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Gries JJ, Lazarus JV, Brennan PN, Siddiqui MS, Targher G, Lang CC, Virani SS, Lavie CJ, Isaacs S, Arab JP, Cusi K, Krittanawong C. Interdisciplinary perspectives on the co-management of metabolic dysfunction-associated steatotic liver disease and coronary artery disease. Lancet Gastroenterol Hepatol 2025; 10:82-94. [PMID: 39674228 DOI: 10.1016/s2468-1253(24)00310-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/11/2024] [Accepted: 09/12/2024] [Indexed: 12/16/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a public health threat as it affects approximately 38% of the adult population worldwide, with its prevalence rising in step with that of obesity and type 2 diabetes. Beyond the implications of MASLD for liver health, it is also associated with cardiovascular and vascular dysfunction. Although the many shared risk factors and common metabolic milieu might indicate that cardiovascular disease and MASLD are discrete outcomes from common systemic pathogeneses, a growing body of evidence has identified a potential causal relationship between MASLD and coronary artery disease, which is the leading cause of morbidity and mortality in people with MASLD and all-cause mortality worldwide. This Review takes an interdisciplinary approach, drawing on hepatology, cardiology, endocrinology, and metabolic and internal medicine specialists to help to delineate the intricate interplay between MASLD and coronary artery disease. It sheds light on novel opportunities for targeted interventions and personalised management strategies.
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Affiliation(s)
- Jacob J Gries
- Department of Internal Medicine, Geisinger Medical Center, Danville, PA, USA
| | - Jeffrey V Lazarus
- CUNY Graduate School of Public Health and Health Policy, New York, NY, USA; Barcelona Institute for Global Health, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Paul N Brennan
- Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK
| | - Mohammad S Siddiqui
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, VA, USA
| | - Giovanni Targher
- Metabolic Diseases Research Unit, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella (VR), Italy
| | - Chim C Lang
- Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK; Faculty of Medicine, National University of Malaysia, Kuala Lumpur, Malaysia
| | - Salim S Virani
- The Aga Khan University, Karachi, Pakistan; Section of Cardiology and Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Carl J Lavie
- John Ochsner Heart and Vascular Institute, Ochsner Clinical School, New Orleans, LA, USA
| | - Scott Isaacs
- Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, Atlanta, GA, USA
| | - Juan Pablo Arab
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, VA, USA; Department of Gastroenterology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, The University of Florida, Gainesville, FL, USA
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Misceo D, Mocciaro G, D'Amore S, Vacca M. Diverting hepatic lipid fluxes with lifestyles revision and pharmacological interventions as a strategy to tackle steatotic liver disease (SLD) and hepatocellular carcinoma (HCC). Nutr Metab (Lond) 2024; 21:112. [PMID: 39716321 DOI: 10.1186/s12986-024-00871-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/13/2024] [Indexed: 12/25/2024] Open
Abstract
Steatotic liver disease (SLD) and Hepatocellular Carcinoma (HCC) are characterised by a substantial rewiring of lipid fluxes caused by systemic metabolic unbalances and/or disrupted intracellular metabolic pathways. SLD is a direct consequence of the interaction between genetic predisposition and a chronic positive energy balance affecting whole-body energy homeostasis and the function of metabolically-competent organs. In this review, we discuss how the impairment of the cross-talk between peripheral organs and the liver stalls glucose and lipid metabolism, leading to unbalances in hepatic lipid fluxes that promote hepatic fat accumulation. We also describe how prolonged metabolic stress builds up toxic lipid species in the liver, and how lipotoxicity and metabolic disturbances drive disease progression by promoting a chronic activation of wound healing, leading to fibrosis and HCC. Last, we provide a critical overview of current state of the art (pre-clinical and clinical evidence) regarding mechanisms of action and therapeutic efficacy of candidate SLD treatment options, and their potential to interfere with SLD/HCC pathophysiology by diverting lipids away from the liver therefore improving metabolic health.
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Affiliation(s)
- Davide Misceo
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Gabriele Mocciaro
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK
| | - Simona D'Amore
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Clinica Medica "G. Baccelli", "Aldo Moro" University of Bari, 70124, Bari, Italy.
| | - Michele Vacca
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK.
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Trujillo Cubillo L, Gurdal M, Zeugolis DI. Corneal fibrosis: From in vitro models to current and upcoming drug and gene medicines. Adv Drug Deliv Rev 2024; 209:115317. [PMID: 38642593 DOI: 10.1016/j.addr.2024.115317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 02/29/2024] [Accepted: 04/18/2024] [Indexed: 04/22/2024]
Abstract
Fibrotic diseases are characterised by myofibroblast differentiation, uncontrolled pathological extracellular matrix accumulation, tissue contraction, scar formation and, ultimately tissue / organ dysfunction. The cornea, the transparent tissue located on the anterior chamber of the eye, is extremely susceptible to fibrotic diseases, which cause loss of corneal transparency and are often associated with blindness. Although topical corticosteroids and antimetabolites are extensively used in the management of corneal fibrosis, they are associated with glaucoma, cataract formation, corneoscleral melting and infection, imposing the need of far more effective therapies. Herein, we summarise and discuss shortfalls and recent advances in in vitro models (e.g. transforming growth factor-β (TGF-β) / ascorbic acid / interleukin (IL) induced) and drug (e.g. TGF-β inhibitors, epigenetic modulators) and gene (e.g. gene editing, gene silencing) therapeutic strategies in the corneal fibrosis context. Emerging therapeutical agents (e.g. neutralising antibodies, ligand traps, receptor kinase inhibitors, antisense oligonucleotides) that have shown promise in clinical setting but have not yet assessed in corneal fibrosis context are also discussed.
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Affiliation(s)
- Laura Trujillo Cubillo
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Charles Institute of Dermatology, Conway Institute of Biomolecular & Biomedical Research and School of Mechanical & Materials Engineering, University College Dublin (UCD), Dublin, Ireland
| | - Mehmet Gurdal
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Charles Institute of Dermatology, Conway Institute of Biomolecular & Biomedical Research and School of Mechanical & Materials Engineering, University College Dublin (UCD), Dublin, Ireland
| | - Dimitrios I Zeugolis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Charles Institute of Dermatology, Conway Institute of Biomolecular & Biomedical Research and School of Mechanical & Materials Engineering, University College Dublin (UCD), Dublin, Ireland.
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Kokkorakis M, Muzurović E, Volčanšek Š, Chakhtoura M, Hill MA, Mikhailidis DP, Mantzoros CS. Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies. Pharmacol Rev 2024; 76:454-499. [PMID: 38697855 DOI: 10.1124/pharmrev.123.001087] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/22/2023] [Accepted: 01/25/2024] [Indexed: 05/05/2024] Open
Abstract
Steatotic liver disease (SLD) displays a dynamic and complex disease phenotype. Consequently, the metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) therapeutic pipeline is expanding rapidly and in multiple directions. In parallel, noninvasive tools for diagnosing and monitoring responses to therapeutic interventions are being studied, and clinically feasible findings are being explored as primary outcomes in interventional trials. The realization that distinct subgroups exist under the umbrella of SLD should guide more precise and personalized treatment recommendations and facilitate advancements in pharmacotherapeutics. This review summarizes recent updates of pathophysiology-based nomenclature and outlines both effective pharmacotherapeutics and those in the pipeline for MASLD/MASH, detailing their mode of action and the current status of phase 2 and 3 clinical trials. Of the extensive arsenal of pharmacotherapeutics in the MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, have shown only marginal benefits and are now being tested as part of combination therapies, yet others are still in development as monotherapies. Although the Food and Drug Administration (FDA) has recently approved resmetirom, additional therapeutic approaches in development will ideally target MASH and fibrosis while improving cardiometabolic risk factors. Due to the urgent need for the development of novel therapeutic strategies and the potential availability of safety and tolerability data, repurposing existing and approved drugs is an appealing option. Finally, it is essential to highlight that SLD and, by extension, MASLD should be recognized and approached as a systemic disease affecting multiple organs, with the vigorous implementation of interdisciplinary and coordinated action plans. SIGNIFICANCE STATEMENT: Steatotic liver disease (SLD), including metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, is the most prevalent chronic liver condition, affecting more than one-fourth of the global population. This review aims to provide the most recent information regarding SLD pathophysiology, diagnosis, and management according to the latest advancements in the guidelines and clinical trials. Collectively, it is hoped that the information provided furthers the understanding of the current state of SLD with direct clinical implications and stimulates research initiatives.
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Affiliation(s)
- Michail Kokkorakis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Emir Muzurović
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Špela Volčanšek
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Marlene Chakhtoura
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Michael A Hill
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Dimitri P Mikhailidis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
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Katsuyama H, Hakoshima M, Kaji E, Mino M, Kakazu E, Iida S, Adachi H, Kanto T, Yanai H. Effects of Once-Weekly Semaglutide on Cardiovascular Risk Factors and Metabolic Dysfunction-Associated Steatotic Liver Disease in Japanese Patients with Type 2 Diabetes: A Retrospective Longitudinal Study Based on Real-World Data. Biomedicines 2024; 12:1001. [PMID: 38790963 PMCID: PMC11118092 DOI: 10.3390/biomedicines12051001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/28/2024] [Accepted: 04/30/2024] [Indexed: 05/26/2024] Open
Abstract
Once-weekly semaglutide is a widely used glucagon-like peptide-1 receptor agonist (GLP-1RA) used for the treatment of type 2 diabetes (T2D). In clinical trials, semaglutide improved glycemic control and obesity, and reduced major cardiovascular events. However, the reports are limited on its real-world efficacy relating to various metabolic factors such as dyslipidemia or metabolic dysfunction-associated steatotic liver disease (MASLD) in Asian patients with T2D. In our retrospective longitudinal study, we selected patients with T2D who were given once-weekly semaglutide and compared metabolic parameters before and after the start of semaglutide. Seventy-five patients were eligible. HbA1c decreased significantly, by 0.7-0.9%, and body weight by 1.4-1.7 kg during the semaglutide treatment. Non-HDL cholesterol decreased significantly at 3, 6 and 12 months after the initiation of semaglutide; LDL cholesterol decreased at 3 and 6 months; and HDL cholesterol increased at 12 months. The effects on body weight, HbA1c and lipid profile were pronounced in patients who were given semaglutide as a first GLP-1RA (GLP-1R naïve), whereas improvements in HbA1c were also observed in patients who were given semaglutide after being switched from other GLP-1RAs. During a 12-month semaglutide treatment, the hepatic steatosis index (HSI) tended to decrease. Moreover, a significant decrease in the AST-to-platelet ratio index (APRI) was observed in GLP-1RA naïve patients. Our real-world study confirmed the beneficial effects of once-weekly semaglutide, namely, improved body weight, glycemic control and atherogenic lipid profile. The beneficial effects on MASLD were also suggested.
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Affiliation(s)
- Hisayuki Katsuyama
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.H.); (E.K.); (S.I.); (H.A.); (H.Y.)
| | - Mariko Hakoshima
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.H.); (E.K.); (S.I.); (H.A.); (H.Y.)
| | - Emika Kaji
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.H.); (E.K.); (S.I.); (H.A.); (H.Y.)
| | - Masaaki Mino
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.M.); (E.K.); (T.K.)
| | - Eiji Kakazu
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.M.); (E.K.); (T.K.)
- Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Sakura Iida
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.H.); (E.K.); (S.I.); (H.A.); (H.Y.)
| | - Hiroki Adachi
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.H.); (E.K.); (S.I.); (H.A.); (H.Y.)
| | - Tatsuya Kanto
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.M.); (E.K.); (T.K.)
- Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Hidekatsu Yanai
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (M.H.); (E.K.); (S.I.); (H.A.); (H.Y.)
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Haber R, Zarzour F, Ghezzawi M, Saadeh N, Bacha DS, Al Jebbawi L, Chakhtoura M, Mantzoros CS. The impact of metformin on weight and metabolic parameters in patients with obesity: A systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab 2024; 26:1850-1867. [PMID: 38468148 DOI: 10.1111/dom.15501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 01/15/2024] [Accepted: 01/30/2024] [Indexed: 03/13/2024]
Abstract
There are conflicting data on the weight-reducing potential of metformin (MTF) in nondiabetic patients with obesity. The purpose of this systematic review and meta-analysis was to evaluate the effect of MTF on weight and cardiometabolic parameters in adults with overweight/obesity with or without nonalcoholic fatty liver disease (NAFLD) (CRD42018085512). We included randomized controlled trials (RCTs) in adults without diabetes mellitus, with mean body mass index (BMI) ≥ 25 kg/m2, with or without NAFLD, comparing MTF to placebo/control, lifestyle modification (LSM) or a US Food and Drug Administration-approved anti-obesity drug, reporting on weight or metabolic parameters, and extending over at least 3 months. We conducted a systematic search in MEDLINE, EMBASE, PubMed and the Cochrane Library without time limitation (until March 2022). We screened and selected eligible articles, abstracted relevant data, and assessed the risk of bias. All steps were in duplicate and independently. We conducted a random-effects model meta-analysis using Review Manager version 5.3, with prespecified subgroup analyses in case of heterogeneity. We identified 2650 citations and included 49 trials (55 publications). Compared to placebo, MTF was associated with a significant reduction in BMI (mean difference [MD] -0.56 [-0.74, -0.37] kg/m2; p < 0.0001), at doses ranging from 500 to 2550 mg/day, and with a significant percentage change in BMI of -2.53% (-2.90, -2.17) at the dose 1700 mg/day. There was no interaction by baseline BMI, MTF dose or duration, nor presence or absence of NAFLD. There was no significant difference between MTF and LSM. Orlistat was more effective than MTF (at doses of 1000-1700 mg/day) in terms of weight loss, with an MD in BMI of -3.17 (-5.88; -0.47) kg/m2, favouring the former. Compared to placebo/control, MTF improved insulin parameters, while no effect was detected when compared to LSM. A few small trials showed heterogenous effects on liver parameters in patients with NAFLD treated with MTF compared to placebo/control. There was a large variability in the expression of outcome measures and RCTs were of low quality. In conclusion, MTF was associated with a modest weight reduction in obese nondiabetic patients. Further high-quality and better powered studies are needed to examine the impact of MTF in patients with insulin resistance and NAFLD.
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Affiliation(s)
- Rachelle Haber
- Department of Internal Medicine, Division of Endocrinology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Fatima Zarzour
- Department of Internal Medicine, Division of Endocrinology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Malak Ghezzawi
- Department of Internal Medicine, Division of Endocrinology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Natalie Saadeh
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Dania S Bacha
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Lama Al Jebbawi
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Marlene Chakhtoura
- Department of Internal Medicine, Division of Endocrinology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
- Department of Medicine, Boston VA Healthcare System, Boston, Massachusetts, USA
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Perazza F, Leoni L, Colosimo S, Musio A, Bocedi G, D’Avino M, Agnelli G, Nicastri A, Rossetti C, Sacilotto F, Marchesini G, Petroni ML, Ravaioli F. Metformin and the Liver: Unlocking the Full Therapeutic Potential. Metabolites 2024; 14:186. [PMID: 38668314 PMCID: PMC11052067 DOI: 10.3390/metabo14040186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 03/20/2024] [Accepted: 03/22/2024] [Indexed: 04/28/2024] Open
Abstract
Metformin is a highly effective medication for managing type 2 diabetes mellitus. Recent studies have shown that it has significant therapeutic benefits in various organ systems, particularly the liver. Although the effects of metformin on metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are still being debated, it has positive effects on cirrhosis and anti-tumoral properties, which can help prevent the development of hepatocellular carcinoma. Furthermore, it has been proven to improve insulin resistance and dyslipidaemia, commonly associated with liver diseases. While more studies are needed to fully determine the safety and effectiveness of metformin use in liver diseases, the results are highly promising. Indeed, metformin has a terrific potential for extending its full therapeutic properties beyond its traditional use in managing diabetes.
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Affiliation(s)
- Federica Perazza
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Laura Leoni
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Santo Colosimo
- Doctorate School of Nutrition Science, University of Milan, 20122 Milan, Italy;
| | | | - Giulia Bocedi
- U.O. Diabetologia, Ospedale C. Magati, Scandiano, 42019 Reggio Emilia, Italy;
| | - Michela D’Avino
- S.C. Endocrinologia Arcispedale Santa Maria Nuova, 42123 Reggio Emilia, Italy;
| | - Giulio Agnelli
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Alba Nicastri
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Chiara Rossetti
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Federica Sacilotto
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Giulio Marchesini
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Maria Letizia Petroni
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
- Division of Hepatobiliary and Immunoallergic Diseases, Department of Internal Medicine, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy
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8
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Tanaka M, Kaji K, Nishimura N, Asada S, Koizumi A, Matsuda T, Yorioka N, Tsuji Y, Fujinaga Y, Sato S, Namisaki T, Akahane T, Yoshiji H. Blockade of angiotensin II modulates insulin-like growth factor 1-mediated skeletal muscle homeostasis in experimental steatohepatitis. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119649. [PMID: 38097064 DOI: 10.1016/j.bbamcr.2023.119649] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/29/2023] [Accepted: 12/01/2023] [Indexed: 12/18/2023]
Abstract
Sarcopenia is associated with mortality in patients with nonalcoholic steatohepatitis (NASH). Angiotensin II receptor blocker (ARB) has been suggested to prevent sarcopenia, but reports on its effect on NASH-derived skeletal muscle atrophy in conjunction with insulin-like growth factor 1 (IGF-1)-mediated muscle homeostasis are few. Our aim was to examine the combined effect of the ARB losartan and IGF-1 replacement on skeletal muscle atrophy in a methionine-choline deficient (MCD) diet-fed murine steatohepatitis model. The MCD-fed mice developed steatohepatitis and skeletal muscle atrophy, as indicated by the reduction of psoas muscle mass and attenuation of forelimb and hindlimb grip strength. Significantly suppressed steatohepatitis and skeletal muscle atrophy was observed after single treatment with ARB or IGF-1, and these effects were augmented after combination treatment. Treatment with ARB and IGF-1 effectively inhibited ubiquitin proteasome-mediated protein degradation by reducing forkhead box protein O1 (FOXO1) and FOXO3a transcriptional activity in the skeletal muscle. Combined ARB and IGF-1 decreased the intramuscular expression of proinflammatory cytokines (i.e., TNFα, IL6, and IL1β) and increased the Trolox equivalent antioxidant capacity and antioxidant enzymes (CAT, GPX1, SOD2, and CYTB). This antioxidant effect was based on downregulation of NADPH oxidase (NOX) 2, normalization of mitochondrial biogenesis and dynamics. Moreover, ARB increased the hepatic and plasma IGF-1 levels and improved steatohepatitis, leading to enhanced skeletal muscle protein synthesis mediated by IGF-1/ AKT/ mechanistic target of rapamycin signaling. Collectively, combined ARB and IGF-1 replacement could be a promising new therapeutic target for NASH-derived skeletal muscle wasting.
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Affiliation(s)
- Misako Tanaka
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Kosuke Kaji
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan.
| | - Norihisa Nishimura
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Shohei Asada
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Aritoshi Koizumi
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Takuya Matsuda
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Nobuyuki Yorioka
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yuki Tsuji
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yukihisa Fujinaga
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Shinya Sato
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Tadashi Namisaki
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Takemi Akahane
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8521, Japan
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9
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Cheng PN, Chen WJ, Hou CJY, Lin CL, Chang ML, Wang CC, Chang WT, Wang CY, Lin CY, Hung CL, Peng CY, Yu ML, Chao TH, Huang JF, Huang YH, Chen CY, Chiang CE, Lin HC, Li YH, Lin TH, Kao JH, Wang TD, Liu PY, Wu YW, Liu CJ. Taiwan Association for the Study of the Liver-Taiwan Society of Cardiology Taiwan position statement for the management of metabolic dysfunction- associated fatty liver disease and cardiovascular diseases. Clin Mol Hepatol 2024; 30:16-36. [PMID: 37793641 PMCID: PMC10776290 DOI: 10.3350/cmh.2023.0315] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 09/22/2023] [Accepted: 09/25/2023] [Indexed: 10/06/2023] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly common liver disease worldwide. MAFLD is diagnosed based on the presence of steatosis on images, histological findings, or serum marker levels as well as the presence of at least one of the three metabolic features: overweight/obesity, type 2 diabetes mellitus, and metabolic risk factors. MAFLD is not only a liver disease but also a factor contributing to or related to cardiovascular diseases (CVD), which is the major etiology responsible for morbidity and mortality in patients with MAFLD. Hence, understanding the association between MAFLD and CVD, surveillance and risk stratification of MAFLD in patients with CVD, and assessment of the current status of MAFLD management are urgent requirements for both hepatologists and cardiologists. This Taiwan position statement reviews the literature and provides suggestions regarding the epidemiology, etiology, risk factors, risk stratification, nonpharmacological interventions, and potential drug treatments of MAFLD, focusing on its association with CVD.
