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Le DHH, Kanokudom S, Nguyen HM, Yorsaeng R, Honsawek S, Vongpunsawad S, Poovorawan Y. Hepatitis C Virus-Core Antigen: Implications in Diagnostic, Treatment Monitoring and Clinical Outcomes. Viruses 2024; 16:1863. [PMID: 39772172 PMCID: PMC11680303 DOI: 10.3390/v16121863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 11/26/2024] [Accepted: 11/28/2024] [Indexed: 01/11/2025] Open
Abstract
The hepatitis C virus (HCV) infection, a global health concern, can lead to chronic liver disease. The HCV core antigen (HCVcAg), a viral protein essential for replication, offers a cost-effective alternative to HCV RNA testing, particularly in resource-limited settings. This review explores the significance of HCVcAg, a key protein in the hepatitis C virus, examining its structure, function, and role in the viral life cycle. It also evaluates its clinical use in diagnosis and treatment monitoring, comparing its performance to the standard HCV RNA assay using data from PubMed and Google Scholar. HCVcAg assays show high pooled sensitivity (93.5%) and pooled specificity (99.2%) compared to HCV RNA assays, correlating closely (r = 0.87) with HCV RNA levels. Hence, HCVcAg testing offers a cost-effective way to diagnose active HCV infections and monitor treatment, especially in resource-limited settings, but its sensitivity can vary and standardization is needed. HCVcAg also predicts liver disease progression and assesses liver damage risk, aiding patient management. It helps to identify patients at risk for fibrosis or carcinoma, making it vital in hepatitis C care. HCVcAg testing can expand access to HCV care, simplify management, and contribute to global elimination strategies, especially in low- and middle-income countries.
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Affiliation(s)
- Duong Hoang Huy Le
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand; (D.H.H.L.); (S.K.); (R.Y.); (S.V.)
- Center of Excellence in Osteoarthritis and Musculoskeleton, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand;
- Medical Biochemistry & Molecular Biology Department, Fundamental Sciences and Basic Medical Sciences, Pham Ngoc Thach University of Medicine, Ho Chi Minh City 700000, Vietnam;
| | - Sitthichai Kanokudom
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand; (D.H.H.L.); (S.K.); (R.Y.); (S.V.)
- Center of Excellence in Osteoarthritis and Musculoskeleton, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand;
| | - Ha Minh Nguyen
- Medical Biochemistry & Molecular Biology Department, Fundamental Sciences and Basic Medical Sciences, Pham Ngoc Thach University of Medicine, Ho Chi Minh City 700000, Vietnam;
- Laboratory Department, Nguyen Tri Phuong Hospital, Ho Chi Minh City 700000, Vietnam
| | - Ritthideach Yorsaeng
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand; (D.H.H.L.); (S.K.); (R.Y.); (S.V.)
| | - Sittisak Honsawek
- Center of Excellence in Osteoarthritis and Musculoskeleton, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand;
| | - Sompong Vongpunsawad
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand; (D.H.H.L.); (S.K.); (R.Y.); (S.V.)
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand; (D.H.H.L.); (S.K.); (R.Y.); (S.V.)
- The Royal Society of Thailand, Sanam Sueapa, Bangkok 10330, Thailand
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Kasai H, Yamashita A, Akaike Y, Tanaka T, Matsuura Y, Moriishi K. HCV infection activates the proteasome via PA28γ acetylation and heptamerization to facilitate the degradation of RNF2, a catalytic component of polycomb repressive complex 1. mBio 2024; 15:e0169124. [PMID: 39329491 PMCID: PMC11559043 DOI: 10.1128/mbio.01691-24] [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: 06/03/2024] [Accepted: 08/26/2024] [Indexed: 09/28/2024] Open
Abstract
We previously reported that hepatitis C virus (HCV) infection or HCV core protein expression induces HOX gene expression by impairing histone H2A monoubiquitination via a proteasome-dependent reduction in the level of RNF2, a key catalytic component of polycomb repressive complex 1 (H. Kasai, K. Mochizuki, T. Tanaka, A. Yamashita, et al., J Virol 95:e01784-20, 2021, https://doi.org/10.1128/jvi.01784-20). In this study, we aimed to investigate the mechanism by which HCV infection accelerates RNF2 degradation. Yeast two-hybrid screening and an immunoprecipitation assay revealed that RNF2 is a PA28γ-binding protein. The proteasome activator PA28γ destabilized the RNF2 protein in a proteasome-dependent manner, since RNF2 degradation was impaired by PA28γ knockout or MG132 treatment. HCV infection or core protein expression reduced the levels of RNF2 and histone H2A K119 monoubiquitination and induced the expression of HOX genes in the presence of PA28γ, while PA28γ knockout reversed these changes. Treatment with a lysine acetyltransferase inhibitor inhibited the acetylation of PA28γ at K195 and the degradation of the RNF2 protein, while treatment with a lysine deacetylase inhibitor accelerated these events in a PA28γ-dependent manner. RNF2 protein degradation was increased by expression of the acetylation mimetic PA28γ mutant but not by expression of the acetylation-defective mutant or the proteasome activation-defective mutant. Furthermore, HCV infection or core protein expression facilitated the interaction between PA28γ and the lysine acetyltransferase CBP/p300 and then accelerated PA28γ acetylation and heptazmerization to promote RNF2 degradation. These data suggest that HCV infection accelerates the acetylation-dependent heptamerization of PA28γ to increase the proteasomal targeting of RNF2.IMPORTANCEHCV is a causative agent of HCV-related liver diseases, including hepatic steatosis, cirrhosis, and hepatocellular carcinoma. PA28γ, which, in heptameric form, activates the 20S core proteasome for the degradation of PA28γ-binding proteins, is responsible for HCV-related liver diseases. HCV core protein expression or HCV infection accelerates RNF2 degradation, leading to the induction of HOX gene expression via a decrease in the level of H2Aub on HOX gene promoters. However, the mechanism of RNF2 degradation in HCV-infected cells has not been clarified. The data presented in this study suggest that PA28γ acetylation and heptamerization are promoted by HCV infection or by core protein expression to activate the proteasome for the degradation of RNF2 and are responsible for HCV propagation. This study provides novel insights valuable for the development of therapies targeting both HCV propagation and HCV-related diseases.
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Affiliation(s)
- Hirotake Kasai
- Department of Microbiology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, University of Yamanashi, Yamanashi, Japan
| | - Atsuya Yamashita
- Department of Microbiology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, University of Yamanashi, Yamanashi, Japan
| | - Yasunori Akaike
- Department of Microbiology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, University of Yamanashi, Yamanashi, Japan
| | - Tomohisa Tanaka
- Department of Microbiology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, University of Yamanashi, Yamanashi, Japan
- Division of Hepatitis Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Yoshiharu Matsuura
- Laboratory of Virus Control, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka, Japan
- Center for Infectious Diseases Education and Research (CiDER), Osaka University, Osaka, Japan
| | - Kohji Moriishi
- Department of Microbiology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, University of Yamanashi, Yamanashi, Japan
- Division of Hepatitis Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
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Tani J, Masaki T, Oura K, Tadokoro T, Morishita A, Kobara H. Extrahepatic Cancer Risk in Patients with Hepatitis C Virus Infection Treated with Direct-Acting Antivirals. Microorganisms 2024; 12:1926. [PMID: 39338599 PMCID: PMC11434491 DOI: 10.3390/microorganisms12091926] [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: 08/31/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
Chronic hepatitis C virus (HCV) infection is associated with an increased risk of extrahepatic cancers, particularly non-Hodgkin lymphoma. The introduction of direct-acting antivirals (DAAs) has revolutionized HCV therapy, resulting in high cure rates. However, concerns have been raised about potential effects on cancer risk. This review summarizes the current evidence on extrahepatic cancer risk in HCV-infected patients treated with DAAs. We examined epidemiologic data on HCV-associated extrahepatic cancers and explored potential mechanisms linking HCV to carcinogenesis outside the liver. Studies evaluating cancer outcomes after DAA therapy were critically reviewed while considering methodological challenges. While some studies suggested a reduced risk of extrahepatic cancers after DAA therapy, others showed no significant change. Limitations included short follow-up periods and confounding variables. Immunological changes following rapid HCV clearance may have complex effects on cancer risk. Long-term prospective studies and mechanistic investigations are needed to fully elucidate the relationship between DAA therapy and extrahepatic cancer risk in HCV patients. Clinicians should remain vigilant for extrahepatic malignancies in this population.
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Affiliation(s)
- Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
| | - Tsutomu Masaki
- Kagawa Saiseikai Hospital, Takamatsu 761-8076, Kagawa, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
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Yadav M, Verma S, Tiwari P, Mugale MN. Unraveling the mechanisms of hepatogenous diabetes and its therapeutic perspectives. Life Sci 2024; 353:122934. [PMID: 39089644 DOI: 10.1016/j.lfs.2024.122934] [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: 05/09/2024] [Revised: 06/26/2024] [Accepted: 07/25/2024] [Indexed: 08/04/2024]
Abstract
The review focused mainly on the pathogenesis of hepatogenous diabetes (HD) in liver cirrhosis (LC). This review reveals parallels between the mechanisms of metabolic dysfunction observed in LC and type II diabetes (T2DM), suggesting a shared pathway leading to HD. It underscores the role of insulin in HD pathogenesis, highlighting key factors such as insulin signaling, glucose metabolism, insulin resistance (IR), and the influence of adipocytes. Furthermore, the impact of adipose tissue accumulation, fatty acid metabolism, and pro-inflammatory cytokines like Tumor necrosis factor-α (TNF-α) on IR are discussed in the context of HD. Altered signaling pathways, disruptions in the endocrine system, liver inflammation, changes in muscle mass and composition, and modifications to the gut microbiota collectively contribute to the complex interplay linking cirrhosis and HD. This study highlights how important it is to identify and treat this complex condition in cirrhotic patients by thoroughly analyzing the link between cirrhosis, IR, and HD. It also emphasizes the vitality of targeted interventions. Cellular and molecular investigations into IR have revealed potential therapeutic targets for managing and preventing HD.
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Affiliation(s)
- Manisha Yadav
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Smriti Verma
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Purnima Tiwari
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India
| | - Madhav Nilakanth Mugale
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Chen J, Qiu P, Zhao T, Jiang H, Tursun K, Ksimu S, Chen X, Wang Q. Measures of insulin resistance and beta cell function before and after treatment of HCV infection. Virol Sin 2024; 39:667-674. [PMID: 38950863 PMCID: PMC11401464 DOI: 10.1016/j.virs.2024.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 06/19/2024] [Indexed: 07/03/2024] Open
Abstract
The association between chronic HCV infection and type 2 diabetes mellitus (T2DM) has been established; however, there is limited research on β-cell function particularly in the pre-diabetic population. Here, we evaluated indices of β-cell function and insulin sensitivity across the spectrum from normal glucose tolerance to T2DM in individuals with and without chronic hepatitis C (CHC), and the effects of antiviral treatments on these variables. A total of 153 non-cirrhotic, non-fibrotic CHC patients with a BMI <25 were enrolled in the study. Among them, 119 were successfully treated with either direct acting antiviral (DAA) drugs or pegylated interferon/ribavirin (IFN/RBV) anti-HCV therapy. Fasting state- and oral glucose tolerance test (OGTT)-derived indexes were used to evaluate β-cell function and insulin sensitivity. Among all subjects, 19 (13%) had T2DM and 21% exhibited pre-diabetes including 8% isolated impaired fasting glucose (IFG) and 13% combined IFG and impaired glucose tolerance (IGT). Early and total insulin secretion adjusted for the degree of insulin resistance were decreased in pre-diabetic CHC patients compared to HCV-uninfected individuals. Viral eradication through DAA or IFN/RBV therapy demonstrated positive impacts on insulin sensitivity and β-cell function in CHC patients who achieved sustained virologic response (SVR), regardless of fasting or OGTT state. These findings emphasize the role of HCV in the development of β-cell dysfunction, while also suggesting that viral eradication can improve insulin secretion, reverse insulin resistance, and ameliorate glycemic control. These results have important implications for managing pre-diabetic CHC patients and could prevent diabetes-related clinical manifestations and complications.
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Affiliation(s)
- Jizheng Chen
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510182, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China; Guangzhou Laboratory, Guangzhou, 510005, China.
| | - Pan Qiu
- Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China
| | - Tingfeng Zhao
- Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China
| | - Haowei Jiang
- Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China
| | - Kebinur Tursun
- The First Affiliated Hospital of Xinjiang Medical University, Urumchi, 830054, China
| | - Sulaiman Ksimu
- The First Affiliated Hospital of Xinjiang Medical University, Urumchi, 830054, China
| | - Xinwen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China; Guangzhou Laboratory, Guangzhou, 510005, China.
| | - Qian Wang
- Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China.
