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Sam NB, Majeed SF, Dramani A. Unraveling Demographic Patterns in Hepatitis B Clinical and Laboratory Profiles: Insights From a Ghanaian Cohort: A Retrospective Study. Health Sci Rep 2025; 8:e70689. [PMID: 40260046 PMCID: PMC12010205 DOI: 10.1002/hsr2.70689] [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: 07/05/2024] [Revised: 03/20/2025] [Accepted: 04/03/2025] [Indexed: 04/23/2025] Open
Abstract
Background and Aims The influence of age and gender on the manifestations of Hepatitis B (HB) disease is underexplored and yields varied findings. This study assessed the impact of age and gender on HB disease manifestations in a Ghanaian population. Methods This retrospective study evaluated 569 patients at Tamale Teaching Hospital. Disease manifestations were compared separately between male and female patients across different age groups and among four distinct age groups within male and female patients. Results It revealed a male-to-female ratio of 5.1:1, with significant differences observed among age categories. HBsAg was significantly more prevalent in adult males (p < 0.05), while polydipsia showed equal prevalence between genders (p < 0.05). Female adults exhibited higher rates of constipation and palpitation compared to males (p < 0.05). In older patients, females had higher ALT and HBeAg prevalence than males (p < 0.05). Disease manifestation did not significantly differ by gender among children and younger patients (p > 0.05). Among males, viral load differed significantly across age groups and correlated positively with age (p < 0.05). Females showed positive correlations of jaundice, HBeAg, low globulin, and high AST with age (p < 0.05), but nausea was negatively correlated (p < 0.05). Conclusion This study highlights unique clinical and laboratory features in reproductive-aged female HB patients.
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Affiliation(s)
- Napoleon Bellua Sam
- Department of Medical Research and InnovationSchool of Medicine, University for Development StudiesTamaleGhana
| | - Saeed Folorunsho Majeed
- Department of Biological ScienceFaculty of Biosciences, University for Development StudiesTamaleGhana
| | - Adams Dramani
- Department of Medical Research and InnovationSchool of Medicine, University for Development StudiesTamaleGhana
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Xie C, Lu D. Evolution and diversity of the hepatitis B virus genome: Clinical implications. Virology 2024; 598:110197. [PMID: 39098184 DOI: 10.1016/j.virol.2024.110197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/14/2024] [Accepted: 07/30/2024] [Indexed: 08/06/2024]
Abstract
Hepatitis B virus (HBV) infection remains a significant global health burden. The genetic variation of HBV is complex. HBV can be divided into nine genotypes, which show significant differences in geographical distribution, clinical manifestations, transmission routes and treatment response. In recent years, substantial progress has been made through various research methods in understanding the development, pathogenesis, and antiviral treatment response of clinical disease associated with HBV genetic variants. This progress provides important theoretical support for a deeper understanding of the natural history of HBV infection, virus detection, drug treatment, vaccine development, mother-to-child transmission, and surveillance management. This review summarizes the mechanisms of HBV diversity, discusses methods used to detect viral diversity in current studies, and the impact of viral genome variation during infection on the development of clinical disease.
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Affiliation(s)
- Chengzuo Xie
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Daiqiang Lu
- Institute of Molecular and Medical Virology, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control, School of Medicine, Jinan University, Guangzhou, Guangdong Province, 510632, China.
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Chen MY, Li SX, Du ZX, Xiong QF, Zhong YD, Liu DX, Yang YF. Liver biopsy-proven non-alcoholic fatty liver disease predicts no impact on antiviral response in patients with chronic hepatitis B. Clinics (Sao Paulo) 2024; 79:100493. [PMID: 39332149 PMCID: PMC11467630 DOI: 10.1016/j.clinsp.2024.100493] [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: 11/10/2023] [Revised: 05/31/2024] [Accepted: 08/25/2024] [Indexed: 09/29/2024] Open
Abstract
OBJECTIVE The role of Non-Alcoholic Fatty Liver Disease (NAFLD) on antiviral response in Chronic Hepatitis B (CHB) remains unclear. Previous studies mainly focus on the impact of the Non-Alcoholic Fatty Liver (NAFL) on antiviral efficacy, whereas the role of Non-Alcoholic Steatohepatitis (NASH) has not been highlighted. The authors aimed to investigate the association of NAFLD (NAFL and NASH), viral and histological characteristics with antiviral response. METHODS The authors collected data of treatment-naïve CHB patients who underwent liver biopsy. All these patients received antiviral monotherapy and 48-week follow-up. The antiviral response was evaluated by Kaplan-Meier analysis. Cox regression analysis identified the variables associated with antiviral response. RESULTS Overall, 120 treatment-naïve CHB patients were enrolled, with 49.2 % (59/120) of them were complicated by NAFLD. Male (Odd Ratio [OR = 4.222], 95 % Confidence Interval [95 % CI 1.620-11.003]) and overweight (OR = 8.709, 95 % CI 3.355-22.606) were independent predictors for concurrent NAFLD. After 48-week follow-up, the authors found that the overall antiviral response did not differ between CHB patients with and without concomitant NAFL/NASH (p > 0.05). High viral load (Hazard Ratio [HR = 0.522], 95 % CI 0.286-0.952), advanced fibrosis (HR = 2.426, 95 % CI 1.256-4.686), and moderate-to-severe interface hepatitis (HR = 2.541, 95 % CI 1.406-4.592) were significantly correlated with antiviral response after 8-week follow-up. CONCLUSION Neither NAFL nor NASH had an impact on antiviral therapy for CHB. It was low hepatitis B load, advanced fibrosis, and moderate-to-severe interface hepatitis that contributed to the virological response.
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Affiliation(s)
- Miao-Yang Chen
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shun-Xin Li
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Zhi-Xiang Du
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Qing-Fang Xiong
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yan-Dan Zhong
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Du-Xian Liu
- Department of Pathology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yong-Feng Yang
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
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Lu Y, Tang W, Zhang H, Liu J, Zhong S. Effect of hepatocyte damage in hepatic fibrogenesis of patients infected with Schistosoma japonicum. Infect Immun 2024; 92:e0002624. [PMID: 38767360 PMCID: PMC11237810 DOI: 10.1128/iai.00026-24] [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: 01/19/2024] [Accepted: 04/22/2024] [Indexed: 05/22/2024] Open
Abstract
Schistosomiasis is a serious public health problem, and previous studies found that liver function and hepatic cells are damaged. To evaluate the serum parameters of liver function and fibrosis in schistosomiasis patients infected with Schistosoma japonicum (Schistosoma J.) and analyze the correlations between liver function and serum fibrosis markers in patients infected with Schistosoma J., this retrospective study enrolled 133 patients. The study population was divided into four groups: healthy people control group (n = 20), chronic schistosomiasis without liver cirrhosis (CS) group (n = 21), schistosomiasis cirrhosis without hypoalbuminemia (SC-HA) group (n = 68), and schistosomiasis cirrhosis with hypoalbuminemia (SC +HA) group (n = 24). Clinical and laboratory data were collected for analysis. In the multiple comparison of abnormal rates of aspartate aminotransferase (AST) and total bilirubin (TBIL), the abnormal rate of the SC +HA group was significantly higher than that of the other three groups (P < 0.05), and the abnormal rate of γ-GT in the SC +HA group was significantly higher than that in the control group (P < 0.05). Multiple comparison results of serum levels of fibrosis markers showed that the SC group had a significantly higher level of indexes than other groups (P < 0.05). The levels of TGF-β1 in the CS group, SC-HA group and SC +HA group were significantly higher than those in the control group (P < 0.001). Our study demonstrated that the liver function and hepatic cells were damaged with the progression of liver disease in patients infected with Schistosoma J., and they played an important role in the occurrence and development of liver fibrosis.
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Affiliation(s)
- Yaqi Lu
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wangxian Tang
- Institute of Liver Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Heng Zhang
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jing Liu
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shan Zhong
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, Hubei, China
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Jagarlamudi N, Reyes M, Fung S, Wong F. The Use of Tenofovir Disoproxil Fumarate in the Management of eAg-Negative Chronic Hepatitis B Infection. J Clin Med 2024; 13:1864. [PMID: 38610629 PMCID: PMC11012673 DOI: 10.3390/jcm13071864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/19/2024] [Accepted: 03/20/2024] [Indexed: 04/14/2024] Open
Abstract
Background/Objectives: Currently, there are insufficient data to recommend the treatment of patients with hepatitis B e antigen (HBeAg)-negative chronic infection who have normal ALT and low HBV DNA, since the prognosis is generally regarded as favorable. The aim of this pilot study was to determine whether the use of tenofovir disoproxil fumarate (TDF) 300 mg/day for 3 years was able to achieve functional cure (HBsAg loss) and HBsAg seroconversion in HBeAb-positive individuals. Methods: Fifty patients not on antiviral therapy (40% men, mean age 48.9 ± 10.9 years, 84% Asians) with minimal fibrosis were enrolled. Results: TDF reduced HBV DNA significantly to undetectable levels after 6 months. Overall, 48.3% of inactive carriers (baseline HBV DNA < 2000 IU/mL) remained HBV DNA negative 6 months after treatment withdrawal, which was significantly higher than the 5.6% in those who were not inactive carriers (baseline HBV DNA ≥ 2000 IU/mL) (p = 0.003). The HBsAg levels did not drop throughout the study period with no difference between inactive carriers versus those who were not. Five inactive carriers achieved functional cure, but none of these were amongst those who were not inactive carriers. No renal dysfunction or ALT flare on treatment withdrawal was observed. Conclusions: TDF could potentially be used to induce functional cure in patients who are inactive carriers with normal ALT, low HBV DNA and without advanced fibrosis.
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Affiliation(s)
| | | | | | - Florence Wong
- Division of Gastroenterology and Hepatology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON M5G2C4, Canada (M.R.); (S.F.)
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Liu YC, Jeng WJ. Should Indications for Antiviral Therapy for Hepatitis B Be Broadened to Include Immune-Tolerant Patients, Inactive Carriers, or Patients in the “Gray Zone”? CURRENT HEPATOLOGY REPORTS 2024; 23:11-21. [DOI: 10.1007/s11901-024-00635-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/04/2024] [Indexed: 01/04/2025]
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Kan K, Wong DKH, Hui RWH, Seto WK, Yuen MF, Mak LY. Plasma interferon-gamma-inducible-protein 10 level as a predictive factor of spontaneous hepatitis B surface antigen seroclearance in chronic hepatitis B patients. J Gastroenterol Hepatol 2024; 39:202-209. [PMID: 37794699 DOI: 10.1111/jgh.16371] [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: 02/20/2023] [Revised: 09/12/2023] [Accepted: 09/18/2023] [Indexed: 10/06/2023]
Abstract
BACKGROUND AND AIM Spontaneous seroclearance of hepatitis B surface antigen (HBsAg) is a rare event that occurs in patients that are chronically infected with the hepatitis B virus. As the functional cure and ultimate treatment endpoint of chronic hepatitis B (CHB), HBsAg seroclearance is an important milestone in the natural history of CHB and serves great clinical value. This study aims to identify host and viral factors associated with HBsAg seroclearance. METHODS This is a retrospective study carried out in the Queen Mary Hospital, Hong Kong. By analyzing the plasma retrieved from the serum archive (collected during 2011-2021) of 100 CHB patients attending the hospital's liver clinic, the longitudinal cytokine profiles between the HBsAg-losers and the control groups were compared. RESULTS Data revealed that plasma levels of IP-10 were significantly lower at 3-5 years prior to HBsAg seroclearance compared with patients who remained HBsAg positive (P < 0.05). Receiver operating characteristic curve analysis reveals that plasma IP-10 levels at multiple time points before HBsAg seroclearance return area under receivor-operating characteristic curve (AUC) greater than 0.7. Plasma IP-10 levels at 42.39 pg/mL produced an AUC = 0.723 with 74.0% sensitivity and 75.5% specificity to predict subsequent HBsAg seroclearance in the next 3-5 years. Low plasma IP-10 identified 91.4% patients with quantitative HBsAg < 100 IU/mL who would subsequently develop HBsAg seroclearance, compared with 37% with higher plasma IP-10 levels (P < 0.001). CONCLUSIONS Low plasma levels of IP-10 are associated with subsequent HBsAg seroclearance, suggesting potential clinical utilities of measurement of IP-10 in predicting HBsAg seroclearance, especially among patients with low HBsAg.
