|
1
|
Rajewski P, Zarębska-Michaluk D, Janczewska E, Gietka A, Mazur W, Tudrujek-Zdunek M, Tomasiewicz K, Belica-Wdowik T, Baka-Ćwierz B, Dybowska D, Halota W, Lorenc B, Sitko M, Garlicki A, Berak H, Horban A, Orłowska I, Simon K, Socha Ł, Wawrzynowicz-Syczewska M, Jaroszewicz J, Deroń Z, Czauż-Andrzejuk A, Citko J, Krygier R, Piekarska A, Laurans Ł, Dobracki W, Białkowska J, Tronina O, Wietlicka-Piszcz M, Pawłowska M, Flisiak R. Hepatitis C Infection as a Risk Factor for Hypertension and Cardiovascular Diseases: An EpiTer Multicenter Study. J Clin Med 2022; 11:5193. [PMID: 36079122 PMCID: PMC9456581 DOI: 10.3390/jcm11175193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/17/2022] [Accepted: 08/29/2022] [Indexed: 11/21/2022] Open
Abstract
Hepatitis C infection is one of the main reasons for liver cirrhosis and hepatocellular carcinoma. In recent years, more and more is being heard about extrahepatic manifestations of the hepatitis C infection including its possible influence on the development of hypertension and cardiovascular diseases. In the given work, the frequency analysis of the incidence of hypertension and cardiovascular diseases among 2898 HCV-infected patients treated in Poland and the assessment of their relevance to the HCV genotype and the progression of liver fibrosis can be found. The prevalence of hypertension in the group of analyzed patients was 39% and was significantly associated with old age (OR = 1.08 (1.07-1.08)) and female sex, as well as the progression of liver fibrosis (OR = 1.54 (1.29-1.85)). Hypertension was found in 47.6% of patients with F4 fibrosis, 42.1% of patients with F3 fibrosis, and 25% of patients with F1 fibrosis. The incidence of cardiovascular disease in the studied group of patients was as follows: all incidents, 131 (4.52%); including ischemic heart disease 104, (3.95%); stroke, 2 (0.07%); atherosclerosis, 21 (0.72%); and aneurysms, 4 (0.14%). The obtained results prove that the prevalence of cardiovascular diseases is significantly associated with the advanced age of patients and the progression of liver fibrosis. The relevance of sex and the HCV genotype to the prevalence frequency of cardiovascular diseases in the study group has not been proven. This being the case, no differences in the frequency of their incidence depending on the HCV genotype, including genotype 3, was found. Hepatitis C infection as a non-classical risk factor for cardiovascular disease and hypertension does require further studying.
Collapse
Affiliation(s)
- Paweł Rajewski
- Department of Internal and Infectious Diseases, Provincial Infectious Disease Hospital, 85-030 Bydgoszcz, Poland
| | - Dorota Zarębska-Michaluk
- Department of Infectious Diseases, Voivodship Hospital and Jan Kochanowski University, 25-369 Kielce, Poland
| | - Ewa Janczewska
- Hepatology Outpatient Clinic, ID Clinic, 41-400 Mysłowice, Poland
| | - Andrzej Gietka
- Department of Internal Medicine and Hepatology, Central Clinical Hospital of the Ministry of Internal Affairs and Administration, 02-507 Warsaw, Poland
| | - Włodzimierz Mazur
- Clinical Department of Infectious Diseases, Specialist Hospital in Chorzów, Medical University of Silesia, 40-055 Katowice, Poland
| | - Magdalena Tudrujek-Zdunek
- Department of Infectious Diseases and Hepatology, Medical University of Lublin, 20-059 Lublin, Poland
| | - Krzysztof Tomasiewicz
- Department of Infectious Diseases and Hepatology, Medical University of Lublin, 20-059 Lublin, Poland
| | - Teresa Belica-Wdowik
- Regional Center for Diagnosis and Treatment of Viral Hepatitis and Hepatology, John Paul II Hospital, 31-202 Kraków, Poland
| | - Barbara Baka-Ćwierz
- Regional Center for Diagnosis and Treatment of Viral Hepatitis and Hepatology, John Paul II Hospital, 31-202 Kraków, Poland
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, 87-100 Toruń, Poland
| | - Waldemar Halota
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, 87-100 Toruń, Poland
| | - Beata Lorenc
- Pomeranian Center of Infectious Diseases, Department of Infectious Diseases, Medical University of Gdańsk, 80-210 Gdańsk, Poland
| | - Marek Sitko
- Department of Infectious and Tropical Diseases, Jagiellonian University Collegium Medicum, 30-252 Kraków, Poland
| | - Aleksander Garlicki
- Department of Infectious and Tropical Diseases, Jagiellonian University Collegium Medicum, 30-252 Kraków, Poland
| | - Hanna Berak
- Hospital for Infectious Diseases in Warsaw, 01-201 Warsaw, Poland
| | - Andrzej Horban
- Hospital for Infectious Diseases in Warsaw, 01-201 Warsaw, Poland
| | - Iwona Orłowska
- Department of Infectious Diseases and Hepatology, Wrocław Medical University, 50-367 Wrocław, Poland
| | - Krzysztof Simon
- Department of Infectious Diseases and Hepatology, Wrocław Medical University, 50-367 Wrocław, Poland
| | - Łukasz Socha
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, 70-204 Szczecin, Poland
| | - Marta Wawrzynowicz-Syczewska
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, 70-204 Szczecin, Poland
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases, Medical University of Silesia in Katowice, 41-902 Bytom, Poland
| | - Zbigniew Deroń
- Ward of Infectious Diseases and Hepatology, Biegański Regional Specialist Hospital, 91-347 Łódź, Poland
| | - Agnieszka Czauż-Andrzejuk
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, 15-089 Białystok, Poland
| | - Jolanta Citko
- Medical Practice of Infections, Regional Hospital, 10-561 Olsztyn, Poland
| | - Rafał Krygier
- Infectious Diseases and Hepatology Outpatient Clinic NZOZ “Gemini”, 62-571 Żychlin, Poland
| | - Anna Piekarska
- Department of Infectious Diseases and Hepatology, Medical University of Łódź, 90-419 Łódź, Poland
| | - Łukasz Laurans
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, 70-204 Szczecin, Poland
- Multidisciplinary Regional Hospital in Gorzów Wielkopolski, 66-400 Gorzów Wielkopolski, Poland
| | | | - Jolanta Białkowska
- Department of Infectious and Liver Diseases, Medical University of Łódź, 90-419 Łódź, Poland
| | - Olga Tronina
- Department of Transplantation Medicine, Nephrology, and Internal Diseases, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Magdalena Wietlicka-Piszcz
- Department of Theoretical Fundations of Biomedical Sciences and Medical Informatics, Nicolaus Copernicus University, 87-100 Toruń, Poland
| | - Małgorzata Pawłowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, 87-100 Toruń, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, 15-089 Białystok, Poland
| |
Collapse
|
|
2
|
Ciardullo S, Mantovani A, Ciaccio A, Carbone M, Invernizzi P, Perseghin G. Hepatitis C virus infection and diabetes: A complex bidirectional relationship. Diabetes Res Clin Pract 2022; 187:109870. [PMID: 35398458 DOI: 10.1016/j.diabres.2022.109870] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/22/2022] [Accepted: 04/04/2022] [Indexed: 11/03/2022]
Abstract
Chronic hepatitis C (CHC) and diabetes represent two severe chronic conditions responsible for a considerable number of deaths worldwide. They have a complex, bidirectional relationship. On the one hand, several cohort studies have shown that chronic HCV infection increases both the risk of developing diabetes in non-diabetic subjects (by inducing insulin resistance and promoting β-cell dysfunction) as well as the risk of developing macro and microvascular complications in patients with known diabetes; on the other hand, diabetes is an independent risk factor for liver-related events among patients with CHC, including a higher incidence of hepatocellular carcinoma, liver-related death and transplantation. Importantly, sustained virological response, which can be obtained in the vast majority of patients with the use of direct antiviral agents, does not only lead to a lower rate of liver-related outcomes, but also to improvements of glycemic control and reduction in the rate of complications among patients with diabetes. The aim of this review is to summarize available clinical evidence on the association among CHC, diabetes and related clinical outcomes. We will also briefly discuss the biological mechanisms underpinning the association between CHC and diabetes, as well as the implications this relationship should have on everyday clinical practice.
Collapse
Affiliation(s)
- Stefano Ciardullo
- Department of Medicine and Rehabilitation, Monza Policlinico di Monza, Monza, Italy; Department of Medicine and Surgery, University of Milan Bicocca, Monza, Italy.
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, University of Verona
| | - Antonio Ciaccio
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Gianluca Perseghin
- Department of Medicine and Rehabilitation, Monza Policlinico di Monza, Monza, Italy; Department of Medicine and Surgery, University of Milan Bicocca, Monza, Italy
| |
Collapse
|
|
3
|
HCV Genotype Has No Influence on the Incidence of Diabetes-EpiTer Multicentre Study. J Clin Med 2022; 11:jcm11020379. [PMID: 35054072 PMCID: PMC8780546 DOI: 10.3390/jcm11020379] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 12/30/2021] [Accepted: 01/05/2022] [Indexed: 12/17/2022] Open
Abstract
HCV infection is one of the main reasons for liver cirrhosis and hepatocellular carcinoma. In recent years, one finds more and more extrahepatic manifestations of HCV infection, including its possible influence on the development of diabetes. In the presented work, one finds the frequency analysis of the incidence of diabetes among 2898 HCV infected patients treated in Poland, and the assessment of their relevance to the HCV genotype and the progression of fibrosis. The results indicate that the hepatitis C infection seems to be a risk factor for diabetes in persons with more advanced liver fibrosis, for older people, and for the male gender. Thus, one found no differences regarding the frequency of its incidence depending on HCV genotype, including genotype 3.
Collapse
|
|
4
|
Ding Y, Li G, Zhou Z, Deng T. Molecular mechanisms underlying hepatitis C virus infection-related diabetes. Metabolism 2021; 121:154802. [PMID: 34090869 DOI: 10.1016/j.metabol.2021.154802] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/27/2021] [Accepted: 05/31/2021] [Indexed: 12/16/2022]
Abstract
Diabetes is a noncommunicable widespread disease that poses the risk of severe complications in patients, with certain complications being life-threatening. Hepatitis C is an infectious disease that mainly causes liver damage, which is also a profound threat to human health. Hepatitis C virus (HCV) infection has many extrahepatic manifestations, including diabetes. Multiple mechanisms facilitate the strong association between HCV and diabetes. HCV infection can affect the insulin signaling pathway in liver and pancreatic tissue and change the profiles of circulating microRNAs, which may further influence the occurrence and development of diabetes. This review describes how HCV infection causes diabetes and discusses the current research progress with respect to HCV infection-related diabetes.
