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Lee HA, Lee HA, Kim HY. Evolution of characteristics of MASLD with and without diabetes: a meta-analysis of placebo arms. Sci Rep 2024; 14:28951. [PMID: 39578601 PMCID: PMC11584620 DOI: 10.1038/s41598-024-79428-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 11/08/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND We explored the changes in metabolic dysfunction-associated steatotic liver disease (MASLD) severity over time by analyzing data from the placebo arms of randomized controlled trials (RCTs), focusing on the presence of diabetes. METHODS RCTs on MASLD that included a placebo arm were identified using a systematic search of the literature. Primary outcomes were changes in hepatic steatosis and fibrosis. RESULTS The meta-analysis included 8 RCTs involving 386 patients without diabetes and 24 RCTs involving 637 patients with diabetes. The pooled estimate of mean change in steatosis grade was - 0.1 in patients without diabetes, and - 0.37 in patients with diabetes (P = 0.066). The mean change in fibrosis stage was 0.05 in patients without diabetes, and - 0.03 in patients with diabetes (P = 0.359). The mean change in nonalcoholic fatty liver disease activity score was - 0.55 in patients without diabetes, and - 1.50 in patients with diabetes (P = 0.100). The mean change in ALT and AST were significantly larger in patients without diabetes compared to those with diabetes (P < 0.05). CONCLUSION Placebo treatment had a greater effect in improving liver steatosis in patients with diabetes compared to those without. These findings highlight the importance of tailored treatment strategies in MASLD, particularly considering diabetes status.
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Affiliation(s)
- Han Ah Lee
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Hye Ah Lee
- Clinical Trial Center, Ewha Womans University College of Medicine, Seoul, Korea
| | - Hwi Young Kim
- Department of Internal Medicine, College of Medicine, Ewha Womans University, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul, 07985, Korea.
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Gish R, Fan JG, Dossaji Z, Fichez J, Laeeq T, Chun M, Boursier J. Review of current and new drugs for the treatment of metabolic-associated fatty liver disease. Hepatol Int 2024; 18:977-989. [PMID: 38850496 DOI: 10.1007/s12072-024-10698-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 05/03/2024] [Indexed: 06/10/2024]
Abstract
In the past 3 decades, metabolic-associated fatty liver disease (MAFLD) has emerged as a widespread liver condition, with its global prevalence on the rise. It ranks as a leading contributor to hepatocellular carcinoma (HCC) and necessitates liver transplantation. Under the multiple parallel hits model, the pathogenesis of MAFLD stems from various liver stressors, notably nutrient overload and sedentary lifestyles. While medical management for MAFLD is well-established, encompassing non-pharmaceutical and pharmaceutical interventions, determining the most effective pharmaceutical therapy has remained elusive. This review discusses diabetic medications for MAFLD treatment, emphasizing recent studies and emerging drugs while reviewing other nondiabetic agents. Emerging evidence suggests that combination therapies hold promise for resolving MAFLD and metabolic steatohepatitis (MASH) while managing side effects. Ongoing trials play a pivotal role in elucidating the effects of mono, dual, and triple receptor agonists in individuals with MASH. With the rising burden of MAFLD/MASH and its severe consequences, the need for effective treatments is more pressing than ever. This review provides a comprehensive overview of the current landscape of pharmaceutical interventions for MAFLD and MASH, shedding light on the potential of newer drugs especially diabetic medications and the importance of ongoing research in this field.
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Affiliation(s)
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, 200092, China
| | - Zahra Dossaji
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at UNLV, 1800 W Charleston Blvd, Las Vegas, NV, 89102, USA.
| | - Jeanne Fichez
- Department of Hepato-Gastroenterology and Digestive Oncology, Angers University Hospital, Angers, France
- HIFIH Laboratory, SFR ICAT 4208, Angers University, Angers, France
| | - Tooba Laeeq
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at UNLV, 1800 W Charleston Blvd, Las Vegas, NV, 89102, USA
| | - Magnus Chun
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at UNLV, 1800 W Charleston Blvd, Las Vegas, NV, 89102, USA
| | - Jerome Boursier
- Department of Hepato-Gastroenterology and Digestive Oncology, Angers University Hospital, Angers, France
- HIFIH Laboratory, SFR ICAT 4208, Angers University, Angers, France
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Nabrdalik K, Kwiendacz H, Irlik K, Hendel M, Drożdż K, Wijata AM, Nalepa J, Janota O, Wójcik W, Gumprecht J, Lip GYH. Machine Learning Identifies Metabolic Dysfunction-Associated Steatotic Liver Disease in Patients With Diabetes Mellitus. J Clin Endocrinol Metab 2024; 109:2029-2038. [PMID: 38330228 PMCID: PMC11244212 DOI: 10.1210/clinem/dgae060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 01/10/2024] [Accepted: 01/26/2024] [Indexed: 02/10/2024]
Abstract
CONTEXT The presence of metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with diabetes mellitus (DM) is associated with a high risk of cardiovascular disease, but is often underdiagnosed. OBJECTIVE To develop machine learning (ML) models for risk assessment of MASLD occurrence in patients with DM. METHODS Feature selection determined the discriminative parameters, utilized to classify DM patients as those with and without MASLD. The performance of the multiple logistic regression model was quantified by sensitivity, specificity, and percentage of correctly classified patients, and receiver operating characteristic (ROC) curve analysis. Decision curve analysis (DCA) assessed the model's net benefit for alternative treatments. RESULTS We studied 2000 patients with DM (mean age 58.85 ± 17.37 years; 48% women). Eight parameters: age, body mass index, type of DM, alanine aminotransferase, aspartate aminotransferase, platelet count, hyperuricaemia, and treatment with metformin were identified as discriminative. The experiments for 1735 patients show that 744/991 (75.08%) and 586/744 (78.76%) patients with/without MASLD were correctly identified (sensitivity/specificity: 0.75/0.79). The area under ROC (AUC) was 0.84 (95% CI, 0.82-0.86), while DCA showed a higher clinical utility of the model, ranging from 30% to 84% threshold probability. Results for 265 test patients confirm the model's generalizability (sensitivity/specificity: 0.80/0.74; AUC: 0.81 [95% CI, 0.76-0.87]), whereas unsupervised clustering identified high-risk patients. CONCLUSION A ML approach demonstrated high performance in identifying MASLD in patients with DM. This approach may facilitate better risk stratification and cardiovascular risk prevention strategies for high-risk patients with DM at risk of MASLD.
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Affiliation(s)
- Katarzyna Nabrdalik
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland
- Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool L69 3BX, UK
| | - Hanna Kwiendacz
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland
| | - Krzysztof Irlik
- Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool L69 3BX, UK
- Students' Scientific Association by the Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland
| | - Mirela Hendel
- Students' Scientific Association by the Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland
| | - Karolina Drożdż
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland
| | - Agata M Wijata
- Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool L69 3BX, UK
- Faculty of Biomedical Engineering, Silesian University of Technology, 41-800 Zabrze, Poland
| | - Jakub Nalepa
- Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool L69 3BX, UK
- Department of Algorithmics and Software, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Oliwia Janota
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland
| | - Wiktoria Wójcik
- Students' Scientific Association by the Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland
| | - Janusz Gumprecht
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool L69 3BX, UK
- Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, 9220 Aalborg, Denmark
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Peppas S, Doumas S, Suvarnakar A, Chou J, Arafat A, Ahmad AI, Lewis JH. Clinical outcomes with metformin use in diabetic patients with compensated cirrhosis: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2024; 36:674-682. [PMID: 38477839 DOI: 10.1097/meg.0000000000002754] [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] [Indexed: 03/14/2024]
Abstract
BACKGROUND Previous studies have demonstrated a beneficial effect of metformin in patients with cirrhosis, but no improvement in liver histology. AIM To investigate the impact of metformin on mortality and hepatic decompensation in people with diabetes with compensated cirrhosis. METHODS Medline, Embase and Cochrane databases were searched from inception to February 2023 for studies reporting results regarding the impact of metformin on all-cause mortality and hepatic decompensation in people with diabetes with compensated cirrhosis. The risk of bias was assessed by ROBINS-I Cochrane tool. R software 4.3.1 was used for all analyses. RESULTS Six observational studies were included in the final analysis. Metformin use was associated with reduced all-cause mortality or liver transplantation [hazard ratio (HR): 0.55; 95% confidence interval (CI) 0.37-0.82], while no benefit was shown in the prevention of hepatic decompensation (HR: 0.97; 95% CI: 0.77-1.22). In the subgroup analysis, metformin use was associated with reduced all-cause mortality or liver transplantation (HR: 0.50; 95% CI 0.38-0.65) in patients with metabolic-associated steatohepatitis cirrhosis, while two studies reported no survival benefit in patients with cirrhosis due to hepatitis C (HR: 0.39; 95% CI 0.12-1.20). CONCLUSION Metformin use is associated with reduced all-cause mortality, but not with the prevention of hepatic decompensation in people with diabetes with compensated cirrhosis. The mortality benefit is most likely driven by better diabetes and cardiovascular health control.
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Affiliation(s)
- Spyros Peppas
- Department of Medicine, MedStar Washington Hospital Center
| | - Stavros Doumas
- Department of Internal Medicine, MedStar Georgetown University Medical Center
| | | | - Jiling Chou
- MedStar Research Health Institute, Hyattsville, Maryland
| | - Ayah Arafat
- MedStar Research Health Institute, Hyattsville, Maryland
| | - Akram I Ahmad
- Divsion of Gastroenterology & Hepatology, Cleveland Clinic Florida, Weston, Florida
| | - James H Lewis
- Division of Gastroenterology & Hepatology, MedStar Georgetown University Medical Center, Washington, DC, USA
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Hwang SJ, Choi YJ, Wang JH, Son CG. Lactobacillus Casei-fermented Amomum Xanthioides Mitigates non-alcoholic fatty liver disease in a high-fat diet mice model. Biomed Pharmacother 2024; 172:116250. [PMID: 38320334 DOI: 10.1016/j.biopha.2024.116250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/30/2024] [Accepted: 02/01/2024] [Indexed: 02/08/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a substantial global health issue owing to its high prevalence and the lack of effective therapies. Fermentation of medicinal herbs has always been considered a feasible strategy for enhancing efficacy in treating various ailments. This study aimed to investigate the potential benefits of the Lactobacillus casei-fermented Amomum xanthioides (LAX) on NAFLD in a high-fat diet model. HFD-fed C57BL6/j mice were administered with 200 mg/kg of LAX or unfermented Amomum xanthioides (AX) or 100 mg/kg of metformin for 6 weeks from the 4th week. The 10-week HFD-induced alterations of hepatic lipid accumulation and hepatic inflammation were significantly attenuated by LAX dominantly (more than AX or metformin), which evidenced by pathohistological findings, lipid contents, inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)- 6 and IL-1β, oxidative parameters such as reactive oxygen species (ROS) and malondialdehyde (MDA), and molecular changes reversely between lipogenic proteins such as glycerol-3-phosphate acyltransferase (GPAM) and sterol regulatory element-binding protein (SREBP)- 1, and lipolytic proteins including peroxisome proliferator-activated receptor (PPAR-α) and AMP-activated kinase (AMPK)-α in the liver tissues. In addition, the abnormal serum lipid parameters (triglyceride, total cholesterol and LDL-cholesterol) notably ameliorated by LAX. In conclusion, these findings support the potential of LAX as a promising plant-derived remedy for NAFLD.
