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Bader El Din NG, Farouk S. Exploring the Impact of Different Inflammatory Cytokines on Hepatitis C Virus Infection. J Interferon Cytokine Res 2024; 44:233-243. [PMID: 38563804 DOI: 10.1089/jir.2024.0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024] Open
Abstract
Hepatitis C virus (HCV) infection is a global health concern affecting millions worldwide. Chronic HCV infection often leads to liver inflammation and can progress to cirrhosis and hepatocellular carcinoma. Inflammatory cytokines are crucial in modulating the immune response during HCV infection. This review aims to investigate the impact of different inflammatory cytokines on HCV infection and associated immune responses. This review was conducted to identify relevant studies on the interplay between inflammatory cytokines and HCV infection. The analysis focused on the effects of key inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 (IL-1), and interferon-gamma (IFN-γ), on HCV replication, immune cell activation, and liver inflammation. The findings reveal that these inflammatory cytokines can significantly influence HCV infection and the subsequent immune response. TNF-α, IL-6, and IL-1 have been shown to enhance HCV replication, while IFN-γ exerts antiviral effects by inhibiting viral replication and promoting immune cell-mediated clearance of infected hepatocytes. Moreover, these cytokines contribute to the recruitment and activation of immune cells, such as natural killer cells, T cells, and macrophages, which play critical roles in controlling HCV infection. Understanding the precise mechanisms by which inflammatory cytokines impact HCV infection is crucial for developing more targeted therapeutic strategies. Modulating the levels or activity of specific cytokines may provide opportunities to attenuate HCV replication, reduce liver inflammation, and improve treatment outcomes. In conclusion, this review highlights the significance of inflammatory cytokines in influencing HCV infection and associated immune responses.
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Affiliation(s)
- Noha G Bader El Din
- Microbial Biotechnology Department, Biotechnology Institute, National Research Center, Cairo, Egypt
| | - Sally Farouk
- Microbial Biotechnology Department, Biotechnology Institute, National Research Center, Cairo, Egypt
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2
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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: 64] [Impact Index Per Article: 12.8] [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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3
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Chu CY, Cheng CH, Chen HL, Lin IT, Wu CH, Lee YK, Bair MJ. Long-term histological change in chronic hepatitis C patients who had received peginterferon plus ribavirin therapy with sustained virological response. J Formos Med Assoc 2018; 118:1129-1137. [PMID: 30472042 DOI: 10.1016/j.jfma.2018.11.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 10/10/2018] [Accepted: 11/07/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The improvement in liver histology is an important aim in the management of hepatitis C virus (HCV) infection. Previous studies suggest that antiviral treatment could reduce the progression of hepatic fibrosis, especially in patients with sustained virological response (SVR). However, most studies were limited by short-term evaluations and the liver stiffness was assessed by non-invasive methods. In our study, we performed a paired liver biopsy study aimed at analyzing the long-term histological changes in patients with SVR. METHODS We included 31 patients who had been previously treated with peginterferon plus ribavirin. All patients achieved SVR and had received pre- and post-treatment liver biopsies. The histological appearance of fibrosis and inflammation were assessed with METAVIR scoring system and Histological Activity Index (HAI) criteria. We analyzed several factors associated with the histological response. RESULTS The median interval between two biopsies was 93.0 months. The percentage of patients with fibrosis regression, stable, and progression were 19%, 45%, and 36%. A total of 71% of patients achieved inflammation improvement, whereas 6% and 23% of patients had stable disease and disease-progression, respectively. We showed that the patients without baseline advanced fibrosis and those having a lower baseline HAI score had higher risk of fibrosis worsening. Baseline fibrosis and necroinflammation status did not influence HAI change significantly. CONCLUSION The progression of hepatic fibrosis and inflammation can be reversed in some patients who had long-term virological suppression. Patients with advanced baseline fibrosis and higher inflammatory stages seemed to receive more histologic benefit from successful antiviral treatments.
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Affiliation(s)
- Chia-Ying Chu
- Department of Pathology, Taitung Mackay Memorial Hospital, Taiwan
| | - Chun-Han Cheng
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taiwan; Mackay Medical College, New Taipei, Taiwan
| | - Huan-Lin Chen
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taiwan; Mackay Medical College, New Taipei, Taiwan
| | - I-Tsung Lin
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taiwan; Mackay Medical College, New Taipei, Taiwan
| | - Chia-Hsien Wu
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taiwan; Mackay Medical College, New Taipei, Taiwan
| | - Yuan-Kai Lee
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taiwan; Mackay Medical College, New Taipei, Taiwan
| | - Ming-Jong Bair
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taiwan; Mackay Medical College, New Taipei, Taiwan.
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Mölleken C, Ahrens M, Schlosser A, Dietz J, Eisenacher M, Meyer HE, Schmiegel W, Holmskov U, Sarrazin C, Sorensen GL, Sitek B, Bracht T. Direct-acting antivirals-based therapy decreases hepatic fibrosis serum biomarker microfibrillar-associated protein 4 in hepatitis C patients. Clin Mol Hepatol 2018; 25:42-51. [PMID: 30449076 PMCID: PMC6435967 DOI: 10.3350/cmh.2018.0029] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 09/04/2018] [Indexed: 12/15/2022] Open
Abstract
Background/Aims An estimated 80 million people worldwide are infected with viremic hepatitis C virus (HCV). Even after eradication of HCV with direct acting antivirals (DAAs), hepatic fibrosis remains a risk factor for hepatocarcinogenesis. Recently, we confirmed the applicability of microfibrillar-associated protein 4 (MFAP4) as a serum biomarker for the assessment of hepatic fibrosis. The aim of the present study was to assess the usefulness of MFAP4 as a biomarker of liver fibrosis after HCV eliminating therapy with DAAs. Methods MFAP4 was measured using an immunoassay in 50 hepatitis C patients at baseline (BL), the end-of-therapy (EoT), and the 12-week follow-up (FU) visit. Changes in MFAP4 from BL to FU and their association with laboratory parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), platelets, the AST to platelet ratio index (APRI), fibrosis-4 score (FIB-4), and albumin were analyzed. Results MFAP4 serum levels were representative of the severity of hepatic fibrosis at BL and correlated well with laboratory parameters, especially APRI (Spearman correlation, R²=0.80). Laboratory parameters decreased significantly from BL to EoT. MFAP4 serum levels were found to decrease from BL and EoT to FU with high statistical significance (Wilcoxon p<0.001 for both). Conclusions Our findings indicate that viral eradication resulted in reduced MFAP4 serum levels, presumably representing a decrease in hepatic fibrogenesis or fibrosis. Hence, MFAP4 may be a useful tool for risk assessment in hepatitis C patients with advanced fibrosis after eradication of the virus.
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Affiliation(s)
- Christian Mölleken
- Department of Gastroenterology and Hepatology, University Hospital Bergmannsheil, Bochum, Germany
| | - Maike Ahrens
- Medizinisches Proteom-Center, Ruhr University Bochum, Bochum, Germany.,Chrestos Concept GmbH & Co. KG, Essen, Germany
| | - Anders Schlosser
- Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Julia Dietz
- Medical Clinic 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Martin Eisenacher
- Medizinisches Proteom-Center, Ruhr University Bochum, Bochum, Germany
| | - Helmut E Meyer
- Medizinisches Proteom-Center, Ruhr University Bochum, Bochum, Germany.,Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany
| | - Wolff Schmiegel
- Department of Gastroenterology and Hepatology, University Hospital Bergmannsheil, Bochum, Germany
| | - Uffe Holmskov
- Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Christoph Sarrazin
- Medical Clinic 1, J.W. Goethe University Hospital, Frankfurt, Germany.,Medical Clinic 2, St. Josefs-Hospital, Wiesbaden, Germany
| | - Grith Lykke Sorensen
- Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Barbara Sitek
- Medizinisches Proteom-Center, Ruhr University Bochum, Bochum, Germany
| | - Thilo Bracht
- Medizinisches Proteom-Center, Ruhr University Bochum, Bochum, Germany
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5
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D'Ambrosio R, Aghemo A, Rumi MG, Degasperi E, Sangiovanni A, Maggioni M, Fraquelli M, Perbellini R, Rosenberg W, Bedossa P, Colombo M, Lampertico P. Persistence of hepatocellular carcinoma risk in hepatitis C patients with a response to IFN and cirrhosis regression. Liver Int 2018; 38:1459-1467. [PMID: 29377616 DOI: 10.1111/liv.13707] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 01/12/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM In patients with HCV-related cirrhosis, a sustained virological response may lead to cirrhosis regression. Whether histological changes translate into prevention of long-term complications, particularly hepatocellular carcinoma is still unknown. This was investigated in a cohort of histological cirrhotics who had been prospectively followed-up for 10 years after the achievement of a sustained virological response to IFN. METHODS In all, 38 sustained virological response cirrhotics who underwent a liver biopsy 5 years post-SVR were prospectively followed to assess the impact of cirrhosis regression on clinical endpoints. RESULTS During a follow-up of 86 (30-96) months from liver biopsy, no patients developed clinical decompensation, whilst 5 (13%) developed hepatocellular carcinoma after 79 (7-88) months. The 8-year cumulative probability of hepatocellular carcinoma was 17%, without differences between patients with or without cirrhosis regression (19% [95% CI 6%-50%] vs 14% [95% CI 4%-44%], P = .88). Patients who developed or did not an hepatocellular carcinoma had similar rates of residual cirrhosis (P = 1.0), collagen content (P = .48), METAVIR activity (P = .34), portal inflammation (P = .06) and steatosis (P = .17). At baseline, patients who developed an hepatocellular carcinoma had higher γGT (HR 1.03, 95% CI 1.00-1.06; P = .014) and glucose (HR 1.02, 95% CI 1.00-1.02; P = .012) values; moreover, they had increased Forns Score (HR 12.8, 95% CI 1.14-143.9; P = .039), Lok Index (HR 6.24, 95% CI 1.03-37.6; P = .046) and PLF (HR 19.3, 95% CI 1.72-217.6; P = .016) values. One regressor died of lung cancer. The 8-year cumulative survival probability was 97%, independently on cirrhosis regression (96% vs 100%, P = 1.0) or hepatocellular carcinoma (100% vs 97%, P = 1.0). CONCLUSIONS Post-SVR cirrhosis regression does not prevent hepatocellular carcinoma occurrence.
