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Boulos M, Mousa RS, Jeries N, Simaan E, Alam K, Bulus B, Assy N. Hidden in the Fat: Unpacking the Metabolic Tango Between Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Syndrome. Int J Mol Sci 2025; 26:3448. [PMID: 40244398 PMCID: PMC11989262 DOI: 10.3390/ijms26073448] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/25/2025] [Accepted: 03/30/2025] [Indexed: 04/18/2025] Open
Abstract
Metabolic syndrome (MetS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related, with rapidly increasing prevalence globally, driving significant public health concerns. Both conditions share common pathophysiological mechanisms such as insulin resistance (IR), adipose tissue dysfunction, oxidative stress, and gut microbiota dysbiosis, which contribute to their co-occurrence and progression. While the clinical implications of this overlap, including increased cardiovascular, renal, and hepatic risk, are well recognized, current diagnostic and therapeutic approaches remain insufficient due to the clinical and individuals' heterogeneity and complexity of these diseases. This review aims to provide an in-depth exploration of the molecular mechanisms linking MetS and MASLD, identify critical gaps in our understanding, and highlight existing challenges in early detection and treatment. Despite advancements in biomarkers and therapeutic interventions, the need for a comprehensive, integrated approach remains. The review also discusses emerging therapies targeting specific pathways, the potential of precision medicine, and the growing role of artificial intelligence in enhancing research and clinical management. Future research is urgently needed to combine multi-omics data, precision medicine, and novel biomarkers to better understand the complex interactions between MetS and MASLD. Collaborative, multidisciplinary efforts are essential to develop more effective diagnostic tools and therapies to address these diseases on a global scale.
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Affiliation(s)
- Mariana Boulos
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Rabia S. Mousa
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Nizar Jeries
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Elias Simaan
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Klode Alam
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Bulus Bulus
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Nimer Assy
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
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Chen L, Wu W, Ye H. Risk Factors for MAFLD and Advanced Liver Fibrosis in Adult-Onset Craniopharyngioma Patients: A Cross-Sectional Study. Diabetes Metab Syndr Obes 2025; 18:859-871. [PMID: 40161287 PMCID: PMC11954395 DOI: 10.2147/dmso.s504968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 02/22/2025] [Indexed: 04/02/2025] Open
Abstract
Purpose To investigate the prevalence of and risk factors for metabolic dysfunction-associated fatty liver disease (MAFLD) and advanced liver fibrosis (ALF) in postoperative adult-onset craniopharyngioma (AOCP) patients. Patients and Methods This cross-sectional study included 242 postoperative AOCP patients at Huashan Hospital (Shanghai, China). Clinical characteristics were compared between patients with and without MAFLD and ALF. Independent risk factors for MAFLD and ALF were identified using binary logistic regression analysis. Results The prevalence of MAFLD in postoperative AOCP patients was 67.4% (95% CI 61.2-73.0%), and 32.5% (95% CI 25.8-40.0%) of patients with MAFLD were diagnosed with ALF. Body mass index (BMI) was independently associated with MAFLD (OR = 1.51, 95% CI 1.33-1.72, P < 0.001). In patients with MAFLD, hypertension (OR = 2.33, 95% CI 1.04-5.20, P = 0.040), glycated hemoglobin (HbA1c) (OR = 1.34, 95% CI 1.01-1.78, P = 0.044), daily hydrocortisone dose (OR = 1.08, 95% CI 1.01-1.15, P = 0.026), and insulin-like growth factor-1 (IGF-1)(OR = 0.99, 95% CI 0.97-0.99, P = 0.011) were independently associated with the presence of ALF. Conclusion MAFLD is a common comorbidity in postoperative AOCP patients and is associated with a high risk of ALF. MAFLD is closely related to BMI, while ALF is significantly associated with hypertension, HbA1c levels, IGF-1 levels, and daily hydrocortisone dose. Strategies such as controlling weight gain, maintaining optimal blood glucose and blood pressure levels, appropriate hormone replacement, and avoiding excessive glucocorticoid use should be implemented to prevent and delay the onset and progression of MAFLD and ALF.
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Affiliation(s)
- Lijiao Chen
- Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China
| | - Wei Wu
- Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China
| | - Hongying Ye
- Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China
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Tsushima Y, Galloway N. Glycemic Targets and Prevention of Complications. J Clin Endocrinol Metab 2025; 110:S100-S111. [PMID: 39998919 DOI: 10.1210/clinem/dgae776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Indexed: 02/27/2025]
Abstract
CONTEXT Complications of diabetes mellitus have significant impacts on morbidity, mortality, quality of life, and health costs for individuals. Setting and achieving glycemic targets to prevent these complications is a top priority when managing diabetes. However, patients often already have complications when diagnosed with diabetes mellitus. Therefore, methods to prevent disease progression become a crucial component of diabetes management. The purpose of this article is to review glycemic targets and methods of screening and managing diabetes-related complications. EVIDENCE ACQUISITION A PubMed review of the literature pertaining to diabetes mellitus, glycemic targets, microvascular complications, and macrovascular complications was conducted. We reviewed articles published between 1993 and 2024. Guidelines published by nationally recognized organizations in the fields of diabetes, nephrology, and cardiology were referenced. Public health statistics obtained by the Center for Disease Control and Prevention and the National Kidney Foundation were used. EVIDENCE SYNTHESIS Achieving glycemic targets and screening for diabetes-related complications at appropriate intervals remains the key factor for early detection and intervention. An algorithmic approach to glycemic management based on individual risk factors is beneficial in choosing pharmacotherapy. CONCLUSION The consequences of diabetes-related complications can be detrimental. However, achieving and maintaining glycemic targets combined with diligent screening, reduction of risk factors, and prompt treatment can halt disease progression.
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Affiliation(s)
- Yumiko Tsushima
- Department of Internal Medicine, University Hospitals Cleveland Medical Center, Diabetes and Metabolic Care Center, Cleveland, OH 44106, USA
| | - Nicholas Galloway
- Department of Internal Medicine, University Hospitals Cleveland Medical Center, Diabetes and Metabolic Care Center, Cleveland, OH 44106, USA
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Yu H, Su X, Tao W, Sun W, Zhang X, Han Q, Zhao Z, Zhang Y, Chen X, Liu X, Jia D, Fang L, Li L. Prevalence and characteristics of liver steatosis and fibrosis in type 2 diabetes mellitus (T2DM) patients: a cross-sectional study in populations of eastern China. BMJ Open 2024; 14:e087550. [PMID: 39672583 PMCID: PMC11647396 DOI: 10.1136/bmjopen-2024-087550] [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: 04/12/2024] [Accepted: 11/22/2024] [Indexed: 12/15/2024] Open
Abstract
OBJECTIVES To describe the prevalence, clinical characteristics and risk factors of liver steatosis and fibrosis in type 2 diabetes mellitus (T2DM) patients in eastern China. DESIGN A cross-sectional, multicentre study based on an ongoing cohort study. SETTING 16 clinics in eastern China, including primary clinics to tertiary hospitals. PARTICIPANTS 1816 patients with T2DM diagnosis who met the inclusion criteria were recruited into the study. INTERVENTION Participants underwent elastography examination. MAIN OUTCOME MEASURES Descriptive analysis was performed to calculate the prevalence and characteristics of liver steatosis and fibrosis. The correlated factors were analysed using single- and multivariate logistic regression analysis. RESULTS The prevalence of liver steatosis in T2DM patients is 69.7%, with 46% moderate to severe steatosis. 34.6% and 6.7% of the patients were detected with liver fibrosis and cirrhosis. Steatosis patients were younger, had higher body mass index (BMI), higher levels of insulin resistance and more severe lipid metabolism disorders. Similar trends of differences were observed in patients with fibrosis. Female gender (OR=0.574, 95% CI 0.381 to 0.865), BMI (OR=1.491, 95% CI 1.375 to 1.616), disease duration, inflammation and serum lipid profile markers were risk factors of steatosis, while BMI (OR=1.204, 95% CI 1.137 to 1.275) and female gender (OR=0.672, 95% CI 0.470 to 0.961) were still the most significant predictors of liver fibrosis. CONCLUSIONS The prevalence of liver steatosis and fibrosis were high in patients with T2DM. Liver steatosis and fibrosis in these patients appeared to be more associated with lipid metabolism disorders and insulin resistance rather than glucose levels. TRIAL REGISTRATION NUMBER Clinical trial: NCT05597709.
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Affiliation(s)
- Hekai Yu
- Department of Endocrinology, Southeast University, Nanjing, Jiangsu, China
- Southeast University, Nanjing, Jiangsu, China
| | - Xianghui Su
- Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Xinjiang, Xinjiang, China
| | - Wenxuan Tao
- Department of Endocrinology, Southeast University, Nanjing, Jiangsu, China
- Southeast University, Nanjing, Jiangsu, China
| | - Weixia Sun
- Department of Endocrinology, Southeast University, Nanjing, Jiangsu, China
- Southeast University, Nanjing, Jiangsu, China
| | - Xiaoyan Zhang
- Department of Endocrinology, Southeast University, Nanjing, Jiangsu, China
| | - Qing Han
- Department of Endocrinology, Southeast University, Nanjing, Jiangsu, China
| | - Zhuoxiao Zhao
- Nanjing Gaochun Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China
| | - Yan Zhang
- Department of Endocrinology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xiaoqian Chen
- Department of Endocrinology, Nanjing Central Hospital, Nanjing, Jiangsu, China
| | - Xinliang Liu
- Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China
| | - Dianrong Jia
- Department of Endocrinology, Taizhou Jiangyan Hospital of Traditional Chinese Medicine, Taizhou, Jiangsu, China
| | - Li Fang
- Nanjing Gaochun Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China
| | - Ling Li
- Department of Endocrinology, School of Medicine, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
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Wada T, Takeda Y, Okekawa A, Komatsu G, Iwasa Y, Onogi Y, Takasaki I, Hamashima T, Sasahara M, Tsuneki H, Sasaoka T. Deletion of platelet-derived growth factor receptor β suppresses tumorigenesis in metabolic dysfunction-associated steatohepatitis (MASH) mice with diabetes. Sci Rep 2024; 14:23829. [PMID: 39394459 PMCID: PMC11470010 DOI: 10.1038/s41598-024-75713-6] [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: 05/28/2024] [Accepted: 10/08/2024] [Indexed: 10/13/2024] Open
Abstract
The platelet-derived growth factor (PDGF) family contributes to the progression of steatohepatitis; however, changes in and the characteristics of isoform-specific expression remain unclear. Since diabetes is a major driver of metabolic dysfunction-associated steatohepatitis (MASH), we characterized the mouse model of diabetic MASH (dMASH) by focusing on PDGF signaling. Pdgfa-d expression was markedly higher in hepatic stellate cells among flow-sorted cells in control mice and also increased in dMASH. In contrast, a reanalysis of human single-cell RNA-Seq data showed the distinct distribution of each PDGF isoform with disease progression. Furthermore, inflammation and fibrosis in the liver were less severe in diabetic MASH using tamoxifen-induced PDGF receptor β (PDGFRβ)-deficient mice (KO) than in control dMASH using floxed mice (FL) at 12 weeks old. Despite the absence of tumors, the expression of tumor-related genes was lower in KO than in FL. Tumorigenesis was significantly lower in 20-week-old KO. An Ingenuity Pathway Analysis of differentially expressed miRNA between FL and KO identified functional networks associated with hepatotoxicity and cancer. Therefore, PDGFRβ signals play important roles in the progression of steatohepatitis and tumorigenesis in MASH, with the modulation of miRNA expression posited as a potential underlying mechanism.
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Affiliation(s)
- Tsutomu Wada
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Yuki Takeda
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Akira Okekawa
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Go Komatsu
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Yuichi Iwasa
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Yasuhiro Onogi
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
- Research Center for Pre-Disease Science, University of Toyama, 2630 Sugitani, Toyama, Japan
| | - Ichiro Takasaki
- Department of Pharmacology, Graduate School of Science and Engineering, University of Toyama, 3190, Gofuku, Toyama, Japan
| | - Takeru Hamashima
- Department of Pathology, University of Toyama, 2630 Sugitani, Toyama, Japan
| | - Masakiyo Sasahara
- Department of Pathology, University of Toyama, 2630 Sugitani, Toyama, Japan
| | - Hiroshi Tsuneki
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
- Department of Integrative Pharmacology, University of Toyama, 2630 Sugitani, Toyama, Japan
| | - Toshiyasu Sasaoka
- Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
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Abuduyimiti T, Goto H, Kimura K, Oshima Y, Tanida R, Kamoshita K, Leerach N, Abuduwaili H, Oo HK, Li Q, Galicia-Medina CM, Takayama H, Ishii KA, Nakano Y, Takeshita Y, Iba T, Naito H, Honda M, Harada K, Yamamoto Y, Takamura T. Diabetes Accelerates Steatohepatitis in Mice: Liver Pathology and Single-Cell Gene Expression Signatures. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:693-707. [PMID: 38309428 DOI: 10.1016/j.ajpath.2024.01.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/27/2023] [Accepted: 01/10/2024] [Indexed: 02/05/2024]
Abstract
Glucose lowering independently reduces liver fibrosis in human nonalcoholic fatty liver disease. This study investigated the impact of diabetes on steatohepatitis and established a novel mouse model for diabetic steatohepatitis. Male C57BL/6J mice were fed a 60% high-fat diet (HFD) and injected with carbon tetrachloride (CCl4) and streptozotocin (STZ) to induce diabetes. The HFD+CCl4+STZ group showed more severe liver steatosis, hepatocyte ballooning, and regenerative nodules compared with other groups. Diabetes up-regulated inflammatory cytokine-associated genes and increased the M1/M2 macrophage ratios in the liver. Single-cell RNA sequencing analysis of nonparenchymal cells in the liver showed that diabetes reduced Kupffer cells and increased bone marrow-derived recruited inflammatory macrophages, such as Ly6Chi-RM. Diabetes globally reduced liver sinusoidal endothelial cells (LSECs). Furthermore, genes related to the receptor for advanced glycation end products (RAGE)/Toll-like receptor 4 (TLR4) were up-regulated in Ly6Chi-RM and LSECs in mice with diabetes, suggesting a possible role of RAGE/TLR4 signaling in the interaction between inflammatory macrophages and LSECs. This study established a novel diabetic steatohepatitis model using a combination of HFD, CCl4, and STZ. Diabetes exacerbated steatosis, hepatocyte ballooning, fibrosis, regenerative nodule formation, and the macrophage M1/M2 ratios triggered by HFD and CCl4. Single-cell RNA sequencing analysis indicated that diabetes activated inflammatory macrophages and impairs LSECs through the RAGE/TLR4 signaling pathway. These findings open avenues for discovering novel therapeutic targets for diabetic steatohepatitis.
