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Albillos A, Bañares R, Hernández-Gea V. Portal hypertension: recommendations for diagnosis and treatment. Consensus document sponsored by the Spanish Association for the Study of the Liver (AEEH) and the Biomedical Research Network Centre for Liver and Digestive Diseases (CIBERehd). GASTROENTEROLOGIA Y HEPATOLOGIA 2025; 48:502208. [PMID: 39756832 DOI: 10.1016/j.gastrohep.2024.502208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/07/2024] [Accepted: 04/09/2024] [Indexed: 01/07/2025]
Abstract
Portal hypertension is a hemodynamic abnormality that complicates the course of cirrhosis, as well as other diseases that affect the portal venous circulation. The development of portal hypertension compromises prognosis, especially when it rises above a certain threshold known as clinically significant portal hypertension (CSPH). In the consensus conference on Portal Hypertension promoted by the Spanish Association for the Study of the Liver and the Hepatic and Digestive diseases area of the Biomedical Research Networking Center (CIBERehd), different aspects of the diagnosis and treatment of portal hypertension caused by cirrhosis or other diseases were discussed. The outcome of this discussion was a set of recommendations that achieved varying degrees of consensus among panelists and are reflected in this consensus document. The six areas under discussion were: the relevance of CSPH and the non-invasive methods used for its diagnosis and that of cirrhosis, the prevention of the first episode of decompensation and its recurrence, the treatment of acute variceal bleeding and other complications of portal hypertension, the indications for the use of TIPS, and finally, the diagnosis and treatment of liver vascular diseases.
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Affiliation(s)
- Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Universidad de Alcalá, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
| | - Rafael Bañares
- Servicio de Medicina de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Universidad Complutense, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
| | - Virginia Hernández-Gea
- Servicio de Hepatología, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universidad de Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, España.
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Albillos A, Bañares R, Hernández-Gea V. Portal hypertension: recommendations for diagnosis and treatment. Consensus document sponsored by the Spanish Association for the Study of the Liver (AEEH) and the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd). REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2025; 117:14-57. [PMID: 39350672 DOI: 10.17235/reed.2024.10805/2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2025]
Abstract
Portal hypertension is a hemodynamic abnormality that complicates the course of cirrhosis, as well as other diseases that affect the portal venous circulation. The development of portal hypertension compromises prognosis, especially when it rises above a certain threshold known as clinically significant portal hypertension (CSPH). In the consensus conference on Portal Hypertension promoted by the Spanish Association for the Study of the Liver and the Hepatic and Digestive diseases area of the Biomedical Research Networking Center (CIBERehd), different aspects of the diagnosis and treatment of portal hypertension caused by cirrhosis or other diseases were discussed. The outcome of this discussion was a set of recommendations that achieved varying degrees of consensus among panelists and are reflected in this consensus document. The six areas under discussion were: the relevance of clinically significant portal hypertension and the non-invasive methods used for its diagnosis and that of cirrhosis, the prevention of the first episode of decompensation and its recurrence, the treatment of acute variceal bleeding and other complications of portal hypertension, the indications for the use of TIPS, and finally, the diagnosis and treatment of liver vascular diseases.
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Affiliation(s)
- Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, España
| | - Rafael Bañares
- Servicio de Medicina de Aparato Digestivo, Hospital General Universitario Gregorio Marañón
| | - Virginia Hernández-Gea
- Servicio de Hepatología, Hospital Clínic. Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
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Archer AJ, May T, Bowers H, Kesten J, Tilden S, Abeysekera K, Gordon FH, Hickman M, Yardley L. Qualitative service evaluation of a multimodal pilot service for early detection of liver disease in high-risk groups: 'Alright My Liver?'. BMJ Open Gastroenterol 2024; 11:e001560. [PMID: 39537216 PMCID: PMC11575350 DOI: 10.1136/bmjgast-2024-001560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024] Open
Abstract
OBJECTIVE Liver disease is a growing cause of premature death in the UK. The National Health Service in England (NHS England) has funded regional early detection programmes through Community Liver Health Check pilots. 'Alright My Liver?' is Bristol and Severn's pilot service offering early detection of liver disease through screening events serving populations at risk, including people with a history of drug or alcohol use, type 2 diabetes and obesity. The service offers point-of-care testing for liver disease and a supported follow-up process. METHODS Semistructured interviews were conducted with 14 service users and six service providers over a 6-month period using diversity sampling. Topic guides encouraged discussion of experiences of the service as well as barriers and facilitators to accessing the service. Data were analysed using thematic analysis, and positive and negative comments pertaining to the service were collated in a 'table of changes' to inform optimisation. RESULTS Three main themes were identified: (1) motivations for engagement, (2) experience of the service and (3) health impacts. Key motivations for engagement were screening as a novel opportunity, a response to immediate health concerns or as reassurance. Service users commented on its convenience and that staff interactions were warm and informative. Some felt that follow-up could be more intensive. Impacts varied depending on perceived risk factors and screening results but generally involved stating a commitment to healthy lifestyle changes, including reducing alcohol use. CONCLUSION Targeted screening for liver disease in high-risk groups through this pilot service was deemed an appropriate and accessible intervention, with important optimisations identified.
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Affiliation(s)
- Ann Jane Archer
- Bristol Medical School, University of Bristol, Bristol, UK
- Department of Liver Medicine, Bristol Royal Infirmary, Bristol, UK
| | - Tom May
- Bristol Medical School, University of Bristol, Bristol, UK
- NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol, Bristol, UK
| | - Hannah Bowers
- Bristol Medical School, University of Bristol, Bristol, UK
- NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol, Bristol, UK
| | - Joanna Kesten
- Bristol Medical School, University of Bristol, Bristol, UK
- NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol, Bristol, UK
| | - Sally Tilden
- Department of Liver Medicine, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Kushala Abeysekera
- Department of Liver Medicine, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
- Bristol Medical School, University of Bristol, Bristol, UK
| | - Fiona H Gordon
- Department of Liver Medicine, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Matthew Hickman
- Bristol Medical School, University of Bristol, Bristol, UK
- NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol, Bristol, UK
| | - Lucy Yardley
- Bristol Medical School, University of Bristol, Bristol, UK
- NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol, Bristol, UK
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Ozaki K, Ohtani T, Ishida T, Takahashi K, Ishida S, Takata K, Sakai T, Higuchi S, Gabata T. Liver fibrosis estimated using extracellular volume fraction obtained from dual-energy CT as a risk factor for hepatocellular carcinoma after sustained virologic response: A preliminary case-control study. Eur J Radiol 2023; 168:111112. [PMID: 37783146 DOI: 10.1016/j.ejrad.2023.111112] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/11/2023] [Accepted: 09/22/2023] [Indexed: 10/04/2023]
Abstract
PURPOSE To assess hepatocellular carcinoma (HCC) risk after sustained virologic response (SVR) through clinical data analyses, including evaluation of liver fibrosis using the extracellular volume fraction (ECV) obtained from dual-energy computed tomography (DECT). METHODS Ninety-two patients (52 men and 40 women; mean age, 69.9 years) with hepatitis C virus infection after SVR underwent DECT of the liver (3-minute equilibrium-phase images) between January 2020 and March 2022. The ECV was calculated by measuring iodine density; fibrous markers, including ECV, fibrosis-4 index, aspartate aminotransferase to platelet ratio index, and platelet count, were statistically analyzed (p < 0.05). The risk factors associated with HCC were analyzed using univariate and multivariate logistic regression analyses. RESULTS The ECV (26.1 ± 4.6 %) in patients with HCC (n,21) was significantly larger than the ECV (20.7 ± 3.3 %) in patients without HCC (n = 71) (p < 0.001). The cutoff value for the ECV was 24.3 %. The area under the operating characteristic curve of the ECV was 0.857, which was higher than that of the serum fibrosis markers. Older age, SVR achieved with interferon, alpha-fetoprotein level (>5 ng/mL), advanced fibrosis before treatment (>F3), and ECV were associated with HCC according to the univariate analysis. Multivariate analyses showed that ECV was the only factor independently associated with HCC (odds ratio 0.619, 95 % confidence interval 0.482-0.795, p < 0.001). CONCLUSION Liver fibrosis estimated using ECV can be a predictive marker in patients with HCC after SVR.
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Affiliation(s)
- Kumi Ozaki
- Departments of Radiology, Faculty of Medical Sciences, University of Fukui, Japan; Department of Radiology, Hamamatsu University School of Medicine, Japan.
| | - Takashi Ohtani
- Radiological Center, University of Fukui Hospital, Japan
| | | | | | - Shota Ishida
- Radiological Center, University of Fukui Hospital, Japan; Department of Radiological Technology, Faculty of Medical Science, Kyoto College of Medical Science, Japan
| | - Kenji Takata
- Departments of Radiology, Faculty of Medical Sciences, University of Fukui, Japan
| | - Toyohiko Sakai
- Departments of Radiology, Faculty of Medical Sciences, University of Fukui, Japan
| | - Shohei Higuchi
- Departments of Pathology, Faculty of Medical Sciences, University of Fukui, Japan
| | - Toshifumi Gabata
- Department of Radiology, Kanazawa University Graduate School of Medicine, Japan
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Baptista-Leite R, Lopes H, Vandewalle B, Félix J, Franco D, Clemens T, Brand H. Epidemiological Modeling of the Impact of Public Health Policies on Hepatitis C: Protocol for a Gamification Tool Targeting Microelimination. JMIR Res Protoc 2023; 12:e38521. [PMID: 37747764 PMCID: PMC10562970 DOI: 10.2196/38521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 09/26/2023] Open
Abstract
BACKGROUND Hepatitis C is a disease with a strong social component, as its main transmission route is via blood, making it associated with lifestyle. Therefore, it is suitable to be worked on from the perspective of public health policy, which still has a lot of room to explore and improve, contrary to diagnoses and treatments, which are already very refined and effective. OBJECTIVE An interactive gamified policy tool, designated as Let's End HepC (LEHC), was created to understand the impact of policies related to hepatitis C on the disease's epidemiology on a yearly basis until 2030. METHODS To this end, an innovative epidemiological model was developed, integrating Markov chains to model the natural history of the disease and adaptive conjoint analysis to reflect the degree of application of each of the 24 public health policies included in the model. This double imputation model makes it possible to assess a set of indicators such as liver transplant, incidence, and deaths year by year until 2030 in different risk groups. Populations at a higher risk were integrated into the model to understand the specific epidemiological dynamics within the total population of each country and within segments that comprise people who have received blood products, prisoners, people who inject drugs, people infected through vertical transmission, and the remaining population. RESULTS The model has already been applied to a group of countries, and studies in 5 of these countries have already been concluded, showing results very close to those obtained through other forms of evaluation. CONCLUSIONS The LEHC model allows the simulation of different degrees of implementation of each policy and thus the verification of its epidemiological impact on each studied population. The gamification feature allows assessing the adequate fulfillment of the World Health Organization goals for the elimination of hepatitis C by 2030. LEHC supports health decision makers and people who practice patient advocacy in making decisions based on science, and because LEHC is democratically shared, it ends up contributing to the increase of citizenship in health. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) RR1-10.2196/38521.
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Affiliation(s)
- Ricardo Baptista-Leite
- Department of International Health, Care and Public Health Research Institute - CAPHRI, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands
- NOVA Center for Global Health - Information Management School, Universidade Nova de Lisboa, Lisbon, Portugal
| | - Henrique Lopes
- NOVA Center for Global Health - Information Management School, Universidade Nova de Lisboa, Lisbon, Portugal
| | | | | | - Diogo Franco
- NOVA Center for Global Health - Information Management School, Universidade Nova de Lisboa, Lisbon, Portugal
| | - Timo Clemens
- Department of International Health, Care and Public Health Research Institute - CAPHRI, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands
| | - Helmut Brand
- Department of International Health, Care and Public Health Research Institute - CAPHRI, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands
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Lara-Aguilar V, Crespo-Bermejo C, Llamas-Adán M, Grande-García S, Cortijo-Alfonso ME, Martín-Carbonero L, Domínguez L, Ryan P, de Los Santos I, Bartolomé-Sanchez S, Valle-Millares D, Jiménez-Sousa MÁ, Briz V, Fernández-Rodríguez A. HCV spontaneous clearers showed low senescence profile in people living with HIV under long ART. J Med Virol 2023; 95:e28955. [PMID: 37465865 DOI: 10.1002/jmv.28955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/30/2023] [Accepted: 06/29/2023] [Indexed: 07/20/2023]
Abstract
Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) increases immune activation, inflammation, and oxidative stress that could lead to premature senescence. Different HCV infections, either acute or chronic infection, could lead to distinct premature cellular senescence in people living with HIV (PLWHIV). Observational study in 116 PLWHIV under antiretroviral treatment with different HCV status: (i) n = 45 chronically infected with HCV (CHC); (ii) n = 36 individuals who spontaneously clarify HCV (SC); (iii) n = 35 HIV controls. Oxidative stress biomarkers were analyzed at lipid, DNA, protein, and nitrates levels, as well as antioxidant capacity and glutathione reductase enzyme. Replicative senescence was evaluated by relative telomere length (RTL) measurement. Additionally, 26 markers of Senescence-Associated Secretory Phenotype (SASP) were analyzed by multiplex immunoassays (Luminex xMAP technology). Differences were evaluated by generalized linear model (GLMs) adjusted by most significant covariates. The SC group had a senescence signature similar to the HIV control group and slightly lower SASP levels. However, significant differences were observed with respect to the CHC group, where an increase in the nitrate concentration [adjusted arithmetic mean ratio, aAMR = 1.73 (1.27-2.35), p < 0.001, q = 0.009] and the secretion of 13 SASP-associated factors [granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-β, interleukin (IL)-1β, IL-2, IL-8, IL-13, tumor necrosis factor (TNF)-α, IL-1α, IL-1RA, IL-7, IL-15, C-X-C motif chemokine ligand 10 (IP-10), stem cell factor (SCF); q < 0.1)] was detected. The CHC group also showed higher values of IL-1α, IP-10, and placental growth factor 1 (PIGF-1) than HIV controls. The SC group showed a slightly lower senescence profile than the HIV group, which could indicate a more efficient control of viral-induced senescence due to their immune strengths. Chronic HCV infection in PLWHIV led to an increase in nitrate and elevated SASP biomarkers favoring the establishment of viral persistence.
