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Liang LB, Zhang HJ, Liu F, Su QL. Hepatitis B core-related antigen as a predictive biomarker for recurrence in primary hepatocellular carcinoma: A meta-analysis. World J Gastrointest Oncol 2025; 17:105148. [DOI: 10.4251/wjgo.v17.i5.105148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 02/24/2025] [Accepted: 04/11/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignancies, with high recurrence rates after treatment. Identifying reliable biomarkers for predicting recurrence is essential for improving patient outcomes. Hepatitis B core-related antigen (HBcrAg) has shown potential as a predictive marker for HCC recurrence.
AIM To evaluate the association between HBcrAg levels and the risk of HCC recurrence.
METHODS A systematic review was conducted following PRISMA guidelines. PubMed, EMBASE, Web of Science, and the Cochrane Library were searched without restrictions on date or language. Observational studies reporting hazard ratios (HRs) for HBcrAg as a predictor of HCC recurrence were included. Data extraction and quality assessment were performed independently by two reviewers. Statistical analyses used a random-effects model to account for heterogeneity (I² ≥ 50%), and sensitivity analysis was performed to ensure the robustness of the results.
RESULTS A total of 1339 articles were initially identified, and 17 studies were included in the final meta-analysis after screening. The pooled analysis showed a significant association between elevated HBcrAg levels and HCC recurrence (HR = 4.42, 95% confidence interval: 3.43-5.41) with substantial heterogeneity (I² = 92.6%). Subgroup analysis revealed higher pooled HRs in studies with ≥ 500 participants (HR = 4.18) and HBcrAg cut-offs ≥ 4.0 LogU/mL (HR = 5.29). Studies with ≥ 10 years of follow-up showed a lower HR (2.89) compared to those with < 10 years (3.27). Patients treated with nucleos(t)ide analogs had a pooled HR of 1.98, while those without nucleos(t)ide analog had a higher HR of 3.87. Sensitivity analysis confirmed the robustness of the results, with no significant publication bias detected.
CONCLUSION This meta-analysis provides strong evidence that elevated HBcrAg levels are associated with an increased risk of HCC recurrence. HBcrAg may serve as a valuable biomarker for predicting recurrence, aiding personalized management and surveillance strategies for HCC patients.
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Affiliation(s)
- Ling-Bo Liang
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hai-Jun Zhang
- General Practice Ward/International Medical Center Ward, West China Healthcare Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Feng Liu
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Qiao-Li Su
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Mimura S, Ono M, Fujita K, Takuma K, Nakahara M, Oura K, Tadokoro T, Tani J, Morishita A, Kagawa S, Okano K, Himoto T, Masaki T. Chronic Hepatitis B in Which HBs Antigen Seroclearance Was Induced by Pegpegylated-interferonα-2a after Hepatocellular Carcinoma Treatment with Nucleos(t)ide Analogues: A Five-year Follow-up. Intern Med 2025; 64:225-229. [PMID: 38811223 PMCID: PMC11802215 DOI: 10.2169/internalmedicine.3643-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/11/2024] [Indexed: 05/31/2024] Open
Abstract
We herein report a 40-year-old Japanese man with chronic hepatitis B genotype C (viral load 6.7 Log copies/mL) who developed hepatocellular carcinoma (HCC) despite achieving undetectable hepatitis B virus (HBV)-DNA levels with nucleos(t)ide analog (NA) treatment (entecavir). Notably, his hepatitis B surface antigen (HBsAg) level remained elevated at 388.4 IU/mL. Given the continued risk of carcinogenesis associated with HBsAg positivity, we initiated pegylated interferon (PEG-IFN) therapy one month after HCC surgery. Following three periods of PEG-IFN treatment, HBsAg seroclearance (HBsAg-negative state) was achieved.
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Affiliation(s)
- Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
| | - Seiko Kagawa
- Department of Pathology, Faculty of Medicine, Kagawa University, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan
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Okumura T, Umemura T. Growing evidence on the highly sensitive iTACT assay of hepatitis B core-related antigen for predicting hepatitis B virus reactivation. J Gastroenterol 2025; 60:129-130. [PMID: 39611969 DOI: 10.1007/s00535-024-02187-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 11/17/2024] [Indexed: 11/30/2024]
Affiliation(s)
- Taiki Okumura
- Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano , 390-8621, Japan.
| | - Takeji Umemura
- Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano , 390-8621, Japan
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Sometani E, Hikita H, Murai K, Toyoda H, Tanaka S, Oze T, Sung J, Shimoda A, Fukuoka M, Shigeno S, Fukutomi K, Shirai K, Tahata Y, Saito Y, Nishio A, Furuta K, Kodama T, Sakamori R, Tatsumi T, Mita E, Umezawa A, Tanaka Y, Takehara T. High serum growth differentiation factor 15 is a risk factor for the occurrence of hepatocellular carcinoma in chronic hepatitis B patients treated with nucleos(t)ide analogs. Hepatol Res 2024; 55:22-33. [PMID: 39291388 DOI: 10.1111/hepr.14111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 08/06/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024]
Abstract
AIM Patients with chronic hepatitis B (CHB) remain at risk for hepatocellular carcinoma (HCC) even with nucleos(t)ide analog therapy. We evaluated risk factors for HCC development, including serum hepatitis B virus (HBV) RNA, hepatitis B core-related antigen level, and growth differentiation factor 15 (GDF15) level, a predictor of HCC development in patients with chronic hepatitis C. METHODS We collected clinical data and stored serum from CHB patients without a history of HCC who were receiving nucleos(t)ide analog treatment for more than 1 year and whose HBV DNA level was less than 3.0 log IU/mL. We measured the serum levels of HBV RNA and GDF15. RESULTS Among 242 CHB patients, 57 had detectable HBV RNA, and GDF15 was quantified in all patients. The median GDF15 level was 0.86 ng/mL. Cox proportional hazards analysis revealed that male sex and higher GDF15, FIB-4 index, alpha-fetoprotein and gamma-glutamyl transpeptidase were independent risk factors for HCC. The presence of HBV RNA above the lower limit of quantification was not a risk factor. When we set cutoff values based on the Youden index, the cumulative incidence of HCC was significantly higher in the male, AFP ≥3.0 ng/mL, gamma-glutamyl transpeptidase ≥22 U/L, FIB-4 index ≥1.93, and GDF-15 ≥1.17 ng/mL groups. In patients with no or more than three of these five risk factors, the 10-year HCC cumulative incidence rates were 0% and 41.0%, respectively. CONCLUSIONS High serum GDF15 is an independent risk factor for the occurrence of HCC in CHB patients treated with nucleos(t)ide analogs.
