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Scoditti E, Sabatini S, Carli F, Gastaldelli A. Hepatic glucose metabolism in the steatotic liver. Nat Rev Gastroenterol Hepatol 2024; 21:319-334. [PMID: 38308003 DOI: 10.1038/s41575-023-00888-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/13/2023] [Indexed: 02/04/2024]
Abstract
The liver is central in regulating glucose homeostasis, being the major contributor to endogenous glucose production and the greatest reserve of glucose as glycogen. It is both a target and regulator of the action of glucoregulatory hormones. Hepatic metabolic functions are altered in and contribute to the highly prevalent steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this Review, we describe the dysregulation of hepatic glucose metabolism in MASLD and MASH and associated metabolic comorbidities, and how advances in techniques and models for the assessment of hepatic glucose fluxes in vivo have led to the identification of the mechanisms related to the alterations in glucose metabolism in MASLD and comorbidities. These fluxes can ultimately increase hepatic glucose production concomitantly with fat accumulation and alterations in the secretion and action of glucoregulatory hormones. No pharmacological treatment has yet been approved for MASLD or MASH, but some antihyperglycaemic drugs approved for treating type 2 diabetes have shown positive effects on hepatic glucose metabolism and hepatosteatosis. A deep understanding of how MASLD affects glucose metabolic fluxes and glucoregulatory hormones might assist in the early identification of at-risk individuals and the use or development of targeted therapies.
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Affiliation(s)
- Egeria Scoditti
- Institute of Clinical Physiology, National Research Council, Lecce, Italy
| | - Silvia Sabatini
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Fabrizia Carli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy.
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2
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Perakakis N, Harb H, Hale BG, Varga Z, Steenblock C, Kanczkowski W, Alexaki VI, Ludwig B, Mirtschink P, Solimena M, Toepfner N, Zeissig S, Gado M, Abela IA, Beuschlein F, Spinas GA, Cavelti-Weder C, Gerber PA, Huber M, Trkola A, Puhan MA, Wong WWL, Linkermann A, Mohan V, Lehnert H, Nawroth P, Chavakis T, Mingrone G, Wolfrum C, Zinkernagel AS, Bornstein SR. Mechanisms and clinical relevance of the bidirectional relationship of viral infections with metabolic diseases. Lancet Diabetes Endocrinol 2023; 11:675-693. [PMID: 37524103 DOI: 10.1016/s2213-8587(23)00154-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 05/09/2023] [Accepted: 05/19/2023] [Indexed: 08/02/2023]
Abstract
Viruses have been present during all evolutionary steps on earth and have had a major effect on human history. Viral infections are still among the leading causes of death. Another public health concern is the increase of non-communicable metabolic diseases in the last four decades. In this Review, we revisit the scientific evidence supporting the presence of a strong bidirectional feedback loop between several viral infections and metabolic diseases. We discuss how viruses might lead to the development or progression of metabolic diseases and conversely, how metabolic diseases might increase the severity of a viral infection. Furthermore, we discuss the clinical relevance of the current evidence on the relationship between viral infections and metabolic disease and the present and future challenges that should be addressed by the scientific community and health authorities.
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Affiliation(s)
- Nikolaos Perakakis
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany.
| | - Hani Harb
- Medical Microbiology and Virology, Technische Universität Dresden, Dresden 01307, Germany
| | - Benjamin G Hale
- Institute of Medical Virology, University of Zürich, Zürich, Switzerland
| | - Zsuzsanna Varga
- Department of Pathology and Molecular Pathology, University of Zürich, Zürich, Switzerland
| | - Charlotte Steenblock
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany
| | - Waldemar Kanczkowski
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany
| | - Vasileia Ismini Alexaki
- Institute for Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden 01307, Germany
| | - Barbara Ludwig
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Peter Mirtschink
- Institute for Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden 01307, Germany
| | - Michele Solimena
- Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; Department of Molecular Diabetology, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Nicole Toepfner
- Department of Pediatrics, Technische Universität Dresden, Dresden 01307, Germany
| | - Sebastian Zeissig
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden 01307, Germany; Department of Medicine I, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany
| | - Manuel Gado
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Irene Alma Abela
- Institute of Medical Virology, University of Zürich, Zürich, Switzerland; Department of Infectious Diseases and Hospital Epidemiology, University of Zürich, Zürich, Switzerland
| | - Felix Beuschlein
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich, University of Zürich, Zürich, Switzerland; Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Giatgen A Spinas
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Claudia Cavelti-Weder
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Philipp A Gerber
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Michael Huber
- Institute of Medical Virology, University of Zürich, Zürich, Switzerland
| | - Alexandra Trkola
- Institute of Medical Virology, University of Zürich, Zürich, Switzerland
| | - Milo A Puhan
- Epidemiology, Biostatistics and Prevention Institute, University of Zürich, Zürich, Switzerland
| | - Wendy Wei-Lynn Wong
- and Department of Molecular Life Science, University of Zürich, Zürich, Switzerland
| | - Andreas Linkermann
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Viswanathan Mohan
- Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialties Centre, Chennai, Tamil Nadu, India
| | - Hendrik Lehnert
- Presidential Office, Paris Lodron Universität Salzburg, Salzburg, Austria
| | - Peter Nawroth
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany
| | - Triantafyllos Chavakis
- Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; Institute for Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Geltrude Mingrone
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; Division of Diabetes and Nutritional Sciences, School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Christian Wolfrum
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zürich, Schwerzenbach, Switzerland
| | - Annelies S Zinkernagel
- Department of Infectious Diseases and Hospital Epidemiology, University of Zürich, Zürich, Switzerland
| | - Stefan R Bornstein
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany; Division of Diabetes and Nutritional Sciences, School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
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3
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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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Burden, Outcome, and Comorbidities of Extrahepatic Manifestations in Hepatitis C Virus Infection. BIOLOGY 2022; 12:biology12010023. [PMID: 36671716 PMCID: PMC9855523 DOI: 10.3390/biology12010023] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/06/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022]
Abstract
Hepatitis C virus (HCV) is a significant cause of chronic liver diseases worldwide and is associated with negative consequences, including cirrhosis, hepatic decompensation, hepatocellular carcinoma, and increased risk of mortality. In addition to liver-related morbidities, HCV is also associated with several extrahepatic manifestations, including mixed cryoglobulinemia, diabetes mellitus, cardiocerebrovascular disease, lymphoma, and autoimmune diseases. These non-liver-related complications of HCV increase the complexity of this disease and can contribute to the economic burden, morbidity, quality of life, and mortality throughout the world. Therefore, understanding how this virus can contribute to each extrahepatic manifestation is worth investigating. Currently, the advancement of HCV treatment with the advent of direct-acting anti-viral agents (DAAs) has led to a high cure rate as a result of sustained virologic response and tremendously reduced the burden of extrahepatic complications. However, HCV-associated extrahepatic manifestations remain a relevant concern, and this review aims to give an updated highlight of the prevalence, risk factors, associated burdens, and treatment options for these conditions.
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Mohamed MA, Bayoumy EM, Swailam MM, Allam AS. Assessment of carotid atherosclerosis in Egyptian chronic hepatitis C patients after treatment by direct-acting antiviral drugs. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00218-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Recent studies suggested association between hepatitis C virus (HCV) infection and cardiovascular disorders, including carotid atherosclerosis with evidence of an effect of HCV clearance on carotid atherosclerosis.
Objectives
We aimed to evaluate the impact of direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection on carotid atherosclerosis.
Subjects and methods
This is a prospective cohort study that was carried out in Internal Medicine and Hepatology Department, and outpatient clinics of the Ain Shams University hospitals included 80 Egyptian patients with chronic HCV infection who started treatment in the form of IFN-free DAA-based regimen and completed the course of treatment and 6-month follow-up period. All patients were subjected to detailed history taking, full physical examination, full laboratory investigations, radiological assessment by abdominal ultrasonography, and high-resolution B-mode ultrasonography of both the common carotid arteries.
Results
The mean age of cases was 58.13 ± 7.56 years, 49 (61.25%) males and 31 (38.75%) females. IMT was significantly decreased after treatment 1.24 versus 1.57 mm p < 0.001. The number of patients with IMT ≥ 1 mm was significantly decreased after 6 months 45 (56.3%) versus 57 (71.3%). There was significant positive correlation between baseline carotid IMT and age, BMI, bilirubin, INR, CTP score, carotid plaques, and total cholesterol. Meanwhile, there was significant negative correlation between baseline carotid IMT and hemoglobin, platelets, albumin, and HDL. In patients who achieved SVR, total cholesterol, triglycerides, LDL, and HDL were significantly increased after treatment. IMT was significantly lower in SVR group compared to non-SVR group (p = 0.016).
Conclusion
Hepatitis C virus eradication by DAAs improves carotid atherosclerosis by decreasing carotid intima-media thickening.
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Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol 2022; 77:219-236. [PMID: 35157957 DOI: 10.1016/j.jhep.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/12/2022] [Accepted: 01/31/2022] [Indexed: 12/16/2022]
Abstract
HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.
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Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmed M Elsharkawy
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, B15 2TH UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
| | - Michele Vacca
- Interdisciplinary Department of Medicine, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
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Saracco GM, Marzano A, Rizzetto M. Therapy of Chronic Viral Hepatitis: The Light at the End of the Tunnel? Biomedicines 2022; 10:534. [PMID: 35327336 PMCID: PMC8945793 DOI: 10.3390/biomedicines10030534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/08/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic viral hepatitis determines significant morbidity and mortality globally and is caused by three main etiological actors (Hepatitis B Virus, Hepatitis C Virus, and Hepatitis D Virus) with different replicative cycles and biological behaviors. Thus, therapies change according to the different characteristics of the viruses. In chronic hepatitis B, long term suppressive treatments with nucleoside/nucleotide analogues have had a dramatic impact on the evolution of liver disease and liver-related complications. However, a conclusive clearance of the virus is difficult to obtain; new strategies that are able to eradicate the infection are currently objects of research. The therapy for Hepatitis D Virus infection is challenging due to the unique virology of the virus, which uses the synthetic machinery of the infected hepatocyte for its own replication and cannot be targeted by conventional antivirals that are active against virus-coded proteins. Recently introduced antivirals, such as bulevertide and lonafarnib, display definite but only partial efficacy in reducing serum HDV-RNA. However, in combination with pegylated interferon, they provide a synergistic therapeutic effect and appear to represent the current best therapy for HDV-positive patients. With the advent of Direct Acting Antiviral Agents (DAAs), a dramatic breakthrough has occurred in the therapeutic scenario of chronic hepatitis C. Cure of HCV infection is achieved in more than 95% of treated patients, irrespective of their baseline liver fibrosis status. Potentially, the goal of global HCV elimination by 2030 as endorsed by the World Health Organization can be obtained if more global subsidised supplies of DAAs are provided.
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Affiliation(s)
- Giorgio Maria Saracco
- Gastro-Hepatoloy Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (A.M.); (M.R.)
