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Xie C, Singal AK. Beyond the Cure: Navigating Hepatocellular Risk and Surveillance after Hepatitis C Eradication in the Direct-acting Antiviral Era. J Clin Transl Hepatol 2025; 13:418-424. [PMID: 40385945 PMCID: PMC12078169 DOI: 10.14218/jcth.2024.00499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/20/2025] [Accepted: 01/24/2025] [Indexed: 05/20/2025] Open
Abstract
Direct-acting antivirals (DAAs) have dramatically changed the landscape of chronic hepatitis C virus (HCV) treatment and significantly reduced the risk of HCV-related hepatocellular carcinoma (HCC) after achieving sustained virologic response. However, the risk of HCC persists, particularly in patients with pre-treatment cirrhosis or fibrosis stage 3 (F3), even after DAA-induced viral eradication. While professional guidelines agree on the need for surveillance in cirrhotic patients, there is no consensus regarding surveillance for the pre-treatment F3 population following HCV eradication. The risk of HCC in the F3 population falls below the threshold for cost-effective surveillance. However, co-existing risk factors-such as diabetes, hepatic steatosis, alcohol use, advanced age, and elevated alpha-fetoprotein levels-may warrant reconsideration of HCC surveillance in this group. This underscores the need for an individualized, risk-based approach to HCC surveillance. This review provided a simplified algorithm to assist clinicians in managing patients with HCV after DAA-induced sustained virologic response.
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Affiliation(s)
- Chencheng Xie
- Department of Gastroenterology, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA
| | - Ashwani K. Singal
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
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2
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Cheng YM, Wang SW, Wang C, Wang CC. Unmet needs of metabolic dysfunction - Associated "fatty or steatotic" liver disease. Tzu Chi Med J 2025; 37:152-156. [PMID: 40321956 PMCID: PMC12048125 DOI: 10.4103/tcmj.tcmj_232_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/28/2024] [Accepted: 12/10/2024] [Indexed: 05/08/2025] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), first named in 1980, is currently the most common chronic liver disease, imposing significant health, social, and economic burdens. However, it is defined as a diagnosis of exclusion, lacking a clear underlying cause in its diagnostic criteria. In 2020, metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed as a replacement for NAFLD, introducing additional criteria related to metabolic dysfunction. In 2023, metabolic dysfunction-associated steatotic liver disease (MASLD) was suggested to replace NAFLD, aiming to avoid the stigmatizing term "fatty" and incorporating cardiometabolic criteria for metabolic dysfunction. This divergence in nomenclature and diagnostic criteria between MAFLD and MASLD presents challenges to medical communication and progress. This review outlines the pros and cons of both terminologies, based on current research evidence, in the hope of fostering global consensus in the future.
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Affiliation(s)
- Yu-Ming Cheng
- Department of Gastroenterology and Hepatology, Tung’s Taichung MetroHarbor Hospital, Taichung, Taiwan
| | - Shao-Wen Wang
- Department of Education, Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare, New Taipei, Taiwan
| | - Ching Wang
- Department of Education, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
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3
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Corma-Gómez A, Corona-Mata D, Martín-Carmona J, Galindo MJ, Camacho A, Martín-Sierra C, Gallo-Marín M, Rincón P, Perez-Valero I, Pérez-García M, Carrasco-Dorado A, Pineda JA, Rivero-Juárez A, Rivero A, Real LM, Macías J. FibroScan-AST Score vs Liver Stiffness for the Prediction of Liver Events After HCV Cure. Open Forum Infect Dis 2025; 12:ofae628. [PMID: 40201720 PMCID: PMC11977108 DOI: 10.1093/ofid/ofae628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 10/12/2024] [Indexed: 04/10/2025] Open
Abstract
Background Liver stiffness (LS) predicts liver complication occurrence in patients with hepatitis C virus (HCV) infection after sustained virological response (SVR). The FibroScan-AST (FAST) score, which includes aspartate aminotransferase (AST) and controlled attenuation parameter (CAP; measured by FibroScan), may improve the prediction ability of isolated LS. Our aim was to compare the predictive capacity of LS vs FAST in this setting. Methods Multicenter cohort study including individuals with HIV/HCV coinfection or HCV monoinfection from Spain if they had (1) LS ≥9.5 kPa pretreatment, (2) SVR with a direct-acting antiviral (DAA)-based regimen, and (3) LS and CAP measurement at SVR. Fatty liver disease (FLD) was defined as CAP ≥248 dB/m. The primary outcome was the occurrence of a liver complication (decompensation or hepatocellular carcinoma [HCC]) after SVR. Results Three hundred patients were included; 213 (71%) had HIV. At SVR, 131 (44%) had FLD. The FAST score was <0.35 in 182 (61%), 0.35-0.67 in 79 (27%), and >0.67 in 34 (12%) patients. After a median (Q1-Q3) follow-up of 73 (53-83) months, 36 (12%) liver complications (15 [5%] HCC) occurred. LS was independently associated with an increased risk of developing liver complications (sub-hazard ratio [sHR], 1.06; 95% CI, 1.04-1.08; P < .001). In a separate model, FAST ≥0.35 was also independently associated with greater risk of liver complications (sHR, 8.12; 95% CI, 3.11-21.17; P < .001). The area under the receiver operating characteristics curve of the model based on LS was 0.83 (95% CI, 0.76-0.91), and that of the model based on FAST was 0.80 (95% CI, 0.72-0.88; P = .158). Conclusions The FAST score predicts the development of liver events after SVR but does not improve the predictive capacity of LS alone at this time point.
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Affiliation(s)
- Anaïs Corma-Gómez
- Grupo de Virología Clínica e ITS Cinical Virology and STIs Group, Unit of Infectious Diseases and Microbiology, de Hospital Universitario Virgen de Valme, Sevilla, Spain
- Instituto de Biomedicina de Sevilla (IBiS)/CSIC, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Diana Corona-Mata
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Clinical Virology and Zoonoses Research Group, Unit of Infectious Diseases, Hospital Universitario Reina Sofía, Córdoba, Spain
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Universidad de Córdoba (UCO), Córdoba, Spain
| | - Jésica Martín-Carmona
- Grupo de Virología Clínica e ITS Cinical Virology and STIs Group, Unit of Infectious Diseases and Microbiology, de Hospital Universitario Virgen de Valme, Sevilla, Spain
- Instituto de Biomedicina de Sevilla (IBiS)/CSIC, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Universidad de Sevilla (US), Sevilla, Spain
| | - María José Galindo
- Unit of Infectious Diseases, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain
| | - Angela Camacho
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Clinical Virology and Zoonoses Research Group, Unit of Infectious Diseases, Hospital Universitario Reina Sofía, Córdoba, Spain
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Universidad de Córdoba (UCO), Córdoba, Spain
| | - Carmen Martín-Sierra
- Grupo de Virología Clínica e ITS Cinical Virology and STIs Group, Unit of Infectious Diseases and Microbiology, de Hospital Universitario Virgen de Valme, Sevilla, Spain
- Instituto de Biomedicina de Sevilla (IBiS)/CSIC, Sevilla, Spain
| | - Marina Gallo-Marín
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Clinical Virology and Zoonoses Research Group, Unit of Infectious Diseases, Hospital Universitario Reina Sofía, Córdoba, Spain
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Universidad de Córdoba (UCO), Córdoba, Spain
| | - Pilar Rincón
- Grupo de Virología Clínica e ITS Cinical Virology and STIs Group, Unit of Infectious Diseases and Microbiology, de Hospital Universitario Virgen de Valme, Sevilla, Spain
| | - Ignacio Perez-Valero
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Clinical Virology and Zoonoses Research Group, Unit of Infectious Diseases, Hospital Universitario Reina Sofía, Córdoba, Spain
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Universidad de Córdoba (UCO), Córdoba, Spain
| | - Margarita Pérez-García
- Grupo de Virología Clínica e ITS Cinical Virology and STIs Group, Unit of Infectious Diseases and Microbiology, de Hospital Universitario Virgen de Valme, Sevilla, Spain
| | - Angela Carrasco-Dorado
- Clinical Virology and Zoonoses Research Group, Unit of Infectious Diseases, Hospital Universitario Reina Sofía, Córdoba, Spain
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Universidad de Córdoba (UCO), Córdoba, Spain
| | - Juan A Pineda
- Grupo de Virología Clínica e ITS Cinical Virology and STIs Group, Unit of Infectious Diseases and Microbiology, de Hospital Universitario Virgen de Valme, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Universidad de Sevilla (US), Sevilla, Spain
| | - Antonio Rivero-Juárez
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Clinical Virology and Zoonoses Research Group, Unit of Infectious Diseases, Hospital Universitario Reina Sofía, Córdoba, Spain
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Universidad de Córdoba (UCO), Córdoba, Spain
| | - Antonio Rivero
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Clinical Virology and Zoonoses Research Group, Unit of Infectious Diseases, Hospital Universitario Reina Sofía, Córdoba, Spain
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Universidad de Córdoba (UCO), Córdoba, Spain
| | - Luis M Real
- Grupo de Virología Clínica e ITS Cinical Virology and STIs Group, Unit of Infectious Diseases and Microbiology, de Hospital Universitario Virgen de Valme, Sevilla, Spain
- Instituto de Biomedicina de Sevilla (IBiS)/CSIC, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Universidad de Sevilla (US), Sevilla, Spain
| | - Juan Macías
- Grupo de Virología Clínica e ITS Cinical Virology and STIs Group, Unit of Infectious Diseases and Microbiology, de Hospital Universitario Virgen de Valme, Sevilla, Spain
- Instituto de Biomedicina de Sevilla (IBiS)/CSIC, Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Universidad de Sevilla (US), Sevilla, Spain
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Elgretli W, Shengir M, Sasson S, Ramanakumar AV, Cinque F, Ballestreros LER, Deschenes M, Wong P, Chen T, Kronfli N, Saeed S, Keeshan A, Tandon S, Cooper C, Sebastiani G. Association of MASLD Phenotypes With Liver Fibrosis in Hepatitis C: The Role of Cardiometabolic Risk Factors. J Viral Hepat 2025; 32:e70004. [PMID: 39868661 PMCID: PMC11771651 DOI: 10.1111/jvh.70004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/08/2025] [Accepted: 01/12/2025] [Indexed: 01/28/2025]
Abstract
Steatotic liver disease is prevalent among people with hepatitis C virus (HCV). The new definition of metabolic dysfunction-associated steatotic liver disease (MASLD) emphasises the metabolic drivers of steatosis and recognises its frequent coexistence with other chronic liver diseases, including HCV. We aimed to evaluate the association of coexisting MASLD and HCV with liver fibrosis. Individuals with HCV who underwent transient elastography (TE) with associated controlled attenuation parameter (CAP) were included from two clinical centres. MASLD and significant liver fibrosis were defined as the presence of steatosis (CAP ≥ 275 dB/m) with at least one cardiometabolic risk factor, and liver stiffness measurement (LSM) ≥ 7.1 kPa measured by TE, respectively. Associated cofactors of significant liver fibrosis were determined using stepwise regression and cross-validation by LASSO models to select confounders. Among 590 participants, 31% were diagnosed with MASLD. The prevalence of significant liver fibrosis was the highest among people with MASLD (58%) followed by HCV-related steatosis (45%) and the non-steatosis group (39%). After adjusting for potential confounders, MASLD was associated with significant liver fibrosis (adjusted odds ratio [aOR] 2.29, 95% confidence interval [CI] 1.07-4.87). Furthermore, specific MASLD phenotypes including diabetes, hypertension and overweight were associated with significant liver fibrosis, with aORs of 4.76 (95% CI 2.16-10.49), 3.44 (95% CI 1.77-6.68) and 2.54 (95% CI 1.27-5.07), respectively. In conclusion, MASLD is associated with liver fibrosis in people with HCV, specifically the diabetes, overweight and hypertensive phenotypes. Beyond pursuing a virological cure, healthcare providers should prioritise managing metabolic conditions, particularly diabetes, hypertension and obesity.
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Affiliation(s)
- Wesal Elgretli
- Division of Experimental MedicineMcGill UniversityMontrealQuebecCanada
| | - Mohamed Shengir
- Division of Experimental MedicineMcGill UniversityMontrealQuebecCanada
| | - Solomon Sasson
- Department of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | | | - Felice Cinque
- Department of PathophysiologyTransplantation University of MilanMilanItaly
- Chronic Viral Illness Service, Division of Infectious Diseases, Department of MedicineMcGill University Health CentreMontrealQuebecCanada
| | - Luz Esther Ramos Ballestreros
- Chronic Viral Illness Service, Division of Infectious Diseases, Department of MedicineMcGill University Health CentreMontrealQuebecCanada
| | - Marc Deschenes
- Division of Gastroenterology and Hepatology, Department of MedicineMcGill University Health CentreMontrealQuebecCanada
| | - Phil Wong
- Division of Gastroenterology and Hepatology, Department of MedicineMcGill University Health CentreMontrealQuebecCanada
| | - Tianyan Chen
- Division of Gastroenterology and Hepatology, Department of MedicineMcGill University Health CentreMontrealQuebecCanada
| | - Nadine Kronfli
- Chronic Viral Illness Service, Division of Infectious Diseases, Department of MedicineMcGill University Health CentreMontrealQuebecCanada
- Centre for Outcomes Research and EvaluationResearch Institute of the McGill University Health CentreMontrealQuebecCanada
| | - Sahar Saeed
- Public Health SciencesQueen's UniversityKingstonOntarioCanada
| | - Alexa Keeshan
- Division of Infectious Diseases, Department of MedicineOttawa Hospital Research Institute, The Ottawa HospitalOttawaOntarioCanada
| | - Saniya Tandon
- Division of Infectious Diseases, Department of MedicineOttawa Hospital Research Institute, The Ottawa HospitalOttawaOntarioCanada
| | - Curtis Cooper
- Division of Infectious Diseases, Department of MedicineOttawa Hospital Research Institute, The Ottawa HospitalOttawaOntarioCanada
| | - Giada Sebastiani
- Division of Experimental MedicineMcGill UniversityMontrealQuebecCanada
- Chronic Viral Illness Service, Division of Infectious Diseases, Department of MedicineMcGill University Health CentreMontrealQuebecCanada
- Division of Gastroenterology and Hepatology, Department of MedicineMcGill University Health CentreMontrealQuebecCanada
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5
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Hui RWH, Mak LY. MASLD after hepatitis C virus eradication: Do not overlook the cardiometabolic risk factors: Editorial on "Dynamic change of metabolic dysfunction-associated steatotic liver disease in chronic hepatitis C patients after viral eradication: A nationwide registry study in Taiwan". Clin Mol Hepatol 2025; 31:290-292. [PMID: 39901340 PMCID: PMC11791562 DOI: 10.3350/cmh.2024.0630] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 08/07/2024] [Indexed: 02/05/2025] Open
Affiliation(s)
- Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
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Radmanic Matotek L, Zidovec-Lepej S, Salek N, Vince A, Papic N. The Impact of Liver Steatosis on Interleukin and Growth Factors Kinetics during Chronic Hepatitis C Treatment. J Clin Med 2024; 13:4849. [PMID: 39200991 PMCID: PMC11355301 DOI: 10.3390/jcm13164849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 08/02/2024] [Accepted: 08/15/2024] [Indexed: 09/02/2024] Open
Abstract
Background/Objectives: Various biological response modifiers play important roles in the immunopathogenesis of chronic hepatitis C (CHC). While serum levels of cytokines and growth factors change with the disease severity and treatment responses, the impact of concomitant liver steatosis on systemic inflammatory response is largely unknown. The aim of this study was to analyze the characteristics and kinetics of serum profiles of interleukins and growth factors in CHC patients with steatotic liver disease (SLD). Methods: Serum concentrations of 12 cytokines (IL-5, IL-13, IL-2, IL-6, IL-9, IL-10, IFN-γ, TNF-α, IL-17A, IL-17F, IL-4 and IL-22) and 6 growth factors (Angiopoietin-2, EGF, EPO, HGF, SCF, VEGF) were analyzed in 56 CHC patients at four time points (baseline, week 4, week 8 and SVR12) with bead-based flow cytometry assay. Results: At baseline, patients with SLD had significantly lower IL-9, IL-10, IL-13 and IL-22 and higher serum concentrations of EGF, VEGF and ANG. In a subgroup of patients with advanced liver fibrosis, SLD was linked with lower serum concentrations of IL-4, IL-5, IL-9, IL-10, IL-13 and IL-22 and higher concentrations of HGH and VEGF. Distinct cytokine kinetics during DAA treatment was observed, and SLD was identified as the main source of variation for IL-5, IL-9, IL-10, IL-13, IL-17A, IL-22, EGF, VEGF and ANG. Patients with SLD at SVR12 had significantly higher VEGF and HGF serum concentrations. Conclusions: SLD is associated with distinct cytokine and growth factor profiles and kinetics during CHC treatment, which might be associated with disease severity and the capacity for liver regeneration and contribute to fibrosis persistence.