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Affiliation(s)
- Emi Sometani
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kazuhiro Murai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Satoshi Tanaka
- Department of Gastroenterology and Hepatology, NHO Osaka National Hospital, Osaka, Japan
| | - Tsugiko Oze
- Department of Gastroenterology and Hepatology, Koga Community Hospital, Yaizu, Japan
| | - Jihyun Sung
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Akiyoshi Shimoda
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Makoto Fukuoka
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Satoshi Shigeno
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Keisuke Fukutomi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kumiko Shirai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yoshinobu Saito
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Akira Nishio
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kunimaro Furuta
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, NHO Osaka National Hospital, Osaka, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Eiji Mita
- Department of Gastroenterology and Hepatology, NHO Osaka National Hospital, Osaka, Japan
| | - Akihiro Umezawa
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, Japan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Kumamoto University, Graduate School of Medical Sciences, Kumamoto, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
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Cao QH, Liu H, Yan LJ, Wang HC, Ding ZN, Mao XC, Li RZ, Pan GQ, Zhang X, Tian BW, Han CL, Dong ZR, Tan SY, Wang DX, Yan YC, Li T. Role of hepatitis B core-related antigen in predicting the occurrence and recurrence of hepatocellular carcinoma in patients with chronic hepatitis B: A systemic review and meta-analysis. J Gastroenterol Hepatol 2024; 39:1464-1475. [PMID: 38686439 DOI: 10.1111/jgh.16558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 03/08/2024] [Accepted: 03/25/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND AND AIM The purpose of the current study was to investigate the predictive value of hepatitis B core-related antigen (HBcrAg) on the occurrence and recurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). METHODS We searched PubMed, Embase, Scopus, and Web of Science from database inception to April 6, 2023. Pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was calculated for the occurrence and recurrence of HCC. RESULTS Of the 464 articles considered, 18 articles recruiting 10 320 patients were included. The pooled results showed that high serum HBcrAg level was an independent risk factor for the occurrence of HCC in CHB patients (adjusted HR = 3.12, 95% CI: 2.40-4.06, P < 0.001, I2 = 43.2%, P = 0.043; OR = 5.65, 95% CI: 3.44-5.82, P < 0.001, I2 = 0.00%, P = 0.42). Further subgroup analysis demonstrated that the predictive ability of HBcrAg for the occurrence of HCC is not influenced by the hepatitis B e antigen (HBeAg) status or the use of nucleoside/nucleotide analogs (NAs). In addition, our meta-analysis also suggests that HBcrAg is a predictor of HCC recurrence (adjusted HR = 1.71, 95% CI: 1.26-2.32, P < 0.001, I2 = 7.89%, P = 0.031). CONCLUSIONS For patients with CHB, serum HBcrAg may be a potential predictive factor for the occurrence of HCC, regardless of HBeAg status or NA treatment. It may also serve as a novel prognostic biomarker for the recurrence of HCC. More studies are needed to confirm our conclusions.
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Affiliation(s)
- Qi-Hang Cao
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Hui Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Han-Chao Wang
- Institute for Financial Studies, Shandong University, Jinan, China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xin-Cheng Mao
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Rui-Zhe Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Guo-Qiang Pan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xiao Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Bao-Wen Tian
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Cheng-Long Han
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Si-Yu Tan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yu-Chuan Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
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Inoue T, Yagi S, Tanaka Y. Two Concepts of Hepatitis B Core-Related Antigen Assay: A Highly Sensitive and Rapid Assay or an Effective Tool for Widespread Screening. Viruses 2024; 16:848. [PMID: 38932141 PMCID: PMC11209401 DOI: 10.3390/v16060848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/20/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatitis B core-related antigen (HBcrAg) reflects the activity of intrahepatic covalently closed circular DNA. HBcrAg can be detected even in chronic hepatitis B patients in whom serum HBV DNA or hepatitis B surface antigen is undetectable. The HBcrAg measurement system was developed based on two concepts. One is a fully-automated and highly-sensitive HBcrAg assay (iTACT-HBcrAg) and the other is a point-of-care testing (POCT) that can be used in in resource-limited areas. iTACT-HBcrAg is an alternative to HBV DNA for monitoring HBV reactivation and predicting the development of hepatocellular carcinoma. This validated biomarker is available in routine clinical practice in Japan. Currently, international guidelines for the prevention of mother-to-child transmission recommend anti-HBV prophylaxis for pregnant women with high viral loads. However, over 95% of HBV-infected individuals live in countries where HBV DNA quantification is widely unavailable. Given this situation, a rapid and simple HBcrAg assay for POCT would be highly effective. Long-term anti-HBV therapy may have potential side effects and appropriate treatment should be provided to eligible patients. Therefore, a simple method of determining the indication for anti-HBV treatment would be ideal. This review provides up-to-date information regarding the clinical value of HBcrAg in HBV management, based on iTACT-HBcrAg or POCT.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
| | - Shintaro Yagi
- Research and Development Department, Advanced Life Science Institute, Inc., Hachioji 192-0031, Japan;
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Inoue T, Watanabe T, Tanaka Y. Hepatitis B core-related antigen: A novel and promising surrogate biomarker to guide anti-hepatitis B virus therapy. Clin Mol Hepatol 2023; 29:851-868. [PMID: 36891607 PMCID: PMC10577333 DOI: 10.3350/cmh.2022.0434] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 02/19/2023] [Accepted: 03/07/2023] [Indexed: 03/10/2023] Open
Abstract
