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Magri A, Manfredi GF, Smirne C, Pigni S, Burlone ME, Bellan M, Vercellino N, Minisini R, Pirisi M. Impact of Age and Sex on Viral Load in Hepatitis C Virus Infection. Viruses 2024; 17:21. [PMID: 39861810 PMCID: PMC11769058 DOI: 10.3390/v17010021] [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] [Received: 12/05/2024] [Revised: 12/24/2024] [Accepted: 12/26/2024] [Indexed: 01/27/2025] Open
Abstract
The determinants of hepatitis C virus (HCV) viral load remain incompletely understood and may differ in females, who are relatively protected from the consequences of HCV infection during their reproductive years. We aimed to evaluate how age affects the relationship between sex and viral load. n = 922 patients (males n = 497, median age 62 years), all naïve to direct antiviral agents, were studied. Females were older (median age 68 vs. 57, p < 0.001) and had a higher prevalence of genotype 2 (33% vs. 20%, p < 0.001) than males; there was no difference between sexes regarding the METAVIR stage. The median HCV RNA concentration was 1.017 × 106 IU/mL (interquartile range, 0.286-2.400). Among males, the METAVIR stage was the strongest independent predictor of a high viral load (defined as the highest two quartiles), with advanced stages inversely associated with viral load (p = 0.008). In females, age was the only independent predictor, with women aged ≥55 years exhibiting higher loads (p = 0.009). These findings are consistent with data showing that estrogens exert an antiviral effect in in vitro models of HCV. Their declining levels after the menopause may explain the "catch-up" phase of HCV-related liver disease, observed in older women.
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Affiliation(s)
- Andrea Magri
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7JT, UK
| | - Giulia Francesca Manfredi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Silvia Pigni
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Michela Emma Burlone
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Mattia Bellan
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Nicole Vercellino
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
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Not A, Saludes V, Gálvez M, Miralpeix A, Bordoy AE, González N, González-Gómez S, Muntané L, Reyes-Urueña J, Majó X, Colom J, Forns X, Lens S, Martró E. Usefulness of dried blood spot samples for monitoring hepatitis C treatment outcome and reinfection among people who inject drugs in a test-and-treat program. J Med Virol 2023; 95:e28544. [PMID: 36727653 DOI: 10.1002/jmv.28544] [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] [Received: 12/02/2022] [Revised: 01/20/2023] [Accepted: 01/30/2023] [Indexed: 02/03/2023]
Abstract
Dried blood spots (DBS) are a reliable tool to diagnose viremic hepatitis C virus (HCV) infection. We evaluated the clinical performance of a DBS-based molecular assay for the assessment of cure and reinfection after on-site treatment at a harm reduction center (HRC). Genotyping from DBS samples was also assessed to discriminate reinfection from treatment failure. People who inject drugs (PWID) from an ongoing test-and-treat pilot at the largest HRC in Barcelona were included in the study. HCV-RNA detection from DBS collected after treatment (with follow-up at 12, 36, and 60 weeks) was compared with a molecular point-of-care test using finger-stick blood (GeneXpert). Baseline and follow-up DBS samples were genotyped by NS5B sequencing or commercial real-time PCR. Among treated patients, 193 follow-up DBS samples were tested. The DBS-based assay showed 100% specificity (129/129), and sensitivity ranged from 84.4% to 96.1% according to different viral load cut-offs (from detectable to 3000 IU/mL). Sensitivity as test of cure (follow-up 12) ranged from 85.1% to 97.4%. Among the 64 patients with recurrent viremia, 10.9% had low viral loads (≤1000 IU/mL); HCV genotyping allowed us to classify 73.5% of viremic cases either as reinfection or as treatment failure. DBS samples are useful to assess cure and differentiate reinfection from relapse after HCV antiviral treatment in the real world, facilitating decentralization of treatment and posttreatment follow-up in PWID. However, a fraction of patients presented with low viral loads, limiting viremia detection and genotyping in DBS and, therefore, repeat testing is recommended.
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Affiliation(s)
- Anna Not
- Microbiology Department, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol (IGTP), Badalona, Spain
- Genetics and Microbiology Department, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
| | - Verónica Saludes
- Microbiology Department, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol (IGTP), Badalona, Spain
- Biomedical Research Networking Centre in Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - Mont Gálvez
- Liver Unit, Hospital Clínic, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Anna Miralpeix
- Liver Unit, Hospital Clínic, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Antoni E Bordoy
- Microbiology Department, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol (IGTP), Badalona, Spain
| | | | - Sara González-Gómez
- Microbiology Department, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol (IGTP), Badalona, Spain
| | - Laura Muntané
- Microbiology Department, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol (IGTP), Badalona, Spain
| | - Juliana Reyes-Urueña
- Biomedical Research Networking Centre in Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
- Center for Epidemiological Studies on HIV/AIDS and STIs of Catalonia (CEEISCAT), ASPCAT, Barcelona, Spain
| | - Xavier Majó
- Program for the Prevention, Control and Care of HIV, Sexually Transmitted Infections and Viral Hepatitis, Agència de Salut Pública de Catalunya (ASPCAT), Barcelona, Spain
| | - Joan Colom
- Program for the Prevention, Control and Care of HIV, Sexually Transmitted Infections and Viral Hepatitis, Agència de Salut Pública de Catalunya (ASPCAT), Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clínic, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Biomedical Research Networking Centre in Liver and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Sabela Lens
- Liver Unit, Hospital Clínic, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Biomedical Research Networking Centre in Liver and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Elisa Martró
- Microbiology Department, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Institut d'Investigació Germans Trias i Pujol (IGTP), Badalona, Spain
- Genetics and Microbiology Department, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
- Biomedical Research Networking Centre in Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
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Gallard C, Lebsir N, Khursheed H, Reungoat E, Plissonnier ML, Bré J, Michelet M, Chouik Y, Zoulim F, Pécheur EI, Bartosch B, Grigorov B. Heparanase-1 is upregulated by hepatitis C virus and favors its replication. J Hepatol 2022; 77:29-41. [PMID: 35085593 DOI: 10.1016/j.jhep.2022.01.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 01/03/2022] [Accepted: 01/13/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Over time, chronic HCV infection can lead to hepatocellular carcinoma (HCC), a process that involves changes to the liver extracellular matrix (ECM). However, the exact mechanisms by which HCV induces HCC remain unclear. Therefore, we sought to investigate the impact of HCV on the liver ECM, with a focus on heparanase-1 (HPSE). METHODS HPSE expression was assessed by quantitative reverse-transcription PCR, immunoblotting and immunofluorescence in liver biopsies infected or not with HCV, and in 10-day-infected hepatoma Huh7.5 cells. Cell lines deficient for or overexpressing HPSE were established to study its role during infection. RESULTS HCV propagation led to significant HPSE induction, in vivo and in vitro. HPSE enhanced infection when exogenously expressed or supplemented as a recombinant protein. Conversely, when HPSE expression was downregulated or its activity blocked, HCV infection dropped, suggesting a role of HPSE in the HCV life cycle. We further studied the underlying mechanisms of such observations and found that HPSE favored HCV release by enhancing CD63 synthesis and exosome secretion, but not by stimulating HCV entry or genome replication. We also showed that virus-induced oxidative stress was involved in HPSE induction, most likely through NF-κB activation. CONCLUSIONS We report for the first time that HCV infection is favored by HPSE, and upregulates HPSE expression and secretion, which may result in pathogenic alterations of the ECM. LAY SUMMARY Chronic hepatitis C virus (HCV) infection can lead to hepatocellular carcinoma development in a process that involves derangement of the extracellular matrix (ECM). Herein, we show that heparanase-1, a protein involved in ECM degradation and remodeling, favors HCV infection and is upregulated by HCV infection; this upregulation may result in pathogenic alterations of the ECM.