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Affiliation(s)
- Leona Radmanic Matotek
- Department of Immunological and Molecular Diagnostics, University Hospital for Infectious Diseases “Dr. Fran Mihaljević”, 10000 Zagreb, Croatia; (L.R.M.); (S.Z.-L.)
| | - Snjezana Zidovec-Lepej
- Department of Immunological and Molecular Diagnostics, University Hospital for Infectious Diseases “Dr. Fran Mihaljević”, 10000 Zagreb, Croatia; (L.R.M.); (S.Z.-L.)
| | - Nikolina Salek
- Department for Viral Hepatitis, University Hospital for Infectious Diseases “Dr. Fran Mihaljević”, 10000 Zagreb, Croatia; (N.S.); (A.V.)
| | - Adriana Vince
- Department for Viral Hepatitis, University Hospital for Infectious Diseases “Dr. Fran Mihaljević”, 10000 Zagreb, Croatia; (N.S.); (A.V.)
| | - Neven Papic
- Department for Viral Hepatitis, University Hospital for Infectious Diseases “Dr. Fran Mihaljević”, 10000 Zagreb, Croatia; (N.S.); (A.V.)
- Department for Infectious Diseases, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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7
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Ricchi P, Pistoia L, Positano V, Spasiano A, Casini T, Putti MC, Borsellino Z, Cossu A, Messina G, Keilberg P, Fatigati C, Costantini S, Renne S, Peritore G, Cademartiri F, Meloni A. Liver steatosis in patients with transfusion-dependent thalassaemia. Br J Haematol 2024; 204:2458-2467. [PMID: 38685724 DOI: 10.1111/bjh.19496] [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: 01/15/2024] [Accepted: 04/17/2024] [Indexed: 05/02/2024]
Abstract
We evaluated the prevalence and the clinical associations of liver steatosis (LS) in patients with transfusion-dependent thalassaemia (TDT). We considered 301 TDT patients (177 females, median age = 40.61 years) enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 25 healthy subjects. Magnetic resonance imaging was used to quantify iron overload and hepatic fat fraction (FF) by T2* technique and cardiac function by cine images. The glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Hepatic FF was significantly higher in TDT patients than in healthy subjects (median value: 1.48% vs. 0.55%; p = 0.013). In TDT, hepatic FF was not associated with age, gender, serum ferritin levels or liver function parameters, but showed a weak inverse correlation with high-density lipoprotein cholesterol. The 36.4% of TDT patients showed LS (FF >3.7%). Active hepatitis C virus (HCV) infection, increased body mass index and hepatic iron were independent determinants of LS. A hepatic FF >3.53% predicted the presence of an abnormal OGTT. Hepatic FF was not correlated with cardiac iron, biventricular volumes or ejection fractions, but was correlated with left ventricular mass index. In TDT, LS is a frequent finding, associated with iron overload, increased weight and HCV, and conveying an increased risk for the alterations of glucose metabolism.
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Affiliation(s)
- Paolo Ricchi
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli", Napoli, Italy
| | - Laura Pistoia
- U.O.C. Ricerca Clinica, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Vincenzo Positano
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Anna Spasiano
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli", Napoli, Italy
| | - Tommaso Casini
- Oncologia, Ematologia e Trapianto di Cellule Staminali Emopoietiche, Meyer Children's Hospital IRCCS, Firenze, Italy
| | - Maria Caterina Putti
- Dipartimento Della Salute Della Donna e del Bambino, Clinica di Emato-Oncologia Pediatrica, Azienda Ospedaliero-Università di Padova, Padova, Italy
| | - Zelia Borsellino
- Unità Operativa Complessa Ematologia Con Talassemia, ARNAS Civico "Benfratelli-Di Cristina", Palermo, Italy
| | - Antonella Cossu
- Servizio Immunoematologia e Medicina Trasfusionale - Dipartimento Dei Servizi, Presidio Ospedaliero "San Francesco" ASL Nuoro, Nuoro, Italy
| | - Giuseppe Messina
- Centro Microcitemie, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy
| | - Petra Keilberg
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Carmina Fatigati
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli", Napoli, Italy
| | - Silvia Costantini
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli", Napoli, Italy
| | - Stefania Renne
- Struttura Complessa di Cardioradiologia-UTIC, Presidio Ospedaliero "Giovanni Paolo II", Lamezia Terme, Italy
| | - Giuseppe Peritore
- Unità Operativa Complessa di Radiologia, ARNAS Civico "Benfratelli-Di Cristina", Palermo, Italy
| | - Filippo Cademartiri
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Antonella Meloni
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
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8
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Hsu WF, Lai HC, Chen SH, Su WP, Wang HW, Chen HY, Huang GT, Peng CY. Effect of metabolic dysfunction on the risk of liver-related events in patients cured of hepatitis C virus. Am J Cancer Res 2024; 14:1914-1925. [PMID: 38726283 PMCID: PMC11076252 DOI: 10.62347/eqir8735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 04/15/2024] [Indexed: 05/12/2024] Open
Abstract
The impact of metabolic dysfunction or metabolic dysfunction-associated fatty liver disease (MAFLD) on liver-related events (LREs) in patients with chronic hepatitis C (CHC) who had achieved a sustained virologic response (SVR) to direct-acting antiviral agents (DAAs) is unknown. A total of 924 patients with cured CHC and documented body mass index (BMI) were included in the analysis, and the data period was from September 2012 to April 2022. Hepatic steatosis was identified either through ultrasonography or blood biomarkers. Metabolic dysfunction was defined as the presence of overweight or obesity (BMI ≥ 23 kg/m2), type 2 diabetes mellitus (DM), and metabolic dysregulation. Patients may have more than one metabolic dysfunction. Variables at 12 or 24 weeks after DAA therapy (PW12) were used to identify predictors of LREs. The median age of the 924 patients was 58 (49-65) years. Of the participants, 418 (45.2%) were male. The median BMI was 24.01 (21.78-26.73) kg/m2, and 174 (18.8%) patients had DM. A multivariable Cox regression analysis revealed that age, male, albumin, total bilirubin, alpha-fetoprotein (AFP), metabolic dysfunction (hazard ratio: 1.709, 95% confidence interval: 1.128-2.591, P = .011), and FIB-4 > 3.25 were independent predictors of LREs. Type 2 DM and metabolic dysregulation exhibited a larger time-dependent area under the receiver operating characteristic curve for LREs than did overweight or obesity. Moreover, metabolic dysfunction was identified to be an independent predictor of hepatocellular carcinoma. Metabolic dysfunction increased the risk of LREs and HCC in patients with CHC who had achieved an SVR to DAA therapy.
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Affiliation(s)
- Wei-Fan Hsu
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University HospitalTaichung, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical UniversityTaichung, Taiwan
- School of Chinese Medicine, China Medical UniversityTaichung, Taiwan
| | - Hsueh-Chou Lai
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University HospitalTaichung, Taiwan
- School of Chinese Medicine, China Medical UniversityTaichung, Taiwan
| | - Sheng-Hung Chen
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University HospitalTaichung, Taiwan
- School of Medicine, China Medical UniversityTaichung, Taiwan
| | - Wen-Pang Su
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University HospitalTaichung, Taiwan
| | - Hung-Wei Wang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University HospitalTaichung, Taiwan
- School of Medicine, China Medical UniversityTaichung, Taiwan
| | - Hung-Yao Chen
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University HospitalTaichung, Taiwan
| | - Guan-Tarn Huang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University HospitalTaichung, Taiwan
- School of Medicine, China Medical UniversityTaichung, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University HospitalTaichung, Taiwan
- School of Medicine, China Medical UniversityTaichung, Taiwan
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9
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Shojaeian A, Nakhaie M, Amjad ZS, Boroujeni AK, Shokri S, Mahmoudvand S. Leveraging metformin to combat hepatocellular carcinoma: its therapeutic promise against hepatitis viral infections. JOURNAL OF CANCER METASTASIS AND TREATMENT 2024. [DOI: 10.20517/2394-4722.2023.147] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Hepatocellular carcinoma (HCC) is categorized among the most common primary malignant liver cancer and a primary global cause of death from cancer. HCC tends to affect males 2-4 times more than females in many nations. The main factors that raise the incidence of HCC are chronic liver diseases, hepatotropic viruses like hepatitis B (HBV) and C (HCV), non-alcoholic fatty liver disease, exposure to toxins like aflatoxin, and non-alcoholic steatohepatitis (NASH). Among these, hepatitis B and C are the most prevalent causes of chronic hepatitis globally. Metformin, which is made from a naturally occurring compound called galegine, derived from the plant Galega officinalis (G. officinalis ), has been found to exhibit antitumor effects in a wide range of malignancies, including HCC. In fact, compared to patients on sulphonylureas or insulin, studies have demonstrated that metformin treatment significantly lowers the risk of HCC in patients with chronic liver disease. This article will first describe the molecular mechanism of hepatitis B and C viruses in the development of HCC. Then, we will provide detailed explanations about metformin, followed by a discussion of the association between metformin and hepatocellular carcinoma caused by the viruses mentioned above.
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10
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Fernandez CJ, Alkhalifah M, Afsar H, Pappachan JM. Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Viral Hepatitis: The Interlink. Pathogens 2024; 13:68. [PMID: 38251375 PMCID: PMC10821334 DOI: 10.3390/pathogens13010068] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 01/23/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one-third of the global population and has become the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) remain significant challenges to liver health even in the 21st century. The co-existence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. A thorough understanding of the pathobiological interactions between MAFLD and these two chronic viral infections is crucial for appropriately managing these patients. In this comprehensive clinical review, we discuss the various mechanisms of chronic viral hepatitis-mediated metabolic dysfunction and the impact of MAFLD on the progression of liver disease.
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Affiliation(s)
- Cornelius J. Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, UK;
| | - Mohammed Alkhalifah
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Department of Family Medicine and Polyclinics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia
- University Diabetes Center, King Saud University Medical City, King Saud University, Riyadh 11411, Saudi Arabia
| | - Hafsa Afsar
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
| | - Joseph M. Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, UK
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, UK
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11
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Du Y, Khera T, Liu Z, Tudrujek-Zdunek M, Dworzanska A, Cornberg M, Xu CJ, Tomasiewicz K, Wedemeyer H. Controlled Attenuation Parameter Is Associated with a Distinct Systemic Inflammatory Milieu after Clearance of HCV Infection. Biomedicines 2023; 11:1529. [PMID: 37371624 DOI: 10.3390/biomedicines11061529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/15/2023] [Accepted: 05/17/2023] [Indexed: 06/29/2023] Open
Abstract
Hepatitis C virus (HCV) infection is closely associated with lipid metabolism defects along with a high prevalence of hepatic steatosis. After HCV clearance, steatosis persists in many patients. However, the reasons behind this phenomenon are not completely clear. To investigate the association between 92 soluble inflammatory mediators (SIMs) and the steatosis grade, we made use of a cohort of 94 patients with chronic HCV infection who cleared HCV after direct-acting antiviral agent (DAA) treatment. Patients were classified into three groups according to their controlled attenuation parameter (CAP). CAP is associated with ALT, γ-GT and liver stiffness after HCV clearance. While stem cell factor (SCF) and tumor necrosis factor ligand superfamily member 12 (TWEAK) levels were significantly reduced in patients with CAP > 299 dB/m, the levels of fibroblast growth factor (FGF)-21 and interleukin-18 receptor 1 (IL-18R1) were higher in those patients at week 96 after virus clearance. These four markers also showed a linear correlation with CAP values. FGF-21 levels correlated with CAP only after HCV clearance. Taken together, these four biomarkers, namely SCF, TWEAK, FGF-21 and IL-18R1, are associated with CAP status after virus clearance. A potential role of these proteins in the pathogenesis of post-sustained viral response (SVR) nonalcoholic steatohepatitis requires further investigation.
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Affiliation(s)
- Yanqin Du
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
- Department of Infectious Diseases, Union Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Tanvi Khera
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
- International AIDS Vaccine Initiative (IAVI), 122002 Gurugram, Haryana, India
| | - Zhaoli Liu
- Centre for Individualized Infection Medicine (CiiM), a Joint Venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), 30625 Hannover, Germany
- TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Centre for Infection Research (HZI) and the Hannover Medical School (MHH), 30625 Hannover, Germany
| | | | - Anna Dworzanska
- Department of Infectious Diseases, Medical University of Lublin, 20-081 Lublin, Poland
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
- TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Centre for Infection Research (HZI) and the Hannover Medical School (MHH), 30625 Hannover, Germany
| | - Cheng-Jian Xu
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
- Centre for Individualized Infection Medicine (CiiM), a Joint Venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), 30625 Hannover, Germany
- TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Centre for Infection Research (HZI) and the Hannover Medical School (MHH), 30625 Hannover, Germany
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Krzysztof Tomasiewicz
- Department of Infectious Diseases, Medical University of Lublin, 20-081 Lublin, Poland
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
- Excellence Cluster Resist, Hannover Medical School, 30625 Hannover, Germany
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12
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Yip TCF, Vilar-Gomez E, Petta S, Yilmaz Y, Wong GLH, Adams LA, de Lédinghen V, Sookoian S, Wong VWS. Geographical similarity and differences in the burden and genetic predisposition of NAFLD. Hepatology 2023; 77:1404-1427. [PMID: 36062393 DOI: 10.1002/hep.32774] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 08/28/2022] [Accepted: 09/01/2022] [Indexed: 12/13/2022]
Abstract
NAFLD has become a major public health problem for more than 2 decades with a growing prevalence in parallel with the epidemic of obesity and type 2 diabetes (T2D). The disease burden of NAFLD differs across geographical regions and ethnicities. Variations in prevalence of metabolic diseases, extent of urban-rural divide, dietary habits, lifestyles, and the prevalence of NAFLD risk and protective alleles can contribute to such differences. The rise in NAFLD has led to a remarkable increase in the number of cases of cirrhosis, hepatocellular carcinoma, hepatic decompensation, and liver-related mortality related to NAFLD. Moreover, NAFLD is associated with multiple extrahepatic manifestations. Most of them are risk factors for the progression of liver fibrosis and thus worsen the prognosis of NAFLD. All these comorbidities and complications affect the quality of life in subjects with NAFLD. Given the huge and growing size of the population with NAFLD, it is expected that patients, healthcare systems, and the economy will suffer from the ongoing burden related to NAFLD. In this review, we examine the disease burden of NAFLD across geographical areas and ethnicities, together with the distribution of some well-known genetic variants for NAFLD. We also describe some special populations including patients with T2D, lean patients, the pediatric population, and patients with concomitant liver diseases. We discuss extrahepatic outcomes, patient-reported outcomes, and economic burden related to NAFLD.
