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Grancini V, Cogliati I, Alicandro G, Gaglio A, Gatti S, Donato MF, Orsi E, Resi V. Assessment of hepatic fibrosis with non-invasive indices in subjects with diabetes before and after liver transplantation. Front Endocrinol (Lausanne) 2024; 15:1359960. [PMID: 38505744 PMCID: PMC10948411 DOI: 10.3389/fendo.2024.1359960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 02/21/2024] [Indexed: 03/21/2024] Open
Abstract
Introduction One of the most common complications of cirrhosis is diabetes, which prevalence is strictly related to severity of hepatopathy. Actually, there are no data on the persistence of post-transplant glucose abnormalities and on a potential impact of diabetes on development of fibrosis in the transplanted liver. To this aim, we evaluated liver fibrosis in cirrhotic subjects before and after being transplanted. Methods The study included 111 individuals who had liver transplantation. The assessment was performed before and two years after surgery to investigate a potential impact of the persistence of diabetes on developing de novo fibrosis in the transplanted liver. The degree of fibrosis was assessed using the Fibrosis Index Based on 4 Factors (FIB-4) and the Aspartate to Platelet Ratio Index (APRI). Results At pre-transplant evaluation, 63 out of 111 (56.8%) subjects were diabetic. Diabetic subjects had higher FIB-4 (Geometric mean, 95% confidence interval: 9.74, 8.32-11.41 vs 5.93, 4.71-7.46, P<0.001) and APRI (2.04, 1.69-2.47 vs 1.18, 0.90-1.55, P<0.001) compared to non-diabetic subjects. Two years after transplantation, 39 out of 111 (35.1%) subjects remained with diabetes and continued to show significantly higher FIB-4 (3.14, 2.57-3.82 vs 1.87, 1.55-2.27, P<0.001) and APRI (0.52, 0.39-0.69 vs 0.26, 0.21-0.32, P<0.001) compared to subjects without diabetes. Discussion Thus, persistence of diabetes after surgery is a possible risk factor for an evolution to fibrosis in the transplanted liver, potentially leading to worsened long-term outcomes in this population.
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Affiliation(s)
- Valeria Grancini
- Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Irene Cogliati
- Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Gianfranco Alicandro
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
- Department of Pediatrics, Cystic Fibrosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Alessia Gaglio
- Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefano Gatti
- Center for Preclinical Research, Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico, Milan, Italy
| | - Maria Francesca Donato
- Hepatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Emanuela Orsi
- Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Veronica Resi
- Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Burden, Outcome, and Comorbidities of Extrahepatic Manifestations in Hepatitis C Virus Infection. BIOLOGY 2022; 12:biology12010023. [PMID: 36671716 PMCID: PMC9855523 DOI: 10.3390/biology12010023] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/06/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022]
Abstract
Hepatitis C virus (HCV) is a significant cause of chronic liver diseases worldwide and is associated with negative consequences, including cirrhosis, hepatic decompensation, hepatocellular carcinoma, and increased risk of mortality. In addition to liver-related morbidities, HCV is also associated with several extrahepatic manifestations, including mixed cryoglobulinemia, diabetes mellitus, cardiocerebrovascular disease, lymphoma, and autoimmune diseases. These non-liver-related complications of HCV increase the complexity of this disease and can contribute to the economic burden, morbidity, quality of life, and mortality throughout the world. Therefore, understanding how this virus can contribute to each extrahepatic manifestation is worth investigating. Currently, the advancement of HCV treatment with the advent of direct-acting anti-viral agents (DAAs) has led to a high cure rate as a result of sustained virologic response and tremendously reduced the burden of extrahepatic complications. However, HCV-associated extrahepatic manifestations remain a relevant concern, and this review aims to give an updated highlight of the prevalence, risk factors, associated burdens, and treatment options for these conditions.
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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.
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Zhu Y, Peng Z, Lu Y, Li H, Zeng X, Zhang Z, Li X, Hu C, Hu A, Zhao Q, Wang H, Yang W. Higher dietary insulinaemic potential is associated with increased risk of liver steatosis and fibrosis. Liver Int 2022; 42:69-79. [PMID: 34521152 DOI: 10.1111/liv.15057] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 08/17/2021] [Accepted: 09/07/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Hyperinsulinaemia and insulin resistance play a central role in the progression of hepatic steatosis and fibrosis, and diet can modulate insulin response. We thus hypothesised that diet with higher insulinaemic potential is associated with an increased risk of these conditions. METHODS Two empirically dietary indices for hyperinsulinaemia (EDIH) and insulin resistance (EDIR) were derived to identify food groups most predictive of fasting concentrations of C-peptide and insulin and homeostatic model assessment for insulin resistance respectively. Hepatic steatosis and fibrosis were defined by controlled attenuation parameter and liver stiffness measurement using transient elastography (TE). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. RESULTS Of the 4171 participants with TE examination, 1436 (age-standardised prevalence, 33.8%) were diagnosed with steatosis, 255 (5.6%) with advanced fibrosis and 101 (2.2%) with cirrhosis. The multivariable-adjusted ORs for participants comparing the highest to the lowest EDIH tertile were 1.17 (95% CI: 0.99-1.39, Ptrend = .005) for steatosis, 1.74 (95% CI: 1.24-2.44, Ptrend = .001) for advanced fibrosis and 2.05 (95% CI: 1.21-3.46, Ptrend = .004) for cirrhosis. Similar associations were observed for EDIR with ORs of 1.32 (95% CI: 1.11-1.55, Ptrend < .001) for steatosis and 1.43 (95% CI: 1.03-1.99, Ptrend = .006) for advance fibrosis. These positive associations remained among never drinkers and individuals who were free of hepatitis B and/or C. CONCLUSIONS Our findings suggest that hyperinsulinaemia and insulin resistance may partially underlie the influence of diet on hepatic steatosis and fibrosis, and highlight the importance of reducing or avoiding insulinaemic dietary pattern.
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Affiliation(s)
- Yu Zhu
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China.,Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Anhui, China.,NHC Key Laboratory of study on Abnormal Gametes and Reproductive Tract, Anhui, China.,Anhui Provincial Key Laboratory of Population Health and Aristogenics/Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China
| | - Zhaohong Peng
- Department of Interventional Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yao Lu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hairong Li
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Xufen Zeng
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Zhuang Zhang
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Xiude Li
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Chunqiu Hu
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Anla Hu
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Qihong Zhao
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China
| | - Wanshui Yang
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China.,Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Anhui, China.,NHC Key Laboratory of study on Abnormal Gametes and Reproductive Tract, Anhui, China.,Anhui Provincial Key Laboratory of Population Health and Aristogenics/Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China
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5
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Urganci N, Kalyoncu D, Geylani-Gulec S. Insulin resistance in children with chronic hepatitis C and its association with response to IFN-alpha and ribavirin. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2021; 86:140-144. [PMID: 32839082 DOI: 10.1016/j.rgmx.2020.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 07/15/2020] [Accepted: 07/15/2020] [Indexed: 06/11/2023]
Abstract
OBJECTIVE The aim of our study was to evaluate the association between insulin resistance and the response to IFN-alpha and ribavirin in pediatric patients with chronic hepatitis C. METHODS Twenty-six patients with chronic hepatitis C (mean age: 12.5 ± 1.96 years, M/F:3.33) were included in the study. Fasting glucose, insulin, and C-peptide levels, together with HOMA-IR, HOMA-B, and QUICKI values, were assessed. The association between those parameters and treatment response was determined. RESULTS Five (19.2%) of the 26 patients analyzed (2 [21.4%] with treatment response and 3 [16.6%] with no treatment response) had insulin resistance (p=1.00). There were no significant differences between the patients with and without treatment response with respect to fasting glucose, insulin, and C-peptide levels or HOMA-IR, HOMA-B, and QUICKI values (p>0.05). CONCLUSIONS No significant association was establihed between insulin resistance and response to IFN-alpha and ribavirin, in children with chronic hepatitis C.
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Affiliation(s)
- N Urganci
- Hospital Universitario y de Investigación Sisli Hamidiye Etfal, División de Gastroenterología Pediátrica, Estambul, Turquía
| | - D Kalyoncu
- Hospital Universitario y de Investigación Sisli Hamidiye Etfal, Departamento de Pediatría, Estambul, Turquía; Hospital Estatal de İstinye, Pediatría, Estambul, Turquía.
| | - S Geylani-Gulec
- Hospital Universitario y de Investigación Sisli Hamidiye Etfal, Departamento de Pediatría, Estambul, Turquía
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6
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Urganci N, Kalyoncu D, Geylani-Gulec S. Insulin resistance in children with chronic hepatitis C and its association with response to IFN-alpha and ribavirin. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2021. [DOI: 10.1016/j.rgmxen.2020.07.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Morgan TR. Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Diseases-Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Hepatology 2020; 71:686-721. [PMID: 31816111 PMCID: PMC9710295 DOI: 10.1002/hep.31060] [Citation(s) in RCA: 510] [Impact Index Per Article: 102.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 11/21/2019] [Indexed: 02/06/2023]
Affiliation(s)
| | - Timothy R. Morgan
- Chief of Hepatology Veterans Affairs Long Beach Healthcare System Long Beach CA
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8
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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: 77] [Impact Index Per Article: 15.4] [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.
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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
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9
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Diabetes Mellitus and Risk of Hepatic Fibrosis/Cirrhosis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5308308. [PMID: 31080822 PMCID: PMC6475555 DOI: 10.1155/2019/5308308] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Accepted: 03/27/2019] [Indexed: 02/06/2023]
Abstract
Development of cirrhosis is two- to threefold greater in patients with diabetes mellitus (DM), and in this setting, the prevalence of cirrhosis is surging worldwide. The present review served to examine clinical ties between DM and liver fibrosis and hepatic cirrhosis and explore related biologic mechanisms. Pathways contributing to various etiologies of cirrhosis in conjunction with DM were key investigative targets.
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Grancini V, Resi V, Palmieri E, Pugliese G, Orsi E. Management of diabetes mellitus in patients undergoing liver transplantation. Pharmacol Res 2019; 141:556-573. [PMID: 30690071 DOI: 10.1016/j.phrs.2019.01.042] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 01/24/2019] [Accepted: 01/24/2019] [Indexed: 02/07/2023]
Abstract
Diabetes is a common feature in cirrhotic individuals both before and after liver transplantation and negatively affects prognosis. Certain aetiological agents of chronic liver disease and loss of liver function per se favour the occurrence of pre-transplant diabetes in susceptible individuals, whereas immunosuppressant treatment, changes in lifestyle habits, and donor- and procedure-related factors contribute to diabetes development/persistence after transplantation. Challenges in the management of pre-transplant diabetes include the profound nutritional alterations characterizing cirrhotic individuals and the limitations to the use of drugs with liver metabolism. Special issues in the management of post-transplant diabetes include the diabetogenic potential of immunosuppressant drugs and the increased cardiovascular risk characterizing solid organ transplant survivors. Overall, the pharmacological management of cirrhotic patients undergoing liver transplantation is complicated by the lack of specific guidelines reflecting the paucity of data on the impact of glycaemic control and the safety and efficacy of anti-hyperglycaemic agents in these individuals.
