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Choi YM, Jang J, Kim DH, Kim Z, Kim E, Choe WH, Kim BJ. PreS1 deletions in genotype C HBV leads to severe hepatic inflammation and hepatocarcinogenesis via the IRE1-JNK axis. JHEP Rep 2025; 7:101274. [PMID: 39980750 PMCID: PMC11840487 DOI: 10.1016/j.jhepr.2024.101274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 10/23/2024] [Accepted: 11/08/2024] [Indexed: 02/22/2025] Open
Abstract
Background & Aims Deletion of 15-21 nucleotides covering the preS1 start codon frequently occurs in patients with chronic HBV (CHB) with HBV genotype C and has been reported to be related to progression to hepatocellular carcinoma (HCC). However, the underlying mechanism causing the distinct phenotype of this HBV variant remains largely unknown. We investigated the mechanism by which preS1Del is related to liver disease progression and enhanced HBV replication, focusing on endoplasmic reticulum (ER) stress. Methods The effects of HBV replicative capacity, ER stress signaling, inflammation, cell death, and tumorigenesis resulting from PreS1 deletions were investigated through in vitro and in vivo experiments. Inhibitors of the IRE1-JNK pathway and IL6 blockade were used to examine HCC tumor load induced by preS1 deletions. Results The PreS1Del variant selectively activates the IRE1 pathway, mainly via enhanced colocalization between the ER and HBsAg in infected hepatocytes. This leads to enhanced HBV replication and production of tumor-promoting inflammatory cytokines and IL6 and COX2 via the IRE1-JNK signaling pathway. Furthermore, in vivo data showed that the activation of IRE1-JNK signaling consequently leads to lipid accumulation and apoptosis within 21Del-HBV-infected hepatocytes, collectively driving severe tumorigenesis in the liver. Notably, several inhibitors of the IRE1-JNK pathway dramatically inhibited HBV replication and inflammation induced by 21Del-HBV but not by the wild-type HBV in infected hepatocytes. Furthermore, IL6 blockade significantly reduced HCC tumor load induced by 21Del-HBV. Conclusions PreS1Del leads to enhanced HBV replication and HCC development through IRE1-JNK-IL6/COX2-mediated hepatocyte proliferation and liver inflammation. Inhibitors interfering with the IRE1-JNK-IL6 pathway could selectively inhibit HBV replication and inflammation in preS1Dels, suggesting their potential for the treatment of patients with CHB with preS1-deleted HBV variants. Impact and implications Deletion of 15-21 nucleotides at the preS1 start codon is common in patients with CHB with HBV genotype C and is linked to HCC progression. However, the mechanisms underlying the distinct phenotype of this variant remain largely unknown. We found that the preS1Del variant selectively activates the IRE1 pathway, primarily through enhanced IRE1-JNK-IL6 signaling. Inhibition of either the IRE1-JNK pathway or IL6 reduced HBV replication and tumor load in in vivo HCC models. This study enhances our understanding of the mechanisms of liver disease progression caused by 5' preS1Del variants and provides new insights into treatment strategies for patients with these variants. We believe our findings will resonate with a diverse audience, including patients and their physicians, the medical community, academia, the life sciences sector, and the general public.