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Affiliation(s)
- Tuerdiguli Abuduyimiti
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan; Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Hisanori Goto
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan; Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Kumi Kimura
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Yu Oshima
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Ryota Tanida
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Kyoko Kamoshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Nontaphat Leerach
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Halimulati Abuduwaili
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Hein Ko Oo
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Qifang Li
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Cynthia M Galicia-Medina
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Hiroaki Takayama
- Life Sciences Division, Engineering and Technology Department, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Kiyo-Aki Ishii
- Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, Obu, Japan
| | - Yujiro Nakano
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Yumie Takeshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Tomohiro Iba
- Department of Vascular Molecular Physiology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Hisamichi Naito
- Department of Vascular Molecular Physiology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
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Takamura T, Kaku K, Yoshida A, Kusakabe H, Nakamura H, Suganami H. Reductions in liver enzymes are associated with anti-hyperglycaemic and anti-obesity effects of tofogliflozin in people with type 2 diabetes: Post-hoc analyses. Endocrinol Diabetes Metab 2024; 7:e461. [PMID: 37986236 PMCID: PMC10782046 DOI: 10.1002/edm2.461] [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: 06/30/2023] [Revised: 10/07/2023] [Accepted: 10/14/2023] [Indexed: 11/22/2023] Open
Abstract
AIMS How the pathology of type 2 diabetes (T2D), including hyperglycaemia and obesity, affects liver enzymes has not been clinically demonstrated. Thus, we compared time courses of gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT) with those of fasting plasma glucose (FPG) and body weight (BW) during treatment with the SGLT2 inhibitor tofogliflozin for T2D. MATERIALS AND METHODS We post-hoc analysed preexisting data on 1046 people with T2D administered tofogliflozin or placebo for 24 weeks in four tofogliflozin studies. First, time courses of percent changes in variables during the intervention were analysed using a mixed effect model to explore the similarity of the time courses and to evaluate time-treatment interactions. Second, clinical factors related to the percent changes in GGT and ALT were clarified using multivariate analyses. RESULTS GGT levels and FPG values rapidly and significantly decreased via tofogliflozin as early as week 4, with decreases maintained until week 24. Conversely, BW and ALT decreased progressively until week 24. Time courses of FPG (p = .365, time-treatment interaction) and GGT (p = .510) reductions were parallel between tofogliflozin and placebo from weeks 4 to 24, while BW and ALT reductions (p < .001, respectively) were not. Reductions in GGT at week 24 were associated with reductions in FPG and BW at week 24, whereas ALT reductions were only associated with reductions in BW. CONCLUSIONS Reductions in GGT and ALT were associated with the anti-hyperglycaemic and anti-obesity effects of tofogliflozin, respectively, in people with T2D. Therefore, GGT and ALT may be surrogate markers for hyperglycaemia and obesity in T2D.
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Affiliation(s)
- Toshinari Takamura
- Department of Endocrinology and MetabolismKanazawa University Graduate School of Medical SciencesKanazawaJapan
| | - Kohei Kaku
- Department of Internal MedicineKawasaki Medical SchoolKurashikiJapan
| | | | | | - Hiroyuki Nakamura
- Department of Hygiene and Public Health, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa UniversityKanazawaJapan
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Pashayee-Khamene F, Hatami B, Cheraghpour M, Yari Z. Keeping an eye on the nutrition: The importance of nutrition management on cardiometabolic risk factors in cirrhotic patients. Clin Nutr ESPEN 2023; 58:186-192. [PMID: 38057004 DOI: 10.1016/j.clnesp.2023.09.927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 08/26/2023] [Accepted: 09/26/2023] [Indexed: 11/07/2023]
Abstract
Chronic liver diseases, especially cirrhosis, are associated with significant morbidity and mortality. Besides predisposing to chronic liver disease per se, diabetes, hypertension, and dyslipidemia worsen the prognosis of patients with cirrhosis induced by other causes. There is no standard of care in the management of these factors in patients with cirrhosis. Also, in particular, it is not known whether nutritional interventions in the modification of cardiometabolic factors can improve the course of cirrhosis or not. This narrative review aimed to investigate the clinical significance of diabetes, hypertension, and dyslipidemia and appropriate nutritional interventions in cirrhotic patients. A comprehensive literature search of the published data was performed in regard to the association of cirrhosis with cardiometabolic factors and the management of cirrhosis and its complications. There is limited evidence on the association of cirrhosis with cardiometabolic risk factors. Cirrhotic cardiometabolic abnormalities are associated with an increased risk of complications, such that the coexistence of diabetes, hypertension, and dyslipidemia increases the risk of clinical decompensation in cirrhosis. Dietary management of cirrhotic patients with risk factors such as diabetes, hypertension, or dyslipidemia does not seem to be considerably different from non-cirrhotic patients.
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Affiliation(s)
- Fereshteh Pashayee-Khamene
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Makan Cheraghpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Zahra Yari
- Department of Nutrition Research, National Nutrition and Food Technology Research Institute and Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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9
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Tatsuta M, Ono M, Kimura S, Zuigyo K, Sato Y, Tomida A, Kobayashi M, Yoshikawa R, Murao S, Tani J, Morishita A, Kobara H, Himoto T, Maeta T, Mori Y, Kohi F, Masaki T. HbA1c of 5.8% or higher as the most useful indicator for recommendation of ultrasonography to detect nonalcoholic fatty liver disease. JGH Open 2023; 7:990-997. [PMID: 38162856 PMCID: PMC10757489 DOI: 10.1002/jgh3.13019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 11/22/2023] [Accepted: 11/27/2023] [Indexed: 01/03/2024]
Abstract
Background and Aim Nonalcoholic fatty liver disease (NAFLD) is closely associated with metabolic syndrome. This study was performed to examine the association between NAFLD and each factor of metabolic syndrome and to identify the factors that are most strongly associated with NAFLD in participants undergoing health checkups. Methods We studied 6538 participants who underwent a health checkup from 2017 to 2018 in our institution. Participants with alcohol intake exceeding 20 g/day or with other chronic liver diseases were excluded. Fatty liver was detected by ultrasonography. Results In total, 4310 participants were enrolled, and 28.4% had fatty liver (NAFLD). The prevalence of NAFLD was highest in the diabetes mellitus (DM)-only group than in the dyslipidemia-only or hypertension-only group. The DM-only group was the only group whose prevalence of NAFLD was >50% in the overall study and in males. The prevalence of NAFLD was higher in males than in females in the DM-only, hypertension-only, and dyslipidemia-only groups. The prevalence of NAFLD was >70% in the dyslipidemia and DM combined group. Multivariate analysis showed that gender and HbA1c were the independent factors most strongly associated with NAFLD. The cutoff value for HbA1c by receiver operating characteristic curve analysis was 5.8% (sensitivity, 57.9%; specificity, 72.6%; area under the curve, 0.70). Conclusion NAFLD was most strongly associated with DM, among the various components of metabolic syndrome. We strongly recommend abdominal ultrasonography to detect NAFLD in patients with an HbA1c of ≥5.8% in general practice and during health checkups.
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Affiliation(s)
- Miwa Tatsuta
- Department of GastroenterologyKKR Takamatsu HospitalKagawaJapan
- Department of Gastroenterology and NeurologyFaculty of Medicine, Kagawa UniversityKagawaJapan
| | - Masafumi Ono
- Division of Innovative Medicine for Hepatobiliary & PancreatologyFaculty of Medicine, Kagawa UniversityKagawaJapan
| | - Shungo Kimura
- Department of Gastroenterology and NeurologyFaculty of Medicine, Kagawa UniversityKagawaJapan
| | - Kaori Zuigyo
- Department of GastroenterologyKKR Takamatsu HospitalKagawaJapan
| | - Yudai Sato
- Department of GastroenterologyKKR Takamatsu HospitalKagawaJapan
| | - Akemi Tomida
- Department of GastroenterologyKKR Takamatsu HospitalKagawaJapan
| | - Mitsuyoshi Kobayashi
- Department of Gastroenterology and NeurologyFaculty of Medicine, Kagawa UniversityKagawaJapan
| | | | - Satoshi Murao
- Department of EndocrinologyKKR Takamatsu HospitalKagawaJapan
| | - Joji Tani
- Department of Gastroenterology and NeurologyFaculty of Medicine, Kagawa UniversityKagawaJapan
| | - Asahiro Morishita
- Department of Gastroenterology and NeurologyFaculty of Medicine, Kagawa UniversityKagawaJapan
| | - Hideki Kobara
- Department of Gastroenterology and NeurologyFaculty of Medicine, Kagawa UniversityKagawaJapan
| | - Takashi Himoto
- Department of Medical TechnologyKagawa Prefectural University of Health SciencesKagawaJapan
| | - Tsuyoshi Maeta
- Department of Internal MedicineKKR Takamatsu HospitalKagawaJapan
| | - Yoshihiro Mori
- Department of Internal MedicineKKR Takamatsu HospitalKagawaJapan
| | - Fumikazu Kohi
- Department of Internal MedicineKKR Takamatsu HospitalKagawaJapan
| | - Tsutomu Masaki
- Department of Gastroenterology and NeurologyFaculty of Medicine, Kagawa UniversityKagawaJapan
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10
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Nadolsky K, Cryer DR, Articolo A, Fisher T, Schneider J, Rinella M. Nonalcoholic steatohepatitis diagnosis and treatment from the perspective of patients and primary care physicians: a cross-sectional survey. Ann Med 2023; 55:2211349. [PMID: 37171239 PMCID: PMC10184582 DOI: 10.1080/07853890.2023.2211349] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND The global prevalence of nonalcoholic steatohepatitis (NASH) is rising. Despite this, NASH is underdiagnosed and does not yet have approved pharmacological treatments. We sought to understand the path to diagnosis, patient interactions with healthcare professionals, treatment regimens, and disease management for patients with NASH. METHODS Cross-sectional online surveys of patients with a self-reported diagnosis of NASH and healthcare professionals treating patients with NASH were conducted from 10th November 2020, to 1st January 2021. This manuscript focuses on responses from 152 patients with NASH and 101 primary care physicians (PCPs). RESULTS Patients (n = 152, mean age = 40, SD = 11) and healthcare professionals (n = 226) were located throughout the US. In the most common patient journey, 72% of patients had initial discussions about symptoms with a PCP but only 30% report receiving their NASH diagnosis from a PCP. Almost half of PCPs (47%) were not aware of any clinical practice guidelines for diagnosis and management of NASH. For ongoing management of NASH, PCPs most frequently prescribed lifestyle changes such as exercise (89%), lifestyle changes focused on diet (79%), and/or metformin (57%). Other healthcare professionals rarely referred patients to PCPs for treatment, but when they did, the primary reasons were patients struggling with lifestyle modifications (58%), needing to lose weight (46%), and needing treatment of comorbidities (42%). CONCLUSIONS PCPs may benefit from greater awareness of NASH and guidelines for its diagnosis and treatment. Given the absence of pharmacological treatments approved for NASH, PCPs can offer support in obesity management, comorbidity management, and risk stratification for liver disease progression.
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Affiliation(s)
- Karl Nadolsky
- MI State University College of Human Medicine, Holland Hospital Endocrinology, Obesity & Diabetes, Holland, MI, USA
| | | | | | | | | | - Mary Rinella
- Department of Medicine, University of Chicago Medicine, Chicago, IL, USA
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11
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Pais R, Cariou B, Noureddin M, Francque S, Schattenberg JM, Abdelmalek MF, Lalazar G, Varma S, Dietrich J, Miller V, Sanyal A, Ratziu V. A proposal from the liver forum for the management of comorbidities in non-alcoholic steatohepatitis therapeutic trials. J Hepatol 2023; 79:829-841. [PMID: 37001695 DOI: 10.1016/j.jhep.2023.03.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 02/08/2023] [Accepted: 03/13/2023] [Indexed: 06/19/2023]
Abstract
The current document has been developed by the Liver Forum who mandated the NAFLD-Associated Comorbidities Working Group - a multistakeholder group comprised of experts from academic medicine, industry and patient associations - to identify aspects of diverse comorbidities frequently associated with non-alcoholic steatohepatitis (NASH) that can interfere with the conduct of therapeutic trials and, in particular, impact efficacy and safety results. The objective of this paper is to propose guidance for the management of relevant comorbidities in both candidates and actual participants in NASH therapeutic trials. We relied on specific guidelines from scientific societies, when available, but adapted them to the particulars of NASH trials with the aim of addressing multiple interacting requirements such as maintaining patient safety, reaching holistic therapeutic objectives, minimising confounding effects on efficacy and safety of investigational agents and allowing for trial completion. We divided the field of action into: first, analysis and stabilisation of the patient's condition before inclusion in the trial and, second, management of comorbidities during trial conduct. For the former, we discussed the concept of acceptable vs. optimal control of comorbidities, defined metabolic and ponderal stability prior to randomisation and weighed the pros and cons of a run-in period. For the latter, we analysed non-hepatological comorbid conditions for changes or acute events possibly occurring during the trial, including changes in alcohol consumption, in order to detail when specific interventions are necessary and how best to manage concomitant drug intake in line with methodological constraints. These recommendations are intended to act as a guide for clinical trialists and are open to further refinement when additional data become available.
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Affiliation(s)
- Raluca Pais
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, France; Centre de Recherche Saint Antoine, INSERM UMRS_938 Paris, France
| | - Bertrand Cariou
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000 Nantes, France
| | | | - Sven Francque
- Department of Gastroenterology Hepatology, Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Belgium
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Manal F Abdelmalek
- Division of Gastroenterology and Hepatology, Duke University, Durham, NC, USA
| | - Gadi Lalazar
- Liver Unit, Digestive Disease Institute, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Sharat Varma
- Novo Nordisk A/S, Vandtårnsvej 108-110, 2860 Søborg Denmark
| | - Julie Dietrich
- GENFIT, Parc Eurasanté 885, Avenue Eugène Avinée, 59120, Loos, France
| | - Veronica Miller
- Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington D.C., USA
| | - Arun Sanyal
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Vlad Ratziu
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, France; INSERM UMRS 1138 CRC, Paris, France.
