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Pozzobon FM, Luiz RR, Parente JG, Guarilha TM, Fontes MPRC, Chindamo MC, de Mello Perez R. Combination of fibrosis-4 score and D-dimer: a practical approach to identify poor outcome in COVID-19. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00503. [PMID: 40207484 DOI: 10.1097/meg.0000000000002966] [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] [Indexed: 04/11/2025]
Abstract
AIM Fibrosis-4 (FIB-4) score and D-dimer (DD) have emerged as prognostic markers in coronavirus disease 2019 (COVID-19). However, precise cutoff points remain undefined, and their combined use has been scarcely studied. We aimed to analyze FIB-4 and DD performance, individually and combined, to predict outcomes among COVID-19 patients. METHODS From March to December 2020, hospitalized COVID-19 patients were evaluated based on clinical and laboratory tests from their first day of hospitalization. Primary outcome was inhospital mortality, and secondary outcomes included hospital stay length, ICU admission and duration, need for hemodialysis, ventilatory support, and extent of lung involvement. Optimal FIB-4 and DD cutoff points to predict mortality were established to maximize sensitivity and specificity. A sequential diagnostic strategy using both markers was subsequently evaluated. RESULTS Among 518 patients (61 ± 16 years, 64% men), the inhospital mortality rate was 18%. FIB-4 outperformed DD in predicting mortality (area under the receiver operating characteristic curve: 0.76 vs. 0.65, P = 0.003) and was chosen as the first step in sequential analysis. Mortality was higher in patients with FIB-4 ≥1.76 vs. FIB-4 <1.76 (26 vs. 5%, P < 0.001) and DD ≥2000 ng/ml vs. DD <2000 ng/ml (38 vs. 16%, P < 0.001). Using FIB-4 as a screening test (cutoff = 1.76, 90% sensitivity) followed by DD (cutoff = 2000 ng/ml; 90% specificity) identified a subgroup with higher mortality when compared with FIB-4 alone (48 vs. 26%, P < 0.001), missing the identification of only 2% of deaths. CONCLUSION Sequential use of FIB-4 and DD represents a comprehensive strategy to identify high-risk COVID-19 patients at hospital admission, potentially minimizing unnecessary DD tests in those deemed low-risk by FIB-4.
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Affiliation(s)
- Fernanda Manhães Pozzobon
- Department of Internal Medicine, Barra D'Or Hospital, Rede D'Or São Luiz, Rio de Janeiro
- Health Assistance Division, Fluminense Federal University (UFF), Niterói
| | - Ronir Raggio Luiz
- D'Or Institute for Research and Education (IDOR)
- Institute for Collective Health Studies, Federal University of Rio de Janeiro (UFRJ)
| | - Júlia Gomes Parente
- Department of Internal Medicine, Barra D'Or Hospital, Rede D'Or São Luiz, Rio de Janeiro
| | - Taísa Melo Guarilha
- Department of Internal Medicine, Barra D'Or Hospital, Rede D'Or São Luiz, Rio de Janeiro
| | | | - Maria Chiara Chindamo
- Department of Internal Medicine, Barra D'Or Hospital, Rede D'Or São Luiz, Rio de Janeiro
- Department of Internal Medicine, Medical School, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Renata de Mello Perez
- D'Or Institute for Research and Education (IDOR)
- Department of Internal Medicine, Medical School, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
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Righetti R, Cinque F, Patel K, Sebastiani G. The role of noninvasive biomarkers for monitoring cell injury in advanced liver fibrosis. Expert Rev Gastroenterol Hepatol 2025; 19:65-80. [PMID: 39772945 DOI: 10.1080/17474124.2025.2450717] [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: 10/09/2024] [Accepted: 01/04/2025] [Indexed: 01/11/2025]
Abstract
INTRODUCTION Accurate and reliable diagnosis and monitoring of hepatic fibrosis is increasingly important given the variable natural history in chronic liver disease (CLD) and expanding antifibrotic therapeutic options targeting reversibility of early-stage cirrhosis. This highlights the need to develop more refined and effective noninvasive techniques for the dynamic assessment of fibrogenesis and fibrolysis. AREAS COVERED We conducted a literature review on PubMed, from 1 December 1970, to 1 November 2024, to evaluate and compare available blood-based and imaging-based noninvasive tools for hepatic fibrosis diagnosis and monitoring. Simple scores such as FIB-4 and NAFLD fibrosis score are suitable for excluding significant or advanced fibrosis, while tertiary centers should adopt complex scores and liver stiffness measurement as part of a secondary diagnostic and more comprehensive evaluation. Moreover, the advent of multiomics for high-resolution molecular profiling, and integration of artificial intelligence for noninvasive diagnostics holds promise for revolutionizing fibrosis monitoring and treatment through novel biomarker discovery and predictive omics-based algorithms. EXPERT OPINION The increased shift toward noninvasive diagnostics for liver fibrosis needs to align with personalized medicine, enabling more effective, tailored management strategies for patients with liver disease in the future.
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Affiliation(s)
- Riccardo Righetti
- Chronic Viral Illness Service, Division of Infectious Diseases, Department of Medicine, McGill University Health Centre, Montreal, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University Health Centre, Montreal, Canada
- Internal Medicine Unit, Department of Medical and Surgical Science for Children and Adults, Azienda Ospedaliero-Universitaria Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Felice Cinque
- Chronic Viral Illness Service, Division of Infectious Diseases, Department of Medicine, McGill University Health Centre, Montreal, Canada
- SC Medicina Indirizzo Metabolico, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
- Department of Pathophysiology, Transplantation University of Milan, Milan, Italy
| | - Keyur Patel
- University Health Network Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Canada
| | - Giada Sebastiani
- Chronic Viral Illness Service, Division of Infectious Diseases, Department of Medicine, McGill University Health Centre, Montreal, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University Health Centre, Montreal, Canada
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Kawaguchi T, Murotani K, Kajiyama H, Obara H, Yamaguchi H, Toyofuku Y, Kaneko F, Seino Y, Uchida S. Effects of luseogliflozin on suspected MASLD in patients with diabetes: a pooled meta-analysis of phase III clinical trials. J Gastroenterol 2024; 59:836-848. [PMID: 39060520 PMCID: PMC11338969 DOI: 10.1007/s00535-024-02122-x] [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: 02/25/2024] [Accepted: 05/29/2024] [Indexed: 07/28/2024]
Abstract
BACKGROUND Luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, potentially exerts pleiotropic effects on the liver. However, the sufficient evidence is still lacking. We aimed to investigate the effects of luseogliflozin on hepatic steatosis, fibrosis, and cardiometabolic risk factors in diabetic patients by a pooled meta-analysis. METHODS In this pooled meta-analysis, we enrolled diabetic patients who participated in phase III clinical trials of luseogliflozin (luseogliflozin group n = 302, placebo group n = 191). The primary outcomes were changes in fatty liver index (FLI) and Hepamet fibrosis score (HFS) after 24 weeks. The secondary outcomes were changes in cardiometabolic risk factors after 24 weeks. Statistical analysis was performed using propensity scoring analysis by the inverse probability of treatment weighting method. RESULTS Primary outcomes: Luseogliflozin significantly decreased FLI compared to placebo after 24 weeks (adjusted coefficient - 5.423, 95%CI - 8.760 to - 2.086, P = 0.0016). There was no significant difference in changes in HFS between the two groups. However, luseogliflozin significantly decreased HFS compared to placebo in diabetic patients with ALT > 30 U/L (adjusted coefficient - 0.039, 95%CI - 0.077 to - 0.001, P = 0.0438) and with FIB-4 index > 1.3 (adjusted coefficient - 0.0453, 95%CI - 0.075 to - 0.016, P = 0.0026). Secondary outcom8es: Luseogliflozin significantly decreased HbA1c level, HOMA-IR value, BMI, and uric acids level, and increased HDL cholesterol level compared to placebo. CONCLUSIONS This pooled meta-analysis demonstrated that 24-week treatment with luseogliflozin improved hepatic steatosis and fibrosis indexes in diabetic patients, especially those with liver injury. Furthermore, luseogliflozin improved various cardiometabolic risk factors. Thus, luseogliflozin may be useful for improving MASLD in diabetic patients.
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Affiliation(s)
- Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-Machi, Kurume, 830-0011, Japan.
- Clinical Research Center, Kurume University Hospital, Kurume, Japan.
| | - Kenta Murotani
- Clinical Research Center, Kurume University Hospital, Kurume, Japan
- Biostatistics Center, Kurume University, Kurume, Japan
- School of Medical Technology, Kurume University, Kurume, Japan
| | | | - Hitoshi Obara
- Clinical Research Center, Kurume University Hospital, Kurume, Japan
- Biostatistics Center, Kurume University, Kurume, Japan
| | | | - Yuko Toyofuku
- Clinical Research Center, Kurume University Hospital, Kurume, Japan
| | - Fumi Kaneko
- Clinical Research Center, Kurume University Hospital, Kurume, Japan
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Chen LZ, Jing XB, Chen X, Xie YC, Chen Y, Cai XB. Non-Invasive Serum Markers of Non-Alcoholic Fatty Liver Disease Fibrosis: Potential Tools for Detecting Patients with Cardiovascular Disease. Rev Cardiovasc Med 2024; 25:344. [PMID: 39355605 PMCID: PMC11440407 DOI: 10.31083/j.rcm2509344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/23/2024] [Accepted: 05/28/2024] [Indexed: 10/03/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), one of the most common chronic liver diseases with a prevalence of 23%-25% globally, is an independent risk factor for cardiovascular diseases (CVDs). Growing evidence indicates that the development of NAFLD, ranging from non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), advanced fibrosis to cirrhosis, and even hepatocellular carcinoma, is at substantial risk for CVDs, which clinically contribute to increased cardiovascular morbidity and mortality. Non-invasive serum markers assessing liver fibrosis, such as fibrosis-4 (FIB-4) score, aspartate transaminase-to-platelet ratio index (APRI), and NAFLD fibrosis score (NFS), are expected to be useful tools for clinical management of patients with CVDs. This review aims to provide an overview of the evidence for the relationship between the progression of NAFLD and CVDs and the clinical application of non-invasive markers of liver fibrosis in managing patients with CVDs.
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Affiliation(s)
- Ling-Zi Chen
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, 515041 Shantou, Guangdong, China
| | - Xu-Bin Jing
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, 515041 Shantou, Guangdong, China
| | - Xiang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, 515041 Shantou, Guangdong, China
| | - Yan-Chun Xie
- Department of Endoscopy Center, Cancer Hospital of Shantou University Medical College, 515041 Shantou, Guangdong, China
| | - Yun Chen
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, 515041 Shantou, Guangdong, China
| | - Xian-Bin Cai
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, 515041 Shantou, Guangdong, China
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Dai R, Sun M, Lu M, Deng L. Deep learning for predicting fibrotic progression risk in diabetic individuals with metabolic dysfunction-associated steatotic liver disease initially free of hepatic fibrosis. Heliyon 2024; 10:e34150. [PMID: 39071617 PMCID: PMC11282990 DOI: 10.1016/j.heliyon.2024.e34150] [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: 05/07/2024] [Revised: 07/04/2024] [Accepted: 07/04/2024] [Indexed: 07/30/2024] Open
Abstract
Objective Metabolic dysfunction-associated steatotic liver disease (MASLD) significantly impacts patients with type 2 diabetes mellitus (T2DM), where current non-invasive assessment methods show limited predictive power for future fibrotic progression. This study aims to develop an enhanced deep learning (DL) model that integrates ultrasound elastography images with clinical data, refining the prediction of fibrotic progression in T2DM patients with MASLD who initially exhibit no signs of hepatic fibrosis. Methods We enrolled 946 diabetic MASLD patients without advanced fibrosis, confirmed by initial liver stiffness measurements (LSM) below 6.5 kPa. Patients were divided into a training dataset of 671 and a testing dataset of 275. Hepatic shear wave elastography (SWE) images measured liver stiffness, classifying participants based on progression. A DL integrated model (DI-model) combining SWE images and clinical data was trained and its predictive performance compared with individual Image and Tabular models, as well as a logistic regression model on the testing dataset. Results Fibrotic progression was observed in 18.1 % of patients over three years. During the training phase, the DI-model outperformed other models, achieving the lowest validation loss of 0.161 and highest accuracy of 0.933 through cross-validation. In the testing phase, it demonstrated robust discrimination with AUCs of 0.884 and 0.903 for the receiver operating characteristic and precision-recall curves, respectively, clearly outperforming other models. Shapley analysis identified BMI, LSM, and glycated hemoglobin as critical predictors. Conclusion The DI-model significantly enhances the prediction of future fibrotic progression in diabetic MASLD patients, demonstrating the benefit of combining clinical and imaging data for early diagnosis and intervention.
