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1
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Sato-Espinoza K, Valdivia-Herrera M, Chotiprasidhi P, Diaz-Ferrer J. Hepatocellular carcinoma in patients without cirrhosis. World J Gastroenterol 2025; 31:107100. [DOI: 10.3748/wjg.v31.i23.107100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Revised: 04/22/2025] [Accepted: 05/27/2025] [Indexed: 06/20/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, the sixth most common cancer worldwide, and the third leading cause of cancer-related death. Cirrhosis is the predominant risk factor for HCC, driven by major etiologies including hepatitis B and C, excessive alcohol consumption, and metabolic dysfunction-associated steatotic liver disease (MASLD). While approximately 80% of HCC cases occur in patients with cirrhosis, its incidence among individuals without cirrhosis has significantly increased, particularly in developed countries, driven by the rising prevalence of MASLD. The prevalence of patients with non-cirrhotic HCC varies geographically, yet data on this subgroup remain limited. Consequently, screening and clinical management guidelines for patients with non-cirrhotic HCC are underdeveloped. Current surveillance is typically not recommended for non-cirrhotic populations, except for individuals with hepatitis B, and diagnostic criteria like Liver Imaging Reporting and Data System are designed explicitly for cirrhotic or hepatitis B-associated HCC. Furthermore, treatment strategies for non-cirrhotic HCC are often extrapolated from studies focused on patients with cirrhosis, leading to gaps in knowledge regarding treatment efficacy, survival outcomes, and etiological variability in non-cirrhotic cohorts. Thus, emerging evidence must be reviewed to guide the development of enhanced diagnostic and therapeutic strategies for patients with non-cirrhotic HCC. To address these gaps, we comprehensively reviewed the epidemiology, clinical and genetic characteristics, diagnostic modalities, and therapeutic approaches for patients with non-cirrhotic HCC.
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Affiliation(s)
- Karina Sato-Espinoza
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN 55902, United States
| | - Mayra Valdivia-Herrera
- Escuela de Medicina Humana, Facultad de Ciencias de la Salud, Universidad Cientifica del Sur, Lima 15067, Peru
| | - Perapa Chotiprasidhi
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN 55902, United States
| | - Javier Diaz-Ferrer
- Hepatology Service, Department of Digestive Diseases, Hospital Nacional Edgardo Rebagliati Martins, Lima 15072, Peru
- Department of Gastroenterology Service, Clinica Internacional, Lima 15036, Peru
- Medicine Faculty, Universidad San Martin de Porres, Lima 15024, Peru
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Soni L, Soopramanien J, Acharya A, Ashrafian H, Giannarou S, Fotiadis N, Darzi A. The use of machine learning in transarterial chemoembolisation/transarterial embolisation for patients with intermediate-stage hepatocellular carcinoma: a systematic review. LA RADIOLOGIA MEDICA 2025:10.1007/s11547-025-02013-y. [PMID: 40317437 DOI: 10.1007/s11547-025-02013-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/25/2025] [Indexed: 05/07/2025]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Intermediate-stage HCC is often treated with either transcatheter arterial chemoembolisation (TACE) or transcatheter arterial embolisation (TAE). Integrating machine learning (ML) offers the possibility of improving treatment outcomes through enhanced patient selection. This systematic review evaluates the effectiveness of ML models in improving the precision and efficacy of both TACE and TAE for intermediate-stage HCC. A comprehensive search of PubMed, EMBASE, Web of Science, and Cochrane Library databases was conducted for studies applying ML models to TACE and TAE in patients with intermediate-stage HCC. Seven studies involving 4,017 patients were included. All included studies were from China. Various ML models, including deep learning and radiomics, were used to predict treatment response, yielding a high predictive accuracy (AUC 0.90). However, study heterogeneity limited comparisons. While ML shows potential in predicting treatment outcomes, further research with standardised protocols and larger, multi-centre trials is needed for clinical integration.
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Affiliation(s)
- Lakshya Soni
- Institute of Global Health Innovation, Imperial College London, London, UK.
- Royal Marsden Hospital, London, UK.
| | | | - Amish Acharya
- Institute of Global Health Innovation, Imperial College London, London, UK
| | - Hutan Ashrafian
- Institute of Global Health Innovation, Imperial College London, London, UK
| | | | - Nicos Fotiadis
- Royal Marsden Hospital, London, UK.
- Institute of Cancer Research, London, UK.
| | - Ara Darzi
- Institute of Global Health Innovation, Imperial College London, London, UK
- Institute of Cancer Research, London, UK
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3
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Liu WJ, Wu WJ, Lin CL, Liu CJ, Huang YW, Hu JT, Yu MW. Impact of age at HBsAg seroclearance on hepatic outcomes and life expectancy in men with chronic HBV infection based on multi-state modeling of the natural history. J Gastroenterol 2025; 60:107-117. [PMID: 39438326 DOI: 10.1007/s00535-024-02162-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 10/13/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND The effects of age at HBsAg seroclearance on clinical outcomes and survival in chronic hepatitis B (CHB) have not been adequately assessed. We evaluated the impact of age at HBsAg seroclearance on long-term outcomes, along with how coexisting factors modified risks and life expectancy in CHB patients. METHODS We used multi-state modeling approach to examine transitions through the CHB continuum in a longitudinal cohort study of male civil servants recruited in 1989-1992. Hepatic outcomes and deaths were identified by clinical evaluation and linkage with national health databases. Four sets of risk factors (CHB-related, metabolic, lifestyle, and genetic factors) were assessed. RESULTS Of 2551 HBsAg carriers, with follow-up until 2021 or death, 695 achieved HBsAg seroclearance, 490 developed cirrhosis (88 decompensated), 252 developed hepatocellular carcinoma (HCC), and 652 died. The cumulative rates for HCC were 1.1% and 1.5% at 10 years after HBsAg seroclearance, respectively, for patients achieving seroclearance at age 50 and 60; correspondingly, the rates for cirrhosis were 2.3% and 3.0%. Developing HBsAg seroclearance was associated with a reduced risk of cirrhosis (HR = 0.37, 95% CI 0.15-0.92) but not HCC. Patients experiencing HBsAg seroclearance lived longer years free of major liver diseases than HBsAg-persistent patients, and achieving seroclearance at age 50 (vs 60) led to a greater increase in the disease-free life expectancy. However, obesity and smoking were associated with adverse hepatic outcomes and loss of the disease-free life expectancy following HBsAg seroclearance. CONCLUSIONS Our findings highlight the benefit of earlier HBsAg seroclearance for gains in disease-free life expectancy and the impact of obesity and smoking on loss of the life years free of major liver diseases following HBsAg seroclearance.
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Affiliation(s)
- Wen-Jie Liu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 522 No.17, Xuzhou Road, Zhongzheng, Taipei, 10055, Taiwan
| | - Wan-Jung Wu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 522 No.17, Xuzhou Road, Zhongzheng, Taipei, 10055, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Wen Huang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jui-Ting Hu
- Liver Center, Cathay General Hospital Medical Center, School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan
| | - Ming-Whei Yu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 522 No.17, Xuzhou Road, Zhongzheng, Taipei, 10055, Taiwan.
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4
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He C, Wu X, You Z, Zhou T, Diao L, Yang Y, Wu L, Yang X, Xu Z, Zhao X, Chen Z, Lin Q, Huang H, Xu X, Zhang M, Wang Y. Evaluation of genotype characteristics and drug resistance mutations in patients with chronic hepatitis B. Sci Rep 2024; 14:27575. [PMID: 39528567 PMCID: PMC11555265 DOI: 10.1038/s41598-024-77362-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Hepatitis B is one of the public health priorities worldwide, especially in the Southwest China. Our study aimed to investigate the relationship between genotypes and drug resistance mutations among HBV patients in Southwest China, with the objective of providing guidance for clinical antiviral treatment. A total of 4266 chronic hepatitis B (CHB) patients treated in the Qianjiang Hospital of Chongqing University were included in our study from 2014 to 2020. Both genotypes and drug-resistant mutations of CHB patients were determined by polymerase chain reaction (PCR). Genotype B and genotype C were the main HBV genotypes in our study. We found 54 mutation patterns, including 9 single-site mutations and 45 multiple-site mutations, accounting for 57.64% and 42.36%, respectively. rtM204I/V/S (485/1936) was the most common single-site mutation type, and rtL180M + rtM204I/V (482/1936) was the most common multiple-site mutation type. 1372 CHB patients were resistant to LAM + LDT, and 342 CHB patients were resistant to ADV. There was only 1 CHB patient who exhibited resistance to LAM + LDT + ADV + ETV, with a specific mutation pattern of rtA181T + rtT184L + rtM204V. Our study demonstrated trends in genetic mutations and drug resistance in CHB patients to enable timely adjustment of antiviral treatment strategies.
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Affiliation(s)
- Changlong He
- Department of Clinical Laboratory, People's Hospital of Jiulongpo District, Chongqing, 400050, China
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Yixue Yuan Road No. 1, Chongqing, 400016, China
| | - Xiaoli Wu
- Department of Clinical Laboratory, Chengdu Sixth People's Hospital, 16 Jianshe South Street, Chenghua District, Chengdu, 610051, China
| | - Zhonglan You
- Department of Infectious Diseases, The First Hospital Affiliated to the Army Medical University (AMU), Chongqing, 400038, China
| | - Tao Zhou
- Department of hepatobiliary Surgery, Chongqing Qianjiang Center Hospital, Chongqing University Qianjiang Hospital, No. 360 South Section, Zhengzhou Road, Qianjiang District, Chongqing, 409000, China
| | - Liping Diao
- Physical Examination Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Ying Yang
- Department of Pain Management, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Liqun Wu
- Advanced Nursing, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Xiaoying Yang
- Department of Clinical Laboratory, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Zhousong Xu
- Department of Clinical Laboratory, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Xiaohong Zhao
- Department of Clinical Laboratory, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Zhongping Chen
- Department of Clinical Laboratory, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Qing Lin
- Department of Infectious Disease, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Huacui Huang
- Department of Clinical Laboratory, People's Hospital of Xindu District, Chengdu, 610599, China
| | - Xin Xu
- Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Mingjun Zhang
- Department of Clinical Laboratory, People's Hospital of Jiulongpo District, Chongqing, 400050, China.
| | - Yonghong Wang
- Department of Clinical Laboratory, Chongqing Qianjiang Central Hospital, Qianjiang Key Laboratory of Chongqing Qianjiang Central Hospital Laboratory Medicine, Chongqing University Qianjiang Hospital, No. 360 South Section, Zhengzhou Road, Qianjiang District, Chongqing, 409000, China.
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Sukowati CHC, Jayanti S, Turyadi T, Muljono DH, Tiribelli C. Hepatitis B virus genotypes in precision medicine of hepatitis B-related hepatocellular carcinoma: Where we are now. World J Gastrointest Oncol 2024; 16:1097-1103. [PMID: 38660644 PMCID: PMC11037070 DOI: 10.4251/wjgo.v16.i4.1097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 01/30/2024] [Accepted: 03/06/2024] [Indexed: 04/10/2024] Open
Abstract
Hepatitis B virus (HBV) infection is a major player in chronic hepatitis B that may lead to the development of hepatocellular carcinoma (HCC). HBV genetics are diverse where it is classified into at least 9 genotypes (A to I) and 1 putative genotype (J), each with specific geographical distribution and possible different clinical outcomes in the patient. This diversity may be associated with the precision medicine for HBV-related HCC and the success of therapeutical approaches against HCC, related to different pathogenicity of the virus and host response. This Editorial discusses recent updates on whether the classification of HBV genetic diversity is still valid in terms of viral oncogenicity to the HCC and its precision medicine, in addition to the recent advances in cellular and molecular biology technologies.