The current requirement for biomarkers to detect hepatitis B virus (HBV) infection is polarized. One is a fully-automated and highly sensitive measurement system; the other is a simple system for point-of-care testing (POCT) in resource-limited areas. Hepatitis B core-related antigen (HBcrAg) reflects intrahepatic covalently closed circular DNA and serum HBV DNA. Even in patients with undetectable serum HBV DNA or HBsAg loss, HBcrAg may remain detectable. Decreased HBcrAg levels are associated with reduction of the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B. Recently, a fully-automated, novel high-sensitivity HBcrAg assay (iTACT-HBcrAg, cut-off value: 2.1 logIU/mL) has been developed. This attractive assay has been released in Japan very recently. iTACT-HBcrAg can be useful for monitoring HBV reactivation and prediction of HCC occurrence, as an alternative to HBV DNA. Moreover, monitoring HBcrAg may be suitable for determining the therapeutic effectiveness of approved drugs and novel drugs under development. Presently, international guidelines recommend anti-HBV prophylaxis for pregnant women with high viral loads to prevent mother-to-child transmission of HBV. However, >95% of HBV-infected individuals live in countries where HBV DNA quantification is not available. Worldwide elimination of HBV needs the scaling-up of examination and medication services in resource-limited areas. Based on this situation, a rapid and easy HBcrAg assay as a POCT is valuable. This review provides the latest information regarding the clinical use of a new surrogate marker, HBcrAg, in HBV management, based on iTACT-HBcrAg or POCT, and introduces novel agents targeting HBV RNA/protein.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
| | - Takehisa Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
- Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Inoue T, Tanaka Y. Noninvasive assessments of liver disease severity based on biomarkers. COMPREHENSIVE GUIDE TO HEPATITIS ADVANCES 2023:31-60. [DOI: 10.1016/b978-0-323-98368-6.00009-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Chang KC, Lin MT, Wang JH, Hung CH, Chen CH, Chiu SYH, Hu TH. HBcrAg Predicts Hepatocellular Carcinoma Development in Chronic B Hepatitis Related Liver Cirrhosis Patients Undergoing Long-Term Effective Anti-Viral. Viruses 2022; 14:v14122671. [PMID: 36560675 PMCID: PMC9782149 DOI: 10.3390/v14122671] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/21/2022] [Accepted: 11/25/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatitis B core-related antigen (HBcrAg) is a predictor of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Studies on anti-viral therapy have shown that the use of NUC therapy in HBV patients could reduce the incidence of HCC. However, the incidence of HCC continues to increase after long-term anti-viral therapy. The relationship between HBcrAg and HCC development in CHB-related liver cirrhosis (LC) patients undergoing long-term anti-viral therapy is still unclear. This study enrolled 1108 treatment-naïve CHB patients diagnosed with HBV-related LC receiving NUC therapy from April 1999 to February 2015. The baseline biomarkers, disease history, and following results were collected by the hospital. Among the 1108 patients, 219 developed HCC within a median follow-up period of 6.85 years. A multivariable Cox regression model was used, with adjustment for age, gender, FIB-4, DM, and HBsAg-HQ. The adjusted hazard ratios for the HBcrAg tertile levels were 1.70 (95%CI: 1.21, 2.39) and 2.14 (95%CI: 1.50, 3.05) for levels 3.4-4.9 and >4.9 logU/mL, respectively, compared with levels ≤3.4. The effect of the HBcrAg level on HCC incidence was found to be significantly modified by HBsAg-HQ, where lower HBsAg-HQ (≤ 3) values were associated with a significantly higher risk, but HBsAg-HQ levels >3 were not. Our results highlight that, after adjustment for potential confounding factors, patients with CHB-related LC and higher HBcrAg levels are at significant risk for HCC development, even while undergoing long-term effective anti-viral therapy. The HBcrAg level is therefore an independent risk factor for HCC development, especially for patients with HBsAg-HQ levels <3.
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Affiliation(s)
- Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Ming-Tsung Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Jing-Houng Wang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Chao-Hung Hung
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Sherry Yueh-Hsia Chiu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Department of Health Care Management, College of Management, and Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan
- Correspondence: (S.Y.-H.C.); (T.-H.H.)
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Correspondence: (S.Y.-H.C.); (T.-H.H.)
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10
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Lok J, Dusheiko G, Carey I, Agarwal K. Review article: novel biomarkers in hepatitis B infection. Aliment Pharmacol Ther 2022; 56:760-776. [PMID: 35770458 DOI: 10.1111/apt.17105] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 06/08/2022] [Accepted: 06/12/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Chronic hepatitis B remains a global health problem with an estimated 296 million people affected worldwide. Individuals are at risk of serious complications such as cirrhosis and hepatocellular carcinoma and accurately predicting these clinical endpoints has proven difficult. However, several viral biomarkers have recently been developed, including quantitative HBV surface antigen (qHBsAg), hepatitis B RNA (HBV RNA) and core-related antigen (HBcrAg), and shown promise in a range of clinical settings. AIMS To critically appraise these novel biomarkers, exploring their potential uses, availability of assays and areas for future development. METHODS We performed a literature search of PubMed, identifying articles published in the field of hepatitis B biomarkers between 2010 and 2022. RESULTS Novel biomarkers such as HBcrAg, HBV RNA and qHBsAg may be useful in predicting treatment outcomes, stratifying the risk of future complications and estimating off-treatment viral reactivation. Furthermore, HBV RNA and HBcrAg titres may accurately reflect cccDNA transcriptional activity, and this is particularly informative in the context of nucleoside analogue therapy. On a cautionary note, most studies have been performed in Caucasian or Asian populations, and methods for detecting HBV RNA lack standardisation. CONCLUSION Novel viral biomarkers have the potential to provide additional insights into the natural history of infection and allow a more bespoke, cost-effective framework of care. However, access remains limited, and further efforts are needed to validate their use in ethnically diverse populations, confirm predictive cut-off values, and establish their role in the era of novel antiviral therapies.
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Affiliation(s)
- James Lok
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Ivana Carey
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK
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Tarao K, Nozaki A, Komatsu H, Ideno N, Komatsu T, Ikeda T, Taguri M, Maeda S. Difference in incidence of developing hepatocellular carcinoma between hepatitis B virus-and hepatitis C virus-infected patients. World J Meta-Anal 2022; 10:186-194. [DOI: 10.13105/wjma.v10.i3.186] [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: 04/13/2022] [Revised: 06/14/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND It is generally accepted that the incidence of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-associated patients is higher than that in hepatitis B virus (HBV)-associated patients. The reason why this difference in the incidence of HCC occurs in patients with HBV and HCV infections remains unclear. We report the possibility that the contributing power of inflammation, which is the main risk factor for developing HCC, may be different with HBV and HCV infections.