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Affiliation(s)
- Karin Kan
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Danny Ka-Ho Wong
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Wai Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
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Liaw YF. Perspectives on Outcome Prediction in Patients With Chronic Hepatitis B Virus Infection. GASTRO HEP ADVANCES 2023; 3:162-166. [PMID: 39129948 PMCID: PMC11307897 DOI: 10.1016/j.gastha.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 11/09/2023] [Indexed: 08/13/2024]
Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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Kim MN, Han K, Yoo J, Hwang SG, Zhang X, Ahn SH. Diabetic MAFLD is associated with increased risk of hepatocellular carcinoma and mortality in chronic viral hepatitis patients. Int J Cancer 2023; 153:1448-1458. [PMID: 37439276 DOI: 10.1002/ijc.34637] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 06/06/2023] [Accepted: 06/09/2023] [Indexed: 07/14/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) can coexist with chronic viral hepatitis. MAFLD is a heterogeneous disease because the diagnostic criteria include various metabolic traits. We aimed to identify patients at high risk of poor long-term outcomes based on MAFLD subgroups in chronic viral hepatitis patients. We evaluated 63 273 chronic hepatitis B and C patients. Patient with a fatty liver index ≥30 was defined to have hepatic steatosis. MAFLD was defined as the presence of hepatic steatosis with any one of the following three conditions, overweight/obesity, type 2 diabetes or ≥2 metabolic risk factors. The prevalence of MAFLD was 38.4% (n = 24 290). During a median 8.8-year follow-up, 1839 HCCs and 2258 deaths were documented in MAFLD patients. Among MAFLD patients, diabetes could identify patients at high risk of HCC and mortality, whereas overweight/obesity and metabolic risk factors did not. Compared with non-MAFLD patients, risk of HCC and mortality was significantly higher in diabetic MAFLD patients (adjusted hazard ratio [aHR] = 1.34, 95% confidence interval [CI] = 1.26-1.43 for HCC; aHR = 1.15, 95% CI = 1.08-1.22 for mortality). Risk of HCC and mortality was significantly higher in diabetic MAFLD patients (aHR = 1.40, 95% CI = 1.26-1.55 for HCC; aHR = 1.77, 95% CI = 1.63-1.93 for mortality) compared with non-diabetic MAFLD patients. Diabetic MAFLD is associated with increased risk of HCC and mortality among chronic viral hepatitis patients. Our findings highlight the need for close surveillance and effective treatment for these high-risk patients to reduce HCC and mortality in patients with chronic viral hepatitis.
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Affiliation(s)
- Mi Na Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Juhwan Yoo
- Department of Biomedicine & Health Science, The Catholic University of Korea, Seoul, South Korea
| | - Seong Gyu Hwang
- Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Xuehong Zhang
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
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Kan K, Wong DKH, Hui RWH, Seto WK, Yuen MF, Mak LY. Anti-HBc: a significant host predictor of spontaneous HBsAg seroclearance in chronic hepatitis B patients - a retrospective longitudinal study. BMC Gastroenterol 2023; 23:348. [PMID: 37803352 PMCID: PMC10557289 DOI: 10.1186/s12876-023-02983-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 09/28/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND AND AIM In chronic hepatitis B infection (CHB), seroclearance of hepatitis B surface antigen (HBsAg) is associated with favourable clinical outcomes compared to those with persistent HBsAg seropositivity, and thus considered as a desired treatment endpoint. This current study explores the possibility of serum antibody to hepatitis B core antigen (anti-HBc) as a potential predictive factor of HBsAg seroclearance. METHODS This is a retrospective study that analyzed the plasma samples of CHB patients using the LUMIPULSE® G1200 analyzer. The longitudinal anti-HBc level between patients who subsequently achieved HBsAg seroclearance (S-losers) and those with persistent HBsAg-positivity (controls) were compared at multiple time points before the event. RESULTS A total of 240 subjects (120 S-losers and 120 controls; age- and gender-matched) were included (mean age 56.42 ± 10.81, 65% male). Compared to controls, S-losers had significantly lower plasma anti-HBc levels prior to HBsAg seroclearance, with a significant trend of declining plasma anti-HBc 8-5 years prior to HBsAg seroclearance (p < 0.01), while such trend was not observed in controls. ROC curve analysis revealed that plasma anti-HBc at multiple time points before HBsAg seroclearance return AUC greater than 0.7. Plasma anti-HBc level at the cut-off value of 82.50 COI was 68.3% sensitive and 90% specific for HBsAg seroclearance within 1 year. Combining with quantitative HBsAg < 100 IU/mL, anti-HBc < 82.5 COI identified 88.2% patients who would develop HBsAg seroclearance within 1 year. CONCLUSION Plasma anti-HBc level began to decline 10 years prior to HBsAg seroclearance and can serve as a potential predictor for subsequent HBsAg seroclearance.
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Affiliation(s)
- Karin Kan
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Danny Ka-Ho Wong
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Wai Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China.
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China.
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
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Ning H, Li K, Peng Z, Jin H, Zhao H, Shang J. The efficacy and safety of pegylated interferon α-2b-based immunotherapy for inactive hepatitis B surface antigen carriers. Eur J Gastroenterol Hepatol 2023; 35:1216-1223. [PMID: 37577817 PMCID: PMC10756704 DOI: 10.1097/meg.0000000000002627] [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: 06/03/2023] [Accepted: 07/11/2023] [Indexed: 08/15/2023]
Abstract
OBJECTIVES Pegylated interferon α-2b (PegIFNα-2b) therapy can help inactive hepatitis B surface antigen (HBsAg) carriers (IHCs) achieve clinical cure. To explore and compare the efficacy, safety, and relevant influential factors of PegIFNα-2b monotherapy and PegIFNα-2b-based immunotherapy for IHCs. METHODS This exploratory, prospective, single-center, randomized controlled trial enrolled 40 IHCs who were randomized into group A (PegIFNα-2b treatment for 68 weeks) and group B (two cycles of PegIFNα-2b treatment with a lead-in period of GM-CSF and vaccine treatment before each cycle). The primary endpoint was 68-week HBsAg loss rate. RESULTS At week 68, the HBsAg loss rates were 45.45% [full analysis set (FAS)] and 46.67% [per-protocol set (PPS)]. There was no statistically significant difference in HBsAg loss rate between groups A and B ( P > 0.05). Univariate analysis revealed that age ≤40 years old, baseline HBsAg <200 IU/ml, and 24-week HBsAg decline ≥2 log 10 IU/ml were significantly associated with HBsAg loss in FAS population ( P < 0.05). Multivariate analysis showed that only 24-week HBsAg decline ≥2 log 10 IU/ml was the independent influencing factor in both FAS and PPS populations ( P < 0.05). The adverse events were common and mild, and the therapies were well-tolerated. CONCLUSION Treatment of IHCs with PegIFNα-2b-based therapy could result in a high HBsAg loss rate. The HBsAg loss rate of combined immunotherapy was similar to that of PegIFNα-2b monotherapy, and the safety was good. CLINICALTRIALSGOV ID NCT05451420.
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Affiliation(s)
- Huibin Ning
- Department of Infectious Diseases, Henan Provincial People’s Hospital, Zhengzhou
| | - Kuan Li
- Department of Infectious Diseases, Henan Provincial People’s Hospital, Zhengzhou
| | - Zhen Peng
- Department of Infectious Diseases, Henan Provincial People’s Hospital, Zhengzhou
| | - Huiming Jin
- Department of Infectious Diseases, Henan Provincial People’s Hospital, Zhengzhou
| | - Hong Zhao
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Jia Shang
- Department of Infectious Diseases, Henan Provincial People’s Hospital, Zhengzhou
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12
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Liaw YF. Impact of ALT Changes on the Risk of HCC in Hepatitis B-Compensated Cirrhotic Patients With Low Viremia. Am J Gastroenterol 2023; 118:1701. [PMID: 37646450 DOI: 10.14309/ajg.0000000000002261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Affiliation(s)
- Yun-Fan Liaw
- College of Medicine, Chang Gung University, Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan
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13
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Zongo SV, Djigma FW, Yonli AT, Sorgho PA, Nagalo BM, Traore L, Somda D, Amegnona LJ, Languie E, Some CCB, Sia LMJ, Sourabie IB, Sombie RA, Serme AK, Obiri-Yeboah D, Simpore J. Association of DRB1*11 and DRB1*12 alleles of the HLA system with the evolution of the Hepatitis B virus infection in Burkina Faso. Mol Biol Rep 2023; 50:5039-5047. [PMID: 37101005 DOI: 10.1007/s11033-023-08353-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 02/22/2023] [Indexed: 04/28/2023]
Abstract
BACKGROUND Hepatitis B Virus (HBV) infection affect all social strata of humanity and in the absence of any management, this infection has a different outcome from one infected person to another. This suggests that there are specific individual factors that influence the outcome of the pathology. Sex, immunogenetics and age of contraction of the virus have been cited as factors that influence the evolution of the pathology. In this study, we looked at two alleles of the Human Leucocyte Antigen (HLA) system to measure their possible involvement in the evolution of HBV infection. METHOD AND RESULTS We conducted a cohort study involving 144 individuals spread over 04 distinct stages of infection and then compared allelic frequencies in these populations. A multiplex PCR was conducted and the data obtained was analyzed using R and SPSS software. Our study revealed a predominance of HLA-DRB1*12 in our study population without, however, showing a significant difference between HLA-DRB1*11 and HLA-DRB1*12. The HLA-DRB1*12 proportion was significantly higher in chronic hepatitis B (CHB) and resolved hepatitis B (RHB) compared to cirrhosis and hepatocellular carcinoma (HCC) (p-value = 0,002). Carrying HLA-DRB1*12 has been associated with a low risk of complication of infection (CHB → cirrhosis; OR 0,33 p-value 0,017; RHB → HCC OR 0,13; p-value = 0,00,045) whereas the presence of HLA-DRB1*11 in the absence of HLA-DRB1*12 increased the risk of developing severe liver disease. However, a strong interaction of these alleles with the environment could modulate the infection. CONCLUSION Our study shown that HLA-DRB1*12 is the most frequent and it's carriage may be protective in the development of infection.
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Affiliation(s)
- Sidnooma Véronique Zongo
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Florencia Wendkuuni Djigma
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso.
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso.