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Affiliation(s)
- Seung-Ju Hwang
- Institute of Bioscience & Integrative Medicine, Daejeon University, 75, Daedukdae-ro 176 bun-gil, Seo-gu, Daejeon 35235, the Republic of Korea; Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University, 75, Daedukdae-ro 176 bun-gil, Seo-gu, Daejeon 35235, the Republic of Korea
| | - Yu-Jin Choi
- Institute of Bioscience & Integrative Medicine, Daejeon University, 75, Daedukdae-ro 176 bun-gil, Seo-gu, Daejeon 35235, the Republic of Korea; Department of Internal Medicine, College of Korean Medicine, Se-Myung University, Semyeong-ro 65, Jecheon-si, Chungcheongbuk-do, 27136, the Republic of Korea
| | - Jing-Hua Wang
- Institute of Bioscience & Integrative Medicine, Daejeon University, 75, Daedukdae-ro 176 bun-gil, Seo-gu, Daejeon 35235, the Republic of Korea; Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University, 75, Daedukdae-ro 176 bun-gil, Seo-gu, Daejeon 35235, the Republic of Korea.
| | - Chang-Gue Son
- Institute of Bioscience & Integrative Medicine, Daejeon University, 75, Daedukdae-ro 176 bun-gil, Seo-gu, Daejeon 35235, the Republic of Korea; Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University, 75, Daedukdae-ro 176 bun-gil, Seo-gu, Daejeon 35235, the Republic of Korea.
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Ciccarelli G, Di Giuseppe G, Cinti F, Moffa S, Mezza T, Giaccari A. Why do some glucose-lowering agents improve non-alcoholic fatty liver disease whereas others do not? A narrative review in search of a unifying hypothesis. Diabetes Metab Res Rev 2023; 39:e3668. [PMID: 37309298 DOI: 10.1002/dmrr.3668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 04/04/2023] [Accepted: 04/15/2023] [Indexed: 06/14/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are metabolic disorders connected by common pathophysiological mechanisms. Since insulin resistance (IR) and metabolic alterations are common to both conditions, almost all glucose-lowering agents which improve IR have also been studied in patients with NAFLD. Some have shown great efficacy, others none. Thus, the mechanisms behind the efficacy of these drugs in improving hepatic steatosis, steatohepatitis, and eventually fibrosis remain controversial. Glycaemic control improves T2D, but probably has limited effects on NAFLD, as all glucose-lowering agents ameliorate glucose control but only a few improve NAFLD features. In contrast, drugs that either improve adipose tissue function, reduce lipid ingestion, or increase lipid oxidation are particularly effective in NAFLD. We therefore hypothesise that improved free fatty acid metabolism may be the unifying mechanism behind the efficacy of some glucose-lowering agents on NAFLD and may represent the key to NAFLD treatment.
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Affiliation(s)
- Gea Ciccarelli
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gianfranco Di Giuseppe
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Cinti
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
| | - Simona Moffa
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
| | - Teresa Mezza
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
| | - Andrea Giaccari
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
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Basheer M, Saad E, Jeries H, Assy N. Liver Fat Storage Is a Better Predictor of Coronary Artery Disease than Visceral Fat. Metabolites 2023; 13:896. [PMID: 37623840 PMCID: PMC10456344 DOI: 10.3390/metabo13080896] [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: 06/16/2023] [Revised: 07/26/2023] [Accepted: 07/27/2023] [Indexed: 08/26/2023] Open
Abstract
Fatty liver is one aspect of metabolic syndrome. The roles and contributions of fatty liver and visceral fat storage to coronary artery disease (CAD) are not clear. This study measured associations among visceral fat storage, fatty liver, insulin resistance, atherosclerosis, and CAD. Patients were divided into three groups: excess visceral fat (visceral fat area >330 ± 99 cm2), non-alcoholic fatty liver disease (NAFLD), and a control group. The definition of fatty liver is liver minus spleen density greater than or equal to -10. We defined early atherosclerosis as intima-media thickness of the common carotid artery >7 mm in men and >0.65 mm in women, measured with Doppler ultrasound. Visceral fat area was defined using CT (>330 ± 99 cm2). Insulin-resistance biomarkers (HOMA), CRP, and oxidant-antioxidant status (MDA-Paraoxonase) were also measured. Patients with high liver or visceral fat showed higher coronary plaque prevalence (50% (p < 0.001), 38% (p < 0.01), respectively vs. 25% in the control group), higher prevalence of coronary stenosis (30% (p < 0.001), 22% (p < 0.01) vs. 11% in the control group), higher intimal thickening (0.98 ± 0.3 (p< 0.01), 0.86 ± 0.1 (p < 0.01) vs. 0.83 ± 0.1 in the control group), higher HOMA (4.0 ± 3.0 (p < 0.005), 3.0 ± 1.0 (p < 0.001) vs. 1.5 ± 1.2 in the control group), and higher triglyceride levels (196.8 ± 103 (p < 0.005), 182.6 ± 90.87 (p < 0.005) vs. 145 ± 60 in the control group). Multiple logistic regression analysis showed that fatty liver predicted CAD (OR 2.7, 95% CI 2.3-4.9, p < 0.001) independently of visceral fat storage (OR 2.01, 95% CI 1.2-2.8, p < 0.001). Liver fat storage is a strong independent risk factor for CAD and carotid atherosclerosis and contributes more than visceral fat storage.
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Affiliation(s)
- Maamoun Basheer
- Internal Medicine Department, Galilee Medical Center, Nahariya 221001, Israel; (M.B.); (E.S.); (H.J.)
| | - Elias Saad
- Internal Medicine Department, Galilee Medical Center, Nahariya 221001, Israel; (M.B.); (E.S.); (H.J.)
- Azrieli Faculty of Medicine, Bar-Ilan University, Safad 1311502, Israel
| | - Helena Jeries
- Internal Medicine Department, Galilee Medical Center, Nahariya 221001, Israel; (M.B.); (E.S.); (H.J.)
| | - Nimer Assy
- Internal Medicine Department, Galilee Medical Center, Nahariya 221001, Israel; (M.B.); (E.S.); (H.J.)
- Azrieli Faculty of Medicine, Bar-Ilan University, Safad 1311502, Israel
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Park MJ, Kim H, Kim MG, Kim K. Comparison of glucagon-like peptide-1 receptor agonists and thiazolidinediones on treating nonalcoholic fatty liver disease: A network meta-analysis. Clin Mol Hepatol 2023; 29:693-704. [PMID: 36907574 PMCID: PMC10366812 DOI: 10.3350/cmh.2022.0330] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 01/25/2023] [Accepted: 03/06/2023] [Indexed: 03/14/2023] Open
Abstract
BACKGROUND/AIMS Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP-1RA) and thiazolidinedione (TZD) can improve nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). However, comprehensive research comparing the effects of GLP-1RA and TZD is limited. Thus, this study aimed to compare the effects of GLP-1RA and TZD on NAFLD or NASH through a network meta-analysis. METHODS The PubMed, Embase, Web of Science, and Scopus databases were searched for randomized controlled trials (RCTs) that explored the efficacy of GLP-1RAs or TZDs in adult patients with NAFLD or NASH. The outcomes were liver biopsy-based (NAFLD activity score [NAS], fibrosis stage, and NASH resolution), noninvasive technique-based (liver fat content on proton magnetic resonance spectroscopy [1H-MRS] and controlled attenuation parameter [CAP]), biological, and anthropometric indicators. A random effects model was used to calculate the mean difference (MD) and relative risk with 95% confidence interval (CI). RESULTS Twenty-five RCTs with 2,237 overweight or obese patients were included. GLP-1RA was significantly superior in reducing liver fat content evaluated using 1H-MRS (MD -2.42, 95% CI -3.84 to -1.00), body mass index (MD -1.60, 95% CI -2.41 to -0.80), and waist circumference (MD -4.89, 95% CI -8.17 to -1.61) than TZD. In liver biopsy-based evaluation and liver fat content assessment using CAP, GLP-1RA tended to surpass TZD, albeit not significantly. Sensitivity analysis showed consistent results with the main results. CONCLUSION Compared with TZD, GLP-1RA had better effects on liver fat content, body mass index, and waist circumference in overweight or obese patients with NAFLD or NASH.
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Affiliation(s)
- Min Jeong Park
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hayeon Kim
- College of Pharmacy, Korea University, Sejong, Korea
| | - Myeong Gyu Kim
- College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Kyungim Kim
- College of Pharmacy, Korea University, Sejong, Korea
- Institute of Pharmaceutical Science, Korea University, Sejong, Korea
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Noureddin M, Abdelmalek MF. Current Treatment Options, Including Diet, Exercise, and Medications: The Impact on Histology. Clin Liver Dis 2023; 27:397-412. [PMID: 37024215 DOI: 10.1016/j.cld.2023.01.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Paralleling the rise in obesity and diabetes, nonalcoholic fatty liver disease (NAFLD) is now the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, may progress to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Despite its public health treat, no approved pharmacotherapies for NAFLD/NASH currently exist. Although the armamentarium of therapies for NASH is limited, current treatment options include life-style modification and the use of medications to treat metabolic comorbidities. This review addresses current approaches to the treatment of NAFLD/NASH, including the impact of diet, exercise, and available pharmacotherapies on the histologic features of liver injury.
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Affiliation(s)
- Mazen Noureddin
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA; Houston Research Institute and Houston Liver Institute, Houston, TX, USA
| | - Manal F Abdelmalek
- Division of Gastroenterology & Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
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10
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Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, Kleiner DE, Loomba R. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 2023; 77:1797-1835. [PMID: 36727674 PMCID: PMC10735173 DOI: 10.1097/hep.0000000000000323] [Citation(s) in RCA: 1051] [Impact Index Per Article: 525.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 01/18/2023] [Indexed: 02/03/2023]
Affiliation(s)
- Mary E. Rinella
- University of Chicago Pritzker School of Medicine, Chicago, Illinois, USA
| | | | | | | | - Stephen Caldwell
- School of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Diana Barb
- University of Florida College of Medicine, Gainesville, Florida, USA
| | | | - Rohit Loomba
- University of California, San Diego, San Diego, California, USA
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11
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The Interlink Between Metabolic-Associated Fatty Liver Disease and Polycystic Ovary Syndrome. Endocrinol Metab Clin North Am 2023. [PMID: 37495343 DOI: 10.1016/j.ecl.2023.01.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
Abstract
Polycystic ovary syndrome (PCOS) affects around 10% of women in the reproductive age group and is characterized by ovulatory dysfunction, hyperandrogenism, and/or polycystic ovarian morphology. PCOS is highly associated with metabolic-associated fatty liver disease (MAFLD) as both diseases share common risk factors. At the time of diagnosis of PCOS, screening for MAFLD is necessary because most patients with MAFLD are asymptomatic. The importance of early detection of MAFLD in patients with PCOS is that a timely intervention in patients with steatosis or steatohepatitis can reduce the probability of liver disease progression.