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Affiliation(s)
- Roberta D'Ambrosio
- A. M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Alessio Aghemo
- Department of Biomedical Sciences, Humanitas University, Rozzano-Milan, Italy.,Humanitas Clinical and Research Center, Rozzano-Milan, Italy
| | - Maria Grazia Rumi
- Division of Hepatology, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy
| | - Elisabetta Degasperi
- A. M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Angelo Sangiovanni
- A. M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Marco Maggioni
- Division of Pathology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Mirella Fraquelli
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Riccardo Perbellini
- A. M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - William Rosenberg
- Center for Hepatology, Division of Medicine, University College of London, London, UK
| | - Pierre Bedossa
- Department of Pathology and INSERM U773, Hopital Beaujon, Universitée Paris-Diderot, Clichy, France
| | - Massimo Colombo
- Humanitas Clinical and Research Center, Rozzano-Milan, Italy
| | - Pietro Lampertico
- A. M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
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6
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Tripodi A, D'Ambrosio R, Padovan L, Tosetti G, Aghemo A, Primignani M, Chantarangkul V, Peyvandi F, Colombo M. Evaluation of coagulation during treatment with directly acting antivirals in patients with hepatitis C virus related cirrhosis. Liver Int 2017; 37:1295-1303. [PMID: 28129465 DOI: 10.1111/liv.13374] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 01/20/2017] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS The effect of direct-acting-antivirals (DAA) on coagulation of hepatitis-C-virus (HCV)-related cirrhosis is unknown. METHODS We investigated 28 patients on DAA treatment and performed prothrombin-time, thrombin generation with and without thrombomodulin, whole-blood thromboelastometry, as well as the individual procoagulants (II, VIII, XIII, von Willebrand) and anticoagulants, antithrombin and protein-C. RESULTS Patients had undetectable HCV-RNA at the end-of- treatment and at 12-weeks after end-of-treatment (sustained virological response). Transaminases were significantly decreased at both end-of-treatment and at 12-weeks. Prothrombin-time declined at 12-weeks, but did not reach statistical significance. Factor-II, protein-C and antithrombin increased significantly at end-of-treatment (P<.001) and persisted at 12-weeks. Factor-VIII decreased at end-of-treatment and to a greater extent at 12-weeks when reached statistical significance (P<.05). Factor-VIII/protein-C ratio decreased sharply, reached statistical significance at end-of-treatment (P<.01) and persisted at 12-weeks. Von-Willebrand decreased at end-of-treatment and reached statistical significance at 12-weeks (P<.001). Endogenous-thrombin-potential without thrombomodulin increased significantly at end-of-treatment (P<.01) and persisted at 12-weeks. No changes were observed after addition of thrombomodulin. Endogenous-thrombin-potential ratio (with/without thrombomodulin) decreased and reached statistical significance at 12-weeks (P<.05). Thromboelastometry clotting time decreased sharply, reached statistical significance at end-of treatment (P<.001) and persisted at 12-weeks. CONCLUSIONS Treatment with DAAs in HCV-related cirrhosis results in improvement of the individual pro- and anticoagulants. It can be hypothesised that the net effect does not substantially modify their balance (as shown by the unchanged thrombin generation in the presence of thrombomodulin) but makes it more stable and less amenable to be perturbed as presumably occurs before treatment when there is a partial deficiency for both.
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Affiliation(s)
- Armando Tripodi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy.,Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.,IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
| | - Roberta D'Ambrosio
- IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.,Division of Gastroenterology and Hepatology, Milano, Italy
| | - Lidia Padovan
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy.,IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
| | - Giulia Tosetti
- IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.,Division of Gastroenterology and Hepatology, Milano, Italy
| | - Alessio Aghemo
- IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.,Division of Gastroenterology and Hepatology, Milano, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
| | - Massimo Primignani
- IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.,Division of Gastroenterology and Hepatology, Milano, Italy
| | | | - Flora Peyvandi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy.,IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
| | - Massimo Colombo
- IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.,Division of Gastroenterology and Hepatology, Milano, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.,Humanitas Clinical and Research Center, Milano, Italy
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7
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Jeffrey AW, Huang Y, de Boer WB, Adams LA, MacQuillan G, Speers D, Joseph J, Jeffrey GP. Improved Hepascore in hepatitis C predicts reversal in risk of adverse outcome. World J Hepatol 2017; 9:850-856. [PMID: 28740596 PMCID: PMC5504360 DOI: 10.4254/wjh.v9.i19.850] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 04/30/2017] [Accepted: 05/19/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To establish if serial Hepascore tests (referred to as delta Hepascore) in those with chronic hepatitis C (CHC) correlate with the increase and/or decrease in risk of liver related complications.
METHODS Three hundred and forty-six CHC patients who had two Hepascore tests performed were studied. During 1944 patient years follow-up 28 (8.1%) reached an endpoint. The Hepascore is a serum test that provides clinically useful data regarding the stage of liver fibrosis and subsequent clinical outcomes in chronic liver disease.
RESULTS Patients with a baseline Hepascore > 0.75 had a significantly increased rate of reaching a composite endpoint consisting of hepatocellular carcinoma, liver death, and/or decompensation (P < 0.001). In those with an initial Hepascore > 0.75, a subsequent improved Hepascore showed a significantly decreased risk for the composite endpoint (P = 0.004). There were no negative outcomes in those with a stable or improved delta Hepascore. The minimum time between tests that was found to give a statically significant result was in those greater than one year (P = 0.03).
CONCLUSION In conclusion, Hepascore is an accurate predictor of liver related mortality and liver related morbidity in CHC patients. Of note, we have found that there is a decreased risk of mortality and morbidity in CHC patients when the patient has an improving delta Hepascore. Repeat Hepascore tests, when performed at a minimum one-year interval, may be of value in routine clinical practice to predict liver related clinical outcomes and to guide patient management.
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8
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Abstract
There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia–Pacific region, where HCC is one of the leading public health problems. Since the “Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines” meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia–Pacific region, which has a diversity of medical environments.
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9
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Liu Z, Wei X, Chen T, Huang C, Liu H, Wang Y. Characterization of fibrosis changes in chronic hepatitis C patients after virological cure: A systematic review with meta-analysis. J Gastroenterol Hepatol 2017; 32:548-557. [PMID: 27503423 DOI: 10.1111/jgh.13500] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/20/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Virological cure becomes available for most patients with chronic hepatitis C (CHC), but residual fibrosis can be an independent risk factor for liver-related complications. We aimed to characterize fibrosis change in CHC patients achieved virological cure. METHODS We did a systematic literature search for studies that had pre and post-treatment evaluations of histologic fibrosis in CHC patients with sustained virological response (SVR). We identified the association of SVR with the incidence, extent, and velocity of fibrosis change. RESULTS Overall, 3243 patients were included. Interferon-based regimens were used for all the patients, achieving a median SVR prevalence of 36.2%. Biopsy interval ranged from 1 to 10 years. Mean baseline fibrosis score (METAVIR) was 2.3 points. Compared with non-SVR patients, SVR patients could have higher incidence of fibrosis regression (35.1% vs 17.0%; OR: 3.3; P < 0.001), regardless of baseline fibrosis severity, way of biopsy evaluation, treatment regimen, or study design, and could have more extent of reduction (-0.31 points vs -0.00 points; P = 0.004). Baseline advanced fibrosis (F > 2) was associated with more rapid regression in both SVR and non-SVR patients (P < 0.05 for both). SVR patients could have lower incidence of fibrosis progression and maintenance than non-SVR patients by 4.8% versus 23.1% (OR: 0.20; P = 0.008) and 42.9% versus 55.2% (OR: 0.53; P < 0.001), respectively. CONCLUSIONS There could be a favorable characteristic of fibrosis regression in SVR patients. However, residential fibrosis may remain an issue because of a non-ignorable prevalence of fibrosis maintenance among these patients.