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12
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Erande S, Mukhopadhyay J, Dange A, Deogaonkar A, Birla A, Doshi C, Revankar S, B SS, Kumar N, Kadam PV. Efficacy and Safety of a Fixed-Dose Combination of Vildagliptin and Pioglitazone in Indian Patients With Type 2 Diabetes Mellitus: A Randomized, Open-Label, Comparative, Phase III Study. Cureus 2023; 15:e44548. [PMID: 37795066 PMCID: PMC10547078 DOI: 10.7759/cureus.44548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/21/2023] [Indexed: 10/06/2023] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) arises due to a range of pathological abnormalities, necessitating a combination therapy to achieve optimal glycemic control. Vildagliptin, an effective and selective DPP-4 inhibitor, and pioglitazone, an insulin sensitizer, offer distinct mechanisms of action. Hence, the integration of these medications represents a logical and justified therapeutic strategy Objective To compare the efficacy, safety, and tolerability of vildagliptin and pioglitazone 50 mg/15 mg fixed-dose combination (FDC) tablets with individual monotherapy vildagliptin 50 mg and pioglitazone 15 mg tablets in Indian T2DM patients who were inadequately controlled on metformin monotherapy. Methods This was a randomized, open-label, comparative, multicenter, phase III study involving 195 T2DM patients with inadequate glycemic control on metformin ≥ 1000 mg/day. Patients were randomly assigned in a 1:1:1 ratio to the test product group (n=65) (vildagliptin 50 mg + pioglitazone 15 mg FDC tablets), reference product group 1 (n=65) (vildagliptin 50 mg tablet), or reference product group 2 (n=65) (pioglitazone 15 mg tablet reference product). The primary endpoint was the mean change in HbA1c levels from baseline to end of the study visit (12 weeks (84 days ±2)). The secondary endpoints were the mean change in fasting plasma glucose (FPG) and 2-hr postprandial plasma glucose (2-hr PPG) levels. Safety parameters were assessed till the end of the study. Results A total of 178 patients completed the study. At 12 weeks, the mean HbA1c level in the test group reduced to 6.85 ± 1.27%, in the reference product 1 group to 7.56 ± 1.72%, and in the reference product 2 groups to 7.37 ± 1.59%. The mean change in Hb1Ac from baseline in the test group was statistically significant compared to the reference groups (p=0.037). Similarly, the mean changes in the FPG and 2hr-PPG with the test product were statistically significant compared to reference products (p=0.041). The adverse events were comparable across all the treatment groups. Conclusion In Indian T2DM patients inadequately controlled on a daily maximum dose of metformin, treatment with vildagliptin and pioglitazone FDC showed better glycemic control than either vildagliptin or pioglitazone along with a good tolerability profile.
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Affiliation(s)
- Suhas Erande
- Diabetes and Endocrinology, Akshay Hospital & Diabetic Speciality Centre, Pune, IND
| | - Jotideb Mukhopadhyay
- General Medicine, Institute of Post Graduate Medical Education & Research, Kolkata, IND
| | | | | | - Ashish Birla
- Scientific Services, USV Private Limited, Mumbai, IND
| | - Chetan Doshi
- Research and Development (R&D), USV Private Limited, Mumbai, IND
| | | | - Sridhar S B
- Clinical Research, USV Private Limited, Mumbai, IND
| | - Neeraj Kumar
- Scientific Services, USV Private Limited, Mumbai, IND
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13
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Sako S, Takeshita Y, Takayama H, Goto H, Nakano Y, Ando H, Tsujiguchi H, Yamashita T, Arai K, Kaneko S, Nakamura H, Harada K, Honda M, Takamura T. Trajectories of Liver Fibrosis and Gene Expression Profiles in Nonalcoholic Fatty Liver Disease Associated With Diabetes. Diabetes 2023; 72:1297-1306. [PMID: 37343270 DOI: 10.2337/db22-0933] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 06/04/2023] [Indexed: 06/23/2023]
Abstract
Understanding the mechanisms linking steatosis to fibrosis is needed to establish a promising therapy against nonalcoholic fatty liver disease (NAFLD). The aim of this study was to clarify clinical features and hepatic gene expression signatures that predict and contribute to liver fibrosis development during the long-term real-world histological course of NAFLD in subjects with and without diabetes. A pathologist scored 342 serial liver biopsy samples from 118 subjects clinically diagnosed with NAFLD during a 3.8-year (SD 3.45 years, maximum 15 years) course of clinical treatment. At the initial biopsy, 26 subjects had simple fatty liver, and 92 had nonalcoholic steatohepatitis (NASH). In the trend analysis, the fibrosis-4 index (P < 0.001) and its components at baseline predicted the future fibrosis progression. In the generalized linear mixed model, an increase in HbA1c, but not BMI, was significantly associated with fibrosis progression (standardized coefficient 0.17 [95% CI 0.009-0.326]; P = 0.038) for subjects with NAFLD and diabetes. In gene set enrichment analyses, the pathways involved in zone 3 hepatocytes, central liver sinusoidal endothelial cells (LSECs), stellate cells, and plasma cells were coordinately altered in association with fibrosis progression and HbA1c elevation. Therefore, in subjects with NAFLD and diabetes, HbA1c elevation was significantly associated with liver fibrosis progression, independent of weight gain, which may be a valuable therapeutic target to prevent the pathological progression of NASH. Gene expression profiles suggest that diabetes-induced hypoxia and oxidative stress injure LSECs in zone 3 hepatocytes, which may mediate inflammation and stellate cell activation, leading to liver fibrosis. ARTICLE HIGHLIGHTS It remains uncertain how diabetes and obesity contribute to histological courses of nonalcoholic fatty liver disease (NAFLD). Clinical features and gene expression signatures that predict or are associated with future liver fibrosis development were assessed in a serial liver biopsy study of subjects with NAFLD. An increase in HbA1c, but not BMI, was associated with liver fibrosis progression in the generalized linear mixed model. Considering hepatic gene set enrichment analyses, diabetes may enhance liver fibrosis via injuring central liver sinusoidal endothelial cells that mediate inflammation and stellate cell activation during NAFLD development.
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Affiliation(s)
- Saori Sako
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Yumie Takeshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hiroaki Takayama
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hisanori Goto
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Yujiro Nakano
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hitoshi Ando
- Department of Cellular and Molecular Function Analysis, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hiromasa Tsujiguchi
- Department of Environmental and Preventive Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hiroyuki Nakamura
- Department of Environmental and Preventive Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
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14
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Nomoto H, Takahashi Y, Takano Y, Yokoyama H, Tsuchida K, Nagai S, Miya A, Kameda H, Cho KY, Nakamura A, Atsumi T. Effect of Switching to Once-Weekly Semaglutide on Non-Alcoholic Fatty Liver Disease: The SWITCH-SEMA 1 Subanalysis. Pharmaceutics 2023; 15:2163. [PMID: 37631377 PMCID: PMC10459529 DOI: 10.3390/pharmaceutics15082163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/17/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an important common comorbidity in individuals with type 2 diabetes (T2DM). Although some glucagon-like peptide-1 receptor agonists (GLP-1RAs) have beneficial effects on NAFLD, the efficacy of once-weekly semaglutide has not been established. This was a subanalysis of the SWITCH-SEMA 1 study, a multicenter, prospective, randomized, parallel-group trial comparing switching from liraglutide or dulaglutide to once-weekly semaglutide in subjects with T2DM (SWITCH) versus continuing current GLP-1RAs (Continue) for 24 weeks. This subanalysis consisted of participants who were suspected to have NAFLD [fatty liver index (FLI) ≥ 30]. In total, 58 participants met the criteria of this subanalysis. There were no statistical differences in baseline characteristics between the SWITCH (n = 31) and Continue groups (n = 27). FLI significantly improved during treatment in the SWITCH group (68.6 to 62.7) but not in the Continue group (71.1 to 72.3) (p < 0.01). The improvement of FLI in the SWITCH group was greater in switching from dulaglutide to semaglutide and significantly correlated with older age (p = 0.016) and lower baseline FLI (p < 0.01). The multiple linear regression analysis revealed that the switch from dulaglutide was associated with an improvement in FLI (p = 0.041). Switching from conventional GLP-1RAs to once-weekly semaglutide might be beneficial for individuals with NAFLD complicated with T2DM.
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Affiliation(s)
- Hiroshi Nomoto
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Hokkaido, Japan
| | - Yuka Takahashi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Hokkaido, Japan
| | - Yoshinari Takano
- Department of Diabetes and Endocrinology, Tonan Hospital, Sapporo 060-0004, Hokkaido, Japan
| | | | | | - So Nagai
- Division of Diabetes and Endocrinology, Department of Medicine, Sapporo Medical Centre, NTT East Corporation, Sapporo 060-0062, Hokkaido, Japan
| | - Aika Miya
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Hokkaido, Japan
| | - Hiraku Kameda
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Hokkaido, Japan
| | - Kyu Yong Cho
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Hokkaido, Japan
| | - Akinobu Nakamura
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Hokkaido, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Hokkaido, Japan
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15
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García-Compeán D, Kumar R, Cueto-Aguilera ÁND, Maldonado-Garza HJ, Villarreal-Pérez JZ. Body weight loss and glycemic control on the outcomes of patients with NAFLD. The role of new antidiabetic agents. Ann Hepatol 2023; 28:100751. [PMID: 36002119 DOI: 10.1016/j.aohep.2022.100751] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/09/2022] [Accepted: 08/12/2022] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide affecting a third of adults and 12% of children in Western countries. In around 50-60%% of cases, NAFLD and type 2 diabetes mellitus (T2DM) coexist and act synergistically to increase the risk of adverse hepatic and extra-hepatic outcomes. T2DM is a strong risk factor for rapid progression of NAFLD to nonalcoholic steatohepatitis (NASH), cirrhosis or hepatocellular carcinoma (HCC), which have become frequent indications of liver transplantation. The pathophysiology of NAFLD is complex and its relationship with T2DM is bidirectional, where lipotoxicity and insulin resistance (IR), act as the strongest pillars. To date, no pharmacological treatment has been approved for NAFLD. However, there is an intense research with numerous drugs focused on reversing inflammation and liver fibrosis through modulation of molecular targets without good results. It has been known for some time that weight reduction >10% is associated to histological improvement of NAFLD. Recently, glycemic control has been shown to induce similar results. Diet and physical exercise for weight reduction have limitations, so alternative methods (pharmacologic, endoscopic or surgical) may be required. Currently, new antidiabetic drugs inducing weight loss, have been recently approved for the treatment of obesity. Nevertheless, their therapeutic effects on NAFLD have not been extensively studied. We will review here, recently published data on the effects of weight loss and glycemic control on the histological and metabolic parameters of NAFLD and recent published data on therapeutic studies of NAFLD with new antidiabetic drugs.
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Affiliation(s)
- Diego García-Compeán
- Gastroenterology Service and Internal Medicine Department, Faculty of Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey 64700, Nuevo León, Mexico.
| | - Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Ángel Noe Del Cueto-Aguilera
- Gastroenterology Service and Internal Medicine Department, Faculty of Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey 64700, Nuevo León, Mexico
| | - Héctor Jesús Maldonado-Garza
- Gastroenterology Service and Internal Medicine Department, Faculty of Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey 64700, Nuevo León, Mexico
| | - Jesús Zacarías Villarreal-Pérez
- Endocrinology Service and Internal Medicine Department, University Hospital. Autonomous University of Nuevo León, México. Madero y Gonzalitos Colonia Mitras CP 64700 Monterrey Nuevo León, México., Monterrey 64700, Mexico
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16
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Le P, Payne JY, Zhang L, Deshpande A, Rothberg MB, Alkhouri N, Herman W, Hernandez AV, Schleicher M, Ye W, Dasarathy S. Disease State Transition Probabilities Across the Spectrum of NAFLD: A Systematic Review and Meta-Analysis of Paired Biopsy or Imaging Studies. Clin Gastroenterol Hepatol 2023; 21:1154-1168. [PMID: 35933075 PMCID: PMC9898457 DOI: 10.1016/j.cgh.2022.07.033] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 07/21/2022] [Accepted: 07/21/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS We conducted a meta-analysis to summarize the rates of progression to and regression of nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and fibrosis in adults with nonalcoholic fatty liver disease (NAFLD). METHODS We searched PubMed/Medline and 4 other databases from 1985 through 2020. We included observational studies and randomized controlled trials in any language that used liver biopsy or imaging to diagnose NAFLD in adults with a follow-up period ≥48 weeks. Rates were calculated as incident cases per 100 person-years and pooled using the random-effects Poisson distribution model. Heterogeneity was assessed using the I2 statistic. RESULTS We screened 9744 articles and included 54 studies involving 26,738 patients. Among observational studies, 20% of healthy adults developed NAFL (incidence rate, 4.8/100 person-years) while 21% of people with fatty liver had resolution of NAFL (incidence rate, 2.4/100 person-years) after a median of approximately 4.5 years. In addition, 31% of patients developed NASH after 4.7 years (incidence rate, 7.4/100 person-years), whereas in 29% of those with NASH, resolution occurred after a median of 3.5 years (incidence rate, 5.1/100 person-years). Time to progress by 1 fibrosis stage was 9.9, 10.3, 13.3, and 22.2 years for F0, F1, F2, and F3, respectively. Time to regress by 1 stage was 21.3, 12.5, 20.4, and 40.0 years for F4, F3, F2, and F1, respectively. Rates estimated from randomized controlled trials were higher than those from observational studies. CONCLUSIONS In our meta-analysis, progression to NASH was more common than regression from NASH. Rates of fibrosis progression were similar across baseline stage, but patients with advanced fibrosis were more likely to regress than those with mild fibrosis.