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Affiliation(s)
- Caecilia H C Sukowati
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia, Jakarta 10340, Indonesia
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
| | - Sri Jayanti
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia, Jakarta 10340, Indonesia
| | - Turyadi Turyadi
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia, Jakarta 10340, Indonesia
| | - David H Muljono
- Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
- Faculty of Medicine and Health, University of Sydney, Sydney 2050, Australia
| | - Claudio Tiribelli
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
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6
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Hao X, Fan R, Zeng HM, Hou JL. Hepatocellular Carcinoma Risk Scores from Modeling to Real Clinical Practice in Areas Highly Endemic for Hepatitis B Infection. J Clin Transl Hepatol 2023; 11:1508-1519. [PMID: 38161501 PMCID: PMC10752803 DOI: 10.14218/jcth.2023.00087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/04/2023] [Accepted: 06/02/2023] [Indexed: 01/03/2024] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and represents a global health challenge. Liver cancer ranks third in cancer-related mortality with 830,000 deaths and sixth in incidence with 906,000 new cases annually worldwide. HCC most commonly occurs in patients with underlying liver disease, especially chronic hepatitis B virus (HBV) infection in highly endemic areas. Predicting HCC risk based on scoring models for patients with chronic liver disease is a simple, effective strategy for identifying and stratifying patients to improve the early diagnosis rate and prognosis of HCC. We examined 23 HCC risk scores published worldwide in CHB patients with (n=10) or without (n=13) antiviral treatment. We also described the characteristics of the risk score's predictive performance and application status. In the future, higher predictive accuracy could be achieved by combining novel technologies and machine learning algorithms to develop and update HCC risk score models and integrated early warning and diagnosis systems for HCC in hospitals and communities.
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Affiliation(s)
- Xin Hao
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Institute of Liver Diseases, Guangzhou, Guangdong, China
| | - Rong Fan
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Institute of Liver Diseases, Guangzhou, Guangdong, China
| | - Hong-Mei Zeng
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jin-Lin Hou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Institute of Liver Diseases, Guangzhou, Guangdong, China
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7
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Aasarey R, Yadav K, Kashyap BK, Prabha S, Kumar P, Kumar A, Ruokolainen J, Kesari KK. Role of Immunological Cells in Hepatocellular Carcinoma Disease and Associated Pathways. ACS Pharmacol Transl Sci 2023; 6:1801-1816. [PMID: 38093838 PMCID: PMC10714437 DOI: 10.1021/acsptsci.3c00216] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/12/2023] [Accepted: 10/13/2023] [Indexed: 03/28/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the predominant causes of cancer-related mortality across the globe. It is attributed to obesity, excessive alcohol consumption, smoking, and infection by the hepatitis virus. Early diagnosis of HCC is essential, and local treatments such as surgical excision and percutaneous ablation are effective. Palliative systemic therapy, primarily with the tyrosine kinase inhibitor Sorafenib, is used in advanced cases. However, the prognosis for advanced HCC remains poor. This Review additionally describes the pathophysiological mechanisms of HCC, which include aberrant molecular signaling, genomic instability, persistent inflammation, and the paradoxical position of the immune system in promoting and suppressing HCC. The paper concludes by discussing the growing body of research on the relationship between mitochondria and HCC, suggesting that mitochondrial dysfunction may contribute to the progression of HCC. This Review focuses on immunological interactions between different mechanisms of HCC progression, including obesity, viral infection, and alcohol consumption.
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Affiliation(s)
- Ram Aasarey
- Department
of Laboratory Medicine, All India Institute
of Medical Science, New Delhi-11029, India
| | - Kajal Yadav
- Department
of Biotechnology, All India Institute of
Medical Science, New Delhi-11029, India
| | - Brijendra Kumar Kashyap
- Department
of Biotechnology Engineering, Institute of Engineering and Technology, Bundelkhand University, Jhansi-284128, Uttar Pradesh, India
| | - Sarit Prabha
- Department
of Biological Science and Engineering, Maulana
Azad National Institute of Technology, Bhopal-462003, Madhya Pradesh,India
| | - Pramod Kumar
- Indian
Council of Medical Research, National Institute
of Cancer Prevention and Research (NICPR), l-7, Sector-39, Noida-201301, National Capital Region, India
| | - Anil Kumar
- Department
of Life Sciences, School of Natural Sciences, Central University of Jharkhand, Cheri-Manatu, Karmre, Kanke-835222, Ranchi, India
| | - Janne Ruokolainen
- Department
of Applied Physics, School of Science, Aalto
University, FI-00076 Espoo, Finland
| | - Kavindra Kumar Kesari
- Department
of Applied Physics, School of Science, Aalto
University, FI-00076 Espoo, Finland
- Research
and Development Cell, Lovely Professional
University, Phagwara-144411, Punjab, India
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8
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Keeshan A, da Silva CF, Vachon A, Giles E, Osiowy C, Coffin C, Cooper CL. Hepatitis B Virus Genotype Influence on Virological and Enzymatic Measures over Time-A Retrospective Longitudinal Cohort Study. J Clin Med 2023; 12:6807. [PMID: 37959272 PMCID: PMC10649073 DOI: 10.3390/jcm12216807] [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: 09/14/2023] [Revised: 10/12/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
HBV is a hepatotropic virus with multiple genotypes. It is uncertain if specific genotype(s) influence virological measures and/or liver markers over time. It is unclear whether nucleos(t)ide analogue therapy response is influenced by genotype. In this retrospective longitudinal study, we utilized data from The Ottawa Hospital Viral Hepatitis Program (TOHVHP) to evaluate the role of HBV genotype on viral load, liver enzymatic levels, fibrosis progression, and parenchymal inflammation and steatosis over time. HBV DNA, ALT, and AST levels, as well as transient elastography scores for fibrosis (E) and inflammation/steatosis (CAP), were modeled using mixed-effects linear regression. Interaction terms between HBV genotype and time were included to investigate if there was a difference in trends between genotypes. A total of 393 HBV patients infected with genotypes A-E were included. The mean age was 44.4 years, and 56% were male. Asian (50.5%), Black (29.1%), and White (6.4%) patients were well-represented. By multivariate analysis, we found no evidence that the trajectories of these commonly measured viral or liver measures varied over time by HBV genotype in those receiving HBV nucleos(t)ides and in those not on antiviral therapy.
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Affiliation(s)
- Alexa Keeshan
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | | | - Alicia Vachon
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
- Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Elizabeth Giles
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R2C 3A9, Canada
| | - Carla Osiowy
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R2C 3A9, Canada
| | - Carla Coffin
- Department of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Curtis L. Cooper
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON K1N 6N5, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
- Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
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Fernandes da Silva C, Keeshan A, Cooper C. Hepatitis B virus genotypes influence clinical outcomes: A review. CANADIAN LIVER JOURNAL 2023; 6:347-352. [PMID: 38020195 PMCID: PMC10652982 DOI: 10.3138/canlivj-2023-0003] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/28/2023] [Indexed: 12/01/2023]
Abstract
Hepatitis B virus (HBV) is a hepatotropic virus that affects approximately 296 million people worldwide. A crucial step to HBV replication is the transcription of its infectious DNA from its viral RNA intermediate. The production of the RNA intermediate hinges on reverse transcription, and therefore the lack of proofreading in that process commonly yields mutants and has led to nine well-described genotypes (A-I) and over 30 known sub-genotypes of the virus. The influence of genotype on HBV infection outcomes, which include fibrosis progression, cirrhosis, and hepatocellular carcinoma (HCC), remain uncertain. This review aims to analyze the influence of HBV genotype on the risk of development of these outcomes. The response to current and future HBV therapies is considered. Further study of larger and more diverse samples will hopefully resolve outstanding uncertainties.
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Affiliation(s)
| | - Alexa Keeshan
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Curtis Cooper
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
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10
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Wu WJ, Lin CL, Liu CJ, Huang YW, Hu JT, Yu MW. Lifetime risk of liver-related outcomes and determinants in male inactive carriers of chronic hepatitis B. J Med Virol 2023; 95:e29138. [PMID: 37796044 DOI: 10.1002/jmv.29138] [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: 06/05/2023] [Revised: 09/11/2023] [Accepted: 09/19/2023] [Indexed: 10/06/2023]
Abstract
The full spectrum of risks for the life course of inactive hepatitis B virus (HBV) carriers remains unclear. In this study, 995 untreated HBV carriers (median age: 42.8 years; median follow-up: 30.2 years) were included. Their data were sourced from a population-based cohort study of male civil servants recruited in 1989-1992. Outcomes were identified by active follow-up examinations and linkage with national health insurance research database. At baseline, 483 subjects were inactive carriers, 385 with indeterminate phase, and 127 with other phases. The joint lifetime risk for incident cirrhosis, decompensation, hepatocellular carcinoma, and liver-related deaths was lower for inactive carriers compared to subjects in other phases (p < 0.0001). There was a trend of increase in incidence among inactive carriers; the 5-, 10-, and 20-year cumulative incidences were 1.86%, 6.03%, and 10.07%, respectively. Of the inactive carriers, 37.7% cleared HBsAg and 36.6% had biochemical relapse during the study. Biochemical relapse, obesity, and advanced age were predictors for disease progression in inactive carriers. Virological relapse was the predominant cause of biochemical relapse. Higher HBV-DNA levels (≥1000 copies/mL or 200 IU/mL) and HBV genotype B (vs. C) were associated with higher virological relapse rate. After 30 years, we found that one-time measure of inactive carrier state continued to have the lowest risk compared with other infection phases. Despite a more favorable prognosis, inactive carriers had a non-negligible risk. Our findings of lifetime risk may provide important clues for the management of such patients and consideration of therapeutic strategies aiming to achieve functional cure.
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Affiliation(s)
- Wan-Jung Wu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Wen Huang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jui-Ting Hu
- Liver Center, Cathay General Hospital Medical Center, School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan
| | - Ming-Whei Yu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
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11
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Ahmed K, Jha S. Oncoviruses: How do they hijack their host and current treatment regimes. Biochim Biophys Acta Rev Cancer 2023; 1878:188960. [PMID: 37507056 DOI: 10.1016/j.bbcan.2023.188960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/05/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023]
Abstract
Viruses have the ability to modulate the cellular machinery of their host to ensure their survival. While humans encounter numerous viruses daily, only a select few can lead to disease progression. Some of these viruses can amplify cancer-related traits, particularly when coupled with factors like immunosuppression and co-carcinogens. The global burden of cancer development resulting from viral infections is approximately 12%, and it arises as an unfortunate consequence of persistent infections that cause chronic inflammation, genomic instability from viral genome integration, and dysregulation of tumor suppressor genes and host oncogenes involved in normal cell growth. This review provides an in-depth discussion of oncoviruses and their strategies for hijacking the host's cellular machinery to induce cancer. It delves into how viral oncogenes drive tumorigenesis by targeting key cell signaling pathways. Additionally, the review discusses current therapeutic approaches that have been approved or are undergoing clinical trials to combat malignancies induced by oncoviruses. Understanding the intricate interactions between viruses and host cells can lead to the development of more effective treatments for virus-induced cancers.
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Affiliation(s)
- Kainat Ahmed
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA
| | - Sudhakar Jha
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA.
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12
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Okumura T, Joshita S, Iwadare T, Wakabayashi SI, Kobayashi H, Yamashita Y, Sugiura A, Kimura T, Umemura T. Kinetics of serum O-glycosylated M-hepatitis B surface antigen with hepatocellular carcinoma history and nucleos(t)ide analogue therapy in hepatitis B patients. J Viral Hepat 2023; 30:731-739. [PMID: 37363934 DOI: 10.1111/jvh.13869] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 05/13/2023] [Accepted: 06/18/2023] [Indexed: 06/28/2023]
Abstract
A newly developed O-glycosylated M-hepatitis B surface antigen (HBsAgGi) measurement system can detect hepatitis B surface antigen (HBsAg) associated with infectious particles. We investigated the association of HBsAgGi levels with clinical parameters and a history of hepatocellular carcinoma (HCC) development in a cross-sectional cohort analysis (Study 1) as well as the quantitative changes in HBsAgGi during nucleos(t)ide analogue (NA) therapy in a longitudinal cohort analysis (Study 2). A total of 124 patients with genotype C chronic HBV infection were analysed in Study 1 to evaluate correlations of HBsAgGi with conventional HBV markers and HCC history. Among those, 36 patients receiving NA therapy were enrolled in Study 2 for quantitative comparisons between pre-treatment baseline and 48 weeks of NA therapy. In Study 1, serum HBsAgGi was significantly associated with HBsAg (r = .5857, p < .00001) and weakly but significantly correlated with HBV DNA (r = .2936, p = .001). Although HBsAgGi (p = .111) was comparable between HCC history (+) group and HCC history (-) group, the HBsAgGi/HBsAg ratio (p = .011) was significantly higher in HCC history (+) patients. In Study 2, HBsAgGi was significantly decreased after 48 weeks of NA therapy (p < .001). HBsAg findings were similar (p = .005) along with an HBV DNA reduction (p < .001). In the baseline hepatitis B e antigen (HBeAg) (+) subgroup, HBsAgGi decreased significantly between baseline and 48 weeks of NA (p = .005), while HBsAg was comparable (p = .051). Low HBsAg and high HBsAgGi were associated with a history of HCC development. HBsAgGi decreased significantly by 48-week NA therapy.
