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1
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Fu MX, Elsharkawy A, Healy B, Jackson C, Bradshaw D, Watkins E, Ushiro-Lumb I, Griffiths J, Neuberger J, Maguire K, Desai M, McDougall N, Priddee N, Barclay ST, Blackmore S, Simmonds P, Irving WL, Harvala H. Occult hepatitis B virus infection: risk for a blood supply, but how about individuals' health? EClinicalMedicine 2025; 81:103095. [PMID: 39975699 PMCID: PMC11836515 DOI: 10.1016/j.eclinm.2025.103095] [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: 11/24/2024] [Revised: 01/14/2025] [Accepted: 01/20/2025] [Indexed: 02/21/2025] Open
Abstract
The implementation of effective blood donation screening for hepatitis B virus (HBV) anti-core antibodies with highly sensitive molecular HBV DNA detection in low-endemic countries like the United Kingdom has improved blood safety. However, the linkage to care and management for blood donors with occult HBV infection (OBI) is a complex dilemma involving virological, clinical, methodological, and social issues. Limited evidence suggests that OBI may accelerate the progression of liver disease and cancer. The need for a specialist referral for donors identified with OBI carries mixed opinions from blood establishments, hepatologists, and public health. Following extensive multidisciplinary discussions, experts agree upon a need for clear messaging for donors and to consider the oncogenic implications of OBI. Proposals for future studies are identified, and the applicability of the recommendations in low-resource, high-endemic regions is considered, as well as the inclusion of OBI in global hepatitis elimination targets.
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Affiliation(s)
- Michael X. Fu
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Ahmed Elsharkawy
- Liver Unit, Queen Elizabeth Hospital Birmingham, NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham, Birmingham, UK
| | - Brendan Healy
- Public Health Wales and Swansea Bay University Health Board, Swansea, UK
| | - Celia Jackson
- West of Scotland Specialist Virology Centre, Glasgow, UK
| | - Daniel Bradshaw
- Virus Reference Department, UK Health Security Agency, London, UK
| | - Emma Watkins
- Clinical Services, NHS Blood and Transplant, Birmingham, UK
| | | | | | - James Neuberger
- Liver Unit, Queen Elizabeth Hospital Birmingham, NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham, Birmingham, UK
| | | | - Monica Desai
- Blood Safety, UK Health Security Agency, London, UK
| | | | - Nicole Priddee
- Donor Services Division, Scottish National Blood Transfusion Service, Edinburgh, UK
| | | | | | - Peter Simmonds
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - William L. Irving
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | - Heli Harvala
- Microbiology Services, NHS Blood and Transplant, Colindale, UK
- Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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2
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Huang SW, Long H, Huang JQ. Surveillance Following Hepatitis B Surface Antigen Loss: An Issue Requiring Attention. Pathogens 2024; 14:8. [PMID: 39860969 PMCID: PMC11768139 DOI: 10.3390/pathogens14010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/25/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Due to the lack of agents that directly target covalently closed circular DNA and integrated HBV DNA in hepatocytes, achieving a complete cure for chronic hepatitis B (CHB) remains challenging. The latest guidelines recommend (hepatitis B surface antigen) HBsAg loss as the ideal treatment target for improving liver function, histopathology, and long-term prognosis. However, even after HBsAg loss, hepatitis B virus can persist, with a risk of recurrence, reactivation, cirrhosis, and hepatocellular carcinoma. Therefore, follow-up and surveillance are still necessary. With increasing treatment options available for achieving HBsAg loss in patients with CHB, developing effective surveillance strategies has become crucial. Recent studies on outcomes following HBsAg loss provide new insights for refining current surveillance strategies, though further improvement is needed through long-term observation and follow-up.
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Affiliation(s)
- Shuai-Wen Huang
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
- Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Hong Long
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
| | - Jia-Quan Huang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
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The proliferation of atypical hepatocytes and CDT1 expression in noncancerous tissue are associated with the postoperative recurrence of hepatocellular carcinoma. Sci Rep 2022; 12:20508. [PMID: 36443564 PMCID: PMC9705552 DOI: 10.1038/s41598-022-25201-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022] Open
Abstract
Recently, we reported that extent of proliferation of atypical hepatocytes (atypical hepatocytes) was most important histological risk factor for development of hepatocellular carcinoma (HCC) from chronic hepatitis C or liver cirrhosis. Here, we aimed to clarify whether the atypical hepatocytes in noncancerous sections is also involved in postoperative recurrence. Furthermore, we investigated significant genes involved in the atypical hepatocytes. Association between the extent of atypical hepatocytes in noncancerous tissue and postoperative recurrence was validated in 356 patients with HCC. Next, we identified putative signature genes involved in extent of atypical hepatocytes. First, atypical hepatocytes or hepatocytes other than the atypical hepatocyte in noncancerous sections of 4 HCC patients were selectively collected by laser capture microdissection (LCM). Second, the gene expression profiles of the selected hepatocyte populations were compared using Ion AmpliSeq Transcriptome Human Gene Expression Kit (Thermo Fisher SCIENTIFIC, Waltham, MA, USA) analysis. Finally, we validated the mRNA expression of the extracted genes in noncancerous frozen liver tissue from 62 patients with HCC by RT-qPCR to identify the signature genes involved in both the extent of atypical hepatocytes and postoperative recurrence. Furthermore, the extent of atypical hepatocytes and CDT1 expression in noncancerous sections from 8 patients with HCC were also validated by selectively collecting samples using LCM. The extent of atypical hepatocytes was associated with postoperative recurrence. Of the genes that showed significant differences in expression levels between two populations, the expression of the chromatin licensing and DNA replication factor 1 (CDT1) gene was most strongly associated with the extent of atypical hepatocytes and was also associated with postoperative recurrence. Furthermore, CDT1-positive cells that exhibited stronger expression resembled those morphologically considered to be atypical hepatocytes. CDT1 and Ki-67 were colocalized in the nuclei of both hepatocytes and cancer cells. The hepatocytes in noncancerous livers were not uniform in each hepatocyte population, suggesting that the accumulation of genetic abnormalities was variable. We found that the strong degree of atypical hepatocytes and high CDT1 mRNA expression represent a high carcinogenic state of the liver. Thus, we consider the evaluation of degree of these could support the personalized medicine.
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Çakal B, Çavuş B, Atasoy A, Poda M, Bulakçi M, Güllüoğlu M, Demirci M, Şener LT, Altunok D, Arslan AB, Akyüz F. What is the clinical impact of occult HBV infections and anti-HBc positivity in patients with chronic hepatitis C? Microbiol Immunol 2022; 66:386-393. [PMID: 35661243 DOI: 10.1111/1348-0421.13012] [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: 02/18/2022] [Revised: 05/20/2022] [Accepted: 06/01/2022] [Indexed: 11/29/2022]
Abstract
Occult hepatitis B infection (OBI) is defined by the persistence of the hepatitis B virus (HBV) genome in the liver of individuals testing negative for hepatitis B surface antigen (HBsAg). Hepatitis B core antibody (anti-HBc) is the serological marker that indicates HBV exposure. The impact of anti-HBc and OBI on patients with chronic hepatitis C remains unclear. The aim of the present study was to determine the prevalence of anti-HBc and OBI and to evaluate their impact on the clinical and pathological outcomes of patients with chronic hepatitis C. The study included 59 HBsAg-negative chronic hepatitis C patients who underwent a liver parenchymal biopsy. The presence of HBV DNA was investigated using an in-house nested PCR method. OBI was detected in 16 (27.1%) of the 59 cases and also in 10 (62.5%) of 22 (37.3%) anti-HBc-positive patients. None of the patients had positive serum HBV DNA. OBI was associated with the presence of anti-HBV antibodies (p<0.05). There was also an association between anti-HBc positivity and the activity grades and fibrosis stages of the liver and also a prevalence of liver steatosis (p<0.05). Positive anti-HBc results may predict OBI and also be associated with the progression of liver injury in HBsAg-negative patients with chronic hepatitis C. Therefore, it is suggested that patients with chronic hepatitis C should be screened for anti-HBc positivity, and anti-HBc-positive patients should be carefully evaluated for disease progression. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Bülent Çakal
- Department of Medical Microbiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Bilger Çavuş
- Division of Gastroenterohepatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Alp Atasoy
- Division of Gastroenterohepatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mehveş Poda
- Department of Genetics, Aziz Sancar Institute for Experimental Medical Research, Istanbul University, Istanbul, Turkey
| | - Mesut Bulakçi
- Department of Radiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mine Güllüoğlu
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mehmet Demirci
- Department of Medical Microbiology, Faculty of Medicine, Kirklareli University, Kirklareli, Turkey
| | - Leyla Türker Şener
- Department of Biophysics Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Damla Altunok
- Division of Gastroenterohepatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | | | - Filiz Akyüz
- Division of Gastroenterohepatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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Enhanced host immune responses in presence of HCV facilitate HBV clearance in coinfection. Virol Sin 2022; 37:408-417. [PMID: 35523417 PMCID: PMC9243674 DOI: 10.1016/j.virs.2022.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 03/21/2022] [Indexed: 01/21/2023] Open
Abstract
Hepatitis B virus (HBV)/Hepatitis C virus (HCV) coinfection is frequently observed because of the common infection routine. Despite the reciprocal inhibition exerted by HBV and HCV genomes, the coinfection of HBV and HCV is associated with more severe forms of liver diseases. However, the complexity of viral interference and underlying pathological mechanism is still unclarified. With the demonstration of absence of direct viral interplay, some in vitro studies suggest the indirect effects of viral-host interaction on viral dominance outcome. Here, we comprehensively investigated the viral replication and host immune responses which might mediate the interference between viruses in HBV/HCV coinfected Huh7-NTCP cells and immunocompetent HCV human receptors transgenic ICR mice. We found that presence of HCV significantly inhibited HBV replication in vitro and in vivo irrespective of the coinfection order, while HBV did not affect HCV replication. Pathological alteration was coincidently reproduced in coinfected mice. In addition to the participation of innate immune response, an involvement of HCV in up-regulating HBV-specific immune responses was described to facilitate HBV clearance. Our systems partially recapitulate HBV/HCV coinfection and unveil the uncharacterized adaptive anti-viral immune responses during coinfection, which renews the knowledge on the nature of indirect viral interaction during HBV/HCV coinfection.
HCV inhibited HBV replication in Huh7-NTCP cells. HCV suppressed HBV in immunocompetent mice. Induced innate immune response by HCV limited HBV replication. Presence of HCV enhanced HBV specific immune response. Moderate and acute live injure was caused by HBV/HCV coinfection.