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Affiliation(s)
- Christophe Gallard
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Nadjet Lebsir
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Hira Khursheed
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Emma Reungoat
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Marie-Laure Plissonnier
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Jennifer Bré
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Maud Michelet
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Yasmina Chouik
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France; Hospices Civils de Lyon, Lyon, France
| | - Fabien Zoulim
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France; Hospices Civils de Lyon, Lyon, France
| | - Eve-Isabelle Pécheur
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France.
| | - Birke Bartosch
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Boyan Grigorov
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France.
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Lin D, Reddy V, Osman H, Lopez A, Koksal AR, Rhadhi SM, Dash S, Aydin Y. Additional Inhibition of Wnt/β-Catenin Signaling by Metformin in DAA Treatments as a Novel Therapeutic Strategy for HCV-Infected Patients. Cells 2021; 10:790. [PMID: 33918222 PMCID: PMC8065725 DOI: 10.3390/cells10040790] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/24/2021] [Accepted: 03/27/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/β-catenin signaling activation due to the inhibition of GSK-3β activity via serine 9 phosphorylation (p-ser9-GSK-3β) leading to stable non-phosphorylated β-catenin. Immunohistochemical staining demonstrated the upregulation of both β-catenin and p-Ser9-GSK-3β in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of β-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/β-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3β-mediated β-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/β-catenin signaling for HCV-infected patients.
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Affiliation(s)
- Dong Lin
- Laboratory Medicine and Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA; (V.R.); (H.O.); (A.L.); (A.R.K.); (S.M.R.); (S.D.)
| | | | | | | | | | | | | | - Yucel Aydin
- Laboratory Medicine and Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA; (V.R.); (H.O.); (A.L.); (A.R.K.); (S.M.R.); (S.D.)
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The Significance of HCV Viral Load in the Incidence of HCC: a Correlation Between Mir-122 and CCL2. J Gastrointest Cancer 2021; 51:412-417. [PMID: 31385234 DOI: 10.1007/s12029-019-00281-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the fifth most common cancer, the third leading cause of cancer deaths worldwide with over 500,000 people affected. It is a major cause of death in patients with chronic hepatitis C virus (HCV) infection. Overwhelming lines of epidemiological evidence have indicated that persistent infection with HCV is a major risk for the development of HCC. Although a proportion of patients with a chronic hepatitis C virus infection progress to HCC, the peak incidence of HCC associated with HCV infection has not yet occurred. AIM This review aimed to assess the impact of hepatitis C viral load on the development of HCC as a correlation between mir-122 and, the key factor in fibrogenesis, CCL2. CONCLUSION According to the detailed explanation of the role of mir-122 and CCL2 in HCV and HCC and the evidence of the inverse correlation between them, it may be concluded that HCV may affect mir-122 expression level of the hepatocytes with different patterns depending on the viral genotype. Collectively, HCV viral load alone is not sufficient to predict the HCC development and progression. Besides the quantitative evaluation of the HCV, mir-122 and CCL2 determinations should also be taken into consideration.
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Saludes V, Antuori A, Folch C, González N, Ibáñez N, Majó X, Colom J, Matas L, Casabona J, Martró E. Utility of a one-step screening and diagnosis strategy for viremic HCV infection among people who inject drugs in Catalonia. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2019; 74:236-245. [PMID: 31706159 DOI: 10.1016/j.drugpo.2019.10.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 10/21/2019] [Accepted: 10/21/2019] [Indexed: 12/23/2022]
Abstract
BACKGROUND In Catalonia (Spain), people who inject drugs (PWID) face numerous barriers to access to mainstream healthcare services for hepatitis C confirmatory diagnosis and treatment, so simplified testing strategies for viremic infection are urgently needed. Among PWID attending harm-reduction services in Catalonia, we aimed (i) to assess the utility of an in-house HCV-RNA detection assay on dried blood spots (DBS) as a one-step screening and confirmatory diagnosis strategy for hepatitis C, (ii) to estimate the prevalence of viremic HCV infection, and (iii) to identify factors associated with unawareness of viremic infection. METHODS A cross-sectional study of current PWID (N = 410) was performed in four harm-reduction services. All participants underwent HCV antibody point-of-care testing and parallel DBS collection for centralized RNA testing. An epidemiological questionnaire was administered. Paired EDTA-plasma samples were additionally collected for HCV viral load testing in 300 participants. RESULTS HCV-RNA testing from DBS was feasible and showed 97.2% sensitivity and 100% specificity for viral loads >3000 IU/mL in real-life conditions. No significant differences in the performance when detecting viremic infections were observed between this one-step testing strategy vs. the conventional two-step algorithm involving venepuncture. Overall HCV seroprevalence was 79.8%, and prevalence of viremic infection was 58.5%. Importantly, 35.8% of viremic HCV participants were unaware of their status, and no specific socio-demographic or bio-behavioral factors independently associated with unawareness of viremic infection were identified. Among participants reporting a past or current HCV infection, 29.0% stated having received HCV antiviral treatment. CONCLUSION The high viremic HCV infection burden among PWID attending HRS, estimated for the first time in Catalonia, together with the low levels of awareness of viremic status and access to treatment, suggest that scaling up this one-step screening and diagnosis strategy to the network of harm-reduction services would help to achieve HCV elimination targets set by the World Health Organization.
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Affiliation(s)
- Verónica Saludes
- Microbiology Department, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Crta. del Canyet s/n, Badalona, 08916 Barcelona, Spain; Genetics and Microbiology Department, Universitat Autònoma de Barcelona, Badalona, Spain; Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain; Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - Adrián Antuori
- Microbiology Department, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Crta. del Canyet s/n, Badalona, 08916 Barcelona, Spain; Genetics and Microbiology Department, Universitat Autònoma de Barcelona, Badalona, Spain; Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
| | - Cinta Folch
- Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain; Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; Centre for Epidemiological Studies on Sexually Transmitted Infections and HIV/AIDS of Catalonia (CEEISCAT), Public Health Agency of Catalonia (ASPCAT), Badalona, Spain
| | - Noemí González
- El Local, Fundació IPSS, Sant Adrià del Besòs, Barcelona, Spain
| | - Núria Ibáñez
- Program on Substance Abuse, ASPCAT, Barcelona, Spain
| | - Xavier Majó
- Program on Substance Abuse, ASPCAT, Barcelona, Spain
| | - Joan Colom
- Program for the Prevention, Control and Care of HIV, Sexually Transmitted Infections and Viral Hepatitis, ASPCAT, Barcelona, Spain
| | - Lurdes Matas
- Microbiology Department, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Crta. del Canyet s/n, Badalona, 08916 Barcelona, Spain; Genetics and Microbiology Department, Universitat Autònoma de Barcelona, Badalona, Spain; Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - Jordi Casabona
- Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain; Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; Centre for Epidemiological Studies on Sexually Transmitted Infections and HIV/AIDS of Catalonia (CEEISCAT), Public Health Agency of Catalonia (ASPCAT), Badalona, Spain
| | - Elisa Martró
- Microbiology Department, Laboratori Clínic Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Crta. del Canyet s/n, Badalona, 08916 Barcelona, Spain; Genetics and Microbiology Department, Universitat Autònoma de Barcelona, Badalona, Spain; Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain; Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.
