significantly associated with all-cause mortality in MASLD patients. The RCS curve showed a significant nonlinear trend between the NHHR and all-cause mortality in patients with MASLD. Subgroup analysis revealed that the NHHR was better suited to predict cardiovascular mortality in patients without advanced fibrosis. CONCLUSIONS Our study revealed the clinical value of the NHHR in the prediction of mortality in the MASLD population. The NHHR can be used as a biomarker for follow-up in people without advanced fibrosis.
Collapse
Affiliation(s)
- Ying Zhang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, Shandong, 250012, China
| | - Peng-Yu Luo
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, Shandong, 250012, China
| | - Yu-Na Tang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, Shandong, 250012, China
| | - Jing Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, Shandong, 250012, China
| | - Shuai Gao
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, Shandong, 250012, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, Shandong, 250012, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, Shandong, 250012, China.
- Hepatology Institute of Shandong University, Jinan, 250012, China.
| |
Collapse
|
|
41
|
Gattu AK, Fourman LT. Metabolic dysfunction-associated steatotic liver disease in people with HIV. Curr Opin HIV AIDS 2025:01222929-990000000-00165. [PMID: 40397552 DOI: 10.1097/coh.0000000000000952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025]
Abstract
PURPOSE OF REVIEW Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent among people with HIV (PWH) and increasingly recognized as a major contributor to morbidity and mortality. The field of MASLD is rapidly evolving with adoption of a new nomenclature and approval of the first FDA-approved therapy within the past year. These developments underscore the need to consider the current state of the science specifically in the context of HIV. RECENT FINDINGS MASLD in PWH (MASLD-HIV) follows a more aggressive clinical course compared to HIV-negative individuals. While MASLD-HIV shares common pathogenic mechanisms with MASLD in the general population, HIV-specific factors - including altered body composition, chronic immune activation, enhanced gut permeability, and antiretroviral therapy - exacerbate disease progression. Despite an expanding pipeline of MASLD therapies, a critical gap remains in evaluating these interventions specifically among PWH. Nonetheless, dedicated studies of glucagon-like peptide-1 receptor agonists and the growth hormone-releasing hormone analog tesamorelin have shown promise in MASLD-HIV. SUMMARY MASLD is a key contributor to liver-related and cardiovascular-morbidity in PWH. While there have been exciting advances to improve diagnosis and management of MASLD in the general population, differences in MASLD pathophysiology demonstrate the need to tailor our approach specifically for PWH.
Collapse
Affiliation(s)
- Arijeet K Gattu
- Metabolism Unit and Division of Endocrinology, Massachusetts General Hospital
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center
- Harvard Medical School, Boston, Massachusetts, USA
| | - Lindsay T Fourman
- Metabolism Unit and Division of Endocrinology, Massachusetts General Hospital
- Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
42
|
Nordestgaard AT, Tybjærg-Hansen A, Mansbach H, Kersten S, Nordestgaard BG, Rosenson RS. Target Populations for Novel Triglyceride-Lowering Therapies. J Am Coll Cardiol 2025; 85:1876-1897. [PMID: 40368577 DOI: 10.1016/j.jacc.2025.02.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 02/10/2025] [Accepted: 02/20/2025] [Indexed: 05/16/2025]
Abstract
Lipoprotein lipase regulates triglyceride hydrolysis and contributes to cellular uptake of triglyceride-rich lipoprotein remnants. Multiple pathways modulate lipoprotein lipase activity, which has prompted interest in the development of drugs that increase lipoprotein lipase activity as means to reduce risk for acute pancreatitis, atherosclerotic cardiovascular disease, and metabolic dysfunction-associated steatohepatitis through reduction of circulating triglycerides and remnant cholesterol. The authors provide an overview of the target populations for agents that lower triglycerides and remnant cholesterol through increased lipoprotein lipase activity, the drugs being developed for these indications, including apolipoprotein C-III and angiopoietin-like protein 3, 3/8, and 4 inhibitors, and the epidemiologic and genetic evidence supporting the use of these drugs for the prevention of atherosclerotic cardiovascular disease and acute pancreatitis. In addition, the authors provide a corresponding overview of fibroblast growth factor-21 analogues that share many characteristics with these novel triglyceride-lowering drugs. Apolipoprotein C-III inhibitors, angiopoietin-like protein 3, 3/8, and 4 inhibitors, and fibroblast growth factor-21 analogues have pronounced triglyceride-lowering and remnant cholesterol-lowering effects. In clinical trials, apolipoprotein C-III inhibitors have been shown to lower risk for acute pancreatitis in patients with severe hypertriglyceridemia and are approved for this indication, while fibroblast growth factor-21 analogues reduce hepatic steatosis and fibrosis in patients with metabolic dysfunction-associated steatohepatitis. It remains to be seen whether these novel drugs may lower risk for atherosclerotic cardiovascular disease as well.