| | - Albert Théophane Yonli
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Pegdwendé Abel Sorgho
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Bolni Marius Nagalo
- Division of Hematology and Oncology, Mayo Clinic, Arizona, 13400 E. Shea Blvd. , Scottsdale, AZ, 85259, USA
| | - Lassina Traore
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Dogfounianalo Somda
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Lanyo Jospin Amegnona
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Eugène Languie
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Couna Christiane Bere Some
- Centre Hospitalier Universitaire Yalgado Ouedraogo (CHU-YO), P.O. Box: 03 BP 7022, Ouagadougou 03, Burkina Faso
| | | | - Issa Boaffi Sourabie
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Roger Arsène Sombie
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Abdel Karim Serme
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Dorcas Obiri-Yeboah
- Department of Microbiology and Immunology, School of Medical Sciences, University of Cape Coast, PMB, Cape Coast, Cape Coast, Ghana
| | - Jacques Simpore
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
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Abstract
Hepatitis B virus (HBV) infection is a major public health problem, with an estimated 296 million people chronically infected and 820 000 deaths worldwide in 2019. Diagnosis of HBV infection requires serological testing for HBsAg and for acute infection additional testing for IgM hepatitis B core antibody (IgM anti-HBc, for the window period when neither HBsAg nor anti-HBs is detected). Assessment of HBV replication status to guide treatment decisions involves testing for HBV DNA, whereas assessment of liver disease activity and staging is mainly based on aminotransferases, platelet count, and elastography. Universal infant immunisation, including birth dose vaccination is the most effective means to prevent chronic HBV infection. Two vaccines with improved immunogenicity have recently been approved for adults in the USA and EU, with availability expected to expand. Current therapies, pegylated interferon, and nucleos(t)ide analogues can prevent development of cirrhosis and hepatocellular carcinoma, but do not eradicate the virus and rarely clear HBsAg. Treatment is recommended for patients with cirrhosis or with high HBV DNA levels and active or advanced liver disease. New antiviral and immunomodulatory therapies aiming to achieve functional cure (ie, clearance of HBsAg) are in clinical development. Improved vaccination coverage, increased screening, diagnosis and linkage to care, development of curative therapies, and removal of stigma are important in achieving WHO's goal of eliminating HBV infection by 2030.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - George V Papatheodoridis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
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15
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Positive hepatitis B core antibody is associated with advanced fibrosis and mortality in nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2023; 35:294-301. [PMID: 36708301 DOI: 10.1097/meg.0000000000002488] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVE Concomitant hepatitis B virus infection and nonalcoholic fatty liver disease (NAFLD) are relatively common, while little is known about the impact of anti-hepatitis B core antibody (anti-HBc) on NAFLD individuals. We aimed to investigate the association of positive anti-HBc with advanced fibrosis and mortality in NAFLD. METHODS We analyzed data from 3268 NAFLD participants who underwent abdominal ultrasonography during the Third National Health and Nutrition Examination Survey (NHANES III). The fibrosis 4 index (FIB-4) score >2.67, NAFLD fibrosis score >0.676, or aspartate aminotransferase to platelet ratio index >1.5 were defined as advanced fibrosis. All-cause and cause-specific mortality were obtained from the NHANES III-linked follow-up file through 31 December 2015. RESULTS A total of 242 (7.4%) patients had positive anti-HBc. Patients with positive anti-HBc had a higher percentage of advanced fibrosis than those with negative anti-HBc (12.2% vs. 5.8%). Positive anti-HBc was significantly associated with advanced fibrosis [adjusted odds ratio = 1.69, 95% confidence interval (CI), 1.05-2.72]. During a median follow-up of 22 years, the cumulative all-cause and cancer-related mortalities were higher in participants with positive anti-HBc than in their counterparts (log-rank test P < 0.001). When demographic and metabolic risk factors were considered, NAFLD cases with positive anti-HBc had a significantly higher cancer-related mortality (adjusted hazard ratio = 1.54, 95% CI, 1.05-2.25). CONCLUSION Our findings suggested that NAFLD cases with positive anti-HBc had higher risks for liver fibrosis and long-term mortality, justifying the medical importance of testing anti-HBc in NAFLD patients.
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16
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Zhang W, Xing M, Sun W, Chen J, Xie N, Cai Y, Wang Y, Li N, Jiang Y, Zhang F, Wang Y, Zeng Q, Ji Y, Xu C, Jiang C, Song J, Li G. Early clinical efficacy of pegylated interferon treatment in patients with different phases of chronic HBV infection: A real-world analysis. J Viral Hepat 2022; 30:427-436. [PMID: 36562258 DOI: 10.1111/jvh.13792] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022]
Abstract
Although there are therapeutic advantages for hepatitis B virus (HBV) withpegylated interferon alpha (peg-IFNα) treatment compared with nucleos(t)ide analog (NAs) therapy, the effect difference in infected population at different phases has not been well established. We studied the clinical efficacy of peg-IFNα in two populations with HBV infection, including inactive HBsAg carrier (IHC) and chronic hepatitis B (CHB). A total of 328 HBV-infected patients were included in this real-world analysis. Patients were divided into two groups according to the infected stages. Peg-IFNα monotherapy or combination therapy with NAs were used in IHCs, and peg-IFNα added-on NAs therapy was applied to patients with CHB. The primary efficacy endpoint was HBsAg loss at Week 24. Results: The Kaplan-Meier cumulative rates of HBsAg loss were 39.50% (n = 47/119) in IHC group and 28.71% (n = 60/209) in CHB group at Week 24 (p < .05). After Propensity Score Matching (PSM), the HBsAg loss rates were 36.84% (n = 35/95) and 32.63% (n = 31/95), respectively (p > .05). Patients with baseline HBsAg level < 100 IU/ml achieved higher rates of HBsAg clearance in IHC and CHB group (before PSM: 47.44% vs. 42.86%, after PSM: 49.12% vs. 45.83%, all p values > .05). Baseline HBsAg level and its level decline from baseline to Week 12 can be as the predictors for HBsAg loss at Week 24 in both groups. Hence, the efficacy of HBsAg clearance was broadly similar between IHCs and NA-treated CHB patients during the early peg-IFNα therapy. A significant downward trend of HBsAg level was observed in both groups during peg-IFNα therapy.
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Affiliation(s)
- Wencong Zhang
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mingyou Xing
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjin Sun
- Department of Infectious Diseases, Ezhou Central Hospital, Ezhou, China
| | - Jia Chen
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nana Xie
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Cai
- Department of Liver Diseases, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, China
| | - Ying Wang
- Department of Liver Diseases, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, China
| | - Niuniu Li
- Department of Liver Diseases, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, China
| | - Yujin Jiang
- Department of Liver Diseases, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, China
| | - Fan Zhang
- Department of Liver Diseases, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, China
| | - Yanfeng Wang
- Department of Liver Diseases, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, China
| | - Qingjin Zeng
- Department of Liver Diseases, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, China
| | - Yanhua Ji
- Department of Liver Diseases, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, China
| | - Cheng Xu
- Department of Liver Diseases, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, China
| | - Chunmei Jiang
- Department of Infectious Diseases, The People's Hospital of Longhua, Shenzhen, China
| | - Jianxin Song
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guojun Li
- Department of Liver Diseases, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, China
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17
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Liaw YF. Perspectives on current controversial issues in the management of chronic HBV infection. J Gastroenterol 2022; 57:828-837. [PMID: 36053366 DOI: 10.1007/s00535-022-01918-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/18/2022] [Indexed: 02/04/2023]
Abstract
Clinical and basic research in the past decades has achieved consensus in the understanding of chronic hepatitis B virus (HBV) infection and the management of chronic hepatitis B and HBV-cirrhosis. However, debatable challenges to the existing consensus in the concept and/or definitions have emerged. These include (1). alanine aminotransferase upper limit of normal: traditional laboratory-defined vs fixed; (2). nomenclature for phases of chronic HBV infection: classical vs EASL proposal; (3). indication of antiviral therapy: to treat patients vs to treat HBV; (4). finite vs indefinite long-term antiviral therapy: A. finite therapy in HBV-cirrhosis; B. retreatment decision: biochemical markers vs HBsAg/ALT kinetics. The pros and cons of these controversial issues were reviewed, assessed, and discussed in depth based on relevant lines of scientific evidence, intended to clarify or solve these controversial issues.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199, Tung Hwa North Road, Taipei, 105, Taiwan.
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18
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Yang M, Wei L. Impact of NAFLD on the outcome of patients with chronic hepatitis B in Asia. Liver Int 2022; 42:1981-1990. [PMID: 35373500 DOI: 10.1111/liv.15252] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 03/01/2022] [Accepted: 03/18/2022] [Indexed: 01/29/2023]
Abstract
Hepatitis B virus (HBV) infection and nonalcoholic fatty liver disease (NAFLD) are two major causes of chronic liver disease (CLD) that can cause liver cirrhosis and hepatocellular carcinoma (HCC). It is a trend to superimpose NAFLD on chronic HBV infection in Asia. This review presents the epidemiology of concurrent NAFLD in chronic hepatitis B (CHB) patients and focuses on the impact of concurrent NAFLD on the outcome of CHB patients in Asia. Although CHB patients tend to have a lower prevalence and incidence of NAFLD than the general population, concurrent NAFLD among CHB patients is still common and has an upward trend over time. Concurrent NAFLD can promote hepatitis B surface antigen (HBsAg) seroclearance and might inhibit HBV replication but exacerbate liver fibrosis. The impacts of concurrent NAFLD on HCC risk, all-cause mortality and antiviral treatment response in CHB patients remain controversial.
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Affiliation(s)
- Ming Yang
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
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19
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Clinical impact and mechanisms of hepatitis B virus infection concurrent with non-alcoholic fatty liver disease. Chin Med J (Engl) 2022; 135:1653-1663. [PMID: 35940901 PMCID: PMC9509100 DOI: 10.1097/cm9.0000000000002310] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
ABSTRACT Chronic hepatitis B (CHB) virus infection is an important threat to global health despite the administration of vaccines and the use of antiviral treatments. In recent years, as the prevalence of obesity and metabolic syndrome has increased, non-alcoholic fatty liver disease (NAFLD) in patients with CHB has become more common. Both diseases can lead to liver fibrosis and even hepatocellular carcinoma, but the risk of dual etiology, outcome, and CHB combined with NAFLD is not fully elucidated. In this review, we assess the overlapping prevalence of NAFLD and CHB, summarize recent studies of clinical and basic research related to potential interactions, and evaluate the progressive changes of treatments for CHB patients with NAFLD. This review increases the understanding of the relationship and mechanisms of interaction between steatosis and hepatitis B virus infection, and it provides new strategies for the future clinical management and treatment of CHB combined with NAFLD.
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20
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Feng M, Lei L, Xu J, Shi Y, Yang W. Platelet-to-Portal Vein Width Ratio and Platelet-to-Spleen Thickness Ratio Can Be Used to Predict Progressive Liver Fibrosis Among Patients With HBV Infection With HBeAg-Negativity and a Normal ALT Level. Front Med (Lausanne) 2022; 9:837898. [PMID: 35801214 PMCID: PMC9253570 DOI: 10.3389/fmed.2022.837898] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 05/25/2022] [Indexed: 11/13/2022] Open
Abstract
Background Some people infected with the hepatitis B virus (HBV) with a normal level of alanine aminotransferase (ALT) are at risk of disease progression. We evaluated the value of platelet-to-portal vein width ratio (PPR) and platelet-to-spleen thickness ratio (PSR) to predict progressive liver fibrosis among patients with HBV infection with HBV e antigen (HBeAg)-negativity and a normal ALT level. Methods HBV surface antigen (HBsAg)-positive and HBeAg-negative individuals with a normal ALT level were enrolled. The inflammation grade (G) and fibrosis stage(S) were analyzed according to pathological features. Then, two groups (<S2 vs. ≥S2) among people with a normal ALT level were divided based on the pathological diagnosis, and the clinical characteristics were summarized. Results Seventy-three individuals among 142 patients with HBsAg-positivity and HBeAg-negativity had a normal ALT level. Also, 83.56% (61/73) individuals showed progressive liver fibrosis (≥S2). The ALT level and aspartate aminotransferase (AST) between the two groups differed (21.01 ± 7.40 vs. 25.37 ± 7.90 U/L, p = 0.08; 29.49 ± 13.56 vs. 30.16 ± 21.88 U/L, p = 0.92, respectively). Portal-vein width, serum levels of albumin and globulin, AST-to-Platelet Ratio Index (APRI), and Fibrosis 4 (FIB-4) score were not significantly different between the two groups (p > 0.05). The platelet count, PPR, and PSR were significantly different between the two groups [(145.92 ± 14.55) ×109/L vs. (126.38 ± 23.85) ×109/L, p = 0.008; 10.80 ± 1.30 vs. 9.01 ± 1.97, p = 0.004; 4.21 ± 0.65 vs. 3.33 ± 0.89, p = 0.02, respectively]. The PPR and PSR decreased gradually upon fibrosis aggravation (p < 0.05). Based on the cut off value of the PPR (9.07) and PSR (3.54), their sensitivity and specificity was 0.917 and 0.525, and 0.833 and 0.541, respectively. Conclusion The PPR and PSR can be employed to assess earlier fibrosis progression among patients with HBV infection with HBeAg-negativity and a normal ALT level.