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Lu G, Pan F, Li X, Zhu Z, Zhao L, Wu Y, Tian W, Peng W, Liu J. Virtual screening strategy for anti-DPP-IV natural flavonoid derivatives based on machine learning. J Biomol Struct Dyn 2024; 42:6645-6659. [PMID: 37489054 DOI: 10.1080/07391102.2023.2237594] [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: 02/27/2023] [Accepted: 07/06/2023] [Indexed: 07/26/2023]
Abstract
Flavonoids, especially their inhibitory effect on DPP-IV activity, have been widely recognized for their antidiabetic effects. However, the variety of natural flavonoid derivatives is very rich, and even subtle structural differences can lead to several orders of magnitude differences in their inhibitory activities against DPP-IV, which makes it challenging to find novel and potent anti-DPP-IV flavonoid derivatives experimentally. Therefore, there is an urgent need to develop an efficient screening pipeline that targets active natural products. Here, we propose a fusion strategy based on a QSAR model, and to simplify this process, it was applied to the discovery of flavonoid derivatives with potent anti-DPP-IV activity. First, the high-quality QSAR model (R test 2 = 0.816, MAEtest = 0.14, MSEtest = 0.026) was composed of seven key molecular property parameters, which were constructed with the genetic algorithm (GA) and passed the leave-one-out cross-validation evaluation. A total of 1,668 flavonoid derivatives were obtained from the natural product enriched by NPCD based on molecular fingerprint similarity (> 0.8). Further, the enriched flavonoid derivatives were further predicted and screened using the QED score combined with the QSAR model, and a total of 33 flavonoid derivatives (IC50pre < 6.5 μM) were found. Subsequently, three flavonoid derivatives (5,7,3',5'-tetrahydroxyflavone, 3,7-dihydroxy-5,3',4'-trimethoxyflavone, and 5,7,2',5'-tetrahydroxyflavone) with highly effective anti-DPP-IV activity were obtained by ADMET analysis. Finally, the DPP-IV inhibitory potential of these three flavonoid derivatives was verified by 100 ns MD simulation and MM/PB(GB)SA.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Gen Lu
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Shenyang Agricultural University, Shenyang, China
| | - Fei Pan
- State Key Laboratory of Resource Insects, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences, Beijing, China
- Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing, China
| | - Xiaotong Li
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Shenyang Agricultural University, Shenyang, China
| | - Zehui Zhu
- Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing, China
| | - Lei Zhao
- Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology and Business University, Beijing, China
| | - Ya Wu
- Institute of Resource Biology and Biotechnology, Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Wenli Tian
- State Key Laboratory of Resource Insects, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Wenjun Peng
- State Key Laboratory of Resource Insects, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Jinling Liu
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, Shenyang Agricultural University, Shenyang, China
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Niu B, Ma L, Yao L, Zhang Y, Su H. HCV affects K ATP channels through GnT-IVa-mediated N-glycosylation of GLUT2 on the surface of pancreatic β-cells leading to impaired insulin secretion. Endocrine 2024; 84:427-440. [PMID: 37962815 PMCID: PMC11076383 DOI: 10.1007/s12020-023-03589-z] [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: 07/03/2023] [Accepted: 10/29/2023] [Indexed: 11/15/2023]
Abstract
PURPOSE To explore the mechanism of insulin secretion dysfunction in pancreatic beta cells induced by N-glycosylation mediated by an infection from the hepatitis C virus (HCV). METHODS Min6 cell models infected with HCV and stimulated with glucose were constructed. Meanwhile, an HCV-infected animal model and a type 2 diabetes mellitus (T2DM) rat model were constructed. Glucose uptake in the Min6 cells was detected, and insulin secretion was detected by ELISA. Flow cytometry, immunofluorescence staining, Western blotting, RT-qPCR, and lectin blotting were used to detect the expression levels of related proteins and mRNA, as well as the level of N-glycosylation. HE staining was used to observe the pathological changes in the pancreatic tissue, and an oral glucose tolerance test (OGTT) was used to evaluate the glucose tolerance of the rats. RESULTS Compared with the NC group, the expression levels of GnT-IVa, GLUT2, galectin-9, and voltage-dependent calcium channel 1.2 (Cav1.2) were significantly downregulated in the HCV-infected group. The ATP-sensitive potassium channel (KATP) component proteins SUR1 and Kir6.2 were significantly upregulated, while intracellular glucose intake and insulin secretion decreased, N-glycosylation levels and ATP levels significantly decreased, and the overexpression of GnT-IVa reversed the effect of the HCV infection. However, treatment with the glycosylation inhibitor kifunensine (KIF) or the KATP channel activator diazine (Dia) reversed the effects of the overexpression of GnT-IVa. In the animal experiments, HE staining revealed serious pathological injuries in the pancreatic tissue of the HCV-infected rats, with decreased glucose tolerance and glycosylation levels, decreased insulin secretion, downregulated expression of GnT-IVa, GLUT2, and Cav1.2, and upregulated expression of SUR1 and Kir6.2. The overexpression treatment of GnT-IVa or the KATP channel antagonist miglinide reversed the effects of HCV. CONCLUSION HCV infection inhibits GLUT2 N-glycosylation on the pancreatic β cell surface by downregulating the expression of GnT-IVa and then activates the KATP pathway, which ultimately leads to disturbances in insulin secretion.
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Affiliation(s)
- Ben Niu
- Department of Endocrinology and Metabolism, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Lijing Ma
- Department of Endocrinology and Metabolism, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Lixuan Yao
- Department of Nephrology, Bao Ji People's Hospital, Baoji, 721000, Shaanxi, China
| | - Yating Zhang
- Department of Endocrinology and Metabolism, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
| | - Heng Su
- Department of Endocrinology and Metabolism, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China.
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Pascual-Oliver A, Casas-Deza D, Yagüe-Caballero C, Arbones-Mainar JM, Bernal-Monterde V. Lipid Profile and Cardiovascular Risk Modification after Hepatitis C Virus Eradication. Pathogens 2024; 13:278. [PMID: 38668233 PMCID: PMC11054742 DOI: 10.3390/pathogens13040278] [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: 02/05/2024] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/29/2024] Open
Abstract
The eradication of the hepatitis C virus (HCV) has revolutionized the hepatology paradigm, halting the progression of advanced liver disease in patients with chronic infection and reducing the risk of hepatocarcinoma. In addition, treatment with direct-acting antivirals can reverse the lipid and carbohydrate abnormalities described in HCV patients. Although HCV eradication may reduce the overall risk of vascular events, it is uncertain whether altered lipid profiles increase the risk of cerebrovascular disease in certain patients. We have conducted a review on HCV and lipid and carbohydrate metabolism, as well as new scientific advances, following the advent of direct-acting antivirals.
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Affiliation(s)
- Andrea Pascual-Oliver
- Gastroenterology Department, Miguel Servet University Hospital, 50009 Zaragoza, Spain; (A.P.-O.); (C.Y.-C.); (V.B.-M.)
| | - Diego Casas-Deza
- Gastroenterology Department, Miguel Servet University Hospital, 50009 Zaragoza, Spain; (A.P.-O.); (C.Y.-C.); (V.B.-M.)
- Adipocyte and Fat Biology Laboratory (AdipoFat), Translational Research Unit, University Hospital Miguel Servet, 50009 Zaragoza, Spain;
- Instituto Aragones de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
- Instituto de Investigación Sanitaria (IIS) Aragon, 50009 Zaragoza, Spain
| | - Carmen Yagüe-Caballero
- Gastroenterology Department, Miguel Servet University Hospital, 50009 Zaragoza, Spain; (A.P.-O.); (C.Y.-C.); (V.B.-M.)
- Adipocyte and Fat Biology Laboratory (AdipoFat), Translational Research Unit, University Hospital Miguel Servet, 50009 Zaragoza, Spain;
- Instituto de Investigación Sanitaria (IIS) Aragon, 50009 Zaragoza, Spain
| | - Jose M. Arbones-Mainar
- Adipocyte and Fat Biology Laboratory (AdipoFat), Translational Research Unit, University Hospital Miguel Servet, 50009 Zaragoza, Spain;
- Instituto Aragones de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
- Instituto de Investigación Sanitaria (IIS) Aragon, 50009 Zaragoza, Spain
- CIBER Fisiopatología Obesidad y Nutrición (CIBERObn), Instituto Salud Carlos III, 28029 Madrid, Spain
| | - Vanesa Bernal-Monterde
- Gastroenterology Department, Miguel Servet University Hospital, 50009 Zaragoza, Spain; (A.P.-O.); (C.Y.-C.); (V.B.-M.)
- Adipocyte and Fat Biology Laboratory (AdipoFat), Translational Research Unit, University Hospital Miguel Servet, 50009 Zaragoza, Spain;
- Instituto Aragones de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
- Instituto de Investigación Sanitaria (IIS) Aragon, 50009 Zaragoza, Spain
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Cheng YC, Lee TY, Li YH, Lu CL, Liu HC, Sheu ML, Lee IT. Hepatitis C virus antibody seropositivity is associated with albuminuria but not peripheral artery disease in patients with type 2 diabetes. Sci Rep 2024; 14:4607. [PMID: 38409227 PMCID: PMC10897399 DOI: 10.1038/s41598-024-55352-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 02/05/2024] [Indexed: 02/28/2024] Open
Abstract
Hepatitis C virus (HCV) infection is prevalent in patients with type 2 diabetes mellitus (DM). We aimed to investigate whether HCV antibody (Ab) seropositivity is associated with diabetic micro- and macro-vascular diseases. In this hospital-based cross-sectional study, we retrospectively collected data from patients who participated in the diabetes pay-for-performance program and underwent HCV Ab screening in the annual comprehensive assessment between January 2021 and March 2022. We examined the relationships of HCV Ab seropositivity with the spot urinary albumin-to-creatinine ratio (UACR) and ankle-brachial index (ABI) in patients aged ≥ 50 years with type 2 DM. A total of 1758 patients were enrolled, and 85 (4.83%) of the enrolled patients had HCV Ab seropositivity. Multivariable regression analyses revealed that albuminuria showed a dose-dependent association with HCV Ab seropositivity (UACR [30-299 mg/g]: odds ratio [OR] = 1.463, 95% confidence interval [CI] 0.872‒2.456); UACR [≥ 300 mg/g]: OR = 2.300, 95% CI 1.160‒4.562; P for trend = 0.015) when compared with normal albuminuria (UACR < 30 mg/g). However, the proportion of patients with peripheral arterial disease, defined as an ABI ≤ 0.9, was not significantly different between the groups with and without HCV Ab seropositivity (3.5% vs. 3.9%, P = 0.999). In conclusion, severely increased albuminuria, but not the ABI, showed a significant association with HCV Ab seropositivity in patients aged ≥ 50 years with type 2 DM.
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Affiliation(s)
- Yu-Cheng Cheng
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, 40705, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan
| | - Teng-Yu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, 40705, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan
| | - Yu-Hsuan Li
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, 40705, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
- Department of Computer Science and Information Engineering, National Taiwan University, Taipei, 10617, Taiwan
| | - Chin-Li Lu
- Graduate Institute of Food Safety, College of Agriculture and Natural Resources, National Chung Hsing University, Taichung, 40227, Taiwan
| | - Hsiu-Chen Liu
- Department of Nursing, Taichung Veterans General Hospital, Taichung, 40705, Taiwan
| | - Meei Ling Sheu
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan
| | - I-Te Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, 40705, Taiwan.
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.
- School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan.
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10
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Diaz O, Legrand AF, El-Orch W, Jacolin F, Lotteau V, Ramière C, Vidalain PO, Perrin-Cocon L. [Role of cellular metabolism in the control of chronic viral hepatitis]. Med Sci (Paris) 2023; 39:754-762. [PMID: 37943136 DOI: 10.1051/medsci/2023125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2023] Open
Abstract
Hepatitis viruses modify the cellular metabolism of hepatocytes by interacting with specific enzymes such as glucokinase. The metabolic changes induced by viruses can have a direct impact on the innate antiviral response. The complex interactions between viral components, innate immunity, and hepatocyte metabolism explain why chronic hepatitis infections lead to liver inflammation, progressing to cirrhosis, fibrosis, and hepatocellular carcinoma. Metabolic regulators could be used in innovative therapies to deprive viruses of key metabolites and induce an antiviral defense.