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12
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Lessons on Drug Development: A Literature Review of Challenges Faced in Nonalcoholic Fatty Liver Disease (NAFLD) Clinical Trials. Int J Mol Sci 2022; 24:ijms24010158. [PMID: 36613602 PMCID: PMC9820446 DOI: 10.3390/ijms24010158] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/24/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
NAFLD is the most common chronic liver disease worldwide, occurring in both obese and lean patients. It can lead to life-threatening liver diseases and nonhepatic complications, such as cirrhosis and cardiovascular diseases, that burden public health and the health care system. Current care is weight loss through diet and exercise, which is a challenging goal to achieve. However, there are no FDA-approved pharmacotherapies for NAFLD. This review thoroughly examines the clinical trial findings from 22 drugs (Phase 2 and above) and evaluates the future direction that trials should take for further drug development. These trialed drugs can broadly be categorized into five groups-hypoglycemic, lipid-lowering, bile-pathway, anti-inflammatory, and others, which include nutraceuticals. The multitude of challenges faced in these yet-to-be-approved NAFLD drug trials provided insight into a few areas of improvement worth considering. These include drug repurposing, combinations, noninvasive outcomes, standardization, adverse event alleviation, and the need for precision medicine with more extensive consideration of NAFLD heterogenicity in drug trials. Understandably, every evolution of the drug development landscape lies with its own set of challenges. However, this paper believes in the importance of always learning from lessons of the past, with each potential improvement pushing clinical trials an additional step forward toward discovering appropriate drugs for effective NAFLD management.
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Huang KH, Lee CH, Cheng YD, Gau SY, Tsai TH, Chung NJ, Lee CY. Correlation between long-term use of metformin and incidence of NAFLD among patients with type 2 diabetes mellitus: A real-world cohort study. Front Endocrinol (Lausanne) 2022; 13:1027484. [PMID: 36531446 PMCID: PMC9748475 DOI: 10.3389/fendo.2022.1027484] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 11/09/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND AND AIMS Studies have demonstrated that the short-term use of metformin benefits liver function among patients with type 2 diabetes mellitus (T2DM). However, few studies have reported on the effects of long-term metformin treatment on liver function or liver histology. This study investigated the correlation between metformin use and the incidence of nonalcoholic fatty liver disease (NAFLD) among patients with T2DM. METHODS This population-based study investigated the risk of NAFLD among patients with T2DM who received metformin treatment between 2001-2018. Metformin users and metformin nonusers were enrolled and matched to compare the risk of NAFLD. RESULTS After 3 years, the patients who received <300 cDDD of metformin and those with metformin use intensity of <10 and 10-25 DDD/month had odds ratios (ORs) of 1.11 (95% confidence interval [CI] = 1.06-1.16), 1.08 (95% CI = 1.02-1.13), and 1.18 (95% CI = 1.11-1.26) for NAFLD, respectively. Moreover, metformin users who scored high on the Diabetes Complications and Severity Index (DCSI) were at high risk of NAFLD. Patients with comorbid hyperlipidemia, hyperuricemia, obesity, and hepatitis C were also at high risk of NAFLD. CONCLUSION Patients with T2DM who received metformin of <300 cDDD or used metformin at an intensity of <10 and 10-25 DDD/month were at a high risk of developing NAFLD. The results of this study also indicated that patients with T2DM receiving metformin and with high scores on the DCSI were at a high risk of developing NAFLD.
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Affiliation(s)
- Kuang-Hua Huang
- Department of Health Services Administration, China Medical University, Taichung, Taiwan
| | - Chiu-Hsiang Lee
- School of Nursing, Chung Shan Medical University, Taichung, Taiwan
- Department of Nursing, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yih-Dih Cheng
- School of Pharmacy, China Medical University, Taichung, Taiwan
- Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan
| | - Shuo-Yan Gau
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Tung-Han Tsai
- Department of Health Services Administration, China Medical University, Taichung, Taiwan
| | - Ning-Jen Chung
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chien-Ying Lee
- Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan
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Wu QL, Zeng SX, Peng JY, Yuan Y, Zhu Z, Xie ZC, Huang ZH, Huang JS, Lai JM, Chen JA, Lin MH. Advances in metformin for the treatment of non-alcoholic fatty liver disease in children. Expert Rev Gastroenterol Hepatol 2022; 16:863-877. [PMID: 36039840 DOI: 10.1080/17474124.2022.2118112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
INTRODUCTION The increased economic and social burdens for NAFLD worldwide make treating such a disease a significant public health issue. Metformin, a kind of insulin sensitizer generally used to treat type 2 diabetes, has been recently found to have efficacy on children's NAFLD in various areas such as glucolipid metabolism, intestinal bacterial metabolism, oxidative stress, and anti-inflammatory response. This article aims to provide an overview of the possible mechanisms of NAFLD in children and the potential therapeutic application of metformin. AREAS COVERED The Cochrane Library, PubMed, Scopus, and EMBASE database was systematically searched on 12 April 2022, using the keywords metformin; non-alcoholic fatty liver disease; and children to identify similar studies. An additional search for recently published research was performed in June 2020. EXPERT OPINION Although metformin has been proved to have an excellent therapeutic effect on children's NAFLD; we can still explore its potential impacts and mechanisms from different angles, such as combined medication. At the same time, we should also pay attention to its side effects.
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Affiliation(s)
- Qian-Long Wu
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | - Shu-Xin Zeng
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | | | | | | | - Zi-Chun Xie
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | - Ze-Hong Huang
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | - Jia-Shuan Huang
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | - Jian-Mei Lai
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | - Jin-An Chen
- Guangzhou Medical University, Guangzhou, Guangdong province, China
| | - Min-Hua Lin
- Guangzhou Medical University, Guangzhou, Guangdong province, China
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The effect of probiotics/synbiotics supplementation on renal and liver biomarkers in patients with type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Br J Nutr 2022; 128:625-635. [PMID: 34544511 DOI: 10.1017/s0007114521003780] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Despite the apparent beneficial effects of probiotics/synbiotics on glucose haemostasis, lipid profile and inflammatory responses, it is not clear whether these beneficial effects also impact renal and hepatic function in diabetes. Therefore, we sought to assess the effect of probiotics/synbiotics supplementation on renal and liver biomarkers in adults with type 2 diabetes mellitus (T2DM) using a systematic review and meta-analysis of randomised controlled trials (RCT). PubMed, Scopus, Web of Science and Cochrane Library were systematically searched, up to February 2021. The pooled weighted mean difference (WMD) was estimated using a random-effects model. The methodological quality of studies, as well as certainty of evidence, was assessed using standard scales. Fifteen related trials were identified. Meta-analysis of six trials, involving 426 participants, indicated that probiotics/synbiotics supplementation reduced serum levels of creatinine (WMD = -0·10 mg/dl, 95 % CI -0·20, -0·00; P = 0·01; I 2 = 87·7 %; P-heterogeneity < 0·001), without any significant effect on blood urea nitrogen (BUN), glomerular filtration rate or microalbuminuria. No significant improvement was found on liver biomarkers following probiotics/synbiotics supplementation. The subgroup analysis showed a significant improvement in BUN when follow-up duration lasted for 12 weeks or more (WMD = -1·215 mg/dl, 95 % CI -1·933, -0·496; P = 0·001) and in creatinine levels in patients with renal dysfunction (WMD = -0·209 mg/dl, 95 % CI -0·322, -0·096; P < 0·001). Our results are insufficient to advocate the use of probiotics/synbiotics for improving renal or liver function in patients with T2DM. Indeed, due to the low certainty of evidence, these findings need to be affirmed in further high-quality RCT.
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Rojano-Toimil A, Rivera-Esteban J, Manzano-Nuñez R, Bañares J, Martinez Selva D, Gabriel-Medina P, Ferrer R, Pericàs JM, Ciudin A. When Sugar Reaches the Liver: Phenotypes of Patients with Diabetes and NAFLD. J Clin Med 2022; 11:jcm11123286. [PMID: 35743358 PMCID: PMC9225139 DOI: 10.3390/jcm11123286] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/03/2022] [Accepted: 06/06/2022] [Indexed: 01/27/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) have been traditionally linked to one another. Recent studies suggest that NAFLD may be increasingly common in other types of diabetes such as type 1 diabetes (T1DM) and less frequently ketone-prone and Maturity-onset Diabetes of the Young (MODY) diabetes. In this review, we address the relationship between hyperglycemia and insulin resistance and the onset and progression of NAFLD. In addition, despite the high rate of patients with T2DM and other diabetes phenotypes that can alter liver metabolism and consequently develop steatosis, fibrosis, and cirrhosis, NALFD screening is not still implemented in the daily care routine. Incorporating a clinical algorithm created around a simple, non-invasive, cost-effective model would identify high-risk patients. The principle behind managing these patients is to improve insulin resistance and hyperglycemia states with lifestyle changes, weight loss, and new drug therapies.
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Affiliation(s)
- Alba Rojano-Toimil
- Endocrinology Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain;
- Vall d’Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain; (J.R.-E.); (R.M.-N.); (J.B.); (D.M.S.)
| | - Jesús Rivera-Esteban
- Vall d’Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain; (J.R.-E.); (R.M.-N.); (J.B.); (D.M.S.)
- Medicine Department Bellaterra, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Liver Unit, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
| | - Ramiro Manzano-Nuñez
- Vall d’Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain; (J.R.-E.); (R.M.-N.); (J.B.); (D.M.S.)
- Liver Unit, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
| | - Juan Bañares
- Vall d’Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain; (J.R.-E.); (R.M.-N.); (J.B.); (D.M.S.)
- Liver Unit, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
| | - David Martinez Selva
- Vall d’Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain; (J.R.-E.); (R.M.-N.); (J.B.); (D.M.S.)
- Spanish Network of Biomedical Research Centers, Diabetes and Metabolic Associated Disorders (CIBERdem), 28029 Madrid, Spain
| | - Pablo Gabriel-Medina
- Biochemistry Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (P.G.-M.); (R.F.)
- Biochemistry and Molecular Biology Department, Universitat Autònoma de Barcelona (UAB), Bellaterra, 08193 Barcelona, Spain
| | - Roser Ferrer
- Biochemistry Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (P.G.-M.); (R.F.)
| | - Juan M Pericàs
- Vall d’Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain; (J.R.-E.); (R.M.-N.); (J.B.); (D.M.S.)
- Liver Unit, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
- Spanish Network of Biomedical Research Centers, Liver and Digestive Diseases (CIBERehd), 28801 Madrid, Spain
- Correspondence: (J.M.P.); (A.C.)
| | - Andreea Ciudin
- Endocrinology Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain;
- Vall d’Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain; (J.R.-E.); (R.M.-N.); (J.B.); (D.M.S.)
- Medicine Department Bellaterra, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Spanish Network of Biomedical Research Centers, Diabetes and Metabolic Associated Disorders (CIBERdem), 28029 Madrid, Spain
- Correspondence: (J.M.P.); (A.C.)