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Affiliation(s)
- Valeria Grancini
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Veronica Resi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Eva Palmieri
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Diabetes Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Emanuela Orsi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
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Ray S, Maulik U, Mukhopadhyay A. A review of computational approaches for analysis of hepatitis C virus-mediated liver diseases. Brief Funct Genomics 2018; 17:428-440. [PMID: 29194530 DOI: 10.1093/bfgp/elx040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Chronic infection of hepatitis C virus (HCV) leads to severe life-threatening liver diseases such as cirrhosis of liver, fibrosis and hepatocellular carcinoma (HCC). Severity of the disease infects >180 million people worldwide. In recent years, many computational approaches have been proposed to study and analyze the progression of liver fibrosis, HCC and other liver diseases developed from chronic HCV infection. In this article, we review the literature published in this area of study. Here we categorize all the approaches into two basic groups: analyzing gene expression and studying protein-protein interaction network among HCV-infected human proteins. We also review functional and pathway-enrichment analysis of HCV-interacted human proteins, which gives a clear understanding of functional perturbations leading to hepatocarcinogenesis. Topological analysis of HCV-human protein interaction network and HCV-HCC association network reveals important information of hepatocarcinogenesis progression in liver tissue. We compare the results of topological analysis performed in different studies. Moreover we observe that the HCV-interacted human proteins, which are also responsible for HCC progression, have relatively higher degree and betweenness centrality than that of the other HCV-interacted proteins.
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Affiliation(s)
- Sumanta Ray
- Department of Computer Science and Engineering, Aliah University, Kolkata, India
| | - Ujjwal Maulik
- Department of Computer Science and Engineering, Jadavpur University, Kolkata, India
| | - Anirban Mukhopadhyay
- Department of Computer Science and Engineering, University of Kalyani, Kalyani, India
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12
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Shahnazarian V, Ramai D, Reddy M, Mohanty S. Hepatitis C virus genotype 3: clinical features, current and emerging viral inhibitors, future challenges. Ann Gastroenterol 2018; 31:541-551. [PMID: 30174390 PMCID: PMC6102453 DOI: 10.20524/aog.2018.0281] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/18/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatitis C virus (HCV) represents a global burden on healthcare that affects over 150 million people worldwide. In the past, HCV genotype 3 was considered difficult to treat relative to other genotypes. Genotype 3 has been associated with a higher rate of complications, including fatty liver disease, fibrosis, hepatocellular carcinoma and mortality. However, with the advent of first- and second-generation direct-acting antivirals, genotype 3 can be treated effectively. Additionally, these new drugs are well tolerated by patients and have significantly fewer side effects compared to ribavirin and interferon-based regimens. However, while great strides have been made in overcoming biological barriers, our next challenge lies in overcoming economic and financial obstacles if we are to eradicate HCV genotype 3. Herein, we review the clinical features associated with HCV genotype 3, current and emerging treatment regimens, and challenges associated with treatment.
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Affiliation(s)
- Vahe Shahnazarian
- Division of Gastroenterology, Hepatology, and Advanced Endoscopy, The Brooklyn Hospital Center, Academic Affiliate of The Icahn School of Medicine at Mount Sinai, Clinical Affiliate of The Mount Sinai Hospital, Brooklyn, NY (Vahe Shahnazarian, Daryl Ramai, Madhavi Reddy), USA
| | - Daryl Ramai
- Division of Gastroenterology, Hepatology, and Advanced Endoscopy, The Brooklyn Hospital Center, Academic Affiliate of The Icahn School of Medicine at Mount Sinai, Clinical Affiliate of The Mount Sinai Hospital, Brooklyn, NY (Vahe Shahnazarian, Daryl Ramai, Madhavi Reddy), USA
- School of Medicine, St George’s University, True Blue, Grenada, WI (Daryl Ramai), USA
| | - Madhavi Reddy
- Division of Gastroenterology, Hepatology, and Advanced Endoscopy, The Brooklyn Hospital Center, Academic Affiliate of The Icahn School of Medicine at Mount Sinai, Clinical Affiliate of The Mount Sinai Hospital, Brooklyn, NY (Vahe Shahnazarian, Daryl Ramai, Madhavi Reddy), USA
| | - Smruti Mohanty
- Division of Gastroenterology and Hepatology, New York Presbyterian Brooklyn Methodist Hospital, Clinical Affiliate of Weill Cornell Medicine, Brooklyn, NY (Smruti Mohanty), USA
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Abstract
As the cirrhosis progresses, development of complication like ascites, hepatic encephalopathy, variceal bleeding, kidney dysfunction, and hepatocellular carcinoma signify increasing risk of short term mortality. Malnutrition and muscle wasting (sarcopenia) is yet other complications that negatively impact survival, quality of life, and response to stressors, such as infection and surgery in patients with cirrhosis. Conventionally, these are not routinely looked for, because nutritional assessment can be a difficult especially if there is associated fluid retention and/or obesity. Patients with cirrhosis may have a combination of loss of skeletal muscle and gain of adipose tissue, culminating in the condition of "sarcopenic obesity." Sarcopenia in cirrhotic patients has been associated with increased mortality, sepsis complications, hyperammonemia, overt hepatic encephalopathy, and increased length of stay after liver transplantation. Assessment of muscles with cross-sectional imaging studies has become an attractive index of nutritional status evaluation in cirrhosis, as sarcopenia, the major component of malnutrition, is primarily responsible for the adverse clinical consequences seen in patients with liver disease. Cirrhosis is a state of accelerated starvation, with increased gluconeogenesis that requires amino acid diversion from other metabolic functions. Protein homeostasis is disturbed in cirrhosis due to several factors such as hyperammonemia, hormonal, and cytokine abnormalities, physical inactivity and direct effects of ethanol and its metabolites. New approaches to manage sarcopenia are being evolved. Branched chain amino acid supplementation, Myostatin inhibitors, and mitochondrial protective agents are currently in various stages of evaluation in preclinical studies to prevent and reverse sarcopenia, in cirrhosis.
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Key Words
- (PG) SGA, patient-generated SGA
- AMPK, 5′ adenosine monophosphate-activated protein kinase
- ASPEN, American Society of Parenteral and Enteral Nutrition
- ATP, adenosine triphosphate
- Akt/PKB, serine/threonine-specific protein kinase B
- BIA, bio-electric impedance analysis
- BMC, bone mineral content
- BMI, body mass index
- CT, computed tomography
- DDLT, deceased donor liver transplantation
- DRM, disease-related malnutrition
- DXA, dual X-ray absorptiometry
- ESPEN, European Society of Parenteral and Enteral Nutrition
- FFI, Fried Frailty Index
- FFM, fat free mass
- FFMI, fat free mass index
- FM, fat mass
- HE, hepatic encephalopathy
- LDLT, living donor liver transplant
- LST, lean soft tissue
- MAC, mid arm circumference
- MAMC, mid arm muscle circumference
- MELD, model for end-stage liver disease
- MNA, Mini Nutritional Assessment
- MRI, magnetic resonance imaging
- NASH, non-alcoholic steatohepatitis
- PCM, protein-calorie nalnutrition
- REE, resting energy expenditure
- RQ, respiratory quotient (or RQ or respiratory coefficient)
- SGA, Subjective Global Assessment
- SMI, Skeletal Muscle Index
- SPPB, Short Physical Performance Battery
- TIPS, trans jugular intrahepatic portocaval shunts
- TNF, tumour necrosis factor
- TSF, triceps skin fild thickness
- WHO, World Health Organisation
- YPA, total psoas area
- aKG, alfa keto glutarate
- cirrhosis
- mTORC1, mammalian target of rapamycin complex 1
- nutrition
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14
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Ciancio A, Bosio R, Bo S, Pellegrini M, Sacco M, Vogliotti E, Fassio G, Bianco Mauthe Degerfeld AGF, Gallo M, Giordanino C, Terzi di Bergamo L, Ribaldone D, Bugianesi E, Smedile A, Rizzetto M, Saracco GM. Significant improvement of glycemic control in diabetic patients with HCV infection responding to direct-acting antiviral agents. J Med Virol 2017; 90:320-327. [DOI: 10.1002/jmv.24954] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 09/19/2017] [Indexed: 02/06/2023]
Affiliation(s)
- Alessia Ciancio
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Roberta Bosio
- Gastroenterology Unit; San Luigi Hospital; University of Turin; Torino Italy
| | - Simona Bo
- Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Marianna Pellegrini
- Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Marco Sacco
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Edoardo Vogliotti
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Giulia Fassio
- Gastroenterology Unit; San Luigi Hospital; University of Turin; Torino Italy
| | | | - Monica Gallo
- Gastroenterology Unit; San Luigi Hospital; University of Turin; Torino Italy
| | - Chiara Giordanino
- Gastroenterology Unit; San Luigi Hospital; University of Turin; Torino Italy
| | - Lodovico Terzi di Bergamo
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Davide Ribaldone
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Elisabetta Bugianesi
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Antonina Smedile
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Mario Rizzetto
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Giorgio Maria Saracco
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
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15
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Abstract
It is critical to recognize that hepatitis C virus (HCV) infection is, in fact, a multifaceted systemic disease with both hepatic and extrahepatic complications. It is also important to recognize that the comprehensive burden of HCV should include not only its clinical burden but also its burden on the economic and patient-reported outcomes. It is only through this comprehensive approach to HCV infection that we can fully appreciate its true burden and understand the full benefit of curing HCV for the patient and the society.
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Affiliation(s)
- Zobair M Younossi
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, 3300 Gallows Road, Falls Church, VA 22042, USA; Department of Medicine, Center for Liver Disease, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042, USA.
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16
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Orsi E, Grancini V, Menini S, Aghemo A, Pugliese G. Hepatogenous diabetes: Is it time to separate it from type 2 diabetes? Liver Int 2017; 37:950-962. [PMID: 27943508 DOI: 10.1111/liv.13337] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 11/29/2016] [Indexed: 12/12/2022]
Abstract
By definition, hepatogenous diabetes is directly caused by loss of liver function, implying that it develops after cirrhosis onset. Therefore, it should be distinguished from type 2 diabetes developing before cirrhosis onset, in which specific causes of liver disease play a major role, in addition to traditional risk factors. Currently, although hepatogenous diabetes shows distinct pathophysiological and clinical features, it is not considered as an autonomous entity. Recent evidence suggests that the failing liver exerts an independent "toxic" effect on pancreatic islets resulting in β-cell dysfunction. Moreover, patients with hepatogenous diabetes usually present with normal fasting glucose and haemoglobin A1c levels and abnormal response to an oral glucose tolerance test, which is therefore required for diagnosis. This article discusses the need to separate hepatogenous diabetes from type 2 diabetes occurring in subjects with chronic liver disease and to identify individuals suffering from this condition for prognostic and therapeutic purposes.
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Affiliation(s)
- Emanuela Orsi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy.,Department of Medical Sciences, University of Milan, Milan, Italy
| | - Valeria Grancini
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy.,Department of Medical Sciences, University of Milan, Milan, Italy
| | - Stefano Menini
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.,Diabetes Unit, Sant'Andrea Hospital, Rome, Italy
| | - Alessio Aghemo
- Division of Gastroenterology and Hepatology, A.M. and A. Migliavacca Center for Liver Disease, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.,Diabetes Unit, Sant'Andrea Hospital, Rome, Italy
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17
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Desbois AC, Cacoub P. Diabetes mellitus, insulin resistance and hepatitis C virus infection: A contemporary review. World J Gastroenterol 2017; 23:1697-1711. [PMID: 28321170 PMCID: PMC5340821 DOI: 10.3748/wjg.v23.i9.1697] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 11/10/2016] [Accepted: 02/08/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To summarise the literature data on hepatitis C virus (HCV)-infected patients concerning the prevalence of glucose abnormalities and associated risk.