AIM To investigate this, we surveyed the hazard ratio of inflammation for HCC development which was identified by serum alanine aminotransferase (ALT) levels between patients with HBV and HCV infections.
METHODS The PubMed database was searched (2001-2021) for studies published in English regarding the incidence of HCC identifying 8924 HBV-and 7376 HCV- infected patients. From these studies, interferon-treated patients with both HBV and HCV infections were excluded. Furthermore, in HBV patients, those administered nucleos(t)ide analogues were excluded, and in HCV patients, those administered direct acting antivirals were also excluded. Studies citing hazard ratios of HCC regarding inflammation (serum elevated alanine aminotransferase levels) were selected. Finally, there were 14 studies of HBV- infected patients and 8 studies of HCV-infected patients. We calculated the hazard ratio in patients in an inflammatory state (serum ALT levels were above the normal range).
RESULTS In the 14 studies of HBV patients, the average hazard ratio (HR) of elevated ALT for developing HCC was 2.74 [1.98-3.77] and that in the 8 studies of HCV-infected patients was 5.51 [3.08-9.83]. The HR of inflammation for HCC development in HCV-associated liver diseases is about twice that in HBV-associated liver diseases. HR in HCV-infected patients was significantly (P = 0.0391) higher than that in HBV-infected patients. In hepatitis B patients, the abnormal range adopted was 28-45 IU/L, and in hepatitis C patients, it was 20-50 IU/L. It was demonstrated that the abnormal ALT levels adopted in hepatitis B and C patients were very similar in this series.
CONCLUSION The difference in the incidence of HCC development between HBV and HCV patients may depend on the difference in the hazard risk of ALT between HBV and HCV infections.
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Affiliation(s)
- Kazuo Tarao
- Department of Gastroenterology, Tarao's Gastroenterological Clinic, Yokohama City 241-0821, Japan
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama City 232-0024, Japan
| | - Hirokazu Komatsu
- Department of Gastroenterology, Yokohama Municipal Citizen’s Hospital, Yokohama City 2211-0855, Japan
| | - Naomi Ideno
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama City 232-0024, Japan
| | - Tatsuji Komatsu
- Department of Clinical Research, National Hospital Organization, Yokohama Medical Center, Yokohama City 2458575, Japan
| | - Takaaki Ikeda
- Department of Gastroenterology, Yokosuka General Hospital Uwamachi, Yokosuka City 238-8567, Japan
| | - Masataka Taguri
- Department of Data Science, Yokohama City University, Yokohama, Yokohama City 236-0004, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama City 236-0004, Japan
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12
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Chang Y, Kim SG, Jeong SW, Jang JY, Yoo JJ, Lee SH, Kim YS, Kim HS, Lee HW, Park S. Efficacy and Safety of Tenofovir Disoproxil Orotate in Chronic Hepatitis B Patients Previously Treated with Tenofovir Disoproxil Fumarate: Multicenter, Open-Label, Prospective Study. J Clin Med 2021; 10:jcm10235628. [PMID: 34884330 PMCID: PMC8658686 DOI: 10.3390/jcm10235628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/20/2021] [Accepted: 11/25/2021] [Indexed: 11/16/2022] Open
Abstract
Background/Aim: We aimed to demonstrate the efficacy and safety of tenofovir disoproxilorotate (TDO) compared with that of tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B. Methods: This multicenter, open-label, prospective clinical trial (KCT0004185) was conducted to evaluate the efficacy and safety of TDO on switching from TDF for 24 weeks in virologically suppressed chronic hepatitis B patients. The primary efficacy endpoint was the maintenance of virologic response. Safety was assessed by evaluating major adverse events, changes in renal function, and occurrence of hepatocellular carcinoma (HCC). Results: TDO treatment was not inferior in terms of virological response when compared with that on TDF treatment, with a noninferiority margin of −10% (risk difference, −3.17%; 95% confidence interval, −7.5–1.15%). The biological response of TDO was also comparable to that of TDF, with no significant difference in the proportion of patients with normalized alanine transaminase levels. After 24 weeks of treatment, hepatitis B core-related antigen (HBcrAg) significantly decreased to a mean titer of 3.91 log U/mL from 4.15 log U/mL at baseline (p = 0.01). There were no cases of grade 3 or higher adverse events and HCC. The mean estimated glomerular filtration rate increased from 91.09 mL/min to 93.34 mL/min (p = 0.056), and the mean serum level of phosphorus increased from 3.33 mg/dL to 3.44 mg/dL (p = 0.045), suggesting improvement in renal function with TDO treatment. Conclusion: In patients with chronic hepatitis B, the efficacy of TDO was noninferior to that of TDF, with a significant decrease in the HBcrAg titer and improved renal function.
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Affiliation(s)
- Young Chang
- Digestive Disease Center, Department of Internal Medicine, Institute for Digestive Research, Soonchunhyang University College of Medicine, Seoul 04401, Korea; (Y.C.); (J.-Y.J.)
| | - Sang-Gyune Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon 14584, Korea; (S.-G.K.); (J.-J.Y.); (Y.-S.K.)
| | - Soung-Won Jeong
- Digestive Disease Center, Department of Internal Medicine, Institute for Digestive Research, Soonchunhyang University College of Medicine, Seoul 04401, Korea; (Y.C.); (J.-Y.J.)
- Correspondence: (S.-W.J.); (H.-W.L.)
| | - Jae-Young Jang
- Digestive Disease Center, Department of Internal Medicine, Institute for Digestive Research, Soonchunhyang University College of Medicine, Seoul 04401, Korea; (Y.C.); (J.-Y.J.)