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Affiliation(s)
- Taiki Okumura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Health Promotion Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takanobu Iwadare
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shun-Ichi Wakabayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hiroyuki Kobayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Health Promotion Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ayumi Sugiura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takefumi Kimura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Health Promotion Medicine, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Advanced Endoscopic Therapy, Shinshu University School of Medicine, Matsumoto, Japan
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan
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13
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Raihan R, Akbar SMF. A Narrative Review on the Specific Pattern of HBV Genotype in Bangladesh: Clinical Implications for Management. Euroasian J Hepatogastroenterol 2023; 13:152-158. [PMID: 38222956 PMCID: PMC10785131 DOI: 10.5005/jp-journals-10018-1412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 11/21/2023] [Indexed: 01/16/2024] Open
Abstract
Background and aims Bangladesh's unique epidemiological landscape presents an intriguing puzzle. This South Asian nation, with its complex sociodemographic and environmental factors, is home to a diverse array of hepatitis-B virus (HBV) genotypes, identified as Genotype C, with Genotypes D and A also making a significant contribution to the viral landscape. Reviewing such insights is necessary not only to underscore the country's regional diversity in HBV strains but also to bring into focus the clinical implications these genetic variations may have on disease progression and management. Methods A thorough database search covered various sources using relevant keywords like "Hepatitis B virus genotypes", "HBV genotypes in Bangladesh", and "HBV clinical implications". The review synthesized findings and analyzed HBV genotype prevalence and clinical implications in Bangladesh. Results Genotypes C and D collectively represent 82% of chronic hepatitis-B infection (CHB) cases in Bangladesh, underscoring their regional prevalence. The geographic context is pivotal in understanding HBV infection dynamics and disease progression in this area. Notably, genotype C and the presence of A1762T/G1764A mutations appear to have a distinct impact on disease development, potentially affecting the immune response in CHB patients. This highlights the need for tailored management approaches in this specific region. Further research is vital to confirm and elaborate on these findings, particularly in relation to how these mutations influence the host's immune response. Conclusion and clinical significance In summary, studies on HBV genotypes in Bangladesh stress the need for genotype-specific clinical considerations and more research to improve diagnostics and therapies. How to cite this article Raihan R, Akbar SMF. A Narrative Review on the Specific Pattern of HBV Genotype in Bangladesh: Clinical Implications for Management. Euroasian J Hepato-Gastroenterol 2023;13(2):152-158.
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Affiliation(s)
- Ruksana Raihan
- Department of Microbiology, US Bangla Medical College and Hospital, University of Malaya, Dhaka, Bangladesh
| | - Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine; Research Center for Global and Local Infectious Diseases, Faculty of Medicine, Oita University, Oita; Miyakawa Memorial Research Foundation, Tokyo, Japan
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14
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Kwon H, Kim J, Song C, Sajjad MA, Ha J, Jung J, Park S, Shin HJ, Kim K. Peptidyl-prolyl cis/trans isomerase Pin1 interacts with hepatitis B virus core particle, but not with HBc protein, to promote HBV replication. Front Cell Infect Microbiol 2023; 13:1195063. [PMID: 37404723 PMCID: PMC10315659 DOI: 10.3389/fcimb.2023.1195063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/01/2023] [Indexed: 07/06/2023] Open
Abstract
Here, we demonstrate that the peptidyl-prolyl cis/trans isomerase Pin1 interacts noncovalently with the hepatitis B virus (HBV) core particle through phosphorylated serine/threonine-proline (pS/TP) motifs in the carboxyl-terminal domain (CTD) but not with particle-defective, dimer-positive mutants of HBc. This suggests that neither dimers nor monomers of HBc are Pin1-binding partners. The 162TP, 164SP, and 172SP motifs within the HBc CTD are important for the Pin1/core particle interaction. Although Pin1 dissociated from core particle upon heat treatment, it was detected as an opened-up core particle, demonstrating that Pin1 binds both to the outside and the inside of the core particle. Although the amino-terminal domain S/TP motifs of HBc are not involved in the interaction, 49SP contributes to core particle stability, and 128TP might be involved in core particle assembly, as shown by the decreased core particle level of S49A mutant through repeated freeze and thaw and low-level assembly of the T128A mutant, respectively. Overexpression of Pin1 increased core particle stability through their interactions, HBV DNA synthesis, and virion secretion without concomitant increases in HBV RNA levels, indicating that Pin1 may be involved in core particle assembly and maturation, thereby promoting the later stages of the HBV life cycle. By contrast, parvulin inhibitors and PIN1 knockdown reduced HBV replication. Since more Pin1 proteins bound to immature core particles than to mature core particles, the interaction appears to depend on the stage of virus replication. Taken together, the data suggest that physical association between Pin1 and phosphorylated core particles may induce structural alterations through isomerization by Pin1, induce dephosphorylation by unidentified host phosphatases, and promote completion of virus life cycle.
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Affiliation(s)
- Hyeonjoong Kwon
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Jumi Kim
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Chanho Song
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Muhammad Azhar Sajjad
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Jiseon Ha
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Jaesung Jung
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Sun Park
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Ho-Joon Shin
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Kyongmin Kim
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
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15
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Fu Y, Fang F, Guo H, Xiao X, Hu Y, Zeng Y, Chen T, Wu S, Lin N, Huang J, Jiang L, Ou Q, Liu C. Compartmentalisation of Hepatitis B virus X gene evolution in hepatocellular carcinoma microenvironment and the genotype-phenotype correlation of tumorigenicity in HBV-related patients with hepatocellular carcinoma. Emerg Microbes Infect 2022; 11:2486-2501. [PMID: 36102940 PMCID: PMC9621239 DOI: 10.1080/22221751.2022.2125344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 08/26/2022] [Accepted: 09/12/2022] [Indexed: 02/08/2023]
Abstract
Hepatitis B virus (HBV) exists as quasispecies (QS). However, the evolutionary characteristics of haplotypes of HBV X gene in the hepatocellular carcinoma (HCC) microenvironment remain unclear. Mutations across X gene are essential for the tumorigenicity of HBV X protein (HBx). However, the functional phenotypes of many mutant HBx remain unknown. This study aims to compare the characteristics of X gene evolution between tumour and non-tumour tissues in HCC patients and investigate the tumorigenic phenotype of HBx harbouring mutation T81P/S101P/L123S. This study included 24 HCC patients. Molecular cloning of X gene was performed to analyse characteristics of haplotypes in liver tissues. HCC cell lines stably expressing wild-type or mutant HBx and subcutaneous tumour xenograft mouse model were used to assess HBx-T81P/S101P/L123S tumorigenicity. The mean heterogeneity of HBV QS across X gene in tumour tissues was lower than that in non-tumour tissues. A location bias was observed in X gene clones with genotype C or D in tumour tissues compared to those with genotype B. Mutations in genotype-C or - D clones were mainly clustered in the dimerization region and aa110-aa140 within the transactivation region. A novel mutation combination at residues 81, 101 and 123 was identified in tumour tissues. Further, HBx-T81P/S101P/L123S promotes cell proliferation and increases genomic instability, which was mediated by MYC. This study elucidates the compartmentalized evolution patterns of HBV X gene between intra tumour and non-tumour tissues in HCC patients and provides a new mechanism underlying HBV-driven hepatocarcinogenesis, suggesting a potential viral marker for monitoring HCC.
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Affiliation(s)
- Ya Fu
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Fengling Fang
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Hongyan Guo
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Xialin Xiao
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Yuhai Hu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Yongbin Zeng
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Tianbin Chen
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Songhang Wu
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Ni Lin
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Jinlan Huang
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Ling Jiang
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Qishui Ou
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
- Qishui Ou Department of Laboratory Medicine, The First Affiliated Hospital, Clinical Laboratory Diagnostics, The First Clinical College, Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Can Liu
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
- Can Liu Department of Laboratory Medicine, The First Affiliated Hospital, Clinical Laboratory Diagnostics, The First Clinical College, Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, People’s Republic of China
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16
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Afifi AM, Elgenidy A, Hashim M, Awad AK, Jalal PK. Hepatitis B virus core-related antigen (HBcrAg) as a prognostic marker for the development of hepatocellular carcinoma: A mini systematic review of the literature. Rev Med Virol 2022; 32:e2353. [PMID: 35441759 DOI: 10.1002/rmv.2353] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 03/17/2022] [Accepted: 03/25/2022] [Indexed: 11/07/2022]
Abstract
Chronic hepatitis B (CHB) infection is a risk factor for hepatocellular carcinoma (HCC). Previous studies showed that elevated levels of Hepatitis B Virus (HBV) DNA and HBsAg are associated with increased HCC risk in patients with chronic HBV infection. Multiple studies showed that high levels of HBV DNA and Hepatitis B Surface Antigen (HBsAg) are associated with higher HCC risk in CHB patients. Patients treated with antiviral therapy may have undetectable or low levels of HBV DNA and HBsAg loss. However, HCC may develop in some patients with low-level HBV DNA and HBsAg seroconversion. In this study, we evaluated the role of HBcrAg in predicting HBV related HCC development. We searched PubMed, Scopus, and Web of Science databases using keywords (hepatitis B core-related antigen, hepatocellular carcinoma, liver neoplasm, hepatocellular and hepatic cancer, to identify studies assessing serum level of HBcrAg in patients with CHB and HCC. The search resulted in 184 studies. Seven studies were included: Four of which were retrospective cohort studies, and the rest were prospective cohort, case controls. Six of them reported a higher HBcrAg positivity rate in the HCC group when compared with the HBV DNA assay, yet with similar hazard ratio (HR) in predicting the incidence of HCC. However, four studies found that HBcrAg positivity was an independent risk factor for HCC development with a HR ranging from 3.27 to 7.05. HBV-related HCC has many proposed biomarkers in its prediction, yet our findings revealed HBcrAg to may have superiority over other biomarkers. High quality studies with bigger sample size research is needed to understand the potential role of HBcrAg in CHB induced HCC.
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Affiliation(s)
- Ahmed M Afifi
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
| | | | - Mahmoud Hashim
- Gastrointestinal Medical Oncology Department, MD Anderson Cancer Center, Houston, Texas, USA
| | - Ahmed K Awad
- Faculty of Medicine, Ain-Shams University, Cairo, Egypt
| | - Prasun K Jalal
- Baylor College of Medicine Departments of Medicine and Surgery Physician (non-surgery), Houston, Texas, USA
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Sayaf K, Gabbia D, Russo FP, De Martin S. The Role of Sex in Acute and Chronic Liver Damage. Int J Mol Sci 2022; 23:10654. [PMID: 36142565 PMCID: PMC9505609 DOI: 10.3390/ijms231810654] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Acute and chronic hepatic damages are caused by xenobiotics or different diseases affecting the liver, characterized by different etiologies and pathological features. It has been demonstrated extensively that liver damage progresses differently in men and women, and some chronic liver diseases show a more favorable prognosis in women than in men. This review aims to update the most recent advances in the comprehension of the molecular basis of the sex difference observed in both acute and chronic liver damage. With this purpose, we report experimental studies on animal models and clinical observations investigating both acute liver failure, e.g., drug-induced liver injury (DILI), and chronic liver diseases, e.g., viral hepatitis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), autoimmune liver diseases, and hepatocellular carcinoma (HCC).