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Affiliation(s)
- Mudan Feng
- Department of Infectious Disease, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Department of Hepatology and Translation Medicine, Fuling Center Hospital of Chongqing City, Chongqing, China
| | - Lan Lei
- Department of Hepatology and Translation Medicine, Fuling Center Hospital of Chongqing City, Chongqing, China
| | - Jian Xu
- Department of Infectious Disease, The People's Hospital of Yubei District of Chongqing City, Chongqing, China
- *Correspondence: Jian Xu
| | - Yuzhi Shi
- Department of Infectious Disease, The People's Hospital of Yubei District of Chongqing City, Chongqing, China
| | - Wenfeng Yang
- Department of Infectious Disease, The People's Hospital of Yubei District of Chongqing City, Chongqing, China
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21
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Choi HS, Tonthat A, Janssen HL, Terrault NA. Aiming for Functional Cure With Established and Novel Therapies for Chronic Hepatitis B. Hepatol Commun 2022; 6:935-949. [PMID: 34894108 PMCID: PMC9035586 DOI: 10.1002/hep4.1875] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/11/2021] [Accepted: 11/18/2021] [Indexed: 12/22/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains difficult to cure due to the persistent, self-replenishing nature of the viral genome and impaired host immune responses. Current treatment goals for chronic hepatitis B (CHB) are to prevent or significantly delay liver-related adverse outcomes and death, and two types of treatments are available: nucleos(t)ide analogues (NAs) and interferons (IFNs). NAs effectively suppress HBV replication, and IFNs improve serological response rates, thereby decreasing the risk of adverse outcomes. However, their efficacy in attaining serological responses, especially functional cure (i.e., loss of serum hepatitis B surface antigen), is very limited. Various strategies such as stopping antiviral therapy or combining therapies have been investigated to enhance response, but efficacy is only modestly improved. Importantly, the development of novel direct-acting antivirals and immunomodulators is underway to improve treatment efficacy and enhance rates of functional cure. The present review provides an overview of the treatment goals and indications, the possibility of expanding indications, and the safety and efficacy of different treatment strategies involving established and/or novel therapies as we continue our search for a cure.
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Affiliation(s)
- Hannah S.J. Choi
- Toronto Center for Liver DiseaseToronto General HospitalTorontoONCanada
| | - Alexander Tonthat
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
| | | | - Norah A. Terrault
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
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22
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Zhou YG, Tian N, Xie WN. Total cholesterol to high-density lipoprotein ratio and nonalcoholic fatty liver disease in a population with chronic hepatitis B. World J Hepatol 2022; 14:791-801. [PMID: 35646261 PMCID: PMC9099113 DOI: 10.4254/wjh.v14.i4.791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/13/2021] [Accepted: 04/03/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is characterized by hypertriglyceridemia, increased low-density lipoprotein cholesterol levels, and reduced high-density lipoprotein cholesterol (HDL-C) particles. Previous studies have shown that the total cholesterol to high-density lipoprotein cholesterol ratio (TC/HDL-C) was superior to other lipid metabolism biomarkers for predicting NAFLD risk and could be a new indicator of NAFLD. However, the association between TC/HDL-C and NAFLD in patients with hepatitis B virus (HBV) has not yet been determined. AIM To investigate the association between TC/HDL-C and NAFLD in a population with chronic hepatitis B (CHB). METHODS In this study, 183 HBV-infected patients were enrolled. All participants underwent blood chemistry examinations and abdominal ultrasound. Univariate and multivariate logistic regression models, curve fitting analysis, and threshold calculation were used to assess the relationship between TC/HDL-C and NAFLD. RESULTS The overall prevalence of NAFLD was 17.49% (n = 32) in the 183 CHB participants. The TC/HDL-C of non-NAFLD and NAFLD patients were 3.83 ± 0.75 and 4.44 ± 0.77, respectively (P < 0.01). Logistic regression analysis showed that TC/HDL-C was not associated with NAFLD after adjusting for other pertinent clinical variables. However, at an optimal cutoff point of 4.9, a non-linear correlation between TC/HDL-C and NAFLD was detected. The effect size of the left and right sides of the inflection point were 5.4 (95% confidence interval: 2.3-12.6, P < 0.01) and 0.5 (95% confidence interval: 0.1-2.2, P = 0.39), respectively. On the left side of the inflection point, TC/HDL-C was positively associated with NAFLD. However, no significant association was observed on the right side of the inflection point. CONCLUSION This study demonstrated a non-linear correlation between TC/HDL-C and NAFLD in a population with CHB. TC/HDL-C was positively associated with NAFLD when TC/HDL-C was less than 4.9 but not when TC/HDL-C was more than 4.9.
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Affiliation(s)
- Yu-Ge Zhou
- Affiliated Guangdong Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Foshan 528200, Guangdong Province, China
| | - Ning Tian
- Preventive Healthcare Center, Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Foshan 528200, Guangdong Province, China
| | - Wei-Ning Xie
- Department of Scientific Research, Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Foshan 528200, Guangdong Province, China.
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Wirth S. Chronic Viral Hepatitis B and C. TEXTBOOK OF PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY AND NUTRITION 2022:833-842. [DOI: 10.1007/978-3-030-80068-0_63] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Jeng WJ, Lok AS. Should Treatment Indications for Chronic Hepatitis B Be Expanded? Clin Gastroenterol Hepatol 2021; 19:2006-2014. [PMID: 32434068 DOI: 10.1016/j.cgh.2020.04.091] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/20/2020] [Accepted: 04/24/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIM Antiviral therapy has greatly improved the outcomes of patients with chronic hepatitis B virus (HBV) infection and active liver disease or advanced fibrosis/cirrhosis. However, current treatment does not eradicate HBV and long-term treatment is needed in most patients to maintain clinical benefit. Thus, professional society guidelines do not recommend treatment of all patients with chronic HBV infection. This review article will examine evidence for and against expansion of treatment to patients in whom treatment is not recommended based on current guidelines. RESULTS Available data support expanding treatment to immune tolerant patients and patients in the grey zones who have evidence of active/advanced liver disease based on liver biopsy or non-invasive tests and those who remain in the immune tolerant phase after age 40. Evidence supporting treatment expansion to confirmed inactive carriers and other immune tolerant patients is lacking. CONCLUSIONS HBV treatment indications can be more liberal when new therapies that can achieve HBsAg loss safely in a high percentage of patients after a finite course of treatment are available.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taiwan; Chang Gung University College of Medicine, Taiwan
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.
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Wu F, Lu R, Liu Y, Wang Y, Tian Y, Li Y, Li M, Wang W, Zhang X, Jia X, Dang S. Efficacy and safety of peginterferon alpha monotherapy in Chinese inactive chronic hepatitis B virus carriers. Liver Int 2021; 41:2032-2045. [PMID: 33896094 DOI: 10.1111/liv.14897] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 02/27/2021] [Accepted: 03/31/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The effectiveness and safety of peginterferon alpha (peg-IFN-α) monotherapy in inactive hepatitis B virus (HBV) carriers (IHCs) have not been fully evaluated. METHODS This observational study prospectively enrolled 298 IHCs in China from 2015 to 2019. Participants were given the right to choose to either receive peg-IFN-α monotherapy (treatment group, n = 142) or be monitored without treatment (control group, n = 156) according to their wishes. The scheduled treatment duration was 48 weeks. All participants were followed up to 72 weeks. The main efficacy endpoint was hepatitis B surface antigen (HBsAg) clearance at 72 weeks. RESULTS Baseline characteristics were similar between both groups. At 72 weeks, intention-to-treat analysis showed that the rates of HBsAg clearance and seroconversion of the treatment group were 47.9% (68/142) and 36.6% (52/142), respectively, which were significantly higher than the HBsAg clearance rate of 1.9% (3/156) and the seroconversion rate of 0.6% (1/156) in the control group (both P < .001). Baseline HBV DNA < 20 IU/mL, lower HBsAg levels at baseline, 12 and 24 weeks, alanine aminotransferase elevation at 12 weeks, and greater HBsAg reduction from baseline to 12 and 24 weeks were independent predictors of HBsAg clearance. Generally, the therapy was well tolerated. Only five participants discontinued therapy as a result of peg-IFNα-related adverse events. CONCLUSIONS Peg-IFN-α monotherapy results in high rates of HBsAg clearance and seroconversion and the treatment is safe for IHCs.
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Affiliation(s)
- Fengping Wu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Rui Lu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yixin Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yikai Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yan Tian
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yaping Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mei Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wenjun Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xin Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaoli Jia
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuangsuo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Stalla F, Armandi A, Marinoni C, Fagoonee S, Pellicano R, Caviglia GP. Chronic hepatitis B virus infection and fibrosis: novel non-invasive approaches for diagnosis and risk stratification. Minerva Gastroenterol (Torino) 2021; 68:306-318. [PMID: 33871225 DOI: 10.23736/s2724-5985.21.02911-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Despite the availability of an effective vaccination, chronic hepatitis B virus (HBV) infection is still a major health concern worldwide. Chronic HBV infection can lead to fibrosis accumulation and overtime to cirrhosis, the principal risk factor for liver failure and hepatocellular carcinoma development. Liver biopsy is still considered the gold standard for fibrosis assessment, even though it is invasive and not exempt of complications. Overtime, several non-invasive methods for the detection of liver fibrosis have been developed and gradually introduced into clinical practice. However, their main limitation is the poor performance for the detection of intermediate stages of fibrosis. Finally, novel serological biomarkers, polygenic risk scores and imaging methods have been proposed in last years as novel promising tools to correctly identify the degree of liver fibrosis and to monitor liver disease progression. In this narrative review, we provide an overview on the novel non-invasive approaches for the evaluation of liver fibrosis and risk stratification of patients with chronic hepatitis B.
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Affiliation(s)
- Francesco Stalla
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Angelo Armandi
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Chiara Marinoni
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, National Research Council, Molecular Biotechnology Center, Torino, Italy
| | - Rinaldo Pellicano
- Division of Gastroenterology, Molinette Hospital - Città della Salute e della Scienza di Torino, Turin, Italy
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Abstract
Chronic hepatitis B (CHB) remains a global healthcare burden. Although the recent developments in the field have led to a reduction in incidence, the morbidity and mortality including liver cirrhosis and hepatocellular carcinoma (HCC) remain a formidable challenge. Advances in understanding the immunopathogenesis of CHB have led to a recent change in clinical categorization. EASL introduced the term hepatitis B 'e' antigen (HBeAg)-negative chronic infection, to replace the historical term 'inactive carrier' disease phase, the commonest CHB phase. Although this disease phase is associated with a favorable prognosis, it is not a truly 'inactive' disease phase with no ostensible liver disease, as inferred by the previous anachronistic terminology, and the risk of spontaneous reactivation and the potential risk of disease progression and HCC development are not negligible. Likewise, the APASL also uses the term "Incidentally Detected Asymptomatic Hepatitis B surface antigen (HBsAg)-positive Subject (IDAHS)", comprising all HBsAg-positive subjects who are incidentally detected during routine tests, without any previous or present symptoms of liver disease. This entity includes HBV infection with varied stages of liver disease. Antiviral treatment is generally reserved for patients with active inflammation and/or at risk of disease progression and HCC development. HBsAg loss is considered an optimal treatment endpoint, and may also be achievable in HBeAg-negative chronic infection and IDAHS. In light of this, and the emerging novel HBV therapies, lowering the treatment threshold and a 'Treat All' approach should now be considered. In this review, we summarize the literature and guidance on HBeAg-negative chronic infection, and we make a concerted effort to present the reasons why the one-dimensional term 'inactive carrier' should be abandoned.
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Zhao Q, Liu K, Zhu X, Yan L, Ding Y, Xu Y, Lou S, Zhao G, Xie Q, Gao Y, Bao S, Wang H. Anti-viral effect in chronic hepatitis B patients with normal or mildly elevated alanine aminotransferase. Antiviral Res 2020; 184:104953. [PMID: 33065138 DOI: 10.1016/j.antiviral.2020.104953] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 10/02/2020] [Accepted: 10/08/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Normal/mildly elevated ALT (<2 × ULN) CHB patients are potentially at risk of progression to cirrhosis and/or hepatocellular carcinoma (HCC). We aimed to assess the outcomes of anti-viral therapy for normal/mild elevation of ALT CHB patients. METHODS CHB patients (n = 432) who have had liver biopsied were determined. It was determined that the outcomes of anti-viral therapy in CHB patients with normal/mild elevation of ALT, in response to nucleoside/nucleotide analogues (NAs) (n = 190) and pegylated interferon (PEG-IFN) (n = 30) treatment for up to 72 weeks. Non-anti-viral treated patients were used as control (n = 40). RESULTS There was about 50% of the CHB patients showed hepatic inflammatory necrosis ≥ G2 and/or fibrosis ≥ S2 among >30-years-old. The rate of undetectable HBV DNA in NAs and PEG-IFN groups was ~50%, ~80% or ~90% at week 24, 48 or 72, respectively. HBeAg clearance rate was lower in NAs treated than that in PEG-IFN group at week 48 (6% vs 20%, P < 0.05). ALT normalization rate was increased by 1.18-fold at week 72. HBsAg decline in HBeAg+ patients treated with NAs or PEG-IFN was 0.418 or 1.217 log IU/mL (P < 0.0001) at week 48; whereas HBsAg decline was 0.176 or 0.816 log IU/mL (P < 0.001) in HBeAg- patients. HBsAg at baseline and week 24 were strong predictors of "low HBsAg at week 48". CONCLUSION Long term anti-viral therapy inhibits HBV replication effectively in ALT<2 × ULN CHB patients. PEG-IFN therapy is recommended for HBeAg+ patients with baseline HBsAg<4.37 log IU/ml and HBeAg- patients with baseline HBsAg<2.66 log IU/ml to achieve "low HBsAg at week 48".