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon 14584, Korea; (S.-G.K.); (J.-J.Y.); (Y.-S.K.)
| | - Sae-Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan 31151, Korea; (S.-H.L.); (H.-S.K.)
| | - Young-Seok Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon 14584, Korea; (S.-G.K.); (J.-J.Y.); (Y.-S.K.)
| | - Hong-Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan 31151, Korea; (S.-H.L.); (H.-S.K.)
| | - Hyun-Woong Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea
- Correspondence: (S.-W.J.); (H.-W.L.)
| | - Suyeon Park
- Department of Biostatistics, Soonchunhyang University Hospital, Seoul 04401, Korea;
- Department of Applied Statistics, Chung-Ang University, Seoul 06974, Korea
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13
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Lok J, Agarwal K. Screening for Hepatocellular Carcinoma in Chronic Hepatitis B: An Update. Viruses 2021; 13:v13071333. [PMID: 34372539 PMCID: PMC8309969 DOI: 10.3390/v13071333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/27/2021] [Accepted: 07/06/2021] [Indexed: 11/24/2022] Open
Abstract
(1) Background: Hepatocellular carcinoma (HCC) is an important cause of mortality in individuals with chronic hepatitis B infection, with screening of high-risk groups recommended in all major international guidelines. Our understanding of the risk factors involved has improved over time, encouraging researchers to develop models that predict future risk of HCC development. (2) Methods: A literature search of the PubMed database was carried out to identify studies that derive or validate models predicting HCC development in patients with chronic hepatitis B. Subsequently, a second literature search was carried out to explore the potential role of novel viral biomarkers in this field. (3) Results: To date, a total of 23 models have been developed predicting future HCC risk, of which 12 have been derived from cohorts of treatment-naïve individuals. Most models have been developed in Asian populations (n = 20), with a smaller number in Caucasian cohorts (n = 3). All of the models demonstrate satisfactory performance in their original derivation cohorts, but many lack external validation. In recent studies, novel viral biomarkers have demonstrated utility in predicting HCC risk in patients with chronic hepatitis B, amongst both treated and treatment-naïve patients. (4) Conclusion: Several models have been developed to predict the risk of HCC development in individuals with chronic hepatitis B infection, but many have not been externally validated outside of the Asian population. Further research is needed to refine these models and facilitate a more tailored HCC surveillance programme in the future.
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Affiliation(s)
- James Lok
- Department of Gastroenterology, St. George’s Hospital, London SW17 0QT, UK
- Correspondence:
| | - Kosh Agarwal
- Institute of Liver Studies, King’s College Hospital, London SE5 9RS, UK;
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14
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Vachon A, Osiowy C. Novel Biomarkers of Hepatitis B Virus and Their Use in Chronic Hepatitis B Patient Management. Viruses 2021; 13:951. [PMID: 34064049 PMCID: PMC8224022 DOI: 10.3390/v13060951] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/15/2022] Open
Abstract
Even though an approved vaccine for hepatitis B virus (HBV) is available and widely used, over 257 million individuals worldwide are living with chronic hepatitis B (CHB) who require monitoring of treatment response, viral activity, and disease progression to reduce their risk of HBV-related liver disease. There is currently a lack of predictive markers to guide clinical management and to allow treatment cessation with reduced risk of viral reactivation. Novel HBV biomarkers are in development in an effort to improve the management of people living with CHB, to predict disease outcomes of CHB, and further understand the natural history of HBV. This review focuses on novel HBV biomarkers and their use in the clinical setting, including the description of and methodology for quantification of serum HBV RNA, hepatitis B core-related antigen (HBcrAg), quantitative hepatitis B surface antigen (qHBsAg), including ultrasensitive HBsAg detection, quantitative anti-hepatitis B core antigen (qAHBc), and detection of HBV nucleic acid-related antigen (HBV-NRAg). The utility of these biomarkers in treatment-naïve and treated CHB patients in several clinical situations is further discussed. Novel HBV biomarkers have been observed to provide critical clinical information and show promise for improving patient management and our understanding of the natural history of HBV.
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Affiliation(s)
- Alicia Vachon
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada
| | - Carla Osiowy
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada
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15
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Wu JW, Kao JH, Tseng TC. Three Heads are Better than Two: HBcrAg as a New Predictor of HBV-related HCC. Clin Mol Hepatol 2021; 27:524-534. [PMID: 33618507 PMCID: PMC8524074 DOI: 10.3350/cmh.2021.0012] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/21/2021] [Indexed: 01/13/2023] Open
Abstract
Patients with chronic hepatitis B virus (HBV) infection are at risk of developing hepatocellular carcinoma (HCC), and serum markers reflecting viral replication are potential predictors for HCC development. Besides the levels of serum HBV DNA and hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) quantification is an emerging serological marker for viral replication. Unlike HBV DNA and HBsAg, HBcrAg is a covalently closed circular DNA-derived protein marker, consisting of hepatitis B e antigen (HBeAg), p22cr, and hepatitis B core antigen. In treatment-naïve HBV patients, higher HBcrAg levels are shown to be associated with an increased risk of HCC in several studies. More importantly, HBcrAg may complement HBV DNA level to predict HCC development. For example, an Asian treatment-naïve cohort study’s data showed that HBcrAg level of 4 log U/mL was effective to stratify HCC risk in HBeAg-negative patients with intermediate viral loads, who may not need antiviral therapy because of the low to moderate risk of HCC. In patients receiving prolonged nucleos(t)ide analogue with profound viral suppression, most data indicated that HBV DNA and HBsAg levels no longer serve as HCC predictors. However, several studies suggested on-treatment HBcrAg levels may remain as an HCC predictor. In summary, HBcrAg level can be a useful biomarker for treatment-naïve patients, but its value in on-treatment patients needs validation. The next challenge is how to combine HBcrAg with the other viral markers to construct a better HCC prediction model, optimizing the management of HBV patients.