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Affiliation(s)
- Pin-Nan Cheng
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Jone Chen
- Department of Internal Medicine, Min-Sheng General Hospital, Taoyuan; Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
| | | | - Chih-Lin Lin
- Department of Gastroenterology, Renai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Wei-Ting Chang
- Division of Cardiology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
- School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Chao-Yung Wang
- Division of Cardiology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
| | - Chun-Yen Lin
- Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chung-Lieh Hung
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei, Taiwan
- Division of Cardiology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Ming-Lung Yu
- School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ting-Hsing Chao
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Hsiang Huang
- Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, Taiwan
| | - Chi-Yi Chen
- Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan
| | - Chern-En Chiang
- General Clinical Research Center, and Cardiovascular Center, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Heng Li
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tsung-Hsien Lin
- Division of Cardiology, Department of Internal Medicine Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Medicine and Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tzung-Dau Wang
- Cardiovascular Center, MacKay Memorial Hospital, Taipei, Taiwan
- MacKay Medical College, New Taipei City, Taiwan
| | - Ping-Yen Liu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yen-Wen Wu
- Division of Cardiology, Cardiovascular Medical Center, and Department of Nuclear Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
- School of Medicine, National Yang Ming Chao Tung University, Taipei, Taiwan
- Graduate Institute of Medicine, Yuan Ze University, Taoyuan City, Taiwan
| | - Chun-Jen Liu
- Hepatitis Research Center, Department of Internal Medicine and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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10
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Grander C, Meyer M, Steinacher D, Claudel T, Hausmann B, Pjevac P, Grabherr F, Oberhuber G, Grander M, Brigo N, Jukic A, Schwärzler J, Weiss G, Adolph TE, Trauner M, Tilg H. 24-Norursodeoxycholic acid ameliorates experimental alcohol-related liver disease and activates hepatic PPARγ. JHEP Rep 2023; 5:100872. [PMID: 37818230 PMCID: PMC10561126 DOI: 10.1016/j.jhepr.2023.100872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 05/23/2023] [Accepted: 07/12/2023] [Indexed: 10/12/2023] Open
Abstract
Background & Aims Alcohol-related liver disease (ALD) is a global healthcare challenge with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a synthetic bile acid with anti-inflammatory properties in experimental and human cholestatic liver diseases. In the present study, we explored the efficacy of norUDCA in experimental ALD. Methods NorUDCA was tested in a preventive and therapeutic setting in an experimental ALD model (Lieber-DeCarli diet enriched with ethanol). Liver disease was phenotypically evaluated using histology and biochemical methods, and anti-inflammatory properties and peroxisome proliferator-activated receptor gamma activation by norUDCA were evaluated in cellular model systems. Results NorUDCA administration ameliorated ethanol-induced liver injury, reduced hepatocyte death, and reduced the expression of hepatic pro-inflammatory cytokines including tumour necrosis factor (Tnf), Il-1β, Il-6, and Il-10. NorUDCA shifted hepatic macrophages towards an anti-inflammatory M2 phenotype. Further, norUDCA administration altered the composition of the intestinal microbiota, specifically increasing the abundance of Roseburia, Enterobacteriaceae, and Clostridum spp. In a therapeutic model, norUDCA also ameliorated ethanol-induced liver injury. Moreover, norUDCA suppressed lipopolysaccharide-induced IL-6 expression in human peripheral blood mononuclear cells and evoked peroxisome proliferator-activated receptor gamma activation. Conclusions NorUDCA ameliorated experimental ALD, protected against hepatic inflammation, and affected gut microbial commensalism. NorUDCA could serve as a novel therapeutic agent in the future management of patients with ALD. Impact and implications Alcohol-related liver disease is a global healthcare concern with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a modified bile acid, which was proven to be effective in human cholestatic liver diseases. In the present study, we found a protective effect of norUDCA in experimental alcoholic liver disease. For patients with ALD, norUDCA could be a potential new treatment option.
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Affiliation(s)
- Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Moritz Meyer
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Daniel Steinacher
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Bela Hausmann
- Joint Microbiome Facility of the Medical University of Vienna, The University of Vienna, Vienna, Austria
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Petra Pjevac
- Joint Microbiome Facility of the Medical University of Vienna, The University of Vienna, Vienna, Austria
- Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Georg Oberhuber
- INNPATH, Tirol-Kliniken University Hospital Innsbruck, Innsbruck, Austria
| | - Manuel Grander
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria
| | - Natascha Brigo
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria
| | - Almina Jukic
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria
| | - Timon E. Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
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11
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Pais R, Cariou B, Noureddin M, Francque S, Schattenberg JM, Abdelmalek MF, Lalazar G, Varma S, Dietrich J, Miller V, Sanyal A, Ratziu V. A proposal from the liver forum for the management of comorbidities in non-alcoholic steatohepatitis therapeutic trials. J Hepatol 2023; 79:829-841. [PMID: 37001695 DOI: 10.1016/j.jhep.2023.03.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 02/08/2023] [Accepted: 03/13/2023] [Indexed: 06/19/2023]
Abstract
The current document has been developed by the Liver Forum who mandated the NAFLD-Associated Comorbidities Working Group - a multistakeholder group comprised of experts from academic medicine, industry and patient associations - to identify aspects of diverse comorbidities frequently associated with non-alcoholic steatohepatitis (NASH) that can interfere with the conduct of therapeutic trials and, in particular, impact efficacy and safety results. The objective of this paper is to propose guidance for the management of relevant comorbidities in both candidates and actual participants in NASH therapeutic trials. We relied on specific guidelines from scientific societies, when available, but adapted them to the particulars of NASH trials with the aim of addressing multiple interacting requirements such as maintaining patient safety, reaching holistic therapeutic objectives, minimising confounding effects on efficacy and safety of investigational agents and allowing for trial completion. We divided the field of action into: first, analysis and stabilisation of the patient's condition before inclusion in the trial and, second, management of comorbidities during trial conduct. For the former, we discussed the concept of acceptable vs. optimal control of comorbidities, defined metabolic and ponderal stability prior to randomisation and weighed the pros and cons of a run-in period. For the latter, we analysed non-hepatological comorbid conditions for changes or acute events possibly occurring during the trial, including changes in alcohol consumption, in order to detail when specific interventions are necessary and how best to manage concomitant drug intake in line with methodological constraints. These recommendations are intended to act as a guide for clinical trialists and are open to further refinement when additional data become available.
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Affiliation(s)
- Raluca Pais
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, France; Centre de Recherche Saint Antoine, INSERM UMRS_938 Paris, France
| | - Bertrand Cariou
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000 Nantes, France
| | | | - Sven Francque
- Department of Gastroenterology Hepatology, Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Belgium
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Manal F Abdelmalek
- Division of Gastroenterology and Hepatology, Duke University, Durham, NC, USA
| | - Gadi Lalazar
- Liver Unit, Digestive Disease Institute, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Sharat Varma
- Novo Nordisk A/S, Vandtårnsvej 108-110, 2860 Søborg Denmark
| | - Julie Dietrich
- GENFIT, Parc Eurasanté 885, Avenue Eugène Avinée, 59120, Loos, France
| | - Veronica Miller
- Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington D.C., USA
| | - Arun Sanyal
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Vlad Ratziu
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, France; INSERM UMRS 1138 CRC, Paris, France.
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12
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Inciardi RM, Mantovani A, Targher G. Non-Alcoholic Fatty Liver Disease as an Emerging Risk Factor for Heart Failure. Curr Heart Fail Rep 2023; 20:308-319. [PMID: 37402108 PMCID: PMC10421789 DOI: 10.1007/s11897-023-00613-1] [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] [Accepted: 06/14/2023] [Indexed: 07/05/2023]
Abstract
PURPOSE OF THE REVIEW Non-alcoholic fatty liver disease (NAFLD) and heart failure (HF) are two chronic diseases that have become important global public health problems. This narrative review provides a comprehensive overview of the association between NAFLD and increased risk of new-onset HF, briefly discusses the putative biological mechanisms linking these two conditions, and summarizes targeted pharmacotherapies for NAFLD that might also beneficially affect cardiac complications leading to new-onset HF. RECENT FINDINGS Recent observational cohort studies supported a significant association between NAFLD and the long-term risk of new-onset HF. Notably, this risk remained statistically significant even after adjustment for age, sex, ethnicity, adiposity measures, pre-existing type 2 diabetes and other common cardiometabolic risk factors. In addition, the risk of incident HF was further increased with more advanced liver disease, especially with higher severity of liver fibrosis. There are multiple potential pathophysiological mechanisms by which NAFLD (especially in its more advanced forms) may increase the risk of new-onset HF. Because of the strong link existing between NAFLD and HF, more careful surveillance of these patients will be needed. However, further prospective and mechanistic studies are required to better decipher the existing but complex link between NAFLD and risk of new-onset HF.
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Affiliation(s)
- Riccardo M Inciardi
- ASST Spedali Civili Di Brescia, Division of Cardiology and Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Alessandro Mantovani
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Verona, Verona, Italy
| | - Giovanni Targher
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Verona, Verona, Italy.
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13
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Gu L, Zhu Y, Lee M, Nguyen A, Ryujin NT, Huang JY, Pandit SK, Chamseddine S, Xiao L, Mohamed YI, Kaseb AO, Karin M, Shalapour S. Angiotensin II receptor inhibition ameliorates liver fibrosis and enhances hepatocellular carcinoma infiltration by effector T cells. Proc Natl Acad Sci U S A 2023; 120:e2300706120. [PMID: 37126700 PMCID: PMC10175751 DOI: 10.1073/pnas.2300706120] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 04/02/2023] [Indexed: 05/03/2023] Open
Abstract
Although viral hepatocellular carcinoma (HCC) is declining, nonviral HCC, which often is the end stage of nonalcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICIs) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a minority of HCC patients show a robust and sustained response to PD-1 blockade, calling for improved understanding of factors that negatively impact response rate and duration and the discovery of new adjuvant treatments that enhance ICI responsiveness. Using a mouse model of NASH-driven HCC, we identified peritumoral fibrosis as a potential obstacle to T cell-mediated tumor regression and postulated that antifibrotic medications may increase ICI responsiveness. We now show that the angiotensin II receptor inhibitor losartan, a commonly prescribed and safe antihypertensive drug, reduced liver and peritumoral fibrosis and substantially enhanced anti-PD-1-induced tumor regression. Although losartan did not potentiate T cell reinvigoration, it substantially enhanced HCC infiltration by effector CD8+ T cells compared to PD-1 blockade alone. The beneficial effects of losartan correlated with blunted TGF-β receptor signaling, reduced collagen deposition, and depletion of immunosuppressive fibroblasts.
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Affiliation(s)
- Li Gu
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, School of Medicine, University of California San Diego, San Diego, CA92093
| | - Yahui Zhu
- Department of Center of Smart Laboratory and Molecular Medicine, School of Medicine, Chongqing University, Chongqing400044, China
| | - Maiya Lee
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, School of Medicine, University of California San Diego, San Diego, CA92093
| | - Albert Nguyen
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, School of Medicine, University of California San Diego, San Diego, CA92093
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX77030
| | - Nicolas T. Ryujin
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX77030
| | - Jian Yu Huang
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, School of Medicine, University of California San Diego, San Diego, CA92093
| | - Shusil K. Pandit
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, School of Medicine, University of California San Diego, San Diego, CA92093
| | - Shadi Chamseddine
- Gastrointestinal Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX77030
| | - Lianchun Xiao
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX77030
| | - Yehia I. Mohamed
- Gastrointestinal Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX77030
| | - Ahmed O. Kaseb
- Gastrointestinal Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX77030
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, School of Medicine, University of California San Diego, San Diego, CA92093
| | - Shabnam Shalapour
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX77030
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Gu L, Zhu Y, Lee M, Nguyen A, Ryujin NT, Huang J, Chamseddine S, Xiao L, Mohamed YI, Kaseb AO, Karin M, Shalapour S. Angiotensin II receptor inhibition ameliorates liver fibrosis and enhances hepatocellular carcinoma infiltration by effector T cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.05.531188. [PMID: 36945365 PMCID: PMC10028807 DOI: 10.1101/2023.03.05.531188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
Although viral hepatocellular carcinoma (HCC) is declining, non-viral HCC, which often is the end-stage of non-alcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICI) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a small portion of HCC patients show a robust and sustained response to PD-1 blockade, calling for improved understanding of factors that negatively impact response rate and duration and the discovery of new adjuvant treatments that enhance ICI responsiveness. Using a mouse model of NASH-driven HCC, we identified peritumoral fibrosis as a potential obstacle to T cell mediated tumor regression and postulated that anti-fibrotic medications may increase ICI responsiveness. We now show that the angiotensin II receptor inhibitor losartan, a commonly prescribed and safe antihypertensive drug, reduced liver and peritumoral fibrosis and substantially enhanced anti-PD-1 induced tumor regression. Although losartan did not potentiate T cell reinvigoration, it substantially enhanced HCC infiltration by effector CD8 + T cells compared to PD-1 blockade alone. The beneficial effects of losartan correlated with inhibition of TGF-β receptor signaling, collagen deposition and depletion of immunosuppressive fibroblasts. Significance Immune checkpoint inhibitors are used in HCC treatment but overall response rates for single agent PD-1/PD-L1 blockers have remained stubbornly low. Using a mouse model of NASH-driven HCC, we show that co-treatment with the safe and inexpensive angiotensin II receptor inhibitor losartan substantially enhanced anti-PD-1 triggered HCC regression. Although losartan did not influence the reinvigoration of exhausted CD8 + T cells it considerably enhanced their intratumoral invasion, which we postulated to be compromised by peritumoral fibrosis. Indeed, the beneficial effect of losartan correlated with inhibition of TGF-β signaling and collagen deposition, and depletion of immunosuppressive fibroblasts. Losartan should be evaluated for its adjuvant activity in HCC patients undergoing PD-1/PD-L1 blocking therapy.