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6
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Olagbenro M, Anderson M, Gaseitsiwe S, Powell EA, Gededzha MP, Selabe SG, Blackard JT. In silico analysis of mutations associated with occult hepatitis B virus (HBV) infection in South Africa. Arch Virol 2021; 166:3075-3084. [PMID: 34468889 PMCID: PMC11930061 DOI: 10.1007/s00705-021-05196-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 06/09/2021] [Indexed: 01/02/2023]
Abstract
Occult hepatitis B virus (OBI) infection is defined by the presence of viral DNA in the liver and/or serum in absence of hepatitis B surface antigen (HBsAg). While multiple studies have identified mutations that are associated with OBI, only a small portion of these mutations have been functionally characterized in vitro. Using complementary in silico approaches, the effects of OBI-associated amino acid mutations on HBV protein function in HBV/HIV-positive ART-naïve South Africans were evaluated. Two OBI-associated mutations in the PreS1 region, one in the PreS2 region, and seven in the surface region of subgenotype A1 sequences were identified as deleterious. In subgenotype A2 sequences, 11 OBI-associated mutations in the PreS1 region, seven in the PreS2 region, and 31 in the surface region were identified as deleterious. In the polymerase region, 14 OBI-associated mutations in subgenotype A1 and 71 OBI-associated mutations in subgenotype A2 were identified as deleterious. This study utilized in silico approaches to characterize the likely impact of OBI-associated mutations on viral function, thereby identifying and prioritizing candidates and reducing the significant cost associated with functional studies that are essential for mechanistic studies of the OBI phenotype.
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Affiliation(s)
- Matthew Olagbenro
- Division of Digestive Diseases, University of Cincinnati College of Medicine, ML 0595, Albert Sabin Way, Cincinnati, OH, 45267-0595, USA
| | | | | | - Eleanor A Powell
- Division of Digestive Diseases, University of Cincinnati College of Medicine, ML 0595, Albert Sabin Way, Cincinnati, OH, 45267-0595, USA
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Maemu P Gededzha
- Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa
- HIV and Hepatitis Research Unit, Department of Virology, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| | - Selokela G Selabe
- HIV and Hepatitis Research Unit, Department of Virology, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| | - Jason T Blackard
- Division of Digestive Diseases, University of Cincinnati College of Medicine, ML 0595, Albert Sabin Way, Cincinnati, OH, 45267-0595, USA.
- HIV and Hepatitis Research Unit, Department of Virology, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa.
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7
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Shaltiel T, Zheng S, Siderides C, Gleeson EM, Carr J, Pletcher ER, Cohen NA, Golas BJ, Magge DR, Labow DM, Branch AD, Sarpel U. Hepatitis C-positive Black patients develop hepatocellular carcinoma at earlier stages of liver disease and present with a more aggressive phenotype. Cancer 2021; 127:1395-1406. [PMID: 33629759 PMCID: PMC8084866 DOI: 10.1002/cncr.33377] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/28/2020] [Accepted: 09/07/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND In the United States, mortality after a diagnosis of hepatocellular carcinoma (HCC) is higher in patients who are Black than in patients of other racial groups. The objective of this study was to clarify factors contributing to this disparity by analyzing liver and tumor characteristics in patients with HCC who have a history of hepatitis C virus (HCV) infection. METHODS Records of patients with HCV and HCC at the authors' institution from 2003 to 2018 were retrospectively reviewed. Race and ethnicity were self-identified. Imaging, laboratory, and pathologic features were compared between Black and non-Black cohorts. RESULTS Among 1195 individuals with HCC, 390 identified as Black. At the time of HCC diagnosis, Black patients had better liver function, as measured by Child-Pugh score, Model of End-Stage Liver Disease score, histology of nontumor tissue, and fibrosis-4 (FIB-4) score (all P < .05). FIB-4 scores were <3.25 in 31% of Black patients. In addition, Black patients had less early stage HCC (20.2% vs 32.3%; P < .05), larger tumors (median [interquartile range]: 3.5 cm [2.2-6.2 cm] vs 3.1 cm [2.1-5.1 cm]; P < .01), more multiple tumors (median, [interquartile range]: 1 tumor [1-3 tumors] vs 1 tumor [1-2 tumors]; P = .03), more poorly differentiated tumors (30.3% vs 20.5%; P < .05), and more microvascular invasion (67.2% vs 56.5%; P < .05). CONCLUSIONS Black patients with HCV exposure develop HCC at earlier stages of liver disease than members of other racial groups. Nearly one-third would not qualify for HCC screening using the common FIB-4 cirrhosis threshold. Practice guidelines that stress HCC surveillance for cirrhotic patients with HCV may need to be revised to be more inclusive for Black patients. In addition, tumors in Black patients carry worse prognostic features, and molecular studies are needed to characterize their biologic properties.
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Affiliation(s)
- Tali Shaltiel
- Department of Surgery, Division of Surgical Oncology, New York, NY
| | - Serena Zheng
- Icahn School of Medicine at Mount Sinai, New York, NY
| | | | | | - Jacquelyn Carr
- Department of Surgery, Division of Surgical Oncology, New York, NY
| | - Eric R. Pletcher
- Department of Surgery, Division of Surgical Oncology, New York, NY
| | - Noah A. Cohen
- Department of Surgery, Division of Surgical Oncology, New York, NY
| | | | - Deepa R. Magge
- Department of Surgery, Division of Surgical Oncology, New York, NY
| | - Daniel M. Labow
- Department of Surgery, Division of Surgical Oncology, New York, NY
| | - Andrea D. Branch
- Department of Medicine, Division of Liver Diseases, New York, NY
| | - Umut Sarpel
- Department of Surgery, Division of Surgical Oncology, New York, NY
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Occult hepatitis B infection and hepatocellular carcinoma: Epidemiology, virology, hepatocarcinogenesis and clinical significance. J Hepatol 2020; 73:952-964. [PMID: 32504662 DOI: 10.1016/j.jhep.2020.05.042] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/21/2020] [Accepted: 05/25/2020] [Indexed: 12/12/2022]
Abstract
Occult hepatitis B infection (OBI) refers to a condition where replication-competent HBV DNA is present in the liver, with or without HBV DNA in the blood, in individuals with serum HBsAg negativity assessed by currently available assays. The episomal covalently closed circular DNA (cccDNA) in OBI is in a low replicative state. Viral gene expression is mediated by epigenetic control of HBV transcription, including the HBV CpG island methylation pathway and post-translational modification of cccDNA-bound histone, with a different pattern from patients with chronic HBV infection. The prevalence of OBI varies tremendously across patient populations owing to numerous factors, such as geographic location, assay characteristics, host immune response, coinfection with other viruses, and vaccination status. Apart from the risk of viral reactivation upon immunosuppression and the risk of transmission of HBV, OBI has been implicated in hepatocellular carcinoma (HCC) development in patients with chronic HCV infection, those with cryptogenic or known liver disease, and in patients with HBsAg seroclearance after chronic HBV infection. An increasing number of prospective studies and meta-analyses have reported a higher incidence of HCC in patients with HCV and OBI, as well as more advanced tumour histological grades and earlier age of HCC diagnosis, compared with patients without OBI. The proposed pathogenetic mechanisms of OBI-related HCC include the influence of HBV DNA integration on the hepatocyte cell cycle, the production of pro-oncogenic proteins (HBx protein and mutated surface proteins), and persistent low-grade necroinflammation (contributing to the development of fibrosis and cirrhosis). There remain uncertainties about exactly how, and in what order, these mechanisms drive the development of tumours in patients with OBI.
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Positive Hepatitis B Core Antibody Is Associated With Cirrhosis and Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease. Am J Gastroenterol 2020; 115:867-875. [PMID: 32149781 DOI: 10.14309/ajg.0000000000000588] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Previous exposure to hepatitis B virus (HBV) may increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. We aim to study the impact of previous HBV infection on the severity and outcomes of patients with nonalcoholic fatty liver disease (NAFLD). METHODS This was a multicenter study of 489 patients with biopsy-proven NAFLD and 69 patients with NAFLD-related or cryptogenic HCC. Antihepatitis B core antibody (anti-HBc) was used to detect the previous HBV infection. RESULTS In the biopsy cohort, positive anti-HBc was associated with lower steatosis grade but higher fibrosis stage. 18.8% and 7.5% of patients with positive and negative anti-HBc had cirrhosis, respectively (P < 0.001). The association between anti-HBc and cirrhosis remained significant after adjusting for age and metabolic factors (adjusted odds ratio 2.232; 95% confidence interval, 1.202-4.147). At a mean follow-up of 6.2 years, patients with positive anti-HBc had a higher incidence of HCC or cirrhotic complications (6.5% vs 2.2%; P = 0.039). Among patients with NAFLD-related or cryptogenic HCC, 73.9% had positive anti-HBc. None of the patients had positive serum HBV DNA. By contrast, antihepatitis B surface antibody did not correlate with histological severity. DISCUSSION Positive anti-HBc is associated with cirrhosis and possibly HCC and cirrhotic complications in patients with NAFLD. Because a significant proportion of NAFLD-related HCC may develop in noncirrhotic patients, future studies should define the role of anti-HBc in selecting noncirrhotic patients with NAFLD for HCC surveillance.
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10
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Elalfy H, Besheer T, Elhammady D, El Mesery A, Shaltout SW, Abd El-Maksoud M, Amin AI, Bekhit AN, Abd El Aziz M, El-Bendary M. Pathological characterization of occult hepatitis B virus infection in hepatitis C virus-associated or non-alcoholic steatohepatitis-related hepatocellular carcinoma. World J Meta-Anal 2020; 8:67-77. [DOI: 10.13105/wjma.v8.i2.67] [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: 11/12/2019] [Revised: 01/08/2020] [Accepted: 04/09/2020] [Indexed: 02/06/2023] Open
Abstract
Occult hepatitis B virus (HBV) infection, by definition, is a state in which infection with this virus does not manifest with the conventional diagnostic laboratory criteria reserved for the obvious form of HBV infection. As a result, occult HBV infection is commonly a surprise finding discovered accidently during the evaluation of other apparent liver diseases, such as hepatitis C virus (HCV) infection or non-alcoholic fatty liver disease and, more importantly, their evolution into life-threatening hepatocellular carcinoma. As infection with HCV and occult HBV is rarely considered when assessing these more obvious conditions, and in an attempt to offer a better understanding of this phenomenon, this study attempted to shed some light onto the uniqueness of occult HBV infection by addressing the natural history of HBV and HCV infections, as well as non-alcoholic fatty liver disease. This was carried out by taking into account the exclusive integration process undertaken by the HBV genome into infected host hepatocytes, with consideration given to conditions which afford reactivation of the occult infection and stress on the molecular mechanisms that underlie occult HBV infection. Finally, the clinical outcome of occult HBV infection and its relation to hepatocellular carcinoma is analyzed.