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Affiliation(s)
- Phuc Le
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio.
| | - Julia Yang Payne
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio; Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Lu Zhang
- Department of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Abhishek Deshpande
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio
| | - Michael B Rothberg
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio
| | - Naim Alkhouri
- Department of Hepatology, Arizona Liver Health, Tucson, Arizona
| | - William Herman
- Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan
| | - Adrian V Hernandez
- Health Outcomes, Policy, and Evidence Synthesis Group, University of Connecticut School of Pharmacy, Storrs, Connecticut; Unidad de Revisiones Sistemáticas y Meta-Análisis, Universidad San Ignacio de Loyola, Lima, Peru
| | - Mary Schleicher
- The Floyd D. Loop Alumni Library, Cleveland Clinic, Cleveland, Ohio
| | - Wen Ye
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan
| | - Srinivasan Dasarathy
- Department of Inflammation and Immunity, Lerner Research Institute, Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
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17
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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: 1047] [Impact Index Per Article: 523.5] [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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18
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Wang Z, Liu N, Guo C. Comment on "Type 2 diabetes complications are associated with liver fibrosis independent of hemoglobin A1c". Ann Hepatol 2023; 28:101113. [PMID: 37121470 DOI: 10.1016/j.aohep.2023.101113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 04/24/2023] [Indexed: 05/02/2023]
Affiliation(s)
- Zhenjing Wang
- Henan Provincial Chest Hospital, Zhengzhou University, Zhengzhou, Henan, China
| | - Nai Liu
- Henan Provincial Chest Hospital, Zhengzhou University, Zhengzhou, Henan, China
| | - Caixia Guo
- Henan Provincial Chest Hospital, Zhengzhou University, Zhengzhou, Henan, China.
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19
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Cazac GD, Lăcătușu CM, Ștefănescu G, Mihai C, Grigorescu ED, Onofriescu A, Mihai BM. Glucagon-like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease-Current Background, Hopes, and Perspectives. Metabolites 2023; 13:metabo13050581. [PMID: 37233622 DOI: 10.3390/metabo13050581] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/27/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease worldwide, reaching one of the highest prevalences in patients with type 2 diabetes mellitus (T2DM). For now, no specific pharmacologic therapies are approved to prevent or treat NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are currently evaluated as potential candidates for NAFLD treatment in patients with T2DM. Some representatives of this class of antihyperglycemic agents emerged as potentially beneficial in patients with NAFLD after several research studies suggested they reduce hepatic steatosis, ameliorate lesions of nonalcoholic steatohepatitis (NASH), or delay the progression of fibrosis in this population. The aim of this review is to summarize the body of evidence supporting the effectiveness of GLP-1RA therapy in the management of T2DM complicated with NAFLD, describing the studies that evaluated the effects of these glucose-lowering agents in fatty liver disease and fibrosis, their possible mechanistic justification, current evidence-based recommendations, and the next steps to be developed in the field of pharmacological innovation.
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Affiliation(s)
- Georgiana-Diana Cazac
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Cristina-Mihaela Lăcătușu
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Gabriela Ștefănescu
- Unit of Medical Semiology and Gastroenterology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Cătălina Mihai
- Unit of Medical Semiology and Gastroenterology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Elena-Daniela Grigorescu
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Alina Onofriescu
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Bogdan-Mircea Mihai
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
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Mantovani A, Taverna A, Cappelli D, Beatrice G, Csermely A, Sani E, Byrne CD, Targher G. Long-Term Adverse Effect of Liver Stiffness on Glycaemic Control in Type 2 Diabetic Patients with Nonalcoholic Fatty Liver Disease: A Pilot Study. Int J Mol Sci 2022; 23:ijms232012481. [PMID: 36293337 PMCID: PMC9604384 DOI: 10.3390/ijms232012481] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/27/2022] [Accepted: 10/11/2022] [Indexed: 12/18/2022] Open
Abstract
Currently, there are limited data regarding the long-term effect of liver stiffness on glycaemic control in patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). We prospectively followed an outpatient sample of 61 consecutive postmenopausal women with T2DM and NAFLD who had baseline data on liver ultrasonography and Fibroscan®-assessed liver stiffness measurement (LSM) in 2017 and who underwent follow-up in 2022. Haemoglobin A1c (HbA1c) was measured both at baseline and follow-up. At baseline, 52 patients had NAFLD (hepatic steatosis) alone, and 9 had NAFLD with coexisting clinically significant fibrosis (defined as LSM ≥ 7 kPa on Fibroscan®). At follow-up, 16 patients had a worsening of glycaemic control (arbitrarily defined as HbA1c increase ≥ 0.5% from baseline). The prevalence of NAFLD and coexisting clinically significant fibrosis at baseline was at least three times greater among patients who developed worse glycaemic control at follow-up, compared with those who did not (31.3% vs. 8.9%; p = 0.030). In logistic regression analysis, the presence of NAFLD and clinically significant fibrosis was associated with an approximately 4.5-fold increased likelihood of developing worse glycaemic control at follow-up (odds ratio 4.66, 95% confidence interval 1.07–20.3; p = 0.041), even after adjustment for baseline confounding factors, such as age, body mass index, haemoglobin A1c (or HOMA-estimated insulin resistance) and use of some glucose-lowering agents that may positively affect NAFLD and liver fibrosis. In conclusion, our results suggest that the presence of Fibroscan®-assessed significant fibrosis was associated with a higher risk of developing worse glycaemic control in postmenopausal women with T2DM and NAFLD.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Antonio Taverna
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Davide Cappelli
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Giorgia Beatrice
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Alessandro Csermely
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Elena Sani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Christopher D. Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK
- Southampton National Institute for Health and Care Research Biomedical Research Centre, and University Hospital Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy
- Correspondence: ; Tel.: +39-045-812-3748
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Takeshita Y, Honda M, Harada K, Kita Y, Takata N, Tsujiguchi H, Tanaka T, Goto H, Nakano Y, Iida N, Arai K, Yamashita T, Mizukoshi E, Nakamura H, Kaneko S, Takamura T. Comparison of Tofogliflozin and Glimepiride Effects on Nonalcoholic Fatty Liver Disease in Participants With Type 2 Diabetes: A Randomized, 48-Week, Open-Label, Active-Controlled Trial. Diabetes Care 2022; 45:2064-2075. [PMID: 35894933 PMCID: PMC9472500 DOI: 10.2337/dc21-2049] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 05/21/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is a liver phenotype of type 2 diabetes and obesity. Currently, the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas in liver pathology and hepatic gene expression profiles for type 2 diabetes with NAFLD are unknown. RESEARCH DESIGN AND METHODS We conducted a 48 week, randomized, open-label, parallel-group trial involving participants with biopsy-confirmed NAFLD. A total of 40 participants were randomly assigned to receive once daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary outcome was the percentage of participants with at least an improvement in all individual scores for histological categories of steatosis, hepatocellular ballooning, lobular inflammation, and fibrosis by at least 1 point. The secondary end points were the changes in liver enzymes, metabolic markers, and hepatic gene expression profiles. RESULTS Fibrosis scores improved in the tofogliflozin group (60%, P = 0.001), whereas the change from baseline did not differ significantly between the groups (P = 0.172). The histological variables of steatosis (65%, P = 0.001), hepatocellular ballooning (55%, P = 0.002), and lobular inflammation (50%, P = 0.003) were improved in the tofogliflozin group, whereas only hepatocellular ballooning was improved in the glimepiride group (25%, P = 0.025). Hepatic gene expression profiling revealed histology-associated signatures in energy metabolism, inflammation, and fibrosis that were reversed with tofogliflozin. CONCLUSIONS Tofogliflozin and, to a lesser degree, glimepiride led to liver histological and metabolic improvement in participants with type 2 diabetes and NAFLD, with no significant difference between the agents. The hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis was well correlated with liver histological changes and rescued by tofogliflozin. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors.
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Affiliation(s)
- Yumie Takeshita
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yuki Kita
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Noboru Takata
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Hiromasa Tsujiguchi
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takeo Tanaka
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hisanori Goto
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yujiro Nakano
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Noriho Iida
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Hiroyuki Nakamura
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
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Rinella M, Cryer DR, Articolo A, Fisher T, Schneider J, Nadolsky K. Nonalcoholic steatohepatitis medical patient journey from the perspective of hepatologists, gastroenterologists and patients: a cross-sectional survey. BMC Gastroenterol 2022; 22:335. [PMID: 35811319 PMCID: PMC9272554 DOI: 10.1186/s12876-022-02410-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 06/22/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Nonalcoholic steatohepatitis (NASH), the inflammatory subtype of nonalcoholic fatty liver disease, is underdiagnosed and expected to become the leading indication for liver transplant in the United States. We aimed to understand the medical journey of patients with NASH and role of hepatologists/gastroenterologists in diagnosing and treating patients with NASH.
Methods
A United States population-based cross-sectional online survey was completed by 226 healthcare professionals (HCPs) who treat patients with NASH and 152 patients with NASH; this study focuses on the patient and 75 hepatologist/gastroenterologist HCP respondents. Tests of differences (chi square, t-tests) between respondent types were performed using SPSS.
Results
Most patients reported receiving their diagnosis of NASH from a hepatologist (37%) or gastroenterologist (26%). Hepatologists/gastroenterologists were more likely than other HCPs to use FibroScan (transient elastography) to diagnose NASH and were more likely to distinguish between NASH with or without fibrosis. Hepatologists/gastroenterologists (68%) and patients (52%) agree that hepatologists/gastroenterologists are the primary coordinators of NASH care. The majority of hepatologists/gastroenterologists (85%) are aware of American Association for the Study of Liver Diseases (AASLD) clinical practice guidance, and 86% of those aware consider them when diagnosing patients with NASH. Hepatologists/gastroenterologists most frequently recommended exercise (86%), diet (70%), and supplements (58%) for ongoing management of NASH. Pharmaceutical medications for comorbidities were prescribed by a minority of hepatologists/gastroenterologists for their patients with NASH. Hepatologists/gastroenterologists cite difficulty (67%) or unwillingness (64%) to adhere to lifestyle changes as primary reasons patients with NASH discontinue NASH treatment.
Conclusions
Hepatologists/gastroenterologists are considered the coordinators of NASH care. While recognizing that patient adherence to lifestyle changes is the basis for successful treatment, important barriers limit successful implementation.
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Progression of Nonalcoholic Fatty Liver Disease-Associated Fibrosis in a Large Cohort of Patients with Type 2 Diabetes. Dig Dis Sci 2022; 67:1379-1388. [PMID: 33779880 DOI: 10.1007/s10620-021-06955-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 03/12/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) can progress to advanced fibrosis, especially in patients with type 2 diabetes. Small studies have shown that fibrosis can also regress. AIM We aimed to provide large-scale data on progression and regression of fibrosis in diabetics with NAFLD. METHODS Adult diabetic patients with the diagnosis of NAFLD based on ICD-9 codes were identified. We used scores from noninvasive tests to identify patients with advanced fibrosis, calculated at first assessment and last follow-up visit. Cutoff values for advanced fibrosis were AST: ALT ratio > 1.4, AST to platelet ratio index > 1.5, FIB-4 score > 2.67, and NAFLD fibrosis score > 0.676. RESULTS Our cohort included 50,695 diabetics with NAFLD (55.3% female; 71% Caucasian; mean age, 51.2 ± 11.6 y). During median follow-up of 84.4 months, 25.8% transitioned from no advanced fibrosis to advanced fibrosis (progression), 6.4% transitioned from advanced fibrosis to no advanced fibrosis (regression), and the rest remained stable. Factors associated with transition to advanced fibrosis were female sex, older age at first evaluation, African-American race, obesity, chronic kidney disease, or coronary artery disease. Use of insulin increased the risk of progression to advanced fibrosis (odds ratio,1.36; p < .001), whereas use of oral hypoglycemic agents, angiotensin 2 receptor blockers, and fibrates was associated with reduced risk (odds ratios, 0.92, 0.94 and 0.90, respectively; all p < .05). CONCLUSIONS In a large cohort of patients with type 2 diabetes and NAFLD, more than a quarter progressed to advanced fibrosis. These findings indicate the need for early detection and staging of NAFLD in diabetics.
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Mirarchi L, Amodeo S, Citarrella R, Licata A, Soresi M, Giannitrapani L. SGLT2 Inhibitors as the Most Promising Influencers on the Outcome of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:3668. [PMID: 35409028 PMCID: PMC8998221 DOI: 10.3390/ijms23073668] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/20/2022] [Accepted: 03/22/2022] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease in the Western world, is a common hepatic manifestation of metabolic syndrome (MetS). A specific cure has not yet been identified, and its treatment is currently based on risk factor therapy. Given that the initial accumulation of triglycerides in the liver parenchyma, in the presence of inflammatory processes, mitochondrial dysfunction, lipotoxicity, glucotoxicity, and oxidative stress, can evolve into non-alcoholic steatohepatitis (NASH). The main goal is to identify the factors contributing to this evolution because, once established, untreated NASH can progress through fibrosis to cirrhosis and, ultimately, be complicated by hepatocellular carcinoma (HCC). Several drugs have been tested in clinical trials for use as specific therapy for NAFLD; most of them are molecules used to cure type 2 diabetes mellitus (T2DM), which is one of the main risk factors for NAFLD. Among the most studied is pioglitazone, either alone or in combination with vitamin E, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors. Actually, the most promising category seems to be sodium-glucose cotransporter (SGLT2) inhibitors. Their action is carried out by inhibiting glucose reabsorption in the proximal renal tubule, leading to its increased excretion in urine and decreased levels in plasma. Experimental studies in animal models have suggested that SGLT2 inhibitors may have beneficial modulatory effects on NAFLD/NASH, and several trials in patients have proven their beneficial effects on liver enzymes, BMI, blood lipids, blood glucose, and insulin resistance in NAFLD patients, thus creating strong expectations for their possible use in preventing the evolution of liver damage in these patients. We will review the main pathogenetic mechanisms, diagnostic modalities, and recent therapies of NAFLD, with particular attention to the use of SGLT2 inhibitors.
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Affiliation(s)
- Luigi Mirarchi
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.M.); (S.A.); (R.C.); (A.L.); (M.S.)
| | - Simona Amodeo
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.M.); (S.A.); (R.C.); (A.L.); (M.S.)
| | - Roberto Citarrella
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.M.); (S.A.); (R.C.); (A.L.); (M.S.)
| | - Anna Licata
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.M.); (S.A.); (R.C.); (A.L.); (M.S.)
| | - Maurizio Soresi
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.M.); (S.A.); (R.C.); (A.L.); (M.S.)
| | - Lydia Giannitrapani
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.M.); (S.A.); (R.C.); (A.L.); (M.S.)
