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Gonzalez-Aldaco K, Torres-Reyes LA, Ojeda-Granados C, Leal-Mercado L, Roman S, Panduro A. Metabolic Dysfunction-Associated Steatotic Liver Disease in Chronic Hepatitis C Virus Infection: From Basics to Clinical and Nutritional Management. Clin Pract 2024; 14:2542-2558. [PMID: 39585028 PMCID: PMC11587073 DOI: 10.3390/clinpract14060200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 11/26/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with obesity and other cardiometabolic risk factors. MASLD has rapidly become the most common cause of liver disease worldwide, currently affecting 38% of the global population. Excess weight causes chronic inflammation and the activation of different pathways involved in liver damage. MASLD can progress from simple steatosis to steatohepatitis, giving way to its inflammatory component, metabolic dysfunction-associated steatohepatitis (MASH), previously recognized as non-alcoholic steatosis hepatitis (NASH). Chronic hepatitis C virus (HCV) infection remains a significant challenge to liver health as it triggers hepatic inflammation, metabolic disruption, and hepatic steatosis. The convergence of MASLD and chronic HCV infection can significantly alter the course of liver disease and accelerate the progression to severe liver damage. Currently, HCV treatment has a high cure rate. However, in patients who achieve a sustained virological response after treatment with direct-acting antivirals, weight gain, and excessive calorie intake may contribute to increased liver steatosis and a higher risk of liver disease progression. Therefore, the effective clinical and nutritional management of HCV patients, both before and after viral eradication, is crucial to reducing the risk of death from hepatocellular carcinoma. Understanding the complex interactions between MASLD and HCV infection is crucial for managing these patients appropriately. Herein, host and viral mechanisms inducing liver damage during the coexistence of MASLD and HCV infection are described, and their therapeutic and dietary management are discussed.
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Affiliation(s)
- Karina Gonzalez-Aldaco
- Centro Universitario de los Valles, Universidad de Guadalajara, Carretera Guadalajara-Ameca Km. 45.5, Ameca 46600, Jalisco, Mexico;
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico; (L.L.-M.); (S.R.); (A.P.)
| | - Luis A. Torres-Reyes
- Centro Universitario de los Valles, Universidad de Guadalajara, Carretera Guadalajara-Ameca Km. 45.5, Ameca 46600, Jalisco, Mexico;
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico; (L.L.-M.); (S.R.); (A.P.)
| | - Claudia Ojeda-Granados
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, 95123 Catania, Italy;
| | - Leonardo Leal-Mercado
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico; (L.L.-M.); (S.R.); (A.P.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Sonia Roman
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico; (L.L.-M.); (S.R.); (A.P.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Arturo Panduro
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico; (L.L.-M.); (S.R.); (A.P.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
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Asgharzadeh F, Memarzia A, Alikhani V, Beigoli S, Boskabady MH. Peroxisome proliferator-activated receptors: Key regulators of tumor progression and growth. Transl Oncol 2024; 47:102039. [PMID: 38917593 PMCID: PMC11254173 DOI: 10.1016/j.tranon.2024.102039] [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: 10/31/2023] [Revised: 04/30/2024] [Accepted: 06/20/2024] [Indexed: 06/27/2024] Open
Abstract
One of the main causes of death on the globe is cancer. Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors, including PPARα, PPARδ and PPARγ, which are important in regulating cancer cell proliferation, survival, apoptosis, and tumor growth. Activation of PPARs by endogenous or synthetic compounds regulates tumor progression in various tissues. Although each PPAR isotype suppresses or promotes tumor development depending on the specific tissues or ligands, the mechanism is still unclear. PPARs are receiving interest as possible therapeutic targets for a number of disorders. Numerous clinical studies are being conducted on PPARs as possible therapeutic targets for cancer. Therefore, this review will focus on the existing and future uses of PPARs agonists and antagonists in treating malignancies. PubMed, Science Direct, and Scopus databases were searched regarding the effect of PPARs on various types of cancers until the end of May 2023. The results of the review articles showed the therapeutic influence of PPARs on a wide range of cancer on in vitro, in vivo and clinical studies. However, further experimental and clinical studies are needed to be conducted on the influence of PPARs on various cancers.
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Affiliation(s)
- Fereshteh Asgharzadeh
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arghavan Memarzia
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vida Alikhani
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Sima Beigoli
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Hossein Boskabady
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Jeremiah SS, Moin ASM, Butler AE. Virus-induced diabetes mellitus: revisiting infection etiology in light of SARS-CoV-2. Metabolism 2024; 156:155917. [PMID: 38642828 DOI: 10.1016/j.metabol.2024.155917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/14/2024] [Accepted: 04/14/2024] [Indexed: 04/22/2024]
Abstract
Diabetes mellitus (DM) is comprised of two predominant subtypes: type 1 diabetes mellitus (T1DM), accounting for approximately 5 % of cases worldwide and resulting from autoimmune destruction of insulin-producing β-cells, and type 2 (T2DM), accounting for approximately 95 % of cases globally and characterized by the inability of pancreatic β-cells to meet the demand for insulin due to a relative β-cell deficit in the setting of peripheral insulin resistance. Both types of DM involve derangement of glucose metabolism and are metabolic diseases generally considered to be initiated by a combination of genetic and environmental factors. Viruses have been reported to play a role as infectious etiological factors in the initiation of both types of DM in predisposed individuals. Among the reported viral infections causing DM in humans, the most studied include coxsackie B virus, cytomegalovirus and hepatitis C virus. The recent COVID-19 pandemic has highlighted the diabetogenic potential of SARS-CoV-2, rekindling interest in the field of virus-induced diabetes (VID). This review discusses the reported mechanisms of viral-induced DM, addressing emerging concepts in VID, as well as highlighting areas where knowledge is lacking, and further investigation is warranted.
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Affiliation(s)
| | - Abu Saleh Md Moin
- Royal College of Surgeons in Ireland - Medical University of Bahrain, Busaiteen, Kingdom of Bahrain.
| | - Alexandra E Butler
- Royal College of Surgeons in Ireland - Medical University of Bahrain, Busaiteen, Kingdom of Bahrain.
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4
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Melano I, Lo YC, Su WC. Characterization of host substrates of SARS-CoV-2 main protease. Front Microbiol 2023; 14:1251705. [PMID: 37670988 PMCID: PMC10475589 DOI: 10.3389/fmicb.2023.1251705] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 07/31/2023] [Indexed: 09/07/2023] Open
Abstract
The main protease (Mpro) plays a crucial role in coronavirus, as it cleaves viral polyproteins and host cellular proteins to ensure successful replication. In this review, we discuss the preference in the recognition sequence of Mpro based on sequence-based studies and structural information and highlight the recent advances in computational and experimental approaches that have aided in discovering novel Mpro substrates. In addition, we provide an overview of the current understanding of Mpro host substrates and their implications for viral replication and pathogenesis. As Mpro has emerged as a promising target for the development of antiviral drugs, further insight into its substrate specificity may contribute to the design of specific inhibitors.
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Affiliation(s)
- Ivonne Melano
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Yan-Chung Lo
- Sinphar Pharmaceutical Co., Ltd., Sinphar Group, Yilan, Taiwan
| | - Wen-Chi Su
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- International Master’s Program of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
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5
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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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Rajsfus BF, Mohana-Borges R, Allonso D. Diabetogenic viruses: linking viruses to diabetes mellitus. Heliyon 2023; 9:e15021. [PMID: 37064445 PMCID: PMC10102442 DOI: 10.1016/j.heliyon.2023.e15021] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 03/31/2023] Open
Abstract
Diabetes Mellitus (DM) is a group of chronic metabolic diseases distinguished by elevated glycemia due to the alterations in insulin metabolism. DM is one of the most relevant diseases of the modern world, with high incidence and prevalence worldwide, associated with severe systemic complications and increased morbidity and mortality rates. Although genetic factors and lifestyle habits are two of the main factors involved in DM onset, viral infections, such as enteroviruses, cytomegalovirus, hepatitis C virus, human immunodeficiency virus, severe acute respiratory syndrome coronavirus 2, among others, have been linked as triggers of type 1 (T1DM) and type 2 (T2DM) diabetes. Over the years, various groups identified different mechanisms as to how viruses can promote these metabolic syndromes. However, this field is still poorly explored and needs further research, as millions of people live with these pathologies. Thus, this review aims to ex-plore the different processes of how viruses can induce DM and their contribution to the prevalence and incidence of DM worldwide.
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Raber J, Rhea EM, Banks WA. The Effects of Viruses on Insulin Sensitivity and Blood-Brain Barrier Function. Int J Mol Sci 2023; 24:2377. [PMID: 36768699 PMCID: PMC9917142 DOI: 10.3390/ijms24032377] [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: 01/02/2023] [Revised: 01/19/2023] [Accepted: 01/23/2023] [Indexed: 01/27/2023] Open
Abstract
In this review manuscript, we discuss the effects of select common viruses on insulin sensitivity and blood-brain barrier (BBB) function and the potential overlapping and distinct mechanisms involved in these effects. More specifically, we discuss the effects of human immunodeficiency virus (HIV), herpes, hepatitis, influenza, respiratory syncytial virus (RSV), and SARS-CoV-2 viruses on insulin sensitivity and BBB function and the proposed underlying mechanisms. These viruses differ in their ability to be transported across the BBB, disrupt the BBB, and/or alter the function of the BBB. For RSV and SARS-CoV-2, diabetes increases the risk of infection with the virus, in addition to viral infection increasing the risk for development of diabetes. For HIV and hepatitis C and E, enhanced TNF-a levels play a role in the detrimental effects. The winter of 2022-2023 has been labeled as a tridemic as influenza, RSV, and COVID-19 are all of concern during this flu season. There is an ongoing discussion about whether combined viral exposures of influenza, RSV, and COVID-19 have additive, synergistic, or interference effects. Therefore, increased efforts are warranted to determine how combined viral exposures affect insulin sensitivity and BBB function.