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Affiliation(s)
- Hatem Elalfy
- Endemic Medicine Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Tarek Besheer
- Endemic Medicine Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Dina Elhammady
- Endemic Medicine Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Ahmed El Mesery
- Endemic Medicine Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Shaker Wagih Shaltout
- Tropical Medicine Department, Faculty of Medicine, Port Said University, Port Said 42511, Egypt
| | - Mohamed Abd El-Maksoud
- Endemic Medicine Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Ahmed I Amin
- Internal Medicine Department, Faculty of Medicine, Port Said University, Port Said 42511, Egypt
| | - Ahmed Nasr Bekhit
- Tropical Medicine Department, Zagazig General Hospital, Zagazig 44511, Egypt
| | - Mahmoud Abd El Aziz
- Endemic Medicine Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Mahmoud El-Bendary
- Endemic Medicine Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
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Abstract
Currently, despite the use of a preventive vaccine for several decades as well as the use of effective and well-tolerated viral suppressive medications since 1998, approximately 250 million people remain infected with the virus that causes hepatitis B worldwide. Hepatitis C virus (HCV) and hepatitis B virus (HBV) are the leading causes of liver cancer and overall mortality globally, surpassing malaria and tuberculosis. Linkage to care is estimated to be very poor both in developing countries and in high-income countries, such as the United States, countries in Western Europe, and Japan. In the United States, by CDC estimates, only one-third of HBV-infected patients or less are aware of their infection. Some reasons for these low rates of surveillance, diagnosis, and treatment include the asymptomatic nature of chronic hepatitis B until the very late stages, a lack of curative therapy with a finite treatment duration, a complex natural history, and a lack of knowledge about the disease by both care providers and patients. In the last 5 years, more attention has been focused on the important topics of HBV screening, diagnosis of HBV infection, and appropriate linkage to care. There have also been rapid clinical developments toward a functional cure of HBV infection, with novel compounds currently being in various phases of progress. Despite this knowledge, many of the professional organizations provide guidelines focused only on specific questions related to the treatment of HBV infection. This focus leaves a gap for care providers on the other HBV-related issues, which include HBV's epidemiological profile, its natural history, how it interacts with other viral hepatitis diseases, treatments, and the areas that still need to be addressed in order to achieve HBV elimination by 2030. Thus, to fill these gaps and provide a more comprehensive and relevant document to regions worldwide, we have taken a global approach by using the findings of global experts on HBV as well as citing major guidelines and their various approaches to addressing HBV and its disease burden.
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12
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The Relationship Between Serum IL-17 Level and Viral Load in Chronic Hepatitis B. ARCHIVES OF CLINICAL INFECTIOUS DISEASES 2019. [DOI: 10.5812/archcid.68172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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13
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Yamaji K, Kai K, Komukai S, Koga H, Ide T, Kawaguchi A, Noshiro H, Aishima S. Occult HBV infection status and its impact on surgical outcomes in patients with curative resection for HCV-associated hepatocellular carcinoma. Hepatobiliary Surg Nutr 2019; 7:443-453. [PMID: 30652089 DOI: 10.21037/hbsn.2018.10.01] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Background We sought to clarify the prevalence of occult hepatitis B virus (HBV) infection (OBI) and to determine whether OBI affects the surgical outcomes in curatively resected Japanese patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). Methods A total of 257 patients with HCV-related HCC who underwent curative surgical resection were enrolled. All enrolled patients were serologically negative for HBV surface antigen and positive for HCV antibody. DNA was extracted from formalin-fixed paraffin-embedded liver tissue. OBI was determined by the HBV-DNA amplification of at least two different sets of primers by TaqMan real-time polymerase chain reaction. Surgical outcomes were evaluated according to overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). Results OBI was identified in 15 of the 257 (5.8%) cases. In the multivariate analyses, the factors significantly correlated with OS were BMI >25 (P=0.0416), portal vein invasion (P=0.0065), and multiple tumors (P=0.0064). The only factor significantly correlated with DSS was T-stage (P=0.0275). The factors significantly correlated with DFS were liver fibrosis (P=0.0017) and T-stage (P=0.0001). The status of OBI did not show any significant correlation with OS, DSS or DFS, but a weak association with DSS (P=0.0603) was observed. Conclusions The prevalence of OBI was 5.8% in 257 cases of HCV-related HCC. Although a weak association between DSS and OBI was observed, and statistical analyses were limited by small number of OBI cases, no significant correlation between OBI and surgical outcomes was detected.
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Affiliation(s)
- Koutaro Yamaji
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.,Department of Pathology & Microbiology, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Keita Kai
- Department of Pathology, Saga University Hospital, Saga 849-8501, Japan
| | - Sho Komukai
- Clinical Research Center, Saga University Hospital, Saga 849-8501, Japan
| | - Hiroki Koga
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Takao Ide
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Atsushi Kawaguchi
- Center for Comprehensive Community Medicine, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Hirokazu Noshiro
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Shinichi Aishima
- Department of Pathology & Microbiology, Saga University Faculty of Medicine, Saga 849-8501, Japan.,Department of Pathology, Saga University Hospital, Saga 849-8501, Japan
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Anderson M, Choga WT, Moyo S, Bell TG, Mbangiwa T, Phinius BB, Bhebhe L, Sebunya TK, Makhema J, Marlink R, Kramvis A, Essex M, Musonda RM, Blackard JT, Gaseitsiwe S. In Silico Analysis of Hepatitis B Virus Occult Associated Mutations in Botswana Using a Novel Algorithm. Genes (Basel) 2018; 9:genes9090420. [PMID: 30134551 PMCID: PMC6162659 DOI: 10.3390/genes9090420] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 08/16/2018] [Indexed: 02/06/2023] Open
Abstract
Occult hepatitis B infections (OBI) represent a reservoir of undiagnosed and untreated hepatitis B virus (HBV), hence the need to identify mutations that lead to this phenotype. Functionally characterizing these mutations by in vitro studies is time-consuming and expensive. To bridge this gap, in silico approaches, which predict the effect of amino acid (aa) variants on HBV protein function, are necessary. We developed an algorithm for determining the relevance of OBI-associated mutations using in silico approaches. A 3 kb fragment of subgenotypes A1 and D3 from 24 chronic HBV-infected (CHB) and 24 OBI participants was analyzed. To develop and validate the algorithm, the effects of 68 previously characterized occult-associated mutations were determined using three computational tools: PolyPhen2, SNAP2, and PROVEAN. The percentage of deleterious mutations (with impact on protein function) predicted were 52 (76.5%) by PolyPhen2, 55 (80.9%) by SNAP2, and 65 (95.6%) by PROVEAN. At least two tools correctly predicted 59 (86.8%) mutations as deleterious. To identify OBI-associated mutations exclusive to Botswana, study sequences were compared to CHB sequences from GenBank. Of the 43 OBI-associated mutations identified, 26 (60.5%) were predicted by at least two tools to have an impact on protein function. To our knowledge, this is the first study to use in silico approaches to determine the impact of OBI-associated mutations, thereby identifying potential candidates for functional analysis to facilitate mechanistic studies of the OBI phenotype.
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Affiliation(s)
- Motswedi Anderson
- Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
- Faculty of Science, Department of Biological Sciences, University of Botswana, Gaborone, Botswana.
| | | | - Sikhulile Moyo
- Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
| | - Trevor Graham Bell
- Hepatitis Virus Diversity Research Unit (HVDRU), Faculty of Health Sciences, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg 2050, South Africa.
| | - Tshepiso Mbangiwa
- Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
- Faculty of Allied Health Sciences, University of Botswana, Gaborone, Botswana.
| | - Bonolo B Phinius
- Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
| | - Lynette Bhebhe
- Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
| | - Theresa K Sebunya
- Faculty of Science, Department of Biological Sciences, University of Botswana, Gaborone, Botswana.
| | - Joseph Makhema
- Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
| | - Richard Marlink
- Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
- Rutgers Global Health Institute, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08854, USA.
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit (HVDRU), Faculty of Health Sciences, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg 2050, South Africa.
| | - Max Essex
- Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
| | | | - Jason T Blackard
- College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
| | - Simani Gaseitsiwe
- Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
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15
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Nirei K, Kanda T, Nakamura H, Matsuoka S, Takayama T, Sugitani M, Moriyama M. Persistent Hepatic Inflammation Plays a Role in Hepatocellular Carcinoma After Sustained Virological Response in Patients with HCV Infection. Int J Med Sci 2018; 15:466-474. [PMID: 29559835 PMCID: PMC5859769 DOI: 10.7150/ijms.23147] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 02/02/2018] [Indexed: 02/07/2023] Open
Abstract
Objective: Hepatitis C virus (HCV) infection has long been treated with interferon therapy (IFN). Currently, more than 90% of IFN-treated patients show a sustained virological response (SVR) when also treated with ribavirin and/or a protease inhibitor. Histological inflammation and fibrosis improve in IFN-treated patients, which indicates HCV clearance. IFN also reduces the incidence of hepatocellular carcinoma (HCC). However, a small proportion of patients with SVR develop HCC. To investigate the causes of hepatic carcinogenesis after SVR, we compared the liver histological findings before IFN to those after the development of HCC. Patients and methods: In total, 602 patients infected with type C chronic hepatitis or with liver cirrhosis who received IFN therapy during the period from 1992 through 2015 were included in this study. We assessed 14 of the 287 patients who achieved an SVR. Results: HCC was diagnosed by computed tomography, angiography or liver biopsy. The longest time from the SVR until HCC detection was 16.5 years, and the mean was 7.2±4.6 years. Nine of the 14 patients underwent surgery and one radiofrequency ablation. The histological findings of 10 patients were available for comparison. The comparison of the histological findings before treatment with those after the HCC diagnosis revealed an amelioration of liver fibrosis and other inflammatory changes. All ten patients showed improvements in fibrosis and steatosis. However, we observed that mild inflammatory change persisted from 1.8 years to 16.5 years after the confirmation of SVR in all cases. Conclusion: We suspect that persistent histological inflammation is one of the factors contributing to hepatocarcinogenesis (i.e., HCC development) even after successful treatment.
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Affiliation(s)
- Kazushige Nirei
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Hitomi Nakamura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | | | | | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
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16
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Koga H, Kai K, Aishima S, Kawaguchi A, Yamaji K, Ide T, Ueda J, Noshiro H. Occult hepatitis B virus infection and surgical outcomes in non-B, non-C patients with curative resection for hepatocellular carcinoma. World J Hepatol 2017; 9:1286-1295. [PMID: 29290910 PMCID: PMC5740092 DOI: 10.4254/wjh.v9.i35.1286] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 09/14/2017] [Accepted: 10/31/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the prevalence, clinicopathological characteristics and surgical outcomes of occult hepatitis B virus (HBV) infection (OBI) in patients with non-B, non-C (NBNC) hepatocellular carcinoma (HCC).
METHODS This study retrospectively examined the cases of 78 NBNC patients with curative resection for HCC for whom DNA could be extracted from formalin-fixed paraffin-embedded tissue. OBI was determined by the HBV-DNA amplification of at least two different sets of primers by TaqMan real-time polymerase chain reaction. Possibly carcinogenetic factors such as alcohol abuse, diabetes mellitus, obesity and non-alcoholic steatohepatitis (NASH) were examined. Surgical outcomes were evaluated according to disease-free survival (DFS), overall survival (OS) and disease-specific survival (DSS).
RESULTS OBI was found in 27/78 patients (34.6%) with NBNC HCC. The OBI patients were significantly younger than the non-OBI cases at the time of surgery (average age 63.0 vs 68.1, P = 0.0334) and the OBI cases overlapped with other etiologies significantly more frequently compared to the non-OBI cases (P = 0.0057). OBI had no impact on the DFS, OS or DSS. Only tumor-related factors affected these surgical outcomes.