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Affiliation(s)
- Ruihong Dai
- Department of Ultrasound, Meng Cheng County Hospital of Chinese Medicine, Bozhou City, Anhui Province, China
| | - Miaomiao Sun
- Department of Ultrasound, Meng Cheng County Hospital of Chinese Medicine, Bozhou City, Anhui Province, China
| | - Mei Lu
- Department of Ultrasound, Meng Cheng County Hospital of Chinese Medicine, Bozhou City, Anhui Province, China
| | - Lanhua Deng
- Department of Ultrasound, Meng Cheng County Hospital of Chinese Medicine, Bozhou City, Anhui Province, China
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Shaikh A, Pedra G, Ruiz-Casas L, Franks B, Dhillon H, Fernandes JDDR, Mangla KK, Augusto M, Romero-Gómez M, Schattenberg JM. Risk factors for fibrosis progression in non-alcoholic steatohepatitis: Analysis of the European cohort in the real-world GAIN study. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:463-472. [PMID: 37890583 DOI: 10.1016/j.gastrohep.2023.10.005] [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: 02/10/2023] [Revised: 08/22/2023] [Accepted: 10/19/2023] [Indexed: 10/29/2023]
Abstract
OBJECTIVE To better understand drivers of disease progression in non-alcoholic steatohepatitis (NASH), we assessed clinical and sociodemographic markers of fibrosis progression in adults with NASH. PATIENTS AND METHODS Physician-reported patient demographics and clinical characteristics were utilised from the real-world Global Assessment of the Impact of NASH (GAIN) study. Factors associated with likelihood of fibrosis progression since NASH diagnosis were identified using a logistic regression model. RESULTS Overall, 2349 patients in Europe from the GAIN study were included; mean age was 54.6 years and 41% were women. Significant covariates included age, years since diagnosis, employment status, fibrosis stage at diagnosis, type 2 diabetes mellitus, hypertension, liver transplant and liver biopsy at diagnosis. Risk of progression was 1.16 (95% confidence interval 1.12-1.20; p<0.001) times higher for each additional year since NASH diagnosis and 5.43 (2.68-11.37; p<0.001) times higher when physicians proposed a liver transplant at diagnosis. Compared with full-time employed patients, risk of progression was 1.77 (1.19-2.60; p=0.004) times higher for unemployed patients and 3.16 (1.30-7.63; p=0.010) times higher for those unable to work due to NASH. CONCLUSIONS Disease duration, NASH severity and presence of other metabolic comorbidities could help to assess risk of progression in patients with NASH.
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Affiliation(s)
- Anum Shaikh
- HCD Economics Ltd., The Innovation Centre, Keckwick Lane, Daresbury, Cheshire WA4 4FS, United Kingdom
| | - Gabriel Pedra
- HCD Economics Ltd., The Innovation Centre, Keckwick Lane, Daresbury, Cheshire WA4 4FS, United Kingdom
| | - Leonardo Ruiz-Casas
- HCD Economics Ltd., The Innovation Centre, Keckwick Lane, Daresbury, Cheshire WA4 4FS, United Kingdom
| | - Bethany Franks
- HCD Economics Ltd., The Innovation Centre, Keckwick Lane, Daresbury, Cheshire WA4 4FS, United Kingdom.
| | - Harpal Dhillon
- HCD Economics Ltd., The Innovation Centre, Keckwick Lane, Daresbury, Cheshire WA4 4FS, United Kingdom
| | | | | | | | - Manuel Romero-Gómez
- UCM Digestive Diseases and CIBEREHD, 28029 Madrid, Spain; Virgen del Rocío University Hospital and Institute of Biomedicine of Seville (HUVR/CSIC/US), University of Seville, 41013 Seville, Spain
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
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Raverdy V, Tavaglione F, Chatelain E, Caiazzo R, Saponaro C, Lassailly G, Verkindt H, Baud G, Marciniak C, Chetboun M, Oukhouya-Daoud N, Gnemmi V, Leteurtre E, Duhamel A, Philippe M, Marot G, Romeo S, Pattou F. Performance of non-invasive tests for liver fibrosis resolution after bariatric surgery. Metabolism 2024; 153:155790. [PMID: 38219973 DOI: 10.1016/j.metabol.2024.155790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 12/05/2023] [Accepted: 01/09/2024] [Indexed: 01/16/2024]
Abstract
BACKGROUND & AIMS The value of non-invasive tests for monitoring the resolution of significant liver fibrosis after treatment is poorly investigated. We compared the performances of six non-invasive tests to predict the resolution of significant fibrosis after bariatric surgery. METHODS Participants were individuals with obesity submitted to needle liver biopsy at the time of bariatric surgery, and 12 and/or 60 months after surgery. We calculated the fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), AST to platelet ratio index (APRI), Hepatic fibrosis score (HFS), Fibrotic NASH index (FNI), and Liver risk score (LRS) at each time point, and compared their performances for predicting significant fibrosis (F ≥ 2) and its resolution following surgery. RESULTS At baseline, 2436 patients had liver biopsy, including 261 (10.7 %) with significant fibrosis. Overall, 672 patients had pre- and post-operative biopsies (564 at M12 and 328 at M60). The fibrosis stage decreased at M12 and M60 (p < 0.001 vs M0). Resolution of significant fibrosis occurred in 58/121 (47.9 %) at M12 and 32/50 (64 %) at M60. The mean value of all tests decreased after surgery, except for FIB-4. Performances for predicting fibrosis resolution was higher at M60 than at M12 for all tests, and maximal at M60 for FNI and LRS: area under the curve 0.843 (95%CI 0.71-0.95) and 0.92 (95%CI 0.84-1.00); positive likelihood ratio 3.75 (95 % CI 1.33-10.59) and 4.58 (95 % CI 1.65-12.70), respectively. CONCLUSIONS Results showed the value and limits of non-invasive tests for monitoring the evolution of liver fibrosis after an intervention. Following bariatric surgery, the best performances to predict the resolution of significant fibrosis were observed at M60 with tests combining liver and metabolic traits, namely FNI and LRS.
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Affiliation(s)
- Violeta Raverdy
- Service de chirurgie générale et endocrinienne, Centre Hospitalier Universitaire de Lille, Lille, France; European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France
| | - Federica Tavaglione
- Operative Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy; Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Estelle Chatelain
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41-UAR 2014-PLBS, billille, F-59000 Lille, France
| | - Robert Caiazzo
- Service de chirurgie générale et endocrinienne, Centre Hospitalier Universitaire de Lille, Lille, France; European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France
| | - Chiara Saponaro
- European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France
| | - Guillaume Lassailly
- CHU Lille, Univ. Lille, Inserm INFINITE-U1286, Department of Hepato-Gastroenterology, F-59000 Lille, France
| | - Helene Verkindt
- Service de chirurgie générale et endocrinienne, Centre Hospitalier Universitaire de Lille, Lille, France; European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France
| | - Gregory Baud
- Service de chirurgie générale et endocrinienne, Centre Hospitalier Universitaire de Lille, Lille, France; European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France
| | - Camille Marciniak
- Service de chirurgie générale et endocrinienne, Centre Hospitalier Universitaire de Lille, Lille, France; European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France
| | - Mikael Chetboun
- Service de chirurgie générale et endocrinienne, Centre Hospitalier Universitaire de Lille, Lille, France; European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France
| | - Naima Oukhouya-Daoud
- Service de chirurgie générale et endocrinienne, Centre Hospitalier Universitaire de Lille, Lille, France; European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France
| | - Viviane Gnemmi
- CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Univ. Lille, Lille, France; Department of Pathology, CHU Lille, Univ. Lille, Lille, France
| | - Emmanuelle Leteurtre
- CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Univ. Lille, Lille, France; Department of Pathology, CHU Lille, Univ. Lille, Lille, France
| | - Alain Duhamel
- Univ. Lille, CHU Lille, ULR 2694 - METRICS: Évaluation des technologies de santé et des pratiques médicales, F-59000 Lille, France
| | - Mathurin Philippe
- CHU Lille, Univ. Lille, Inserm INFINITE-U1286, Department of Hepato-Gastroenterology, F-59000 Lille, France
| | - Guillemette Marot
- Univ. Lille, CHU Lille, ULR 2694 - METRICS: Évaluation des technologies de santé et des pratiques médicales, F-59000 Lille, France; Inria, MODAL: Models for Data Analysis and Learning, F-59000 Lille, France
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
| | - François Pattou
- Service de chirurgie générale et endocrinienne, Centre Hospitalier Universitaire de Lille, Lille, France; European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France.
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Gopalakrishna H, Nair GB, Roghani RS, Ravendhran N, Rotman Y. Optimizing surveillance of low-risk metabolic dysfunction associated steatotic liver disease using transient elastography. Eur J Gastroenterol Hepatol 2024; 36:476-481. [PMID: 38407839 PMCID: PMC10923068 DOI: 10.1097/meg.0000000000002713] [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] [Indexed: 02/27/2024]
Abstract
BACKGROUND Most people with metabolic dysfunction-associated steatotic liver disease (MASLD) lack significant fibrosis and are considered low-risk. Surveillance strategy for low-risk MASLD remains uncertain. AIM Identify which low-risk subjects can avoid follow-up vibration-controlled transient elastography (VCTE) within 1 year. METHODS Retrospective analysis of two independent low-risk MASLD cohorts (baseline liver stiffness [LS] < 8kPa) with routine 6-12 months follow-up VCTE. The primary outcome was LS ≥ 8kPa on follow-up, requiring referral and further work-up according to current guidance. Predictors of the primary outcome on univariate and multivariate logistic regression were incorporated into a decision algorithm, and validated in an independent cohort. RESULTS Of 206 subjects in the derivation cohort, 96 were low-risk. After a median of 10 months, 24 (25%) low-risk subjects had LS ≥ 8kPa. Baseline LS ( P < 0.01) and ALT change from baseline ( P = 0.02) (multivariate AUROC = 0.84 [0.74-0.94]) predicted the primary outcome, and were incorporated to a two-step decision algorithm. Low-risk subjects with baseline LS < 5.5 kPa can avoid repeating VCTE in a year, while those with LS > 6.8 kPa require one. For intermediate baseline LS (5.5-6.8kPa), repeat VCTE is only indicated when ALT increase > 6 U/L. The algorithm had 92% negative predictive value, 78% specificity, and 78% accuracy in the derivation cohort. In the validation cohort (n = 64), it had 91% NPV, 72% specificity, and 71% accuracy. CONCLUSION In low-risk MASLD, a simple algorithm combining baseline LS and ALT change can be used to safely avoid a repeat VCTE in a year.
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Affiliation(s)
- Harish Gopalakrishna
- Liver & Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Gayatri B Nair
- Department of Pulmonary and Sleep Medicine, Medstar Georgetown University Hospital, Washington DC, USA
| | - Roham Salman Roghani
- Liver & Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
- Department of Internal Medicine, Eisenhower Health, Rancho Mirage, CA, USA
| | - Natarajan Ravendhran
- Digestive Disease Associates, Baltimore, MD, USA
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Yaron Rotman
- Liver & Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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Borisov AN, Kutz A, Christ ER, Heim MH, Ebrahimi F. Canagliflozin and Metabolic Associated Fatty Liver Disease in Patients With Diabetes Mellitus: New Insights From CANVAS. J Clin Endocrinol Metab 2023; 108:2940-2949. [PMID: 37149821 PMCID: PMC10584001 DOI: 10.1210/clinem/dgad249] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/24/2023] [Accepted: 05/02/2023] [Indexed: 05/08/2023]
Abstract
CONTEXT Metabolic dysfunction-associated fatty liver disease (MAFLD) is highly prevalent among patients with type 2 diabetes mellitus (T2DM); however, there is still no approved pharmacological treatment. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been suggested to beneficially modify liver-related outcomes in patients with diabetes. OBJECTIVE We aimed to investigate the effects of the SGLT-2 inhibitor canagliflozin on liver-related outcomes in patients with advanced T2DM and high cardiovascular risk. METHODS We performed a secondary post hoc analysis of 2 large double-blind randomized controlled trials, CANVAS (NCT01032629) and CANVAS-R (NCT01989754), which included patients with T2DM and high cardiovascular risk who were randomized to receive either canagliflozin or placebo once daily. The primary endpoint was a composite of improvement of alanine aminotransferase (ALT) levels >30% or normalization of ALT levels. Secondary endpoints included change in noninvasive tests of fibrosis and weight reduction of >10%. RESULTS In total, 10 131 patients were included, with a median follow-up of 2.4 years (mean age 62 years; mean duration of diabetes 13.5 years; 64.2% male). Of those patients, 8967 (88.5%) had MAFLD according to hepatic steatosis index and 2599 (25.7%) exhibited elevated liver biochemistry at baseline. The primary composite endpoint occurred in 35.2% of patients receiving canagliflozin and in 26.4% with placebo (adjusted odds ratio [aOR] 1.51; 95% CI, 1.38-1.64; P < .001). Canagliflozin led to improvements in some noninvasive tests of fibrosis (NFS, APRI, FNI). Significant weight reduction of >10% (within 6 years) was achieved in 12.7% with canagliflozin compared to 4.1% with placebo (aOR 3.45; 95% CI, 2.91-4.10; P < .001). CONCLUSION In patients with T2DM, treatment with canagliflozin vs placebo resulted in improvements in liver biochemistry and metabolism and might beneficially affect liver fibrosis.