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Affiliation(s)
- Qingqing Zhao
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Kehui Liu
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Department of Infectious Diseases, Ruijin North Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201801, China
| | - Xiaojun Zhu
- Department of Hepatopathy, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lei Yan
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yezhou Ding
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yumin Xu
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Shike Lou
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Gangde Zhao
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yueqiu Gao
- Department of Hepatopathy, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Shisan Bao
- Discipline of Pathology, School of Medical Sciences, Charles Perkin Centre, Faculty of Medicine and Health, the University of Sydney, Sydney, Australia.
| | - Hui Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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Seo SI, Kim HS, Yang BK, Kang JG, Shin WG, Lee JH, Kim HY, Jang MK. Predictive factors for risk of hepatocellular carcinoma in immune inactive chronic hepatitis B. Clin Res Hepatol Gastroenterol 2020; 44:711-717. [PMID: 31959567 DOI: 10.1016/j.clinre.2019.10.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 10/01/2019] [Accepted: 10/12/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS The risk factors for hepatocellular carcinoma (HCC) in immune inactive chronic hepatitis B (CHB) have not been clarified. The aim of this study was to investigate the predictive factors for HCC inimmune inactive CHB. METHODS A total of 337 patients in immune inactive CHB were consecutively enrolled in Kangdong Sacred Heart Hospital from 1995 to 2017. Univariate and multivariate analyses were performed to identify the independent risk factors for HCC development. RESULTS During the mean 63 months of follow-up, the incidence of HCC of study population was 4.5% (15/337). Patients who developed HCC were older, had more cirrhosis at baseline, and were more likely to experience ALT elevation>2 X upper limit of normal (ULN) during follow-up than those without HCC. In Cox regression analysis, increased ALT levels>2 X ULN during follow-up (hazard ratio [HR], 3.774; 95% confidence interval [CI], 1.145-12.443; P=0.029] and presence of cirrhosis (HR, 11.768; 95% CI, 3.350-41.336; P<0.001) were identified as the independent factors for HCC in immune inactive CHB. With increasing number of risk factors, the respective cumulative incidence of HCC at 10 years was 6.3%, 8.8%, and 63.5%. CONCLUSIONS Underlying cirrhosis and hepatic inflammation reflected by increased ALT levels>2 X ULN were significant predictors for HCC in immune inactive CHB. ALT elevation showed a synergistic effect in HCC development combined with cirrhosis. It suggests that patients with high serum ALT levels, especially those with cirrhosis, are required closer surveillance for HCC even in immune inactive CHB.
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Affiliation(s)
- Seung In Seo
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 150, Sungnae-gil, Kangdong-gu, Seoul, Republic of Korea 134-701
| | - Hyoung Su Kim
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 150, Sungnae-gil, Kangdong-gu, Seoul, Republic of Korea 134-701.
| | - Bo Kyung Yang
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 150, Sungnae-gil, Kangdong-gu, Seoul, Republic of Korea 134-701
| | - Jin Gu Kang
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 150, Sungnae-gil, Kangdong-gu, Seoul, Republic of Korea 134-701
| | - Woon Geon Shin
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 150, Sungnae-gil, Kangdong-gu, Seoul, Republic of Korea 134-701
| | - Jin Heon Lee
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 150, Sungnae-gil, Kangdong-gu, Seoul, Republic of Korea 134-701
| | - Hak Yang Kim
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 150, Sungnae-gil, Kangdong-gu, Seoul, Republic of Korea 134-701
| | - Myoung Kuk Jang
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 150, Sungnae-gil, Kangdong-gu, Seoul, Republic of Korea 134-701
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Japan Society of Hepatology Guidelines for the Management of Hepatitis B Virus Infection: 2019 update. Hepatol Res 2020; 50:892-923. [PMID: 32343469 DOI: 10.1111/hepr.13504] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/16/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023]
Abstract
The Drafting Committee for Hepatitis Management Guidelines established by the Japan Society of Hepatology published the first version of the Guidelines for the Management of Hepatitis B in 2013 (first English version in 2014), and has since been publishing updates to the Guidelines as new drugs become available, with the latest original Japanese version being Version 3.1. Herein, the Drafting Committee publishes the second English version that contains all the changes made since the first English version of the guidelines was published in 2014. This 2019 version covers: (i) the nucleos(t)ide analogs, tenofovir disoproxil fumarate and tenofovir alafenamide; (ii) updates to treatment recommendations and management of drug-resistant hepatitis B virus that reflect the new availability of these drugs; and (iii) new information about hepatitis B virus reactivation with each update. This latest update also contains information about treatment goals, indications for treatment and cessation of nucleos(t)ide analog therapy, most of which were covered by the first version.
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Chang ML, Cheng JS, Chien RN, Liaw YF. Hepatitis Flares Are Associated With Better Outcomes Than No Flare in Patients With Decompensated Cirrhosis and Chronic Hepatitis B Virus Infection. Clin Gastroenterol Hepatol 2020; 18:2064-2072.e2. [PMID: 31982607 DOI: 10.1016/j.cgh.2020.01.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 12/27/2019] [Accepted: 01/11/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Little is known about the effects of baseline hepatitis flares (level of alanine aminotransferase ≥5-fold above the upper limit of normal) on the outcomes of patients with chronic hepatitis B virus (HBV) infection with decompensated cirrhosis treated with nucleos(t)ide analogues. We aimed to investigate these effects. METHODS We performed a cohort study of 511 consecutive patients (78.1% men; 58.7% with flares at baseline) with chronic HBV infection and decompensated cirrhosis who were treated with nucleos(t)ide analogues as soon as decompensation was noted. Patients were enrolled from January 2002 to March 2018 at a tertiary care center in Taiwan and followed up for 16 years. RESULTS Patients with hepatitis flares had higher mean baseline levels of HBV DNA (6.44 ± 1.52 vs 6.08 ± 1.46 log10 IU/mL; P = .003), hepatitis B surface antigen, and total bilirubin; prolonged prothrombin time; higher platelet counts (108.0 ± 42.9 vs 83.6 ± 44.7 103/μL; P < .001); and a higher proportion were infected with HBV genotype B, compared with patients without flares. Patients with flares had lower ratios of neutrophils to lymphocytes than patients with flares (6.14 ± 9.18 vs 9.12 ± 1.36; P = .019); were less likely than patients without flares to be positive for hepatitis B e antigen, ascites, esophageal varices, or splenomegaly; and a lower proportion died or underwent liver transplantation (46.5% vs 73.2% of patients without flares; P < .001), even though the patients without flares had similar short-term (<3 mo) outcomes. Factors associated independently with baseline flares were esophageal varices (odds ratio [OR], 0.165; 95% CI, 0.067-0.406), ascites (OR, 0.415; 95% CI, 0.178-0.969), levels of total bilirubin (OR, 1.158; 95% CI, 1.041-1.269), prolonged prothrombin time (OR, 1.095; 95% CI, 1.033-1.168), and higher platelet counts (OR, 1.009; 95% CI, 1.00-1.018). After we used propensity score matching to match patients with and without baseline flares, factors associated with the cumulative incidence of death or liver transplantation were flares (hazard ratio [HR], 0.491; 95% CI, 0.317-0.76), ratio of neutrophils to lymphocytes (HR, 1.278; 95% CI, 1.027-1.591), and prolonged prothrombin time (HR, 1.223; 95% CI, 1.052-1.423). CONCLUSIONS In a 16-year study of patients with chronic HBV infection and decompensated cirrhosis treated with nucleos(t)ide analogues, a baseline flare of hepatitis was associated independently with better long-term (≥3 mo) outcomes than no flare.
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Affiliation(s)
- Ming-Ling Chang
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Taoyuan, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - Jur-Shan Cheng
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Emergency Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Taoyuan, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Taoyuan, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Schwabe RF, Tabas I, Pajvani UB. Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis. Gastroenterology 2020; 158:1913-1928. [PMID: 32044315 PMCID: PMC7682538 DOI: 10.1053/j.gastro.2019.11.311] [Citation(s) in RCA: 402] [Impact Index Per Article: 80.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 11/18/2019] [Accepted: 11/20/2019] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease is the most prevalent liver disease worldwide, affecting 20%-25% of the adult population. In 25% of patients, nonalcoholic fatty liver disease progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of cirrhosis, liver failure, and hepatocellular carcinoma. In patients with NASH, liver fibrosis is the main determinant of mortality. Here, we review how interactions between different liver cells culminate in fibrosis development in NASH, focusing on triggers and consequences of hepatocyte-macrophage-hepatic stellate cell (HSC) crosstalk. We discuss pathways through which stressed and dead hepatocytes instigate the profibrogenic crosstalk with HSC and macrophages, including the reactivation of developmental pathways such as TAZ, Notch, and hedgehog; how clearance of dead cells in NASH via efferocytosis may affect inflammation and fibrogenesis; and insights into HSC and macrophage heterogeneity revealed by single-cell RNA sequencing. Finally, we summarize options to therapeutically interrupt this profibrogenic hepatocyte-macrophage-HSC network in NASH.
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Affiliation(s)
- Robert F Schwabe
- Department of Medicine, Columbia University, New York, New York; Institute of Human Nutrition, Columbia University, New York, New York.
| | - Ira Tabas
- Department of Medicine, Columbia University, New York, New York; Institute of Human Nutrition, Columbia University, New York, New York; Department of Physiology and Cellular Biophysics, Columbia University, New York, New York
| | - Utpal B Pajvani
- Department of Medicine, Columbia University, New York, New York; Institute of Human Nutrition, Columbia University, New York, New York
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Cho JY, Jeong JY, Sohn W. Risk of metabolic syndrome in participants within the normal range of alanine aminotransferase: A population-based nationwide study. PLoS One 2020; 15:e0231485. [PMID: 32267895 PMCID: PMC7141677 DOI: 10.1371/journal.pone.0231485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/24/2020] [Indexed: 11/18/2022] Open
Abstract
This study aimed to investigate the risk of metabolic syndrome (MS) in participants whose alanine aminotransferase (ALT) levels were within the normal range in the general population. A cross-sectional study was conducted using nationally representative samples from the Korea National Health and Nutrition Examination Survey 2007-2015. A total of 43,402 adults (men, 17,535; women, 25,867) with ALT ≤40 U/L without a history of hepatitis B and C, liver cirrhosis, or liver cancer were analyzed. The risk of MS was evaluated according to the ALT level. The prevalence of MS significantly increased as the ALT levels increased. The proportions of MS in men were 12.6%, 25.2%, and 39.7% in the ALT levels of <15, 15~30, and 30~40 U/L, respectively (p < 0.001), and those of women were 7.2%, 23.3%, and 44.7% in the ALT levels of <10, 10~20, and 20~40 U/L, respectively (p < 0.001). There was an ALT-dependent relationship in the risk of MS in participants with normal ALT level after adjustment for age, alcohol intake, and body mass index. The adjusted odds ratio (aOR) of MS in men was 2.48 (95% confidence interval [CI], 2.16-2.85) in an ALT level of 30~40 U/L compared with that in ALT <15 U/L (p < 0.001), and the aOR of MS in women was 2.67 (95% CI, 2.26-3.15) in an ALT level of 20~40 U/L compared with that in ALT <10 U/L (p < 0.001). Although within the normal range of ALT, the risk of MS increases as the ALT levels increase. The ALT level in the general population without a history of chronic liver disease may be a useful marker to evaluate for MS.