Collapse
Affiliation(s)
- Yujin Ding
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Guangdi Li
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410011, Hunan, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Tuo Deng
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
| |
Collapse
|
|
5
|
Compagnoni S, Bruno EM, Madonia G, Cannizzaro M, Madonia S. Direct antiviral agents in hepatitis C virus related liver disease: Don't count the chickens before they're hatched. World J Gastroenterol 2021; 27:2771-2783. [PMID: 34135553 PMCID: PMC8173378 DOI: 10.3748/wjg.v27.i21.2771] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/26/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023] Open
Abstract
Since molecules with direct-acting antiviral (DAA) became available, the landscape of the treatment of hepatitis C virus (HCV) infection has completely changed. The new drugs are extremely effective in eradicating infection, and treatment is very well tolerated with a duration of 8-12 wk. This review aims to report the outstanding clinical benefits of DAA and to highlight their critical disadvantages, identifying some clinically relevant hot topics. First, do the rates of virological response remain as high when patients with more advanced cirrhosis are considered? Large studies have shown slightly lower but still satisfactory rates of response in these patients. Nevertheless, modified schedules with an extended treatment duration and use of ribavirin may be necessary. Second, does the treatment of HCV infection affect the risk of occurrence and recurrence of liver cancer? Incidence is reduced after viral eradication but remains high enough to warrant periodic surveillance for an early diagnosis. In contrast, the risk of recurrence seems to be unaffected by viral clearance; however, DAA treatment improves survival because of the reduced risk of progression of liver disease. Third, can HCV treatment also have favorable effects on major comorbidities? HCV eradication is associated with a reduced incidence of diabetes, an improvement in glycemic control and a decreased risk of cardiovascular events; nevertheless, a risk of hypoglycemia during DAA treatment has been reported. Finally, is it safe to treat patients with HCV/ hepatitis B virus (HBV) coinfection? In this setting, HCV is usually the main driver of viral activity, while HBV replication is suppressed. Because various studies have described HBV reactivation after HCV clearance, a baseline evaluation for HBV coinfection and a specific follow-up is mandatory.
Collapse
Affiliation(s)
- Stella Compagnoni
- Department of Internal Medicine, V. Cervello Hospital, University of Palermo, Palermo 90146, Italy
| | - Erica Maria Bruno
- Department of Internal Medicine, V. Cervello Hospital, University of Palermo, Palermo 90146, Italy
| | - Giorgio Madonia
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo 90127, Italy
| | - Marco Cannizzaro
- Department of Emergency Medicine, A. Ajello Hospital, Trapani 91026, Italy
| | - Salvatore Madonia
- Department of Internal Medicine, V. Cervello Hospital, Palermo 90146, Italy
| |
Collapse
|
|
6
|
Shengir M, Elgara M, Sebastiani G. Metabolic and cardiovascular complications after virological cure in hepatitis C: What awaits beyond. World J Gastroenterol 2021; 27:1959-1972. [PMID: 34007133 PMCID: PMC8108037 DOI: 10.3748/wjg.v27.i17.1959] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/06/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
The association between chronic hepatitis C (CHC) infection and extrahepatic manifestations (EHMs), particularly cardiometabolic diseases, has been extensively examined. However, there has still been insufficient evaluation for these EHMs after virological cure. Several multidirectional mechanisms have been proposed explaining the ability of hepatitis C virus (HCV) developing EHMs, cardiometabolic ones, as well as the effect of antiviral therapy to resolve these EHMs. Data on these manifestations after achieving sustained virologic response (SVR) are still conflicting. However, current evidence suggests that reversal of hepatic steatosis and its coexistent hypocholesterolemia after successful viral eradication led to unfavorable lipid profile, which increases cardiovascular disease (CVD) risk. Additionally, most observations showed that metabolic alterations, such as insulin resistance and diabetes mellitus (DM), undergo some degree of reduction after viral clearance. These changes seem HCV-genotype dependent. Interferon-based antiviral therapy and direct acting antiviral drugs were shown to minimize incidence of DM. Large epidemiological studies that investigated the effect of SVR on CVD showed great discrepancies in terms of results, with predominant findings indicating that CVD events decreased in patients with SVR compared to non-responders or untreated ones. In this review, we present a summary of the current knowledge regarding extrahepatic sequelae of CHC following SVR, which may have an impact on healthcare providers’ clinical practice.
Collapse
Affiliation(s)
- Mohamed Shengir
- Department of Medicine, McGill University, Montreal, Quebec H3A0G4, Canada
| | - Mohamed Elgara
- Department of Internal Medicine, Hamad Medical Corporation, Doha 3050, Qatar
| | - Giada Sebastiani
- Department of Medicine, McGill University Health Center, Montreal, Quebec H4A3J1, Canada
| |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Unraveling the Role of Leptin in Liver Function and Its Relationship with Liver Diseases. Int J Mol Sci 2020; 21:ijms21249368. [PMID: 33316927 PMCID: PMC7764544 DOI: 10.3390/ijms21249368] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/19/2020] [Accepted: 12/04/2020] [Indexed: 02/06/2023] Open
Abstract
Since its discovery twenty-five years ago, the fat-derived hormone leptin has provided a revolutionary framework for studying the physiological role of adipose tissue as an endocrine organ. Leptin exerts pleiotropic effects on many metabolic pathways and is tightly connected with the liver, the major player in systemic metabolism. As a consequence, understanding the metabolic and hormonal interplay between the liver and adipose tissue could provide us with new therapeutic targets for some chronic liver diseases, an increasing problem worldwide. In this review, we assess relevant literature regarding the main metabolic effects of leptin on the liver, by direct regulation or through the central nervous system (CNS). We draw special attention to the contribution of leptin to the non-alcoholic fatty liver disease (NAFLD) pathogenesis and its progression to more advanced stages of the disease as non-alcoholic steatohepatitis (NASH). Likewise, we describe the contribution of leptin to the liver regeneration process after partial hepatectomy, the mainstay of treatment for certain hepatic malignant tumors.
Collapse
|
|
9
|
Chang ML, Yang Z, Yang SS. Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression. Int J Mol Sci 2020; 21:E8308. [PMID: 33167521 PMCID: PMC7663948 DOI: 10.3390/ijms21218308] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 10/30/2020] [Accepted: 11/01/2020] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett's esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.
Collapse
Affiliation(s)
- Ming-Ling Chang
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Zinger Yang
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA;
| | - Sien-Sing Yang
- Liver Center, Cathay General Hospital Medical Center, Taipei 10630, Taiwan;
| |
Collapse
|
|
10
|
Wang CC, Cheng PN, Kao JH. Systematic review: chronic viral hepatitis and metabolic derangement. Aliment Pharmacol Ther 2020; 51:216-230. [PMID: 31746482 DOI: 10.1111/apt.15575] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 08/08/2019] [Accepted: 10/17/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND The liver has a critical role in the metabolism of glucose and lipids. Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection leads to a spectrum of liver disease including chronic hepatitis, cirrhosis and hepatocellular carcinoma. Metabolic syndrome (MetS) has a rising incidence owing to an epidemic of type 2 diabetes mellitus (T2DM) and obesity. Non-alcoholic fatty liver disease is a liver manifestation of MetS and has become the most common cause of chronic liver disease worldwide. AIM To summarise the interplay among hepatitis viruses, MetS and its components. METHODS We searched the literature about HBV, HCV infection, MetS, fatty liver and its components from PubMed. RESULTS With respect to the viral replication cycle, lipids are important mediators between viral entry and hepatocyte in HCV infection, but not in HBV infection. Thus, HCV infection is inversely associated with hyperlipidaemia and lipid rebound occurs following sustained viral response induced by interferon-based therapy or direct antiviral agents. In addition, HCV infection is positively associated with insulin resistance, hepatic steatosis, MetS and the risk of T2DM and atherosclerosis. In contrast, HBV infection may protect infected subjects from the development of MetS and hepatic steatosis. Accumulating evidence suggests that HBV infection is inversely associated with lipid metabolism, and exhibits no conclusive association with insulin resistance or the risk of T2DM and arteriosclerosis. CONCLUSIONS In patients with viral hepatitis and concurrent metabolic diseases, a multidisciplinary approach should be given rather than simply antiviral treatment.
Collapse
Affiliation(s)
- Chia-Chi Wang
- Department of Gastroenterology and Hepatology, Buddhist Tzu Chi Medical Foundation and School of Medicine, Taipei Tzu Chi Hospital, Tzu Chi University, Hualien, Taiwan
| | - Pin-Nan Cheng
- Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, Department of Medical Research and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| |
Collapse
|
|
11
|
Babiker A, Hassan M, Muhammed S, Taylor G, Poonia B, Shah A, Bagchi S. Inflammatory and cardiovascular diseases biomarkers in chronic hepatitis C virus infection: A review. Clin Cardiol 2019; 43:222-234. [PMID: 31785111 PMCID: PMC7068107 DOI: 10.1002/clc.23299] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/09/2019] [Accepted: 11/12/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infects 180 million people worldwide and over 4 million people in the United States. HCV infection is a major cause of chronic liver disease and is recognized as a risk factor for clinical cardiovascular disease (CVD). Many studies have shown increased prevalence of cardiac and inflammatory biomarkers in patients with chronic HCV infection (CHC), and though these markers may be used to risk stratify people for cardiac disease in the general population their role in the HCV population is unknown. Patients with CHC have elevated cardiac and inflammatory biomarkers compared to noninfected controls which may play a role in CVD risk stratification. We undertook a systematic review of inflammatory and cardiac biomarkers in people with HCV infection with a focus on the effect of CHC on serum levels of these markers and their utility as predictors of CVD in this population. Medline, EMBASE, and Cochrane databases were searched for relevant articles until June 2019. A total of 2430 results were reviewed with 115 studies included. Our review revealed that HCV infection significantly alters serum levels of markers of inflammation, endothelial function, and cardiac dysfunction prior to HCV treatment, and some of which may change in response to HCV therapy. Current risk stratification tools for development of CVD in the general population may not account for the increased inflammatory markers that appear to be elevated among HCV‐infected patients contributing to increased CVD risk.
Collapse
Affiliation(s)
- Ahmed Babiker
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Mohamed Hassan
- Division of General Internal Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Safwan Muhammed
- Department of Medicine, University of Maryland Medical Center, Baltimore, Maryland.,Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Gregory Taylor
- Department of Family Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Bhawna Poonia
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Anoop Shah
- Division of Cardiology, University of Edinburgh, Little France, Edinburgh
| | - Shashwatee Bagchi
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.,Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
12
|
Zhao L, Zheng Q, Zou Y, Wang Y, Wu Y, Liu X. Chitooligosaccharide Biguanidine Alleviates Liver Injury and Insulin Resistance in Type 2 Diabetic Rats. STARCH-STARKE 2019. [DOI: 10.1002/star.201900203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Liyan Zhao
- School of Material Science and EngineeringTianjin Key Laboratory of Composite and Functional MaterialsTianjin University Tianjin 300350 China
| | - Qifang Zheng
- School of Material Science and EngineeringTianjin Key Laboratory of Composite and Functional MaterialsTianjin University Tianjin 300350 China
| | - Yalu Zou
- School of Material Science and EngineeringTianjin Key Laboratory of Composite and Functional MaterialsTianjin University Tianjin 300350 China
| | - Yuanyuan Wang
- School of Material Science and EngineeringTianjin Key Laboratory of Composite and Functional MaterialsTianjin University Tianjin 300350 China
| | - Yuntang Wu
- Department of Nutrition and Food ScienceSchool of Public HealthTianjin Medical University Tianjin 300070 China
| | - Xiaofei Liu
- School of Material Science and EngineeringTianjin Key Laboratory of Composite and Functional MaterialsTianjin University Tianjin 300350 China
| |
Collapse
|
|
13
|
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.