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Affiliation(s)
- Olivier Diaz
- CIRI, Centre international de recherche en infectiologie, équipe VIRIMI, Univ Lyon, Inserm U1111, université Claude Bernard Lyon 1, CNRS, UMR5308, École normale supérieure (ENS) de Lyon, F-69007, Lyon, France
| | - Anne-Flore Legrand
- CIRI, Centre international de recherche en infectiologie, équipe VIRIMI, Univ Lyon, Inserm U1111, université Claude Bernard Lyon 1, CNRS, UMR5308, École normale supérieure (ENS) de Lyon, F-69007, Lyon, France
| | - Walid El-Orch
- CIRI, Centre international de recherche en infectiologie, équipe VIRIMI, Univ Lyon, Inserm U1111, université Claude Bernard Lyon 1, CNRS, UMR5308, École normale supérieure (ENS) de Lyon, F-69007, Lyon, France
| | - Florentine Jacolin
- CIRI, Centre international de recherche en infectiologie, équipe VIRIMI, Univ Lyon, Inserm U1111, université Claude Bernard Lyon 1, CNRS, UMR5308, École normale supérieure (ENS) de Lyon, F-69007, Lyon, France
| | - Vincent Lotteau
- CIRI, Centre international de recherche en infectiologie, équipe VIRIMI, Univ Lyon, Inserm U1111, université Claude Bernard Lyon 1, CNRS, UMR5308, École normale supérieure (ENS) de Lyon, F-69007, Lyon, France
| | - Christophe Ramière
- CIRI, Centre international de recherche en infectiologie, équipe VIRIMI, Univ Lyon, Inserm U1111, université Claude Bernard Lyon 1, CNRS, UMR5308, École normale supérieure (ENS) de Lyon, F-69007, Lyon, France - Service de virologie, hospices civils de Lyon, hôpital de la Croix-Rousse, Lyon, France
| | - Pierre-Olivier Vidalain
- CIRI, Centre international de recherche en infectiologie, équipe VIRIMI, Univ Lyon, Inserm U1111, université Claude Bernard Lyon 1, CNRS, UMR5308, École normale supérieure (ENS) de Lyon, F-69007, Lyon, France
| | - Laure Perrin-Cocon
- CIRI, Centre international de recherche en infectiologie, équipe VIRIMI, Univ Lyon, Inserm U1111, université Claude Bernard Lyon 1, CNRS, UMR5308, École normale supérieure (ENS) de Lyon, F-69007, Lyon, France
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11
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Aldubaie MH, Suryavamshi PM, Irfan UM, Al-Hamed HA, Almogbel TA, Almatroudi A, Alrumaihi F, Allemailem K. Prevalence of Hepatitis C Viral Infection among Diabetes Mellitus Patients in Qassim Region, Saudi Arabia. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2023; 17:1722-1736. [DOI: 10.22207/jpam.17.3.37] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The worldwide prevalence of Diabetes Mellitus (DM) associated with Hepatitis C Virus (HCV) infection are reported with higher rates of morbidity and mortality. The frequency of HCV is approximately 3-4 million cases each year and in parallel the incidence of DM is increasing alarmingly. World Health Organization (WHO) has specified that DM will be the 7th leading cause of mortality by 2030. The increasing association between HCV and DM has been indicated by some significant reports recently. HCV infection leads to hepatic steatosis and rapid insulin resistance, which in turn upsurges the risk factors for hepatic fibrosis and hepatocellular carcinoma. This study is designed to examine the association between HCV and DM, and different risk factors associated with HCV infection in Qassim region, Kingdom of Saudi Arabia (KSA). A total of 634 blood samples were obtained from diabetic and non-diabetic patients. These blood samples were first screened for HCV infection by enzyme-linked immunosorbent assay (ELISA) and positive samples were again confirmed by TaqMan HCV quantitative test and the viral load in different samples was estimated. The HCV prevalence was identified as 2.5% in diabetic patients with a positive association between HCV and DM (RR= 1.24, OR= 1.77) which is not significant statistically. However, the HCV prevalence among diabetic females was significantly different from males (p<0.05). The behavioural factors had no significant impact to acquire HCV infection. This study indicated a positive association between HCV and DM. Gender was an association factor in the HCV and DM status. Further studies with larger sample size is significant to properly assess the temporal relationship between HCV and DM.
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12
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Konishi F, Miyake T, Watanabe T, Tokumoto Y, Furukawa S, Matsuura B, Yoshida O, Miyazaki M, Shiomi A, Kanzaki S, Nakaguchi H, Nakamura Y, Imai Y, Koizumi M, Yamamoto Y, Koizumi Y, Hirooka M, Takeshita E, Kumagi T, Ikeda Y, Abe M, Hiasa Y. Association of abnormal glucose tolerance with liver-related disease and cardiovascular diseases in patients with chronic hepatitis C. Hepatol Res 2023; 53:806-814. [PMID: 37183992 DOI: 10.1111/hepr.13925] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/06/2023] [Accepted: 05/08/2023] [Indexed: 05/16/2023]
Abstract
AIM Hepatitis C complicated by diabetes mellitus (DM) is considered a risk factor for the progression of fibrosis and development of hepatocellular carcinoma (HCC) and cardiovascular diseases. However, several studies may have lacked appropriate diagnosis of glucose intolerance. We aimed to examine the risk associated with abnormal glucose intolerance in the development of liver-related diseases, including HCC and complications of liver cirrhosis, such as ascites, esophageal and gastric varices, and hepatic encephalopathy, and cardiovascular diseases in patients with hepatitis C accurately diagnosed with impaired glucose tolerance. METHODS This longitudinal retrospective study included 365 patients with chronic hepatitis C admitted to Ehime University Hospital for anti-hepatitis C therapy between September 1991 and January 2015. Patients were classified into normal glucose tolerance (NGT), prediabetes, and DM groups based on 75-g oral glucose tolerance test results. RESULTS Both univariate and multivariate (adjusted for potential confounders) analyses revealed a significantly higher risk of developing HCC and cardiovascular events in the DM group than in the NGT group. However, in multivariate analysis, liver-related events, particularly liver cirrhosis complications, revealed no significant association. In addition, the prediabetes group had no significant risk of any outcome. CONCLUSIONS Patients with hepatitis C complicated by DM, compared with patients with hepatitis C with NGT or complicated with prediabetes, have a higher risk of HCC and cardiovascular disease events, but not liver-related events, particularly in not developing liver cirrhosis complications. Therefore, appropriate follow-up is required for patients with hepatitis C based on their glucose tolerance status.
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Affiliation(s)
| | - Teruki Miyake
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Shinya Furukawa
- Health Services Center, Ehime University, Matsuyama, Ehime, Japan
| | - Bunzo Matsuura
- Department of Lifestyle-related Medicine and Endocrinology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Masumi Miyazaki
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Akihito Shiomi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Sayaka Kanzaki
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Hironobu Nakaguchi
- Department of Lifestyle-related Medicine and Endocrinology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yoshiko Nakamura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yusuke Imai
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Mitsuhito Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yasunori Yamamoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Eiji Takeshita
- Department of Inflammatory Bowel Diseases and Therapeutics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Teru Kumagi
- Postgraduate Medical Education Center, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yoshio Ikeda
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
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13
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Gomes D, Sobolewski C, Conzelmann S, Schaer T, Lefai E, Alfaiate D, Tseligka ED, Goossens N, Tapparel C, Negro F, Foti M, Clément S. ANGPTL4 is a potential driver of HCV-induced peripheral insulin resistance. Sci Rep 2023; 13:6767. [PMID: 37185283 PMCID: PMC10130097 DOI: 10.1038/s41598-023-33728-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 04/18/2023] [Indexed: 05/17/2023] Open
Abstract
Chronic hepatitis C (CHC) is associated with the development of metabolic disorders, including both hepatic and extra-hepatic insulin resistance (IR). Here, we aimed at identifying liver-derived factor(s) potentially inducing peripheral IR and uncovering the mechanisms whereby HCV can regulate the action of these factors. We found ANGPTL4 (Angiopoietin Like 4) mRNA expression levels to positively correlate with HCV RNA (r = 0.46, p < 0.03) and HOMA-IR score (r = 0.51, p = 0.01) in liver biopsies of lean CHC patients. Moreover, we observed an upregulation of ANGPTL4 expression in two models recapitulating HCV-induced peripheral IR, i.e. mice expressing core protein of HCV genotype 3a (HCV-3a core) in hepatocytes and hepatoma cells transduced with HCV-3a core. Treatment of differentiated myocytes with recombinant ANGPTL4 reduced insulin-induced Akt-Ser473 phosphorylation. In contrast, conditioned medium from ANGPTL4-KO hepatoma cells prevented muscle cells from HCV-3a core induced IR. Treatment of HCV-3a core expressing HepG2 cells with PPARγ antagonist resulted in a decrease of HCV-core induced ANGPTL4 upregulation. Together, our data identified ANGPTL4 as a potential driver of HCV-induced IR and may provide working hypotheses aimed at understanding the pathogenesis of IR in the setting of other chronic liver disorders.
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Affiliation(s)
- Diana Gomes
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
- Koch Institute for Integrative Cancer Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Cyril Sobolewski
- Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
- U1286-INFINITE-Institute for Translational Research in Inflammation, CHU Lille, Inserm, University Lille, 59000, Lille, France
| | - Stéphanie Conzelmann
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Tifany Schaer
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Etienne Lefai
- Unité de Nutrition Humaine, INRAE, Université Clermont Auvergne, 63000, Clermont-Ferrand, France
| | - Dulce Alfaiate
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
- Department of Infectious Diseases, Hôpital de la Croix Rousse, Lyon University Hospitals, Lyon, France
| | - Eirini D Tseligka
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Nicolas Goossens
- Gastroenterology and Hepatology Division, University Hospitals, Geneva, Switzerland
| | - Caroline Tapparel
- Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
| | - Francesco Negro
- Gastroenterology and Hepatology Division, University Hospitals, Geneva, Switzerland
- Clinical Pathology Division, University Hospitals, Geneva, Switzerland
| | - Michelangelo Foti
- Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Sophie Clément
- Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
- Clinical Pathology Division, University Hospitals, Geneva, Switzerland.
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14
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Zheng H, Yang F, Deng K, Wei J, Liu Z, Zheng YC, Xu H. Relationship between iron overload caused by abnormal hepcidin expression and liver disease: A review. Medicine (Baltimore) 2023; 102:e33225. [PMID: 36930080 PMCID: PMC10019217 DOI: 10.1097/md.0000000000033225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 02/16/2023] [Indexed: 03/18/2023] Open
Abstract
Iron is essential to organisms, the liver plays a vital role in its storage. Under pathological conditions, iron uptake by the intestine or hepatocytes increases, allowing excess iron to accumulate in liver cells. When the expression of hepcidin is abnormal, iron homeostasis in humans cannot be regulated, and resulting in iron overload. Hepcidin also regulates the release of iron from siderophores, thereby regulating the concentration of iron in plasma. Important factors related to hepcidin and systemic iron homeostasis include plasma iron concentration, body iron storage, infection, inflammation, and erythropoietin. This review summarizes the mechanism and regulation of iron overload caused by hepcidin, as well as related liver diseases caused by iron overload and treatment.
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Affiliation(s)
- Haoran Zheng
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China
| | - Fan Yang
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Kaige Deng
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Jiaxin Wei
- Department of Emergency, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhenting Liu
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China
| | - Yong-Chang Zheng
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Haifeng Xu
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
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15
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Cook TW, Wilstermann AM, Mitchell JT, Arnold NE, Rajasekaran S, Bupp CP, Prokop JW. Understanding Insulin in the Age of Precision Medicine and Big Data: Under-Explored Nature of Genomics. Biomolecules 2023; 13:257. [PMID: 36830626 PMCID: PMC9953665 DOI: 10.3390/biom13020257] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023] Open
Abstract
Insulin is amongst the human genome's most well-studied genes/proteins due to its connection to metabolic health. Within this article, we review literature and data to build a knowledge base of Insulin (INS) genetics that influence transcription, transcript processing, translation, hormone maturation, secretion, receptor binding, and metabolism while highlighting the future needs of insulin research. The INS gene region has 2076 unique variants from population genetics. Several variants are found near the transcriptional start site, enhancers, and following the INS transcripts that might influence the readthrough fusion transcript INS-IGF2. This INS-IGF2 transcript splice site was confirmed within hundreds of pancreatic RNAseq samples, lacks drift based on human genome sequencing, and has possible elevated expression due to viral regulation within the liver. Moreover, a rare, poorly characterized African population-enriched variant of INS-IGF2 results in a loss of the stop codon. INS transcript UTR variants rs689 and rs3842753, associated with type 1 diabetes, are found in many pancreatic RNAseq datasets with an elevation of the 3'UTR alternatively spliced INS transcript. Finally, by combining literature, evolutionary profiling, and structural biology, we map rare missense variants that influence preproinsulin translation, proinsulin processing, dimer/hexamer secretory storage, receptor activation, and C-peptide detection for quasi-insulin blood measurements.
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Affiliation(s)
- Taylor W. Cook
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
| | | | - Jackson T. Mitchell
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
| | - Nicholas E. Arnold
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
| | - Surender Rajasekaran
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
- Office of Research, Corewell Health, Grand Rapids, MI 49503, USA
| | - Caleb P. Bupp
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
- Division of Medical Genetics, Corewell Health, Grand Rapids, MI 49503, USA
| | - Jeremy W. Prokop
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
- Office of Research, Corewell Health, Grand Rapids, MI 49503, USA
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16
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Nakatsuka T, Tateishi R. Development and prognosis of hepatocellular carcinoma in patients with diabetes. Clin Mol Hepatol 2023; 29:51-64. [PMID: 35903020 PMCID: PMC9845683 DOI: 10.3350/cmh.2022.0095] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/03/2022] [Indexed: 02/02/2023] Open
Abstract
The incidence of diabetes mellitus and hepatocellular carcinoma (HCC) has been increasing worldwide during the last few decades, in the context of an increasing prevalence of obesity and non-alcoholic fatty liver disease (NAFLD). Epidemiologic studies have revealed that patients with diabetes have a 2- to 3-fold increased risk of developing HCC, independent of the severity and cause of the underlying liver disease. A bidirectional relationship exists between diabetes and liver disease: advanced liver disease promotes the onset of diabetes, and HCC is an important cause of death in patients with diabetes; conversely, diabetes is a risk factor for liver fibrosis progression and HCC development, and may worsen the long-term prognosis of patients with HCC. The existence of close interconnections among diabetes, obesity, and NAFLD causes insulin resistance-related hyperinsulinemia, increased oxidative stress, and chronic inflammation, which are assumed to be the underlying causes of hepatocarcinogenesis in patients with diabetes. No appropriate surveillance methods for HCC development in patients with diabetes have been established, and liver diseases, including HCC, are often overlooked as complications of diabetes. Although some antidiabetic drugs are expected to prevent HCC development, further research on the optimal use of antidiabetic drugs aimed at hepatoprotection is warranted. Given the increasing medical and socioeconomic impact of diabetes on HCC development, diabetologists and hepatologists need to work together to develop strategies to address this emerging health issue. This article reviews the current knowledge on the impact of diabetes on the development and progression of HCC.