METHODS We conducted a PubMed search and selected all studies found with the key words "HCV" or "hepatitis C virus" and "diabetes" or "insulin resistance". We included only comparative studies written in English or in French, published from January 2000 to April 2015. We collected the literature data on HCV-infected patients concerning the prevalence of glucose abnormalities [diabetes mellitus (DM) and insulin resistance (IR)] and associated risk [i.e., severe liver fibrosis, response to antivirals, and the occurrence of hepatocellular carcinoma (HCC)].
RESULTS HCV infection is significantly associated with DM/IR compared with healthy volunteers and patients with hepatitis B virus infection. Glucose abnormalities were associated with advanced liver fibrosis, lack of sustained virologic response to interferon alfa-based treatment and with a higher risk of HCC development. As new antiviral therapies may offer a cure for HCV infection, such data should be taken into account, from a therapeutic and preventive point of view, for liver and non-liver consequences of HCV disease. The efficacy of antidiabetic treatment in improving the response to antiviral treatment and in decreasing the risk of HCC has been reported by some studies but not by others. Thus, the effects of glucose abnormalities correction in reducing liver events need further studies.
CONCLUSION Glucose abnormalities are strongly associated with HCV infection and show a negative impact on the main liver related outcomes.
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18
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Saeed MJ, Olsen MA, Powderly WG, Presti RM. Diabetes Mellitus is Associated With Higher Risk of Developing Decompensated Cirrhosis in Chronic Hepatitis C Patients. J Clin Gastroenterol 2017; 51:70-76. [PMID: 27306942 PMCID: PMC5154898 DOI: 10.1097/mcg.0000000000000566] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
GOALS To investigate the association of diabetes with risk of decompensated cirrhosis in patients with chronic hepatitis C (CHC). BACKGROUND Direct-acting antivirals are highly effective in treating CHC but very expensive. CHC patients at high risk of progression to symptomatic liver disease may benefit most from early treatment. STUDY We conducted a retrospective cohort study using the 2006 to 2013 Truven Health Analytics MarketScan Commercial Claims and Encounters database including inpatient, outpatient, and pharmacy claims from private insurers. CHC and cirrhosis were identified using ICD-9-CM diagnosis codes; baseline diabetes was identified by diagnosis codes or antidiabetic medications. CHC patients were followed to identify decompensated cirrhosis. Multivariable Cox proportional hazards regression was used to model the risk of decompensated cirrhosis by baseline cirrhosis. RESULTS There were 75,805 CHC patients with median 1.9 years follow-up. A total of 10,317 (13.6%) of the CHC population had diabetes. The rates of decompensated cirrhosis per 1000 person-years were: 185.5 for persons with baseline cirrhosis and diabetes, 119.8 for persons with cirrhosis and no diabetes, 35.3 for persons with no cirrhosis and diabetes, and 17.1 for persons with no cirrhosis and no diabetes. Diabetes was associated with increased risk of decompensated cirrhosis in persons with baseline cirrhosis (adjusted hazard ratio=1.4; 95% confidence interval, 1.3-1.6) and in persons without baseline cirrhosis (adjusted hazard ratio=1.9; 95% confidence interval, 1.7-2.1). CONCLUSIONS In a privately insured US population with CHC, the adjusted risk of decompensated cirrhosis was higher in diabetic compared with nondiabetic patients. Diabetes status should be included in prioritization of antiviral treatment.
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Affiliation(s)
- Mohammed J Saeed
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Margaret A Olsen
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - William G Powderly
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Rachel M Presti
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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19
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Lonardo A, Ballestri S, Guaraldi G, Nascimbeni F, Romagnoli D, Zona S, Targher G. Fatty liver is associated with an increased risk of diabetes and cardiovascular disease - Evidence from three different disease models: NAFLD, HCV and HIV. World J Gastroenterol 2016; 22:9674-9693. [PMID: 27956792 PMCID: PMC5124973 DOI: 10.3748/wjg.v22.i44.9674] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 09/29/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023] Open
Abstract
Fatty liver, which frequently coexists with necro-inflammatory and fibrotic changes, may occur in the setting of nonalcoholic fatty liver disease (NAFLD) and chronic infections due to either hepatitis C virus (HCV) or human immunodeficiency virus (HIV). These three pathologic conditions are associated with an increased prevalence and incidence of cardiovascular disease (CVD) and type 2 diabetes (T2D). In this multidisciplinary clinical review, we aim to discuss the ever-expanding wealth of clinical and epidemiological evidence supporting a key role of fatty liver in the development of T2D and CVD in patients with NAFLD and in those with HCV or HIV infections. For each of these three common diseases, the epidemiological features, pathophysiologic mechanisms and clinical implications of the presence of fatty liver in predicting the risk of incident T2D and CVD are examined in depth. Collectively, the data discussed in this updated review, which follows an innovative comparative approach, further reinforce the conclusion that the presence of fatty/inflamed/fibrotic liver might be a shared important determinant for the development of T2D and CVD in patients with NAFLD, HCV or HIV. This review may also open new avenues in the clinical and research arenas and paves the way for the planning of future, well-designed prospective and intervention studies.
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20
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Sinclair M, Gow PJ, Grossmann M, Shannon A, Hoermann R, Angus PW. Low serum testosterone is associated with adverse outcome in men with cirrhosis independent of the model for end-stage liver disease score. Liver Transpl 2016; 22:1482-1490. [PMID: 27542090 DOI: 10.1002/lt.24607] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 07/25/2016] [Accepted: 08/02/2016] [Indexed: 12/13/2022]
Abstract
Low serum testosterone has been retrospectively associated with mortality in men on the liver transplant waiting list. The impact of testosterone deficiency on other outcomes has not previously been assessed. We conducted a single center prospective observational study of all men with cirrhosis seen between 2013 and 2014. Baseline data included sex hormone profile, Model for End-Stage Liver Disease (MELD) score, and standard biochemistry. Outcomes were recorded over 12 months including major infection, liver transplantation, and death. Of 268 cirrhotic men, the median MELD score was 10 (interquartile range [IQR], 8-15) and median serum testosterone was 17.4 nmol/L (IQR, 8.9-25.0 nmol/L). During the study period, 32 (12%) men died, 18 (7%) received a liver transplant, and 51 (19%) suffered a major infection. Mortality markedly increased when total testosterone fell below a threshold value of 8.3 nmol/L, and this cutoff was used for further analysis. Testosterone below 8.3 nmol/L was associated with the combined outcome of death or transplantation independently of the MELD score (hazard ratio [HR], 2.36; IQR, 1.16-4.81; P = 0.02) for testosterone (and HR, 1.22; IQR, 1.18-1.27; P < 0.001 for MELD). Low total testosterone was also an independent risk factor for major infection (HR, 3.61; IQR, 1.61-8.06; P < 0.001) and nearly significant for mortality alone (HR, 2.39; IQR, 0.97-5.88; P = 0.057). Low free testosterone (<139 pmol/L) was similarly independently associated with death or transplantation (HR, 2.43; IQR, 1.12-5.29; P = 0.03) and infection (HR, 3.3; IQR, 1.46-7.46; P = 0.004). In conclusion, low testosterone is a novel prognostic marker in men with cirrhosis that is numerically associated with increased mortality or need for transplantation, as well as risk for major infection. Interventional studies of testosterone therapy are required to investigate whether correcting low testosterone can reduce mortality and improve other clinical outcomes. Liver Transplantation 22 1482-1490 2016 AASLD.
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Affiliation(s)
- Marie Sinclair
- Liver Transplant Unit, University of Melbourne, Melbourne, Victoria, Australia. .,Department of Medicine, Gastroenterology and Hepatology, Austin Health, Melbourne, Victoria, Australia.
| | - Paul J Gow
- Liver Transplant Unit, University of Melbourne, Melbourne, Victoria, Australia.,Department of Medicine, Gastroenterology and Hepatology, Austin Health, Melbourne, Victoria, Australia
| | - Mathis Grossmann
- Liver Transplant Unit, University of Melbourne, Melbourne, Victoria, Australia.,Endocrine Unit, Endocrinology, Austin Health, Melbourne, Victoria, Australia
| | - Adam Shannon
- Liver Transplant Unit, University of Melbourne, Melbourne, Victoria, Australia
| | - Rudolf Hoermann
- Liver Transplant Unit, University of Melbourne, Melbourne, Victoria, Australia
| | - Peter W Angus
- Liver Transplant Unit, University of Melbourne, Melbourne, Victoria, Australia.,Department of Medicine, Gastroenterology and Hepatology, Austin Health, Melbourne, Victoria, Australia
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21
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Sinclair M, Grossmann M, Hoermann R, Angus PW, Gow PJ. Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: A randomised controlled trial. J Hepatol 2016; 65:906-913. [PMID: 27312945 DOI: 10.1016/j.jhep.2016.06.007] [Citation(s) in RCA: 174] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/02/2016] [Accepted: 06/07/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Low testosterone and sarcopenia are common in men with cirrhosis and both are associated with increased mortality. Whether testosterone therapy in cirrhosis improves muscle mass and other outcomes is unknown. METHODS We conducted a 12-month, double-blinded, placebo-controlled trial of intramuscular testosterone undecanoate in 101 men with established cirrhosis and low serum testosterone (total testosterone <12nmol/L or free testosterone <230pmol/L) in a single tertiary centre. Body composition was assessed using dual-energy X-ray absorptiometry at baseline, 6 and 12months. RESULTS At study completion, appendicular lean mass was significant higher in testosterone-treated subjects, with a mean adjusted difference (MAD) of +1.69kg, (CI +0.40; +2.97kg, p=0.021). Secondary outcomes included a substantially higher total lean mass in the active group (MAD +4.74kg, CI +1.75; +7.74kg, p=0.008), matched by reduced fat mass (MAD -4.34kg, CI -6.65; -2.04, p<0.001). Total bone mass increased (MAD +0.08kg, CI +0.01; +0.15kg, p=0.009) as did bone mineral density at the femoral neck (MAD +0.287points, CI +0.140; +0.434, p<0.001). Haemoglobin was higher with testosterone therapy (MAD +10.2g/L, CI +1.50; +18.9g/L, p=0.041) and percentage glycosylated haemoglobin (HbA1c) lower (MAD -0.35%, CI -0.05; -0.54, p=0.028). Mortality was non-significantly lower in testosterone-treated patients (16% vs. 25.5%, p=0.352). There was no increase in adverse events in testosterone-treated subjects. CONCLUSION Testosterone therapy in men with cirrhosis and low serum testosterone safely increases muscle mass, bone mass and haemoglobin, and reduces fat mass and HbA1c. This is the first evidence-based therapy for sarcopenia in cirrhosis and thus requires larger-scale investigation into its potential impact on mortality. LAY SUMMARY Both low testosterone and muscle wasting are associated with increased risk of death in men with severe liver disease. Administering testosterone to men with liver disease who have low testosterone levels significantly increases their muscle mass. In addition, testosterone has non-muscle beneficial effects which may be able to increase survival in this population. CLINICAL TRIAL NUMBER Australian New Zealand Clinical Trials Registry trial number ACTRN 12614000526673.