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Colussi G, Donnini D, Brizzi RF, Maier S, Valenti L, Catena C, Cavarape A, Sechi LA, Soardo G. Sustained virologic response to direct-acting antiviral agents predicts better outcomes in hepatitis C virus-infected patients: A retrospective study. World J Gastroenterol 2019; 25:6094-6106. [PMID: 31686765 PMCID: PMC6824275 DOI: 10.3748/wjg.v25.i40.6094] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 08/09/2019] [Accepted: 09/09/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Direct-acting antiviral agents (DAAs) are extremely effective in eradicating hepatitis C virus (HCV) in chronically infected patients. However, the protective role of the sustained virologic response (SVR) achieved by second- and third-generation DAAs against the onset of hepatocellular carcinoma (HCC) and mortality is less well established.
AIM To examine the occurrence of HCC or death from any cause in a retrospective-prospective study of patients treated with DAAs.
METHODS Patients were enrolled from a tertiary academic hospital center for liver disease management that collects subject data mainly from northeastern Italy. The study was conducted in 380 patients (age: 60 ± 13 years, 224 males, 32% with cirrhosis) treated with DAAs with or without SVR (95/5%), with a median follow up of 58 wk (interquartile range: 38-117). The baseline anthropometric features, HCV viral load, severity of liver disease, presence of extra-hepatic complications, coinfection with HIV and/or HBV, alcohol consumption, previous interferon use, alpha-fetoprotein levels, and renal function were considered to be confounders.
RESULTS The incidence rate of HCC in patients with and without SVR was 1.3 and 59 per 100 person-years, respectively (incidence rate ratio: 44, 95%CI: 15-136, P < 0.001). Considering the combined endpoint of HCC or death from any cause, the hazard ratio (HR) for the SVR patients was 0.070 (95%CI: 0.025-0.194, P < 0.001). Other independent predictors of HCC or death were low HCV viremia (HR: 0.808, P = 0.030), low platelet count (HR: 0.910, P = 0.041), and presence of mixed cryoglobulinemia (HR: 3.460, P = 0.044). Considering SVR in a multi-state model, the independent predictors of SVR achievement were absence of cirrhosis (HR: 0.521, P < 0.001) and high platelet count (HR: 1.019, P = 0.026). Mixed cryoglobulinemia predicted the combined endpoint in patients with and without SVR (HR: 5.982, P = 0.028 and HR: 5.633, P = 0.047, respectively).
CONCLUSION DAA treatment is effective in inducing SVR and protecting against HCC or death. A residual risk of HCC persists in patients with advanced liver disease or with complications, such as mixed cryoglobulinemia or renal failure.
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Affiliation(s)
| | - Debora Donnini
- Department of Medicine, University of Udine, Udine 33100, Italy
| | | | - Silvia Maier
- Department of Medicine, University of Udine, Udine 33100, Italy
| | - Luca Valenti
- Department of Medicine, University of Udine, Udine 33100, Italy
| | | | | | | | - Giorgio Soardo
- Department of Medicine, University of Udine, Udine 33100, Italy
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Freiman JM, Wang J, Easterbrook PJ, Horsburgh CR, Marinucci F, White LF, Kamkamidze G, Krajden M, Loarec A, Njouom R, Nguyen KV, Shiha G, Soliman R, Solomon SS, Tsertsvadze T, Denkinger CM, Linas B. Deriving the optimal limit of detection for an HCV point-of-care test for viraemic infection: Analysis of a global dataset. J Hepatol 2019; 71:62-70. [PMID: 30797050 PMCID: PMC7014921 DOI: 10.1016/j.jhep.2019.02.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 01/03/2019] [Accepted: 02/04/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Affordable point-of-care tests for hepatitis C (HCV) viraemia are needed to improve access to treatment in low- and middle-income countries. Our aims were to determine the target limit of detection (LOD) necessary to diagnose the majority of people with HCV eligible for treatment, and identify characteristics associated with low-level viraemia (LLV) (defined as the lowest 3% of the distribution of HCV RNA) to understand those at risk of being misdiagnosed. METHODS We established a multi-country cross-sectional dataset of first available quantitative HCV RNA measurements linked to demographic and clinical data. We excluded individuals on HCV treatment. We analysed the distribution of HCV RNA and determined critical thresholds for detection of HCV viraemia. We then performed logistic regression to evaluate factors associated with LLV, and derived relative sensitivities for significant covariates. RESULTS The dataset included 66,640 individuals with HCV viraemia from across the world. The LOD for the 95th and 99th percentiles were 3,311 IU/ml and 214 IU/ml. The LOD for the 97th percentile was 1,318 IU/ml (95% CI 1,298.4-1,322.3). Factors associated with LLV, defined as HCV RNA <1,318 IU/ml, were younger age 18-30 vs. 51-64 years (odds ratios [OR] 2.56; 95% CI 2.19-2.99), female vs. male sex (OR 1.32; 95% CI 1.18-1.49), and advanced fibrosis stage F4 vs. F0-1 (OR 1.44; 95% CI 1.21-1.69). Only the younger age group had a decreased relative sensitivity below 95%, at 93.3%. CONCLUSIONS In this global dataset, a test with an LOD of 1,318 IU/ml would identify 97% of viraemic HCV infections among almost all populations. This LOD will help guide manufacturers in the development of affordable point-of-care diagnostics to expand HCV testing and linkage to care in low- and middle-income countries. LAY SUMMARY We created and analysed a dataset from 12 countries with 66,640 participants with chronic hepatitis C virus infection. We determined that about 97% of those with viraemic infection had 1,300 IU/ml or more of circulating virus at the time of diagnosis. While current diagnostic tests can detect as little as 12 IU/ml of virus, our findings suggest that increasing the level of detection closer to 1,300 IU/ml would maintain good test accuracy and will likely enable development of more affordable portable tests for use in low- and middle-income countries.