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Affiliation(s)
- Zhipeng Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Guangzhou, China.,Department of Hepatobiliary Surgery, Zhujiang Hospital, Guangzhou, China
| | - Xuewu Wei
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Guangzhou, China.,Department of Hepatobiliary Surgery, Zhujiang Hospital, Guangzhou, China
| | - Ting Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Guangzhou, China.,Department of Hepatobiliary Surgery, Zhujiang Hospital, Guangzhou, China
| | - Chuhong Huang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Guangzhou, China.,Department of Hepatobiliary Surgery, Zhujiang Hospital, Guangzhou, China
| | - Haiyan Liu
- Department of Hepatobiliary Surgery, Zhujiang Hospital, Guangzhou, China
| | - Yan Wang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Guangzhou, China.,Southern Medical University Biomedical Research Center, Southern Medical University, Guangzhou, China
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10
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Sáez-Royuela F, Badia E. Hepatitis C: Is Regression of Advanced Fibrosis Possible After Treatment? EUROPEAN MEDICAL JOURNAL 2016. [DOI: 10.33590/emj/10310547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
Abstract
Liver cirrhosis represents a severe complication for hepatitis C patients. Patients with cirrhosis require immediate treatment; a sustained virological response has been demonstrated to reduce the probability of complications and to improve the prognosis. The optimal outcome of treatment is regression, which in many cases is difficult to achieve due to histological changes. Nevertheless, cirrhosis regression has been reported in >50% of patients treated with antiviral drugs who were assessed by biopsy both before and after treatment. Similar results were obtained when transient elastography was used to estimate fibrosis stage. However, more studies with longer follow-up periods are necessary to confirm whether the decrease in liver stiffness resulting from a sustained virological response to a direct-acting antiviral is correlated with improved clinical outcomes.
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Affiliation(s)
- Federico Sáez-Royuela
- Department of Gastroenterology and Hepatology, Hospital Universitario de Burgos, Burgos, Spain
| | - Ester Badia
- Department of Gastroenterology and Hepatology, Hospital Universitario de Burgos, Burgos, Spain
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11
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D’Ambrosio R, Degasperi E, Aghemo A, Fraquelli M, Lampertico P, Rumi MG, Facchetti F, Grassi E, Casazza G, Rosenberg W, Bedossa P, Colombo M. Serological Tests Do Not Predict Residual Fibrosis in Hepatitis C Cirrhotics with a Sustained Virological Response to Interferon. PLoS One 2016; 11:e0155967. [PMID: 27304619 PMCID: PMC4909284 DOI: 10.1371/journal.pone.0155967] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 05/07/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIM Liver biopsy (LB) has lost popularity to stage liver fibrosis in the era of highly effective anti-hepatitis C virus (HCV) therapy, yet diagnosis of persistent cirrhosis may have important implications following HCV eradication. As performance of serological non-invasive tests (NITs) to predict residual fibrosis in non-viremic HCV patients is unknown, we investigated accuracy of NITs to predict residual fibrosis in cirrhotics after a sustained virological response (SVR) to interferon (IFN). METHODS Thirty-eight patients with a pre-treatment histological diagnosis of cirrhosis and a 48-104 months post-SVR LB were tested with APRI, CDS, FIB-4, FibroQ, Forns Score, GUCI Index, King Score, Lok Index, PLF, ELF. In 23 (61%) patients, cirrhosis had histologically regressed. RESULTS All NITs values declined after SVR without any significant difference between regressors and non-regressors (AUROC 0.52-0.75). Using viremic cut-offs, PPV ranged from 34% to 100%, with lower NPV (63% - 68%). NITs performance did not improve using derived cut-offs (PPV: 40% - 80%; NPV: 66% - 100%). PLF, which combines several NITs with transient elastography, had the best diagnostic performance (AUROC 0.75, Sn 61%, Sp 90%, PPV 80%, NPV 78%). After treatment, none of the NITs resulted significantly associated with any of the histological features (activity grade, fibrosis stage, area of fibrosis). CONCLUSIONS The diagnostic estimates obtained using both viremic and derived cut-off values of NITs were suboptimal, indicating that none of these tests helps predicting residual fibrosis and that LB remains the gold standard for this purpose.
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Affiliation(s)
- Roberta D’Ambrosio
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano, Milan, Italy
- * E-mail: ;
| | - Elisabetta Degasperi
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano, Milan, Italy
| | - Alessio Aghemo
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano, Milan, Italy
| | - Mirella Fraquelli
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano, Milan, Italy
| | - Maria Grazia Rumi
- Division of Hepatology, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy
| | - Floriana Facchetti
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano, Milan, Italy
| | - Eleonora Grassi
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano, Milan, Italy
| | - Giovanni Casazza
- Department of Biomedical and Clinical Sciences, Luigi Sacco, Università di Milano, Milan, Italy
| | - William Rosenberg
- Centre for Hepatology, Division of Medicine, University College of London, London, United Kingdom
| | - Pierre Bedossa
- Department of Pathology and INSERM U773, Beaujon Hopital, Universitée Paris-Diderot, Clichy, France
| | - Massimo Colombo
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano, Milan, Italy
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D'Ambrosio R, Colombo M. Should surveillance for liver cancer be modified in hepatitis C patients after treatment-related cirrhosis regression? Liver Int 2016; 36:783-90. [PMID: 26936383 DOI: 10.1111/liv.13106] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 02/24/2016] [Indexed: 02/13/2023]
Abstract
Surveillance of hepatocellular carcinoma (HCC) with abdominal ultrasound (US) is recommended for patients with advanced liver fibrosis because of hepatitis C virus (HCV) infections who achieve a sustained virological response (SVR) to antiviral therapy. HCC, in fact, may still develop following SVR as a consequence of long-standing carcinogenic activity of either HCV or hepatic fibrosis, whereas HCC risk in non-viraemic patients may also be driven by cofactors like alcohol abuse or diabetes. This explains the debate on whether surveillance for HCC should be continued in patients with documented cirrhosis regression following a SVR too. While regression of cirrhosis was documented to occur in a majority of patients with compensated cirrhosis 5 years after an SVR to interferon, it should be noted that this clinical benefit could be the consequence of treating a selected population with well-compensated liver disease who in fact were interferon able. This may not be the case for most real-life patients with advanced cirrhosis receiving direct antivirals, in whom liver fibrosis may have reached a point of no-return thus potentially preventing the recovery of a normal liver architecture following SVR. Both invasive and non-invasive tools have suboptimal diagnostic accuracy for fibrosis regression in non-viraemic patients, and this prompts to follow international societies' recommendation to perform surveillance in patients with advanced liver fibrosis achieving a SVR, independently on liver histology outcome.
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Affiliation(s)
- Roberta D'Ambrosio
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano, Milan, Italy
| | - Massimo Colombo
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano, Milan, Italy
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Yegin EG, Yegin K, Ozdogan OC. Digital image analysis in liver fibrosis: basic requirements and clinical implementation. BIOTECHNOL BIOTEC EQ 2016. [DOI: 10.1080/13102818.2016.1181989] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Affiliation(s)
- Ender Gunes Yegin
- Department of Gastroenterology, Bozyaka State Hospital, Izmir, Turkey
| | - Korkut Yegin
- Electrical and Electronics Engineering Department, Ege University, Izmir, Turkey
| | - Osman Cavit Ozdogan
- Faculty of Medicine, Department of Gastroenterology, Marmara University, Istanbul, Turkey
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Akhtar E, Manne V, Saab S. Cirrhosis regression in hepatitis C patients with sustained virological response after antiviral therapy: a meta-analysis. Liver Int 2015; 35:30-6. [PMID: 24766091 DOI: 10.1111/liv.12576] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 04/19/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Chronic hepatitis C may be associated with cirrhosis, liver failure and hepatocellular carcinoma. Studies have demonstrated improved clinical outcome in patients who achieved a sustained viral response (SVR). METHODS A systematic literature search was performed to identify studies that assessed the association between SVR and cirrhosis regression. The main outcome studied was cirrhosis regression in patients with a SVR as compared with patients without a SVR. Six studies totalling 443 patients were included. Dichotomous outcomes were reported as risk ratios (RR) with 95% confidence intervals (CI). RESULTS Of the 443 patients with cirrhosis, 137 achieved a SVR. Of these 137 patients who achieved an SVR, 73 (53%) patients had regression of cirrhosis. The risk ratio of cirrhosis regression was 2.69 [Confidence Interval (CI) 1.45-4.97, P < 0.01] in patients who achieved a SVR. The risk of cirrhosis regression was consistently in favour of patients who achieved a SVR regardless of the length of the biopsy or whether the biopsy was reviewed by a single or multiple pathologists. The risk ratio of cirrhosis regression was related to the duration of follow-up between biopsies. The relative risk for regression of cirrhosis in studies in which the mean or median time for the follow-up liver biopsy was greater than 36-month was 4.33 (CI 1.1-17.0, P = 0.04) as compared to a relative risk of 1.79 (CI 1.26-2.29, P < 0.01) in studies with a mean or median time between the follow-up biopsy of less than 36-month. CONCLUSIONS Our results suggest that the majority of patients with cirrhosis who achieve a SVR develop cirrhosis regression. Time between biopsies appears to be an important determinant of the likelihood of cirrhosis regression.