CONCLUSION Our findings indicate that OBI had no impact on surgical outcomes. The surgical outcomes of NBNC HCC depend on early tumor detection; this reconfirms the importance of a periodic medical examination for individuals who have NBNC HCC risk factors.
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Affiliation(s)
- Hiroki Koga
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Keita Kai
- Department of Pathology, Saga University Hospital, Saga 849-8501, Japan
| | - Shinichi Aishima
- Department of Pathology, Saga University Hospital, Saga 849-8501, Japan
- Department of Pathology and Microbiology, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Atsushi Kawaguchi
- Center for Comprehensive Community Medicine, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Koutaro Yamaji
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
- Department of Pathology and Microbiology, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Takao Ide
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Junji Ueda
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Hirokazu Noshiro
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
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17
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Kawagishi N, Suda G, Onozawa M, Kimura M, Maehara O, Ohara M, Izumi T, Umemura M, Ito J, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N. Comparing the risk of hepatitis B virus reactivation between direct-acting antiviral therapies and interferon-based therapies for hepatitis C. J Viral Hepat 2017. [PMID: 28632923 DOI: 10.1111/jvh.12737] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) reactivation has been reported during antihepatitis C treatment in patients with hepatitis C virus (HCV) and HBV co-infection. We aimed to evaluate the frequency and risk factors of HBV reactivation during anti-HCV therapy and compared those between interferon (IFN)-free direct-acting antiviral (DAA) therapies and IFN-based therapies. Three hundred and twenty-two patients with HCV infection receiving anti-HCV therapy were retrospectively screened. The baseline HBV infection statuses of all eligible patients and the HBV-DNA level of all patients with current or previous HBV infection were examined at the end of treatment. In patients with baseline anti-HBs positivity, changes in anti-HBs titre were evaluated. Of 287 patients who met the inclusion criteria, 157 had current (n=4) or previous (n=153) HBV infection; 85 were treated with IFN-free DAA therapies and 72 were treated with IFN-based therapies. Six patients experienced HBV reactivation (n=2) or HBV reappearance (n=4) after IFN-free DAA therapies, while no patient developed HBV reactivation after IFN-based therapies. The risk factors of HBV reactivation or reappearance were DAA therapies and a reduction in anti-HBs titre to <12 mIU mL-1 by the end of treatment. The decline changes of anti-HBs titre were significantly higher in patients treated with DAA therapies. Although HBV reactivation hepatitis was not observed, three of four patients with HBV reactivation or reappearance after achieving HCV eradication had viremia 8 weeks after completion of therapy. A significant proportion of patients develop HBV reactivation or reappearance without hepatitis after IFN-free DAA therapies. Low levels of anti-HBs and their decrease to <12 mIU mL-1 after treatment are significant risk factors for HBV reactivation or reappearance.
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Affiliation(s)
- N Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - G Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - M Onozawa
- Department of Hematology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - M Kimura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - O Maehara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - M Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - T Izumi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - M Umemura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - J Ito
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - M Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - T Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - M Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - K Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - K Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - N Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
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18
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Mittal M, Hu KQ. Clinical Implications and Management of Chronic Occult Hepatitis B Virus Infection. CURRENT HEPATOLOGY REPORTS 2017; 16:90-96. [DOI: 10.1007/s11901-017-0339-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
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19
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Cho J, Lee SS, Choi YS, Jeon Y, Chung JW, Baeg JY, Si WK, Jang ES, Kim JW, Jeong SH. Occult hepatitis B virus infection is not associated with disease progression of chronic hepatitis C virus infection. World J Gastroenterol 2016; 22:9427-9436. [PMID: 27895431 PMCID: PMC5107707 DOI: 10.3748/wjg.v22.i42.9427] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 08/18/2016] [Accepted: 09/06/2016] [Indexed: 02/07/2023] Open
Abstract
AIM To clarify the prevalence of occult hepatitis B virus (HBV) infection (OBI) and the association between OBI and liver disease progression, defined as development of liver cirrhosis or hepatocellular carcinoma (HCC), worsening of Child-Pugh class, or mortality in cases of chronic hepatitis C virus (HCV) infection.
METHODS This prospective cohort study enrolled 174 patients with chronic HCV infection (chronic hepatitis, n = 83; cirrhosis, n = 47; HCC, n = 44), and evaluated disease progression during a mean follow-up of 38.7 mo. OBI was defined as HBV DNA positivity in 2 or more different viral genomic regions by nested polymerase chain reaction using 4 sets of primers in the S, C, P and X open reading frame of the HBV genome.
RESULTS The overall OBI prevalence in chronic HCV patients at enrollment was 18.4%, with 16.9%, 25.5% and 13.6% in the chronic hepatitis C, liver cirrhosis and HCC groups, respectively (P = 0.845). During follow-up, 52 patients showed disease progression, which was independently associated with aspartate aminotransferase > 40 IU/L, Child-Pugh score and sustained virologic response (SVR), but not with OBI positivity. In 136 patients who were not in the SVR state during the study period, OBI positivity was associated with neither disease progression, nor HCC development.
CONCLUSION The prevalence of OBI in chronic HCV patients was 18.4%, and OBI was not associated with disease progression in South Koreans.
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20
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Makvandi M. Update on occult hepatitis B virus infection. World J Gastroenterol 2016; 22:8720-8734. [PMID: 27818588 PMCID: PMC5075547 DOI: 10.3748/wjg.v22.i39.8720] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 06/13/2016] [Accepted: 07/20/2016] [Indexed: 02/06/2023] Open
Abstract
The event of mutations in the surface antigen gene of hepatitis B virus (HBV) results in undetectable hepatitis B surface antigen with positive/negative anti-hepatitis B core (anti-HBc) antibody status in serum and this phenomenon is named occult hepatitis B infection (OBI). The presence of anti-HBc antibody in serum is an important key for OBI tracking, although about 20% of OBI cases are negative for anti-HBc antibody. The diagnosis of OBI is mainly based on polymerase chain reaction (PCR) and real-time PCR assays. However, real-time PCR is a more reliable method than PCR. OBI is a great issue for the public health problem and a challenge for the clinical entity worldwide. The persistence of OBI may lead to the development of cirrhosis and hepatocellular carcinoma. With regard to OBI complications, the screening of HBV DNA by the highly sensitive molecular means should be implemented for: (1) patients with a previous history of chronic or acute HBV infection; (2) patients co-infected with hepatitis C virus/human immunodeficiency virus; (3) patients undergoing chemotherapy or anti-CD20 therapy; (4) recipients of organ transplant; (5) blood donors; (6) organ transplant donors; (7) thalassemia and hemophilia patients; (8) health care workers; (9) patients with liver related disease (cryptogenic); (10) hemodialysis patients; (11) patients undergoing lamivudine or interferon therapy; and (12) children in time of HBV vaccination especially in highly endemic areas of HBV. Active HBV vaccination should be implemented for the close relatives of patients who are negative for OBI markers. Thus, the goal of this review is to evaluate the rate of OBI with a focus on status of high risk groups in different regions of the world.
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Coppola N, Onorato L, Pisaturo M, Macera M, Sagnelli C, Martini S, Sagnelli E. Role of occult hepatitis B virus infection in chronic hepatitis C. World J Gastroenterol 2015; 21:11931-11940. [PMID: 26576082 PMCID: PMC4641115 DOI: 10.3748/wjg.v21.i42.11931] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 06/28/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
The development of sensitive assays to detect small amounts of hepatitis B virus (HBV) DNA has favored the identification of occult hepatitis B infection (OBI), a virological condition characterized by a low level of HBV replication with detectable levels of HBV DNA in liver tissue but an absence of detectable surface antigen of HBV (HBsAg) in serum. The gold standard to diagnose OBI is the detection of HBV DNA in the hepatocytes by highly sensitive and specific techniques, a diagnostic procedure requiring liver tissue to be tested and the use of non-standardized non-commercially available techniques. Consequently, in everyday clinical practice, the detection of anti-hepatitis B core antibody (anti-HBc) in serum of HBsAg-negative subjects is used as a surrogate marker to identify patients with OBI. In patients with chronic hepatitis C (CHC), OBI has been identified in nearly one-third of these cases. Considerable data suggest that OBI favors the increase of liver damage and the development of hepatocellular carcinoma (HCC) in patients with CHC. The data from other studies, however, indicate no influence of OBI on the natural history of CHC, particularly regarding the risk of developing HCC.
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22
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Patel BB, Lipka S, Shen H, Davis-Yadley AH, Viswanathan P. Establishing the link between hepatitis B virus infection and colorectal adenoma. J Gastrointest Oncol 2015; 6:492-7. [PMID: 26487942 DOI: 10.3978/j.issn.2078-6891.2015.049] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) infection has been associated with malignancy, most notably hepatocellular carcinoma. Previous research has shown that hepatitis C is associated with increased colorectal adenomas and neoplasia. Currently, there are no studies on the association of CHB and colorectal adenomas. We aimed to identify a possible link between CHB and colorectal adenoma. METHODS A retrospective chart review was performed on 588 consecutive patients undergoing screening or diagnostic colonoscopy that were previously screened or diagnosed with hepatitis B. Comparisons between categorical variables were analyzed with Chi Square test and t-test for continuous variables. Unconditional logistic regression was used to generate age-, gender-and race-adjusted odds ratios and their 95% confidence intervals (CI) comparing medication users with non-users. Statistical analyses were performed with SAS 9.3 software. RESULTS A total of 487 patients were analyzed in the control group vs. 71 in the hepatitis B group. The adenoma detection rate was 23.9% in hepatitis B vs. 15.9% in the non-hepatitis B group for all cause colonoscopy; however this did not reach statistical significance. There was a significantly higher number of adenomas present in the distal colon compared to control (OR =2.16; 95% CI, 1.06-4.43; P=0.04). There were no significant findings between hepatitis B infection with size, multiplicity or presence of proximal adenomas. There was a significant difference noted in regards to smoking history, BMI and age between two groups. CONCLUSIONS Although the adenoma detection rate was higher in hepatitis B population vs. the non-hepatitis B group this did not reach statistical significance. However, we did find an association between CHB infection and the presence of distal colorectal adenomas. Larger prospective studies are needed to strengthen our findings along with future studies examining hepatitis B virus (HBV) and mechanisms inducing colorectal carcinogenesis.