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Affiliation(s)
- Marie Sinclair
- The University of Melbourne, Australia; Gastroenterology and Hepatology, Austin Health, Melbourne, Australia.
| | - Mathis Grossmann
- The University of Melbourne, Australia; Endocrinology, Austin Health, Melbourne, Australia
| | | | - Peter W Angus
- The University of Melbourne, Australia; Gastroenterology and Hepatology, Austin Health, Melbourne, Australia
| | - Paul J Gow
- The University of Melbourne, Australia; Gastroenterology and Hepatology, Austin Health, Melbourne, Australia
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22
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Younossi ZM, Birerdinc A, Henry L. Hepatitis C infection: A multi-faceted systemic disease with clinical, patient reported and economic consequences. J Hepatol 2016; 65:S109-S119. [PMID: 27641981 DOI: 10.1016/j.jhep.2016.07.005] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 07/02/2016] [Accepted: 07/04/2016] [Indexed: 12/21/2022]
Abstract
Hepatitis C virus infection (HCV) affects approximately 170-200 million individuals globally. HCV is one of the primary causes of hepatocellular carcinoma (HCC) and cirrhosis and has been identified as the leading indication for liver transplantation in most Western countries. Because HCV is a systemic disease with hepatic, extrahepatic, economic and patient reported consequences, it is important for healthcare practitioners to understand the comprehensive and multi-faceted picture of this disease. In this context, it is important to fully appreciate the impact of HCV on the individual patient and the society. With the recent advent of the new generation of direct antiviral agents, the long standing goal of eradicating HCV in most infected patients has been accomplished. Therefore, now more than ever, it is critical to assess the total benefits of sustained virological response in a comprehensive manner. This should not be limited to the clinical benefits of HCV cure, but also to account for the improvement of patient reported health and economic outcomes of HCV cure. It is only through this comprehensive approach to HCV and its treatment that we will understand the full impact of this disease and the tremendous gains that have been achieved with the new antiviral regimens.
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Affiliation(s)
- Zobair M Younossi
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, USA.
| | - Aybike Birerdinc
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, USA
| | - Linda Henry
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, USA
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23
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Sinclair M, Gow PJ, Grossmann M, Angus PW. Review article: sarcopenia in cirrhosis--aetiology, implications and potential therapeutic interventions. Aliment Pharmacol Ther 2016; 43:765-77. [PMID: 26847265 DOI: 10.1111/apt.13549] [Citation(s) in RCA: 220] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 12/12/2015] [Accepted: 01/14/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Sarcopenia (loss of muscle mass) is common in cirrhosis and is associated with poor outcomes. Current teaching recommends the use of protein supplementation and exercise, however, this fails to address many other factors which contribute to muscle loss in this setting. AIMS To summarise existing knowledge regarding the aetiology of sarcopenia in cirrhosis, diagnostic modalities and the clinical significance of this condition. In addition to discuss recent research findings that may allow the development of more effective treatments. METHODS We conducted a Medline and PubMed search using the search terms 'sarcopenia', 'muscle', 'body composition', 'cirrhosis', 'liver' and 'malnutrition' from inception to October 2015. RESULTS Cirrhotic patients with sarcopenia have reduced survival, experience increased rates of infection and have worse outcomes following liver transplantation. The aetiology of this condition is more complex than simple protein and calorie malnutrition. Cirrhosis also results in depleted glycogen stores and metabolic alterations that cause excessive protein catabolism, increased activation of the ubiquitin-proteasome pathway and inappropriate muscle autophagy. Satellite cell differentiation and proliferation is also reduced due to a combination of elevated myostatin levels, reduced IGF-1 and hypogonadism. Although there is some evidence supporting the use of late evening snacks, branched chain amino acid supplementation and high protein/high calorie diets, well designed clinical trials addressing the effects of treatment on body composition in cirrhosis are lacking. CONCLUSION Sarcopenia in cirrhosis has a complex pathogenesis and simple dietary interventions are insufficient. Improved understanding of the multiple mechanisms involved should allow the development of more effective therapies, which target the specific underlying metabolic derangements.
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Affiliation(s)
- M Sinclair
- Liver Transplant Unit, Austin Hospital, Melbourne, Vic., Australia.,Department of Medicine, The University of Melbourne, Melbourne, Vic., Australia
| | - P J Gow
- Liver Transplant Unit, Austin Hospital, Melbourne, Vic., Australia.,Department of Medicine, The University of Melbourne, Melbourne, Vic., Australia
| | - M Grossmann
- Endocrinology Unit, Austin Hospital, Melbourne, Vic., Australia.,Department of Medicine, The University of Melbourne, Melbourne, Vic., Australia
| | - P W Angus
- Liver Transplant Unit, Austin Hospital, Melbourne, Vic., Australia.,Department of Medicine, The University of Melbourne, Melbourne, Vic., Australia
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24
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Calzadilla-Bertot L, Vilar-Gomez E, Torres-Gonzalez A, Socias-Lopez M, Diago M, Adams LA, Romero-Gomez M. Impaired glucose metabolism increases risk of hepatic decompensation and death in patients with compensated hepatitis C virus-related cirrhosis. Dig Liver Dis 2016; 48:283-90. [PMID: 26797261 DOI: 10.1016/j.dld.2015.12.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 11/30/2015] [Accepted: 12/03/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Glucose metabolism abnormalities frequently coexist with liver cirrhosis; however, the impact of these on liver-related outcomes has not been fully investigated. AIMS We examined the influence of glucose abnormalities on overall mortality and liver-related complications in cirrhotic patients. METHODS A prospective cohort of 250 subjects with compensated hepatitis C virus-related cirrhosis and without known diabetes underwent an oral glucose tolerance test and were subsequently followed for a median 201 weeks. RESULTS At baseline, 67 (27%) had type 2 diabetes. During follow-up, 28 deaths and 55 first events of decompensation occurred. After adjustment for potential confounding covariates, overall mortality/liver transplant (sHR: 2.2, 95% CI: 1.04-4.6, P=0.04) and hepatic decompensation events (sHR: 1.9, 95% CI: 1.05-3.3, P=0.03) were significantly higher in diabetic patients. Subjects with a HOMA-IR >5 showed higher rates of mortality (sHR: 2.2, 95% CI: 1.03-4.8, P=0.04). The rates of hepatic decompensation were higher in patients with HOMA-IR >3 (sHR: 1.7, 95% CI: 1.04-2.9, P=0.03). Overall, 2h-plasma glucose was the most robust predictor of overall mortality (sHR: 2.5, 95% CI: 1.03-6, P=0.04) and decompensation (sHR: 2.7, 95% CI: 1.4-5.5, P<0.01). CONCLUSIONS In compensated HCV-related cirrhotic patients, diabetes and marked insulin resistance are independently associated with poorer overall survival and increased risk of hepatic decompensation.
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Affiliation(s)
| | - Eduardo Vilar-Gomez
- Department of Hepatology, National Institute of Gastroenterology, Havana, Cuba; Unit for the Clinical Management of Digestive Diseases, Macarena and Virgen del Rocio University Hospital, Ciberehd, Institute of Biomedicine, University of Seville, Seville, Spain.
| | - Ana Torres-Gonzalez
- Department of Hepatology, National Institute of Gastroenterology, Havana, Cuba
| | - Maray Socias-Lopez
- Department of Hepatology, National Institute of Gastroenterology, Havana, Cuba
| | - Moises Diago
- Liver Unit, Department of Gastroenterology, Valencia University General Hospital, Valencia, Spain
| | - Leon A Adams
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital, Perth, Australia
| | - Manuel Romero-Gomez
- Unit for the Clinical Management of Digestive Diseases, Macarena and Virgen del Rocio University Hospital, Ciberehd, Institute of Biomedicine, University of Seville, Seville, Spain
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25
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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.
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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.
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26
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Watt GP, Vatcheva KP, Beretta L, Pan JJ, Fallon MB, McCormick JB, Fisher-Hoch SP. Hepatitis C virus in Mexican Americans: a population-based study reveals relatively high prevalence and negative association with diabetes. Epidemiol Infect 2016; 144:297-305. [PMID: 26088260 PMCID: PMC5013540 DOI: 10.1017/s0950268815001247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
This study aimed to estimate the prevalence and risk factors for hepatitis C virus (HCV) infection in Mexican Americans living in South Texas. We tested plasma for the presence of HCV antibody from the Cameron County Hispanic Cohort (CCHC), a randomized, population-based cohort in an economically disadvantaged Mexican American community on the United States/Mexico border with high rates of chronic disease. A weighted prevalence of HCV antibody of 2·3% [n = 1131, 95% confidence interval (CI) 1·2-3·4] was found. Participants with diabetes had low rates of HCV antibody (0·4%, 95% CI 0·0-0·9) and logistic regression revealed a statistically significant negative association between HCV and diabetes (OR 0·20, 95% CI 0·05-0·77) after adjusting for sociodemographic and clinical factors. This conflicts with reported positive associations of diabetes and HCV infection. No classic risk factors were identified, but important differences between genders emerged in analysis. This population-based study of HCV in Mexican Americans suggests that national studies do not adequately describe the epidemiology of HCV in this border community and that unique risk factors may be involved.
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Affiliation(s)
- G P Watt
- School of Public Health,University of Texas Health Science Center at Houston,Brownsville Regional Campus,Brownsville,TX,USA
| | - K P Vatcheva
- School of Public Health,University of Texas Health Science Center at Houston,Brownsville Regional Campus,Brownsville,TX,USA
| | - L Beretta
- Department of Molecular and Cellular Oncology,University of Texas MD Anderson Cancer Center,Houston,TX,USA
| | - J J Pan
- Department of Internal Medicine,University of Texas Health Science Center at Houston Medical School,Houston,TX,USA
| | - M B Fallon
- Department of Internal Medicine,University of Texas Health Science Center at Houston Medical School,Houston,TX,USA
| | - J B McCormick
- School of Public Health,University of Texas Health Science Center at Houston,Brownsville Regional Campus,Brownsville,TX,USA
| | - S P Fisher-Hoch
- School of Public Health,University of Texas Health Science Center at Houston,Brownsville Regional Campus,Brownsville,TX,USA
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Gürbüz Y, Tülek NE, Tütüncü EE, Koruk ST, Aygen B, Demirtürk N, Kınıklı S, Kaya A, Yıldırmak T, Süer K, Korkmaz F, Ural O, Akhan S, Günal Ö, Tuna N, Köse Ş, Gönen İ, Örmen B, Türker N, Saltoğlu N, Batırel A, Tuncer G, Bulut C, Sırmatel F, Ulçay A, Karagöz E, Tosun D, Şener A, Aynıoğlu A, Altunok ES. Evaluation of Dual Therapy in Real Life Setting in Treatment-Naïve Turkish Patients with HCV Infection: A Multicenter, Retrospective Study. Balkan Med J 2016; 33:18-26. [PMID: 26966614 DOI: 10.5152/balkanmedj.2015.15859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 09/30/2015] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Before the introduction of direct-acting antivirals in the treatment of chronic hepatitis C patients, the combination of peginterferon alpha and ribavirin was the standard therapy. Observational studies that investigated sustained virological response (SVR) rates by these drugs yielded different outcomes. AIMS The goal of the study was to demonstrate real life data concerning SVR rate achieved by peginterferon alpha plus ribavirin in patients who were treatment-naïve. STUDY DESIGN A multicenter, retrospective observational study. METHODS The study was conducted retrospectively on 1214 treatment naïve-patients, being treated with peginterferon alpha-2a or 2b plus ribavirin in respect of the current guidelines between 2005 and 2013. The patients' data were collected from 22 centers via a standard form, which has been prepared for this study. The data included demographic and clinical characteristics (gender, age, body weight, initial Hepatitis C virus RNA (HCV RNA) level, disease staging) as well as course of treatment (duration of treatment, outcomes, discontinuations and adverse events). Renal insufficiency, decompensated liver disease, history of transplantation, immunosuppressive therapy or autoimmune liver disease were exclusion criteria for the study. Treatment efficacy was assessed according to the patient's demographic characteristics, baseline viral load, genotype, and fibrosis scores. RESULTS The mean age of the patients was 50.74 (±0.64) years. Most of them were infected with genotype 1 (91.8%). SVR was achieved in 761 (62.7%) patients. SVR rate was 59.1% in genotype 1, 89.4% in genotype 2, 93.8% in genotype 3, and 33.3% in genotype 4 patients. Patients with lower viral load yielded higher SVR (65.8% vs. 58.4%, p=0.09). SVR rates according to histologic severity were found to be 69.3%, 66.3%, 59.9%, 47.3%, and 45.5% in patients with fibrosis stage 0, 1, 2, 3 and 4, respectively. The predictors of SVR were male gender, genotype 2/3, age less than 45 years, low fibrosis stage, low baseline viral load and presence of early virological response. SVR rates to each peginterferon were found to be similar in genotype 1/4 although SVR rates were found to be higher for peginterferon alpha-2b in patients with genotype 2/3. The number of patients who failed to complete treatment due to adverse effects was 33 (2.7%). The number of patients failed to complete treatment due to adverse effects was 33 (2.7%). CONCLUSION Our findings showed that the rate of SVR to dual therapy was higher in treatment-naïve Turkish patients than that reported in randomized controlled trials. Also peginterferon alpha-2a and alpha-2b were found to be similar in terms of SVR in genotype 1 patients.