Collapse
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
| |
Collapse
|
|
14
|
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] [MESH Headings] [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.
Collapse
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
| |
Collapse
|
|
15
|
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.
Collapse
Affiliation(s)
- Adit Singhal
- Geisinger Commonwealth School of Medicine, Scranton, PA, USA
| | | | - Jun Ling
- Geisinger Commonwealth School of Medicine, Scranton, PA, USA
| |
Collapse
|
|
16
|
Chang ML, Kuo CJ, Pao LH, Hsu CM, Chiu CT. The evolving relationship between adiponectin and insulin sensitivity in hepatitis C patients during viral clearance. Virulence 2017; 8:1255-1264. [PMID: 28267407 PMCID: PMC5711434 DOI: 10.1080/21505594.2017.1300734] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 02/04/2017] [Accepted: 02/24/2017] [Indexed: 02/09/2023] Open
Abstract
BACKGROUND The evolution of the relationship between adiponectin and insulin sensitivity in hepatitis C virus (HCV) patients during viral clearance is unclear and warrants investigation. METHODS A prospective study including 747 consecutive chronic hepatitis C (CHC) patients, of whom 546 had completed a course of anti-HCV therapy and underwent pre-, peri- and post-therapy surveys for anthropomorphic, viral, metabolic and hepatic profiles and adiponectin levels, was conducted in a tertiary care center. RESULTS Multivariate analyses indicated associations of sex, triglyceride levels and hepatic steatosis with adiponectin levels and of triglyceride levels and interferon λ3 (IFNL3) genotype with homeostasis model assessment-estimated insulin resistance (HOMA-IR) levels before anti-HCV therapy. In patients with a sustained virological response (SVR; n = 455), at 24 weeks post-therapy, sex, BMI, aspartate aminotransferase to platelet ratio index (APRI), HOMA-IR and steatosis were associated with adiponectin levels, and IFNL3 genotype was associated with HOMA-IR levels. GEE analysis demonstrated that SVR affected longitudinal trends in adiponectin levels. Compared with pre-therapy levels, adiponectin and APRI levels decreased 24 weeks post-therapy in SVR patients, regardless of baseline insulin resistance (IR). However, HOMA-IR levels decreased in SVR patients with baseline IR but increased in those without baseline IR. Compared with controls, immunohistochemical studies showed that pre-therapy CHC patients had higher hepatic adiponectin expression associated with hepatic fibrosis. CONCLUSIONS During HCV infection, adiponectin may affect insulin sensitivity through triglycerides. After viral clearance, adiponectin levels were directly associated with insulin sensitivity and decreased upon improved hepatic fibrosis; with a link to the IFNL3 genotype, insulin sensitivity improved only in patients with baseline IR.
Collapse
Affiliation(s)
- Ming-Ling Chang
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Jung Kuo
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Li-Heng Pao
- Graduate Institute of Health-Industry Technology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
- Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Chen-Ming Hsu
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Cheng-Tang Chiu
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| |
Collapse
|
|
17
|
Higher CD163 levels are associated with insulin resistance in hepatitis C virus-infected and HIV-infected adults. AIDS 2017; 31:385-393. [PMID: 28081037 DOI: 10.1097/qad.0000000000001345] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES HIV/hepatitis C virus (HCV) coinfection is associated with insulin resistance, but the mechanism is unclear. We hypothesized that intestinal epithelial damage and the consequent monocyte/macrophage activation and inflammation explain this perturbation. DESIGN Cross-sectional study of 519 adults (220 HIV+/HCV-; 64 HIV-/HCV+; 89 HIV+/HCV+; 146 HIV-/HCV-). METHODS We used multivariable linear regression to evaluate associations of HIV and HCV with the homeostasis model assessment of insulin resistance (HOMA-IR) and if intestinal fatty (FA) acid binding protein (I-FABP, a marker of gut epithelial integrity), soluble CD14 (sCD14) and soluble CD163 (sCD163) (markers of monocyte/macrophage activation), and IL-6 (an inflammatory cytokine) mediated this association. RESULTS HIV+/HCV+ and HIV-/HCV+ had greater demographic-adjusted HOMA-IR [mean (95% confidence interval (CI)): 1.96 (1.51, 2.54) and 1.65 (1.22, 2.24)] than HIV+/HCV- and HIV-/HCV-[1.41 (1.18, 1.67) and 1.44 (1.17, 1.75), respectively]. After additional adjustment for lifestyle and metabolic factors, HIV+/HCV+ remained associated with 36% (95% CI: 4, 80%) greater HOMA-IR relative to HIV-/HCV-, whereas HIV-/HCV+ and HIV+/HCV- had smaller differences. Adjustment for sCD163 substantially attenuated the difference between HIV+/HCV+ and HIV-/HCV-; adjustment for I-FABP, sCD14, and IL-6 had little effect. Higher sCD163 was independently associated with 19% (95% CI: 7, 33%), 26% (95% CI: 15, 39%), 25% (95% CI: 14, 37%), and 23% (95% CI: 11, 36%) greater HOMA-IR in HIV+/HCV+, HIV-/HCV+, HIV+/HCV-, and HIV-/HCV- (all estimates per doubling of sCD163). I-FABP, sCD14, and IL-6 were not associated with HOMA-IR. CONCLUSION HIV/HCV coinfection is associated with greater HOMA-IR, even after controlling for demographic, lifestyle, and metabolic factors. sCD163, which appears independent of intestinal epithelial damage and inflammation, partly explains this association. Our findings that the association of sCD163 with HOMA-IR occurred even in the absence of HIV and HCV, indicate that viral and nonviral factors affect sCD163 levels. Its role in insulin resistance needs elucidation.
Collapse
|
|
18
|
Chang ML, Kuo CJ, Huang HC, Chu YY, Chiu CT. Association between Leptin and Complement in Hepatitis C Patients with Viral Clearance: Homeostasis of Metabolism and Immunity. PLoS One 2016; 11:e0166712. [PMID: 27870883 PMCID: PMC5117713 DOI: 10.1371/journal.pone.0166712] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Accepted: 11/02/2016] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The association between leptin and complement in hepatitis C virus (HCV) infection remains unknown. METHODS A prospective study was conducted including 474 (250 genotype 1, 224 genotype 2) consecutive chronic hepatitis C (CHC) patients who had completed an anti-HCV therapy course and undergone pre-therapy and 24-week post-therapy assessments of interferon λ3-rs12979860 and HCV RNA/genotypes, anthropometric measurements, metabolic and liver profiles, and complement component 3 (C3), C4, and leptin levels. RESULTS Of the 474 patients, 395 had a sustained virological response (SVR). Pre-therapy leptin levels did not differ between patients with and without an SVR. Univariate and multivariate analyses showed that sex (pre- and post-therapy, p<0.001), body mass index (BMI) (pre- and post-therapy, p<0.001), and C3 levels (pre-therapy, p = 0.027; post-therapy, p = 0.02) were independently associated with leptin levels with or without HCV infection. Pre-therapy BMI, total cholesterol (TC), C4 levels, and the rs12979860 genotype were independently associated with pre-therapy C3 levels in all patients. Post-therapy BMI, alanine aminotransferase, TC, C4 levels, white blood cell counts, and hepatic steatosis were independently associated with the post-therapy C3 levels of SVR patients. Compared with pre-therapy levels, SVR patients showed higher 24-week post-therapy C4 (20.32+/-7.30 vs. 21.55+/-7.07 mg/dL, p<0.001) and TC (171.68+/-32.67 vs. 186.97+/-36.09 mg/dL, p<0.001) levels; however, leptin and C3 levels remained unchanged after therapy in patients with and without an SVR. CONCLUSIONS Leptin and C3 may maintain immune and metabolic homeostasis through association with C4 and TC. Positive alterations in C4 and TC levels reflect viral clearance after therapy in CHC patients.
Collapse
Affiliation(s)
- Ming-Ling Chang
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Jung Kuo
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Hsin-Chih Huang
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yin-Yi Chu
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Cheng-Tang Chiu
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| |
Collapse
|
|
19
|
Pateria P, Jeffrey GP, MacQuillan G, Speers D, Ching H, Chinnaratha MA, Watts GF, Adams LA. The association between chronic hepatitis C infection and cardiovascular risk. Intern Med J 2016; 46:63-70. [PMID: 26477784 DOI: 10.1111/imj.12936] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 09/29/2015] [Accepted: 10/10/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Vascular disease is a common cause of death in patients with chronic hepatitis C (CHC) infection; however, the association between CHC and atherosclerosis is unclear. AIMS To determine whether patients with CHC have increased subclinical vascular disease and whether genotype or antiviral treatment modifies this risk. METHODS Fifty CHC patients and 22 age-matched and sex-matched healthy controls underwent clinical and biochemical assessment for vascular risk factors. In addition, vascular risk was assessed by measuring arterial stiffness (aortic augmentation index and carotid-femoral pulse wave velocity (PWV)), endothelial dysfunction (brachial artery flow-mediated dilatation (FMD) and dilatation post-glycerol trinitrate administration) and carotid intima-media thickness (CIMT). Assessment was repeated in subset of CHC patients (n = 12) undergoing antiviral treatment 18 months after initiation of treatment. RESULTS Baseline vascular risk factors and measures of arterial stiffness, endothelial dysfunction and CIMT were not different between cases and controls (P > 0.2 for all). Genotype 1 CHC patients had greater endothelial dysfunction with lower FMD (8.2 ± 3.5% vs 10.9 ± 5.2%, P = 0.03) and higher right CIMT (0.6 ± 0.1 mm vs 0.5 ± 0.07 mm, P = 0.04) compared with non-genotype 1. Patients who achieved sustained virological response (7/12) showed significant improvement in insulin resistance (homeostasis model of assessment of insulin resistance 2.3 ± 1.2 vs 1.8 ± 0.8, P = 0.02) and arterial stiffness (PWV 7.4 ± 1.1 m/s vs 6.5 ± 0.6 m/s, P = 0.04). CONCLUSIONS Subclinical vascular disease is not greater in CHC subjects compared with controls. However, among CHC subjects, genotype 1 infection is associated with greater endothelial dysfunction and increased carotid-intima medial thickness compared with non-genotype 1 infection. Successful viral eradication may improve insulin resistance and arterial stiffness.