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15
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Yang Z, Tian R, Zhang XJ, Cai J, She ZG, Li H. Effects of treatment of non-alcoholic fatty liver disease on heart failure with preserved ejection fraction. Front Cardiovasc Med 2023; 9:1120085. [PMID: 36712249 PMCID: PMC9877359 DOI: 10.3389/fcvm.2022.1120085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 12/30/2022] [Indexed: 01/14/2023] Open
Abstract
In the past few decades, non-alcoholic fatty liver disease (NAFLD) and heart failure with preserved ejection fraction (HFpEF) have become the most common chronic liver disease and the main form of heart failure (HF), respectively. NAFLD is closely associated with HFpEF by sharing common risk factors and/or by boosting systemic inflammation, releasing other secretory factors, and having an expansion of epicardial adipose tissue (EAT). Therefore, the treatments of NAFLD may also affect the development and prognosis of HFpEF. However, no specific drugs for NAFLD have been approved by the Food and Drug Administration (FDA) and some non-specific treatments for NAFLD are applied in the clinic. Currently, the treatments of NAFLD can be divided into non-pharmacological and pharmacological treatments. Non-pharmacological treatments mainly include dietary intervention, weight loss by exercise, caloric restriction, and bariatric surgery. Pharmacological treatments mainly include administering statins, thiazolidinediones, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, and metformin. This review will mainly focus on analyzing how these treatments may affect the development and prognosis of HFpEF.
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Affiliation(s)
- Zifeng Yang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Ruifeng Tian
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Xiao-Jing Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Jingjing Cai
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
- Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
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Badr AM, Sherif IO, Mahran YF, Attia HA. Role of Renin-Angiotensin System in the Pathogenesis and Progression of Non-alcoholic Fatty Liver. ADVANCES IN BIOCHEMISTRY IN HEALTH AND DISEASE 2023:179-197. [DOI: 10.1007/978-3-031-23621-1_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2023]
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Zou CY, Sun Y, Liang J. Comparative efficacy of diabetes medications on liver enzymes and fat fraction in patients with nonalcoholic fatty liver disease: A network meta-analysis ,. Clin Res Hepatol Gastroenterol 2023; 47:102053. [PMID: 36403941 DOI: 10.1016/j.clinre.2022.102053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/03/2022] [Accepted: 11/16/2022] [Indexed: 11/18/2022]
Abstract
OBJECTIVES This network meta-analysis (NMA) aimed to evaluate the relative rank-order of existing diabetes medications in patients with nonalcoholic fatty liver disease (NAFLD) with or without type 2 diabetes mellitus (T2DM). METHODS A systematic literature search was conducted using the Medline, Embase and Cochrane databases. Clinical trials comparing the efficacy of diabetes medications with other interventions, including lifestyle modification and placebo, in patients with NAFLD were included. The results from the NMA are presented as the weighted mean difference (WMD) of the continuous results and the corresponding 95% confidence intervals (95% CIs). RESULTS The articles presented the results of 49 trials involving 3,836 subjects published between 2013 and 2021. According to our results, thiazolidinedione (TZD) was ranked as the best diabetes medication in the reduction of alanine aminotransferase (ALT) (WMD = -10.10, 95% CI: -15.18, -5.01), followed by dipeptidyl peptidase-4 inhibitor (DPP4i) (WMD = -8.90, 95% CI: -14.41, -3.40). DPP4i also resulted in the greatest reduction in aspartate aminotransferase (AST) (WMD = -6.89, 95% CI: -11.72, -2.07). γ-Glutamyl transferase (γ-GT) reduction was highest in patients treated with glucagon-like peptide 1 receptor agonists (GLP1RAs) (WMD = -15.48, 95% CI: -30.93, -0.02). Ultimately, SGLT2is and GLP1RAs were superior to other diabetes medications or placebo in reducing liver fat fraction (LFF) (WMD = -6.09, 95% CI: -10.50, -1.68; WMD = -5.55, 95% CI: -10.40, -0.69, respectively). CONCLUSION Diabetes medications, including TZD, DPP4i and GLP1RAs, were found to be suitable alternatives for liver enzyme reduction in the treatment of NAFLD patients. SGLT2is are considered the most effective therapies for lipid modulation in these patients.
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Affiliation(s)
- Cai-Yan Zou
- Medical College, Soochow University, Suzhou, Jiangsu 215123, China; Department of Endocrinology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, China
| | - Yan Sun
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, China
| | - Jun Liang
- Medical College, Soochow University, Suzhou, Jiangsu 215123, China; Department of Endocrinology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, China.
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18
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Combination Therapies for Nonalcoholic Fatty Liver Disease. J Pers Med 2022; 12:jpm12071166. [PMID: 35887662 PMCID: PMC9322793 DOI: 10.3390/jpm12071166] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/01/2022] [Accepted: 07/13/2022] [Indexed: 11/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered a highly prevalent disease associated with various co-morbidities that lead to socioeconomic burden. Despite large-scale investigation, no pharmacological treatment has been approved specifically for NAFLD to date. Lifestyle modifications and diet are regarded as highly beneficial for the management of NAFLD, albeit with poor compliance, thus rendering pharmacological treatment highly important. Based on the current failure to discover a “magic bullet” to treat all patients with NAFLD and considering the multifaceted pathophysiology of the disease, combination therapies may be considered to be a rational alternative approach. In this regard, several drug categories have been considered, including, but not limited to, lipid-lowering, anti-hypertensive, glucose-lowering, anti-obesity, anti-oxidant, anti-inflammatory and anti-fibrotic medications. The aim of this review is, in addition to summarizing some of the multiple factors contributing to the pathophysiology of NAFLD, to focus on the efficacy of pharmacological combinations on the management of NAFLD. This may provide evidence for a more personalized treatment of patients with NAFLD in the future.
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Mitsala A, Tsalikidis C, Romanidis K, Pitiakoudis M. Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing? Curr Oncol 2022; 29:4478-4510. [PMID: 35877216 PMCID: PMC9325209 DOI: 10.3390/curroncol29070356] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 12/02/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.
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20
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Duell PB, Welty FK, Miller M, Chait A, Hammond G, Ahmad Z, Cohen DE, Horton JD, Pressman GS, Toth PP. Nonalcoholic Fatty Liver Disease and Cardiovascular Risk: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol 2022; 42:e168-e185. [PMID: 35418240 DOI: 10.1161/atv.0000000000000153] [Citation(s) in RCA: 323] [Impact Index Per Article: 107.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition that is believed to affect >25% of adults worldwide. Unless specific testing is done to identify NAFLD, the condition is typically silent until advanced and potentially irreversible liver impairment occurs. For this reason, the majority of patients with NAFLD are unaware of having this serious condition. Hepatic complications from NAFLD include nonalcoholic steatohepatitis, hepatic cirrhosis, and hepatocellular carcinoma. In addition to these serious complications, NAFLD is a risk factor for atherosclerotic cardiovascular disease, which is the principal cause of death in patients with NAFLD. Accordingly, the purpose of this scientific statement is to review the underlying risk factors and pathophysiology of NAFLD, the associations with atherosclerotic cardiovascular disease, diagnostic and screening strategies, and potential interventions.
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21
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Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO). Eat Weight Disord 2022; 27:1603-1619. [PMID: 34914079 PMCID: PMC9123074 DOI: 10.1007/s40519-021-01287-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 07/29/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the past years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato, the Società Italiana di Diabetologia and the Società Italiana dell'Obesità reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure and Istituto Superiore di Sanità. Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources.Level of evidence Level of evidence of recommendations for each PICO question were reported according to available evidence.
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22
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Potential Therapeutic Targets and Promising Agents for Combating NAFLD. Biomedicines 2022; 10:biomedicines10040901. [PMID: 35453652 PMCID: PMC9032837 DOI: 10.3390/biomedicines10040901] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 01/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is a growing cause of liver cirrhosis and liver cancer worldwide because of the global increases in obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus. Contrary to the advancements in therapies for viral hepatitis, effective treatments remain unestablished for patients with NAFLD. NAFLD, including NASH, is characterized by steatosis, inflammation, hepatic necrosis, and fibrosis. Despite our understanding of its pathophysiology, there are currently no effective treatments for NAFLD. In this review, we provide an update on the known pathophysiological mechanisms involved in the development of NAFLD and the role of hepatic stellate cells, and summarize the potential therapeutic agents, including natural products, for NAFLD.
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23
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Lange NF, Graf V, Caussy C, Dufour JF. PPAR-Targeted Therapies in the Treatment of Non-Alcoholic Fatty Liver Disease in Diabetic Patients. Int J Mol Sci 2022; 23:ijms23084305. [PMID: 35457120 PMCID: PMC9028563 DOI: 10.3390/ijms23084305] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 02/06/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors of the nuclear hormone receptor superfamily, have been identified as key metabolic regulators in the liver, skeletal muscle, and adipose tissue, among others. As a leading cause of liver disease worldwide, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) cause a significant burden worldwide and therapeutic strategies are needed. This review provides an overview of the evidence on PPAR-targeted treatment of NAFLD and NASH in individuals with type 2 diabetes mellitus. We considered current evidence from clinical trials and observational studies as well as the impact of treatment on comorbid metabolic conditions such as obesity, dyslipidemia, and cardiovascular disease. Future areas of research, such as possible sexually dimorphic effects of PPAR-targeted therapies, are briefly reviewed.
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Affiliation(s)
- Naomi F. Lange
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
- Graduate School for Health Sciences, University of Bern, 3012 Bern, Switzerland
- Correspondence: (N.F.L.); (J.-F.D.)
| | - Vanessa Graf
- Department of Diabetes, Endocrinology, Clinical Nutrition, and Metabolism, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland;
| | - Cyrielle Caussy
- Univ Lyon, CarMen Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, 69495 Pierre-Bénite, France;
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
| | - Jean-François Dufour
- Centre des Maladies Digestives, 1003 Lausanne, Switzerland
- Swiss NASH Foundation, 3011 Bern, Switzerland
- Correspondence: (N.F.L.); (J.-F.D.)