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Affiliation(s)
- Brijesh B Patel
- 1 Department of Internal Medicine, 2 Department of Gastroenterology, Division of Digestive Diseases and Nutrition, University of South Florida, Tampa, FL, USA ; 3 Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Seth Lipka
- 1 Department of Internal Medicine, 2 Department of Gastroenterology, Division of Digestive Diseases and Nutrition, University of South Florida, Tampa, FL, USA ; 3 Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Huafeng Shen
- 1 Department of Internal Medicine, 2 Department of Gastroenterology, Division of Digestive Diseases and Nutrition, University of South Florida, Tampa, FL, USA ; 3 Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Ashley H Davis-Yadley
- 1 Department of Internal Medicine, 2 Department of Gastroenterology, Division of Digestive Diseases and Nutrition, University of South Florida, Tampa, FL, USA ; 3 Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Prakash Viswanathan
- 1 Department of Internal Medicine, 2 Department of Gastroenterology, Division of Digestive Diseases and Nutrition, University of South Florida, Tampa, FL, USA ; 3 Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
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Song K, Han C, Dash S, Balart LA, Wu T. MiR-122 in hepatitis B virus and hepatitis C virus dual infection. World J Hepatol 2015; 7:498-506. [PMID: 25848473 PMCID: PMC4381172 DOI: 10.4254/wjh.v7.i3.498] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 09/06/2014] [Accepted: 12/17/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the most common causes of chronic liver diseases and hepatocelluar carcinomas. Over the past few years, the liver-enriched microRNA-122 (miR-122) has been shown to differentially regulate viral replication of HBV and HCV. It is notable that the level of miR-122 is positively and negatively regulated by HCV and HBV, respectively. Consistent with the well-documented phenomenon that miR-122 promotes HCV accumulation, inhibition of miR-122 has been shown as an effective therapy for the treatment of HCV infection in both chimpanzees and humans. On the other hand, miR-122 is also known to block HBV replication, and HBV has recently been shown to inhibit miR-122 expression; such a reciprocal inhibition between miR-122 and HBV suggests an intriguing possibility that miR-122 replacement may represent a potential therapy for treatment of HBV infection. As HBV and HCV have shared transmission routes, dual infection is not an uncommon scenario, which is associated with more advanced liver disease than either HBV or HCV mono-infection. Thus, there is a clear need to further understand the interaction between HBV and HCV and to delineate the role of miR-122 in HBV/HCV dual infection in order to devise effective therapy. This review summarizes the current understanding of HBV/HCV dual infection, focusing on the pathobiological role and therapeutic potential of miR-122.
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Raouf HE, Yassin AS, Megahed SA, Ashour MS, Mansour TM. Seroprevalence of occult hepatitis B among Egyptian paediatric hepatitis C cancer patients. J Viral Hepat 2015; 22:103-11. [PMID: 24754376 DOI: 10.1111/jvh.12260] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Accepted: 03/26/2014] [Indexed: 12/12/2022]
Abstract
Occult hepatitis B infection is characterized by the presence of hepatitis B virus (HBV) DNA in the serum in the absence of hepatitis B surface antigen (HBsAg). Prevalence of hepatitis C virus (HCV) infections in Egypt is among the highest in the world. In this study, we aim at analysing the rates of occult HBV infections among HCV paediatric cancer patients in Egypt. The prevalence of occult HBV was assessed in two groups of paediatric cancer patients (HCV positive and HCV negative), in addition to a third group of paediatric noncancer patients, which was used as a general control. All groups were negative for HBsAg and positive for HCV antibody. HBV DNA was detected by nested PCR and real-time PCR. HCV was detected by real-time PCR. Sequencing was carried out in order to determine HBV genotypes to all HBV patients as well as to detect any mutation that might be responsible for the occult phenotype. Occult hepatitis B infection was observed in neither the non-HCV paediatric cancer patients nor the paediatric noncancer patients but was found in 31% of the HCV-positive paediatric cancer patients. All the detected HBV patients belonged to HBV genotype D, and mutations were found in the surface genome of HBV leading to occult HBV. Occult HBV infection seems to be relatively frequent in HCV-positive paediatric cancer patients, indicating that HBsAg negativity is not sufficient to completely exclude HBV infection. These findings emphasize the importance of considering occult HBV infection in HCV-positive paediatric cancer patients especially in endemic areas as Egypt.
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Affiliation(s)
- H E Raouf
- Department of Microbiology and Immunology, Faculty of Pharmacy, Modern Sciences and Arts University, Giza, Egypt
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Kwak MS, Kim YJ. Occult hepatitis B virus infection. World J Hepatol 2014; 6:860-869. [PMID: 25544873 PMCID: PMC4269905 DOI: 10.4254/wjh.v6.i12.860] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 09/23/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
Occult hepatitis B virus (HBV) infection (OBI) refers to the presence of HBV DNA in the absence of detectable hepatitis B surface antigen. Since OBI was first described in the late 1970s, there has been increasing interest in this topic. The prevalence of OBI varies according to the different endemicity of HBV infection, cohort characteristics, and sensitivity and specificity of the methods used for detection. Although the exact mechanism of OBI has not been proved, intra-hepatic persistence of viral covalently closed circular DNA under the host’s strong immune suppression of HBV replication and gene expression seems to be a cause. OBI has important clinical significance in several conditions. First, OBI can be transmitted through transfusion, organ transplantation including orthotopic liver transplantation, or hemodialysis. Donor screening before blood transfusion, prophylaxis for high-risk organ transplantation recipients, and dialysis-specific infection-control programs should be considered to reduce the risk of transmission. Second, OBI may reactivate and cause acute hepatitis in immunocompromised patients or those receiving chemotherapy. Close HBV DNA monitoring and timely antiviral treatment can prevent HBV reactivation and consequent clinical deterioration. Third, OBI may contribute to the progression of hepatic fibrosis in patients with chronic liver disease including hepatitis C. Finally, OBI seems to be a risk factor for hepatocellular carcinoma by its direct proto-oncogenic effect and by indirectly causing persistent hepatic inflammation and fibrosis. However, this needs further investigation. We review published reports in the literature to gain an overview of the status of OBI and emphasize the clinical importance of OBI.
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Alvarez-Muñoz MT, Maldonado-Rodriguez A, Rojas-Montes O, Torres-Ibarra R, Gutierrez-Escolano F, Vazquez-Rosales G, Gomez A, Muñoz O, Torres J, Lira R. Occult hepatitis B virus infection among Mexican human immunodeficiency virus-1-infected patients. World J Gastroenterol 2014; 20:13530-13537. [PMID: 25309083 PMCID: PMC4188904 DOI: 10.3748/wjg.v20.i37.13530] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/30/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the frequency of occult hepatitis B infection (OHBI) in a group of human immunodeficiency virus (HIV)-1+/ hepatitis B surface antigen negative (HBsAg)- patients from Mexico.
METHODS: We investigated the presence of OHBI in 49 HIV-1+/HBsAg- patients. Hepatitis B virus (HBV) DNA was analyzed using nested PCR to amplify the Core (C) region and by real-time PCR to amplify a region of the S and X genes. The possible associations between the variables and OHBI were investigated using Pearson’s χ2 and/or Fisher’s exact test.
RESULTS: We found that the frequency of OHBI was 49% among the group of 49 HIV-1+/HBsAg- patients studied. The presence of OHBI was significantly associated with the HIV-1 RNA viral load [odds ratio (OR) = 8.75; P = 0.001; 95%CI: 2.26-33.79] and with HIV-antiretroviral treatment with drugs that interfere with HBV replication (lamivudine, tenofovir or emtricitabine) (OR = 0.25; P = 0.05; 95%CI: 0.08-1.05).
CONCLUSION: The OHBI frequency is high among 49 Mexican HIV-1+/HBsAg- patients and it was more frequent in patients with detectable HIV RNA, and less frequent in patients who are undergoing HIV-ARV treatment with drugs active against HBV.
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Jang JY, Park EJ. [Occult hepatitis B virus infection in chronic hepatitis C]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2014; 62:154-9. [PMID: 24077625 DOI: 10.4166/kjg.2013.62.3.154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Occult HBV infection is defined as the presence of HBV DNA in the liver (with or without detectable or undetectable HBV DNA in the serum) of individuals testing negative for HBsAg. Studies on occult HBV infection in hepatitis C patients have reported highly variable prevalence, because the prevalence of occult HBV infection varies depending on the hepatitis B risk factors and methodological approaches. The most reliable diagnostic approach for detecting occult HBV detection is through examination of liver DNA extracts. HCV has been suspected to strongly suppress HBV replication up to the point where it may be directly responsible for occult HBV infection development. However, more data are needed to arrive at a definitive conclusion regarding the role of HCV in inducing occult HBV infection. Occult HBV infection in chronic hepatitis C patients is a complex biological entity with possible relevant clinical implications. Influence of occult HBV infection on the clinical outcomes of chronic hepatitis C may be considered negative. However, recent studies have shown that occult HBV infection could be associated with the development of hepatocellular carcinoma and contribute to the worsening of the course of chronic liver disease over time in chronic hepatitis C patients. Nevertheless, the possible role of occult HBV infection in chronic hepatitis C is still unresolved and no firm conclusion has been made up until now. It still remains unclear how occult HBV infection affects the treatment of chronic hepatitis C. Therefore, in order to resolve current controversies and understand the pathogenic role and clinical impacts of occult HBV infection in chronic hepatitis C patients, well-designed clinical studies are needed.
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Affiliation(s)
- Jae Young Jang
- Institution for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea
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Pollicino T, Saitta C. Occult hepatitis B virus and hepatocellular carcinoma. World J Gastroenterol 2014; 20:5951-5961. [PMID: 24876718 PMCID: PMC4033435 DOI: 10.3748/wjg.v20.i20.5951] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/15/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Occult hepatitis B virus (HBV) infection (OBI) is a challenging pathobiological and clinical issue that has been widely debated for several decades. By definition, OBI is characterized by the persistence of HBV DNA in the liver tissue (and in some cases also in the serum) in the absence of circulating HBV surface antigen (HBsAg). Many epidemiological and molecular studies have indicated that OBI is an important risk factor for hepatocellular carcinoma (HCC) development. OBI may exert direct pro-oncogenic effects through the activation of the same oncogenic mechanisms that are activated in the course of an HBsAg-positive infection. Indeed, in OBI as in HBV-positive infection, HBV DNA can persist in the hepatocytes both integrated into the host genome as well as free episome, and may maintain the capacity to produce proteins-mainly X protein and truncated preS-S protein - provided with potential transforming properties. Furthermore, OBI may indirectly favor HCC development. It has been shown that the persistence of very low viral replicative activity during OBI may induce mild liver necro-inflammation continuing for life, and substantial clinical evidence indicates that OBI can accelerate the progression of liver disease towards cirrhosis that is considered the most important risk factor for HCC development.
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29
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Occult HBV infection: a faceless enemy in liver cancer development. Viruses 2014; 6:1590-611. [PMID: 24717680 PMCID: PMC4014712 DOI: 10.3390/v6041590] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Revised: 03/13/2014] [Accepted: 03/20/2014] [Indexed: 12/12/2022] Open
Abstract
The hepatitis B virus (HBV) represents a worldwide public health problem; the virus is present in one third of the global population. However, this rate may in fact be higher due to occult hepatitis B virus infection (OBI). This condition is characterized by the presence of the viral genome in the liver of individuals sero-negative for the virus surface antigen (HBsAg). The causes of the absence of HBsAg in serum are unknown, however, mutations have been identified that produce variants not recognized by current immunoassays. Epigenetic and immunological host mechanisms also appear to be involved in HBsAg suppression. Current evidence suggests that OBI maintains its carcinogenic potential, favoring the progression of fibrosis and cirrhosis of the liver. In common with open HBV infection, OBI can contribute to the establishment of hepatocellular carcinoma. Epidemiological data regarding the global prevalence of OBI vary due to the use of detection methods of different sensitivity and specificity. In Latin America, which is considered an area of low prevalence for HBV, diagnostic screening methods using gene amplification tests for confirmation of OBI are not conducted. This prevents determination of the actual prevalence of OBI, highlighting the need for the implementation of cutting edge technology in epidemiological surveillance systems.