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Affiliation(s)
- Yu-Min Choi
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
- Institute of Endemic Disease, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Junghwa Jang
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
| | - Dong Hyun Kim
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
| | - Ziyun Kim
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
| | - Eunseo Kim
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
| | - Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul 05030, Republic of Korea
| | - Bum-Joon Kim
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
- Institute of Endemic Disease, Seoul National University Medical Research Center, Seoul, Republic of Korea
- Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
- Liver Research Institute, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
- Cancer Research Institute, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
- Seoul National University Medical Research Center (SNUMRC), Seoul 03080, Republic of Korea
- BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea
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Adu F, Aniakwaa-Bonsu E, Badu Nyarko S, Obeng AS, Ateko RO, Anyanful A, Thomford NE. Host cytokine genetic polymorphisms in a selected population of persons living with hepatitis B virus infection in the central region of Ghana. BMC Gastroenterol 2024; 24:374. [PMID: 39434005 PMCID: PMC11494869 DOI: 10.1186/s12876-024-03456-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 10/09/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a public health concern in resource limited settings like Ghana. Over the past decades, it is noted that the natural course of HBV in persons infected are taking a worse turn leading to liver cirrhosis and cancer. The outcome of HBV infection is influenced by viral and host factors including genetics. Cytokine variations affect virus survival and progression and may even influence associated complications. Cytokines such as tumor necrosis factor alpha (TNF-α), interleukins (IL-4, IL-6, IL-8, IL-10, IL-18), interferon gamma (IFN)-γ, and tumor growth factor-beta (TGF-β) have key roles in HBV infection and modulation. In this study, polymorphisms occurring in five cytokines were analysed to understand how they can influence prognosis of HBV infection. METHODS The study is a single centre cross-sectional study involving 227 participants made up of HBV infected participants and HBV-negative controls. Recruitment was from March 2021 to April 2022. Blood samples were taken for full blood count, HBV antigen profile, liver function tests, HBV DNA quantification and cytokine genotyping. FIB score was calculated using available tools. Statistical analysis was undertaken with p < 0.05 set as statistically significant. RESULTS The 20-39-year-old group formed majority of the HBV infected participants with 60% of all participants being classified as healthy HBsAg carriers. IL2 rs1479920 GG carriers ((1258.93; 0.00-5011.87) IU/mL had reduced HBV DNA in comparison to IL2 rs1479920 AA ((5011.87; 2113.49-5956.62) /AG (3548.13; 0.00-6309.57) IU/mL carriers. TNF-α rs1800629 AA carriers (1258.93; 0.00-3981.07) IU/mL had a reduction in HBV DNA levels in comparison to TNF-α rs1800629 GG carriers (1584.89; 0.00-5011.87) IU/mL. The results of univariate (OR = 0.08, 0.00-0.93; p = 0.043) and multivariate (OR = 0.02, 0.00-0.67; p = 0.029) analysis, showed that carrying TNF-α rs1800629 AA genotype reduce susceptibility to high FIB score compared with GG genotypes. In univariate analysis, subjects aged 20-39 years (OR = 5.00, 1.13-6.10; p = 0.034) and 40-59 years (OR = 41.99, 3.74-47.21; p = 0.0002) were more susceptible to high FIB score compared to subjects aged 1-19 years. Being female (OR = 2.42, 1.03-5.71; p = 0.043) in the univariate models showed higher odds of having high levels of HBV DNA in the multivariate model. There was a reduced likelihood of herbal medicine usage influencing HBV DNA levels significantly (OR = 0.29, 0.10-0.86; p = 0.025). CONCLUSION In conclusion, variations in IL2 rs1479920 GG and IL2 rs1479921 AA could offer protective effects by reducing HBV DNA. TNF-α rs179924CT may also cause elevation in HBV DNA levels whiles TNF-α -308A/G, showed a potential protective effect on liver scarring in HBV infected participants. It is therefore important to take a further look at such variations for understanding of HBV modulation in the Ghanaian population.
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Affiliation(s)
- Faustina Adu
- Department of Medical Biochemistry, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
- Pharmacogenomics and Genomic Medicine Group & Lab, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Ebenezer Aniakwaa-Bonsu
- Department of Microbiology & Immunology, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Samuel Badu Nyarko
- Department of Medical Biochemistry, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
- Pharmacogenomics and Genomic Medicine Group & Lab, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Aikins Sarpong Obeng
- Department of Medical Biochemistry, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Richmond Owusu Ateko
- Department of Chemical Pathology, University of Ghana Medical School University of Ghana, Legon, Accra, Ghana
- Division of Chemical Pathology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Akwasi Anyanful
- Department of Medical Biochemistry, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Nicholas Ekow Thomford
- Department of Medical Biochemistry, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.