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Affiliation(s)
- Katia Sayaf
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35131 Padova, Italy
| | - Daniela Gabbia
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35131 Padova, Italy
- Gastroenterology and Multivisceral Transplant Units, Azienda Ospedale—Università di Padova, 35131 Padova, Italy
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
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18
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Liver Histology of Treatment-Naïve Children with Chronic Hepatitis B Virus Infection in Shanghai China. Int J Infect Dis 2022; 123:112-118. [PMID: 36028208 DOI: 10.1016/j.ijid.2022.08.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 08/05/2022] [Accepted: 08/17/2022] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND & AIMS Chronic hepatitis B (CHB) is associated with high morbidity and mortality. We aimed to investigate associations between hepatic histology and clinical characteristics in treatment-naïve children with CHB in Shanghai, China. METHODS The liver biopsy specimens of 278 treatment-naïve children with CHB virus infection were scored for inflammation and fibrosis, and correlations with clinical and laboratory data were determined. RESULTS CHB clinical, virologic and pathologic features were studied in 278 treatment-naïve children (177 males (63.7%)) from Shanghai, China. Maternal sera were hepatitis B surface antigen (HBsAg) positive for 277 children. At biopsy, 87.4% of patients were hepatitis B e antigen positive. The median age at biopsy was 5.1 years (interquartile range 2.8-8.4 years). Hepatitis B virus (HBV) DNA levels were generally high (mean 7.4 log10 IU/ml), as were levels of serum alanine aminotransferase (ALT, median 105 U/L). Using the Metavir histology activity index scoring system, no, mild, moderate and severe inflammation was seen in 2.9%, 22.3%, 73.4%, and 1.4% of patients, respectively. No fibrosis, mild fibrosis, moderate fibrosis, and cirrhosis was seen in 11.5%, 32.7%, 47.5%, and 8.3% of patients, respectively. When the serum ALT level was ≤80 (2× the upper limit of normal) and >80 U/L, the inflammation score (P<0.0001) was significantly different. And the fibrosis score was significantly different (P<0.0001), either. Inflammation and fibrosis were aggravated with increasing ALT levels. Fibrosis scores were significantly higher in children aged ≤3 than aged >3 years (P<0.0001). The rates of moderate fibrosis and cirrhosis were higher in children aged ≤3 years at biopsy. No correlations were found between histologic changes and sex, HBV genotype or HBV DNA level. CONCLUSION Substantial heterogeneity in inflammatory and fibrotic levels was observed in treatment-naïve children with CHB in Shanghai, China. Serum ALT levels >80 U/L may be a strong indicator of the degree of hepatic inflammation and fibrosis severity. Moderate fibrosis and cirrhosis can appear in children aged <3 years or younger.
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Cisneros-Garza L, González-Huezo M, Moctezuma-Velázquez C, Ladrón de Guevara-Cetina L, Vilatobá M, García-Juárez I, Alvarado-Reyes R, Álvarez-Treviño G, Allende-Pérez S, Bornstein-Quevedo L, Calderillo-Ruiz G, Carrillo-Martínez M, Castillo-Barradas M, Cerda-Reyes E, Félix-Leyva J, Gabutti-Thomas J, Guerrero-Ixtlahuac J, Higuera-de-la-Tijera F, Huitzil-Meléndez D, Kimura-Hayama E, López-Hernández P, Malé-Velázquez R, Méndez-Sánchez N, Morales-Ruiz M, Ruíz-García E, Sánchez-Ávila J, Torrecillas-Torres L. The second Mexican consensus on hepatocellular carcinoma. Part I: Epidemiology and diagnosis. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2022; 87:216-234. [DOI: 10.1016/j.rgmxen.2021.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/21/2021] [Indexed: 12/24/2022] Open
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20
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Cisneros-Garza LE, González-Huezo MS, Moctezuma-Velázquez C, Ladrón de Guevara-Cetina L, Vilatobá M, García-Juárez I, Alvarado-Reyes R, Álvarez-Treviño GA, Allende-Pérez S, Bornstein-Quevedo L, Calderillo-Ruiz G, Carrillo-Martínez MA, Castillo-Barradas M, Cerda-Reyes E, Félix-Leyva JA, Gabutti-Thomas JA, Guerrero-Ixtlahuac J, Higuera-de-la-Tijera F, Huitzil-Meléndez D, Kimura-Hayama E, López-Hernández PA, Malé-Velázquez R, Méndez-Sánchez N, Morales-Ruiz MA, Ruíz-García E, Sánchez-Ávila JF, Torrecillas-Torres L. The second Mexican consensus on hepatocellular carcinoma. Part I: Epidemiology and diagnosis. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2022; 87:216-234. [PMID: 35431142 DOI: 10.1016/j.rgmx.2021.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/21/2021] [Indexed: 01/04/2025]
Abstract
Hepatocellular carcinoma (HCC) is more frequently manifesting as one of the main complications of cirrhosis of the liver, its principal risk factor. There have been modifications in its incidence over the past decade, related to an epidemiologic transition in the etiology of cirrhosis, with a decrease in the prevalence of hepatitis C and an increase in nonalcoholic fatty liver disease (NAFLD) as a cause, as well as the development of HCC in the non-cirrhotic liver due to NAFLD. Genetic markers associated with the disease have been identified, and surveillance and diagnosis have improved. Regarding treatment, surgical techniques, in both resection and transplantation, have advanced and radiologic techniques, at the curative stage of the disease, have enhanced survival in those patients. And finally, there have been radical changes in the systemic approach, with much more optimistic expectations, when compared with the options available a decade ago. Therefore, the Asociación Mexicana de Hepatología decided to carry out the Second Mexican Consensus on Hepatocellular Carcinoma, which is an updated review of the available national and international evidence on the epidemiology, risk factors, surveillance, diagnosis, and treatment of the disease, to offer the Mexican physician current information on the different topics regarding hepatocellular carcinoma. In this first part of the document, the topics related to epidemiology and diagnosis are presented.
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Affiliation(s)
- L E Cisneros-Garza
- Hospital Christus Muguerza Alta Especialidad, Monterrey, Nuevo León, Mexico
| | | | - C Moctezuma-Velázquez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - M Vilatobá
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - I García-Juárez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - G A Álvarez-Treviño
- Unidad de Medicina de Alta Especialidad 25 IMSS, Monterrey, Nuevo León, Mexico
| | | | - L Bornstein-Quevedo
- InmunoQ, Laboratorio de Patología, Inmunohistoquímica y Biología Molecular, Mexico City, Mexico
| | | | | | | | | | | | - J A Gabutti-Thomas
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | | | - D Huitzil-Meléndez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - P A López-Hernández
- Unidad de Medicina de Alta Especialidad 25 IMSS, Monterrey, Nuevo León, Mexico
| | - R Malé-Velázquez
- Instituto de Salud Digestiva y Hepática SA de CV, Guadalajara, Jalisco, Mexico
| | | | - M A Morales-Ruiz
- Centro Oncológico Estatal Issemym, Toluca, Estado de México, Mexico
| | - E Ruíz-García
- Instituto Nacional de Cancerología, Mexico City, Mexico
| | - J F Sánchez-Ávila
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Monterrey, Nuevo León, Mexico
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Disproportionate Distribution of HBV Genotypes A and D and the Recombinant Genotype D/E in the High and Low HBV Endemic Regions of Uganda: A Wake-Up Call for Regional Specific HBV Management. Int J Hepatol 2022; 2022:3688547. [PMID: 35070455 PMCID: PMC8767397 DOI: 10.1155/2022/3688547] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 11/08/2021] [Accepted: 12/17/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is the leading cause of liver-related diseases. In Uganda, there is a regional disparity in the HBV burden. Our study was aimed at establishing the circulating genotypes in a low and a high endemic region to give plausible explanations for the differences in regional burden and guide the future management of the disease. METHODS A total of 200 HBsAg-seropositive subjects were recruited into the study by convenience sampling. The HBsAg Rapid Test Strip (Healgen Scientific Limited Liability Company, Houston, TX77047- USA) was used to screen for HBsAg while the Roche machine (Roche, Basel Switzerland/Abbot Technologies (USA)) was used to determine the viral load. The Chemistry Analyzer B120 (Mindray, China) was used for chemistry analysis. For HBV genotyping, total DNA was extracted from whole blood using the QIAamp® DNA extraction kit. Nested PCR amplification was performed using Platinum Taq DNA Polymerase (Invitrogen Corporation, USA) to amplify the 400 bp HBV polymerase gene. Purification of nested PCR products was performed using Purelink PCR product purification kit (Life Technologies, USA). Automated DNA sequencing was performed using BigDye Terminator v3.1 Cycle Sequencing Kit on 3130 Genetic Analyzer (Applied Biosystems, USA). The NCBI HBV genotyping tool (https://www.ncbi.nlm.nih.gov/projects/genotyping/formpage.cgi) was used for determination of genotype for each HBV sequence. Pearson's chi-square, multinomial logistic regression, and Mann-Whitney U tests were used for the analysis. All the analyses were done using SPSS version 26.0 and MedCalc software version 19.1.3 at 95% CI. A p < 0.05 was considered statistically significant. RESULTS Majority of our study subjects were female (64.5%), youth (51.0%), and married (62.0%). Overall, genotype A was the most prevalent (46%). Genotype D and the recombinant genotype D/E were proportionately more distributed in the high endemic (38.2%) and low endemic (36.5%) regions, respectively. Genotype D was significantly more prevalent in the high endemic region and among the elderly (p < 0.05). Genotype D was significantly associated with elevated viral load and direct bilirubin (p < 0.05). The recombinant genotype D/E was significantly associated with elevated viral load (p < 0.05). Similarly, genotype A was significantly associated with elevated AST and GGT, lowered viral load, and normal direct bilirubin levels (p < 0.05). CONCLUSION There is disproportionate distribution of genotypes A and D and the recombinant genotype D/E in the low and high endemic regions of Uganda. This probably could explain the differences in endemicity of HBV in our country signifying the need for regional specific HBV management and control strategies.
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Kar P, Goswami B, Mahanta J, Bhimo T, Das AK, Deka M, Lynrah KG, Kotwal MR, Bhaumik P, Jini M, Karna R, Karra VK, Kaur H. Epidemiology, Genotyping, Mutational and Phylogenetic Analysis of Hepatitis B Virus Infection in North-east India. J Clin Exp Hepatol 2022; 12:43-51. [PMID: 35068784 PMCID: PMC8766538 DOI: 10.1016/j.jceh.2021.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 04/01/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND/OBJECTIVE Hepatitis B virus (HBV) infection is a major public health problem globally. Northeast India is home to indigenous tribes with different ethnicity and high rates of drug abuse and HIV infection. The study was designed to estimate the burden of HBV infection across various spectrums of liver diseases from this region. HBV genotypes and subgenotypes play a role in the chronicity of disease, response to treatment and its progression. As very limited data are available from this region, we tried to elucidate the role of HBV genotypes, HBV mutants and their phylogenetic analysis. METHOD We designed a prospective multicentric study, and included 7464 liver disease cases, 7432 blood donors and 650 health care workers, who were screened for HBV infection. HBV DNA positive patients were genotyped and subjected to surface protein, precore and core mutation and phylogenetic analysis. RESULTS The prevalence of HBV infection with respect to different types of liver diseases, blood donors and health care workers was 9.9% (1550/15,546). 49.5% (768/1550) cases were found to be HBV DNA positive. The most common genotype was found to be genotype D 74.2% (570/768), followed by genotype C 6.5% (50/768), A 4.4% (34/768) and I 0.9% (7/768). CONCLUSION This study highlights the high hepatitis B burden in Northeast India, reflecting lacunae in health care needs of the region. Also, the different genotype distribution and presence of mutations may translate into different rates of liver disease progression, prognosis and ultimately, clinical significance. However, further prospective cohort study from Northeast India is warranted, to elucidate the clinical significance of multiple genotypes and mutation in this unique population.