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9
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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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Haykal M, Matsumori A, Saleh A, Fayez M, Negm H, Shalaby M, Bassuony S. Diagnosis and treatment of HCV heart diseases. Expert Rev Cardiovasc Ther 2021; 19:493-499. [PMID: 33861939 DOI: 10.1080/14779072.2021.1917383] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection is an important cause of a variety of otherwise unexplained heart diseases and myocardial injury. A high prevalence of HCV infection has been noted in patients with hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia/cardiomyopathy and myocarditis. Various arrhythmias, conduction disturbances and QT prolongation were also associated with HCV infection. A possible role of HCV infection in the pathogenesis of diabetes and atherosclerosis, and the role of immunogenetics of HCV cardiomyopathies is discussed. Recent studies suggest that mononuclear cells may be the major target of HCV, and clinical applications to test this new hypothesis are discussed. AREAS COVERED In this review, we will evaluate the evidence that HCV causes various cardiovascular diseases, and discuss on the pathogenesis of these disorders. EXPERT OPINION HCV is the cause of many different forms of heart disease worldwide, but their existence has not been recognized by most of cardiologists. The recognition and diagnosis are indispensable for the early treatment of these diseases. The diverse clinical manifestation of HCV infection and the presence of multiple extrahepatic disease syndromes could be explained by a new hypothesis that the target of HCV is leukocytes.
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Affiliation(s)
- Mohammad Haykal
- Cardiovascular and Ultrasonography Research Unit (CURU), Research Institute of Ophthalmology (RIO), Cairo, Egypt
| | - Akira Matsumori
- Clinical Research Center, Kyoto Medical Center, Kyoto, Japan
| | - Ahmed Saleh
- Cardiovascular and Ultrasonography Research Unit (CURU), Research Institute of Ophthalmology (RIO), Cairo, Egypt
| | - Moatez Fayez
- Cardiovascular and Ultrasonography Research Unit (CURU), Research Institute of Ophthalmology (RIO), Cairo, Egypt
| | - Hany Negm
- Cardiovascular and Ultrasonography Research Unit (CURU), Research Institute of Ophthalmology (RIO), Cairo, Egypt
| | - Mohammad Shalaby
- Cardiovascular and Ultrasonography Research Unit (CURU), Research Institute of Ophthalmology (RIO), Cairo, Egypt
| | - Samar Bassuony
- Cardiovascular and Ultrasonography Research Unit (CURU), Research Institute of Ophthalmology (RIO), Cairo, Egypt
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11
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Sacco M, Saracco GM. The impact of direct-acting antiviral treatment on glycemic homeostasis in patients with chronic hepatitis C. Minerva Gastroenterol (Torino) 2021; 67:264-272. [PMID: 33856147 DOI: 10.23736/s2724-5985.21.02835-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND there is robust epidemiological evidence suggesting the link of chronic Hepatitis C Virus (HCV) infection with type 2 diabetes mellitus (DM). Viral clearance achieved by Direct Acting Antiviral Agents (DAAs) has been associated to significant improvements in glycometabolic control but data on the long-term effect of Sustained Virological Response on diabetic disease are limited. AIM the aim of this review is to evaluate the influence of SVR after DAA-based therapy on Insulin Resistance (IR) and DM incidence in non-diabetic patients, on the glycemic homeostasis in diabetic patients and on their long-term hepatic and metabolic outcomes. METHODS an electronic search of Embase, PubMed, MEDLINE, Ovid and the Cochrane Database of Systematic Reviews was performed for papers regarding the effect of DAAinduced SVR on the glycometabolic control and clinical outcomes of HCV-positive diabetic patients up to September 30, 2020. RESULTS among non-diabetic patients, a significant reduction in the risk of IR and DM was reported by the vast majority of the studies; the glycometabolic control significantly improved in diabetic patients during and immediately after the end of antiviral treatment. However, whether this beneficial effect is long lasting is still matter of debate. Furthermore, at variance with data obtained during the Interferon (IFN) era, DM does not seem to be an unfavourable predictive factor of Hepatocellular Carcinoma (HCC) in cured patients. CONCLUSIONS a favourable influence of DAA-induced SVR on IR and DM incidence and on glycemic control is reported by several studies. However, the long-term biochemical, metabolic and clinical impact of this endocrine benefit remains largely unknown.
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Affiliation(s)
- Marco Sacco
- Gastro-hepatoloy Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giorgio M Saracco
- Gastro-hepatoloy Unit, Department of Medical Sciences, University of Turin, Turin, Italy -
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12
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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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Ciancio A, Ribaldone DG, Dotta A, Giordanino C, Sacco M, Fagoonee S, Pellicano R, Saracco GM. Long-term follow-up of diabetic and non-diabetic patients with chronic hepatitis C successfully treated with direct-acting antiviral agents. Liver Int 2021; 41:276-287. [PMID: 32998174 DOI: 10.1111/liv.14676] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/05/2020] [Accepted: 09/16/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIMS Clearance of hepatitis C virus (HCV) is associated with improved glycometabolic control in patients with diabetes mellitus (DM) but whether this effect is maintained over the long term with a reduction in liver-related events (LRE) is still debated. To address these issues, we conducted a long-term prospective study on diabetic and non-diabetic patients with chronic hepatitis C cured by direct antiviral agents (DAAs). METHODS Among 893 recruited patients, 15.7% were diabetic (Group 1) and 84.3% non-diabetic (Group 2); changes in fasting glucose (FG) and glycated haemoglobin (HbA1c) levels were assessed in Group 1 while the incidence of LRE was established in the whole cohort. Differences between groups were evaluated and independent predictors of unfavourable clinical outcome were established. RESULTS After a mean follow up of 44.5 months, a significant reduction in FG and HbA1c values was found in Group 1. Death was reported in 5.7% of patients in Group 1 vs 1.6% in Group 2 (P = .003), hepatocellular carcinoma (HCC)-free survival was significantly lower in Group 2 (P = .015) as well as LRE-free survival in Group 1 cirrhotic patients (P = .0006). After adjustment for baseline variables, cirrhosis and albumin levels emerged as independent predictors of LRE; low albumin levels, DM and central obesity were associated with HCC risk in cirrhotic patients while insulin therapy emerged as unfavourable predictor among diabetics. CONCLUSIONS SVR achieved by DAAs is associated with long-term improvement of glycometabolic control in diabetic patients, but among cirrhotics DM still exerts a detrimental effect on the liver.
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Affiliation(s)
- Alessia Ciancio
- Gastro-Hepatology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Davide G Ribaldone
- Gastro-Hepatology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Anna Dotta
- Gastro-Hepatology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Chiara Giordanino
- Gastro-Hepatology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Marco Sacco
- Gastro-Hepatology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging (CNR) c/o Molecular Biotechnology Center, Turin, Italy
| | - Rinaldo Pellicano
- Gastro-Hepatology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giorgio M Saracco
- Gastro-Hepatology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
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Cirrhosis and insulin resistance: current knowledge, pathophysiological mechanisms, complications and potential treatments. Clin Sci (Lond) 2020; 134:2117-2135. [PMID: 32820802 DOI: 10.1042/cs20200022] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 07/17/2020] [Accepted: 07/31/2020] [Indexed: 12/12/2022]
Abstract
End-stage chronic liver diseases are often associated with insulin resistance (IR) and diabetes mellitus (DM). Indeed, to quantify insulin sensitivity the euglycemic clamp technique was utilized, allowing the following to be stated: in small groups of patients, an IR in almost all cirrhotic patients can be observed, compared with a control group. Additionally, it has been demonstrated that IR in cirrhosis is linked to a decreased peripheral (muscle) glucose uptake rather than an increased liver glucose production. The homoeostasis model of IR (HOMA-IR) technique, devised only later, was then exploited to assess this same phenomenon in a larger sample population. The research established that even in patients with preserved liver function, cirrhosis is associated with significant alterations in glucose homoeostasis levels. The purpose of the present paper is to present the current research around the affiliation of cirrhosis and IR, discuss potential mechanisms explaining the association between cirrhosis and IR (i.e. endocrine perturbation, liver inflammation, altered muscle mass and composition, altered gut microbiota and permeability), complications that can arise as well as treatment options, through a critical review of the literature surrounding this subject. This research will also be investigating the beneficial impact, if there is any, of identifying and curing IR in patients with cirrhosis.
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Methionine metabolism in chronic liver diseases: an update on molecular mechanism and therapeutic implication. Signal Transduct Target Ther 2020; 5:280. [PMID: 33273451 PMCID: PMC7714782 DOI: 10.1038/s41392-020-00349-7] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/30/2020] [Accepted: 09/18/2020] [Indexed: 02/06/2023] Open
Abstract
As one of the bicyclic metabolic pathways of one-carbon metabolism, methionine metabolism is the pivot linking the folate cycle to the transsulfuration pathway. In addition to being a precursor for glutathione synthesis, and the principal methyl donor for nucleic acid, phospholipid, histone, biogenic amine, and protein methylation, methionine metabolites can participate in polyamine synthesis. Methionine metabolism disorder can aggravate the damage in the pathological state of a disease. In the occurrence and development of chronic liver diseases (CLDs), changes in various components involved in methionine metabolism can affect the pathological state through various mechanisms. A methionine-deficient diet is commonly used for building CLD models. The conversion of key enzymes of methionine metabolism methionine adenosyltransferase (MAT) 1 A and MAT2A/MAT2B is closely related to fibrosis and hepatocellular carcinoma. In vivo and in vitro experiments have shown that by intervening related enzymes or downstream metabolites to interfere with methionine metabolism, the liver injuries could be reduced. Recently, methionine supplementation has gradually attracted the attention of many clinical researchers. Most researchers agree that adequate methionine supplementation can help reduce liver damage. Retrospective analysis of recently conducted relevant studies is of profound significance. This paper reviews the latest achievements related to methionine metabolism and CLD, from molecular mechanisms to clinical research, and provides some insights into the future direction of basic and clinical research.