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Affiliation(s)
- Terry Cheuk-Fung Yip
- Medical Data Analytics Center, Department of Medicine and Therapeutics , The Chinese University of Hong Kong , Hong Kong
- State Key Laboratory of Digestive Disease , The Chinese University of Hong Kong , Hong Kong
| | - Eduardo Vilar-Gomez
- Division of Gastroenterology and Hepatology, Department of Medicine , Indiana University School of Medicine , Indianapolis , Indiana , USA
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE) , University of Palermo , Palermo , Italy
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine , Recep Tayyip Erdogan University , Rize , Turkey
- Liver Research Unit , Institute of Gastroenterology , Marmara University , Istanbul , Turkey
| | - Grace Lai-Hung Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics , The Chinese University of Hong Kong , Hong Kong
- State Key Laboratory of Digestive Disease , The Chinese University of Hong Kong , Hong Kong
| | - Leon A Adams
- Department of Hepatology , Sir Charles Gairdner Hospital , Perth , Australia
- Medical School , University of Western Australia , Perth , Australia
| | - Victor de Lédinghen
- Hepatology Unit , Hôpital Haut Lévêque, Bordeaux University Hospital , Bordeaux , France
- INSERM U1312 , Bordeaux University , Bordeaux , France
| | - Silvia Sookoian
- School of Medicine, Institute of Medical Research A Lanari , University of Buenos Aires , Ciudad Autónoma de Buenos Aires , Argentina
- Department of Clinical and Molecular Hepatology, Institute of Medical Research (IDIM) , National Scientific and Technical Research Council (CONICET), University of Buenos Aires , Ciudad Autónoma de Buenos Aires , Argentina
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics , The Chinese University of Hong Kong , Hong Kong
- State Key Laboratory of Digestive Disease , The Chinese University of Hong Kong , Hong Kong
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13
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Chemerin and Chemokine-like Receptor 1 Expression Are Associated with Hepatocellular Carcinoma Progression in European Patients. Biomedicines 2023; 11:biomedicines11030737. [PMID: 36979716 PMCID: PMC10044805 DOI: 10.3390/biomedicines11030737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 02/22/2023] [Accepted: 02/27/2023] [Indexed: 03/05/2023] Open
Abstract
The chemoattractant protein chemerin is protective in experimental hepatocellular carcinoma (HCC), and high expression in HCC tissues of Asian patients was related to a favorable prognosis. Studies from Asia found reduced expression of chemerin in HCC compared to para-tumor tissues while our previous analysis observed the opposite. Aim of this study was to correlate chemerin expression in HCC tissues with disease severity of European patients Hepatocyte chemerin protein expression was assessed by immunohistochemistry in HCC tissue of 383 patients, and was low in 24%, moderate in 49% and high in 27%. High chemerin protein in the HCC tissues was related to the T stage, vessel invasion, histologic grade, Union for International Cancer Control (UICC) stage and tumor size. Chemokine-like receptor 1 (CMKLR1) is a functional chemerin receptor. CMKLR1 protein in hepatocytes was low expressed in HCC tissues of 36%, moderate in tissues of 32% and high in 32% of the HCCs. Tumor CMKLR1 was associated with the T stage, vessel invasion, histologic grade and UICC stage. Notably, sex-specific analysis revealed that associations of chemerin and CMKLR1 expression with HCC progression were significant in males but not in females. The tumor chemerin and CMKLR1 protein expression were not related to steatosis, inflammation and fibrosis grades. In summary, chemerin as well as CMKLR1 protein were related to disease severity of European HCC patients, and this was significant in males. This observation is in contrast to Asian patients where higher chemerin in the tumors was protective. Current analysis provides evidence for ethnicity and sex-related differences of tumor expressed chemerin and HCC severity.
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14
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Expression and Function of BMP and Activin Membrane-Bound Inhibitor (BAMBI) in Chronic Liver Diseases and Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:ijms24043473. [PMID: 36834884 PMCID: PMC9964332 DOI: 10.3390/ijms24043473] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) is a transmembrane pseudoreceptor structurally related to transforming growth factor (TGF)-β type 1 receptors (TGF-β1Rs). BAMBI lacks a kinase domain and functions as a TGF-β1R antagonist. Essential processes such as cell differentiation and proliferation are regulated by TGF-β1R signaling. TGF-β is the best-studied ligand of TGF-βRs and has an eminent role in inflammation and fibrogenesis. Liver fibrosis is the end stage of almost all chronic liver diseases, such as non-alcoholic fatty liver disease, and at the moment, there is no effective anti-fibrotic therapy available. Hepatic BAMBI is downregulated in rodent models of liver injury and in the fibrotic liver of patients, suggesting that low BAMBI has a role in liver fibrosis. Experimental evidence convincingly demonstrated that BAMBI overexpression is able to protect against liver fibrosis. Chronic liver diseases have a high risk of hepatocellular carcinoma (HCC), and BAMBI was shown to exert tumor-promoting as well as tumor-protective functions. This review article aims to summarize relevant studies on hepatic BAMBI expression and its role in chronic liver diseases and HCC.
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15
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Chee D, Ng CH, Chan KE, Huang DQ, Teng M, Muthiah M. The Past, Present, and Future of Noninvasive Test in Chronic Liver Diseases. Med Clin North Am 2023; 107:397-421. [PMID: 37001944 DOI: 10.1016/j.mcna.2022.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
Chronic liver disease is a major global health threat and is the 11th leading cause of death globally. A liver biopsy is frequently required in assessing the degree of steatosis and fibrosis, information that is important in diagnosis, management, and prognostication. However, liver biopsies have limitations and carry a considerable risk, leading to the development of various modalities of noninvasive testing tools. These tools have been developed in recent years and have improved markedly in diagnostic accuracy. Moving forward, they may change the practice of hepatology.
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Affiliation(s)
- Douglas Chee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore
| | - Cheng Han Ng
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore
| | - Kai En Chan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore
| | - Daniel Q Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore; National University Centre for Organ Transplantation, National University Health System, Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore
| | - Margaret Teng
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore; National University Centre for Organ Transplantation, National University Health System, Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore; National University Centre for Organ Transplantation, National University Health System, Tower Block Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore.
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16
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Schelbert S, Schindeldecker M, Drebber U, Witzel HR, Weinmann A, Dries V, Schirmacher P, Roth W, Straub BK. Lipid Droplet-Associated Proteins Perilipin 1 and 2: Molecular Markers of Steatosis and Microvesicular Steatotic Foci in Chronic Hepatitis C. Int J Mol Sci 2022; 23:ijms232415456. [PMID: 36555099 PMCID: PMC9778710 DOI: 10.3390/ijms232415456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/29/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Chronic infection with hepatitis C (HCV) is a major risk factor in the development of cirrhosis and hepatocellular carcinoma. Lipid metabolism plays a major role in the replication and deposition of HCV at lipid droplets (LDs). We have demonstrated the importance of LD-associated proteins of the perilipin family in steatotic liver diseases. Using a large collection of 231 human liver biopsies with HCV, perilipins 1 and 2 have been localized to LDs of hepatocytes that correlate with the degree of steatosis and specific HCV genotypes, but not significantly with the HCV viral load. Perilipin 1- and 2-positive microvesicular steatotic foci were observed in 36% of HCV liver biopsies, and also in chronic hepatitis B, autoimmune hepatitis and mildly steatotic or normal livers, but less or none were observed in normal livers of younger patients. Microvesicular steatotic foci did not frequently overlap with glycogenotic/clear cell foci as determined by PAS stain in serial sections. Steatotic foci were detected in all liver zones with slight architectural disarrays, as demonstrated by immunohistochemical glutamine synthetase staining of zone three, but without elevated Ki67-proliferation rates. In conclusion, microvesicular steatotic foci are frequently found in chronic viral hepatitis, but the clinical significance of these foci is so far not clear.
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Affiliation(s)
- Selina Schelbert
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
- Institute of Pathology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
| | | | - Uta Drebber
- Institute of Pathology, University Clinic Cologne, 50931 Cologne, Germany
| | - Hagen Roland Witzel
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
| | - Arndt Weinmann
- Department of Internal Medicine, University Medical Center, 55131 Mainz, Germany
| | - Volker Dries
- Institute of Pathology, University Clinic Cologne, 50931 Cologne, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Medical Center Heidelberg, 69120 Heidelberg, Germany
| | - Wilfried Roth
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
| | - Beate Katharina Straub
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
- Correspondence: ; Tel.: +49-6131-17-7307
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17
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Kim RG, Chu JN, Vittinghoff E, Deng J, Reaso JN, Grenert JP, Khalili M. Racial/ethnic differences in fibrosis prevalence and progression in biopsy-proven steatosis: A focus on the Asian American population. Hepatol Commun 2022; 6:3024-3035. [PMID: 36087033 PMCID: PMC9592793 DOI: 10.1002/hep4.2078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 06/10/2022] [Accepted: 08/01/2022] [Indexed: 12/14/2022] Open
Abstract
Fatty liver disease (FLD) is a leading cause of chronic liver disease (CLD) globally, and vulnerable populations are disproportionately affected. Prior studies have suggested racial/ethnic differences in FLD prevalence and severity; however, these studies often excluded Asian Americans. This study aims to evaluate racial/ethnic differences in the prevalence of, and predictors associated with steatohepatitis, advanced fibrosis, and fibrosis progression over time within a diverse population. Using descriptive analyses and multivariable modeling, we performed a longitudinal evaluation of 648 patients with histologic evidence of FLD (steatosis or steatohepatitis) from August 2009 to February 2020 within San Francisco's safety-net health care system. Overall demographics were median age of 53 years, 54% male, and 38% Asian (40% Hispanic, 14% White). On histology, 61% had steatohepatitis and 30% had advanced fibrosis (≥F3). The comparison between steatosis and steatohepatitis groups showed differences in sex, race/ethnicity, metabolic risk factors, and co-existing CLD (predominantly viral hepatitis); patients with steatosis were more likely to be Asian (50%), and those with steatohepatitis were more likely to be Hispanic (51%). On multivariable modeling, while Asian race (vs. non-Asian) was not associated with steatohepatitis or advanced fibrosis when models included all relevant clinical predictors, Asian race was associated with higher relative risk of fibrosis progression as defined by change in Fibrosis-4 category over time (relative risk ratio = 1.9; p = 0.047). Conclusion: In this vulnerable population with a large proportion of Asian Americans, Asian race was associated with progression of fibrosis. Given the relative paucity of data in this high-risk group, future studies should confirm these findings.
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Affiliation(s)
- Rebecca G. Kim
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Division of Gastroenterology and HepatologyZuckerberg San Francisco GeneralSan FranciscoCaliforniaUSA
| | - Janet N. Chu
- Division of General Internal MedicineDepartment of MedicineUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
| | - Eric Vittinghoff
- Department of Epidemiology and BiostatisticsUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
| | - Jasmine Deng
- David Geffen School of Medicine at University of California, Los AngelesLos AngelesCaliforniaUSA
| | - Jewel N. Reaso
- Division of Gastroenterology and HepatologyZuckerberg San Francisco GeneralSan FranciscoCaliforniaUSA
| | - James P. Grenert
- Division of Surgical PathologyDepartment of Pathology and Laboratory MedicineUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Liver CenterUniversity of California San FranciscoSan FranciscoCaliforniaUSA
| | - Mandana Khalili
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
- Division of Gastroenterology and HepatologyZuckerberg San Francisco GeneralSan FranciscoCaliforniaUSA
- Liver CenterUniversity of California San FranciscoSan FranciscoCaliforniaUSA
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18
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El Ray A, Paradis V, Montasser A, Elghannam M, Shemis M, Nessim I, Abu-Taleb H, Asselah T, Mohamed A, Poté N, Akl M, Marcellin P. Usefulness of the SAF score to characterize NAFLD/NASH in non-cirrhotic HCV patients. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00209-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The SAF score (steatosis, activity, and fibrosis) has been developed for the assessment of the histological severity of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The aim of this study was to assess the usefulness of the SAF score in a homogenous cohort of Egyptian patients with chronic HCV infection (CHC) without any alcohol consumption and without cirrhosis. We performed a prospective cross-sectional study including 70 consecutive Egyptian patients with chronic HCV infection to assess the usefulness of the SAF score to characterize NAFLD/NASH in non-cirrhotic HCV patients. The inclusion criteria included positive serum anti-HCV IgG antibody and positive HCVRNA, absence of treatment, and absence of cirrhosis (fibrosis score < F4). Patients were divided into two groups: with metabolic syndrome (MS) and without metabolic syndrome (non-MS). All patients were exposed to thorough history taking, full clinical examination, and laboratory and ultrasound assessment. Histopathologic evaluation of the liver biopsy for the assessment of steatosis, activity, grade, and fibrosis stage was assessed by 2 pathologists with experience in liver diseases.
Results
We found that the degree of fibrosis increases with aging. Liver biopsies from CHC patients with metabolic syndrome (MS) exhibited a significantly higher stage of fibrosis than biopsies from those without MS; however, the grade of inflammation did not differ significantly between the two groups. No significant correlation was found between the SAF score and the body mass index (BMI) or serum HCV RNA. No significant relation between SAF score, fibrosis, and MS. No significant relation was found between the MS and the level of HCV viremia.
Conclusion
We concluded that steatosis was associated with the fibrosis stage, independently of MS. This suggests that in this population, steatosis might be more related to HCV infection than to NAFLD and that fibrosis progression might be related, at least in part, to the steatosis process, i.e., virus-associated fatty liver disease (VAFLD).
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19
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Agnetti J, Desterke C, Gassama-Diagne A. Impact of HCV Infection on Hepatocyte Polarity and Plasticity. Pathogens 2022; 11:pathogens11030337. [PMID: 35335661 PMCID: PMC8955246 DOI: 10.3390/pathogens11030337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/23/2022] [Accepted: 03/07/2022] [Indexed: 02/01/2023] Open
Abstract
The hepatitis C virus (HCV) is an oncogenic virus that alters the cell polarization machinery in order to enter the hepatocyte and replicate. While these alterations are relatively well defined, their consequences in the evolution of the disease remain poorly documented. Since 2012, HCV infection can be effectively cured with the advent of direct acting antivirals (DAA). Nevertheless, patients cured of their HCV infection still have a high risk of developing hepatocellular carcinoma (HCC). Importantly, it has been shown that some of the deregulations induced by HCV are maintained despite a sustained virologic response (SVR), including the down-regulation of some hepatocyte functions such as bile acid metabolism, exemplifying cell dedifferentiation, and the up-regulation of the epithelial–mesenchymal transition (EMT). EMT is a process by which epithelial cells lose their differentiation and their specific polarity to acquire mesenchymal cell properties, including migration and extracellular matrix remodeling capabilities. Of note, epithelial cell polarity acts as a gatekeeper against EMT. Thus, it remains important to elucidate the mechanisms by which HCV alters polarity and promotes EMT that could participate in viral-induced hepatic carcinogenesis. In this review, we define the main steps involved in the polarization process of epithelial cells and recall the essential cellular actors involved. We also highlight the particularities of hepatocyte polarity, responsible for their unique morphology. We then focus on the alterations by HCV of epithelial cell polarity and the consequences of the transformation of hepatocytes involved in the carcinogenesis process.