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24
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Chen YW, Diamante G, Ding J, Nghiem TX, Yang J, Ha SM, Cohn P, Arneson D, Blencowe M, Garcia J, Zaghari N, Patel P, Yang X. PharmOmics: A species- and tissue-specific drug signature database and gene-network-based drug repositioning tool. iScience 2022; 25:104052. [PMID: 35345455 PMCID: PMC8957031 DOI: 10.1016/j.isci.2022.104052] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/29/2022] [Accepted: 03/08/2022] [Indexed: 12/29/2022] Open
Abstract
Drug development has been hampered by a high failure rate in clinical trials due to our incomplete understanding of drug functions across organs and species. Therefore, elucidating species- and tissue-specific drug functions can provide insights into therapeutic efficacy, potential adverse effects, and interspecies differences necessary for effective translational medicine. Here, we present PharmOmics, a drug knowledgebase and analytical tool that is hosted on an interactive web server. Using tissue- and species-specific transcriptome data from human, mouse, and rat curated from different databases, we implemented a gene-network-based approach for drug repositioning. We demonstrate the potential of PharmOmics to retrieve known therapeutic drugs and identify drugs with tissue toxicity using in silico performance assessment. We further validated predicted drugs for nonalcoholic fatty liver disease in mice. By combining tissue- and species-specific in vivo drug signatures with gene networks, PharmOmics serves as a complementary tool to support drug characterization and network-based medicine.
Development of PharmOmics, a platform for drug repositioning and toxicity prediction Contains >18000 species/tissue-specific gene signatures for 941 drugs and chemicals Benchmarked and validated network-based drug repositioning and toxicity prediction PharmOmics is freely accessible via an online web server to facilitate user access
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Affiliation(s)
- Yen-Wei Chen
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular Toxicology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Graciel Diamante
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular Toxicology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jessica Ding
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular, Cellular, & Integrative Physiology, Los Angeles, Los Angeles, CA 90095, USA
| | - Thien Xuan Nghiem
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jessica Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Sung-Min Ha
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Peter Cohn
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Douglas Arneson
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Montgomery Blencowe
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular, Cellular, & Integrative Physiology, Los Angeles, Los Angeles, CA 90095, USA
| | - Jennifer Garcia
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Nima Zaghari
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Paul Patel
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular Toxicology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular, Cellular, & Integrative Physiology, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Corresponding author
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A Network Pharmacology Study on the Active Components and Targets of the Radix Ginseng and Radix Bupleuri Herb Pair for Treating Nonalcoholic Fatty Liver Disease. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1638740. [PMID: 35178098 PMCID: PMC8846978 DOI: 10.1155/2022/1638740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To explore the potential active components and corresponding target herb pairs of Radix Ginseng (Renshen) and Radix Bupleuri (Chaihu) in the treatment of nonalcoholic fatty liver disease (NAFLD) through network pharmacology and in vitro experiments. METHODS The active components and potential targets of the herb pair of Renshen and Chaihu were screened through a network database system, and Venn analysis was performed with the obtained NAFLD targets. The intersecting targets were analysed for gene ontology (GO) functions and Kyoto Encyclopedia of Genes and Genome (KEGG) pathways, and a protein-protein interaction (PPI) network was generated. Cytoscape software was used to construct active component-target networks of the Renshen and Chaihu herb pair. Free fatty acids were added to the HepG2 cell line to create high-fat models that were treated with different concentrations of stigmasterol. The effect of stigmasterol on the lipid metabolism in HepG2 cells and PPARγ-knockdown cells was determined by oil red O staining, Nile red staining, and TG level. PPARγ and UCP-1 mRNA, and protein expression levels were detected by qRT-PCR and Western blot analyses, respectively. RESULTS Twenty active components obtained from the Renshen and Chaihu herb pair were identified. The herb pair active component-target network showed that both Renshen and Chaihu contained stigmasterol and kaempferol as active components. The PPI network comprised 63 protein nodes. GO enrichment analysis and KEGG pathway enrichment analysis showed that the targets were mainly involved in lipid metabolism. Eight core targets were identified: AKT1, PPARG, MAPK3, TNF, TP53, SIRT1, STAT3, and PPARA. In vitro experiments demonstrated that stigmasterol reduced lipid accumulation and TG levels in HepG2 cells, and the mechanism may have been related to the activation of the PPARγ-UCP-1 signalling pathway. CONCLUSION This study preliminarily illustrated the potential components and corresponding core targets of the Renshen and Chaihu herb pair in treating NAFLD. The effect of stigmasterol on the PPARγ-UCP-1 signalling pathway in enhancing lipid metabolism may represent one of the mechanisms of the Renshen and Chaihu herb pair in the treatment of NAFLD. The results provide new evidence and research insights to reveal the roles of Renshen and Chaihu in the management of NAFLD.
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Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO). Dig Liver Dis 2022; 54:170-182. [PMID: 34924319 DOI: 10.1016/j.dld.2021.04.029] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 03/22/2021] [Accepted: 04/21/2021] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell'Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources. Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.
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Marchesini G, Bugianesi E, Burra P, Marra F, Miele L, Alisi A, Vajro P, Masarone M, Petta S, Persico M, Svegliati-Baroni G, Valenti L, Federici M, Purrello F, Sasso FC, Targher G, Busetto L, Petroni ML, Santini F, Cammà C, Colli A. Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO). Nutr Metab Cardiovasc Dis 2022; 32:1-16. [PMID: 34924246 DOI: 10.1016/j.numecd.2021.04.028] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell'Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources. Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.
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Tokushige K, Ikejima K, Ono M, Eguchi Y, Kamada Y, Itoh Y, Akuta N, Yoneda M, Iwasa M, Yoneda M, Otsuka M, Tamaki N, Kogiso T, Miwa H, Chayama K, Enomoto N, Shimosegawa T, Takehara T, Koike K. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020. J Gastroenterol 2021; 56:951-963. [PMID: 34533632 PMCID: PMC8531062 DOI: 10.1007/s00535-021-01796-x] [Citation(s) in RCA: 174] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 05/14/2021] [Indexed: 02/04/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non-viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease (CVD) event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow-up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary provides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan.
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Affiliation(s)
- Katsutoshi Tokushige
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan.
| | - Kenichi Ikejima
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masafumi Ono
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yuichiro Eguchi
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshihiro Kamada
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshito Itoh
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Norio Akuta
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masato Yoneda
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Motoh Iwasa
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masashi Yoneda
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Motoyuki Otsuka
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Nobuharu Tamaki
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tomomi Kogiso
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuaki Chayama
- The Japan Society of Hepatology, Kashiwaya 2 Building 5F, 3-28-10 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tetsuo Takehara
- The Japan Society of Hepatology, Kashiwaya 2 Building 5F, 3-28-10 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
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Tokushige K, Ikejima K, Ono M, Eguchi Y, Kamada Y, Itoh Y, Akuta N, Yoneda M, Iwasa M, Yoneda M, Otsuka M, Tamaki N, Kogiso T, Miwa H, Chayama K, Enomoto N, Shimosegawa T, Takehara T, Koike K. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020. Hepatol Res 2021; 51:1013-1025. [PMID: 34533266 DOI: 10.1111/hepr.13688] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non-viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow-up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary pro- vides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan.
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Affiliation(s)
- Katsutoshi Tokushige
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Kenichi Ikejima
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Masafumi Ono
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Yuichiro Eguchi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Yoshihiro Kamada
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Yoshito Itoh
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Norio Akuta
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Masato Yoneda
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Motoh Iwasa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Masashi Yoneda
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Motoyuki Otsuka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Nobuharu Tamaki
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Tomomi Kogiso
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | | | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | | | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
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Mahjoubin-Tehran M, De Vincentis A, Mikhailidis DP, Atkin SL, Mantzoros CS, Jamialahmadi T, Sahebkar A. Non-alcoholic fatty liver disease and steatohepatitis: State of the art on effective therapeutics based on the gold standard method for diagnosis. Mol Metab 2021; 50:101049. [PMID: 32673798 PMCID: PMC8324680 DOI: 10.1016/j.molmet.2020.101049] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/19/2020] [Accepted: 06/26/2020] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE The prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NAFLD/NASH) is increasing. NAFLD/NASH may progress to cirrhosis and hepatocellular carcinoma. However, most patients with NAFLD/NASH will die from a vascular cause. There are no approved pharmacological treatments for NASH/NAFLD. Many clinical trials have been, or are being, undertaken; however, the challenge is the assessment of the clinical endpoint. The main objective of this narrative review was to evaluate the efficacy of drugs used in clinical trials for the treatment of NAFLD/NASH that included a liver biopsy as the gold standard. METHODS A literature search was conducted using 3 databases (PubMed, Scopus, and Google Scholar) to identify the clinical trials that included liver biopsy assessment before and after treatment. RESULTS Interventional clinical trials (n = 33) involving 18 different agents, alone and in combination, were identified. Pioglitazone is the only agent that has shown consistent benefit and efficacy in clinical trials. Pentoxifylline, rosiglitazone, and ursodeoxycholic acid had both positive and negative results from clinical trials. There is also evidence for vitamin E and metformin. Other drugs, including bicyclol, cysteamine bitartrate, l-carnitine, liraglutide, obeticholic acid, oligofructose, selonsertib, silymarin, and statins, each had a single clinical study. CONCLUSIONS In summary, the available molecules demonstrated a significant improvement in NASH and/or liver fibrosis in a minority of patients; thus, other drugs should be identified, possibly those acting on alternative pathophysiological pathways, and tested for their safety and efficacy.
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Affiliation(s)
- Maryam Mahjoubin-Tehran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Antonio De Vincentis
- Clinical Medicine and Hepatology Unit, Campus Bio-Medico University of Rome, via Alvaro del Portillo, 200, 00128 Rome, Italy
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom
| | | | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
| | - Tannaz Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran; Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland.
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Zhang C, Yang M. Current Options and Future Directions for NAFLD and NASH Treatment. Int J Mol Sci 2021; 22:7571. [PMID: 34299189 PMCID: PMC8306701 DOI: 10.3390/ijms22147571] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/12/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with a broad spectrum ranging from simple steatosis to advanced stage of nonalcoholic steatohepatitis (NASH). Although there are many undergoing clinical trials for NAFLD treatment, there is no currently approved treatment. NAFLD accounts as a major causing factor for the development of hepatocellular carcinoma (HCC), and its incidence rises accompanying the prevalence of obesity and diabetes. Reprogramming of antidiabetic and anti-obesity medicine is a major treatment option for NAFLD and NASH. Liver inflammation and cellular death, with or without fibrosis account for the progression of NAFLD to NASH. Therefore, molecules and signaling pathways involved in hepatic inflammation, fibrosis, and cell death are critically important targets for the therapy of NAFLD and NASH. In addition, the avoidance of aberrant infiltration of inflammatory cytokines by treating with CCR antagonists also provides a therapeutic option. Currently, there is an increasing number of pre-clinical and clinical trials undergoing to evaluate the effects of antidiabetic and anti-obesity drugs, antibiotics, pan-caspase inhibitors, CCR2/5 antagonists, and others on NAFLD, NASH, and liver fibrosis. Non-invasive serum diagnostic markers are developed for fulfilling the need of diagnostic testing in a large amount of NAFLD cases. Overall, a better understanding of the underlying mechanism of the pathogenesis of NAFLD is helpful to choose an optimized treatment.