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Affiliation(s)
- Angel N Borisov
- Department of Gastroenterology and Hepatology, University Center for Gastrointestinal and Liver Diseases, CH-4031 Basel, Switzerland
- Division of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland
| | - Alexander Kutz
- Division of Endocrinology, Diabetes, and Metabolism, University Department of Medicine, Kantonsspital Aarau, 5001 Aarau, Switzerland
- Division of General and Emergency Medicine, University Department of Medicine, Kantonsspital Aarau, 5001 Aarau, Switzerland
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Emanuel R Christ
- Division of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland
| | - Markus H Heim
- Department of Gastroenterology and Hepatology, University Center for Gastrointestinal and Liver Diseases, CH-4031 Basel, Switzerland
| | - Fahim Ebrahimi
- Department of Gastroenterology and Hepatology, University Center for Gastrointestinal and Liver Diseases, CH-4031 Basel, Switzerland
- Division of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17165 Stockholm, Sweden
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Andreea MM, Surabhi S, Razvan-Ionut P, Lucia C, Camelia N, Emil T, Tiberiu NI. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Harms or Unexpected Benefits? MEDICINA (KAUNAS, LITHUANIA) 2023; 59:742. [PMID: 37109700 PMCID: PMC10143699 DOI: 10.3390/medicina59040742] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/29/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023]
Abstract
There is a need for innovative pharmaceutical intervention in light of the increasing prevalence of metabolic disease and cardiovascular disease. The kidneys' sodium-glucose cotransporter 2 inhibitors (SGLT2) receptors are targeted to reduce glucose reabsorption by SGLT2. Patients with type 2 diabetes mellitus (T2DM) benefit the most from reduced blood glucose levels, although this is just one of the numerous physiological consequences. To establish existing understanding and possible advantages and risks for SGLT2 inhibitors in clinical practice, this article will explore the influence of SGLT2 inhibitors on six major organ systems. In addition, this literature review will discuss the benefits and potential drawbacks of SGLT2 inhibitors on various organ systems and their potential application in therapeutic settings.
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Affiliation(s)
- Munteanu Madalina Andreea
- Department of Cardiology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
- “Theodor Burghele” Clinical Hospital, 050653 Bucharest, Romania
| | - Swarnkar Surabhi
- Department of Cardiovascular Science, University Medical Center Gottingen, 37075 Gottingen, Germany
| | - Popescu Razvan-Ionut
- “Theodor Burghele” Clinical Hospital, 050653 Bucharest, Romania
- Department of Urology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
| | - Ciobotaru Lucia
- Department of Nephrology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
| | - Nicolae Camelia
- Department of Cardiology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
- “Theodor Burghele” Clinical Hospital, 050653 Bucharest, Romania
| | - Tufanoiu Emil
- Department of Neurology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
- Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Nanea Ioan Tiberiu
- Department of Cardiology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
- “Theodor Burghele” Clinical Hospital, 050653 Bucharest, Romania
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11
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GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. Int J Mol Sci 2023; 24:ijms24021703. [PMID: 36675217 PMCID: PMC9865319 DOI: 10.3390/ijms24021703] [Citation(s) in RCA: 97] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.
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12
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Muacevic A, Adler JR, Sameera M, Fahad M, Brendan O, Deion S, Pemminati S. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Benefits Versus Risk. Cureus 2023; 15:e33939. [PMID: 36819350 PMCID: PMC9937770 DOI: 10.7759/cureus.33939] [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] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
With the growing burden of metabolic disease, cardiovascular disease, and diabetes mellitus, there is an implication for new pharmacological intervention. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a class of drugs that work on SGLT2 receptors in the kidneys to decrease glucose reabsorption. Lowering glucose levels mainly aids those with type 2 diabetes (T2DM), but they also have many other effects on the body. This article will investigate the impact of SGLT2i on six relevant organ systems; to establish current knowledge and potential benefits and risk for SGLTi in clinical practice. The medications that inhibit SGLT2 suffix with flozins are known to help decrease hypertension, acute cardiac failure, and bradycardia in the cardiovascular system. Flozins were found to aid with acute pulmonary edema, asthma, bronchitis, and chronic obstructive pulmonary disease (COPD) in the pulmonary system. SGLT2 is also found in the blood-brain barrier (BBB), and as such, SGLT2i can also affect the central nervous system (CNS). They reduced reactive oxygen species (ROS), BBB leakage, microglia burden, and acetylcholinesterase (AChE) levels. In the liver, this class of drugs can also assist with non-alcoholic fatty liver disease (NAFLD), hepatotoxicity, and weight loss. In the pancreas, SGLT2i has been shown to help with primarily diabetes and hyperglycemia. Finally, SGLT2i's are known to aid in decreasing nephrotoxicity and stopping the progression of the glomerular filtration rate (GFR) decrease. New studies have shown that the flozin drugs have been helpful for those who were receiving kidney transplants. Despite the positive effects, there are some concerns about SGLT2i and its notable adverse effects. Flozin drugs are known to cause urinary tract infections (UTIs), dehydration, orthostatic hypotension, postural dizziness, syncope, hypotension, hyperkalemia-induced cardiac arrest, and pancreatitis. This literature review will discuss, in detail, the benefits and risks that SGTL2i have on different organ systems and implicate the role they may play in clinical practice.
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13
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Rojano A, Sena E, Manzano-Nuñez R, Pericàs JM, Ciudin A. NAFLD as the metabolic hallmark of obesity. Intern Emerg Med 2023; 18:31-41. [PMID: 36357606 DOI: 10.1007/s11739-022-03139-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/17/2022] [Indexed: 11/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide, associated with a high risk of progression to NASH, liver cirrhosis and hepatocarcinoma. Its prevalence is closely related to obesity (understood as adipose-based disease and insulin resistance), which makes that at present NAFLD can be considered a metabolic dysfunction hallmark, regardless of the body mass index. Despite being such a prevalent condition, with such severe consequences, at present there are no reliable biomarkers for its diagnosis or specific treatment. Significant and sustained weight loss, as well as some antidiabetic treatments, has shown promising results for NAFLD but data needs confirmation in larger clinical trials and longer follow-up. Efforts should be made for a better and more accurate baseline diagnosis (including large-scale genetics), identification of patients at higher risk for progression to NASH as well as adequate treatment, to allow us to offer a personalized approach in NAFLD in the context of precision medicine.
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Affiliation(s)
- Alba Rojano
- Endocrinology and Nutrition Department, Vall d'HebronInstitut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain
| | - Elena Sena
- Liver Unit, Internal Medicine Department, Vall d'HebronInstitut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain
| | - Ramiro Manzano-Nuñez
- Liver Unit, Internal Medicine Department, Vall d'HebronInstitut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain
| | - Juan M Pericàs
- Liver Unit, Internal Medicine Department, Vall d'HebronInstitut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Digestivas Y Hepáticas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
| | - Andreea Ciudin
- Endocrinology and Nutrition Department, Vall d'HebronInstitut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain.
- CIBER de Diabetes Y Enfermedades Metabólicas Asociadas (CIBERDem), Instituto de Salud Carlos III, Madrid, Spain.
- Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.
- Pathology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain.
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14
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Tapper EB, Fleming C, Rendon A, Fernandes J, Johansen P, Augusto M, Nair S. The Burden of Nonalcoholic Steatohepatitis: A Systematic Review of Epidemiology Studies. GASTRO HEP ADVANCES 2022; 1:1049-1087. [PMID: 39131247 PMCID: PMC11307414 DOI: 10.1016/j.gastha.2022.06.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 06/30/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Nonalcoholic steatohepatitis (NASH) is associated with increased mortality and risk of complications but is often asymptomatic and under-recognized. A systematic review of NASH epidemiology was conducted to provide information on the burden of NASH and highlight important evidence gaps for future research. Methods Medline, EMBASE, and Cochrane Library databases were searched for English-language publications published from 2010 to January 2022 that reported on natural history, risk factors, comorbidities, and complications of a NASH population or subpopulation. Results Overall, 173 publications were included. NASH was shown to have a variable disease course and high prevalence of comorbid disease. Although many patients progressed to cirrhosis and end-stage liver disease, disease regression or resolution was reported in up to half of patients in some studies. Reported risk factors for disease progression or resolution included levels of (or changes in) serum fibrosis markers, liver enzymes, and platelets. The presence of NASH increased the risk of liver cirrhosis and other serious diseases such as hepatocellular carcinoma, colorectal cancer, chronic kidney disease, and cardiovascular disease. In 2017, NASH was responsible for ∼118,000 cirrhosis deaths globally, and an increasing proportion of patients are receiving liver transplantation for NASH in Europe and the United States. Consolidation of data was hampered by heterogeneity across the studies in terms of patient populations, follow-up time, and outcomes measured. Conclusion NASH is associated with significant morbidity and mortality, an increased risk of comorbidities, and imposes an increasing burden among liver transplantation recipients. Longer studies with harmonized study criteria are required to better understand the impact of NASH on patient outcomes.
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Affiliation(s)
- Elliot B. Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Adriana Rendon
- Global Medical Affairs, Novo Nordisk A/S, Søborg, Denmark
| | - João Fernandes
- Payer Evidence Generation, Novo Nordisk A/S, Søborg, Denmark
| | - Pierre Johansen
- Novo Nordisk Denmark A/S, Region North & West Europe, Ørestad, Denmark
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15
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Lee J, Mulder F, Leeflang M, Wolff R, Whiting P, Bossuyt PM. QUAPAS: An Adaptation of the QUADAS-2 Tool to Assess Prognostic Accuracy Studies. Ann Intern Med 2022; 175:1010-1018. [PMID: 35696685 DOI: 10.7326/m22-0276] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Whereas diagnostic tests help detect the cause of signs and symptoms, prognostic tests assist in evaluating the probable course of the disease and future outcome. Studies to evaluate prognostic tests are longitudinal, which introduces sources of bias different from those for diagnostic accuracy studies. At present, systematic reviews of prognostic tests often use the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool to assess risk of bias and applicability of included studies because no equivalent instrument exists for prognostic accuracy studies. QUAPAS (Quality Assessment of Prognostic Accuracy Studies) is an adaptation of QUADAS-2 for prognostic accuracy studies. Questions likely to identify bias were evaluated in parallel and collated from QUIPS (Quality in Prognosis Studies) and PROBAST (Prediction Model Risk of Bias Assessment Tool) and paired to the corresponding question (or domain) in QUADAS-2. A steering group conducted and reviewed 3 rounds of modifications before arriving at the final set of domains and signaling questions. QUAPAS follows the same steps as QUADAS-2: Specify the review question, tailor the tool, draw a flow diagram, judge risk of bias, and identify applicability concerns. Risk of bias is judged across the following 5 domains: participants, index test, outcome, flow and timing, and analysis. Signaling questions assist the final judgment for each domain. Applicability concerns are assessed for the first 4 domains. The authors used QUAPAS in parallel with QUADAS-2 and QUIPS in a systematic review of prognostic accuracy studies. QUAPAS improved the assessment of the flow and timing domain and flagged a study at risk of bias in the new analysis domain. Judgment of risk of bias in the analysis domain was challenging because of sparse reporting of statistical methods.
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Affiliation(s)
- Jenny Lee
- Department of Epidemiology and Data Science, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands (J.L., M.L., P.M.B.)
| | - Frits Mulder
- Department of Vascular Medicine, Cardiovascular Sciences, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands (F.M.)
| | - Mariska Leeflang
- Department of Epidemiology and Data Science, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands (J.L., M.L., P.M.B.)
| | - Robert Wolff
- Kleijnen Systematic Reviews, Escrick, United Kingdom (R.W.)
| | - Penny Whiting
- Bristol Medical School, University of Bristol, Bristol, United Kingdom (P.W.)
| | - Patrick M Bossuyt
- Department of Epidemiology and Data Science, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands (J.L., M.L., P.M.B.)
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Kahl S, Ofstad AP, Zinman B, Wanner C, Schüler E, Sattar N, Inzucchi SE, Roden M. Effects of empagliflozin on markers of liver steatosis and fibrosis and their relationship to cardiorenal outcomes. Diabetes Obes Metab 2022; 24:1061-1071. [PMID: 35166009 DOI: 10.1111/dom.14670] [Citation(s) in RCA: 15] [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: 08/27/2021] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 12/24/2022]
Abstract
AIMS Empagliflozin treatment reduced liver fat in small type 2 diabetes cohorts. This post-hoc study evaluated effects of empagliflozin on risk for non-alcoholic fatty liver disease-related steatosis and fibrosis, as well as the relationship between risk categories and cardiorenal outcomes in the randomized, placebo-controlled EMPA-REG OUTCOME trial. MATERIALS AND METHODS EMPA-REG OUTCOME treated 7020 people with type 2 diabetes and cardiovascular disease with 10/25 mg/day empagliflozin or placebo. For this analysis, the Dallas steatosis index, hepatic steatosis index, non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score were calculated to assess steatosis and fibrosis risk. Changes from baseline in scores were examined by mixed model repeated measures and their associations with cardiorenal outcomes and mortality by Cox regression. RESULTS At baseline, 73% and 84% of participants had high steatosis risk by Dallas steatosis index and hepatic steatosis index, whereas 23% and 4% had a high risk of advanced fibrosis by non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score. Percentages of people at high steatosis risk slightly decreased with empagliflozin only, whereas empagliflozin did not improve percentages of individuals at high fibrosis risk over time compared with placebo. The high risk of advanced fibrosis at baseline related to higher risk for cardiovascular events. Effects of empagliflozin on cardiorenal and all-cause mortality outcomes were consistent across all risk groups. CONCLUSIONS Empagliflozin may reduce steatosis but not fibrosis risk in individuals with type 2 diabetes and cardiovascular disease. The improvements in cardiorenal outcomes and mortality associated with empagliflozin therapy appear to be independent of steatosis and fibrosis risk.