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Affiliation(s)
- Ju-Yeon Cho
- Division of Gastroenterology, Department of Internal Medicine, Chosun University Hospital, Gwang-Ju, Republic of Korea
| | - Jae Yoon Jeong
- Division of Gastroenterology, Department of Internal Medicine, National Medical Center, Seoul, Republic of Korea
| | - Won Sohn
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- * E-mail:
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Zhang J, Lin S, Jiang D, Li M, Chen Y, Li J, Fan J. Chronic hepatitis B and non-alcoholic fatty liver disease: Conspirators or competitors? Liver Int 2020; 40:496-508. [PMID: 31903714 DOI: 10.1111/liv.14369] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/16/2019] [Accepted: 01/02/2020] [Indexed: 02/06/2023]
Abstract
Despite the widespread use of vaccines and antiviral drugs, approximately 350-400 million patients with chronic hepatitis B (CHB) remain worldwide, who carry high risk of cirrhosis and liver carcinoma. Moreover, owing to improvements in global living standards and lifestyle changes, non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease. Coexistence of NAFLD and CHB is commonly observed, especially in Asian CHB populations; however, little is known regarding the relationship between these two diseases as comorbidities. In this review, we summarize recent advances in clinical and basic researches related to the underlying mutual interactions, as well as potential animal models to facilitate further investigation.
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Affiliation(s)
- Jianbin Zhang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Shuangzhe Lin
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Daixi Jiang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Mengting Li
- Department of Gastroenterology, Yinzhou People's Hospital, Zhejiang, China
| | - Yuanwen Chen
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiangao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Radu-Ionita F, Pyrsopoulos NT, Jinga M, Tintoiu IC, Sun Z, Bontas E. Viral Hepatitis B. LIVER DISEASES 2020. [PMCID: PMC7122759 DOI: 10.1007/978-3-030-24432-3_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
Hepatitis B virus (HBV) was first discovered on aboriginal Australians in 1963. Epidemiological studies soon recognized that HBV is a global chronic liver disease, with the highest prevalence rates in Asia and Africa. HBV is highly infectious, and in most cases transmitted from family members. Infections acquired during the perinatal period have a 90% chance of progressing to persistent HBV infection. This rate decreases to 2.3% when infection occurs at college student age. The persistent HBV infection starts with the immune tolerance phase when our immune system may recognize HBV antigens, but does not produce significant inflammation. An immune clearance reaction may develop to terminate HBV replication two to four decades later. When this immune clearance reaction successfully suppresses HBV replication, HBsAg carriers may progress to the residual phase. About 50% of HBsAg carriers ultimately clear HBsAg at age 80. Those patients unable to clear HBV replication smoothly have increased risk of chronic hepatitis, liver cirrhosis, and hepatocarcinogenesis. Current therapies decrease hepatic decompensation and increase survival rate. However, the sustained virologic response rate is lower than 40%. About 50% of patients experience a clinical flare within one year after therapy ends. Further studies will be needed to improve sustained virologic response rate.
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Affiliation(s)
- Florentina Radu-Ionita
- Faculty of Medicine, “Titu Maiorescu” University, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania
| | | | - Mariana Jinga
- Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania
| | - Ion C. Tintoiu
- Faculty of Medicine, “Titu Maiorescu” University, Central Military Emergency University Hospital “Dr. Carol Davila”, Bucharest, Romania
| | - Zhonghua Sun
- Medical Radiation Sciences, Curtin University, Perth, WA Australia
| | - Ecaterina Bontas
- “Prof. C.C. Iliescu” Emergency Institute for Cardiovascular Diseases, Bucharest, Romania
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Irham LM, Wong HSC, Perwitasari DA, Chou WH, Yang HI, Chang WC. Single-nucleotide polymorphism of rs7944135 (macrophage-expressed gene 1) is associated with hepatitis B surface antigen seroclearance in chronic hepatitis B infection: A cohort study. Medicine (Baltimore) 2019; 98:e17936. [PMID: 31860948 PMCID: PMC6940119 DOI: 10.1097/md.0000000000017936] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Clearance of the hepatitis B surface antigen (HBsAg) is the ultimate aim of treatment for patients with chronic hepatitis B (CHB) infection. Genetic, factor age, and gender were reported to be involved in the clearance of HBsAg. However, the rate of HBsAg seroclearance in CHB patients is still low globally and few of the single-nucleotide polymorphism (SNP) had been identified to associated with HBsAg seroclearance in CHB patients.Recently, 3 associated SNPs (rs7944135, rs171941, and rs6462008) were reported in the clearance of HBsAg in the Korean population. However, these SNPs have not been investigated in the CHB Taiwanese population. In present study, these 3 SNPs were genotyped in 2565 Taiwanese CHB patients including 493 CHB patients with HBsAg seroclearance and 2072 without HBsAg seroclearance.We observed that SNP rs7944135 was solely associated with HBsAg seroclearance. Subjects with the AA genotype at rs7944135 of macrophage-expressed gene 1 had a higher susceptibility to HBsAg clearance, compared to those with the AG or GG genotype under the genotypic model (odds ratio [OR] = 1.76. 95% confidence interval [CI] = 1.14-2.72, P = .045). Furthermore, we found a 1.74-fold increased risk of acquiring HBsAg seroclearance associated with the AA genotype compared to AG + GG of rs7944135 under the recessive model (OR = 1.74. 95% CI = 1.13-2.66, P = .014). According to the cumulative fraction curve with the log-rank test revealed that patients with the AA genotype of rs7944135 showed higher susceptibility to occur HBsAg seroclearance (P = .039) and HBV DNA undetectable (P = .0074) compared to those with the AG or GG genotype.This study examined the associations of 3 SNPs (rs7944135, rs171941, and rs6462008) with HBsAg seroclearance, and we identified that rs7944135 is solely associated with HBsAg seroclearance in Taiwanese CHB patients.
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Affiliation(s)
- Lalu Muhammad Irham
- Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Faculty of Pharmacy, University of Ahmad Dahlan, Yogyakarta, Indonesia
| | - Henry Sung-Ching Wong
- Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | | | - Wan-Hsuan Chou
- Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica
- Institute of Clinical Medicine, National Yang-Ming University
| | - Wei-Chiao Chang
- Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Genomics Research Center, Academia Sinica
- Integrative Research Center for Critical Care, Wan fang Hospital, Taipei Medical University, Taipei
- Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
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Clinical utility of HBV surface antigen quantification in HBV e antigen-negative chronic HBV infection. Nat Rev Gastroenterol Hepatol 2019; 16:631-641. [PMID: 31477873 DOI: 10.1038/s41575-019-0197-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2019] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a serious problem owing to its worldwide distribution and potential adverse sequelae that include cirrhosis and/or hepatocellular carcinoma. Current antiviral therapies have much improved outcomes, but few patients achieve the ultimate goal of hepatitis B surface antigen (HBsAg) loss (functional cure). As hepatitis B e antigen (HBeAg)-negative chronic HBV infection is the final phase prior to HBsAg loss, the management of patients in this phase together with quantification of HBsAg has attracted increasing clinical and research interest. This Review integrates the findings from research in HBsAg kinetics and discusses how they might inform our understanding and management of HBeAg-negative chronic HBV infection. Studies have shown that HBsAg levels are highly predictive of the presence of inactive HBV infection and that serial changes in HBsAg levels might predict HBsAg loss within 1-3 years. Data also suggest that quantitative HBsAg monitoring is important during hepatitis flare and antiviral therapy, especially in the timing of the decision to stop therapy and to start off-therapy retreatment. These findings have shed new light on the natural course of HBV infection and might lead to optimization of the management of HBeAg-negative chronic HBV infection and contribute to the paradigm shift from indefinite to finite therapy for patients with HBV infection.
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Xie Y, Yi W, Zhang L, Lu Y, Hao HX, Gao YJ, Ran CP, Lu HH, Chen QQ, Shen G, Wu SL, Chang M, Ping-Hu L, Liu RY, Sun L, Wan G, Li MH. Evaluation of a logistic regression model for predicting liver necroinflammation in hepatitis B e antigen-negative chronic hepatitis B patients with normal and minimally increased alanine aminotransferase levels. J Viral Hepat 2019; 26 Suppl 1:42-49. [PMID: 31380591 DOI: 10.1111/jvh.13163] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Accepted: 05/15/2019] [Indexed: 12/26/2022]
Abstract
Liver necroinflammation is the indicator for treating patients with chronic hepatitis B (CHB) infection. However, there is no suitable non-invasive index for diagnosing liver necroinflammation. This study aimed to create a non-invasive index to predict liver necroinflammation in patients who lack clear-cut clinical inflammation parameters. Patients who were hepatitis B e antigen (HBeAg)-negative and underwent liver histological diagnosis, had a normal or minimally increased alanine aminotransferase (ALT) level were enrolled. Liver necroinflammation was defined as histological active index ≥4. A logistic regression model (LRM) was established based on the parameters independently associated with liver necroinflammation. Of all 550 patients, 36.73% had necroinflammation. In patients with an abnormal ALT level, the rate of necroinflammation was 52.49%. The area under the curve (AUC) of the ALT level for predicting necroinflammation was 0.655 (95% confidence interval [CI], 0.609-0.702), and that of the HBV DNA level ≥2000 IU/mL combined with an abnormal ALT level was 0.618. By using the LRM, the AUC improved to 0.769 (95% CI, 0.723-0.815) with a Youden index of 0.519 and diagnostic accuracy of 75.3%. The cutoff value ≥0.7 in the LRM had a specificity of 97.4% and positive predictive value of 85.0% for predicting necroinflammation. By using the cutoff value <0.15 in the LRM, the presence of necroinflammation could be excluded with a negative predictive value of 90.8%. This study indicated that the LRM can be used to effectively diagnose liver necroinflammation in HBeAg-negative patients with CHB who have normal or minimally elevated ALT levels.
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Affiliation(s)
- Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wei Yi
- Department of Gynecology and Obstetrics, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hong-Xiao Hao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuan-Jiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Chong-Ping Ran
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hui-Hui Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Qi-Qi Chen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shu-Ling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ming Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lei Ping-Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Rui-Yu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lei Sun
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Gang Wan
- Medical Records and Statistics Department, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ming-Hui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Hsu TH, Tsui PH, Yu WT, Huang SF, Tai J, Wan YL, Tai DI. Cutoff Values of Acoustic Radiation Force Impulse Two-Location Measurements in Different Etiologies of Liver Fibrosis. J Med Ultrasound 2019; 27:130-134. [PMID: 31867175 PMCID: PMC6905267 DOI: 10.4103/jmu.jmu_7_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 01/17/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acoustic radiation force impulse (ARFI) imaging is a popular modality to measure liver fibrosis. ARFI selects optimal locations for measurement under imaging guiding. However, there are concerns on study locations and observers bias. To decrease the variations, ARFI at two locations was measured with standardized protocol. This study attempted to establish its cutoff values according to Metavir fibrosis score in different etiologies. METHODS A consecutive series of patients who received liver histology study were prospectively enrolled. All cases had hemogram, liver biochemistry, viral markers, and ARFI two-location measurements within 4 weeks of histology study. A standardized protocol was performed by single technologist. We excluded patients with alanine aminotransferase >5x upper limit normal. RESULTS Five hundred and ten patients that included 153 seronegative for both HBsAg and anti-HCV Non-B non-C (NBNC), 33 autoimmune liver diseases (AILD), 261 chronic hepatitis B (CHB), and 63 chronic hepatitis C (CHC) were enrolled. About 83% of NBNC patients had fat cell >5%. For diagnosis of liver cirrhosis, the area under receiver operating characteristic curve of NBNC, AILD, CHB, and CHC groups was 0.937, 0.929, 0.784, and 0.937; the cutoff values for mean ARFI were 1.788, 2.095, 1.455, and 1.710 m/s, respectively. The sensitivity and specificity are both over 0.818 for patients with nonalcoholic fatty liver diseases, CHC, and AILD, but the corresponding data are only 0.727-0.756 in CHB. The Fibrosis-4 Score is as good as ARFI on fibrosis assessment in NBNC. CONCLUSION The performance of ARFI two-location measurement is excellent in NBNC, AILD, and CHC, but is only satisfactory in CHB.