Collapse
Affiliation(s)
- P Pateria
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital
| | - G P Jeffrey
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital.,School of Medicine and Pharmacology, University of Western Australia
| | - G MacQuillan
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital.,School of Medicine and Pharmacology, University of Western Australia
| | - D Speers
- PathWest Laboratory Medicine WA, Queen Elizabeth II Medical Centre
| | - H Ching
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital.,School of Medicine and Pharmacology, University of Western Australia
| | - M A Chinnaratha
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital
| | - G F Watts
- School of Medicine and Pharmacology, University of Western Australia.,Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia
| | - L A Adams
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital.,School of Medicine and Pharmacology, University of Western Australia
| |
Collapse
|
|
20
|
Thabet K, Asimakopoulos A, Shojaei M, Romero-Gomez M, Mangia A, Irving WL, Berg T, Dore GJ, Grønbæk H, Sheridan D, Abate ML, Bugianesi E, Weltman M, Mollison L, Cheng W, Riordan S, Fischer J, Spengler U, Nattermann J, Wahid A, Rojas A, White R, Douglas MW, McLeod D, Powell E, Liddle C, van der Poorten D, George J, Eslam M. MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C. Nat Commun 2016; 7:12757. [PMID: 27630043 PMCID: PMC5027609 DOI: 10.1038/ncomms12757] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 07/29/2016] [Indexed: 02/08/2023] Open
Abstract
Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibrosis progression. At functional level, rs641738 associated with MBOAT7 transcript and protein levels in liver and blood, and with serum inflammatory, oxidative stress and macrophage activation markers. MBOAT7 was expressed in immune cell subsets, implying a role in hepatic inflammation. We conclude that the MBOAT7 rs641738 polymorphism is a novel risk variant for liver inflammation in hepatitis C, and thereby for liver fibrosis.
Collapse
Affiliation(s)
- Khaled Thabet
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 6111, Egypt
| | - Anastasia Asimakopoulos
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Maryam Shojaei
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, New South Wales 2145, Australia
- Nepean Genomic Research Group, ICU, Nepean Hospital, Kingswood, New South Wales 2747, Australia
| | - Manuel Romero-Gomez
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, 41014 Sevilla, Spain
| | - Alessandra Mangia
- Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, 71013 San Giovanni Rotondo, Italy
| | - William L. Irving
- NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham NG7 2UH, UK
| | - Thomas Berg
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, 04103 Leipzig, Germany
| | - Gregory J. Dore
- Kirby Institute, The University of New South Wales, Sydney, New South Wales 2052, Australia
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8000 Aarhus, Denmark
| | - David Sheridan
- Institute of Translational and Stratified Medicine, Plymouth University, Plymouth PL4 8AA, UK
| | - Maria Lorena Abate
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, 10126 Turin, Italy
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, 10126 Turin, Italy
| | - Martin Weltman
- Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, New South Wales 2747, Australia
| | - Lindsay Mollison
- Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, Western Australia 6160, Australia
| | - Wendy Cheng
- Department of Gastroenterology and Hepatology, Royal Perth Hospital, Western Australia 6000, Australia
| | - Stephen Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, New South Wales 2031, Australia
| | - Janett Fischer
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, 04103 Leipzig, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, 53105 Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, 53105 Bonn, Germany
| | - Ahmed Wahid
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 6111, Egypt
| | - Angela Rojas
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, 41014 Sevilla, Spain
| | - Rose White
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Mark W. Douglas
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
- Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia
| | - Duncan McLeod
- Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, New South Wales 2145, Australia
| | - Elizabeth Powell
- Princess Alexandra Hospital, School of Medicine, The University of Queensland, Woolloongabba, Queensland 4102, Australia
| | - Christopher Liddle
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - David van der Poorten
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| |
Collapse
|
|
21
|
Gong L, Liu J, Wang J, Lou GQ, Shi JP. Hepatic Steatosis as a Predictive Factor of Antiviral Effect of Pegylated Interferon Therapy in Patients With Hepatitis B. Transplant Proc 2016; 47:2886-91. [PMID: 26707308 DOI: 10.1016/j.transproceed.2015.10.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 10/08/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS This study sought to evaluate the impact of hepatic steatosis, a common hepatocyte change in nonalcoholic fatty liver disease, upon response to pegylated interferon (PEG-IFN) therapy in patients with chronic hepatitis B (CHB). METHODS Eighty-nine consecutive CHB patients from the Affiliated Hospital of Hangzhou Normal University receiving 48 weeks of PEG-IFN therapy were enrolled in this study, and 56 patients were followed up for 48 weeks among subjects with completed therapy. Baseline characteristics, end-of-treatment response (ETR), and sustained viral response (SVR) to PEG-IFN therapy were evaluated. Univariate analysis and multivariate logistic regression were applied to find independent factors of hepatic steatosis and PEG-IFN treatment failure. RESULTS Steatosis was present in 34.5% (31 of 89) of liver biopsy samples. ETR to PEG-IFN therapy was 56.17% (50 of 89) at 48 weeks, and SVR to PEG-IFN therapy was 57.6% (32 of 56) at 96 weeks. There was no significant difference in ETR between the patients with hepatic steatosis and those without hepatic steatosis at 48 weeks (P > .05), whereas SVR was higher in patients without hepatic steatosis than in those with hepatic steatosis at 96 weeks (P < .05). Multivariate analysis showed that the sustained response rate was independently associated with steatosis, fibrosis, aspartate aminotransferase, C-reactive protein, and ferritin. Hepatic steatosis was a prediction factor with the sustained response. CONCLUSIONS Hepatic steatosis may be a predictive factor of response to PEG-IFN therapy in patients with CHB.
Collapse
Affiliation(s)
- L Gong
- Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, China
| | - J Liu
- Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, China
| | - J Wang
- Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, China
| | - G Q Lou
- Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, China
| | - J P Shi
- Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, China.
| |
Collapse
|
|
22
|
Petta S. Hepatitis C virus and cardiovascular: A review. J Adv Res 2016; 8:161-168. [PMID: 28149651 PMCID: PMC5272956 DOI: 10.1016/j.jare.2016.06.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 06/05/2016] [Accepted: 06/11/2016] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a systemic disease that leads to increased risks of cirrhosis and its complications, as well as extrahepatic disturbances, including immune-related disorders and metabolic alterations such as insulin resistance and steatosis. Recent accumulating evidence suggests that HCV infection can increase cardiovascular risk, and that viral eradication can improve cardiovascular outcomes in the clinical setting. These data are strengthened by evidence identifying potential mechanisms (in)directly linking HCV infection to vascular damage. However, the high prevalence of both HCV infection and cardiovascular alterations, as well as the presence of contrasting results not identifying any association between HCV infection and cardiovascular dysfunction, provides uncertainty about a direct association of HCV infection with cardiovascular risk. Further studies are needed to clarify definitively the role of HCV infection in cardiovascular alterations, as well as the impact of viral eradication on cardiovascular outcomes. These features are now more attractive, considering the availability of new, safe, and very effective interferon-free antiviral agents for the treatment of HCV infection. This review aims to discuss carefully available data on the relationship between HCV infection and cardiovascular risk.
Collapse
Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia, Dipartimento Biomedico di Medicina Interna e Specialistica, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| |
Collapse
|
|
23
|
Kralj D, Jukić LV, Stojsavljević S, Duvnjak M, Smolić M, Čurčić IB. Hepatitis C Virus, Insulin Resistance, and Steatosis. J Clin Transl Hepatol 2016; 4:66-75. [PMID: 27047774 PMCID: PMC4807145 DOI: 10.14218/jcth.2015.00051] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 02/15/2016] [Accepted: 02/16/2016] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide. Liver steatosis is a common finding in many hepatic and extrahepatic disorders, the most common being metabolic syndrome (MS). Over time, it has been shown that the frequent coexistence of these two conditions is not coincidental, since many epidemiological, clinical, and experimental studies have indicated HCV to be strongly associated with liver steatosis and numerous metabolic derangements. Here, we present an overview of publications that provide clinical evidence of the metabolic effects of HCV and summarize the available data on the pathogenetic mechanisms of this association. It has been shown that HCV infection can induce insulin resistance (IR) in the liver and peripheral tissues through multiple mechanisms. Substantial research has suggested that HCV interferes with insulin signaling both directly and indirectly, inducing the production of several proinflammatory cytokines. HCV replication, assembly, and release from hepatocytes require close interactions with lipid droplets and host lipoproteins. This modulation of lipid metabolism in host cells can induce hepatic steatosis, which is more pronounced in patients with HCV genotype 3. The risk of steatosis depends on several viral factors (including genotype, viral load, and gene mutations) and host features (visceral obesity, type 2 diabetes mellitus, genetic predisposition, medication use, and alcohol consumption). HCV-related IR and steatosis have been shown to have a remarkable clinical impact on the prognosis of HCV infection and quality of life, due to their association with resistance to antiviral therapy, progression of hepatic fibrosis, and development of hepatocellular carcinoma. Finally, HCV-induced IR, oxidative stress, and changes in lipid and iron metabolism lead to glucose intolerance, arterial hypertension, hyperuricemia, and atherosclerosis, resulting in increased cardiovascular mortality.
Collapse
Affiliation(s)
- Dominik Kralj
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Lucija Virović Jukić
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Sanja Stojsavljević
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Marko Duvnjak
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Martina Smolić
- Department of Pharmacology, Faculty of Medicine, University of Osijek, Osijek, Croatia
| | - Ines Bilić Čurčić
- Department of Pharmacology, Faculty of Medicine, University of Osijek, Department of Endocrinology and metabolism disorders, University Hospital Center, Osijek, Osijek, Croatia
| |
Collapse
|
|
24
|
Vanni E, Bugianesi E, Saracco G. Treatment of type 2 diabetes mellitus by viral eradication in chronic hepatitis C: Myth or reality? Dig Liver Dis 2016; 48:105-11. [PMID: 26614641 DOI: 10.1016/j.dld.2015.10.016] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 10/05/2015] [Accepted: 10/16/2015] [Indexed: 12/15/2022]
Abstract
Chronic hepatitis C is a systemic disease inducing metabolic alterations leading to extrahepatic consequences. In particular, hepatitis C virus (HCV) infection seems to increase the risk of incident type 2 diabetes mellitus in predisposed individuals, independently of liver disease stage. The mechanisms through which hepatitis C induces T2DM involve direct viral effects, insulin resistance, pro-inflammatory cytokines and other immune-mediated processes. Many studies have reported the clinical consequences of type 2 diabetes mellitus on hepatitis C outcome, but very few studies have addressed the issue of microangiopathic complications among patients with hepatitis C only, who develop type 2 diabetes mellitus. Moreover, clinical trials in HCV-positive patients have reported improvement in glucose metabolism after antiviral treatment; recent studies have suggested that this metabolic amelioration might have a clinical impact on type 2 diabetes mellitus-related complications. These observations raise the question as to whether the HCV eradication may also have an impact on the future morbidity and mortality due to type 2 diabetes mellitus. The scope of this review is to summarise the current evidence linking successful antiviral treatment and the prevention of type 2 diabetes mellitus and its complications in hepatitis C-infected patients.