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Key Words
- AFP, alpha fetoprotein
- ALT, alanine transaminase
- AVH, acute viral hepatitis
- BCP, basal core promoter mutations
- CAH: chronic active hepatitis, CHB: chronic hepatitis B
- CLD, chronic liver disease
- DNA, deoxyribose nucleic acid
- EASL, European Association for the study of the liver
- FHF, fulminant hepatic failure
- FNAC, fine needle aspiration cytology
- HBV
- HBV, hepatitis B virus
- HBcAg, icosahedral core
- HBsAg, surface proteins
- HCC, hepatocellular carcinoma
- PCR, polymerase chain reaction
- RT, reverse transcriptase
- SGOT, serum glutamic oxaloacetic transaminase
- SGPT, serum glutamic pyruvic transaminase
- SHB, small hepatitis B surface antigen
- ULN, upper limit of normal
- epidemiology
- evolution
- genotype
- mutation
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Affiliation(s)
- Premashis Kar
- Maulana Azad Medical College, University of Delhi, New Delhi, India,Address for correspondence. Premashis Kar, Director Professor of Medicine Maulana Azad Medical College, University of Delhi, New Delhi, India.
| | - Bhabadev Goswami
- Department of Gastroenterology, Gauhati Medical College, Guwahati, Assam, India
| | | | - Thngam Bhimo
- Department of Medicine, Regional Institute of Medical Sciences, Regional Medical College, Imphal, Manipur, India
| | - Anup K. Das
- Department of Medicine, Assam Medical College, Dibrugarh, Assam, India
| | - Manab Deka
- Department of Biotechnology, Gauhati University, Assam, India
| | | | | | - Pradip Bhaumik
- Department of Medicine, Agartala Govt. Medical College, Agartala, Tripura, India
| | - Moji Jini
- General Hospital, Naharlagun, Arunachal Pradesh, India
| | - Rahul Karna
- Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Vijay K. Karra
- Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, Department of Health Research, New Delhi, India
| | - Harpreet Kaur
- Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, Department of Health Research, New Delhi, India
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More DNA and RNA of HBV SP1 splice variants are detected in genotypes B and C at low viral replication. Sci Rep 2021; 11:23838. [PMID: 34903774 PMCID: PMC8668879 DOI: 10.1038/s41598-021-03304-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 11/29/2021] [Indexed: 12/13/2022] Open
Abstract
HBV produces unspliced and spliced RNAs during replication. Encapsidated spliced RNA is converted into DNA generating defective virions that are detected in plasma and associated with HCC development. Herein we describe a quantitative real-time PCR detection of splice variant SP1 DNA/RNA in HBV plasma. Three PCR primers/probe sets were designed detecting the SP1 variants, unspliced core, or X gene. Plasmids carrying the three regions were constructed for the nine HBV genotypes to evaluate the three sets, which were also tested on DNA/RNA extracted from 193 HBV plasma with unknown HCC status. The assay had an LOD of 80 copies/ml and was equally efficient for detecting all nine genotypes and three targets. In testing 84 specimens for both SP1 DNA (77.4%) and RNA (82.1%), higher viral loads resulted in increased SP1 levels. Most samples yielded < 1% of SP1 DNA, while the average SP1 RNA was 3.29%. At viral load of ≤ 5 log copies/ml, the detectable SP1 DNA varied by genotype, with 70% for B, 33.3% for C, 10.5% for E, 4% for D and 0% for A, suggesting higher levels of splicing in B and C during low replication. At > 5 log, all samples regardless of genotype had detectable SP1 DNA.
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Lee JH, Kim HS. Current laboratory tests for diagnosis of hepatitis B virus infection. Int J Clin Pract 2021; 75:e14812. [PMID: 34487586 DOI: 10.1111/ijcp.14812] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/03/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) has a long history in human infectious diseases. HBV infection can progress chronically, leading to cancer. After introduction of a vaccine, the overall incidence rate of HBV infection has decreased, although it remains a health problem in many countries. PURPOSE The aim of this review was to summarise current diagnostic efforts for HBV infection and future HBV diagnosis perspectives. METHODS We reviewed and summarised current laboratory diagnosis related with HBV infection in clinical practice. RESULTS There have been various serologic- and molecular-based methods to diagnose acute or chronic HBV infection. Since intrahepatic covalently closed circular DNAs (cccDNAs) function as robust HBV replication templates, cure of chronic HBV infection is limited. Recently, new biomarkers such as hepatitis B virus core-related antigen (HBcrAg) and HBV RNA have emerged that appear to reflect intrahepatic cccDNA status. These new biomarkers should be validated before clinical usage. CONCLUSION An effective diagnostic approach and current updated knowledge of treatment response monitoring are important for HBV infection management. Brand new ultrasensitive and accurate immunologic methods may pave the way to manage HBV infection in parallel with immunotherapy era.
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Affiliation(s)
- Jong-Han Lee
- Department of Laboratory Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Hyon-Suk Kim
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
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Abstract
Hepatitis B was discovered by researchers who were investigating jaundice associated with blood transfusions as well as parenterally administered medications. Through trial and error, the HBV was identified. There are specific tests that detect HBV infection, whether it is a previous exposure or active infection. The various HBV serologies are reviewed in this work as well. Hepatitis B surface antigen has emerged as a tool in defining treatment endpoint and its significance is reviewed. HBV genotypes are distributed uniquely throughout the world, in particular, genotype C is associated with higher rates of hepatocellular carcinoma. Various HBV genotypes and their impact on the clinical course are discussed. The relationship of HBV serologies and HBV DNA to disease progression is outlined. There are specific recommendations on monitoring those infected with HBV and this is reviewed here. HBV mutations have an impact on the disease course and those of significance are also discussed.
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Wang G, Duan Z. Guidelines for Prevention and Treatment of Chronic Hepatitis B. J Clin Transl Hepatol 2021; 9:769-791. [PMID: 34722192 PMCID: PMC8516840 DOI: 10.14218/jcth.2021.00209] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/20/2021] [Accepted: 08/03/2021] [Indexed: 12/12/2022] Open
Abstract
To achieve the goal of the World Health Organization to eliminate viral hepatitis as a major public health threat by 2030, the Chinese Society of Infectious Diseases and the Chinese Society of Hepatology convened an expert panel in 2019 to update the guidelines for the prevention and treatment of chronic hepatitis B (CHB). The current guidelines cover recent advances in basic, clinical, and preventive studies of CHB infection and consider the actual situation in China. These guidelines are intended to provide support for the prevention, diagnosis, and treatment of CHB.
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Affiliation(s)
- Guiqiang Wang
- Center for Liver Diseases, Department of Infectious Diseases, Peking University First Hospital; Department of Infectious and Liver Diseases, Peking University International Hospital, Beijing, China
| | - Zhongping Duan
- Center for Difficult and Complicated Liver Diseases and Artificial Liver, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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27
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Liu Q, Tian Y, Li Y, Zhang W, Cai W, Liu Y, Ren Y, Liang Z, Zhou P, Zhang Y, Bao Y, Li Y. In vivo therapeutic effects of affinity-improved-TCR engineered T-cells on HBV-related hepatocellular carcinoma. J Immunother Cancer 2021; 8:jitc-2020-001748. [PMID: 33323464 PMCID: PMC7745518 DOI: 10.1136/jitc-2020-001748] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2020] [Indexed: 12/24/2022] Open
Abstract
Background In patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), virus-specific cytotoxic T lymphocytes (CTLs) fail to eliminate HCC cells expressing HBV antigens. As the expression of viral antigen in HBV-associated HCC may decrease to allow tumor to escape immune attacks, we hypothesized that an HBV surface antigen (HBsAg)-specific affinity-improved-T-cell receptor (TCR) will enable T cells to target HCC more effectively than corresponding wild-type-TCR. We also postulated that TCR promiscuity can be exploited to efficiently capture HBV variants that can hinder CTL-based therapeutics. Methods We applied flexi-panning to isolate affinity-improved TCRs binding to a variant antigen, the human leukocyte antigen (HLA)-A*02:01-restricted nonapeptide HBs371-379-ILSPFLPLL, from libraries constructed with a TCR cloned using the decapeptide HBs370-379-SIVSPFIPLL. The potency and safety of the affinity-improved-TCR engineered T-cells (Ai-TCR-T) were verified with potentially cross-reactive human and HBV-variant peptides, tumor and normal cells, and xenograft mouse models. Results Ai-TCR-T cells retained cognate HBV antigen specificity and recognized a wide range of HBV genotypic variants with improved sensitivity and cytotoxicity. Cell infusions produced complete elimination of HCC without recurrence in the xenograft mouse models. Elevated accumulation of CD8+ Ai-TCR-T cells in tumors correlated with tumor shrinkage. Conclusion The in vitro and in vivo studies demonstrated that HBsAg-specific Ai-TCR-T cells had safety profiles similar to those of their wild-type counterparts and significantly enhanced potency. This study presents an approach to develop new therapeutic strategies for HBV-related HCC.
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Affiliation(s)
- Qi Liu
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,University of the Chinese Academy of Sciences, Beijing, China
| | - Ye Tian
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Yanyan Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Wei Zhang
- Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Hefei, Anhui, China
| | - Wenxuan Cai
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Yaju Liu
- Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Hefei, Anhui, China
| | - Yuefei Ren
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhaoduan Liang
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Peipei Zhou
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, China
| | - Yajing Zhang
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,University of the Chinese Academy of Sciences, Beijing, China
| | - Yifeng Bao
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Yi Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China .,University of the Chinese Academy of Sciences, Beijing, China
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28
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Li YT, Wu HL, Liu CJ. Molecular Mechanisms and Animal Models of HBV-Related Hepatocellular Carcinoma: With Emphasis on Metastatic Tumor Antigen 1. Int J Mol Sci 2021; 22:9380. [PMID: 34502289 PMCID: PMC8431721 DOI: 10.3390/ijms22179380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/22/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an important cause of cancer death worldwide, and hepatitis B virus (HBV) infection is a major etiology, particularly in the Asia-Pacific region. Lack of sensitive biomarkers for early diagnosis of HCC and lack of effective therapeutics for patients with advanced HCC are the main reasons for high HCC mortality; these clinical needs are linked to the molecular heterogeneity of hepatocarcinogenesis. Animal models are the basis of preclinical and translational research in HBV-related HCC (HBV-HCC). Recent advances in methodology have allowed the development of several animal models to address various aspects of chronic liver disease, including HCC, which HBV causes in humans. Currently, multiple HBV-HCC animal models, including conventional, hydrodynamics-transfection-based, viral vector-mediated transgenic, and xenograft mice models, as well as the hepadnavirus-infected tree shrew and woodchuck models, are available. This review provides an overview of molecular mechanisms and animal models of HBV-HCC. Additionally, the metastatic tumor antigen 1 (MTA1), a cancer-promoting molecule, was introduced as an example to address the importance of a suitable animal model for studying HBV-related hepatocarcinogenesis.
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Affiliation(s)
- Yung-Tsung Li
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Hui-Lin Wu
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei 100, Taiwan
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Campos-Valdez M, Monroy-Ramírez HC, Armendáriz-Borunda J, Sánchez-Orozco LV. Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability. Viruses 2021; 13:v13061167. [PMID: 34207116 PMCID: PMC8235420 DOI: 10.3390/v13061167] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/16/2022] Open
Abstract
The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.