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Affiliation(s)
- Jean Agnetti
- INSERM, UMR-S 1193, Université Paris-Sud, F-94800 Villejuif, France;
| | | | - Ama Gassama-Diagne
- INSERM, UMR-S 1193, Université Paris-Sud, F-94800 Villejuif, France;
- Correspondence:
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20
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Kusano H, Kondo R, Ogasawara S, Omuraya M, Okudaira M, Mizuochi S, Mihara Y, Kinjo Y, Yano Y, Nakayama M, Naito Y, Akiba J, Nakashima O, Yano H. Utility of sonic hedgehog and keratin 8/18 immunohistochemistry for detecting ballooned hepatocytes. Histopathology 2022; 80:974-981. [DOI: 10.1111/his.14631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 02/21/2022] [Accepted: 02/21/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Hironori Kusano
- Department of Pathology Kurume University School of Medicine Kurume Japan
- Department of Clinical Laboratory, National Hospital Organization Kokura Medical Center, Kitakyushu Japan
| | - Reiichiro Kondo
- Department of Pathology Kurume University School of Medicine Kurume Japan
| | - Sachiko Ogasawara
- Department of Pathology Kurume University School of Medicine Kurume Japan
| | | | | | - Shinji Mizuochi
- Department of Pathology Kurume University School of Medicine Kurume Japan
| | - Yutaro Mihara
- Department of Pathology Kurume University School of Medicine Kurume Japan
| | - Yoshinao Kinjo
- Department of Pathology Kurume University School of Medicine Kurume Japan
| | - Yuta Yano
- Department of Pathology Kurume University School of Medicine Kurume Japan
| | - Masamichi Nakayama
- Department of Pathology Kurume University School of Medicine Kurume Japan
| | - Yoshiki Naito
- Department of Diagnostic Pathology Kurume University Hospital Kurume Japan
| | - Jun Akiba
- Department of Diagnostic Pathology Kurume University Hospital Kurume Japan
| | - Osamu Nakashima
- Department of Clinical Laboratory Medicine Kurume University Hospital Kurume Japan
| | - Hirohisa Yano
- Department of Pathology Kurume University School of Medicine Kurume Japan
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Prata TVG, Manchiero C, Dantas BP, Nunes AKDS, Tengan FM, Magri MC. Effect of MTTP -493G/T, I128T, Q95H and Q244E polymorphisms on hepatic steatosis in patients with chronic hepatitis. Clinics (Sao Paulo) 2022; 77:100094. [PMID: 36027755 PMCID: PMC9424342 DOI: 10.1016/j.clinsp.2022.100094] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/21/2022] [Accepted: 07/12/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Chronic hepatitis C is characterized by a progressive deterioration of liver function and is involved in metabolic complications, such as hepatic steatosis. OBJECTIVE The aim of this study was to investigate the role of host and viral characteristics associated with -493G/T (rs1800591), I128T (rs3816873), Q95H (rs61733139), and Q244E (rs17599091) Single Nucleotide Polymorphisms (SNPs) in the Microsomal Triglyceride Transfer Protein (MTTP) gene on hepatic steatosis in chronic hepatitis C. METHODS SNPs were genotyped by PCR-RFLP and analyzed in combination with host and viral characteristics by multiple logistic regression in different genetic models of inheritance. RESULTS The authors analyzed 236 patients with chronic hepatitis C, and 53% had hepatic steatosis. The mutated allele frequencies were > 5%, and the genotypes were in Hardy-Weinberg equilibrium (p ≥ 0.05). It was observed that patients with HCV genotype 3 infection (OR = 2.74, 95% CI 1.24‒6.06, p = 0.013), female sex (OR = 2.28, 95% CI 1.21‒4.28, p = 0.011) and moderate- and high-intensity liver inflammatory activity (A2-A3) (OR = 3.61, 95% CI 1.86‒7.01, p < 0.001) alone exhibited a higher risk of steatosis. The results of multiple logistic regression analysis for interaction showed that for the -493G/T SNP, when the GT/TT genotype (dominant model) and the GT genotype (codominant model) were each combined with HCV genotype 3 infection, an 11.51-fold (95% CI 2.08‒63.59, p = 0.005) and a 15.69-fold (95% CI 2.46‒99.85, p = 0.004) increased risk of steatosis, respectively, was observed. For the I128T SNP, when both the IT/TT genotype (dominant model) and the IT genotype (codominant model) were combined with HCV genotype 3 infection, an 8.51-fold (95% CI 1.59‒45.54, p = 0.012) and an 8.40 fold (95% CI 1.51‒46.91, p = 0.015) increased risk of steatosis, respectively, was observed. CONCLUSION The present study showed that the viral genotype combined with the -493G/T and I128T SNPs in the MTTP gene influences hepatic steatosis.
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Affiliation(s)
- Thamiris Vaz Gago Prata
- Laboratorio de Investigacao Médica em Hepatologia por Virus (LIM-47), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Caroline Manchiero
- Laboratorio de Investigacao Médica em Hepatologia por Virus (LIM-47), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Bianca Peixoto Dantas
- Laboratorio de Investigacao Médica em Hepatologia por Virus (LIM-47), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Arielle Karen da Silva Nunes
- Laboratorio de Investigacao Médica em Hepatologia por Virus (LIM-47), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Fátima Mitiko Tengan
- Laboratorio de Investigacao Médica em Hepatologia por Virus (LIM-47), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil; Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil
| | - Mariana Cavalheiro Magri
- Laboratorio de Investigacao Médica em Hepatologia por Virus (LIM-47), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil.
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22
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Innes H, Jepsen P, McDonald S, Dillon J, Hamill V, Yeung A, Benselin J, Went A, Fraser A, Bathgate A, Ansari MA, Barclay ST, Goldberg D, Hayes PC, Johnson P, Barnes E, Irving W, Hutchinson S, Guha IN. Performance of models to predict hepatocellular carcinoma risk among UK patients with cirrhosis and cured HCV infection. JHEP Rep 2021; 3:100384. [PMID: 34805817 PMCID: PMC8585647 DOI: 10.1016/j.jhepr.2021.100384] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/21/2021] [Accepted: 09/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) prediction models can inform clinical decisions about HCC screening provided their predictions are robust. We conducted an external validation of 6 HCC prediction models for UK patients with cirrhosis and a HCV virological cure. METHODS Patients with cirrhosis and cured HCV were identified from the Scotland HCV clinical database (N = 2,139) and the STratified medicine to Optimise Treatment of Hepatitis C Virus (STOP-HCV) study (N = 606). We calculated patient values for 4 competing non-genetic HCC prediction models, plus 2 genetic models (for the STOP-HCV cohort only). Follow-up began at the date of sustained virological response (SVR) achievement. HCC diagnoses were identified through linkage to nation-wide cancer, hospitalisation, and mortality registries. We compared discrimination and calibration measures between prediction models. RESULTS Mean follow-up was 3.4-3.9 years, with 118 (Scotland) and 40 (STOP-HCV) incident HCCs observed. The age-male sex-ALBI-platelet count score (aMAP) model showed the best discrimination; for example, the Concordance index (C-index) in the Scottish cohort was 0.77 (95% CI 0.73-0.81). However, for all models, discrimination varied by cohort (being better for the Scottish cohort) and by age (being better for younger patients). In addition, genetic models performed better in patients with HCV genotype 3. The observed 3-year HCC risk was 3.3% (95% CI 2.6-4.2) and 5.1% (3.5-7.0%) in the Scottish and STOP-HCV cohorts, respectively. These were most closely matched by aMAP, in which the mean predicted 3-year risk was 3.6% and 5.0% in the Scottish and STOP-HCV cohorts, respectively. CONCLUSIONS aMAP was the best-performing model in terms of both discrimination and calibration and, therefore, should be used as a benchmark for rival models to surpass. This study underlines the opportunity for 'real-world' risk stratification in patients with cirrhosis and cured HCV. However, auxiliary research is needed to help translate an HCC risk prediction into an HCC-screening decision. LAY SUMMARY Patients with cirrhosis and cured HCV are at high risk of developing liver cancer, although the risk varies substantially from one patient to the next. Risk calculator tools can alert clinicians to patients at high risk and thereby influence decision-making. In this study, we tested the performance of 6 risk calculators in more than 2,500 patients with cirrhosis and cured HCV. We show that some risk calculators are considerably better than others. Overall, we found that the 'aMAP' calculator worked the best, but more work is needed to convert predictions into clinical decisions.
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Key Words
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- C-index, Concordance index
- External validation
- GGT, gamma glutamyl transferase
- GRS, genetic risk score
- Genetic risk scores
- HCC, hepatocellular carcinoma
- ICD, International Classification of Diseases
- IDU, injecting-drug user
- IF, interferon
- PNPLA3, patatin-like phospholipase domain-containing protein 3
- Primary liver cancer
- Prognosis
- Risk prediction
- SMR01, Scottish Inpatient Hospital Admission Database
- SMR06, Scottish Cancer Register
- STOP-HCV, STratified medicine to Optimise Treatment of Hepatitis C Virus
- SVR, sustained virological response
- THRI, Toronto HCC Risk Index
- VHA, Veteran Health Affairs
- aMAP, age-male sex-ALBI-platelet count score
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Affiliation(s)
- Hamish Innes
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Public Health Scotland, Glasgow, UK
- Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK
| | - Peter Jepsen
- Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Scott McDonald
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Public Health Scotland, Glasgow, UK
| | - John Dillon
- Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, UK
| | - Victoria Hamill
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Public Health Scotland, Glasgow, UK
| | - Alan Yeung
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Public Health Scotland, Glasgow, UK
| | - Jennifer Benselin
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | | | - Andrew Fraser
- Aberdeen Royal Infirmary, Aberdeen, UK
- Queen Elizabeth University Hospital, Glasgow, UK
| | | | - M. Azim Ansari
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the Oxford NIHR Biomedical Research Centre, Oxford University, Oxford, UK
| | | | - David Goldberg
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Public Health Scotland, Glasgow, UK
| | | | - Philip Johnson
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the Oxford NIHR Biomedical Research Centre, Oxford University, Oxford, UK
| | - William Irving
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Sharon Hutchinson
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Public Health Scotland, Glasgow, UK
| | - Indra Neil Guha
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
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Siphepho PY, Liu YT, Shabangu CS, Huang JF, Huang CF, Yeh ML, Yu ML, Wang SC. The Impact of Steatosis on Chronic Hepatitis C Progression and Response to Antiviral Treatments. Biomedicines 2021; 9:1491. [PMID: 34680608 PMCID: PMC8533513 DOI: 10.3390/biomedicines9101491] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/12/2021] [Accepted: 10/13/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolic derangement is characteristic in patients with hepatitis C virus (HCV) infection. Aside from established liver injury, various extrahepatic metabolic disorders impact the natural history of the disease, clinical outcomes, and the efficacy of antiviral therapy. The presence of steatosis, recently redefined as metabolic-associated fatty liver disease (MAFLD), is a common feature in HCV-infected patients, induced by host and/or viral factors. Most chronic HCV-infected (CHC) patients have mild steatosis within the periportal region of the liver with an estimated prevalence of 40% to 86%. Indeed, this is higher than the 19% to 50% prevalence observed in patients with other chronic liver diseases such as chronic hepatitis B (CHB). The histological manifestations of HCV infection are frequently observed in genotype 3 (G-3), where relative to other genotypes, the prevalence and severity of steatosis is also increased. Steatosis may independently influence the treatment efficacy of either interferon-based or interferon-free antiviral regimens. This review aimed to provide updated evidence of the prevalence and risk factors behind HCV-associated steatosis, as well as explore the impact of steatosis on HCV-related outcomes.
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Affiliation(s)
- Phumelele Yvonne Siphepho
- Program in Tropical Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.Y.S.); (M.-L.Y.)
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
| | - Yi-Ting Liu
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Ciniso Sylvester Shabangu
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jee-Fu Huang
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Lung Yu
- Program in Tropical Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.Y.S.); (M.-L.Y.)
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Shu-Chi Wang
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
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PIAS1 Regulates Hepatitis C Virus-Induced Lipid Droplet Accumulation by Controlling Septin 9 and Microtubule Filament Assembly. Pathogens 2021; 10:pathogens10101327. [PMID: 34684276 PMCID: PMC8537804 DOI: 10.3390/pathogens10101327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/07/2021] [Accepted: 10/13/2021] [Indexed: 01/22/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection often leads to fibrosis and chronic hepatitis, then cirrhosis and ultimately hepatocellular carcinoma (HCC). The processes of the HVC life cycle involve intimate interactions between viral and host cell proteins and lipid metabolism. However, the molecules and mechanisms involved in this tripartite interaction remain poorly understood. Herein, we show that the infection of HCC-derived Huh7.5 cells with HCV promotes upregulation of the protein inhibitor of activated STAT1 (PIAS1). Reciprocally, PIAS1 regulated the expression of HCV core protein and HCV-induced LD accumulation and impaired HCV replication. Furthermore, PIAS1 controlled HCV-promoted septin 9 filament formation and microtubule polymerization. Subsequently, we found that PIAS1 interacted with septin 9 and controlled its assembly on filaments, which thus affected septin 9-induced lipid droplet accumulation. Taken together, these data reveal that PIAS1 regulates the accumulation of lipid droplets and offer a meaningful insight into how HCV interacts with host proteins.
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25
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Cespiati A, Petta S, Lombardi R, Di Marco V, Calvaruso V, Bertelli C, Pisano G, Fatta E, Sigon G, Iuculano F, Crapanzano L, Gibilaro G, Francione P, Craxì A, Fargion S, Fracanzani AL. Metabolic comorbidities and male sex influence steatosis in chronic hepatitis C after viral eradication by direct-acting antiviral therapy (DAAs): Evaluation by the controlled attenuation parameter (CAP). Dig Liver Dis 2021; 53:1301-1307. [PMID: 33214063 DOI: 10.1016/j.dld.2020.11.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/30/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Chronic hepatitis C (CHC) is associated with hepatic steatosis, related to both a direct viral action and metabolic features. Vice-versa data on hepatic steatosis after viral eradication by direct-acting antiviral agents (DAA) are undefined although the presence of metabolic alterations could strongly influence the occurrence of steatosis as in NAFLD. The controlled attenuation parameter (CAP) (FibroscanⓇ) allows the qualitative and quantitative evaluation of fatty liver. AIM to evaluate in patients with CHC whether hepatic steatosis diagnosed by CAP modifies after DAAs-induced sustained virologic response (SVR). METHODS Data were collected the day of DAAs therapy starting and six months after SVR. CAP ≥ 248 dB/m defined the presence of steatosis. RESULTS 794 CHC SVR patients referring to 2 Italian Units were enrolled. Mean age was 64 ± 16 ys, 50% males, BMI 25.4 ± 4 kg/m2, genotype type-1 in 73%, type-3 in 8%. Prevalence of hepatic steatosis at baseline was 32% by US and 46% by CAP. De novo steatosis developed in 125 (29%), resolution in 122 (30%). At multivariate analysis de novo steatosis was independently associated with male sex (OR 1.7, CI 95% 1.09-2.67; p = 0.02) and baseline BMI (for unit increase OR 1.19, CI 95%1.11-1.29; p < 0.001). Baseline BMI (for unit increase OR 0.47, CI 95% 0.25-0.89; p = 0.02) and triglycerides (for unit increase OR 0.93, CI 95% 0.87-0.99; p = 0.03) prevented steatosis resolution after therapy. CONCLUSIONS after SVR de novo steatosis and resolution of baseline steatosis are closely related to the presence of metabolic comorbidities.