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Affiliation(s)
- Jacob Raber
- Departments of Behavioral Neuroscience, Neurology and Radiation Medicine; Affiliate Scientist, Division of Neuroscience, ONPRC, Oregon Health & Science University, Portland, OR 97239, USA
| | - Elizabeth M. Rhea
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
- Department of Medicine, University of Washington, Seattle, WA 98108, USA
| | - William A. Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
- Department of Medicine, University of Washington, Seattle, WA 98108, USA
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8
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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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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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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: 5] [Impact Index Per Article: 1.7] [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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11
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Recipient IL28B genotype CT is a predictor of new onset diabetes mellitus in liver transplant patients with chronic hepatitis C. Int J Diabetes Dev Ctries 2021. [DOI: 10.1007/s13410-021-01015-6] [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: 10/20/2022] Open
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12
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Ding Y, Li G, Zhou Z, Deng T. Molecular mechanisms underlying hepatitis C virus infection-related diabetes. Metabolism 2021; 121:154802. [PMID: 34090869 DOI: 10.1016/j.metabol.2021.154802] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/27/2021] [Accepted: 05/31/2021] [Indexed: 12/16/2022]
Abstract
Diabetes is a noncommunicable widespread disease that poses the risk of severe complications in patients, with certain complications being life-threatening. Hepatitis C is an infectious disease that mainly causes liver damage, which is also a profound threat to human health. Hepatitis C virus (HCV) infection has many extrahepatic manifestations, including diabetes. Multiple mechanisms facilitate the strong association between HCV and diabetes. HCV infection can affect the insulin signaling pathway in liver and pancreatic tissue and change the profiles of circulating microRNAs, which may further influence the occurrence and development of diabetes. This review describes how HCV infection causes diabetes and discusses the current research progress with respect to HCV infection-related diabetes.
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Affiliation(s)
- Yujin Ding
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Guangdi Li
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410011, Hunan, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Tuo Deng
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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Abstract
The immune and endocrine systems collectively control homeostasis in the body. The endocrine system ensures that values of essential factors and nutrients such as glucose, electrolytes and vitamins are maintained within threshold values. The immune system resolves local disruptions in tissue homeostasis, caused by pathogens or malfunctioning cells. The immediate goals of these two systems do not always align. The immune system benefits from optimal access to nutrients for itself and restriction of nutrient availability to all other organs to limit pathogen replication. The endocrine system aims to ensure optimal nutrient access for all organs, limited only by the nutrients stores that the body has available. The actual state of homeostatic parameters such as blood glucose levels represents a careful balance based on regulatory signals from the immune and endocrine systems. This state is not static but continuously adjusted in response to changes in the current metabolic needs of the body, the amount of resources it has available and the level of threats it encounters. This balance is maintained by the ability of the immune and endocrine systems to interact and co-regulate systemic metabolism. In context of metabolic disease, this system is disrupted, which impairs functionality of both systems. The failure of the endocrine system to retain levels of nutrients such as glucose within threshold values impairs functionality of the immune system. In addition, metabolic stress of organs in context of obesity is perceived by the immune system as a disruption in local homeostasis, which it tries to resolve by the excretion of factors which further disrupt normal metabolic control. In this chapter, we will discuss how the immune and endocrine systems interact under homeostatic conditions and during infection with a focus on blood glucose regulation. In addition, we will discuss how this system fails in the context of metabolic disease.
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14
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Xie J, Wang M, Cheng A, Jia R, Zhu D, Liu M, Chen S, Zhao X, Yang Q, Wu Y, Zhang S, Luo Q, Wang Y, Xu Z, Chen Z, Zhu L, Liu Y, Yu Y, Zhang L, Chen X. The role of SOCS proteins in the development of virus- induced hepatocellular carcinoma. Virol J 2021; 18:74. [PMID: 33849568 PMCID: PMC8045357 DOI: 10.1186/s12985-021-01544-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 04/03/2021] [Indexed: 01/08/2023] Open
Abstract
Background Liver cancer has become one of the most common cancers and has a high mortality rate. Hepatocellular carcinoma is one of the most common liver cancers, and its occurrence and development process are associated with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Main body The serious consequences of chronic hepatitis virus infections are related to the viral invasion strategy. Furthermore, the viral escape mechanism has evolved during long-term struggles with the host. Studies have increasingly shown that suppressor of cytokine signaling (SOCS) proteins participate in the viral escape process. SOCS proteins play an important role in regulating cytokine signaling, particularly the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Cytokines stimulate the expression of SOCS proteins, in turn, SOCS proteins inhibit cytokine signaling by blocking the JAK-STAT signaling pathway, thereby achieving homeostasis. By utilizing SOCS proteins, chronic hepatitis virus infection may destroy the host’s antiviral responses to achieve persistent infection. Conclusions This review provides recent knowledge regarding the role of SOCS proteins during chronic hepatitis virus infection and provides some new ideas for the future treatment of chronic hepatitis.
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Affiliation(s)
- Jinyan Xie
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China. .,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China. .,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.
| | - Renyong Jia
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Dekang Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Mafeng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - XinXin Zhao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Qiao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Ying Wu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Shaqiu Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Qihui Luo
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Yin Wang
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Zhiwen Xu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Zhengli Chen
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Ling Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Yunya Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Yanling Yu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Ling Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Xiaoyue Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
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15
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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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Strauhs-Nitsch L, Campiolo MF, Morsoletto DBG, Pissaia Junior A, Ivantes CAP. CURING HEPATITIS C WITH THE NEW DIRECT ACTING ANTIVIRALS DID NOT IMPROVE INSULIN RESISTANCE AFTER ONE YEAR. ARQUIVOS DE GASTROENTEROLOGIA 2021; 57:267-271. [PMID: 33027477 DOI: 10.1590/s0004-2803.202000000-50] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 06/30/2020] [Indexed: 01/10/2023]
Abstract
BACKGROUND Chronic hepatitis C still figures as an important cause of morbidity among the Brazilian population, and is closely associated with metabolic disturbances, including insulin resistance (IR), which can be evaluated by the Homeostatic Model Assessment (HOMA-IR). IR may entail lower sustained virologic response (SVR) on certain therapeutic regimens and faster progression to advanced hepatic fibrosis. With the arrival of the direct acting agents (DAA) in hepatitis C treatment, there is an increased need in observing the impact in patients' IR profile while using such therapies. OBJECTIVE - 1) To compare the results of HOMA-IR in patients affected by chronic hepatitis C before treatment with DAA and 12 months after finishing it with SVR. 2) To evaluate the evolution of weight after curing chronic hepatitis C. METHODS We included patients older than 18 from two tertiary care in Curitiba - PR, of both sexes, with chronic hepatitis C, treated with DAA, from July 2015 to September 2017. We also evaluated the patients' levels of fasting insulin, fasting glucose and glycated hemoglobin before starting treatment and 12 months after finishing it. We also used epidemiologic data, such as age, sex, hepatic fibrosis degree, body mass index, abdominal circumference, viral genotype and the presence of diabetes mellitus before and after treatment. IR was assessed before and after treatment and calculated by the HOMA-IR score. Insulin resistance was defined by a HOMA-IR greater than 2.5. We excluded patients who lost follow-up, those who did not achieve SRV and those who did not have a laboratory profile. The results of quantitative variables were described by means, medians, and standard deviations. P values <0.05 indicated statistical significance. RESULTS We included 75 patients in this study, with a mean age of 55.2 years and 60% of males. Forty-three patients had advanced fibrosis. Twenty one (28%) had a previous diabetes mellitus diagnosis. We identified 31 (41.3%) patients with IR before antiviral treatment, and this number increased to 39 (52%) after 12 months of finishing treatment, according to HOMA-IR. There was no statistic difference between insulin, glucose and HOMA-IR measurements before and after curing hepatitis C. We observed a weight gain in patients shortly after curing hepatitis C, but this did not persist at the end of the study. We also had no significant difference in IR prevalence when viral genotype was concerned. CONCLUSION In this study, there was no statistically significant difference between HOMA-IR results in patients before and 12 months after treatment for hepatitis C. Even though patients gained weight after the cure, this was not statistically significant after a year (P=0.131).
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Affiliation(s)
- Lohanna Strauhs-Nitsch
- Hospital Nossa Senhora das Graças, Departamento de Gastroenterologia e Hepatologia, Curitiba, PR, Brasil
| | - Marcela Ferro Campiolo
- Hospital Nossa Senhora das Graças, Departamento de Gastroenterologia e Hepatologia, Curitiba, PR, Brasil
| | | | - Alcindo Pissaia Junior
- Hospital Nossa Senhora das Graças, Departamento de Gastroenterologia e Hepatologia, Curitiba, PR, Brasil
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17
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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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18
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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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19
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Chiu HC, Chiu YC, Yang EH, Chang TT, Chien SC, Wu IC, Wu CH, Cheng PN. Effectiveness and safety of ledipasvir/sofosbuvir for genotype 2 chronic hepatitis C infection: Real-world experience from Taiwan. J Formos Med Assoc 2020; 120:983-990. [PMID: 32891488 DOI: 10.1016/j.jfma.2020.08.033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 05/27/2020] [Accepted: 08/20/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/PURPOSE Genotype 2 (GT2) hepatitis C virus infection is the second common genotype in Taiwan. Real-world experience of ledipasvir/sofosbuvir (LDV/SOF) for GT2 infection is limited. The aim of this study is to evaluate the effectiveness and safety of LDV/SOF in patients with GT2 chronic hepatitis C (CHC) infection. METHODS CHC patients with GT2 infection receiving 12 weeks LDV/SOF from three hospitals were enrolled. HCV RNA was checked at baseline, end-of-treatment and 12 weeks after completing treatment. Demographic data, adverse events, renal function and metabolic profiles were recorded. RESULTS Among 392 enrolled patients, 33 patients (8.4%) were cirrhotic. Sustained virological response (SVR) rate was 96.7% (379/392) by intention-to-treat analysis and 97.2% (379/390) by per-protocol analysis. The SVR rate was lower in cirrhotic patients than in non-cirrhotic patients (90.6% vs 97.8%, p = 0.053). Two cirrhotic patients who took LDV/SOF plus ribavirin both achieved SVR. Neither drug-related severe adverse events nor discontinuation due to drug-related adverse event were reported. The estimated glomerular filtration rate (eGFR) remained stable in patients with chronic kidney disease 3a/3b. CONCLUSION Twelve weeks of LDV/SOF treatment provided an excellent and safe regimen for GT2 CHC infection, particularly in non-cirrhotic patients.