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Affiliation(s)
- Violeta Lara-Aguilar
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - Celia Crespo-Bermejo
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - Manuel Llamas-Adán
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - Sergio Grande-García
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - María Engracia Cortijo-Alfonso
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | | | - Lourdes Domínguez
- VIH Unit, Internal Medicine Service, Doce de Octubre Hospital Biomedical Research Institute (imas12), Madrid, Spain
- King's College London University, London, UK
| | - Pablo Ryan
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Institute of Health Carlos III, Madrid, Spain
- Department of Infectious Diseases, HIV/Hepatitis Internal Medicine Service, Infanta Leonor University Hospital, Madrid, España
| | - Ignacio de Los Santos
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Institute of Health Carlos III, Madrid, Spain
- Internal Medicine-Infectious Diseases Service, La Princesa University Hospital, Madrid, España
| | - Sofía Bartolomé-Sanchez
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - Daniel Valle-Millares
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - María Ángeles Jiménez-Sousa
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Institute of Health Carlos III, Madrid, Spain
| | - Verónica Briz
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
| | - Amanda Fernández-Rodríguez
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Madrid, Majadahonda, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Institute of Health Carlos III, Madrid, Spain
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Takimoto Y, Chu PS, Nakamoto N, Hagihara Y, Mikami Y, Miyamoto K, Morikawa R, Teratani T, Taniki N, Fujimori S, Suzuki T, Koda Y, Ishihara R, Ichikawa M, Honda A, Kanai T. Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis. iScience 2023; 26:106220. [PMID: 36876136 PMCID: PMC9982274 DOI: 10.1016/j.isci.2023.106220] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 08/25/2022] [Accepted: 02/13/2023] [Indexed: 02/18/2023] Open
Abstract
The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b+ cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4-expressing Ly6c2-low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro. Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo. These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy.
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Affiliation(s)
- Yoichi Takimoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yuya Hagihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Kentaro Miyamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Miyarisan Pharmaceutical Co., Ltd, Kita-ku, Tokyo 114-0016, Japan
| | - Rei Morikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Sota Fujimori
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Research Unit/Immunology and Inflammation, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan
| | - Takahiro Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Miyarisan Pharmaceutical Co., Ltd, Kita-ku, Tokyo 114-0016, Japan
| | - Yuzo Koda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Research Unit/Immunology and Inflammation, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan
| | - Rino Ishihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masataka Ichikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Akira Honda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Inashiki-gun, Ibaraki 300-0395, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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Davitkov P, Hoffman K, Falck-Ytter Y, Wilson B, Stojadinovikj G, Anthony DD, Cohen SM, Cooper G. Increasing liver stiffness is associated with higher incidence of hepatocellular carcinoma in hepatitis C infection and non-alcoholic fatty liver disease-A population-based study. PLoS One 2023; 18:e0280647. [PMID: 36693057 PMCID: PMC9873178 DOI: 10.1371/journal.pone.0280647] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 01/04/2023] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND & AIMS Both non-alcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection commonly result in hepatic fibrosis and may lead to cirrhosis. This study aims to determine the incidence of HCC in patients with HCV or NAFLD complicated by advanced fibrosis, inferred from measurements of liver stiffness. METHODS Using Veterans Affairs (VA) Informatics and Computing Infrastructure (VINCI), we identified a nationwide cohort of patients with an existing diagnosis of HCV or NAFLD with liver transient elastography (TE) testing from 2015 to 2019. HCC cases, along with a random sample of non-HCC patients, were identified and validated, leading to calculation of incidence rates for HCC after adjustment for confounders. RESULTS 26,161 patients carried a diagnosis of HCV and 13,629 were diagnosed with NAFLD at the time of testing. In those with HCV, rates of HCC increased with liver stiffness with incidences of 0.28 (95% CI 0.24, 0.34), 0.93 (95% CI 0.72, 1.17), 1.28 (95% CI 0.89, 1.79), and 2.79 (95% CI 2.47, 3.14)/100,000 person years for TE score ranges <9.5 kPa, 9.5-12.5 kPa, 12.5-14.5 kPa and >14.5 kPa, respectively, after a median follow-up of 2.3 years. HCC incidence also increased with higher TE liver stiffness measures in NAFLD after a median follow-up of 1.1 years. CONCLUSION In this retrospective cohort, the incidence of HCC in HCV and NAFLD increases with higher TE liver stiffness measures, confirming that advanced fibrosis portends risk in viral and non-viral fibrotic liver diseases. Additional comparative studies are needed to determine the optimal cut point of TE liver stiffness to inform HCC screening guidelines and approaches.
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Affiliation(s)
- Perica Davitkov
- Gastroenterology and Hepatology Section, VA Northeast Ohio Healthcare System, Cleveland, Ohio, United States of America
- Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Kyle Hoffman
- Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
- Section of Internal Medicine, VA Northeast Ohio Healthcare System, Cleveland, Ohio, United States of America
- Department of Medicine, University Hospitals Cleveland Medical Center / Seidman Cancer Center, Cleveland, Ohio, United States of America
| | - Yngve Falck-Ytter
- Gastroenterology and Hepatology Section, VA Northeast Ohio Healthcare System, Cleveland, Ohio, United States of America
- Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Brigid Wilson
- Gastroenterology and Hepatology Section, VA Northeast Ohio Healthcare System, Cleveland, Ohio, United States of America
| | - Gjorgje Stojadinovikj
- Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Donald D. Anthony
- Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
- Section of Internal Medicine, VA Northeast Ohio Healthcare System, Cleveland, Ohio, United States of America
| | - Stanley Martin Cohen
- Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
- Digestive Health Institute, University Hospitals Cleveland Medical Center / Seidman Cancer Center, Cleveland, Ohio, United States of America
| | - Gregory Cooper
- Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
- Digestive Health Institute, University Hospitals Cleveland Medical Center / Seidman Cancer Center, Cleveland, Ohio, United States of America
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9
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Wang S, Li K, Pickholz E, Dobie R, Matchett KP, Henderson NC, Carrico C, Driver I, Jensen MB, Chen L, Petitjean M, Bhattacharya D, Fiel MI, Liu X, Kisseleva T, Alon U, Adler M, Medzhitov R, Friedman SL. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci Transl Med 2023; 15:eadd3949. [PMID: 36599008 PMCID: PMC10686705 DOI: 10.1126/scitranslmed.add3949] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 11/01/2022] [Indexed: 01/05/2023]
Abstract
Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions worldwide and is the strongest predictor of mortality in nonalcoholic steatohepatitis (NASH); however, there are no approved antifibrotic therapies. To identify antifibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single-nucleus RNA sequencing and tissue clearing in a robust murine NASH model. In advanced fibrosis, we found that an autocrine HSC signaling circuit emerged that was composed of 68 receptor-ligand interactions conserved between murine and human NASH. These predicted interactions were supported by the parallel appearance of markedly increased direct stellate cell-cell contacts in murine NASH. As proof of principle, pharmacological inhibition of one such autocrine interaction, neurotrophic receptor tyrosine kinase 3-neurotrophin 3, inhibited human HSC activation in culture and reversed advanced murine NASH fibrosis. In summary, we uncovered a repertoire of antifibrotic drug targets underlying advanced fibrosis in vivo. The findings suggest a therapeutic paradigm in which stage-specific therapies could yield enhanced antifibrotic efficacy in patients with advanced hepatic fibrosis.
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Affiliation(s)
- Shuang Wang
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai; New York NY, 10029, USA
| | - Kenneth Li
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai; New York NY, 10029, USA
| | - Eliana Pickholz
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai; New York NY, 10029, USA
| | - Ross Dobie
- Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, UK
| | - Kylie P. Matchett
- Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, UK
| | - Neil C. Henderson
- Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, UK
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH16 4TJ, UK
| | | | - Ian Driver
- Gordian Biotechnology, San Francisco CA, 94107, USA
| | | | - Li Chen
- PharmaNest, Inc, Princeton NJ, 08540, USA
| | | | - Dipankar Bhattacharya
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai; New York NY, 10029, USA
| | - Maria I. Fiel
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai; New York NY, 10029, USA
| | - Xiao Liu
- Department of Surgery, University of California, San Diego, La Jolla CA, 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla CA, 92093, USA
| | - Uri Alon
- Department Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel
| | - Miri Adler
- Tananbaum Center for Theoretical and Analytical Human Biology, Yale University School of Medicine, New Haven, CT, 06510, USA
| | - Ruslan Medzhitov
- Howard Hughes Medical Institute, Department of Immunobiology, Yale University School of Medicine, New Haven CT, 06510, USA
| | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai; New York NY, 10029, USA
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10
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Hung CT, Tsai YW, Wu YS, Yeh CF, Yang KC. The novel role of ER protein TXNDC5 in the pathogenesis of organ fibrosis: mechanistic insights and therapeutic implications. J Biomed Sci 2022; 29:63. [PMID: 36050716 PMCID: PMC9438287 DOI: 10.1186/s12929-022-00850-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022] Open
Abstract
Fibrosis-related disorders account for an enormous burden of disease-associated morbidity and mortality worldwide. Fibrosis is defined by excessive extracellular matrix deposition at fibrotic foci in the organ tissue following injury, resulting in abnormal architecture, impaired function and ultimately, organ failure. To date, there lacks effective pharmacological therapy to target fibrosis per se, highlighting the urgent need to identify novel drug targets against organ fibrosis. Recently, we have discovered the critical role of a fibroblasts-enriched endoplasmic reticulum protein disulfide isomerase (PDI), thioredoxin domain containing 5 (TXNDC5), in cardiac, pulmonary, renal and liver fibrosis, showing TXNDC5 is required for the activation of fibrogenic transforming growth factor-β signaling cascades depending on its catalytic activity as a PDI. Moreover, deletion of TXNDC5 in fibroblasts ameliorates organ fibrosis and preserves organ function by inhibiting myofibroblasts activation, proliferation and extracellular matrix production. In this review, we detailed the molecular and cellular mechanisms by which TXNDC5 promotes fibrogenesis in various tissue types and summarized potential therapeutic strategies targeting TXNDC5 to treat organ fibrosis.
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Affiliation(s)
- Chen-Ting Hung
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, 100, Taiwan
| | - Yi-Wei Tsai
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, 100, Taiwan
| | - Yu-Shuo Wu
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, 100, Taiwan
| | - Chih-Fan Yeh
- Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Kai-Chien Yang
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, 100, Taiwan. .,Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan. .,Research Center for Developmental Biology & Regenerative Medicine, National Taiwan University, Taipei, Taiwan. .,Center for Frontier Medicine, National Taiwan University Hospital, Taipei, Taiwan. .,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. .,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
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11
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Hung CT, Su TH, Chen YT, Wu YF, Chen YT, Lin SJ, Lin SL, Yang KC. Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non-canonical TGFβ signalling. Gut 2022; 71:1876-1891. [PMID: 34933915 DOI: 10.1136/gutjnl-2021-325065] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 12/05/2021] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND OBJECTIVES Liver fibrosis (LF) occurs following chronic liver injuries. Currently, there is no effective therapy for LF. Recently, we identified thioredoxin domain containing 5 (TXNDC5), an ER protein disulfide isomerase (PDI), as a critical mediator of cardiac and lung fibrosis. We aimed to determine if TXNDC5 also contributes to LF and its potential as a therapeutic target for LF. DESIGN Histological and transcriptome analyses on human cirrhotic livers were performed. Col1a1-GFPTg , Alb-Cre;Rosa26-tdTomato and Tie2-Cre/ERT2;Rosa26-tdTomato mice were used to determine the cell type(s) where TXNDC5 was induced following liver injury. In vitro investigations were conducted in human hepatic stellate cells (HSCs). Col1a2-Cre/ERT2;Txndc5fl/fl (Txndc5cKO ) and Alb-Cre;Txndc5fl/fl (Txndc5Hep-cKO ) mice were generated to delete TXNDC5 in HSCs and hepatocytes, respectively. Carbon tetrachloride treatment and bile duct ligation surgery were employed to induce liver injury/fibrosis in mice. The extent of LF was quantified using histological, imaging and biochemical analyses. RESULTS TXNDC5 was upregulated markedly in human and mouse fibrotic livers, particularly in activated HSC at the fibrotic foci. TXNDC5 was induced by transforming growth factor β1 (TGFβ1) in HSCs and it was both required and sufficient for the activation, proliferation, survival and extracellular matrix production of HSC. Mechanistically, TGFβ1 induces TXNDC5 expression through increased ER stress and ATF6-mediated transcriptional regulation. In addition, TXNDC5 promotes LF by redox-dependent JNK and signal transducer and activator of transcription 3 activation in HSCs through its PDI activity, activating HSCs and making them resistant to apoptosis. HSC-specific deletion of Txndc5 reverted established LF in mice. CONCLUSIONS ER protein TXNDC5 promotes LF through redox-dependent HSC activation, proliferation and excessive extracellular matrix production. Targeting TXNDC5, therefore, could be a potential novel therapeutic strategy to ameliorate LF.