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Affiliation(s)
- Sabine Kahl
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research, München-Neuherberg, Germany
| | | | - Bernard Zinman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | | | | | - Naveed Sattar
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre (GCRC), Glasgow, UK
| | | | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research, München-Neuherberg, Germany
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17
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Multidisciplinary lifestyle intervention is associated with improvements in liver damage and in surrogate scores of NAFLD and liver fibrosis in morbidly obese patients. Eur J Nutr 2022; 61:2725-2735. [PMID: 35277756 PMCID: PMC9279260 DOI: 10.1007/s00394-022-02846-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 02/16/2022] [Indexed: 02/07/2023]
Abstract
Purpose Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Particularly morbidly obese patients are at risk of developing progressive liver disease. Nutritional and lifestyle intervention is recommended as the standard of care in NAFLD. However, there is a striking lack of evidence to support the efficacy of lifestyle intervention to treat NAFLD in morbidly obese patients. Here, we aimed to assess the impact of lifestyle intervention on NAFLD in the morbidly obese in a real-world setting. Methods 136 obese patients were included in an industry-independent, multiprofessional lifestyle intervention program with a lead-in phase of 12 weeks of formula diet and a total of 48 weeks intensive counselling. Body weight and markers of the metabolic syndrome were analyzed. Presence of NAFLD was screened for by use of non-invasive markers of fatty liver, non-alcoholic steatohepatitis and liver fibrosis. Results Weight loss goals (i.e. > 5% or > 10% of initial body weight, respectively, depending on baseline BMI) were achieved in 89.7% of subjects in the intention-to-treat analysis and 93.9% in the per-protocol analysis. This was associated with a pronounced improvement in serum ALT values. The percentage of subjects who fulfilled non-invasive criteria for fatty liver dropped from 95.2 to 54.8%. Risk of NASH improved and the number of patients at risk of liver fibrosis declined by 54.1%. Conclusion Lifestyle intervention was associated with a marked improvement of serum ALT and an improvement of surrogate scores indicative of NAFLD and, importantly, advanced fibrosis, in a real-world cohort of morbidly obese patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00394-022-02846-7.
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Ciardullo S, Perseghin G. Advances in fibrosis biomarkers in nonalcoholic fatty liver disease. Adv Clin Chem 2022; 106:33-65. [PMID: 35152974 DOI: 10.1016/bs.acc.2021.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult world population and the degree of liver fibrosis represents the best predictor of the development of liver-related outcomes. Easily applicable and well performing non-invasive fibrosis tests can overcome the limitations of liver biopsy and are of paramount importance to identify at-risk subjects in clinical practice. While tests with optimal performance and ease of use do not exist at this stage, available markers can be divided in three broad groups: simple serum tests, complex serum tests and elastographic methods. Simple scores (such as Fibrosis-4 and NAFLD Fibrosis Score) are based on readily available biochemical data and clinical features, while complex/proprietary tests (such as Fibrotest, Enhanced Liver Fibrosis and Hepascore) directly measure markers of fibrogenesis and fibrolysis, but have higher costs. Elastography techniques estimate the degree of fibrosis from liver stiffness and are based on either ultrasound or magnetic resonance (MR) imaging. MR elastography has better performance compared with sonographic techniques and is not affected by obesity and inflammation, but is highly costly and less available. In general, non-invasive tests are able to exclude the presence of fibrosis, but their positive predictive value is low to moderate and they lead to a high number of indeterminate results. In this context, a combination of different tests might increase accuracy while reducing gray-zone results. Their ability to predict future events and response to treatment is suboptimal and needs to be studied further. Finally, recent studies have tried different approaches, spanning from "omics" to the microbiome and micro-RNAs, with some promising results.
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Affiliation(s)
- Stefano Ciardullo
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy; School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
| | - Gianluca Perseghin
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy; School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy.
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Xia J, Jin G, Hua Q, Cui S, Li J. Nomogram for Quantitatively Estimating the Risk of Fibrosis Progression in Type 2 Diabetic Patients With Nonalcoholic Fatty Liver Disease: A Pilot Study. Front Endocrinol (Lausanne) 2022; 13:917304. [PMID: 35837300 PMCID: PMC9273858 DOI: 10.3389/fendo.2022.917304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Correct identification of the fibrosis progression risk is a critical step in the management of patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD), because liver fibrosis, especially advanced liver fibrosis, is difficult to reverse. However, the progression of liver fibrosis is typically unnoticeable, leading to many patients failing to adhere to long-term therapeutic interventions. Reliable clinical tools for the quantification of the fibrosis progression risk may have effects on following long-term therapeutic recommendations to avoid further liver injury. OBJECTIVE This study aims to develop a nomogram for quantitatively estimating the risk of fibrosis progression in T2DM patients with NAFLD during lifestyle intervention. METHODS A total of 432 medical records of T2DM patients with NAFLD were retrospectively analyzed in this study. We divided patients into the progression and no-progression groups according to whether the value of liver stiffness measurement (LSM) increased by > 2 kPa at the last visit. The independent factors associated with the fibrosis progression, which were screened by univariate and multivariate Logistic regression, constituted the nomogram to determine the likelihood of fibrosis progression in T2DM patients with NAFLD. RESULTS Sixty-five of the 432 individuals (15%) were found to have fibrosis progression. Changes in body mass index [odds ratio (OR) = 1.586], glycosylated hemoglobin A1c (OR = 6.636), alanine aminotransferase (OR = 1.052), and platelet counts (OR = 0.908) were independently associated with fibrosis progression (all P < 0.05) and functioned as components of the newly developed nomogram. It showed satisfied discrimination and calibration after 1,000 bootstrapping. The DCA indicated that the nomogram yielded clinical net benefit when the threshold probability was < 0.8. CONCLUSION We developed a nomogram incorporating dynamic alterations in clinical features to estimate the risk of fibrosis progression in T2DM patients with NAFLD, which aids the patients' compliance with long-term life interventions while allowing for prompt intervention adjustments.
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Affiliation(s)
- Jinying Xia
- Department of Endocrinology, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Guang Jin
- Department of Ultrasound, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Qifeng Hua
- Department of Radiology, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Shihan Cui
- Department of Radiology, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Jianhui Li
- Department of Endocrinology, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
- *Correspondence: Jianhui Li, , orcid.org/0000-0001-7032-4404
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Ruiz-Casas L, Pedra G, Shaikh A, Franks B, Dhillon H, Fernandes JDDR, Mangla KK, Augusto M, Schattenberg JM, Romero-Gómez M. Clinical and sociodemographic determinants of disease progression in patients with nonalcoholic steatohepatitis in the United States. Medicine (Baltimore) 2021; 100:e28165. [PMID: 34918671 PMCID: PMC8677997 DOI: 10.1097/md.0000000000028165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 11/17/2021] [Indexed: 01/05/2023] Open
Abstract
One fifth of patients with nonalcoholic fatty liver disease (NAFLD) may progress to nonalcoholic steatohepatitis (NASH), which can increase the risk of cirrhosis, cancer, and death. To date, reported predictors of NASH progression have been heterogeneous.We identified determinants of fibrosis progression in patients with NASH in the United States using physician-reported data from the real-world Global Assessment of the Impact of NASH (GAIN) study, including demographics and clinical characteristics, NASH diagnostic information, fibrosis stage, comorbidities, and treatment. We developed a logistic regression model to assess the likelihood of fibrosis progression since diagnosis, controlling for sociodemographic and clinical variables. An iterative nested model selection approach using likelihood ratio test determined the final model.A total of 989 patients from the GAIN US cohort were included; 46% were women, 58% had biopsy-proven NAFLD, and 74% had fibrosis stage F0-F2 at diagnosis. The final multivariable model included age, years since diagnosis, sex, employment status, smoking status, obesity, fibrosis stage, diagnostic biopsy, Vitamin E, and liver transplant proposed at diagnosis. Odds of progression were 17% higher (odds ratio, 1.17 [95% CI: 1.11-1.23]; P < .001) with each year since NASH diagnosis, 41% lower (0.59 [0.38-0.90]; P = .016) for women than men, 131% higher (2.31 [1.30-4.03]; P = .004) for smokers versus non-smokers, and 89% higher (1.89 [1.26-2.86]; P = .002) with obesity. Odds of progression were also higher with part-time, retired, unemployed, and unable to work due to NASH status versus full-time employment, and when a liver transplant was proposed at diagnosis.Disease duration and severity, obesity, smoking, and lack of full-time employment were significant determinants of fibrosis progression. These findings can support clinical and health-policy decisions to improve NASH management in the US.
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Affiliation(s)
| | | | - Anum Shaikh
- HCD Economics, Daresbury, Cheshire, United Kingdom
| | | | | | | | | | | | - Jörn M. Schattenberg
- Metabolic Liver Research Program, University Medical Center Mainz, Mainz, Germany
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21
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Jin J, Liu Y, Xu X, Wang Z, Niu J. The association between Fc gamma RIIb expression levels and chronic hepatitis B virus infection progression. BMC Infect Dis 2021; 21:1235. [PMID: 34879827 PMCID: PMC8653572 DOI: 10.1186/s12879-021-06918-7] [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: 07/28/2021] [Accepted: 11/17/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Fc gamma receptor IIb (FcγRIIb) is an important inhibitory receptor that plays vital roles in regulating various immune response processes and the pathogenesis of many infectious diseases. The purpose of our research was to evaluate FcγRIIb expression in serum and liver biopsy specimens from hepatitis B virus (HBV)-infected patients and to explore the association of FcγRIIb with chronic HBV infection. METHODS Enzyme-linked immunosorbent assay (ELISA) was adopted to measure the serum FcγRIIb levels in 119 HBV-infected patients and 24 healthy controls. An immunohistochemical method was then employed to identify FcγRIIb expression in biopsy specimens from patients with chronic hepatitis B (CHB). The integrated optical density (IOD) value was measured to represent FcγRIIb expression levels. RESULTS Serum FcγRIIb levels were decreased in CHB patients compared to controls (P < 0.001). The FcγRIIb levels in the CHB patient group were remarkably lower than those in the HBV carrier group (P < 0.001). In addition, FcγRIIb levels were negatively associated with AST and ALT (r = -0.3936, P = 0.0063; r = -0.3459, P = 0.0097, respectively). The IOD values of FcγRIIb expression in the moderate and severe CHB groups were significantly lower than those in the control group (P = 0.006 and P < 0.001, respectively). The FcγRIIb level tended to be lower with pathological changes related to hepatitis. Furthermore, correlation analysis revealed that FcγRIIb had negative correlations with AST and ALT (r = -0.688, P = 0.0016; r = -0.686, P = 0.0017, respectively) but a positive association with the platelet count (r = 0.6464, P = 0.0038). CONCLUSIONS FcγRIIb levels are significantly related to chronic HBV infection and the progression of CHB. Changes in FcγRIIb may affect the progression of liver inflammation and fibrosis in CHB patients.
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Affiliation(s)
- Jinglan Jin
- Department of Hepatology, First Bethune Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin, 130021, People's Republic of China
| | - Yuwei Liu
- Department of Hepatology, First Bethune Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin, 130021, People's Republic of China
| | - Xiaotong Xu
- Department of Hepatology, First Bethune Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin, 130021, People's Republic of China
| | - Zhongfeng Wang
- Department of Hepatology, First Bethune Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin, 130021, People's Republic of China
| | - Junqi Niu
- Department of Hepatology, First Bethune Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin, 130021, People's Republic of China.
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22
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Haufe S, Hupa-Breier KL, Bayerle P, Boeck HT, Rolff S, Sundermeier T, Kerling A, Eigendorf J, Kück M, Hanke AA, Ensslen R, Nachbar L, Lauenstein D, Böthig D, Hilfiker-Kleiner D, Stiesch M, Terkamp C, Wedemeyer H, Haverich A, Tegtbur U. Telemonitoring-Supported Exercise Training in Employees With Metabolic Syndrome Improves Liver Inflammation and Fibrosis. Clin Transl Gastroenterol 2021; 12:e00371. [PMID: 34140456 PMCID: PMC8216678 DOI: 10.14309/ctg.0000000000000371] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 04/28/2021] [Indexed: 01/03/2023] Open
Abstract
INTRODUCTION Metabolic syndrome (MetS) is a major health problem worldwide and the main risk factor for metabolic-associated fatty liver disease (MAFLD). Established treatment options are lifestyle interventions facilitating dietary change and increased physical activity. Here, we tested the effect of a telemonitoring-supported intervention on liver parameter of inflammation and fibrosis in individuals with MetS. METHODS This was a prospective, randomized, parallel-group, and assessor-blind study performed in workers of the main Volkswagen factory (Wolfsburg, Germany). Volunteers with diagnosed MetS were randomly assigned (1:1) to a 6-month lifestyle intervention focusing on supervised, activity-tracker-guided exercise or to a waiting-list control group. This secondary analysis assessed the effect of the intervention on liver enzymes and MAFLD-related parameters. RESULTS We screened 543 individuals between October 10, 2017, and February 27, 2018, of whom 314 were randomly assigned to the intervention group (n = 160) or control group (n = 154). Liver transaminases, alkaline phosphatase, and gamma-glutamyl transferase significantly decreased after 6 months in the intervention group compared with the CG. Furthermore, an aspartate aminotransferase-to-platelet ratio index score as a marker for liver fibrosis significantly decreased in the intervention group. These improvements were associated with changes in obesity and exercise capacity. DISCUSSION A 6-month lifestyle intervention based on exercise training with individualized telemonitoring-based supervision led to improvements of liver inflammation and fibrosis in employees with MetS. Therefore, this intervention shows therapeutic potential for individuals at high risk of MAFLD (ClinicalTrials.gov Identifier: NCT03293264).