Collapse
Affiliation(s)
- Ask T Nordestgaard
- Center for Cardiovascular Disease Prevention, Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Clinical Biochemistry and the Copenhagen General Population Study, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark.
| | - Anne Tybjærg-Hansen
- Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Sander Kersten
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry and the Copenhagen General Population Study, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Robert S Rosenson
- Metabolism and Lipids Unit, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| |
Collapse
|
|
43
|
Marengo M, Briet C, Munier M, Boursier J, Rodien P, Suteau V. Fatty Liver Disease Along Cushing Syndrome Evolution. J Clin Endocrinol Metab 2025; 110:e2037-e2044. [PMID: 39193719 DOI: 10.1210/clinem/dgae568] [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: 02/20/2024] [Revised: 06/09/2024] [Accepted: 08/27/2024] [Indexed: 08/29/2024]
Abstract
CONTEXT The clinical manifestations of Cushing syndrome are variable, but an important number of patients present a metabolic syndrome, strongly associated with hepatic steatosis. OBJECTIVE The aim of this study was to determine the prevalence of metabolic dysfunction associated steatotic liver disease (MASLD) at the diagnosis of Cushing syndrome. METHODS We conducted a single-center retrospective study at Angers Hospital (France) between 2010 and 2020. Forty-nine patients followed for Cushing syndrome with available abdominal imaging at diagnosis were included. A mean liver/spleen density ratio < 1 on computed tomography was diagnostic of hepatic steatosis. Simple clinico-biological scores predictive of hepatic fibrosis (FIB-4, NAFLD Fibrosis Score, and eLIFT) were calculated for patients with hepatic steatosis. RESULTS Of the 49 patients, 13 (26.5%) had hepatic steatosis at diagnosis of Cushing syndrome. All 13 had MASLD. These patients had a higher prevalence of type 2 diabetes and higher triglyceride levels in multivariate analysis. There was no difference according to the intensity or duration of Cushing syndrome. Among the 13 patients with MASLD, 2 (15.4%) had a significant fibrosis predictive score. Of the 4 patients with follow-up imaging after remission of Cushing syndrome, 3 had remission of steatosis between 1 and 5 years after remission of Cushing syndrome. No patient without MASLD at diagnosis had a worsening liver/spleen ratio after remission. CONCLUSION We estimated the prevalence of hepatic steatosis at the diagnosis of Cushing syndrome at 26.5%. The presence of metabolic factors was associated with the occurrence of hepatic steatosis.