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Ng CH, Xiao J, Lim WH, Chin YH, Yong JN, Tan DJH, Tay P, Syn N, Foo R, Chan M, Chew N, Tan EX, Huang DQ, Dan YY, Tamaki N, Siddiqui MS, Sanyal AJ, Loomba R, Noureddin M, Muthiah MD. Placebo effect on progression and regression in NASH: Evidence from a meta-analysis. Hepatology 2022; 75:1647-1661. [PMID: 34990037 DOI: 10.1002/hep.32315] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/26/2021] [Accepted: 01/03/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS The evaluation of the natural history of NASH has been limited. Currently, liver biopsy remains the gold standard in the assessment of NASH. Placebo-controlled trials represent a controlled environment with paired biopsies for the evaluation of NASH. This meta-analysis thus seeks to quantify the change severity of NASH over time, with patients on placebo arms from randomized controlled trials (RCTs) to examine the natural history of NASH. METHODS A search was conducted to include NASH RCTs with placebo treatment arms. Primary outcomes were (1) the resolution of NASH without worsening of fibrosis, (2) two-point reduction in NAFLD activity score without worsening of fibrosis, and (3) at least one-point reduction in fibrosis. Generalized linear mix model was used to estimate pooled proportion and mean differences. RESULTS This meta-analysis of 43 RCTs included 2649 placebo-treated patients. The pooled estimate of NASH resolution and two-point NAFLD activity score reduction without worsening of fibrosis was 11.65% (95% CI: 7.98-16.71) and 21.11% (95% CI: 17.24-25.57). The rate of ≥1 stage reduction and progression of fibrosis was 18.82% (95% CI: 15.65-22.47) and 22.74% (CI: 19.63-26.17), respectively. Older age and African American ethnicity was associated with lower NASH resolution rate in placebo-treated patients. CONCLUSIONS Despite the absence of any pharmacological interventions, a significant proportion of patients in the placebo arm demonstrated improvements in liver histology, highlighting the possibility that NASH is a disease that can not only progress but regress spontaneously over time. Additionally, histologic response in placebo-treated patients is helpful in future design of phase 2B and phase 3 trials.
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Affiliation(s)
- Cheng Han Ng
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Jieling Xiao
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Wen Hui Lim
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Yip Han Chin
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Jie Ning Yong
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Phoebe Tay
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Nicholas Syn
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Roger Foo
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of CardiologyNational University Heart CentreNational University HospitalSingapore
| | - Mark Chan
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of CardiologyNational University Heart CentreNational University HospitalSingapore
| | - Nicholas Chew
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of CardiologyNational University Heart CentreNational University HospitalSingapore
| | - Eunice Xx Tan
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Division of Gastroenterology and HepatologyDepartment of MedicineNational University HospitalSingaporeSingapore
- National University Center for Organ TransplantationNational University Health SystemSingapore
| | - Daniel Q Huang
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Division of Gastroenterology and HepatologyDepartment of MedicineNational University HospitalSingaporeSingapore
- National University Center for Organ TransplantationNational University Health SystemSingapore
| | - Yock Young Dan
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Division of Gastroenterology and HepatologyDepartment of MedicineNational University HospitalSingaporeSingapore
- National University Center for Organ TransplantationNational University Health SystemSingapore
| | - Nobuharu Tamaki
- NAFLD Research CenterDivision of Gastroenterology and HepatologyDepartment of MedicineUniversity of California at San DiegoSan DiegoCaliforniaUSA
| | - Mohammad Shadab Siddiqui
- Cedars-Sinai Fatty Liver ProgramDivision of Digestive and Liver DiseasesDepartment of MedicineComprehensive Transplant CenterCedars-Sinai Medical CentreLos AngelesCaliforniaUSA
| | - Arun J Sanyal
- Department of Internal MedicineDivision of Gastroenterology, Hepatology and NutritionVirginia Commonwealth UniversityRichmondVirginiaUSA
- Division of Gastroenterology, Hepatology and NutritionDepartment of Internal MedicineVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Rohit Loomba
- NAFLD Research CenterDivision of Gastroenterology and HepatologyDepartment of MedicineUniversity of California at San DiegoSan DiegoCaliforniaUSA
| | - Mazen Noureddin
- Cedars-Sinai Fatty Liver ProgramDivision of Digestive and Liver DiseasesDepartment of MedicineComprehensive Transplant CenterCedars-Sinai Medical CentreLos AngelesCaliforniaUSA
| | - Mark D Muthiah
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Division of Gastroenterology and HepatologyDepartment of MedicineNational University HospitalSingaporeSingapore
- National University Center for Organ TransplantationNational University Health SystemSingapore
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Ma R, Zhan Y, Zhang Y, Wu L, Wang X, Guo M. Schisandrin B ameliorates non-alcoholic liver disease through anti-inflammation activation in diabetic mice. Drug Dev Res 2022; 83:735-744. [PMID: 34927282 PMCID: PMC9299884 DOI: 10.1002/ddr.21905] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 11/14/2021] [Accepted: 12/01/2021] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic risk factor associated with non-alcoholic liver disease (NAFLD). Schisandrin B (Sch B) is a promising agent for NAFLD. However, the actions of Sch B on diabetes-associated NAFLD and the underlying mechanisms are not characterized. This study aimed to assess whether Sch B has beneficial effects on T2DM-associated NAFLD. Sch B (50 mg/kg, gavage) was administrated to C57BL/KSJ db/db mice for 2 weeks. Body weight, liver weight, blood glucose, and insulin resistance were measured. Serum lipid level and liver function were detected using the biochemistry analyzer. Quantitative Real-Time PCR assay was used to evaluate mRNA levers of lipid metabolism genes. Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) staining was performed to measure apoptosis in the liver. Pathological analysis and immunohistochemistry assessment were used to analyze hepatic steatosis and inflammatory infiltration. Sch B supplementation significantly decrease body weight, related liver weight, blood glucose, and serum insulin, and improved insulin resistance in db/db mice. Sch B obviously corrected NAFLD phenotypes including lipid deposition, steatohepatitis, and high levels of hepatic enzymes and serum lipid. In addition, mRNA levels of Sterol response element-bind protein 1c (SREBP-1c), fatty acid synthetase (Fasn), and acetyl-CoA carboxylase (ACC) were markedly downregulated by Sch B treatment. TUNEL-positive cells were also decreased by Sch B. Furthermore, Sch B inhibited the Kupffer cells, IL-1β, and TNF-α infiltration to the liver. Sch B ameliorated insulin resistance and lipid accumulation under high glucose conditions, which was partly associated with its inhibition of apoptosis and anti-inflammatory actions.
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Affiliation(s)
- Ruojia Ma
- Department of CardiologyAffiliated Xiaoshan Hospital, Hangzhou Normal UniversityHangzhouChina
| | - Yike Zhan
- Department of CardiologyJieyang People's Hospital (Jieyang Affiliated Hospital, Sun Yat‐sen University)JieyangChina
| | - Yamei Zhang
- Department of CardiologyAffiliated Xiaoshan Hospital, Hangzhou Normal UniversityHangzhouChina
| | - Liangan Wu
- Department of CardiologyAffiliated Xiaoshan Hospital, Hangzhou Normal UniversityHangzhouChina
| | - Xing Wang
- Department of CardiologyAffiliated Xiaoshan Hospital, Hangzhou Normal UniversityHangzhouChina
| | - Ming Guo
- Department of CardiologyAffiliated Xiaoshan Hospital, Hangzhou Normal UniversityHangzhouChina
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Ng CH, Muthiah MD, Xiao J, Chin YH, Lim G, Lim WH, Tay P, Tan DJH, Yong JN, Pan XH, Koh JWH, Chew N, Syn N, Tan E, Huang DQ, Siddiqui MS, Loomba R, Sanyal AJ, Noureddin M. Meta-analysis: analysis of mechanistic pathways in the treatment of non-alcoholic steatohepatitis. Evidence from a Bayesian network meta-analysis. Aliment Pharmacol Ther 2022; 55:1076-1087. [PMID: 35285529 DOI: 10.1111/apt.16808] [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: 11/30/2021] [Revised: 12/29/2021] [Accepted: 01/26/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Non-alcoholic steatohepatitis (NASH) is the most common cause of liver disease. However, there is lack of comparison of efficacy between different NASH drug classes. We conducted a network meta-analysis evaluating drug classes through comparing histological outcomes and targets of drugs. APPROACH AND RESULTS Medline, EMBASE and CENTRAL were searched for randomised controlled trials evaluating NASH drugs in biopsy-proven NASH patients. Primary outcomes included NASH resolution without worsening of fibrosis, at least 2-point reduction in Non-alcoholic fatty liver disease Activity Score (NAS) without worsening of fibrosis and at least 1-point reduction in fibrosis. Treatments were classified into inflammation, energy, bile acid and fibrosis modulators. The analysis was conducted with Bayesian network model and surface under the cumulative ranking curve (SUCRA) analysis. Among 49 included trials, treatments modulating energy (Risk ratio (RR): 1.92, Credible intervals (Crl): 1.59-2.34) were most likely to achieve NASH resolution followed by treatments modulating fibrosis (RR 1.66, Crl: 0.65-4.50), bile acids (RR: 1.37, Crl: 0.99-1.92) and inflammation (RR: 1.00, Crl: 0.75-1.33). Energy and bile acids modulation were effective in at least 2-point NAS reduction without worsening of fibrosis (RR: 1.52, Crl 1.30-1.77; RR: 1.69, Crl 1.41-2.03) and at least 1-point reduction in fibrosis (RR: 1.26, Crl:1.05-1.49; RR: 1.54, Crl: 1.20-1.97). CONCLUSIONS This network analysis demonstrates the relative superiority of drugs modulating energy pathways and bile acids in NASH treatment. This guides the development and selection of drugs for combination therapies.
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Affiliation(s)
- Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Mark D Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore.,National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Jieling Xiao
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yip Han Chin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Grace Lim
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Phoebe Tay
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jie Ning Yong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Xin-Hui Pan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Nicholas Chew
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Nicholas Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Eunice Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore.,National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Daniel Q Huang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore.,National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Mohammad Shadab Siddiqui
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, San Diego, California, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Mazen Noureddin
- Cedars-Sinai Fatty Liver Program, Division of Digestive and Liver Diseases, Department of Medicine, Comprehensive Transplant Center, Cedars-Sinai Medical Centre, Los Angeles, California, USA
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Kahl S, Pützer J, Roden M. Novel Antidiabetic Strategies and Diabetologists' Views in Nonalcoholic Steatohepatitis. Semin Liver Dis 2022; 42:48-60. [PMID: 34289506 DOI: 10.1055/s-0041-1732354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide with high prevalence, especially in individuals with obesity and type 2 diabetes. Among individuals with type 2 diabetes, the severe insulin resistant subgroup has the greatest risk of NAFLD, likely due to dysfunctional adipose tissue mass but also genetic factors, and may progress earlier to inflammatory and profibrotic nonalcoholic steatohepatitis (NASH). NASH has been associated with increased liver-related as well as cardiovascular morbidity and mortality. International diabetes associations recommend certain screening and treatment strategies for NASH in type 2 diabetes, which, however, bear several limitations such as lack of accurate noninvasive diagnostic tools and targeted treatments. Currently, antihyperglycemic drug concepts based on glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors offer metabolic as well as cardiorenal benefits and provide treatment options for both hyperglycemia and NASH in type 2 diabetes.