Collapse
Affiliation(s)
- Ester Vanni
- Gastro-hepatology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Elisabetta Bugianesi
- Gastro-hepatology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giorgio Saracco
- Gastroenterology Unit, Oncology Department, University of Turin, Italy.
| |
Collapse
|
|
25
|
González-Reimers E, López-Prieto J, Quintero-Platt G, Pelazas-González R, Alemán-Valls MR, Pérez-Hernández O, de-la-Vega-Prieto MJ, Gómez-Rodríguez MA, Martín-González C, Santolaria-Fernández F. Adipokines, cytokines and body fat stores in hepatitis C virus liver steatosis. World J Hepatol 2016; 8:74-82. [PMID: 26783423 PMCID: PMC4705455 DOI: 10.4254/wjh.v8.i1.74] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify patients with or without liver steatosis and its severity in treatment-naïve patients affected by hepatitis C virus (HCV) infection.
METHODS: We included 56 HCV infected patients, and assessed the amount of liver fat by histomorphometry, and its relationships with fat and lean mass at different parts of the body (by densitometry), hormones [insulin, homeostatic model assessment (HOMA)], adipokines (resistin, adiponectin, leptin), and cytokines (tumor necrosis factor α, interleukin-6).
RESULTS: Although the intensity of liver steatosis is related to trunk fat mass and HOMA, 33% of patients showed no liver steatosis, and this finding was not related to body mass index or genotype. Besides trunk fat mass, no other factor was related to the presence or not of liver steatosis, or to the intensity of it, by multivariate analysis. Lean mass was not related to liver steatosis. Adiponectin levels were lower among patients. No differences were observed in leptin and resistin.
CONCLUSION: Steatosis in HCV infection is common (67.2%), and closely related to trunk fat, and insulin resistance, but not with leg fat mass or adipokines.
Collapse
|
|
26
|
González-Reimers E, Quintero-Platt G, Rodríguez-Gaspar M, Alemán-Valls R, Pérez-Hernández O, Santolaria-Fernández F. Liver steatosis in hepatitis C patients. World J Hepatol 2015; 7:1337-1346. [PMID: 26052379 PMCID: PMC4450197 DOI: 10.4254/wjh.v7.i10.1337] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 01/31/2015] [Accepted: 03/09/2015] [Indexed: 02/06/2023] Open
Abstract
There is controversy regarding some aspects of hepatitis C virus (HCV) infection-associated liver steatosis, and their relationship with body fat stores. It has classically been found that HCV, especially genotype 3, exerts direct metabolic effects which lead to liver steatosis. This supports the existence of a so called viral steatosis and a metabolic steatosis, which would affect HCV patients who are also obese or diabetics. In fact, several genotypes exert metabolic effects which overlap with some of those observed in the metabolic syndrome. In this review we will analyse the pathogenic pathways involved in the development of steatosis in HCV patients. Several cytokines and adipokines also become activated and are involved in “pure” steatosic effects, in addition to inflammation. They are probably responsible for the evolution of simple steatosis to steatohepatitis, making it difficult to explain why such alterations only affect a proportion of steatosic patients.
Collapse
|
|
27
|
Kukla M, Piotrowski D, Waluga M, Hartleb M. Insulin resistance and its consequences in chronic hepatitis C. Clin Exp Hepatol 2015; 1:17-29. [PMID: 28856251 PMCID: PMC5421163 DOI: 10.5114/ceh.2015.51375] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 03/10/2015] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Hepatitis C virus (HCV) may contribute to a broad spectrum of metabolic disturbances - namely, steatosis, insulin resistance (IR), increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus (T2DM), lipid metabolism abnormalities and atherosclerosis. HCV can directly or indirectly cause both IR and steatosis, but it is still not resolved whether this viral impact bears the same prognostic value as the metabolic counterparts. As the population exposed to HCV ages, the morbidity due to this disease is increasing. The rising epidemic of obesity contributes to higher prevalence of IR and T2DM. Our understanding of the mutual association between both disease states continues to grow, but is still far from complete. This review briefly discusses the most probable mechanisms involved in IR development in the course of CHC. Molecular mechanisms for the direct and indirect influence of HCV on intracellular insulin signaling are described. Subsequently, the consequences of IR/T2DM for disease progression and management are summarized.
Collapse
Affiliation(s)
- Michał Kukla
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Damian Piotrowski
- Department of Infectious Diseases in Bytom, Medical University of Silesia in Katowice, Poland
| | - Marek Waluga
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Marek Hartleb
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| |
Collapse
|
|
28
|
Metformin suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-+Leprdb/+Leprdb mice. PLoS One 2015; 10:e0124081. [PMID: 25879666 PMCID: PMC4399835 DOI: 10.1371/journal.pone.0124081] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 03/03/2015] [Indexed: 12/22/2022] Open
Abstract
Obesity and related metabolic disorders, such as diabetes mellitus, raise the risk of liver carcinogenesis. Metformin, which is widely used in the treatment of diabetes, ameliorates insulin sensitivity. Metformin is also thought to have antineoplastic activities and to reduce cancer risk. The present study examined the preventive effect of metformin on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb (db/db) obese and diabetic mice. The mice were given a single injection of DEN at 2 weeks of age and subsequently received drinking water containing metformin for 20 weeks. Metformin administration significantly reduced the multiplicity of hepatic premalignant lesions and inhibited liver cell neoplasms. Metformin also markedly decreased serum levels of insulin and reduced insulin resistance, and inhibited phosphorylation of Akt, mammalian target of rapamycin (mTOR), and p70S6 in the liver. Furthermore, serum levels of leptin were decreased, while those of adiponectin were increased by metformin. These findings suggest that metformin prevents liver tumorigenesis by ameliorating insulin sensitivity, inhibiting the activation of Akt/mTOR/p70S6 signaling, and improving adipokine imbalance. Therefore, metformin may be a potent candidate for chemoprevention of liver tumorigenesis in patients with obesity or diabetes.
Collapse
|
|
29
|
Martinez D, Palmer C, Simar D, Cameron BA, Nguyen N, Aggarwal V, Lloyd AR, Zekry A. Characterisation of the cytokine milieu associated with the up-regulation of IL-6 and suppressor of cytokine 3 in chronic hepatitis C treatment non-responders. Liver Int 2015; 35:463-72. [PMID: 24461080 DOI: 10.1111/liv.12473] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 01/16/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS In chronic hepatitis C virus infection (CHC), expression of suppressor of cytokine signalling-3 (SOCS3) has been shown to be associated with obesity and non-response to antiviral therapy. In this study, we aimed to determine the effect of SOCS3 induction on the cytokine response in patients receiving Pegylated interferon (PegIFN) and ribavirin (RBV) therapy. METHODS Peripheral blood mononuclear cells (PBMC) collected at baseline and at 12 weeks from CHC patients receiving PegIFN/RBV therapy were examined for mRNA and protein SOCS3 expression. Immunological assays were employed to examine cytokine production. RESULTS There was increased expression of SOCS3 in PBMC of non-responders at week 12 of therapy, when compared to treatment responders (P = 0.0001). The expression of SOCS3 correlated with body mass index (BMI) (r = 0.54; P = 0.01). Patients with low SOCS3 expression at week 12 of therapy had lower HCV-specific IFN-γ production in enzyme-linked immunosorbent spot (ELISpot) assays (P = 0.01), and reduced ex-vivo production of the anti-HCV effector cytokines interleukin (IL)-2 and tumour necrosis factor (TNF)-α(P = 0.01 and P = 0.04 respectively). Analysis of serum cytokine levels revealed higher levels of IL-6 at week 12 in the high SOCS3 expression group (P = 0.02) while IL-6 levels correlated with SOCS3 expression in the entire cohort (P = 0.04). Ex-vivo studies confirmed that IL-6 induced SOCS3, and neutralisation of IL-6 reduced levels of SOCS3. CONCLUSION In subjects with increased BMI and non-response to antiviral therapy, the IL-6/SOCS3 axis appears to play a crucial role in altering the anti-HCV-cytokine response associated with antiviral therapy.
Collapse
Affiliation(s)
- Danica Martinez
- School of Medical Sciences, Inflammation and Infection Research Centre (IIRC), Sydney, New South Wales, Australia
| | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Mathew S, Ali A, Abdel-Hafiz H, Fatima K, Suhail M, Archunan G, Begum N, Jahangir S, Ilyas M, Chaudhary AGA, Al Qahtani M, Mohamad Bazarah S, Qadri I. Biomarkers for virus-induced hepatocellular carcinoma (HCC). INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2014; 26:327-339. [PMID: 24956436 DOI: 10.1016/j.meegid.2014.06.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 06/14/2014] [Accepted: 06/14/2014] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and is advanced by severe viral hepatitis B or C (HBV or HCV) as well as alcoholic liver disease. Many patients with early disease are asymptomatic therefore HCC is frequently diagnosed late requiring costly surgical resection or transplantation. The available non-invasive detections systems are based on the clinical utility of alpha fetoprotein (AFP) measurement, together with ultrasound and other more sensitive imaging techniques. The hallmark of liver disease and its propensity to develop into fully blown HCC is depended on several factors including the host genetic make-up and immune responses. While common symptoms involve diarrhea, bone pain, dyspnea, intraperitoneal bleeding, obstructive jaundice, and paraneoplastic syndrome, the evolution of cell and immune markers is important to understand viral induced liver cancers in humans. The circulating miRNA, cell and immune based HCC biomarkers are imperative candidates to successfully develop strategies to restrain liver injury. The current molecular genetics and proteomic analysis have lead to the identification of number of key biomarkers for HCC for earlier diagnosis and more effective treatment of HCC patients. In this review article, we provide latest updates on the biomarkers of HBV or HCV-associated HCC and their co-evolutionary relationship with liver cancer.