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Affiliation(s)
- Takuma Nakatsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan,Corresponding author : Ryosuke Tateishi Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Tel: +81-3-3815-5411, Fax: +81-3-3814-0021, E-mail:
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17
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Diaz O, Vidalain PO, Ramière C, Lotteau V, Perrin-Cocon L. What role for cellular metabolism in the control of hepatitis viruses? Front Immunol 2022; 13:1033314. [PMID: 36466918 PMCID: PMC9713817 DOI: 10.3389/fimmu.2022.1033314] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/02/2022] [Indexed: 11/26/2023] Open
Abstract
Hepatitis B, C and D viruses (HBV, HCV, HDV, respectively) specifically infect human hepatocytes and often establish chronic viral infections of the liver, thus escaping antiviral immunity for years. Like other viruses, hepatitis viruses rely on the cellular machinery to meet their energy and metabolite requirements for replication. Although this was initially considered passive parasitism, studies have shown that hepatitis viruses actively rewire cellular metabolism through molecular interactions with specific enzymes such as glucokinase, the first rate-limiting enzyme of glycolysis. As part of research efforts in the field of immunometabolism, it has also been shown that metabolic changes induced by viruses could have a direct impact on the innate antiviral response. Conversely, detection of viral components by innate immunity receptors not only triggers the activation of the antiviral defense but also induces in-depth metabolic reprogramming that is essential to support immunological functions. Altogether, these complex triangular interactions between viral components, innate immunity and hepatocyte metabolism may explain why chronic hepatitis infections progressively lead to liver inflammation and progression to cirrhosis, fibrosis and hepatocellular carcinoma (HCC). In this manuscript, we first present a global overview of known connections between the innate antiviral response and cellular metabolism. We then report known molecular mechanisms by which hepatitis viruses interfere with cellular metabolism in hepatocytes and discuss potential consequences on the innate immune response. Finally, we present evidence that drugs targeting hepatocyte metabolism could be used as an innovative strategy not only to deprive viruses of key metabolites, but also to restore the innate antiviral response that is necessary to clear infection.
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Affiliation(s)
- Olivier Diaz
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Pierre-Olivier Vidalain
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Christophe Ramière
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
- Laboratoire de Virologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Vincent Lotteau
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Laure Perrin-Cocon
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
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18
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Alzahrani N. Hepatitis C Virus, Insulin Resistance, and Diabetes: A Review. Microbiol Immunol 2022; 66:453-459. [PMID: 35941761 DOI: 10.1111/1348-0421.13023] [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: 01/25/2022] [Revised: 07/19/2022] [Accepted: 08/03/2022] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) infection and diabetes mellitus (DM) are two chronic diseases that are a cause of significant health and economic burdens worldwide. HCV is associated with the development of insulin resistance (IR) and diabetes mellitus (DM). The mechanisms through which HCV induces IR and DM include direct viral effects, pro-inflammatory cytokines and other immune-mediated processes. Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are both chronic diseases that involve impaired glucose homeostasis, albeit through different mechanisms. T1DM is an autoimmune disease that leads to the destruction of pancreatic beta cells resulting in insulin deficiency. In T2DM, a combination of peripheral insulin resistance and irregular production of insulin eventually lead to beta cell destruction and insulin insufficiency. Both type 1 and type 2 DM etiologies involve a combination of genetic and environmental factors. The data on HCV and T1DM association is limited, unlike T2DM, where a large body of evidence linking HCV to T2DM is available. Here, we intend to outline the current state of knowledge on HCV, IR, and DM. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Nabeel Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud bin Abdulaziz University for Health Sciences, Riyadh, 14611, Saudi Arabia
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19
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Nakatsuka T, Tateishi R, Koike K. Changing clinical management of NAFLD in Asia. Liver Int 2022; 42:1955-1968. [PMID: 34459096 DOI: 10.1111/liv.15046] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/30/2021] [Accepted: 08/21/2021] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, affecting approximately 25% of the world's population. Recently, because of the sedentary lifestyle and overnutrition resulting from urbanisation, the burden of NAFLD has rapidly increased in many Asian countries. Currently, the prevalence of NAFLD in Asia is approximately 30%, as is the case in many Western countries. In Asia, the prevalence and presentation of NAFLD vary widely across regions because of the substantial diversity in race, socioeconomic status and living environment. Furthermore, the dual aetiology of fatty liver, particularly with viral hepatitis in Asia, makes it complex and challenging to manage. Because Asians are likely to have central adiposity and insulin resistance, approximately 7%-20% of non-obese Asians with body mass indexes of less than 25 kg/m2 are estimated to have NAFLD. Accumulating evidence indicates that NAFLD is associated with various extrahepatic comorbidities such as cardiovascular disease, chronic kidney disease, malignancy, in addition to liver-specific complications. Therefore, NAFLD should be managed as a multisystem disease in conjunction with metabolic syndrome. Lifestyle modification remains the basis of NAFLD management, but few patients can achieve adequate weight loss and maintain it long term. While various pharmacological agents are in phase 3 trials for steatohepatitis, Asian patients are underrepresented in most trials. This article reviews the epidemiological trends, clinical features, optimal assessment and current management practices for NAFLD in Asia.
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Affiliation(s)
- Takuma Nakatsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
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20
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Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol 2022; 77:219-236. [PMID: 35157957 DOI: 10.1016/j.jhep.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/12/2022] [Accepted: 01/31/2022] [Indexed: 12/16/2022]
Abstract
HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.
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Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmed M Elsharkawy
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, B15 2TH UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
| | - Michele Vacca
- Interdisciplinary Department of Medicine, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
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21
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Liu X, Liang Z, Duan H, Yu J, Qin Z, Li J, Zhu L, Wu Q, Xiao W, Shen C, Wan C, Wu K, Ye H, Zhang B, Zhao W. Dengue virus is involved in insulin resistance via the downregulation of IRS-1 by inducing TNF-α secretion. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166472. [PMID: 35752384 DOI: 10.1016/j.bbadis.2022.166472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 11/29/2022]
Abstract
During the epidemic, the individuals with underlying diseases usually have a higher rate of mortality. Diabetes is highly prevalent worldwide, making it a frequent comorbidity in dengue fever patients. Therefore, understanding the relationship between dengue virus (DENV) infection and diabetes is important. We first demonstrated that DENV-3 infection down-regulated the expression of IRS-1. In vitro, treatment of HepG2 cells with TNF-α inhibitors and siRNA proved that after DENV-3 infection in HepG2 cells, cellular TNF-α secretion was increased, which negatively regulated IRS-1, thereby leading to an insulin-resistant state. In vivo, DENV-3 induced insulin resistance (IR) in hepatocytes by promoting the secretion of TNF-α and inhibiting the expression of IRS-1 was proved. In vivo approaches also showed that after DENV-3 infection, TNF-α levels in the serum of C57BL/6 mice with insulin resistance increased, and upon TNF-α antagonist III treatment, IRS-1 expression in the liver, reduced by infection, was upregulated. In addition, transcriptomic analysis revealed more negative regulatory events in the insulin receptor signaling pathway after DENV-3 infection. This is the first report of a link between DENV-3 infection and insulin resistance, and it lays a foundation for further research.
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Affiliation(s)
- Xuling Liu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Zuxin Liang
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Hongwei Duan
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Jianhai Yu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Zhiran Qin
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Jingshu Li
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Li Zhu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Qinghua Wu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Weiwei Xiao
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Chenguang Shen
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Chengsong Wan
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Kefeng Wu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China
| | - Hua Ye
- Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China.
| | - Bao Zhang
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China.
| | - Wei Zhao
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China.
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22
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Biomarkers for the Detection and Management of Hepatocellular Carcinoma in Patients Treated with Direct-Acting Antivirals. Cancers (Basel) 2022; 14:cancers14112700. [PMID: 35681679 PMCID: PMC9179595 DOI: 10.3390/cancers14112700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Chronic Hepatitis C virus (HCV) represents the main etiological factor for hepatocellular carcinoma (HCC) in developed countries. The introduction of direct-acting antivirals (DAAs) improved the eradication of the hepatitis C virus (HCV) but not the reduction in the incidence of HCV-associated HCC. Some patients still develop HCC, even after reaching a sustained virological response (SVR). This review is a summary of pre-clinical studies that investigated predictive biomarkers for HCC occurrence and recurrence in HCV-infected patients treated with DAAs. The presented biomarkers are found dysregulated in serum or tissue at specific time points (before, during, after DAA treatment or post SVR) and correlated with HCC-predisposing conditions. Thus, this review aims to improve the management of patients developing HCV-induced HCC. Abstract Hepatocellular carcinoma (HCC) is the sixth-most common type of cancer worldwide and chronic Hepatitis C virus (HCV) represents the main etiological factor in developed countries. HCV promotes hepatocarcinogenesis through persistent liver inflammation and dysregulation of cell signaling pathways. The introduction of direct-acting antivirals (DAAs) resulted in a significant improvement in the eradication of the virus, with an expected reduction of HCC incidence. However, the risk of HCC development can persist after DAA treatment. Recent studies have investigated the potential use of molecular biomarkers that predict HCC occurrence or recurrence helping the stratification of patients under surveillance. This review aimed to summarize all pre-clinical exploration of predictive biomarkers to identify DAA-treated patients at risk for HCC development. Dysregulated microRNAs, lncRNAs, histone modifications, cytokines, proteins, and sphingolipids represent various classes of HCC risk predictors identified in two different biological sources (tissue and serum). The non-invasive serum markers can provide a more accessible means to perform clinical monitoring and predict the risk of HCC. In addition, conditions like cirrhosis, predisposing to HCC, strongly correlate with most of the molecular predictors identified, supporting the value of these molecules as possible biomarkers of HCC in DAA-treated patients.
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Hyperglycemia and Loss of Redox Homeostasis in COVID-19 Patients. Cells 2022; 11:cells11060932. [PMID: 35326383 PMCID: PMC8946177 DOI: 10.3390/cells11060932] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/05/2022] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
The infection with SARS-CoV-2 impairs the glucose−insulin axis and this contributes to oxidative (OS) and nitrosative (NSS) stress. Here, we evaluated changes in glucose metabolism that could promote the loss of redox homeostasis in COVID-19 patients. This was comparative cohort and analytical study that compared COVID-19 patients and healthy subjects. The study population consisted of 61 COVID-19 patients with and without comorbidities and 25 healthy subjects (HS). In all subjects the plasma glucose, insulin, 8-isoprostane, Vitamin D, H2S and 3-nitrotyrosine were determined by ELISA. The nitrites (NO2−), lipid-peroxidation (LPO), total-antioxidant-capacity (TAC), thiols, glutathione (GSH) and selenium (Se) were determined by spectrophotometry. The glucose, insulin and HOMA-IR (p < 0.001), 8-isoprostanes, 3-nitrotyrosine (p < 0.001) and LPO were increased (p = 0.02) while Vitamin D (p = 0.01), H2S, thiols, TAC, GSH and Se (p < 0.001) decreased in COVID-19 patients in comparison to HS. The SARS-CoV-2 infection resulted in alterations in the glucose−insulin axis that led to hyperglycemia, hyperinsulinemia and IR in patients with and without comorbidities. These alterations increase OS and NSS reflected in increases or decreases in some oxidative markers in plasma with major impact or fatal consequences in patients that course with metabolic syndrome. Moreover, subjects without comorbidities could have long-term alterations in the redox homeostasis after infection.