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Affiliation(s)
- Annalisa Cespiati
- Unit of Internal Medicine and Metabolic Disease, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Italy; Department of Pathophysiology and Transplantation, University of Milan, Italy
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Italy
| | - Rosa Lombardi
- Unit of Internal Medicine and Metabolic Disease, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Italy; Department of Pathophysiology and Transplantation, University of Milan, Italy.
| | - Vito Di Marco
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Italy
| | - Vincenza Calvaruso
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Italy
| | - Cristina Bertelli
- Unit of Internal Medicine and Metabolic Disease, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Italy
| | - Giuseppina Pisano
- Unit of Internal Medicine and Metabolic Disease, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Italy
| | - Erika Fatta
- Unit of Internal Medicine and Metabolic Disease, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Italy
| | - Giordano Sigon
- Unit of Internal Medicine and Metabolic Disease, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Italy; Department of Pathophysiology and Transplantation, University of Milan, Italy
| | - Federica Iuculano
- Unit of Internal Medicine and Metabolic Disease, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Italy; Department of Pathophysiology and Transplantation, University of Milan, Italy
| | - Luciano Crapanzano
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Italy
| | - Gerlando Gibilaro
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Italy
| | - Paolo Francione
- Unit of Internal Medicine and Metabolic Disease, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Italy; Department of Pathophysiology and Transplantation, University of Milan, Italy
| | - Antonio Craxì
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, University of Milan, Italy
| | - Anna Ludovica Fracanzani
- Unit of Internal Medicine and Metabolic Disease, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Italy; Department of Pathophysiology and Transplantation, University of Milan, Italy
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26
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Diagnostic accuracy of ultrasound-guided attenuation parameter as a noninvasive test for steatosis in non-alcoholic fatty liver disease. J Med Ultrason (2001) 2021; 48:471-480. [PMID: 34415481 DOI: 10.1007/s10396-021-01123-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 07/09/2021] [Indexed: 10/20/2022]
Abstract
The purpose of this study was to evaluate the diagnostic accuracy of the ultrasound-guided attenuation parameter (UGAP) using the LOGEQ E10 for hepatic steatosis in non-alcoholic fatty liver disease (NAFLD) patients and directly compare UGAP with attenuation imaging (ATI) and controlled attenuation parameter (CAP). We prospectively analyzed 105 consecutive patients with NAFLD who underwent UGAP, ATI, CAP, and liver biopsy on the same day between October 2019 and April 2021. The diagnostic ability of the UGAP-determined attenuation coefficient (AC) was evaluated using receiver operating characteristic (ROC) curve analysis, and its correlation with ATI-determined AC values or CAP values was investigated. The success rate of UGAP was 100%. The median IQR/med obtained by UGAP was 4.0%, which was lower than that of ATI and CAP (P < 0.0001). The median ACs obtained by UGAP for grades S0 (control), S1, S2, and S3 were 0.590, 0.670, 0.750, and 0.845 dB/cm/MHz, respectively, demonstrating a stepwise increase with increasing hepatic steatosis severity (P < 0.0001). The areas under the ROC curve of UGAP for identifying ≥ S1, ≥ S2, and S3 were 0.890, 0.906, and 0.912, respectively, which were significantly better than the results obtained with CAP for identifying S3. Furthermore, the correlation coefficient between UGAP-AC and ATI-AC values was 0.803 (P < 0.0001), indicating a strong relationship. Our results indicate that UGAP has high diagnostic accuracy for detecting and grading hepatic steatosis in patients with NAFLD.
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GALAD Score Detects Early-Stage Hepatocellular Carcinoma in a European Cohort of Chronic Hepatitis B and C Patients. Pharmaceuticals (Basel) 2021; 14:ph14080735. [PMID: 34451832 PMCID: PMC8401792 DOI: 10.3390/ph14080735] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 12/23/2022] Open
Abstract
Despite vaccination programs and direct antiviral treatments, the incidence of virus-related hepatocellular carcinoma (HCC) remains high, while ultrasound-based detection rates for early-stage HCC is continuously low. To address this insufficiency, we set out to characterize whether the GALAD score, which incorporates gender, age, and serum levels of AFP, AFP isoform L3 (AFP-L3), and des-gamma-carboxy-prothrombin (DCP), can improve early-stage HCC detection in a Caucasian HBV/HCV cohort. In a retrospective German single-center study, 182 patients with HBV, 223 with HCV and 168 with other etiology (OE) of chronic liver disease (CLD) were enrolled. HCC was confirmed in 52 HBV, 84 HCV and 60 OE CLD patients. The diagnostic performance of the single biomarkers in HCC detection was compared to the GALAD model. At initial diagnosis, most patients were at (very) early BCLC 0 (n = 14/7%) or A (n = 56/29%) or intermediate stage BCLC B (n = 93/47%) HCC in all three subgroups. In the BCLC 0/A cohort, GALAD exhibited an AUC of 0.94 discriminating HCC from non-HCC, surpassing AFP (AUC 0.86), AFP-L3 (AUC 0.83) and DCP (AUC 0.83). In the HBV population, GALAD achieved an AUC of 0.96, in HCV an AUC of 0.98 and in OE an AUC of 0.99, clearly superior to the biomarkers alone. Furthermore, in HCV patients GALAD showed a significantly higher specificity (89%) versus AFP (64%) alone. In chronic viral hepatitis, the GALAD model showed superior performance in detection of early-stage HCC, while exhibiting higher specificity in HCV patients compared to AFP alone. We conclude that the GALAD score shows potential for HCC surveillance in Caucasian HBV/HCV patients.
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Saldarriaga OA, Dye B, Pham J, Wanninger TG, Millian D, Kueht M, Freiberg B, Utay N, Stevenson HL. Comparison of liver biopsies before and after direct-acting antiviral therapy for hepatitis C and correlation with clinical outcome. Sci Rep 2021; 11:14506. [PMID: 34267267 PMCID: PMC8282660 DOI: 10.1038/s41598-021-93881-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023] Open
Abstract
Direct-acting antivirals (DAA) have replaced interferon (IFN)-based therapies for hepatitis C virus. In this retrospective clinical study, we examined differences in histopathologic features in paired liver biopsies collected from the same patient before and after DAA and correlated these findings with clinical outcome. Biopsies (n = 19) were evaluated by quantitative imaging analysis to measure steatosis and fibrosis. Most patients had decreased steatosis in their post-treatment, follow-up biopsies. However, one patient had a striking increase in steatosis (from 0.86 to 6.32%) and later developed decompensated cirrhosis and hepatocellular carcinoma (HCC). This patient had a marked increase in fibrosis between biopsies, with a CPA of 6.74 to 32.02. Another patient, who already had bridging fibrosis at the time of her pre-treatment biopsy, developed cholangiocarcinoma after DAA. Even though the overall inflammatory activity in the post-treatment biopsies significantly decreased after treatment, 60% of patients had persistent portal lymphocytic inflammation. In summary, DAAs decreased steatosis and hepatic inflammation in most patients, although some may have persistence of lymphocytic portal inflammation. Patients known to have advanced fibrosis at treatment initiation and who have other risk factors for ongoing liver injury, such as steatosis, should be followed closely for the development of adverse outcomes, such as portal hypertension and primary liver cancers.
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Affiliation(s)
- Omar A Saldarriaga
- Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Bradley Dye
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Judy Pham
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Timothy G Wanninger
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Daniel Millian
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Michael Kueht
- Dept. of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Benjamin Freiberg
- Digital Pathology, Araceli Biosciences, 7425 NE Evergreen Pkwy, Hillsboro, OR, 97124, USA
| | - Netanya Utay
- Department of Internal Medicine, University of Texas Health Science Center at Houston, 7000 Fannin St # 1200, Houston, TX, 77030, USA
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA.
- Department of Pathology, The University of Texas Medical Branch, 712 Texas Avenue, Clinical Services Wing-Room 5.506Q, Galveston, TX, 77555-0416, USA.
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Boeckmans J, Rombaut M, Demuyser T, Declerck B, Piérard D, Rogiers V, De Kock J, Waumans L, Magerman K, Cartuyvels R, Rummens JL, Rodrigues RM, Vanhaecke T. Infections at the nexus of metabolic-associated fatty liver disease. Arch Toxicol 2021; 95:2235-2253. [PMID: 34027561 PMCID: PMC8141380 DOI: 10.1007/s00204-021-03069-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 04/29/2021] [Indexed: 02/07/2023]
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease that affects about a quarter of the world population. MAFLD encompasses different disease stadia ranging from isolated liver steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Although MAFLD is considered as the hepatic manifestation of the metabolic syndrome, multiple concomitant disease-potentiating factors can accelerate disease progression. Among these risk factors are diet, lifestyle, genetic traits, intake of steatogenic drugs, male gender and particular infections. Although infections often outweigh the development of fatty liver disease, pre-existing MAFLD could be triggered to progress towards more severe disease stadia. These combined disease cases might be underreported because of the high prevalence of both MAFLD and infectious diseases that can promote or exacerbate fatty liver disease development. In this review, we portray the molecular and cellular mechanisms by which the most relevant viral, bacterial and parasitic infections influence the progression of fatty liver disease and steatohepatitis. We focus in particular on how infectious diseases, including coronavirus disease-19, hepatitis C, acquired immunodeficiency syndrome, peptic ulcer and periodontitis, exacerbate MAFLD. We specifically underscore the synergistic effects of these infections with other MAFLD-promoting factors.
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Affiliation(s)
- Joost Boeckmans
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium.
| | - Matthias Rombaut
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Thomas Demuyser
- Department of Microbiology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
- Center for Neurosciences, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Baptist Declerck
- Department of Microbiology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
| | - Denis Piérard
- Department of Microbiology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
| | - Vera Rogiers
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Joery De Kock
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Luc Waumans
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium
| | - Koen Magerman
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium
- Department of Immunology and Infection, Hasselt University, Martelarenlaan 42, 3500, Hasselt, Belgium
| | - Reinoud Cartuyvels
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium
| | - Jean-Luc Rummens
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium
| | - Robim M Rodrigues
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
| | - Tamara Vanhaecke
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
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30
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Florea M, Serban T, Tirpe GR, Tirpe A, Lupsor-Platon M. Noninvasive Assessment of Hepatitis C Virus Infected Patients Using Vibration-Controlled Transient Elastography. J Clin Med 2021; 10:jcm10122575. [PMID: 34200885 PMCID: PMC8230562 DOI: 10.3390/jcm10122575] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/06/2021] [Accepted: 06/08/2021] [Indexed: 02/08/2023] Open
Abstract
Chronic infection with hepatitis C virus (HCV) is one of the leading causes of cirrhosis and hepatocellular carcinoma (HCC). Surveillance of these patients is an essential strategy in the prevention chain, including in the pre/post-antiviral treatment states. Ultrasound elastography techniques are emerging as key methods in the assessment of liver diseases, with a number of advantages such as their rapid, noninvasive, and cost-effective characters. The present paper critically reviews the performance of vibration-controlled transient elastography (VCTE) in the assessment of HCV patients. VCTE measures liver stiffness (LS) and the ultrasonic attenuation through the embedded controlled attenuation parameter (CAP), providing the clinician with a tool for assessing fibrosis, cirrhosis, and steatosis in a noninvasive manner. Moreover, standardized LS values enable proper staging of the underlying fibrosis, leading to an accurate identification of a subset of HCV patients that present a high risk for complications. In addition, VCTE is a valuable technique in evaluating liver fibrosis prior to HCV therapy. However, its applicability in monitoring fibrosis regression after HCV eradication is currently limited and further studies should focus on extending the boundaries of VCTE in this context. From a different perspective, VCTE may be effective in identifying clinically significant portal hypertension (CSPH). An emerging prospect of clinical significance that warrants further study is the identification of esophageal varices. Our opinion is that the advantages of VCTE currently outweigh those of other surveillance methods.
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Affiliation(s)
- Mira Florea
- Community Medicine Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Teodora Serban
- Medical Imaging Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - George Razvan Tirpe
- Department of Radiology and Medical Imaging, County Emergency Hospital Cluj-Napoca, 3-5 Clinicilor Street, 400000 Cluj-Napoca, Romania;
| | - Alexandru Tirpe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania;
| | - Monica Lupsor-Platon
- Medical Imaging Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
- Medical Imaging Department, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- Correspondence:
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31
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High Rates of Liver Cirrhosis and Hepatocellular Carcinoma in Chronic Hepatitis B Patients with Metabolic and Cardiovascular Comorbidities. Microorganisms 2021; 9:microorganisms9050968. [PMID: 33946154 PMCID: PMC8146494 DOI: 10.3390/microorganisms9050968] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 12/12/2022] Open
Abstract
Background: The prevalence of metabolic and cardiovascular diseases is rising worldwide. However, little is known about the impact of such disorders on hepatic disease progression in chronic hepatitis B (CHB) during the era of potent nucleo(s)tide analogues (NAs). Methods: We retrospectively analyzed a single-center cohort of 602 CHB patients, comparing the frequency of liver cirrhosis at baseline and incidences of liver-related events during follow-up (hepatocellular carcinoma, liver transplantation and liver-related death) between CHB patients with a history of diabetes, obesity, hypertension or coronary heart disease (CHD). Results: Rates of cirrhosis at baseline and liver-related events during follow-up (median follow-up time: 2.51 years; NA-treated: 37%) were substantially higher in CHB patients with diabetes (11/23; 3/23), obesity (6/13; 2/13), CHD (7/11; 2/11) or hypertension (15/43; 4/43) compared to CHB patients without the indicated comorbidities (26/509; 6/509). Multivariate analysis identified diabetes as the most significant predictor for cirrhosis (p = 0.0105), while comorbidities did not correlate with liver-related events in pre-existing cirrhosis. Conclusion: The combination of metabolic diseases and CHB is associated with substantially increased rates of liver cirrhosis and secondary liver-related events compared to CHB alone, indicating that hepatitis B patients with metabolic comorbidities warrant particular attention in disease surveillance and evaluation of treatment indication.