Collapse
Affiliation(s)
- Maria Marengo
- Department of Endocrinology, Diabetology and Nutrition, Angers University Hospital, 49100 Angers, France
| | - Claire Briet
- Department of Endocrinology, Diabetology and Nutrition, Angers University Hospital, 49100 Angers, France
- Angers University, MITOVASC, CarMe team, CNRS UMR 6015, INSERM U1083, 49100 Angers, France
| | - Mathilde Munier
- Department of Endocrinology, Diabetology and Nutrition, Angers University Hospital, 49100 Angers, France
- Angers University, MITOVASC, CarMe team, CNRS UMR 6015, INSERM U1083, 49100 Angers, France
- Centre de Référence des Maladies Rares de la Thyroïde et des Récepteurs Hormonaux, University Hospital Angers, 49100 Angers, France
| | - Jérôme Boursier
- Department of Hepato-Gastroenterology, Angers University Hospital, 49100 Angers, France
- HIFIH Laboratory, Angers University, UPRES EA3859, SFR 4208, 49100 Angers, France
| | - Patrice Rodien
- Department of Endocrinology, Diabetology and Nutrition, Angers University Hospital, 49100 Angers, France
- Angers University, MITOVASC, CarMe team, CNRS UMR 6015, INSERM U1083, 49100 Angers, France
- Centre de Référence des Maladies Rares de la Thyroïde et des Récepteurs Hormonaux, University Hospital Angers, 49100 Angers, France
| | - Valentine Suteau
- Department of Endocrinology, Diabetology and Nutrition, Angers University Hospital, 49100 Angers, France
- Angers University, MITOVASC, CarMe team, CNRS UMR 6015, INSERM U1083, 49100 Angers, France
| |
Collapse
|
|
44
|
Wegermann K, Chouairi F, Karachaliou GS, Ahlers C, Au S, Miller K, Biering-Sørensen T, Abdelmalek MF, Diehl AM, Moylan CA, Fudim M. Incident heart failure is common and underrecognized in patients with biopsy-proven metabolic dysfunction-associated steatotic liver disease. Eur J Heart Fail 2025. [PMID: 40389356 DOI: 10.1002/ejhf.3697] [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: 12/12/2024] [Revised: 04/02/2025] [Accepted: 04/23/2025] [Indexed: 05/21/2025] Open
Abstract
AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with heart failure (HF), independent of shared risk factors. Our aim was to describe the incidence of HF in patients with biopsy-proven MASLD. METHODS AND RESULTS We followed patients with biopsy-proven MASLD from the prospective Duke NAFLD Biorepository and Clinical Database from liver biopsy (2007-2013) until death or 5 January 2023. Clinical and echocardiographic data were abstracted via manual chart review. Incident HF was defined as one of the following: (1) hospitalization for HF, (2) medical record diagnosis of HF, (3) ≥1 sign/symptom of HF and elevated natriuretic peptide, or (4) diastolic dysfunction on transthoracic echocardiography with ≥1 sign/symptom of HF. Univariable and multivariable logistic regression models were evaluated. Overall, 570 patients with biopsy-proven MASLD were included. The mean age was 49.5 years, 42.5% were male and 87.0% were non-Hispanic White. Ten patients (1.8%) had baseline HF, leaving 560 patients to assess for incident HF. Over a median follow up of 4009 days (11.0 years) (interquartile range 2270-4672 days), 100 (17.9%) patients developed incident HF while 268 (47.9%) met criteria for HF suspicion. In a multivariable model, increasing age (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02-1.08, p < 0.001) and female sex (OR 1.85, 95% CI 1.12-3.04, p = 0.02) were associated with incident HF. CONCLUSIONS We found a high incidence of HF in patients with biopsy-proven MASLD. Despite nearly half of patients having suspected HF, very few carried a chart diagnosis. Screening for HF in high-risk patients and establishment of formal care pathways to address early HF may reduce morbidity and mortality.