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Svegliati-Baroni G, Gaggini M, Carli F, Barbieri C, Cucco M, Youne R, Rosso C, Bugianesi E, Gastaldelli A. Mechanisms for increased risk of diabetes in chronic liver diseases. Liver Int 2020; 40:2489-2499. [PMID: 32515880 DOI: 10.1111/liv.14556] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 05/25/2020] [Accepted: 05/29/2020] [Indexed: 02/13/2023]
Abstract
OBJECTIVE Patients with chronic liver disease (CLD), both non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC), are at high risk of diabetes (T2D), but mechanisms are still unknown. Muscle/liver insulin resistance (IR) and pancreatic dysfunction are the major metabolic defects leading to T2D. However, if the risk of T2D in CLD patients is because of reduced insulin response and/or to IR, and the impact of liver histology has not been investigated. DESIGN We studied 220 non-T2D patients with chronic liver disease (129 NAFLD, BMI = 27.3 kg/m2 ; 91 CHC, BMI = 25.0 kg/m2 ) that received a 75-gram oral glucose tolerance test (OGTT) with the measurement of glucose and insulin concentrations for 2 hours, glucose tolerance (NGT vs IGT) and liver biopsy. The results were compared to 26 controls (CT-NGT, BMI = 25.6 kg/m2 ). We evaluated peripheral insulin sensitivity (OGIS), OGTT-insulin response (ΔAUC-I/ΔAUC-G) and disposition-index (DI = OGIS∙ΔAUC-I/ΔAUC-G) for the risk to develop T2D. RESULTS NAFLD had increased muscle IR (associated to NASH, steatosis and fibrosis), higher than in CHC or CT-NGT (OGIS = 8.9 vs 11.3 and 10.5 mL/min kg, P < .0001). In NAFLD, OGTT-insulin response (ΔAUC-I/ΔAUC-G) was the highest while it was significantly decreased in CHC (2.2 vs 1.1 and 1.6, NAFLD vs. CHC and CT-NGT, P < .005). The highest T2D risk (low DI) was observed in CHC-IGT (7.5), CHC-NGT (13.5) and NAFLD-IGT (10.8) vs CT-NGT (14.9, all P < .0001), but not in NAFL-NGT or NASH-NGT. CONCLUSION We observed an increased T2D risk in NAFLD-IGT, CHC-IGT and CHC-NGT mainly because of reduced OGTT-insulin response, while insulin response in NAFLD-NGT compensates the IR thus maintaining normal glycaemia.
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Affiliation(s)
- Gianluca Svegliati-Baroni
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.,Liver Injury and Transplant Unit, Ospedali Riuniti di Ancona, Ancona, Italy.,Obesity Center, Polytechnic University of Marche, Ancona, Italy
| | | | | | | | - Monica Cucco
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Ramy Youne
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Chiara Rosso
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy
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Chronic hepatitis C virus infection impairs insulin secretion by regulation of p38δ MAPK-dependent exocytosis in pancreatic β-cells. Clin Sci (Lond) 2020; 134:529-542. [PMID: 32100852 DOI: 10.1042/cs20190900] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 02/13/2020] [Accepted: 02/26/2020] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis C virus (HCV) infection has a close association with type 2 diabetes mellitus. Although the mechanisms of insulin resistance in chronic hepatitis C (CHC) patients have been extensively studied, little attention has been given to the role of β-cell function in HCV-associated diabetes. Here, we analysed β-cell function in CHC patients and HCV-infected mouse model and found in addition to insulin resistance, impaired pancreatic β-cell function occurred in CHC patients and HCV-infected C/OTg mice, not only in diabetic individuals but also in individuals with impaired fasting glucose levels. Both first-phase and second-phase insulin secretion were impaired, at least partially due to the reduction of exocytosis of secretory insulin-containing granules following HCV infection. Up-regulated p38δ in HCV-infected β-cells resulted in inactivation of protein kinase D (PKD), which was responsible for impaired insulin secretory capacity of β-cells. Thus, impaired insulin secretion due to HCV infection in β-cells contributes to HCV-associated type 2 diabetes. These findings provided a new inspiration for the important prognostic and therapeutic implications in the management of CHC patients with impaired fasting glucose.
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Berk J, Lorigiano TJ, Sulkowski M, Mixter S. REPLACING INSULIN WITH ANTI-VIRALS: A CLINICAL VIGNETTE ON DIABETES AND HCV TREATMENT. AACE Clin Case Rep 2020; 6:e59-e61. [PMID: 32524011 DOI: 10.4158/accr-2019-0369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 11/20/2019] [Indexed: 11/15/2022] Open
Abstract
Objective There is growing evidence to support a connection between type 2 diabetes mellitus (T2DM) and chronic hepatitis C virus (HCV). Patients with hepatitis C have a substantially higher risk for developing type 2 diabetes and recently there have been several proposed mechanisms. Several retrospective studies have demonstrated a small but significant improvement in glycemic control after treatment of underlying hepatitis C virus. We describe a case that demonstrates the greatest recorded improvement in glycemic control after treatment of HCV in the setting of self-discontinuation of insulin therapy without behavioral modification. Methods A 38-year-old obese female with uncontrolled T2DM (hemoglobin A1c [HbA1c] of 11.6% [103 mmol/mol]) was temporarily lost to follow-up and reported nonadherence to insulin therapy, metformin therapy, diet, or exercise. During this time, she was successfully treated for hepatitis C and became euglycemic without other interventions. Results The patient's HbA1c decreased from 11.6 to 5.7% (103 to 39 mmol/mol) in the presence of weight gain and in the absence of any intervention other than hepatitis C treatment. Conclusion Hepatitis C treatment may offer significant potential for improving insulin sensitivity and decreasing long-term complications of type 2 diabetes in certain patients. Universal treatment of HCV could offer benefits in both hepatic and extrahepatic clinical outcomes.
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Abstract
Hepatits C virus (HCV) infection has been largely associated with extrahepatic comorbidities such as diseases related to dysregulation of the immune system, neuropsychiatric disorders, and cardiometabolic alterations. These clinical consequences, together with experimental evidence, suggest a potential (in)direct effect of HCV, contributing to the pathogenesis of these diseases. Various studies have reported a positive effect of viral eradication on occurrence and outcomes of extrahepatic diseases. These observations and the availability of safe and effective direct antiviral agents further underline the need to search for virological eradication in all infected individuals independent of the severity of the liver disease.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, PROMISE, Università di Palermo, Italia.
| | - Antonio Craxì
- Sezione di Gastroenterologia e Epatologia, PROMISE, Università di Palermo, Italia
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The Prevalence and Impact of Hepatic Steatosis on Response to Direct-Acting Antiviral Therapy in HIV-HCV Coinfection. BIOLOGY 2020; 9:biology9040087. [PMID: 32344543 PMCID: PMC7235799 DOI: 10.3390/biology9040087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 12/15/2022]
Abstract
(1) Background: Direct-acting antiviral therapy for chronic hepatitis C virus (HCV) infection is associated with high sustained virologic response (SVR) and overcomes negative predictive factors, including steatosis, in patients without human immunodeficiency virus (HIV) coinfection. The impact of steatosis on SVR in patients with HIV–HCV coinfection is unknown. (2) Methods: A retrospective analysis of patients treated with direct-acting antivirals was performed. Demographic, laboratory and direct-acting antiviral regimen data were prospectively collected. Metabolic syndrome and its components—diabetes mellitus, hypertension, dyslipidemia and obesity—were assessed. Hepatic steatosis (≥5%) was defined by liver biopsy or controlled attenuation parameter (CAP) measurement during vibration-controlled transient elastography (VCTE). (3) Results: A total of 151 HIV–HCV-coinfected patients on combined antiretroviral therapy and direct-acting antiviral therapy were included in this analysis. Prevalence of steatosis by liver biopsy (n = 34) or CAP (≥263 db/m) during VCTE (n = 92) was 27% and was independently associated with obesity (OR 3.11; 95% CI 1.43–6.82; p = 0.004) and the metabolic syndrome (OR 1.08; 95% CI 1.01–0.15; p = 0.01). The overall SVR rate (n = 148) was 95% and was not impacted by the presence of steatosis (p = 0.42). (4) Conclusions: Hepatic steatosis is common in HIV–HCV coinfection, correlates with obesity and the metabolic syndrome and does not impact SVR.
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The Effect of Viral Clearance Achieved by Direct-Acting Antiviral Agents on Hepatitis C Virus Positive Patients with Type 2 Diabetes Mellitus: A Word of Caution after the Initial Enthusiasm. J Clin Med 2020; 9:jcm9020563. [PMID: 32092892 PMCID: PMC7074145 DOI: 10.3390/jcm9020563] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 02/11/2020] [Accepted: 02/17/2020] [Indexed: 02/07/2023] Open
Abstract
The causal link between chronic hepatitis C and glycometabolic alterations has been confirmed by much biochemical, clinical, and epidemiological research work, but what is still controversial is the long-term clinical impact of sustained virologic response (SVR) achieved by direct-acting antiviral agents (DAAs) on patients with type 2 diabetes mellitus (DM). The aim of this paper is to summarize the biochemical and clinical consequences to DM of DAA-based therapy for hepatitis C virus (HCV) infection. An electronic search of Embase, PubMed, MEDLINE, Ovid, and the Cochrane Database of Systematic Reviews was conducted for publications assessing whether clearance of HCV achieved by interferon (IFN)-free antiviral therapy determines significant changes in glycometabolic control and clinical outcomes of diabetic patients. A beneficial effect of SVR obtained by DAA therapy on DM prevention and the short-term outcome of glycometabolic alterations are acknowledged by most of the studies. Whether this effect is maintained over the long term with a significant clinical impact on diabetic and liver disease is still a matter of debate.
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Sevastianos VA, Voulgaris TA, Dourakis SP. Hepatitis C, systemic inflammation and oxidative stress: correlations with metabolic diseases. Expert Rev Gastroenterol Hepatol 2020; 14:27-37. [PMID: 31868062 DOI: 10.1080/17474124.2020.1708191] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Hepatitis C chronic infection has long been correlated with numerous systemic diseases, such as diabetes mellitus and hepatic steatosis. Recent studies have also revealed an association with atherosclerosis.Areas covered: An analysis is presented on the mechanisms through which the hepatitis C viral infection can lead to a systemic increase in pro-inflammatory markers, especially tumor necrosis factor-a and interleukin-6. The immunological imbalance created may, through different mechanisms, act on the metabolic pathways that contribute to the development of insulin resistance, the accumulation of lipids in the liver, and even the formation of atherosclerotic plaques. Moreover, an additional contributing factor to the above-mentioned metabolic derangements is the unopposed oxidative stress observed in chronic hepatitis C viral infection. The virus itself contributes to the formation of oxidative stress, through alterations in the trace metal homeostasis and its effect on pro-inflammatory cytokines, such as tumor necrosis factor-a.Expert opinion: The scope of this review is to emphasize the importance of the metabolic manifestations of hepatitis C viral infection and to elucidate the pathophysiological mechanisms behind their emergence.