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Affiliation(s)
- Chunye Zhang
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA;
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65211, USA
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Hartl L, Elias J, Prager G, Reiberger T, Unger LW. Individualized treatment options for patients with non-cirrhotic and cirrhotic liver disease. World J Gastroenterol 2021; 27:2281-2298. [PMID: 34040322 PMCID: PMC8130039 DOI: 10.3748/wjg.v27.i19.2281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/19/2021] [Accepted: 04/25/2021] [Indexed: 02/06/2023] Open
Abstract
The obesity pandemic has led to a significant increase in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). While dyslipidemia, type 2 diabetes mellitus and cardiovascular diseases guide treatment in patients without signs of liver fibrosis, liver related morbidity and mortality becomes relevant for MAFLD's progressive form, non-alcoholic steatohepatitis (NASH), and upon development of liver fibrosis. Statins should be prescribed in patients without significant fibrosis despite concomitant liver diseases but are underutilized in the real-world setting. Bariatric surgery, especially Y-Roux bypass, has been proven to be superior to conservative and/or medical treatment for weight loss and resolution of obesity-associated diseases, but comes at a low but existent risk of surgical complications, reoperations and very rarely, paradoxical progression of NASH. Once end-stage liver disease develops, obese patients benefit from liver transplantation (LT), but may be at increased risk of perioperative infectious complications. After LT, metabolic comorbidities are commonly observed, irrespective of the underlying liver disease, but MAFLD/NASH patients are at even higher risk of disease recurrence. Few studies with low patient numbers evaluated if, and when, bariatric surgery may be an option to avoid disease recurrence but more high-quality studies are needed to establish clear recommendations. In this review, we summarize the most recent literature on treatment options for MAFLD and NASH and highlight important considerations to tailor therapy to individual patient's needs in light of their risk profile.
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Affiliation(s)
- Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna A-1090, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna A-1090, Austria
| | - Joshua Elias
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Gerhard Prager
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna A-1090, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna A-1090, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna A-1090, Austria
| | - Lukas W Unger
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna A-1090, Austria
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33
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Koutoukidis DA, Morris E, Henry JA, Shammoon Y, Zimmerman M, Michalopoulou M, Jebb SA, Aveyard P. What proportion of people have a follow-up biopsy in randomized trials of treatments for non-alcoholic steatohepatitis?: A systematic review and meta-analysis. PLoS One 2021; 16:e0250385. [PMID: 33882107 PMCID: PMC8059856 DOI: 10.1371/journal.pone.0250385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/02/2021] [Indexed: 12/30/2022] Open
Abstract
Background and aim Trials of treatments for non-alcoholic steatohepatitis require endpoint assessment with liver biopsies. Previous large-scale trials have calculated their sample size expecting high retention but on average did not achieve this. We aimed to quantify the proportion of participants with a valid follow-up biopsy. Methods We conducted a systematic review of MEDLINE and Embase until May 2020 and included randomized clinical trials of any intervention in non-alcoholic steatohepatitis with at least 1-year follow-up. We were guided by Cochrane methods to run a meta-analysis with generalized linear mixed models with random effects. Results Forty-one trials (n = 6,695) were included. The proportion of participants with a valid follow-up biopsy was 82% (95%CI: 78%-86%, I2 = 92%). There was no evidence of a difference by location, trial length, or by allocated treatment group. Reasons for missing follow-up biopsies were, in ranked order, related to participants (95 per 1,000 participants (95%CI: 69–129, I2 = 92%), medical factors, protocol, trial conduct, and other/unclear. Biopsy-related serious adverse events occurred in 16 per 1,000 participants (95% CI: 8–33, I2 = 54%). No biopsy-related deaths were reported. Conclusions The proportion of participants with a valid follow-up biopsy in therapeutic trials in non-alcoholic steatohepatitis is on average 82%, with around 1 in 10 participants declining a follow-up biopsy. These findings can inform adequately-powered trials.
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Affiliation(s)
- Dimitrios A. Koutoukidis
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals, NHS Foundation Trust, Oxford, United Kingdom
- * E-mail:
| | - Elizabeth Morris
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
| | - John A. Henry
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
| | - Yusra Shammoon
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
| | - Matthew Zimmerman
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
| | - Moscho Michalopoulou
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals, NHS Foundation Trust, Oxford, United Kingdom
| | - Susan A. Jebb
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals, NHS Foundation Trust, Oxford, United Kingdom
| | - Paul Aveyard
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals, NHS Foundation Trust, Oxford, United Kingdom
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Lian J, Fu J. Efficacy of Various Hypoglycemic Agents in the Treatment of Patients With Nonalcoholic Liver Disease With or Without Diabetes： A Network Meta-Analysis. Front Endocrinol (Lausanne) 2021; 12:649018. [PMID: 33841337 PMCID: PMC8024567 DOI: 10.3389/fendo.2021.649018] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 03/05/2021] [Indexed: 12/11/2022] Open
Abstract
Objective To comprehensively evaluate and compare the therapeutic effects of various hypoglycemic agents in NAFLD patients with or without diabetes. Methods All literature from the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Clinical Trials was searched, and the language was limited to English. Two reviewers independently assessed study eligibility, continuous data extraction, and independent assessment of bias risk. Our primary outcomes were alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride levels, while our secondary outcomes were high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels, body weight, BMI, and fasting glucose and glycosylated hemoglobin (HbA1c) levels. Results The review identified 20 eligible trials that met the inclusion criteria. We found that, compared to other drugs, thiazolidinediones, especially pioglitazone, had a greater effect on the levels of ALT (-8.01 (95% CI -14.3 to 2.02)) and AST (-5.0 (95% CI -9.21 to -1,22)) and other biological indicators, but they were also associated with an increased risk of weight gain (3.62 (95% CI 2.25 to 4.99) and increased BMI (0.59 (95% Cl -0.13 to 1.29). GLP1 RAs and metformin also had better therapeutic effects than other drugs as measured by the levels of ALT (liraglutide: -9.36 (95% Cl -18 to -0.34), metformin: -2.84 (95% CI -11.09 to 5.28)) and AST (liraglutide: -5.14 (95% CI -10.69 to 0.37), metformin: -2.39 (95% CI -7.55, 2.49)) and other biological indicators. Conclusion Despite the significant risk of weight gain, thiazolidinediones, especially pioglitazone, are beneficial in normalizing liver and glucose metabolism in NAFLD patients. In clinical practice, we believe that GLP1 RAs such as liraglutide and exenatide or metformin can be used in combination to offset the risk of weight gain associated with thiazolidinediones. However, long-term studies are still needed to verify the efficacy and safety of individual hypoglycemic agents. Systematic Review Registration [PROSPERO], identifier [CRD42020212025].
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Affiliation(s)
| | - Jianfang Fu
- Department of Endocrinology, Xijing Hospital of Air Force Medical University, Xi’an, China
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Mantovani A, Dalbeni A. Treatments for NAFLD: State of Art. Int J Mol Sci 2021; 22:ijms22052350. [PMID: 33652942 PMCID: PMC7956331 DOI: 10.3390/ijms22052350] [Citation(s) in RCA: 138] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is to date the most common chronic liver disease in clinical practice and, consequently, a major health problem worldwide. It affects approximately 30% of adults in the general population and up to 70% of patients with type 2 diabetes (T2DM). Despite the current knowledge of the epidemiology, pathogenesis, and natural history of NAFLD, no specific pharmacological therapies are until now approved for this disease and, consequently, general strategies have been proposed to manage it. They include: (a) lifestyle change in order to promote weight loss by diet and physical activity, (b) control of the main cardiometabolic risk factors, (c) correction of all modifiable risk factors leading the development and progression of advanced forms of NAFLD, and (d) prevention of hepatic and extra-hepatic complications. In the last decade, several potential agents have been widely investigated for the treatment of NAFLD and its advanced forms—shedding some light but casting a few shadows. They include some glucose-lowering drugs (such as pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose co-transporter-2 (SGLT-2) inhibitors), antioxidants (such as vitamin E), statins or other lipid lowering agents, bile and non-bile acid farnesoid X activated receptor (FXR) agonists, and others. This narrative review discusses in detail the different available approaches with the potential to prevent and treat NAFLD and its advanced forms.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy
- Correspondence:
| | - Andrea Dalbeni
- Section of General Medicine, Hypertension and Liver Unit, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37134 Verona, Italy;
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Mantovani A, Byrne C, Scorletti E, Mantzoros C, Targher G. Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials. DIABETES & METABOLISM 2020; 46:427-441. [DOI: 10.1016/j.diabet.2019.12.007] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 12/26/2019] [Accepted: 12/27/2019] [Indexed: 12/12/2022]
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Patel P, Muller C, Paul S. Racial disparities in nonalcoholic fatty liver disease clinical trial enrollment: A systematic review and meta-analysis. World J Hepatol 2020; 12:506-518. [PMID: 32952877 PMCID: PMC7475777 DOI: 10.4254/wjh.v12.i8.506] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/09/2020] [Accepted: 07/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has a heterogeneous distribution across racial and ethnic groups, with a disproportionate burden among Hispanics. Although there are currently no approved therapies for treatment of NAFLD, several therapies have been investigated in clinical trials.
AIM To analyze the inclusion of racial and ethnic minority groups in clinical trials for NAFLD.
METHODS We performed a systematic review of North American, English-language, prospective studies for NAFLD therapies published from 2005 to 2019. Racial and ethnic enrollment data were recorded for each eligible study. Meta-analysis was performed to compute pooled prevalence of different racial and ethnic groups, followed by further subgroup analyses. These analyses were based on diagnosis of non-alcoholic steatohepatitis (NASH) and timing of study on enrollment by ethnicity. Descriptive statistics were performed to compare racial and ethnic study enrollment to previously reported NAFLD population prevalence.
RESULTS Thirty-eight studies met criteria for inclusion in the systematic review. When reported, median age of enrolled subjects was 49 years (range 41.5-58) with 56% female participants. NAFLD was defined through biopsy findings in 79% (n = 30) of the studies. Of the included articles, treatment modalities ranged from medications (n = 28, 74%), lifestyle interventions (n = 5, 13%), bariatric surgery (n = 4, 11%) and phlebotomy (n = 1, 2%). Twenty-eight studies (73%) included racial and/or ethnic demographic information, while only 17 (45%) included information regarding Hispanic participation. Of the 2983 patients enrolled in all eligible trials, a total of only 346 (11.6%) Hispanic participants was reported. Meta-analysis revealed a pooled Hispanic prevalence of 24.3% (95% confidence interval 16.6-32.0, I2 94.6%) among studies documenting Hispanic enrollment. Hispanic enrollment increased over time from 15% from 2005-2014 to 37% from 2015-2019.
CONCLUSION In a meta-analysis of NAFLD trials, documentation of racial/ethnic demographic data occurred in less than half of studies. Standardization of reporting of race/ethnicity and targeted interventions toward minority recruitment are needed to improve diversity of enrollment.
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Affiliation(s)
- Parita Patel
- Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, IL 60637, United States
| | - Charles Muller
- Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, IL 60637, United States
| | - Sonali Paul
- Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, IL 60637, United States
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Azzu V, Vacca M, Virtue S, Allison M, Vidal-Puig A. Adipose Tissue-Liver Cross Talk in the Control of Whole-Body Metabolism: Implications in Nonalcoholic Fatty Liver Disease. Gastroenterology 2020; 158:1899-1912. [PMID: 32061598 DOI: 10.1053/j.gastro.2019.12.054] [Citation(s) in RCA: 220] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 11/20/2019] [Accepted: 12/04/2019] [Indexed: 02/06/2023]
Abstract
Adipose tissue and the liver play significant roles in the regulation of whole-body energy homeostasis, but they have not evolved to cope with the continuous, chronic, nutrient surplus seen in obesity. In this review, we detail how prolonged metabolic stress leads to adipose tissue dysfunction, inflammation, and adipokine release that results in increased lipid flux to the liver. Overall, the upshot of hepatic fat accumulation alongside an insulin-resistant state is that hepatic lipid enzymatic pathways are modulated and overwhelmed, resulting in the selective buildup of toxic lipid species, which worsens the pro-inflammatory and pro-fibrotic shift observed in nonalcoholic steatohepatitis.