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Affiliation(s)
- Chen-Ting Hung
- Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tung-Hung Su
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Ting Chen
- Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yueh-Feng Wu
- Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan
| | - You-Tzung Chen
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Sung-Jan Lin
- Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan.,Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.,Research Center for Developmental Biology & Regenerative Medicine, National Taiwan University, Taipei, Taiwan.,Center for Frontier Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shuei-Liong Lin
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Research Center for Developmental Biology & Regenerative Medicine, National Taiwan University, Taipei, Taiwan.,Graduate Institute and Department of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei, Taiwan
| | - Kai-Chien Yang
- Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan .,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Research Center for Developmental Biology & Regenerative Medicine, National Taiwan University, Taipei, Taiwan.,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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12
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Biomarkers for the Detection and Management of Hepatocellular Carcinoma in Patients Treated with Direct-Acting Antivirals. Cancers (Basel) 2022; 14:cancers14112700. [PMID: 35681679 PMCID: PMC9179595 DOI: 10.3390/cancers14112700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Chronic Hepatitis C virus (HCV) represents the main etiological factor for hepatocellular carcinoma (HCC) in developed countries. The introduction of direct-acting antivirals (DAAs) improved the eradication of the hepatitis C virus (HCV) but not the reduction in the incidence of HCV-associated HCC. Some patients still develop HCC, even after reaching a sustained virological response (SVR). This review is a summary of pre-clinical studies that investigated predictive biomarkers for HCC occurrence and recurrence in HCV-infected patients treated with DAAs. The presented biomarkers are found dysregulated in serum or tissue at specific time points (before, during, after DAA treatment or post SVR) and correlated with HCC-predisposing conditions. Thus, this review aims to improve the management of patients developing HCV-induced HCC. Abstract Hepatocellular carcinoma (HCC) is the sixth-most common type of cancer worldwide and chronic Hepatitis C virus (HCV) represents the main etiological factor in developed countries. HCV promotes hepatocarcinogenesis through persistent liver inflammation and dysregulation of cell signaling pathways. The introduction of direct-acting antivirals (DAAs) resulted in a significant improvement in the eradication of the virus, with an expected reduction of HCC incidence. However, the risk of HCC development can persist after DAA treatment. Recent studies have investigated the potential use of molecular biomarkers that predict HCC occurrence or recurrence helping the stratification of patients under surveillance. This review aimed to summarize all pre-clinical exploration of predictive biomarkers to identify DAA-treated patients at risk for HCC development. Dysregulated microRNAs, lncRNAs, histone modifications, cytokines, proteins, and sphingolipids represent various classes of HCC risk predictors identified in two different biological sources (tissue and serum). The non-invasive serum markers can provide a more accessible means to perform clinical monitoring and predict the risk of HCC. In addition, conditions like cirrhosis, predisposing to HCC, strongly correlate with most of the molecular predictors identified, supporting the value of these molecules as possible biomarkers of HCC in DAA-treated patients.
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13
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Abd El-Wahab EW, Abd Elgawad WM, Said M, Mikheal AI, Shatat HZ. Liver Disease Outcomes after Sustained Virological Response in Patients with Chronic Hepatitis C Infection Treated with Generic Direct-Acting Antivirals. Am J Trop Med Hyg 2022; 106:tpmd210918. [PMID: 35226870 PMCID: PMC9128674 DOI: 10.4269/ajtmh.21-0918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 12/22/2021] [Indexed: 11/07/2022] Open
Abstract
The introduction of generic direct-acting antivirals (DAAs) in Egypt is associated with a superior cure rate of hepatitis C virus (HCV) infection. However, the course of progressive liver damage and developing liver related complications in patients with sustained virologic response (SVR) remain unclear. This study was designed to examine the long-term outcomes of generic DAA-induced virological cure in a real-life cohort of HCV patients with or without comorbid schistosomiasis. We prospectively enrolled a cohort of 506 recently cured HCV patients (437 Child-Pugh class A [Child-A] and 69 Child-Pugh class B [Child-B]). All patients were clinically evaluated at different time points during a 2-year follow-up (November 2018 to February 2021). Over the course of treatment and follow-up, 77 (15.2%) patients (42 [9.6%] Child-A and 35 [50.7%] Child-B) experienced complications at different time points. The overall mortality rate was approximately 1/1,000 person-years. The incidence of hepatic insufficiency was approximately 5.5/1,000 person-years, and that of de novo hepatocellular carcinoma (HCC) was approximately 8.3/1,000 person-years. A sustained improvement in liver indices up to 2 years of follow-up was observed. In the Cox regression model, pretreatment decompensated cirrhosis predicted the occurrence of adverse liver events and HCC after therapy. In conclusion, in HCV patients with advanced cirrhosis or coexisting hepatic schistosomiasis, generic DAA-induced SVR remains robust with favorable clinical outcomes although the risk of hepatocarcinogenesis cannot be eliminated. Surveillance of patients with treated HCV infection is an important aspect of postcure care for early detection and management of liver disease-related adverse events.
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Affiliation(s)
- Ekram W. Abd El-Wahab
- Department of Tropical Health, High Institute of Public Health, Alexandria University, Alexandria, Egypt
| | - Waleed M. Abd Elgawad
- Department of Tropical Health, High Institute of Public Health, Alexandria University, Alexandria, Egypt
- Department of Endemic and Infectious Diseases, Damanhour Fever Hospital, Ministry of Health and Population, Damanhour, Egypt
| | - Mohamed Said
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ashraf I. Mikheal
- Department of Endemic and Infectious Diseases, Damanhour Fever Hospital, Ministry of Health and Population, Damanhour, Egypt
| | - Hanan Z. Shatat
- Department of Tropical Health, High Institute of Public Health, Alexandria University, Alexandria, Egypt
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14
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Friedman SL, Pinzani M. Hepatic fibrosis 2022: Unmet needs and a blueprint for the future. Hepatology 2022; 75:473-488. [PMID: 34923653 DOI: 10.1002/hep.32285] [Citation(s) in RCA: 250] [Impact Index Per Article: 83.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/12/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022]
Abstract
Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to the expectation of effective antifibrotic drugs, yet none has been approved. Thus, an assessment of the field is timely, to clarify priorities and accelerate progress. Here, we highlight the successes to date but, more importantly, identify gaps and unmet needs, both experimentally and clinically. These include the need to better define cell-cell interactions and etiology-specific elements of fibrogenesis and their link to disease-specific drivers of portal hypertension. Success in treating viral hepatitis has revealed the remarkable capacity of the liver to degrade scar in reversing fibrosis, yet we know little of the mechanisms underlying this response. Thus, there is an exigent need to clarify the cellular and molecular mechanisms of fibrosis regression in order for therapeutics to mimic the liver's endogenous capacity. Better refined and more predictive in vitro and animal models will hasten drug development. From a clinical perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate to supplant biopsy. More urgently, digital pathology methods that leverage machine learning and artificial intelligence must be validated in order to capture more prognostic information from liver biopsies and better quantify the response to therapies. For more refined treatment of NASH, orthogonal approaches that integrate genetic, clinical, and pathological data sets may yield treatments for specific subphenotypes of the disease. Collectively, these and other advances will strengthen and streamline clinical trials and better link histologic responses to clinical outcomes.
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Affiliation(s)
- Scott L Friedman
- Division of Liver DiseasesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Massimo Pinzani
- Institute for Liver and Digestive HealthUniversity College LondonLondonUK
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15
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Kouroumalis E, Voumvouraki A. Hepatitis C virus: A critical approach to who really needs treatment. World J Hepatol 2022; 14:1-44. [PMID: 35126838 PMCID: PMC8790391 DOI: 10.4254/wjh.v14.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/14/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction of effective drugs in the treatment of hepatitis C virus (HCV) infection has prompted the World Health Organization to declare a global eradication target by 2030. Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status. A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease. Huge financial resources were redirected, and the pandemic became the first priority in every country. In this review, we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection. We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination. Alcohol consumption, HIV coinfection and the presence of components of metabolic syndrome including obesity, hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liver-related morbidity and mortality of HCV. We also examined the significance of special subpopulations like people who inject drugs and males having sex with males. Finally, we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income. We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University of Crete Medical School, Heraklion 71500, Crete, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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16
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Karkampouna S, van der Helm D, Scarpa M, van Hoek B, Verspaget HW, Goumans MJ, Coenraad MJ, Kruithof BP, Kruithof-de Julio M. Oncofetal Protein CRIPTO Is Involved in Wound Healing and Fibrogenesis in the Regenerating Liver and Is Associated with the Initial Stages of Cardiac Fibrosis. Cells 2021; 10:3325. [PMID: 34943832 PMCID: PMC8699799 DOI: 10.3390/cells10123325] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/18/2021] [Accepted: 11/22/2021] [Indexed: 12/20/2022] Open
Abstract
Oncofetal protein, CRIPTO, is silenced during homeostatic postnatal life and often re-expressed in different neoplastic processes, such as hepatocellular carcinoma. Given the reactivation of CRIPTO in pathological conditions reported in various adult tissues, the aim of this study was to explore whether CRIPTO is expressed during liver fibrogenesis and whether this is related to the disease severity and pathogenesis of fibrogenesis. Furthermore, we aimed to identify the impact of CRIPTO expression on fibrogenesis in organs with high versus low regenerative capacity, represented by murine liver fibrogenesis and adult murine heart fibrogenesis. Circulating CRIPTO levels were measured in plasma samples of patients with cirrhosis registered at the waitlist for liver transplantation (LT) and 1 year after LT. The expression of CRIPTO and fibrotic markers (αSMA, collagen type I) was determined in human liver tissues of patients with cirrhosis (on a basis of viral hepatitis or alcoholic disease), in cardiac tissue samples of patients with end-stage heart failure, and in mice with experimental liver and heart fibrosis using immuno-histochemical stainings and qPCR. Mouse models with experimental chronic liver fibrosis, induced with multiple shots of carbon tetrachloride (CCl4) and acute liver fibrosis (one shot of CCl4), were evaluated for CRIPTO expression and fibrotic markers. CRIPTO was overexpressed in vivo (Adenoviral delivery) or functionally sequestered by ALK4Fc ligand trap in the acute liver fibrosis mouse model. Murine heart tissues were evaluated for CRIPTO and fibrotic markers in three models of heart injury following myocardial infarction, pressure overload, and ex vivo induced fibrosis. Patients with end-stage liver cirrhosis showed elevated CRIPTO levels in plasma, which decreased 1 year after LT. Cripto expression was observed in fibrotic tissues of patients with end-stage liver cirrhosis and in patients with heart failure. The expression of CRIPTO in the liver was found specifically in the hepatocytes and was positively correlated with the Model for End-stage Liver Disease (MELD) score for end-stage liver disease. CRIPTO expression in the samples of cardiac fibrosis was limited and mostly observed in the interstitial cells. In the chronic and acute mouse models of liver fibrosis, CRIPTO-positive cells were observed in damaged liver areas around the central vein, which preceded the expression of αSMA-positive stellate cells, i.e., mediators of fibrosis. In the chronic mouse models, the fibrosis and CRIPTO expression were still present after 11 weeks, whereas in the acute model the liver regenerated and the fibrosis and CRIPTO expression resolved. In vivo overexpression of CRIPTO in this model led to an increase in fibrotic markers, while blockage of CRIPTO secreted function inhibited the extent of fibrotic areas and marker expression (αSMA, Collagen type I and III) and induced higher proliferation of residual healthy hepatocytes. CRIPTO expression was also upregulated in several mouse models of cardiac fibrosis. During myocardial infarction CRIPTO is upregulated initially in cardiac interstitial cells, followed by expression in αSMA-positive myofibroblasts throughout the infarct area. After the scar formation, CRIPTO expression decreased concomitantly with the αSMA expression. Temporal expression of CRIPTO in αSMA-positive myofibroblasts was also observed surrounding the coronary arteries in the pressure overload model of cardiac fibrosis. Furthermore, CRIPTO expression was upregulated in interstitial myofibroblasts in hearts cultured in an ex vivo model for cardiac fibrosis. Our results are indicative for a functional role of CRIPTO in the induction of fibrogenesis as well as a potential target in the antifibrotic treatments and stimulation of tissue regeneration.
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Affiliation(s)
- Sofia Karkampouna
- Department for Biomedical Research, Urology Research Laboratory, Bern University, 3008 Bern, Switzerland; (S.K.); (M.S.)
| | - Danny van der Helm
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.v.d.H.); (B.v.H.); (H.W.V.); (M.J.C.)
| | - Mario Scarpa
- Department for Biomedical Research, Urology Research Laboratory, Bern University, 3008 Bern, Switzerland; (S.K.); (M.S.)