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Affiliation(s)
- Vassilios A Sevastianos
- Department of Internal Medicine and Liver Outpatient Clinic, "Evangelismos" General Hospital, Athens, Greece
| | - Theodoros A Voulgaris
- Department of Internal Medicine and Liver Outpatient Clinic, "Evangelismos" General Hospital, Athens, Greece
| | - Spyros P Dourakis
- Department of Internal Μedicine, Medical School, National and Kapodistrian University of Athens, General Hospital of Athens Ippokrateio, Athens, Greece
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Altered Metabolic Profile and Adipocyte Insulin Resistance Mark Severe Liver Fibrosis in Patients with Chronic Liver Disease. Int J Mol Sci 2019; 20:ijms20246333. [PMID: 31888144 PMCID: PMC6940758 DOI: 10.3390/ijms20246333] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/06/2019] [Accepted: 12/09/2019] [Indexed: 02/07/2023] Open
Abstract
Metabolomics/lipidomics are important tools to identify novel biomarkers associated with liver damage. Patients with chronic liver disease (CLD) and hepatitis C virus (HCV) infection often have alterations in glucose, lipid and protein metabolism. The aim of this study was to evaluate if dysfunctional lipid and amino acid metabolism was associated with fibrosis severity and insulin resistance in CLD/HCV patients. We analyzed the baseline sera of 75 subjects with CLD/HCV infection HCV genotype-1, with proven liver biopsy prior to antiviral treatment. We measured amino acid (AA) and lipid concentration by gas and liquid chromatography-mass spectrometry respectively. Alterations in peripheral glucose metabolism due to insulin resistance (IR) were assesed by HOMA-IR (Glucose x Insulin/22.5), while adipose tissue IR was estimated as (Adipo-IR = Free Fatty Acids x Insulin). Baseline HOMA-IR and Adipo-IR were related to the degree of liver fibrosis. Reduction in ceramides 18:1/22:0, 18:1/24:0, diacylglycerol 42:6 and increased phosphocholine 40:6 were associated with higher fibrosis. Adipo-IR was related to lower levels of lysophosphatidylcholine 14:0 and 18:2 and with higher levels of sphingomyelin 18:2/24:0 and 18:2/24:1. Almost all AA were positively associated with Adipo-IR but not with HOMA-IR. We further confirmed the potential use of metabolomics and lipidomics in CLD/HCV subjects finding novel biomarkers of hepatic fibrosis and show that the adipose tissue IR is associated with more severe liver disease and is an important marker not only of altered lipid but also AA metabolism.
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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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Lim TR, Hazlehurst JM, Oprescu AI, Armstrong MJ, Abdullah SF, Davies NP, Flintham R, Balfe P, Mutimer DJ, McKeating JA, Tomlinson JW. Hepatitis C virus infection is associated with hepatic and adipose tissue insulin resistance that improves after viral cure. Clin Endocrinol (Oxf) 2019; 90:440-448. [PMID: 30586166 PMCID: PMC6446809 DOI: 10.1111/cen.13924] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 12/10/2018] [Accepted: 12/20/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Chronic hepatitis C (CHC) is associated with systemic insulin resistance, yet there are limited data on the tissue-specific contribution in vivo to this adverse metabolic phenotype, and the effect of HCV cure. METHODS We examined tissue-specific insulin sensitivity in a cohort study involving 13 patients with CHC compared to 12 BMI-matched healthy control subjects. All subjects underwent a two-step clamp incorporating the use of stable isotopes to measure carbohydrate and lipid flux (hepatic and global insulin sensitivity) with concomitant subcutaneous adipose tissue microdialysis and biopsy (subcutaneous adipose tissue insulin sensitivity). Investigations were repeated in seven patients with CHC following antiviral therapy with a documented sustained virological response. RESULTS Adipose tissue was more insulin resistant in patients with CHC compared to healthy controls, as evidence by elevated glycerol production rate and impaired insulin-mediated suppression of both circulating nonesterified fatty acids (NEFA) and adipose interstitial fluid glycerol release during the hyperinsulinaemic euglycaemic clamp. Hepatic and muscle insulin sensitivity were similar between patients with CHC and controls. Following viral eradication, hepatic insulin sensitivity improved as demonstrated by a reduction in endogenous glucose production rate. In addition, circulating NEFA decreased with sustained virological response (SVR) and insulin was more effective at suppressing adipose tissue interstitial glycerol release with a parallel increase in the expression of insulin signalling cascade genes in adipose tissue consistent with enhanced adipose tissue insulin sensitivity. CONCLUSION Chronic hepatitis C patients have profound subcutaneous adipose tissue insulin resistance in comparison with BMI-matched controls. For the first time, we have demonstrated that viral eradication improves global, hepatic and adipose tissue insulin sensitivity.
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Affiliation(s)
- Teegan R. Lim
- NIHR Liver Biomedical Research UnitUniversity of BirminghamBirminghamUK
- CRUK Clinical Trials UnitUniversity of BirminghamBirminghamUK
| | | | - Andrei I. Oprescu
- NIHR Liver Biomedical Research UnitUniversity of BirminghamBirminghamUK
| | - Matthew J. Armstrong
- NIHR Liver Biomedical Research UnitUniversity of BirminghamBirminghamUK
- CRUK Clinical Trials UnitUniversity of BirminghamBirminghamUK
| | - Sewa F. Abdullah
- School of Sport, Exercise & Rehabilitation SciencesUniversity of BirminghamBirminghamUK
| | | | | | - Peter Balfe
- NIHR Liver Biomedical Research UnitUniversity of BirminghamBirminghamUK
| | - David J. Mutimer
- NIHR Liver Biomedical Research UnitUniversity of BirminghamBirminghamUK
- CRUK Clinical Trials UnitUniversity of BirminghamBirminghamUK
| | | | - Jeremy W. Tomlinson
- Oxford Centre for Diabetes, Endocrinology & MetabolismUniversity of OxfordOxfordUK
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Abstract
Amongst the primary tumors of the liver, hepatocellular carcinoma (HCC) is the most common. It is also one of the most prevalent types of cancers in Asia. Mostly, HCC occurs on a background of chronic liver disease and liver cirrhosis; however, de novo HCCs can also arise in apparently normal looking livers on imaging. There are multiple risk factors for HCC, including hepatitis B and C infections, diabetes mellitus, alcohol, and nonalcoholic steatohepatitis. Other common risk factors which are known to be involved in the pathogenesis of HCC are obesity, food contaminated with aflatoxin and hemochromatosis. Many of these factors are commonly found in this part of the world, hence the high burden of disease. Besides these, smoking and familial predisposition to HCC also seem to have an important role to play in its development. Majority of HCC are missed at an early stage despite the emphasis on adequate screening and surveillance strategies. Therefore, most of the time these tumors are diagnosed at a fairly advanced stage, when palliative treatment is the only therapeutic option left. Hence, prevention of HCC by controlling and minimizing the possible risk factors is the need of the hour. How to cite this article: Jafri W, Kamran M. Hepatocellular Carcinoma in Asia: A Challenging Situation. Euroasian J Hepatogastroenterol 2019; 9(1):27-33.
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Affiliation(s)
- Wasim Jafri
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - Muhammad Kamran
- Department of Medicine, Baqai Medical University, Karachi, Pakistan
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Zubkin ML, Chervinko VI, Ovchinnikov YV, Kryukov EV, Kotenko ON. [Chronic HCV infection: An internist's opinion (Part 2)]. TERAPEVT ARKH 2018. [PMID: 28635834 DOI: 10.17116/terarkh20168811138-148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) infection results in not only chronic hepatitis and subsequent complications as liver cirrhosis and hepatocellular carcinoma, but also in a significant number of other diseases, the so-called extrahepatic manifestations of chronic HCV infection. In addition to lymphoproliferative and autoimmune disorders discussed in Part 1 of this review, many other diseases turned to be associated with chronic HCV infection. Part 2 of this review is dedicated to the analysis of the relationship of chronic HCV-infection to the development of some endocrine diseases, such as thyroiditis and diabetes mellitus, and cardiovascular disorders. It also provides the characteristics of the currently available antiviral agents and considers whether they may be used in patents with extrahepatic manifestations of chronic HCV infection.
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Affiliation(s)
- M L Zubkin
- G.N. Gabrichevsky Moscow Research Institute for Epidemiology and Microbiology, Russian Federal Service for Supervision of Consumer Rights Protection and Human Welfare, Moscow, Russia; Branch, S.M. Kirov Military Medical Academy, Moscow, Russia
| | - V I Chervinko
- Branch, S.M. Kirov Military Medical Academy, Moscow, Russia
| | | | - E V Kryukov
- N.N. Burdenko Main Military Clinical Hospital, Moscow, Russia
| | - O N Kotenko
- City Clinical Hospital Fifty-Two, Moscow Healthcare Department, Moscow, Russia
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Control of progression towards liver fibrosis and hepatocellular carcinoma by SOCS3 polymorphisms in chronic HCV-infected patients. INFECTION GENETICS AND EVOLUTION 2018; 66:1-8. [PMID: 30172885 DOI: 10.1016/j.meegid.2018.08.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/15/2018] [Accepted: 08/29/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Chronic Hepatitis C is one of the most important risk factors of liver cirrhosis and hepatocellular carcinoma. Before reaching these ultimate steps, insulin resistance triggered by hepatitis C virus infection is known to participate in the progression of liver disease. The present study aims to investigate the influence of two functional polymorphisms on SOCS3 mRNA expression and on the outcomes of CHC progression in a North African context. PATIENTS & METHODS In this case-control study, 601 Moroccan subjects composed of 200 healthy controls, 101 resolvers and 300 patients with persistent HCV infection including 95 mild chronic hepatitis, 131 Advanced Liver Diseases and 74 HCC were enrolled. They were genotyped for the 4874 A/G (rs4969170) and A + 930- > G (rs4969168) SOCS3 variants using TaqMan SNPs assays. SOCS3 mRNA expression was assessed using Real Time PCR technique. RESULTS Logistic regression analysis showed that variation at rs4969168 was associated with spontaneous clearance of HCV (P < 0.05). In addition, minor allele frequencies were significantly higher in AdLD patients when compared to the mCHC group both for rs4969168 (P = 7.0 E-04) and rs4969170 (P = 4.0 E-05). A significant association between haplotype and liver disease progression was also found. Moreover, SOCS3 mRNA was significantly more expressed in peripheral leukocytes from patients with HCC than in those from mCHC. Finally, rs4969170 was significantly associated with LDL-lipoprotein (P = 0.04), total cholesterol (P = 5.0 E-04), and higher fasting glucose levels (P = 0.005) in patients with persistent HCV infection. CONCLUSIONS Our results underline the importance of the functional SOCS3 polymorphisms in the modulation of CHC progression and suggest their contribution to HCC development by affecting its mRNA expression and perturbing key metabolic parameters.
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Chronic Hepatitis C Association with Diabetes Mellitus and Cardiovascular Risk in the Era of DAA Therapy. Can J Gastroenterol Hepatol 2018; 2018:6150861. [PMID: 30186821 PMCID: PMC6110000 DOI: 10.1155/2018/6150861] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 07/31/2018] [Indexed: 12/15/2022] Open
Abstract
Patients with chronic hepatitis C have both higher prevalence of diabetes mellitus type 2 (T2DM) and increased cardiovascular risk compared to never infected people. Sustained viral response (SVR) achievement led to decreasing incidence and prevalence of T2DM during the interferon era of HCV treatment. Currently, direct-acting antiviral drugs (DAA) are the gold standard for treating HCV infection, while yielding SVR in nearly all patients. In chronic HCV patients with T2DM (prediabetes most likely too), DAA therapy is associated with both better fasting glucose and glycated hemoglobin (HbA1C) controls; thus reducing pharmacotherapy in a certain part of patients is possible. Papers mentioned in the review confirmed DAA role in both total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) increase. This alteration was accompanied by an increase in high-density lipoprotein cholesterol (HDL-C) and a decrease in triglycerides (TG) verified by most of the studies. However, the clinical significance of lipoprotein alterations caused by DAA therapy has not been explained yet. Moreover, DAA treatment of chronic hepatitis C improves hypertension control and atherosclerotic plaques. It is very likely that DAA therapeutic regimens will decrease both T2DM prevalence and cardiovascular risk in chronic hepatitis C patients; further research, however, is needed.