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Huang X, Hollinger FB. Occult hepatitis B virus infection and hepatocellular carcinoma: a systematic review. J Viral Hepat 2014; 21:153-62. [PMID: 24438677 DOI: 10.1111/jvh.12222] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 12/08/2013] [Indexed: 12/13/2022]
Abstract
Occult hepatitis B (OHB) infection has been reported to play an important role in the development of hepatocellular carcinoma (HCC). In this systematic review, a significantly higher prevalence of OHB was observed in patients with HCC in the presence or absence of HCV infection when compared with control populations without HCC. Correspondingly, among adequately designed prospective studies, the cumulative probability of developing HCC was significantly greater among patients with OHB than among HBV DNA-negative patients in the presence or absence of HCV infection. Study design, inclusion criteria, treatment options, methodology and potential confounding variables were evaluated, and immunopathogenic mechanisms that could be involved in OHB as a risk factor in HCC were reviewed. From this analysis, we conclude that although OHB is an independent risk factor in HCC development in anti-HCV-negative patients, a synergistic or additive role in the occurrence of HCC in HCV-coinfected patients is more problematic due to the HCC risk attributable to HCV alone, especially in patients with advanced fibrosis and cirrhosis.
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Affiliation(s)
- X Huang
- Department of Blood Transfusion, The General Hospital of Jinan Military Command, Jinan, China
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31
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Reddy A, May E, Ehrinpreis M, Mutchnick M. Latent hepatitis B is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C. World J Gastroenterol 2013; 19:9328-9333. [PMID: 24409059 PMCID: PMC3882405 DOI: 10.3748/wjg.v19.i48.9328] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Accepted: 09/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the potential association between hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC), cirrhosis and latent hepatitis B (LHB) infection, defined as the absence of detectable serum hepatitis B surface antigen (HBsAg) and the presence of hepatitis B core antibody (HBcAb).
METHODS: This retrospective analysis is comprised of 185 cirrhotic patients with HCC who were hepatitis C virus antibody (HCV Ab) (+) and HBsAg(-) at Wayne State University between 1999 and 2008. From these, 108 patients had HCV polymerase chain reaction confirmation of viremia while the remaining (77) were considered to have CHC on the basis of a positive HCV Ab and the absence of any other cause of liver disease. Controls were drawn from our institutional database from the same time period and consisted of 356 HBsAg(-) age, race and gender matched patients with HCV RNA-confirmed CHC and without evidence of HCC. A subgroup of controls included 118 matched patients with liver cirrhosis. χ2 test and t test were used for data analysis.
RESULTS: Seventy-seven percent of patients in all 3 groups were African Americans. Patients with HCC had a significantly higher body mass index (P = 0.03), a higher rate of co-infection with human immunodeficiency virus (HIV) (P = 0.05) and a higher prevalence of alcohol abuse (P = 0.03) than the controls. More patients with HCC had LHB than controls (78% vs 39%, P = 0.01). Sixty three percent of patients with HCC were both hepatitis B surface antigen (HBsAb)(-) and HBcAb(+) compared to 23% of controls (P < 0.01). When compared to cirrhotic controls, the frequency of HBcAb(+) remained higher in patients with HCC (78% vs 45%, P = 0.02). Patients with HCC were more likely to be both HBsAb(-) and HBcAb(+) than the cirrhotic controls (63% vs 28%, P = 0.01). Although not statistically significant, 100% of CHC and HIV co-infected patients with HCC (n = 11) were HBcAb(+) when compared to controls (44%; n = 9).
CONCLUSION: These data suggest that LHB occurs at a significantly increased frequency in patients with CHC and HCC than in patients with CHC without HCC.
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Tsubouchi N, Uto H, Kumagai K, Sasaki F, Kanmura S, Numata M, Moriuchi A, Oketani M, Ido A, Hayashi K, Kusumoto K, Shimoda K, Stuver SO, Tsubouchi H. Impact of antibody to hepatitis B core antigen on the clinical course of hepatitis C virus carriers in a hyperendemic area in Japan: A community-based cohort study. Hepatol Res 2013; 43:1130-8. [PMID: 23413835 PMCID: PMC3710530 DOI: 10.1111/hepr.12075] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 01/14/2013] [Accepted: 01/16/2013] [Indexed: 01/01/2023]
Abstract
AIM Subjects positive for antibody to hepatitis B core antigen (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are considered to have occult hepatitis B virus (HBV) infection. The aim of this study was to determine the impact of occult HBV infection on aggravation of the clinical course in hepatitis C virus (HCV) carriers. METHODS A prospective cohort study was performed in 400 subjects who were positive for anti-HCV antibody and negative for HBsAg. Among these subjects, 263 were HCV core antigen positive or HCV RNA positive (HCV carriers). We examined whether the presence of HBcAb affected the clinical course in these HCV carriers from 1996-2005. RESULTS The HBcAb positive rates were 53.6% and 52.6% in HCV carriers and HCV RNA negative subjects, respectively. There were no differences in the incidence of hepatocellular carcinoma (HCC) and cumulative mortality associated with liver-related death between HCV carriers who were positive and negative for HBcAb. In multivariate analysis, age (≥65 years) and alanine aminotransferase level (≥31 IU/L) emerged as independent risk factors for HCC development and liver-related death, but the HBcAb status was not a risk factor. In addition, increased serum hepatic fibrosis markers (measured from 2001-2004) were not associated with HBcAb status. CONCLUSION In our cohort study, the presence of HBcAb had no impact on HCC development, liver-related death and hepatic fibrosis markers in HCV carriers. Thus, our results indicate that occult HBV infection has no impact on the clinical course in HCV carriers.
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Affiliation(s)
- Naoko Tsubouchi
- Digestive and Lifestyle Diseases, Department of Human and
Environmental Sciences, Kagoshima University Graduate School of Medical and Dental
Sciences, Kagoshima, Japan
| | - Hirofumi Uto
- Digestive and Lifestyle Diseases, Department of Human and
Environmental Sciences, Kagoshima University Graduate School of Medical and Dental
Sciences, Kagoshima, Japan
| | - Kotaro Kumagai
- Digestive and Lifestyle Diseases, Department of Human and
Environmental Sciences, Kagoshima University Graduate School of Medical and Dental
Sciences, Kagoshima, Japan
| | - Fumisato Sasaki
- Digestive and Lifestyle Diseases, Department of Human and
Environmental Sciences, Kagoshima University Graduate School of Medical and Dental
Sciences, Kagoshima, Japan
| | - Shuji Kanmura
- Digestive and Lifestyle Diseases, Department of Human and
Environmental Sciences, Kagoshima University Graduate School of Medical and Dental
Sciences, Kagoshima, Japan
| | - Masatsugu Numata
- Digestive and Lifestyle Diseases, Department of Human and
Environmental Sciences, Kagoshima University Graduate School of Medical and Dental
Sciences, Kagoshima, Japan
| | - Akihiro Moriuchi
- Digestive and Lifestyle Diseases, Department of Human and
Environmental Sciences, Kagoshima University Graduate School of Medical and Dental
Sciences, Kagoshima, Japan
| | - Makoto Oketani
- Digestive and Lifestyle Diseases, Department of Human and
Environmental Sciences, Kagoshima University Graduate School of Medical and Dental
Sciences, Kagoshima, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Department of Human and
Environmental Sciences, Kagoshima University Graduate School of Medical and Dental
Sciences, Kagoshima, Japan
| | - Katsuhiro Hayashi
- Center for Medical Education, Faculty of Medicine, University of
Miyazaki, Miyazaki, Japan
| | - Kazunori Kusumoto
- Division of Gastroenterology and Hematology, Department of Internal
Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Kazuya Shimoda
- Division of Gastroenterology and Hematology, Department of Internal
Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Sherri O Stuver
- Department of Epidemiology, Boston University School of Public
Health, Boston, MA
| | - Hirohito Tsubouchi
- Digestive and Lifestyle Diseases, Department of Human and
Environmental Sciences, Kagoshima University Graduate School of Medical and Dental
Sciences, Kagoshima, Japan
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Taha SE, El-Hady SA, Ahmed TM, Ahmed IZ. Detection of occult HBV infection by nested PCR assay among chronic hepatitis C patients with and without hepatocellular carcinoma. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2013. [DOI: 10.1016/j.ejmhg.2013.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Nakano M, Kawaguchi T, Nakamoto S, Kawaguchi A, Kanda T, Imazeki F, Kuromatsu R, Sumie S, Satani M, Yamada S, Torimura T, Kakuma T, Yokosuka O, Sata M. Effect of occult hepatitis B virus infection on the early-onset of hepatocellular carcinoma in patients with hepatitis C virus infection. Oncol Rep 2013; 30:2049-55. [PMID: 23982634 DOI: 10.3892/or.2013.2700] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2013] [Accepted: 08/02/2013] [Indexed: 11/05/2022] Open
Abstract
Although overt hepatitis B virus (HBV) infection promotes the onset of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients, the effect of occult HBV infection remains unclear. The aim of this study was to investigate the effect of occult HBV infection on the early-onset of HCC in HCV-infected patients. A total of 173 HCC patients with HCV infection were enrolled and classified into 2 groups according to the median age of HCC onset: the early-onset group (n=91; 61.1±5.6 years) and the late-onset group (n=82; 73.8±3.7 years). Independent factors associated with the early-onset of HCC were assessed by multivariate analysis. In the overall analysis, independent risk factors for the early-onset of HCC were the white blood cell count and alanine aminotransferase level, but not the presence of HBV DNA. In a stratification analysis according to albumin levels of ≥3.5 g/dl, the presence of HBV DNA was a significant independent risk factor for the early-onset of HCC (OR 145.18, 95% CI 1.38-15296.61, P=0.036), whereas the presence of antibodies against hepatitis B core antigen was not found to be a risk factor. The presence of HBV DNA was not a risk factor for the early-onset of HCC in the overall analysis. However, its presence was an independent factor for the early-onset of HCC in HCV-infected patients with an albumin level of ≥3.5 g/dl. Thus, occult HBV infection may accelerate hepatocarcino-genesis in HCV-infected patients with relatively low carcinogenic potential.