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.v.d.H.); (B.v.H.); (H.W.V.); (M.J.C.)
| | - Hein W. Verspaget
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.v.d.H.); (B.v.H.); (H.W.V.); (M.J.C.)
| | - Marie-Jose Goumans
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (M.-J.G.); (B.P.T.K.)
| | - Minneke J. Coenraad
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (D.v.d.H.); (B.v.H.); (H.W.V.); (M.J.C.)
| | - Boudewijn P.T. Kruithof
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (M.-J.G.); (B.P.T.K.)
- Department of Cardiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Marianna Kruithof-de Julio
- Department for Biomedical Research, Urology Research Laboratory, Bern University, 3008 Bern, Switzerland; (S.K.); (M.S.)
- Department of Urology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland
- Translational Organoid Resource Core, Department for BioMedical Research, Bern University, 3008 Bern, Switzerland
- Bern Center for Precision Medicine, Inselspital, University Hospital of Bern, 3010 Bern, Switzerland
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17
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Knop V, Hoppe D, Vermehren J, Troetschler S, Herrmann E, Vermehren A, Friedrich-Rust M, Sarrazin C, Trebicka J, Zeuzem S, Welker MW. Non-invasive assessment of fibrosis regression and portal hypertension in patients with advanced chronic hepatitis C virus (HCV)-associated liver disease and sustained virologic response (SVR): 3 years follow-up of a prospective longitudinal study. J Viral Hepat 2021; 28:1604-1613. [PMID: 34342081 DOI: 10.1111/jvh.13587] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 07/21/2021] [Accepted: 07/24/2021] [Indexed: 12/14/2022]
Abstract
Long-term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)-based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen elastography to assess potential regression of cirrhosis and portal hypertension 3 years post-treatment. Fifty-four patients with HCV-associated cirrhosis and DAA-induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post-treatment by transient liver elastography (L-TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L-ARFI) and spleen (S-ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L-TE decreased between BL [median (range), 32.5(9.1-75) kPa] and EOT [21.3(6.7-73.5) kPa; p < .0001] and EOT and FU144 [16(4.1-75) kPa; p = .006]. L-ARFI values improved between EOT [2.5(1.2-4.1) m/s] and FU144 [1.7(0.9-4.1) m/s; p = .001], while spleen stiffness remained unchanged. Overall, L-TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L-ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L-ARFI values (p = .048) at EOT or regression of cirrhosis (<12.5 kPa) by L-TE at FU144 (p = .005), respectively. Liver stiffness, but not spleen stiffness, continued to decline in a considerable proportion of patients with advanced liver disease after HCV eradication.
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Affiliation(s)
- Viola Knop
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Daniel Hoppe
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.,St. Elisabeth-Krankenhaus, Leipzig, Germany
| | - Johannes Vermehren
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Sven Troetschler
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.,Ketteler Krankenhaus, Offenbach, Germany
| | - Eva Herrmann
- Institut für Biostatistik und mathematische Modellierung, Goethe-Universität Frankfurt, Frankfurt am Main, Germany
| | - Annika Vermehren
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | | | - Christoph Sarrazin
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.,St-Josefs-Hospital, Wiesbaden, Germany
| | - Jonel Trebicka
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Martin-Walter Welker
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
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18
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Caligiuri A, Gentilini A, Pastore M, Gitto S, Marra F. Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression. Cells 2021; 10:cells10102759. [PMID: 34685739 PMCID: PMC8534788 DOI: 10.3390/cells10102759] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.
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19
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Reiter FP, Ye L, Ofner A, Schiergens TS, Ziesch A, Brandl L, Ben Khaled N, Hohenester S, Wimmer R, Artmann R, He Y, Lee SM, Mayr D, Zhang C, Gerbes AL, Mayerle J, Denk G, De Toni EN. p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in Mice. Cell Mol Gastroenterol Hepatol 2021; 13:95-112. [PMID: 34537439 PMCID: PMC8593664 DOI: 10.1016/j.jcmgh.2021.09.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Progression of chronic liver disease (CLD) to liver cirrhosis and liver cancer is a major global cause of morbidity and mortality. Treatment options capable of inhibiting progression of liver fibrosis when etiological treatment of CLD is not available or fails have yet to be established. We investigated the role of serine/threonine kinase p70 ribosomal protein S6 kinase (p70S6K) as checkpoint of fibrogenesis in hepatic stellate cells (HSCs) and as target for the treatment of liver fibrosis. APPROACH & RESULTS Immunohistochemistry was used to assess p70S6K expression in liver resection specimen. Primary human or murine HSCs from wild-type or p70S6K-/- mice as well as LX-2 cells were used for in vitro experiments. Specific small interfering RNA or CEP-1347 were used to silence or inhibit p70S6K and assess its functional relevance in viability, contraction and migration assays, fluorescence-activated cell sorting, and Western blot. These results were validated in vivo by a chemical model of fibrogenesis using wild-type and p70S6K-/- mice. Expression of p70S6K was significantly increased in human cirrhotic vs noncirrhotic liver-tissue and progressively increased in vitro through activation of primary human HSCs. Conversely, p70S6K induced fibrogenic activation of HSCs in different models, including the small interfering RNA-based silencing of p70S6K in HSC lines, experiments with p70S6K-/- cells, and the pharmacological inhibition of p70S6K by CEP-1347. These findings were validated in vivo as p70S6K-/- mice developed significantly less fibrosis upon exposure to CCl4. CONCLUSIONS We establish p70S6K as a checkpoint of fibrogenesis in vitro and in vivo and CEP-1347 as potential treatment option that can safely be used for long-term treatment.
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Affiliation(s)
- Florian P. Reiter
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany,Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany,Liver Center, University Hospital, LMU Munich, Munich, Germany,Correspondence Address correspondence to: Florian P. Reiter, MD, Department of Medicine II, Liver Center Munich, University of Munich, Marchioninistraße 15, D-81377 Munich, Germany. fax: +49-931-201-640023.
| | - Liangtao Ye
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany,Liver Center, University Hospital, LMU Munich, Munich, Germany,Center for Digestive Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Andrea Ofner
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany,Liver Center, University Hospital, LMU Munich, Munich, Germany
| | - Tobias S. Schiergens
- Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany,Biobank of the Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany
| | - Andreas Ziesch
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany,Liver Center, University Hospital, LMU Munich, Munich, Germany
| | - Lydia Brandl
- Institute of Pathology, LMU Munich, Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany,Liver Center, University Hospital, LMU Munich, Munich, Germany
| | - Simon Hohenester
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany,Liver Center, University Hospital, LMU Munich, Munich, Germany
| | - Ralf Wimmer
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany,Liver Center, University Hospital, LMU Munich, Munich, Germany
| | - Renate Artmann
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany,Liver Center, University Hospital, LMU Munich, Munich, Germany
| | - Yulong He
- Center for Digestive Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Serene M.L. Lee
- Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany,Biobank of the Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany
| | - Doris Mayr
- Institute of Pathology, LMU Munich, Munich, Germany
| | - Changhua Zhang
- Center for Digestive Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Alexander L. Gerbes
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany,Liver Center, University Hospital, LMU Munich, Munich, Germany
| | - Julia Mayerle
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany,Liver Center, University Hospital, LMU Munich, Munich, Germany
| | - Gerald Denk
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany,Liver Center, University Hospital, LMU Munich, Munich, Germany,Transplantation Center Munich, University Hospital, LMU Munich, Munich, Germany
| | - Enrico N. De Toni
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany,Liver Center, University Hospital, LMU Munich, Munich, Germany
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20
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Amygdalin isolated from Amygdalus mongolica protects against hepatic fibrosis in rats. ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2021; 71:459-471. [PMID: 36654093 DOI: 10.2478/acph-2021-0022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/21/2020] [Indexed: 01/20/2023]
Abstract
The aim of this research was to investigate the effect of amygdalin on hepatic fibrosis in rats. Amygdalin was purified and identified from the seeds of Amygdalus mongo lica. Sprague Dawley rats in the control and model groups were administered water. Sprague Dawley rats were divided into the low-, middle-, and high-dose amygdalin groups that received 20, 40, and 80 mg kg-1 amygdalin, respectively. whereas the silymarin group was treated with 50 mg kg-1 silymarin. The control and model groups were administered water. Liver tissue analysis revealed significantly lower activities of ALT, AST, ALP, SOD, and MDA in the drug-treated groups compared to the model group. Serum analysis revealed significantly lower HYC and C-IV in the middle-dose amygdalin-treated group compared to the model group. The histopathological changes were less severe in the drug-treated groups as observed by the formation of pseudolobuli and decreased collagen fiber deposition. Hepatic fibrosis-related genes were expressed at significantly lower levels in the amygdalin-treated groups than in the model group. Amygdalin from A. mongolica represents a therapeutic candidate for hepatic fibrosis prevention and treatment.
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21
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Higuchi M, Tamaki N, Kurosaki M, Inada K, Kirino S, Yamashita K, Hayakawa Y, Sekiguchi S, Osawa L, Takaura K, Maeyashiki C, Kaneko S, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Enomoto N, Izumi N. Changes of liver stiffness measured by magnetic resonance elastography during direct-acting antivirals treatment in patients with chronic hepatitis C. J Med Virol 2021; 93:3744-3751. [PMID: 32890408 DOI: 10.1002/jmv.26490] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 08/17/2020] [Accepted: 09/01/2020] [Indexed: 12/21/2022]
Abstract
Almost all patients achieved sustained virological response (SVR) by direct-acting antivirals (DAA) therapy, but it is not clear as to what extent DAA therapy affects changes in liver fibrosis after achieving SVR. In this study, we investigated the changes of liver stiffness by magnetic resonance elastogaraphy (MRE) during DAA therapy. A total of 308 patients were enrolled in the study. Liver stiffness was measured twice before and after DAA treatment using MRE and time-course change of liver stiffness was investigated. The median (interquartile range) values for liver stiffness were 4.2 (3.2-6.1) kPa at baseline and 3.3 (2.6-4.8) kPa at SVR, demonstrating a significant improvement (p < .01). A total of 44% of patients had no improvement in liver stiffness despite achieving SVR. In patients with advanced fibrosis (lower level of albumin [Alb] or histological fibrosis stage F4), it was difficult to improve liver stiffness. Except for Alb, there were no blood tests associated with nonimprovement in liver stiffness, making these cases difficult to predict. In conclusion, despite obtaining SVR, improvement in liver stiffness could not be obtained in some cases, especially in patients with advanced fibrosis. In these patients, liver stiffness must be followed even if SVR is obtained.
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Affiliation(s)
- Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Koji Yamashita
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yuka Hayakawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shuhei Sekiguchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Leona Osawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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22
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Yuen MF, Liu SH, Seto WK, Mak LY, Corman SL, Hsu DC, Lee MYK, Khan TK, Puenpatom A. Cost-Utility of All-Oral Direct-Acting Antiviral Regimens for the Treatment of Genotype 1 Chronic Hepatitis C Virus-Infected Patients in Hong Kong. Dig Dis Sci 2021; 66:1315-1326. [PMID: 32385703 PMCID: PMC7990846 DOI: 10.1007/s10620-020-06281-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 04/16/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Direct-acting antivirals (DAAs) are entering the hepatitis C virus (HCV) treatment landscape in Hong Kong, prompting the need for cost-effectiveness evaluations of these interventions to enable optimal use of healthcare resources. AIMS This study aimed to compare the cost-effectiveness of DAAs to standard-of-care pegylated interferon plus ribavirin (RBV) in treatment-naïve patients without significant liver fibrosis and to compare different DAAs in patients who are treatment-experienced and/or have advanced liver disease. METHODS A Markov model was constructed to evaluate cost-effectiveness over a lifetime time horizon from the payer perspective. The target population was treatment-naïve and treatment-experienced HCV genotype 1 patients, stratified by degree of liver fibrosis. The model consists of 16 health states encompassing METAVIR fibrosis score (F0-F4), treatment success or failure, decompensated cirrhosis, hepatocellular carcinoma, liver transplant, and liver-related death. The proportions of patients achieving sustained virologic response were obtained from clinical trials. Other inputs were obtained from published and local data. The primary outcome was incremental cost-utility ratio for each DAA versus pegylated interferon + ribavirin and among different DAAs. RESULTS In treatment-naïve F0-2 HCV patients, all DAAs were cost-effective in genotype 1a and daclatasvir + asunaprevir, elbasvir/grazoprevir, ledipasvir/sofosbuvir, and glecaprevir/pibrentasvir were cost-effective compared to pegylated interferon + ribavirin in genotype 1b. In genotypes 1a and 1b, treatment-experienced patients, and F3-4 patients, elbasvir/grazoprevir was the least costly DAA and economically dominant over most other DAAs. CONCLUSIONS DAAs can be a cost-effective option for the treatment of genotype 1 HCV patients in Hong Kong, and elbasvir/grazoprevir is cost-effective.