Collapse
Affiliation(s)
- Shilu Mathew
- Post Graduate Department of Biotechnology, Jamal Mohamed College, Tiruchirappalli 620 020, India; Center of Excellence in Genomic Medicine Research, King AbdulAziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia; Department of Animal Science, Bharathidasan University, Tiruchirappalli 620 024, India
| | - Ashraf Ali
- King Fahd Medical Research Center, King AbdulAziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia
| | | | - Kaneez Fatima
- IQ-Institute of Infection and Immunity, Lahore, Pakistan
| | - Mohd Suhail
- King Fahd Medical Research Center, King AbdulAziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia
| | - Govindaraju Archunan
- Department of Animal Science, Bharathidasan University, Tiruchirappalli 620 024, India
| | - Nargis Begum
- Post Graduate Department of Biotechnology, Jamal Mohamed College, Tiruchirappalli 620 020, India
| | - Syed Jahangir
- Post Graduate Department of Biotechnology, Jamal Mohamed College, Tiruchirappalli 620 020, India
| | - Muhammad Ilyas
- Post Graduate Department of Botany, Jamal Mohamed College, Tiruchirappalli 620 020, Tamil Nadu, India
| | - Adeel G A Chaudhary
- King Fahd Medical Research Center, King AbdulAziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia
| | - Mohammad Al Qahtani
- Center of Excellence in Genomic Medicine Research, King AbdulAziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia
| | - Salem Mohamad Bazarah
- Department of Gastroenterology, School of Medicine, King AbdulAziz University Hospital, P.O. Box 80215, Jeddah 21589, Saudi Arabia
| | - Ishtiaq Qadri
- King Fahd Medical Research Center, King AbdulAziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia.
| |
Collapse
|
|
31
|
Milner KL, Jenkins AB, Trenell M, Tid-Ang J, Samocha-Bonet D, Weltman M, Xu A, George J, Chisholm DJ. Eradicating hepatitis C virus ameliorates insulin resistance without change in adipose depots. J Viral Hepat 2014; 21:325-32. [PMID: 24716635 DOI: 10.1111/jvh.12143] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 06/17/2013] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis C (CHC) is associated with lipid-related changes and insulin resistance; the latter predicts response to antiviral therapy, liver disease progression and the risk of diabetes. We sought to determine whether insulin sensitivity improves following CHC viral eradication after antiviral therapy and whether this is accompanied by changes in fat depots or adipokine levels. We compared 8 normoglycaemic men with CHC (genotype 1 or 3) before and at least 6 months post viral eradication and 15 hepatitis C antibody negative controls using an intravenous glucose tolerance test and two-step hyperinsulinaemic-euglycaemic clamp with [6,6-(2) H2 ] glucose to assess peripheral and hepatic insulin sensitivity. Magnetic resonance imaging and spectroscopy quantified abdominal fat compartments, liver and intramyocellular lipid. Peripheral insulin sensitivity improved (glucose infusion rate during high-dose insulin increased from 10.1 ± 1.6 to 12 ± 2.1 mg/kg/min/, P = 0.025), with no change in hepatic insulin response following successful viral eradication, without any accompanying change in muscle, liver or abdominal fat depots. There was corresponding improvement in incremental glycaemic response to intravenous glucose (pretreatment: 62.1 ± 8.3 vs post-treatment: 56.1 ± 8.5 mm, P = 0.008). Insulin sensitivity after viral clearance was comparable to matched controls without CHC. Post therapy, liver enzyme levels decreased but, interestingly, levels of glucagon, fatty acid-binding protein and lipocalin-2 remained elevated. Eradication of the hepatitis C virus improves insulin sensitivity without alteration in fat depots, adipokine or glucagon levels, consistent with a direct link of the virus with insulin resistance.
Collapse
Affiliation(s)
- K-L Milner
- Garvan Institute of Medical Research, University of New South Wales, Sydney, NSW, Australia; Department of Endocrinology, Prince of Wales Hospital, University of New South Wales, Sydney, NSW, Australia
| | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Silva TE, Colombo G, Schiavon LL. Adiponectin: A multitasking player in the field of liver diseases. DIABETES & METABOLISM 2014; 40:95-107. [PMID: 24486145 DOI: 10.1016/j.diabet.2013.11.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 11/19/2013] [Accepted: 11/21/2013] [Indexed: 12/18/2022]
Abstract
Adiponectin is the most abundant adipokine synthesized by adipose tissue and has been shown to be a key component in the relationship between adiposity, insulin resistance and inflammation. It circulates in plasma at physiological concentrations that represent 0.05% of all plasma proteins. Adiponectin has trimeric, hexameric and multimeric forms that bind to receptors AdipoR1, AdipoR2 and T-cadherin especially in liver, muscle and endothelial cells. Adiponectin is considered a potent modulator of lipid and glucose metabolism with antidiabetic, antiatherogenic and anti-inflammatory properties, and plays an important role in the pathogenesis of metabolic diseases. The hepatoprotective effects of adiponectin, especially in non-alcoholic fatty liver disease (NAFLD), have been widely investigated, and its antisteatotic, anti-inflammatory and antifibrogenic effects have already been described. Adiponectin levels are reduced in individuals with fatty liver disease independently of body mass index, insulin resistance and other adipokines, and are inversely related to the severity of steatosis and necroinflammation, suggesting an important role in the relationship between adipose tissue, the liver and insulin sensitivity. Adiponectin has also been found to be reduced in cases of hepatitis B and C infection, and in cholestatic and autoimmune diseases, but is increased in patients with cirrhosis of different aetiologies. In addition, an important role for the liver in the regulation of adiponectin secretion by adipocytes, mediated by bile acids, has recently been proposed. The present report describes the importance of adiponectin in hepatic diseases as well as some future perspectives of the role of adiponectin as a biomarker and therapeutic target in liver diseases.
Collapse
Affiliation(s)
- T E Silva
- Division of Gastroenterology, Federal University of Santa Catarina Campus, Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, Brazil 88040970.
| | - G Colombo
- Division of Gastroenterology, Federal University of Santa Catarina Campus, Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, Brazil 88040970
| | - L L Schiavon
- Division of Gastroenterology, Federal University of Santa Catarina Campus, Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, Brazil 88040970
| |
Collapse
|
|
33
|
Vespasiani-Gentilucci U, Gallo P, Vincentis AD, Galati G, Picardi A. Hepatitis C virus and metabolic disorder interactions towards liver damage and atherosclerosis. World J Gastroenterol 2014; 20:2825-2838. [PMID: 24659875 PMCID: PMC3961987 DOI: 10.3748/wjg.v20.i11.2825] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/25/2013] [Accepted: 01/03/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide, and alterations of glucose metabolism have reached pandemic proportions in western countries. However, the frequent coexistence between these two conditions is more than simply coincidental, since HCV can induce insulin resistance through several mechanisms. Indeed, the virus interferes with insulin signaling both directly and indirectly, inducing the production of pro-inflammatory cytokines. Furthermore, the entire viral life cycle has strict interconnections with lipid metabolism, and HCV is responsible for a "viral" steatosis which is frequently superimposed to a "metabolic" one. Several evidences suggest that HCV-induced metabolic disorders contribute both to the evolution of liver fibrosis and, likely, to the progression of the other disorders which are typically associated with altered metabolism, in particular atherosclerosis. In the present review, we will examine in depth the links between HCV infection and insulin resistance, liver steatosis and diabetes, and analyze the impact of these interactions on the progression of liver fibrosis and atherosclerosis. Special attention will be focused on the highly debated topic of the relationship between HCV infection and cardiovascular disease. The available clinical literature on this item will be broadly reviewed and all the mechanisms possibly implied will be discussed.
Collapse
|
|
34
|
Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia, Di.Bi.M.I.S, University of Palermo, , Palermo, Italy
| | | | | |
Collapse
|
|
35
|
Chan CHY, Hansen RD, Gilliver RS, Jones BE. Sustained virological response following chronic hepatitis C treatment is associated with improvement in insulin resistance. Intern Med J 2014; 43:656-62. [PMID: 23506416 DOI: 10.1111/imj.12136] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Accepted: 03/10/2013] [Indexed: 12/19/2022]
Abstract
BACKGROUND Insulin resistance (IR) is a key factor in the development of hepatic steatosis and fibrosis in chronic hepatitis C virus infection. Little is known about the impact of viral clearance on IR. AIM The aim of this study was to determine the impact of viral clearance on IR. METHODS Eighty-six patients treated according to standard clinical practice at an Australian teaching hospital between 2003 and 2007 were prospectively studied. Demographic, biochemical and histological data were collected. RESULTS The mean pretreatment homeostatic model assessment-IR (HOMA-IR) was similar in the sustained virological response (SVR) and non-SVR groups (2.7 ± 0.5 and 2.8 ± 0.4, respectively), and both values were consistent with significant IR. There was a significant improvement in HOMA-IR (from 3.0 ± 1.0 to 2.2 ± 0.5, P = 0.04) at the end of treatment in the SVR group only. This trended towards significance at 6 months post-treatment. Multiple regression analysis found improvement in both gamma-glutamyl transpeptidase and alanine aminotransferase predicted improvement in HOMA-IR when controlled for other potential factors (P = 0.01). CONCLUSIONS Hepatitis C virus clearance is associated with improvement in IR. Although baseline hepatic fibrosis is a predictor of IR, changes in IR appear to be independent of changes in liver fibrosis. Treatment-related improvement in gamma-glutamyl transpeptidase and alanine aminotransferase seen with improved IR may be a possible marker of reduction of hepatic oxidative stress.
Collapse
Affiliation(s)
- C H Y Chan
- Department of Gastroenterology and Hepatology, Royal North Shore Hospital, Sydney, Australia
| | | | | | | |
Collapse
|
|
36
|
Mera K, Uto H, Mawatari S, Ido A, Yoshimine Y, Nosaki T, Oda K, Tabu K, Kumagai K, Tamai T, Moriuchi A, Oketani M, Shimada Y, Hidaka M, Eguchi S, Tsubouchi H. Serum levels of apoptosis inhibitor of macrophage are associated with hepatic fibrosis in patients with chronic hepatitis C. BMC Gastroenterol 2014; 14:27. [PMID: 24524410 PMCID: PMC3937012 DOI: 10.1186/1471-230x-14-27] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Accepted: 02/05/2014] [Indexed: 12/18/2022] Open
Abstract
Background Apoptosis inhibitor of macrophage (AIM) and adipocytokines are involved in the metabolic syndrome, which has been putatively associated with the progression of chronic hepatitis C (CHC). However, the association between these cytokines and CHC is not fully elucidated. The aim of this study is to test whether serum levels of AIM and adipocytokines are associated with histological features, homeostasis model assessment-insulin resistance index (HOMA-IR), or whole body insulin sensitivity index (WBISI) in CHC patients. Methods Serum samples were obtained from 77 patients with biopsy-proven CHC. In 39 patients without overt diabetes mellitus, a 75 g oral glucose tolerance test (OGTT) was performed and HOMA-IR and WBISI were calculated. Results A serum AIM level of ≥1.2 μg/ml was independently associated with advanced hepatic fibrosis (F2 or F3) (odds ratio [OR], 5.612; 95% confidence interval [CI], 1.103–28.563; P = 0.038) based on a multivariate analysis, but there was no significant association between AIM and hepatic steatosis or inflammation. Furthermore, a serum leptin level of ≥8.6 ng/ml was independently associated with the presence of hepatic steatosis (≥5%) (OR, 6.195; 95% CI, 1.409–27.240; P = 0.016), but not hepatic fibrosis or inflammation. No relationship was observed between levels of adiponectin or resistin and hepatic histological parameters based on a multivariate analysis. Although serum levels of leptin, resistin, and adiponectin were significantly correlated with HOMA-IR and WBISI, there was no significant relationship between serum AIM levels and HOMA-IR or WBISI, respectively. Conclusion High serum levels of AIM in CHC patients are potentially related to advanced hepatic fibrosis. AIM and adipocytokines are possibly associated with pathological changes via a different mechanism.