Collapse
Affiliation(s)
- Kara Wegermann
- Division of Gastroenterology, Department of Medicine, Duke University Health System, Durham, NC, USA
| | - Fouad Chouairi
- Department of Medicine, Duke University Health System, Durham, NC, USA
| | - Georgia Sofia Karachaliou
- Division of Gastroenterology, Department of Medicine, Duke University Health System, Durham, NC, USA
| | - Carolyn Ahlers
- Department of Medicine, Duke University Health System, Durham, NC, USA
| | - Sandra Au
- Department of Medicine, Duke University Health System, Durham, NC, USA
| | - Kaela Miller
- Department of Medicine, Duke University Health System, Durham, NC, USA
| | - Tor Biering-Sørensen
- Department of Cardiology, Copenhagen University Hospital-Herlev and Gentofte, Copenhagen, Denmark
- Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Copenhagen, Denmark
| | - Manal F Abdelmalek
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Anna Mae Diehl
- Division of Gastroenterology, Department of Medicine, Duke University Health System, Durham, NC, USA
| | - Cynthia A Moylan
- Division of Gastroenterology, Department of Medicine, Duke University Health System, Durham, NC, USA
- Department of Medicine, Durham Veterans Affairs Medical Center, Durham, NC, USA
| | - Marat Fudim
- Division of Cardiology, Department of Medicine, Duke University Health System, Durham, NC, USA
- Duke Clinical Research Institute, Durham, NC, USA
| |
Collapse
|
|
45
|
Li W. Knowledge, attitudes, and practices regarding metabolic associated fatty liver disease (MAFLD) in elderly patients. Sci Rep 2025; 15:17215. [PMID: 40382373 PMCID: PMC12085599 DOI: 10.1038/s41598-025-02153-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 05/12/2025] [Indexed: 05/20/2025] Open
Abstract
This study investigates the knowledge, attitudes, and practices (KAP) of elderly patients with metabolic associated fatty liver disease (MAFLD). A cross-sectional study was conducted from August to October 2024, involving 404 patients in the Geriatrics Department of Shanghai Sixth People's Hospital. Participants provided demographic information and completed a structured questionnaire to assess KAP scores. A score of ≥ 70% was considered good for knowledge, attitudes, and practices. Structural equation modeling (SEM) was employed to analyze direct and indirect relationships among the KAP dimensions and identify the pathways through which knowledge and attitudes influence practices. The average age of participants was 72.43 ± 7.88 years. Knowledge, attitude, and practice scores were 13.47 ± 5.40, 28.68 ± 5.04, and 28.01 ± 4.61, respectively. SEM findings indicated that knowledge significantly influenced practice (β = 0.39, P < 0.001), and attitudes also notably impacted practice (β = 0.34, P < 0.001), though knowledge's indirect influence through attitudes was not significant (β = 0.03, P = 0.363). Overall, these findings highlight inadequate KAP among elderly patients with MAFLD, exemplified by 75.2% being unfamiliar of MAFLD's progression to cirrhosis or cancer, underscoring the need for targeted educational initiatives to improve self-management and health outcomes.
Collapse
Affiliation(s)
- Wei Li
- Department of Gerontology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| |
Collapse
|
|
46
|
Munk Lauridsen M, Ravnskjaer K, Gluud LL, Sanyal AJ. Disease classification, diagnostic challenges, and evolving clinical trial design in MASLD. J Clin Invest 2025; 135:e189953. [PMID: 40371650 PMCID: PMC12077896 DOI: 10.1172/jci189953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosis and management have evolved rapidly alongside the increasing prevalence of obesity and related complications. Hepatology has expanded its focus beyond late-stage cirrhosis and portal hypertension to earlier, complex MASLD cases in younger patients, necessitating closer collaboration with endocrinology. The renaming of nonalcoholic fatty liver disease (NAFLD) to MASLD reflects its pathophysiology, reduces stigma, and has prompted new research directions. Noninvasive tests such as liver stiffness measurement now play a crucial role in diagnosis, reducing reliance on invasive liver biopsies. However, advanced omics technologies, despite their potential to enhance diagnostic precision and patient stratification, remain underutilized in routine clinical practice. Behavioral factors, including posttraumatic stress disorder (PTSD) and lifestyle choices, influence disease outcomes and must be integrated into patient management strategies. Primary care settings are critical for early screening to prevent progression to advanced disease, yet sizable challenges remain in implementing effective screening protocols. This Review explores these evolving aspects of MASLD diagnosis and management, emphasizing the need for improved diagnostic tools, multidisciplinary collaboration, and holistic care approaches to address existing gaps and ensure comprehensive patient care across all healthcare levels.