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Affiliation(s)
- Yunus Gürbüz
- Department of Infectious Diseases and Clinical Microbiology, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
| | - Necla Eren Tülek
- Department of Infectious Diseases and Clinical Microbiology, Ankara Training and Research Hospital, Ankara, Turkey
| | - Emin Ediz Tütüncü
- Department of Infectious Diseases and Clinical Microbiology, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
| | - Süda Tekin Koruk
- Department of Infectious Diseases and Clinical Microbiology, Harran University Faculty of Medicine, Şanlıurfa, Turkey
| | - Bilgehan Aygen
- Department of Infectious Diseases and Clinical Microbiology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Neşe Demirtürk
- Department of Infectious Diseases and Clinical Microbiology, Afyon Kocatepe University Faculty of Medicine, Afyonkarahisar, Turkey
| | - Sami Kınıklı
- Department of Infectious Diseases and Clinical Microbiology, Ankara Training and Research Hospital, Ankara, Turkey
| | - Ali Kaya
- Department of Infectious Diseases and Clinical Microbiology, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Taner Yıldırmak
- Department of Infectious Diseases and Clinical Microbiology, Okmeydanı Training and Research Hospital, İstanbul, Turkey
| | - Kaya Süer
- Department of Infectious Diseases and Clinical Microbiology, Near East University Faculty of Medicine, Nicosia, North Cyprus
| | - Fatime Korkmaz
- Department of Infectious Diseases and Clinical Microbiology, Konya Training and Research Hospital, Konya, Turkey
| | - Onur Ural
- Department of Infectious Diseases and Clinical Microbiology, Selçuk University Faculty of Medicine, Konya, Turkey
| | - Sıla Akhan
- Department of Infectious Diseases and Clinical Microbiology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Özgür Günal
- Department of Infectious Diseases and Clinical Microbiology, Gaziosmanpaşa University Faculty of Medicine, Tokat, Turkey
| | - Nazan Tuna
- Department of Infectious Diseases and Clinical Microbiology, Sakarya University Faculty of Medicine, Sakarya, Turkey
| | - Şükran Köse
- Department of Infectious Diseases and Clinical Microbiology, Tepecik Training and Research Hospital, İzmir, Turkey
| | - İbak Gönen
- Department of Infectious Diseases and Clinical Microbiology, Süleyman Demirel University Faculty of Medicine, Isparta, Turkey
| | - Bahar Örmen
- Department of Infectious Diseases and Clinical Microbiology, İzmir Katip Çelebi University Atatürk Training and Research Hospital, İzmir, Turkey
| | - Nesrin Türker
- Department of Infectious Diseases and Clinical Microbiology, İzmir Katip Çelebi University Atatürk Training and Research Hospital, İzmir, Turkey
| | - Neşe Saltoğlu
- Department of Infectious Diseases and Clinical Microbiology, İstanbul University Cerrahpaşa Faculty of Medicine, İstanbul, Turkey
| | - Ayşe Batırel
- Department of Infectious Diseases and Clinical Microbiology, Kartal Dr. Lütfi Kırdar Training and Research Hospital, İstanbul, Turkey
| | - Günay Tuncer
- Department of Infectious Diseases and Clinical Microbiology, Ankara Training and Research Hospital, Ankara, Turkey
| | - Cemal Bulut
- Department of Infectious Diseases and Clinical Microbiology, Ankara Training and Research Hospital, Ankara, Turkey
| | - Fatma Sırmatel
- Department of Infectious Diseases and Clinical Microbiology, Abant İzzet Baysal University Faculty of Medicine, Bolu, Turkey
| | - Asım Ulçay
- Department of Infectious Diseases and Clinical Microbiology, GATA Haydarpaşa Training and Research Hospital, İstanbul, Turkey
| | - Ergenekon Karagöz
- Department of Infectious Diseases and Clinical Microbiology, GATA Haydarpaşa Training and Research Hospital, İstanbul, Turkey
| | - Derviş Tosun
- Department of Infectious Diseases and Clinical Microbiology, Ulus State Hospital, Ankara, Turkey
| | - Alper Şener
- Department of Infectious Diseases and Clinical Microbiology, Çanakkale Onsekiz Mart University Faculty of Medicine, Çanakkale, Turkey
| | - Aynur Aynıoğlu
- Department of Infectious Diseases and Clinical Microbiology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Elif Sargın Altunok
- Department of Infectious Diseases and Clinical Microbiology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
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Read SA, Tay ES, Shahidi M, McLauchlan J, George J, Douglas MW. The Mechanism of Interferon Refractoriness During Hepatitis C Virus Infection and Its Reversal with a Peroxisome Proliferator-Activated Receptor α Agonist. J Interferon Cytokine Res 2015; 35:488-97. [PMID: 25734487 DOI: 10.1089/jir.2014.0209] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Patients who respond poorly to therapies for hepatitis C virus (HCV) infection display a characteristic phenotype with high basal hepatic interferon-stimulated gene (ISG) expression, but limited induction following interferon (IFN) treatment. The molecular pathways that mediate this refractory state are not known. We examined whether the AMPK activator metformin, the PPARγ agonist pioglitazone, or the PPARα agonist WY-14643 could potentiate IFN responses, reverse IFN refractoriness, and enhance viral eradication in hepatocytes. WY-14643 demonstrated the strongest antiviral synergy with IFN-α and so was tested in the context of chronic IFN activation. Cells rendered refractory to IFN by IFN-α pretreatment were resensitized by WY-14643, as demonstrated by improved STAT1 phosphorylation, promoter activation, and ISG expression. WY-14643 treatment reduced the expression of key negative regulators of IFN signaling: the AXL receptor tyrosine kinase, suppressor of cytokine signaling (SOCS) 1 and 3, which are upregulated in the IFN-refractory state. AXL is a novel regulator of IFN-α signaling that is induced by HCV infection in vitro and which may drive SOCS3 expression. Our data suggests that PPARα agonists could be a useful adjunct treatment for chronic HCV infection by reducing the expression of AXL/SOCS and increasing the sensitivity to IFN.
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Affiliation(s)
- Scott A Read
- 1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia
| | - Enoch S Tay
- 1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia
| | - Mahsa Shahidi
- 1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia
| | - John McLauchlan
- 2 MRC-University of Glasgow Centre for Virus Research , Glasgow, United Kingdom
| | - Jacob George
- 1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia
| | - Mark W Douglas
- 1 Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, Australia .,2 MRC-University of Glasgow Centre for Virus Research , Glasgow, United Kingdom .,3 Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital , Westmead, Australia
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29
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Grammatikos G, Ferreiros N, Bon D, Schwalm S, Dietz J, Berkowski C, Fitting D, Herrmann E, Zeuzem S, Sarrazin C, Pfeilschifter J. Variations in serum sphingolipid levels associate with liver fibrosis progression and poor treatment outcome in hepatitis C virus but not hepatitis B virus infection. Hepatology 2015; 61:812-22. [PMID: 25348752 DOI: 10.1002/hep.27587] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Accepted: 10/24/2014] [Indexed: 12/16/2022]
Abstract
UNLABELLED Ablation of very-long-chain ceramides (Cers) with consecutive elevations in sphinganine levels has been shown to cause a severe hepatopathy in a knockout mouse model. We have recently shown that serum sphingolipids (SLs) are deregulated in patients with chronic liver disease. However, their role as possible biomarkers in liver fibrosis remains to date unexplored. We assessed, using liquid chromatography/tandem mass spectrometry, serum concentrations of various SL metabolites in 406 patients with chronic viral hepatitis, 203 infected with genotype 1 hepatitis C virus (HCV) and 203 with hepatitis B virus (HBV), respectively. We observed significant variations of serum SLs, with sphingosine and sphinganine being, both in univariate (P<0.05) as well as in multivariate analysis, significantly associated to severity of liver fibrosis in HCV-infected patients (odds ratio [OR]: 1.111; confidence interval [CI]: 1.028-1.202; P=0.007 and OR, 0.634; CI, 0.435-0.925; P=0.018, respectively). Serum SLs correlated significantly with serum triglyceride and cholesterol levels as well as with insulin resistance, defined by the homeostatic model assessment index, in HCV patients. Sustained viral response rates in HCV patients were independently predicted by serum C24Cer (OR, 0.998; CI, 0.997-0.999; P=0.001), its unsaturated derivative C24:1Cer (OR, 1.001; CI, 1.000-1.002; P=0.059), and C18:1Cer (OR, 0.973; CI, 0.947-0.999; P=0.048), together with ferritin (OR, 1.006; CI, 1.003-1.010; P<0.001), alkaline phosphatase (OR, 1.020; CI, 1.001-1.039; P=0.032), and interleukin-28B genotype (OR, 9.483; CI, 3.139-28.643; P<0.001). CONCLUSION Our study demonstrates a tight interaction between variations in serum SL levels and progression of liver fibrosis as well as responsiveness to antiviral therapy. Particularly, sphingosine, sphinganine, and C24Cer appear as promising novel biomarkers in chronic HCV infection and should be further evaluated within the noninvasive prediction of liver fibrosis.