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Salomone F, Catania M, Montineri A, Bertino G, Godos J, Rizzo L, Magrì G, Li Volti G. Hepatitis C virus eradication by direct antiviral agents improves glucose tolerance and reduces post-load insulin resistance in nondiabetic patients with genotype 1. Liver Int 2018; 38:1206-1211. [PMID: 29265719 DOI: 10.1111/liv.13669] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 12/11/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Genotype 1 chronic hepatitis C is associated with an impairment of glucose homoeostasis, especially in the advanced stages of the disease. Glucose tolerance is an independent predictor of liver-related mortality in patients with cirrhosis because of chronic hepatitis C. However, no study has demonstrated so far weather hepatitis C virus clearance affects glucose tolerance. METHODS To this aim, we performed a prospective study assessing the effects of direct antiviral agents treatment in nondiabetic cirrhotic patients with genotypes 1a/1b and impaired glucose tolerance based on a 75-g oral glucose tolerance test. Impaired glucose tolerance was diagnosed by a 2-hour plasma glucose between 140 and 199 mg/dL. Insulin resistance was estimated by the oral glucose insulin sensitivity index, an oral glucose tolerance test-derived measure. RESULTS After meeting the inclusion criteria, the study population included 32 outpatients (26/6 genotypes 1b/1a; age 62 ± 7.4 years; 18 males) with compensated Child-A cirrhosis. All patients achieved a sustained virological response following direct antiviral agents treatment. After viral eradication, we did not observe change in fasting plasma glucose (103.5 ± 7.1 vs 102.8 ± 7.2 mg/dL, P = .15) but 2-hour plasma glucose was reduced (165.2 ± 22.7 vs 138.5 ± 21.3 mg/dL, P < .001). Hepatitis C virus eradication led also to a significant reduction in HbA1c (6.1 ± 0.2% vs 5.7 ± 0.3%, P < .001) and post-load insulin resistance as assessed by the oral glucose insulin sensitivity index (6.92 ± 1.56 vs 9.52 ± 1.39 mg/kg/min, P < .001). These effects were observed despite no change in body mass index from baseline to follow-up (25.6 ± 4.3 vs 25.8 ± 4.4, P > .5). CONCLUSIONS Our results indicate that hepatitis C virus eradication may early improve glucose tolerance in patients with hepatitis C virus-related cirrhosis.
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Affiliation(s)
- Federico Salomone
- Division of Gastroenterology, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, Catania, Italy
| | - Maurizio Catania
- Division of Laboratory Medicine, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, Catania, Italy
| | - Arturo Montineri
- Division of Infectious Diseases, Ospedale "Ferrarotto", Catania, Italy
| | - Gaetano Bertino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Justyna Godos
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | | | - Giovanni Magrì
- Division of Gastroenterology, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, Catania, Italy
| | - Giovanni Li Volti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
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Petta S, Adinolfi LE, Fracanzani AL, Rini F, Caldarella R, Calvaruso V, Cammà C, Ciaccio M, Di Marco V, Grimaudo S, Licata A, Marrone A, Nevola R, Pipitone RM, Pinto A, Rinaldi L, Torres D, Tuttolomondo A, Valenti L, Fargion S, Craxì A. Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with severe liver fibrosis. J Hepatol 2018; 69:18-24. [PMID: 29505844 DOI: 10.1016/j.jhep.2018.02.015] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 02/14/2018] [Accepted: 02/19/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Recent studies suggest an association between hepatitis C virus (HCV) infection and cardiovascular damage, including carotid atherosclerosis, with a possible effect of HCV clearance on cardiovascular outcomes. We aimed to examine whether HCV eradication by direct-acting antiviral agents (DAA) improves carotid atherosclerosis in HCV-infected patients with advanced fibrosis/compensated cirrhosis. MATERIALS AND METHODS One hundred eighty-two consecutive patients with HCV and advanced fibrosis or compensated cirrhosis were evaluated. All patients underwent DAA-based antiviral therapy according to AISF/EASL guidelines. Intima-media thickness (IMT), carotid thickening (IMT ≥1 mm) and carotid plaques, defined as focal thickening of ≥1.5 mm at the level of the common carotid, were evaluated by ultrasonography (US) at baseline and 9-12 months after the end of therapy. Fifty-six percent of patients were male, mean age 63.1 ± 10.4 years, and 65.9% had compensated cirrhosis. One in five had diabetes, 14.3% were obese, 41.8% had arterial hypertension and 35.2% were smokers. At baseline, mean IMT was 0.94 ± 0.29 mm, 42.8% had IMT ≥1 mm, and 42.8% had carotid plaques. RESULTS All patients achieved a 12-week sustained virological response. IMT significantly decreased from baseline to follow-up (0.94 ± 0.29 mm vs. 0.81 ± 0.27, p <0.001). Consistently, a significant reduction in the prevalence of patients with carotid thickening from baseline to follow-up was observed (42.8% vs. 17%, p <0.001), while no changes were reported for carotid plaques (42.8% vs. 47.8%, p = 0.34). These results were confirmed in subgroups of patients stratified for cardiovascular risk factors and liver disease severity. CONCLUSION HCV eradication by DAA improves carotid atherosclerosis in patients with severe fibrosis with or without additional metabolic risk factors. The impact of this improvement in the atherosclerotic burden in terms of reduction of major cardiovascular outcomes is worth investigating in the long term. LAY SUMMARY Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with advanced fibrosis/compensated cirrhosis. The improvement in intima-media thickness and carotid thickening was confirmed after stratification for severity of liver disease and cardiovascular risk factors. Hepatitis C virus eradication by direct-acting antiviral agents also lead to improvement in glucose homeostasis and increased cholesterol levels.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy.
| | - Luigi Elio Adinolfi
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | - Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Italy
| | - Francesca Rini
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Rosalia Caldarella
- Department of Biopathology and Medical Biotechnologies, University of Palermo, Palermo, Italy
| | - Vincenza Calvaruso
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Marcello Ciaccio
- Department of Biopathology and Medical Biotechnologies, University of Palermo, Palermo, Italy
| | - Vito Di Marco
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Stefania Grimaudo
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Anna Licata
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Aldo Marrone
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | - Riccardo Nevola
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | | | - Antonio Pinto
- Sezione di Medicina Interna con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università di Palermo, Italy
| | - Luca Rinaldi
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | - Daniele Torres
- Sezione di Medicina Interna con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università di Palermo, Italy
| | - Antonino Tuttolomondo
- Sezione di Medicina Interna con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università di Palermo, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
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Puchades Renau L, Berenguer M. Introduction to hepatitis C virus infection: Overview and history of hepatitis C virus therapies. Hemodial Int 2018; 22 Suppl 1:S8-S21. [DOI: 10.1111/hdi.12647] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Lorena Puchades Renau
- Department of Gastroenterology, Hepatology Unit & Instituto de Investigación La Fe; Hospital Universitari i Politècnic La Fe; Valencia Spain
| | - Marina Berenguer
- Department of Gastroenterology, Hepatology Unit & Instituto de Investigación La Fe; Hospital Universitari i Politècnic La Fe; Valencia Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Valencia Spain
- School of Medicine; University of Valencia; Valencia Spain
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33
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Campana B, Calabrese D, Matter MS, Terracciano LM, Wieland SF, Heim MH. In vivo analysis at the cellular level reveals similar steatosis induction in both hepatitis C virus genotype 1 and 3 infections. J Viral Hepat 2018; 25:262-271. [PMID: 29086446 DOI: 10.1111/jvh.12816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 09/26/2017] [Indexed: 12/12/2022]
Abstract
Steatosis is a frequent histological feature of hepatitis C virus (HCV) infection. Cohort studies of patients with chronic hepatitis C identified HCV genotype 3 (HCV GT3) as the prevalent steatotic genotype. Moreover, Huh-7 cells over-expressing HCV GT3 core protein accumulate more triglyceride in larger lipid droplets than cells expressing core proteins of other HCV genotypes. However, little is known about the relationship of steatosis and HCV infection at the cellular level in vivo. In this study, we used highly sensitive multiplex in situ hybridization methodology together with lipid staining to investigate HCV-induced lipid droplet accumulation at the cellular level in liver biopsies. Consistent with previous reports, histological steatosis grades were significantly higher in GT3 compared to GT1 infected livers, but independent of viral load. Using nile red lipid stainings, we observed that the frequency of lipid droplet containing cells was similar in HCV GT1- and HCV GT3-infected livers. Lipid droplet formation preferentially occurred in HCV-infected cells irrespective of the genotype, but was also observed in noninfected cells. These findings demonstrate that the main difference between GT1- and GT3-induced steatosis is the size of lipid droplets, but not the number or relative distribution of lipid droplets in infected vs uninfected hepatocytes.
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Affiliation(s)
- B Campana
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.,Division of Gastroenterology and Hepatology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - D Calabrese
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - M S Matter
- Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, University of Basel, Basel, Switzerland
| | - L M Terracciano
- Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, University of Basel, Basel, Switzerland
| | - S F Wieland
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - M H Heim
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.,Division of Gastroenterology and Hepatology, University Hospital Basel, University of Basel, Basel, Switzerland
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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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Adinolfi LE, Jacobson I, Bondin M, Cacoub P. Expert opinion on managing chronic HCV infection in patients with type 2 diabetes mellitus. Antivir Ther 2018; 23:11-21. [PMID: 30451154 DOI: 10.3851/imp3255] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/27/2018] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes mellitus (T2DM) has been identified as an extrahepatic manifestation of chronic HCV infection. Conversely, in the context of chronic HCV infection, T2DM can accelerate the course of HCV-induced liver disease leading to increased risk of fibrosis, cirrhosis and hepatocellular carcinoma. The presence of T2DM negatively impacts the efficacy of interferon-based antiviral therapy, but real-world data with high-efficacy direct-acting antiviral therapies suggest high viral clearance rates in T2DM patients. In HCV-infected individuals, viral eradication is associated with a reduced risk of de novo T2DM in non-diabetic patients and beneficial metabolic changes in patients with T2DM, highlighting the importance of antiviral treatment and physician awareness of this association.