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Affiliation(s)
- Marina Campos-Valdez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Hugo C. Monroy-Ramírez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Juan Armendáriz-Borunda
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Campus Guadalajara, Zapopan 45201, Jalisco, México
| | - Laura V. Sánchez-Orozco
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Correspondence: ; Tel.: +52-33-3954-5677
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30
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Lok AS, Perrillo R, Lalama CM, Fried MW, Belle SH, Ghany MG, Khalili M, Fontana RJ, Sterling RK, Terrault N, Feld JJ, Di Bisceglie AM, Lau DT, Hassan M, Janssen HL, Hepatitis B Research Network (HBRN), Roberts LR, Lisker‐Melman M, Wong DK, Juan J, Yim C, Patel K, Lee WM, Murakami CS, Do S, Han SB, Tran TT, Cooper SL, Tsai N, Younoszai B, Muir A, Evon D, Darling JM, Carithers RC, Kowdley KV, Wang CC, Luketic VA, Jake Liang T, Hoofnagle JH, Doo E, Chang K, Park J, Wahed A, King WC, Kleiner D. Low Incidence of Adverse Outcomes in Adults With Chronic Hepatitis B Virus Infection in the Era of Antiviral Therapy. Hepatology 2021; 73:2124-2140. [PMID: 32936969 PMCID: PMC8546406 DOI: 10.1002/hep.31554] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/28/2020] [Accepted: 08/19/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Outcomes of persons with chronic hepatitis B virus (HBV) infection in the era of antiviral therapy (AVT) are not well characterized. We determined the incidence and factors associated with clinical outcomes in a multiethnic, North American cohort of adults with chronic HBV infection, who were not on AVT at enrollment. APPROACH AND RESULTS Adults with chronic HBV infection, not receiving AVT, and without a history of decompensation, HCC, or liver transplantation (LT), were prospectively followed. Participants with known human immunodeficiency virus (HIV), hepatitis C virus, or hepatitis D virus (HDV) coinfection were excluded. During follow-up, treatment could be initiated per standard of care. Clinical outcomes included: incident cirrhosis, decompensation, HCC, OLT, and HBV-related death. Among 1,418 participants analyzed, 51.5% were women, median age was 41.1 years, 75% were Asian, 10% White, 13% Black, 24% HBeAg(+), and 1.5% cirrhosis at baseline. During the study, 274 started treatment, 83 had an alanine aminotransferase flare, 118 of 330 initially HBeAg(+) became HBeAg(-), and 90 of 1,329 became HBsAg(-). After 6,641 person-years follow-up, 8 participants (4 of 21 with baseline cirrhosis) had 12 clinical outcomes (2 decompensation, 5 HCC, 2 OLT, and 3 HBV-related deaths) and 19 of 1,397 had incident cirrhosis. Twenty-one of 26 participants had first outcome before treatment, none had become HBsAg(-), whereas 5/9 HBeAg(+) had become HBeAg(-) at time of first outcome. Cumulative percentage of clinical outcomes was 16% at year 4 in participants with baseline cirrhosis and 2% (including incident cirrhosis) at year 7 in those without. CONCLUSIONS Incidence of adverse outcomes was low in this closely monitored, large cohort of North American adults with predominantly inactive, chronic HBV without cirrhosis. Our data highlight the benefits of HBsAg loss and the importance of early diagnosis and treatment to prevent cirrhosis and other complications of chronic HBV infection.
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Affiliation(s)
- Anna S. Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Robert Perrillo
- Hepatology Division, Baylor Scott and White Medical Center, Dallas, TX
| | | | - Michael W. Fried
- UNC Liver Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Steven H. Belle
- Epidemiology and Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | | | - Mandana Khalili
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California San Francisco, San Francisco, CA
| | - Robert J. Fontana
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Richard K. Sterling
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, VA
| | - Norah Terrault
- Division of Gastrointestinal and Liver Diseases, Keck Medicine of University of Southern California, Los Angeles, CA
| | - Jordan J. Feld
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Adrian M. Di Bisceglie
- Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO
| | - Daryl T.Y. Lau
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
| | - Mohamed Hassan
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolois, MN
| | - Harry L.A. Janssen
- Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada
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Epidemiology of HPB malignancy in the elderly. Eur J Surg Oncol 2021; 47:503-513. [PMID: 32360064 DOI: 10.1016/j.ejso.2020.03.222] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 03/17/2020] [Accepted: 03/26/2020] [Indexed: 02/08/2023] Open
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Tarao K, Nozaki A, Chuma M, Taguri M, Maeda S. Effectiveness of entecavir in preventing hepatocellular carcinoma development is genotype-dependent in hepatitis B virus-associated liver cirrhosis. World J Hepatol 2021; 13:144-150. [PMID: 33584993 PMCID: PMC7856867 DOI: 10.4254/wjh.v13.i1.144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/16/2020] [Accepted: 11/29/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The oral nucleos(t)ide analogue, entecavir (ETV) was demonstrated to reduce the rate of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)-associated liver cirrhosis. However, the reduction of HCC differs in various regions of the world.
AIM To investigate the reduction of HCC development due to ETV therapy by meta-analysis.
METHODS We surveyed the differences in HCC development following ETV treatment based on published articles using PubMed (2004-2019).
RESULTS The regions with the most marked reduction in HCC development due to ETV therapy were Spain (1.0%/year) and Canada (Southern part, 1.3%/year), and the most ineffective areas were South Korea (3.6%-3.8%/year), China (3.3%/year), Taiwan (2.4%-3.1%/year), and Hong Kong (2.8%/year). Following ETV administration, the incidence of HCC in genotype D regions (1.89% ± 0.28%/year, mean ± SE) was significantly lower than that in genotype C regions (2.91% ± 0.24%/year, P < 0.01). With regard to the initial HBV-DNA level, in genotype C patients (average: 5.61 Log10IU/mL) this was almost the same as that in genotype D patients (average: 5.46 Log10IU/mL). Moreover, there was no association between the prevalence ratio of HBV and the incidence of HCC on ETV treatment.
CONCLUSION The effectiveness of ETV in preventing HCC development in HBV-associated liver cirrhosis is genotype-dependent.
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Affiliation(s)
- Kazuo Tarao
- Department of Gastroenterology, Tarao’s Gastroenterological Clinic, Yokohama City 241-0821, Japan
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Masataka Taguri
- Department of Data Science, Yokohama City University School of Data Science, Yokohama 236-0004, Japan
| | - Shin Maeda
- Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
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Yang HC, Su TH. Viral and Host Factors Affecting Disease Progression of Hepatitis B Virus Infection. HEPATITIS B VIRUS AND LIVER DISEASE 2021:205-230. [DOI: 10.1007/978-981-16-3615-8_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Block PD, Shinn B, Kim JH, Hann HW. Hepatitis B-related hepatocellular carcinoma and stress: untangling the host immune response from clinical outcomes. Hepat Oncol 2020; 8:HEP35. [PMID: 33680431 PMCID: PMC7907965 DOI: 10.2217/hep-2020-0028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major public health challenge on the global scale. Affecting hundreds of millions worldwide, HBV is a leading risk factor for hepatocellular carcinoma (HCC). Clinical outcomes from chronic HBV infection are varied and appear to be influenced by a complex and dysregulated host immune response. In turn, much attention has been given to the immunologic response to HBV in an effort to identify host factors that lead to the development of HCC. However, the role of nonimmunologic host factors, such as chronic stress, in HBV-related HCC is poorly defined. Indeed, a growing appreciation for the effects of stress on chronic liver diseases raises the question of its role in chronic HBV infection. In this light, the present review will untangle the roles of key host factors in HBV-related HCC with an emphasis on chronic stress as a viable contributor. First discussed is the interplay of stress, inflammation and chronic liver disease. The host immune response's role as a driver of HBV-related HCC is then reviewed, allowing for a close exploration of the effects of stress on immune function in chronic hepatitis B and as a potential risk factor for HBV-related HCC.
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Affiliation(s)
- Peter D Block
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Brianna Shinn
- Department of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Jin Hyang Kim
- Bristol-Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ 08648, USA
| | - Hie-Won Hann
- Department of Gastroenterology & Hepatology, Liver Disease Prevention Center, Philadelphia, PA 19107, USA
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Huang BY, Tsai MR, Hsu JK, Lin CY, Lin CL, Hu JT, Huang YW, Liu CJ, Wu WJ, Wu CF, Sung FY, Chen PJ, Liang HJ, Lin SM, Yu MW. Longitudinal change of metabolite profile and its relation to multiple risk factors for the risk of developing hepatitis B-related hepatocellular carcinoma. Mol Carcinog 2020; 59:1269-1279. [PMID: 32914490 DOI: 10.1002/mc.23255] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/03/2020] [Accepted: 08/26/2020] [Indexed: 12/19/2022]
Abstract
Despite considerable knowledge of viral pathogenesis, the pathophysiological changes related to the multifactorial, multistep process of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) development remains unclear. Longitudinal metabolomics study can reveal biological process for disease progression. We performed metabolite profiling with longitudinal prediagnostic plasma samples from two nested case-control studies of hepatitis B surface antigen carriers participating in ultrasound screening for HCC, one within a government employee cohort (870 samples from 109 HCC cases and 107 controls) and the other within a hospital-based cohort (266 samples from 63 HCC cases and 114 controls). Of the 34 measured metabolites, tyrosine, isoleucine, and glutamine were consistently associated with HCC. In analyses combining longitudinal data, a high metabolic risk score based on the three amino acids was robustly associated with increased risk of HCC (OR = 3.71, 95% confidence interval: 2.53-5.42), even after adjustment for clinical factors, or when assessed for different times up to ≥8 years before diagnosis. Similar association was observed in an independent, prospective analysis comprising 633 randomly selected individuals of the government employee cohort. More importantly, this metabolite signature was longitudinally influenced by HBV-infection phase and involved in gradual progression to liver fibrosis and cirrhosis. Furthermore, mediation analysis showed that the score mediated substantial proportions of the associations of key viral factors, insulin resistance, and diabetes status with HCC risk. Our results suggest that an amino-acid dysregulation metabotype may play a role in HBV-related HCC development, and may also be linked to common pathways that mediate increased HCC risks.
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Affiliation(s)
- Bo-Yuan Huang
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Min-Ru Tsai
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Jia-Kai Hsu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Ching-Yu Lin
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Jui-Ting Hu
- Liver Center, Cathay General Hospital Medical Center, School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan
| | - Yi-Wen Huang
- Department of Internal Medicine, Division of Gastroenterology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Internal Medicine, Division of Gastroenterology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, Division of Gastroenterology, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wan-Jung Wu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chih-Feng Wu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Feng-Yu Sung
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Pei-Jer Chen
- Department of Internal Medicine, Division of Gastroenterology, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hao-Jan Liang
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Shi-Ming Lin
- Division of Hepatology, Liver Research Unit, Department of Gastroenterology and Hepatology, College of Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
| | - Ming-Whei Yu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
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36
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Japan Society of Hepatology Guidelines for the Management of Hepatitis B Virus Infection: 2019 update. Hepatol Res 2020; 50:892-923. [PMID: 32343469 DOI: 10.1111/hepr.13504] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/16/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023]
Abstract
The Drafting Committee for Hepatitis Management Guidelines established by the Japan Society of Hepatology published the first version of the Guidelines for the Management of Hepatitis B in 2013 (first English version in 2014), and has since been publishing updates to the Guidelines as new drugs become available, with the latest original Japanese version being Version 3.1. Herein, the Drafting Committee publishes the second English version that contains all the changes made since the first English version of the guidelines was published in 2014. This 2019 version covers: (i) the nucleos(t)ide analogs, tenofovir disoproxil fumarate and tenofovir alafenamide; (ii) updates to treatment recommendations and management of drug-resistant hepatitis B virus that reflect the new availability of these drugs; and (iii) new information about hepatitis B virus reactivation with each update. This latest update also contains information about treatment goals, indications for treatment and cessation of nucleos(t)ide analog therapy, most of which were covered by the first version.
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37
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Affiliation(s)
| | | | - Priya Abraham
- Department of Virology, Christian Medical College, Vellore, 632 004, India
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38
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Elimination of Hepatitis B in Highly Endemic Settings: Lessons Learned in Taiwan and Challenges Ahead. Viruses 2020; 12:v12080815. [PMID: 32731536 PMCID: PMC7472725 DOI: 10.3390/v12080815] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/26/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection and its related liver diseases are important health problems worldwide, particularly in the Asia-Pacific region. For the past 4-5 decades, Taiwan's government and scientists have cooperated together to control this virus infection and its related liver diseases. These efforts and achievements have made progress toward the elimination of HBV. Taiwan's government initiated the Viral Hepatitis Control Program (VHCP) in the1970s, and then launched the national vaccination program in 1984. This universal vaccination program effectively decreased the rate of hepatitis B carriage and the development of hepatocellular carcinoma (HCC) in the younger generation. Since 2003, approved anti-HBV treatments were reimbursed nationwide. This reimbursement program resulted in a higher uptake of anti-HBV treatments, which contributed to a decrease in liver-related disease progression and subsequently reduced attributable mortality in Taiwan. This experience can be shared by countries in other parts of the world regarding the control of chronic viral hepatitis B.