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Affiliation(s)
- Georgios Grammatikos
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany; Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany
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30
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Abstract
The efficacy of antiviral treatment depends on which of the seven genotypes (G1-G7) of hepatitis C virus (HCV) has infected the patient. Conventionally, clinicians regarded G2 and G3 infections as 'easy-to-treat': dual therapy with pegylated interferon and ribavirin produces a sustained virologic response in approximately 40-50% of patients with G1 infection, compared with 80% when analyses report combined data for G2 and G3 patients, which is standard practice in many clinical studies. However, sustained virologic response rates appear to be lower in certain subgroups of people infected with G3 compared with those with G2 or the general HCV-infected population. This review examines the growing evidence that factors related to the virus (e.g., baseline viral load and a rapid virologic response) and host characteristics (e.g., steatosis and fibrosis, metabolic syndrome, host polymorphisms and ethnicity) contribute to variations in therapeutic success in G3 HCV.
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Affiliation(s)
- Maria Buti
- Liver Unit, Hospital Universitario Valle Hebron and Ciberehd del Instituto, Carlos III Paseo Valle Hebron 119, Barcelona 08035, Spain
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31
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Shah SC, Kornak J, Khalili M. Depression is not associated with peripheral insulin resistance in patients with chronic hepatitis C infection. J Viral Hepat 2015; 22:272-80. [PMID: 25196736 PMCID: PMC4386832 DOI: 10.1111/jvh.12306] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Depression is common in individuals infected with hepatitis C virus (HCV), and both depression and HCV infection are independently associated with insulin resistance (IR). To evaluate the relationship between depression and IR, among other factors, in an HCV-infected cohort. In this cross-sectional analysis, seventy-four non-type 2 diabetic, noncirrhotic, HCV-infected patients underwent comprehensive clinical, histologic and metabolic evaluation. IR was assessed directly with an insulin suppression test by measuring steady-state plasma glucose (SSPG) levels during continuous infusions of octreotide, glucose and insulin. Logistic regression modelling was used to evaluate predictors associated with depression. Thirty-nine (53%) patients were depressed, and 21 (54%) depressed patients were on at least one antidepressant. A higher estimated proportion of depressed patients were Caucasian (51% vs 20%, P = 0.005), unemployed (69% vs 49%, P = 0.07), heavier smokers (18 pack-years vs 13 pack-years, P = 0.07), on substance abuse therapy (16% vs 3%, P = 0.06) and had lower HDL levels (1.2 mmol/L vs 1.4 mmol/L, P = 0.01). The mean SSPG levels in depressed and nondepressed patients were 7.3 and 8.3 mmol/L (P = 0.45), respectively. In multipredictor adjusted analysis, only Caucasian race (OR 4.19, 95% CI 1.42-12.35, P = 0.009) and lower HDL (OR 0.95, 95% CI 0.89-0.99, P = 0.046) were associated with depression. In conclusion, although prevalent, depression was not associated with peripheral IR in this HCV-infected cohort. Attention to other modifiable factors associated with depression in the HCV-infected population is warranted.
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Affiliation(s)
- S. C. Shah
- Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA
| | - J. Kornak
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
| | - M. Khalili
- Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA,Liver Center, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA
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32
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Sinclair M, Grossmann M, Gow PJ, Angus PW. Testosterone in men with advanced liver disease: abnormalities and implications. J Gastroenterol Hepatol 2015; 30:244-51. [PMID: 25087838 DOI: 10.1111/jgh.12695] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2014] [Indexed: 12/12/2022]
Abstract
Serum testosterone is reduced in up to 90% of men with cirrhosis, with levels falling as liver disease advances. Testosterone is an important anabolic hormone, with effects on muscle, bone, and hematopoiesis. Many of the features of advanced liver disease are similar to those seen in hypogonadal men, including sarcopenia, osteoporosis, gynecomastia, and low libido. However, the relative contribution of testosterone deficiency to the symptomatology of advanced liver disease has not been well established. More recently, it has been demonstrated that low testosterone in men with cirrhosis is associated with increased mortality, independent of the classically recognized prognostic factors, such as the Model for End-Stage Liver Disease score. Only several small clinical trials have examined the role of testosterone therapy in men with cirrhosis, none of which have resolved the issue of whether or not testosterone is beneficial. However, in men with organic hypogonadism due to structural hypothalamic-pituitary-testicular axis disease, testosterone therapy has been shown to improve muscle mass and bone mineral density, increase hemoglobin, and reduce insulin resistance. Despite initial concerns linking testosterone with hepatocellular carcinoma, more recent data suggest that this risk has been overstated. There is, therefore, now a strong rationale to assess the efficacy and safety of testosterone therapy in cirrhosis in well-designed randomized controlled trials.
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Affiliation(s)
- Marie Sinclair
- Liver Transplant Unit, The Austin Hospital, Heidelberg, Victoria, Australia; Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia
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33
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Berg T, Andreone P, Pol S, Roberts S, Younossi Z, Diago M, Lawitz EJ, Focaccia R, Foster GR, Horban A, Lonjon-Domanec I, DeMasi R, Picchio G, Luo D, De Meyer S, Zeuzem S. Low-density lipoprotein and other predictors of response with telaprevir-based therapy in treatment-experienced HCV genotype 1 patients: REALIZE study. Liver Int 2015; 35:448-54. [PMID: 25319731 DOI: 10.1111/liv.12703] [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: 01/22/2014] [Accepted: 10/10/2014] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIMS Predictors of response to treatment with peginterferon plus ribavirin are well established. In these post-hoc analyses of the REALIZE study, we sought to identify predictors of response for telaprevir-based triple therapy. METHODS Patients from the REALIZE study with baseline data for all predictors evaluated (including baseline disease characteristics and demographics, prior treatment response and baseline laboratory assessments) were included in the post-hoc analyses (n = 465). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS Sustained viral response (SVR) rates were 86% in prior relapsers, 63% in prior partial responders and 32% in prior null-responders. In the final multivariate analysis, baseline factors predicting SVR were prior response to treatment [Odds ratio (OR) = 2.80; 95% confidence interval (CI), 2.13-3.69], low-density lipoprotein (LDL) (≥2.6 mmol/L) (OR = 2.11; 95% CI, 1.52-2.93), HCV genotype (OR = 0.58; 95% CI, 0.36-0.93), and maximum alanine amino transferase and aspartate amino transferase (OR = 0.62; 95% CI, 0.40-0.97). CONCLUSIONS Prior response to peginterferon plus ribavirin treatment and LDL levels are the main independent predictive markers of response with telaprevir-based triple therapy.
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Affiliation(s)
- Thomas Berg
- Universitätsklinikum Leipzig, Sektion Hepatologie, Klinik für Gastroenterologie und Rheumatologie, Leipzig, Germany
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Abd El-Wahab EW, Mikheal A, Sidkey F, Shatat HZ. Insulin resistance as a predictor of early virologic response to HCV therapy among chronic HCV Egyptian patients. J Med Virol 2015; 87:428-40. [PMID: 25583244 DOI: 10.1002/jmv.24092] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2014] [Indexed: 12/19/2022]
Abstract
Prior assessment of insulin resistance by HOMA-IR is emerging as an important milestone in the treatment of patients with chronic hepatitis C. This cost-effective tool is recommended to individualize treatment duration, or to exclude those with low insulin sensitivity from being treated until ameliorating their state of insulin resistance (IR). The present work aims to elucidate further the effect IR state on early viral kinetic response to Chronic hepatitis C virus (HCV) therapy and the impact of HCV treatment and viral eradication on insulin sensitivity. Insulin sensitivity was assessed using the HOMA-IR method. All enrolled patients were treated with a dual therapy (pegylated interferon-alpha plus ribavirin) for 48 weeks and evaluated using qRT-PCR for early virologic response as well as the impact of treatment on insulin sensitivity throughout the early period of therapy. Of a total 392 chronic HCV cases, early virologic response was achieved by 318 (81.1%). IR was detected in 241 (61.5%) chronic HCV patient of which 73.4% responded to treatment. Early virologic response among patients with > 2.18 HOMA-IR value were significantly lower than those with HOMA-IR values ≤2.18 (P < 0.0001). IR was significantly associated with high baseline BMI. Steatosis and fibrosis correlated with IR but neither independently predicted early virologic response. Pretreatment IR < 2.18, low fasting blood glucose, low and intermediate HCV viral load, normal BMI, and non-smoking were independent factors associated with early virologic response. IR interferes with early virologic response to the antiviral care. Clinical application of pretreatment HOMA-IR assessment could help in predicting early treatment outcome and thus enable treatment regimens to be optimized and individually tailored.
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Affiliation(s)
- Ekram W Abd El-Wahab
- Tropical Health Department, High Institute of Public Health, Alexandria University, Egypt
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35
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Iwane S, Mizuta T, Kawaguchi Y, Takahashi H, Oza N, Oeda S, Nakashita S, Kuwashiro T, Otsuka T, Kawazoe S, Eguchi Y, Anzai K, Ozaki I, Fujimoto K. Impact of Body Weight Reduction via Diet and Exercise on the Anti-Viral Effects of Pegylated Interferon Plus Ribavirin in Chronic Hepatitis C Patients with Insulin Resistance: A Randomized Controlled Pilot Trial. Intern Med 2015; 54:3113-9. [PMID: 26666596 DOI: 10.2169/internalmedicine.54.5574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE Insulin resistance (IR) modifies the anti-viral effects of interferon (IFN) therapy in patients with chronic hepatitis C (CHC). This prospective study evaluated whether lifestyle interventions improve the anti-viral response to treatment with pegylated (PEG)-IFN plus ribavirin (RBV) in patients with CHC. METHODS The study cohort consisted of 60 patients chronically infected with a high viral load of hepatitis C virus genotype 1b and a homeostasis model assessment of IR (HOMA-IR) value above 2. The patients were divided into two groups, an intervention group (n=26) and a control group (n=34). The patients in the intervention group were prescribed diet and exercise treatment for 3-6 months to reduce their body weight by ≥5% before starting treatment with PEG-IFN plus RBV. RESULTS Diet and exercise significantly reduced the HOMA-IR values in the intervention group, from 3.4 to 2.5 (p=0.0009), especially among the 15 patients who achieved a body weight reduction of ≥5%. The viral disappearance rate at 12 weeks was significantly higher in the intervention group among the patients with a ≥5% weight reduction than in the control group (53.3% vs. 23.5%, p=0.01). However, the sustained viral response (SVR) rates were similar. CONCLUSION Improvements in IR achieved through weight reduction via lifestyle interventions may enhance the early viral response to PEG-IFN plus RBV in patients with CHC. However, this intervention program has no effect on the SVR rate.
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Affiliation(s)
- Shinji Iwane
- Department of Internal Medicine, Saga University Hospital, Japan
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Lim T. Metabolic syndrome in chronic hepatitis C infection: does it still matter in the era of directly acting antiviral therapy? Hepat Med 2014; 6:113-8. [PMID: 25506251 PMCID: PMC4259863 DOI: 10.2147/hmer.s60083] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Metabolic syndrome is prevalent in patients with hepatitis C virus (HCV) infection. Given the pandemic spread of HCV infection and metabolic syndrome, the burden of their interaction is a major public health issue. The presence of metabolic syndrome accelerates the progression of liver disease in patients with HCV infection. New drug development in HCV has seen an unprecedented rise in the last year, which resulted in better efficacy, better tolerance, and a shorter treatment duration. This review describes the underlying mechanisms and clinical effects of metabolic syndrome in HCV infection, as well as their importance in the era of new directly acting antiviral therapy.