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Affiliation(s)
- Ehsaan Akhtar
- Department of Medicine, Harbor UCLA Medical Center, Torrance, CA, USA
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Abstract
INTRODUCTION Cirrhosis is a major milestone in patients with chronic liver disease because of its impact on patient morbidity and mortality. Chronic hepatitis B (CHB) and hepatitis C (CHC) are important causes of cirrhosis. This systematic review examines the relevant literature and evidence to assess whether cirrhosis can be reversible in patients with cirrhosis from viral hepatitis through long viral suppression. METHODS A MEDLINE and Cochrane Library search was conducted to identify all articles pertinent to the subject matter. Fourteen publications were included in the final analysis: 4 hepatitis B studies and 10 hepatitis C studies. Data abstracted from individual studies included patient demographics, antiviral therapy used, length of treatment, liver biopsy scoring system, length of biopsy, and time between biopsies. RESULTS In CHB, the 7 studies reviewed included a total of 463 cirrhotic patients. Regression of cirrhosis was noted in a median of 70% (range, 33% to 80%) of patients. In CHC, the 13 studies reviewed included a total of 58 cirrhotic patients. Regression of cirrhosis was seen in a median of 64% (range, 33% to 100%) of patients with sustained viral response. CONCLUSIONS The results of our review suggest that viral suppression in CHB and sustained virologic response in CHC can be associated with histologic regression of cirrhosis in select patients.
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16
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Demiroren K, Dogan Y, Kocamaz H, Ozercan IH, Ilhan S, Ustundag B, Bahcecioglu IH. Protective effects of L-carnitine, N-acetylcysteine and genistein in an experimental model of liver fibrosis. Clin Res Hepatol Gastroenterol 2014; 38:63-72. [PMID: 24239319 DOI: 10.1016/j.clinre.2013.08.014] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 08/27/2013] [Accepted: 08/28/2013] [Indexed: 02/04/2023]
Abstract
AIM Liver fibrosis is a reversible wound-healing response that occurs following liver injury. In this study, we aimed to investigate the possible protective effects of L-carnitine, N-acetylcysteine and genistein in liver fibrosis induced by carbon tetrachloride (CCl4). In addition, the effects of these agents were compared in the same study. METHODS In this study, rats were randomly allocated into 8 groups, consisting of 10 rats each, as follows: a control group, CCl4, L-carnitine, N-acetylcysteine, genistein, CCl4 and L-carnitine, CCl4 and N-acetylcysteine, and CCl4 and genistein. At the end of 6 weeks, blood and liver tissue specimens were collected. Alanine aminotransferase (ALT); aspartate aminotransferase (AST); complete blood count, tumor necrosis factor-α (TNF-α); platelet-derived growth factor-BB (PDGF-BB); interleukin-6 (IL-6); liver glutathione level; oxidant/antioxidant status; scores of hepatic steatosis, necrosis, inflammation, and fibrosis; and the expression of α-smooth muscle actin were studied. RESULTS Although the ALT and AST values in the group administered CCl4 were significantly higher than in all the other groups (P<0.05), there was no significant difference between the control group and the groups administered CCl4 combined with L-carnitine, N-acetylcysteine and genistein (P>0.05). There were significant differences in the levels of TNF-α, PDGF-BB and IL-6 (P<0.05) between the CCl4 group and the groups with L-carnitine, N-acetylcysteine and genistein added to CCl4. N-acetylcysteine and genistein had positive effects on the oxidant/antioxidant status and on liver necrosis and fibrosis scores. CONCLUSIONS In our study, L-carnitine, N-acetylcysteine and genistein showed significant protective effects in liver fibrosis induced by CCl4.
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Affiliation(s)
- Kaan Demiroren
- Yuzuncu Yil University, Dursun Odabas Medical Center, Pediatric Gastroentrology, Van, Turkey.
| | - Yasar Dogan
- Yuzuncu Yil University, Dursun Odabas Medical Center, Pediatric Gastroentrology, Van, Turkey
| | - Halil Kocamaz
- Yuzuncu Yil University, Dursun Odabas Medical Center, Pediatric Gastroentrology, Van, Turkey
| | - Ibrahim Hanifi Ozercan
- Yuzuncu Yil University, Dursun Odabas Medical Center, Pediatric Gastroentrology, Van, Turkey
| | - Selcuk Ilhan
- Yuzuncu Yil University, Dursun Odabas Medical Center, Pediatric Gastroentrology, Van, Turkey
| | - Bilal Ustundag
- Yuzuncu Yil University, Dursun Odabas Medical Center, Pediatric Gastroentrology, Van, Turkey
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D'Ambrosio R, Aghemo A, Fraquelli M, Rumi MG, Donato MF, Paradis V, Bedossa P, Colombo M. The diagnostic accuracy of Fibroscan for cirrhosis is influenced by liver morphometry in HCV patients with a sustained virological response. J Hepatol 2013; 59:251-6. [PMID: 23528378 DOI: 10.1016/j.jhep.2013.03.013] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 03/05/2013] [Accepted: 03/08/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Transient elastography (TE) is a validated non-invasive tool to evaluate hepatic fibrosis in patients with hepatitis C virus (HCV) infection. Whether TE may sense changes of liver fibrosis following therapeutic HCV eradication has never been evaluated. METHODS 37 HCV cirrhotics with paired pre- and post-sustained virological response (SVR) liver biopsies (LB) underwent TE at the time of post-SVR LB. Liver fibrosis was staged with the METAVIR scoring system and the area of fibrosis (%) was assessed morphometrically. RESULTS Thirty-three patients had valid TE measurements after 61 (48-104) months from an SVR, and 20 (61%) of them had cirrhosis regression. On post-SVR LB, the median area of fibrosis was 2.3%, being significantly reduced from baseline (p<0.0001). Median TE value was 9.8 kPa being lower in regressed vs. not regressed patients (9.1 kPa vs. 12.9 kPa, p=0.01). TE was <12 kPa in 5 (38%) F4 patients and in 19 (95%) ≤F3 patients (p=0.0007). The diagnostic accuracy of TE for diagnosing F4 after treatment was 61% sensitivity, 95% specificity, 12.3 LR+, 0.4 LR-, and AUROC 0.77. A significant correlation was found between TE and both fibrosis stage (r=0.56; p=0.001) and morphometry (r=0.56, p=0.001) as well as between fibrosis stage and area of fibrosis (r=0.72, p=0001). CONCLUSIONS Following therapeutic eradication of HCV, the predictive power of the viremic cut-off of 12 kPa was low as a consequence of liver remodelling and fibrosis reabsorption. LB still remains the only reliable approach to stage liver fibrosis following an SVR.
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Affiliation(s)
- Roberta D'Ambrosio
- A.M. and A. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
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18
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D'Ambrosio R, Aghemo A. Treatment of patients with HCV related cirrhosis: many rewards with very few risks. HEPATITIS MONTHLY 2012; 12:361-8. [PMID: 22879824 PMCID: PMC3412551 DOI: 10.5812/hepatmon.6095] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/01/2012] [Revised: 01/18/2012] [Accepted: 06/01/2012] [Indexed: 12/11/2022]
Abstract
Antiviral treatment of chronic hepatitis C virus (HCV) is aimed at the persistent eradication of the virus, the so-called sustained virological response (SVR), with the aim ultimately being to prevent the development of liver-related complications and improve patients' survival. Patients with HCV-related compensated cirrhosis are the group most likely to benefit from viral clearance, as several retrospective studies have shown liver complications rates to be positively modified by the achievement of a SVR. Whether these benefits rely on viral clearance or on the histological improvements seen following successful interferon (IFn)-based therapies has recently been a matter for debate, as studies have shown cirrhosis to regress in some patients with a SVR. Whatever the mechanisms, cirrhosis has the uncanny ability to be both a dominant indication for therapy, as well as one of the strongest baseline factors associated with reduced efficacy of any IFn-based regimen. This has led to the development of alternative treatment strategies, such as low dose pegylated IFn (PegIFn) monotherapy, that unfortunately has proven to be of limited efficacy. For this reason regimens able to clear the virus without relying on the broad antiviral effect of IFN are eagerly awaited.
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Affiliation(s)
- Roberta D'Ambrosio
- First Division of Gastroenterology, Cà Granda Hospital Foundation IRCCS Maggiore Policlinico, University of Milan, Milan, Italy
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19
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Theise ND, Bodenheimer HC, Ferrell LD. Acute and chronic viral hepatitis. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:361-401. [DOI: 10.1016/b978-0-7020-3398-8.00007-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Tencate V, Sainz B, Cotler SJ, Uprichard SL. Potential treatment options and future research to increase hepatitis C virus treatment response rate. Hepat Med 2010; 2010:125-145. [PMID: 21331152 PMCID: PMC3039485 DOI: 10.2147/hmer.s7193] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) is a liver-tropic blood-borne pathogen that affects more than 170 million people worldwide. Although acute infections are usually asymptomatic, up to 90% of HCV infections persist with the possibility of long-term consequences such as liver fibrosis, cirrhosis, steatosis, insulin resistance, or hepatocellular carcinoma. As such, HCV-associated liver disease is a major public health concern. Although the currently available standard of care therapy of pegylated interferon α plus ribavirin successfully treats infection in a subset of patients, the development of more effective, less toxic HCV antivirals is a health care imperative. This review not only discusses the limitations of the current HCV standard of care but also evaluates upcoming HCV treatment options and how current research elucidating the viral life cycle is facilitating the development of HCV-specific therapeutics that promise to greatly improve treatment response rates both before and after liver transplantation.