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Affiliation(s)
- J Morgan Freiman
- Boston Medical Center, Section of Infectious Diseases, Boston University School of Public Health, Boston, USA.
| | - Jianing Wang
- Boston Medical Center, Section of Infectious Diseases, Boston University School of Public Health, Boston, USA
| | | | - C Robert Horsburgh
- Department of Biostatistics, Section of Infectious Diseases, Boston University School of Public Health, Boston, USA; Department of Epidemiology, Section of Infectious Diseases, Boston University School of Public Health, Boston, USA; Global Health, Section of Infectious Diseases, Boston University School of Public Health, Boston, USA
| | | | - Laura F White
- Department of Biostatistics, Section of Infectious Diseases, Boston University School of Public Health, Boston, USA
| | | | - Mel Krajden
- British Columbia Centre for Disease Control, Vancouver, Canada
| | - Anne Loarec
- Epicentre, Medecins Sans Frontières, Paris, France
| | | | - Kihn V Nguyen
- National Hospital of Tropical Diseases, Hanoi, Viet Nam
| | - Gamal Shiha
- Department of Internal Medicine, University of Mansoura, Egypt; Egyptian Liver Research Institute and Hospital, Mansoura, Egypt
| | - Reham Soliman
- Egyptian Liver Research Institute and Hospital, Mansoura, Egypt
| | - Sunil S Solomon
- YR Gaitonde Centre for AIDS Research and Education, Chennai, India; Johns Hopkins University School of Medicine, Baltimore, USA
| | | | | | - Benjamin Linas
- Boston Medical Center, Section of Infectious Diseases, Boston University School of Public Health, Boston, USA; Department of Epidemiology, Section of Infectious Diseases, Boston University School of Public Health, Boston, USA.
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9
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Different kinetics of liver stiffness using shear wave elastography in patients with chronic hepatitis C infection treated with interferon-free regimens. Eur J Gastroenterol Hepatol 2019; 31:67-74. [PMID: 30239347 DOI: 10.1097/meg.0000000000001259] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Direct-acting antivirals (DAAs) lead to a high rate of sustained virologic response (SVR) in chronic hepatitis C infection. The aim was to evaluate liver stiffness kinetics, using acoustic radiation force impulse (ARFI) imaging elastography, during and after DAAs in patients who had reached SVR. PATIENTS AND METHODS A total of 275 consecutive chronic hepatitis C virus-infected patients were included in this longitudinal prospective single-centre study. All patients received DAAs for 8 to 24 weeks, and liver stiffness measurements (LSMs) by ARFI at baseline, at week 4, week 12, week 24, and 24 weeks (SVR24) and 48 weeks (FU48) after the end of treatment were recorded. Transient elastography was performed at baseline and at SVR24. RESULTS A decrease in LSM was detected at SVR24 by ARFI and transient elastography (P<0.001 and <0.001, respectively). A continuous gradual decrease in ARFI was observed in patients with cirrhosis versus a nonsignificant change in patients without cirrhosis until FU48 (P<0.001 vs. 0.877, respectively). At SVR24, higher baseline ARFI values (P=0.038) were associated with a decrease in LSM in patients with cirrhosis versus normal international normalization ratio (P=0.003), lower bilirubin (P=0.003), and higher albumin (P=0.007) in patients without cirrhosis. The incidence of liver stiffness decrease from baseline was higher in patients with cirrhosis than in those without cirrhosis (P<0.001), whereas the incidence of liver stiffness progression was more pronounced in advanced than in compensated cirrhosis (P<0.001). CONCLUSION After DAAs in patients with SVR, liver stiffness improves in patients with cirrhosis, whereas non-cirrhotic patients show no true change in liver stiffness. Liver stiffness worsens in patients with advanced liver disease.
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Abstract
BACKGROUND & AIMS Chronic hepatitis C virus (HCV)-infected patients with cirrhosis are a high-priority population for treatment. To help inform the benefit-risk profile of the all-oral direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir (OBV/PTV/r±DSV) in patients with Child-Pugh A cirrhosis, we undertook a comprehensive review of AbbVie-sponsored clinical trials enrolling patients with Child-Pugh A cirrhosis. METHODS Twelve phase II or III clinical trials of the 2-DAA regimen of OBV/PTV/r±ribavirin (RBV) or the 3-DAA regimen of OBV/PTV/r+DSV±RBV that included patients with Child-Pugh A cirrhosis were reviewed; patients who completed treatment by November 16, 2015 were included in a pooled, post hoc safety assessment. The number and percentage of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs consistent with hepatic decompensation were reported. RESULTS In 1,066 patients with Child-Pugh A cirrhosis, rates of serious TEAEs and TEAEs leading to study drug discontinuation were 5.3% (95% confidence interval [CI]: 4.1-6.8) and 2.2% (95% CI: 1.4-3.2), respectively. Thirteen patients (1.2%; 95% CI: 0.7-2.1) had a TEAE that was consistent with hepatic decompensation. The most frequent TEAEs consistent with hepatic decompensation were ascites (n=8), esophageal variceal hemorrhage (n=4), and hepatic encephalopathy (n=2). CONCLUSIONS This pooled analysis in 1,066 HCV-infected patients with Child-Pugh A cirrhosis confirms the safety of OBV/PTV/r±DSV±RBV in this population. These results support the use of OBV/PTV/r±DSV±RBV in this high-priority population. Lay summary: This pooled safety analysis in 1,066 HCV-infected patients with compensated cirrhosis, receiving treatment with ombitasvir, paritaprevir, and ritonavir with or without dasabuvir, with or without ribavirin, shows that the rate of hepatic decompensation events was similar to previously reported rates in untreated patients.
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11
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Childs K, Merritt E, Considine A, Sanchez-Fueyo A, Agarwal K, Martinez-Llordella M, Carey I. Immunological Predictors of Nonresponse to Directly Acting Antiviral Therapy in Patients With Chronic Hepatitis C and Decompensated Cirrhosis. Open Forum Infect Dis 2017; 4:ofx067. [PMID: 28584852 PMCID: PMC5450903 DOI: 10.1093/ofid/ofx067] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 03/31/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Sustained virological response rates (SVRs) to directly acting antiviral (DAA) therapy for hepatitis C virus (HCV) are lower in decompensated cirrhosis. Markers of innate immunity predict nonresponse to interferon-based HCV treatment; however, whether they are associated with the response to DAAs in patients with decompensation is not known. METHODS Information on demographics, adherence, viral kinetics, and resistance were gathered prospectively from a cohort with decompensated cirrhosis treated with 12 weeks of DAAs. C-X-C motif chemokine-10 (CXCL-10) level and T-cell and natural killer (NK) cell phenotype were analyzed pretreatment and at 4 and 12 weeks of treatment. RESULTS Of 32 patients, 24 of 32 (75%) achieved SVR (responders). Eight of 32 (25%) experienced relapse after the end of treatment (nonresponders). There were no differences in demographics or adherence between groups. Nonresponders had higher CXCL-10; 320 pg/mL (179461) vs 109 pg/mL (88170) in responders (P < .001) and differential CXCL-10 dynamics. Nonresponders had lower NK cell frequency, higher expression of activation receptor NKp30, and lower frequency of the NK subset CD56-CD16+. CONCLUSIONS Nonresponders to DAAs displayed a different NK phenotype and CXCL-10 profile to responders. Nonresponders did not have poorer adherence or baseline virological resistance, and this shows that immunological parameters are associated with treatment response to interferon-free treatment for HCV in individuals with decompensated cirrhosis.