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MESH Headings
- Antiviral Agents/therapeutic use
- Blood Glucose/drug effects
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/prevention & control
- Diabetes Mellitus, Type 2/virology
- Disease Management
- Drug Combinations
- Glycated Hemoglobin/antagonists & inhibitors
- Glycated Hemoglobin/metabolism
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/pathology
- Hepatitis C, Chronic/virology
- Humans
- Insulin Resistance
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Liver/virology
- Liver Cirrhosis/drug therapy
- Liver Cirrhosis/etiology
- Liver Cirrhosis/pathology
- Liver Cirrhosis/virology
- Liver Neoplasms/drug therapy
- Liver Neoplasms/etiology
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Risk Factors
- Treatment Outcome
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Affiliation(s)
- Luigi Elio Adinolfi
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Università degli Studi della Campania 'Luigi Vanvitelli', Naples, Italy
| | | | | | - Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France
- INSERM, UMR_S 959, Paris, France
- CNRS, FRE3632, Paris, France
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
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Aby ES, Dong TS, Kawamoto J, Pisegna JR, Benhammou JN. Impact of sustained virologic response on chronic kidney disease progression in hepatitis C. World J Hepatol 2017; 9:1352-1360. [PMID: 29359019 PMCID: PMC5756725 DOI: 10.4254/wjh.v9.i36.1352] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 11/14/2017] [Accepted: 12/06/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine how sustained virological response at 12 wk (SVR12) with direct acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) infection affects chronic kidney disease (CKD) progression.
METHODS A retrospective analysis was performed in patients aged ≥ 18 years treated for HCV with DAAs at the VA Greater Los Angeles Healthcare System from 2014-2016. The treatment group was compared to patients with HCV from 2011-2013 who did not undergo HCV treatment, prior to the introduction of DAAs; the control group was matched to the study group in terms of age, gender, and ethnicity. Analysis of variance and co-variance was performed to compare means between SVR12 subgroups adjusting for co-variates.
RESULTS Five hundred and twenty-three patients were evaluated. When comparing the rate of change in estimated glomerular filtration rate (eGFR) one-year after HCV treatment to one-year before treatment, patients who achieved SVR12 had a decline in GFR of 3.1 mL/min ± 0.75 mL/min per 1.73 m2 compared to a decline in eGFR of 11.0 mL/min ± 2.81 mL/min per 1.73 m2 in patients who did not achieve SVR12 (P = 0.002). There were no significant clinical differences between patients who achieved SVR12 compared to those who did not in terms of cirrhosis, treatment course, treatment experience, CKD stage prior to treatment, diuretic use or other co-morbidities. The decline in eGFR in those with untreated HCV over 2 years was 2.8 mL/min ± 1.0 mL/min per 1.73 m2, which was not significantly different from the eGFR decline noted in HCV-treated patients who achieved SVR12 (P = 0.43).
CONCLUSION Patients who achieve SVR12 have a lesser decline in renal function, but viral eradication in itself may not be associated improvement in renal disease progression.
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Affiliation(s)
- Elizabeth S Aby
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States
- the Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA Los Angeles, Department of Medicine, University of California David Geffen School of Medicine, Los Angeles, CA 90095, United States
| | - Tien S Dong
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States
- the Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA Los Angeles, Department of Medicine, University of California David Geffen School of Medicine, Los Angeles, CA 90095, United States
| | - Jenna Kawamoto
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States
| | - Joseph R Pisegna
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States
- the Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA Los Angeles, Department of Medicine, University of California David Geffen School of Medicine, Los Angeles, CA 90095, United States
| | - Jihane N Benhammou
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States
- the Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA Los Angeles, Department of Medicine, University of California David Geffen School of Medicine, Los Angeles, CA 90095, United States
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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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Chen J, Zhang Z, Wang N, Guo M, Chi X, Pan Y, Jiang J, Niu J, Ksimu S, Li JZ, Chen X, Wang Q. Role of HDAC9-FoxO1 Axis in the Transcriptional Program Associated with Hepatic Gluconeogenesis. Sci Rep 2017; 7:6102. [PMID: 28733598 PMCID: PMC5522426 DOI: 10.1038/s41598-017-06328-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 06/08/2017] [Indexed: 12/31/2022] Open
Abstract
Histone deacetylase 9 (HDAC9) regulates hepatic gluconeogenesis by deacetylating Forkhead box O 1 (FoxO1). HDAC9 upregulation is involved in hepatitis C virus (HCV)-associated exaggerated gluconeogenesis. Herein, we found in addition to FoxO1, HDAC9 also regulates other gluconeogenic transcription factors, including peroxisomeproliferator-activated receptor-γ coactivator-1α (PGC-1α), cyclic AMP-responsive element-binding protein (CREB), and glucocorticoid receptor (GR). Unlike FoxO1, which is regulated by post-translational modification responses to HDAC9, HDAC9 regulates PGC-1α, CREB and GR by altering gene expression. Similar to PGC-1α, CREB and GR were found to be novel regulatory targets of FoxO1 by examination of the FoxO1 binding site in their promoter. PGC-1α, CREB and GR were upregulated in response to HDAC9 via FoxO1 deacetylation. These findings indicate that HDAC9-FoxO1 signalling contributes to gluconeogenesis by modulating the expression of gluconeogenic transcription factors. In particular, metabolic profiling demonstrated a clear shift towards gluconeogenesis metabolism, and HDAC9-FoxO1 signalling can be strongly induced to upregulate gluconeogenic transcription factors following HCV infection. The positive correlation between HDAC9 and gluconeogenic transcription factor expression levels in the livers of both HCV-infected patients and normal individuals further emphasizes the clinical relevance of these results. Thus, HDAC9-FoxO1 signalling axis is involved in regulating gluconeogenic transcription factors, gluconeogenesis, and HCV-induced type 2 diabetes.
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Affiliation(s)
- Jizheng Chen
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Zhilei Zhang
- Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China
| | - Ning Wang
- Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China
| | - Min Guo
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China
| | - Xiumei Chi
- Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yu Pan
- Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Jing Jiang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Sulaiman Ksimu
- The Center for Technology and Education, The first Affiliated Hospital of Xinjiang Medical University, Urumchi, 830054, China
| | - John Zhong Li
- Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China
| | - Xinwen Chen
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Qian Wang
- Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China.
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Hepatitis B and C virus infection and diabetes mellitus: A cohort study. Sci Rep 2017; 7:4606. [PMID: 28676706 PMCID: PMC5496892 DOI: 10.1038/s41598-017-04206-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 05/10/2017] [Indexed: 02/06/2023] Open
Abstract
The role of hepatitis virus infection in glucose homeostasis is uncertain. We examined the associations between hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and the development of diabetes in a cohort (N = 439,708) of asymptomatic participants in health screening examinations. In cross-sectional analyses, the multivariable-adjusted odds ratio for prevalent diabetes comparing hepatitis B surface antigen (HBsAg) (+) to HBsAg (−) participants was 1.17 (95% CI 1.06–1.31; P = 0.003). The corresponding odds ratio comparing hepatitis C antibodies (HCV Ab) (+) to HCV Ab (−) participants was 1.43 (95% CI 1.01–2.02, P = 0.043). In prospective analyses, the multivariable-adjusted hazard ratio for incident diabetes comparing HBsAg (+) to HbsAg (−) participants was 1.23 (95% CI 1.08–1.41; P = 0.007). The number of incident cases of diabetes among HCV Ab (+) participants (10 cases) was too small to reliably estimate the prospective association between HCV infection and diabetes. In this large population at low risk of diabetes, HBV and HCV infections were associated with diabetes prevalence and HBV infection with the risk of incident diabetes. Our studies add evidence suggesting that diabetes is an additional metabolic complication of HBV and HCV infection.
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Orsi E, Grancini V, Menini S, Aghemo A, Pugliese G. Hepatogenous diabetes: Is it time to separate it from type 2 diabetes? Liver Int 2017; 37:950-962. [PMID: 27943508 DOI: 10.1111/liv.13337] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 11/29/2016] [Indexed: 12/12/2022]
Abstract
By definition, hepatogenous diabetes is directly caused by loss of liver function, implying that it develops after cirrhosis onset. Therefore, it should be distinguished from type 2 diabetes developing before cirrhosis onset, in which specific causes of liver disease play a major role, in addition to traditional risk factors. Currently, although hepatogenous diabetes shows distinct pathophysiological and clinical features, it is not considered as an autonomous entity. Recent evidence suggests that the failing liver exerts an independent "toxic" effect on pancreatic islets resulting in β-cell dysfunction. Moreover, patients with hepatogenous diabetes usually present with normal fasting glucose and haemoglobin A1c levels and abnormal response to an oral glucose tolerance test, which is therefore required for diagnosis. This article discusses the need to separate hepatogenous diabetes from type 2 diabetes occurring in subjects with chronic liver disease and to identify individuals suffering from this condition for prognostic and therapeutic purposes.
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Affiliation(s)
- Emanuela Orsi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy.,Department of Medical Sciences, University of Milan, Milan, Italy
| | - Valeria Grancini
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy.,Department of Medical Sciences, University of Milan, Milan, Italy
| | - Stefano Menini
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.,Diabetes Unit, Sant'Andrea Hospital, Rome, Italy
| | - Alessio Aghemo
- Division of Gastroenterology and Hepatology, A.M. and A. Migliavacca Center for Liver Disease, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.,Diabetes Unit, Sant'Andrea Hospital, Rome, Italy
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Lerat H, Imache MR, Polyte J, Gaudin A, Mercey M, Donati F, Baudesson C, Higgs MR, Picard A, Magnan C, Foufelle F, Pawlotsky JM. Hepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice. J Biol Chem 2017; 292:12860-12873. [PMID: 28559285 DOI: 10.1074/jbc.m117.785030] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 05/18/2017] [Indexed: 12/15/2022] Open
Abstract
Virus-related type 2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV); however, the underlying molecular mechanisms remain unknown. Our aim was to unravel these mechanisms using FL-N/35 transgenic mice expressing the full HCV ORF. We observed that these mice displayed glucose intolerance and insulin resistance. We also found that Glut-2 membrane expression was reduced in FL-N/35 mice and that hepatocyte glucose uptake was perturbed, partly accounting for the HCV-induced glucose intolerance in these mice. Early steps of the hepatic insulin signaling pathway, from IRS2 to PDK1 phosphorylation, were constitutively impaired in FL-N/35 primary hepatocytes via deregulation of TNFα/SOCS3. Higher hepatic glucose production was observed in the HCV mice, despite higher fasting insulinemia, concomitant with decreased expression of hepatic gluconeogenic genes. Akt kinase activity was higher in HCV mice than in WT mice, but Akt-dependent phosphorylation of the forkhead transcription factor FoxO1 at serine 256, which triggers its nuclear exclusion, was lower in HCV mouse livers. These findings indicate an uncoupling of the canonical Akt/FoxO1 pathway in HCV protein-expressing hepatocytes. Thus, the expression of HCV proteins in the liver is sufficient to induce insulin resistance by impairing insulin signaling and glucose uptake. In conclusion, we observed a complete set of events leading to a prediabetic state in HCV-transgenic mice, providing a valuable mechanistic explanation for HCV-induced diabetes in humans.