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Affiliation(s)
- Veronica Tencate
- Department of Medicine, Section of Hepatology, University of Illinois at Chicago, Chicago, IL, USA
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21
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Hines CDG, Bley TA, Lindstrom MJ, Reeder SB. Repeatability of magnetic resonance elastography for quantification of hepatic stiffness. J Magn Reson Imaging 2010; 31:725-31. [PMID: 20187219 DOI: 10.1002/jmri.22066] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To determine the sources of variability of MRE hepatic stiffness measurements using healthy volunteers and patients and to calculate the minimum change required for statistical significance. Hepatic stiffness measured with magnetic resonance elastography (MRE) has demonstrated tremendous potential as a noninvasive surrogate of hepatic fibrosis, although the underlying repeatability of MRE for longitudinal tracking of liver disease has not been documented. MATERIALS AND METHODS MRE stiffness measurements from 20 healthy volunteers and 10 patients were obtained twice on the same day, and repeated 2-4 weeks later for volunteers in this institutional review board-approved study. A linear mixed effects model was used to estimate the component sources of variability in the data. RESULTS The standard deviation of MRE measurements of the same individual on different days is 11.9% (percent of the measured stiffness) using the same reader and 12.0% using different readers. The standard deviation of the difference between two measurements (i.e., longitudinal change in an individual) is 17.4%; the corresponding 95% confidence interval for zero change is (-27.0%, 37.0%). CONCLUSION MRE is a repeatable method for quantifying liver stiffness. Using the described MRE technique, changes greater than 37.0% of the smaller measured stiffness value represent meaningful changes in longitudinal liver stiffness measurements.
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Affiliation(s)
- Catherine D G Hines
- Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin 53792-3252, USA
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22
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Younossi ZM, Afendy A, Stepanova M, Hossain N, Younossi I, Ankrah K, Gramlich T, Baranova A. Gene expression profile associated with superimposed non-alcoholic fatty liver disease and hepatic fibrosis in patients with chronic hepatitis C. Liver Int 2009; 29:1403-12. [PMID: 19515216 DOI: 10.1111/j.1478-3231.2009.02060.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hepatic steatosis occurs in 40-70% of patients chronically infected with hepatitis C virus [chronic hepatitis C (CH-C)]. Hepatic steatosis in CH-C is associated with progressive liver disease and a low response rate to antiviral therapy. AIM Gene expression profiles were examined in CH-C patients with and without hepatic steatosis, non-alcoholic steatohepatitis (NASH) and fibrosis. METHODS This study included 65 CH-C patients who were not receiving antiviral treatment. Total RNA was extracted from peripheral blood mononuclear cells, quantified and used for one-step reverse transcriptase-polymerase chain reaction to profile 153 mRNAs that were normalized with six 'housekeeping' genes and a reference RNA. Multiple regression and stepwise selection assessed differences in gene expression and the models' performances were evaluated. RESULTS Models predicting the grade of hepatic steatosis in patients with CH-C genotype 3 involved two genes: SOCS1 and IFITM1, which progressively changed their expression level with the increasing grade of steatosis. On the other hand, models predicting hepatic steatosis in non-genotype 3 patients highlighted MIP-1 cytokine encoding genes: CCL3 and CCL4 as well as IFNAR and PRKRIR. Expression levels of PRKRIR and SMAD3 differentiated patients with and without superimposed NASH only in the non-genotype 3 cohort (area under the receiver operating characteristic curve=0.822, P-value 0.006]. Gene expression signatures related to hepatic fibrosis were not genotype specific. CONCLUSIONS Gene expression might predict moderate to severe hepatic steatosis, NASH and fibrosis in patients with CH-C, providing potential insights into the pathogenesis of hepatic steatosis and fibrosis in these patients.
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Affiliation(s)
- Zobair M Younossi
- Center for Liver Diseases at Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042, USA.
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Al Ashgar H, Helmy A, Khan MQ, Al Kahtani K, Al Quaiz M, Rezeig M, Kagevi I, Alshehri A, Al Kalbani A, Al Swat K, Dahab S, Elkum N, Al Fadda M. Predictors of sustained virological response to a 48-week course of pegylated interferon alfa-2a and ribavirin in patients infected with hepatitis C virus genotype 4. Ann Saudi Med 2009; 29:4-14. [PMID: 19139619 PMCID: PMC2813618 DOI: 10.4103/0256-4947.51816] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Knowledge of the predictors of sustained viral response (SVR) to pegylated interferon (PEG-INF) alfa-2a and ribavirin (RBV) therapy in patients with hepatitis C genotype-4 (HCV-4) is crucial for selecting patients who would benefit most from therapy. We assessed the predictors of SVR to this combination therapy in Saudi patients with chronic HCV-4 infection. PATIENTS AND METHODS This retrospective study included 148 patients with HCV-4 infection who underwent clinical, biochemical and virological assessments before treatment and at 12, 24, 48 and 72 weeks post-treatment. RESULTS Of the 148 patients, 90 (60.8%) were males. Mean (SD) for age was 48.5 (12.7) years and BMI was 27.9 (7.5) kg/m(2). Seventy-nine of 148 (60.1%) patients were treatment naïve and 110 (74.3%) underwent pre-treatment liver biopsy. Eighteen (12.2%) patients did not complete therapy because of side effects or they were lost to follow up. Early virological response was achieved in 84 of 91 (92.3%) patients. In the 130 (87.8%) patients who completed therapy, 34 (26.2%) were non-responders and 96 (63.8%) achieved end-of-treatment virological response (ETVR). SVR and virological relapse (24 weeks after ETVR) occurred in 66/130 (50.7%) and 30/130 (31.2%) patients, respectively. Compared to relapsers, sustained responders were significantly younger (P=.005), non-diabetic (P=.005), had higher serum albumin (P=.028), lower alpha-fetoprotein level (P=.026), lower aspartate aminotransferase (AST) (P=.04) levels, and were treatment-naïve (P=.008). In a multivariate regression analysis, the independent predictors of SVR were younger age (P=.016), lower serum AST (P=.012), and being treatment naïve (P=.021). CONCLUSION Approximately half of HCV-4 patients who complete the course of combination therapy achieve an SVR, especially if they are young, treatment naA ve and have lower AST levels.
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Affiliation(s)
- Hamad Al Ashgar
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
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Everson GT, Balart L, Lee SS, Reindollar RW, Shiffman ML, Minuk GY, Pockros PJ, Govindarajan S, Lentz E, Heathcote EJ. Histological benefits of virological response to peginterferon alfa-2a monotherapy in patients with hepatitis C and advanced fibrosis or compensated cirrhosis. Aliment Pharmacol Ther 2008; 27:542-51. [PMID: 18208570 DOI: 10.1111/j.1365-2036.2008.03620.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Patients with chronic hepatitis C virus and advanced fibrosis or cirrhosis are at risk for disease progression and hepatic decompensation. AIM To determine the effects on hepatic histology of treatment with peginterferon alfa-2a (90 or 180 mug/week) or interferon alfa-2a (3 million units three times weekly) for 48 weeks in patients with paired biopsies. METHODS Liver biopsies were obtained at baseline and 6 months after end of treatment. Histological and virological responses were compared. RESULTS Patients attaining sustained virological response (n = 40) demonstrated the greatest improvements in fibrosis (-1.0, P < 0.0001) and inflammation (-0.65, P < 0.0001). Patients who cleared hepatitis C virus during treatment, but later relapsed (n = 59), experienced less improvement in fibrosis (-0.04, P < 0.0001) and inflammation (-0.14, P = 0.0768). Nonresponders (n = 85) showed no significant improvement in inflammation or fibrosis. Multiple regression analysis showed that the only factors contributing to improvement in fibrosis were sustained virological response (vs. nonresponder, P = 0.0005; vs. relapse, P = 0.7525) and body mass index < or =30 kg/m2 (P = 0.0995). CONCLUSIONS These findings indicate that virological response to peginterferon alfa-2a improves inflammation and fibrosis in hepatitis C virus patients with advanced fibrosis or cirrhosis. Improving virological response and maintaining ideal body weight are critical for achieving optimal histological outcomes in hepatitis C virus patients.
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Affiliation(s)
- G T Everson
- Section of Hepatology, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA.
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Al Ashgar H, Khan MQ, Helmy A, Al Swat K, Al Shehri A, Al Kalbani A, Peedikayel M, Al Kahtani K, Al Quaiz M, Rezeig M, Kagevi I, Al Fadda M. Sustained virologic response to peginterferon alpha-2a and ribavirin in 335 patients with chronic hepatitis C: a tertiary care center experience. Saudi J Gastroenterol 2008; 14:58-65. [PMID: 19568501 PMCID: PMC2702904 DOI: 10.4103/1319-3767.39619] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2007] [Accepted: 12/24/2007] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND/AIM This retrospective study assessed the efficacy, safety, and the predictors of sustained viral response (SVR) to a 48-week-course of peginterferon alpha-2a (Pegasys) and ribavirin combination therapy in 335 consecutive Saudi patients with chronic hepatitis C virus (HCV) infection. MATERIALS AND METHODS Clinical, biochemical, and virological parameters were collected at time 0 (pretreatment) and at 12, 24, 48, and 72 weeks posttreatment. The mean +/- SD age was 49.1 +/- 13.0 years; 229 (68.4%) were males, mean +/- SD body mass index was 27.8 +/- 7.4, 85 (25.4%) were diabetic, 25 (7.5%) had renal impairment, 136 (40.6%) had previously received interferon +/- ribavirin therapy, and 247 (73.7%) underwent pretreatment liver biopsy. Patients with genotypes 1, 2 or 3, 4 and mixed genotype were 60 (22.15%), 30 (11.0%), 148 (54.4%), and 34 (12.5%), respectively. RESULTS Early viral response (>or=2-log10 HCV-RNA decline 12 weeks posttreatment) was achieved in 253 (75.3%). Patients who completed 48 weeks of treatment were 292 (87.1%); of these, 121 (75.6%) achieved ETVR, 161 (55.1%) continued to have SVR and 60 (20.5%) had a viral relapse following end-of-treatment response, that is 48.1 and 17.9% of all patients (n = 335), respectively. Nonresponders (NR) were 71 (24.3%) patients and 43 (12.8%) were unable to complete treatment (due to side effects or loss to follow up). Compared to the relapsers, patients with SVR were significantly younger (P = 0.000), nondiabetics (P = 0.015), had higher serum albumin (P = 0.007), had less pretreatment inflammatory grade (P = 0.011), infected with genotypes 2 or 3 (P = 0.014), and treatment-naïve patients (P = 0.001). However, in stepwise multivariate logistic regression analysis, only treatment naiveté and low pretreatment inflammatory score were the independent predictors of SVR (P = 0.005 and P = 0.018, respectively). CONCLUSION Combination therapy, if tolerated and completed, is effective in treating chronic HCV patients, especially those with no previous interferon therapy and lower pretreatment inflammatory grade.