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Affiliation(s)
- Sabine Kahl
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.,German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany.,Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Jennifer Pützer
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.,German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.,German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany.,Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
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21
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Plaz MC, Tsochatzis EA. Metabolic Complications Before and After Liver Transplantation. TEXTBOOK OF LIVER TRANSPLANTATION 2022:357-371. [DOI: 10.1007/978-3-030-82930-8_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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22
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Satiya J, Snyder HS, Singh SP, Satapathy SK. Narrative review of current and emerging pharmacological therapies for nonalcoholic steatohepatitis. Transl Gastroenterol Hepatol 2021; 6:60. [PMID: 34805582 PMCID: PMC8573363 DOI: 10.21037/tgh-20-247] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 09/25/2020] [Indexed: 12/28/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease today, and it has now emerged as the leading etiology of end-stage liver disease requiring liver transplantation. It is a progressive form of non-alcoholic fatty liver disease which can not only progress to cirrhosis of liver and hepatocellular carcinoma (HCC), but is associated with increased cardiovascular risks too. Despite all the advances in the understanding of the risk factors and the pathogenetic pathways involved in the pathogenesis and progression of NASH, an effective therapy for NASH has not been developed yet. Although lifestyle modifications including dietary modifications and physical activity remain the mainstay of therapy, there is an unmet need to develop a drug or a combination of drugs which can not only reduce the fatty infiltration of the liver, but also arrest the development and progression of fibrosis and advancement to cirrhosis of liver and HCC. The pharmacologic therapies which are being developed target the various components believed to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)/NASH which includes insulin resistance, lipid metabolism oxidative stress, lipid peroxidation, inflammatory and cell death pathways, and fibrosis. In this review, we summarize the current state of knowledge on pharmacotherapy of NASH, and also highlight the recent developments in the field, for optimizing the management and treatment of NASH.
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Affiliation(s)
- Jinendra Satiya
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | | | - Shivaram Prasad Singh
- Department of Gastroenterology, S.C.B. Medical College, Cuttack, India
- Kalinga Gastroenterology Foundation, Beam Diagnostics Centre, Cuttack, India
| | - Sanjaya K. Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Northwell Health, Manhasset, NY, USA
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23
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Majnooni MB, Ataee M, Bahrami G, Heydarpour F, Aneva IY, Farzaei MH, Ahmadi-Juoibari T. The effects of co-administration of artichoke leaf extract supplementation with metformin and vitamin E in patients with nonalcoholic fatty liver disease: A randomized clinical trial. Phytother Res 2021; 35:6324-6334. [PMID: 34533249 DOI: 10.1002/ptr.7279] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 06/29/2021] [Accepted: 08/28/2021] [Indexed: 01/20/2023]
Abstract
Medicinal plants are widely used as a complementary therapy to treat complex diseases, such as nonalcoholic fatty liver disease (NAFLD). Therefore, this study was done to investigate the effect of co-administration of artichoke leaf extract supplement (ALES) with conventional medicines on patients with NAFLD. The clinical trial was based on patients randomly divided into three groups involving metformin-vitamin E (ME), metformin-ALES (MA), and vitamin E-ALES (EA). The effectiveness of treatment in the treated groups was evaluated using liver ultrasonography and biochemical markers. After 12 weeks of treatment, the results showed that the rate of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was significantly reduced within all the study groups (p < .05). Liver ultrasonographic findings revealed that the rate of fat accumulation in liver of patients was decreased significantly within all the study groups and it was increased in the subjects with grade 0 fatty liver (without fat accumulation) in the MA and EA groups by 23.3 and 17.2%, respectively. In summary, the results of the present study showed that the concomitant use of ALES with metformin and vitamin E can have beneficial effects on amelioration of complications in patients with NAFLD. However, larger-scale clinical trial studies are required in this regard.
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Affiliation(s)
| | - Mari Ataee
- Clinical Research Development Center, Imam Khomeini and Dr Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Gholamreza Bahrami
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Heydarpour
- Social Development and Health Promotion Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ina Yosifova Aneva
- Institute of Biodiversity and Ecosystem Research, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Touraj Ahmadi-Juoibari
- Clinical Research Development Center, Imam Khomeini and Dr Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
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24
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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: 47] [Impact Index Per Article: 11.8] [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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25
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Middleton P, Vergis N. Mitochondrial dysfunction and liver disease: role, relevance, and potential for therapeutic modulation. Therap Adv Gastroenterol 2021; 14:17562848211031394. [PMID: 34377148 PMCID: PMC8320552 DOI: 10.1177/17562848211031394] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 06/18/2021] [Indexed: 02/04/2023] Open
Abstract
Mitochondria are key organelles involved in energy production as well as numerous metabolic processes. There is a growing interest in the role of mitochondrial dysfunction in the pathogenesis of common chronic diseases as well as in cancer development. This review will examine the role mitochondria play in the pathophysiology of common liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, chronic hepatitis B and hepatocellular carcinoma. Mitochondrial dysfunction is described widely in the literature in studies examining patient tissue and in disease models. Despite significant differences in pathophysiology between chronic liver diseases, common mitochondrial defects are described, including increased mitochondrial reactive oxygen species production and impaired oxidative phosphorylation. We review the current literature on mitochondrial-targeted therapies, which have the potential to open new therapeutic avenues in the management of patients with chronic liver disease.
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Affiliation(s)
| | - Nikhil Vergis
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
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26
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Le Bastard Q, Berthelot L, Soulillou JP, Montassier E. Impact of non-antibiotic drugs on the human intestinal microbiome. Expert Rev Mol Diagn 2021; 21:911-924. [PMID: 34225544 DOI: 10.1080/14737159.2021.1952075] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION The gut microbiota is composed of trillions of microbial cells and viruses that interact with hosts. The composition of the gut microbiota is influenced by several factors including age, diet, diseases, or medications. The impact of drugs on the microbiota is not limited to antibiotics and many non-antibiotic molecules significantly alter the composition of the intestinal microbiota. AREAS COVERED This review focuses on the impact of four of the most widely prescribed non-antibiotic drugs in the world: Proton-pump inhibitors, metformin, statins, and non-steroidal anti-inflammatory. We conducted a systematic review by searching online databases including Medline, Web of science, and Scopus for indexed articles published in English until February 2021. We included studies assessing the intestinal microbiome alterations associated with proton pump inhibitors (PPIs), metformin, statins, and nonsteroidal anti-inflammatory drugs (NSAIDs). Only studies using culture-independent molecular techniques were included. EXPERT OPINION The taxonomical signature associated with non-antibiotic drugs are not yet fully described, especially in the field of metabolomic. The identification of taxonomic profiles associated a specific molecule provides information on its mechanism of action through interaction with the intestinal microbiota. Many side effects could be related to the dysbiosis induced by these molecules.
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Affiliation(s)
- Quentin Le Bastard
- Microbiota Hosts Antibiotics and Bacterial Resistances (Mihar), Université De Nantes, Nantes, France.,Service Des Urgences, CHU De Nantes, Nantes, France
| | - Laureline Berthelot
- Centre De Recherche En Transplantation Et Immunologie UMR 1064, INSERM, Université De Nantes, Nantes, France.,Institut De Transplantation Urologie Néphrologie (ITUN), CHU De Nantes, Nantes, France
| | - Jean-Paul Soulillou
- Centre De Recherche En Transplantation Et Immunologie UMR 1064, INSERM, Université De Nantes, Nantes, France.,Institut De Transplantation Urologie Néphrologie (ITUN), CHU De Nantes, Nantes, France
| | - Emmanuel Montassier
- Microbiota Hosts Antibiotics and Bacterial Resistances (Mihar), Université De Nantes, Nantes, France.,Service Des Urgences, CHU De Nantes, Nantes, France
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27
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Muzurović E, Mikhailidis DP, Mantzoros C. Non-alcoholic fatty liver disease, insulin resistance, metabolic syndrome and their association with vascular risk. Metabolism 2021; 119:154770. [PMID: 33864798 DOI: 10.1016/j.metabol.2021.154770] [Citation(s) in RCA: 164] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 02/07/2023]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases, is rising. About 25% of adults worldwide are probably affected by NAFLD. Insulin resistance (IR) and fat accumulation in the liver are strongly related. The association between NAFLD, metabolic syndrome (MetS) and IR is established, but an independent impact of NAFLD on vascular risk and progression of cardiovascular (CV) disease (CVD) still needs to be confirmed. This narrative review considers the evidence regarding the link between NAFLD, IR and CVD risk. There is strong evidence for a "concomitantly rising incidence" of NAFLD, IR, MetS and CVD but there is no definitive evidence regarding whether NAFLD is, or is not, an independent and significant risk factor the development of CVD. There are also considerations that type 2 diabetes mellitus (T2DM) may be a common link between NAFLD/non-alcoholic steatohepatitis (NASH) and CVD. NAFLD may be associated with widespread abnormal peri-organ or intra-organ fat (APIFat) deposition (e.g. epicardial adipose tissue) which may further contribute to CV risk. It is clear that NAFLD patients have a greater CV risk (independent or not) which needs to be addressed in clinical practice.
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Affiliation(s)
- Emir Muzurović
- Department of Internal Medicine, Endocrinology Section, Clinical Centre of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro; Faculty of Medicine, University of Montenegro, Kruševac bb, 81000 Podgorica, Montenegro.
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), Pond Street, London NW3 2QG, UK; Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Christos Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA 02115, USA
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28
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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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29
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Roskilly A, Hicks A, Taylor EJ, Jones R, Parker R, Rowe IA. Fibrosis progression rate in a systematic review of placebo-treated nonalcoholic steatohepatitis. Liver Int 2021; 41:982-995. [PMID: 33283415 DOI: 10.1111/liv.14749] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 10/06/2020] [Accepted: 10/28/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Liver fibrosis is the critical determinant of liver-related outcomes in persons with nonalcoholic fatty liver disease. The rate that fibrosis develops determines the time taken to reach cirrhosis and consequent clinical outcomes. Estimates of the fibrosis progression rate (FPR) are uncertain having been defined in small observational series that rely largely on nonstandardised repeat biopsy in selected patients. The aim of this study was to evaluate the FPR in placebo-treated participants with nonalcoholic steatohepatitis (NASH) in randomised controlled trials (RCTs). METHODS Systematic review and meta-analysis of RCTs in NASH with data on fibrosis change extracted. Calculated fibrosis progression rates were pooled in meta-analysis. The pooled estimate was then used to model the proportion of hypothetical cohorts starting with no fibrosis at the age of 30 who develop cirrhosis. RESULTS A total of 35 trials including 1419 placebo-treated participants who underwent repeat liver biopsy were evaluated. Considering all trials, the overall FPR was 0.00 stages per year, increasing to 0.03 stages per year in both trials at low risk of bias and trials including >50 placebo-treated participants. This estimate was markedly lower than the value derived from previously pooled analyses of observational data. Using a FPR of 0.03 resulted in a substantial reduction in the proportion of patients developing cirrhosis compared with the FPR derived from observational studies (13% vs 28%). CONCLUSIONS The FPR in placebo-treated participants in RCTs is lower than that described from observational data. Slower fibrosis progression predicts fewer persons with NASH will progress to cirrhosis than previously estimated.