- Institute for Biomedical Research and Innovation (IRIB), National Research Council, 90146 Palermo, Italy
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25
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García-Compeán D, Orsi E, Nishida T, Kumar R. Glycemic control, the unconsidered outcome in the treatment of nonalcoholic fatty liver disease. Ann Hepatol 2022; 27:100648. [PMID: 34871785 DOI: 10.1016/j.aohep.2021.100648] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 10/25/2021] [Indexed: 02/07/2023]
Affiliation(s)
- Diego García-Compeán
- Department of Gastroenterology. University Hospital. Autonomous University of Nuevo León. Madero y Gonzalitos Colonia Mitras CP 64700 Monterrey, N.L. México.
| | - Emanuela Orsi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Tsutomu Nishida
- Department of Gastroenterology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka 560-8565 Japan
| | - Ramesh Kumar
- Department of Gastroenterology, OPD Block, All India Institute of Medical Sciences, Phulwari Sharif, Patna -801507, India
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Alexopoulos A, Crowley MJ, Wang Y, Moylan CA, Guy CD, Henao R, Piercy DL, Seymour KA, Sudan R, Portenier DD, Diehl AM, Coviello AD, Abdelmalek MF. Glycemic Control Predicts Severity of Hepatocyte Ballooning and Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease. Hepatology 2021; 74:1220-1233. [PMID: 33724511 PMCID: PMC8518519 DOI: 10.1002/hep.31806] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 02/09/2021] [Accepted: 03/01/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Whether glycemic control, as opposed to diabetes status, is associated with the severity of NAFLD is open for study. We aimed to evaluate whether degree of glycemic control in the years preceding liver biopsy predicts the histological severity of NASH. APPROACH AND RESULTS Using the Duke NAFLD Clinical Database, we examined patients with biopsy-proven NAFLD/NASH (n = 713) and the association of liver injury with glycemic control as measured by hemoglobin A1c (HbA1c). The study cohort was predominantly female (59%) and White (84%) with median (interquartile range) age of 50 (42, 58) years; 49% had diabetes (n = 348). Generalized linear regression models adjusted for age, sex, race, diabetes, body mass index, and hyperlipidemia were used to assess the association between mean HbA1c over the year preceding liver biopsy and severity of histological features of NAFLD/NASH. Histological features were graded and staged according to the NASH Clinical Research Network system. Group-based trajectory analysis was used to examine patients with at least three HbA1c (n = 298) measures over 5 years preceding clinically indicated liver biopsy. Higher mean HbA1c was associated with higher grade of steatosis and ballooned hepatocytes, but not lobular inflammation. Every 1% increase in mean HbA1c was associated with 15% higher odds of increased fibrosis stage (OR, 1.15; 95% CI, 1.01, 1.31). As compared with good glycemic control, moderate control was significantly associated with increased severity of ballooned hepatocytes (OR, 1.74; 95% CI, 1.01, 3.01; P = 0.048) and hepatic fibrosis (HF; OR, 4.59; 95% CI, 2.33, 9.06; P < 0.01). CONCLUSIONS Glycemic control predicts severity of ballooned hepatocytes and HF in NAFLD/NASH, and thus optimizing glycemic control may be a means of modifying risk of NASH-related fibrosis progression.
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Affiliation(s)
- Anastasia‐Stefania Alexopoulos
- Division of EndocrinologyDepartment of MedicineDuke UniversityDurham,NC
- Durham Veterans Affairs Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT)DurhamNC
| | - Matthew J. Crowley
- Division of EndocrinologyDepartment of MedicineDuke UniversityDurham,NC
- Durham Veterans Affairs Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT)DurhamNC
| | - Ying Wang
- Division of GastroenterologyDepartment of MedicineDuke UniversityDurham,NC
| | - Cynthia A. Moylan
- Division of GastroenterologyDepartment of MedicineDuke UniversityDurham,NC
- Division of GastroenterologyDurham Veterans Affairs Medical CenterDurhamNC
| | | | - Ricardo Henao
- Division of Biostatistics and BioinformaticsDuke UniversityDurhamNC
| | - Dawn L. Piercy
- Division of GastroenterologyDepartment of MedicineDuke UniversityDurham,NC
| | - Keri A. Seymour
- Division of Metabolic SurgeryDepartment of SurgeryDuke UniversityDurhamNC
| | - Ranjan Sudan
- Division of Metabolic SurgeryDepartment of SurgeryDuke UniversityDurhamNC
| | - Dana D. Portenier
- Division of Metabolic SurgeryDepartment of SurgeryDuke UniversityDurhamNC
| | - Anna Mae Diehl
- Division of GastroenterologyDepartment of MedicineDuke UniversityDurham,NC
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Tuleta I, Frangogiannis NG. Fibrosis of the diabetic heart: Clinical significance, molecular mechanisms, and therapeutic opportunities. Adv Drug Deliv Rev 2021; 176:113904. [PMID: 34331987 PMCID: PMC8444077 DOI: 10.1016/j.addr.2021.113904] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/19/2021] [Accepted: 07/24/2021] [Indexed: 01/02/2023]
Abstract
In patients with diabetes, myocardial fibrosis may contribute to the pathogenesis of heart failure and arrhythmogenesis, increasing ventricular stiffness and delaying conduction. Diabetic myocardial fibrosis involves effects of hyperglycemia, lipotoxicity and insulin resistance on cardiac fibroblasts, directly resulting in increased matrix secretion, and activation of paracrine signaling in cardiomyocytes, immune and vascular cells, that release fibroblast-activating mediators. Neurohumoral pathways, cytokines, growth factors, oxidative stress, advanced glycation end-products (AGEs), and matricellular proteins have been implicated in diabetic fibrosis; however, the molecular links between the metabolic perturbations and activation of a fibrogenic program remain poorly understood. Although existing therapies using glucose- and lipid-lowering agents and neurohumoral inhibition may act in part by attenuating myocardial collagen deposition, specific therapies targeting the fibrotic response are lacking. This review manuscript discusses the clinical significance, molecular mechanisms and cell biology of diabetic cardiac fibrosis and proposes therapeutic targets that may attenuate the fibrotic response, preventing heart failure progression.
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Affiliation(s)
- Izabela Tuleta
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY, USA
| | - Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY, USA.
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Differences among Three Skeletal Muscle Mass Indices in Predicting Non-Alcoholic Fatty Liver Disease: Korean Nationwide Population-Based Study. Life (Basel) 2021; 11:life11080751. [PMID: 34440495 PMCID: PMC8401633 DOI: 10.3390/life11080751] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/16/2021] [Accepted: 07/25/2021] [Indexed: 02/06/2023] Open
Abstract
Recent studies have investigated the relationship between sarcopenia and non-alcoholic fatty liver disease (NAFLD); however, there is no unified definition of sarcopenia. Thus, we aimed to investigate the differences among three skeletal muscle mass indices (SMI) in predicting NAFLD. This study included 8133 adults from the 2008–2010 Korea National Health and Nutrition Survey. SMI was calculated as appendicular skeletal muscle mass divided by height-square (hSMI), weight (wSMI), or body mass index (bSMI). The presence of NAFLD was defined by using the NAFLD-liver fat score. On the receiver operating characteristic curve analysis, the predictive power of wSMI for NAFLD was significantly higher than those of hSMI and bSMI in men (wSMI vs. hSMI, p = 0.003; wSMI vs. bSMI, p < 0.001). In women, the predictive power of hSMI was only significantly higher than that of bSMI (p = 0.023), and other predictive powers were not significantly different. In addition, hSMI was correlated with insulin resistance and NAFLD-liver fat score in the opposite direction to wSMI and bSMI in both men and women. Among the three definitions of SMI, wSMI showed the highest diagnostic performance for predicting NAFLD in men, suggesting the importance of defining sarcopenia for its association with specific diseases.
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Tuleta I, Frangogiannis NG. Diabetic fibrosis. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166044. [PMID: 33378699 PMCID: PMC7867637 DOI: 10.1016/j.bbadis.2020.166044] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/25/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022]
Abstract
Diabetes-associated morbidity and mortality is predominantly due to complications of the disease that may cause debilitating conditions, such as heart and renal failure, hepatic insufficiency, retinopathy or peripheral neuropathy. Fibrosis, the excessive and inappropriate deposition of extracellular matrix in various tissues, is commonly found in patients with advanced type 1 or type 2 diabetes, and may contribute to organ dysfunction. Hyperglycemia, lipotoxic injury and insulin resistance activate a fibrotic response, not only through direct stimulation of matrix synthesis by fibroblasts, but also by promoting a fibrogenic phenotype in immune and vascular cells, and possibly also by triggering epithelial and endothelial cell conversion to a fibroblast-like phenotype. High glucose stimulates several fibrogenic pathways, triggering reactive oxygen species generation, stimulating neurohumoral responses, activating growth factor cascades (such as TGF-β/Smad3 and PDGFs), inducing pro-inflammatory cytokines and chemokines, generating advanced glycation end-products (AGEs) and stimulating the AGE-RAGE axis, and upregulating fibrogenic matricellular proteins. Although diabetes-activated fibrogenic signaling has common characteristics in various tissues, some organs, such as the heart, kidney and liver develop more pronounced and clinically significant fibrosis. This review manuscript summarizes current knowledge on the cellular and molecular pathways involved in diabetic fibrosis, discussing the fundamental links between metabolic perturbations and fibrogenic activation, the basis for organ-specific differences, and the promises and challenges of anti-fibrotic therapies for diabetic patients.
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Affiliation(s)
- Izabela Tuleta
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, USA
| | - Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, USA.
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Seino H. Efficacy and Safety of Luseogliflozin in Patients with Type 2 Diabetes Complicated by Hepatic Dysfunction: A Single-Site, Single-Arm, Open-Label, Exploratory Trial. Diabetes Ther 2021; 12:863-877. [PMID: 33594581 PMCID: PMC7947107 DOI: 10.1007/s13300-021-01014-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 01/27/2021] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Improvements in glycemic control and hepatic function are clinically important goals in the treatment of patients with type 2 diabetes mellitus (T2DM) complicated by hepatic dysfunction. The favorable effects of the sodium-glucose co-transporter inhibitor luseogliflozin on hepatic dysfunction were anticipated for humans. Nevertheless, few clinical studies have confirmed its real-world efficacy on hepatic dysfunction. This trial assessed the efficacy and safety of luseogliflozin in patients with T2DM complicated by hepatic dysfunction. METHODS This prospective, single-site, single-arm, open-label, exploratory trial included 55 subjects with T2DM complicated by hepatic dysfunction. Subjects were administered luseogliflozin and observed for 52 weeks. The primary endpoints were the change in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), and hemoglobin A1c (HbA1c) from baseline to week 52. The secondary endpoints included body weight, body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose (FPG), homeostatic model assessment beta (HOMA-β), homeostatic model assessment of insulin resistance (HOMA-IR), ferritin, Mac-2 binding protein (M2-BP), fatty liver index (FLI), fibrosis-4 (FIB-4) index, type IV collagen 7S domain, nonalcoholic fatty liver disease (NAFLD) fibrosis score, high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6). RESULTS AST, ALT, γ-GTP, and HbA1c significantly decreased from baseline to week 52. Body weight, BMI, waist circumference, and FPG also significantly decreased. HOMA-IR significantly decreased but HOMA-β was unchanged. FLI, ferritin, M2-BP, and NAFLD fibrosis scores significantly decreased whereas the FIB-4 index and type IV collagen 7S domain did not significantly change. The hs-CRP and IL-6 levels did not significantly change. CONCLUSION Luseogliflozin administration in patients with T2DM complicated by hepatic dysfunction was well tolerated, did not worsen the hepatic condition, and might even be beneficial to improve hepatic function, reduce liver fat, and attenuate liver injury and fibrosis. TRIAL REGISTRATION This study was registered under the University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) (No. UMIN000025808) and the Japan Registry of Clinical Trials (jRCT) (No. jRCTs021180017).
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Affiliation(s)
- Hiroaki Seino
- Seino Internal Medical Clinic, Kaisei, Koriyama, Fukushima, Japan.
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Jensen VS, Fledelius C, Zachodnik C, Damgaard J, Nygaard H, Tornqvist KS, Kirk RK, Viuff BM, Wulff EM, Lykkesfeldt J, Hvid H. Insulin treatment improves liver histopathology and decreases expression of inflammatory and fibrogenic genes in a hyperglycemic, dyslipidemic hamster model of NAFLD. J Transl Med 2021; 19:80. [PMID: 33596938 PMCID: PMC7890970 DOI: 10.1186/s12967-021-02729-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/29/2021] [Indexed: 11/24/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent comorbidities in patients with Type 2 diabetes. While many of these patients eventually will need treatment with insulin, little is known about the effects of insulin treatment on histopathological parameters and hepatic gene expression in diabetic patients with co-existing NAFLD and NASH. To investigate this further, we evaluated the effects of insulin treatment in NASH diet-fed hamsters with streptozotocin (STZ) -induced hyperglycemia. Methods Forty male Syrian hamsters were randomized into four groups (n = 10/group) receiving either a NASH-inducing (high fat, fructose and cholesterol) or control diet (CTRL) for four weeks, after which they were treated with STZ or sham-injected and from week five treated with either vehicle (CTRL, NASH, NASH-STZ) or human insulin (NASH-STZ-HI) for four weeks by continuous s.c. infusion via osmotic minipumps. Results NASH-STZ hamsters displayed pronounced hyperglycemia, dyslipidemia and more severe liver pathology compared to both CTRL and NASH groups. Insulin treatment attenuated dyslipidemia in NASH-STZ-HI hamsters and liver pathology was considerably improved compared to the NASH-STZ group, with prevention/reversal of hepatic steatosis, hepatic inflammation and stellate cell activation. In addition, expression of inflammatory and fibrotic genes was decreased compared to the NASH-STZ group. Conclusions These results suggest that hyperglycemia is important for development of inflammation and profibrotic processes in the liver, and that insulin administration has beneficial effects on liver pathology and expression of genes related to inflammation and fibrosis in a hyperglycemic, dyslipidemic hamster model of NAFLD.