Collapse
Affiliation(s)
- Mette Munk Lauridsen
- Stravitz-Sanyal Liver Institute, Department of Gastroenterology & Hepatology, Virginia Commonwealth University Medical Clinic, Richmond, Virginia, USA
- University Hospital of Southern Denmark, Liver Research Group, Department of Gastroenterology and Hepatology, Esbjerg, Denmark
| | - Kim Ravnskjaer
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Lise Lotte Gluud
- Gastro Unit, Copenhagen University Hospital, Hvidovre, Denmark, and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Arun J. Sanyal
- Stravitz-Sanyal Liver Institute, Department of Gastroenterology & Hepatology, Virginia Commonwealth University Medical Clinic, Richmond, Virginia, USA
| |
Collapse
|
|
47
|
Sarkar M, Kushner T. Metabolic dysfunction-associated steatotic liver disease and pregnancy. J Clin Invest 2025; 135:e186426. [PMID: 40371643 PMCID: PMC12077888 DOI: 10.1172/jci186426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is rising among reproductive-aged individuals and in pregnancy. MASLD in pregnancy does increase such risks as gestational diabetes, preeclampsia, and preterm birth. Although routine screening for MASLD has not been established in pregnancy, individuals with metabolic comorbidities, such as type 2 diabetes mellitus, should be evaluated by liver imaging and liver panel. Preconception counseling should address potential risks as well as need for optimized metabolic health before and during pregnancy. Fibrosis assessment should ideally be completed before pregnancy, to identify cases of cirrhosis that may warrant additional preconception management, such as variceal screening, as well as comanagement with maternal-fetal medicine specialists. In patients with MASLD, aspirin is advised at 12 weeks of gestational age to lower preeclampsia risk. In the absence of cirrhosis, no additional blood test monitoring is needed. In the general population, breastfeeding has beneficial effects on metabolic health in birthing parents and offspring and thus should be encouraged in the setting of MASLD, including access to enhanced lactation support. Research needs include evaluation of the long-term risks of MASLD in pregnancy on metabolic health in birthing parents and infants, as well as safety data for MASLD-directed therapies during pregnancy and lactation.
Collapse
Affiliation(s)
- Monika Sarkar
- Division of Gastroenterology and Hepatology, Department of Medicine, UCSF, San Francisco, California, USA
| | - Tatyana Kushner
- Department of Obstetrics & Gynecology, Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York, USA
| |
Collapse
|
|
48
|
Carbone F, Després JP, Ioannidis JPA, Neeland IJ, Garruti G, Busetto L, Liberale L, Ministrini S, Vilahur G, Schindler TH, Macedo MP, Di Ciaula A, Krawczyk M, Geier A, Baffy G, Faienza MF, Farella I, Santoro N, Frühbeck G, Yárnoz-Esquiroz P, Gómez-Ambrosi J, Chávez-Manzanera E, Vázquez-Velázquez V, Oppert JM, Kiortsis DN, Sbraccia P, Zoccali C, Portincasa P, Montecucco F. Bridging the gap in obesity research: A consensus statement from the European Society for Clinical Investigation. Eur J Clin Invest 2025:e70059. [PMID: 40371883 DOI: 10.1111/eci.70059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/12/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Most forms of obesity are associated with chronic diseases that remain a global public health challenge. AIMS Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation. MATERIALS AND METHODS This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood. RESULTS The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies. DISCUSSION The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity. CONCLUSION This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.