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Affiliation(s)
- Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong
- State Key Laboratory of Liver Disease, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Sze-Hang Liu
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong
- State Key Laboratory of Liver Disease, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Shelby L Corman
- Pharmerit International, 4350 East-West Highway Suite 1100, Bethesda, MD, 20814, USA.
| | - Danny C Hsu
- Merck Sharp & Dohme (Asia) Ltd., Hong Kong, Hong Kong
| | - Mary Y K Lee
- Merck Sharp & Dohme (Asia) Ltd., Hong Kong, Hong Kong
| | - Tsz K Khan
- Merck Sharp & Dohme (Asia) Ltd., Hong Kong, Hong Kong
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23
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Chaillon A, Thurairajah PH, Hsiang JC, Martin NK. What is required for achieving hepatitis C virus elimination in Singapore? A modeling study. J Gastroenterol Hepatol 2021; 36:1110-1117. [PMID: 32777859 PMCID: PMC8174139 DOI: 10.1111/jgh.15211] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 07/09/2020] [Accepted: 08/05/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM The vast majority of hepatitis C virus (HCV) infection in Singapore is among those with a history of injecting drug use (IDU), yet harm reduction is not available and what is required to achieve the World Health Organization (WHO) HCV elimination targets (80% incidence reduction and 65% mortality reduction by 2030) is unknown. We model the intervention scale-up required to achieve WHO targets in Singapore. METHODS A dynamic model of HCV transmission and progression among those with a history of IDU was calibrated to Singapore, a setting with declining IDU and no harm reduction (~11 000 people with IDU history in 2017 and 45% HCV seropositive). We projected HCV treatment scale-up from 2019 required to achieve WHO targets with varying prioritization scenarios, with/without opiate substitution therapy scale-up (to 40% among people who inject drugs [PWID]). RESULTS We estimated 3855 (95% confidence interval: 2635-5446) chronically HCV-infected individuals with a history of IDU and 148 (87-284) incident HCV cases in Singapore in 2019. Reaching the HCV incidence target requires 272 (187-384) treatments in 2019, totaling 2444 (1683-3452) across 2019-2030. By prioritizing PWID or PWID and cirrhotics, 60% or 30% fewer treatments are required, respectively, whereas the target cannot be achieved with cirrhosis prioritization. Opiate substitution therapy scale-up reduces treatments required by 21-24%. Achieving both WHO targets requires treating 631 (359-1047) in 2019, totaling 3816 (2664-5423) across 2019-2030. CONCLUSIONS Hepatitis C virus elimination is achievable in Singapore but even with declining IDU requires immediate treatment scale-up among PWID. Harm reduction provision reduces treatments required and provides additional benefits.
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Affiliation(s)
- Antoine Chaillon
- Division of Infectious Diseases and Global Public Health, University of California, 9500 Gilman Dr La Jolla, CA 92093-0507
| | | | - John C Hsiang
- Department of Gastroenterology, Sengkang General Hospital, Singapore, 110 Sengkang E Way Singapore 544886
| | - Natasha K Martin
- Division of Infectious Diseases and Global Public Health, University of California, 9500 Gilman Dr La Jolla, CA 92093-0507,Population Health Sciences, University of Bristol, Senate House, Tyndall Ave Bristol BS8 1TH UK
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24
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Rockey DC, Friedman SL. Fibrosis Regression After Eradication of Hepatitis C Virus: From Bench to Bedside. Gastroenterology 2021; 160:1502-1520.e1. [PMID: 33529675 PMCID: PMC8601597 DOI: 10.1053/j.gastro.2020.09.065] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/01/2020] [Accepted: 09/06/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection and its complications have been the major cause of cirrhosis and its complications for several decades in the Western world. Until recently, treatment for HCV with interferon-based regimens was associated with moderate success but was difficult to tolerate. More recently, however, an arsenal of novel and highly effective direct-acting antiviral (DAA) drugs has transformed the landscape by curing HCV in a broad range of patients, including those with established advanced fibrosis, cirrhosis, comorbidities, and even those with complications of cirrhosis. Fibrosis is a dynamic process comprising both extracellular matrix deposition, as well as its degradation. With almost universal sustained virologic response (SVR) (ie, elimination of HCV), it is timely to explore whether HCV eradication can reverse fibrosis and cirrhosis. Indeed, fibrosis in several types of liver disease is reversible, including HCV. However, we do not know with certainty in whom fibrosis regression can be expected after HCV elimination, how quickly it occurs, and whether antifibrotic therapies will be indicated in those with persistent cirrhosis. This review summarizes the evidence for reversibility of fibrosis and cirrhosis after HCV eradication, its impact on clinical outcomes, and therapeutic prospects for directly promoting fibrosis regression in patients whose fibrosis persists after SVR.
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Affiliation(s)
- Don C Rockey
- The Medical University of South Carolina, Charleston, South Carolina.
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
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25
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Ma YJ, Du LY, Yan LB, Liao J, Cheng X, Xie WW, Tang H. Long-term follow-up of HCV patients with sustained virological response after treatment with pegylated interferon plus ribavirin. Hepatobiliary Pancreat Dis Int 2021; 20:137-141. [PMID: 32146076 DOI: 10.1016/j.hbpd.2020.02.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 02/13/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND The progress of liver diseases may not stop after viral eradication. This study aimed to provide data on long-term prognosis of patients with hepatitis C virus (HCV) infection who underwent pegylated interferon plus ribavirin (PR) regimen and achieved a sustained virological response 24 weeks post-treatment (SVR24). METHODS Responders to the PR regimen in our hospital from January 2011 to June 2014 were enrolled and prospectively followed up. Baseline characteristics were profiled. The incidence of hepatocellular carcinoma (HCC), progression of liver disease (increase in liver stiffness or occurrence of decompensated complication), and HCV recurrence was all monitored. The accumulative and annualized incidence rates (AIRs) of these adverse events were analyzed, and the risk factors were also examined. RESULTS In total, 151 patients reached a median follow-up time of 103 weeks. Among them, two had an incidence of HCC during the surveillance with AIR of 0.68% (95% CI: 0.00-1.63%). Six patients showed progression of liver disease with AIR of 2.05% (95% CI: 0.42%-3.68%). Three patients who had risky behaviors encountered HCV reinfection. The cirrhotic patients faced higher risk of poor prognosis than non-cirrhotic patients, including HCC and progression of liver disease (AIR: 6.17% vs. 1.42%, P = 0.039). CONCLUSIONS The incidence of HCC and progression of liver disease was evident in PR responders during the long-term follow-up period, but the risk level was low. Cirrhotic responders were more vulnerable to develop HCC post SVR24 compared with non-cirrhotic ones. HCV recurrence was rare in responders with SVR24 who had corrected their risky behaviors.
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Affiliation(s)
- Yuan-Ji Ma
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Ling-Yao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Li-Bo Yan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Juan Liao
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Xing Cheng
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Wu-Wei Xie
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China.
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26
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Huang R, Rao HY, Yang M, Gao YH, Wang J, Jin Q, Ma DL, Wei L. Histopathology and the predominantly progressive, indeterminate and predominately regressive score in hepatitis C virus patients after direct-acting antivirals therapy. World J Gastroenterol 2021; 27:404-415. [PMID: 33584072 PMCID: PMC7856841 DOI: 10.3748/wjg.v27.i5.404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/14/2020] [Accepted: 12/27/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Histological changes after direct-acting antivirals (DAAs) therapy in hepatitis C virus (HCV) patients has not been elucidated. Whether the predominantly progressive, indeterminate and predominately regressive (P-I-R) score, evaluating fibrosis activity in hepatitis B virus patients has predictive value in HCV patients has not been investigated.
AIM To identify histological changes after DAAs therapy and to evaluate the predictive value of the P-I-R score in HCV patients.
METHODS Chronic HCV patients with paired liver biopsy specimens before and after DAAs treatment were included. Sustained virologic response (SVR) was defined as an undetectable serum HCV RNA level at 24 wk after treatment cessation. The Ishak system and P-I-R score were assessed. Inflammation improvement and fibrosis regression were defined as a ≥ 2-points decrease in the histology activity index (HAI) score and a ≥ 1-point decrease in the Ishak fibrosis score, respectively. Fibrosis progression was defined as a ≥ 1-point increase in the Ishak fibrosis score. Histologic improvement was defined as a ≥ 2-points decrease in the HAI score without worsening of the Ishak fibrosis score after DAAs therapy. The P-I-R score was also assessed. “absolutely reversing or advancing” was defined as the same directionality implied by both change in the Ishak score and posttreatment P-I-R score; and “probably reversing or advancing” was defined as only one parameter showing directionality.
RESULTS Thirty-eight chronic HCV patients with paired liver biopsy specimens before and after DAAs treatment were included. The mean age of these patients was 40.9 ± 14.6 years and there were 53% (20/38) males. Thirty-four percent (13/38) of patients were cirrhotic. Eighty-two percent (31/38) of patients achieved inflammation improvement. The median HAI score decreased significantly after SVR (pretreatment 7.0 vs posttreatment 2.0, Z = -5.146, P = 0.000). Thirty-seven percent (14/38) of patients achieved fibrosis improvement. The median Ishak score decreased significantly after SVR (pretreatment 4.0 vs posttreatment 3.0, Z = -2.354, P = 0.019). Eighty-two percent (31/38) of patients showed histological improvement. The P-I-R score was evaluated in 61% (23/38) of patients. The progressive group showed lower platelet (P = 0.024) and higher HAI scores (P = 0.070) before treatment. In patients with stable Ishak stage after treatment: Progressive injury was seen in 22% (4/18) of patients, 33% (6/18) were classified as indeterminate and regressive changes were seen in 44% (8/18) of patients who were judged as probably reversing by the Ishak and P-I-R systems.
CONCLUSION Significant improvement of necroinflammation and partial remission of fibrosis in HCV patients occurred shortly after DAAs therapy. The P-I-R score has potential in predicting fibrosis in HCV patients.
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Affiliation(s)
- Rui Huang
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University People’s Hospital, Beijing 100044, China
| | - Hui-Ying Rao
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University People’s Hospital, Beijing 100044, China
| | - Ming Yang
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
| | - Ying-Hui Gao
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University People’s Hospital, Beijing 100044, China
| | - Jian Wang
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University People’s Hospital, Beijing 100044, China
| | - Qian Jin
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University People’s Hospital, Beijing 100044, China
| | - Dan-Li Ma
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University People’s Hospital, Beijing 100044, China
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
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Selicean S, Wang C, Guixé-Muntet S, Stefanescu H, Kawada N, Gracia-Sancho J. Regression of portal hypertension: underlying mechanisms and therapeutic strategies. Hepatol Int 2021; 15:36-50. [PMID: 33544313 PMCID: PMC7886770 DOI: 10.1007/s12072-021-10135-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/05/2021] [Indexed: 12/12/2022]
Abstract
Portal hypertension is the main non-neoplastic complication of chronic liver disease, being the cause of important life-threatening events including the development of ascites or variceal bleeding. The primary factor in the development of portal hypertension is a pathological increase in the intrahepatic vascular resistance, due to liver microcirculatory dysfunction, which is subsequently aggravated by extra-hepatic vascular disturbances including elevation of portal blood inflow. Evidence from pre-clinical models of cirrhosis has demonstrated that portal hypertension and chronic liver disease can be reversible if the injurious etiological agent is removed and can be further promoted using pharmacological therapy. These important observations have been partially demonstrated in clinical studies. This paper aims at providing an updated review of the currently available data regarding spontaneous and drug-promoted regression of portal hypertension, paying special attention to the clinical evidence. It also considers pathophysiological caveats that highlight the need for caution in establishing a new dogma that human chronic liver disease and portal hypertension is reversible.
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Affiliation(s)
- Sonia Selicean
- Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland
| | - Cong Wang
- Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland
| | - Sergi Guixé-Muntet
- Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland
| | - Horia Stefanescu
- Department of Hepatology, Prof. Dr. Octavian Fodor Regional Institute of Gastroenterology and Hepatology, Liver Research Club, Cluj-Napoca, Romania
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Jordi Gracia-Sancho
- Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland.
- Liver Vascular Biology Research Group, IDIBAPS Research Institute, CIBEREHD, Barcelona, Spain.
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Noninvasive biomarkers predict improvement in liver fibrosis after successful generic DAAs based therapy of chronic hepatitis C in Egypt. CLINICAL EPIDEMIOLOGY AND GLOBAL HEALTH 2020. [DOI: 10.1016/j.cegh.2020.04.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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29
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Knop V, Mauss S, Goeser T, Geier A, Zimmermann T, Herzer K, Postel N, Friedrich-Rust M, Hofmann WP. Dynamics of liver stiffness by transient elastography in patients with chronic hepatitis C virus infection receiving direct-acting antiviral therapy-Results from the German Hepatitis C-Registry. J Viral Hepat 2020; 27:690-698. [PMID: 32096310 DOI: 10.1111/jvh.13280] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 01/20/2020] [Accepted: 02/09/2020] [Indexed: 12/13/2022]
Abstract
The impact of direct-acting antiviral (DAA) therapies on fibrosis regression remains uncertain. In the current study, we prospectively evaluated dynamics of liver stiffness by transient elastography (TE) in patients with chronic HCV infection receiving DAA-based treatment. Patients (260) were enrolled in the German Hepatitis C-Registry (DHC-R), a national multicentre real-world cohort. Liver stiffness (LS) was assessed at baseline, end of treatment (EOT) and 24 weeks after EOT (FU24) by TE. Biochemical, virological and clinical data were obtained in parallel. In patients with SVR, there was a significant improvement of LS between baseline (median [range], 8.6 [1.7-73.5] kPa) and FU24 (7.9 [1.7-75 kPa]; P < .0001) as well as between EOT (8.4 [1.7-73.5 kPa]) and FU24 [P < .0001]. Stratified by fibrosis stage, patients classified into F4 had higher magnitude of LS reduction between BL (median [range], 25.1 [13.5-73.5] kPa) and FU24 (21.5 [3.1-75] kPa; P = .002) compared to those with F2-F3 (8.9 [7.1-12.4] kPa and 8.8 [4.2-29.1]; P = .060) or F0-F1 (5.3 [1.7-7] kPa and 5.2 [1.7-7.7]; P = .064). In cirrhotic patients, low platelets were significantly associated with lack of liver stiffness improvement, both at EOT (P = .018) and at FU24 (P = .012). LS significantly correlated with ALT (r = .371), AST (r = .552), platelets (r = -.499), GGT (r = .250), bilirubin (r = .230), APRI score (r = .512), FIB-4 score (r = .517) and FORNS index (r = .562); P < .0001. Liver elastography improved significantly in our real-world cohort after DAA-based therapy. As LS correlates similarly with transaminase levels and serum fibrosis markers, it might reflect both reduction of necroinflammation and fibrosis regression.