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Affiliation(s)
- Masahito Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
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Nishikawa H, Osaki Y. Clinical significance of occult hepatitis B infection in progression of liver disease and carcinogenesis. J Cancer 2013; 4:473-80. [PMID: 23901347 PMCID: PMC3726709 DOI: 10.7150/jca.6609] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 07/05/2013] [Indexed: 01/04/2023] Open
Abstract
Occult hepatitis B infection (OBI) is defined as long-lasting persistence of hepatitis B virus (HBV) DNA in the liver of patients with hepatitis B surface antigen (HBsAg)-negative status, with or without serological markers of previous exposure (antibodies to HBsAg and/or to hepatitis B core antigen). Over the past two decades, significant progress has been made in understanding OBI and its clinical implications. OBI as a cause of chronic liver disease in patients with HBsAg-negative status is becoming an important disease entity. In conditions of immunocompetence, OBI is inoffensive in itself and detection of HBV DNA in the liver does not always indicate active hepatitis. However, when other factors that cause liver damage, such as hepatitis C virus infection, obesity and alcohol abuse are present, the minimal lesions produced by the immunological response to OBI might worsen the clinical course of the underlying liver disease. Several lines of evidence suggest that OBI is associated with progression of liver fibrosis and the development of hepatocellular carcinoma in patients with chronic liver disease. The major interest in OBI is primarily associated with the growing, widely discussed evidence of its clinical impact. The aim of this review is to highlight recent data for OBI, with a major focus on disease progression or carcinogenesis in patients with chronic liver disease.
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Affiliation(s)
- Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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36
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Ultrastructural and stereological study of the liver in chronic mixed HCV+HBV infection. Bull Exp Biol Med 2012; 152:764-7. [PMID: 22803184 DOI: 10.1007/s10517-012-1626-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
The stereological values of the structural density of hepatocyte cytoplasmic organelles were similar in chronic mixed HCV+HBV infection irrespective of the form of HBV infection (seropositive or latent). High incidence of HBsAg- and HBeAg-negative forms of HBV infection determines the leading role of PCR diagnosis and studies of liver biopsy specimens with detection of HBcAg structural markers and HBV DNA in native liver tissue in the diagnosis of mixed HCV+HBV infection.
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Martin CM, Welge JA, Rouster SD, Shata MT, Sherman KE, Blackard JT. Mutations associated with occult hepatitis B virus infection result in decreased surface antigen expression in vitro. J Viral Hepat 2012; 19:716-23. [PMID: 22967103 PMCID: PMC3442934 DOI: 10.1111/j.1365-2893.2012.01595.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Occult hepatitis B virus (HBV) infection is characterized by the absence of detectable hepatitis B surface antigen (HBsAg) in the serum, despite detectable HBV DNA. Investigations of the mechanisms underlying the development of occult HBV infection are lacking in the current literature, although viral mutations in the surface region, resulting in decreased HBsAg expression or secretion, represent one potential mechanism. Wild-type HBsAg expression vectors were constructed from genotype-matched chronic HBV sequences. Site-directed mutagenesis was then utilized to introduce three genotype A mutations - M103I, K122R and G145A - associated with occult HBV infection in vivo, alone and in combination, into the wild-type HBsAg vectors. Transfection of Huh7 and HepG2 cell lines was performed, and cell culture supernatants and cell lysates were collected over 7 days to assess the effects of these mutations on extracellular and intracellular HBsAg levels. The G145A mutation resulted in significantly decreased extracellular and intracellular HBsAg expression in vitro. The most pronounced reduction in HBsAg expression was observed when all three mutations were present. The mutations evaluated in vitro in the current study resulted in decreased HBsAg expression and potentially increased hepatic retention and/or decreased hepatic secretion of synthesized HBsAg, which could explain the lack of HBsAg detection that is characteristic of occult HBV infection in vivo.
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Affiliation(s)
- Christina M. Martin
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267
| | - Jeffrey A. Welge
- Departments of Psychiatry and Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267
| | - Susan D. Rouster
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267
| | - Mohamed Tarek Shata
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267
| | - Kenneth E. Sherman
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267
| | - Jason T. Blackard
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267, Address requests for reprints to: Jason Blackard, PhD Division of Digestive Diseases University of Cincinnati College of Medicine ML 0595, 231 Albert Sabin Way Cincinnati, OH 45267 Phone: (513) 558-4389 Fax: (513) 558-1744
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Abstract
Chronic hepatitis B virus (HBV) infection is a complex clinical entity frequently associated with cirrhosis and hepatocellular carcinoma (HCC). The persistence of HBV genomes in the absence of detectable surface antigenemia is termed occult HBV infection. Mutations in the surface gene rendering HBsAg undetectable by commercial assays and inhibition of HBV by suppression of viral replication and viral proteins represent two fundamentally different mechanisms that lead to occult HBV infections. The molecular mechanisms underlying occult HBV infections, including recently identified mechanisms associated with the suppression of HBV replication and inhibition of HBV proteins, are reviewed in detail. The availability of highly sensitive molecular methods has led to increased detection of occult HBV infections in various clinical settings. The clinical relevance of occult HBV infection and the utility of appropriate diagnostic methods to detect occult HBV infection are discussed. The need for specific guidelines on the diagnosis and management of occult HBV infection is being increasingly recognized; the aspects of mechanistic studies that warrant further investigation are discussed in the final section.
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Abstract
Chronic hepatitis B virus (HBV) infection is a complex clinical entity frequently associated with cirrhosis and hepatocellular carcinoma (HCC). The persistence of HBV genomes in the absence of detectable surface antigenemia is termed occult HBV infection. Mutations in the surface gene rendering HBsAg undetectable by commercial assays and inhibition of HBV by suppression of viral replication and viral proteins represent two fundamentally different mechanisms that lead to occult HBV infections. The molecular mechanisms underlying occult HBV infections, including recently identified mechanisms associated with the suppression of HBV replication and inhibition of HBV proteins, are reviewed in detail. The availability of highly sensitive molecular methods has led to increased detection of occult HBV infections in various clinical settings. The clinical relevance of occult HBV infection and the utility of appropriate diagnostic methods to detect occult HBV infection are discussed. The need for specific guidelines on the diagnosis and management of occult HBV infection is being increasingly recognized; the aspects of mechanistic studies that warrant further investigation are discussed in the final section.
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Shi Y, Wu YH, Wu W, Zhang WJ, Yang J, Chen Z. Association between occult hepatitis B infection and the risk of hepatocellular carcinoma: a meta-analysis. Liver Int 2012; 32:231-40. [PMID: 21745272 DOI: 10.1111/j.1478-3231.2011.02481.x] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND The association between occult hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) remains controversial. AIMS We conducted a meta-analysis of prospective studies and retrospective studies to examine whether occult HBV infection increases the risk of HCC. METHODS Two independent reviewers searched databases for eligible studies published in English or Chinese dated from 1966 to 6 April 2010. The odds ratios or the relative risks (RRs) of each study were considered respectively. RESULTS We identified 16 eligible studies. A significantly increased risk of HCC was found in subjects with occult HBV infection in comparison with non-infected controls in both retrospective [OR(unadjusted) =6.08, 95% confidence interval (CI)=3.45-10.72] and prospective studies (RR(adjusted) =2.86, 95% CI=1.59-4.13), and occult HBV increased the risk for HCC in both hepatitis C virus (HCV)-infected populations (summary RR=2.83, 95% CI=1.56-4.10) and in non-infected populations (OR(unadjusted) =10.65, 95% CI=5.94-19.08). A higher prevalence of occult HBV was observed in individuals who were positive for anti-HBs and anti-HBc (OR(unadjusted) =1.81, 95% CI=1.06, 3.09). CONCLUSION Our findings suggest that occult HBV infection was associated with an increased risk of HCC. Occult HBV may serve as a cofactor in the development of HCV-related HCC, and it may also play a direct role in promoting Non-B and Non-C HCC growth. Suggestive evidence indicates that individuals with a concomitant presence of anti-HBs and anti-HBc had an increased risk of occult HBV infection. However, further studies are needed to clarify these observations.
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Affiliation(s)
- Yu Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Persico M, Bruno S, Costantino A, Mazza M, Almasio PL. The impact of antiviral therapy and the influence of metabolic cofactors on the outcome of chronic HCV infection. Int J Hepatol 2011; 2011:314301. [PMID: 22164334 PMCID: PMC3230116 DOI: 10.4061/2011/314301] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2010] [Revised: 08/09/2011] [Accepted: 08/18/2011] [Indexed: 12/20/2022] Open
Abstract
NATURAL HISTORY OF HCV RELATED CHRONIC HEPATITIS IS INFLUENCED AND MODIFIED BY MANY FACTORS: virus features, coinfections and host characteristics. In particular, a peculiar genetic background of the host by conditioning the occurrence of intracellular metabolic derangements (i.e., insulin resistance) might contribute to accelerate the rate of progression to cirrhosis and eventually the occurrence of hepatocellular carcinoma (HCC) and death. Likely, direct interplays between virus genotype and host genetic background might be hypothesized at this level. Morbidity and mortality in cirrhosis is primarily associated with complications of liver cirrhosis (ascites, hepatic encephalopathy, jaundice, and gastroesophageal bleeding) and HCC occurrence. Therefore the main goal of therapy is to clear viral infection and decrease liver necro-inflammation that directly relates to development of cirrhosis and HCC. Among patients treated with Interferon-based therapy, those with sustained viral response showed a significant reduction of progression to cirrhosis and development of HCC. However, a residual risk of hepatocellular carcinoma still remains indicating the need for careful follow-up using ultrasonography every six months in cirrhotic patients, even in those showing persistently normal ALT and undetectable HCV RNA levels after antiviral therapy.
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Affiliation(s)
- Marcello Persico
- Internal Medicine and Hepatology Division, Second University of Naples, Via Del Parco Carelli 36, 80123 Naples, Italy
| | - Savino Bruno
- Department of Internal Medicine, AO Fatebenefratelli e Oftalmico, Corso di Porta Nuova 23, 20121 Milano, Italy
| | - Andrea Costantino
- Gastroenterology & Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Marta Mazza
- Gastroenterology & Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Piero Luigi Almasio
- Gastroenterology & Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
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Arababadi MK, Pourfathollah AA, Jafarzadeh A, Hassanshahi G, Salehi M, Ahmadabadi BN, Kennedy D. Hepatitis B virus genotype, HBsAg mutations and co-infection with HCV in occult HBV infection. Clin Res Hepatol Gastroenterol 2011; 35:554-9. [PMID: 21835725 DOI: 10.1016/j.clinre.2011.04.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Revised: 03/16/2011] [Accepted: 04/20/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND The association between mutations in the hepatitis B surface antigen (HBsAg) gene and the occurrence of occult HBV (OBI) in patients has not been studied adequately to determine if the two are correlated. The current study was aimed to investigate HBsAg mutations, the genotype of HBV and co-infection with HCV in OBI in the central part of Iran to determine any possible associations. MATERIAL AND METHODS In this study, 3700 plasma samples were examined for the presence of HBsAg, anti-HBc and HBV-DNA. All HBsAg(-)/anti-HBc(+)/HBV-DNA(+) samples were regarded as OBI. The genotype of HBV was identified using Gap-PCR and RT-PCR was used to determine possible co-infection with HCV. Finally, direct sequencing was performed to analyse mutations within the surface antigen gene of HBV in occult versus acute HBV infection. RESULTS Of the 3700 patient samples analysed, 352 (9.5%) cases were determined to be HBsAg(-)/anti-HBc(+) in which HBV-DNA was detected in 57 (16.1%), these latter patients were classified as OBI. All of the patients studied carried the D genotype. Direct sequencing of the S-gene from occult and acute HBV patients revealed one silent and one glycine to arginine mutation but the acute HBV patients showed an additional mutation (alanine to threonine). All the mutations were outside the range of the α-determinant. Furthermore, none of the OBI patients were co-infected with HCV. CONCLUSIONS The absence of conformational mutations in the α-determinant of HBsAg confirmed that this antigen could be detected by commercial Elisa kits and therefore was not responsible for false negatives during blood screening. However, it can be concluded that suitable amounts of HBsAg were not expressed by HBV in the OBI patients to be detected by Elisa. Low level expression of HBsAg might be related to the D genotype of the virus. Furthermore, our results suggest that OBI is not related to co-infection with HCV.