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Affiliation(s)
- Tr Lim
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, University of Birmingham and Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, UK
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Antonelli A, Ferrari SM, Giuggioli D, Di Domenicantonio A, Ruffilli I, Corrado A, Fabiani S, Marchi S, Ferri C, Ferrannini E, Fallahi P. Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. World J Diabetes 2014; 5:586-600. [PMID: 25317237 PMCID: PMC4138583 DOI: 10.4239/wjd.v5.i5.586] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 04/10/2014] [Accepted: 07/12/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus (T1DM) and T2DM. T2DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2DM and chronic hepatitis C (CHC) infection. The processes through which CHC is associated with T2DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immune-mediated mechanisms. Few data have been reported on the association of CHC and T1DM and reports on the potential association between T1DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-α therapy can stimulate pancreatic autoimmunity and in certain cases lead to the development of T1DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with non-diabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effective programmes for the surveillance and treatment of diabetic CHC patients.
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Morbitzer KA, Taber DJ, Pilch NA, Meadows HB, Fleming JN, Bratton CF, McGillicuddy JW, Baliga PK, Chavin KD. The impact of diabetes mellitus and glycemic control on clinical outcomes following liver transplant for hepatitis C. Clin Transplant 2014; 28:862-8. [PMID: 24893750 DOI: 10.1111/ctr.12391] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2014] [Indexed: 12/15/2022]
Abstract
Hepatitis C is the leading indication for liver transplantation in the USA and recurrence is universal. The impact of preexisting diabetes, new-onset diabetes after transplant (NODAT), and glycemic control on fibrosis progression has not been studied. This retrospective longitudinal cohort study included adult liver recipients with hepatitis C transplanted between 2000 and 2011. Patients were divided into three groups: preexisting diabetes (n = 41), NODAT (n = 59), and no diabetes (n = 103). Patients with preexisting diabetes (70%) or NODAT (59%) were more likely to develop hepatitis C recurrence (≥stage 1 fibrosis), as compared to non-diabetics (36%, p = 0.006). There was also a trend toward a higher incidence of at least Stage 2 fibrosis (36% and 48% vs. 23%, respectively; p = 0.063). Patients with tight glycemic control had a lower rate of Stage 2 fibrosis development (78% vs. 60%, p = 0.027), while those with good control (<150 mg/dL) also had lower rates of Stage 2 fibrosis (84% vs. 62%, p = 0.004). Multivariable analysis verified a decreased rate of recurrence for patients with blood glucose <138 mg/dL (p = 0.021), after controlling for confounders. These results demonstrate that diabetes is strongly associated with an increased risk of hepatitis C virus-related fibrosis development and glycemic control may reduce the risk and severity of recurrence.
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Affiliation(s)
- Kathryn A Morbitzer
- Division of Practice Advancement and Clinical Education, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pharmacy Services, Medical University of South Carolina, Charleston, SC, USA
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Cao WX, Ding H, Wang XG, Zhang B, Jin HH. Antiviral efficacy and related factors in chronic hepatitis C patients with nonalcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2014; 22:2323-2326. [DOI: 10.11569/wcjd.v22.i16.2323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the antiviral efficacy and some related factors in patients with chronic hepatitis C (CHC) and nonalcoholic fatty liver disease.
METHODS: Thirty-three patients with CHC only (group A) and 27 patients with CHC and nonalcoholic fatty liver disease (group B) were included in this study. Blood lipids, homeostasis model of assessment for insulin resistance index (HOMA-IR) and the negative conversion rate of HCV-RNA were compared between the two groups after 4 weeks of therapy with PEG-IFNα and ribavirin.
RESULTS: Before treatment, total cholesterol (CH) (5.12 mmol/L ± 0.93 mmol/L vs 3.94 mmol/L ± 0.75 mmol/L), low density lipoprotein (LDL) (3.95 mmol/L ± 0.46 mmol/L vs 3.15 mmol/L ± 0.34 mmol/L), triglyceride (TRIG) (3.75 mmol/L ± 2.27 mmol/L vs 1.89 mmol/L ± 0.52 mmol/L), alanine transarninase (ALT) (149.30 U/L ± 26.13 U/L vs 74.50 U/L ± 25.4 U/L), serum insulin (5.52 mmol/L ± 1.33 mmol/L vs 5.43 mmol/L ± 0. 71 mmol/L) and HOMA-IR (1.56 mmol/L ± 0.62 mmol/L vs 1.60 mmol/L ± 0.61 mmol/L) in group B were significantly higher than those in group A (P < 0.01), while high density lipoprotein (HDL) was slightly lower. After treatment, the negative conversion rate of HCV-RNA (40.74 vs 75.75%) was significantly lower in group B (P < 0.01).
CONCLUSION: The curative effect of PEG-IFNα therapy in CHC patients with nonalcoholic fatty liver disease is decreased, which may be caused by insulin resistance. Improving the lipid metabolism may enhance the antiviral efficacy in these patients.
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Kawaguchi Y, Mizuta T. Interaction between hepatitis C virus and metabolic factors. World J Gastroenterol 2014; 20:2888-2901. [PMID: 24659880 PMCID: PMC3961972 DOI: 10.3748/wjg.v20.i11.2888] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/15/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection disrupts the normal metabolism processes, but is also influenced by several of the host’s metabolic factors. An obvious and significantly detrimental pathophysiological feature of HCV infection is insulin resistance in hepatic and peripheral tissues. Substantial research efforts have been put forth recently to elucidate the molecular mechanism of HCV-induced insulin resistance, and several cytokines, such as tumor necrosis factor-α, have been identified as important contributors to the development of insulin resistance in the distant peripheral tissues of HCV-infected patients and animal models. The demonstrated etiologies of HCV-induced whole-body insulin resistance include oxidative stress, lipid metabolism abnormalities, hepatic steatosis and iron overload. In addition, myriad effects of this condition have been characterized, including glucose intolerance, resistance to antiviral therapy, progression of hepatic fibrosis, development of hepatocellular carcinoma, and general decrease in quality of life. Metabolic-related conditions and disorders, such as visceral obesity and diabetes mellitus, have been shown to synergistically enhance HCV-induced metabolic disturbance, and are associated with worse prognosis. Yet, the molecular interactions between HCV-induced metabolic disturbance and host-associated metabolic factors remain largely unknown. The diet and lifestyle recommendations for chronic hepatitis C are basically the same as those for obesity, diabetes, and metabolic syndrome. Specifically, patients are suggested to restrict their dietary iron intake, abstain from alcohol and tobacco, and increase their intake of green tea and coffee (to attain the beneficial effects of caffeine and polyphenols). While successful clinical management of HCV-infected patients with metabolic disorders has also been achieved with some anti-diabetic (i.e., metformin) and anti-lipid (i.e., statins) medications, it is recommended that sulfonylurea and insulin be avoided.
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Hsu LI, Wang YH, Chiou HY, Wu MM, Yang TY, Chen YH, Tseng CH, Chen CJ. The association of diabetes mellitus with subsequent internal cancers in the arsenic-exposed area of Taiwan. JOURNAL OF ASIAN EARTH SCIENCES 2013; 73:452-459. [DOI: 10.1016/j.jseaes.2013.04.048] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
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Mangia A, Ripoli M. Insulin resistance, steatosis and hepatitis C virus. Hepatol Int 2013; 7 Suppl 2:782-9. [PMID: 24587848 PMCID: PMC3918408 DOI: 10.1007/s12072-013-9460-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Accepted: 06/30/2013] [Indexed: 02/07/2023]
Abstract
Epidemiological studies have shown an increased occurrence of metabolic disorders such as insulin resistance (IR) and steatosis in patients with hepatitis C virus (HCV) infection. IR is believed to represent one of the central clinical features of the "metabolic syndrome" and the major pathogenetic factor for type 2 diabetes mellitus. In patients with chronic HCV hepatitis, IR may have several dangerous consequences such as accelerated progression of liver fibrosis, resistance to antiviral therapy and development of hepatocellular carcinoma. According to recent evidence, the global epidemic of metabolic disorders related to incorrect diets will lead physicians to deal with 1.2 billion patients with diabetes in the world in 2025. Given the high prevalence of HCV infection in several countries, metabolic manifestations will contribute to increasing morbidity and mortality in patients with HCV chronic infection in the near future. HCV treatment, shown able to decrease both the occurrence of HCV-related IR and diabetes, may reduce the risk of the associated morbidities.
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Affiliation(s)
- Alessandra Mangia
- Liver Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Maria Ripoli
- Liver Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
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Kawaguchi Y, Mizuta T, Eguchi Y, Sakurai E, Motomura Y, Isoda H, Kuwashiro T, Oeda S, Iwane S, Takahashi H, Anzai K, Ozaki I. Whole-body insulin resistance is associated with elevated serum α-fetoprotein levels in patients with chronic hepatitis C. Intern Med 2013; 52:2393-400. [PMID: 24190142 DOI: 10.2169/internalmedicine.52.0992] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
OBJECTIVE Little is known about the relationship between elevated serum α-fetoprotein (AFP) levels and insulin resistance, which adversely influence the clinical course of chronic hepatitis C (CHC). Therefore, we investigated the association between serum AFP and insulin resistance in patients with CHC. METHODS We retrospectively investigated 300 patients with CHC without hepatoma who underwent liver biopsies and oral glucose tolerance tests. Patients taking antidiabetic drugs were excluded. We analyzed factors associated with elevated AFP levels (≥ 10.0 ng/mL) in 265 eligible patients. Twenty patients with a homeostasis model assessment for insulin resistance value of ≥ 2.0 and a whole-body insulin sensitivity index of <5.0 received prospective lifestyle intervention. RESULTS A univariate analysis showed that the body mass index, platelet count, levels of albumin, aspartate aminotransferase, alanine aminotransferase and γ-glutamyl transpeptidase, glucose metabolism, hepatic inflammation, fibrosis and steatosis were associated with elevated AFP levels. In a multivariate analysis, a platelet count of < 15 × 10(4) /μL, aspartate aminotransferase level of ≥ 50 IU/L, γ-glutamyl transpeptidase level of ≥ 35 IU/L, whole-body insulin sensitivity index of <5.0 and stage 3-4 fibrosis were independently associated with an elevated AFP level. A Bayesian Network analysis showed that the aspartate aminotransferase level, whole-body insulin sensitivity index and hepatic fibrosis were directly associated with an elevated AFP level. The lifestyle intervention significantly improved the serum AFP level, homeostasis model assessment for insulin resistance and whole-body insulin sensitivity index. CONCLUSION Whole-body insulin resistance is associated with an elevated serum AFP level in patients with CHC. Lifestyle interventions targeting insulin resistance can reduce the serum AFP level and may ameliorate the clinical course of CHC.