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Affiliation(s)
- Viola Knop
- Department of Internal Medicine I, Goethe University Hospital, Frankfurt, Germany
| | - Stefan Mauss
- Center for HIV and Hepatogastroenterology, Düsseldorf, Germany
| | | | | | - Tim Zimmermann
- I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Kerstin Herzer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg, Essen, Germany
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- Leberstiftungs-GmbH Deutschland, Hannover, Germany
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30
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Bloch EM, Kipiani E, Shadaker S, Alkhazashvili M, Gvinjilia L, Kuchuloria T, Chitadze N, Keating SM, Gamkrelidze A, Turdziladze A, Getia V, Nasrullah M, Averhoff F, Izoria M, Skaggs B. Blood transfusion safety in the country of Georgia: collateral benefit from a national hepatitis C elimination program. Transfusion 2020; 60:1243-1252. [PMID: 32542715 DOI: 10.1111/trf.15815] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/14/2020] [Accepted: 03/23/2020] [Indexed: 01/24/2023]
Abstract
BACKGROUND In April 2015, the government of Georgia (country) initiated the world's first national hepatitis C elimination program. An analysis of blood donor infectious screening data was conducted to inform a strategic plan to advance blood transfusion safety in Georgia. STUDY DESIGN AND METHODS Descriptive analysis of blood donation records (2015-2017) was performed to elucidate differences in demographics, donor type, remuneration status, and seroprevalence for infectious markers (hepatitis C virus antibody [anti-HCV], human immunodeficiency virus [HIV], hepatitis B virus surface antigen [HBsAg], and Treponema pallidum). For regression analysis, final models included all variables associated with the outcome in bivariate analysis (chi-square) with a p value of less than 0.05. RESULTS During 2015 to 2017, there were 251,428 donations in Georgia, representing 112,093 unique donors; 68.5% were from male donors, and 51.2% of donors were paid or replacement (friends or family of intended recipient). The overall seroprevalence significantly declined from 2015 to 2017 for anti-HCV (2.3%-1.4%), HBsAg (1.5%-1.1%), and T. pallidum (1.1%-0.7%) [p < 0.0001]; the decline was not significant for HIV (0.2%-0.1%). Only 41.0% of anti-HCV seropositive donors underwent additional testing to confirm viremia. Infectious marker seroprevalence varied by age, sex, and geography. In multivariable analysis, first-time and paid donor status were associated with seropositivity for all four infectious markers. CONCLUSION A decline during the study period in infectious markers suggests improvement in blood safety in Georgia. Areas that need further improvement are donor recruitment, standardization of screening and diagnostic follow-up, quality assurance, and posttransfusion surveillance.
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Affiliation(s)
- Evan M Bloch
- Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Eteri Kipiani
- National Center for Disease Control and Public Health, Tbilisi, Georgia
| | - Shaun Shadaker
- Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | | | - Lia Gvinjilia
- South Caucasus Office of the U.S. Centers for Disease Control (CDC), Tbilisi, Georgia
| | - Tinatin Kuchuloria
- South Caucasus Office of the U.S. Centers for Disease Control (CDC), Tbilisi, Georgia
| | | | - Sheila M Keating
- Vitalant Research Institute (formerly Blood Systems Research Institute), San Francisco, California, USA.,University of California San Francisco, San Francisco, California, USA
| | | | | | - Vladimer Getia
- National Center for Disease Control and Public Health, Tbilisi, Georgia
| | - Muazzam Nasrullah
- Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Francisco Averhoff
- Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Mariam Izoria
- National Center for Disease Control and Public Health, Tbilisi, Georgia
| | - Beth Skaggs
- South Caucasus Office of the U.S. Centers for Disease Control (CDC), Tbilisi, Georgia
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31
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Dash S, Aydin Y, Wu T. Integrated stress response in hepatitis C promotes Nrf2-related chaperone-mediated autophagy: A novel mechanism for host-microbe survival and HCC development in liver cirrhosis. Semin Cell Dev Biol 2020; 101:20-35. [PMID: 31386899 PMCID: PMC7007355 DOI: 10.1016/j.semcdb.2019.07.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/26/2019] [Accepted: 07/30/2019] [Indexed: 02/06/2023]
Abstract
The molecular mechanism(s) how liver damage during the chronic hepatitis C virus (HCV) infection evolve into cirrhosis and hepatocellular carcinoma (HCC) is unclear. HCV infects hepatocyte, the major cell types in the liver. During infection, large amounts of viral proteins and RNA replication intermediates accumulate in the endoplasmic reticulum (ER) of the infected hepatocyte, which creates a substantial amount of stress response. Infected hepatocyte activates a different type of stress adaptive mechanisms such as unfolded protein response (UPR), antioxidant response (AR), and the integrated stress response (ISR) to promote virus-host cell survival. The hepatic stress is also amplified by another layer of innate and inflammatory response associated with cellular sensing of virus infection through the production of interferon (IFN) and inflammatory cytokines. The interplay between various types of cellular stress signal leads to different forms of cell death such as apoptosis, necrosis, and autophagy depending on the intensity of the stress and nature of the adaptive cellular response. How do the adaptive cellular responses decode such death programs that promote host-microbe survival leading to the establishment of chronic liver disease? In this review, we discuss how the adaptive cellular response through the Nrf2 pathway that promotes virus and cell survival. Furthermore, we provide a glimpse of novel stress-induced Nrf2 mediated compensatory autophagy mechanisms in virus-cell survival that degrade tumor suppressor gene and activation of oncogenic signaling during HCV infection. Based on these facts, we hypothesize that the balance between hepatic stress, inflammation and different types of cell death determines liver disease progression outcomes. We propose that a more nuanced understanding of virus-host interactions under excessive cellular stress may provide an answer to the fundamental questions why some individuals with chronic HCV infection remain at risk of developing cirrhosis, cancer and some do not.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA.
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA
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Huang R, Rao H, Yang M, Gao Y, Wang J, Jin Q, Ma D, Wei L. Noninvasive Measurements Predict Liver Fibrosis Well in Hepatitis C Virus Patients After Direct-Acting Antiviral Therapy. Dig Dis Sci 2020; 65:1491-1500. [PMID: 31654313 DOI: 10.1007/s10620-019-05886-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 10/09/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Short-time usage of direct-acting antiviral agents (DAA) limited knowledge regarding histological outcomes and predictive values of noninvasive measurements in patients with hepatitis C virus (HCV) after sustained virologic response (SVR) with DAA. AIMS This study aimed to indicate histological changes and assess predictive value of noninvasive measurements for fibrosis in these patients. METHODS HCV patients who achieved SVR by DAA were identified. Pre- and post-SVR clinical and histological data were collected. RESULTS Of patients, 83% (33/40), 38% (15/40) and 83% (33/40) achieved inflammation improvement, fibrosis regression and histological improvement, respectively. Liver stiffness measurements (LSM), APRI, and FIB-4 could predict post-SVR fibrosis well without significant differences. Areas under receiver operating characteristic curves of LSM, APRI, and FIB-4 were 0.78, 0.81, and 0.87 for post-SVR advanced fibrosis (≥ F4) and 0.86, 0.86, and 0.85 for post-SVR cirrhosis (≥ F5), respectively. Pre-SVR LSM, APRI, and FIB-4 values were significantly lower in patients with fibrosis regression (P = 0.003-0.012), while FIB-4 was significantly lower in patients with histological improvement (P = 0.012-0.033). Patients with higher pre-SVR Ishak scores tended to have bigger decline in APRI (P = 0.025) and FIB-4 (P = 0.024) after SVR. CONCLUSIONS DAA could improve liver inflammation and fibrosis of HCV patients in a short time after SVR. LSM, APRI, and FIB-4 predict fibrosis well even after SVR by DAA. Most of the cutoff values for advanced fibrosis (≥ F4) and cirrhosis (≥ F5) of these noninvasive measurements decreased significantly after SVR, maybe because of the inflammation improvement.
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Affiliation(s)
- Rui Huang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Huiying Rao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Ming Yang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China.,Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Yinghui Gao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Jian Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Qian Jin
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Danli Ma
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Lai Wei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China. .,Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China.
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33
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Dash S, Aydin Y, Widmer KE, Nayak L. Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment. J Hepatocell Carcinoma 2020; 7:45-76. [PMID: 32346535 PMCID: PMC7167284 DOI: 10.2147/jhc.s221187] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 03/06/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFN-α) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA70112, USA
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
- Department of Medicine, Division of Gastroenterology, Tulane University Health Sciences Center, New Orleans, LA70112, USA
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA70112, USA
| | - Kyle E Widmer
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
| | - Leela Nayak
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
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Patel K, Sebastiani G. Limitations of non-invasive tests for assessment of liver fibrosis. JHEP Rep 2020; 2:100067. [PMID: 32118201 PMCID: PMC7047178 DOI: 10.1016/j.jhepr.2020.100067] [Citation(s) in RCA: 169] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 01/05/2020] [Accepted: 01/08/2020] [Indexed: 02/07/2023] Open
Abstract
The diagnostic assessment of liver injury is an important step in the management of patients with chronic liver disease (CLD). Although liver biopsy is the reference standard for the assessment of necroinflammation and fibrosis, the inherent limitations of an invasive procedure, and need for repeat sampling, have led to the development of several non-invasive tests (NITs) as alternatives to liver biopsy. Such non-invasive approaches mostly include biological (serum biomarker algorithms) or physical (imaging assessment of tissue stiffness) assessments. However, currently available NITs have several limitations, such as variability, inadequate accuracy and risk factors for error, while the development of a newer generation of biomarkers for fibrosis may be limited by the sampling error inherent to the reference standard. Many of the current NITs were initially developed to diagnose significant fibrosis in chronic hepatitis C, subsequently refined for the diagnosis of advanced fibrosis in patients with non-alcoholic fatty liver disease, and further adapted for prognostication in CLD. An important consideration is that despite their increased use in clinical practice, these NITs were not designed to reflect the dynamic process of fibrogenesis, differentiate between adjacent disease stages, diagnose non-alcoholic steatohepatitis, or follow longitudinal changes in fibrosis or disease activity caused by natural history or therapeutic intervention. Understanding the strengths and limitations of these NITs will allow for more judicious interpretation in the clinical context, where NITs should be viewed as complementary to, rather than as a replacement for, liver biopsy.
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Key Words
- AGA, American Gastroenterology Association
- ALT, alanine aminotransferase
- APRI, AST-platelet ratio index
- AST, aspartate aminotransferase
- AUC, area under the curve
- BMI, body mass index
- Biomarkers
- CAP, controlled attenuation parameter
- CHB, chronic hepatitis B
- CHC, chronic hepatitis C
- CLD, chronic liver disease
- CPA, collagen proportionate area
- DAA, direct-acting antiviral
- ELF, enhanced liver fibrosis
- Elastography
- FIB-4, fibrosis-4
- FLIP, fatty liver inhibition of progression
- HCC, hepatocellular carcinoma
- IFN, interferon
- LSM, liver stiffness measure
- Liver biopsy
- MR, magnetic resonance
- MRE, magnetic resonance elastography
- NAFLD, non-alcoholic fatty liver disease
- NFS, NAFLD fibrosis score
- NITs, non-invasive tests
- Non-alcoholic fatty liver disease
- SVR, sustained virologic response
- US, ultrasound
- VCTE, vibration-controlled transient elastography
- Viral hepatitis
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Affiliation(s)
- Keyur Patel
- Division of Gastroenterology, University Health Network Toronto, Toronto General Hospital, Toronto, ON, Canada
- Corresponding author. Address: Division of Gastroenterology, University of Toronto Health Network, Toronto General Hospital, 200 Elizabeth Street, 9EN, Toronto, ON M5G 2C4.
| | - Giada Sebastiani
- Division of Gastroenterology and Hepatology, McGill University Health Center, Montreal, QC, Canada
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Hinz B, Lagares D. Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases. Nat Rev Rheumatol 2020; 16:11-31. [PMID: 31792399 PMCID: PMC7913072 DOI: 10.1038/s41584-019-0324-5] [Citation(s) in RCA: 389] [Impact Index Per Article: 77.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2019] [Indexed: 12/15/2022]
Abstract
Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis. Myofibroblasts are scar-forming cells that are ultimately responsible for the excessive synthesis, deposition and remodelling of extracellular matrix proteins in fibrosis. Advances have been made in our understanding of the mechanisms that keep myofibroblasts in an activated state and control myofibroblast functions. However, the mechanisms that help myofibroblasts to persist in fibrotic tissues remain poorly understood. Myofibroblasts evade apoptosis by activating molecular mechanisms in response to pro-survival biomechanical and growth factor signals from the fibrotic microenvironment, which can ultimately lead to the acquisition of a senescent phenotype. Growing evidence suggests that myofibroblasts and senescent myofibroblasts, rather than being resistant to apoptosis, are actually primed for apoptosis owing to concomitant activation of cell death signalling pathways; these cells are poised to apoptose when survival pathways are inhibited. This knowledge of apoptotic priming has paved the way for new therapies that trigger apoptosis in myofibroblasts by blocking pro-survival mechanisms, target senescent myofibroblast for apoptosis or promote the reprogramming of myofibroblasts into scar-resolving cells. These novel strategies are not only poised to prevent progressive tissue scarring, but also have the potential to reverse established fibrosis and to regenerate chronically injured tissues.