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39
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Lau KC, Joshi SS, Gao S, Giles E, Swidinsky K, van Marle G, Bathe OF, Urbanski SJ, Terrault NA, Burak KW, Osiowy C, Coffin CS. Oncogenic HBV variants and integration are present in hepatic and lymphoid cells derived from chronic HBV patients. Cancer Lett 2020; 480:39-47. [PMID: 32229190 DOI: 10.1016/j.canlet.2020.03.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 03/12/2020] [Accepted: 03/23/2020] [Indexed: 12/12/2022]
Abstract
The hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC), partly driven by viral integration and specific oncogenic HBV variants. However, the biological significance of HBV genomes within lymphoid cells (i.e., peripheral blood mononuclear cells, PBMCs) is unclear. Here, we collected available plasma, PBMC, liver, and tumor from 52 chronic HBV (CHB) carriers: 32 with HCC, 19 without HCC, and one with dendritic cell sarcoma, DCS. Using highly sensitive sequencing techniques, next generation sequencing, and AluPCR, we demonstrate that viral genomes (i.e., HBV DNA, RNA, and cccDNA), oncogenic variants, and HBV-host integration are often found in all sample types collected from 52 patients (including lymphoid cells and a DCS tumor). Viral integration was recurrently identified (n = 90 such hits) in genes associated with oncogenic consequences in lymphoid and liver cells. Further, HBV genomes increased in PBMCs derived from 7 additional (treated or untreated) CHB carriers after extracellular mitogen stimulation. Our study shows novel HBV molecular data and replication not only liver, but also within 63.8% of lymphoid cells analysed (including a representative lymphoid cell malignancy), that was enhanced in ex vivo stimulated PBMC.
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Affiliation(s)
- Keith Ck Lau
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada; Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Shivali S Joshi
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada; Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Shan Gao
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada; Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Elizabeth Giles
- Viral Hepatitis and Bloodborne Pathogens, National Microbiology Laboratory, Winnipeg, Manitoba, Canada
| | - Ken Swidinsky
- Viral Hepatitis and Bloodborne Pathogens, National Microbiology Laboratory, Winnipeg, Manitoba, Canada
| | - Guido van Marle
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Oliver F Bathe
- Department of Surgery and Oncology, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Stefan J Urbanski
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Norah A Terrault
- Department of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, CA, USA
| | - Kelly W Burak
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Carla Osiowy
- Viral Hepatitis and Bloodborne Pathogens, National Microbiology Laboratory, Winnipeg, Manitoba, Canada
| | - Carla S Coffin
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada; Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta, Canada.
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Jangam D, Butzmann A, Sridhar K, Deresinski S, Banaei N, Shigeo Ohgami R. Significance of bacterial and viral genotypes as a risk factor in driving cancer (Review). Mol Clin Oncol 2020; 13:3-12. [PMID: 32499911 PMCID: PMC7265216 DOI: 10.3892/mco.2020.2043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 01/08/2020] [Indexed: 12/13/2022] Open
Abstract
Microbes have been known to drive human cancers for over half a century. However, despite the association of bacterial and viral infections with a high risk of cancer, most infections do not result in the development of cancer. Additionally, certain bacteria and viruses, considered to drive oncogenesis, are commonly prevalent in the global population. The current study performed a comprehensive meta-analysis of primary literature data to identify particular aspects of microbial genotypes as crucial factors that dictate the cancer risks associated with infection. The results indicated the importance of incorporating microbial genotype information with human genotypes into clinical assays for the more efficient diagnosis and prognosis of patients with cancer. The current review focuses on the importance of microbial genotypes and specific genes and genetic differences that are important to human oncogenesis.
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Affiliation(s)
- Diwash Jangam
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Alexandra Butzmann
- Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA
| | - Kaushik Sridhar
- Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA
| | | | - Niaz Banaei
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Robert Shigeo Ohgami
- Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA
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41
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In silico Analysis of Genetic Diversity of Human Hepatitis B Virus in Southeast Asia, Australia and New Zealand. Viruses 2020; 12:v12040427. [PMID: 32283837 PMCID: PMC7232418 DOI: 10.3390/v12040427] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/06/2020] [Accepted: 04/08/2020] [Indexed: 02/08/2023] Open
Abstract
The extent of whole genome diversity amongst hepatitis B virus (HBV) genotypes is not well described. This study aimed to update the current distribution of HBV types and to investigate mutation rates and nucleotide diversity between genotypes in Southeast Asia, Australia and New Zealand. We retrieved 930 human HBV complete genomes from these regions from the NCBI nucleotide database for genotyping, detection of potential recombination, serotype prediction, mutation identification and comparative genome analyses. Overall, HBV genotypes B (44.1%) and C (46.2%) together with predicted serotypes adr (36%), adw2 (29%) and ayw1 (19.9%) were the most commonly circulating HBV types in the studied region. The three HBV variants identified most frequently were p.V5L, c.1896G>A and double mutation c.1762A>T/c.1764G>A, while genotypes B and C had the widest range of mutation types. The study also highlighted the distinct nucleotide diversity of HBV genotypes for whole genome and along the genome length. Therefore, this study provided a robust update to HBV currently circulating in Southeast Asia, Australia and New Zealand as well as an insight into the association of HBV genetic hypervariability and prevalence of well reported mutations.
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42
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Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: New trends. J Hepatol 2020; 72:250-261. [PMID: 31954490 PMCID: PMC6986771 DOI: 10.1016/j.jhep.2019.08.025] [Citation(s) in RCA: 762] [Impact Index Per Article: 152.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 08/28/2019] [Accepted: 08/30/2019] [Indexed: 02/07/2023]
Abstract
The burden of hepatocellular carcinoma (HCC) is highest in East Asia and Africa, although its incidence and mortality are rapidly rising in the United States and Europe. With the implementation of hepatitis B vaccination and hepatitis C treatment programmes worldwide, the epidemiology of HCC is shifting away from a disease predominated by viral hepatitis - an increasing proportion of cases are now attributable to non-alcoholic steatohepatitis. Surveillance using ultrasound, with or without alpha-fetoprotein, every 6 months has been associated with improved early detection and improved overall survival; however, limitations in implementation lead to a high proportion of HCC being detected at late stages in clinical practice. Herein, we review the current state of HCC surveillance and highlight areas for future research, including improved risk stratification of at-risk patients, surveillance tools with higher sensitivity and specificity for early HCC, and interventions to increase surveillance utilisation.
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Affiliation(s)
- Amit G Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Pietro Lampertico
- CRC "A. M. and A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Pierre Nahon
- Centre de Recherche des Cordeliers, Sorbonne Universités, Université Paris Descartes, Université Paris Diderot, Université Paris, Paris, France; Functional Genomics of Solid Tumors, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris, Paris, France; Service d'hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France
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Davies J, Smith EL, Littlejohn M, Edwards R, Sozzi V, Jackson K, Mcguire K, Binks P, Cowie BC, Locarnini S, Davis JS, Tong SYC. Towards Genotype-Specific Care for Chronic Hepatitis B: The First 6 Years Follow Up From the CHARM Cohort Study. Open Forum Infect Dis 2019; 6:ofz469. [PMID: 32864387 PMCID: PMC7445891 DOI: 10.1093/ofid/ofz469] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 10/30/2019] [Indexed: 02/07/2023] Open
Abstract
Objective There is increasing evidence to suggest that, among those with chronic hepatitis B virus infection, the natural history and rate of progression to cirrhosis and hepatocellular carcinoma is influenced by hepatitis B virus genotype. The unique hepatitis B virus genotype C4 circulates among Indigenous Australians. The aim of this work is to describe the process of establishing this cohort and review the first 6 years of available data in an effort to understand the real-world clinical care and natural history of this subgenotype. Method We followed a longitudinal cohort of Indigenous Australians from the Northern Territory of Australia with established subgenotype C4 infections. We assigned phases of disease according to Gastroenterological Society of Australia and Asian Pacific Association for the Study of the Liver criteria using clinical and laboratory information that had been collected for clinical management. Results Of 193 patients followed over a median of 38 months, 58 (30%) individuals transitioned from 1 disease phase to another, 10 (5%) cleared hepatitis B e antigen, and 6 cleared hepatitis B surface antigen (3%). In this relatively young cohort (median age 40.3 years), 26 (13%) had cirrhosis by the end of the follow up period, with the majority of these being in the immune control phase of disease. Conclusions In this cohort of hepatitis B subgenotype C4 patients, we report an aggressive and dynamic clinical phenotype. High rates of cirrhosis at a young age appear to occur in the early phases of disease.
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Affiliation(s)
- Jane Davies
- Global and Tropical Health, Menzies School of Health Research, Darwin, Northern Territory, Australia
- Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia
| | - Emma L Smith
- Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia
- Correspondence: Emma Louise Smith, MBChB, MSc, Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, Australia, 3121 E-mail:
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Rosalind Edwards
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Vitina Sozzi
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Katie Mcguire
- Global and Tropical Health, Menzies School of Health Research, Darwin, Northern Territory, Australia
| | - Paula Binks
- Global and Tropical Health, Menzies School of Health Research, Darwin, Northern Territory, Australia
| | - Benjamin C Cowie
- World Health Organization Collaborating Centre for Viral Hepatitis, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- Department of Medicine, Royal Melbourne Hospital, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| | - Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Joshua S Davis
- Global and Tropical Health, Menzies School of Health Research, Darwin, Northern Territory, Australia
- Department of Infectious Diseases, John Hunter Hospital, Newcastle, New South Wales, Australia
| | - Steven Y C Tong
- Global and Tropical Health, Menzies School of Health Research, Darwin, Northern Territory, Australia
- Victorian Infectious Disease Service, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
- Doherty Department University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
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Liu X, Baecker A, Wu M, Zhou JY, Yang J, Han RQ, Wang PH, Jin ZY, Liu AM, Gu X, Zhang XF, Wang XS, Su M, Hu X, Sun Z, Li G, Fu A, Jung SY, Mu L, He N, Li L, Zhao JK, Zhang ZF. Family history of liver cancer may modify the association between HBV infection and liver cancer in a Chinese population. Liver Int 2019; 39:1490-1503. [PMID: 31228882 PMCID: PMC6705127 DOI: 10.1111/liv.14182] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 06/07/2019] [Accepted: 06/08/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The potential interaction between family history of liver cancer and HBV infection on liver cancer has not been fully examined. METHODS We conducted a population-based case-control study composed of 2011 liver cancer cases and 7933 controls in Jiangsu province, China from 2003 to 2010. Data on major risk or protective factors were collected and HBV/HCV sero-markers were assayed using blood samples. Semi-Bayes (SB) adjustments were applied to provide posterior estimates. RESULTS Both family history of liver cancer (adjusted odds ratios [OR]: 4.32, 95% confidence intervals [CI]: 3.25-5.73) and hepatitis B surface antigen (HBsAg) positivity (adjusted OR: 9.94, 95% CI: 8.33-11.87) were strongly associated with liver cancer development. For individuals with different combinations of serological markers, the adjusted ORs were 8.45 (95% CI: 5.16-13.82) for HBsAg- and HBcAb-positive; 7.57 (95% CI: 4.87-11.77) for HBsAg-, HBeAg- and HBcAb-positive; and 3.62 (95% CI: 2.47-5.31) for HBsAg-, HBeAb- and HBcAb-positive, compared to all negatives in HBV serological markers. One log increase in HBV DNA level was associated with 17% increased risk (adjusted OR: 1.17, 95% CI: 1.03-1.32). The SB-adjusted OR of HBV-positive individuals with family history of liver cancer was 41.34 (95% posterior interval [PI]: 23.69-72.12) compared with those HBV-negative without family history. Relative excess risk due to additive interaction, the attributable proportion and synergy index were 73.13, 0.87 and 8.04 respectively. Adjusted ratio of OR for multiplicative interaction was 2.84 (95% CI: 1.41-5.75). CONCLUSIONS Super-additive and super-multiplicative interactions may exist between family history of liver cancer and HBV infection on the development of liver cancer.