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Affiliation(s)
- Hervé Lerat
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France; Université Paris-Est Créteil Val de Marne, 94010 Créteil, France.
| | - Mohamed Rabah Imache
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Jacqueline Polyte
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Aurore Gaudin
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Marion Mercey
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Flora Donati
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Camille Baudesson
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Martin R Higgs
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Alexandre Picard
- Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, 75013 Paris, France
| | - Christophe Magnan
- Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, 75013 Paris, France
| | - Fabienne Foufelle
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, 75006 Paris, France
| | - Jean-Michel Pawlotsky
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France; Université Paris-Est Créteil Val de Marne, 94010 Créteil, France; National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, AP-HP, 94010 Créteil, France
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Kwok RM, Tran TT. Management of Cirrhotic Patients After Successful HCV Eradication. ACTA ACUST UNITED AC 2017; 15:305-315. [PMID: 28439747 DOI: 10.1007/s11938-017-0134-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OPINION STATEMENT Chronic hepatitis C (HCV) is a hepatotropic virus which, when untreated, can lead to progressive inflammation and fibrosis resulting in cirrhosis, hepatocellular carcinoma (HCC), and decompensations related to end-stage liver disease. The relatively recent introduction of all oral, interferon-free, direct-acting antiviral medications against HCV has transformed the management of these patients. Previous treatment regimens were prolonged, poorly tolerated, and frequently did not result in cure. Current therapies achieve sustained viral response (SVR) in the vast majority of patients including those with decompensated liver disease; a previously challenging population to treat. These successes will result in significant numbers of cirrhotic patients requiring management after SVR. Although many complications of cirrhosis are improved in this setting, regular follow-up of HCC, esophageal varices, and other sequelae of cirrhosis will be necessary. This chapter will review the management of cirrhosis in HCV patients achieving cure.
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Affiliation(s)
- Ryan M Kwok
- Division of Gastroenterology/Hepatology, Walter Reed National Military Medical Center, 8901 Wisconsin Ave, Bethesda, MD, 20889, USA.
| | - Tram T Tran
- Cedars-Sinai Medical Center Liver Transplantation, 8700 Beverly Blvd., Los Angeles, CA, 90048, USA
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Davis TME, Davis WA, Jeffrey G. Successful Withdrawal of Insulin Therapy After Post-Treatment Clearance of Hepatitis C Virus in a Man with Type 2 Diabetes. AMERICAN JOURNAL OF CASE REPORTS 2017; 18:414-417. [PMID: 28413215 PMCID: PMC5402856 DOI: 10.12659/ajcr.903600] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Patient: Male, 55 Final Diagnosis: Hepatitis C Symptoms: Icterus Medication: — Clinical Procedure: — Specialty: Endocrinology and Metabolic
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Affiliation(s)
- Timothy M E Davis
- School of Medicine, University of Western Australia, Fremantle Hospital, Fremantle, WA, Australia
| | - Wendy A Davis
- School of Medicine, University of Western Australia, Fremantle Hospital, Fremantle, WA, Australia
| | - Gary Jeffrey
- School of Medicine, University of Western Australia, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.,Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
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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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45
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Shiffman ML, Gunn NT. Impact of hepatitis C virus therapy on metabolism and public health. Liver Int 2017; 37 Suppl 1:13-18. [PMID: 28052632 DOI: 10.1111/liv.13282] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 10/20/2016] [Indexed: 12/22/2022]
Abstract
Chronic hepatitis C virus (HCV) is associated with insulin resistance (IR) and leads to type 2 diabetes mellitus (T2DM) and hepatic steatosis in many patients. These metabolic complications of HCV have been shown to accelerate the progression of fibrosis to cirrhosis and increase the risk of hepatocellular carcinoma. The metabolic syndrome is a common disorder that also includes IR, T2DM and hepatic steatosis. Approximately 20%-30% of patients with chronic HCV also have co-existent metabolic syndrome. The cause of steatosis in patients with the features of both the metabolic syndrome and chronic HCV is sometime difficult to determine. Patients with metabolic syndrome and chronic HCV are also at risk of developing renal, cardiovascular and cerebrovascular disease. Recent data suggest that HCV is an independent risk factor for renal, coronary and cerebral vascular disease, and may increase mortality associated with these disorders. The treatment of HCV can now result in a sustained virological response and cure nearly all patients with chronic HCV. The eradication of HCV reduces the risk of developing IR and T2DM, improves IR and 2TDM, reduces the risk of developing chronic kidney disease, end-stage renal disease, acute cardiac syndrome and stroke in patients with 2TDM. Thus, treatment of chronic HCV can provide a significant public health benefit, but only if all patients with chronic HCV are identified and universally treated.
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Affiliation(s)
- Mitchell L Shiffman
- Liver Institute of Virginia, Bon Secours Health System, Richmond and Newport News, VA, USA
| | - Nadege T Gunn
- Liver Institute of Virginia, Bon Secours Health System, Richmond and Newport News, VA, USA
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Nahon P, Bourcier V, Layese R, Audureau E, Cagnot C, Marcellin P, Guyader D, Fontaine H, Larrey D, De Lédinghen V, Ouzan D, Zoulim F, Roulot D, Tran A, Bronowicki JP, Zarski JP, Leroy V, Riachi G, Calès P, Péron JM, Alric L, Bourlière M, Mathurin P, Dharancy S, Blanc JF, Abergel A, Serfaty L, Mallat A, Grangé JD, Attali P, Bacq Y, Wartelle C, Dao T, Benhamou Y, Pilette C, Silvain C, Christidis C, Capron D, Bernard-Chabert B, Zucman D, Di Martino V, Thibaut V, Salmon D, Ziol M, Sutton A, Pol S, Roudot-Thoraval F, Marcellin P, Guyader D, Pol S, Fontaine H, Larrey D, De Lédinghen V, Ouzan D, Zoulim F, Roulot D, Tran A, Bronowicki JP, Zarski JP, Leroy V, Riachi G, Calès P, Péron JM, Alric L, Bourlière M, Mathurin P, Blanc JF, Abergel A, Serfaty L, Mallat A, Grangé JD, Attali P, Bacq Y, Wartelle C, Dao T, Benhamou Y, Pilette C, Silvain C, Christidis C, Capron D, Thiefin G, Hillaire S, Di Martino V. Eradication of Hepatitis C Virus Infection in Patients With Cirrhosis Reduces Risk of Liver and Non-Liver Complications. Gastroenterology 2017; 152:142-156.e2. [PMID: 27641509 DOI: 10.1053/j.gastro.2016.09.009] [Citation(s) in RCA: 394] [Impact Index Per Article: 49.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 09/06/2016] [Accepted: 09/07/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We performed a prospective study to investigate the effects of a sustained viral response (SVR) on outcomes of patients with hepatitis C virus (HCV) infection and compensated cirrhosis. METHODS We collected data from 1323 patients included in the prospective Agence Nationale pour la Recherche sur le SIDA et les hépatites virales (ANRS) viral cirrhosis (CirVir) cohort, recruited from 35 clinical centers in France from 2006 through 2012. All patients had HCV infection and biopsy-proven cirrhosis, were Child-Pugh class A, and had no prior liver complications. All patients received anti-HCV treatment before or after inclusion (with interferon then with direct antiviral agents) and underwent an ultrasound examination every 6 months, as well as endoscopic evaluations. SVR was considered as a time-dependent covariate; its effect on outcome was assessed by the Cox proportional hazard regression method. We used a propensity score to minimize confounding by indication of treatment and capacity to achieve SVR. RESULTS After a median follow-up period of 58.2 months, 668 patients (50.5%) achieved SVR. SVR was associated with a decreased incidence of hepatocellular carcinoma (hazard ratio [HR] compared with patients without an SVR, 0.29; 95% confidence interval [CI], 0.19-0.43; P < .001) and hepatic decompensation (HR, 0.26; 95% CI, 0.17-0.39; P < .001). Patients with SVRs also had a lower risk of cardiovascular events (HR, 0.42; 95% CI, 0.25-0.69; P = .001) and bacterial infections (HR, 0.44; 95% CI, 0.29-0.68; P < .001). Metabolic features were associated with a higher risk of hepatocellular carcinoma in patients with SVRs, but not in patients with viremia. SVR affected overall mortality (HR, 0.27 compared with patients without SVR; 95% CI, 0.18-0.42; P < .001) and death from liver-related and non-liver-related causes. Similar results were obtained in a propensity score-matched population. CONCLUSIONS We confirmed a reduction in critical events, liver-related or not, in a prospective study of patients with HCV infection and compensated cirrhosis included in the CirVir cohort who achieved an SVR. We found an SVR to reduce overall mortality and risk of death from liver-related and non-liver-related causes. A longer follow-up evaluation is required to accurately describe and assess specific risk factors for complications in this population.
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Affiliation(s)
- Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France; Université Paris 13, Sorbonne Paris Cité, "Equipe Labellisée Ligue Contre le Cancer," Saint-Denis, France; Inserm, UMR-1162, "Génomique Fonctionnelle des Tumeur Solides," Paris, France.