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Affiliation(s)
- Hung-Chih Chiu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yen-Cheng Chiu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Er-Hsiang Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ting-Tsung Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shih-Chieh Chien
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - I-Chin Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun-Hsien Wu
- Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan
| | - Pin-Nan Cheng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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20
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Hsu CS, Liu WL, Li Q, Lowey B, Hertz L, Chao YC, Liang TJ, Chen DS, Kao JH. Hepatitis C virus genotypes 1-3 infections regulate lipogenic signaling and suppress cholesterol biosynthesis in hepatocytes. J Formos Med Assoc 2020; 119:1382-1395. [PMID: 32284164 PMCID: PMC11492201 DOI: 10.1016/j.jfma.2020.03.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/18/2020] [Accepted: 03/23/2020] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Patients with different hepatitis C virus (HCV) genotype infections are associated with varying metabolic disorders. Although alteration of lipid metabolism has been confirmed as a virus-induced metabolic derangement in chronic hepatitis C patients, the impact of various HCV genotypes on hepatic cholesterol metabolism remains elusive. In this study, we thus investigated the HCV genotype-specific lipogenic and cholesterol metabolism profiles in an in vitro cell culture system. METHODS We first conducted HCV cell culture system (HCVcc) assays by infecting Huh7.5.1 cells with multiple infection-competent HCV strains, including the genotype 2a JFH1 and JFH1-based intergenotypic recombinants 1b and 3a. We then examined the expression levels of various lipid and cholesterol-related genes. RESULTS The data showed that infection with individual HCV genotypes exerted unique gene expression regulatory effects on lipoproteins and cholesterol metabolism genes. Of note, all HCV strains suppressed cholesterol biosynthesis in hepatocytes through downregulating the expression of HMG-CoA reductase (HMGCR) and farnesyl-diphosphate farnesyltransferase 1 (FDFT1) - two essential enzymes for cholesterol biosynthesis. These HCV-mediated inhibitory effects could be reversed by treatment with sofosbuvir, a pangenotypic NS5B inhibitor. In addition, overexpression of HCV genotype 1b, 2a or 3a core protein significantly suppressed HMGCR mRNA transcription and translation, thus diminished cellular cholesterol biosynthesis. Nonetheless, the core protein had no effect on FDFT1 expression. CONCLUSION Although HCV infection regulates host lipid metabolism in a genotype-specific manner, its inhibition on hepatocellular cholesterogenic gene expression and total cholesterol biosynthesis is a common effect among HCV genotype 1b, 2a and 3a.
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Affiliation(s)
- Ching-Sheng Hsu
- Liver Diseases Research Center, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan; School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - Wei-Liang Liu
- National Mosquito-Borne Diseases Control Research Center, National Health Research Institutes, Miaoli, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Qisheng Li
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Brianna Lowey
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Laura Hertz
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - You-Chen Chao
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ding-Shinn Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Nankang, 11549, Taiwan
| | - Jia-Horng Kao
- National Mosquito-Borne Diseases Control Research Center, National Health Research Institutes, Miaoli, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.
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21
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Bender D, Hildt E. Effect of Hepatitis Viruses on the Nrf2/Keap1-Signaling Pathway and Its Impact on Viral Replication and Pathogenesis. Int J Mol Sci 2019; 20:ijms20184659. [PMID: 31546975 PMCID: PMC6769940 DOI: 10.3390/ijms20184659] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/16/2019] [Accepted: 09/17/2019] [Indexed: 12/15/2022] Open
Abstract
With respect to their genome and their structure, the human hepatitis B virus (HBV) and hepatitis C virus (HCV) are complete different viruses. However, both viruses can cause an acute and chronic infection of the liver that is associated with liver inflammation (hepatitis). For both viruses chronic infection can lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) play a central role in a variety of chronic inflammatory diseases. In light of this, this review summarizes the impact of both viruses on ROS-generating and ROS-inactivating mechanisms. The focus is on the effect of both viruses on the transcription factor Nrf2 (nuclear factor erythroid 2 (NF-E2)-related factor 2). By binding to its target sequence, the antioxidant response element (ARE), Nrf2 triggers the expression of a variety of cytoprotective genes including ROS-detoxifying enzymes. The review summarizes the literature about the pathways for the modulation of Nrf2 that are deregulated by HBV and HCV and describes the impact of Nrf2 deregulation on the viral life cycle of the respective viruses and the virus-associated pathogenesis.
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Affiliation(s)
- Daniela Bender
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straβe 51-59, D-63225 Langen, Germany.
| | - Eberhard Hildt
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straβe 51-59, D-63225 Langen, Germany.
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22
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Gastaldi G, Gomes D, Schneiter P, Montet X, Tappy L, Clément S, Negro F. Treatment with direct-acting antivirals improves peripheral insulin sensitivity in non-diabetic, lean chronic hepatitis C patients. PLoS One 2019; 14:e0217751. [PMID: 31170218 PMCID: PMC6553748 DOI: 10.1371/journal.pone.0217751] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 05/08/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS Hepatitis C virus (HCV) infection is associated with insulin resistance, which may lead to type 2 diabetes and its complications. Although HCV infects mainly hepatocytes, it may impair insulin sensitivity at the level of uninfected extrahepatic tissues (muscles and adipose tissue). The aim of this study was to assess whether an interferon-free, antiviral therapy may improve HCV-associated hepatic vs. peripheral insulin sensitivity. METHODS In a single-arm exploratory trial, 17 non-diabetic, lean chronic hepatitis C patients without significant fibrosis were enrolled, and 12 completed the study. Patients were treated with a combination of sofosbuvir/ledipasvir and ribavirin for 12 weeks, and were submitted to a 2-step euglycemic hyperinsulinemic clamp with tracers, together with indirect calorimetry measurement, to measure insulin sensitivity before and after 6 weeks of antivirals. A panel of 27 metabolically active cytokines was analyzed at baseline and after therapy-induced viral suppression. RESULTS Clamp analysis performed in 12 patients who achieved complete viral suppression after 6 weeks of therapy showed a significant improvement of the peripheral insulin sensitivity (13.1% [4.6-36.7], p = 0.003), whereas no difference was observed neither in the endogenous glucose production, in lipolysis suppression nor in substrate oxidation. A distinct subset of hepatokines, potentially involved in liver-to-periphery crosstalk, was modified by the antiviral therapy. CONCLUSION Pharmacological inhibition of HCV improves peripheral (but not hepatic) insulin sensitivity in non-diabetic, lean individuals with chronic hepatitis C without significant fibrosis.
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Affiliation(s)
- Giacomo Gastaldi
- Division of Endocrinology, diabetology, hypertension and nutrition, Geneva University Hospitals, Geneva, Switzerland
| | - Diana Gomes
- Department of Pathology and immunology, University of Geneva, Geneva, Switzerland
| | - Philippe Schneiter
- Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Xavier Montet
- Division of Radiology, Geneva University Hospitals, Geneva, Switzerland
| | - Luc Tappy
- Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Sophie Clément
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
| | - Francesco Negro
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
- Division of Gastroenterology and hepatology, Geneva University Hospitals, Geneva, Switzerland
- * E-mail:
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23
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Advances in the role of HCV nonstructural protein 5a (NS5A) of 3a genotype in inducing insulin resistance by possible phosphorylation of AKT/PKB. Sci Rep 2019; 9:6150. [PMID: 30992506 PMCID: PMC6468007 DOI: 10.1038/s41598-019-42602-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 03/15/2019] [Indexed: 12/15/2022] Open
Abstract
HCV genes interfere with host cellular genes and play crucial role in pathogenesis. The mechanism under which HCV genes induce insulin resistance is not much clear. This study is aimed to examine the role of HCV NS5A in inducing insulin resistance by examining its affect in the phosphorylation level of AKT/PKB. In the present study, HepG2 cells were transfected with HCV NS5A and after 24 hours of transfection, protein was extracted from cells that were pre induced with insulin at three different time intervals i.e. 1hour, 2 hours and 3hours. Dot Blot analysis was performed to study the phosphorylation level of AKT. Results showed that there is clear upregulation of serine 473 phosphorylation level of AKT in NS5A transfected cells as compared with control (without NS5A). In conclusion, upregulation of serine 473 phosphorylation by NS5A of HCV genotype 3a suggests that this gene impairs the normal insulin AKT/PKB signaling pathway that leads towards insulin resistance and Type 2 diabetes mellitus. Therefore, HCV non-structural protein NS5A should be considered as promising candidate to be studied in detail for HCV induced insulin resistance and should be regarded as a therapeutically important target for the prevention of chronic liver diseases.