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Affiliation(s)
- Victoria Svop Jensen
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg, Denmark. .,Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark.
| | - Christian Fledelius
- Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | - Christina Zachodnik
- Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | - Jesper Damgaard
- Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | - Helle Nygaard
- Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | | | - Rikke Kaae Kirk
- Pathology & Imaging, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | | | - Erik Max Wulff
- Gubra ApS, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
| | - Jens Lykkesfeldt
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg, Denmark
| | - Henning Hvid
- Pathology & Imaging, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
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Sumida Y, Yoneda M, Tokushige K, Kawanaka M, Fujii H, Yoneda M, Imajo K, Takahashi H, Eguchi Y, Ono M, Nozaki Y, Hyogo H, Koseki M, Yoshida Y, Kawaguchi T, Kamada Y, Okanoue T, Nakajima A, Japan Study Group of NAFLD (JSG-NAFLD). FIB-4 First in the Diagnostic Algorithm of Metabolic-Dysfunction-Associated Fatty Liver Disease in the Era of the Global Metabodemic. Life (Basel) 2021; 11:143. [PMID: 33672864 PMCID: PMC7917687 DOI: 10.3390/life11020143] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/16/2022] Open
Abstract
The prevalence of obesity or metabolic syndrome is increasing worldwide (globally metabodemic). Approximately 25% of the adult general population is suffering from nonalcoholic fatty liver disease (NAFLD), which has become a serious health problem. In 2020, global experts suggested that the nomenclature of NAFLD should be updated to metabolic-dysfunction-associated fatty liver disease (MAFLD). Hepatic fibrosis is the most significant determinant of all cause- and liver -related mortality in MAFLD. The non-invasive test (NIT) is urgently required to evaluate hepatic fibrosis in MAFLD. The fibrosis-4 (FIB-4) index is the first triaging tool for excluding advanced fibrosis because of its accuracy, simplicity, and cheapness, especially for general physicians or endocrinologists, although the FIB-4 index has several drawbacks. Accumulating evidence has suggested that vibration-controlled transient elastography (VCTE) and the enhanced liver fibrosis (ELF) test may become useful as the second step after triaging by the FIB-4 index. The leading cause of mortality in MAFLD is cardiovascular disease (CVD), extrahepatic malignancy, and liver-related diseases. MAFLD often complicates chronic kidney disease (CKD), resulting in increased simultaneous liver kidney transplantation. The FIB-4 index could be a predictor of not only liver-related mortality and incident hepatocellular carcinoma, but also prevalent and incident CKD, CVD, and extrahepatic malignancy. Although NITs as milestones for evaluating treatment efficacy have never been established, the FIB-4 index is expected to reflect histological hepatic fibrosis after treatment in several longitudinal studies. We here review the role of the FIB-4 index in the management of MAFLD.
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Affiliation(s)
- Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan;
| | - Masashi Yoneda
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan;
| | - Katsutoshi Tokushige
- Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan;
| | - Miwa Kawanaka
- Department of General Internal Medicine2, Kawasaki Medical School, Okayama 700-8505, Japan;
| | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 558-8585, Japan;
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (M.Y.); (K.I.); (A.N.)
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (M.Y.); (K.I.); (A.N.)
| | - Hirokazu Takahashi
- Department of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 840-8502, Japan;
| | | | - Masafumi Ono
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Women’s Medical University Medical Center East, Tokyo 116-8567, Japan;
| | - Yuichi Nozaki
- Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo 162-8655, Japan;
| | - Hideyuki Hyogo
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima 738-8503, Japan;
| | - Masahiro Koseki
- Division of Cardiovascular Medicine, Department of Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan;
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Suita Municipal Hospital, Osaka 564-8567, Japan;
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan;
| | - Yoshihiro Kamada
- Department of Advanced Gastroenterology & Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan;
| | - Takeshi Okanoue
- Hepatology Center, Saiseikai Suita Hospital, Osaka 564-0013, Japan;
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; (M.Y.); (K.I.); (A.N.)
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Kawata N, Takahashi H, Iwane S, Inoue K, Kojima M, Kohno M, Tanaka K, Mori H, Isoda H, Oeda S, Matsuda Y, Egashira Y, Nojiri J, Irie H, Eguchi Y, Anzai K. FIB-4 index-based surveillance for advanced liver fibrosis in diabetes patients. Diabetol Int 2021; 12:118-125. [PMID: 33479587 DOI: 10.1007/s13340-020-00453-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 06/30/2020] [Indexed: 12/12/2022]
Abstract
Liver fibrosis is associated with lifestyle-related diseases, including diabetes. The identification of diabetic patients with severe liver fibrosis is important, but a simple and reliable diagnostic procedure remains to be determined. We conducted an observational study to evaluate the performance of a FIB-4 index-based screening strategy for the diagnosis of advanced liver fibrosis in patients with diabetes or prediabetes. Two hundred and forty-two patients underwent abdominal imaging in our Study. According to the abdominal imaging findings, fatty liver, liver cirrhosis, and hepatocellular carcinoma were defined, and their association with FIB-4 index evaluated. The prevalences of liver cirrhosis and hepatocellular carcinoma in patients with a high (≥ 2.67; liver cirrhosis: 42.9%, hepatocellular carcinoma: 14.3%) FIB-4 index were significantly higher than in those with an intermediate (1.3 ≤ FIB-4 < 2.67; liver cirrhosis: 1.6%, hepatocellular carcinoma: 0.8%) or low FIB-4 index (< 1.3; liver cirrhosis: 1.2%, hepatocellular carcinoma: 0%). The diagnostic accuracy, specificity, and sensitivity of the FIB-4 index for the diagnosis of liver cirrhosis or hepatocellular carcinoma were 84.3%, 85.5%, and 89.3%, respectively, with an optimized cut-off value of 2.96 (sensitivity = 0.86, specificity = 0.98). Using an optimized cut-off value, FIB-4 index might be useful to identify liver cirrhosis or hepatocellular carcinoma in diabetes patients with high diagnostic accuracy.
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Affiliation(s)
- Nozomi Kawata
- Division of Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Japan
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Japan
| | | | - Kanako Inoue
- Division of Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Japan
| | - Motoyasu Kojima
- Division of Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Japan
| | - Michiko Kohno
- Division of Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Japan
| | - Kenichi Tanaka
- Division of Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Japan
| | - Hitoe Mori
- Division of Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Japan
| | | | | | - Yayoi Matsuda
- Division of Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Japan.,Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshiaki Egashira
- Department of Radiology, Faculty of Medicine, Saga University, Saga, Japan
| | - Jyunichi Nojiri
- Department of Radiology, Faculty of Medicine, Saga University, Saga, Japan
| | - Hiroyuki Irie
- Department of Radiology, Faculty of Medicine, Saga University, Saga, Japan
| | | | - Keizo Anzai
- Division of Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Japan
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Vincent RK, Williams DM, Evans M. A look to the future in non-alcoholic fatty liver disease: Are glucagon-like peptide-1 analogues or sodium-glucose co-transporter-2 inhibitors the answer? Diabetes Obes Metab 2020; 22:2227-2240. [PMID: 32945071 DOI: 10.1111/dom.14196] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/19/2020] [Accepted: 09/03/2020] [Indexed: 12/18/2022]
Abstract
The increasing prevalence of diabetes and non-alcoholic fatty liver disease (NAFLD) is a growing public health concern associated with significant morbidity, mortality and economic cost, particularly in those who progress to cirrhosis. Medical treatment is frequently limited, with no specific licensed treatments currently available for people with NAFLD. Its association with diabetes raises the possibility of shared mechanisms of disease progression and treatment. With the ever-growing interest in the non-glycaemic effects of diabetes medications, studies and clinical trials have investigated hepatic outcomes associated with the use of drug classes used for people with type 2 diabetes (T2D), such as glucagon-like peptide-1 (GLP-1) analogues or sodium-glucose co-transporter-2 (SGLT2) inhibitors. Studies exploring the use of GLP-1 analogues or SGLT2 inhibitors in people with NAFLD have observed improved measures of hepatic inflammation, liver enzymes and radiological features over short periods. However, these studies tend to have variable study populations and inconsistent reported outcomes, limiting comparison between drugs and drug classes. As these drugs appear to improve biomarkers of NAFLD, clinicians should consider their use in patients with NAFLD and T2D. However, further evidence with greater participant numbers and longer trial durations is required to support specific licensing for people with NAFLD. Larger trials would allow reporting of major adverse hepatic events, akin to cardiovascular and renal outcome trials, to be determined. This would provide a more meaningful evaluation of the impact of these drugs in NAFLD. Nevertheless, these drugs represent a future potential therapeutic avenue in this difficult-to-treat population and may beget significant health and economic impacts.
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Affiliation(s)
- Rebecca K Vincent
- Department of Gastroenterology, University Hospital Llandough, Cardiff, UK
| | - David M Williams
- Department of Diabetes and Endocrinology, University Hospital Llandough, Cardiff, UK
| | - Marc Evans
- Department of Diabetes and Endocrinology, University Hospital Llandough, Cardiff, UK
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Davis TM, Peters KE, Chubb SAP, Adams LA, Jeffrey GP, Davis WA. Changes in the Epidemiology of Hepatobiliary Disease Complicating Type 2 Diabetes over 25 Years: The Fremantle Diabetes Study. J Clin Med 2020; 9:jcm9113409. [PMID: 33114323 PMCID: PMC7690874 DOI: 10.3390/jcm9113409] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/13/2020] [Accepted: 10/22/2020] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE To determine whether the incidence/outcome of hepatobiliary disease (HBD) has increased over recent decades in community-based Australians with and without type 2 diabetes (T2D). METHODS Longitudinal data from the Fremantle Diabetes Study Phase I (FDS1; recruitment 1993-1996; n = 1291 with T2D) and Phase II (FDS2; 2008-2011; n = 1509) were analyzed. Participants with T2D from both Phases were age-, sex-, and postcode-matched 1:4 to people without diabetes. Incident HBD and associated mortality were ascertained from hospitalization, cancer registration, and/or death certification codes. Incidence rates (IRs) and IR ratios (IRRs) for those with versus without diabetes in FDS1 and FDS2 were calculated. RESULTS HBD IRs for people without diabetes did not change between Phases. The IRR (95% CI) for people with T2D in FDS2 versus FDS1 was 1.30 (1.01-1.68) with the highest IRRs in participants aged <65 years. Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) events were 54% greater in FDS2 than FDS1 in the presence of greater abdominal adiposity. NAFLD/NASH was coded in one in 11 HBD events in FDS2 and in 10% of HBD deaths (<4% of total mortality). CONCLUSIONS HBD is more frequent in people with versus without T2D and this discrepancy is increasing. Hospitalizations/deaths due to NAFLD/NASH remain uncommon.
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Affiliation(s)
- Timothy M.E. Davis
- University of Western Australia Medical School, Fremantle Hospital, Fremantle 6959, WA, Australia; (K.E.P.); (W.A.D.)
- Correspondence: ; Tel.: +618-9431-3229; Fax: +618-9431-2977
| | - Kirsten E. Peters
- University of Western Australia Medical School, Fremantle Hospital, Fremantle 6959, WA, Australia; (K.E.P.); (W.A.D.)
- Proteomics International, Nedlands 6009, WA, Australia
| | - S. A. Paul Chubb
- PathWest Laboratory Medicine Western Australia, Fiona Stanley Hospital, Murdoch 6150, WA, Australia;
| | - Leon A. Adams
- University of Western Australia Medical School, Sir Charles Gairdner Hospital, Nedlands 6009, WA, Australia; (L.A.A.); (G.P.J.)
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands 6009, WA, Australia
| | - Gary P. Jeffrey
- University of Western Australia Medical School, Sir Charles Gairdner Hospital, Nedlands 6009, WA, Australia; (L.A.A.); (G.P.J.)
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands 6009, WA, Australia
| | - Wendy A. Davis
- University of Western Australia Medical School, Fremantle Hospital, Fremantle 6959, WA, Australia; (K.E.P.); (W.A.D.)
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Mohammed ED, Abdel-Naim AB, Kangpeng J, Jiang R, Wei J, Sun B. The mother relationship between insulin resistance and non-alcoholic steatohepatitis: Glucosinolates hydrolysis products as a promising insulin resistance-modulator and fatty liver-preventer. Life Sci 2020; 264:118615. [PMID: 33096115 DOI: 10.1016/j.lfs.2020.118615] [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: 09/18/2020] [Revised: 10/09/2020] [Accepted: 10/14/2020] [Indexed: 11/25/2022]
Abstract
Non-alcoholic fatty liver disease (NFLD) is one of the present public health problems which have no specific and effective treatment. The speed of the disease progression depends on the patient's lifestyle. Due to life stresses and lack of time, a high number of people depend on fast food containing a high amount of fats which one of the main causes of insulin resistance (IR). IR is one of the metabolic disorders which strongly intersected with molecular NAFLD and leading to its progression into non-alcoholic steatohepatitis (NASH). In this review, we introduced the updated statistics of NAFLD and NASH progression all over the world shows its importance, etiologies, and pathogenesis. Also, IR and its role in NASH initiation and progression explored, and current treatments with its limitations have been explained. Glucosinolates (GLS) is a group of phytochemicals which known by its potent hydrolysis products with promising anti-cancer effect. In this review, we have collected the recent experimental studies of different GLS hydrolysis products against IR and chronic liver diseases supported by our lab finding. Finally, we recommend this group of phytochemicals as promising molecules to be studied experimentally and clinically against a wide range of chronic liver diseases with an acceptable safety margin.
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Affiliation(s)
- Eman D Mohammed
- Department of Clinical Pharmacology, Nanjing Drum Tower Hospital, Pharmacy Collage of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China; Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210093, Jiangsu Province, China; Natural Products Unit, Medicinal and Aromatic Plants Department, Desert Research Centre, Cairo, Egypt
| | - Ashraf B Abdel-Naim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jin Kangpeng
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210093, Jiangsu Province, China
| | - Runqiu Jiang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210093, Jiangsu Province, China
| | - Jifu Wei
- Research Division of Clinical Pharmacology, The First Affiliated Hospital, Pharmacy College of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210093, Jiangsu Province, China; Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China.
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The Appropriate Opportunity for Evaluating Liver Fibrosis by Using the FIB-4 Index in Patients with Nonalcoholic Fatty Liver Disease in Japan. Diagnostics (Basel) 2020; 10:diagnostics10100842. [PMID: 33086582 PMCID: PMC7603133 DOI: 10.3390/diagnostics10100842] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/07/2020] [Accepted: 10/19/2020] [Indexed: 12/16/2022] Open
Abstract
In patients with nonalcoholic fatty liver disease (NAFLD), liver fibrosis is the predictive factor for liver-related events and prognosis. This retrospective study aimed to evaluate longitudinal changes in the FIB-4 index and to determine a strategy for diagnosing and following patients with NAFLD using this index. We analyzed the FIB-4 index at baseline and after 1 and 5 years in 272 consecutive patients with biopsy-proven NAFLD. Of these, 52 patients underwent serial biopsies. The change in the FIB-4 index was correlated with changes in the fibrosis stage among these patients (p = 0.048). The median FIB-4 index was 1.64 at baseline, 1.45 at 1 year, and 1.74 at 5 years. The negative predictive value for advanced fibrosis at a low cutoff point was 90.4/90.1 at baseline/1 year. Its specificity at a high cutoff point increased from 65.0% at baseline to 82.3% at 1 year. Multivariate analysis identified the FIB-4 index at 1 year as a predictive factor for a FIB-4 index > 2.67 at 5 years. A FIB-4 index < 1.30 was acceptable for excluding advanced fibrosis at baseline. In contrast, to evaluate and predict advanced liver fibrosis with the FIB-4 index at a high cutoff point, we should use the index at 1 year after appropriate therapy.