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Affiliation(s)
- Sven Haufe
- Institute of Sports Medicine, Hannover Medical School, Hannover, Germany;
- Institute of Sports Science, Leibniz University Hannover, Hannover, Germany;
| | - Katharina L. Hupa-Breier
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany;
| | - Pauline Bayerle
- Institute of Sports Medicine, Hannover Medical School, Hannover, Germany;
| | - Hedwig T. Boeck
- Institute of Sports Medicine, Hannover Medical School, Hannover, Germany;
| | - Simone Rolff
- Institute of Sports Medicine, Hannover Medical School, Hannover, Germany;
| | | | - Arno Kerling
- Institute of Sports Medicine, Hannover Medical School, Hannover, Germany;
| | - Julian Eigendorf
- Institute of Sports Medicine, Hannover Medical School, Hannover, Germany;
| | - Momme Kück
- Institute of Sports Medicine, Hannover Medical School, Hannover, Germany;
| | - Alexander A. Hanke
- Institute of Sports Medicine, Hannover Medical School, Hannover, Germany;
| | | | | | | | - Dietmar Böthig
- Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Germany;
| | | | - Meike Stiesch
- Department of Prosthetic Dentistry and Biomedical Materials Science, Hannover Medical School, Hannover, Germany.
| | - Christoph Terkamp
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany;
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany;
| | - Axel Haverich
- Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Germany;
| | - Uwe Tegtbur
- Institute of Sports Medicine, Hannover Medical School, Hannover, Germany;
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23
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Petta S, Sebastiani G, Viganò M, Ampuero J, Wai-Sun Wong V, Boursier J, Berzigotti A, Bugianesi E, Fracanzani AL, Cammà C, Enea M, Grottes MD, Di Marco V, Younes R, Keyrouz A, Mazzola S, Mendoza Y, Pennisi G, Romero-Gomez M, Craxì A, de Ledinghen V. Monitoring Occurrence of Liver-Related Events and Survival by Transient Elastography in Patients With Nonalcoholic Fatty Liver Disease and Compensated Advanced Chronic Liver Disease. Clin Gastroenterol Hepatol 2021; 19:806-815.e5. [PMID: 32621970 DOI: 10.1016/j.cgh.2020.06.045] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 06/13/2020] [Accepted: 06/17/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with advanced fibrosis related to nonalcoholic fatty liver disease (NAFLD) are at risk of developing hepatic and extrahepatic complications. We investigated whether, in a large cohort of patients with NAFLD and compensated advanced chronic liver disease, baseline liver stiffness measurements (LSMs) and their changes can be used to identify patients at risk for liver-related and extrahepatic events. METHODS We performed a retrospective analysis of consecutive patients with NAFLD (n = 1039) with a histologic diagnosis of F3-F4 fibrosis and/or LSMs>10 kPa, followed for at least 6 months, from medical centers in 6 countries. LSMs were made by FibroScan using the M or XL probe and recorded at baseline and within 1 year from the last follow-up examination. Differences between follow up and baseline LSMs were categorized as: improvement (reduction of more than 20%), stable (reduction of 20% to an increase of 20%), impairment (an increase of 20% or more). We recorded hepatic events (such as liver decompensation, ascites, encephalopathy, variceal bleeding, jaundice, or hepatocellular carcinoma [HCC]) and overall and liver-related mortality during a median follow-up time of 35 months (interquartile range, 19-63 months). RESULTS Based on Cox regression analysis, baseline LSM was independently associated with occurrence of hepatic decompensation (hazard ratio [HR], 1.03; 95% CI, 1.02-1.04; P < .001), HCC (HR, 1.03; 95% CI, 1.00-1.04; P = .003), and liver-related death (HR, 1.02; 95% CI, 1.02-1.03; P = .005). In 533 patients with available LSMs during the follow-up period, change in LSM was independently associated with hepatic decompensation (HR, 1.56; 95% CI, 1.05-2.51; P = .04), HCC (HR, 1.72; 95% CI, 1.01-3.02; P = .04), overall mortality (HR, 1.73; 95% CI, 1.11-2.69; P = .01), and liver-related mortality (HR, 1.96; 95% CI, 1.10-3.38; P = .02). CONCLUSIONS In patients with NAFLD and compensated advanced chronic liver disease, baseline LSM and change in LSM are associated with risk of liver-related events and mortality.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, Mother and Child Care, Internal Medicine and Medical Specialties, Università di Palermo, Palermo, Italy.
| | - Giada Sebastiani
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Mauro Viganò
- Hepatology Unit, Ospedale San Giuseppe, University of Milan, Milan, Italy
| | - Javier Ampuero
- Digestive Diseases Unit, Hospital Universitario Virgen del Rocío, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Instituto de Biomedicina de Sevilla, University of Seville, Seville, Spain
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Jerome Boursier
- Hepato-Gastroenterology Department, Angers University Hospital, Angers, France
| | - Annalisa Berzigotti
- Hepatology Group, University Clinic for Visceral Surgery and Medicine, Inselspital, Department for Biomedical Research, University of Bern, Bern, Switzerland
| | - Elisabetta Bugianesi
- Division of Gastroenterology, Department of Medical Sciences, University of Torino, Turin, Italy
| | - Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Milan, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia e Epatologia, Mother and Child Care, Internal Medicine and Medical Specialties, Università di Palermo, Palermo, Italy
| | - Marco Enea
- Dipartimento di Scienze Economiche, Aziendali e Statistiche, University of Palermo, Palermo, Italy
| | - Marraud des Grottes
- Centre d'Investigation de la Fibrose Hépatique, INSERM U1053, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France
| | - Vito Di Marco
- Sezione di Gastroenterologia e Epatologia, Mother and Child Care, Internal Medicine and Medical Specialties, Università di Palermo, Palermo, Italy
| | - Ramy Younes
- Division of Gastroenterology, Department of Medical Sciences, University of Torino, Turin, Italy
| | - Aline Keyrouz
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Sergio Mazzola
- Clinical Epidemiology and Cancer Registry Operative Unit, University Hospital Policlinico "Paolo Giaccone," Palermo, Italy
| | - Yuly Mendoza
- Hepatology Group, University Clinic for Visceral Surgery and Medicine, Inselspital, Department for Biomedical Research, University of Bern, Bern, Switzerland
| | - Grazia Pennisi
- Sezione di Gastroenterologia e Epatologia, Mother and Child Care, Internal Medicine and Medical Specialties, Università di Palermo, Palermo, Italy
| | - Manuel Romero-Gomez
- Digestive Diseases Unit, Hospital Universitario Virgen del Rocío, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Instituto de Biomedicina de Sevilla, University of Seville, Seville, Spain
| | - Antonio Craxì
- Sezione di Gastroenterologia e Epatologia, Mother and Child Care, Internal Medicine and Medical Specialties, Università di Palermo, Palermo, Italy
| | - Victor de Ledinghen
- Centre d'Investigation de la Fibrose Hépatique, INSERM U1053, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France
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24
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Kogachi S, Noureddin M. Noninvasive Evaluation for Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Clin Ther 2021; 43:455-472. [PMID: 33581876 DOI: 10.1016/j.clinthera.2021.01.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/26/2020] [Accepted: 01/04/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and has the potential risk for progressing to nonalcoholic steatohepatitis (NASH), which is associated with a greater risk for complications of chronic liver disease. Noninvasive testing has been evaluated for diagnosis, risk stratification, disease progression, and assessing response to therapy. The purpose of this narrative review was to outline the current noninvasive testing modalities for the diagnostic evaluation of NAFLD and NASH, while discussing possible markers that could be used for monitoring response to therapies. METHODS The PubMed and Cochrane databases were searched for relevant articles that evaluated the diagnosis of NAFLD/NASH with serum biomarkers and/or imaging. FINDINGS Serum biomarkers, imaging modalities, and combinations/serial algorithms involved in the diagnosis of NAFLD and NASH are outlined. In addition, noninvasive modalities that have been used for assessing response to therapies in clinical trials are discussed. IMPLICATIONS Liver biopsy currently remains the gold standard for diagnosis and is often used in clinical trials to assess treatment response. However, developing safe and accessible noninvasive modalities for diagnosis and monitoring will have greater impact and relevance, as biopsy may not always be feasible in all clinical settings.
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Affiliation(s)
- Shannon Kogachi
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Mazen Noureddin
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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25
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Lee J, Vali Y, Boursier J, Spijker R, Anstee QM, Bossuyt PM, Zafarmand MH. Prognostic accuracy of FIB-4, NAFLD fibrosis score and APRI for NAFLD-related events: A systematic review. Liver Int 2021; 41:261-270. [PMID: 32946642 PMCID: PMC7898346 DOI: 10.1111/liv.14669] [Citation(s) in RCA: 210] [Impact Index Per Article: 52.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/27/2020] [Accepted: 09/07/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Fibrosis is the strongest predictor for long-term clinical outcomes among patients with non-alcoholic fatty liver disease (NAFLD). There is growing interest in employing non-invasive methods for risk stratification based on prognosis. FIB-4, NFS and APRI are models commonly used for detecting fibrosis among NAFLD patients. We aimed to synthesize existing literature on the ability of these models in prognosticating NAFLD-related events. METHODS A sensitive search was conducted in two medical databases to retrieve studies evaluating the prognostic accuracy of FIB-4, NFS and APRI among NAFLD patients. Target events were change in fibrosis, liver-related event and mortality. Two reviewers independently performed reference screening, data extraction and quality assessment (QUAPAS tool). RESULTS A total of 13 studies (FIB-4:12, NFS: 11, APRI: 10), published between 2013 and 2019, were retrieved. All studies were conducted in a secondary or tertiary care setting, with follow-up ranging from 1 to 20 years. All three markers showed consistently good prognostication of liver-related events (AUC from 0.69 to 0.92). For mortality, FIB-4 (AUC of 0.67-0.82) and NFS (AUC of 0.70-0.83) outperformed APRI (AUC of 0.52-0.73) in all studies. All markers had inconsistent performance for predicting change in fibrosis stage. CONCLUSIONS FIB-4, NFS, and APRI have demonstrated ability to risk stratify patients for liver-related morbidity and mortality, with comparable performance to a liver biopsy, although more head-to-head studies are needed to validate this. More refined models to prognosticate NAFLD-events may further enhance performance and clinical utility of non-invasive markers.
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Affiliation(s)
- Jenny Lee
- Epidemiology and Data ScienceAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Yasaman Vali
- Epidemiology and Data ScienceAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Jerome Boursier
- Hepato‐Gastroenterology DepartmentAngers University HospitalAngersFrance,HIFIH LaboratoryUPRES EA3859Angers UniversityAngersFrance
| | - Rene Spijker
- Medical LibraryAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands,Cochrane NetherlandsJulius Center for Health Sciences and Primary CareUniversity Medical Center UtrechtUtrecht UniversityUtrechtThe Netherlands
| | - Quentin M. Anstee
- The Newcastle Liver Research GroupFaculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK,Newcastle NIHR Biomedical Research CentreNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | - Patrick M. Bossuyt
- Epidemiology and Data ScienceAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Mohammad H. Zafarmand
- Epidemiology and Data ScienceAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
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Kalopitas G, Antza C, Doundoulakis I, Siargkas A, Kouroumalis E, Germanidis G, Samara M, Chourdakis M. Impact of Silymarin in individuals with nonalcoholic fatty liver disease: A systematic review and meta-analysis. Nutrition 2020; 83:111092. [PMID: 33418491 DOI: 10.1016/j.nut.2020.111092] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/01/2020] [Accepted: 11/17/2020] [Indexed: 12/18/2022]
Abstract
OBJECTIVES Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting a significant proportion of the general population. Recently, randomized clinical trials have been conducted examining the efficacy of silymarin in individuals with NAFLD, with conflicting results. The aim of this meta-analysis was to evaluate the efficacy of silymarin in the treatment of NAFLD by examining changes in liver biochemistry, body mass index, and liver histology. METHODS We searched major electronic databases PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, as well as gray-literature sources, up to June 2020 for randomized clinical trials examining the efficacy of treatment with silymarin in individuals with NAFLD compared to placebo. The primary outcomes were changes in the mean values of transaminases (alanine aminotransferase and aspartate aminotransferase). Secondary outcomes included changes in body mass index and liver histology. Quality analysis was performed with the risk-of-bias tool 2.0. We synthesized results using weighted mean differences for continuous outcomes, along with 95% confidence intervals. RESULTS In the meta-analysis, eight randomized clinical trials were included. A cutoff level of 0.05 was considered to provide statistically significant results. Silymarin treatment led to a statistically significant greater reduction in the levels of transaminases compared to placebo, irrespective of weight loss. CONCLUSIONS Silymarin seems to be effective in reducing transaminase levels in individuals with NAFLD. Despite the statistical benefits, we call attention to potential flaws related to the quality of the included studies. Further well-designed studies should be carried out to examine whether this reduction in transaminase levels corresponds to histologic improvement.
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Affiliation(s)
- Georgios Kalopitas
- Division of Gastroenterology and Hepatology, 1st Department of Internal Medicine, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Christina Antza
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece; Third Department of Internal Medicine, G. H. "Papageorgiou", School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Doundoulakis
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Antonis Siargkas
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Elias Kouroumalis
- Department of Gastroenterology and Hepatology, University Hospital of Heraklion, School of Medicine, University of Crete, Greece
| | - Georgios Germanidis
- Division of Gastroenterology and Hepatology, 1st Department of Internal Medicine, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Myrto Samara
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Michail Chourdakis
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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Adams LA, Chan WK. Noninvasive Tests in the Assessment of NASH and NAFLD Fibrosis: Now and Into the Future. Semin Liver Dis 2020; 40:331-338. [PMID: 32526784 DOI: 10.1055/s-0040-1713006] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Noninvasive serum and imaging methods offer accessible, accurate, and safe assessment of fibrosis severity in nonalcoholic fatty liver disease. In contrast, current serum and imaging methods for the prediction of nonalcoholic steatohepatitis are not sufficiently accurate for routine clinical use. Serum fibrosis markers that incorporate direct measures of fibrogenesis (for example, hyaluronic acid) or fibrinolysis are generally more accurate than biomarkers not incorporating direct measures of fibrogenesis. Elastography methods are more accurate than serum markers for fibrosis assessment and particularly for the determination of cirrhosis, but have a significant failure and/or unreliability rate in obese individuals. To overcome this, combining serum and elastography methods in a sequential manner minimizes indeterminate results and maintains accuracy. The accuracy of current noninvasive methods for monitoring fibrosis response to treatment are limited; however, new tools derived from "omic" methodologies offer promise for the future.