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24
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Hamed AE, Elsahar M, Elwan NM, El-Nakeep S, Naguib M, Soliman HH, Ahmed Aboubakr A, AbdelMaqsod A, Sedrak H, Assaad SN, Elwakil R, Esmat G, Salh S, Mostafa T, Mogawer S, Sadek SE, Saber MM, Ezelarab H, Mahmoud AA, Sultan S, El Kassas M, Kamal E, ElSayed NM, Moussa S. Managing diabetes and liver disease association. Arab J Gastroenterol 2018; 19:166-179. [PMID: 30420265 DOI: 10.1016/j.ajg.2018.08.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/26/2018] [Indexed: 02/05/2023]
Abstract
There is strong association between liver diseases and diabetes (DM) which is higher than expected by a chance association of two very common disorders. It can be classified into three categories: Liver disease related to diabetes, hepatogenous diabetes (HD), and liver disease occurring coincidentally with DM. The criteria for the diagnosis of diabetes associating liver disease are the same for primary diabetes. Two hours post glucose load is a better screening test for HD. HbA1c may not be suitable for diagnosis or monitoring of diabetes associating advanced liver disease. Apart from the increased cardiovascular risk in patients with type 2 DM (T2 DM) and NAFLD, the cardiovascular and retinopathy risk is low in HD. Patients with metabolic derangement should be screened for NAFLD which in turn may predict T2 DM development. Similarly, patients with established T2 DM should also be screened for NAFLD which further contributes to diabetes worsening. Diabetes is a significant risk factor for progression of the chronic liver disease. It is associated with poor patient survival. Treatment of diabetes associating liver disease appears beneficial. Metformin, if tolerated and not contraindicated, is recommended as a first-line therapy for patients with diabetes and chronic liver disease (CLD). If the hepatic disease is severe, insulin secretagogues should be avoided because of the increased risk of hypoglycaemia. Pioglitazone may be useful in patients with fatty liver disease. DPP-4 inhibitors showed effectiveness and safety for the treatment of T2 DM in CLD patients up to those with child B stage. GLP-1 receptor agonists and SGLT-2 inhibitors exhibit positive effects on weight and are associated with minimal risk of hypoglycaemia. Insulin must be used with caution, as hypoglycaemia may be a problem. Insulin analogues are preferred in the context of hypoglycaemia Statins can be used to treat dyslipidaemia in NAFLD, also the use of angiotensin II receptor antagonist for hypertension is safe and beneficial Given the clear association between diabetes mellitus and hepatocellular carcinoma, the strict control of glycaemia with insulin sensitizers can be essential in its prevention. The addition of DM to the currently used scores (Child-Pugh and MELD scores) may enhance the sensitivity and the specificity for prediction of morbidity and mortality rates in cirrhotic patients. In the new era of directly acting antiviral agents (DAAs) for HCV treatment, it is recommended to follow up lipid profile and blood sugar levels following SVR in order to adjust doses of medications used in diabetic (SVR is associated with reduction in insulin requirements) and dyslipidaemic patients (rebound increase in the lipid profile after clearing the virus may increase risk of cardiovascular disease (CVD)). The issues of post liver transplant diabetes and relation between DM and chronic HBV are highlighted. This narrative review and Consensus-based practice guidance (under revision and criticism) are based on a formal review and analysis of the recently published world literature on the topic (Medline search up to September 2017); and the experience of the authors and independent reviewers.
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Affiliation(s)
- Abd Elkhalek Hamed
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt.
| | - Medhat Elsahar
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Police Medical Academy, Egypt
| | | | | | | | | | - Ashraf Ahmed Aboubakr
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | | | | | | | - Reda Elwakil
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Ain Shams University, Egypt
| | - Gamal Esmat
- The Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD), Egypt; Kasr Al Aini, Egypt
| | - Samira Salh
- Department of Pharmacy, Cairo University, Egypt
| | | | | | - Sameh Emil Sadek
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | - Maha M Saber
- Department of Clinical Nutrition National Research Centre, Egypt
| | - Hanan Ezelarab
- Department of Clinical Nutrition National Research Centre, Egypt
| | - Asem Ashraf Mahmoud
- Department of Internal Medicine, Hepatology, and Diabetes, Egyptian Military Medical Academy, Egypt
| | | | | | - Ehab Kamal
- Medical Department, National Research Centre, Egypt
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Shahnazarian V, Ramai D, Reddy M, Mohanty S. Hepatitis C virus genotype 3: clinical features, current and emerging viral inhibitors, future challenges. Ann Gastroenterol 2018; 31:541-551. [PMID: 30174390 PMCID: PMC6102453 DOI: 10.20524/aog.2018.0281] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/18/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatitis C virus (HCV) represents a global burden on healthcare that affects over 150 million people worldwide. In the past, HCV genotype 3 was considered difficult to treat relative to other genotypes. Genotype 3 has been associated with a higher rate of complications, including fatty liver disease, fibrosis, hepatocellular carcinoma and mortality. However, with the advent of first- and second-generation direct-acting antivirals, genotype 3 can be treated effectively. Additionally, these new drugs are well tolerated by patients and have significantly fewer side effects compared to ribavirin and interferon-based regimens. However, while great strides have been made in overcoming biological barriers, our next challenge lies in overcoming economic and financial obstacles if we are to eradicate HCV genotype 3. Herein, we review the clinical features associated with HCV genotype 3, current and emerging treatment regimens, and challenges associated with treatment.
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Affiliation(s)
- Vahe Shahnazarian
- Division of Gastroenterology, Hepatology, and Advanced Endoscopy, The Brooklyn Hospital Center, Academic Affiliate of The Icahn School of Medicine at Mount Sinai, Clinical Affiliate of The Mount Sinai Hospital, Brooklyn, NY (Vahe Shahnazarian, Daryl Ramai, Madhavi Reddy), USA
| | - Daryl Ramai
- Division of Gastroenterology, Hepatology, and Advanced Endoscopy, The Brooklyn Hospital Center, Academic Affiliate of The Icahn School of Medicine at Mount Sinai, Clinical Affiliate of The Mount Sinai Hospital, Brooklyn, NY (Vahe Shahnazarian, Daryl Ramai, Madhavi Reddy), USA
- School of Medicine, St George’s University, True Blue, Grenada, WI (Daryl Ramai), USA
| | - Madhavi Reddy
- Division of Gastroenterology, Hepatology, and Advanced Endoscopy, The Brooklyn Hospital Center, Academic Affiliate of The Icahn School of Medicine at Mount Sinai, Clinical Affiliate of The Mount Sinai Hospital, Brooklyn, NY (Vahe Shahnazarian, Daryl Ramai, Madhavi Reddy), USA
| | - Smruti Mohanty
- Division of Gastroenterology and Hepatology, New York Presbyterian Brooklyn Methodist Hospital, Clinical Affiliate of Weill Cornell Medicine, Brooklyn, NY (Smruti Mohanty), USA
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26
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Chen YY, Fang WH, Wang CC, Kao TW, Chang YW, Yang HF, Wu CJ, Sun YS, Chen WL. Increased body fat percentage in patients with hepatitis B and C virus infection. PLoS One 2018; 13:e0200164. [PMID: 29965999 PMCID: PMC6028118 DOI: 10.1371/journal.pone.0200164] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 06/20/2018] [Indexed: 12/31/2022] Open
Abstract
Accumulated evidence has suggested associations between glucose abnormalities and insulin resistance with hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. However, few studies have reported the effect of hepatitis virus infections on body composition. Our aim was to explore the association of hepatitis virus infections with percent body fat (PBF) in a cross-sectional analysis. A total of 69226 subjects obtained from the health examinations at Tri-Service General Hospital (TSGH) from 2010 to 2016 were enrolled in the study. Participants were divided into subgroups based on the presence of hepatitis B surface antigen (HBsAg) and anti-HCV. PBF was measured by bioelectrical impedance analysis (BIA). A multivariable linear regression model was applied to test the association of hepatitis virus infections with PBF and glycemic status. In male participants, hepatitis virus infections were closely associated with increased PBF, especially in those subjects with HCV/HBV coinfection. HCV/HBV coinfection was positively correlated with fasting plasma glucose and postprandial glucose while HCV and HBV mono-infection were not. The impact of hepatitis virus infection on increased PBF was observed in general population with gender difference. A further study on the treatment of hepatitis virus infection might help prevent the development of obesity-related diseases.
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Affiliation(s)
- Yuan-Yuei Chen
- Department of Internal Medicine, Tri-Service General Hospital Songshan Branch, Taipei, Taiwan, Republic of China
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Wen-Hui Fang
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Chung-Ching Wang
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Tung-Wei Kao
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Graduate Institute of Clinical Medical, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
| | - Yaw-Wen Chang
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Hui-Fang Yang
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Chen-Jung Wu
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Division of Family Medicine, Department of Community Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan, Republic of China
| | - Yu-Shan Sun
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Wei-Liang Chen
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
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Singhal A, Agrawal A, Ling J. Regulation of insulin resistance and type II diabetes by hepatitis C virus infection: A driver function of circulating miRNAs. J Cell Mol Med 2018; 22:2071-2085. [PMID: 29411512 PMCID: PMC5867149 DOI: 10.1111/jcmm.13553] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 01/04/2018] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a serious worldwide healthcare issue. Its association with various liver diseases including hepatocellular carcinoma (HCC) is well studied. However, the study on the relationship between HCV infection and the development of insulin resistance and diabetes is very limited. Current research has already elucidated some underlying mechanisms, especially on the regulation of metabolism and insulin signalling by viral proteins. More studies have emerged recently on the correlation between HCV infection‐derived miRNAs and diabetes and insulin resistance. However, no studies have been carried out to directly address if these miRNAs, especially circulating miRNAs, have causal effects on the development of insulin resistance and diabetes. Here, we proposed a new perspective that circulating miRNAs can perform regulatory functions to modulate gene expression in peripheral tissues leading to insulin resistance and diabetes, rather than just a passive factor associated with these pathological processes. The detailed rationales were elaborated through comprehensive literature review and bioinformatic analyses. miR‐122 was identified to be one of the most potential circulating miRNAs to cause insulin resistance. This result along with the idea about the driver function of circulating miRNAs will promote further investigations that eventually lead to the development of novel strategies to treat HCV infection‐associated extrahepatic comorbidities.