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Sharma A, Virmani T, Sharma A, Chhabra V, Kumar G, Pathak K, Alhalmi A. Potential Effect of DPP-4 Inhibitors Towards Hepatic Diseases and Associated Glucose Intolerance. Diabetes Metab Syndr Obes 2022; 15:1845-1864. [PMID: 35733643 PMCID: PMC9208633 DOI: 10.2147/dmso.s369712] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/10/2022] [Indexed: 11/23/2022] Open
Abstract
Dipeptidyl-peptidase-4 (DPP-4) is an enzyme having various properties and physiological roles in lipid accumulation, resistance to anticancer agents, and immune stimulation. DPP-4 includes membrane-bound peptidases and is a kind of enzyme that cleaves alanine or proline-containing peptides such as incretins, chemokines, and appetite-suppressing hormones (neuropeptide) at their N-terminal dipeptides. DPP-4 plays a role in the final breakdown of peptides produced by other endo and exo-peptidases from nutritious proteins and their absorption in these tissues. DPP-4 enzyme activity has different modes of action on glucose metabolism, hunger regulation, gastrointestinal motility, immune system function, inflammation, and pain regulation. According to the literature survey, as DPP-4 levels increase in individuals with liver conditions, up-regulation of hepatic DPP-4 expression is likely to be the cause of glucose intolerance or insulin resistance. This review majorly focuses on the cleavage of alanine or proline-containing peptides such as incretins by the DPP-4 and its resulting conditions like glucose intolerance and cause of DPP-4 level elevation due to some liver conditions. Thus, we have discussed the various effects of DPP-4 on the liver diseases like hepatitis C, non-alcoholic fatty liver, hepatic regeneration and stem cell, hepatocellular carcinoma, and the impact of elevated DPP-4 levels in association with liver diseases as a cause of glucose intolerance and their treatment drug of choices. In addition, the effect of DPP-4 inhibitors on obesity and their negative aspects are also discussed in brief.
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Affiliation(s)
- Ashwani Sharma
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Tarun Virmani
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Anjali Sharma
- Freelancer, Pharmacovigilance Expert, Uttar Pradesh, India
| | - Vaishnavi Chhabra
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Girish Kumar
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Kamla Pathak
- Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Uttar Pradesh, 206130, India
| | - Abdulsalam Alhalmi
- Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, Yemen
- Correspondence: Abdulsalam Alhalmi, Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, Yemen, Email
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25
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Klein K, Nelson J, Long C, Speeg K, Alkhouri N, Hall R. Effect of Hepatitis C Viremia on Posttransplant Diabetes Mellitus in Liver Transplant Recipients. Prog Transplant 2021; 32:73-77. [PMID: 34874192 DOI: 10.1177/15269248211064879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Posttransplant diabetes mellitus (PTDM) can increase morbidity and mortality in liver transplant recipients. Although hepatitis C seropositivity is a known risk factor for PTDM, the impact of viremia versus no viremia at time of transplant is unknown. PROJECT AIMS This program evaluation sought to compare PTDM in hepatitis C seropositive patients with and without viremia at the time of liver transplant. DESIGN This single-center retrospective review included adult hepatitis C seropositive liver transplant recipients transplanted between January 1, 2010 to September 5, 2017 without pretransplant diabetes. Primary outcome was PTDM within 1 year. Secondary outcomes included evaluating 1-year posttransplant death-censored graft loss, mortality, and metabolic outcomes. RESULTS Fifty-seven liver transplant recipients with hepatitis C were included, of which 53% (n = 30) were viremic at transplant. Baseline characteristics were similar between groups. Significantly more patients with pretransplant viremia developed PTDM by 1-year posttransplant compared to the patients without viremia (43% vs 11%, P = 0.01). There were no differences between groups outside of more patients with viremia requiring antihypertensives by 1-year posttransplant compared to patients without viremia (57% vs 22%, P = 0.01). CONCLUSION Liver transplant patients with hepatitis C viremia at transplant were more likely to develop PTDM at 1 year compared to those without pretransplant viremia. This is an added consideration when deciding the timing of direct-acting antiviral (DAA) utilization in the context of liver transplant for hepatitis C seropositive patients.
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Affiliation(s)
- Kelsey Klein
- 43159University Health System, San Antonio, TX, USA.,43159University Health System, San Antonio, TX, USA.,University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.,University of Texas at Austin College of Pharmacy, Austin, TX, USA
| | - Joelle Nelson
- 43159University Health System, San Antonio, TX, USA.,43159University Health System, San Antonio, TX, USA.,University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.,University of Texas at Austin College of Pharmacy, Austin, TX, USA
| | - Christina Long
- 43159University Health System, San Antonio, TX, USA.,University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.,130378University of the Incarnate Word Feik School of Pharmacy, San Antonio, TX, USA
| | - Kermit Speeg
- 43159University Health System, San Antonio, TX, USA.,14742University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | | | - Reed Hall
- 43159University Health System, San Antonio, TX, USA.,43159University Health System, San Antonio, TX, USA.,University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.,University of Texas at Austin College of Pharmacy, Austin, TX, USA
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26
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Diao P, Jia F, Wang X, Hu X, Kimura T, Nakajima T, Aoyama T, Moriya K, Koike K, Tanaka N. Mechanisms of Steatosis-Derived Hepatocarcinogenesis: Lessons from HCV Core Gene Transgenic Mice. ENGINEERING 2021; 7:1797-1805. [DOI: 10.1016/j.eng.2021.08.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
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Abstract
Fibrosis is not a unidirectional, linear process, but a dynamic one resulting from an interplay of fibrogenesis and fibrolysis depending on the extent and severity of a biologic insult, or lack thereof. Regression of fibrosis has been documented best in patients treated with phlebotomies for hemochromatosis, and after successful suppression and eradication of chronic hepatitis B and C infections. This evidence mandates a reconsideration of the term "cirrhosis," which implies an inevitable progression towards liver failure. Furthermore, it also necessitates a staging system that acknowledges the bidirectional nature of evolution of fibrosis, and has the ability to predict if the disease process is progressing or regressing. The Beijing classification attempts to fill this gap in contemporary practice. It is based on microscopic features termed "the hepatic repair complex," defined originally by Wanless and colleagues. The elements of the hepatic repair complex represent the 3 processes of fragmentation and regression of scar, vascular remodeling (resolution), and parenchymal regeneration. However, regression of fibrosis does not imply resolution of cirrhosis, which is more than just a stage of fibrosis. So far, there is little to no evidence to suggest that large regions of parenchymal extinction can be repopulated by regenerating hepatocytes. Similarly, the vascular lesions of cirrhosis persist, and there is no evidence of complete return to normal microcirculation in cirrhotic livers. In addition, the risk of hepatocellular carcinoma is higher compared with the general population and these patients need continued screening and surveillance.
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Koike K. The Way to Decoding Pathogenesis and Conquering of National Afflictions, Viral Hepatitis and Liver Cancer. JMA J 2021; 4:332-338. [PMID: 34796287 PMCID: PMC8580653 DOI: 10.31662/jmaj.2021-0099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 06/02/2021] [Indexed: 12/28/2022] Open
Abstract
Viral hepatitis and liver cancer are worldwide health problems, and they have been called national afflictions in Japan. We have been studying the mechanism of hepatocarcinogenesis, chiefly using experimental animal models, starting from clinical observations of patients. Observations of the early development of liver cancer in young patients with chronic hepatitis B with minimal hepatic inflammation and fibrosis, as well as the frequent development of hepatic steatosis in patients with chronic hepatitis C, prompted us to study direct roles of hepatitis viruses B and C in such liver pathogenesis. In addition, our establishment of a new paradigm, “hepatitis C as a metabolic disease,” further led us to elucidating the mechanism of nonviral, metabolism-associated liver cancer. Most hepatologists may appreciate a conquest in the war against viral hepatitis and associated liver cancer. However, even if we conquer the external enemies, hepatitis viruses B and C, an intrinsic enemy, metabolism-associated liver disease, would be waiting for us as an alternative cause of liver cancer. Confrontation of liver cancer has never ended.
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Affiliation(s)
- Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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29
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Haykal M, Matsumori A, Saleh A, Fayez M, Negm H, Shalaby M, Bassuony S. Diagnosis and treatment of HCV heart diseases. Expert Rev Cardiovasc Ther 2021; 19:493-499. [PMID: 33861939 DOI: 10.1080/14779072.2021.1917383] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection is an important cause of a variety of otherwise unexplained heart diseases and myocardial injury. A high prevalence of HCV infection has been noted in patients with hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia/cardiomyopathy and myocarditis. Various arrhythmias, conduction disturbances and QT prolongation were also associated with HCV infection. A possible role of HCV infection in the pathogenesis of diabetes and atherosclerosis, and the role of immunogenetics of HCV cardiomyopathies is discussed. Recent studies suggest that mononuclear cells may be the major target of HCV, and clinical applications to test this new hypothesis are discussed. AREAS COVERED In this review, we will evaluate the evidence that HCV causes various cardiovascular diseases, and discuss on the pathogenesis of these disorders. EXPERT OPINION HCV is the cause of many different forms of heart disease worldwide, but their existence has not been recognized by most of cardiologists. The recognition and diagnosis are indispensable for the early treatment of these diseases. The diverse clinical manifestation of HCV infection and the presence of multiple extrahepatic disease syndromes could be explained by a new hypothesis that the target of HCV is leukocytes.
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Affiliation(s)
- Mohammad Haykal
- Cardiovascular and Ultrasonography Research Unit (CURU), Research Institute of Ophthalmology (RIO), Cairo, Egypt
| | - Akira Matsumori
- Clinical Research Center, Kyoto Medical Center, Kyoto, Japan
| | - Ahmed Saleh
- Cardiovascular and Ultrasonography Research Unit (CURU), Research Institute of Ophthalmology (RIO), Cairo, Egypt
| | - Moatez Fayez
- Cardiovascular and Ultrasonography Research Unit (CURU), Research Institute of Ophthalmology (RIO), Cairo, Egypt
| | - Hany Negm
- Cardiovascular and Ultrasonography Research Unit (CURU), Research Institute of Ophthalmology (RIO), Cairo, Egypt
| | - Mohammad Shalaby
- Cardiovascular and Ultrasonography Research Unit (CURU), Research Institute of Ophthalmology (RIO), Cairo, Egypt
| | - Samar Bassuony
- Cardiovascular and Ultrasonography Research Unit (CURU), Research Institute of Ophthalmology (RIO), Cairo, Egypt
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30
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Nevola R, Rinaldi L, Zeni L, Romano C, Marrone A, Galiero R, Pafundi PC, Acierno C, Vetrano E, Adinolfi LE. Changes in clinical scenarios, management, and perspectives of patients with chronic hepatitis C after viral clearance by direct-acting antivirals. Expert Rev Gastroenterol Hepatol 2021; 15:643-656. [PMID: 33445990 DOI: 10.1080/17474124.2021.1877136] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) causes a systemic infection inducing hepatic and extrahepatic diseases. These latter involve cardiovascular system, kidney, brain, endocrine, glucose, and lipid metabolism, and the immune system. HCV infection is associated with an increased risk of morbidity and mortality for both hepatic and extrahepatic events. Direct-acting antivirals (DAA), introduced in the most recent years for HCV treatment, are effective in up to 99% of cases and have changed the clinical scenarios and management of these patients. AREAS COVERED The literature on the impact of HCV clearance by DAA on both hepatic and extrahepatic disease outcomes has been analyzed and discussed in this review in order to summarize the full therapeutic potential and its weaknesses. EXPERT OPINION Patients achieving HCV clearance have improved hepatic and extrahepatic diseases, quality of life and survival. They have lower incidence of cardiovascular disease, type 2 diabetes, kidney damage, and immuno-mediated manifestations. However, the improvements are related to the degree of pre-treatment organ damage. Therefore, a significant percentage of patients with advanced disease remains at risk of morbidity and mortality and must be monitored in the post-treatment. In addition, data emphasize the importance of starting treatment during the early stages of HCV infection.
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Affiliation(s)
- Riccardo Nevola
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luca Rinaldi
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Letizia Zeni
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Ciro Romano
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Aldo Marrone
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Raffaele Galiero
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Pia Clara Pafundi
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Carlo Acierno
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Erica Vetrano
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luigi Elio Adinolfi
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
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31
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Shengir M, Elgara M, Sebastiani G. Metabolic and cardiovascular complications after virological cure in hepatitis C: What awaits beyond. World J Gastroenterol 2021; 27:1959-1972. [PMID: 34007133 PMCID: PMC8108037 DOI: 10.3748/wjg.v27.i17.1959] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/06/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
The association between chronic hepatitis C (CHC) infection and extrahepatic manifestations (EHMs), particularly cardiometabolic diseases, has been extensively examined. However, there has still been insufficient evaluation for these EHMs after virological cure. Several multidirectional mechanisms have been proposed explaining the ability of hepatitis C virus (HCV) developing EHMs, cardiometabolic ones, as well as the effect of antiviral therapy to resolve these EHMs. Data on these manifestations after achieving sustained virologic response (SVR) are still conflicting. However, current evidence suggests that reversal of hepatic steatosis and its coexistent hypocholesterolemia after successful viral eradication led to unfavorable lipid profile, which increases cardiovascular disease (CVD) risk. Additionally, most observations showed that metabolic alterations, such as insulin resistance and diabetes mellitus (DM), undergo some degree of reduction after viral clearance. These changes seem HCV-genotype dependent. Interferon-based antiviral therapy and direct acting antiviral drugs were shown to minimize incidence of DM. Large epidemiological studies that investigated the effect of SVR on CVD showed great discrepancies in terms of results, with predominant findings indicating that CVD events decreased in patients with SVR compared to non-responders or untreated ones. In this review, we present a summary of the current knowledge regarding extrahepatic sequelae of CHC following SVR, which may have an impact on healthcare providers’ clinical practice.