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Affiliation(s)
- Hamad Al Ashgar
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
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Bani-Sadr F, Lapidus N, Bedossa P, De Boever CM, Perronne C, Halfon P, Pol S, Carrat F, Cacoub P. Progression of Fibrosis in HIV and Hepatitis C Virus-Coinfected Patients Treated with Interferon plus Ribavirin-Based Therapy: Analysis of Risk Factors. Clin Infect Dis 2008; 46:768-74. [DOI: 10.1086/527565] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
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Abdel Salam OME, Oraby FH, Hassan NS. Vinpocetine ameliorates acute hepatic damage caused by administration of carbon tetrachloride in rats. ACTA BIOLOGICA HUNGARICA 2007; 58:411-9. [PMID: 18277467 DOI: 10.1556/abiol.58.2007.4.8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Vinpocetine is a widely used drug for the treatment of cerebrovascular and memory disorders. This study aimed to investigate the effect of vinpocetine on the acute hepatic injury caused in the rat by the administration of CCl4 in vivo. Vinpocetine (2.1, 4.2, 8.4 mg/kg) or silymarin (30 mg/kg) was given once daily orally simultaneously with CCl4 and for 15 days thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. Stained sections were subjected to morphometric evaluation using computerized image analyzer. The results showed that vinpocetine administered to CCl4-treated rats decreased the elevated alanine aminotransferase (ALT) by 49.3, 58.1 and 63.6%, aspartate aminotransferase (AST) by 10.5, 22.6 and 27.2% and alkaline phosphatase (ALP) by 52.5, 59.6 and 64.9%, respectively, and in a dose-dependent manner. Meanwhile, silymarin reduced elevated ALT, AST and ALP levels by 53.1, 26.9 and 66%, respectively. Histological examination of liver specimens revealed a marked reduction in liver cell necrosis in vinpocetine and silymarin-treated rats compared with vehicle-treated CCl4-treated rats. Quantitative analysis of the area of damage showed 85.3% reduction in the area of damage after silymarin and 72.2, 78.9 and 82.6% reduction after vinpocetine treatment at 2.1, 4.2, 8.4 mg/kg, respectively. It is concluded that administration of vinpocetine in a model of CCl4-induced liver injury in rats reduced liver damage. The reduction obtained by 4.2 mg/kg of vinpocetine was similar to that obtained by 30 mg/kg silymarin. Therefore, it is suggested that vinpocetine might be a good pharmacological agent in the treatment of liver disease besides its neuroprotective effects.
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Affiliation(s)
- O M E Abdel Salam
- Department of Pharmacology, National Research Centre, Tahrir St., Dokki, Cairo, Egypt.
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Abstract
Hepatitis B virus (HBV) is the most common cause of chronic hepatitis and end-stage liver disease worldwide. Untreated, chronic hepatitis B acquired early in life results in cirrhosis, liver failure, or hepatocellular carcinoma in up to 40% of individuals. Until recently, the options for a patient who had end-stage hepatitis B cirrhosis were severely limited, but during the past 15 years great strides have been made in prevention and treatment of hepatitis B cirrhosis. This article reviews recent advances in the understanding of the natural history, prevention, and medical management of HBV-related end-stage liver disease.
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Affiliation(s)
- Ilan S Weisberg
- Division of Gastroenterology and Hepatology, New York Weill Cornell Medical Center, 525 E. 68th Street, New York, NY 10021, USA
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Izzo F, Montella M, Orlando AP, Nasti G, Beneduce G, Castello G, Cremona F, Ensor CM, Holtzberg FW, Bomalaski JS, Clark MA, Curley SA, Orlando R, Scordino F, Korba BE. Pegylated arginine deiminase lowers hepatitis C viral titers and inhibits nitric oxide synthesis. J Gastroenterol Hepatol 2007; 22:86-91. [PMID: 17201887 DOI: 10.1111/j.1440-1746.2006.04463.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The arginine-degrading enzyme, arginine deiminase conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw), reduces extracellular arginine, has minimal toxicity, decreases tumor burden and improves liver function in patients with chronic hepatitis C virus infection (HCV) and inoperable hepatocellular carcinoma (HCC). Reduced extracellular arginine inhibits viral replication through unknown mechanisms. It is hypothesized that ADI-SS PEG 20,000 mw reduces HCV viral titers through nitric oxide (NO)-dependent effects. METHODS The effects of ADI-SS PEG 20,000 mw (dose, 160 IU/m2; three cycles of four once-weekly i.m. injections) on HCV titers, serum NO and plasma arginine, were evaluated using archived plasma from patients with HCC and HCV and in vitro cell model measurements of HCV replication. RESULTS ADI-SS PEG 20,000 mw selectively inhibited HCV replication in vitro (IC50 = 0.027 IU/mL). Fifteen HCC/HCV patients completed treatment. The HCV titers were reduced by up to 99% in five out of 10 (50%) HCV-serotype 1b patients (P = 0.0093). These patients also experienced significant improvements in liver function (P = 0.0091). There were concomitant reductions of plasma arginine and serum NO levels. The HCV titer was not reduced in HCV-type 2c patients. CONCLUSION Reduction of extracellular arginine by ADI-SS PEG 20,000 mw in HCC patients reduces HCV viral titers and improves liver function, possibly through suppression of NO.
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Affiliation(s)
- Francesco Izzo
- National Cancer Institute G Pascale Foundation, Naples, Italy.
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Barreiro P, Labarga P, Martín-Carbonero L, Amor A, Ruiz-Sancho A, Castellares C, González-Lahoz J, Soriano V. Sustained Virological Response following HCV Therapy is Associated with Non-Progression of Liver Fibrosis in HCV/HIV-Coinfected Patients. Antivir Ther 2006; 11:869-77. [PMID: 17302249 DOI: 10.1177/135965350601100706] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background Chronic hepatitis C leads to progressive liver fibrosis, which is accelerated in HIV-coinfected patients. Unfortunately, hepatitis C virus (HCV) therapy provides sustained virological response (SVR) to only 40% of coinfected patients. Little is known about the regression of hepatic fibrosis in treated patients. Methods All coinfected patients who had completed a full course of HCV therapy at our institution were identified. Liver fibrosis staging was estimated using non-invasive procedures at the time of initiating HCV therapy and reassessed at the last patient's follow-up using elastometry (FibroScan®). Results A total of 103 coinfected patients were identified. HCV genotype distribution was 1 (63%), 3 (29%) and 4 (8%). SVR had been attained by 34 individuals, while the remaining 69 were non-responders and/or relapsers. The mean lag time between the end of HCV therapy and the current assessment of liver fibrosis was 40 months, without differences between groups. Metavir score estimates were comparable before initiating HCV therapy in SVR and non-SVR patients. By contrast, current Metavir scores were lower in SVR than in non-SVR patients; for instance, F3-F4 estimates were 12% versus 54%, respectively ( P<0.001). Moreover, the longer the time elapsed after HCV therapy, the lower the liver fibrosis in SVR patients (ρ=-0.39; P=0.02). Conversely, liver fibrosis staging directly correlated with the lag following HCV therapy in non-SVR patients (ρ=0.25; P=0.03). Conclusions SVR after HCV therapy is associated with non-progression of liver fibrosis in HCV/HIV-coinfected patients, although this benefit may not be universal and improvement only been recognizable after several years of follow-up.
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Affiliation(s)
- Pablo Barreiro
- Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain
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Abstract
Given that the complications of hepatitis C are due to fibrosis, we hypothesized that the antifibrotic effects of interferon gamma on stellate cells would lead to beneficial effects in patients with hepatitis C. Thus, we evaluated the safety and efficacy of interferon gamma-1b in patients with hepatitis C. A cohort of 20 patients with chronic hepatitis C who failed or were intolerant to previous interferon-alpha-based regimens received 200 mug of interferon gamma-1b subcutaneously three times weekly for 24 weeks. Liver biopsy was performed prior to and at the end of treatment. Biopsies were evaluated by a single blinded pathologist using the Knodell system modified by Ishak, and fibrosis was also quantitated by morphometric analysis. The study population was 75% male and 70% Caucasian. Mean age was 47.9 +/- 7.5 years. Eighteen of 20 patients completed therapy. One patient discontinued therapy because of constitutional symptoms. One patient discontinued therapy because of elevated aminotransferases greater than twice baseline. No serious adverse events occurred. Morphometric analysis revealed that six patients (30%) had >1% absolute reduction in fibrosis score. Four of 20 (20%) patients had improvement in Ishak fibrosis scores after treatment. In conclusion, interferon gamma therapy is safe and well tolerated in patients with chronic hepatitis C. Although we did not detect an overall reduction in fibrosis, interferon gamma-1b treatment led to a reduction in fibrosis in selected patients. These data provide a basis for further study of interferon gamma-1b in patients with chronic fibrosing liver disease.