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Affiliation(s)
- Adit Singhal
- Geisinger Commonwealth School of Medicine, Scranton, PA, USA
| | | | - Jun Ling
- Geisinger Commonwealth School of Medicine, Scranton, PA, USA
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Abstract
Metabolic disorders are common in patients with chronic hepatitis C virus (HCV) infection. Epidemiologic and clinical data indicate an overprevalence of lipids abnormalite, steatosis, insuline resistance (IR) and diabetes mellitus in HCV patients, suggesting that HCV itself may interact with glucido-lipidic metabolism. HCV interacts with the host lipid metabolism by several mechanisms leading to hepatic steatosis and hypolipidemia which are reversible after viral eradication. Liver and peripheral IR are HCV genotype/viral load dependent and improved after viral eradication. This article examines examine the relationship between HCV, lipid abnormalities, steatosis, IR, and diabetes and the pathogenic mechanisms accounting for these events in HCV-infected patients.
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Affiliation(s)
- Lawrence Serfaty
- Hepatology Department, INSERM UMR_S 938, APHP, Saint-Antoine Hospital, UPMC Univ Paris 06, Paris, France.
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29
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Nishida T. Diagnosis and Clinical Implications of Diabetes in Liver Cirrhosis: A Focus on the Oral Glucose Tolerance Test. J Endocr Soc 2017; 1:886-896. [PMID: 29264539 PMCID: PMC5686620 DOI: 10.1210/js.2017-00183] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 05/18/2017] [Indexed: 02/08/2023] Open
Abstract
The liver and skeletal muscles are responsible for maintaining glucose metabolism. As chronic liver disease progresses to cirrhosis, the loss of liver function is exacerbated and leads to the deterioration of skeletal muscle. Consequently, impaired glucose tolerance (IGT) and insulin resistance are often observed in patients with liver cirrhosis. Early stage cirrhosis with hepatogenous diabetes is characterized by marked postprandial hyperglycemia and hyperinsulinemia. Generally, it is possible to underestimate IGT when using either the conventional fasting plasma glucose (FPG) criterion or hemoglobin A1c (HbA1c) levels despite their status as the gold standard for diagnosing diabetes. The number of cirrhotic patients with diabetes tends to be underestimated because many of these patients show lower FPG levels or HbA1c, which masks their IGT. In such cases, the oral glucose tolerance test is recommended to evaluate patients with suspected postprandial hyperglycemia who present with a normal FPG. Moreover, in addition to the Child-Pugh score, the early detection of diabetes may be a useful prognostic marker for patients with liver cirrhosis.
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Affiliation(s)
- Tsutomu Nishida
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565 Japan
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30
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Gastaldi G, Goossens N, Clément S, Negro F. Current level of evidence on causal association between hepatitis C virus and type 2 diabetes: A review. J Adv Res 2017; 8:149-159. [PMID: 28149650 PMCID: PMC5272937 DOI: 10.1016/j.jare.2016.11.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Revised: 11/16/2016] [Accepted: 11/23/2016] [Indexed: 12/15/2022] Open
Abstract
The association between hepatitis C virus (HCV) infection and type 2 diabetes (T2D) has been known for over 20 years. Cross-sectional and longitudinal studies have shown a higher prevalence and incidence, respectively, of T2D in patients with chronic HCV infection. HCV induces glucose metabolism alterations mostly interfering with the insulin signaling chain in hepatocytes, although extrahepatic mechanisms seem to contribute. Both IR and T2D accelerate the histological and clinical progression of chronic hepatitis C as well as the risk of extra-hepatic complications such as nephropathy, acute coronary events and ischemic stroke. Before the availability of direct-acting antivirals (DAAs), the therapeutic choice was limited to interferon (IFN)-based therapy, which reduced the incidence of the extra-hepatic manifestations but was burdened with several contraindications and poor tolerability. A better understanding of HCV-associated glucose metabolism derangements and their reversibility is expected with the use of DAAs.
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Affiliation(s)
- Giacomo Gastaldi
- Divisions of Endocrinology, Diabetology, Hypertension and Nutrition, Geneva University Hospitals, Rue Gabrielle Perret-Gentil, 1211 Genève 14, Switzerland
| | - Nicolas Goossens
- Gastroenterology and Hepatology, Geneva University Hospitals, Rue Gabrielle Perret-Gentil, 1211 Genève 14, Switzerland
| | - Sophie Clément
- Clinical Pathology, Geneva University Hospitals, Rue Gabrielle Perret-Gentil, 1211 Genève 14, Switzerland
| | - Francesco Negro
- Gastroenterology and Hepatology, Geneva University Hospitals, Rue Gabrielle Perret-Gentil, 1211 Genève 14, Switzerland
- Clinical Pathology, Geneva University Hospitals, Rue Gabrielle Perret-Gentil, 1211 Genève 14, Switzerland
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Morales AL, Junga Z, Singla MB, Sjogren M, Torres D. Hepatitis C eradication with sofosbuvir leads to significant metabolic changes. World J Hepatol 2016; 8:1557-1563. [PMID: 28050236 PMCID: PMC5165269 DOI: 10.4254/wjh.v8.i35.1557] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 09/20/2016] [Accepted: 10/24/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the effect of sofosbuvir (SOF) based regimens on glycemic and lipid control.
METHODS This is a retrospective analysis of hepatitis C virus (HCV)-infected patients treated and cured with a SOF regimen [SOF/ribavirin/interferon, SOF/simeprevir, or SOF/ledipasvir (LDV) ± ribavirin] from January 2014 to March 2015. Patients with hemoglobin A1C (HbA1C) and lipid panels within six months before and six months after therapy were identified and included in our study. Due to the known hemolytic effect of ribavirin, HbA1C was obtained a minimum of three months post-treatment for the patients treated with a ribavirin regimen. Medical history, demographics, HCV genotype, pre-therapy RNA, and liver biopsies were included in our analysis. The patients who started a new medication or had an adjustment of baseline medical management for hyperlipidemia or diabetes mellitus (DM) were excluded from our analysis.
RESULTS Two hundred and thirty-four patients were reviewed, of which 60 patients met inclusion criteria. Sixty-three point three percent were male, 26.7% were Caucasian, 41.7% were African American and 91.7% were infected with hepatitis C genotype 1. Mean age was 60.6 ± 6.7 years. Thirty-nine patients had HbA1C checked before and after treatment, of which 22 had the diagnosis of DM type 2. HbA1C significantly decreased with treatment of HCV (pretreatment 6.66% ± 0.95% vs post-treatment 6.14% ± 0.65%, P < 0.005). Those treated with SOF/LDV had a lower HbA1C response than those treated with other regimens (0.26% ± 0.53% vs 0.71% ± 0.83%, P = 0.070). Fifty-two patients had pre- and post-treatment lipid panels; there was a significant increase in low-density lipoprotein (LDL) and total cholesterol (TC) after treatment (LDL: 99.5 ± 28.9 mg/dL vs 128.3 ± 34.9 mg/dL, P < 0.001; TC: 171.6 ± 32.5 mg/dL vs 199.7 ± 40.0 mg/dL, P < 0.001). Pre-treatment body-mass index (BMI) did not differ from post-treatment BMI (P = 0.684).
CONCLUSION Eradication of HCV with a SOF regimen resulted in a significant drop in HbA1C and an increase in LDL and TC post therapy.
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Ezzikouri S, Jadid FZ, Hamdi S, Wakrim L, Tsukiyama-Kohara K, Benjelloun S. Supplementing Conventional Treatment with Pycnogenol® May Improve Hepatitis C Virus-Associated Type 2 Diabetes: A Mini Review. J Clin Transl Hepatol 2016; 4:228-233. [PMID: 27777890 PMCID: PMC5075005 DOI: 10.14218/jcth.2016.00021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 06/20/2016] [Accepted: 07/07/2016] [Indexed: 12/20/2022] Open
Abstract
Hepatitis C virus (HCV) infection and type 2 diabetes mellitus (T2DM) present a significant health burden, with increasing complications and mortality rates worldwide. Pycnogenol® (PYC), a natural product, possesses antidiabetic and antiviral properties that may improve HCV-associated T2DM. In this review, we present previously published data on the effectiveness of PYC against HCV replication and T2DM. We believe that supplementing conventional treatment with PYC may improve the current HCV therapy, attenuate HCV-associated T2DM, and reduce the risk of complications such as cirrhosis or hepatocellular carcinoma and cardiovascular disease.
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Affiliation(s)
- Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
- *Correspondence to: Sayeh Ezzikouri, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, 1 Place Louis Pasteur, Casablanca 20360, Morocco. Tel: +212-5-27016076, +212-5-22434450, Fax: +212-5-22260957, E-mail:
| | - Fatima Zahra Jadid
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Salsabil Hamdi
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Lahcen Wakrim
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Kyoko Tsukiyama-Kohara
- Laboratory of Animal Hygiene, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan
| | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
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Adinolfi LE, Rinaldi L, Guerrera B, Restivo L, Marrone A, Giordano M, Zampino R. NAFLD and NASH in HCV Infection: Prevalence and Significance in Hepatic and Extrahepatic Manifestations. Int J Mol Sci 2016; 17:ijms17060803. [PMID: 27231906 PMCID: PMC4926337 DOI: 10.3390/ijms17060803] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 05/15/2016] [Accepted: 05/19/2016] [Indexed: 02/06/2023] Open
Abstract
The aim of this paper is to review and up to date the prevalence of hepatitis C virus (HCV)-associated non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) and their significance in both accelerating progression of HCV-related liver disease and development of HCV-associated extrahepatic diseases. The reported mean prevalence of HCV-related NAFLD was 55%, whereas NASH was reported in 4%–10% of cases. HCV genotype 3 directly induces fatty liver deposition, namely “viral steatosis” and it is associated with the highest prevalence and degree of severity, whereas, HCV non-3 genotype infection showed lower prevalence of steatosis, which is associated with metabolic factors and insulin resistance. The host’s genetic background predisposes him or her to the development of steatosis. HCV’s impairment of lipid and glucose metabolism causes fatty liver accumulation; this seems to be a viral strategy to optimize its life cycle. Irrespective of insulin resistance, HCV-associated NAFLD, in a degree-dependent manner, contributes towards accelerating the liver fibrosis progression and development of hepatocellular carcinoma by inducing liver inflammation and oxidative stress. Furthermore, NAFLD is associated with the presence of metabolic syndrome, type 2 diabetes, and atherosclerosis. In addition, HCV-related “metabolic steatosis” impairs the response rate to interferon-based treatment, whereas it seems that “viral steatosis” may harm the response rate to new oral direct antiviral agents. In conclusion, a high prevalence of NAFLD occurs in HCV infections, which is, at least in part, induced by the virus, and that NAFLD significantly impacts progression of the liver disease, therapeutic response, and some extrahepatic diseases.