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Affiliation(s)
- Mohamed Shengir
- Department of Medicine, McGill University, Montreal, Quebec H3A0G4, Canada
| | - Mohamed Elgara
- Department of Internal Medicine, Hamad Medical Corporation, Doha 3050, Qatar
| | - Giada Sebastiani
- Department of Medicine, McGill University Health Center, Montreal, Quebec H4A3J1, Canada
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Chaudhari R, Fouda S, Sainu A, Pappachan JM. Metabolic complications of hepatitis C virus infection. World J Gastroenterol 2021; 27:1267-1282. [PMID: 33833481 PMCID: PMC8015302 DOI: 10.3748/wjg.v27.i13.1267] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 02/10/2021] [Accepted: 03/12/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a systemic disease that is implicated in multiple extrahepatic organ dysfunction contributing to its protean manifestations. HCV is associated with diverse extrahepatic disorders including atherosclerosis, glucose and lipid metabolic disturbances, alterations in the iron metabolic pathways, and lymphoproliferative diseases over and above the traditional liver manifestations of cirrhosis and hepatocellular carcinoma. The orchestration between HCV major proteins and the liver-muscle-adipose axis, poses a major burden on the global health of human body organs, if not adequately addressed. The close and inseparable associations between chronic HCV infection, metabolic disease, and cardiovascular disorders are specifically important considering the increasing prevalence of obesity and metabolic syndrome, and their economic burden to patients, the healthcare systems, and society. Cellular and molecular mechanisms governing the interplay of these organs and tissues in health and disease are therefore of significant interest. The coexistence of metabolic disorders and chronic hepatitis C infection also enhances the progression to liver fibrosis and hepatocellular carcinoma. The presence of metabolic disorders is believed to influence the chronicity and virulence of HCV leading to liver disease progression. This comprehensive review highlights current knowledge on the metabolic manifestations of hepatitis C and the potential pathways in which these metabolic changes can influence the natural history of the disease.
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Affiliation(s)
- Rahul Chaudhari
- Department of Medicine, Pennsylvania Hospital of the University of Pennsylvania, Pennsylvania, PA 19104, United States
| | - Sherouk Fouda
- School of Health and Biomedical Sciences, RMIT University, Melbourne VIC 3000, Australia
| | - Ashik Sainu
- Department of Gastroenterology and Hepatology, Aster Oman Hospital, Al Ghubra, Muscat OM 133, Oman
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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Urganci N, Kalyoncu D, Geylani-Gulec S. Insulin resistance in children with chronic hepatitis C and its association with response to IFN-alpha and ribavirin. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2021; 86:140-144. [PMID: 32839082 DOI: 10.1016/j.rgmx.2020.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 07/15/2020] [Accepted: 07/15/2020] [Indexed: 06/11/2023]
Abstract
OBJECTIVE The aim of our study was to evaluate the association between insulin resistance and the response to IFN-alpha and ribavirin in pediatric patients with chronic hepatitis C. METHODS Twenty-six patients with chronic hepatitis C (mean age: 12.5 ± 1.96 years, M/F:3.33) were included in the study. Fasting glucose, insulin, and C-peptide levels, together with HOMA-IR, HOMA-B, and QUICKI values, were assessed. The association between those parameters and treatment response was determined. RESULTS Five (19.2%) of the 26 patients analyzed (2 [21.4%] with treatment response and 3 [16.6%] with no treatment response) had insulin resistance (p=1.00). There were no significant differences between the patients with and without treatment response with respect to fasting glucose, insulin, and C-peptide levels or HOMA-IR, HOMA-B, and QUICKI values (p>0.05). CONCLUSIONS No significant association was establihed between insulin resistance and response to IFN-alpha and ribavirin, in children with chronic hepatitis C.
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Affiliation(s)
- N Urganci
- Hospital Universitario y de Investigación Sisli Hamidiye Etfal, División de Gastroenterología Pediátrica, Estambul, Turquía
| | - D Kalyoncu
- Hospital Universitario y de Investigación Sisli Hamidiye Etfal, Departamento de Pediatría, Estambul, Turquía; Hospital Estatal de İstinye, Pediatría, Estambul, Turquía.
| | - S Geylani-Gulec
- Hospital Universitario y de Investigación Sisli Hamidiye Etfal, Departamento de Pediatría, Estambul, Turquía
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Urganci N, Kalyoncu D, Geylani-Gulec S. Insulin resistance in children with chronic hepatitis C and its association with response to IFN-alpha and ribavirin. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2021. [DOI: 10.1016/j.rgmxen.2020.07.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Induction of HOX Genes by Hepatitis C Virus Infection via Impairment of Histone H2A Monoubiquitination. J Virol 2021; 95:JVI.01784-20. [PMID: 33328315 DOI: 10.1128/jvi.01784-20] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/08/2020] [Indexed: 12/19/2022] Open
Abstract
Hepatitis C virus (HCV) infection causes liver pathologies, including hepatocellular carcinoma (HCC). Homeobox (HOX) gene products regulate embryonic development and are associated with tumorigenesis, although the regulation of HOX genes by HCV infection has not been clarified in detail. We examined the effect of HCV infection on HOX gene expression. In this study, HCV infection induced more than half of the HOX genes and reduced the level of histone H2A monoubiquitination on lysine 119 (K119) (H2Aub), which represses HOX gene promoter activity. HCV infection also promoted proteasome-dependent degradation of RNF2, which is an E3 ligase mediating H2A monoubiquitination as a component of polycomb repressive complex 1. Since full-genomic replicon cells but not subgenomic replicon cells exhibited reduced RNF2 and H2Aub levels and induction of HOX genes, we focused on the core protein. Expression of the core protein reduced the amounts of RNF2 and H2Aub and induced HOX genes. Treatment with LY-411575, which can reduce HCV core protein expression via signal peptide peptidase (SPP) inhibition without affecting other viral proteins, dose-dependently restored the amounts of RNF2 and H2Aub in HCV-infected cells and impaired the induction of HOX genes and production of viral particles but not viral replication. The chromatin immunoprecipitation assay results also indicated infection- and proteasome-dependent reductions in H2Aub located in HOX gene promoters. These results suggest that HCV infection or core protein induces HOX genes by impairing histone H2A monoubiquitination via a reduction in the RNF2 level.IMPORTANCE Recently sustained virologic response can be achieved by direct-acting antiviral (DAA) therapy in most hepatitis C patients. Unfortunately, DAA therapy does not completely eliminate a risk of hepatocellular carcinoma (HCC). Several epigenetic factors, including histone modifications, are well known to contribute to hepatitis C virus (HCV)-associated HCC. However, the regulation of histone modifications by HCV infection has not been clarified in detail. In this study, our data suggest that HCV infection or HCV core protein expression impairs monoubiquitination of histone H2A K119 in the homeobox (HOX) gene promoter via destabilization of RNF2 and then induces HOX genes. Several lines of evidence suggest that the expression of several HOX genes is dysregulated in certain types of tumors. These findings reveal a novel mechanism of HCV-related histone modification and may provide information about new targets for diagnosis and prevention of HCC occurrence.
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Nishikawa H, Enomoto H, Nishiguchi S, Iijima H. Sarcopenic Obesity in Liver Cirrhosis: Possible Mechanism and Clinical Impact. Int J Mol Sci 2021; 22:1917. [PMID: 33671926 PMCID: PMC7919019 DOI: 10.3390/ijms22041917] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 02/07/2023] Open
Abstract
The picture of chronic liver diseases (CLDs) has changed considerably in recent years. One of them is the increase of non-alcoholic fatty liver disease. More and more CLD patients, even those with liver cirrhosis (LC), tend to be presenting with obesity these days. The annual rate of muscle loss increases with worsening liver reserve, and thus LC patients are more likely to complicate with sarcopenia. LC is also characterized by protein-energy malnutrition (PEM). Since the PEM in LC can be invariable, the patients probably present with sarcopenic obesity (Sa-O), which involves both sarcopenia and obesity. Currently, there is no mention of Sa-O in the guidelines; however, the rapidly increasing prevalence and poorer clinical consequences of Sa-O are recognized as an important public health problem, and the diagnostic value of Sa-O is expected to increase in the future. Sa-O involves a complex interplay of physiological mechanisms, including increased inflammatory cytokines, oxidative stress, insulin resistance, hormonal disorders, and decline of physical activity. The pathogenesis of Sa-O in LC is diverse, with a lot of perturbations in the muscle-liver-adipose tissue axis. Here, we overview the current knowledge of Sa-O, especially focusing on LC.
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Affiliation(s)
- Hiroki Nishikawa
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan; (H.E.); (H.I.)
- Center for Clinical Research and Education, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Hirayuki Enomoto
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan; (H.E.); (H.I.)
| | - Shuhei Nishiguchi
- Department of Internal Medicine, Kano General Hospital, Osaka 531-0041, Japan;
| | - Hiroko Iijima
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan; (H.E.); (H.I.)
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Cheng CH, Chu CY, Chen HL, Lin IT, Wu CH, Lee YK, Bair MJ. Virus Elimination by Direct-Acting Antiviral Agents Impacts Glucose Homeostasis in Chronic Hepatitis C Patients. Front Endocrinol (Lausanne) 2021; 12:799382. [PMID: 35095765 PMCID: PMC8792856 DOI: 10.3389/fendo.2021.799382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/20/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND AIMS Chronic hepatitis C virus (HCV) infection is associated with dysregulation of glucose homeostasis, including insulin resistance (IR) and type 2 diabetes. However, independent risk factors associated with IR in chronic HCV-infected patients have not been detailly elucidated. Previous data regarding the impact of HCV elimination by direct-acting antiviral agents (DAAs) on glucose homeostasis is insufficient and controversial. This study aimed to analyze the independent factors associated with IR and to evaluate the changes in glucose homeostasis in chronic HCV-infected patients treated with DAAs therapies. METHODS We screened 704 patients with chronic HCV infection who underwent treatment with interferon-free DAAs. Patients' baseline characteristics, biochemical and virological data were collected. The outcome measurements were their IR and β-cell function assessed by the homeostasis model assessment (HOMA) method at baseline and 12-weeks post-treatment. RESULTS High IR (HOMA-IR ≥ 2.5) was observed in 35.1% of the patients. Multivariable logistic regression analysis revealed that body mass index (BMI) >25 kg/m2, treatment experience, elevated baseline levels of alanine aminotransferase (ALT) and triglyceride, as well as Fibrosis-4 score >3.25 were independently associated with high IR. In patients who achieved sustained virological response (SVR), no significant change in mean HOMA-IR was observed from baseline to 12-weeks post-treatment (2.74 ± 2.78 to 2.54 ± 2.20, p = 0.128). We observed a significant improvement in β-cell secretion stress from 121.0 ± 110.1 to 107.6 ± 93.0 (p = 0.015). Subgroup analysis revealed that SVR was associated with a significant reduction in mean HOMA-IR in patients with baseline HOMA-IR ≥ 2.5 (5.31 ± 3.39 to 3.68 ± 2.57, p < 0.001), HCV genotype 1 (3.05 ± 3.11 to 2.62 ± 2.05, p = 0.027), and treatment experience (4.00 ± 3.37 to 3.01 ± 2.49, p = 0.039). CONCLUSIONS There were several independent factors associated with IR in patients with chronic HCV infection, including obesity, treatment experience, high serum ALT and triglyceride levels, as well as advanced hepatic fibrosis. After viral elimination by DAAs, we observed a significant reduction in mean HOMA-IR in patients with baseline high IR, HCV genotype 1, and treatment experience.
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Affiliation(s)
- Chun-Han Cheng
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
| | - Chia-Ying Chu
- Department of Pathology, Taitung Mackay Memorial Hospital, Taitung, Taiwan
| | - Huan-Lin Chen
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
| | - I-Tsung Lin
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
| | - Chia-Hsien Wu
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
| | - Yuan-Kai Lee
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
| | - Ming-Jong Bair
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
- *Correspondence: Ming-Jong Bair,
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Abstract
Persistent infection with hepatitis C virus (HCV) is a major risk factor for hepatocellular carcinoma (HCC). Accumulating evidence suggests that not only inflammation and subsequent fibrosis but also HCV itself are associated with hepatocarcinogenesis. To date, studies using transgenic mouse and cell-culture models, in which HCV proteins are expressed, indicate the direct pathogenicity of HCV, including oncogenic activity. In particular, the core protein of HCV induces excessive oxidative stress by impairing the mitochondrial electron transfer system by disrupting the function of the molecular chaperone, prohibitin. HCV also modulates intracellular signaling pathways, including mitogen-activated protein kinase, promoting the proliferation of hepatocytes. In addition, HCV induces disorders in lipid and glucose metabolism, thereby accelerating the progression of liver fibrosis and the development of HCC. Due to the development of direct-acting antivirals, which was made possible by basic research, HCV can be eradicated from almost all infected patients. However, such patients can develop HCC long after eradication of HCV, suggesting the genetic and/or epigenetic changes induced by HCV may be persistent. These results enhance our understanding of the role of HCV in hepatocarcinogenesis and will facilitate the development of therapeutic and preventive strategies for HCV-induced HCC.