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Affiliation(s)
- Leon A Adams
- Medical School, Faculty of Medicine and Health Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.,Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
| | - Wah-Kheong Chan
- Department of Medicine, Gastroenterology and Hepatology Unit, University of Malaysia, Kuala Lumpur, Malaysia
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Long MT, Gandhi S, Loomba R. Advances in non-invasive biomarkers for the diagnosis and monitoring of non-alcoholic fatty liver disease. Metabolism 2020; 111S:154259. [PMID: 32387227 PMCID: PMC7529729 DOI: 10.1016/j.metabol.2020.154259] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 04/29/2020] [Accepted: 05/01/2020] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease in the United States, affecting approximately 1 out of every 4 Americans. NAFLD is a spectrum of disorders including simple steatosis, characterized by the presence of hepatic steatosis with minimal inflammation, and nonalcoholic steatohepatitis (NASH), characterized by the presence of hepatic steatosis with lobular inflammation, ballooning with or without peri-sinusoidal fibrosis. NASH may lead to progressive fibrosis, and therefore, Individuals with NASH and, in particular, hepatic fibrosis are at increased risk for both liver- and cardiovascular-related outcomes compared to those with steatosis alone. New treatments for NASH and hepatic fibrosis are emerging, so now, more than ever, it is important to identify individuals with more advanced disease who may be candidates for therapy. Noninvasive methods to accurately diagnosis, risk stratify, and monitor both NASH and fibrosis are critically needed. Moreover, since clinically relevant outcomes, such as developing end stage liver disease or liver cancer, take many years to develop, reliable surrogate markers of outcome measures are needed to identify and evaluate potential therapies. In this review, we discuss methods to noninvasively diagnosis and monitor both NASH and fibrosis.
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Affiliation(s)
- Michelle T Long
- Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, MA, United States of America.
| | - Sanil Gandhi
- Boston University, Boston, MA, United States of America
| | - Rohit Loomba
- Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, United States of America; NAFLD Research Center, University of California at San Diego, La Jolla, CA, United States of America; Division of Epidemiology, Department of Family and Preventive, University of California at San Diego, La Jolla, CA, United States of America.
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Ikeda S, Sugihara T, Hoshino Y, Matsuki Y, Nagahara T, Okano JI, Kitao S, Fujioka Y, Yamamoto K, Isomoto H. Pemafibrate Dramatically Ameliorated the Values of Liver Function Tests and Fibrosis Marker in Patients with Non-Alcoholic Fatty Liver Disease. Yonago Acta Med 2020; 63:188-197. [PMID: 32884438 DOI: 10.33160/yam.2020.08.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 07/30/2020] [Indexed: 12/14/2022]
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease related to metabolic syndrome, which can progress to liver cirrhosis. Standard medication has not been established. Pemafibrate is a selective peroxisome proliferator-activated receptor (PPAR) α modulator. We retrospectively evaluated the efficacy of pemafibrate in patients with NAFLD. Methods We retrospectively enrolled 17 patients (ten men, seven women; median age, 63 years; range, 27-81 years). They were all proven to have fatty liver through imaging and had little or no history of drinking (ethanol consumption of < 20 g/day for women and < 30 g/day for men). They were administered pemafibrate from October 2018 to June 2020. Results After administration, serum triglyceride (TG) tended to be decreased (300.5 ± 22.5 to 239.5 ± 34.3 mg/dL, P = 0.06). Serum high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol levels did not change. ALT was significantly decreased (-47.4%) for six months (57.5 ± 8.8 to 30.3 ± 5.8 U/L, P < 0.01). The values of serum GGT significantly decreased (-48.7%) for sixth months (63.9 ± 10.3 to 32.8 ± 6.6 U/L, P < 0.01). Aspartate aminotransferase (AST) to platelet ratio (APRI), a fibrosis marker, also was significantly decreased in the sixth month (0.7 ± 0.1 to 0.4 ± 0.1, P < 0.05). Body mass index (BMI) and hemoglobin A1c (HbA1c) showed no significant change. Conclusion Pemafibrate dramatically ameliorated the values of liver function tests and APRI in patients with NAFLD.
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Affiliation(s)
- Suguru Ikeda
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
| | - Takaaki Sugihara
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
| | - Yoshiki Hoshino
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
| | - Yukako Matsuki
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
| | - Takakazu Nagahara
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
| | - Jun-Ichi Okano
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
| | - Sonoko Kitao
- Division of Medicine and Clinical Science, Department of Cardiovascular Medicine and Endocrinology and Metabolism, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Youhei Fujioka
- Division of Medicine and Clinical Science, Department of Cardiovascular Medicine and Endocrinology and Metabolism, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Kazuhiro Yamamoto
- Division of Medicine and Clinical Science, Department of Cardiovascular Medicine and Endocrinology and Metabolism, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Hajime Isomoto
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
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Pandey E, Nour AS, Harris EN. Prominent Receptors of Liver Sinusoidal Endothelial Cells in Liver Homeostasis and Disease. Front Physiol 2020; 11:873. [PMID: 32848838 PMCID: PMC7396565 DOI: 10.3389/fphys.2020.00873] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/29/2020] [Indexed: 12/12/2022] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) are the most abundant non-parenchymal cells lining the sinusoidal capillaries of the hepatic system. LSECs are characterized with numerous fenestrae and lack basement membrane as well as a diaphragm. These unique morphological characteristics of LSECs makes them the most permeable endothelial cells of the mammalian vasculature and aid in regulating flow of macromolecules and small lipid-based structures between sinusoidal blood and parenchymal cells. LSECs have a very high endocytic capacity aided by scavenger receptors (SR), such as SR-A, SR-B (SR-B1 and CD-36), SR-E (Lox-1 and mannose receptors), and SR-H (Stabilins). Other high-affinity receptors for mediating endocytosis include the FcγRIIb, which assist in the antibody-mediated removal of immune complexes. Complemented with intense lysosomal activity, LSECs play a vital role in the uptake and degradation of many blood borne waste macromolecules and small (<280 nm) colloids. Currently, seven Toll-like receptors have been investigated in LSECs, which are involved in the recognition and clearance of pathogen-associated molecular pattern (PAMPs) as well as damage associated molecular pattern (DAMP). Along with other SRs, LSECs play an essential role in maintaining lipid homeostasis with the low-density lipoprotein receptor-related protein-1 (LRP-1), in juxtaposition with hepatocytes. LSECs co-express two surface lectins called L-Specific Intercellular adhesion molecule-3 Grabbing Non-integrin Receptor (L-SIGN) and liver sinusoidal endothelial cell lectin (LSECtin). LSECs also express several adhesion molecules which are involved in the recruitment of leukocytes at the site of inflammation. Here, we review these cell surface receptors as well as other components expressed by LSECs and their functions in the maintenance of liver homeostasis. We further discuss receptor expression and activity and dysregulation associated with the initiation and progression of many liver diseases, such as hepatocellular carcinoma, liver fibrosis, and cirrhosis, alcoholic and non-alcoholic fatty liver diseases and pseudocapillarization with aging.
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Affiliation(s)
- Ekta Pandey
- Department of Biochemistry, Universityof Nebraska, Lincoln, NE, United States
| | - Aiah S Nour
- Department of Biochemistry, Universityof Nebraska, Lincoln, NE, United States
| | - Edward N Harris
- Department of Biochemistry, Universityof Nebraska, Lincoln, NE, United States
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31
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Loomba R, Adams LA. Advances in non-invasive assessment of hepatic fibrosis. Gut 2020; 69:1343-1352. [PMID: 32066623 PMCID: PMC7945956 DOI: 10.1136/gutjnl-2018-317593] [Citation(s) in RCA: 215] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 01/27/2020] [Accepted: 01/28/2020] [Indexed: 12/14/2022]
Abstract
Liver fibrosis should be assessed in all individuals with chronic liver disease as it predicts the risk of future liver-related morbidity and thus need for treatment, monitoring and surveillance. Non-invasive fibrosis tests (NITs) overcome many limitations of liver biopsy and are now routinely incorporated into specialist clinical practice. Simple serum-based tests (eg, Fibrosis Score 4, non-alcoholic fatty liver disease Fibrosis Score) consist of readily available biochemical surrogates and clinical risk factors for liver fibrosis (eg, age and sex). These have been extensively validated across a spectrum of chronic liver diseases, however, tend to be less accurate than more 'complex' serum tests, which incorporate direct measures of fibrogenesis or fibrolysis (eg, hyaluronic acid, N-terminal propeptide of type three collagen). Elastography methods quantify liver stiffness as a marker of fibrosis and are more accurate than simple serum NITs, however, suffer increasing rates of unreliability with increasing obesity. MR elastography appears more accurate than sonographic elastography and is not significantly impacted by obesity but is costly with limited availability. NITs are valuable for excluding advanced fibrosis or cirrhosis, however, are not sufficiently predictive when used in isolation. Combining serum and elastography techniques increases diagnostic accuracy and can be used as screening and confirmatory tests, respectively. Unfortunately, NITs have not yet been demonstrated to accurately reflect fibrosis change in response to treatment, limiting their role in disease monitoring. However, recent studies have demonstrated lipidomic, proteomic and gut microbiome profiles as well as microRNA signatures to be promising techniques for fibrosis assessment in the future.
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Affiliation(s)
- Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Epidemiology, University of California at San Diego, La Jolla, California, USA
| | - Leon A Adams
- Medicine and Pharmacology, The University of Western Australia, Nedlands, Western Australia, Australia
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Altamirano J, Qi Q, Choudhry S, Abdallah M, Singal AK, Humar A, Bataller R, Borhani AA, Duarte-Rojo A. Non-invasive diagnosis: non-alcoholic fatty liver disease and alcoholic liver disease. Transl Gastroenterol Hepatol 2020; 5:31. [PMID: 32258535 DOI: 10.21037/tgh.2019.11.14] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 10/30/2019] [Indexed: 12/18/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are becoming the leading causes of chronic liver disease worldwide, significantly impacting public health and healthcare cost. The development of fibrosis is the main factor leading to early mortality and morbidity in NAFLD and ALD. Thus, it is important to timely and reliably evaluate these diseases at early stages, when fibrosis is not advanced or when steatosis predominates. Liver biopsy has been the standard of reference for fibrosis and steatosis, however, its invasiveness precludes its widespread use. There is growing research on non-invasive methods for diagnosing and stratifying fibrosis and steatosis in NAFLD and ALD. This review presents clinical evidence on the use of non-invasive assessment of liver disease (blood-based and imaging-based) in patients with NALFD and ALD, and proposes algorithms incorporating these tests into their management.
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Affiliation(s)
- Jose Altamirano
- Department of Internal Medicine (Hepatology Section), Hospital Quironsalud Barcelona, Spain
| | - Qiaochu Qi
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sabina Choudhry
- Department of Radiology, University of South Dakota, Vermillion, SD, USA
| | - Mohamed Abdallah
- Department of Internal Medicine (Hepatology Section), University of South Dakota, Vermillion, SD, USA
| | - Ashwani K Singal
- Department of Medicine, University of South Dakota Sanford School of Medicine, Avera McKennan University Hospital Transplant Hepatology, Sioux Falls, SD, USA
| | - Abhinav Humar
- Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ramón Bataller
- Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.,Division of Gastroenterology and Hepatology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Amir Ali Borhani
- Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Andrés Duarte-Rojo
- Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.,Division of Gastroenterology and Hepatology, University of Pittsburgh, Pittsburgh, PA, USA
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Patel PJ, Cheng JCY, Banh X, Gracen L, Radford-Smith D, Hossain F, Horsfall LU, Hayward KL, Williams S, Johnson T, Brown NN, Saad N, Stuart KA, Russell AW, Valery PC, Clouston AD, Irvine KM, Bernard A, Powell EE. Clinically Significant Fibrosis Is Associated With Longitudinal Increases in Fibrosis-4 and Nonalcoholic Fatty Liver Disease Fibrosis Scores. Clin Gastroenterol Hepatol 2020; 18:710-718.e4. [PMID: 31352092 DOI: 10.1016/j.cgh.2019.07.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 07/09/2019] [Accepted: 07/19/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There is limited knowledge regarding the longitudinal utility of biomarkers of fibrosis, such as the nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) or the fibrosis-4 score (FIB-4) score. We examined longitudinal changes in the NFS and the FIB-4 score in patients with NAFLD, with and without clinically significant fibrosis (CSF). METHODS We performed a retrospective study of 230 patients with NAFLD, collecting clinical and laboratory records to calculate NFS and FIB-4 scores at 6 monthly intervals for 5 years before hepatology assessment of fibrosis. Linear mixed models with random intercept and slope and adjusted for age at baseline were used to assess the progression of NFS and log-transformed FIB-4 scores over time in subjects with and without CSF, determined by liver stiffness measurements of 8.2 kPa or greater. RESULTS Patients had a median of 11 (minimum, 10; maximum, 11) retrospective observations over a median time period of 5 years (minimum, 4.5 y; maximum, 5 y). Of patients with low baseline NFS and FIB-4 scores, 31.11% and 37.76%, respectively, had CSF at the time of hepatology assessment. There was a correlation between NFS and log10 FIB-4 over time (repeated measure r = 0.55; 95% CI, 0.52-0.59). The rate of increase in NFS and log10 FIB-4 was significantly higher in patients with than without CSF (both P < .001). Predicted NFS increased by 0.17 and 0.06 units per year in subjects with and without CSF, respectively. Predicted log10 FIB-4 score increased by 0.032 and 0.0003 units per year in subjects with and without CSF, respectively. CONCLUSIONS Noninvasively measured fibrosis scores increase progressively in patients with NAFLD and CSF. Further studies are needed to determine whether repeated measurements can identify patients at risk for CSF.