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Sumida Y, Shima T, Mitsumoto Y, Katayama T, Umemura A, Yamaguchi K, Itoh Y, Yoneda M, Okanoue T. Epidemiology: Pathogenesis, and Diagnostic Strategy of Diabetic Liver Disease in Japan. Int J Mol Sci 2020; 21:E4337. [PMID: 32570776 PMCID: PMC7352222 DOI: 10.3390/ijms21124337] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/08/2020] [Accepted: 06/16/2020] [Indexed: 12/14/2022] Open
Abstract
Type 2 diabetes (T2D) is closely associated with nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to cirrhosis, hepatocellular carcinoma (HCC), and hepatic decompensation. Patients with T2D have twice the risk of HCC incidence compared with those without T2D. Because the hepatic fibrosis grade is the main determinant of mortality in patients with NAFLD, identifying patients with advanced fibrosis using non-invasive tests (NITs) or imaging modalities is crucial. Globally, the fibrosis-4 index (FIB-4 index), NAFLD fibrosis score, and enhanced liver fibrosis test have been established to evaluate hepatic fibrosis. Two-step algorithms using FIB-4 index as first triaging tool are globally accepted. It remains unknown which kinds of NITs or elastography are best as the second step tool. In Japan, type IV collagen 7s or the CA-fibrosis index (comprising type IV collagen 7s and aspartate aminotransferase (AST)) is believed to precisely predict advanced fibrosis in NAFLD. Patients with NAFLD who have high non-invasive test results should be screened for HCC or esophageal varices. Risk factors of rapid fibrosis progression in NAFLD includes age, severe obesity, presence of T2D, menopause in women, and a patatin-like phospholipase domain containing the 3 GG genotype. Patients with NAFLD who have these risk factors should be intensively treated with lifestyle modification or pharmacotherapies for preventing liver-related mortality.
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Affiliation(s)
- Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan;
| | - Toshihide Shima
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka 564-0013, Japan; (T.S.); (Y.M.); (T.K.); (T.O.)
| | - Yasuhide Mitsumoto
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka 564-0013, Japan; (T.S.); (Y.M.); (T.K.); (T.O.)
| | - Takafumi Katayama
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka 564-0013, Japan; (T.S.); (Y.M.); (T.K.); (T.O.)
| | - Atsushi Umemura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (A.U.); (K.Y.); (Y.I.)
| | - Kanji Yamaguchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (A.U.); (K.Y.); (Y.I.)
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (A.U.); (K.Y.); (Y.I.)
| | - Masashi Yoneda
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan;
| | - Takeshi Okanoue
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka 564-0013, Japan; (T.S.); (Y.M.); (T.K.); (T.O.)
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Takeshita Y, Kanamori T, Tanaka T, Kaikoi Y, Kita Y, Takata N, Iida N, Arai K, Yamashita T, Harada K, Gabata T, Nakamura H, Kaneko S, Takamura T. Study Protocol for Pleiotropic Effects and Safety of Sodium-Glucose Cotransporter 2 Inhibitor Versus Sulfonylurea in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. Diabetes Ther 2020; 11:549-560. [PMID: 31956961 PMCID: PMC6995806 DOI: 10.1007/s13300-020-00762-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Clinicopathological analyses revealed that reduction in HbA1c and use of insulin independently contribute to reduction in liver fibrosis scores during the course of nonalcoholic fatty liver disease (NAFLD) development. We will test our hypothesis that lowering glucose and increasing insulin reduce liver fibrosis in NAFLD. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower insulin levels and sulfonylureas increase insulin levels, while both lower glucose levels. METHODS This study is a 48-week, one-center (only Kanazawa University Hospital), open-label, randomized, parallel trial. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily 20 mg tofogliflozin or 0.5 mg glimepiride. The sample size was calculated to be 14 in each group with a significance level of 0.05 and power of 0.90. The design required 40 evaluable patients in this study. The primary endpoint of this study will be the improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. The secondary efficacy endpoints in the present study include organ-specific insulin sensitivity, insulin/glucagon secretion, ectopic fat accumulation, bioelectrical impedance analysis, sympathetic nerve activity, comprehensive gene expression analyses in the liver and blood cells, and gut microbiota profiling. PLANNED OUTCOMES Recruitment into this study started in November 2015 and will end in September 2020, with 40 patients randomized into the two groups. The treatment follow-up of the participants is currently ongoing and is due to finish by the end of 2022. The findings of this trial will be disseminated through peer-reviewed publications and international presentations. TRIAL REGISTRATION This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000020544) and ClinicalTrials.gov (NCT02649465).
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Affiliation(s)
- Yumie Takeshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Takehiro Kanamori
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Takeo Tanaka
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yuka Kaikoi
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yuki Kita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Noboru Takata
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Noriho Iida
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan
| | - Toshifumi Gabata
- Department of Radiology, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Hiroyuki Nakamura
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.
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Shao SC, Chang KC, Chien RN, Lin SJ, Hung MJ, Chan YY, Kao Yang YH, Lai ECC. Effects of sodium-glucose co-transporter-2 inhibitors on serum alanine aminotransferase levels in people with type 2 diabetes: A multi-institutional cohort study. Diabetes Obes Metab 2020; 22:128-134. [PMID: 31486260 DOI: 10.1111/dom.13875] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 08/06/2019] [Accepted: 08/28/2019] [Indexed: 12/25/2022]
Abstract
Clinical trials have indicated that sodium-glucose co-transporter-2 (SGLT2) inhibitors have a favourable effect on serum alanine aminotransferase (ALT) levels in people with type 2 diabetes (T2D), but supporting evidence from real-world studies is lacking. We identified patients with T2D who initiated SGLT2 inhibitors during the period 2016 to 2017 from Chang Gung Research Database, which covers 1.3 million individuals from seven hospitals (6% of the Taiwan population). We classified patients by baseline ALT level and evaluated changes in ALT values from baseline to 1 year after initiation of SGLT2 inhibitors. We identified 11 690 new users of SGLT2 inhibitors with a mean (SD) age of 59.3 (11.8) years. The mean (SD) glycated haemoglobin and ALT levels were 8.9 (1.7)% and 34.7 (28.9) U/L at baseline, respectively. The mean change in ALT levels was -5.0 U/L (95% confidence interval [CI] -6.4, -3.5) 1 year after initiation of SGLT2 inhibitors. In patients with ALT levels ≤1× the upper limit of normal (ULN), the change in ALT levels was 1.6 U/L (95% CI -0.1, 3.4), while in those with ALT levels >1× ULN, the change in ALT levels was -26.5 U/L (95% CI -28.6, -24.3). The higher the baseline ALT level, the greater the decline after SGLT2 inhibitor treatment. Our findings suggest the initiation of SGLT2 inhibitors for T2D management could improve serum ALT levels in clinical practice, particularly in patients with especially high ALT levels.
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Affiliation(s)
- Shih-Chieh Shao
- Department of Pharmacy, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kai-Cheng Chang
- Department of Pharmacy, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Liver Research Unit, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Swu-Jane Lin
- Department of Pharmacy Systems, Outcomes and Policy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Ming-Jui Hung
- Division of Cardiology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
- Chang Gung University, College of Medicine, Taoyuan, Taiwan
| | - Yuk-Ying Chan
- Department of Pharmaceutical Material Management, Chang Gung Medical Foundation, Taoyuan, Taiwan
| | - Yea-Huei Kao Yang
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Edward Chia-Cheng Lai
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, National Cheng Kung University Hospital, Tainan, Taiwan
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Arrese M, Barrera F, Triantafilo N, Arab JP. Concurrent nonalcoholic fatty liver disease and type 2 diabetes: diagnostic and therapeutic considerations. Expert Rev Gastroenterol Hepatol 2019; 13:849-866. [PMID: 31353974 DOI: 10.1080/17474124.2019.1649981] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: The relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) is complex and bidirectional. NAFLD increases the risk of incident diabetes and is very prevalent in T2DM patients and T2DM is an aggravating factor for NAFLD. Timely T2DM diagnosis and treatment in subjects with NAFLD and diagnosis, staging and treatment of NAFLD in those with T2DM are critical issues. Areas covered: PubMed/MEDLINE was searched for articles related to concomitant occurrence of NAFLD and T2DM between January 2013 and May 2019. Areas covered included epidemiological, diagnostic and therapeutic aspects. Expert opinion: there is a need for increased awareness on NAFLD adding liver disease as an end-organ complication of T2DM. Emphasis on use of simple non-invasive tools to triage patients with potentially severe liver disease should be made. Management of patients with NAFLD and T2DM relies on lifestyle optimization to achieve significant weight loss. Currently, there is no drug approved for treatment of NAFLD in patients with T2DM although Vitamin E and pioglitazone might be used in selected patients. Approved diabetic medications hold promise for NAFLD treatment and several liver-specific drugs are in evaluation clinical trials. A combination approach will likely represent the future of NAFLD therapeutics.
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Affiliation(s)
- Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile , Santiago , Chile.,Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas Pontificia Universidad Católica de Chile, Centro de Envejecimiento y Regeneración (CARE) , Santiago , Chile
| | - Francisco Barrera
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Nicolas Triantafilo
- Departamento de Hematologia y oncología, Escuela de Medicina, Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile , Santiago , Chile
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Tanaka K, Takahashi H, Hyogo H, Ono M, Oza N, Kitajima Y, Kawanaka M, Chayama K, Saibara T, Anzai K, Eguchi Y. Epidemiological survey of hemoglobin A1c and liver fibrosis in a general population with non-alcoholic fatty liver disease. Hepatol Res 2019; 49:296-303. [PMID: 30367534 DOI: 10.1111/hepr.13282] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 07/10/2018] [Accepted: 10/22/2018] [Indexed: 12/16/2022]
Abstract
AIM The association between glycemia and liver fibrosis was analyzed using hemoglobin A1c (HbA1c) and the Fibrosis-4 (FIB-4) index in a large general population cohort that underwent a health checkup. METHODS A total of 6927 subjects without hepatitis B or C virus infection or habitual alcohol intake were enrolled. Non-alcoholic fatty liver disease (NAFLD) was diagnosed by ultrasonography and potential liver fibrosis (FIB-4 index ≥1.3) in NAFLD was analyzed in relation to HbA1c level. Factors associated with potential liver fibrosis of NAFLD were also analyzed. RESULTS The overall frequency of NAFLD was 27.9% (1935 subjects) and the frequency of NAFLD by HbA1c level (<4.9%, 5.0-5.9%, 6.0-6.9%, 7.0-7.9%, ≥8.0%) was 16%, 27%, 54%, 53%, and 54%, respectively. Among the 1935 NAFLD cases, the frequency of potential liver fibrosis was 25.2% (487 subjects) overall and 19%, 22%, 30%, 52%, and 31%, respectively, by HbA1c category. From multivariate analysis, an HbA1c level ≥6.5% was significantly associated with potential liver fibrosis (P = 0.017, hazard ratio = 1.7). CONCLUSIONS The prevalence of NAFLD and liver fibrosis of NAFLD increased according to glycemia, up to 8.0% HbA1c. Measuring HbA1c and calculating the FIB-4 index in health checkups could help to identify potential cases of liver fibrosis of NAFLD, which should then be further evaluated using other techniques to confirm liver fibrosis.
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Affiliation(s)
- Kenichi Tanaka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.,Clinical Gastroenterology, Eguchi Hospital, Saga, Japan
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.,Clinical Gastroenterology, Eguchi Hospital, Saga, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Hepatology, JA Hiroshima General Hospital, Hiroshima, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
| | - Noriko Oza
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.,Department of Hepatobiliary and Pancreatology, Saga-Ken Medical Centre Koseikan, Saga, Japan
| | - Yoichiro Kitajima
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.,Clinical Gastroenterology, Eguchi Hospital, Saga, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Toshiji Saibara
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
| | - Keizo Anzai
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
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Yu C, Wang L, Xue H, Lin H, Li Y, Chan SO. Association of glycated hemoglobin with the risk of advanced fibrosis in non-alcoholic fatty liver disease patients without diabetes. Clin Res Hepatol Gastroenterol 2019; 43:58-66. [PMID: 30274911 DOI: 10.1016/j.clinre.2018.08.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 06/20/2018] [Accepted: 08/13/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Association of diabetes with non-alcoholic steatohepatitis has been well documented. However, it remains unclear whether there is an association between levels of glycated hemoglobin (HbA1c) with severity of non-alcoholic fatty liver disease (NAFLD). This study was aimed to explore the relationship between levels of HbA1c and the risk of advanced fibrosis in patients with NAFLD. METHODS A cross-sectional study was performed on 4826 apparently healthy Chinese, who underwent a health check between January 2015 and December 2016. NAFLD was defined as hepatic steatosis on ultrasonography in the absence of excessive alcohol use or other identifiable causes. The risk of advanced fibrosis was assessed by NAFLD fibrosis Score. RESULTS Among 4826 individuals studied, 1630 were diagnosed with NAFLD. In a multivariable-adjusted model, high HbA1c levels were associated independently with increased prevalence of NAFLD. The adjusted odds ratio [95% confidence interval (95% CI)] for NAFLD, when compared with the highest HbA1c quartile and the lowest HbA1c quartile, was 2.72 (2.07-3.58; P for trend < 0.001). A strong association was also observed between HbA1c level and the risk of fibrosis in patients with NAFLD in multivariable analyses, with the extreme-quartile odds ratio of 2.69 (95% CI: 1.60-4.53; P for trend < 0.001). This association remained significant even in subjects without diabetes. CONCLUSIONS We concluded that high HbA1c level was associated strongly and independently with increased risk of advanced fibrosis in NAFLD patients without diabetes.