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Affiliation(s)
- Xing Liu
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Aileen Baecker
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California
| | - Ming Wu
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Jin-Yi Zhou
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Jie Yang
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Ren-Qiang Han
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Pei-Hua Wang
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Zi-Yi Jin
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Ai-Min Liu
- Dafeng Center for Disease Control and Prevention, Dafeng, Jiangsu, China
| | - Xiaoping Gu
- Dafeng Center for Disease Control and Prevention, Dafeng, Jiangsu, China
| | - Xiao-Feng Zhang
- Ganyu Center for Disease Control and Prevention, Ganyu, Jiangsu, China
| | - Xu-Shan Wang
- Ganyu Center for Disease Control and Prevention, Ganyu, Jiangsu, China
| | - Ming Su
- Chuzhou County Center for Disease Control and Prevention, Chuzhou, Jiangsu, China
| | - Xu Hu
- Chuzhou County Center for Disease Control and Prevention, Chuzhou, Jiangsu, China
| | - Zheng Sun
- Tongshan County Center for Disease control and Prevention, Tongshan, Jiangsu, China
| | - Gang Li
- Tongshan County Center for Disease control and Prevention, Tongshan, Jiangsu, China
| | - Alan Fu
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California
| | - Su Yon Jung
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
- School of Nursing, UCLA, Los Angeles, California
| | - Lina Mu
- Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, New York
| | - Na He
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Liming Li
- Department of Epidemiology, School of Public Health, Peking University, Beijing, China
| | - Jin-Kou Zhao
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Zuo-Feng Zhang
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
- Center for Human Nutrition, David Geffen School of Medicine, UCLA, Los Angeles, California
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2019; 25:93-159. [PMID: 31185710 PMCID: PMC6589848 DOI: 10.3350/cmh.2019.1002] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
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DNA Methylation and SNPs in VCX are Correlated with Sex Differences in the Response to Chronic Hepatitis B. Virol Sin 2019; 34:489-500. [PMID: 31161555 DOI: 10.1007/s12250-019-00117-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Accepted: 03/25/2019] [Indexed: 02/07/2023] Open
Abstract
The study was conducted to explore the mechanisms of sex differences in the response to chronic hepatitis B (CHB) in terms of DNA methylation, SNP genotype, and gene expression. Genomic DNA was isolated from peripheral blood mononuclear cells (PBMCs) of CHB patients and healthy controls and evaluated using the Human Methylation 450 K Assay. The DNA methylation level at hg37 chromosome (CHR) X: 7810800 was further validated using pyrosequencing. SNP genotypes, VCX mRNA expression of PBMCs, and plasma VCX protein concentration were further examined using SNaPshot, RT-qPCR, and Western blot, respectively. Results showed that a total of 5529 CpG loci were differentially methylated between male and female CHB patients. DNA methylation level and CC + CT frequency at CHR X: 7810800, VCX mRNA expression of PBMCs, and plasma VCX protein concentration were higher in female than in male CHB patients. The CHR X: 7810800 locus was hypermethylated in CHB patients with CC + CT genotypes in comparison with those with the TT genotype. In cases of CC + CT genotypes, VCX mRNA expression was negatively correlated with the DNA methylation level. CHB patients with higher levels of HBV DNA, AST, and GGT or higher GPRI scores exhibited lower VCX expression. In conclusion, SNPs and DNA methylation at the CHR X: 7810800 locus cooperatively regulate VCX expression in CHB. The upregulated VCX expression in female CHB patients might represent a mechanism of protection from more severe liver dysfunction and extensive fibrosis, as observed in male CHB patients.
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Lee HW, Park JY, Lee JW, Yoon KT, Kim CW, Park H, Kim YS, Paik SK, Lee JI, Kim BK, Han KH, Ahn SH. Long-term Efficacy of Tenofovir Disoproxil Fumarate Monotherapy for Multidrug-Resistant Chronic HBV infection. Clin Gastroenterol Hepatol 2019; 17:1348-1355.e2. [PMID: 30613003 DOI: 10.1016/j.cgh.2018.10.037] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 10/07/2018] [Accepted: 10/18/2018] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS There are no globally agreed upon treatment guidelines for patients with chronic hepatitis B virus (HBV) with multidrug resistance (MDR). We conducted a multicenter, prospective, real-world cohort study of effects of tenofovir disoproxyl fumarate (TDF) monotherapy and TDF-based combination therapy, as rescue therapy, in patients with multidrug-resistant chronic HBV infections. METHODS We recruited patients with chronic HBV infection with resistance to antivirals from 8 tertiary hospitals in Korea. Patients (n=423) received rescue therapy with TDF monotherapy (n=174) or TDF-based combination therapy (n=249). The median follow-up period was 180 weeks. A virologic response was defined as a serum HBV DNA level of <20 IU/mL. RESULTS Cumulative rates of virologic response did not differ significantly between the groups that received TDF monotherapy vs combination therapy at 48 weeks (71.7% vs 68.9%), 96 weeks (85.1% vs 84.2%), 144 weeks (92.1% vs 92.7%), 192 weeks (93.4% vs 95.7%), or 240 weeks (97.7% vs 97.2%). Serum levels of HBV DNA below 4.0 log10 IU/mL (odds ratio, 2.478; 95% CI 1.959-3.135; P < .001) and the absence of mutations associated with resistance to adefovir (odds ratio, 1.570; 95% CI 1.279-1.926; P < .001) were associated with virologic response in patients with MDR. There was no significant difference of virologic response among patients of different ages, sex, patients with vs without cirrhosis, positivity for hepatitis B e antigen, or renal function (all P > .05). CONCLUSION In a multicenter, real-world cohort study, long-term use of TDF monotherapy showed non-inferior antiviral efficacy compared with that of TDF-based combination therapy in patients with MDR.
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Affiliation(s)
- Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jin Woo Lee
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Republic of Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea
| | - Chang Wook Kim
- Department of Internal Medicine, Catholic University College of Medicine, Seoul, Republic of Korea
| | - Hana Park
- Department of Internal Medicine, CHA University College of Medicine, Bundang, Republic of Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea
| | - Soon Ku Paik
- Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
| | - Jung Il Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Wang YH, Chuang YH, Wu CF, Jan MC, Wu WJ, Lin CL, Liu CJ, Yang YC, Chen PJ, Lin SM, Tsai MH, Huang YW, Yu MW. Smoking and Hepatitis B Virus-Related Hepatocellular Carcinoma Risk: The Mediating Roles of Viral Load and Alanine Aminotransferase. Hepatology 2019; 69:1412-1425. [PMID: 30382583 DOI: 10.1002/hep.30339] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Accepted: 10/26/2018] [Indexed: 12/17/2022]
Abstract
Smoking interacts with hepatitis B virus (HBV) to increase the risk of hepatocellular carcinoma (HCC), which might be explained by its role in antiviral immunity. We evaluated the potential mediating role of viral load and/or alanine aminotransferase (ALT) in the relation of smoking with HBV-associated HCC risk. Using multiple mediation analyses to analyze data from 209 HCC cases and 1,256 controls nested within a cohort of 4,841 male HBV carriers, we found that the effect of smoking on the risk of subsequent HCC was substantially mediated through viral load (percent mediated, 31.7%; P = 0.0054), and a significant mediation effect by both viral load and ALT was also evidenced. Among the 1,143 subjects with repeated measures of viral load and ALT over periods of up to 16 years, we further observed that a higher number of pack-years of smoking was associated with higher viral load, maintenance of a high viral load (>4.39 log copies/mL), more severe hepatotoxicity grade, and increased likelihood of ALT ≥80 U/L (odds ratio, 3.14; 95% confidence interval, 1.03-9.64; odds ratio, 6.06; 95% confidence interval, 1.10-33.25, respectively, for 10-19 and ≥20 pack-years versus nonsmokers) during follow-up. Furthermore, plasma interferon-γ levels were reduced in smokers compared with nonsmokers (interferon-γ-positive rate, 14.9% versus 28.7%; P < 0.0001) at baseline. Smoking was also associated with a reduced natural killer (NK) cell frequency in peripheral blood, characterized by reduced NK function through a systems immunology approach, after long-term follow-up in a subsample (n = 171). The combination of smoking and reduced NK cell frequency further increased viral load and the likelihood of ALT ≥80 U/L. Conclusion: The data highlight a role of smoking in HBV viral load, underlining the importance of smoking prevention and cessation in hepatitis B management.
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Affiliation(s)
- Ya-Hui Wang
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.,Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Ya-Hui Chuang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chih-Feng Wu
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Meng-Chin Jan
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.,Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wan-Jung Wu
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ya-Chien Yang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Shi-Ming Lin
- Division of Hepatology, Liver Research Unit, Department of Gastroenterology and Hepatology, College of Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
| | - Mong-Hsun Tsai
- Institute of Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Yi-Wen Huang
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ming-Whei Yu
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
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Profiling of LINE-1-Related Genes in Hepatocellular Carcinoma. Int J Mol Sci 2019; 20:ijms20030645. [PMID: 30717368 PMCID: PMC6387036 DOI: 10.3390/ijms20030645] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 01/26/2019] [Accepted: 01/29/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a prime public health concern that accounts for most of the primary liver malignancies in humans. The most common etiological factor of HCC is hepatitis B virus (HBV). Despite recent advances in treatment strategies, there has been little success in improving the survival of HCC patients. To develop a novel therapeutic approach, evaluation of a working hypothesis based on different viewpoints might be important. Long interspersed element 1 (L1) retrotransposons have been suggested to play a role in HCC. However, the molecular machineries that can modulate L1 biology in HBV-related HCC have not been well-evaluated. Here, we summarize the profiles of expression and/or activation status of L1-related genes in HBV-related HCC, and HBV- and HCC-related genes that may impact L1-mediated tumorigenesis. L1 restriction factors appear to be suppressed by HBV infection. Since some of the L1 restriction factors also limit HBV, these factors may be exhausted in HBV-infected cells, which causes de-suppression of L1. Several HBV- and HCC-related genes that interact with L1 can affect oncogenic processes. Thus, L1 may be a novel prime therapeutic target for HBV-related HCC. Studies in this area will provide insights into HCC and other types of cancers.
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50
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Şahin A, Namıduru M, Balkan A, Karaoğlan İ, Gülşen MT. Assessment of histopathological alterations in patients with chronic hepatitis B infection following long-term oral antiviral therapy. Saudi Med J 2019; 39:999-1005. [PMID: 30284582 PMCID: PMC6201023 DOI: 10.15537/smj.2018.10.23056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objectives: To evaluate the histopathological changes in the liver after oral antiviral therapy in patients with chronic hepatitis B. Methods: A total of 79 HBeAg-negative and positive patients who had been on lamivudine, entecavir, or tenofovir disoproxil for at least 3 years prior to inclusion were enrolled between March 2015 and 2016, retrospectively. There were 23 patients on lamivudine, 21 patients on entecavir, and 35 on tenofovir. All patients underwent a follow-up liver biopsy. Biochemical, serological, virological and histopathological data were recorded in all patients and were compared after at least 3 years of treatment with oral antiviral agents. Results: Histological activity index scores were reduced in patients who received lamivudine (p=0.011), entecavir (p=0.002), and tenofovir (p=0.001). Also, in contrast with a significant improvement in fibrosis scores in lamivudine (p=0.033) and tenofovir (p=0.001) groups no improvements were found in patients who received entecavir (p=0.090). Conclusion: Long term treatment with oral antiviral agents was associated with biochemical, virological, serological, and histopathological improvements. Long-term use of anti-viral agents as well as continuous suppression of HBV DNA are prerequisites for histopathological improvement.
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Affiliation(s)
- Ahmet Şahin
- Department of Infectious Diseases and Clinical Microbiology, Çankırı State Hospital, Çankırı, Turkey. E-mail:.
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