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Affiliation(s)
- Kate Childs
- Liver Sciences, King's College London, United Kingdom; and
| | - Elliot Merritt
- Liver Sciences, King's College London, United Kingdom; and
| | - Aisling Considine
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | | | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | | | - Ivana Carey
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
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12
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Clinical Impact of Viral Load on the Development of Hepatocellular Carcinoma and Liver-Related Mortality in Patients with Hepatitis C Virus Infection. Gastroenterol Res Pract 2016; 2016:7476231. [PMID: 27656205 PMCID: PMC5021494 DOI: 10.1155/2016/7476231] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Revised: 07/15/2016] [Accepted: 08/03/2016] [Indexed: 01/16/2023] Open
Abstract
Aim. This study aimed to assess clinical impact of hepatitis C viral load on the development of hepatocellular carcinoma (HCC) and liver-related mortality in HCV-infected patients. Methods. A total of 111 subjects with chronic HCV infection who were available for serum quantitation of HCV RNA were recruited in this retrospective cohort. Cox-proportional hazards models were used to calculate hazard ratio (HR) of developing HCC and liver-related mortality according to serum HCV RNA titers. Results. HCC was developed in 14 patients during follow-up period. The cumulative risk of HCC development was higher in subjects with high HCV RNA titer (log HCV RNA IU/mL > 6) than subjects with low titer (log HCV RNA IU/mL ≦ 6) (HR = 4.63, P = 0.032), giving an incidence rate of 474.1 and 111.5 per 10,000 person-years, respectively. Old age (HR = 9.71, P = 0.014), accompanying cirrhosis (HR = 19.34, P = 0.004), and low platelet count (HR = 13.97, P = 0.009) were other independent risk factors for the development of HCC. Liver-related death occurred in 7 patients. Accompanying cirrhosis (HR = 6.13, P = 0.012) and low albumin level (HR = 9.17, P = 0.002), but not HCV RNA titer, were significant risk factors related to liver-related mortality. Conclusion. Serum HCV RNA titer may be considered an independent risk factor for the development of HCC but not liver-related mortality.
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Lee MH, Yang HI, Yuan Y, L’Italien G, Chen CJ. Epidemiology and natural history of hepatitis C virus infection. World J Gastroenterol 2014; 20:9270-80. [PMID: 25071320 PMCID: PMC4110557 DOI: 10.3748/wjg.v20.i28.9270] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 03/04/2014] [Accepted: 04/27/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) affects 130-210 million people worldwide and is one of the major risk factors for hepatocellular carcinoma. Globally, at least one third of hepatocellular carcinoma cases are attributed to HCV infection, and 350000 people died from HCV related diseases per year. There is a great geographical variation of HCV infection globally, with risk factors for the HCV infection differing in various countries. The progression of chronic hepatitis C to end-stage liver disease also varies in different study populations. A long-term follow-up cohort enrolling participants with asymptomatic HCV infection is essential for elucidating the natural history of HCV-caused hepatocellular carcinoma, and for exploring potential seromarkers that have high predictability for risk of hepatocellular carcinoma. However, prospective cohorts comprising individuals with HCV infection are still uncommon. The risk evaluation of viral load elevation and associated liver disease/cancer in HCV (REVEAL-HCV) study has followed a cohort of 1095 residents seropositive for antibodies against hepatitis C virus living in seven townships in Taiwan for more than fifteen years. Most of them have acquired HCV infection through iatrogenic transmission routes. As the participants in the REVEAL-HCV study rarely receive antiviral therapies, it provides a unique opportunity to study the natural history of chronic HCV infection. In this review, the prevalence, risk factors and natural history of HCV infection are comprehensively reviewed. The study cohort, data collection, and findings on liver disease progression of the REVEAL-HCV study are described.
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14
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Rao H, Wei L, Lopez-Talavera JC, Shang J, Chen H, Li J, Xie Q, Gao Z, Wang L, Wei J, Jiang J, Sun Y, Yang R, Li H, Zhang H, Gong Z, Zhang L, Zhao L, Dou X, Niu J, You H, Chen Z, Ning Q, Gong G, Wu S, Ji W, Mao Q, Tang H, Li S, Wei S, Sun J, Jiang J, Lu L, Jia J, Zhuang H. Distribution and clinical correlates of viral and host genotypes in Chinese patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol 2014; 29:545-53. [PMID: 24090188 PMCID: PMC4272577 DOI: 10.1111/jgh.12398] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/17/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Chronic hepatitis C virus (HCV) infection is relatively frequent in China. This study investigated the clinical, demographic, and viral and host genetic characteristics that may influence disease manifestations and clinical management. METHODS In this cross-sectional observational study, treatment-naïve Han ethnic adults with recently confirmed chronic HCV infection were enrolled at 28 hospitals across China. HCV genotype and host interleukin 28B (IL28B) genotypes were determined and compared with patient demographic parameters and medical status. RESULTS Among the 997 HCV-positive patients analyzed, 56.8% were infected with HCV genotype 1b, followed in prevalence by genotypes 2, 3, and 6, with substantial regional variation. Overall, 84.1% of patients were IL28B genotype CC (rs12979860), with little regional variation. Cirrhosis was reported in 10.1% of patients and was significantly associated with hepatitis B virus coinfection, low HCV viral load, low serum alanine aminotransferase, high serum aspartate aminotransferase, diabetes, and high pickled food consumption. Medical procedures were common transmission risk factors; however, lifestyle-associated risk factors, including intravenous drug abuse and tattoos or piercings, were more common in patients with HCV genotype 3 or 6. CONCLUSIONS Most HCV-infected Han Chinese patients were IL28B genotype CC (rs12979860). HCV genotypes varied by geographic region, and disease characteristics differed according to HCV genotype. Relatively frequent detection of advanced liver disease may reflect limitations on access to antiviral therapy, and suggests that greater awareness of factors that influence HCV-associated disease may help avoid clinical complications and improve patient outcomes.