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Affiliation(s)
- Preya Janubhai Patel
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia; Centre for Liver Disease Research, University of Queensland, Brisbane, Australia
| | | | - Xuan Banh
- Centre for Liver Disease Research, University of Queensland, Brisbane, Australia
| | - Lucy Gracen
- Centre for Liver Disease Research, University of Queensland, Brisbane, Australia
| | | | | | - Leigh Ula Horsfall
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia; Centre for Liver Disease Research, University of Queensland, Brisbane, Australia
| | - Kelly Lee Hayward
- Centre for Liver Disease Research, University of Queensland, Brisbane, Australia
| | | | | | | | - Nivene Saad
- Faculty of Medicine, University of Queensland, Brisbane, Australia; Department of Radiology, Princess Alexandra Hospital, Brisbane, Australia
| | - Katherine Anne Stuart
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia
| | - Anthony William Russell
- Faculty of Medicine, University of Queensland, Brisbane, Australia; Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, Australia
| | | | | | - Katharine Margaret Irvine
- Centre for Liver Disease Research, University of Queensland, Brisbane, Australia; Mater Research, Translational Research Institute, University of Queensland, Brisbane, Australia
| | - Anne Bernard
- QFAB Bioinformatics, Institute for Molecular Bioscience, Queensland Bioscience Precinct, University of Queensland, Brisbane, Australia
| | - Elizabeth Ellen Powell
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia; Centre for Liver Disease Research, University of Queensland, Brisbane, Australia.
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Gastaldelli A, Repetto E, Guja C, Hardy E, Han J, Jabbour SA, Ferrannini E. Exenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes. Diabetes Obes Metab 2020; 22:393-403. [PMID: 31692226 PMCID: PMC7064910 DOI: 10.1111/dom.13907] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 10/18/2019] [Accepted: 10/31/2019] [Indexed: 12/14/2022]
Abstract
AIM To assess the efficacy of exenatide (EXE) once weekly + dapagliflozin once daily (DAPA) versus each drug alone in reducing biomarkers of fatty liver/steatosis and fibrosis in a post hoc analysis of DURATION-8, a 104-week study in 695 patients with type 2 diabetes uncontrolled by metformin monotherapy. MATERIALS AND METHODS We evaluated the impact of the study treatments on non-invasive markers of hepatic steatosis (fatty liver index [FLI] and non-alcoholic fatty liver disease [NAFLD] liver fat score), fibrosis (fibrosis-4 index [FIB-4]) and severe fibrosis (NAFLD fibrosis score), along with liver enzymes and insulin resistance, at weeks 28 and 52. All outcomes in this analysis were exploratory, with nominal P values reported. RESULTS At week 28, biomarkers of fatty liver/steatosis and fibrosis were reduced from baseline in all treatment groups. At week 28, EXE once weekly + DAPA effects for decrease in FLI were stronger than those of EXE once weekly + placebo (PLB; -2.92, 95% confidence interval [CI] -5.11, -0.73; P = 0.0092) or DAPA+PLB (-2.77 [95% CI -4.93, -0.62]; P = 0.0119), and stronger than those of EXE once weekly + PLB at week 52 (-3.23 [95% CI -5.79, -0.68]; P = 0.0134). FIB-4 showed reduction versus baseline only in the EXE once weekly + DAPA group at both week 28 (-0.06 [95% CI -0.11, -0.01]; P = 0.0135) and week 52 (-0.05 [95% CI -0.09, -0.004]; P = 0.0308). CONCLUSIONS The EXE once weekly + DAPA combination showed stronger effects than EXE once weekly + PLB or DAPA + PLB in ameliorating markers of hepatic steatosis and fibrosis in patients with type 2 diabetes. Prospective trials are needed to validate these findings.
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Affiliation(s)
| | - Enrico Repetto
- Global Medical CVRM, BioPharmaceuticals Medical, AstraZenecaGaithersburgMarylandUnited States
| | - Cristian Guja
- Department of Diabetes, Nutrition and Metabolic DiseasesCarol Davila University of Medicine and PharmacyBucharestRomania
| | - Elise Hardy
- Late CVRM, BioPharmaceuticals R&DGaithersburgMarylandUnited States
| | - Jenny Han
- Pharmapace Inc., San DiegoCaliforniaUnited States
| | - Serge A. Jabbour
- Division of Endocrinology, Diabetes and Metabolic DiseasesSidney Kimmel Medical College of Thomas Jefferson UniversityPhiladelphiaPennsylvaniaUnited States
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Ajmera VH, Liu A, Singh S, Yachoa G, Ramey M, Bhargava M, Zamani A, Lopez S, Mangla N, Bettencourt R, Rizo E, Valasek M, Behling C, Richards L, Sirlin C, Loomba R. Clinical Utility of an Increase in Magnetic Resonance Elastography in Predicting Fibrosis Progression in Nonalcoholic Fatty Liver Disease. Hepatology 2020; 71:849-860. [PMID: 31556124 PMCID: PMC7828573 DOI: 10.1002/hep.30974] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 09/03/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Cross-sectional studies have shown that magnetic resonance elastography (MRE) is accurate in the noninvasive detection of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD). However, there are limited data on the longitudinal association between an increase in liver stiffness on MRE and fibrosis progression in NAFLD. Therefore, using a well-characterized prospective cohort of patients with biopsy-proven NAFLD, we aimed to examine the longitudinal association between a 15% increase in liver stiffness on MRE and fibrosis progression in NAFLD. APPROACH AND RESULTS This prospective cohort study included 102 patients (62.7% women) with biopsy-proven NAFLD who underwent contemporaneous MRE and liver biopsy at baseline followed by a repeat paired liver biopsy and MRE assessment. The primary outcome was odds of fibrosis progression by one or more stage as assessed by the Nonalcoholic Steatohepatitis Clinical Research Network histologic scoring system. The mean (±SD) of age and body mass index (BMI) were 52 (±14) years and 32.6 (±5.3) kg/m2 , respectively. The median time interval between the two paired assessments was 1.4 years (interquartile range 2.15 years). The number of patients with fibrosis stages 0, 1, 2, 3, and 4 was 27, 36, 12, 17, and 10, respectively. In unadjusted analysis, a 15% increase in MRE was associated with increased odds of histologic fibrosis progression (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.17-10.76; P = 0.0248). These findings remained clinically and statistically significant even after multivariable adjustment for age, sex, and BMI (adjusted OR, 3.36; 95% CI, 1.10-10.31; P = 0.0339). A 15% increase in MRE was the strongest predictor of progression to advanced fibrosis (OR, 4.90; 95% CI, 1.35-17.84; P = 0.0159). CONCLUSIONS A 15% increase in liver stiffness on MRE may be associated with histologic fibrosis progression and progression from early fibrosis to advanced fibrosis.
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Affiliation(s)
- Veeral H. Ajmera
- NAFLD Research Center,Division of Gastroenterology, Department of Medicine
| | | | | | | | | | | | | | | | | | | | | | - Mark Valasek
- Department of Pathology, University of California at San Diego, La Jolla, CA
| | | | | | - Claude Sirlin
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA
| | - Rohit Loomba
- NAFLD Research Center,Division of Gastroenterology, Department of Medicine
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Noureddin N, Schattenberg JM, Alkhouri N, Noureddin M. Noninvasive Testing Using Magnetic Resonance Imaging Techniques as Outcomes in Nonalcoholic Steatohepatitis Clinical Trials: How Full Is the Glass? Hepatol Commun 2020; 4:141-144. [PMID: 32025600 PMCID: PMC6996378 DOI: 10.1002/hep4.1473] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 12/03/2019] [Indexed: 12/14/2022] Open
Affiliation(s)
- Nabil Noureddin
- Department of MedicineUniversity of Nevada Las Vegas School of MedicineLas VegasNV
| | - Jörn M. Schattenberg
- Department of MedicineUniversity Medical CentreJohannes Gutenberg UniversityMainzGermany
| | - Naim Alkhouri
- Texas Liver InstituteUniversity of Texas Health Science CenterSan AntonioTX
| | - Mazen Noureddin
- Fatty Liver ProgramDivision of Digestive and Liver DiseasesComprehensive Transplant ProgramCedars Sinai Medical CenterLos AngelesCA
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The Role of Noninvasive Tests for Differentiating NASH From NAFL and Diagnosing Advanced Fibrosis Among Patients With NAFLD. J Clin Gastroenterol 2020; 54:107-113. [PMID: 31789757 PMCID: PMC7945957 DOI: 10.1097/mcg.0000000000001284] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Assessing for the presence of non-alcoholic steatohepatitis (NASH) and the presence of advanced fibrosis is vital among patients with non-alcoholic fatty liver disease (NAFLD) as each is predictive of disease outcomes. A liver biopsy is the gold standard method for doing so but is impossible to perform among all patients with NAFLD. Reliable methods for noninvasively detecting for the presence of NASH and advanced fibrosis are thus a pressing need. The search for noninvasive tests has been more successful for advanced fibrosis than for NASH. Clinical prediction models and elastography have acceptable accuracy for ruling out advanced fibrosis; when used together, as in a fibrosis prediction algorithm presented in this review, it can avoid the need for liver biopsy among many patients with NAFLD. Several biomarkers for identifying the presence of NASH have been studied but none are sufficiently accurate or validated. Of those studied, the most promising include CK-18 fragments, lipodomic and metabolomics candidates, and magnetic resonance elastography with proton density fat fraction. However, none are ready for clinical use and ultimately large multicenter prospective cohort studies are needed to validate select novel biomarkers.
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Challenges and opportunities in drug development for nonalcoholic steatohepatitis. Eur J Pharmacol 2020; 870:172913. [PMID: 31926994 DOI: 10.1016/j.ejphar.2020.172913] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/04/2019] [Accepted: 01/07/2020] [Indexed: 12/22/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are considered major global medical burdens with high prevalence and steeply rising incidence. Despite the characterization of numerous pathophysiologic pathways leading to metabolic disorder, lipid accumulation, inflammation, fibrosis, and ultimately end-stage liver disease or liver cancer formation, so far no causal pharmacological therapy is available. Drug development for NAFLD and NASH is limited by long disease duration and slow progression and the need for sequential biopsies to monitor the disease stage. Additional non-invasive biomarkers could therefore improve design and feasibility of such. Here, the current concepts on preclinical models, biomarkers and clinical endpoints and trial designs are briefly reviewed.
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Danford CJ, Lai M. NAFLD: a multisystem disease that requires a multidisciplinary approach. Frontline Gastroenterol 2019; 10:328-329. [PMID: 31682642 PMCID: PMC6788273 DOI: 10.1136/flgastro-2019-101235] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 04/29/2019] [Indexed: 02/04/2023] Open
Affiliation(s)
- Christopher J Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Michelle Lai
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, United States
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Newsome P, Francque S, Harrison S, Ratziu V, Van Gaal L, Calanna S, Hansen M, Linder M, Sanyal A. Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Aliment Pharmacol Ther 2019; 50:193-203. [PMID: 31246368 PMCID: PMC6617813 DOI: 10.1111/apt.15316] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/19/2019] [Accepted: 05/01/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment. AIM To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD. METHODS Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight. RESULTS Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change. CONCLUSIONS Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.