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Affiliation(s)
- Luigi Elio Adinolfi
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Luca Rinaldi
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Barbara Guerrera
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Luciano Restivo
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Aldo Marrone
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Mauro Giordano
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Rosa Zampino
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
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Affiliation(s)
- Gautam Das
- Prince Charles Hospital, Cwm Taf University Health Board; Merthyr Tydfil UK
| | - Hemanth Bolusani
- University Hospital of Wales, Cardiff and Vale University Health Board; Cardiff UK
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Kumar A, Gupta V, Sharma P, Bansal N, Singla V, Arora A. Association of Overt Diabetes Mellitus with the Non-CC but not the CC Genotype of Interleukin-28B in Hepatitis C Virus Infected Patients. J Clin Transl Hepatol 2016; 4:26-31. [PMID: 27047769 PMCID: PMC4807140 DOI: 10.14218/jcth.2016.00040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Revised: 12/30/2015] [Accepted: 01/05/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Interleukin-28B (IL-28B) polymorphism is an important predictor for hepatitis C virus (HCV) treatment response. Whether IL-28b genotypes also influence other nontreatment related clinical parameters is unclear. METHODS Patients with HCV-related chronic liver diseases who attended our department during 2012-2014 were retrospectively analyzed. The single nucleotide polymorphisms (SNPs) of rs12979860 (IL-28B) were correlated with various clinical parameters. We also compared these parameters in patients with and without overt diabetes to identify possible associations. RESULTS A total of 115 patients were included (median age 48, range 15-76 years; 70% males). Overall, 43/115 (37%) patients had chronic hepatitis, while the remaining 72/115 (63%) had cirrhosis. The most common IL-28B genotype was CC, which was found in 53% of patients (61/115), while the remaining 47% were nonCC [CT 42% (48/115) and TT 5% (6/115)]. Clinical and laboratory parameters like Hb, white blood cell (WBC), platelets, bilirubin, transaminases, and albumin were similar in the CC and nonCC genotypes. Overt diabetes mellitus was present in 22% (25/115) of patients. Patients with nonCC genotype had significantly higher prevalence of overt diabetes mellitus than patients with CC genotype (31% [17/54] versus 13% [8/61]; p < 0.05). When parameters were compared in patients with and without overt diabetes mellitus, only IL-28B and age were significantly associated with overt diabetes mellitus (p < 0.05). CONCLUSION In HCV patients, overt diabetes mellitus was more commonly associated with the nonCC genotype of IL-28B than the CC genotype. Carriers of the T-allele of SNP rs12979860 were more likely to have insulin resistance than CC homozygotes, and this finding may explain the higher prevalence of diabetes in non-CC genotypes. Thus, an IL-28B test may be useful in patients of HCV in order to determine their likelihood of developing diabetes mellitus.
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Affiliation(s)
- Ashish Kumar
- Institute of Liver, Gastroenterology, & Panceatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
- Correspondence to: Ashish Kumar, Institute of Liver, Gastroenterology, & Panceatico-Biliary Sciences, Ganga Ram Institute for Postgraduate Medical Education & Research (GRIPMER), Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India. Tel: +91-9312792573, Fax: +91-11-25861002,
| | - Varun Gupta
- Institute of Liver, Gastroenterology, & Panceatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
| | - Praveen Sharma
- Institute of Liver, Gastroenterology, & Panceatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
| | - Naresh Bansal
- Institute of Liver, Gastroenterology, & Panceatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
| | - Vikas Singla
- Institute of Liver, Gastroenterology, & Panceatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
| | - Anil Arora
- Institute of Liver, Gastroenterology, & Panceatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
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Influence of insulin resistance on the development of hepatocellular carcinoma after antiviral treatment for non-cirrhotic patients with chronic hepatitis C. Infect Agent Cancer 2016; 11:9. [PMID: 26913058 PMCID: PMC4765113 DOI: 10.1186/s13027-016-0056-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 02/04/2016] [Indexed: 02/07/2023] Open
Abstract
Background Insulin resistance is considered to be an important factor in the progression of fibrosis and the enhancement of the risk of hepatocellular carcinoma (HCC) for chronic hepatitis C patients. The aim of this study was to assess the effect of insulin resistance on the development of HCC by non-cirrhotic chronic hepatitis C patients treated with pegylated interferon alpha-2b (PEG-IFNα2b) and ribavirin. Methods This retrospective study consisted of 474 Japanese non-cirrhotic patients with chronic hepatitis C. The cumulative incidence of HCC was estimated using the Kaplan-Meier method, according to insulin resistance by the homeostasis model assessment of insulin resistance (HOMA-IR) and treatment outcome. Results The overall sustained virological response (SVR) rate was 45.1 % (214/474, genotype 1: 35.4 % [129/364] and genotype 2: 77.3 % [85/110]). Twenty-one (4.4 %) patients developed HCC during the follow-up period. The 5-year cumulative incidence of HCC of the SVR group (2.6 %) was significantly lower than that of the non-SVR group (9.7 %) (log-rank test: P = 0.025). In multivariable logistic regression analysis, HOMA-IR (≥2.5) (hazard ratio [HR] 12.8, P = 0.0006), fibrosis status (F3) (HR 8.85, P < 0.0001), and post-treatment alanine aminotransferase (ALT) level (≥40 U/L) (HR 4.33, P = 0.036) were independently correlated to the development of HCC. Receiver operating characteristic analysis to determine the optimal threshold value of HOMA-IR for predicting the development of HCC in the non-SVR group showed that the areas under the curve was high (0.80, cutoff value: 3.0). Only three patients (1.4 %) who achieved SVR developed HCC. Two of them had severe insulin resistance and did not show improvement in HOMA-IR after achieving SVR. Conclusions Insulin resistance has a strong impact on the development of HCC by non-cirrhotic patients who have PEG-IFNα2b and ribavirin treatment failure.
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Huang YW, Wang TC, Yang SS, Lin SY, Fu SC, Hu JT, Liu CJ, Kao JH, Chen DS. Increased risk of hepatocellular carcinoma in chronic hepatitis C patients with new onset diabetes: a nation-wide cohort study. Aliment Pharmacol Ther 2015. [PMID: 26211742 DOI: 10.1111/apt.13341] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The impact of diabetes for hepatocellular carcinoma (HCC) development in chronic hepatitis C (CHC) patients remains controversial. AIM To investigate the risk of HCC in CHC patients who develop new onset diabetes. METHODS We conducted a nation-wide cohort study by using Taiwanese National Health Insurance Research Database, which comprised of data from >99% of entire population. Among randomly sampled one million enrollees, 6251 adult CHC patients were identified from 1997 to 2009. Diabetes was defined as new onset in the patient who was given the diagnosis in the years 1999-2009 but not in 1997-1998. The cohorts of CHC with new onset diabetes (n = 1100) and 1:1 ratio age-, gender-, and inception point (onset date of diabetes) matched nondiabetes (n = 1087) were followed up from the inception point until the development of HCC, withdrawal from insurance, or December 2009. RESULTS After adjustment for competing mortality, patients with new onset diabetes had a significantly higher cumulative incidence of HCC (Relative Risk = 1.544, 95% CI = 1.000-2.387, modified log-rank test, P = 0.047) as compared to those without. After adjustment for age, gender, cirrhosis, hyperlipidaemia, CHC treatment, diabetes treatment, comorbidity index, obesity and statins therapy by Cox proportional hazard model, diabetes was still an independent predictor for HCC (hazard ratio (HR) = 1.906, 95% CI = 1.102-3.295, P = 0.021). The risk for HCC was increased in those who were 40-59 years old, independent of other variables (HR = 3.086, 95% CI = 1.045-9.112, P = 0.041), and after adjustment for competing mortality (modified log-rank test, P = 0.009). CONCLUSION Chronic hepatitis C patients who develop diabetes are at an increased risk of hepatocellular carcinoma over time.