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Affiliation(s)
- Anna Roskilly
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Amy Hicks
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | | | - Rebecca Jones
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Richard Parker
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Ian A Rowe
- Leeds Liver Unit, St James's University Hospital, Leeds, UK.,Leeds Institute for Medical Research and Leeds Institute for Data Analytics, University of Leeds, Leeds, UK
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30
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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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31
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Gerges SH, Wahdan SA, Elsherbiny DA, El-Demerdash E. Non-alcoholic fatty liver disease: An overview of risk factors, pathophysiological mechanisms, diagnostic procedures, and therapeutic interventions. Life Sci 2021; 271:119220. [PMID: 33592199 DOI: 10.1016/j.lfs.2021.119220] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/25/2021] [Accepted: 01/29/2021] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disorder of excessive fat accumulation in the liver, known as steatosis, without alcohol overconsumption. NAFLD can either manifest as simple steatosis or steatohepatitis, known as non-alcoholic steatohepatitis (NASH), which is accompanied by inflammation and possibly fibrosis. Furthermore, NASH might progress to hepatocellular carcinoma. NAFLD and NASH prevalence is in a continuous state of growth, and by 2018, NAFLD became a devastating metabolic disease with a global pandemic prevalence. The pathophysiology of NAFLD and NASH is not fully elucidated, but is known to involve the complex interplay between different metabolic, environmental, and genetic factors. In addition, unhealthy dietary habits and pre-existing metabolic disturbances together with other risk factors predispose NAFLD development and progression from simple steatosis to steatohepatitis, and eventually to fibrosis. Despite their growing worldwide prevalence, to date, there is no FDA-approved treatment for NAFLD and NASH. Several off-label medications are used to target disease risk factors such as obesity and insulin resistance, and some medications are used for their hepatoprotective effects. Unfortunately, currently used medications are not sufficiently effective, and research is ongoing to investigate the beneficial effects of different drugs and phytochemicals in NASH. In this review article, we outline the different risk factors and pathophysiological mechanisms involved in NAFLD, diagnostic procedures, and currently used management techniques.
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Affiliation(s)
- Samar H Gerges
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbasia, Cairo 11566, Egypt
| | - Sara A Wahdan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbasia, Cairo 11566, Egypt
| | - Doaa A Elsherbiny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbasia, Cairo 11566, Egypt
| | - Ebtehal El-Demerdash
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbasia, Cairo 11566, Egypt.
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Pinyopornpanish K, Leerapun A, Pinyopornpanish K, Chattipakorn N. Effects of Metformin on Hepatic Steatosis in Adults with Nonalcoholic Fatty Liver Disease and Diabetes: Insights from the Cellular to Patient Levels. Gut Liver 2021; 15:827-840. [PMID: 33820884 PMCID: PMC8593497 DOI: 10.5009/gnl20367] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 12/05/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) patients with diabetes constitute a subgroup of patients with a high rate of liver-related complications. Currently, there are no specific drug recommendations for these patients. Metformin, a conventional insulin sensitizer agent, has been widely prescribed in patients with diabetes. Metformin treatment has been shown to be effective at alleviating hepatic lipogenesis in animal models of NAFLD, with a variety of mechanisms being deemed responsible. To date, most studies have enrolled diabetic patients who are treated with metformin, with the drug being taken continuously throughout the study. Although evidence exists regarding the benefits of metformin for NAFLD in preclinical studies, reports on the efficacy of metformin in adult NAFLD patients have had some discrepancies regarding changes in liver biochemistry and hepatic fat content. Evidence has also suggested possible effects of metformin as regards the prevention of hepatocellular carcinoma tumorigenesis. This review was performed to comprehensively summarize the available in vitro, in vivo and clinical studies regarding the effects of metformin on liver steatosis for the treatment of adult NAFLD patients with diabetes. Consistent reports as well as controversial findings are included in this review, and the mechanistic insights are also provided. In addition, this review focuses on the efficacy of metformin as a monotherapy and as a combined therapy with other antidiabetic medications.
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Affiliation(s)
| | - Apinya Leerapun
- Division of Gastroenterology, Department of Internal Medicine, Chiang Mai, Thailand
| | | | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Chiang Mai, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
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Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are strongly associated. Both also associate with an increased risk of cardiovascular disease (CVD). RECENT FINDINGS Several studies have provided evidence that NAFLD could be an independent CVD risk factor. Given the strong association between NAFLD and T2DM, assessing the independent CV effect of these two conditions remains challenging. However, patients with T2DM and NAFLD exhibit higher risk of CVD compared with T2DM without NAFLD suggesting a potential synergistic increase of CV risk in patients with both T2DM and NAFLD supported by several shared pathophysiological pathways. Several anti-diabetic therapies have shown beneficial effect on both NAFLD and CVD. Patients with T2DM and NAFLD should be considered at high risk of CVD and could benefit from more intensive CV prevention. Additional long-term follow-up is needed to demonstrate that the treatment of NAFLD effectively reduces the risk of CVD.
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Affiliation(s)
- Cyrielle Caussy
- Hôpital Lyon Sud, Département Endocrinologie, Diabète et Nutrition, Hospices Civils de Lyon, 69495, Pierre-Bénite, France.
| | - Adrien Aubin
- Hôpital Lyon Sud, Département Endocrinologie, Diabète et Nutrition, Hospices Civils de Lyon, 69495, Pierre-Bénite, France
| | - Rohit Loomba
- Department of Medicine, NAFLD Research Center, University of California at San Diego, La Jolla, CA, USA.
- Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, USA.
- Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA, USA.
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34
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Dedov II, Shestakova MV, Melnichenko GA, Mazurina NV, Andreeva EN, Bondarenko IZ, Gusova ZR, Dzgoeva FK, Eliseev MS, Ershova EV, Zhuravleva MV, Zakharchuk TA, Isakov VA, Klepikova MV, Komshilova KA, Krysanova VS, Nedogoda SV, Novikova AM, Ostroumova OD, Pereverzev AP, Rozhivanov RV, Romantsova TI, Ruyatkina LA, Salasyuk AS, Sasunova AN, Smetanina SA, Starodubova AV, Suplotova LA, Tkacheva ON, Troshina EA, Khamoshina MV, Chechelnitskaya SM, Shestakova EA, Sheremet’eva EV. INTERDISCIPLINARY CLINICAL PRACTICE GUIDELINES "MANAGEMENT OF OBESITY AND ITS COMORBIDITIES". OBESITY AND METABOLISM 2021; 18:5-99. [DOI: 10.14341/omet12714] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Affiliation(s)
| | | | | | | | | | | | | | | | - M. S. Eliseev
- Research Institute of Rheumatogy named after V.A. Nasonova
| | | | | | | | - V. A. Isakov
- Federal Research Center of Nutrition, Biotechnology and Food Safety
| | - M. V. Klepikova
- Russian Medical Academy of Continuous Professional Education
| | | | | | | | - A. M. Novikova
- Research Institute of Rheumatogy named after V.A. Nasonova
| | - O. D. Ostroumova
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry
| | - A. P. Pereverzev
- Russian National Research Medical University named after N.I. Pirogov
| | | | | | | | | | - A. N. Sasunova
- Federal Research Center of Nutrition, Biotechnology and Food Safety
| | | | | | | | - O. N. Tkacheva
- Russian National Research Medical University named after N.I. Pirogov
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35
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LaMoia TE, Shulman GI. Cellular and Molecular Mechanisms of Metformin Action. Endocr Rev 2021; 42:77-96. [PMID: 32897388 PMCID: PMC7846086 DOI: 10.1210/endrev/bnaa023] [Citation(s) in RCA: 418] [Impact Index Per Article: 104.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/04/2020] [Indexed: 02/07/2023]
Abstract
Metformin is a first-line therapy for the treatment of type 2 diabetes, due to its robust glucose-lowering effects, well-established safety profile, and relatively low cost. While metformin has been shown to have pleotropic effects on glucose metabolism, there is a general consensus that the major glucose-lowering effect in patients with type 2 diabetes is mostly mediated through inhibition of hepatic gluconeogenesis. However, despite decades of research, the mechanism by which metformin inhibits this process is still highly debated. A key reason for these discrepant effects is likely due to the inconsistency in dosage of metformin across studies. Widely studied mechanisms of action, such as complex I inhibition leading to AMPK activation, have only been observed in the context of supra-pharmacological (>1 mM) metformin concentrations, which do not occur in the clinical setting. Thus, these mechanisms have been challenged in recent years and new mechanisms have been proposed. Based on the observation that metformin alters cellular redox balance, a redox-dependent mechanism of action has been described by several groups. Recent studies have shown that clinically relevant (50-100 μM) concentrations of metformin inhibit hepatic gluconeogenesis in a substrate-selective manner both in vitro and in vivo, supporting a redox-dependent mechanism of metformin action. Here, we review the current literature regarding metformin's cellular and molecular mechanisms of action.
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Affiliation(s)
- Traci E LaMoia
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.,Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
| | - Gerald I Shulman
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.,Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
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36
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David D, Eapen CE. What Are the Current Pharmacological Therapies for Nonalcoholic Fatty Liver Disease? J Clin Exp Hepatol 2021; 11:232-238. [PMID: 33746449 PMCID: PMC7953000 DOI: 10.1016/j.jceh.2020.09.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 09/02/2020] [Indexed: 12/12/2022] Open
Abstract
Of the currently available drugs tested to treat nonalcoholic fatty liver disease (NAFLD), the most efficacious drugs are pioglitazone (an insulin sensitizer) and vitamin E (an antioxidant). By targeting insulin resistance, the key pathogenic mechanism underlying metabolic syndrome and NAFLD, pioglitazone maybe the preferred drug to treat NAFLD. As we await the results of research trials into multiple new drugs to treat NAFLD, when should we use the currently available patients to treat NAFLD at the present time? To date, no drug has been approved by regulatory agency specifically to treat NAFLD. However, many drugs have been approved to treat other components of metabolic syndrome such as diabetes mellitus and dyslipidemia. Are we underutilizing the currently available drugs to treat NAFLD? Herein, we review the benefits and concerns of the use of these currently available drugs to treat NAFLD and suggest clinical scenarios, wherein the clinician should consider using these drugs.
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Affiliation(s)
- Deepu David
- Gastroenterology Department, Christian Medical College, Vellore, Tamil Nadu, India
| | - Chundamannil E. Eapen
- Hepatology Department, Christian Medical College, Vellore, Tamil Nadu, India,Address for correspondence: C E Eapen, Professor and Head, Department of Hepatology, Christian Medical College Hospital, Vellore, Tamil Nadu, India.