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Affiliation(s)
- A J Muir
- Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
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Tsui TY, Lau CK, Ma J, Glockzin G, Obed A, Schlitt HJ, Fan ST. Adeno-associated virus-mediated heme oxygenase-1 gene transfer suppresses the progression of micronodular cirrhosis in rats. World J Gastroenterol 2006; 12:2016-23. [PMID: 16610050 PMCID: PMC4087678 DOI: 10.3748/wjg.v12.i13.2016] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To test the hypothesis that enhancement of the activity of heme oxygenase can interfere with processes of fibrogenesis associated with recurrent liver injury, we investigated the therapeutic potential of over-expression of heme oxygense-1 in a CCl4-induced micronodular cirrhosis model.
METHODS: Recombinant adeno-associated viruses carrying rat HO-1 or GFP gene were generated. 1×1012 vg of adeno-associated viruses were administered through portal injection at the time of the induction of liver fibrosis.
RESULTS: Conditioning the rat liver with over-expression of HO-1 by rAAV/HO-1 significantly increased the HO enzymatic activities in a stable manner. The development of micronodular cirrhosis was significantly inhibited in rAAV/HO-1-transduced animals as compared to controls. Portal hypertension was markedly diminished in rAAV/HO-1-transduced animals as compared to controls, whereas there are no significant changes in systolic blood pressure. This finding was accompanied with improved liver biochemistry, less infiltrating macrophages and less activated hepatic stellate cells (HSCs) in rAAV/HO-1-transduced livers.
CONCLUSIONS: Enhancement of HO activity in the livers suppresses the development of cirrhosis.
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Affiliation(s)
- Tung-Yu Tsui
- Department of Surgery, Center for the Study of Liver Disease, the University of Hong Kong, Pokfulam, Hong Kong.
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Huang YH, Shi MN, Zheng WD, Zhang LJ, Chen ZX, Wang XZ. Therapeutic effect of interleukin-10 on CCl 4-induced hepatic fibrosis in rats. World J Gastroenterol 2006; 12:1386-91. [PMID: 16552806 PMCID: PMC4124315 DOI: 10.3748/wjg.v12.i9.1386] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the therapeutic effect of exogenous interleukin-10 on CCl4-induced hepatic fibrosis in rats and its possible mechanisms.
METHODS: Fourty-seven SD rats were randomly divided into control group (group N) and CCl4-induced hepatic fibrosis model group (group C). After CCl4 was given for 9 wk, the model group was divided into three groups. Rats in group M were put to death immediately, rats in group T were treated with IL-10 for another three wk and then put to death, rats in group R recovered after three weeks and were then killed. The degree of hepatic fibrosis was measured by HE staining and histological activity index (HAI). Histological activity index (HAI), change of collagen types I and III were measured by Picrosirius staining. The expression of TNF-α, MMP-2 and TIMP-1 in liver tissue was measured by S-P immunohistochemistry.
RESULTS: CCl4- induced experimental rat hepatic fibrosis model was established successfully. The degree of hepatic fibrosis was markedly lower in group T than in groups M and R, and there was no difference between the two groups. The expression of collagen types I and III was significantly suppressed in group T and was slightly suppressed in groups M and R. The positive levels of TNF-α, MMP-2 and TIMP-1 in group M increased significantly compared to those in group N (P < 0.01). The positive signals decreased significantly in groups T and R (P < 0.01), but positive score was significantly lower in group T than in group R (P < 0.01).
CONCLUSION: Exogenous IL-10 can reverse CCl4-induced hepatic fibrosis in rats. IL-10 may exert its reversible effects on hepatic fibrosis by blocking CCl4-induced inflammation, inhibiting expression of MMP-2 and TIMP-1 and promoting resolution of collagen types I and III.
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Affiliation(s)
- Yue-Hong Huang
- Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou 350001, Fujian Province, China
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Bräu N, Salvatore M, Ríos-Bedoya CF, Fernández-Carbia A, Paronetto F, Rodríguez-Orengo JF, Rodríguez-Torres M. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol 2006; 44:47-55. [PMID: 16182404 DOI: 10.1016/j.jhep.2005.07.006] [Citation(s) in RCA: 266] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2005] [Revised: 06/27/2005] [Accepted: 07/01/2005] [Indexed: 01/05/2023]
Abstract
BACKGROUND/AIMS HIV/HCV-coinfected patients reportedly have a faster fibrosis progression rate (FPR) than HCV-monoinfected patients. This study examined whether HIV suppression through highly active antiretroviral therapy (HAART) attenuates this accelerated fibrosis progression. METHODS In two hepatitis C centers, a retrospective analysis identified 656 consecutive treatment-naïve HCV-infected patients who had undergone a liver biopsy, had a presumed date of HCV infection, and had been tested for HIV, 274 of them HIV-positive (95.2% on HAART) and 382 HIV-negative. The primary outcome measure was the FPR, defined as Ishak fibrosis score [0-6] over estimated duration of HCV infection. RESULTS Among HIV/HCV-coinfected patients, 51.2% had undetectable HIV RNA (< 400 copies/mL). There was no difference in FPR between HIV/HCV-coinfected and HCV-monoinfected patients (0.136 vs. 0.128 Ishak fibrosis units/year, P=0.29). However, HIV/HCV-coinfected patients with any detectable HIV viral load >400 copies/mL had a faster FPR (0.151) than HCV-monoinfected patients (0.128, P=0.015) and than HIV/HCV-coinfected patients with undetectable plasma HIV RNA (0.122, P=0.013) who in turn had the same FPR as HCV-monoinfected subjects (0.128, P=0.52). An accelerated FPR in HIV viremic patients was seen with CD4+ cells <500/mm(3) (0.162 vs. 0.123, undetectable HIV RNA, P=0.005) but not with CD4+ cells >500/mm(3) (0.118 vs. 0.121, P=0.89). In multivariable linear regression analysis of HIV/HCV-coinfected patients, log(10) HIV RNA level, necroinflammation, and age at HCV infection were independently correlated to FPR, but not alcohol use or CD4+ cell count (r(2)=0.45 for model). CONCLUSIONS HIV/HCV-coinfected patients with undetectable HIV RNA through HAART have a slower FPR than those with any HIV RNA level and an FPR similar to HCV-monoinfected individuals.
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Affiliation(s)
- Norbert Bräu
- Infectious Diseases Section 111F, Bronx Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA.
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Lazzarini AL, Levine RA, Ploutz-Snyder RJ, Sanderson SO. Advances in digital quantification technique enhance discrimination between mild and advanced liver fibrosis in chronic hepatitis C. Liver Int 2005; 25:1142-9. [PMID: 16343064 DOI: 10.1111/j.1478-3231.2005.01155.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS The necessity of liver biopsy for staging fibrosis and its quantification in patients with chronic hepatitis C (CHC) remains controversial. Semiquantitative scoring of fibrosis is considered more subjective and less objective than digital quantification by image analysis. However, measurement of fibrosis using digital image analysis is thought to be less reliable in determining early stage fibrosis as compared with advanced fibrosis or cirrhosis. Our aims were to correlate all Ishak stages of fibrosis (0-6) with fibrosis percentage (%) using computerized digital image analysis, and thereby seek to improve discrimination between varying levels of liver fibrosis. METHODS Fibrosis % data were obtained by image analysis on 164 trichrome-stained liver biopsies from untreated patients with CHC, representing all Ishak stages of fibrosis. RESULTS Digital analysis of fibrosis % was highly correlated with Ishak scores of fibrosis (Kendall's tau-beta=0.86, P<0.001). Receiver-operator characteristic curves showed reliable discriminative capability of our digital image measurement of fibrosis when compared with semiquantitative assessments of fibrosis. Excellent interobserver reliability was found. CONCLUSIONS Recent advances in digital quantification of fibrosis have resulted in improved discrimination between the varying stages of liver fibrosis, including mild fibrosis. This method is reproducible, can detect early as well as advanced fibrosis or cirrhosis, may prove to be the best assessment of mild fibrosis, and may be more precise than semiquantitative estimation of changes for monitoring fibrosis progression or regression during clinical therapeutic trials.
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Affiliation(s)
- Amy L Lazzarini
- Department of Medicine, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA
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Astone JM, Strauss SM, Hagan H, Des Jarlais DC. Outpatient drug treatment program directors' hepatitis C-related beliefs and their relationship to the provision of HCV services. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2005; 30:783-97. [PMID: 15624549 DOI: 10.1081/ada-200037544] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The hepatitis C virus (HCV) continues to penetrate populations within the United States, especially within the drug-abusing population. Therefore, drug users need access to HCV testing and medical care, and drug treatment programs are well situated to provide these services. Because directors of these programs are gatekeepers who can influence decisions about service provision, their beliefs about the value of providing particular services for drug treatment program patients are of considerable importance. Directors of 121 outpatient drug treatment programs throughout the United States responded to an in-depth telephone survey that included questions on their beliefs about providing HCV services in drug treatment programs. We constructed an eight-item scale to examine these beliefs and investigated the relationship between them and the actual HCV services offered. Overall, directors were moderately supportive of the provision of HCV medical services (on-site or through referral) during drug treatment. Our findings indicate that there is a positive significant relationship between director's beliefs and the provision of HCV antibody testing, follow-up testing, and the provision of HCV medication.