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Affiliation(s)
- Y-W Huang
- Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan.,School of Medicine, Taipei Medical University College of Medicine, Taipei, Taiwan.,Division of Gastroenterology, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - T-C Wang
- Department of Medical Research, Cathay General Hospital Medical Center, Taipei, Taiwan
| | - S-S Yang
- Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan.,School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan
| | - S-Y Lin
- Department of General Medicine, School of Medicine, Taipei Medical University College of Medicine, Taipei, Taiwan
| | - S-C Fu
- Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan
| | - J-T Hu
- Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan.,School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan
| | - C-J Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - J-H Kao
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, Taipei Medical University College of Medicine, Taipei, Taiwan
| | - D-S Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Genomics Research Center, Academia Sinica, Nankang, Taiwan
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38
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Desrochers GF, Sherratt AR, Blais DR, Nasheri N, Ning Z, Figeys D, Goto NK, Pezacki JP. Profiling Kinase Activity during Hepatitis C Virus Replication Using a Wortmannin Probe. ACS Infect Dis 2015; 1:443-52. [PMID: 27617927 DOI: 10.1021/acsinfecdis.5b00083] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
To complete its life cycle, the hepatitis C virus (HCV) induces changes to numerous aspects of its host cell. As kinases act as regulators of many pathways utilized by HCV, they are likely enzyme targets for virally induced inhibition or activation. Herein, we used activity-based protein profiling (ABPP), which allows for the identification of active enzymes in complex protein samples and the quantification of their activity, to identify kinases that displayed differential activity in HCV-expressing cells. We utilized an ABPP probe, wortmannin-yne, based on the kinase inhibitor wortmannin, which contains a pendant alkyne group for bioconjugation using bioorthogonal chemistry. We observed changes in the activity of kinases involved in the mitogen-activated protein kinase pathway, apoptosis pathways, and cell cycle control. These results establish changes to the active kinome, as reported by wortmannin-yne, in the proteome of human hepatoma cells actively replicating HCV. The observed changes include kinase activity that affect viral entry, replication, assembly, and secretion, implying that HCV is regulating the pathways that it uses for its life cycle through modulation of the active kinome.
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Affiliation(s)
- Geneviève F. Desrochers
- Life Sciences Division, National Research Council of Canada, 100
Sussex Drive, Ottawa, Canada
| | - Allison R. Sherratt
- Life Sciences Division, National Research Council of Canada, 100
Sussex Drive, Ottawa, Canada
| | - David R. Blais
- Life Sciences Division, National Research Council of Canada, 100
Sussex Drive, Ottawa, Canada
| | - Neda Nasheri
- Life Sciences Division, National Research Council of Canada, 100
Sussex Drive, Ottawa, Canada
| | | | | | | | - John Paul Pezacki
- Life Sciences Division, National Research Council of Canada, 100
Sussex Drive, Ottawa, Canada
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Read SA, Tay ES, Shahidi M, O’Connor KS, Booth DR, George J, Douglas MW. Hepatitis C Virus Driven AXL Expression Suppresses the Hepatic Type I Interferon Response. PLoS One 2015; 10:e0136227. [PMID: 26313459 PMCID: PMC4551482 DOI: 10.1371/journal.pone.0136227] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Accepted: 07/30/2015] [Indexed: 01/06/2023] Open
Abstract
Treatment of chronic hepatitis C virus (HCV) infection is evolving rapidly with the development of novel direct acting antivirals (DAAs), however viral clearance remains intimately linked to the hepatic innate immune system. Patients demonstrating a high baseline activation of interferon stimulated genes (ISGs), termed interferon refractoriness, are less likely to mount a strong antiviral response and achieve viral clearance when placed on treatment. As a result, suppressor of cytokine signalling (SOCS) 3 and other regulators of the IFN response have been identified as key candidates for the IFN refractory phenotype due to their regulatory role on the IFN response. AXL is a receptor tyrosine kinase that has been identified as a key regulator of interferon (IFN) signalling in myeloid cells of the immune system, but has not been examined in the context of chronic HCV infection. Here, we show that AXL is up-regulated following HCV infection, both in vitro and in vivo and is likely induced by type I/III IFNs and inflammatory signalling pathways. AXL inhibited type IFNα mediated ISG expression resulting in a decrease in its antiviral efficacy against HCV in vitro. Furthermore, patients possessing the favourable IFNL3 rs12979860 genotype associated with treatment response, showed lower AXL expression in the liver and a stronger induction of AXL in the blood, following their first dose of IFN. Together, these data suggest that elevated AXL expression in the liver may mediate an IFN-refractory phenotype characteristic of patients possessing the unfavourable rs12979860 genotype, which is associated with lower rates of viral clearance.
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Affiliation(s)
- Scott A. Read
- Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia
| | - Enoch S. Tay
- Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia
| | - Mahsa Shahidi
- Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia
| | - Kate S. O’Connor
- Centre for Immunology and Allergy Research, University of Sydney at Westmead Hospital, Westmead, Australia
| | - David R. Booth
- Centre for Immunology and Allergy Research, University of Sydney at Westmead Hospital, Westmead, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia
| | - Mark W. Douglas
- Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia
- Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, Australia
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40
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Chien CH, Lin CL, Hu CC, Chang JJ, Chien RN. Clearance of Hepatitis C Virus Improves Insulin Resistance During and After Peginterferon and Ribavirin Therapy. J Interferon Cytokine Res 2015; 35:981-9. [PMID: 26308911 DOI: 10.1089/jir.2014.0200] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Patients with chronic hepatitis C virus (HCV) infection are at a greater risk of developing insulin resistance (IR). However, little is known about when insulin sensitivity may improve during or after treatment for hepatitis C. In this study, we examined the effect of combination therapy with pegylated interferon-α and ribavirin on IR in patients with chronic HCV infection. We also analyzed factors associated with changes in insulin sensitivity. IR was estimated by homeostasis model assessment (HOMA-IR). HOMA-IR was measured before therapy, during therapy (12 and 24 weeks), and at the end of therapy (EOT; 24 or 48 weeks). We analyzed 78 HCV patients receiving combination therapy. Twenty-two patients (28.2%) exhibited pretreatment IR (HOMA-IR >2.5). In all patients, HOMA-IR was not significantly different from baseline values at 12 weeks (P = 0.823), 24 weeks (P = 0.417), or at EOT (P = 0.158). In patients with pretreatment IR, a significant decrease in HOMA-IR was observed at 12 weeks (P = 0.023), 24 weeks (P = 0.008), and at EOT (P = 0.002). Multivariate analysis using a logistic regression model showed that baseline HOMA-IR is the only factor associated with the decline in HOMA-IR during and after therapy. The eradication of HCV infection was associated with improved insulin sensitivity among patients with pretreatment IR. This significant improvement in insulin sensitivity may occur as early as 12 weeks after the initiation of antiviral therapy.
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Affiliation(s)
- Cheng-Hung Chien
- Liver Research Unit, College of Medicine, Chang Gung Memorial Hospital, Chang Gung University , Keelung, Taiwan
| | - Chih-Lang Lin
- Liver Research Unit, College of Medicine, Chang Gung Memorial Hospital, Chang Gung University , Keelung, Taiwan
| | - Ching-Chih Hu
- Liver Research Unit, College of Medicine, Chang Gung Memorial Hospital, Chang Gung University , Keelung, Taiwan
| | - Jia-Jang Chang
- Liver Research Unit, College of Medicine, Chang Gung Memorial Hospital, Chang Gung University , Keelung, Taiwan
| | - Rong-Nan Chien
- Liver Research Unit, College of Medicine, Chang Gung Memorial Hospital, Chang Gung University , Keelung, Taiwan
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Pazienza V, Panebianco C, Andriulli A. Hepatitis viruses exploitation of host DNA methyltransferases functions. Clin Exp Med 2015; 16:265-72. [PMID: 26148656 DOI: 10.1007/s10238-015-0372-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 06/23/2015] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV), hepatitis C virus (HCV) and Delta (HDV) infections are a global health burden. With different routes of infection and biology, HBV, HCV and HDV are capable to induce liver cirrhosis and cancer by impinging on epigenetic mechanisms altering host cell's pathways. In the present manuscript, we reviewed the published studies taking into account the relationship between the hepatitis viruses and the DNA methyltransferases proteins.
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Affiliation(s)
- Valerio Pazienza
- Gastroenterology Unit, Fondazione "Casa Sollievo della Sofferenza" IRCCS Hospital, San Giovanni Rotondo, FG, Italy.
| | - Concetta Panebianco
- Gastroenterology Unit, Fondazione "Casa Sollievo della Sofferenza" IRCCS Hospital, San Giovanni Rotondo, FG, Italy
| | - Angelo Andriulli
- Gastroenterology Unit, Fondazione "Casa Sollievo della Sofferenza" IRCCS Hospital, San Giovanni Rotondo, FG, Italy
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González-Reimers E, Quintero-Platt G, Rodríguez-Gaspar M, Alemán-Valls R, Pérez-Hernández O, Santolaria-Fernández F. Liver steatosis in hepatitis C patients. World J Hepatol 2015; 7:1337-1346. [PMID: 26052379 PMCID: PMC4450197 DOI: 10.4254/wjh.v7.i10.1337] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 01/31/2015] [Accepted: 03/09/2015] [Indexed: 02/06/2023] Open
Abstract
There is controversy regarding some aspects of hepatitis C virus (HCV) infection-associated liver steatosis, and their relationship with body fat stores. It has classically been found that HCV, especially genotype 3, exerts direct metabolic effects which lead to liver steatosis. This supports the existence of a so called viral steatosis and a metabolic steatosis, which would affect HCV patients who are also obese or diabetics. In fact, several genotypes exert metabolic effects which overlap with some of those observed in the metabolic syndrome. In this review we will analyse the pathogenic pathways involved in the development of steatosis in HCV patients. Several cytokines and adipokines also become activated and are involved in “pure” steatosic effects, in addition to inflammation. They are probably responsible for the evolution of simple steatosis to steatohepatitis, making it difficult to explain why such alterations only affect a proportion of steatosic patients.
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Kukla M, Piotrowski D, Waluga M, Hartleb M. Insulin resistance and its consequences in chronic hepatitis C. Clin Exp Hepatol 2015; 1:17-29. [PMID: 28856251 PMCID: PMC5421163 DOI: 10.5114/ceh.2015.51375] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 03/10/2015] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Hepatitis C virus (HCV) may contribute to a broad spectrum of metabolic disturbances - namely, steatosis, insulin resistance (IR), increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus (T2DM), lipid metabolism abnormalities and atherosclerosis. HCV can directly or indirectly cause both IR and steatosis, but it is still not resolved whether this viral impact bears the same prognostic value as the metabolic counterparts. As the population exposed to HCV ages, the morbidity due to this disease is increasing. The rising epidemic of obesity contributes to higher prevalence of IR and T2DM. Our understanding of the mutual association between both disease states continues to grow, but is still far from complete. This review briefly discusses the most probable mechanisms involved in IR development in the course of CHC. Molecular mechanisms for the direct and indirect influence of HCV on intracellular insulin signaling are described. Subsequently, the consequences of IR/T2DM for disease progression and management are summarized.