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Affiliation(s)
- Boris Hinz
- Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
| | - David Lagares
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Fibrosis Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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Khomich O, Ivanov AV, Bartosch B. Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis. Cells 2019; 9:24. [PMID: 31861818 PMCID: PMC7016711 DOI: 10.3390/cells9010024] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/09/2019] [Accepted: 12/18/2019] [Indexed: 12/17/2022] Open
Abstract
Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.
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Affiliation(s)
- Olga Khomich
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, CEDEX 03, 69424 Lyon, France;
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Alexander V. Ivanov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Birke Bartosch
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, CEDEX 03, 69424 Lyon, France;
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Hu C, Zhao L, Tao J, Li L. Protective role of melatonin in early-stage and end-stage liver cirrhosis. J Cell Mol Med 2019; 23:7151-7162. [PMID: 31475778 PMCID: PMC6815834 DOI: 10.1111/jcmm.14634] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 06/13/2019] [Accepted: 07/28/2019] [Indexed: 02/06/2023] Open
Abstract
The liver is composed of hepatocytes, cholangiocytes, Kupffer cells, sinusoidal endothelial cells, hepatic stellate cells (HSCs) and dendritic cells; all these functional and interstitial cells contribute to the synthesis and secretion functions of liver tissue. However, various hepatotoxic factors including infection, chemicals, high‐fat diet consumption, surgical procedures and genetic mutations, as well as biliary tract diseases such as sclerosing cholangitis and bile duct ligation, ultimately progress into liver cirrhosis after activation of fibrogenesis. Melatonin (MT), a special hormone isolated from the pineal gland, participates in regulating multiple physiological functions including sleep promotion, circadian rhythms and neuroendocrine processes. Current evidence shows that MT protects against liver injury by inhibiting oxidation, inflammation, HSC proliferation and hepatocyte apoptosis, thereby inhibiting the progression of liver cirrhosis. In this review, we summarize the circadian rhythm of liver cirrhosis and its potential mechanisms as well as the therapeutic effects of MT on liver cirrhosis and earlier‐stage liver diseases including liver steatosis, nonalcoholic fatty liver disease and liver fibrosis. Given that MT is an antioxidative and anti‐inflammatory agent that is effective in eliminating liver injury, it is a potential agent with which to reverse liver cirrhosis in its early stage.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lingfei Zhao
- Kidney Disease Center, College of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang, China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jingjing Tao
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lanjuan Li
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
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van der Helm D, Barnhoorn MC, de Jonge-Muller ESM, Molendijk I, Hawinkels LJAC, Coenraad MJ, van Hoek B, Verspaget HW. Local but not systemic administration of mesenchymal stromal cells ameliorates fibrogenesis in regenerating livers. J Cell Mol Med 2019; 23:6238-6250. [PMID: 31245923 PMCID: PMC6714167 DOI: 10.1111/jcmm.14508] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/29/2019] [Accepted: 06/01/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic liver injury leads to the accumulation of myofibroblasts resulting in increased collagen deposition and hepatic fibrogenesis. Treatments specifically targeting fibrogenesis are not yet available. Mesenchymal stromal cells (MSCs) are fibroblast-like stromal (stem) cells, which stimulate tissue regeneration and modulate immune responses. In the present study we assessed whether liver fibrosis and cirrhosis can be reversed by treatment with MSCs or fibroblasts concomitant to partial hepatectomy (pHx)-induced liver regeneration. After carbon tetrachloride-induced fibrosis and cirrhosis, mice underwent a pHx and received either systemically or locally MSCs in one of the two remaining fibrotic/cirrhotic liver lobes. Eight days after treatment, liver fibrogenesis was evaluated by Sirius-red staining for collagen deposition. A significant reduction of collagen content in the locally treated lobes of the regenerated fibrotic and cirrhotic livers was observed in mice that received high dose MSCs. In the non-MSC-treated counterpart liver lobes no changes in collagen deposition were observed. Local fibroblast administration or intravenous administration of MSCs did not ameliorate fibrosis. To conclude, local administration of MSCs after pHx, in contrast to fibroblasts, results in a dose-dependent on-site reduction of collagen deposition in mouse models for liver fibrosis and cirrhosis.
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Affiliation(s)
- Danny van der Helm
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marieke C Barnhoorn
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Ilse Molendijk
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Luuk J A C Hawinkels
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Minneke J Coenraad
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Hein W Verspaget
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
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Lens S, Torres F, Bonacci M, Bartres C, Pocurull A, Mariño Z, Londoño MC, Rodríguez-Tajes S, Forns X. Simplified follow-up of patients with mild chronic hepatitis C in areas with limited access to antiviral therapy. Dig Liver Dis 2019; 51:875-881. [PMID: 30558865 DOI: 10.1016/j.dld.2018.11.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 11/06/2018] [Accepted: 11/20/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS In some areas of the world, antiviral therapy for chronic hepatitis C (CHC) is not available for all patients. The optimal interval for liver stiffness measures (LSM) and noninvasive scores to assess fibrosis progression has not been studied. We evaluated the usefulness of consecutive LSM, APRI, FIB-4 and Forns scores to predict disease progression. METHODS Patients with CHC and at least two annual LSM within 3 years were followed for a minimum of 5 years. Noninvasive scores were assessed. Evolution of LSM and scores were expressed as change/year (Delta). RESULTS 623 non-cirrhotic patients were included. Median baseline LSM was 6.6 kPa (IQR 5.4-8.4). During a median follow-up of 6 years, 61(9.7%) patients developed cirrhosis. Baseline LSM ≥ F2 and Forns ≥ 6.9 were the main predictors of cirrhosis (C-index 0.97). The addition of Delta variables did not improve its prediction. In patients with mild fibrosis (F0-1), progression to ≥F2 occurred in 80 (23%) within the first 3 years. Baseline BMI ≥ 24 kg/m2 and LSM ≥ 5.9 kPa were associated to progression. CONCLUSIONS Baseline LSM and Forns are highly predictive of cirrhosis development. In patients with mild CHC, BMI < 24 and LSM < 5.9, the likelihood of progression is very low, allowing for a significant spacing of noninvasive assessments over time.
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Affiliation(s)
- Sabela Lens
- Liver Unit, Hospital Clinic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain.
| | - Ferran Torres
- Biostatistics and Data Management Platform, IDIBAPS, Hospital Clinic, Barcelona, Spain; Biostatistics Unit, Autonomous University of Barcelona, Barcelona, Spain
| | - Martin Bonacci
- Liver Unit, Hospital Clinic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Concepció Bartres
- Liver Unit, Hospital Clinic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Anna Pocurull
- Liver Unit, Hospital Clinic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Zoe Mariño
- Liver Unit, Hospital Clinic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - María-Carlota Londoño
- Liver Unit, Hospital Clinic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Sergio Rodríguez-Tajes
- Liver Unit, Hospital Clinic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clinic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
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Musialik J, Kolonko A, Kwiecień K, Owczarek AJ, Więcek A. Effectiveness and safety of sofosbuvir-based therapy against chronic hepatitis C infection after successful kidney transplantation. Transpl Infect Dis 2019; 21:e13090. [PMID: 30972854 DOI: 10.1111/tid.13090] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 03/15/2019] [Accepted: 03/31/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Direct-acting antivirals (DAAs), including sofosbuvir (SOF), are recommended for treatment of chronic hepatitis C virus (HCV) infection. However, few studies have investigated the effectiveness and safety of new DAAs in kidney transplant recipients (KTRs). OBJECTIVES To assess the effectiveness and safety of SOF-based therapy in stable KTRs. PATIENTS AND METHODS Forty KTRs were treated with SOF-based regimens. Rapid, end-therapeutic, and sustained virologic responses were assessed, as was liver stiffness by elastometry. Safety was monitored by measuring the estimated glomerular filtration rate (eGFR), blood hemoglobin (Hb) concentration, proteinuria, and blood trough levels of calcineurin inhibitors (CNIs). Other side effects were also recorded. RESULTS The effectiveness of DAAs was 100% at all time points. The therapy did not significantly influence eGFR or proteinuria, but significantly decreased mean blood Hb levels (13.5 ± 2.0 vs 11.6 ± 1.9, respectively, P < 0.001), which required a dose reduction or cessation of ribavirin (RBV) in 50% of patients. A profound, significant decrease in initial CNI concentrations was also observed during treatment in the majority of patients within the first month of therapy. CONCLUSIONS In this cohort of KTRs, the new SOF-based therapies were characterized by 100% effectiveness and good safety profiles. However, in patients co-treated with RBV, close blood Hb monitoring and early RBV dose reduction are necessary. In the majority of KTRs, antiviral therapy leads to a substantial and early decrease in CNIs levels, thus frequent measurement of CNI levels is necessary during SOF-based therapy.
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Affiliation(s)
- Joanna Musialik
- Department of Nephrology, Transplantation and Internal Medicine, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Aureliusz Kolonko
- Department of Nephrology, Transplantation and Internal Medicine, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Katarzyna Kwiecień
- Department of Nephrology, Transplantation and Internal Medicine, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Aleksander J Owczarek
- Department of Statistics, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Andrzej Więcek
- Department of Nephrology, Transplantation and Internal Medicine, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
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41
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Affiliation(s)
- Julius Wilder
- Division of Gastroenterology, Duke University Health System, Durham, North Carolina
| | - Steve S Choi
- Durham Veterans Affairs Medical Center, Durham, North Carolina
| | - Cynthia A Moylan
- Division of Gastroenterology, Duke University Health System, Durham, North Carolina
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Miyanishi K, Tanaka S, Sakamoto H, Kato J. The role of iron in hepatic inflammation and hepatocellular carcinoma. Free Radic Biol Med 2019; 133:200-205. [PMID: 30017991 DOI: 10.1016/j.freeradbiomed.2018.07.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 07/08/2018] [Accepted: 07/10/2018] [Indexed: 02/06/2023]
Abstract
Iron is an essential for organisms and the liver plays a major role in its storage. In pathologic conditions, where iron absorption from the intestine or iron uptake into the hepatocytes is increased, excess iron accumulates in the hepatocytes, leading to hepatocyte injury through the production of free radicals. Iron exerts its toxicity by catalyzing the generation of reactive oxygen species (ROS). ROS causes cell injury by inducing damage to the lysosomal, cytoplasmic, nuclear and mitochondrial membranes, apoptosis through activation of the caspase cascade, and hyperoxidation of fatty chains. In this manuscript, we reviewed the articles regarding role of iron in hepatic inflammation and hepatocellular carcinoma.
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Affiliation(s)
- Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan.
| | - Shingo Tanaka
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan; Department of Infection Control, and Laboratory Medicine, Sapporo Medical University, School of Medicine, Japan
| | - Hiroki Sakamoto
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan
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Huang P, Liu M, Zang F, Yao Y, Yue M, Wang J, Fan H, Zhuo L, Wu J, Xia X, Feng Y, Yu R. The development of hepatocellular carcinoma in HCV-infected patients treated with DAA: A comprehensive analysis. Carcinogenesis 2018; 39:1497-1505. [PMID: 30602007 DOI: 10.1093/carcin/bgy099] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 07/20/2018] [Indexed: 12/14/2022] Open
Abstract
It has been proven that hepatitis C virus (HCV) eradication after interferon-based treatment can reduce the risk of hepatocarcinogenesis. However, there were some arguments about whether the treatment of direct-acting antivirals (DAAs) boosts the development of hepatocellular carcinoma (HCC). We systematically review this crucial topic by combining all the relevant articles to calculate the pooled HCC density after DAA treatment. Studies reporting the recurrence or occurrence in chronic hepatitis C patients who received DAA regimen were selected from three retrieval library screening. Data on baseline and outcomes were extracted independently by three observers. Primary outcomes were incidence density of HCC. Pooled estimates of HCC occurrence and recurrence rate per 100 person-years (py) were undertaken by random-effects meta-analysis. Sixteen studies with 61334 patients, embracing 20 cohorts, were enrolled in this study and divided into two groups (HCC occurrence and HCC recurrence). In the pooled analysis, HCC developed at a rate of 3.5/100 py [95% confidence interval (CI): 2.4, 5.3] among patients without a history of HCC compared with 17.4/100 py (95% CI: 7.8, 39.0) among patients existed. Furthermore, HCC occurrence rate following DAA-induced sustained virological response (SVR) was 2.1/100 py (95% CI: 1.4, 3.4); however, the rate in patients without SVR was 9.1/100 py (95% CI: 5.4, 15.3). HCV cured after DAA therapy could induce a reduction of 78% in the risk of HCC occurrence compared with non-responders. There is no strong evidence for an increased risk of HCC occurrence or recurrence in patients treated by DAA. There was a significant decline in the incidence of HCC occurrence after SVR.