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Affiliation(s)
- Vian Azzu
- Wellcome Trust-Medical Research Council Institute of Metabolic Science-Metabolic Research Laboratories, Addenbrooke's Hospital; The Liver Unit, Department of Medicine, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge.
| | - Michele Vacca
- Wellcome Trust-Medical Research Council Institute of Metabolic Science-Metabolic Research Laboratories, Addenbrooke's Hospital
| | - Samuel Virtue
- Wellcome Trust-Medical Research Council Institute of Metabolic Science-Metabolic Research Laboratories, Addenbrooke's Hospital
| | - Michael Allison
- The Liver Unit, Department of Medicine, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge
| | - Antonio Vidal-Puig
- Wellcome Trust-Medical Research Council Institute of Metabolic Science-Metabolic Research Laboratories, Addenbrooke's Hospital; Wellcome Trust Sanger Institute, Hinxton, United Kingdom
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Biondo LA, Teixeira AAS, de O. S. Ferreira KC, Neto JCR. Pharmacological Strategies for Insulin Sensitivity in Obesity and Cancer: Thiazolidinediones and Metformin. Curr Pharm Des 2020; 26:932-945. [PMID: 31969093 DOI: 10.2174/1381612826666200122124116] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 12/21/2019] [Indexed: 12/19/2022]
Abstract
Background:
Chronic diseases, such as obesity and cancer, have high prevalence rates. Both diseases
have hyperinsulinemia, hyperglycemia, high levels of IGF-1 and inflammatory cytokines in common. Therefore,
these can be considered triggers for cancer development and growth. In addition, low-grade inflammation that
modulates the activation of immune cells, cellular metabolism, and production of cytokines and chemokines are
common in obesity, cancer, and insulin resistance. Pharmacological strategies are necessary when a change in
lifestyle does not improve glycemic homeostasis. In this regard, thiazolidinediones (TZD) possess multiple molecular
targets and regulate PPARγ in obesity and cancer related to insulin resistance, while metformin acts
through the AMPK pathway.
Objective:
The aim of this study was to review TZD and metformin as pharmacological treatments for insulin
resistance associated with obesity and cancer.
Conclusions:
Thiazolidinediones restored adiponectin secretion and leptin sensitivity, reduced lipid droplets in
hepatocytes and orexigen peptides in the hypothalamus. In cancer cells, TZD reduced proliferation, production of
reactive oxygen species, and inflammation by acting through the mTOR and NFκB pathways. Metformin has
similar effects, though these are AMPK-dependent. In addition, both drugs can be efficient against certain side
effects caused by chemotherapy.
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Affiliation(s)
- Luana A. Biondo
- Immunometabolism Research Group, Department of Cell Biology and Development, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Alexandre A. S. Teixeira
- Immunometabolism Research Group, Department of Cell Biology and Development, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Karen C. de O. S. Ferreira
- Immunometabolism Research Group, Department of Cell Biology and Development, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Jose C. R. Neto
- Immunometabolism Research Group, Department of Cell Biology and Development, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
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Pan CS, Stanley TL. Effect of Weight Loss Medications on Hepatic Steatosis and Steatohepatitis: A Systematic Review. Front Endocrinol (Lausanne) 2020; 11:70. [PMID: 32153507 PMCID: PMC7046622 DOI: 10.3389/fendo.2020.00070] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 02/03/2020] [Indexed: 12/25/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity in individuals with obesity. Although multiple pharmacotherapeutics are in development, currently there are limited strategies specifically targeting NAFLD. This systematic review summarizes the existing literature on hepatic effects of medications used for weight loss. Glucagon-like peptide 1 (GLP-1) agonists are the best-studied in this regard, and evidence consistently demonstrates reduction in liver fat content, sometimes accompanied by improvements in histological features of steatohepatitis and reductions in serum markers of hepatic injury such as alanine aminotransferase (ALT). It remains unclear whether these benefits are independent of the weight loss caused by these agents. Literature is limited regarding effects of orlistat, but a small number of reports suggest that orlistat reduces liver fat content and improves histologic features of NASH, benefits which may also be driven primarily by weight loss. A sizeable body of literature on hepatic effects of metformin yields mixed results, with a probability of modest benefit, but no consistent signal for strong benefit. There are insufficient data on hepatic effects of topiramate, phentermine, naltrexone, bupropion, and lorcaserin. Finally, a few studies to date suggest that sodium-glucose co-transporter-2 (SGLT2) inhibitors may reduce liver fat content and cause modest reductions in ALT, but further study is needed to better characterize these effects. Based on available data, GLP-1 agonists have the strongest evidence base demonstrating beneficial effects on NAFLD, but it is not clear if any weight loss medication has effects on NAFLD superior to those of nutritional modification and exercise alone.
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Affiliation(s)
- Chelsea S. Pan
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Takara L. Stanley
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Pediatric Endocrine Division, Massachusetts General Hospital for Children and Harvard Medical School, Boston, MA, United States
- *Correspondence: Takara L. Stanley
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Treatments of nonalcoholic fatty liver disease in adults who have no other illness: A Review article. Arab J Gastroenterol 2019; 20:189-197. [DOI: 10.1016/j.ajg.2019.11.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 11/26/2019] [Indexed: 12/28/2022]
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Abstract
Introduction: Liver cirrhosis is the most deleterious consequence of chronic liver diseases of different etiologies. Progression of liver diseases to cirrhosis, irrespective of etiology, involves chronic parenchymal injury, persistent activation of inflammatory response, sustained activation of fibrogenesis and wound-healing response. Despite intensive research on antifibrotic drugs, novel therapeutics specifically for liver have not been yet licensed. This review will examine compounds currently under development and key challenges in specific settings as for example that of NAFLD associated fibrosis.Areas covered: Results of the main phase II and III trial, including those with negative results, are presented and discussed. The endpoints selected and their limitations highlighted in order to suggest potential options to move forward.Expert opinion: Strategies based on single-molecule targets, associated so far with some disappointing results, may be unlikely to succeed in the context of such complex pathogenesis. Blocking at the same time different pathways that drive fibrosis progression may be required to provide significant benefit.
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Affiliation(s)
- Rosanna Santoro
- Liver Unit, IRCCS "Ospedale Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - Alessandra Mangia
- Liver Unit, IRCCS "Ospedale Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
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Blazina I, Selph S. Diabetes drugs for nonalcoholic fatty liver disease: a systematic review. Syst Rev 2019; 8:295. [PMID: 31783920 PMCID: PMC6884753 DOI: 10.1186/s13643-019-1200-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 10/15/2019] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Fatty liver is associated with obesity, type 2 diabetes, hyperlipidemia, hypertension, and metabolic syndrome. While there are no approved drugs for the treatment of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis, strategies to ameliorate fatty liver often target these related diseases. We sought to determine if any medications approved by the US Food and Drug Administration to treat diabetes are helpful in reducing weight and improving steatohepatitis in patients with NAFLD. METHODS We conducted a systematic review of published and unpublished studies evaluating the comparative effectiveness and harms of diabetes medications for the treatment of NAFLD. We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials through 3rd quarter, 2019 using terms for included drugs and indications. RESULTS We screened 1591 citations and included 18 trials of diabetes drugs to treat NAFLD. Studies of metformin found no difference from placebo in steatosis, fibrosis, NAFLD activity score, or resolution of NASH. While weight and glucose control were improved with metformin, it did not substantially impact liver disease. Studies of pioglitazone in NASH patients found benefits in liver function, liver fat, and NASH resolution, though significant increases in weight may be cause for concern. Evidence for other thiazolinediones was more limited and had somewhat mixed results, but findings were generally consistent with those for pioglitazone: liver fat and function and glucose measures improved, but weight also increased. We found some evidence that liraglutide improves liver fat, liver function, and HbA1c and is effective at resolving NASH and reducing weight. Exenatide performed less well but also resulted in significant reductions in liver fat and weight. CONCLUSIONS Consistent with existing clinical practice guidelines, which recommend lifestyle intervention and treatment for comorbidities related to fatty liver disease as first-line treatment, trial evidence supports the efficacy of some diabetes drugs (especially pioglitazone) in patients with NAFLD or NASH, though weight gain with some diabetes drugs may warrant caution. Larger trials are needed to better characterize the efficacy and harms of diabetes pharmacotherapy in these patients.
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Affiliation(s)
- Ian Blazina
- Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mailcode: BICC, Portland, OR, 97239, USA.
| | - Shelley Selph
- Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mailcode: BICC, Portland, OR, 97239, USA
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Ganguli S, DeLeeuw P, Satapathy SK. A Review Of Current And Upcoming Treatment Modalities In Non-Alcoholic Fatty Liver Disease And Non-Alcoholic Steatohepatitis. Hepat Med 2019; 11:159-178. [PMID: 31814783 PMCID: PMC6863115 DOI: 10.2147/hmer.s188991] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 10/03/2019] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the West. Non-alcoholic steatohepatitis (NASH) is the progressive form of NAFLD and can lead to cirrhosis, hepatocellular carcinoma, and is associated with increased cardiovascular risks. Multiple components and risk factors are thought to be involved in the pathogenesis of NAFLD and NASH. Optimal therapy has not yet been found, but many advances have been made with the discovery of potential therapeutic options. In this paper, we aim to provide a comprehensive review of approved, studied, and upcoming treatment options for NAFLD and NASH. Non-pharmacologic therapy (lifestyle modifications and bariatric surgery) and pharmacologic therapy are both reviewed. Pharmacologic therapy target components thought to be involved in the pathogenesis of this disease process including insulin resistance, oxidative stress, inflammation, lipid metabolism, and fibrosis are reviewed in this paper. Results of the emerging treatment targets in phase 2 and 3 clinical trials are also included.
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Affiliation(s)
- Surosree Ganguli
- Division of Internal Medicine, University of Louisville, Louisville, KY40202, USA
| | - Peter DeLeeuw
- Division of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN38163, USA
| | - Sanjaya K Satapathy
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Manhasset, NY11030, USA
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Khan RS, Bril F, Cusi K, Newsome PN. Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease. Hepatology 2019; 70:711-724. [PMID: 30556145 DOI: 10.1002/hep.30429] [Citation(s) in RCA: 291] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 11/06/2018] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has an estimated prevalence of 25% in the general population, and cirrhosis secondary to nonalcoholic steatohepatitis (NASH) is predicted to become the leading cause of liver transplantation, yet there is a lack of effective licensed treatments for these conditions. There is a close relationship between insulin resistance (IR) and NAFLD, with prevalence of NAFLD being 5-fold higher in patients with diabetes compared to those without. IR is implicated both in pathogenesis of NAFLD and in disease progression from steatosis to NASH. Thus, modulation of IR represents a potential strategy for NAFLD treatment. This review highlights key proposed mechanisms linking IR and NAFLD, such as changes in rates of adipose tissue lipolysis and de novo lipogenesis, impaired mitochondrial fatty acid β-oxidation (FAO), changes in fat distribution, alterations in the gut microbiome, and alterations in levels of adipokines and cytokines. Furthermore, this review will discuss the main pharmacological strategies used to treat IR in patients with NAFLD and their efficacy based on recently published experimental and clinical data. These include biguanides, glucagon-like peptide 1 receptor (GLP-1) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, peroxisome proliferator-activated receptor (PPAR-γ/α/δ) agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors, and farnesoid X receptor (FXR) agonists, with further novel treatments on the horizon. Ideally, treatment would improve IR, reduce cardiovascular risk, and produce demonstrable improvements in NASH histology-this is likely to be achieved with a combinatorial approach.