- Pharmacogenomics and Genomic Medicine Group & Lab, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.
- Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town, 7925, South Africa.
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Pastras P, Zazas E, Kalafateli M, Aggeletopoulou I, Tsounis EP, Kanaloupitis S, Zisimopoulos K, Kottaridou EEK, Antonopoulou A, Drakopoulos D, Diamantopoulou G, Tsintoni A, Thomopoulos K, Triantos C. Predictive Risk Factors and Scoring Systems Associated with the Development of Hepatocellular Carcinoma in Chronic Hepatitis B. Cancers (Basel) 2024; 16:2521. [PMID: 39061161 PMCID: PMC11274905 DOI: 10.3390/cancers16142521] [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: 06/05/2024] [Revised: 07/04/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Chronic hepatitis B (CHB) infection constitutes a leading cause of hepatocellular carcinoma (HCC) development. The identification of HCC risk factors and the development of prognostic risk scores are essential for early diagnosis and prognosis. The aim of this observational, retrospective study was to evaluate baseline risk factors associated with HCC in CHB. Six hundred thirty-two consecutive adults with CHB (n = 632) [median age: 46 (IQR: 24)], attending the outpatients' Hepatology clinics between 01/1993-09/2020 were evaluated. Core promoter mutations and cirrhosis-HCC (GAG-HCC), Chinese University-HCC (CU-HCC), risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B), Fibrosis-4 (FIB-4), and Platelet Age Gender-HBV (PAGE-B) prognostic scores were calculated, and receiver operating curves were used to assess their prognostic performance. HCC was developed in 34 (5.38%) patients. In the multivariable Cox regression analysis, advanced age (HR: 1.086, 95% CI: 1.037-1.137), male sex (HR: 7.696, 95% CI: 1.971-30.046), alcohol abuse (HR: 2.903, 95% CI: 1.222-6.987) and cirrhosis (HR: 21.239, 95% CI: 6.001-75.167) at baseline were independently associated with the development of HCC. GAG-HCC and PAGE-B showed the highest performance with c-statistics of 0.895 (95% CI: 0.829-0.961) and 0.857 (95% CI: 0.791-0.924), respectively. In the subgroup of patients with cirrhosis, the performance of all scores declined. When treated and untreated patients were studied separately, the discriminatory ability of the scores differed. In conclusion, HCC development was independently associated with advanced age, male sex, alcohol abuse, and baseline cirrhosis among a diverse population with CHB. GAG-HCC and PAGE-B showed high discriminatory performance to assess the risk of HCC development in these patients, but these performances declined in the subgroup of patients with cirrhosis. Further research to develop scores more specific to certain CHB subgroups is needed.
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Affiliation(s)
- Ploutarchos Pastras
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
| | - Evaggelos Zazas
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
| | - Maria Kalafateli
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
| | - Efthymios P. Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
| | - Stavros Kanaloupitis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
| | - Konstantinos Zisimopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
| | - Eirini-Eleni-Konstantina Kottaridou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
| | - Aspasia Antonopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
| | - Dimosthenis Drakopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
| | - Georgia Diamantopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
| | - Aggeliki Tsintoni
- Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece;
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (E.Z.); (M.K.); (I.A.); (E.P.T.); (S.K.); (K.Z.); (E.-E.-K.K.); (A.A.); (D.D.); (G.D.); (K.T.)