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Affiliation(s)
- Philip Newsome
- National Institute for Health Research Birmingham Biomedical Research Centre and Liver Unit at University Hospitals Birmingham NHS Foundation TrustBirminghamUK,Centre for Liver & Gastrointestinal Research, Institute of Immunology and ImmunotherapyUniversity of BirminghamBirminghamUK
| | - Sven Francque
- Department of Gastroenterology and HepatologyAntwerp University HospitalEdegem, AntwerpBelgium
| | | | - Vlad Ratziu
- ICAN – Institute for Cardiometabolism and NutritionHôpital Pitié Salpêtrière, Sorbonne UniversityParisFrance
| | - Luc Van Gaal
- Department of Endocrinology, Diabetology and MetabolismAntwerp University HospitalEdegem, AntwerpBelgium
| | | | | | | | - Arun Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal MedicineVirginia Commonwealth UniversityRichmondVirginia
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41
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Brandman D, Terrault NA. Alcohol use in patients with non-alcoholic fatty liver: a tangled web of causality. Hepatobiliary Surg Nutr 2019; 8:277-279. [PMID: 31245413 DOI: 10.21037/hbsn.2019.01.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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42
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Schattenberg JM. Reading the stars for hepatic fibrosis or how to predict the severity of liver disease in patients with NASH. Liver Int 2019; 39:812-814. [PMID: 31020772 DOI: 10.1111/liv.13999] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 10/29/2018] [Accepted: 10/30/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Jörn M Schattenberg
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
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43
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Zhou JH, Cai JJ, She ZG, Li HL. Noninvasive evaluation of nonalcoholic fatty liver disease: Current evidence and practice. World J Gastroenterol 2019; 25:1307-1326. [PMID: 30918425 PMCID: PMC6429343 DOI: 10.3748/wjg.v25.i11.1307] [Citation(s) in RCA: 154] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/20/2019] [Accepted: 02/23/2019] [Indexed: 02/06/2023] Open
Abstract
With the increasing number of individuals with diabetes and obesity, nonalcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent, affecting one-quarter of adults worldwide. The spectrum of NAFLD ranges from simple steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). NAFLD, especially NASH, may progress to fibrosis, leading to cirrhosis and hepatocellular carcinoma. NAFLD can impose a severe economic burden, and patients with NAFLD-related terminal or deteriorative liver diseases have become one of the main groups receiving liver transplantation. The increasing prevalence of NAFLD and the severe outcomes of NASH make it necessary to use effective methods to identify NAFLD. Although recognized as the gold standard, biopsy is limited by its sampling bias, poor acceptability, and severe complications, such as mortality, bleeding, and pain. Therefore, noninvasive methods are urgently needed to avoid biopsy for diagnosing NAFLD. This review discusses the current noninvasive methods for assessing NAFLD, including steatosis, NASH, and NAFLD-related fibrosis, and explores the advantages and disadvantages of measurement tools. In addition, we analyze potential noninvasive biomarkers for tracking disease processes and monitoring treatment effects, and explore effective algorithms consisting of imaging and nonimaging biomarkers for diagnosing advanced fibrosis and reducing unnecessary biopsies in clinical practice.
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Affiliation(s)
- Jiang-Hua Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Institute of Model Animal of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Jing-Jing Cai
- Department of Cardiology, The 3rd Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Institute of Model Animal of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Hong-Liang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Institute of Model Animal of Wuhan University, Wuhan 430071, Hubei Province, China
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44
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45
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Fc gamma RIIb expression levels in human liver sinusoidal endothelial cells during progression of non-alcoholic fatty liver disease. PLoS One 2019; 14:e0211543. [PMID: 30695042 PMCID: PMC6350999 DOI: 10.1371/journal.pone.0211543] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 01/16/2019] [Indexed: 12/15/2022] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) play a pivotal role in hepatic function and homeostasis. LSEC dysfunction has been recognized to be closely involved in various liver diseases, including non-alcoholic steatohepatitis (NASH), but not much is known about the fate of the scavenger receptors in LSECs during NASH. Fc gamma receptor IIb (FcγRIIb), known as a scavenger receptor, contributes to receptor-mediated endocytosis and immune complexes clearance. In this study, to elucidate the fate of FcγRIIb in the progression of non-alcoholic fatty liver disease (NAFLD), we examined FcγRIIb levels in NAFLD biopsy specimens by immunohistochemistry, and investigated their correlation with the exacerbation of biological indexes and clinicopathological scores of NASH. The FcγRIIb expression levels indicated significant negative correlations with serum levels of blood lipids (triglyceride, total cholesterol, high-density lipoprotein-cholesterol), type 4 collagen and hyaluronic acid, which are involved in hepatic lipid metabolism disorder, fibrosis, and inflammation, respectively. However, there was no significant difference of FcγRIIb expression levels among the pathological grades of NAFLD. During NAFLD progression, inflammation and fibrosis may influence the expression of FcγRIIb and their scavenger functions to maintain hepatic homeostasis.
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46
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Shiffman M, Freilich B, Vuppalanchi R, Watt K, Chan JL, Spada A, Hagerty DT, Schiff E. Randomised clinical trial: emricasan versus placebo significantly decreases ALT and caspase 3/7 activation in subjects with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2019; 49:64-73. [PMID: 30430605 PMCID: PMC6587784 DOI: 10.1111/apt.15030] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 07/24/2018] [Accepted: 09/29/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Lipotoxicity leading to excessive caspase-mediated apoptosis and inflammation is believed to drive liver damage in NAFLD. Emricasan is a pan-caspase inhibitor that decreased serum ALT and apoptotic and inflammatory markers in subjects with chronic hepatitis. AIMS To assess whether 28 days of emricasan would reduce elevated levels of serum ALT, AST, cleaved cytokeratin-18, full-length cytokeratin-18, and caspase 3/7 in subjects with NAFLD and raised aminotransferases. METHODS Double-blind, placebo-controlled, office-practice study assessed the efficacy, safety, and tolerability of emricasan in subjects with NAFLD and ALT levels ≥1.5 x ULN during screening. Subjects were randomised to emricasan 25 mg twice daily or matching placebo. Subjects with cirrhosis and other causes for raised aminotransferases were excluded. The primary endpoint was the change in ALT at day 28 in the emricasan group vs placebo. RESULTS 38 subjects were randomised, 19 each to emricasan or placebo. Baseline disease factors were well balanced except for lower median ALT values in emricasan subjects. Three subjects randomised to placebo discontinued prior to day 28. ALT values decreased significantly in emricasan-treated subjects vs placebo at days 7 (P < 0.0001) and 28 (P = 0.02). cCK18 (day 7), flCK18 (days 7 and 28), and caspase 3/7 (day 7) were also significantly decreased in emricasan-treated subjects vs placebo. Emricasan treatment was generally safe and well tolerated. CONCLUSIONS Emricasan decreased ALT and biomarkers in subjects with NAFLD and raised aminotransferases after 28 days. These results support the further development of emricasan in patients with NAFLD. TRIAL REGISTRATION ClinicalTrials.gov, Identifier: NCT02077374.
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Affiliation(s)
- Mitchell Shiffman
- Liver Institute of VirginiaBon Secours Health SystemRichmond and Newport NewsVirginia
| | | | - Raj Vuppalanchi
- Division of Gastroenterology and HepatologyIndiana University School of MedicineIndianapolisIndiana
| | - Kymberly Watt
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMinnesota
| | | | - Al Spada
- Conatus Pharmaceuticals Inc.San DiegoCalifornia
| | | | - Eugene Schiff
- Schiff Center for Liver DiseasesUniversity of Miami Miller School of MedicineMiamiFlorida
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47
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Croce AC, Ferrigno A, Bottiroli G, Vairetti M. Autofluorescence-based optical biopsy: An effective diagnostic tool in hepatology. Liver Int 2018; 38:1160-1174. [PMID: 29624848 DOI: 10.1111/liv.13753] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 03/27/2018] [Indexed: 12/15/2022]
Abstract
Autofluorescence emission of liver tissue depends on the presence of endogenous biomolecules able to fluoresce under suitable light excitation. Overall autofluorescence emission contains much information of diagnostic value because it is the sum of individual autofluorescence contributions from fluorophores involved in metabolism, for example, NAD(P)H, flavins, lipofuscins, retinoids, porphyrins, bilirubin and lipids, or in structural architecture, for example, fibrous proteins, in close relationship with normal, altered or diseased conditions of the liver. Since the 1950s, hepatocytes and liver have been historical models to study NAD(P)H and flavins as in situ, real-time autofluorescence biomarkers of energy metabolism and redox state. Later investigations designed to monitor organ responses to ischaemia/reperfusion were able to predict the risk of dysfunction in surgery and transplantation or support the development of procedures to ameliorate the liver outcome. Subsequently, fluorescent fatty acids, lipofuscin-like lipopigments and collagen were characterized as optical biomarkers of liver steatosis, oxidative stress damage, fibrosis and disease progression. Currently, serum AF is being investigated to improve non-invasive optical diagnosis of liver disease. Validation of endogenous fluorophores and in situ discrimination of cancerous from non-cancerous tissue belong to the few studies on liver in human subjects. These reports along with other optical techniques and the huge work performed on animal models suggest many optically based applications in hepatology. Optical diagnosis is currently offering beneficial outcomes in clinical fields ranging from the respiratory and gastrointestinal tracts, to dermatology and ophthalmology. Accordingly, this review aims to promote an effective bench to bedside transfer in hepatology.
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Affiliation(s)
- Anna Cleta Croce
- Institute of Molecular Genetics, Italian National Research Council (CNR), Pavia, Italy.,Department of Biology & Biotechnology, University of Pavia, Pavia, Italy
| | - Andrea Ferrigno
- Internal Medicine and Therapy Department, University of Pavia, Pavia, Italy
| | - Giovanni Bottiroli
- Institute of Molecular Genetics, Italian National Research Council (CNR), Pavia, Italy.,Department of Biology & Biotechnology, University of Pavia, Pavia, Italy
| | - Mariapia Vairetti
- Internal Medicine and Therapy Department, University of Pavia, Pavia, Italy
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48
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Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 2018; 68:526-549. [PMID: 28989095 PMCID: PMC5818315 DOI: 10.1016/j.jhep.2017.09.016] [Citation(s) in RCA: 506] [Impact Index Per Article: 72.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/24/2017] [Accepted: 09/25/2017] [Indexed: 01/27/2023]
Abstract
Patients who develop chronic fibrotic liver disease, caused by viral or metabolic aetiologies, are at a high risk of developing hepatocellular carcinoma (HCC). Even after complete HCC tumour resection or ablation, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo HCC tumours, which progress into incurable, advanced-stage disease in most patients. Thus, early detection and prevention of HCC development is, in principle, the most impactful strategy to improve patient prognosis. However, a "one-size-fits-all" approach to HCC screening for early tumour detection, as recommended by clinical practice guidelines, is utilised in less than 20% of the target population, and the performance of screening modalities, including ultrasound and alpha-fetoprotein, is suboptimal. Furthermore, optimal screening strategies for emerging at-risk patient populations, such as those with chronic hepatitis C after viral cure, or those with non-cirrhotic, non-alcoholic fatty liver disease remain controversial. New HCC biomarkers and imaging modalities may improve the sensitivity and specificity of HCC detection. Clinical and molecular HCC risk scores will enable precise HCC risk prediction followed by tailoured HCC screening of individual patients, maximising cost-effectiveness and optimising allocation of limited medical resources. Several aetiology-specific and generic HCC chemoprevention strategies are evolving. Epidemiological and experimental studies have identified candidate chemoprevention targets and therapies, including statins, anti-diabetic drugs, and selective molecular targeted agents, although their clinical testing has been limited by the lengthy process of cancer development that requires long-term, costly studies. Individual HCC risk prediction is expected to overcome the challenge by enabling personalised chemoprevention, targeting high-risk patients for precision HCC prevention and substantially improving the dismal prognosis of HCC.
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Affiliation(s)
- Naoto Fujiwara
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, USA; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Japan
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, USA
| | - Nicolas Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, USA.
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49
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Emerging metabolic risk factors in hepatocellular carcinoma and their influence on the liver microenvironment. Biochim Biophys Acta Mol Basis Dis 2018; 1864:607-617. [PMID: 29197664 DOI: 10.1016/j.bbadis.2017.11.026] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 11/14/2017] [Accepted: 11/28/2017] [Indexed: 12/14/2022]
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50
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Vilar-Gomez E, Chalasani N. Non-invasive assessment of non-alcoholic fatty liver disease: Clinical prediction rules and blood-based biomarkers. J Hepatol 2018; 68:305-315. [PMID: 29154965 DOI: 10.1016/j.jhep.2017.11.013] [Citation(s) in RCA: 432] [Impact Index Per Article: 61.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 11/03/2017] [Accepted: 11/09/2017] [Indexed: 12/04/2022]
Abstract
The correct identification of patients at increased risk of non-alcoholic steatohepatitis (NASH) and advanced fibrosis is a critical step in the assessment of non-alcoholic fatty liver disease (NAFLD). Since liver biopsy is invasive, expensive and prone to sampling error, several clinical prediction rules and blood-based biomarkers have been developed as attractive and affordable alternatives for identification of patients at high risk of NASH and advanced fibrosis. Current biomarkers constitute predictive models (e.g. NAFLD fibrosis score, FIB-4 index and BARD score) or direct measures of inflammation (e.g. circulating keratin 18 fragments), or fibrosis (e.g. FibroTest®, ELF™ or Pro-C3 tests). In the clinical setting, biomarkers may discriminate between patients with NASH or advanced fibrosis, predict dynamic changes in NASH/fibrosis over time, and provide long-term prognostic information. Although clinically useful, current biomarker predictions may be influenced by hepatic and extrahepatic conditions (e.g. age, patient comorbidities, and fibrosis or NASH prevalence), which may lead to inaccurate estimates in small subsamples of patients. No highly sensitive and specific tests are available to differentiate NASH from simple steatosis. However, diagnostic accuracy can be improved by combining blood biomarkers. NAFLD fibrosis score and FIB-4 index are both cost-effective and highly sensitive tools to exclude patients with advanced fibrosis. Moreover, their higher scores may identify patients at higher risk of non-liver- and liver-related morbidity and mortality. More expensive tests such as FibroTest or ELF are more specific for detection of patients with significant and advanced fibrosis. Recent efforts have concentrated on "omics" approaches for developing and validating novel biomarkers. Herein, we describe currently available clinical prediction rules and blood-based biomarkers for identifying NASH and advanced fibrosis in patients with NAFLD, discussing their advantages and disadvantages, as well as their potential clinical utility for predicting dynamic changes over time and identifying patients at increased risk of adverse outcomes.
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Affiliation(s)
- Eduardo Vilar-Gomez
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, IN, USA.
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, IN, USA.
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