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Affiliation(s)
- Tse-Hwa Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Po-Hsiang Tsui
- Department of Medical Imaging and Radiological Sciences, College of Medicine, Institute for Radiological Research, Chang Gung University, Taoyuan, Taiwan
| | - Wan-Ting Yu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Shiu-Feng Huang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taipei, Taiwan
| | - Jennifer Tai
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Yung-Liang Wan
- Department of Medical Imaging and Radiological Sciences, College of Medicine, Institute for Radiological Research, Chang Gung University, Taoyuan, Taiwan
| | - Dar-In Tai
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Address for correspondence: Prof. Dar-In Tai, Department of Gastroenterology and Hepatology, College of Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, No. 199 Tung-Hwa North Road, Taipei 105, Taiwan. E-mail:
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Choi GH, Kim GA, Choi J, Han S, Lim YS. High risk of clinical events in untreated HBeAg-negative chronic hepatitis B patients with high viral load and no significant ALT elevation. Aliment Pharmacol Ther 2019; 50:215-226. [PMID: 31135074 DOI: 10.1111/apt.15311] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 12/30/2018] [Accepted: 04/29/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND It remains unknown whether antiviral treatment for HBeAg-negative chronic hepatitis B (CHB) patients having high viral loads without significant elevation of alanine aminotransferase (ALT) levels would reduce the risks of clinical events. AIM To compare clinical outcomes of high viral load CHB patients untreated for normal or mildly elevated ALT vs those treated for ALT ≥ 2 upper limit of normal (ULN). METHODS This historical cohort study included 5414 HBeAg-negative CHB patients without cirrhosis at a tertiary hospital in Korea from 2000 to 2013. Inactive phase was defined as serum hepatitis B virus [HBV] DNA < 2000 IU/mL and persistently normal ALT (n = 3572). High viral load (HBV DNA ≥ 2000 IU/mL) patients were classified into three phases by ALT levels: Replicative (persistently normal ALT, n = 900); Mildly active (ALT 1-2ULN, n = 396); and Active (ALT ≥ 2ULN, n = 546) phases. All Active phase patients were treated with nucleos(t)ide analogues. RESULTS The mean age of the patients was 47 years without a significant difference among the groups. Compared with the treated Active phase group, the untreated Replicative phase group showed a significantly higher risk of hepatocellular carcinoma (HCC; HR 1.76; 95% CI 1.00 - 3.10, P = 0.05) and death/transplantation (HR 2.14; 5% CI 1.09 - 4.21, P = 0.03) by propensity score-matched analysis. The untreated mildly active phase patients had further increase in risk of HCC and death/transplantation compared with the treated Active phase group by unadjusted, PS-matched, competing risks, and multivariable-adjusted analyses. CONCLUSIONS Untreated high viral load HBeAg-negative CHB patients without significant ALT elevation had higher risks of clinical events than treated Active phase patients with elevated ALT.
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Affiliation(s)
- Gwang Hyeon Choi
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Gi-Ae Kim
- Departments of Internal Medicine, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Jonggi Choi
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seungbong Han
- Department of Applied Statistics, Gachon University, SeongNam, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Chen CJ, Tsay PK, Huang SF, Tsui PH, Yu WT, Hsu TH, Tai J, Tai DI. Effects of Hepatic Steatosis on Non-Invasive Liver Fibrosis Measurements Between Hepatitis B and Other Etiologies. APPLIED SCIENCES 2019; 9:1961. [DOI: 10.3390/app9091961] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Fibrosis-4 (FIB4), transient elastography (TE), and acoustic radiation force impulse (ARFI) are popular modalities to assess liver fibrosis. Their cutoff values for degrees of fibrosis vary between studies. The influence of hepatic steatosis on fibrosis measurements for different etiologies was evaluated. Data from a consecutive series of patients who received fibrosis measurement were included for the training group. An additional series with histology served as the validation group. A standardized protocol was performed for both TE and ARFI, mostly by a single technician. Patients with alcoholism, autoimmune disease, active inflammation, or who were receiving therapy were excluded. The training group included 215 patients and the validation group included 221. The correlation of liver stiffness between TE and ARFI was good (R2 linear = 0.798; p < 0.001). Different correlations between ARFI and TE were noted between high and low control attenuation parameter (CAP) values (cutoff: 290 dB/m), especially in the non-hepatitis B subgroups. Relatively lower FIB4 and TE values were seen in the high CAP versus low CAP in patients with histology-proven non-alcoholic fatty liver disease and chronic hepatitis C. FIB4 cutoff values were >25% lower among F2-F4 stages and the TE cutoff value for F4 was 8.5% lower in the high versus low CAP group. Such findings were not observed in chronic hepatitis B. Different fibrogenesis mechanisms between hepatitis B and non-B are discussed. We conclude that hepatic steatosis significantly impacts FIB4 and TE fibrosis measurements in non-hepatitis B-related liver diseases. Fibrosis grade should be interpreted with caution in severe steatosis.
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Affiliation(s)
- Cheng-Jen Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Tao-Yuan 333, Taiwan
| | - Pei-Kwei Tsay
- Department of Public Health and Center of Biostatistics, Chang Gung University College of Medicine, Tao-Yuan 333, Taiwan
| | - Shiu-Feng Huang
- Division of Molecular and Genomic Medicine, National Health Research Institute, Taipei 115, Taiwan
| | - Po-Hsiang Tsui
- Department of Medical imaging and Radiological Sciences, College of Medicine, Institute for Radiological Research, Chang Gung University, Taoyuan 333, Taiwan
| | - Wan-Ting Yu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Tao-Yuan 333, Taiwan
| | - Tse-Hwa Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Tao-Yuan 333, Taiwan
| | - Jennifer Tai
- Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, Tao-Yuan 333, Taiwan
| | - Dar-In Tai
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Tao-Yuan 333, Taiwan
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Jiang ZJ, Shen QH, Chen HY, Yang Z, Shuai MQ, Zheng SS. Galectin-1 gene silencing inhibits the activation and proliferation but induces the apoptosis of hepatic stellate cells from mice with liver fibrosis. Int J Mol Med 2018; 43:103-116. [PMID: 30365068 PMCID: PMC6257862 DOI: 10.3892/ijmm.2018.3950] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 10/09/2018] [Indexed: 12/19/2022] Open
Abstract
Liver fibrosis is a serious threat to human health, and there is currently no effective clinical drug for treatment of the disease. Although Galectin-1 is effective, its role in liver function, inflammation, matrix metalloproteinases and the activation of hepatic stellate cells (HSCs) remains to be elucidated. The aim of the present study was to elucidate the effect of Galectin-1 on the activation, proliferation and apoptosis of HSCs in a mouse model of liver fibrosis. Following successful model establishment and tissue collection, mouse HSCs (mHSCs) were identified and an mHSC line was constructed. Subsequently, to determine the role of Galectin-1 in liver fibrosis, the expression levels of transforming growth factor (TGF)-β1, connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA) pre- and post-transfection were evaluated by reverse transcription-quantitative polymerase chain reaction and western blot analyses. In addition, the effects of Galectin-1 on the biological behavior and mitochondrial function of mHSCs were determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry and a scratch test. It was first observed that the expression levels of Galectin-1, TGF-β1, CTGF and α-SMA were downregulated by silencing the gene expression of Galectin-1. Additionally, silencing the gene expression of Galectin-1 inhibited cell cycle progression, proliferation and migration but induced the apoptosis of mHSCs from mice with liver fibrosis. Furthermore, the in vivo experimental results suggested that silencing the gene expression of Galectin-1 improved liver fibrosis. Collectively, it was concluded that silencing the gene expression of Galectin-1 ameliorates liver fibrosis and that functionally suppressing Galectin-1 may be a future therapeutic strategy for liver fibrosis.
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Affiliation(s)
- Zhi-Jun Jiang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Qing-Hua Shen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine (Jinyun Branch), Jinyun, Zhejiang 321400, P.R. China
| | - Hai-Yong Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Zhe Yang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Ming-Qi Shuai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Shu-Sen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
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Shim JJ, Kim JW, Oh CH, Lee YR, Lee JS, Park SY, Kim BH, Oh IH. Serum alanine aminotransferase level and liver-related mortality in patients with chronic hepatitis B: A large national cohort study. Liver Int 2018; 38:1751-1759. [PMID: 29377574 DOI: 10.1111/liv.13705] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 01/17/2018] [Indexed: 02/13/2023]
Abstract
BACKGROUND The serum alanine aminotransferase (ALT) level has been used to identify at-risk patients with chronic hepatitis B (CHB) who need antiviral therapy. However, the level associated with increased liver-related mortality requiring active treatment is still unclear. METHODS We used a Health Examination Cohort of the National Health Insurance Service of Korea that included approximately 0.5 million individuals aged 40-79 years. In total, 12 486 patients with CHB and no other concurrent liver disease were enrolled, and patients' liver-related mortality, including that owing to liver cancer, was investigated over 9 years. RESULTS The serum ALT level was correlated positively with liver-related mortality. The rates in men were 0.14, 0.17, 0.24, 0.57, 0.63 and 0.85 per 100 person-years (%) for serum ALT levels of <20, 20-29, 30-39, 40-49, 50-79 and ≥80 U/L, respectively, and the corresponding liver-related mortality rates in women were 0.03%, 0.09%, 0.12%, 0.63%, 0.65% and 0.32%. In patients with ALT levels of 40-79 U/L, the liver-related mortality rates were 0.60% in men and 0.64% in women, which were similar to the overall mortality rate of age- and sex-matched subjects without CHB (0.69%). The best cut-off values for liver-related mortality prediction were >34 U/L in men and >30 U/L in women. CONCLUSIONS The liver-related mortality rate increased significantly, even in CHB patients with relatively low serum ALT levels. Careful monitoring or earlier antiviral therapy should be considered for patients aged >40 years with serum ALT levels above the upper limit of normal.
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Affiliation(s)
- Jae-Jun Shim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Jung Wook Kim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Chi Hyuk Oh
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Ye-Rin Lee
- Department of Preventive Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Ji Sung Lee
- Clinical Research Center, Asan Medical Center, Seoul, Korea
| | - So-Youn Park
- Department of Medical Education and Humanities, Kyung Hee University School of Medicine, Seoul, Korea
| | - Byung-Ho Kim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - In-Hwan Oh
- Department of Preventive Medicine, Kyung Hee University School of Medicine, Seoul, Korea
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Tseng TC, Liu CJ, Su TH, Yang WT, Chen CL, Yang HC, Kuo SFT, Liu CH, Chen PJ, Chen DS, Kao JH. Fibrosis-4 index predicts cirrhosis risk and liver-related mortality in 2075 patients with chronic HBV infection. Aliment Pharmacol Ther 2018; 47:1480-1489. [PMID: 29601647 DOI: 10.1111/apt.14619] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 01/26/2018] [Accepted: 02/28/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Fibrosis-4 index (FIB-4) is a surrogate marker for hepatic fibrosis in hepatitis B virus (HBV) carriers. AIM To investigate whether FIB-4 index stratifies the risks of adverse liver events. METHODS A total of 2075 treatment-naïve, noncirrhotic the patients with chronic HBV infection were included. Most of them (82.1%) were HBeAg-negative patients and their baseline FIB-4 levels were explored to stratify the risks of cirrhosis, cirrhosis-related complications and liver-related mortality. RESULTS During a mean follow-up period of 15.47 years, we found a higher baseline FIB-4 index was associated with increased incidence rates of cirrhosis in addition to the common host and viral factors. Patients with FIB-4 >1.29, compared to those with FIB-4 <1.29, were associated with increased risks of cirrhosis, cirrhosis-related complications and liver-related mortality with the hazard ratio (95% confidence interval) of 6.19 (4.76-8.05), 6.88, (3.68-12.86) and 7.79, (4.54-13.37) respectively. Within the first 3 years of follow-up, FIB-4 remained stable and its kinetics were consistently associated with the develoopment of adverse liver events. Furthermore, FIB-4 index of 1.29 was able to stratify all the risks of adverse liver events even in HBeAg-negative patients with a low risk of disease progression (HBV DNA <2000 IU/mL, HBsAg <1000 IU/mL and ALT <40 U/L). Only 1 patient with FIB-4 index <1.29 developed cirrhosis but not other events within 15 years of follow-up. CONCLUSIONS In noncirrhotic patients with chronic HBV infection, a higher FIB-4 index was associated with increased risks of adverse liver events. FIB-4 index <1.29 is useful for the prediction of the lowest risks of disease progression.