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Association of insulin resistance, viral load, and adipokine levels with liver histology in patients with chronic hepatitis C: an observational, multicenter study in Turkey. Eur J Gastroenterol Hepatol 2012; 24:1393-9. [PMID: 23114743 DOI: 10.1097/meg.0b013e3283585863] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To evaluate the association of insulin resistance (IR), viral load, and adipokine levels with liver histology in patients with chronic hepatitis C (CHC). PATIENTS AND METHODS In this noninterventional, multicenter study carried out at 11 infectious diseases clinics in Turkey, 103 CHC patients [mean (SD) age: 50.2 (11.0) years, 60 (58.3%) women] planned to be treated by ribavirin and peginterferon-α2a were included. Data on hepatic fibrosis and steatosis, IR, viral load, and hepatitis C virus-RNA genotyping, adipokine, and cytokine levels were collected. RESULTS The mean (SD) Knodell score was 8.1 (3.6); grade I steatosis was evident in 46 (44.7%) patients and IR was identified in 56 (54.9%). There was a significant positive correlation of the homeostasis model assessment-IR index with Knodell fibrosis (r=0.235; P=0.027) and hepatic steatosis (r=0.435; P<0.001). There was a significant positive correlation of leptin levels with Knodell fibrosis (r=0.265; P=0.013) and hepatic activity index (r=0.218; P=0.041). Hepatic steatosis was correlated negatively with adiponectin (r=-0.320; P=0.001) and positively with leptin (r=-0.368; P<0.001) levels. Logistic regression analysis showed that increase in age [odds ratio (OR), 1.056; 95% confidence interval (CI), 1.005-1.110; P=0.030] was the only significant predictor of hepatic fibrosis (OR, 1.056; 95% CI, 1.005-1.110; P=0.030), whereas increase in age (OR, 1.066; 95% CI, 1.006-1.130; P=0.030), the presence of IR (OR, 5.621; 95% CI, 1.547-20.425; P=0.009), and decrease in adiponectin levels (OR, 0.808; 95% CI, 0.682-0.957; P=0.013) were the significant predictors of hepatic steatosis. CONCLUSION Our findings indicate a significant relationship of hepatic fibrosis and hepatic steatosis with IR and leptin levels, but not with the viral load in Turkish patients with CHC.
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Lee JG, Lee S, Kim YJ, Cho BM, Park JS, Kim HH, Cheong J, Jeong DW, Lee YH, Cho YH, Bae MJ, Choi EJ. Association of chronic viral hepatitis B with insulin resistance. World J Gastroenterol 2012; 18:6120-6. [PMID: 23155341 PMCID: PMC3496889 DOI: 10.3748/wjg.v18.i42.6120] [Citation(s) in RCA: 35] [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: 07/12/2012] [Revised: 09/19/2012] [Accepted: 09/22/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between chronic viral hepatitis B (CVHB) and insulin resistance (IR) in Korean adults.
METHODS: A total of 7880 adults (3851 men, 4029 women) who underwent a comprehensive medical examination were enrolled in this study. Subjects diagnosed with either diabetes mellitus, or any other disorder that could influence their insulin sensitivity, were rejected. Anthropometry, metabolic risk factors, hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, fasting plasma glucose and insulin were measured for all subjects. Homeostasis model assessment (HOMA), quantitative insulin check index (QUICKI), and Mffm index were used for determining insulin sensitivity. Each participant was categorized into a negative, recovery, or CVHB group. To compare variables between groups, a t-test and/or one-way analysis of variance were used. Partial correlation coefficients were computed to present the association between insulin resistance and other variables. Multiple logistic regression analysis was used to assess the independent association between CVHB and IR.
RESULTS: The mean age of men and women were 48.9 and 48.6 years, respectively. Subjects in the CVHB group had significantly higher waist circumference [(86.0 ± 7.7 cm vs 87.3 ± 7.8 cm, P = 0.004 in men), (78.3 ± 8.6 cm vs 80.5 ± 8.5 cm, P < 0.001 in women)], cystatin C [(0.96 ± 0.15 mg/dL vs 1.02 ± 0.22 mg/dL, P < 0.001 in men), (0.84 ± 0.15 mg/dL vs 0.90 ± 0.16 mg/dL, P < 0.001 in women)], fasting insulin [(5.47 ± 3.38 μU/mL vs 6.12 ± 4.62 μU/mL, P < 0.001 in men), (4.57 ± 2.82 μU/mL vs 5.06 ± 3.10 μU/mL, P < 0.001 in women)] and HOMA index [(1.24 ± 0.86 vs 1.43 ± 1.24, P < 0.001 in men), (1.02 ± 0.76 vs 1.13 ± 0.87, P = 0.033 in women)] compared to control group. The HOMA index revealed a positive correlation with body mass index (BMI) (r = 0.378, P < 0.001), waist circumference (r =0.356, P < 0.001), percent body fat (r = 0.296, P < 0.001), systolic blood pressure (r = 0.202, P < 0.001), total cholesterol (r = 0.134, P < 0.001), triglycerides (r = 0.292, P < 0.001), cystatin C (r = 0.069, P < 0.001) and uric acid (r = 0.142, P < 0.001). The QUICKI index revealed a negative correlation with BMI (r = -0.254, P < 0.001), waist circumference (r = 0-0.243, P < 0.001), percent body fat (r = -0.217, P < 0.001), systolic blood pressure (r = -0.132, P < 0.001), total cholesterol (r = -0.106, P < 0.001), triglycerides (r = -0.205, P < 0.001), cystatin C (r = -0.044, P < 0.001) and uric acid (r = -0.096, P < 0.001). For subjects identified with IR, the odds ratio of an accompanying diagnosis of chronic hepatitis B was 1.534 (95% CI: 1.158-2.031, HOMA index criteria) or 1.566 (95% CI: 1.124-2.182, QUICKI criteria) after adjustment for age, gender, BMI, and amount of alcohol consumption.
CONCLUSION: Our study demonstrates that CVHB is associated with IR. CVHB may need to be monitored for occurrence of IR and diabetes mellitus.
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Association of serum adipocytokines with insulin resistance and liver injury in patients with chronic hepatitis C genotype 4. J Clin Gastroenterol 2012; 46:871-9. [PMID: 22664476 DOI: 10.1097/mcg.0b013e318256b68a] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [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.
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Abstract
BACKGROUND Chronic hepatitis C (CHC) infection is associated with insulin resistance and with oxidative stress, but the relationship between the two has not been thoroughly examined. PURPOSE To evaluate the association between insulin resistance and oxidative stress in CHC patients. METHOD In 115 CHC patients (68 with genotype 1 and 47 with genotype 3), the relationship between the serum concentration of malondialdehyde (MDA), a marker of oxidative stress and insulin resistance as defined by the homeostasis model (HOMA-IR) was examined. RESULTS There was no significant difference in MDA levels between genotype 1- and genotype 3-infected subjects (12.882 vs. 12.426 ng/mL, p = 0.2). By univariate analysis, factors associated with HOMA-IR in both genotypes were oxidative stress as measured by MDA (p = 0.002), body mass index (BMI), portal activity, and fibrosis. Genotype-specific differences in HOMA-IR association were steatosis and triglycerides (TG) for genotype 1, and age and glutathione (GSH) for genotype 3. In a stepwise multiple linear regression analysis in both genotypes, MDA was a significant and independent predictor of HOMA-IR (p = 0.04). As expected, BMI and fibrosis were likewise independently correlated to HOMA-IR. In addition, MDA levels were higher (p < 0.001) and GSH levels were lower (p = 0.023) in insulin-resistant subjects compared to their insulin-sensitive counterparts. CONCLUSIONS It is concluded that in CHC, oxidative stress is an independent predictor of HOMA-IR, irrespective of virus genotype. Further studies on the role of oxidative stress in the development of insulin resistance in CHC are warranted.
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Qu SM, Han F, Wu D, Zhang L. Factors influencing rapid and early virological response to interferon therapy in patients with chronic hepatitis C. Shijie Huaren Xiaohua Zazhi 2012; 20:2281-2287. [DOI: 10.11569/wcjd.v20.i24.2281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the predictive factors associated with rapid and early virological response to pegylated interferon and ribavirin treatment in patients with chronic hepatitis C to provide the basis for treatment selection and outcome prediction of antiviral therapy.
METHODS: Eighty-one patients with chronic hepatitis C treated with pegylated interferon and ribavirin were followed up at 4, 12, 24, 48 wk and at least 24 wk after discontinuing treatment. Information for the patients was recorded in detail, including sex, age, baseline HCVRNA level, body mass index (BMI), diabetes mellitus, cirrhosis, history of alcohol consumption, fatty liver, blood transfusion history, and previous antiviral treatment history. Patients were divided into rapid virological response (RVR) group, early virological response (EVR) group, no response (NR) group, relapse (RL) group, and sustained virological response (SVR) group according to the treatment situation. Univariate analysis and multivariate logistic stepwise regression analysis were used to analyze the influencing and predicting factors of RVR and EVR.
RESULTS: Of 81 patients, 51 achieved RVR, 65 achieved EVR, 65 achieved SVR, 10 had NR, and 6 had RL. The rates of RVR, EVR, SVR, NR and RL were 62.9%, 80.2%, 80.2%, 12.3% and 7.4%, respectively. In the RVR group, 88.2% of the cases achieved SVR, while in the EVR group the rate of SVR was 90.8%. Sixteen cases (19.8%) did not achieve RVR and EVR, and 6 of them (37.5%) achieved SVR and had no recurrence. The SVR rates were significantly different among the RVR, EVR, and non-RVR/EVR groups (χ2 = 20.622, P < 0.05), but the RL rate had no significant difference among them. The rates of RVR and EVR among the SVR, NR and RL groups were significantly different. Univariate analysis showed that RVR was associated with age ≤ 40 years old, HCV RNA < 4 × 105 IU/mL, and no cirrhosis, while EVR was associated with age ≤ 40 years old, HCV RNA < 4 × 105 IU/mL, no cirrhosis, and BMI < 24 kg/m2. Multivariate logistic stepwise regression analysis showed that baseline HCV RNA load and cirrhosis were independent factors for predicting RVR and EVR.
CONCLUSION: The acquisition of RVR and EVR is a significant predictor of SVR. In non-RVR and non-EVR groups, a minority of patients still could achieve SVR after one year of treatment. RVR and EVR can not predict recurrence. Predicting factors including age, baseline viral load, liver cirrhosis, and body mass index are closely related to RVR and EVR. Baseline viral load and liver cirrhosis are independent predictive factors for RVR and EVR.
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Das GC, Hollinger FB. Molecular pathways for glucose homeostasis, insulin signaling and autophagy in hepatitis C virus induced insulin resistance in a cellular model. Virology 2012; 434:5-17. [PMID: 22862962 DOI: 10.1016/j.virol.2012.07.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 07/01/2012] [Indexed: 12/14/2022]
Abstract
Chronic HCV infection induces insulin resistance (IR). We studied this in a persistently infected cell line with defects in glucose homeostasis resulting from the phosphorylation of glycogen synthase (GS Ser641) and GS kinase isoform 3β (GSK 3βSer9). Reversal of these effects in cells cured of HCV with interferon supports viral specificity. Insulin signaling was disrupted by IRS-1 Ser312 phosphorylation and dysregulation of the Akt pathway. In infected cells, active autophagy was revealed by the formation of LC3 puncta or by increased levels (50-200%) of the markers Beclin 1 and conjugated Atg5/Atg12. Inhibition of autophagy by 3-methyl-adenine (3-MA) reduced Beclin1 levels, inhibited IRS-1 Ser312 or GS Ser641 phosphorylation and decreased viral load. Furthermore, IRS-1 Ser312 and Beclin1 were co-immunoprecipitated suggesting that they interact. It thus appears that HCV infection disturbs glucose homeostasis or insulin signaling to induce IR and also elicits autophagy that may contribute to this process.
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Affiliation(s)
- Gokul C Das
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States.
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