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Affiliation(s)
- Jer-Wei Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine Taipei, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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16
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Zeng G, Gill US, Kennedy PTF. Prioritisation and the initiation of HCC surveillance in CHB patients: lessons to learn from the COVID-19 crisis. Gut 2020; 69:1907-1912. [PMID: 32451325 PMCID: PMC7295856 DOI: 10.1136/gutjnl-2020-321627] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Georgia Zeng
- Faculty of Medicine, UNSW, Sydney, New South Wales, Australia
| | - Upkar S Gill
- Barts Liver Centre, Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Patrick T F Kennedy
- Barts Liver Centre, Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
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17
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Matsumoto A, Nishiguchi S, Enomoto H, Tanaka Y, Shinkai N, Okuse C, Kang JH, Matsui T, Miyase S, Yatsuhashi H, Nagaoka S, Kanda T, Enomoto M, Yamada R, Hiramatsu N, Saito S, Takaguchi K, Ito K, Masaki T, Morihara D, Tsuge M, Chayama K, Ikeda F, Kagawa T, Kondo Y, Murata K, Tanaka E. Pilot study of tenofovir disoproxil fumarate and pegylated interferon-alpha 2a add-on therapy in Japanese patients with chronic hepatitis B. J Gastroenterol 2020; 55:977-989. [PMID: 32666202 DOI: 10.1007/s00535-020-01707-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/25/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND A prospective pilot study of tenofovir disoproxil fumarate (TDF) and pegylated interferon alpha 2a (P-IFN) add-on therapy was conducted to evaluate its efficacy in reducing viral antigen levels in Japanese patients with chronic hepatitis B (UMIN 000020179). METHODS Patients with chronic hepatitis B receiving maintenance TDF therapy and exhibiting hepatitis B surface antigen (HBsAg) level > 800 IU/ml were divided into two arms. P-IFN was added for 48 weeks in the add-on arm (n = 32), while TDF monotherapy was maintained in the control arm (n = 51). Both groups were followed for 96 weeks after baseline measurements. RESULTS Almost all patients in the control arm displayed a slow and constant reduction in HBsAg during follow-up. In contrast, roughly half of the add-on arm exhibited a sharp decline in HBsAg during P-IFN administration, which disappeared after halting P-IFN. At 96 weeks after baseline, 41% (13/32) of patients in the add-on arm had shown a rapid decrease in HBsAg, versus 2% (1/51) in the control arm (p < 0.001). Add-on therapy and increased cytotoxic T-cell response were significant factors associated with a rapid decrease in HBsAg according to multivariate analysis. In addition, higher HB core-related antigen (HBcrAg) level at baseline (p = 0.001) and add-on therapy (p = 0.036) were significant factors associated with a rapid reduction in HBcrAg. CONCLUSIONS TDF and P-IFN add-on therapy in Japanese patients with chronic hepatitis B facilitated rapid decreases in HBsAg and HBcrAg. Further studies are needed to improve early HBsAg clearance rate.
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Affiliation(s)
- Akihiro Matsumoto
- Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Noboru Shinkai
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Chiaki Okuse
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kawasaki Municipal Tama Hospital, Kawasaki, Japan
| | - Jong-Hon Kang
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Takeshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Shiho Miyase
- Department of Gastroenterology and Hepatology, Kumamoto Shinto General Hospital, Kumamoto, Japan
| | - Hiroshi Yatsuhashi
- The Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan
| | - Shinya Nagaoka
- The Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Medical School, Osaka, Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Naoki Hiramatsu
- Department of Gastroenterology, Osaka Rosai Hospital, Sakai, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Kiyoaki Ito
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Daisuke Morihara
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Fusao Ikeda
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Yasuteru Kondo
- Department of Hepatology, Sendai Kousei Hospital, Sendai, Japan
| | - Kazumoto Murata
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Japan
| | - Eiji Tanaka
- Department for the Promotion of Regional Medicine, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, 390-8621, Japan.
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Detectable HBV DNA during nucleos(t)ide analogues stratifies predictive hepatocellular carcinoma risk score. Sci Rep 2020; 10:13021. [PMID: 32747646 PMCID: PMC7400741 DOI: 10.1038/s41598-020-69522-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 06/05/2020] [Indexed: 02/08/2023] Open
Abstract
Nucleos(t)ide analogs (NA) suppress hepatitis B virus (HBV) replication and reduce the risk of hepatocellular carcinoma (HCC). However, NA cannot suppress carcinogenesis completely in patients with chronic hepatitis B. The aims of this study were to identify risk factors for HCC and develop a refined carcinogenesis prediction model. Patients receiving NA therapy (n = 1,183) were recruited retrospectively from the 16 hospitals. All patients had been receiving NA continuously for more than 1 year until the end of the follow-up. During a median follow-up of 4.9 (1.0–12.9) years, 52 (4.4%) patients developed HCC. A multivariate analysis revealed that male gender, older age, lower platelet counts at the baseline, and detectable HBV DNA during NA therapy were independent predictive factors of HCC development. The PAGE-B score was calculated by using these factors. 240 (20.3%), 661 (55.9%), and 282 (23.8%) patients were classified into low-, intermediate-, and high-risk groups, respectively. In the intermediate- and high-risk group, detectable HBV DNA was significantly associated with a higher risk of HCC development compared with continuously undetectable HBV DNA, respectively (HR 3.338; 95% CI 1.045–10.66/HR 3.191; 95% CI 1.543–6.597). PAGE-B–DNA, which is the combined PAGE-B and HBV DNA status, was valuable for a more refined stratification of PAGE-B.