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Affiliation(s)
- Huiying Rao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver DiseaseBeijing, China
| | - Lai Wei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver DiseaseBeijing, China
| | | | - Jia Shang
- Henan Provincial People's HospitalZhengzhou, China
| | - Hong Chen
- First Hospital of Lanzhou UniversityLanzhou, China
| | - Jun Li
- First Affiliated Hospital with Nanjing Medical UniversityNanjing, China
| | - Qing Xie
- Shanghai Ruijin HospitalShanghai, China
| | - Zhiliang Gao
- Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, China
| | - Lei Wang
- Second Hospital of Shandong UniversityJinan, China
| | - Jia Wei
- First Affiliated Hospital of Kunming Medical CollegeKunming, China
| | - Jianning Jiang
- First Affiliated Hospital of Guangxi Medical UniversityNanning, China
| | - Yongtao Sun
- Fourth Military Medical University, Tangdu HospitalXi'an, China
| | - Ruifeng Yang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver DiseaseBeijing, China
| | - Hong Li
- Bristol-Myers SquibbWallingford, Connecticut, USA
| | - Haiying Zhang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver DiseaseBeijing, China
| | - Zuojiong Gong
- People's Hospital of Hubei Wuhan UniversityWuhan, China
| | - Lunli Zhang
- First Affiliated Hospital of Nanchang UniversityNanchang, China
| | - Longfeng Zhao
- First Affiliated Hospital of Shanxi Medical UniversityTaiyuan, China
| | - Xiaoguang Dou
- Shengjing Hospital of China Medical UniversityShenyang, China
| | - Junqi Niu
- First Hospital of Jilin UniversityChangchun, China
| | - Hong You
- Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
| | - Zhi Chen
- First Affiliated Hospital of Medical College ZheJiang UniversityHangzhou, China
| | - Qin Ning
- Affiliated Tongji Hospital of Tongji Medical College of Huazhong University of Science and TechnologyWuhan, China
| | - Guozhong Gong
- Second Xiangya Hospital of Central South UniversityChangsha, China
| | - Shuhuan Wu
- First Affiliated Hospital of Zhengzhou UniversityZhengzhou, China
| | - Wei Ji
- Ningxia People's HospitalYinchuan, China
| | - Qing Mao
- Southwest HospitalChongqing, China
| | | | - Shuchen Li
- Second Affiliated Hospital of Harbin Medical UniversityHarbin, China
| | - Shaofeng Wei
- First Affiliated Hospital of Anhui Medical UniversityHefei, China
| | - Jian Sun
- Nanfang Hospital, Southern Medical UniversityGuangzhou, China
| | - Jiaji Jiang
- First Affiliated Hospital of Fujian Medical UniversityFuzhou, China
| | - Lungen Lu
- Shanghai First People's Hospital, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
| | - Hui Zhuang
- Peking University Health Science CenterBeijing, China
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Sato S, Genda T, Hirano K, Tsuzura H, Kanemitsu Y, Narita Y, Kikuchi T, Ijima K, Ichida T. Differences in the factors associated with serum viral load between genotypes 1 and 2 in patients with chronic hepatitis C. Hepatol Int 2011; 7:508-15. [PMID: 21484111 DOI: 10.1007/s12072-011-9273-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2010] [Accepted: 03/21/2011] [Indexed: 01/15/2023]
Abstract
PURPOSE The serum hepatitis C virus (HCV) load is persistently stable in patients with untreated chronic hepatitis C, but its differences between individuals vary widely (above 4 logU/mL). Because serum viral load is an important factor for predicting clinical outcome of interferon-based antiviral therapy, this study was performed to clarify the factors associated with serum viral load in chronic hepatitis C patients. METHODS We retrospectively analyzed data from 669 chronic hepatitis C patients with HCV genotype 1 or 2 infection. Stepwise regression analysis was used to estimate the relationship between demographic, viral, or biochemical variables and serum viral load. RESULTS In univariate analysis, serum lipid profiles, such as total cholesterol, low-density lipoprotein (LDL) and triglyceride levels, and hemoglobin A1c (HbA1c) were correlated with the serum HCV viral load. In multivariate analysis, HCV genotype 1 infection and higher total cholesterol levels were associated with higher viral load. After stratification by HCV genotype, the serum viral load was associated with triglyceride and HbA1c in genotype 1 and with platelet counts and LDL in genotype 2. Histological data (413 patients) showed correlation between severe liver fibrosis and decreased serum viral load in patients with HCV genotype 2 but not genotype 1 infection. CONCLUSIONS These results suggest that viral kinetics is affected by different host factors for genotypes 1 and 2.
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Affiliation(s)
- Shunsuke Sato
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan.
| | - Takuya Genda
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Katsuharu Hirano
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Hironori Tsuzura
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Yoshio Kanemitsu
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Yutaka Narita
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Tetsu Kikuchi
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Katsuyori Ijima
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Takafumi Ichida
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
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Salama H, Zekri ARN, Bahnassy AA, Medhat E, Halim HA, Ahmed OS, Mohamed G, Alim SAA, Sherif GM. Autologous CD34 + and CD133 + stem cells transplantation in patients with end stage liver disease. World J Gastroenterol 2010; 16:5297-305. [PMID: 21072892 PMCID: PMC2980678 DOI: 10.3748/wjg.v16.i42.5297] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the utility of an autologous CD34+ and CD133+ stem cells infusion as a possible therapeutic modality in patients with end-stage liver diseases.
METHODS: One hundred and forty patients with end-stage liver diseases were randomized into two groups. Group 1, comprising 90 patients, received granulocyte colony stimulating factor for five days followed by autologous CD34+ and CD133+ stem cell infusion in the portal vein. Group 2, comprising 50 patients, received regular liver treatment only and served as a control group.
RESULTS: Near normalization of liver enzymes and improvement in synthetic function were observed in 54.5% of the group 1 patients; 13.6% of the patients showed stable states in the infused group. None of the patients in the control group showed improvement. No adverse effects were noted.
CONCLUSION: Our data showed that a CD34+ and CD133+ stem cells infusion can be used as supportive treatment for end-stage liver disease with satisfactory tolerability.
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17
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Lee MH, Yang HI, Lu SN, Jen CL, Yeh SH, Liu CJ, Chen PJ, You SL, Wang LY, Chen WJ, Chen CJ. Hepatitis C virus seromarkers and subsequent risk of hepatocellular carcinoma: long-term predictors from a community-based cohort study. J Clin Oncol 2010; 28:4587-93. [PMID: 20855826 DOI: 10.1200/jco.2010.29.1500] [Citation(s) in RCA: 131] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
PURPOSE Hepatitis C virus (HCV) contributes to one third of hepatocellular carcinoma cases worldwide. Long-term predictors for HCV-related hepatocellular carcinoma are essential for early intervention. Serum HCV RNA and ALT levels and HCV genotype were assessed for their predictability of hepatocellular carcinoma risk. METHODS A prospective cohort of 925 participants positive for antibodies against HCV and age 30 to 65 years was recruited and followed from 1991 to 2006. Serum HCV RNA and ALT levels and HCV genotypes at enrollment and during follow-up were examined. Newly developed hepatocellular carcinoma was identified by health examination and computerized linkage with national cancer registration and death certification profiles. Multivariate adjusted hazard ratios with 95% CIs were estimated using Cox regression models. RESULTS Fifty-five participants newly developed hepatocellular carcinoma during 8,476 person-years of follow-up, giving an incidence rate of 648.9 per 100,000 person-years. The cumulative hepatocellular carcinoma risk increased from 1.1% for HCV RNA seronegative status to 6.4% for low HCV RNA levels and to 14.7% for high HCV RNA levels (P < .001). The cumulative risk also increased with elevated serum ALT levels from 1.7% for persistently ≤ 15 U/L to 4.2% for ever more than 15 U/L but never more than 45 U/L and to 13.8% for ALT ever ≥ 45 U/L (P < .001). Having HCV genotype 1 was associated with a higher cumulative hepatocellular carcinoma risk (12.6%) than not having HCV genotype 1 (4.5%; P < .001). CONCLUSION Elevated serum levels of HCV RNA and ALT and HCV genotype 1 infection are independent risk predictors of hepatocellular carcinoma. These findings have strong implications for the management of chronic HCV.