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Takahashi H, Nakahara T, Kogiso T, Imajo K, Kessoku T, Kawaguchi T, Ide T, Kawanaka M, Hyogo H, Fujii H, Ono M, Kamada Y, Sumida Y, Anzai K, Shimizu M, Torimura T, Nakajima A, Tokushige K, Chayama K, Eguchi Y. Eradication of hepatitis C virus with direct-acting antivirals improves glycemic control in diabetes: A multicenter study. JGH OPEN 2020; 5:228-234. [PMID: 33553660 PMCID: PMC7857302 DOI: 10.1002/jgh3.12474] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 11/29/2020] [Accepted: 11/30/2020] [Indexed: 12/19/2022]
Abstract
Background and Aim Hepatitis C virus (HCV) infection causes insulin resistance and diabetes as extrahepatic manifestations. We aimed to analyze the effect of HCV eradication by direct‐acting antiviral (DAA) agents on glucose tolerance. Methods The hemoglobin A1c (HbA1c) of 272 patients with HCV infection who achieved a sustained virologic response (SVR) was analyzed at baseline before DAA treatment, at the end of DAA therapy (ETR), and 12 weeks after therapy (Post12W). Results There were no significant differences in HbA1c between baseline, ETR, and Post12W in the overall patients. When the data were stratified according to the presence or absence of diabetes, median HbA1c significantly decreased from baseline (7.2%) to ETR (6.8%) and Post12W (6.8%) in the 55 patients with diabetes, whereas there were no significant changes in the patients without diabetes. Basal HbA1c, fasting plasma glucose, and age were independently associated with the changes in HbA1c according to multivariate analysis, and the predictive formula for changes in HbA1c was found to be ΔHbA1c (%) = 1.449–0.4* HbA1c (%) + 0.012 × Age (year). There were no changes in body mass in diabetic or nondiabetic patients. In diabetic patients taking medication, 63.4% of patients needed less medication. Conclusions Eradication of HCV improves glycemic control, indicated by a 0.4% decrease in HbA1c in diabetes.
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Affiliation(s)
- Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine Saga University Saga Japan.,Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan
| | - Takashi Nakahara
- Department of Internal Medicine and Gastroenterology Tokyo Women's Medical University Tokyo Japan
| | - Tomomi Kogiso
- Department of Gastroenterology and Hepatology Yokohama City University Graduate School of Medicine Yokohama Japan
| | - Kento Imajo
- Division of Gastroenterology, Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Takaomi Kessoku
- Division of Gastroenterology, Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Takumi Kawaguchi
- Department of General Internal Medicine 2 General Medical Center, Kawasaki Medical School Okayama Japan
| | - Tatsuya Ide
- Department of General Internal Medicine 2 General Medical Center, Kawasaki Medical School Okayama Japan
| | - Miwa Kawanaka
- Department of Gastroenterology and Hepatology JA Hiroshima General Hospital Hiroshima Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Hepatology Osaka City Juso Hospital Osaka Japan
| | - Hideki Fujii
- Department of Premier Preventive Medicine Osaka City University Graduate School of Medicine Osaka Japan.,Tokyo Women's Medical University Medical Center East Internal Medicine Tokyo Japan
| | - Masafumi Ono
- Department of Molecular Biochemistry and Clinical Investigation Osaka University Graduate School of Medicine Suita Japan
| | - Yoshihiro Kamada
- Division of Hepatology and Pancreatology, Department of Internal Medicine Aichi Medical University Nagakute Japan
| | - Yoshio Sumida
- Department of Gastroenterology Gifu University Graduate School of Medicine Yanagido Japan
| | - Keizo Anzai
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan
| | | | - Takuji Torimura
- Department of General Internal Medicine 2 General Medical Center, Kawasaki Medical School Okayama Japan
| | - Atsushi Nakajima
- Division of Gastroenterology, Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Katsutoshi Tokushige
- Department of Gastroenterology and Hepatology Yokohama City University Graduate School of Medicine Yokohama Japan
| | - Kazuaki Chayama
- Department of Internal Medicine and Gastroenterology Tokyo Women's Medical University Tokyo Japan
| | - Yuichiro Eguchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan
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Adinolfi LE, Petta S, Fracanzani AL, Nevola R, Coppola C, Narciso V, Rinaldi L, Calvaruso V, Pafundi PC, Lombardi R, Staiano L, Di Marco V, Solano A, Marrone A, Saturnino M, Rini F, Guerrera B, Troina G, Giordano M, Craxì A, Sasso FC. Reduced incidence of type 2 diabetes in patients with chronic hepatitis C virus infection cleared by direct-acting antiviral therapy: A prospective study. Diabetes Obes Metab 2020; 22:2408-2416. [PMID: 32761721 DOI: 10.1111/dom.14168] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/30/2020] [Accepted: 08/03/2020] [Indexed: 12/12/2022]
Abstract
AIM To assess the effect of hepatitis C virus (HCV) eradication on type 2 diabetes mellitus (T2DM). incidence. METHODS A prospective multicentre case-control study was performed, which included 2426 patients with HCV, 42% of whom had liver fibrosis stage F0-F2 and 58% of whom had liver fibrosis stage F3-F4. The study population consisted of a control group including 1099 untreated patients and 1327 cases treated with direct-acting antivirals (DAAs). T2DM incidence was assessed during a median (interquartile range) follow-up period of 30 (28-42) months. Risk factors for T2DM were assessed using a Cox regression model (relative risk [RR], hazard ratio [HR], Kaplan-Meier analysis). Insulin sensitivity was evaluated by homeostatic model assessment (HOMA) and changes by repeated-measures ANOVA. Factors independently associated with T2DM were assessed by multivariate analysis. RESULTS The absolute incidence of T2DM for controls and cases was 28 and 7/1000 person-years, respectively (P = 0.001). In cases compared to controls, HCV clearance reduced the RR and HR of T2DM by 81% and 75% to 93%, respectively (P = 0.001). It was calculated that, for every 15 patients who obtained HCV clearance, one case of T2DM was saved. HCV clearance was associated with significant reductions in HOMA-insulin resistance and HOMA-β-cell function and an increase in HOMA-insulin sensitivity, as assessed in 384 patients before and after HCV clearance. At multivariate analysis, HCV clearance emerged as independently associated with a reduced T2DM risk. CONCLUSION The results showed that HCV clearance by DAA treatment reduces T2DM incidence probably by restoring the HCV-induced alteration of glucose homeostasis mechanisms.
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Affiliation(s)
- Luigi E Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Salvatore Petta
- Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Anna L Fracanzani
- Department of Pathophysiology and Transplantation, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Riccardo Nevola
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Carmine Coppola
- Unit of Internal Medicine and Hepatolology, Gragnano Hospital, ASL Napoli 3 Sud, Naples, Italy
| | - Vincenzo Narciso
- Unit of Hepatology, Pellegrini Hospital, ASL Napoli 1 Centro, Naples, Italy
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Vincenza Calvaruso
- Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Pia Clara Pafundi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Rosa Lombardi
- Department of Pathophysiology and Transplantation, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Laura Staiano
- Unit of Internal Medicine and Hepatolology, Gragnano Hospital, ASL Napoli 3 Sud, Naples, Italy
| | - Vito Di Marco
- Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Antonio Solano
- Unit of Hepatology, Pellegrini Hospital, ASL Napoli 1 Centro, Naples, Italy
| | - Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Mariarosaria Saturnino
- Unit of Internal Medicine and Hepatolology, Gragnano Hospital, ASL Napoli 3 Sud, Naples, Italy
| | - Francesca Rini
- Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Barbara Guerrera
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Graziano Troina
- Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Mauro Giordano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Antonio Craxì
- Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Ferdinando C Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
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Nevola R, Acierno C, Pafundi PC, Adinolfi LE. Chronic hepatitis C infection induces cardiovascular disease and type 2 diabetes: mechanisms and management. Minerva Med 2020; 112:188-200. [PMID: 33205641 DOI: 10.23736/s0026-4806.20.07129-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Despite the availability of effective treatments, hepatitis C virus (HCV) still remains a threat to public health. HCV is capable to trigger, behind liver damage, extrahepatic manifestations, including cardiovascular disease and type 2 diabetes (T2DM). A close association has been reported between HCV infection and cardiovascular disease due to imbalances in metabolic pathways and chronic inflammation. HCV through both direct and indirect mechanisms causes a higher incidence of ischemic stroke, acute coronary syndrome, heart failure and peripheral arterial disease. In addition, a higher risk of death from cardiovascular events has been showed in HCV patients. Insulin resistance is a hallmark of HCV infection and represents the link between HCV and T2DM, which is one of the most frequent HCV-associated extrahepatic manifestations. The pathological basis of the increased risk of T2DM in HCV infection is provided by the alterations of the molecular mechanisms of IR induced both by the direct effects of the HCV proteins, and by the indirect effects mediated by chronic inflammation, oxidative stress and hepatic steatosis. T2DM increases the risk of compensated and decompensate cirrhosis and hepatocellular carcinoma as well as increases the risk of cardiovascular disease, lower limb amputation and end stage renal disease. Current evidence suggests that HCV eradication reduces the incidence and mortality of cardiovascular disease and T2DM, further underling the importance of public health strategies for eradication the infection. The aim of this review was to update evidence and management of interaction between HCV, cardiovascular disease, and T2DM in the era of DAA treatment.
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Affiliation(s)
- Riccardo Nevola
- Unit of Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, Naples, Italy
| | - Carlo Acierno
- Unit of Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, Naples, Italy
| | - Pia C Pafundi
- Unit of Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, Naples, Italy
| | - Luigi E Adinolfi
- Unit of Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, Naples, Italy -
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Saleh P, Infectious and Tropical Disease Research Center, Department of Infectious and Tropical Disease, Tabriz University of Medical Sciences, Tabriz, Iran, Sheikholeslami A, Infectious and Tropical Disease Research Center, Department of Infectious and Tropical Disease, Tabriz University of Medical Sciences, Tabriz, Iran, Salman Mohajer A, Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran, Babapour S, Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran, Hosseini MS, Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran. Association between Different Hepatitis C Virus Genotypes Infection and Type-2 Diabetes Mellitus: A Descriptive-Analytical Study from the Northwest of Iran. JOURNAL OF MEDICAL MICROBIOLOGY AND INFECTIOUS DISEASES 2020; 8:137-142. [DOI: 10.29252/jommid.8.4.137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
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Chung W, Promrat K, Wands J. Clinical implications, diagnosis, and management of diabetes in patients with chronic liver diseases. World J Hepatol 2020; 12:533-557. [PMID: 33033564 PMCID: PMC7522556 DOI: 10.4254/wjh.v12.i9.533] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/03/2020] [Accepted: 08/15/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus (DM) negatively affects the development and progression of chronic liver diseases (CLD) of various etiologies. Concurrent DM and CLD are also associated with worse clinical outcomes with respect to mortality, the occurrence of hepatic decompensation, and the development of hepatocellular carcinoma (HCC). Unfortunately, early diagnosis and optimal treatment of DM can be challenging, due to the lack of established clinical guidelines as well as the medical complexity of this patient population. We conducted an exploratory review of relevant literature to provide an up-to-date review for internists and hepatologists caring for this patient population. We reviewed the epidemiological and pathophysiological associations between DM and CLD, the impact of insulin resistance on the progression and manifestations of CLD, the pathogenesis of hepatogenic diabetes, as well as the practical challenges in diagnosis and monitoring of DM in this patient population. We also reviewed the latest clinical evidence on various pharmacological antihyperglycemic therapies with an emphasis on liver disease-related clinical outcomes. Finally, we proposed an algorithm for managing DM in patients with CLD and discussed the clinical and research questions that remain to be addressed.