Collapse
Affiliation(s)
| | - Hirofumi Uto
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
|
|
38
|
Chiou YL, Shih CJ, Ko WS. The increased ratio of CD4+/CD8+ was positively correlated with inflammation in hepatitis C patients with metabolic syndrome. Clin Biochem 2013; 46:745-9. [PMID: 23562575 DOI: 10.1016/j.clinbiochem.2013.03.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2012] [Revised: 03/12/2013] [Accepted: 03/25/2013] [Indexed: 12/25/2022]
Abstract
BACKGROUND/AIMS The incidence of metabolic syndrome (MS) in hepatitis C patients in Taiwan is not well known. Although the ratio of CD4(+)/CD8(+) T lymphocytes is considered to possibly affect the pathogenesis of hepatitis C, the effects of MS on CD4(+)/CD8(+) T lymphocytes remain unknown. The aims of this study to assess (1) the incidence of MS, (2) the inflammation status and fatty changes of liver, and (3) changes in their CD4(+)/CD8(+) T-lymphocyte ratio in patients with hepatitis C. METHODS 60 hepatitis C patients were classified into MS or non-MS group. The terms of anthropometric data, MS components, and T-lymphocytes were assessed. RESULTS The proportion of hepatitis C patients suffering from MS was 26.7% in this study. The CD4(+)/CD8(+) T-lymphocyte ratios were higher in patients with MS than non-MS group. Hepatitis C patients with MS also had higher levels of ferritin than non-MS. Moreover, the level of ferritin positively correlated with the severity of fatty liver. The CD4(+)/CD8(+) T-lymphocyte ratio is also positively correlated with ferritin level and the severity of fatty liver. CONCLUSIONS Hepatitis C patients with MS had higher ratio of CD4(+)/CD8(+) T lymphocyte, which is associated with a high inflammatory response and a fatty change of liver.
Collapse
Affiliation(s)
- Ya-Ling Chiou
- Department of Nutrition & Institute of BioMedical Nutrition, Hungkuang University, Taichung, Taiwan
| | | | | |
Collapse
|
|
39
|
Khattab MA, Eslam M, Aly MM, Shatat M, Hussen A, Moussa YI, Elsaghir G, Abdalhalim H, Aly A, Gaber S, Harrison SA. Association of serum adipocytokines with insulin resistance and liver injury in patients with chronic hepatitis C genotype 4. J Clin Gastroenterol 2012; 46:871-879. [PMID: 22664476 DOI: 10.1097/mcg.0b013e318256b68a] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection, especially genotypes 1 and 4, is associated with metabolic dysfunction. We investigated the potential role of adipocytokines in HCV-induced insulin resistance (IR) and modulating the progression of liver disease in patients with HCV-4. METHODS Serum adiponectin, high molecular weight adiponectin, leptin, tumor necrosis factor-α, interluekin-6, homeostasis model for the assessment of insulin resistance, and M30 protein were measured in 147 HCV patients and 89 controls. Liver biopsies were evaluated for steatosis/inflammation/fibrosis, adiponectin mRNA/protein, AdipoR1/-R2 mRNA, and phosphoenolpyruvate carboxykinase gene expression, and adiponectin and CD95 immunoreactivity. RESULTS CD95 immunoreactivity and adiponectin immunoreactivity were detected in all biopsies examined. Hepatic adiponectin immunostaining correlated positively with the intensity of hepatic CD95/Fas immunostaining (r=0.424; P=0.001). Hepatocyte CD95/Fas upregulation correlated with fibrosis, inflammation, and steatosis (r=0.52, P=0.0001; r=0.16, P=0.04; r=0.24, P=0.0001; respectively). Significant correlations of serum adiponectin, its receptors mRNA expression, hepatic adiponectin immunostaining, and mRNA transcription for phosphoenolpyruvate carboxykinase were identified with steatosis. A positive association between adiponectin and hepatic inflammation and fibrosis was identified. This correlation remained significant even after adjusting for age, sex, and body mass index. Among body mass index, age, and sex-matched HCV-negative controls, patients with HCV-4 have higher serum leptin, adiponectin, and high molecular weight adiponectin, and these changes are independently correlated with IR. CONCLUSIONS Our findings in patients with HCV-4 show that adiponectin correlates with IR and with the different stages of liver injury. Steatosis upregulates hepatocyte CD95/Fas and thus increases apoptosis, which facilitates inflammation and fibrosis. These findings may provide potential clues for novel therapeutic intervention.
Collapse
|
|
40
|
Harrison SA, Lincoln MJ, Roberts KK. Insulin resistance in chronic hepatitis C: the search for effective drug treatment continues. Expert Rev Gastroenterol Hepatol 2012; 6:401-3. [PMID: 22928890 DOI: 10.1586/egh.12.29] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
|
41
|
Chang ML, Yeh HC, Tsou YK, Wang CJ, Cheng HY, Sung CM, Ho YP, Chen TH, Yeh CT. HCV core-induced nonobese hepatic steatosis is associated with hypoadiponectinemia and is ameliorated by adiponectin administration. Obesity (Silver Spring) 2012; 20:1474-1480. [PMID: 22421894 DOI: 10.1038/oby.2012.45] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Obesity-related hepatic steatosis is commonly associated with central fat accumulation and alterations in adipocytokine secretion; however, the connection between nonobese hepatic steatosis and adipocytokines remains unclear. We aim to investigate this connection using an animal model of conditional hepatitis C virus (HCV) core-transgenic mice. Double transgenic mice (DTM) with doxycycline (dox)-regulated hepatic overexpression of the HCV core protein were fed standard rodent chow ad libitum following 1 month of a dox-rich diet. The mice exhibited nonobese hepatic steatosis at 2 months of age. The levels of leptin and adiponectin were assessed in 2-month-old DTM (i.e., HCV core-tetracycline transactivator (tTA)) and single transgenic mice (STM; i.e., tTA). The total fat mass and the body fat distribution of the mice were evaluated using dual-energy X-ray absorptiometry (DEXA) and magnetic resonance imaging (MRI). Microarray analyses and quantitative real-time PCR were conducted using RNA obtained from the visceral fat of paired DTM and STM. Adiponectin was administered intraperitoneally to the 2-month-old DTM. No significant differences of the various fat components were noted between the DTM and STM. Leptin mRNA was downregulated in the visceral fat of DTM (P = 0.011), and serum adiponectin protein levels were reduced in the DTM compared with those in the STM (P = 0.035). Adiponectin treatment also significantly ameliorated hepatic steatosis in the DTM compared to the controls (P = 0.024). In conclusion, HCV core-induced nonobese hepatic steatosis is associated with downregulation of the leptin gene in visceral fat and concurrent hypoadiponectinemia; however, these effects may be ameliorated by adiponectin treatment.
Collapse
Affiliation(s)
- Ming-Ling Chang
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linko, Taiwan.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Bugianesi E, Salamone F, Negro F. The interaction of metabolic factors with HCV infection: does it matter? J Hepatol 2012; 56 Suppl 1:S56-65. [PMID: 22300466 DOI: 10.1016/s0168-8278(12)60007-5] [Citation(s) in RCA: 137] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Given the pandemic spread of the hepatitis C virus (HCV) infection and the metabolic syndrome (MS), the burden of their interaction is a major public health issue, bound to increase in the near term. A better appreciation of the clinical consequences of the relationship between HCV and MS is needed, not only due to their potential synergism on liver disease severity, but also because of the multifaceted interactions between HCV and glucose and lipid metabolism. HCV infection per se does not carry an increased risk of MS, but is able to perturb glucose homeostasis through several direct and indirect mechanisms, leading to both hepatic and extrahepatic insulin resistance. This translates into accelerated liver disease progression (including the development of hepatocellular carcinoma), reduced response to antivirals and, in susceptible individuals, increased risk of developing full-blown type 2 diabetes. HCV may also cause hepatic steatosis, especially in patients infected with genotype 3, although the clinical impact of viral steatosis is debated. Possibly as a result of HCV-induced insulin resistance, and despite a paradoxically favourable lipid profile, the cardiovascular risk is moderately increased in chronic hepatitis C. In addition, the interaction with the MS further increases the risks of cirrhosis, hepatocellular carcinoma, diabetes, and cardiovascular events. Thus, targeted lifestyle and pharmacological measures are urgently warranted in chronic hepatitis C with metabolic alterations.
Collapse
|
|
43
|
El-Zayadi AR, Anis M. Hepatitis C virus induced insulin resistance impairs response to anti viral therapy. World J Gastroenterol 2012; 18:212-24. [PMID: 22294824 PMCID: PMC3261538 DOI: 10.3748/wjg.v18.i3.212] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2011] [Revised: 06/20/2011] [Accepted: 06/21/2011] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is an important risk factor for insulin resistance (IR). The latter is the pathogenic foundation underlying metabolic syndrome, steatosis and cirrhosis, and possibly hepatocellular carcinoma (HCC). The interplay between genetic and environmental risk factors ultimately leads to the development of IR. Obesity is considered a major risk factor, with dysregulation of levels of secreted adipokines from distended adipose tissue playing a major role in IR. HCV-induced IR may be due to the HCV core protein inducing proteasomal degradation of insulin receptor substrates 1 and 2, blocking intracellular insulin signaling. The latter is mediated by increased levels of both tumour necrosis factor-α (TNF-α) and suppressor of cytokine signaling 3 (SOC-3). IR, through different mechanisms, plays a role in the development of steatosis and its progression to steatohepatitis, cirrhosis and even HCC. In addition, IR has a role in impairing TNF signaling cascade, which in turn blocks STAT-1 translocation and interferon stimulated genes production avoiding the antiviral effect of interferon.
Collapse
|
|
44
|
Talaat RM, Esmail AA, Elwakil R, Gurgis AA, Nasr MI. Tumor necrosis factor-alpha -308G/A polymorphism and risk of hepatocellular carcinoma in hepatitis C virus-infected patients. CHINESE JOURNAL OF CANCER 2012; 31:29-35. [PMID: 22200181 PMCID: PMC3777466 DOI: 10.5732/cjc.011.10258] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Revised: 09/20/2011] [Accepted: 09/21/2011] [Indexed: 12/14/2022]
Abstract
Tumor necrosis factor-alpha (TNF-α) is an important cytokine in generating an immune response against infection with hepatitis C virus (HCV). The functions of TNF-α may be altered by single-nucleotide polymorphisms (SNPs) in its gene structure. We hypothesized that SNPs in TNF-α may be important in determining the outcome of an HCV infection. To test this hypothesis, we investigated the role of the polymorphism -308G/A, which is located in the promoter region of the TNF-α gene, in the progression of HCV infection in Egyptian patients using a quantitative real-time polymerase chain reaction (qRT-PCR). The distribution of this polymorphism and its impact on the serum level of TNF-α was compared between 90 HCV-infected patients [45 with HCV-induced cirrhosis and 45 with HCV-related hepatocellular carcinoma (HCC)] and 45 healthy Egyptian volunteers without any history of liver disease. Our results showed that at the TNF-α -308 position, the G/G allele was most common (78.5%) in the study population, with the G/A and A/A alleles occurring less frequently (13.3% and 8.1%, respectively). Frequencies of G/G, G/A, and A/A genotypes were 87%, 7%, and 6% in patients with liver cirrhosis and were 94%, 4%, and 2% in patients with HCC, respectively. Serum levels of TNF-α were significantly higher in HCV-infected patients than in healthy controls, indicating that the TNF-α -308 polymorphism does not influence the production of TNF-α. The serum level of TNF-α was positively correlated with HCV infection. Taken together, these findings suggest that the TNF-α -308 polymorphism may not be a host genetic factor associated with the severity of HCV infection, but may be an independent risk factor for HCC.