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Attallah AM, Ismail H, Shiha GE, Abou-Dobara MI, El-Sherbiny RE, El-Dosoky I. Immunochemical identification and partial characterization of a native hepatitis C viral non-structural 4 antigen in sera of HCV infected patients. Clin Chim Acta 2008; 388:115-22. [PMID: 18021744 DOI: 10.1016/j.cca.2007.10.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2007] [Revised: 10/11/2007] [Accepted: 10/15/2007] [Indexed: 11/26/2022]
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Cooper CL, Cooper CL, MacPherson P, Cameron W. Analytical and biological variables influencing quantitative hepatitis C virus (HCV) measurement in HIV-HCV coinfection. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2006; 20:31-5. [PMID: 16432557 PMCID: PMC2538965 DOI: 10.1155/2006/187241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The present review considers issues pertaining to the precision and variability of quantitative hepatitis C virus (HCV) measurement in general, outlines the characteristics of HCV RNA in HIV-HCV coinfection and evaluates those factors which may affect this measure. The clinical relevance of accurate HCV measurement in HIV-HCV coinfection is discussed.
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Pavio N, Battaglia S, Boucreux D, Arnulf B, Sobesky R, Hermine O, Brechot C. Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-beta pathway. Oncogene 2005; 24:6119-32. [PMID: 16007207 DOI: 10.1038/sj.onc.1208749] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV) is a major risk factor for human hepatocellular carcinoma (HCC) but the mechanisms underlying HCV-induced carcinogenesis are still poorly understood. We have hypothesized that viral variants, selected during long-term infection, might contribute to cellular transformation. To address this issue, we have investigated the effect of natural HCV core variants isolated from liver tumors (T), or their non-tumor (NT) counterparts, on the tumor growth factor-beta (TGF-beta) pathway, a major regulator of cellular proliferation, differentiation and apoptosis. We have found a significant reduction in TGF-beta reporter gene activity with the expression of core sequences isolated from liver tumors. In contrast, moderate or no effects were observed with non-tumor mutants or a core reference sequence. The molecular mechanisms have been characterized and involved the inhibition, by tumor-derived cores, of the DNA-binding activity of the Smad3/4 transcription factors complex. This inhibition occurs through a direct interaction between the central domain (amino acids 59-126) of tumor-derived core and the MH1 DNA-binding domain of Smad3, thus preventing its binding to DNA. We have therefore identified a new cell-signaling pathway targeted by HCV core and inhibited by tumor-derived core sequences. These results suggest that during chronic infection, there is selection of viral variants that may promote cell transformation by providing, to clonally expanding cells, resistance to TGF-beta antiproliferative effects.
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Affiliation(s)
- Nicole Pavio
- Inserm U370, Paris V University, Pasteur Institute, 156 rue de Vaugirard 75730 Paris cedex 15, France.
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Abstract
Four virological markers of hepatitis C virus (HCV) infection are used clinically for management of patients with hepatitis C, namely the HCV genotype, HCV RNA, HCV core antigen, and antibody to HCV (anti-HCV). The diagnosis of acute and chronic hepatitis C is based on both anti-HCV detection using enzyme immunoassays (EIA) and HCV RNA detection using a sensitive molecular biology-based technique. Other virological tools, including HCV genotype determination and HCV RNA quantification, are now used to tailor treatment to the individual patient and to determine its efficacy. This article reviews the kinetics of HCV markers during acute and chronic HCV infection, together with current assays and their practical use in the management of HCV-infected patients.
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Affiliation(s)
- Jean-Michel Pawlotsky
- Department of Virology (EA 3489), Henri Mondor Hospital, University of Paris XII, Créteil, France.
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Puoti C, Castellacci R, Bellis L, Montagnese R, Corvisieri P, Festuccia P, Mellozzi M, Villani AR. Hepatitis C virus RNA quantitation in hepatic veins and peripheral blood in patients with liver cirrhosis: evidence for low level intrahepatic hepatitis C virus replication in advanced liver disease. Dig Liver Dis 2002; 34:802-7. [PMID: 12546516 DOI: 10.1016/s1590-8658(02)80074-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Very few data exist concerning the level of hepatitis C virus replication within the cirrhotic liver and its relationship to disease severity and progression. AIMS To quantitate hepatitis C virus RNA in hepatic vein blood and peripheral blood in patients with cirrhosis, to evaluate the correlation of hepatitis C virus levels in paired blood samples, and to compare the results with clinical features. PATIENTS A series of 25 patients with hepatitis C virus-related liver cirrhosis undergoing hepatic vein catheterization were studied: 11 belonged to Child Pugh class A, 8 to class B and 6 to class C. RESULTS Hepatitis C virus RNA levels did not differ between hepatic vein blood and peripheral blood (p = 0.26), despite a trend towards higher peripheral hepatitis C virus RNA levels. Hepatitis C virus RNA levels did not differ between patients with genotype 1b and non-1b either in hepatic veins or peripheral blood. Hepatitis C virus loads varied according to the severity of cirrhosis. The patients with more severe liver disease had significantly lower RNA titres than those with less advanced cirrhosis, both in hepatic veins (p = 0.002) and peripheral blood (p = 0.004). No differences in hepatitis C virus load were observed between patients in Child Pugh classes B and C. CONCLUSIONS The present data show that in patients with cirrhosis hepatitis C virus RNA concentrations do not differ between hepatic blood and peripheral blood and, furthermore, confirm that hepatitis C virus replication is reduced in patients with advanced cirrhosis, compared with patients with less severe liver disease. These findings might indicate that patients with liver cirrhosis maintain an efficient intrahepatic hepatitis C virus replication even in end-stage disease, although hepatitis C virus viraemia decreases according to the severity of liver disease.
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Affiliation(s)
- C Puoti
- Dept. of Gastroenterology and Internal Medicine, Genzano Hospital, Rome, Italy.
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Abstract
Four virological markers of hepatitis C virus (HCV) infection are used clinically for management of patients with hepatitis C, namely the HCV genotype, HCV RNA, HCV core antigen, and antibody to HCV (anti-HCV). The diagnosis of acute and chronic hepatitis C is based on both anti-HCV detection using enzyme immunoassays (EIA) and HCV RNA detection using a sensitive molecular biology-based technique. Other virological tools, including HCV genotype determination and HCV RNA quantification, are now used to tailor treatment to the individual patient and to determine its efficacy. This article reviews the kinetics of HCV markers during acute and chronic HCV infection, together with current assays and their practical use in the management of HCV-infected patients.
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Affiliation(s)
- Jean-Michel Pawlotsky
- Department of Virology (EA 3489), Henri Mondor Hospital, University of Paris XII, Créteil, France.
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24
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Cooper CL, Cameron DW. Review of the effect of highly active antiretroviral therapy on hepatitis C virus (HCV) RNA levels in human immunodeficiency virus and HCV coinfection. Clin Infect Dis 2002; 35:873-9. [PMID: 12228825 DOI: 10.1086/342388] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2001] [Revised: 05/03/2002] [Indexed: 12/26/2022] Open
Abstract
The effect of anti-human immunodeficiency virus (HIV) treatment on hepatitis C virus (HCV) RNA levels in HIV-HCV-coinfected persons is uncertain. Although it is commonly believed that, with the initiation of HIV treatment, there may be an initial increase followed by a gradual decrease of HCV RNA levels to lower than those at pretreatment, the published studies evaluating this are of small and heterogeneous populations, are limited in follow-up, and have conflicting results. A prospective clinical trial of sufficient size and duration may help clarify this issue. This may be clinically relevant, because lower HCV RNA levels are a predictive factor for favorable response to HCV antiviral therapy.