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Inoue T, Tanaka Y. Novel biomarkers for the management of chronic hepatitis B. Clin Mol Hepatol 2020; 26:261-279. [PMID: 32536045 PMCID: PMC7364351 DOI: 10.3350/cmh.2020.0032] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/11/2020] [Accepted: 04/13/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) cannot be eliminated completely from infected hepatocytes because of the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), it is important to manage CHB to prevent HCC development in high-risk patients with high viral replicative activity or advanced fibrosis. Serum biomarkers are noninvasive and valuable for the management of CHB. Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with hopeful outcomes. Therefore, HBcrAg can predict HCC occurrence or recurrence. Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. Because elevated M2BPGi in CHB is related to liver fibrosis and the prediction of HCC development, monitoring its progression is essential. Because alpha fetoprotein (AFP) has insufficient sensitivity and specificity for early-stage HCC, a combination of AFP plus protein induced by vitamin K absence factor II, or AFP plus Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein might improve the diagnosis of HCC development. Additionally, Dickkopf-1 and circulating immunoglobulin G antibodies are the novel markers to diagnose HCC or assess HCC prognosis. This review provides an overview of novel HBV biomarkers used for the management of intrahepatic viral replicative activity, liver fibrosis, and HCC development.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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20
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SIRT1 enhances hepatitis virus B transcription independent of hepatic autophagy. Biochem Biophys Res Commun 2020; 527:64-70. [PMID: 32446392 DOI: 10.1016/j.bbrc.2020.04.031] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 04/09/2020] [Indexed: 02/02/2023]
Abstract
Autophagy is an intracellular process that can lead to the degradation of malfunctioned proteins and damaged organelles to maintain homeostasis during cellular stress. Here, we evaluated the change in hepatitis B virus (HBV) production by regulating hepatic autophagy in HBV-producing cells. We examined focusing on a relation with a positive autophagy regulator, sirtuin1 (SIRT1). Starvation and rapamycin treatment induced autophagy with increasing SIRT1 protein, HBc protein and pregenomic RNA (pgRNA) levels in HBV- producing cells. Knockdown of Atg7 or Atg13 suppressed hepatic autophagy, and it did not change SIRT1 protein, HBc protein or pgRNA levels in HBV- producing cells. Resveratrol, which increases SIRT1 expression and activity, promoted autophagy and increased HBc protein and pgRNA levels. siRNA-mediated knockdown of SIRT1 inhibited autophagy and decreased HBc protein and pgRNA levels. In SIRT1-knockdown cells, starvation promoted autophagy but did not increase HBc protein and pgRNA levels. In conclusion, HBc protein and pgRNA levels are upregulated not by the autophagic process itself but by the SIRT1 expression level.
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Liu L. Clinical features of hepatocellular carcinoma with hepatitis B virus among patients on Nucleos(t) ide analog therapy. Infect Agent Cancer 2020; 15:8. [PMID: 32042307 PMCID: PMC7001249 DOI: 10.1186/s13027-020-0277-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 01/23/2020] [Indexed: 02/07/2023] Open
Abstract
Background The clinical manifestation of hepatocellular carcinoma (HCC) with hepatitis B virus (HBV) varies significantly between patients treated with or without nucleos(t) ide analog (NUC) therapy. To have a better understanding of HCC with HBV, we compared the clinical features of patients with HCC receiving or not receiving NUC therapy. Methods We retrospectively reviewed the medical records of 76 patients with HBV-caused HCC who received treatment at the Hunan Provincial Peoples' Hospital starting from January 1, 2008 to December 31, 2017. They were categorized into two groups, namely, NUC group and non-NUC group, based on whether they had received NUC therapy or not. Results The percentage of liver pain (36.36% vs. 79.07%; p < 0.05) and appetite loss (30.30% vs. 70.27%; p < 0.05) in the NUC group was lower than that in the non-NUC group. We observed a similar trend for the percentage of undetectable HBV-DNA (11.63% vs. 63.64%; p < 0.05) and normal ALT (25.58% vs. 75.76%; p < 0.05) between non-NUC and NUC groups. There were no significant differences between the two groups with respect to TBiL (p = 0.370) and ALB (p = 0.475). The same trend was observed for the proportion of HBeAg negative (p = 0.719) and AFP ≤ 14.65 ng/mL (p = 0.199) in both groups. Single tumor nodule was more common in the NUC group compared to the non-NUC group (66.67% vs. 6.98%; p < 0.05). An opposite trend was observed for portal vein invasion (18.18% vs. 79.07%; p < 0.05) and metastasis (0% vs. 44.19%; p < 0.05). Conclusions Nucleos(t) ide analog therapy exerts a significant impact on the clinical and radiological characteristics of hepatocellular carcinoma with HBV. Patients receiving nucleos(t) ide analog therapy were found to have milder symptoms and fewer radiographic findings.
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Affiliation(s)
- Li Liu
- Infectious disease department, Hunan provincial peoples ~ hospital (The first affiliated hospital of Hunan Normal university), Hunan province, Changsha, 410000 China
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Masrour-Roudsari J, Hasanjani-Roushan M, Yahyapour Y, Barari-Savadkoohi R, Bijani A, Sadeghi F, Mohammadnia-Afroozi M. HBS Ag seroclearance and seroconversion time in Patients with chronic hepatitis B Infection. CASPIAN JOURNAL OF INTERNAL MEDICINE 2020; 11:205-210. [PMID: 32509250 PMCID: PMC7265509 DOI: 10.22088/cjim.11.2.205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 04/19/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND Hepatitis B Surface antigen (HBsAg) seroclearance and seroconversion (development of antibodies against HBsAg) can increases the survival of Chronic hepatitis B (CHB) patients. The aim of this study was to determine the percentage and timing of HBsAg seroclearance and seroconversion in patients with chronic hepatitis B infection. METHODS 1026 patients with CHB infection who referred to a private clinic were included. These patients had been followed-up for an average of 15 years. The patients whose HBs Ag was cleared from the blood and remained negative until the end of follow-up were designated as HBs Ag serocleared and the patients whose HBs Ab was positive during follow-upwas designated as HBs Ag seroconverted. The time of seroclearance and seroconversion of patients was recorded. Liver function tests, alpha-fetoprotein (AFP) and Hepatitis B early antigen (HBe Ag) status were extracted from the patients' medical records. Data were analysis with SPSS 17. RESULTS The duration of follow-up was from 2 to 410 months and most patients were males (58.2%).The survival rate of HBs Ag positivity after 5, 10 and 15 years were 95.6, 89.4 and 80.7%, and 98, 93.5 and 84.9% of patients had not yet developed anti-HBs antibodies after 5, 10 and 15 years, respectively. Age, gender and taking medication had no effect on HBs Ag clearance from the blood or anti-HBs production. CONCLUSION The HBs Ag seroconversion is a rare occurrence, but the incidence of this may increase with time, age and drug consumption. Though there was no relationship in our patients.