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Affiliation(s)
- Michał Kukla
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Damian Piotrowski
- Department of Infectious Diseases in Bytom, Medical University of Silesia in Katowice, Poland
| | - Marek Waluga
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Marek Hartleb
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
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44
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Lappas M. Double stranded viral RNA induces inflammation and insulin resistance in skeletal muscle from pregnant women in vitro. Metabolism 2015; 64:642-53. [PMID: 25707553 DOI: 10.1016/j.metabol.2015.02.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 02/05/2015] [Accepted: 02/07/2015] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Maternal peripheral insulin resistance and increased inflammation are two features of pregnancies complicated by pre-existing maternal obesity and gestational diabetes mellitus (GDM). There is now increasing evidence that activation of Toll-like receptor (TLR) signalling pathways by viral products may play a role in the pathophysiology of diabetes. Thus, the aim of this study was to assess the effect of the TLR3 ligand and viral dsRNA analogue polyinosinic polycytidilic acid (poly(I:C)) on inflammation and the insulin signalling pathway in skeletal muscle from pregnant women. MATERIALS/METHODS Human skeletal muscle tissue explants were performed to determine the effect of poly(I:C) on the expression and secretion of markers of inflammation, and the insulin signalling pathway and glucose uptake. RESULTS Poly(I:C) significantly increased the expression of a number of inflammatory markers in skeletal muscle from pregnant women. Specifically, there was an increase in the expression and/or secretion of the pro-inflammatory cytokines TNF-α, and IL-6 and the pro-inflammatory chemokines IL-8 and MCP-1. These effect of poly(I:C) appear to mediated via a number of signalling molecules including the pro-inflammatory transcription factor NF-κB, and the serine threonine kinases GSK3 and AMPKα. Additionally, poly(I:C) decreased insulin stimulated GLUT-4 expression and glucose uptake in skeletal muscle from pregnant women. CONCLUSIONS The in vitro data presented in this study suggests that viral infection may contribute to the pathophysiology of pregnancies complicated by pre-existing maternal obesity and/or GDM. It should be noted that the in vitro studies cannot be directly used to infer the same outcomes in the intact subject.
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Affiliation(s)
- Martha Lappas
- Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
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Gao TT, Qin ZL, Ren H, Zhao P, Qi ZT. Inhibition of IRS-1 by hepatitis C virus infection leads to insulin resistance in a PTEN-dependent manner. Virol J 2015; 12:12. [PMID: 25645159 PMCID: PMC4323155 DOI: 10.1186/s12985-015-0241-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 01/15/2015] [Indexed: 12/18/2022] Open
Abstract
Background Hepatitis C virus (HCV) infection was recently recognized as an independent risk factor for insulin resistance (IR), the onset phase of type 2 diabetes mellitus (T2DM). Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates PI3K/Akt signaling pathway, which is critical for IR development and progression of cirrhosis to hepatocellular carcinoma (HCC). Here, we investigate the role of PTEN in HCV-associated IR and explored the mechanisms by which HCV regulates PTEN. Methods Western blotting was used to detect the levels of insulin signaling pathway components, including insulin receptor substrate-1 (IRS-1), phosphorylated IRS-1 (pIRS-1) at serine 307 (Ser307), both phosphorylated Akt (pAkt) and total Akt. A time-course experiment measuring activation of the insulin signaling pathway was performed to assess the effect of HCV infection on insulin sensitivity by examining the phosphorylation levels of Akt and GSK3β, a downstream target of Akt. Huh7.5.1 cells were transduced with a lentiviral vector expressing PTEN or PTEN shRNA, and IRS-1 and pIRS-1 (Ser307) levels were determined in both HCV-infected and uninfected cells. The pc-JFH1-core plasmid was constructed to explore the underlying mechanisms by which HCV regulated PTEN and therefore IRS-1 levels. Results HCV infection inhibited the insulin signaling pathway by reducing the levels of IRS-1 and pAkt/Akt while increasing phosphorylation of IRS-1 Ser307. In addition, HCV infection decreased the sensitivity to insulin-induced stimulation by inhibiting Akt and GSK3β phosphorylation. Furthermore, PTEN mRNA and protein levels were reduced upon HCV infection as well as transfection with the pc-JFH1-core plasmid. The reduction in IRS-1 level observed in HCV-infected cells was rescued to a limited extent by overexpression of PTEN, which in turn slightly reduced pIRS-1 (Ser307) level. In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser-307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon HCV infection occurred in a PTEN-dependent manner. Conclusions HCV infection suppresses the insulin signaling pathway and promotes IR by repressing PTEN, subsequently leading to decreased levels of IRS-1 and increased levels of pIRS-1 at Ser307. The findings provide new insight on the mechanism of HCV-associated IR.
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Affiliation(s)
- Ting-ting Gao
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
| | - Zhao-ling Qin
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
| | - Hao Ren
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
| | - Ping Zhao
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
| | - Zhong-tian Qi
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
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Hammerstad SS, Grock SF, Lee HJ, Hasham A, Sundaram N, Tomer Y. Diabetes and Hepatitis C: A Two-Way Association. Front Endocrinol (Lausanne) 2015; 6:134. [PMID: 26441826 PMCID: PMC4568414 DOI: 10.3389/fendo.2015.00134] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 08/17/2015] [Indexed: 12/15/2022] Open
Abstract
Diabetes and hepatitis C infection are both prevalent diseases worldwide, and are associated with increased morbidity and mortality. Most studies, but not all, have shown that patients with chronic hepatitis C are more prone to develop type 2 diabetes (T2D) compared to healthy controls, as well as when compared to patients with other liver diseases, including hepatitis B. Furthermore, epidemiological studies have revealed that patients with T2D may also be at higher risk for worse outcomes of their hepatitis C infection, including reduced rate of sustained virological response, progression to fibrosis and cirrhosis, and higher risk for development of hepatocellular carcinoma. Moreover, hepatitis C infection and mainly its treatment, interferon α, can trigger the development of type 1 diabetes. In this review, we discuss the existing data on this two-way association between diabetes and hepatitis C infection with emphasis on possible mechanisms. It remains to be determined whether the new curative therapies for chronic hepatitis C will improve outcomes in diabetic hepatitis C patients, and conversely whether treatment with Metformin will reduce complications from hepatitis C virus infection. We propose an algorithm for diabetes screening and follow-up in hepatitis C patients.
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Affiliation(s)
- Sara Salehi Hammerstad
- Department of Medicine, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pediatrics, Oslo University Hospital Ullevål, Oslo, Norway
| | - Shira Frankel Grock
- Department of Medicine, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hanna J. Lee
- Department of Medicine, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alia Hasham
- Department of Medicine, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nina Sundaram
- Department of Medicine, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yaron Tomer
- Department of Medicine, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- James J. Peters VA Medical Center, Bronx, NY, USA
- *Correspondence: Yaron Tomer, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, Box 1055, One Gustave L. Levy Place, New York, NY 10029, USA,
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Safi SZ, Shah H, Siok Yan GO, Qvist R. Insulin resistance provides the connection between hepatitis C virus and diabetes. HEPATITIS MONTHLY 2014; 15:e23941. [PMID: 25741369 PMCID: PMC4344647 DOI: 10.5812/hepatmon.23941] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Accepted: 12/08/2014] [Indexed: 02/06/2023]
Affiliation(s)
- Sher Zaman Safi
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
- Corresponding Author: Sher Zaman Safi, Department of Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Tel: 60-379674750, Fax: 60-379568841, E-mail:
| | - Humaira Shah
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Gracie Ong Siok Yan
- Department of Anesthesiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Rajes Qvist
- Department of Anesthesiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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Lim T. Metabolic syndrome in chronic hepatitis C infection: does it still matter in the era of directly acting antiviral therapy? Hepat Med 2014; 6:113-8. [PMID: 25506251 PMCID: PMC4259863 DOI: 10.2147/hmer.s60083] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Metabolic syndrome is prevalent in patients with hepatitis C virus (HCV) infection. Given the pandemic spread of HCV infection and metabolic syndrome, the burden of their interaction is a major public health issue. The presence of metabolic syndrome accelerates the progression of liver disease in patients with HCV infection. New drug development in HCV has seen an unprecedented rise in the last year, which resulted in better efficacy, better tolerance, and a shorter treatment duration. This review describes the underlying mechanisms and clinical effects of metabolic syndrome in HCV infection, as well as their importance in the era of new directly acting antiviral therapy.
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Affiliation(s)
- Tr Lim
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, University of Birmingham and Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, UK
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Hepatitis C virus resistance to interferon therapy: an alarming situation. Open Life Sci 2014. [DOI: 10.2478/s11535-014-0352-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractHepatitis C virus is presently a major public health problem across the globe. The main objective in treating hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). Interferon-α (IFN-α) and pegylated interferon (PegIFN) in combination with Ribavirin (RBV) are the choice of treatment nowadays against chronic hepatitis C. There are several mechanisms evolved by the hepatitis C virus that facilitate the persistence of virus and further lead the patient’s status as non responder. Various factors involved in patient’s lack ofresponse to the therapy include: (1) viral factors, (2) host factors, (3) molecular mechanisms related to the lack of response and (4) social factors. Herein we have made an attempt to summarize all the related predictors of drug resistance in one article so that the future polices can be planned to overcome this obstacle and potential therapies can be designed by considering these factors.
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