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Affiliation(s)
- Peng Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
- Key Laboratory of Infectious Diseases, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Mei Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Feng Zang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yinan Yao
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ming Yue
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jie Wang
- Department of Basic and Community Nursing, School of Nursing, Nanjing Medical University, Nanjing, China
| | - Haozhi Fan
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Lingyun Zhuo
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jingjing Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xueshan Xia
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Chenggong District, Kunming, Yunnan, China
| | - Yue Feng
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Chenggong District, Kunming, Yunnan, China
| | - Rongbin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
- Key Laboratory of Infectious Diseases, School of Public Health, Nanjing Medical University, Nanjing, China
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Sakurada A, Miyanishi K, Tanaka S, Sato M, Sakamoto H, Kawano Y, Takada K, Nakabeppu Y, Kobune M, Kato J. An intronic single nucleotide polymorphism in the MUTYH gene is associated with increased risk for HCV-induced hepatocellular carcinoma. Free Radic Biol Med 2018; 129:88-96. [PMID: 30218772 DOI: 10.1016/j.freeradbiomed.2018.09.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 08/30/2018] [Accepted: 09/11/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The role of base excision repair genes in human hepatocarcinogenesis has not yet been explored. Here, we investigated relationships between variants of these genes and the risk of developing hepatocellular carcinoma (HCC). METHODS Nineteen tagging SNPs in base excision repair genes (including MUTYH, OGG1 and MTH1) were genotyped using iPLEX assays; one significant SNP was found and confirmed in Japanese patients with chronic hepatitis C (CHC) (n = 38 HCC and 55 controls). The effects of modifying the intronic variants were determined by luciferase assays. MUTYH-null mice were used to examine the involvement of oxidative stress and DNA repair enzymes in hepatocarcinogenesis. RESULTS Significant associations were found for a single intron SNP (rs3219487) in the MUTYH gene. The risk of developing HCC in patients with A/A or G/A genotypes was higher than in those with the G/G genotype (OR = 9.27, 95% CI = 2.39 -32.1, P = 0.0005). MUTYH mRNA levels in both peripheral mononuclear cells were significantly lower in G/A or A/A genotyped subjects (P = 0.0157 and 0.0108, respectively). We found that -2000 in the MUTYH promoter region is involved in enhanced expression of MUTYH by insertion of a major allele sequence of rs3219487. Liver tumors were observed in MUTYH-null mice after 12 months´ high iron diet, but no tumors developed when dietary anti-oxidant (N-Acetyl-L-cysteine) was also provided. CONCLUSIONS CHC patients with the rs3219487 adenine allele had a significantly increased risk of developing HCC. MUTYH-null mice with iron-associated oxidative stress were susceptible to development of liver tumors unless prevented by dietary anti-oxidants.
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MESH Headings
- Aged
- Animals
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Case-Control Studies
- DNA Glycosylases/genetics
- DNA Repair Enzymes/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Genotype
- Hep G2 Cells
- Hepacivirus/pathogenicity
- Hepacivirus/physiology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/pathology
- Hepatitis C, Chronic/virology
- Humans
- Introns
- Iron/administration & dosage
- Liver Neoplasms/etiology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Phosphoric Monoester Hydrolases/genetics
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- Reactive Oxygen Species/metabolism
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Affiliation(s)
- Akira Sakurada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan.
| | - Shingo Tanaka
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masanori Sato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroki Sakamoto
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yutaka Kawano
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kohichi Takada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
| | - Masayoshi Kobune
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan.
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Huang CF, Yeh ML, Huang CI, Liang PC, Lin YH, Lin ZY, Chen SC, Huang JF, Dai CY, Chuang WL, Yu ML. Post-treatment fibrotic modifications overwhelm pretreatment liver fibrosis in predicting HCC in CHC patients with curative antivirals. Hepatol Int 2018; 12:544-551. [PMID: 30426395 DOI: 10.1007/s12072-018-9908-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 10/24/2018] [Indexed: 12/23/2022]
Abstract
BACKGROUND/AIMS Liver fibrosis determined hepatocellular carcinoma (HCC) occurrence in chronic hepatitis C patients with sustained virological response (SVR). We aimed to determine whether post-treatment fibrotic modification overwhelmed pretreatment fibrotic status in terms of long-term HCC prediction. METHODS 265 SVR patients with paired biopsies before and after antiviral therapy were enrolled for analysis of the association of fibrotic changes with HCC. RESULTS Eighteen (6.8%) of the 265 patients developed HCC over 1931 person-years. Cox regression analysis without post-treatment fibrosis as a covariant revealed that factors predicted HCC included age (hazard ratio [HR]/confidence intervals [CI] 1.07/1.01-1.13, p = 0.01), male gender (HR/CI 4.57/1.45-14.36, p = 0.009), diabetes (HR/CI 3.60/1.32-9.85, p = 0.01) and pretreatment advanced fibrosis (HR/CI 2.73/1.05-7.07, p = 0.039). Advanced fibrosis in post-treatment status replaced pretreatment fibrosis as the most critical determinant of HCC when it was included for analysis (HR/CI 3.53/1.34-9.30, p = 0.01). The incidences of HCC among patients with fibrotic modification from F0-2 to F0-2, F34 to F0-2, F0-2 to F34 and F34 to F34 were 0.41%, 0.84%, 1.68%, and 3.05%, respectively (p = 0.004). Compared to patients whose fibrotic stage remained at F0-2 before and after treatment, the HCC risk decreased and did not differ among those whose fibrotic stage improved from F34 to F0-2. However, HCC risk increased significantly and gradually in patients whose fibrotic stages changed from F0-2 to F34 (HR/CI 4.13/1.11-15.36, p = 0.035) and whose fibrotic stages remained at F34 before and after treatment (HR/CI 7.47/2.37-23.55, p = 0.001) (trend p = 0.003). CONCLUSIONS Post-treatment fibrotic modifications overwhelmed pretreatment fibrotic statuses in predicting HCC.
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Affiliation(s)
- Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-I Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Gastroenterology and Hepatology, Chi-Mei Medical Center Liouying, Tainan, Taiwan.
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
- College of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan.
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Huang CF, Yeh ML, Huang CI, Lin ZY, Chen SC, Huang JF, Dai CY, Chuang WL, Chen JJ, Yu ML. Tolloid-like 1 genetic variants determine fibrosis regression in chronic hepatitis C patients with curative antivirals. Sci Rep 2018; 8:15058. [PMID: 30305682 PMCID: PMC6180045 DOI: 10.1038/s41598-018-33448-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 09/24/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) eradication by antivirals promote fibrosis modification. Whether host genetics determined fibrosis regression in chronic hepatitis C (CHC) patients with sustained virological response (SVR) is to be determined. One hundred and fifty-six SVR patients with paired liver biopsy before and after antivirals were enrolled. Host genetic factors including single nucleotide polymorphism rs17047200 of tolloid-like 1(TLL-1) were analyzed for their association with fibrosis modification. The proportions of improved, unchanged and worsening fibrotic stags were 39.1% (n = 61), 39.1% (n = 61), and 21.8% (n = 34), respectively. The rate of annual fibrotic improvement was 0.16 ± 0.79. There was a significant trend of increased fibrotic improvement rate in patients from F01 to F4 (P < 0.001). However, the rate of improvement seemed more limited in cirrhotic patients among those with advanced liver disease. Patients with fibrotic improvement had a significantly higher proportion of TLL-1 rs17047200 AA genotype compared to those without (92.5% vs. 79.3%, p = 0.039). Logistic regression analysis revealed that the TLL-1 rs17047200 AA genotype was the only independent factor associated with fibrosis improvement (odds ratio/95% confidence intervals: 3.2/1.01-10.12, p = 0.047). Compared with TLL-1 rs17047200 non-AA carriers, a significantly higher proportion of fibrosis improvement in AA genotype carriers was observed among patients with F0-2 (33.3% vs. 0%, p = 0.005) but not with F34 (70% vs. 80%, p = 1). We concluded that TLL-1 genetic variants determined fibrotic improvement in CHC with curative antivirals, particularly in patients with mild liver disease.
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Affiliation(s)
- Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-I Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jyh-Jou Chen
- Division of Gastroenterology and Hepatology, Chi-Mei Medical Center, Liouying, Taiwan.
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
- College of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan.
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High proportions of liver fibrosis and cirrhosis in an ageing population of people who use drugs in Amsterdam, The Netherlands. Eur J Gastroenterol Hepatol 2018; 30:1168-1176. [PMID: 30028776 DOI: 10.1097/meg.0000000000001213] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The incidence and prevalence of hepatitis C virus (HCV) infection among people who use drugs (PWUD) peaked in the 1980s in Amsterdam. As liver cirrhosis develops several decades after HCV infection and PWUD have other risk factors for liver fibrosis, we hypothesized that significant liver fibrosis or cirrhosis is now common among PWUD in Amsterdam. METHODS PWUD were recruited from the Amsterdam Cohort Studies, methadone programmes and addiction clinics during 2009-2016. Transient elastography was performed to assess liver stiffness. We estimated METAVIR fibrosis levels on the basis of the following liver stiffness measurements (LSMs) cut-offs: F0-F2 (no/mild) less than 7.65 kPa; F2-F3 (moderate/severe) at least 7.65 to less than 13 kPa; and F4 (cirrhosis) at least 13 kPa. Using linear regression models, we assessed the association between LSM and sociodemographic, clinical and behavioural determinants in (a) all PWUD and (b) chronic hepatitis C virus (cHCV)-infected PWUD. RESULTS For 140 PWUD, the median LSM was 7.6 kPa (interquartile range=4.9-12.0); 26.4% had moderate/severe fibrosis and 22.9% had cirrhosis. Of 104 chronically infected PWUD, 57.7% had evidence of significant fibrosis (≥F2). In multivariable analysis including all PWUD, increased LSM was associated significantly with cHCV monoinfection and HIV/HCV coinfection. In cHCV-infected PWUD, older age was associated significantly with increased LSM. In all groups, longer duration of heavy alcohol drinking was associated with increased LSM. CONCLUSION A high proportion of PWUD had significant fibrosis or cirrhosis that were associated with cHCV infection, HIV/HCV coinfection and duration of heavy alcohol drinking. Increased uptake of HCV treatment and interventions to reduce alcohol use are needed to decrease the liver disease burden in this population.
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Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection. Viruses 2018; 10:v10100531. [PMID: 30274202 PMCID: PMC6212901 DOI: 10.3390/v10100531] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/25/2018] [Accepted: 09/27/2018] [Indexed: 02/07/2023] Open
Abstract
Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.
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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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Sato M, Miyanishi K, Tanaka S, Sakurada A, Sakamoto H, Kawano Y, Takada K, Kobune M, Kato J. Increased Duodenal Iron Absorption through Upregulation of Ferroportin 1 due to the Decrement in Serum Hepcidin in Patients with Chronic Hepatitis C. Can J Gastroenterol Hepatol 2018; 2018:2154361. [PMID: 30186818 PMCID: PMC6112088 DOI: 10.1155/2018/2154361] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 07/03/2018] [Accepted: 07/12/2018] [Indexed: 12/15/2022] Open
Abstract
Hepatic iron accumulation is generally increased in the chronic hepatitis C (CHC) liver; however, the precise mechanism of such accumulation remains unclear. We evaluated iron absorption from the gastrointestinal tract of patients with CHC and control participants. We measured the expression of a panel of molecules associated with duodenal iron absorption and serum hepcidin levels to determine the mechanism of iron accumulation in the CHC liver. We enrolled 24 patients with CHC and 9 patients with chronic gastritis without Helicobacter pylori infection or an iron metabolism disorder as control participants. An oral iron absorption test (OIAT) was administered which involved a dosage of 100 mg of sodium ferrous citrate. Serum level of hepcidin-25 was measured by liquid chromatography-tandem mass spectrometry. Ferroportin 1 (FPN) mRNA was measured by RT-PCR and FPN protein was analyzed by western blot. Samples were obtained from duodenum biopsy tissue from each CHC patient and control participant. Caco-2/TC7 cells were incubated in Costar transwells (0.4 μm pores). The OIAT showed significantly greater iron absorption in CHC patients than control participants. Serum hepcidin-25 in the CHC group was significantly lower than in the control group. Compared with control participants, duodenal FPN mRNA expression in CHC patients was significantly upregulated. The FPN mRNA levels and protein levels increased significantly in Caco-2/TC7 cell monolayers cultured in transwells with hepcidin. Lower serum hepcidin-25 levels might upregulate not only FPN protein expression but also mRNA expression in the duodenum and cause iron accumulation in patients with CHC.
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Affiliation(s)
- Masanori Sato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Shingo Tanaka
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Akira Sakurada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Hiroki Sakamoto
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Yutaka Kawano
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Kohichi Takada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Masayoshi Kobune
- Department of Medical Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo 060-8543, Japan
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