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Affiliation(s)
| | - Mohammadreza Hasanjani-Roushan
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Yousef Yahyapour
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Rahim Barari-Savadkoohi
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Ali Bijani
- Social Determinants Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Farzin Sadeghi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mousa Mohammadnia-Afroozi
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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23
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Hasegawa K, Nishikawa H, Enomoto H, Iwata Y, Sakai Y, Ikeda N, Takashima T, Aizawa N, Takata R, Yoh K, Ishii N, Yuri Y, Nishimura T, Iijima H, Hatano E, Fujimoto J, Nishiguchi S. Proposed model for the prediction of intrahepatic covalently closed circular DNA level in patients with chronic hepatitis B. Hepatol Res 2019; 49:271-283. [PMID: 30358027 DOI: 10.1111/hepr.13280] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/04/2018] [Accepted: 10/19/2018] [Indexed: 02/08/2023]
Abstract
AIM We sought to create a prediction model for intrahepatic covalently closed circular DNA (IH-cccDNA) level in chronic hepatitis B (CHB) patients and to validate the model's predictive accuracy. METHODS Patients who did not receive previous nucleoside analogue (NA) therapy were assigned to the training cohort (n = 57), and those who received previous NA therapy were assigned to the validation cohort (n = 69). Factors linked to IH-cccDNA levels in the training cohort were analyzed and a formula to predict IH-cccDNA levels was constructed. Next, the reproducibility of that formula was assessed. RESULTS In the multivariate analysis for the prediction of IH-cccDNA level in the training cohort, fasting blood sugar (FBS) (P = 0.0227), hepatitis B e antigen (HBeAg) (P = 0.0067) and log10 (HB surface antigen [HBsAg]) (P = 0.0497) were significant, whereas HB core-related antigen (HBcrAg) tended to be significant (P = 0.0562). The formula was constructed and named the FBS-cres score based on the variables used (FBS, HBcrAg, HBeAg, and HBsAg). The FBS-cres score was calculated as: 3.1686 - (0.0148 × FBS) + (0.1982 × HBcrAg) + (0.0008168 × HBeAg) + (0.1761 × log10 (HBsAg)). In the training cohort, a significant correlation was noted between HBcrAg and IH-cccDNA levels (P < 0.0001, r = 0.67), whereas the FBS-cres score was more closely correlated to IH-cccDNA level (P < 0.0001, r = 0.81). In the validation cohort, significant correlation was found between HBcrAg and IH-cccDNA levels (P = 0.0012, r = 0.38), whereas the FBS-cres score was more closely linked to IH-cccDNA levels (P < 0.0001, r = 0.51). Similar tendencies were observed in all subgroup analyses. CONCLUSION Our proposed model for the prediction of IH-cccDNA level could be helpful in CHB patients.
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Affiliation(s)
- Kunihiro Hasegawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroki Nishikawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yoshinori Iwata
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yoshiyuki Sakai
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Naoto Ikeda
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tomoyuki Takashima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Nobuhiro Aizawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Ryo Takata
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kazunori Yoh
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Noriko Ishii
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yukihisa Yuri
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Takashi Nishimura
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroko Iijima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Etsuro Hatano
- Division of Hepatobiliary and Pancreatic disease, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Jiro Fujimoto
- Division of Hepatobiliary and Pancreatic disease, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
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24
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Zhang L, Zhang FK. Recent advances in assessment and treatment of chronic hepatitis B. Shijie Huaren Xiaohua Zazhi 2019; 27:209-219. [DOI: 10.11569/wcjd.v27.i4.209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
This paper reviews the recent advances in the assessment and treatment of chronic hepatitis B with regard to predicting inflammation and fibrosis with non-invasive biomarkers and transient elastography, clinical benefits of long-term nucleos(t)ide analog (NA) antiviral therapy, serological benefits (HBeAg and HBsAg loss) of concurrent or sequential NAs and pegylated interferon, as well as risk factors for the development of hepatocellular carcinoma.
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Affiliation(s)
- Li Zhang
- Department of Gastroenterology, Beijing Shijingshan Hospital, Beijing 100043, China
| | - Fu-Kui Zhang
- Department of Gastroenterology, Beijing Shijingshan Hospital, Beijing 100043, China
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25
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Wakasugi H, Takahashi H, Niinuma T, Kitajima H, Oikawa R, Matsumoto N, Takeba Y, Otsubo T, Takagi M, Ariizumi Y, Suzuki M, Okuse C, Iwabuchi S, Nakano M, Akutsu N, Kang JH, Matsui T, Yamada N, Sasaki H, Yamamoto E, Kai M, Sasaki Y, Sasaki S, Tanaka Y, Yotsuyanagi H, Tsutsumi T, Yamamoto H, Tokino T, Nakase H, Suzuki H, Itoh F. Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment. Cancer Lett 2018; 434:91-100. [PMID: 30026054 DOI: 10.1016/j.canlet.2018.07.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 06/04/2018] [Accepted: 07/12/2018] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a-3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk.
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Affiliation(s)
- Hideki Wakasugi
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hideaki Takahashi
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; Division of Gastroenterology, Department of Internal Medicine, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Yokohama, Japan
| | - Takeshi Niinuma
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Kitajima
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ritsuko Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Naoki Matsumoto
- Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Yuko Takeba
- Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Takehito Otsubo
- Department of Gastroenterological and General Surgery, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Masayuki Takagi
- Department of Pathology, St. Marianna University, Kawasaki, Japan
| | - Yasushi Ariizumi
- Department of Pathology, St. Marianna University, Kawasaki, Japan
| | - Michihiro Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; Division of Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital, Japan
| | - Chiaki Okuse
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; Division of Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital, Japan
| | - Shogo Iwabuchi
- Center for Hepato-Biliary-Pancreatic and Digestive Disease, Shonan Fujisawa Tokushukai Hospital, Kanagawa, Japan
| | - Masayuki Nakano
- Department of Pathology, Shonan Fujisawa Tokushukai Hospital, Kanagawa, Japan
| | - Noriyuki Akutsu
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Jong-Hon Kang
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Takeshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Norie Yamada
- Department of Internal Medicine, Center for Liver Diseases, Kiyokawa Hospital, Tokyo, Japan
| | - Hajime Sasaki
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Eiichiro Yamamoto
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masahiro Kai
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yasushi Sasaki
- Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shigeru Sasaki
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yasuhito Tanaka
- Department of Virology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases and Applied Immunology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takeya Tsutsumi
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Japan
| | - Hiroyuki Yamamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Takashi Tokino
- Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
| | - Fumio Itoh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
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