Collapse
Affiliation(s)
- Federico Carbone
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
| | - Jean-Pierre Després
- Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, Québec, Canada
- VITAM - Centre de Recherche en santé Durable, Centre intégré Universitaire de santé et de Services Sociaux de la Capitale-Nationale, Québec, Québec, Canada
| | - John P A Ioannidis
- Department of Medicine, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
- Department of Epidemiology and Population Health, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
- Department of Biomedical Science, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
| | - Ian J Neeland
- Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Cardiovascular Disease, Harrington Heart and Vascular Institute, Cleveland, Ohio, USA
| | - Gabriella Garruti
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Luca Busetto
- Department of Medicine, University of Padua, Padua, Italy
| | - Luca Liberale
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
| | - Stefano Ministrini
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
- Cardiology Department, Luzerner Kantonspital, Lucerne, Switzerland
| | - Gemma Vilahur
- Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, IIB-Sant Pau, Barcelona, Spain
- CiberCV, Institute Carlos III, Madrid, Spain
| | - Thomas H Schindler
- Washington University in St. Louis, Mallinckrodt Institute of Radiology, Division of Nuclear Medicine, Cardiovascular Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Maria Paula Macedo
- APDP - Diabetes Portugal, Education and Research Center, Lisbon, Portugal
- iNOVA4Health, NOVA Medical School | Faculdade de Ciências Médicas, NMS | FCM, Universidade Nova de Lisboa, Lisbon, Portugal
| | - Agostino Di Ciaula
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Marcin Krawczyk
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Andreas Geier
- Interdisciplinary Amyloidosis Center of Northern Bavaria, University Hospital of Würzburg, Würzburg, Germany
- Department of Internal Medicine II, Hepatology, University Hospital of Würzburg, Würzburg, Germany
| | - Gyorgy Baffy
- Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts, USA
| | - Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Ilaria Farella
- Department of Medicine and Surgery, LUM University, Casamassima, Italy
| | - Nicola Santoro
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Medicine and Health Sciences, "V. Tiberio" University of Molise, Campobasso, Italy
| | - Gema Frühbeck
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Yárnoz-Esquiroz
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Gómez-Ambrosi
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Emma Chávez-Manzanera
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - Jean-Michel Oppert
- Department of Nutrition, Pitié-Salpêtrière Hospital (AP-HP), Human Nutrition Research Center Ile-de-France (CRNH IdF), Sorbonne University, Paris, France
| | - Dimitrios N Kiortsis
- Atherothrombosis Research Centre, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Paolo Sbraccia
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Carmine Zoccali
- Renal Research Institute, New York, New York, USA
- Institute of Molecular Biology and Genetics (Biogem), Ariano Irpino, Italy
- Associazione Ipertensione Nefrologia Trapianto Renale (IPNET), c/o Nefrologia, Grande Ospedale Metropolitano, Reggio Calabria, Italy
| | - Piero Portincasa
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Fabrizio Montecucco
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
| |
Collapse
|
|
49
|
Zhou X, Tian Z, Li S, Jing R, Liu Z, Wu P, Shao J, Bai J, Huang R, Pan Y, Zhou K. Preventing metabolic-associated fatty liver disease with fermented cordyceps preparation: an electronic medical record based study. Front Med (Lausanne) 2025; 12:1576029. [PMID: 40438375 PMCID: PMC12116537 DOI: 10.3389/fmed.2025.1576029] [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: 02/17/2025] [Accepted: 04/30/2025] [Indexed: 06/01/2025] Open
Abstract
Background Metabolic-associated fatty liver disease (MAFLD) is a prevalent chronic liver condition with significant health implications. Fermented Cordyceps Preparation (FCP) has shown promise in managing metabolic disorders, prompting interest in its potential for MAFLD prevention. There is, however, a lack of large-scale clinical evidence regarding its preventive efficacy and long-term safety. Aim We aimed to assess the preventive efficacy and safety of FCP, as regards combatting MAFLD. Methods Propensity score matching was used to select 343 FCP users and 1372 non-users with metabolic syndrome, (MS) as recorded in EMR. These two groups were followed for 750 days, to track the incidence of MAFLD. The Kaplan Meier method was used to calculate the cumulative risk of MAFLD events in each subgroup. A Multiple linear regression model was used to compare the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as between the two groups. Results Compared with non-users, FCP users were associated with a 26% decreased risk of MAFLD (hazard ratio 0.74, 95% confidence interval 0.56-0.97). During the follow-up, the changes in both ALT and AST, were insignificantly different between the two groups. Conclusion These findings highlight the potential of FCP in MAFLD prevention and offer insight into its safety profile, suggesting avenues for further clinical validation and drug repurposing efforts.