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Affiliation(s)
- Chao Yu
- Center for Health Examination, The 3rd Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, PR China; Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangdong, PR China.
| | - Liqing Wang
- Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Hongliang Xue
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangdong, PR China
| | - Hongmei Lin
- Center for Health Examination, The 3rd Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, PR China
| | - Yanping Li
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangdong, PR China
| | - Sun-On Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, PR China
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Seko Y, Nishikawa T, Umemura A, Yamaguchi K, Moriguchi M, Yasui K, Kimura M, Iijima H, Hashimoto T, Sumida Y, Okanoue T, Itoh Y. Efficacy and safety of canagliflozin in type 2 diabetes mellitus patients with biopsy-proven nonalcoholic steatohepatitis classified as stage 1-3 fibrosis. Diabetes Metab Syndr Obes 2018; 11:835-843. [PMID: 30568471 PMCID: PMC6267487 DOI: 10.2147/dmso.s184767] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
AIM Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is known to be associated with type 2 diabetes mellitus (T2DM) in high rate. The improvement in hepatic function due to sodium-glucose co-transporter 2 (SGLT2) inhibitors has been reported in T2DM patients with and without NAFLD. However, only a few studies have attempted to evaluate the role of SGLT2 inhibitors in T2DM patients with biopsy-proven NASH, and no detailed prospective studies including the individual hepatic fibrosis stage have been reported. Therefore, we investigated the effect of canagliflozin on hepatic function in T2DM patients with biopsy-confirmed NASH. METHODS T2DM patients with NASH (hepatic fibrosis stage 1-3 confirmed via liver biopsy, n=10) were enrolled and received canagliflozin (100 mg) once a day for 12 weeks. The primary end point was change in serum alanine aminotransferase (ALT) levels from baseline to week 12. Secondary end points were liver function/fibrosis markers, metabolic parameters, and safety. RESULTS The change in ALT from baseline to week 12 was -23.9 U/L (95% CI -48.1 to 0.3, P=0.0526). Significant improvements in several hepatic function/fibrosis markers, such as aspartate aminotransferase, fibrosis-4 index, and FM-fibro index, and metabolic parameters including hemoglobin A1c and body weight were found. No serious or liver-related adverse events were reported. Regarding individual patients, different trends in ALT-lowering effects between stage 1 and stage 2/3 subjects were observed; the degree of ALT-lowering effect tended to be greater in the stage 1 group than in the stage 2/3 group. CONCLUSION Our results suggest that canagliflozin is effective and well-tolerated in patients with T2DM and NASH. Canagliflozin may be useful for the treatment of T2DM patients with NASH, especially those in early stages of NASH.
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Affiliation(s)
- Yuya Seko
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan,
| | - Taichiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan,
| | - Atsushi Umemura
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan,
| | - Kanji Yamaguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan,
| | - Michihisa Moriguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan,
| | - Kohichiroh Yasui
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan,
| | - Mayumi Kimura
- Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan
| | - Hiroaki Iijima
- Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Toshio Hashimoto
- Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Aichi, Japan
| | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan,
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy. The efficacy of vitamin E and pioglitazone has been established in nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD. GLP-1RA and SGLT2 inhibitors, which are currently approved for use in diabetes, have shown early efficacy in NASH, and also have beneficial cardiovascular or renal effects. Innovative NASH therapies include four main pathways. The first approach is targeting hepatic fat accumulation. Medications in this approach include modulation of peroxisome proliferator-activator receptors (e.g., pemafibrate, elafibranor), medications targeting farnesoid X receptor axis [obeticholic acid; OCA)], inhibitors of de novo lipogenesis (aramchol, ACC inhibitor), and fibroblast growth factor-21 analogues. A second target is oxidative stress, inflammation, and apoptosis. This class of drug includes apoptosis signaling kinase 1 (ASK1) inhibitor and emricasan (an irreversible caspase inhibitor). A third target is intestinal microbiomes and metabolic endotoxemia. Several agents are in ongoing trials, including IMMe124, TLR4 antagonist, and solithromycin (macrolide antibiotics). The final target is hepatic fibrosis, which is strongly associated with all-cause or liver-related mortality in NASH. Antifibrotic agents are a cysteine-cysteine motif chemokine receptor-2/5 antagonist (cenicriviroc; CVC) and galectin 3 antagonist. Among a variety of medications in development, four agents such as OCA, elafibranor, ASK1 inhibitor, and CVC are currently being evaluated in an international phase 3 trial for the treatment of NASH. Within the next few years, the availability of therapeutic options for NASH will hopefully curb the rising trend of NASH-related diseases.
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Affiliation(s)
- Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, 480-1195, Japan.
| | - Masashi Yoneda
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, 480-1195, Japan
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Lonardo A, Nascimbeni F, Maurantonio M, Marrazzo A, Rinaldi L, Adinolfi LE. Nonalcoholic fatty liver disease: Evolving paradigms. World J Gastroenterol 2017; 23:6571-6592. [PMID: 29085206 PMCID: PMC5643282 DOI: 10.3748/wjg.v23.i36.6571] [Citation(s) in RCA: 137] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 08/21/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
In the last years new evidence has accumulated on nonalcoholic fatty liver disease (NAFLD) challenging the paradigms that had been holding the scene over the previous 30 years. NAFLD has such an epidemic prevalence as to make it impossible to screen general population looking for NAFLD cases. Conversely, focusing on those cohorts of individuals exposed to the highest risk of NAFLD could be a more rational approach. NAFLD, which can be diagnosed with either non-invasive strategies or through liver biopsy, is a pathogenically complex and clinically heterogeneous disease. The existence of metabolic as opposed to genetic-associated disease, notably including "lean NAFLD" has recently been recognized. Moreover, NAFLD is a systemic condition, featuring metabolic, cardiovascular and (hepatic/extra-hepatic) cancer risk. Among the clinico-laboratory features of NAFLD we discuss hyperuricemia, insulin resistance, atherosclerosis, gallstones, psoriasis and selected endocrine derangements. NAFLD is a precursor of type 2 diabetes (T2D) and metabolic syndrome and progressive liver disease develops in T2D patients in whom the course of disease is worsened by NAFLD. Finally, lifestyle changes and drug treatment options to be implemented in the individual patient are also critically discussed. In conclusion, this review emphasizes the new concepts on clinical and pathogenic heterogeneity of NAFLD, a systemic disorder with a multifactorial pathogenesis and protean clinical manifestations. It is highly prevalent in certain cohorts of individuals who are thus potentially amenable to selective screening strategies, intensive follow-up schedules for early identification of liver-related and extrahepatic complications and in whom earlier and more aggressive treatment schedules should be carried out whenever possible.
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Affiliation(s)
- Amedeo Lonardo
- Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Modena, Italy
| | - Fabio Nascimbeni
- Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Modena, Italy
- University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Mauro Maurantonio
- Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Modena, Italy
| | - Alessandra Marrazzo
- Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Modena, Italy
- University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Luca Rinaldi
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy
| | - Luigi Elio Adinolfi
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy
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Fujii Y, Nanashima A, Hiyoshi M, Imamura N, Yano K, Hamada T. Risk factors for development of nonalcoholic fatty liver disease after pancreatoduodenectomy. Ann Gastroenterol Surg 2017; 1:226-231. [PMID: 29863141 PMCID: PMC5881353 DOI: 10.1002/ags3.12024] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 06/11/2017] [Indexed: 12/14/2022] Open
Abstract
Considerable attention has been focused on nonalcoholic fatty liver disease (NAFLD) which occasionally develops after pancreatoduodenectomy (PD). The present study aimed to clarify the prevalence, sequential change in properties and risk factors for NAFLD development after PD. We enrolled 196 patients who underwent PD and a computed tomography (CT) scan 1 month, 6 months and 1 year after surgery. NAFLD was defined as a liver‐to‐spleen attenuation ratio on plain CT of <0.9. We compared various clinical factors between the NAFLD group and the control group. Individual prevalence of NAFLD at 1 month, 6 months and 1 year after surgery was 12%, 21% and 15%. Significantly different factors by univariate analysis were as follows: 1 month: age, sex, total protein (TP), total cholesterol (TC) and copper (Cu); 6 months: sex, disease, surgical method, portal vein resection (PVR), frequency of defecation, TC and Cu; 1 year: age, sex, disease, surgical method, PVR, frequency of defecation, TP and Cu. Risk factors by multivariate analysis were as follows: 1 month: not elderly age, female sex and a decrease in Cu; 6 months: female sex and a decrease in Cu; 1 year: a decrease in Cu. NAFLD after PD frequently developed in women with a decrease in serum Cu and was influenced by various factors related to poor digestion and absorption associated with pancreatic exocrine insufficiency.
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Affiliation(s)
- Yoshiro Fujii
- Department of Hepato-Biliary-Pancreatic Surgery Faculty of Medicine University of Miyazaki Miyazaki Japan
| | - Atsushi Nanashima
- Department of Hepato-Biliary-Pancreatic Surgery Faculty of Medicine University of Miyazaki Miyazaki Japan
| | - Masahide Hiyoshi
- Department of Hepato-Biliary-Pancreatic Surgery Faculty of Medicine University of Miyazaki Miyazaki Japan
| | - Naoya Imamura
- Department of Hepato-Biliary-Pancreatic Surgery Faculty of Medicine University of Miyazaki Miyazaki Japan
| | - Koichi Yano
- Department of Hepato-Biliary-Pancreatic Surgery Faculty of Medicine University of Miyazaki Miyazaki Japan
| | - Takeomi Hamada
- Department of Hepato-Biliary-Pancreatic Surgery Faculty of Medicine University of Miyazaki Miyazaki Japan
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Bouchi R, Fukuda T, Takeuchi T, Nakano Y, Murakami M, Minami I, Izumiyama H, Hashimoto K, Yoshimoto T, Ogawa Y. Gender difference in the impact of gynoid and android fat masses on the progression of hepatic steatosis in Japanese patients with type 2 diabetes. BMC OBESITY 2017; 4:27. [PMID: 28702206 PMCID: PMC5504846 DOI: 10.1186/s40608-017-0163-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 06/29/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Increased visceral adiposity is strongly associated with non-alcoholic fatty liver disease (NAFLD). However, little attention has been paid to the association between the change in subcutaneous adipose mass and the progression of non-alcoholic fatty liver disease (NAFLD). We aimed to investigate whether increased subcutaneous adipose tissue (gynoid fat mass) could be protective against the progression of NAFLD in Japanese patients with type 2 diabetes. METHODS This is a retrospective observational study of 294 Japanese patients with type 2 diabetes (65 ± 10 years old, 40% female). Liver attenuation index (LAI) measured by abdominal computed tomography was used for the assessment of hepatic steatosis. Both gynoid (kg) and android (kg) fat masses were measured by the whole body dual-energy X-ray absorptiometry. One-year changes in LAI, gynoid, and android fat masses were evaluated in both male and female patients. Linear regression analysis with a stepwise procedure was used for the statistical analyses to investigate the association of the changes in gynoid and android fat masses with the change in LAI. RESULTS LAI levels at baseline were 1.15 ± 0.31 and 1.10 ± 0.34 in female and male patients (p = 0.455). The change in gynoid fat mass was significantly and positively associated with the change in LAI in both univariate (standardized β 0.331, p = 0.049) and multivariate (standardized β 0.360, p = 0.016) models in the female patients. However, no significant association was observed in males. In contrast, the increase in android fat mass was significantly associated with the reduced LAI in both genders in the multivariate models (standardized β -0.651, p < 0.001 in females and standardized β -0.519, p = 0.042 in males). CONCLUSIONS This study provides evidence that increased gynoid fat mass may be protective against the progression of NAFLD in female Japanese patients with type 2 diabetes.
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Affiliation(s)
- Ryotaro Bouchi
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519 Japan
| | - Tatsuya Fukuda
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519 Japan
| | - Takato Takeuchi
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519 Japan
| | - Yujiro Nakano
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519 Japan
| | - Masanori Murakami
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519 Japan
| | - Isao Minami
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519 Japan
| | - Hajime Izumiyama
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519 Japan.,Center for Medical Welfare and Liaison Services, Tokyo Medical and Dental University, Tokyo, Japan
| | - Koshi Hashimoto
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519 Japan.,Department of Preemptive Medicine and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takanobu Yoshimoto
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519 Japan
| | - Yoshihiro Ogawa
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519 Japan.,CREST, Japan Agency for Medical Research and Development, Tokyo, Japan
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Bouchi R, Nakano Y, Fukuda T, Takeuchi T, Murakami M, Minami I, Izumiyama H, Hashimoto K, Yoshimoto T, Ogawa Y. Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: a randomized control trial. Endocr J 2017; 64:269-281. [PMID: 27916783 DOI: 10.1507/endocrj.ej16-0449] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Liraglutide, an analogue of human glucagon-like peptide 1, reduces cardiovascular events in patients with type 2 diabetes; however, it has still been unknown by which mechanisms liraglutide could reduce cardiovascular events. Type 2 diabetic patients with insulin treatment were enrolled in this randomized, open-label, comparative study. Participants were randomly assigned to liraglutide plus insulin (liraglutide group) and insulin treatment (control group) at 1:1 allocation. Primary endpoint was the change in viscera fat are (VFA, cm2) at 24 weeks. Liver attenuation index (LAI) measured by abdominal computed tomography, urinary albumin-to-creatinine ratio (ACR, mg/g), and C-reactive protein (CRP) levels, skeletal muscle index (SMI), and quality of life (QOL) related to diabetes treatment were also determined. Seventeen patients (8; liraglutide group, 9; control group, mean age 59 ± 13 years; 53% female) completed this study. Liraglutide treatment significantly reduced VFA at 24 weeks; whereas, SFA was unchanged. ACR, LAI, and CRP levels were significantly reduced by liraglutide at 24 weeks and there was no difference in SMI between the two groups. Changes in VFA from baseline to 24 weeks were significantly associated with those in LAI, albuminuria, and HbA1c. Liraglutide treatment significantly improved QOL scores associated with anxiety and dissatisfaction with treatment and satisfaction with treatment. No severe adverse events were observed in both groups. Our data suggest that liraglutide could reduce visceral adiposity in parallel with attenuation of hepatic fat accumulation, albuminuria and micro-inflammation and improve QOL related to diabetes care in insulin-treated patients with type 2 diabetes.
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Affiliation(s)
- Ryotaro Bouchi
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
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