| | - Valérie Bourcier
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France
| | - Richard Layese
- AP-HP, Hôpital Henri Mondor, Département de Santé Publique, and Université Paris-Est, Ageing-Thorax-Vessels-Blood Département Hospitalo-Universitaire, Clinical Epidemiology and Aging Unit, Université Paris-Est Créteil, Créteil, France
| | - Etienne Audureau
- AP-HP, Hôpital Henri Mondor, Département de Santé Publique, and Université Paris-Est, Ageing-Thorax-Vessels-Blood Département Hospitalo-Universitaire, Clinical Epidemiology and Aging Unit, Université Paris-Est Créteil, Créteil, France
| | - Carole Cagnot
- Unit for Basic and Clinical Research on Viral Hepatitis, Association Nationale pour la Recherche sur le SIDA et les hépatites virales (ANRS), France REcherche Nord and sud Sida-HIV Hépatites, Paris, France
| | | | - Dominique Guyader
- Centre Hospitalo-Universitaire Pontchaillou, Service d'Hépatologie, Rennes, France
| | | | | | | | - Denis Ouzan
- Institut Arnaud Tzanck, Service d'Hépatologie, St Laurent du Var, France
| | - Fabien Zoulim
- Hospices Civils de Lyon, Service d'Hépatologie et Université de Lyon, Lyon, France
| | | | - Albert Tran
- Centre Hospitalo-Universitaire de Nice, Service d'Hépatologie, Nice, France; Inserm U1065, C3M, Team 8, "Hepatic Complications in Obesity," Nice, France
| | - Jean-Pierre Bronowicki
- Inserm 954, Centre Hospitalo-Universitaire de Nancy, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | | | - Vincent Leroy
- Hôpital Michallon, Service d'Hépatologie, Grenoble, France
| | - Ghassan Riachi
- Hôpital Charles-Nicolle, Service d'Hépatologie, Rouen, France
| | - Paul Calès
- Centre Hospitalo-Universitaire d'Angers, Service d'Hépato-Gastroentérologie, Angers, France
| | | | - Laurent Alric
- Centre Hospitalo-Universitaire Toulouse, Service de Médecine Interne-Pôle Digestif UMR 152, Toulouse, France
| | - Marc Bourlière
- Hôpital Saint Joseph, Service d'Hépatologie, Marseille, France
| | | | | | | | - Armand Abergel
- Hôpital Hôtel Dieu, Service d'Hépatologie, Clermont-Ferrand, France
| | - Lawrence Serfaty
- AP-HP, Hôpital Saint-Antoine, Service d'Hépatologie, Paris, France
| | - Ariane Mallat
- AP-HP, Hôpital Henri Mondor, Service d'Hépatologie, Créteil, France
| | | | - Pierre Attali
- AP-HP, Hôpital Paul Brousse, Service d'Hépatologie, Villejuif, France
| | - Yannick Bacq
- Hôpital Trousseau, Unité d'Hépatologie, Centre Hospitalier Régional Universitaire de Tours, France
| | - Claire Wartelle
- Hôpital d'Aix-en-Provence, Service d'Hépatologie, Aix-En-Provence, France
| | - Thông Dao
- Hôpital de la Côte de Nacre, Service d'Hépatologie, Caen, France
| | - Yves Benhamou
- AP-HP, Groupe Hospitalier de La Pitié-Salpêtrière, Service d'Hépatologie, Paris, France
| | - Christophe Pilette
- Centre Hospitalo-Universitaire Le Mans, Service d'Hépatologie, Le Mans, France
| | - Christine Silvain
- Centre Hospitalo-Universitaire de Poitiers, Service d'Hépatologie, Poitiers, France
| | | | | | | | - David Zucman
- Hôpital Foch, Service de Médecine Interne, Suresnes, France
| | | | - Vincent Thibaut
- Centre Hospitalo-Universitaire Pontchaillou, Service de Virologie, Rennes, France
| | - Dominique Salmon
- AP-HP, Hôpital Cochin, Service de Maladies Infectieuses, Université Paris Descartes, Paris, France
| | - Marianne Ziol
- Université Paris 13, Sorbonne Paris Cité, "Equipe Labellisée Ligue Contre le Cancer," Saint-Denis, France; Inserm, UMR-1162, "Génomique Fonctionnelle des Tumeur Solides," Paris, France; AP-HP, Hôpital Jean Verdier, Service d'Anatomopathologie, Bondy, France; Centre de Ressources Biologiques (Liver Disease Biobank) Groupe Hospitalier Paris, Seine-Saint-Denis, France
| | - Angela Sutton
- Centre de Ressources Biologiques (Liver Disease Biobank) Groupe Hospitalier Paris, Seine-Saint-Denis, France; AP-HP, Hôpital Jean Verdier, Service de Biochimie, Bondy, France; Inserm U1148, Université Paris 13, Bobigny, France
| | - Stanislas Pol
- AP-HP, Hôpital Cochin, Département d'Hépatologie, France; Inserm UMS20 et U1223, Institut Pasteur, Université Paris Descartes, Paris, France
| | - Françoise Roudot-Thoraval
- AP-HP, Hôpital Henri Mondor, Département de Santé Publique, and Université Paris-Est, Ageing-Thorax-Vessels-Blood Département Hospitalo-Universitaire, Clinical Epidemiology and Aging Unit, Université Paris-Est Créteil, Créteil, France
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Immune-Inflammatory and Metabolic Effects of High Dose Furosemide plus Hypertonic Saline Solution (HSS) Treatment in Cirrhotic Subjects with Refractory Ascites. PLoS One 2016; 11:e0165443. [PMID: 27941973 PMCID: PMC5152809 DOI: 10.1371/journal.pone.0165443] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 10/07/2016] [Indexed: 02/08/2023] Open
Abstract
Introduction Patients with chronic liver diseases are usually thin as a result of hypermetabolism and malnutrition expressed by reduced levels of leptin and impairment of other adyponectins such as visfatin. Aims We evaluated the metabolic and inflammatory effects of intravenous high-dose furosemide plus hypertonic saline solutions (HSS) compared with repeated paracentesis and a standard oral diuretic schedule, in patients with cirrhosis and refractory ascites. Methods 59 consecutive cirrhotic patients with refractory ascites unresponsive to outpatient treatment. Enrolled subjects were randomized to treatment with intravenous infusion of furosemide (125–250mg⁄bid) plus small volumes of HSS from the first day after admission until 3 days before discharge (Group A, n:38), or repeated paracentesis from the first day after admission until 3 days before discharge (Group B, n: 21). Plasma levels of ANP, BNP, Leptin, visfatin, IL-1β, TNF-a, IL-6 were measured before and after the two type of treatment. Results Subjects in group A were observed to have a significant reduction of serum levels of TNF-α, IL-1β, IL-6, ANP, BNP, and visfatin, thus regarding primary efficacy endpoints, in Group A vs. Group B we observed higher Δ-TNF-α, Δ-IL-1β, Δ-IL-6, Δ-ANP, Δ-BNP, Δ-visfatin, Δ-Leptin at discharge. Discussion Our findings underline the possible inflammatory and metabolic effect of saline overload correction in treatment of cirrhosis complications such as refractory ascites, suggesting a possible role of inflammatory and metabolic-nutritional variables as severity markers in these patients.
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Kinoshita C, Nagano T, Seki N, Tomita Y, Sugita T, Aida Y, Itagaki M, Satoh K, Sutoh S, Abe H, Tsubota A, Aizawa Y. Hepatitis C virus G1b infection decreases the number of small low-density lipoprotein particles. World J Gastroenterol 2016; 22:6716-6725. [PMID: 27547014 PMCID: PMC4970482 DOI: 10.3748/wjg.v22.i29.6716] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 06/11/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate how hepatitis C virus (HCV) G1b infection influences the particle number of lipoproteins.
METHODS: The numbers of lipoprotein particles in fasting sera from 173 Japanese subjects, 82 with active HCV G1b infection (active HCV group) and 91 with cleared HCV infection (SVR group), were examined. Serum lipoprotein was fractionated by high-performance liquid chromatography into twenty fractions. The cholesterol and triglyceride concentrations in each fraction were measured using LipoSEARCH. The number of lipoprotein particles in each fraction was calculated using a newly developed algorithm, and the relationship between chronic HCV G1b infection and the lipoprotein particle number was determined by multiple linear regression analysis.
RESULTS: The median number of low-density lipoprotein (LDL) particles was significantly lower in the active HCV group [1182 nmol/L, interquartile range (IQR): 444 nmol/L] than in the SVR group (1363 nmol/L, IQR: 472 nmol/L, P < 0.001), as was that of high-density lipoprotein (HDL) particles (14168 nmol/L vs 15054 nmol/L, IQR: 4114 nmol/L vs 3385 nmol/L, P = 0.042). The number of very low-density lipoprotein (VLDL) particles was similar between the two groups. Among the four LDL sub-fractions, the number of large LDL particles was similar between the two groups. However, the numbers of medium (median: 533.0 nmol/L, IQR: 214.7 nmol/L vs median: 633.5 nmol/L, IQR: 229.6 nmol/L, P < 0.001), small (median: 190.9 nmol/L, IQR: 152.4 nmol/L vs median: 263.2 nmol/L, IQR: 159.9 nmol/L; P < 0.001), and very small LDL particles (median: 103.5 nmol/L, IQR: 66.8 nmol/L vs median: 139.3 nmol/L, IQR: 67.3 nmol/L, P < 0.001) were significantly lower in the active HCV group than in the SVR group, respectively. Multiple linear regression analysis indicated an association between HCV G1b infection and the decreased numbers of medium, small, and very small LDL particles. However, active HCV infection did not affect the number of large LDL particles or any sub-fractions of VLDL and HDL particles.
CONCLUSION: HCV G1b infection decreases the numbers of medium, small, and very small LDL particles.
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Sorenson A, Owens L, Caltabiano M, Cadet-James Y, Hall R, Govan B, Clancy P. The Impact of Prior Flavivirus Infections on the Development of Type 2 Diabetes Among the Indigenous Australians. Am J Trop Med Hyg 2016; 95:265-8. [PMID: 27001762 PMCID: PMC4973169 DOI: 10.4269/ajtmh.15-0727] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 02/22/2016] [Indexed: 12/21/2022] Open
Abstract
It is estimated that 5% of Australians over the age of 18 have diabetes, with the number of new cases increasing every year. Type 2 diabetes (T2D) also represents a significant disease burden in the Australian indigenous population, where prevalence is three times greater than that of non-indigenous Australians. Prevalence of T2D has been found to be higher in rural and remote indigenous Australian populations compared with urban indigenous Australian populations. Several studies have also found that body mass index and waist circumference are not appropriate for the prediction of T2D risk in indigenous Australians. Regional and remote areas of Australia are endemic for a variety of mosquito-borne flaviviruses. Studies that have investigated seroprevalence of flaviviruses in remote aboriginal communities have found high proportions of seroconversion. The family Flaviviridae comprises several genera of viruses with non-segmented single-stranded positive sense RNA genomes, and includes the flaviviruses and hepaciviruses. Hepatitis C virus (HCV) has been shown to be associated with insulin resistance and subsequent development of T2D. Flaviviruses and HCV possess conserved proteins and subgenomic RNA structures that may play similar roles in the development of insulin resistance. Although dietary and lifestyle factors are associated with increased risk of developing T2D, the impact of infectious diseases such as arboviruses has not been assessed. Flaviviruses circulating in indigenous Australian communities may play a significant role in inducing glucose intolerance and exacerbating T2D.
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Affiliation(s)
- Alanna Sorenson
- College of Public Health, Medical and Veterinary Sciences, James Cook University, Queensland, Australia.
| | - Leigh Owens
- College of Public Health, Medical and Veterinary Sciences, James Cook University, Queensland, Australia
| | - Marie Caltabiano
- College of Healthcare Sciences, James Cook University, Queensland, Australia
| | - Yvonne Cadet-James
- Anton Breinl Research Centre for Health Systems Strengthening, James Cook University, Queensland, Australia
| | - Roy Hall
- School of Chemistry and Molecular Biosciences, University of Queensland, Queensland, Australia
| | - Brenda Govan
- College of Public Health, Medical and Veterinary Sciences, James Cook University, Queensland, Australia
| | - Paula Clancy
- College of Public Health, Medical and Veterinary Sciences, James Cook University, Queensland, Australia
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Tseng CH, Hsu YC, Chang CY, Lin CW, Lin JT, Mo LR. Change in insulin resistance according to virological response during antiviral treatment for hepatitis C virus infection. ADVANCES IN DIGESTIVE MEDICINE 2016. [DOI: 10.1016/j.aidm.2014.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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