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Grimm J, Peschel G, Müller M, Schacherer D, Wiest R, Weigand K, Buechler C. Rapid Decline of Serum Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) in Non-Cirrhotic Patients with Chronic Hepatitis C Infection Receiving Direct-Acting Antiviral Therapy. J Clin Med 2021; 10:1621. [PMID: 33920491 PMCID: PMC8069657 DOI: 10.3390/jcm10081621] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/30/2021] [Accepted: 04/06/2021] [Indexed: 02/06/2023] Open
Abstract
Direct-acting antivirals (DAAs) efficiently eradicate the hepatitis C virus (HCV). Low-density lipoprotein (LDL) levels increase rapidly upon DAA treatment. Proprotein convertase subtilisin/kexin 9 (PCSK9) induces degradation of the hepatic LDL receptor and thereby elevates serum LDL. The aim of this study was to determine serum PCSK9 concentrations during and after DAA therapy to identify associations with LDL levels. Serum PCSK9 was increased in 82 chronic HCV-infected patients compared to 55 patients not infected with HCV. Serum PCSK9 was low in HCV patients with liver cirrhosis, but patients with HCV-induced liver cirrhosis still exhibited higher serum PCSK9 than patients with non-viral liver cirrhosis. Serum PCSK9 correlated with measures of liver injury and inflammation in cirrhotic HCV patients. In patients without liver cirrhosis, a positive association of serum PCSK9 with viral load existed. Serum PCSK9 was not different between viral genotypes. Serum PCSK9 did not correlate with LDL levels in HCV patients irrespective of cirrhotic status. Serum PCSK9 was reduced, and LDL was increased at four weeks after DAA therapy start in non-cirrhotic HCV patients. Serum PCSK9 and LDL did not change upon DAA treatment in the cirrhotic group. The rapid decline of PCSK9 after the start of DAA therapy in conjunction with raised LDL levels in non-cirrhotic HCV patients shows that these changes are not functionally related.
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Affiliation(s)
- Jonathan Grimm
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (J.G.); (G.P.); (M.M.); (D.S.); (K.W.)
| | - Georg Peschel
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (J.G.); (G.P.); (M.M.); (D.S.); (K.W.)
| | - Martina Müller
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (J.G.); (G.P.); (M.M.); (D.S.); (K.W.)
| | - Doris Schacherer
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (J.G.); (G.P.); (M.M.); (D.S.); (K.W.)
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, University Inselspital, 3010 Bern, Switzerland;
| | - Kilian Weigand
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (J.G.); (G.P.); (M.M.); (D.S.); (K.W.)
| | - Christa Buechler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (J.G.); (G.P.); (M.M.); (D.S.); (K.W.)
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33
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Zarębska-Michaluk D. Genotype 3-hepatitis C virus’ last line of defense. World J Gastroenterol 2021; 27:1006-1021. [PMID: 33776369 PMCID: PMC7985731 DOI: 10.3748/wjg.v27.i11.1006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 01/24/2021] [Accepted: 03/01/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with hepatitis C virus (HCV) is one of the leading causes of liver disease globally, affecting approximately 71 million people. The majority of them are infected with genotype (GT) 1 but infections with GT3 are second in frequency. For many years, GT3 was considered to be less pathogenic compared to other GTs in the HCV family due to its favorable response to interferon (IFN)-based regimen. However, the growing evidence of a higher rate of steatosis, more rapid progression of liver fibrosis, and lower efficacy of antiviral treatment compared to infection with other HCV GTs has changed this conviction. This review presents the specifics of the course of GT3 infection and the development of therapeutic options for GT3-infected patients in the era of direct-acting antivirals (DAA). The way from a standard of care therapy with pegylated IFN-alpha (pegIFNα) and ribavirin (RBV) through a triple combination of pegIFNα + RBV and DAA to the highly potent IFN-free pangenotypic DAA regimens is discussed along with some treatment options which appeared to be dead ends. Although the implementation of highly effective pangenotypic regimens is the most recent stage of revolution in the treatment of GT3 infection, there is still room for improvement, especially in patients with liver cirrhosis and those who fail to respond to DAA therapies, particularly those containing inhibitors of HCV nonstructural protein 5A.
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Affiliation(s)
- Dorota Zarębska-Michaluk
- Department of Infectious Diseases, Jan Kochanowski University, Kielce 25-369, Świętokrzyskie, Poland
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34
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Kalyesubula M, Mopuri R, Asiku J, Rosov A, Yosefi S, Edery N, Bocobza S, Moallem U, Dvir H. High-dose vitamin B1 therapy prevents the development of experimental fatty liver driven by overnutrition. Dis Model Mech 2021; 14:dmm.048355. [PMID: 33608323 PMCID: PMC7988776 DOI: 10.1242/dmm.048355] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/11/2021] [Indexed: 12/16/2022] Open
Abstract
Fatty liver is an abnormal metabolic condition of excess intrahepatic fat. This condition, referred to as hepatic steatosis, is tightly associated with chronic liver disease and systemic metabolic morbidity. The most prevalent form in humans, i.e. non-alcoholic fatty liver, generally develops due to overnutrition and sedentary lifestyle, and has as yet no approved drug therapy. Previously, we have developed a relevant large-animal model in which overnourished sheep raised on a high-calorie carbohydrate-rich diet develop hyperglycemia, hyperinsulinemia, insulin resistance, and hepatic steatosis. Here, we tested the hypothesis that treatment with thiamine (vitamin B1) can counter the development of hepatic steatosis driven by overnutrition. Remarkably, the thiamine-treated animals presented with completely normal levels of intrahepatic fat, despite consuming the same amount of liver-fattening diet. Thiamine treatment also decreased hyperglycemia and increased the glycogen content of the liver, but it did not improve insulin sensitivity, suggesting that steatosis can be addressed independently of targeting insulin resistance. Thiamine increased the catalytic capacity for hepatic oxidation of carbohydrates and fatty acids. However, at gene-expression levels, more-pronounced effects were observed on lipid-droplet formation and lipidation of very-low-density lipoprotein, suggesting that thiamine affects lipid metabolism not only through its known classic coenzyme roles. This discovery of the potent anti-steatotic effect of thiamine may prove clinically useful in managing fatty liver-related disorders.This article has an associated First Person interview with the joint first authors of the paper.
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Affiliation(s)
- Mugagga Kalyesubula
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel.,Department of Animal Science, The Hebrew University of Jerusalem, Rehovot 7610001, Israel
| | - Ramgopal Mopuri
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel
| | - Jimmy Asiku
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel.,Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 7610001, Israel
| | - Alexander Rosov
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel
| | - Sara Yosefi
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel
| | - Nir Edery
- Pathology Laboratory, Kimron Veterinary Institute, Veterinary Services, Rishon LeZion 50250, Israel
| | - Samuel Bocobza
- Institute of Plant Sciences, Volcani Center - ARO, Rishon LeZion 7528809, Israel
| | - Uzi Moallem
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel
| | - Hay Dvir
- Institute of Animal Science, Volcani Center - Agricultural Research Organization (ARO), Rishon LeZion 7528809, Israel
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35
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Barré T, Rojas Rojas T, Lacombe K, Protopopescu C, Poizot-Martin I, Nishimwe ML, Zucman D, Esterle L, Billaud E, Aumaitre H, Bouchaud O, Rey D, Piroth L, Salmon-Ceron D, Wittkop L, Sogni P, Carrieri MP, Serfaty L, Marcellin F. Cannabis use and reduced risk of elevated fatty liver index in HIV-HCV co-infected patients: a longitudinal analysis (ANRS CO13 HEPAVIH). Expert Rev Anti Infect Ther 2021; 19:1147-1156. [PMID: 33538612 DOI: 10.1080/14787210.2021.1884545] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background: Cannabis use and elevated fatty liver index (FLI≥ 60) (a biomarker of hepatic steatosis in the general population) have been identified as predictors of HCV-related and overall mortality, respectively, in HIV-HCV co-infected patients. However, the relationship between cannabis use and the risk of elevated FLI has never been explored.Methods: Using five-year follow-up data from 997 HIV-HCV co-infected patients (ANRS CO13 HEPAVIH cohort), we analyzed the relationship between cannabis use and FLI using mixed-effects multivariable logistic (outcome: elevated FLI yes/no) and linear (outcome: continuous FLI) regression models.Results: At the last follow-up visit, 27.4% of patients reported regular or daily cannabis use and 27.8% had elevated FLI. After multivariable adjustment, regular or daily cannabis use was associated with a 55% lower risk of elevated FLI (adjusted odds ratio [95% confidence interval]: 0.45 [0.22; 0.94]; p = 0.033) and lower FLI values (adjusted model coefficient: -4.24 [-6.57; -1.91], p < 0.0001).Conclusions: Cannabis use is associated with a reduced risk of elevated fatty liver index in HIV-HCV co-infected patients. Further research is needed to confirm whether and how cannabinoids may inhibit the development of hepatic steatosis or other metabolic disorders in high-risk populations.
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Affiliation(s)
- Tangui Barré
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques & Sociales De La Santé & Traitement De l'Information Médicale, Marseille, France.,Ors Paca, Observatoire Régional De La Santé Provence-Alpes-Côte d'Azur, Marseille, France
| | - Teresa Rojas Rojas
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques & Sociales De La Santé & Traitement De l'Information Médicale, Marseille, France.,Ors Paca, Observatoire Régional De La Santé Provence-Alpes-Côte d'Azur, Marseille, France.,APHM Sainte-Marguerite, Clinical Immunohematology Unit, Aix Marseille University, Marseille, France
| | - Karine Lacombe
- Infectious and Tropical Disease Unit, Paris Public Hospitals, Saint-Antoine Hospital, Paris, France.,UMR S1136, Pierre Louis Epidemiology and Public Health Institute, Pierre and Marie Curie University, Paris, France
| | - Camelia Protopopescu
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques & Sociales De La Santé & Traitement De l'Information Médicale, Marseille, France.,Ors Paca, Observatoire Régional De La Santé Provence-Alpes-Côte d'Azur, Marseille, France
| | - Isabelle Poizot-Martin
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques & Sociales De La Santé & Traitement De l'Information Médicale, Marseille, France.,APHM Sainte-Marguerite, Clinical Immunohematology Unit, Aix Marseille University, Marseille, France
| | - Marie Libérée Nishimwe
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques & Sociales De La Santé & Traitement De l'Information Médicale, Marseille, France.,Ors Paca, Observatoire Régional De La Santé Provence-Alpes-Côte d'Azur, Marseille, France
| | - David Zucman
- Department of Internal Medicine, Réseau Ville Hôpital Val De Seine, Foch Hospital, Suresnes, France
| | - Laure Esterle
- Univ. Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, Team MORPH3EUS, UMR 1219, Bordeaux, France
| | - Eric Billaud
- Department of Infectious Disease, CHU Hôtel-Dieu, Nantes, France.,COREVIH Pays De La Loire, CHU Hôtel-Dieu, Nantes, France
| | - Hugues Aumaitre
- Infectious and Tropical Disease Unit, Perpignan Hospital Center, Perpignan, France
| | - Olivier Bouchaud
- Infectious and Tropical Disease Unit, Paris Public Hospitals, Avicenne Hospital, Bobigny, France.,Laboratoire d'Educations et Pratiques en Santé EA 3412, Université Sorbonne Paris Nord, Bobigny, France
| | - David Rey
- Le Trait d'Union, HIV-Infection Care Center, Hôpitaux Universitaires De Strasbourg, Strasbourg, France
| | - Lionel Piroth
- Department of Infectiology, Dijon University Hospital Center, Dijon, France.,INSERM-CIC 1342, Bourgogne University, Dijon, France
| | - Dominique Salmon-Ceron
- Service Maladies Infectieuses Et Tropicales, AP-HP, Hôpital Cochin, Paris, France.,Université Paris Descartes, Paris, France
| | - Linda Wittkop
- Univ. Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, Team MORPH3EUS, UMR 1219, Bordeaux, France.,Pole De Sante Publique, CHU De Bordeaux, Bordeaux, France
| | - Philippe Sogni
- Université Paris Descartes, Paris, France.,INSERM U-1223, Institut Pasteur, Paris, France.,Service d'Hépatologie, Hôpital Cochin, Assistance Publique - Hôpitaux De Paris, France
| | - Maria Patrizia Carrieri
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques & Sociales De La Santé & Traitement De l'Information Médicale, Marseille, France.,Ors Paca, Observatoire Régional De La Santé Provence-Alpes-Côte d'Azur, Marseille, France
| | - Lawrence Serfaty
- Service d'Hépato-gastroentérologie, Hôpital Hautepierre, Hôpitaux Universitaires De Strasbourg, France.,INSERM UMR 938, Université Paris Sorbonne, Paris, France
| | - Fabienne Marcellin
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques & Sociales De La Santé & Traitement De l'Information Médicale, Marseille, France.,Ors Paca, Observatoire Régional De La Santé Provence-Alpes-Côte d'Azur, Marseille, France
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Liou JW, Mani H, Yen JH, Hsu HJ, Chang CC. Hepatitis C virus core protein: Not just a nucleocapsid building block, but an immunity and inflammation modulator. Tzu Chi Med J 2021; 34:139-147. [PMID: 35465281 PMCID: PMC9020238 DOI: 10.4103/tcmj.tcmj_97_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 03/12/2021] [Accepted: 06/02/2021] [Indexed: 11/13/2022] Open
Abstract
Coevolution occurs between viruses and their hosts. The hosts need to evolve means to eliminate pathogenic virus infections, and the viruses, for their own survival and multiplication, have to develop mechanisms to escape clearance by hosts. Hepatitis C virus (HCV) of Flaviviridae is a pathogen which infects human liver and causes hepatitis, a condition of liver inflammation. Unlike most of the other flaviviruses, HCV has an excellent ability to evade host immunity to establish chronic infection. The persistent liver infection leads to chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC), as well as extrahepatic HCV-related diseases. HCV genomic RNA only expresses 10 proteins, many of which bear functions, in addition to those involved in HCV life cycle, for assisting the virus to develop its persistency. HCV core protein is a structural protein which encapsulates HCV genomic RNA and assembles into nucleocapsids. The core protein is also found to exert functions to affect host inflammation and immune responses by altering a variety of host pathways. This paper reviews the studies regarding the HCV core protein-induced alterations of host immunity and inflammatory responses, as well as the involvements of the HCV core protein in pro- and anti-inflammatory cytokine stimulations, host cellular transcription, lipid metabolism, cell apoptosis, cell proliferations, immune cell differentiations, oxidative stress, and hepatocyte steatosis, which leads to liver fibrosis, cirrhosis, and HCC. Implications of roles played by the HCV core protein in therapeutic resistance are also discussed.
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Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res 2020; 149:1-61. [PMID: 33579421 PMCID: PMC8796122 DOI: 10.1016/bs.acr.2020.10.001] [Citation(s) in RCA: 527] [Impact Index Per Article: 105.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC), the primary malignancy of hepatocytes, is a diagnosis with bleak outcome. According to National Cancer Institute's SEER database, the average five-year survival rate of HCC patients in the US is 19.6% but can be as low as 2.5% for advanced, metastatic disease. When diagnosed at early stages, it is treatable with locoregional treatments including surgical resection, Radio-Frequency Ablation, Trans-Arterial Chemoembolization or liver transplantation. However, HCC is usually diagnosed at advanced stages when the tumor is unresectable, making these treatments ineffective. In such instances, systemic therapy with tyrosine kinase inhibitors (TKIs) becomes the only viable option, even though it benefits only 30% of patients, provides only a modest (~3months) increase in overall survival and causes drug resistance within 6months. HCC, like many other cancers, is highly heterogeneous making a one-size fits all option problematic. The selection of liver transplantation, locoregional treatment, TKIs or immune checkpoint inhibitors as a treatment strategy depends on the disease stage and underlying condition(s). Additionally, patients with similar disease phenotype can have different molecular etiology making treatment responses different. Stratification of patients at the molecular level would facilitate development of the most effective treatment option. With the increase in efficiency and affordability of "omics"-level analysis, considerable effort has been expended in classifying HCC at the molecular, metabolic and immunologic levels. This review examines the results of these efforts and the ways they can be leveraged to develop targeted treatment options for HCC.