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Affiliation(s)
- Curtis L Cooper
- Division of Infectious Diseases, Ottawa Hospital, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada.
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25
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Abstract
AIM: To establish a cell culture system with long-term replication of hepatitis C virus in vitro.
METHODS: Human hepatoma cell line 7721 was tested for its susceptibility to HCV by incubating with a serum from a patient with chronic hepatitis C. Cells and supernatant were harvested at various phases during the culturing periods. The presence of HCV RNA, the expression of HCV antigens in cells and/or supernatant were examined by RT-PCR, in situ hybridization and immunohisto-chemistry respectively.
RESULTS: The intracellular HCV RNA was first detected on d2 after infection and then could be intermittently detected in both cells and supernatant over a period of at least three months. The expression of HCV NS3, CP10 antigens could be observed in cells. The fresh cells could be infected by supernatant from cultured infected cells and the transmission of viral genome from HCV-infected 7721 cells to PBMCs was also observed.
CONCLUSION: The hepatoma line 7721 is not only susceptible to HCV but also supports its long-term replication in vitro.
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Affiliation(s)
- Z Q Song
- Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
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Adinolfi LE, Utili R, Andreana A, Tripodi MF, Marracino M, Gambardella M, Giordano M, Ruggiero G. Serum HCV RNA levels correlate with histological liver damage and concur with steatosis in progression of chronic hepatitis C. Dig Dis Sci 2001; 46:1677-83. [PMID: 11508667 DOI: 10.1023/a:1010697319589] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The role of HCV RNA levels and host factors in the severity of liver injury was studied. Enrolled were 298 consecutive liver biopsy-proven chronic hepatitis (CH) C patients (179 men; median age: 52 years, range 19-68; CH, 198; cirrhosis, 100) and 18 chronic hepatitis C with normal ALT. HCV genotypes were: 1a, 4.3%; 1b, 53%; 2a/c, 28%; 3a, 7%; 4, 1.3%, and mixed 6.4%. Serum HCV RNA levels were similar for all genotypes (median: 2.8 x 10(6) eq/ml; range <0.2-69). In patients with chronic hepatitis without cirrhosis, the serum HCV RNA levels reflected the grade of liver necroinflammatory activity (R = 0.45; P < 0.001) and the stage of fibrosis (R = 0.51; P < 0.001), regardless of age, gender, HCV genotype, hepatic steatosis, and hepatic iron overload. Patients with high serum HCV RNA levels (> or =3 x 10(6) eq/ml) had higher ALT values (P < 0.002) than those with lower HCV RNA levels. Patients with normal ALT showed low HCV RNA levels (median: 0.82 x 10(6) eq/ml) and histological features of minimal or mild chronic hepatitis. Cirrhotic patients showed significantly lower levels of viremia than those with chronic hepatitis with a similar HAI. The data of a subgroup of 62 patients with an established time of infection showed that for a similar duration of disease, patients with serum HCV RNA levels > or =3 x 10(6) eq/ml had a significantly higher fibrosis score than those with lower levels. HAI and fibrosis score were significantly higher in patients with HCV RNA levels > or =3 x 10(6) eq/ml and grade 3-4 steatosis than those with lower HCV RNA levels and steatosis grades. The data indicate that the liver damage is correlated with the HCV RNA levels and that a high viral load acts together with steatosis in accelerating the progression of liver injury.
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Affiliation(s)
- L E Adinolfi
- Institute of Medical Therapy, Faculty of Medicine, Second University of Naples, Italy
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Rullier A, Trimoulet P, Urbaniak R, Winnock M, Zauli D, Ballardini G, Rosenbaum J, Balabaud C, Bioulac-Sage P, Le Bail B. Immunohistochemical detection of hcv in cirrhosis, dysplastic nodules, and hepatocellular carcinomas with parallel-tissue quantitative RT-PCR. Mod Pathol 2001; 14:496-505. [PMID: 11353061 DOI: 10.1038/modpathol.3880338] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hepatitis C virus is a major risk factor for hepatocarcinogenesis in humans. In situ detection of the virus in early sequential lesions of hepatocarcinogenesis could provide information about the role of the virus in the transformation and promotion process. Parallel in situ detection of HCV proteins and RNA in human tissues were performed in 55 posthepatitis C cirrhosis, 17 dysplastic nodules (DN), and 25 hepatocellular carcinomas (HCC), using immunohistochemistry and tissue quantitative RT-PCR. A consistent cytoplasmic hepatocellular staining was obtained in 73% of cirrhosis cases (with or without HCC) and in 55% DN cases. A few tumoral hepatocytes were unambiguously stained in 28% HCC. The percentage of positive cells and the intensity of immunostaining significantly decreased from cirrhosis to HCC through DN, whereas there was no difference in the prevalence of positivity or the number of viral copies between cirrhosis and HCC using tissue-quantitative RT-PCR. Finally, RT-PCR levels were found parallel with the immunostaining in cirrhosis but not in HCC. These results suggest that HCV protein synthesis may persist but be down-regulated during sequential hepatocarcinogenesis. A putative role of HCV proteins on cell proliferation and differentiation during the early steps of carcinogenesis cannot therefore be excluded.
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Affiliation(s)
- A Rullier
- Service d'Anatomie Pathologique, Hôpital Pellegrin, Bordeause, France
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Lefkowitch JH. Pathology of the liver. Curr Opin Gastroenterol 2000; 16:200-7. [PMID: 17023877 DOI: 10.1097/00001574-200005000-00002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
At the close of the 20th century, a selection of articles published in 1999 with relevance to liver pathology reflects the wealth of technological and intellectual progress made during the span of the century. Immunohistochemical staining for hepatitis B virus antigens focused attention on a correlation between cytoplasmic expression of core antigen in individuals with precore mutants and higher activity of hepatitis. Infection of ducklings with a presurface mutant strain of duck hepatitis B virus produced cytopathic liver cell damage. Fibrosing cholestatic hepatitis, originally described as an unusual form of recurrent hepatitis B after liver transplantation, has now been described in hepatitis C virus-positive patients with renal transplants. It may be related to the emergence or selection of hepatitis C virus quasispecies. In biliary tract disease, researchers investigated the canal of Hering as a possible source of hepatic stem cells, sporadic mutations in the JAGGED1 gene (involved in cell differentiation) in Alagille syndrome, and several models of nonsuppurative destructive cholangitis. Further work was accomplished on nonalcoholic steatohepatitis, including a proposal of a grading and staging system as well as its detection in workers exposed to volatile petrochemicals. Among hepatic neoplasms and proliferative disorders, epithelioid hemangioendothelioma, angiomyolipoma and Langerhans' cell histiocytosis received coverage in articles describing the diagnostic pathology in collected series of patients.
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Affiliation(s)
- J H Lefkowitch
- College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA
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