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Panneerselvam S, Wilson C, Kumar P, Abirami D, Pamarthi J, Reddy MS, Varghese J. Overview of hepatocellular carcinoma: from molecular aspects to future therapeutic options. Cell Adh Migr 2023; 17:1-21. [PMID: 37726886 PMCID: PMC10512929 DOI: 10.1080/19336918.2023.2258539] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 09/08/2023] [Indexed: 09/21/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the seventh most highly prevalent malignant tumor globally and the second most common cause of mortality. HCC develops with complex pathways that occur through multistage biological processes. Non-alcoholic fatty liver disease, metabolic-associated fatty liver disease, alcoholic liver disease, autoimmune hepatitis, hepatitis B, and hepatitis C are the causative etiologies of HCC. HCC develops as a result of epigenetic changes, protein-coding gene mutations, and altered signaling pathways. Biomarkers and potential therapeutic targets for HCC open up new possibilities for treating the disease. Immune checkpoint inhibitors are included in the treatment options in combination with molecular targeted therapy.
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Affiliation(s)
- Sugan Panneerselvam
- Department of Hepatology and Transplant Hepatology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Cornelia Wilson
- Natural and Applied Sciences, School of Psychology and Life Sciences, Canterbury Christ Church University, Discovery Park, Sandwich, UK
| | - Prem Kumar
- Department of Hepatology and Transplant Hepatology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Dinu Abirami
- Department of Gastroenterology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Jayakrishna Pamarthi
- Multi-Disciplinary Research Unit, Madras Medical College, Chennai, Tamil Nadu, India
| | - Mettu Srinivas Reddy
- The Director and Head, Liver Transplant and HPB surgery, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Joy Varghese
- Department of Gastroenterology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
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Wang X, Liu X, Wang P, Yu L, Yan F, Yan H, Zhou D, Yang Z. Antiviral Therapy Reduces Mortality in Hepatocellular Carcinoma Patients with Low-Level Hepatitis B Viremia. J Hepatocell Carcinoma 2021; 8:1253-1267. [PMID: 34708007 PMCID: PMC8544274 DOI: 10.2147/jhc.s330301] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 10/04/2021] [Indexed: 12/14/2022] Open
Abstract
Background and Aims Although antiviral treatment has been shown to reduce mortality in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients with high HBV-DNA levels, it is still unclear whether it is useful in reducing mortality in patients with low HBV-DNA levels. Methods A retrospective analysis of 756 HBV-associated HCC patients at the Beijing Ditan Hospital with HBV-DNA levels < 500 IU/mL was conducted between January 2008 and June 2017. Patients were divided into antiviral and non-antiviral groups based on whether they received nucleos(t)ide analogue (NA) treatment when they were diagnosed with HCC in our hospital for the first time. We used 1:4 frequency matching by age, gender, tumor size, Barcelona Clinic Liver Cancer (BCLC) staging, anti-tumor therapy, cirrhosis, diabetes, and hyperlipoidemia to compare the antiviral (n = 366) and non-antiviral (n = 100) groups. A Cox multivariate regression analysis was employed to evaluate the effects of NA therapy on the hazard ratio (HR), and the Kaplan–Meier survival curve was used to determine the mortality risk in patients with HCC. A Log rank test was performed to analyze the effects of NA therapy on the survival rate of patients with HCC. Results After propensity score matching, the 1-, 3-, and 5-year overall survival (OS) rates for the antiviral and non-antiviral groups were 82.5%, 68.6%, and 52.2%, and 61.0%, 51.0%, and 38.0%, respectively. The l-year progression-free survival (PFS) rates for the two groups were 68.0% and 47.0%, respectively. The OS of the antiviral group was significantly higher than that of the control group (P < 0.001, P = 0.001, and P = 0.013, respectively). The 1-year PFS for the antiviral group was also significantly better than that for the non-antiviral groups (P = 0.005). After adjusting for confounding prognostic factors in the Cox model, the HR of 5-year death after antiviral treatment was 0.721 (95% confidence interval [CI], 0.530–0.980, P = 0.037). Antiviral therapy is an independent protective factor for 5-year mortality in patients with HCC and low-level viremia. Conclusion Antiviral therapy significantly reduced mortality in HCC patients with low HBV-DNA levels.