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Affiliation(s)
- Saranya Chidambaranathan-Reghupaty
- C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States.
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38
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Peschel G, Grimm J, Gülow K, Müller M, Buechler C, Weigand K. Chemerin Is a Valuable Biomarker in Patients with HCV Infection and Correlates with Liver Injury. Diagnostics (Basel) 2020; 10:diagnostics10110974. [PMID: 33228201 PMCID: PMC7699464 DOI: 10.3390/diagnostics10110974] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/18/2020] [Accepted: 11/18/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatitis C virus (HCV)-induced inflammation contributes to progressive liver disease. The chemoattractant protein chemerin is associated with systemic inflammation. We hypothesized that chemerin is a biomarker that predicts the severity of liver disease in HCV patients. Furthermore, we investigated whether serum chemerin levels change during the course of HCV treatment using direct-acting antivirals (DAAs). Therefore, we measured serum concentration of chemerin in a cohort of 82 HCV-infected patients undergoing DAA treatment. Serum chemerin was positively associated with leukocyte count and negatively with markers of hepatic function and the model of end-stage liver disease (MELD) score. Low circulating chemerin levels significantly correlated with advanced liver fibrosis and cirrhosis as measured by the fibrosis-4 (FIB-4) score, the aminotransferase/platelet (AST/PLT) ratio index (APRI) score and the non-alcoholic fatty liver disease (NAFLD) score. Chemerin did not correlate with viral load or viral genotype. Treatment with DAAs did not improve MELD score and leukocyte count within the observation period, up to three months after the end of DAA treatment. Accordingly, chemerin levels remained unchanged during the treatment period. We conclude that low circulating chemerin is a noninvasive biomarker for hepatic dysfunction and advanced liver fibrosis and cirrhosis in HCV infection.
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Li S, Liu R, Pan Q, Wang G, Cheng D, Yang J, Chen H, Xu G. De novo lipogenesis is elicited dramatically in human hepatocellular carcinoma especially in hepatitis C virus-induced hepatocellular carcinoma. MedComm (Beijing) 2020; 1:178-187. [PMID: 34766116 PMCID: PMC8491216 DOI: 10.1002/mco2.15] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/30/2020] [Accepted: 06/02/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Abnormal de novo lipogenesis is reported to be involved in hepatocarcinogenesis. In current study, de novo lipogenesis and its association with patient survival rate were investigated in human HCC samples induced by hepatitis B virus (HBV), hepatitis C virus (HCV), or nonviral factors. Hepatic mRNA and protein levels of lipogenic transcription factors and lipid synthesis enzymes were examined by realtime‐PCR (RT‐PCR) and western blot. Association of gene expression and patient survival was analyzed using The Cancer Genome Atlas (TCGA) data. Lipogenic pathway regulators such as AKT2, SREBP1c, PPARγ, and lipogenic enzymes such as ACC and FAS were increased in human HCC when compared with control livers. Notably, a more robust increase in de novo lipogenesis was observed in HCV‐HCC when compared to HBV‐HCC and nonviral HCC. High FAS and ACC expression correlated with poor overall survival (OS) in HCV‐HCC. High expression of lipogenesis gene panel significantly correlated with poor OS in HCV‐HCC, but not in HBV‐HCC or nonviral HCC. In sum, de novo lipogenesis is stimulated dramatically in human HCC especially in HCV‐HCC.
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Affiliation(s)
- Shaojian Li
- Department of Physiology School of Medicine Jinan University Guangzhou China
| | - Ruonan Liu
- Department of Physiology School of Medicine Jinan University Guangzhou China
| | - Qinling Pan
- Department of Physiology School of Medicine Jinan University Guangzhou China
| | - Genshu Wang
- Department of Hepatic Surgery and Liver Transplantation Center The Third Affiliated Hospital of Sun Yat-sen University Guangzhou China
| | - Daorou Cheng
- Hepatobiliary Pancreaticosplenic Surgery Shunde Hospital of Southern Medical University Foshan China
| | - Jie Yang
- Department of Physiology School of Medicine Jinan University Guangzhou China
| | - Hui Chen
- Guangdong Key Laboratory of Liver Disease Research The Third Affiliated Hospital of Sun Yat-sen University Guangzhou China
| | - Geyang Xu
- Department of Physiology School of Medicine Jinan University Guangzhou China
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40
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Tallorin L, Villareal VA, Hsia CY, Rodgers MA, Burri DJ, Pfeil MP, Llopis PM, Lindenbach BD, Yang PL. Hepatitis C virus NS3-4A protease regulates the lipid environment for RNA replication by cleaving host enzyme 24-dehydrocholesterol reductase. J Biol Chem 2020; 295:12426-12436. [PMID: 32641492 PMCID: PMC7458815 DOI: 10.1074/jbc.ra120.013455] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 06/29/2020] [Indexed: 12/12/2022] Open
Abstract
Many RNA viruses create specialized membranes for genome replication by manipulating host lipid metabolism and trafficking, but in most cases, we do not know the molecular mechanisms responsible or how specific lipids may impact the associated membrane and viral process. For example, hepatitis C virus (HCV) causes a specific, large-fold increase in the steady-state abundance of intracellular desmosterol, an immediate precursor of cholesterol, resulting in increased fluidity of the membrane where HCV RNA replication occurs. Here, we establish the mechanism responsible for HCV's effect on intracellular desmosterol, whereby the HCV NS3-4A protease controls activity of 24-dehydrocholesterol reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol. Our cumulative evidence for the proposed mechanism includes immunofluorescence microscopy experiments showing co-occurrence of DHCR24 and HCV NS3-4A protease; formation of an additional, faster-migrating DHCR24 species (DHCR24*) in cells harboring a HCV subgenomic replicon RNA or ectopically expressing NS3-4A; and biochemical evidence that NS3-4A cleaves DHCR24 to produce DHCR24* in vitro and in vivo. We further demonstrate that NS3-4A cleaves DHCR24 between residues Cys91 and Thr92 and show that this reduces the intracellular conversion of desmosterol to cholesterol. Together, these studies demonstrate that NS3-4A directly cleaves DHCR24 and that this results in the enrichment of desmosterol in the membranes where NS3-4A and DHCR24 co-occur. Overall, this suggests a model in which HCV directly regulates the lipid environment for RNA replication through direct effects on the host lipid metabolism.
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Affiliation(s)
- Lorillee Tallorin
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Valerie A Villareal
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Chih-Yun Hsia
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Mary A Rodgers
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Dominique J Burri
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Marc-Philipp Pfeil
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Paula Montero Llopis
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Brett D Lindenbach
- Department of Microbial Pathogenesis, Yale Medical School, New Haven, Connecticut, USA
| | - Priscilla L Yang
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA
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The Prevalence and Impact of Hepatic Steatosis on Response to Direct-Acting Antiviral Therapy in HIV-HCV Coinfection. BIOLOGY 2020; 9:biology9040087. [PMID: 32344543 PMCID: PMC7235799 DOI: 10.3390/biology9040087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 12/15/2022]
Abstract
(1) Background: Direct-acting antiviral therapy for chronic hepatitis C virus (HCV) infection is associated with high sustained virologic response (SVR) and overcomes negative predictive factors, including steatosis, in patients without human immunodeficiency virus (HIV) coinfection. The impact of steatosis on SVR in patients with HIV–HCV coinfection is unknown. (2) Methods: A retrospective analysis of patients treated with direct-acting antivirals was performed. Demographic, laboratory and direct-acting antiviral regimen data were prospectively collected. Metabolic syndrome and its components—diabetes mellitus, hypertension, dyslipidemia and obesity—were assessed. Hepatic steatosis (≥5%) was defined by liver biopsy or controlled attenuation parameter (CAP) measurement during vibration-controlled transient elastography (VCTE). (3) Results: A total of 151 HIV–HCV-coinfected patients on combined antiretroviral therapy and direct-acting antiviral therapy were included in this analysis. Prevalence of steatosis by liver biopsy (n = 34) or CAP (≥263 db/m) during VCTE (n = 92) was 27% and was independently associated with obesity (OR 3.11; 95% CI 1.43–6.82; p = 0.004) and the metabolic syndrome (OR 1.08; 95% CI 1.01–0.15; p = 0.01). The overall SVR rate (n = 148) was 95% and was not impacted by the presence of steatosis (p = 0.42). (4) Conclusions: Hepatic steatosis is common in HIV–HCV coinfection, correlates with obesity and the metabolic syndrome and does not impact SVR.
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Gomez PA, Zucker KM, Chang J, Rowley MW, Seetharam AB. Severe pretreatment hepatic steatosis influences response to direct acting antiviral therapy for chronic hepatitis C in a real world setting. Clin Res Hepatol Gastroenterol 2020; 44:e35-e37. [PMID: 31208924 DOI: 10.1016/j.clinre.2019.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 05/23/2019] [Indexed: 02/07/2023]
Affiliation(s)
- Paul A Gomez
- Internal Medicine, University of Arizona College of Medicine Phoenix, Banner University Medical Center Phoenix, Phoenix, AZ, USA
| | - Kelly M Zucker
- Internal Medicine, University of Arizona College of Medicine Phoenix, Banner University Medical Center Phoenix, Phoenix, AZ, USA
| | - Jean Chang
- University of Washington School of Medicine, Seattle, WA, USA
| | - Michael W Rowley
- Internal Medicine, University of Arizona College of Medicine Phoenix, Banner University Medical Center Phoenix, Phoenix, AZ, USA
| | - Anil B Seetharam
- University of Arizona College of Medicine Phoenix, Transplant and Advanced Liver Disease Center, Banner University Medical Center Phoenix, Phoenix, AZ, USA.
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Poordad F, Shiffman ML, Ghesquiere W, Wong A, Huhn GD, Wong F, Ramji A, Shafran SD, McPhee F, Yang R, Noviello S, Linaberry M. Daclatasvir and sofosbuvir with ribavirin for 24 weeks in chronic hepatitis C genotype-3-infected patients with cirrhosis: a Phase III study (ALLY-3C). Antivir Ther 2020; 24:35-44. [PMID: 30382942 DOI: 10.3851/imp3278] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/08/2018] [Indexed: 01/13/2023]
Abstract
BACKGROUND Optimal treatment for patients with HCV genotype-3 infection and liver cirrhosis remains a medical priority. Daclatasvir+sofosbuvir and ribavirin is a recommended option for such patients, but clinical trial data are lacking for treatment >16 weeks. METHODS This was a single-arm, Phase III study of daclatasvir+sofosbuvir+ribavirin for 24 weeks in patients with compensated cirrhosis and HCV genotype-3 infection. The primary end point was sustained virological response at post-treatment week 12 (SVR12); the primary objective was to demonstrate statistical superiority to historical SVR12 data for 12 weeks' daclatasvir+sofosbuvir without ribavirin in genotype-3-infected patients with cirrhosis (95% CI lower bound >79.0%). RESULTS A total of 78 patients were treated (54 treatment-naive, 24 treatment-experienced including 8 with prior sofosbuvir exposure). SVR12 was achieved by 87% (68/78; 95% CI 77.7, 93.7%) of patients in the primary analysis of central laboratory data. One additional patient achieved SVR12 by local testing resulting in an overall SVR12 rate of 88% (95% CI 79.2, 94.6%) and the lower bound of the 95% CI above the historical threshold. SVR12 rates were 93% (50/54) for treatment-naive and 79% (19/24) for treatment-experienced patients. Of the nine non-SVR12 patients, four were lost to follow-up, two relapsed (both sofosbuvir-experienced), two had end-of-treatment virological failure and one discontinued early. There were no unexpected safety signals; only one patient discontinued for an adverse event. CONCLUSIONS Daclatasvir+sofosbuvir+ribavirin for 24 weeks was well tolerated and efficacious in HCV genotype-3-infected patients with compensated cirrhosis, with SVR12 outcomes comparable to previously reported outcomes in patients treated with this regimen for 12-16 weeks. ClinicalTrials.gov ID NCT02673489.
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Affiliation(s)
- Fred Poordad
- The Texas Liver Institute, University of Texas Health, San Antonio, TX, USA
| | - Mitchell L Shiffman
- Bon Secours Liver Institute of Richmond, Bon Secours Health System of Virginia, Richmond, VA, USA
| | | | - Alexander Wong
- Regina General Hospital, University of Saskatchewan, Regina, SK, Canada
| | | | - Florence Wong
- Toronto General Hospital, University of Toronto, Toronto, ON, Canada
| | - Alnoor Ramji
- Gastroenterology Division, St Paul's Hospital, Vancouver, BC, Canada
| | | | - Fiona McPhee
- Bristol-Myers Squibb Research and Development, Wallingford, CT, USA
| | - Rong Yang
- Bristol-Myers Squibb Research and Development, Wallingford, CT, USA
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Li X, Wang L, Gao P. Chronic hepatitis C virus infection: Relationships between inflammatory marker levels and compensated liver cirrhosis. Medicine (Baltimore) 2019; 98:e17300. [PMID: 31574855 PMCID: PMC6775411 DOI: 10.1097/md.0000000000017300] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
We investigated associations between inflammatory marker levels and hepatitis C virus (HCV)-related compensated liver cirrhosis risk in patients with chronic hepatitis C (CHC) infection in China. We used a case-control design and data from the records of 110 Chinese patients with CHC and cirrhosis for the study; 458 CHC patients who did not have a diagnosis of cirrhosis were matched to the case group by age and sex characteristics. We also investigated fatty liver disease risk factors. The group of patients with CHC infection and cirrhosis had lower platelet-to-lymphocyte ratio (PLR) values (60.63 [44.09, 89.31]) compared with the control group patients (80.24 [57.85, 111.08]). The results indicated that the group of patients with cirrhosis had higher 4-factor fibrosis index and aspartate aminotransferase (AST)-to-platelet ratio index (APRI) values compared with the group of patients with CHC-only (1.66 [0.98, 2.60] vs 0.71 [0.45, 1.17], respectively; P < .001 and 2.12 [0.97, 4.25] vs 0.99 [0.51, 2.01], respectively; P < .001). Compared with the control group, the AST/alanine aminotransferase ratio (AAR) values in the group of patients with cirrhosis were significantly higher (P < .001). Logistic regression analysis that included model adjustment for demographic characteristics and other factors that could affect cirrhosis risk revealed that greater 1/PLR values were associated with an increased odds of having cirrhosis (adjusted odds ratio [AOR], 95% confidence interval [CI] 0.991 [0.985-0.996]); APRI and AAR values were also independent predictors of the presence of compensated cirrhosis. We found that compared with the patients with CHC-only, the triglyceride, cholesterol, and low-density lipoprotein cholesterol levels in the patients with both CHC and fatty liver disease were significantly higher. The multivariate analysis of the risk of fatty liver development in patients with CHC infection found that cholesterol level was a statistically significant risk factor (AOR [95% CI] 1.380 [1.089-1.750], P = .008). Increased 1/PLR, APRI, and AAR values were associated with increased risks for development of cirrhosis in this population of Chinese patients with CHC infection. Higher cholesterol levels increased the risk of development of fatty liver disease in patients with CHC.