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Affiliation(s)
- Waihong Chung
- Division of Gastroenterology, Department of Medicine, Rhode Island Hospital, Providence, RI 02905, United States.
| | - Kittichai Promrat
- Division of Gastroenterology and Hepatology, Providence VA Medical Center, Providence, RI 02908, United States
| | - Jack Wands
- Liver Research Center, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States
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Ogawa E, Takayama K, Hiramine S, Hayashi T, Toyoda K. Association between steatohepatitis biomarkers and hepatocellular carcinoma after hepatitis C elimination. Aliment Pharmacol Ther 2020; 52:866-876. [PMID: 32697871 DOI: 10.1111/apt.15976] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/21/2020] [Accepted: 06/27/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND A strong association between chronic hepatitis C (CHC) and hepatic steatosis has been reported. However, the influence of steatohepatitis on hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) elimination remains unclear. AIM To evaluate the development of HCC after HCV cure using a new steatohepatitis-related biomarker. METHODS This cohort study analysed the prospective database of 290 CHC patients without a history of HCC who achieved HCV elimination by direct-acting antivirals. We calculated the FibroScan-aspartate aminotransferase (FAST) score 12 weeks after the end of treatment (pw12). The risk of HCC was analysed using the multivariable Cox proportional hazard model. RESULTS HCV genotype (GT)1 was most prevalent at 72.4%, followed by GT2 (26.6%). Median follow-up period was 4.2 years (IQR 3.1-4.5). The cumulative HCC incidence for a FAST score ≥ 0.35 was significantly higher than that for a FAST score < 0.35 (log-rank test: P < 0.001). The annual HCC incidence rate for a FAST score ≥ 0.35 was significantly higher than that for a FAST score < 0.35, in patients with liver stiffness measurement (LSM) ≥10 kPa (adjusted hazard ratio [HR] 4.41, 95% confidence interval [CI] 1.30-15.0, P = 0.018). After adjusting for variables, including age, albumin, alpha-fetoprotein, the patatin-like phospholipase domain-containing the 3 (PNPLA3) rs738409 genotype, and pw12 fibrosis markers with FIB-4, non-alcoholic fatty liver disease fibrosis score, and LSM, FAST score ≥ 0.35 was associated with the development of HCC (adjusted HR 4.42, 95% CI 1.02-19.9, P = 0.043). CONCLUSIONS Steatohepatitis-related biomarkers with the FAST score are helpful for predicting the development of HCC after HCV elimination.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Koji Takayama
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Satoshi Hiramine
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Takeo Hayashi
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Kazuhiro Toyoda
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
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da Silva CB, Vieira DA, de Melo LF, Chagas ALS, Gomes AD, Faria Jr CLLD, Teixeira R, de Magalhães Queiroz DM, Rocha GA, Soares MMS, Bezerra JMT, Silva LD. Interleukin-6-174G/C polymorphism is associated with a decreased risk of type 2 diabetes in patients with chronic hepatitis C virus. World J Hepatol 2020; 12:137-148. [PMID: 32685106 PMCID: PMC7336292 DOI: 10.4254/wjh.v12.i4.137] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 02/28/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic hepatitis C (CHC) is associated with type 2 diabetes mellitus. Although the pathogenesis remains to be elucidated, a growing evidence has suggested a role of pro-inflammatory immune response. Increased serum concentrations of Interleukin 6 (IL-6) have been associated with insulin resistance, type 2 diabetes mellitus as well as advanced forms of liver disease in chronic hepatitis C infection.
AIM To investigate the frequency of IL-6-174G/C (rs1800795) single nucleotide polymorphism (SNP) in CHC patients and in healthy subjects of the same ethnicity. Associations between type 2 diabetes mellitus (dependent variable) and demographic, clinical, nutritional, virological and, IL-6 genotyping data were also investigated in CHC patients.
METHODS Two hundred and forty-five patients with CHC and 179 healthy control subjects (blood donors) were prospectively included. Type 2 diabetes mellitus was diagnosed according to the criteria of the American Diabetes Association. Clinical, biochemical, histological and radiological methods were used for the diagnosis of the liver disease. IL-6 polymorphism was evaluated by Taqman SNP genotyping assay. The data were analysed by logistic regression models.
RESULTS Type 2 diabetes mellitus, blood hypertension and liver cirrhosis were observed in 20.8% (51/245), 40.0% (98/245) and 38.4% (94/245) of the patients, respectively. The frequency of the studied IL-6 SNP did not differ between the CHC patients and controls (P = 0.81) and all alleles were in Hardy-Weinberg equilibrium (P = 0.38). In the multivariate analysis, type 2 diabetes mellitus was inversely associated with GC and CC genotypes of IL-6-174 (OR = 0.42; 95%CI = 0.22-0.78; P = 0.006) and positively associated with blood hypertension (OR = 5.56; 95%CI = 2.79-11.09; P < 0.001).
CONCLUSION This study was the first to show that GC and CC genotypes of IL-6-174 SNP are associated with a decreased risk of type 2 diabetes mellitus in patients chronically infected with hepatitis C virus. The identification of potential inflammatory mediators involved in the crosstalk between hepatitis C virus and the axis pancreas-liver remains important issues that deserve further investigations.
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Affiliation(s)
- Cliviany Borges da Silva
- Sciences Applied to Adult Health Care Post-Graduate Programme, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
- Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Diego Alves Vieira
- Medical undergraduate student, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
- Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Luisa Freitas de Melo
- Medical undergraduate student, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
- Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Anna Luiza Soares Chagas
- Medical undergraduate student, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
- Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Adriana Dias Gomes
- Laboratory of Research in Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - César Lúcio Lopes de Faria Jr
- Laboratory of Research in Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Rosângela Teixeira
- Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
- Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Dulciene Maria de Magalhães Queiroz
- Laboratory of Research in Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Gifone Aguiar Rocha
- Laboratory of Research in Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Maria Marta Sarquis Soares
- Division of Endocrinology, Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Juliana Maria Trindade Bezerra
- Epidemiology of Infectious and Parasitic Diseases Laboratory, Department of Parasitology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
| | - Luciana Diniz Silva
- Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
- Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
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Goto K, Roca Suarez AA, Wrensch F, Baumert TF, Lupberger J. Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip. Int J Mol Sci 2020; 21:ijms21093057. [PMID: 32357520 PMCID: PMC7246584 DOI: 10.3390/ijms21093057] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/20/2020] [Accepted: 04/24/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC). Novel treatments with direct-acting antivirals achieve high rates of sustained virologic response; however, the HCC risk remains elevated in cured patients, especially those with advanced liver disease. Long-term HCV infection causes a persistent and accumulating damage of the liver due to a combination of direct and indirect pro-oncogenic mechanisms. This review describes the processes involved in virus-induced disease progression by viral proteins, derailed signaling, immunity, and persistent epigenetic deregulation, which may be instrumental to develop urgently needed prognostic biomarkers and as targets for novel chemopreventive therapies.
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Affiliation(s)
- Kaku Goto
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
| | - Armando Andres Roca Suarez
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
| | - Florian Wrensch
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
| | - Thomas F. Baumert
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
- Pôle Hépato-digestif, Institut Hopitalo-Universitaire, F-67000 Strasbourg, France
- Institut Universitaire de France, F-75231 Paris, France
- Correspondence: (T.F.B.); (J.L.); Tel.: +33-3-68-85-37-03 (T.F.B. & J.L.); Fax: +33-3-68-85-37-24 (T.F.B. & J.L.)
| | - Joachim Lupberger
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
- Correspondence: (T.F.B.); (J.L.); Tel.: +33-3-68-85-37-03 (T.F.B. & J.L.); Fax: +33-3-68-85-37-24 (T.F.B. & J.L.)
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The association between metabolic syndrome and Hepatitis C virus infection in the United States. Cancer Causes Control 2020; 31:569-581. [PMID: 32300943 DOI: 10.1007/s10552-020-01300-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Accepted: 04/07/2020] [Indexed: 12/19/2022]
Abstract
PURPOSE Hepatitis C virus (HCV) infection is the prevalent risk factor for chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. The association between metabolic syndrome (MetS) and HCV infection has not been studied effectively, particularly among different ethnic/racial groups in the US. METHODS A retrospective cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey (1999-2014). Unadjusted and adjusted associations were summarized using the prevalence ratio (PR) and 95% confidence interval (CI) after exploring possible interactions. RESULTS In the overall population, MetS was significantly associated with HCV infection with an interaction of age. After adjusting for all potential confounders, MetS was found to be significantly associated with HCV among non-obese and younger adults of age less than 60 years (PR 1.67, 95% CI 1.21-2.30, p = 0.002). MetS was also associated with an increased prevalence of HCV in each racial/ethnic group, while the association was strongly modified by age and obesity status of the subjects in different ethnic/racial groups. CONCLUSIONS MetS or its components are associated with an increased prevalence of HCV in some sub-populations of all ethnic/racial groups in the US. A better understanding of the pathophysiology of MetS associated with HCV is important as MetS may have a role in HCV infection treatment outcomes.
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Shawky M, Mohammed A, Hassan A, Ali B, Moustafa H. Insulin resistance in nondiabetic Egyptian patients with chronic hepatitis C virus. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2020. [DOI: 10.1016/j.rgmxen.2019.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Shawky MA, Mohammed AQ, Hassan AM, Ali BH, Moustafa HM. Insulin resistance in nondiabetic Egyptian patients with chronic hepatitis C virus. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2020; 85:173-179. [PMID: 31784195 DOI: 10.1016/j.rgmx.2019.05.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 05/27/2019] [Accepted: 05/31/2019] [Indexed: 02/08/2023]
Abstract
INTRODUCTION AND OBJECTIVE Insulin resistance and diabetes mellitus are frequently associated with chronic hepatitis C virus (HCV) infection, and it is thought that the presence of insulin resistance aggravates liver disease. We aimed to evaluate insulin resistance in nondiabetic Egyptian patients with chronic HCV infection. MATERIALS AND METHODS Sixty nondiabetic patients with chronic HCV infection and 30 healthy nondiabetic non-HCV-infected volunteers were enrolled in our study. They were divided into 3 groups: group 1 included 30 patients with chronic HCV infection with no cirrhosis, group 2 included 30 patients with chronic HCV infection and cirrhosis of the liver, and group 3 included 30 healthy volunteers as controls. The entire study population underwent a detailed clinical history and physical examination, weight and height measurement, routine laboratory tests, and viral marker determination that included hepatitis B surface antigen and HCV antibodies. PCR analysis was carried out on the patients with positive HCV antibodies. Fasting blood sugar and fasting insulin levels were measured in all the patients, and insulin resistance was calculated according to the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS Patients with cirrhosis of the liver (2 patients with Child class A, 12 patients with Child class B, and 16 patients with Child class C) showed higher insulin resistance levels (2.76±0.97) than the patients with chronic HCV infection and no cirrhosis (2.03±0.743) and the control group (1.22±0.38). The p value was significantly different between the 3 groups. There were direct and significant correlations between insulin resistance, fasting blood sugar, and fasting insulin levels. Patients with chronic HCV infection showed significantly higher fasting insulin and glucose levels than the control group. CONCLUSION Chronic HCV-infected patients showed significantly higher insulin resistance levels than the normal population, even in the absence of hepatic dysfunction and cirrhosis.
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Affiliation(s)
- M A Shawky
- Departamento de Medicina Tropical y Gastroenterología, Universidad de Al-Azhar, Assiut, Egipto.
| | - A Q Mohammed
- Departamento de Medicina Tropical y Gastroenterología, Universidad de Al-Azhar, Assiut, Egipto
| | - A M Hassan
- Departamento de Medicina Tropical y Gastroenterología, Universidad de Al-Azhar, Assiut, Egipto
| | - B H Ali
- Medicina Interna, Centro Sohag de Hepatología y Cardiología, Sohag, Egipto
| | - H M Moustafa
- Departamento de Medicina Tropical y Gastroenterología, Universidad de Al-Azhar, Assiut, Egipto
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Russo FP, Zanetto A, Gambato M, Bortoluzzi I, Al Zoairy R, Franceschet E, De Marchi F, Marzi L, Lynch EN, Floreani A, Farinati F, Schaefer B, Burra P, Zoller H, Mega A. Hepatitis C virus eradication with direct-acting antiviral improves insulin resistance. J Viral Hepat 2020; 27:188-194. [PMID: 31596996 DOI: 10.1111/jvh.13215] [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: 05/09/2019] [Revised: 08/20/2019] [Accepted: 09/01/2019] [Indexed: 12/15/2022]
Abstract
Sustained virological response (SVR) after interferon-based therapy is associated with improvement of insulin resistance (IR) in HCV-infected patients. Few data are available in the direct-acting antivirals (DAAs) era, especially in cirrhotic patients. We prospectively evaluated the long-term effect of DAAs on IR. Patients treated with DAAs between May 2015 and December 2016 in 3 tertiary care centres were recruited. Patients with diabetes were excluded. Biochemical and virological data were collected at baseline, 12/24/48 weeks (W) after the end of therapy (EOT). Presence of IR was defined by a 'homeostasis model assessment index for IR' [HOMA-IR])> 2.5. Liver fibroscan was performed at baseline, at 24/48W after EOT. Hundred and thirty-eight patients were enrolled (mean age 58 years, M/F 85/53, GT1 61%, 68.8% cirrhotic). Sixty-eight patients (94/138) had IR. Patients with IR had significantly higher stiffness than patients without it (23 ± 12 vs 15 ± 8; P < .0001). SVR12 was achieved in 135 (98%) patients, and 124 (90%) patients reached the 48W post-EOT. At this time point, the percentage of patients with IR significantly decreased to 49% (P = 0,01). HOMA-IR was significantly lower than baseline (1.8 vs 3; P < .001), and this was related to a significant reduction of insulin level (11.7 ± 6.3 vs 16.4 ± 8.3). High BMI was associated with a significantly lower probability of achieving a non-IR status at 24W (P = .05) and 48W (P = .03).In conclusion, SVR following DAAs led to a significant reduction of IR, even in patients with cirrhosis. Nevertheless, IR can persist after the achievement of SVR, especially in patients with high BMI.
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Affiliation(s)
- Francesco Paolo Russo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Alberto Zanetto
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Martina Gambato
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | | | - Ramona Al Zoairy
- Department of Medicine I, Department of Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Innsbruck, Austria
| | - Enrica Franceschet
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | | | - Luca Marzi
- Division of Gastroenterology, Bolzano Regional Hospital, Bolzano, Italy
| | - Erica Nicola Lynch
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Annarosa Floreani
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Benedikt Schaefer
- Department of Medicine I, Department of Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Innsbruck, Austria
| | - Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Heinz Zoller
- Department of Medicine I, Department of Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Innsbruck, Austria
| | - Andrea Mega
- Division of Gastroenterology, Bolzano Regional Hospital, Bolzano, Italy
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