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Affiliation(s)
- Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Xiaoli Liu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Peng Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Lihua Yu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Fengna Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Huiwen Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Dongdong Zhou
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Zhiyun Yang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
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Datfar T, Doulberis M, Papaefthymiou A, Hines IN, Manzini G. Viral Hepatitis and Hepatocellular Carcinoma: State of the Art. Pathogens 2021; 10:pathogens10111366. [PMID: 34832522 PMCID: PMC8619105 DOI: 10.3390/pathogens10111366] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/26/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis is one of the main causes leading to hepatocellular carcinoma (HCC). The continued rise in incidence of HCC suggests additional factors following infection may be involved. This review examines recent studies investigating the molecular mechanisms of chronic hepatitis and its association with hepatocarcinogenesis. Hepatitis B virus patients with genotype C display an aggressive disease course leading to HCC more than other genotypes. Furthermore, hepatitis B excretory antigen (HBeAg) seems to be a more sensitive predictive tumor marker exhibiting a six-fold higher relative risk in patients with positive HBsAg and HBeAg than those with HBsAg only. Single or combined mutations of viral genome can predict HCC development in up to 80% of patients. Several mutations in HBx-gene are related with higher HCC incidence. Overexpression of the core protein in HCV leads to hepatocellular lipid accumulation associated with oncogenesis. Reduced number and decreased functionality of natural killer cells in chronic HCV individuals dysregulate their surveillance function in tumor and viral cells resulting in HCC. Furthermore, high T-cell immunoglobulin and mucin 3 levels supress CD8+ T-cells, which lead to immunological dysregulation. Hepatitis D promotes HCC development indirectly via modifications to innate immunity, epigenetic alterations and production of reactive oxygen species with the LHDAg being the most highly associated with HCC development. Summarizing the results, HBV and HCV infection represent the most associated forms of viral hepatitis causing HCC. Further studies are warranted to further improve the prediction of high-risk patients and development of targeted therapeutics preventing the transition from hepatic inflammation–fibrosis to cancer.
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Affiliation(s)
- Toofan Datfar
- Department of General and Visceral Surgery, Hospital of Aarau, 5001 Aarau, Switzerland;
- Correspondence: ; Tel.: +41-76-4930834
| | - Michael Doulberis
- Department of Gastroenterology and Hepatology, Hospital of Aarau, 5001 Aarau, Switzerland;
| | | | - Ian N. Hines
- Department of Nutrition Science, East Carolina University, Greenville, NC 27858, USA;
| | - Giulia Manzini
- Department of General and Visceral Surgery, Hospital of Aarau, 5001 Aarau, Switzerland;
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Nishida Y, Imamura M, Teraoka Y, Morio K, Fujino H, Ono A, Nakahara T, Murakami E, Yamauchi M, Kawaoka T, Miki D, Tsuge M, Hiramatsu A, Abe-Chayama H, Hayes CN, Aikata H, Sasaki N, Sekiguchi T, Kinukawa H, Yoshimura T, Chayama K. Serum PreS1 and HBsAg ratio reflects liver fibrosis and predicts the development of hepatocellular carcinoma in chronic hepatitis B patients. J Viral Hepat 2021; 28:1304-1311. [PMID: 34105859 DOI: 10.1111/jvh.13557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/11/2021] [Accepted: 05/20/2021] [Indexed: 12/09/2022]
Abstract
While the preS1 region of the large hepatitis B surface protein plays an essential role in hepatitis B virus (HBV) infection, the effect of preS1 on liver fibrosis and hepatocarcinogenesis in chronic hepatitis B (CHB) patients is not well known. In this study, we measured serum preS1 levels by chemiluminescent immunoassay technology in 690 CHB patients and evaluated the correlation between serum preS1 levels and HBV, liver function markers and liver inflammation, fibrosis assessed by histological findings. Predictive factors for hepatocellular carcinoma (HCC) development in patients who had no previous history of HCC at the time of preS1 level measurement were also analysed. Median hepatitis B surface antigen (HBsAg) and preS1 levels were 3.08 log IU/mL and 98 ng/mL, respectively. PreS1 values were significantly correlated with serum HBsAg (p <0.001), hepatitis B core-related antigen (HBcrAg) (p <0.001) and HBV DNA levels (p <0.01). PreS1 values were also significantly correlated with serum alanine aminotransferase levels (p <0.001) and were significantly higher in patients who had higher grading of liver inflammatory activity (p <0.05). HBsAg level was correlated, but preS1/HBsAg ratio reflected liver fibrosis staging more directly than HBsAg alone. Multivariate analysis identified age ≥53 years (hazard ratio [HR], 18.360 for <53 years; p = 0.021) and preS1/HBsAg ratio ≥0.12 (HR, 6.205 for <0.12; p = 0.040) as significant and independent factors for HCC development in CHB patients. The preS1/HBsAg ratio directly reflects liver fibrosis, and the ratio might be a predictive marker for HCC development in CHB patients.