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37
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The Relationship between Insulin Resistance and Liver Damage in non-alcoholic Fatty Liver Patients. MEDICAL BULLETIN OF SISLI ETFAL HOSPITAL 2020; 54:411-415. [PMID: 33364879 PMCID: PMC7751232 DOI: 10.14744/semb.2018.83604] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 12/17/2018] [Indexed: 11/27/2022]
Abstract
Objectives: Non-alcoholic fatty liver disease (NAFLD) is closely associated with diseases, such as obesity, diabetes mellitus, metabolic syndrome, which are characterized by insulin resistance. NAFLD is thought to be a manifestation of metabolic syndrome in the liver. Liver fibrosis has a high prognostic significance in non-alcoholic steatohepatitis (NASH). In this study, the relationship between insulin resistance and the histopathological changes in the liver was investigated in biopsy-proven NAFLD patients. Methods: In this study, 85 biopsy-proven NAFLD patients (64 NASH, 21 non-NASH) and 40 healthy control subjects were enrolled. Insulin resistance was calculated using the “homeostasis model assessment of insulin resistance” (HOMA-IR). Results: C reactive protein, total cholesterol, low-density lipoprotein, triglyceride, body mass index (BMI), HOMA-IR levels were significantly higher in the NAFLD group compared to the control group. In the NASH group, the HOMA-IR level was significantly higher than the non-NASH group (p=0.026). When NAFLD patients with advanced fibrosis (stage 3-4, n=27) and without fibrosis (stage 0-2, n=58) are compared, in advanced fibrosis group BMI (35.2±4.6 kg/m2 and 32.7±4.1 kg/m2, respectively; p=0.031) and HOMA-IR (6.3 [5.8-6.8] and 3.4 [2.6-4.8], respectively, p=0.001) levels were higher significantly. In the covariance analysis, when confounding factors, such as BMI, age and gender, were corrected, it was observed that the elevation of HOMA-IR level in the advanced fibrosis group continued statistically significantly. Conclusion: HOMA-IR levels were high in NAFLD patients with advanced fibrosis. HOMA-IR, which can be easily measured in daily practice, is an independent predictor for fibrosis.
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38
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Hanif H, Khan MM, Ali MJ, Shah PA, Satiya J, Lau DT, Aslam A. A New Endemic of Concomitant Nonalcoholic Fatty Liver Disease and Chronic Hepatitis B. Microorganisms 2020; 8:1526. [PMID: 33020450 PMCID: PMC7601829 DOI: 10.3390/microorganisms8101526] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection remains a global public problem despite the availability of an effective vaccine. In the past decades, nonalcoholic fatty liver disease (NAFLD) has surpassed HBV as the most common cause of chronic liver disease worldwide. The prevalence of concomitant chronic hepatitis B (CHB) and NAFLD thus reaches endemic proportions in geographic regions where both conditions are common. Patients with CHB and NAFLD are at increased risk of liver disease progression to cirrhosis and hepatocellular carcinoma. Due to the complexity of the pathogenesis, accurate diagnosis of NAFLD in CHB patients can be challenging. Liver biopsy is considered the gold standard for diagnosing and determining disease severity, but it is an invasive procedure with potential complications. There is a growing body of literature on the application of novel noninvasive serum biomarkers and advanced radiological modalities to diagnose and evaluate NAFLD, but most have not been adequately validated, especially for patients with CHB. Currently, there is no approved therapy for NAFLD, although many new agents are in different phases of development. This review provides a summary of the epidemiology, clinical features, diagnosis, and management of the NAFLD and highlights the unmet needs in the areas of CHB and NAFLD coexistence.
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Affiliation(s)
- Hira Hanif
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Muzammil M. Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Mukarram J. Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Pir A. Shah
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
- Department of Internal Medicine, University of Texas, San Antonio, TX 78229, USA
| | - Jinendra Satiya
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Daryl T.Y. Lau
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Aysha Aslam
- Department of Medicine, Louis A Weiss Memorial Hospital, Chicago, IL 60640, USA
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39
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Chung W, Promrat K, Wands J. Clinical implications, diagnosis, and management of diabetes in patients with chronic liver diseases. World J Hepatol 2020; 12:533-557. [PMID: 33033564 PMCID: PMC7522556 DOI: 10.4254/wjh.v12.i9.533] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/03/2020] [Accepted: 08/15/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus (DM) negatively affects the development and progression of chronic liver diseases (CLD) of various etiologies. Concurrent DM and CLD are also associated with worse clinical outcomes with respect to mortality, the occurrence of hepatic decompensation, and the development of hepatocellular carcinoma (HCC). Unfortunately, early diagnosis and optimal treatment of DM can be challenging, due to the lack of established clinical guidelines as well as the medical complexity of this patient population. We conducted an exploratory review of relevant literature to provide an up-to-date review for internists and hepatologists caring for this patient population. We reviewed the epidemiological and pathophysiological associations between DM and CLD, the impact of insulin resistance on the progression and manifestations of CLD, the pathogenesis of hepatogenic diabetes, as well as the practical challenges in diagnosis and monitoring of DM in this patient population. We also reviewed the latest clinical evidence on various pharmacological antihyperglycemic therapies with an emphasis on liver disease-related clinical outcomes. Finally, we proposed an algorithm for managing DM in patients with CLD and discussed the clinical and research questions that remain to be addressed.
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Affiliation(s)
- Waihong Chung
- Division of Gastroenterology, Department of Medicine, Rhode Island Hospital, Providence, RI 02905, United States.
| | - Kittichai Promrat
- Division of Gastroenterology and Hepatology, Providence VA Medical Center, Providence, RI 02908, United States
| | - Jack Wands
- Liver Research Center, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States
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40
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Sanai FM, Abaalkhail F, Hasan F, Farooqi MH, Nahdi NA, Younossi ZM. Management of nonalcoholic fatty liver disease in the Middle East. World J Gastroenterol 2020; 26:3528-3541. [PMID: 32742124 PMCID: PMC7366060 DOI: 10.3748/wjg.v26.i25.3528] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/15/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) in the Middle East is increasing in parallel to an increase in the prevalence of associated risk factors such as obesity, metabolic syndrome, and type 2 diabetes mellitus. About 20% to 30% of the patients progress to develop nonalcoholic steatohepatitis (NASH), a histological subtype of NAFLD, with features of hepatocyte injury such as hepatocyte ballooning. NASH can progress to fibrosis, cirrhosis, and even hepatocellular carcinoma. NAFLD thus causes a substantial burden on healthcare systems and it is imperative that appropriate strategies are discussed at a regional level to facilitate effective management tailored to the needs of the region. To fulfil this unmet need, expert gastroenterologists, hepatologists, and endocrinologists from the region came together in three advisory board meetings that were conducted in Saudi Arabia, United Arab Emirates, and Kuwait, to discuss current local challenges in NAFLD screening and diagnosis, and the different available management options. The experts discussed the disease burden of NAFLD/NASH in the Middle East; screening, diagnosis, and referral patterns in NAFLD; and available treatment options for NAFLD and NASH. This paper summarizes the discussions and opinion of the expert panel on the management of NAFLD/NASH and also presents an extensive literature review on the topic.
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Affiliation(s)
- Faisal M Sanai
- Gastroenterology Unit, Department of Medicine, King Abdulaziz Medical City, Jeddah 21423, Saudi Arabia
| | - Faisal Abaalkhail
- Department of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Department of Liver Transplant, King Fahad Specialist Hospital, Dammam 32253, Saudi Arabia
| | - Fuad Hasan
- Department of Internal Medicine, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait
| | | | - Nawal Al Nahdi
- Department of Gastroenterology and Hepatology, Dubai Health Authority, Rashid hospital, Dubai 00000, United Arab Emirates
| | - Zobair M Younossi
- Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA 22042, United States
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41
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Protective effect of metformin against palmitate-induced hepatic cell death. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165621. [DOI: 10.1016/j.bbadis.2019.165621] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 10/31/2019] [Accepted: 11/21/2019] [Indexed: 12/12/2022]
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42
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International Liver Transplantation Consensus Statement on End-stage Liver Disease Due to Nonalcoholic Steatohepatitis and Liver Transplantation. Transplantation 2019; 103:45-56. [PMID: 30153225 DOI: 10.1097/tp.0000000000002433] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nonalcoholic steatohepatitis (NASH)-related cirrhosis has become one of the most common indications for liver transplantation (LT), particularly in candidates older than 65 years. Typically, NASH candidates have concurrent obesity, metabolic, and cardiovascular risks, which directly impact patient evaluation and selection, waitlist morbidity and mortality, and eventually posttransplant outcomes. The purpose of these guidelines is to highlight specific features commonly observed in NASH candidates and strategies to optimize pretransplant evaluation and waitlist survival. More specifically, the working group addressed the following clinically relevant questions providing recommendations based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system supported by rigorous systematic reviews and consensus: (1) Is the outcome after LT similar to that of other etiologies of liver disease? (2) Is the natural history of NASH-related cirrhosis different from other etiologies of end-stage liver disease? (3) How should cardiovascular risk be assessed in the candidate for LT? Should the assessment differ from that done in other etiologies? (4) How should comorbidities (hypertension, diabetes, dyslipidemia, obesity, renal dysfunction, etc.) be treated in the candidate for LT? Should treatment and monitoring of these comorbidities differ from that applied in other etiologies? (5) What are the therapeutic strategies recommended to improve the cardiovascular and nutritional status of a NASH patient in the waiting list for LT? (6) Is there any circumstance where obesity should contraindicate LT? (7) What is the optimal time for bariatric surgery: before, during, or after LT? (8) How relevant is donor steatosis for LT in NASH patients?
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43
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Marchisello S, Di Pino A, Scicali R, Urbano F, Piro S, Purrello F, Rabuazzo AM. Pathophysiological, Molecular and Therapeutic Issues of Nonalcoholic Fatty Liver Disease: An Overview. Int J Mol Sci 2019; 20:ijms20081948. [PMID: 31010049 PMCID: PMC6514656 DOI: 10.3390/ijms20081948] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 04/18/2019] [Accepted: 04/20/2019] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) represents the leading cause of liver disease in developed countries but its diffusion is currently also emerging in Asian countries, in South America and in other developing countries. It is progressively becoming one of the main diseases responsible for hepatic insufficiency, hepatocarcinoma and the need for orthotopic liver transplantation. NAFLD is linked with metabolic syndrome in a close and bidirectional relationship. To date, NAFLD is a diagnosis of exclusion, and liver biopsy is the gold standard for diagnosis. NAFLD pathogenesis is complex and multifactorial, mainly involving genetic, metabolic and environmental factors. New concepts are constantly arising in the literature promising new diagnostic and therapeutic tools. One of the challenges will be to better characterize not only NAFLD development but overall NAFLD progression, in order to better identify NAFLD patients at higher risk of metabolic, cardiovascular and neoplastic complications. This review analyses NAFLD epidemiology and the different prevalence of the disease in distinct groups, particularly according to sex, age, body mass index, type 2 diabetes and dyslipidemia. Furthermore, the work expands on the pathophysiology of NAFLD, examining multiple-hit pathogenesis and the role of different factors in hepatic steatosis development and progression: genetics, metabolic factors and insulin resistance, diet, adipose tissue, gut microbiota, iron deposits, bile acids and circadian clock. In conclusion, the current available therapies for NAFLD will be discussed.