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Affiliation(s)
- M K Arababadi
- Department of Microbiology, Hematology and Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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Lok AS, Everhart JE, Di Bisceglie AM, Kim HY, Hussain M, Morgan TR. Occult and previous hepatitis B virus infection are not associated with hepatocellular carcinoma in United States patients with chronic hepatitis C. Hepatology 2011; 54:434-42. [PMID: 21374690 PMCID: PMC3134544 DOI: 10.1002/hep.24257] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
UNLABELLED Previous studies have suggested that prior exposure to hepatitis B virus (HBV) infection may increase the risk of development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The aim of this study was to compare the prevalence of previous or occult HBV infection in a cohort of hepatitis B surface antigen-negative patients with histologically advanced chronic hepatitis C in the United States who did or did not develop HCC. Stored sera from 91 patients with HCC and 182 matched controls who participated in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial were tested for hepatitis B core antibody (anti-HBc), hepatitis B surface antibody, and HBV DNA. Frozen liver samples from 28 HCC cases and 55 controls were tested for HBV DNA by way of real-time polymerase chain reaction. Anti-HBc (as a marker of previous HBV infection) was present in the serum of 41.8% HCC cases and 45.6% controls (P=0.54); anti-HBc alone was present in 16.5% of HCC cases and 24.7% of controls. HBV DNA was detected in the serum of only one control subject and no patients with HCC. HBV DNA (as a marker of occult HBV infection) was detected in the livers of 10.7% of HCC cases and 23.6% of controls (P=0.18). CONCLUSION Although almost half the patients in the HALT-C Trial had serological evidence of previous HBV infection, there was no difference in prevalence of anti-HBc in serum or HBV DNA in liver between patients who did or did not develop HCC. In the United States, neither previous nor occult HBV infection is an important factor in HCC development among patients with advanced chronic hepatitis C.
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Affiliation(s)
- Anna S. Lok
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - James E. Everhart
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
| | - Adrian M. Di Bisceglie
- Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO
| | | | - Munira Hussain
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - Timothy R. Morgan
- Division of Gastroenterology, University of California Irvine, Irvine, CA, Gastroenterology Service, VA Long Beach Healthcare System, Long Beach, CA
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Said ZNA. An overview of occult hepatitis B virus infection. World J Gastroenterol 2011; 17:1927-1938. [PMID: 21528070 PMCID: PMC3082745 DOI: 10.3748/wjg.v17.i15.1927] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2010] [Revised: 01/18/2011] [Accepted: 01/25/2011] [Indexed: 02/06/2023] Open
Abstract
Occult hepatitis B virus (HBV) infection (OBI), alternatively defined as occult hepatitis B (OHB), is a challenging clinical entity. It is recognized by two main characteristics: absence of HBsAg, and low viral replication. The previous two decades have witnessed a remarkable progress in our understanding of OBI and its clinical implications. Appropriate diagnostic techniques must be adopted. Sensitive HBV DNA amplification assay is the gold standard assay for detection of OBI. Viral as well as host factors are implicated in the pathogenesis of OBI. However, published data reporting the infectivity of OBI by transfusion are limited. Several aspects including OBI transmission, infectivity and its relation to the development of chronic liver diseases and hepatocellular carcinoma have to be resolved. The aim of the present review is to highlight recent data on OBI with a focus on its virological diagnosis and clinical outcome.
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Lledó JL, Fernández C, Gutiérrez ML, Ocaña S. Management of occult hepatitis B virus infection: An update for the clinician. World J Gastroenterol 2011; 17:1563-8. [PMID: 21472122 PMCID: PMC3070127 DOI: 10.3748/wjg.v17.i12.1563] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Revised: 09/18/2010] [Accepted: 09/25/2010] [Indexed: 02/06/2023] Open
Abstract
Occult hepatitis B virus (HBV) infection (OBI) is defined by the presence of HBV DNA in the liver tissue of individuals who test negative for hepatitis B surface antigen (HBsAg). Patients who have recovered from acute hepatitis B can carry HBV genomes for a long time and show histological patterns of mild necro-inflammation, even fibrosis, years after the resolution of acute hepatitis, without showing any clinical or biochemical evidence of liver disease. At least in conditions of immunocompetence, OBI is inoffensive itself, but when other relevant causes of liver damage are present it might make the course of the liver disease worse. The risk of HBV transmission through transfusion is related to blood donations negative for HBsAg that have been collected during the pre-seroconversion period or during chronic OBI. Use of HBV nucleic acid amplification testing and multivalent anti-HBs antibodies in the HBsAg assays is recommended for detection of true and false OBI, respectively. It is not known if prior hepatitis B immunization with an optimal anti-HBs response in cases of HBV transmission through organ transplantation can effectively modulate or abort the infection. Use of antiviral agents as prophylaxis in patients with serological evidence of past HBV infection prevents reactivation of OBI after transplantation in most cases. Reactivation of OBI has been observed in other conditions that cause immunosuppression, in which antiviral therapy could be delayed until the HBV DNA or HBsAg becomes detectable. OBI might contribute to the progression of liver fibrosis and hepatocellular carcinoma development in patients with chronic liver disease.
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Fernandez-Rodriguez CM, Gutierrez ML, Lledó JL, Casas ML. Influence of occult hepatitis B virus infection in chronic hepatitis C outcomes. World J Gastroenterol 2011; 17:1558-62. [PMID: 21472121 PMCID: PMC3070126 DOI: 10.3748/wjg.v17.i12.1558] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Revised: 10/26/2010] [Accepted: 11/02/2010] [Indexed: 02/06/2023] Open
Abstract
Persistence of hepatitis B virus-DNA in the sera, peripheral blood mononuclear cells or in the liver of hepatitis B surface antigen (HBsAg)-negative patients with or without serological markers of previous exposure (antibodies to HBsAg and/or to HB-core antigen) defines the entity called occult hepatitis B infection (OBI). Co-infection with hepatitis B and hepatitis C viruses is frequent in highly endemic areas. While this co-infection increases the risk of liver disease progression, development of cirrhosis and hepatocellular carcinoma and also increases the rate of therapeutic failure to interferon-based treatments than either virus alone, a potentially negative effect of OBI on clinical outcomes and of therapeutic response to current antiviral regimes of patients with chronic hepatitis C remains inconclusive.
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Brechot C, Kremsdorf D, Soussan P, Pineau P, Dejean A, Paterlini-Brechot P, Tiollais P. Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC): molecular mechanisms and novel paradigms. ACTA ACUST UNITED AC 2010; 58:278-87. [PMID: 20667665 DOI: 10.1016/j.patbio.2010.05.001] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2010] [Accepted: 05/03/2010] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Most HCCs complicate the evolution of an active or inactive cirrhosis. However, some tumors occur on livers with minimal histological changes; the prevalence of such cases varies from one geographical region to the other, being much higher in the Southern half of Africa (around 40% of HCCs) than in Asia, America and Europe, where at least 90% of HCCs are associated in the cirrhosis. This heterogeneity is probably a reflection of different environmental and genetic factors. This review will summarise the current knowledge on the mechanisms involved in HBV-related liver carcinogenesis. It will show in particular how viruses can be viewed as tools to discover and dissect new cellular pathways involved in cancer development and emphasize the potential synergistic effects between HBV and hepatitis C virus (HCV), as well as between viral infections and other environmental factors, such as alcohol.
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Affiliation(s)
- C Brechot
- Inserm U785, Liver Hepatology centre, Paul Brousse Hospital, university Paris-XI, 12, avenue Paul-Vaillant-Couturier, 94804 Villejuif cedex 15, France.
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Abstract
The underlying liver diseases that put patients at risk for the development of hepatocellular carcinoma (HCC) are well known. However, it is equally well known that not all patients with these conditions will develop HCC. Therefore within the disease groups (hepatitis B, cirrhosis, etc.,) there are other factors that indicate greater or lesser risk. Some markers of risk are common to all causes of HCC, such as cellular dysplasia, advancing age and male gender. Others factors are specific to individual diseases. This has been well established for hepatitis B in which viral load, genotype and antigen status are major contributors to increased risk of HCC. For both hepatitis B and hepatitis C attempts have been made to identify those individuals at greatest risk using data from large cohort studies. In addition to the common causes of liver disease that are recognized to be causes of HCC non-alcoholic fatty liver disease and possibly diabetes are newly emerging risk factors.
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Abstract
Detection of occult hepatitis B requires assays of the highest sensitivity and specificity with a lower limit of detection of less than 10 IU/mL for hepatitis B virus (HBV) DNA and <0.1 ng/mL for hepatitis B surface antigen (HBsAg). This covert condition is relatively common in patients with chronic hepatitis C virus (HCV) that seems to exert some influence on the replicative capacity and latency of HBV. Detection of virus-specific nucleic acid does not always translate into infectivity, and the occurrence of primer-generated HBV DNA that is of partial genomic length in immunocompetent individuals who have significant levels of hepatitis B surface antibody (anti-HBs) may not be biologically relevant. Acute flares of alanine aminotransferase (ALT) that occur during the early phase of therapy for HCV or ALT levels that remain elevated at the end of therapy in biochemical nonresponders should prompt an assessment for occult hepatitis B. Similarly, the plasma from patients with chronic hepatitis C that is hepatitis B core antibody (anti-HBc) positive (+/-anti-HBs at levels of <100 mIU/mL) should be examined for HBV DNA with the most sensitive assay available. If a liver biopsy is available, immunostaining for hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) should be contemplated and a portion of the sample tested for HBV DNA. This is another reason for optimal collection of a specimen (e.g. two passes with a 16-guage needle under ultrasound guidance). Transmission of HBV to immunosuppressed orthotopic liver transplant recipients by donors with occult hepatitis B (OHB) will continue to occupy the interests of the transplant hepatologist. As patients with OHB may have detectable HBV DNA in serum, peripheral blood mononuclear cells (PBMC) and/or liver that can be reactivated following immunosuppression or intensive cytotoxic chemotherapy, the patient needs to be either monitored or treated depending on the pretreatment serological results such as an isolated anti-HBc reaction or a detectable HBV DNA.
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