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Affiliation(s)
- T-C Tseng
- Department of Internal Medicine, National Taiwan University Hospital, New Taipei City, Taiwan.,Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - C-J Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - T-H Su
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - W-T Yang
- Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - C-L Chen
- Graduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - H-C Yang
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Microbiology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - S F-T Kuo
- Royal Hobart Hospital, Hobart, Australia
| | - C-H Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - P-J Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - D-S Chen
- Genomics Research Center Academia Sinica, Taipei, Taiwan
| | - J-H Kao
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Medical Research, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
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45
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Hernandez C, Huebener P, Pradere JP, Antoine DJ, Friedman RA, Schwabe RF. HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis. J Clin Invest 2018; 128:2436-2451. [PMID: 29558367 DOI: 10.1172/jci91786] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 03/13/2018] [Indexed: 12/15/2022] Open
Abstract
Cell death is a key driver of disease progression and carcinogenesis in chronic liver disease (CLD), highlighted by the well-established clinical correlation between hepatocellular death and risk for the development of cirrhosis and hepatocellular carcinoma (HCC). Moreover, hepatocellular death is sufficient to trigger fibrosis and HCC in mice. However, the pathways through which cell death drives CLD progression remain elusive. Here, we tested the hypothesis that high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) with key roles in acute liver injury, may link cell death to injury responses and hepatocarcinogenesis in CLD. While liver-specific HMGB1 deficiency did not significantly affect chronic injury responses such as fibrosis, regeneration, and inflammation, it inhibited ductular/progenitor cell expansion and hepatocyte metaplasia. HMGB1 promoted ductular expansion independently of active secretion in a nonautonomous fashion, consistent with its role as a DAMP. Liver-specific HMGB1 deficiency reduced HCC development in 3 mouse models of chronic injury but not in a model lacking chronic liver injury. As with CLD, HMGB1 ablation reduced the expression of progenitor and oncofetal markers, a key determinant of HCC aggressiveness, in tumors. In summary, HMGB1 links hepatocyte death to ductular reaction, progenitor signature, and hepatocarcinogenesis in CLD.
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Affiliation(s)
- Celine Hernandez
- Department of Medicine, Columbia University, New York, New York, USA
| | - Peter Huebener
- Department of Medicine, Columbia University, New York, New York, USA.,Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jean-Philippe Pradere
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France
| | - Daniel J Antoine
- MRC Centre for Inflammation Research, University of Edinburgh, United Kingdom
| | - Richard A Friedman
- Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics, Columbia University, New York, New York, USA
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, New York, USA
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46
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Konerman MA, Lok AS. Epidemiology, Diagnosis, and Natural History of Hepatitis B. ZAKIM AND BOYER'S HEPATOLOGY 2018:474-484.e4. [DOI: 10.1016/b978-0-323-37591-7.00032-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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47
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Wang TH, Yu CC, Lin YS, Chen TC, Yeh CT, Liang KH, Shieh TM, Chen CY, Hsueh C. Long noncoding RNA CPS1-IT1 suppresses the metastasis of hepatocellular carcinoma by regulating HIF-1α activity and inhibiting epithelial-mesenchymal transition. Oncotarget 2017; 7:43588-43603. [PMID: 27248828 PMCID: PMC5190046 DOI: 10.18632/oncotarget.9635] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 05/09/2016] [Indexed: 01/04/2023] Open
Abstract
Recently, increasing numbers of long noncoding RNAs (lncRNAs), with both oncogenic and tumor-suppressive potential, have been found to be aberrantly expressed in various human cancers. However, the function of lncRNAs in hepatocellular carcinoma (HCC) progression remains largely unknown. In this study, we performed a comprehensive microarray analysis of lncRNA expression using human HCC specimens. After validation in 119 human HCC tissues, we identified a novel tumor suppressor lncRNA, CPS1 intronic transcript 1 (CPS1-IT1). To elucidate the clinical significance of CPS1-IT1 in HCC, correlations between CPS1-IT1 levels, clinical parameters, and survival outcomes were analyzed. In vitro and in vivo functional assays were also performed to dissect the potential underlying mechanisms. Expression of CPS1-IT1 was significantly decreased in 73% of HCC tissues, and patients with low CPS1-IT1 expression had poor survival outcomes. Furthermore, in vitro functional assays indicated that CPS1-IT1 significantly reduced cell proliferation, migration and invasion capacities through reduced Hsp90 binding to and activation of HIF-1α, thereby suppressing the epithelial-mesenchymal transition (EMT). An in vivo animal model also demonstrated the tumor suppressor role of CPS1- IT1 via decreased tumor growth and metastasis. In conclusion, lncRNA CPS1-IT1 acts as a tumor suppressor in HCC by reducing HIF-1α activation and suppressing EMT. The findings of this study establish a function for CPS1-IT1 in HCC progression and suggest its potential as a new prognostic biomarker and target for HCC therapy.
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Affiliation(s)
- Tong-Hong Wang
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.,Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan.,Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan
| | - Cheng-Chia Yu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.,Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.,Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Yong-Shiang Lin
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
| | - Tse-Ching Chen
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - Kung-Hao Liang
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - Tzong-Ming Shieh
- Department of Dental Hygiene, College of Health Care, China Medical University, Taichung, Taiwan
| | - Chi-Yuan Chen
- Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan.,Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan
| | - Chuen Hsueh
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.,Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
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48
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Guardiola-Arévalo A, Gómez Rodríguez R, Romero Gutiérrez M, Gómez Moreno AZ, García Vela A, Sánchez Simón R, Gómez Hernando C, Andrés Esteban EM. Hepatitis B virus e antigen-negative chronic infection. Treatment based on glutamic pyruvic transaminase and hepatitis B virus deoxyribonucleic acid cut-off values. GASTROENTEROLOGIA Y HEPATOLOGIA 2017; 41:153-162. [PMID: 29279233 DOI: 10.1016/j.gastrohep.2017.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 09/13/2017] [Accepted: 11/09/2017] [Indexed: 11/17/2022]
Abstract
OBJECTIVES To identify glutamic pyruvic transaminase (GPT) and hepatitis B virus DNA (HBV-DNA) cut-off values at diagnosis in patients with hepatitis B virus e antigen-negative chronic infection (HBeAg(-)), which may be predictors of clinical course, prognosis and/or the need for antiviral therapy. METHODS A retrospective and observational cohort study of patients diagnosed with HBeAg(-) chronic infection (2005-2012). A normal GPT cut-off value at diagnosis that predicts abnormal GPT values in the clinical course of the infection, a baseline HBV-DNA cut-off value that predicts an increase in HBV-DNA above 2,000IU/ml, and GPT and HBV-DNA as predictors of the need for treatment were investigated using ROC curves. RESULTS 126 patients were enrolled (follow-up: 42.1±21.5months), 93 of which had normal GPT levels at diagnosis. In the ROC curve analysis, 900IU/ml was found to be the HBV-DNA cut-off value that best predicted this value's increase above 2,000IU/ml (sensitivity: 90%; specificity: 88%; PPV: 79%; NPV: 100%; diagnostic precision: 89%), while 25mU/ml was the normal GPT cut-off value at diagnosis that best predicted subsequently elevated GPT levels (sensitivity: 95.4%; specificity: 81.6%; PPV: 67%; NPV: 96%; diagnostic precision: 80.6%). Patients with GPT 26-40mU/ml at diagnosis presented with more complications or required more treatment than subjects with GPT≤25mU/ml (P<.05). The combined GPT and HBV-DNA values that elicited the highest treatment need were 38mU/ml of GPT and 6,000IU/ml of HBV-DNA (sensitivity: 75%; specificity: 93.4%; PPV: 60%; NPV: 96.6%). CONCLUSION HBeAg(-) patients with GPT<25mU/ml and HBV-DNA<900IU/ml at diagnosis have positive outcomes and may not require such stringent follow-up in the first years after diagnosis.
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Affiliation(s)
- Antonio Guardiola-Arévalo
- Servicio de Aparato Digestivo, Hospital Virgen de la Salud, Toledo, España; Servicio de Aparato Digestivo, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, España.
| | | | | | - Ana Zaida Gómez Moreno
- Servicio de Aparato Digestivo, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, España
| | - Almudena García Vela
- Servicio de Aparato Digestivo, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, España
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49
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Rajoriya N, Combet C, Zoulim F, Janssen HLA. How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualised approach? J Hepatol 2017; 67:1281-1297. [PMID: 28736138 DOI: 10.1016/j.jhep.2017.07.011] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 06/27/2017] [Accepted: 07/12/2017] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B virus (HBV) infection remains a global problem. Several HBV genotypes exist with different biology and geographical prevalence. Whilst the future aim of HBV treatment remains viral eradication, current treatment strategies aim to suppress the virus and prevent the progression of liver disease. Current strategies also involve identification of patients for treatment, namely those at risk of progressive liver disease. Identification of HBV genotype, HBV mutants and other predictive factors allow for tailoured treatments, and risk-surveillance pathways, such as hepatocellular cancer screening. In the future, these factors may enable stratification not only of treatment decisions, but also of patients at risk of higher relapse rates when current therapies are discontinued. Newer technologies, such as next-generation sequencing, to assess drug-resistant or immune escape variants and quasi-species heterogeneity in patients, may allow for more information-based treatment decisions between the clinician and the patient. This article serves to discuss how HBV genotypes and genetic variants impact not only upon the disease course and outcomes, but also current treatment strategies. Adopting a personalised genotypic approach may play a role in future strategies to combat the disease. Herein, we discuss new technologies that may allow more informed decision-making for response guided therapy in the battle against HBV.
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Affiliation(s)
- Neil Rajoriya
- Toronto Centre for Liver Diseases, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada
| | - Christophe Combet
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon 69XXX, France
| | - Fabien Zoulim
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon 69XXX, France; Department of Hepatology, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France
| | - Harry L A Janssen
- Toronto Centre for Liver Diseases, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
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50
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Lee CH, Wan YL, Hsu TH, Huang SF, Yu MC, Lee WC, Tsui PH, Chen YC, Lin CY, Tai DI. Interpretation US Elastography in Chronic Hepatitis B with or without Anti-HBV Therapy. APPLIED SCIENCES 2017; 7:1164. [DOI: 10.3390/app7111164] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inflammation has significant impacts on liver fibrosis measurement by ultrasound elastography. The interpretation requires further optimization in patients with or without anti-viral therapy. We prospectively enrolled a consecutive series of patients with chronic hepatitis B who received liver histology analysis and acoustic radiation force impulse (ARFI). 146 patients who underwent liver biopsy (50.9%) or tumor resection (49.1%) were enrolled. 34 patients (23.3%) had been receiving anti-hepatitis B therapy of various duration. The areas under the receiver-operating characteristic (AUROC) for the diagnosis of Metavir F4 by mean ARFI was 0.820 in the non-treatment group and 0.796 in the treatment group. The ARFI tended to be not lower (100%) than the corresponding Metavir grading in patients with treatment within 12 months, equal (75%) from 13 to 31 months, and lower (71.4%) after 32 months. We conclude that ARFI is a reliable tool for measurement of liver fibrosis in chronic hepatitis B patients with ALT (alanine aminotransferase) <5x the upper limit of normal. For those patients under anti-HBV therapy, the optimal timing for ARFI analysis will be over 1–2.5 years of nucleos(t)ide analogue therapy. The ARFI measurement after 2.5 years tends to be lower than the corresponding histology grading.
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Affiliation(s)
- Cheng-Han Lee
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taipei 105, Taiwan
| | - Yung-Liang Wan
- Department of Medical imaging and Intervention, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Department of Medical imaging and Radiological Sciences, College of Medicine, Institute for Radiological Research, Chang Gung University, Taoyuan 333, Taiwan
| | - Tse-Hwa Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taipei 105, Taiwan
| | - Shiu-Feng Huang
- Division of Molecular and Genomic Medicine, National Health Research Institute, Taipei 115, Taiwan
| | - Ming-Chin Yu
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Wei-Chen Lee
- Department of Liver and Transplantation Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Po-Hsiang Tsui
- Department of Medical imaging and Radiological Sciences, College of Medicine, Institute for Radiological Research, Chang Gung University, Taoyuan 333, Taiwan
| | - Yi-Cheng Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taipei 105, Taiwan
| | - Chun-Yen Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taipei 105, Taiwan
| | - Dar-In Tai
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taipei 105, Taiwan
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