Collapse
Affiliation(s)
- Xiaozhou Zhou
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Zijian Tian
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing, China
| | - Shaoyun Li
- Fifth People’s Hospital of Chongqing, Chongqing, China
| | - Ruifeng Jing
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Ziqing Liu
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Peng Wu
- College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
| | - Jian Shao
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Jie Bai
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
- College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
| | - Rong Huang
- Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Ying Pan
- Department of General Practice, Kunshan Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu, China
| | - Kaixin Zhou
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| |
Collapse
|
|
50
|
Wu J, Yu W, Huang L, Hou S, Huang Y, Huang Z, Dai Z, Yin J, Nie Z. The HbA1c/HDL-C ratio as a screening indicator of NAFLD in U.S. adults: a cross-sectional NHANES analysis (2017-2020). BMC Gastroenterol 2025; 25:369. [PMID: 40369422 PMCID: PMC12076897 DOI: 10.1186/s12876-025-03974-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Accepted: 05/06/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD), a metabolic liver disorder closely associated with obesity and diabetes, urgently requires early screening. This population-based study is the first to explore the relationship between glycemic control and a novel dyslipidemia composite index-the glycated hemoglobin/high-density lipoprotein cholesterol (HbA1c/HDL-C) ratio in individuals with NAFLD and liver fibrosis. METHODS Data from 5,891 adults in the 2017-2020 National Health and Nutrition Examination Survey (NHANES) were analyzed. Binary logistic regression and restricted cubic spline (RCS) analyses were used to evaluate the association between HbA1c/HDL-C ratio and the risk of NAFLD and liver fibrosis. The reliability of the results was confirmed using subgroup, interaction, and sensitivity analyses. Screening performance was assessed using receiver operating characteristic (ROC) curves, and differences between various indicators were compared using the DeLong test. RESULTS After adjusting for confounding factors, each 1% increase in the HbA1c/HDL-C ratio was associated with a 20% higher risk of NAFLD (odds ratio [OR] = 1.20, 95% confidence interval [CI]: 1.14-1.27, P < 0.001). Sensitivity analyses confirmed the robustness of these findings (P < 0.001). However, the associations with liver fibrosis (P = 0.064) and moderate-to-severe liver fibrosis (P = 0.130) were not statistically significant. Participants in the highest HbA1c/HDL-C quartile had significantly higher odds of NAFLD than those in the lowest quartile (OR = 2.21, 95% CI: 1.74-2.79). RCS analysis revealed a non-linear positive correlation between the HbA1c/HDL-C and NAFLD risk (P for non-linear = 0.003). Subgroup and interaction analyses showed that this association was more pronounced in the non-diabetic population. The ROC curve yielded an AUC of 0.713 for NAFLD screening. CONCLUSION In U.S. adults, the HbA1c/HDL-C appears to be an effective tool for NAFLD screening. As a novel composite index, it also holds considerable reference value for identifying NAFLD risk in the non-diabetic population.
Collapse
Affiliation(s)
- Ju Wu
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China
- Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China
| | - Wenjing Yu
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China
- Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China
| | - Linglong Huang
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China
- Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China
| | - Shuangshuang Hou
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China
- Department of General Surgery, FuYang Normal University Second Affiliated Hospital, FuYang, 236000, China
| | - Yanan Huang
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China
- Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China
| | - Zhihua Huang
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China
- Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China
| | - Zhiyuan Dai
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China
- Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China
| | - Jiajun Yin
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China.
- Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China.
| | - Zhequn Nie
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China.
- Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, China.
| |
Collapse
|