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Affiliation(s)
- Janetta M Astone
- National Development and Research Institutes, Inc., 71 West 23rd St., 8th floor, New York, NY 10010, USA.
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N/A, 朱 焱, 林 勇, 谢 渭. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13:367-370. [DOI: 10.11569/wcjd.v13.i3.367] [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] [Indexed: 02/06/2023] Open
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Yoshiji H, Kuriyama S, Noguchi R, Yoshii J, Ikenaka Y, Yanase K, Namisaki T, Kitade M, Yamazaki M, Tsujinoue H, Fukui H. Combination of interferon-beta and angiotensin-converting enzyme inhibitor, perindopril, attenuates the murine liver fibrosis development. Liver Int 2005; 25:153-61. [PMID: 15698413 DOI: 10.1111/j.1478-3231.2005.01038.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Recent studies have revealed that both interferon (IFN) and angiotensin-converting enzyme inhibitor (ACE-I) exert an anti-fibrotic effect. The aim of this study was to examine the combined effect of the ACE-I and IFN on the murine hepatic fibrosis development. A model of CCl(4)-induced hepatic fibrosis was used to assess the effect of the clinically used ACE-I, perindopril (PE), and IFN-beta. The PE and IFN were administered after 2-week treatment with CCl(4), and the hepatic indices of fibrosis were assessed at 8 weeks. Single treatment with either PE or IFN at the clinically available comparable doses significantly attenuated liver fibrogenesis associated with suppression of the hepatic hydroxyproline and serum fibrosis markers. The number of alpha-smooth muscle actin-positive cells, and the hepatic alpha1(I)-procollagen mRNA were also markedly inhibited. The inhibitory effect of PE was more potent than IFN, and the combination treatment with PE and IFN almost completely attenuated liver fibrosis development. In vitro, the angiotensin-II (AT-II) type 1 receptor blocker and IFN suppressed the AT-II-induced proliferation and alpha1(I)-procollagen mRNA expression of the activated hepatic stellate cells. The combination treatment of the clinically used PE and IFN may provide a new strategy for anti-liver fibrosis therapy.
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Affiliation(s)
- Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Japan.
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Abstract
Major progress has been made in the treatment of chronic hepatitis C virus (HCV) infection over the 18 years since Hoofnagle et al. initially documented response of non-A non-B hepatitis to interferon alfa. Current optimal therapy with pegylated interferon alfa (PEG-IFN) and ribavirin results in sustained virologic response rates of just over 50%. With an estimated 2.7 million Americans with active HCV infection, we can anticipate a large number of potential treatment failures with the current standard of care. At this time, no therapy is approved by the US Food and Drug Administration for treatment failures of PEG-IFN and ribavirin. Maintenance interferon therapy with the goal of prevention of disease progression rather than viral eradication appears to offer an option for HCV treatment failures with advanced disease. Alternative medical strategies to reduce hepatic fibrosis are also under investigation. With the relatively static number of available organs for transplantation, prevention of disease progression and decompensation is essential for an impact to be made upon the predicted rates of HCV morbidity and mortality in the next 10 to 20 years.
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Affiliation(s)
- T Barry Kelleher
- Department of Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 8E, Boston, MA 02115, USA
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Nomura H, Tanimoto H, Kajiwara E, Shimono J, Maruyama T, Yamashita N, Nagano M, Higashi M, Mukai T, Matsui Y, Hayashi J, Kashiwagi S, Ishibashi H. Factors contributing to ribavirin-induced anemia. J Gastroenterol Hepatol 2004; 19:1312-7. [PMID: 15482540 DOI: 10.1111/j.1440-1746.2004.03459.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Interferon and ribavirin combination therapy for chronic hepatitis C produces hemolytic anemia. This study was conducted to identify the factors contributing to ribavirin-induced anemia. METHODS Eighty-eight patients with chronic hepatitis C who received interferon-alpha-2b at a dose of 6 MU administered intramuscularly for 24 weeks in combination with ribavirin administered orally at a dose of 600 mg or 800 mg participated in the study. A hemoglobin concentration of <10 g/dL was defined as ribavirin-induced anemia. RESULTS Ribavirin-induced anemia occurred in 18 (20.5%) patients during treatment. A 2 g/dL decrease in hemoglobin concentrations in patients with anemia was observed at week 2 after the start of treatment. The hemoglobin concentration in patients with > or =2 g/dL decrease at week 2 was observed to be significantly lower even after week 2 than in patients with <2 g/dL decrease (P < 0.01). A significant relationship was observed between the rate of reduction of hemoglobin concentrations at week 2 and the severity of anemia (P < 0.01). Such factors as sex (female), age (> or =60 years old), and the ribavirin dose by body weight (12 mg/kg or more) were significant by univariate analysis. CONCLUSIONS Careful administration is necessary in patients > or =60 years old, in female patients, and in patients receiving a ribavirin dose of 12 mg/kg or more. Patients who experience a fall in hemoglobin concentrations of 2 g/dL or more at week 2 after the start of treatment should be monitored with particular care.
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Affiliation(s)
- Hideyuki Nomura
- Department of Internal Medicine, Shin-Kokura Hospital, Kitakyushu, Fukuoka, Japan.
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Lechuga CG, Hernández-Nazara ZH, Domínguez Rosales JA, Morris ER, Rincón AR, Rivas-Estilla AM, Esteban-Gamboa A, Rojkind M. TGF-beta1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70S6k. Am J Physiol Gastrointest Liver Physiol 2004; 287:G974-87. [PMID: 15246963 DOI: 10.1152/ajpgi.00264.2003] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Transforming growth factor-beta1 (TGF-beta1), the main cytokine involved in liver fibrogenesis, induces expression of the type I collagen genes in hepatic stellate cells by a transcriptional mechanism, which is hydrogen peroxide and de novo protein synthesis dependent. Our recent studies have revealed that expression of type I collagen and matrix metalloproteinase-13 (MMP-13) mRNAs in hepatic stellate cells is reciprocally modulated. Because TGF-beta1 induces a transient elevation of alpha1(I) collagen mRNA, we investigated whether this cytokine was able to induce the expression of MMP-13 mRNA during the downfall of the alpha1(I) collagen mRNA. In the present study, we report that TGF-beta1 induces a rapid decline in steady-state levels of MMP-13 mRNA at the time that it induces the expression of alpha1(I) collagen mRNA. This change in MMP-13 mRNA expression occurs within the first 6 h postcytokine administration and is accompanied by a twofold increase in gene transcription and a fivefold decrease in mRNA half-life. This is followed by increased expression of MMP-13 mRNA, which reaches maximal values by 48 h. Our results also show that this TGF-beta1-mediated effect is de novo protein synthesis-dependent and requires the activity of p38MAPK, phosphatidylinositol 3-kinase, AKT, and p70(S6k). Altogether, our data suggest that regulation of MMP-13 by TGF-beta1 is a complex process involving transcriptional and posttranscriptional mechanisms.
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Affiliation(s)
- Carmen G Lechuga
- Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA
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Nomura H, Sou S, Tanimoto H, Nagahama T, Kimura Y, Hayashi J, Ishibashi H, Kashiwagi S. Short-term interferon-alfa therapy for acute hepatitis C: a randomized controlled trial. Hepatology 2004; 39:1213-9. [PMID: 15122749 DOI: 10.1002/hep.20196] [Citation(s) in RCA: 125] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Acute hepatitis C often progresses to chronic infection. We undertook a randomized controlled trial to determine whether short-term therapy with interferon (IFN) during acute hepatitis C is effective in preventing the development of chronic hepatitis. Thirty patients with acute hepatitis C were randomized into 1 of 2 treatment groups. IFN therapy was initiated 8 weeks after the onset of acute hepatitis in the early-intervention group and after 1 year of observation in the late-intervention group. Short-term therapy consisted of natural IFN-alfa (6 million units) administered on consecutive days for a period of 4 weeks. Any signs of recrudescence of disease were immediately followed by interval IFN therapy (3 times weekly for 20 weeks). In the early-intervention group, short-term therapy was associated with a sustained virological response in 13 of 15 patients (87%). Follow-up treatment was associated with a sustained virological response in both of the remaining 2 patients (100%). The sustained virological response rate was significantly higher in the early-intervention group (87%, 13 of 15 patients after short-term therapy alone, and 100%, 15 of 15 patients after short-term with or without follow-up therapy) than in the late-intervention group (40%, 6 of 15 patients after short-term therapy alone, and 53%, 8 of 15 patients after short-term therapy with or without follow-up therapy, P =.021 and P =.006, respectively). In conclusion, short-term (4 weeks) IFN treatment of patients with acute hepatitis C may be associated with satisfactory results, if initiated at an early stage of the disease.
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Affiliation(s)
- Hideyuki Nomura
- Department of Internal Medicine, Shin-Kokura Hospital, Fukuoka, Japan.
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