Collapse
Affiliation(s)
- Roba M Talaat
- Molecular Biology Department, Menofia University, Sadat, Egypt.
| | | | | | | | | |
Collapse
|
|
45
|
HOMA-AD in Assessing Insulin Resistance in Lean Noncirrhotic HCV Outpatients. Int J Hepatol 2012; 2012:576584. [PMID: 22848841 PMCID: PMC3405643 DOI: 10.1155/2012/576584] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Revised: 05/22/2012] [Accepted: 05/22/2012] [Indexed: 12/26/2022] Open
Abstract
Introduction. There is an association between HCV and insulin resistance (IR), which is currently assessed by HOMA-IR. There is evidence that HOMA-adiponectin (HOMA-AD) is more accurate, but its role in HCV patients is unknown. The purpose of this study was to evaluate IR in an HCV sample and controls, in order to compare the accuracy of HOMA-IR and HOMA-AD. Methods. Ninety-four HCV outpatients aged <60 years who met the criteria of nondiabetic, nonobese, noncirrhotic, and nonalcohol abusers were included and compared to 29 controls. Fasting glucose, insulin, adiponectin, and lipid profiles were determined. IR was estimated by HOMA-IR and HOMA-AD. Results. The groups were similar regarding sex and BMI, but the HCV patients were older. The median insulin level was higher in the HCV group (8.6 mU/mL (6.5-13.7) versus 6.5 (4.3-10.7), P = 0.004), as was median HOMA-IR (1.94 (1.51 to 3.48) versus 1.40 (1.02 to 2.36), P = 0.002) and the prevalence of IR (38.3% versus 10.3% (P = 0.009)). No differences were found in adiponectin levels (P = 0.294) and HOMA-AD (P = 0.393). Conclusion. IR is highly prevalent even in low-risk HCV outpatients. Adiponectin is not influenced by the presence of HCV. HOMA-AD does not seem to be useful in assessing IR in HCV patients.
Collapse
|
|
46
|
Chen D, Liu JL, Liu Y, Zhu J, Wang SW. Lack of an association between -308G>A polymorphism of the TNF-α gene and liver cirrhosis risk based on a meta-analysis. GENETICS AND MOLECULAR RESEARCH 2011; 10:2765-74. [PMID: 22095602 DOI: 10.4238/2011.november.8.2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
TNF-α is a potential proinflammatory cytokine that plays an important role in the pathogenesis of liver cirrhosis. We investigated a possible association between TNF-α -308G>A polymorphism and liver cirrhosis risk by conducting a meta-analysis. Publications addressing the association between TNF-α -308G>A and liver cirrhosis risk were selected from the Pubmed and Embase databases. Data were extracted from the studies by two independent reviewers; odds ratio (OR) with a 95% confidence interval (CI) was calculated from these data. The meta-analysis was performed by Review Manager Version 5.0.24 and STATA Version 9.2. Eleven studies were retrieved, reporting a total of 1796 liver cirrhosis cases and 2113 healthy controls. A meta-analysis of these 11 studies identified no significant association between TNF-α -308G>A polymorphism and liver cirrhosis risk in all comparisons of G vs A allele; GG vs GA + AA; GG + GA vs AA; GG vs AA; GG vs GA (OR = 1.14, 95%CI = 0.85-1.55, P = 0.38; OR = 1.24, 95%CI = 0.87- 1.77, P = 0.24; OR = 0.90, 95%CI = 0.62-1.30, P = 0.57; OR = 1.03, 95%CI = 0.56-1.89, P = 0.92; OR = 1.30, 95%CI = 0.90-1.88, P = 0.17; respectively). In conclusion, we found no association between TNF-α -308G>A polymorphism and liver cirrhosis risk, both in Caucasian and Asian populations.
Collapse
Affiliation(s)
- D Chen
- Department of Emergency, The Fourth Affiliated Hospital of China Medical University, Shenyang, PR China
| | | | | | | | | |
Collapse
|
|
47
|
Konishi I, Hiasa Y, Tokumoto Y, Abe M, Furukawa S, Toshimitsu K, Matsuura B, Onji M. Aerobic exercise improves insulin resistance and decreases body fat and serum levels of leptin in patients with hepatitis C virus. Hepatol Res 2011; 41:928-35. [PMID: 21707884 DOI: 10.1111/j.1872-034x.2011.00833.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM Hepatitis C virus infection often complicates glucose intolerance, which can be caused by insulin resistance. Aerobic exercise can improve insulin resistance and decrease body fat in patients with diabetes. The aim of the present study is to clarify whether aerobic exercise improves insulin resistance and decreases body fat in patients with chronic hepatitis C (CH-C). METHODS Seventeen patients with CH-C received nutrition education at entry and every two months thereafter. The following were evaluated before and after 6 months of walking at least 8000 steps/day monitored using a pedometer that started 2 months after entry: body composition, fat and muscle weight, visceral and subcutaneous fat areas (VFA and SFA, respectively), liver function tests, the Homeostatic Model of Assessment of Insulin Resistance (HOMA-IR), serum tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, adiponectin, leptin and the Short Form-36. RESULTS Fifteen of the 17 patients completed the study protocol. Bodyweight, body mass index, fat weight, VFA, SFA, alanine aminotransferase level and HOMA-IR were significantly decreased at the end of the study (P = 0.004, =0.004, =0.008, =0.041, =0.001, =0.023 and =0.002, respectively). Serum levels of TNF-α, IL-6 and adiponectin did not change, whereas those of leptin significantly decreased (P = 0.002). CONCLUSION Patients with CH-C could safely walk as aerobic exercise. Furthermore, walking improved insulin resistance and decreased body fat while lowering serum levels of leptin.
Collapse
Affiliation(s)
- Ichiro Konishi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine Nutrition Division, Ehime University Hospital, Ehime, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Hung CH, Lee CM, Lu SN. Hepatitis C virus-associated insulin resistance: pathogenic mechanisms and clinical implications. Expert Rev Anti Infect Ther 2011; 9:525-33. [PMID: 21609264 DOI: 10.1586/eri.11.33] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
It is now widely recognized that chronic hepatitis C is a metabolic disease, strongly associated with Type 2 diabetic mellitus and insulin resistance (IR). Chronic hepatitis C virus (HCV) infection promotes IR mainly through interfering with the insulin signaling pathway in hepatocytes, increasing the inflammatory response with production of cytokines such as TNF-α and IL-6, and increasing oxidative stress. Accumulated evidence indicates that HCV-associated IR may lead to fibrosis progression, resistance to antiviral therapy, hepatocarcinogenesis and extrahepatic manifestations. Thus, HCV-associated IR is a therapeutic target at any stage of HCV infection. However, specific pharmaceutical treatments of IR are still being evaluated in clinical trials, but available data do not warrant their use in all chronic hepatitis C patients with IR.
Collapse
Affiliation(s)
- Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | | | | |
Collapse
|
|
49
|
Kaddai V, Negro F. Current understanding of insulin resistance in hepatitis C. Expert Rev Gastroenterol Hepatol 2011; 5:503-16. [PMID: 21780897 DOI: 10.1586/egh.11.43] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Important breakthroughs have been made in recent years into understanding the close interaction between hepatitis C virus (HCV) infection and glucose homeostasis. Both cross-sectional and longitudinal studies have demonstrated that infection with HCV is associated with an increased risk of developing insulin resistance and Type 2 diabetes. A direct effect of HCV on hepatocyte insulin signaling has been shown in experimental models. Some preliminary observations seem to suggest that indirect mechanisms involving extrahepatic organs might also play a role. The interaction between HCV and glucose metabolism has significant clinical consequences. Insulin resistance and Type 2 diabetes not only accelerate the histological and clinical progression of chronic hepatitis C, but also reduce the virological response to IFN-α-based therapy. Thus, understanding the mechanisms underlying HCV-associated glucose metabolism derangements is of paramount interest in order to improve the clinical management of chronic hepatitis C. This article will focus on the studies that consistently argue in favor of an interrelation between HCV and insulin resistance and will highlight the latest discoveries in this field.
Collapse
Affiliation(s)
- Vincent Kaddai
- Department of Pathology and Immunology, Centre Médical Universitaire, Rue Michel-Servet 1, Geneva, Switzerland
| | | |
Collapse
|
|
50
|
Corbetta S, Redaelli A, Pozzi M, Bovo G, Ratti L, Redaelli E, Pellegrini C, Beck-Peccoz P, Spada A. Fibrosis is associated with adiponectin resistance in chronic hepatitis C virus infection. Eur J Clin Invest 2011; 41:898-905. [PMID: 21539538 DOI: 10.1111/j.1365-2362.2011.02498.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection is frequently associated with insulin resistance which has been suggested to promote fibrotic progression. Adiponectin, an adipocyte-derived insulin-sensitizing hormone, might play a protective role against hepatic fibrosis. MATERIALS AND METHODS This observational case-control study investigated the adiponectin status in insulin resistant, nondiabetic, chronic HCV-infected patients (n=54; 13 women, 41 men) compared with age-, sex- and BMI-matched healthy controls. Liver biopsies from patients with chronic HCV hepatitis were analysed for the adiponectin and adiponectin receptors (ADIPOR) 1 and 2 mRNA and protein expressions. RESULTS Serum adiponectin levels were higher in patients with chronic HCV hepatitis than in healthy controls (12·1±4·7 vs. 9·5±4·4 mg L(-1) in men, P = 0·01; 18·2±4·4 vs. 13·6±5·3mgL(-1) in women, P=0·02). BMI, HDL cholesterol and triglycerides levels correlated with adiponectin levels both in patients and in controls, while no correlation with glucose, insulin and HOMA-IR values could be detected. Nonetheless, insulin resistance was predictive of steatosis and fibrosis in chronic HCV-infected patients. Interestingly, patients with none or mild fibrosis showed serum adiponectin levels similar to those in healthy controls, while hyperadiponectinemia was associated with moderate to severe stages of fibrosis. Hyperadiponectinemia was unlikely sustained by liver production as hepatocytes did not express the protein. ADIPOR1 mRNA, but not ADIPOR2 levels, was reduced in chronic HCV hepatitis. The reduced ADIPOR1 expression was confirmed by immunohistochemistry. CONCLUSIONS In patients with chronic HCV hepatitis, fibrosis was associated with hyperadiponectinemia. Chronic HCV-infected hepatocytes showed reduced ADIPOR1 expression, suggesting a pattern of adiponectin resistance.
Collapse
Affiliation(s)
- Sabrina Corbetta
- Endocrinology and Diabetology Unit, Department of Medical-Surgical Sciences, University of Milan, Milan, Italy.
| | | | | | | | | | | | | | | | | |
Collapse
|