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Affiliation(s)
- Reenam S Khan
- National Institute for Health Research Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, The University of Florida, Gainesville, FL.,Malcom Randall Veterans Administration Medical Center, Gainesville, FL
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, The University of Florida, Gainesville, FL.,Malcom Randall Veterans Administration Medical Center, Gainesville, FL
| | - Philip N Newsome
- National Institute for Health Research Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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Abstract
PURPOSE OF REVIEW We aim to provide an in-depth review of recent literature highlighting the role of inflammation involving the adipose tissue, liver, skeletal muscles, and gastrointestinal tract in the development of metabolic complications among persons living with HIV (PLWH). RECENT FINDINGS Recent studies in PLWH have demonstrated a significant association between circulating inflammatory markers and development of insulin resistance and metabolic complications. In adipose tissue, pro-inflammatory cytokine expression inhibits adipocyte insulin signaling, which alters lipid and glucose homeostasis. Increased lipolysis and lipogenesis elevate levels of circulating free fatty acids and promote ectopic fat deposition in liver and skeletal muscles. This leads to lipotoxicity characterized by a pro-inflammatory response with worsening insulin resistance. Finally, HIV is associated with gastrointestinal tract inflammation and changes in the gut microbiome resulting in reduced diversity, which is an additional risk factor for diabetes. Metabolic complications in PLWH are in part due to chronic, multisite tissue inflammation resulting in dysregulation of glucose and lipid trafficking, utilization, and storage.
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Rates of and Factors Associated With Placebo Response in Trials of Pharmacotherapies for Nonalcoholic Steatohepatitis: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2019; 17:616-629.e26. [PMID: 29913275 DOI: 10.1016/j.cgh.2018.06.011] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 06/06/2018] [Accepted: 06/09/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS It is important to know the extent of the placebo effect in designing randomized controlled trials for patients with nonalcoholic steatohepatitis (NASH), to accurately calculate sample size and define treatment endpoints. METHODS We performed a systematic review and meta-analysis of the placebo groups from randomized controlled trials of adults with NASH that provided histologic and/or magnetic resonance image-based assessments. We identified trials through a comprehensive search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus, from each database's inception through January 2, 2018. RESULTS We identified 39 randomized controlled trials, comprising 1463 patients who received placebo. Histologic assessment data (the nonalcoholic fatty liver disease activity scores, NAS) were available from 956 patients; magnetic resonance spectroscopy data were available from 295 patients and magnetic resonance proton density fat fraction measurements from 61 patients. Overall, 25% of patients given placebo had an improvement in NAS by 2 or more points (95% CI, 21%-29%) with a small amount of heterogeneity (I2 = 27%). There were improvements by at least 1 point in steatosis scores of 33% ± 3% of patients, in hepatocyte ballooning scores of 30% ± 3% of patients, in lobular inflammation scores of 32% ± 3% of patients, and in fibrosis scores of 21% ± 3% of patients, with a moderate amount of heterogeneity among trials (I2 range, 51%-63%). Patients given placebo had a statistically significant improvement in NAS (by 0.72 ± 0.19), with a large amount of heterogeneity (I2 = 96%). Univariate and multivariate meta-regression showed that trials with a higher baseline NAS, those conducted in South America, and those in which patients had a decrease in body mass index, were associated with greater improvements in NAS among patients given placebo. Patients given placebo had significant reductions in intrahepatic triglyceride, measured by magnetic resonance spectroscopy (by 1.45% ± 0.54%) with moderate heterogeneity (I2 = 40%), and in magnetic resonance proton density fat fraction (by 2.43 ± 0.89), without heterogeneity (I2 = 0). Mean serum levels of alanine and aspartate aminotransferases decreased significantly (by 11.7 ± 3.8 U/L and 5.9 ± 2.1 U/L, respectively; P < .01 for both). CONCLUSIONS In a meta-analysis of randomized controlled trials of NASH, patients given placebo have significant histologic, radiologic, and biochemical responses. The placebo response should be considered in designing trials of agents for treatment of NASH.
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48
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Choudhary NS, Kumar N, Duseja A. Peroxisome Proliferator-Activated Receptors and Their Agonists in Nonalcoholic Fatty Liver Disease. J Clin Exp Hepatol 2019; 9:731-739. [PMID: 31889755 PMCID: PMC6926194 DOI: 10.1016/j.jceh.2019.06.004] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 06/23/2019] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. In addition to the liver-related morbidity and mortality, NAFLD is now also associated with various extrahepatic diseases. Pathogenesis of NAFLD is multifactorial with limited pharmacotherapy options for the treatment of patients with NAFLD. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in the transcriptional regulation of lipid metabolism, glucose homeostasis, energy balance, inflammation, and atherosclerosis. PPAR agonists are attractive options for treatment of NAFLD as they can act at multiple targets involved in the pathogenesis of NAFLD. We reviewed the available literature on the pathophysiological role of PPARs and use of PPAR agonists in the treatment of NAFLD. Original studies and review articles available on PubMed regarding the role of PPARs in the pathogenesis and utility of PPAR agonists in the treatment of NAFLD were included in this review article. ClinicalTrials.gov and Clinical Trials Registry-India sites were searched for ongoing studies on saroglitazar. The available literature suggests that PPARs play an important role in the pathogenesis of NAFLD. Use of PPAR gamma agonists is associated with histological improvement in NAFLD. Dual PPAR agonists with no or minimal PPAR gamma activity are being explored in the treatment of NAFLD. Because of the pathophysiological role of PPARs in NAFLD, PPAR agonists are attractive options for the treatment of patients with NAFLD. Dual PPAR agonists without significant gamma activity appear promising for the treatment of NAFLD.
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Affiliation(s)
- Narendra S. Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, India
| | | | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India,Address for correspondence: Dr. Ajay Duseja MD, DM, FAMS, FAASLD, FACG, FSGEI Professor, Department of Hepatology, Sector 12, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
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Thiagarajan P, Aithal GP. Drug Development for Nonalcoholic Fatty Liver Disease: Landscape and Challenges. J Clin Exp Hepatol 2019; 9:515-521. [PMID: 31516268 PMCID: PMC6728526 DOI: 10.1016/j.jceh.2019.03.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 03/05/2019] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease in industrialized economies. With no licensed treatment currently available, together with a growing prevalence that parallels global increases in obesity and type 2 diabetes, NAFLD will dominate the landscape of hepatology for the foreseeable future. A multifaceted etiopathogenesis, paucity of reproducible preclinical models that effectively recreate human NAFLD, and lack of robust surrogate trial endpoints have presented major hurdles in drug discovery and development. Smooth collaboration between bench scientists, biotechnology, pharmaceutical industries, and clinicians will be pivotal to target identification, development of effective therapies, biomarker discovery, and ultimately to bring pipeline drugs to market. This review examines the key challenges remaining in NAFLD drug development, outlines early and late phase clinical trials of candidate treatments, and discusses the journey toward biomarker discovery which may facilitate development of novel endpoints in NAFLD clinical trials, enabling meaningful response to be determined noninvasively.
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Key Words
- BMI, Body Mass Index
- DGAT, Diacyl Glycerol Acyl Transferase
- ELF, Extended Liver Fibrosis Panel
- FIB-4, Fibrosis 4
- FXR, Farnesoid X Receptor
- HCC, Hepatocellular Carcinoma
- HOMA-IR, Homeostasis Model Assessment of Insulin Resistance
- HVPG, Hepatic Venous Pressure Gradient
- HbA1C, Hemoglobin A1C
- MCD, Methionine-Choline–Deficient Diet
- MRE, MR Elastography
- MRI, Magnetic Resonance Imaging
- MRS, Magnetic Resonance Spectroscopy
- NAFLD
- NAFLD, Nonalcoholic Fatty Liver Disease
- NASH, Nonalcoholic Steatohepatitis
- OCA, Obeticholic Acid
- OGTT, Oral Glucose Tolerance Test
- Pro-C3, Pro-collagen 3
- TE, Transient Elastography
- endpoints
- preclinical models
- targets
- therapeutics
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Affiliation(s)
| | - Guruprasad P. Aithal
- Address for correspondence: Guruprasad P. Aithal, NIHR Nottingham Digestive Diseases Biomedical Research Centre, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, NG72UH, United Kingdom.
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Chang Y, Cho YK, Kim Y, Sung E, Ahn J, Jung HS, Yun KE, Shin H, Ryu S. Nonheavy Drinking and Worsening of Noninvasive Fibrosis Markers in Nonalcoholic Fatty Liver Disease: A Cohort Study. Hepatology 2019; 69:64-75. [PMID: 30019340 DOI: 10.1002/hep.30170] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 06/22/2018] [Indexed: 02/06/2023]
Abstract
The effect of modest alcohol consumption on fibrosis progression in the general population with nonalcoholic fatty liver disease (NAFLD) remains unclear. We examined the association of nonheavy alcohol consumption with worsening of noninvasive fibrosis indices in a large-scale, low-risk population with NAFLD. A cohort study was performed in 58,927 Korean adults with NAFLD and low fibrosis scores who were followed for a median of 4.9 years. Non-, light, and moderate drinkers were defined as 0 g/day, 1-9.9 g/day, and 10-29.9 g/day (10-19.9 g/day for women), respectively. Progression from low to intermediate or high probability of advanced fibrosis was assessed using noninvasive indices including NAFLD fibrosis score (NFS) and Fibrosis-4 Index (FIB-4). A parametric proportional hazards model was used to estimate the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). During 347,925.4 person-years of follow-up, 5,630 subjects with low FIB-4 progressed to intermediate or high FIB-4. The multivariable-adjusted HRs (95% CI) for worsening of FIB-4 comparing light and moderate drinkers with nondrinkers were 1.06 (0.98-1.16) and 1.29 (1.18-1.40), respectively. Similarly, using NFS, corresponding HRs (95% CI) comparing light and moderate drinkers with nondrinkers were 1.09 (1.02-1.16) and 1.31 (1.23-1.40), respectively. Furthermore, the association of moderate drinkers with worsening of either FIB-4 or NFS remained significant after introducing alcohol use and confounders treated as time-varying covariates. Conclusion: In this large-scale cohort of young and middle-aged individuals with NAFLD, nonheavy alcohol consumption, especially moderate alcohol consumption, was significantly and independently associated with worsening of noninvasive markers of fibrosis, indicating that even moderate alcohol consumption might be harmful.
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Affiliation(s)
- Yoosoo Chang
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Department of Clinical Research Design & Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Yong Kyun Cho
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Yejin Kim
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Eunju Sung
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Department of Family Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jiin Ahn
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hyun-Suk Jung
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kyung Eun Yun
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hocheol Shin
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Department of Family Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Seungho Ryu
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Department of Clinical Research Design & Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea
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