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Affiliation(s)
- Yuno Nishida
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe-Chayama
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Noriko Sasaki
- Diagnostics Division, Abbott Japan LLC, Matsudo, Japan
| | | | | | | | - Kazuaki Chayama
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Collaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Sciences, Hiroshima University, Yokohama, Japan.,Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Yokohama, Japan
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8
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Lu H, Yi W, Sun F, Zeng Z, Zhang L, Li M, Xie Y. Comprehensive investigation of HBV-related hepatocellular carcinoma and choice of anti-HBV therapy. BIOSAFETY AND HEALTH 2021. [DOI: 10.1016/j.bsheal.2021.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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9
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Liu Y, Veeraraghavan V, Pinkerton M, Fu J, Douglas MW, George J, Tu T. Viral Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma Occurrence and Recurrence. Front Microbiol 2021; 12:665201. [PMID: 34194408 PMCID: PMC8236856 DOI: 10.3389/fmicb.2021.665201] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 05/06/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the fourth leading cause of cancer-related death. The most common risk factor for developing HCC is chronic infection with hepatitis B virus (HBV). Early stages of HBV-related HCC (HBV-HCC) are generally asymptomatic. Moreover, while serum alpha-fetoprotein (AFP) and abdominal ultrasound are widely used to screen for HCC, they have poor sensitivity. Thus, HBV-HCC is frequently diagnosed at an advanced stage, in which there are limited treatment options and high mortality rates. Serum biomarkers with high sensitivity and specificity are crucial for earlier diagnosis of HCC and improving survival rates. As viral-host interactions are key determinants of pathogenesis, viral biomarkers may add greater diagnostic power for HCC than host biomarkers alone. In this review, we summarize recent research on using virus-derived biomarkers for predicting HCC occurrence and recurrence; including circulating viral DNA, RNA transcripts, and viral proteins. Combining these viral biomarkers with AFP and abdominal ultrasound could improve sensitivity and specificity of early diagnosis, increasing the survival of patients with HBV-HCC. In the future, as the mechanisms that drive HBV-HCC to become clearer, new biomarkers may be identified which can further improve early diagnosis of HBV-HCC.
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Affiliation(s)
- Yuanyuan Liu
- Department of Infectious Diseases, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, Xi'an, China.,Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia
| | - Vaishnavi Veeraraghavan
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.,School of Medical Science, The University of Sydney, Camperdown, NSW, Australia
| | - Monica Pinkerton
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.,School of Medical Science, The University of Sydney, Camperdown, NSW, Australia
| | - Jianjun Fu
- Department of Infectious Diseases, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mark W Douglas
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.,Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia.,Centre for Infectious Diseases and Microbiology, Westmead Hospital, Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia
| | - Thomas Tu
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.,Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia
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