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Affiliation(s)
- Xu Li
- Department of Hepatology
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education
| | - Le Wang
- Department of Ultrasound, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Pujun Gao
- Department of Hepatology
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education
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45
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Wójcik K, Piekarska A, Dąbrowicz A, Stasiak M, Gawryś K, Jabłonowska E. Hepatic Expression of Phosphorylated Kinase Akt and Glycogen Synthase Kinase-3 Isoforms in Patients with Chronic Hepatitis C. Viral Immunol 2019; 32:179-185. [PMID: 31091179 DOI: 10.1089/vim.2018.0141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Some patients with chronic hepatitis C also demonstrate liver steatosis, but the mechanism remains elusive. To analyze the hepatic expression of phosphorylated kinase Akt at Thr 308 and phosphorylated GSK-3 (Glycogen synthase kinase-3) isoforms, GSK3α at Ser 21 and GSK3β at Ser 9, in chronic hepatitis C patients with normal body weight, glucose, and lipid profiles depending on homeostasis model assessment of insulin resistance (HOMA-IR) levels and histological parameters. The study group consisted of 31 patients with chronic hepatitis C. The hepatic expression of kinase Akt (Thr308), GSK3β (Ser9), and GSK3α (Ser21) was measured using Western blot assay. Liver steatosis was observed in 41.93% of patients with HCV infection, in those with increased HOMA-IR index (p = 0.02). However, the hepatic expression of Akt (Thr308), GSK3β (Ser9), and GSK3α (Ser21) was not related to progression of liver steatosis, inflammation, and fibrosis. There was no significant difference in the hepatic expression of kinase Akt (Thr308), GSK3β (Ser9), and GSK3α (Ser21) in relation to HOMA-IR. Liver steatosis was found to be positively associated with HOMA-IR levels in patients with chronic hepatitis C without metabolic disorders. However, the hepatic expression of Akt (Thr308), GSK3β (Ser9), and GSK3α (Ser21) did not correspond to progression of liver disease.
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Affiliation(s)
- Kamila Wójcik
- 1 Department of Infectious Diseases and Hepatology, Medical University of Lodz, Lodz, Poland
| | - Anna Piekarska
- 1 Department of Infectious Diseases and Hepatology, Medical University of Lodz, Lodz, Poland
| | - Alina Dąbrowicz
- 2 Department of Pathology, Bieganski Hospital of Lodz, Lodz, Poland
| | - Marta Stasiak
- 3 Department of Cytobiology and Proteomics, Medical University of Lodz, Lodz, Poland
| | - Katarzyna Gawryś
- 3 Department of Cytobiology and Proteomics, Medical University of Lodz, Lodz, Poland
| | - Elżbieta Jabłonowska
- 1 Department of Infectious Diseases and Hepatology, Medical University of Lodz, Lodz, Poland
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Zhang J, Gao X, Yuan Y, Sun C, Zhao Y, Xiao L, Yang Y, Gu Y, Yang R, Hu P, Zhang L, Wang C, Ye J. Perilipin 5 alleviates HCV NS5A-induced lipotoxic injuries in liver. Lipids Health Dis 2019; 18:87. [PMID: 30954078 PMCID: PMC6451786 DOI: 10.1186/s12944-019-1022-7] [Citation(s) in RCA: 8] [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: 12/20/2018] [Accepted: 03/19/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The homeostasis of lipid droplets (LDs) plays a crucial role in maintaining the physical metabolic processes in cells, and is regulated by many LD-associated proteins, including perilipin 5 (Plin5) in liver. As the putative sites of hepatitis C virus (HCV) virion assembly, LDs are vital to viral infection. In addition, the hepatic LD metabolism can be disturbed by non-structural HCV proteins, such as NS5A, but the details are still inexplicit. METHODS HCV NS5A was overexpressed in the livers and hepatocytes of wild-type and Plin5-null mice. BODIPY 493/503 and oil red O staining were used to detect the lipid content in mouse livers and hepatocytes. The levels of lipids, lipid peroxidation and inflammation biomarkers were further determined. Immunofluorescence assay and co-immunoprecipitation assay were performed to investigate the relationship of Plin5 and NS5A. RESULTS One week after adenovirus injection, livers expressing NS5A showed more inflammatory cell aggregation and more severe hepatic injuries in Plin5-null mice than in control mice, which was consistent with the increased serum levels of IL-2 and TNF-α (P < 0.05) observed in Plin5-null mice. Moreover, Plin5 deficiency in the liver and hepatocytes aggravated the elevation of MDA and 4-HNE levels induced by NS5A expression (P < 0.01). The triglyceride (TG) content was increased approximately 25% by NS5A expression in the wild-type liver and hepatocytes but was unchanged in the Plin5-null liver and hepatocytes. More importantly, Plin5 deficiency in the liver and hepatocytes exacerbated the elevation of non-esterified fatty acids (NEFAs) stimulated by NS5A expression (P < 0.05 and 0.01 respectively). Using triacsin C to block acyl-CoA biosynthesis, we found that Plin5 deficiency aggravated the NS5A-induced lipolysis of TG. In contrast, Plin5 overexpression in HepG2 cells ameliorated the NS5A-induced lipolysis and lipotoxic injuries. Immunofluorescent staining demonstrated that NS5A expression stimulated the targeting of Plin5 to the surface of the LDs in hepatocytes without altering the protein levels of Plin5. By co-IP, we found that the N-terminal domain (aa 32-128) of Plin5 was pivotal for its binding with NS5A. CONCLUSIONS Our data highlight a protective role of Plin5 against hepatic lipotoxic injuries induced by HCV NS5A, which is helpful for understanding the steatosis and injuries in liver during HCV infection.
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Affiliation(s)
- Jin Zhang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Xing Gao
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Yuan Yuan
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Chao Sun
- Department of Neurology, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Yuanlin Zhao
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Liming Xiao
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Ying Yang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Yu Gu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Risheng Yang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Peizhen Hu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Lijun Zhang
- Department of Clinical Laboratory Medicine, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, 710038, People's Republic of China
| | - Chao Wang
- Department of Pathology, The General Hospital of Western Theater Command, No. 270, Tianhui Road, Rongdu Avenue, Chengdu, 610083, People's Republic of China.
| | - Jing Ye
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China.
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de Matos MLM, Ferrufino RQ, Nastri ACDSS, Odongo FCA, Campos AF, Luiz AM, Lisboa-Neto G, Witkin SS, Mendes-Correa MC. Characteristics of a hepatitis C patient cohort at a specialized tertiary care facility: Identifying criteria to improve the allocation of public health resources. Clinics (Sao Paulo) 2019; 74:e1286. [PMID: 31664420 PMCID: PMC6807686 DOI: 10.6061/clinics/2019/e1286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 07/30/2019] [Indexed: 12/09/2022] Open
Abstract
OBJECTIVES Our objective was to analyze, in a population treated for hepatitis C infection at a tertiary care treatment unit, the prevalence of comorbidities and extrahepatic manifestations, the range and degree of the clinical complexity and the associations between advanced liver disease and clinical variables. METHODS Medical records from chronically infected hepatitis C patients seen at a dedicated treatment facility for complex cases in the Infectious Diseases Division of Hospital das Clínicas in Brazil were analyzed. Clinical complexity was defined as the presence of one or more of the following conditions: advanced liver disease (Metavir score F3 or F4 and/or clinical manifestations or ultrasound/endoscopy findings consistent with cirrhosis) or hepatocellular carcinoma and/or 3 or more extrahepatic manifestations and/or comorbidities concomitantly. RESULTS Among the 1574 patients analyzed, only 41% met the definition of being clinically complex. Cirrhosis or hepatocarcinoma was identified in 22.2% and 1.8% of patients, respectively. According to multiple logistic regression analysis, male sex (p=0.007), age>40 years (p<0.001) and the presence of metabolic syndrome (p=0.008) were independently associated with advanced liver disease. CONCLUSION The majority of patients did not meet the criteria for admittance to this specialized tertiary service, reinforcing the need to reevaluate public health policies. Enhanced utilization of existing basic and intermediate complexity units for the management of less complex hepatitis C cases could improve care and lower costs.
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Affiliation(s)
- Maria Laura Mariano de Matos
- Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, SP, BR
| | - Rosário Quiroga Ferrufino
- Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, SP, BR
| | | | | | - Aléia Faustina Campos
- Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, SP, BR
| | - André Machado Luiz
- Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, SP, BR
| | - Gaspar Lisboa-Neto
- Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, SP, BR
| | - Steven S. Witkin
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York (S.S.W.), USA
| | - Maria Cássia Mendes-Correa
- Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, SP, BR
- Laboratorio de Virologia – LIM 52, Instituto de Medicina Tropical (IMT), Sao Paulo, SP, BR
- *Corresponding author. E-mail:
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Gebrekristos G, Teweldemedhin M, Hagos L, Gebrewahid T, Gidey B, Gebreyesus H. Hepatitis C virus infections and associated risk factors in patients with diabetes mellitus; case control study in North West Tigray, Ethiopia. BMC Res Notes 2018; 11:873. [PMID: 30526647 PMCID: PMC6288925 DOI: 10.1186/s13104-018-3983-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 12/04/2018] [Indexed: 12/19/2022] Open
Abstract
Objective The objective of this study was to determine the seroprevalence of Hepatitis C virus among patients with Diabetes mellitus and healthy control groups in North West Tigray. Blood samples from each study subject was tested for Hepatitis C virus by using anti Hepatitis C virus antibody rapid test kits and confirmed using enzyme linked immuno sorbent assy. Result The overall seroprevalence of Hepatitis C virus, Hepatitis C virus among diabetic and non diabetic study subjects were found (16.7, 28, and 6) % respectively. Multi varate logistic regression analysis result shows that study subject with uvulotomy, previous history of immunosuppressive disease, and study subjects with fast blood glucose (≥ 126 mg/dl) showed statistically significant association with anti Hepatitis C virus antibody sero status [AOR (12.4 (3.5–18.3); 0.1 (0.03–0.5); and 8.6 (1.7–13)] respectively.
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Affiliation(s)
- Gebretsakan Gebrekristos
- Department of Medical Laboratory Sciences, College of Health Sciences, Aksum University, P.O. Box 298, Aksum, Tigray, Ethiopia.
| | - Mebrahtu Teweldemedhin
- Department of Medical Laboratory Sciences, College of Health Sciences, Aksum University, P.O. Box 298, Aksum, Tigray, Ethiopia
| | - Letebrhan Hagos
- Department of Medical Laboratory Sciences, College of Health Sciences, Aksum University, P.O. Box 298, Aksum, Tigray, Ethiopia
| | - Tuom Gebrewahid
- Department of Medical Laboratory Sciences, College of Health Sciences, Aksum University, P.O. Box 298, Aksum, Tigray, Ethiopia
| | - Berihu Gidey
- Department of Public Health, College of Health Science, Aksum University, Aksum, Tigray, Ethiopia
| | - Hailay Gebreyesus
- Department of Public Health, College of Health Science, Aksum University, Aksum, Tigray, Ethiopia
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Kim NH, Cho YK, Kim BI, Kim HJ. Effect of Metabolic Syndrome on the Clinical Outcomes of Chronic Hepatitis B Patients with Nucleos(t)ide Analogues Treatment. Dig Dis Sci 2018; 63:2792-2799. [PMID: 29948568 DOI: 10.1007/s10620-018-5165-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 06/05/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND No data are available about the effect of MS on oral nucleos(t)ide analogues (NUCs) treatment and clinical outcomes in chronic hepatitis B (CHB) patients. AIMS We aimed to elucidate whether coexistence of MS and CHB affects the long-term prognosis of CHB patients with oral NUCs treatment. METHODS We performed a retrospective data analysis for a total of 587 CHB patients who started oral NUCs treatment for the first time in our institution from January 2006 to March 2016. RESULTS Among the 587 patients, 70 (11.9%) had MS, but 517 (88.1%) had no evidence of MS when oral NUCs treatment was initiated. Cumulative occurrence rates of viral breakthrough, genotypic resistance, HCC, disease progression (PD), and overall adverse outcomes (OAO) were significantly higher in CHB patients with MS than in those without MS, although HBV-DNA suppression and cumulative occurrence rates of HBeAg negative conversion and seroconversion were not significantly different between the two groups. The overall survival (OS) was also significantly shorter in CHB patients with MS than in those without MS. Multivariate analysis indicated that the MS was an independent, poor prognostic factor for occurrence of genotypic resistance (adjusted hazard ratio [aHR], 22.3; 95% confidence interval [CI] 6.61-75.02; P < 0.001), HCC (aHR, 3.98; 95% CI 2.07-7.66; P < 0.001), PD (aHR, 6.18; 95% CI 3.43-11.14; P < 0.001), OAO (aHR, 8.10; 95% CI 4.68-14.02; P < 0.001), and OS (aHR, 12.29; 95% CI 2.25-67.24; P < 0.001). CONCLUSIONS MS is an independent determinant of poor prognosis in CHB patients receiving oral NUCs treatment.
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Affiliation(s)
- Nam Hee Kim
- Preventive Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong Kyun Cho
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29, Saemunan-Ro, Jongno-Gu, Seoul, 03181, Korea
| | - Byung Ik Kim
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29, Saemunan-Ro, Jongno-Gu, Seoul, 03181, Korea
| | - Hong Joo Kim
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29, Saemunan-Ro, Jongno-Gu, Seoul, 03181, Korea.
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50
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Zahra M, Azzazy H, Moustafa A. Transcriptional Regulatory Networks in Hepatitis C Virus-induced Hepatocellular Carcinoma. Sci Rep 2018; 8:14234. [PMID: 30250040 PMCID: PMC6155139 DOI: 10.1038/s41598-018-32464-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 09/04/2018] [Indexed: 01/09/2023] Open
Abstract
Understanding the transcriptional regulatory elements that influence the progression of liver disease in the presence of hepatitis C virus (HCV) infection is critical for the development of diagnostic and therapeutic approaches. Systems biology provides a roadmap by which these elements may be integrated. In this study, a previously published dataset of 124 microarray samples was analyzed in order to determine differentially expressed genes across four tissue types/conditions (normal, cirrhosis, cirrhosis HCC, and HCC). Differentially expressed genes were assessed for their functional clustering and those genes were annotated with their potential transcription factors and miRNAs. Transcriptional regulatory networks were constructed for each pairwise comparison between the 4 tissue types/conditions. Based on our analysis, it is predicted that the disruption in the regulation of transcription factors such as AP-1, PPARγ, and NF-κB could contribute to the liver progression from cirrhosis to steatosis and eventually to HCC. Whereas the condition of the liver digresses, the downregulation of miRNAs' (such as miR-27, Let-7, and miR-106a) expression makes the transition of the liver through each pathological stage more apparent. This preliminary data can be used to guide future experimental work. An understanding of the transcriptional regulatory attributes acts as a road map to help design interference strategies in order to target the key regulators of progression of HCV induced HCC.
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Affiliation(s)
- Marwa Zahra
- Biotechnology Graduate Program, American University, New Cairo, 11835, Egypt
| | - Hassan Azzazy
- Biotechnology Graduate Program, American University, New Cairo, 11835, Egypt. .,Department of Chemistry, The American University in Cairo, School of Sciences & Engineering, New Cairo, 11835, Egypt.
| | - Ahmed Moustafa
- Biotechnology Graduate Program, American University, New Cairo, 11835, Egypt.,Department of Biology, The American University in Cairo, New Cairo, 11835, Egypt
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