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Affiliation(s)
- Simona Marchisello
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Antonino Di Pino
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Roberto Scicali
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Francesca Urbano
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Salvatore Piro
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Francesco Purrello
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Agata Maria Rabuazzo
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
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44
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Arab JP, Arrese M, Trauner M. Recent Insights into the Pathogenesis of Nonalcoholic Fatty Liver Disease. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 13:321-350. [PMID: 29414249 DOI: 10.1146/annurev-pathol-020117-043617] [Citation(s) in RCA: 387] [Impact Index Per Article: 64.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches based on a profound understanding of its pathogenesis to halt disease progression to advanced fibrosis or cirrhosis and cancer. The pathogenesis of NAFLD involves a complex interaction among environmental factors (i.e., Western diet), obesity, changes in microbiota, and predisposing genetic variants resulting in a disturbed lipid homeostasis and an excessive accumulation of triglycerides and other lipid species in hepatocytes. Insulin resistance is a central mechanism that leads to lipotoxicity, endoplasmic reticulum stress, disturbed autophagy, and, ultimately, hepatocyte injury and death that triggers hepatic inflammation, hepatic stellate cell activation, and progressive fibrogenesis, thus driving disease progression. In the present review, we summarize the currently available data on the pathogenesis of NAFLD, emphasizing the most recent advances. A better understanding of NAFLD/NASH pathogenesis is crucial for the design of new and efficient therapeutic interventions.
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Affiliation(s)
- Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile.,Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile.,Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna A-1090, Austria;
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45
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Green CJ, Marjot T, Tomlinson JW, Hodson L. Of mice and men: Is there a future for metformin in the treatment of hepatic steatosis? Diabetes Obes Metab 2019; 21:749-760. [PMID: 30456918 DOI: 10.1111/dom.13592] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/06/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases, of which the first stage is steatosis. It is one of the most common liver diseases in developed countries and there is a clear association between type 2 diabetes (T2DM) and NAFLD. It is estimated that 70% of people with T2DM have NAFLD and yet there is currently no licensed pharmacological agent to treat it. Whilst lifestyle modification may ameliorate liver fat, it is often difficult to achieve or sustain; thus, there is great interest in pharmacological treatments for NAFLD. Metformin is the first-line medication in the management of T2DM and evidence from animal and human studies has suggested that it may be useful in reducing liver fat via inhibition of lipogenesis and increased fatty acid oxidation. Findings from the majority of studies undertaken in rodent models clearly suggest that metformin may be a powerful therapeutic agent specifically to reduce liver fat accumulation; data from human studies are less convincing. In the present review we discuss the evidence for the specific effects of metformin treatment on liver fat accumulation in animal and human studies, as well as the underlying proposed mechanisms, to try and understand and reconcile the difference in findings between rodent and human work in this area.
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Affiliation(s)
- Charlotte J Green
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
| | - Thomas Marjot
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK
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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: 98] [Impact Index Per Article: 16.3] [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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Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis. J Transl Med 2019; 99:4-16. [PMID: 30258096 DOI: 10.1038/s41374-018-0120-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 07/27/2018] [Accepted: 08/02/2018] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the form of nonalcoholic fatty liver disease that can evolve into cirrhosis. Lifestyle modifications achieving 10% weight loss reverse NASH, but there are no effective approved drug treatments. We previously identified defective adaptive thermogenesis as a factor contributing to metabolic syndrome and hepatic steatosis. We have now tested whether increasing nonshivering thermogenesis can improve preexisting NASH in mice. In high-fat diet-fed foz/foz mice with established NASH, treatment with β3AR agonist restored brown adipose tissue (BAT) function, decreased body weight, improved glucose tolerance, and reduced hepatic lipid content compared to untreated counterparts, but had no impact on liver inflammation or on nonalcoholic fatty liver disease activity score (NAS). Similarly, β3AR agonist did not alter liver pathology in other steatohepatitis models, including MCD diet-fed diabetic obese db/db mice. Caloric restriction alone alleviated the hepatic inflammatory signature in foz/foz mice. Addition of a β3AR agonist to mice subjected to caloric restriction enhanced weight loss and glucose tolerance, and improved liver steatosis, hepatocellular injury, and further reduced liver inflammation. These changes contributed to a significantly lower NAS score such as no (0/9) animals in this group fulfilled the criteria for NASH pathology compared to eight out of ten mice under caloric restriction alone. In conclusion, β3AR agonist counteracts features of the metabolic syndrome and alleviates steatosis, but does not reverse NASH. However, when coupled with weight loss therapy, BAT stimulation provides additional therapeutic advantages and reverses NASH.
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Sui Y, Kong X, Fan R, Ye Y, Mai H, Zhuo S, Lu W, Ruan P, Fang S, Yang T. Long-term treatment with metformin in the prevention of fatty liver in Zucker diabetic fatty rats. Diabetol Metab Syndr 2019; 11:94. [PMID: 31749893 PMCID: PMC6852932 DOI: 10.1186/s13098-019-0491-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 11/04/2019] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Treatment with metformin, the biguanide of hepatic insulin sensitizer, in patients with non-alcoholic fatty liver disease (NAFLD) has been reported with contradictory findings regarding the effectiveness on blood lipids and liver histology. In this study, we aimed to explore the preventive effects of metformin on NAFLD in Zucker diabetic fatty (ZDF) rats. METHODS Male ZDF rats and Zucker lean rats aged 4-8 weeks were subjected to vehicle or metformin treatment for 6 months. Liver cDNA microarray assay, and protein semiquantitative and histological examinations were performed. RESULTS Data demonstrated that ZDF rats developed hyperglycemia, hyperlipidemia, liver deficiency and hepatocyte degeneration. The metformin treatment significantly reduced post-load blood glucose levels, but not blood lipid profiles or liver enzyme levels. Hepatocyte degeneration was not attenuated after the treatment. The metformin-treated ZDF rats showed activation of AMP-activated protein kinase by Western blot and overexpression of cytochrome c oxidase by immunofluorescent microscopy. Gene expression microarray assay demonstrated that a panel of genes participating in glucose and lipid metabolisms were changed in the ZDF rats, and most of the altered genes involved in glucose and cholesterol metabolisms, but not those in fatty acid metabolisms, were corrected by the metformin treatment. No genes associated with inflammation, apoptosis, fibrosis, or cell death were overexpressed in the metformin-treated ZDF rats. CONCLUSIONS These results suggest that long-term metformin treatment presents no preventive effect for NAFLD in ZDF rats.
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Affiliation(s)
- Yi Sui
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Xianhe Kong
- Endoscopy Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655 China
| | - Rongrong Fan
- Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
| | - Yanbin Ye
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Haiyan Mai
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Shuyu Zhuo
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Wei Lu
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Peishan Ruan
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Shi Fang
- Department of Clinical Nutrition, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Tao Yang
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399 China
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Antidiabetic Drugs in NAFLD: The Accomplishment of Two Goals at Once? Pharmaceuticals (Basel) 2018; 11:ph11040121. [PMID: 30413050 PMCID: PMC6316860 DOI: 10.3390/ph11040121] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 11/02/2018] [Accepted: 11/03/2018] [Indexed: 02/06/2023] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in Western countries, accounting for 20–30% of general population and reaching a prevalence of 55% in patients with type 2 diabetes mellitus (T2DM). Insulin resistance plays a key role in pathogenic mechanisms of NAFLD. Many drugs have been tested but no medications have yet been approved. Antidiabetic drugs could have a role in the progression reduction of the disease. The aim of this review is to summarize evidence on efficacy and safety of antidiabetic drugs in patients with NAFLD. Metformin, a biguanide, is the most frequently used drug in the treatment of T2DM. To date 15 randomized controlled trials (RCTs) and four meta-analysis on the use of metformin in NAFLD are available. No significant improvement in histological liver fibrosis was shown, but it can be useful in the treatment of co-factors of NAFLD, like body weight, transaminase or cholesterol levels, and HbA1c levels. A possible protective role in various types of cancer has been reported for Metformin. Thiazolidinediones modulate insulin sensitivity by the activation of PPAR-γ. The RCTs and the meta-analysis available about the role of these drugs in NAFLD show an improvement in ballooning, lobular inflammation, and perhaps fibrosis, but some side effects, in particular cardiovascular, were showed. GLP-1 analogues stimulate insulin secretion by pancreatic beta cell and inhibit glucagon release; Liraglutide is the most used drug in this class and significantly improves steatosis, hepatocyte ballooning and transaminase levels. Scanty data about the role of DPP-4 and SGLT inhibitors were published. No data about insulin effects on NAFLD are available but it was showed a possible association between insulin use and the development of solid neoplasms, in particular HCC. In conclusion, antidiabetic drugs seem to be promising drugs, because they are able to treat both NAFLD manifestations and diabetes, preventing worsening of hepatic damage, but data are still conflicting. All antidiabetic drugs can be safely used in patients with compensated cirrhosis, while insulin is the preferred drug in decompensated Child C cirrhosis.
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Handzlik G, Holecki M, Kozaczka J, Kukla M, Wyskida K, Kędzierski L, Pawlicki K, Duława J. Evaluation of metformin therapy using controlled attenuation parameter and transient elastography in patients with non-alcoholic fatty liver disease. Pharmacol Rep 2018; 71:183-188. [PMID: 30780126 DOI: 10.1016/j.pharep.2018.10.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 10/11/2018] [Accepted: 10/25/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is among the most common causes of liver disease worldwide. There is growing evidence on pathogenesis and pathophysiology of NAFLD. However, there is still no universally accepted pharmacotherapy protocol. METHODS The study was conducted on 42 patients with NAFLD. They were randomized to dietary treatment alone (n = 21) or to diet and metformin therapy (n = 21). Liver ultrasonography, controlled attenuation parameter (CAP), liver stiffness (LS), complete blood count, anthropometric and biochemical parameters were obtained before treatment (baseline), and after 3 and 5 months of the therapy. RESULTS Patients treated with diet and metformin exhibited significantly decreased CAP values at 3 and 5 months of the therapy compared to baseline (319 dB/m vs. 285 dB/m; p < 0.05; 319 dB/m vs. 295 dB/m; p < 0.05 respectively). Five months of diet and the metformin therapy resulted in significant reduction of LS value (6.2 kPa vs. 5.2 kPa; p < 0.05), while patients treated with diet alone had no significant changes in liver CAP and LS measurements. CONCLUSIONS Metformin therapy combined with dietary treatment seems to be effective for the reduction of hepatic steatosis and fibrosis. However, considering limitations of the study and inconsistent results of previous investigations in this area, there is a need for further research on metformin efficacy in this group of patients.
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Affiliation(s)
- Gabriela Handzlik
- Department of Internal Medicine and Metabolic Diseases, School of Health Sciences, Medical University of Silesia, Katowice, Poland.
| | - Michał Holecki
- Department of Internal Medicine, Autoimmune and Metabolic Diseases, School of Medicine, Medical University of Silesia, Katowice, Poland
| | - Joanna Kozaczka
- Department of Internal Medicine and Metabolic Diseases, School of Health Sciences, Medical University of Silesia, Katowice, Poland
| | - Michał Kukla
- Department of Gastroenterology and Hepatology, School of Medicine, Medical University of Silesia, Katowice, Poland
| | - Katarzyna Wyskida
- Health Promotion and Obesity Management Unit, Department of Pathophysiology, School of Medicine, Medical University of Silesia, Katowice, Poland
| | - Leszek Kędzierski
- Department of Internal Medicine and Metabolic Diseases, School of Health Sciences, Medical University of Silesia, Katowice, Poland
| | - Krzysztof Pawlicki
- Department of Biophysics, School of Medicine, Medical University of Silesia, Katowice, Poland
| | - Jan Duława
- Department of Internal Medicine and Metabolic Diseases, School of Health Sciences, Medical University of Silesia, Katowice, Poland
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