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Marrapu S, Kumar R. Chronic hepatitis B: Prevent, diagnose, and treat before the point of no return. World J Hepatol 2024; 16:1331-1337. [DOI: 10.4254/wjh.v16.i10.1331] [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: 07/27/2024] [Revised: 09/26/2024] [Accepted: 10/10/2024] [Indexed: 11/22/2024] Open
Abstract
Hepatitis B remains a significant global health challenge, contributing to substantial morbidity and mortality. Approximately 254 million people worldwide live with Chronic hepatitis B (CHB), with the majority of cases occurring in sub-Saharan Africa and the Western Pacific regions. Alarmingly, only about 13.4% of the individuals infected with this disease have been diagnosed, and awareness of hepatitis B virus (HBV) infection status is as low as 1% in sub-Saharan Africa. In 2022, CHB led to 1.1 million deaths globally. The World Health Organization (WHO) has set a target of eliminating hepatitis B as a public health concern by 2030; however, this goal appears increasingly unattainable due to multiple challenges. These challenges include low vaccination coverage; a large number of undiagnosed cases; a low proportion of patients eligible for treatment under current guidelines; limited access to healthcare; and the costs associated with lifelong treatment. Treatment of HBV can yield significant clinical benefits within a long window of opportunity. However, the benefits of therapy are markedly diminished when the disease is detected at the advanced cirrhosis stage. This editorial aim to highlight the current challenges in hepatitis care and the necessary steps to achieve the WHO's hepatitis elimination goals for 2030.
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Affiliation(s)
- Sudheer Marrapu
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
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Marrapu S, Kumar R. Chronic hepatitis B: Prevent, diagnose, and treat before the point of no return. World J Hepatol 2024; 16:1151-1157. [PMID: 39474571 PMCID: PMC11514616 DOI: 10.4254/wjh.v16.i10.1151] [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: 07/27/2024] [Revised: 09/26/2024] [Accepted: 10/10/2024] [Indexed: 10/21/2024] Open
Abstract
Hepatitis B remains a significant global health challenge, contributing to substantial morbidity and mortality. Approximately 254 million people worldwide live with Chronic hepatitis B (CHB), with the majority of cases occurring in sub-Saharan Africa and the Western Pacific regions. Alarmingly, only about 13.4% of the individuals infected with this disease have been diagnosed, and awareness of hepatitis B virus (HBV) infection status is as low as 1% in sub-Saharan Africa. In 2022, CHB led to 1.1 million deaths globally. The World Health Organization (WHO) has set a target of eliminating hepatitis B as a public health concern by 2030; however, this goal appears increasingly unattainable due to multiple challenges. These challenges include low vaccination coverage; a large number of undiagnosed cases; a low proportion of patients eligible for treatment under current guidelines; limited access to healthcare; and the costs associated with lifelong treatment. Treatment of HBV can yield significant clinical benefits within a long window of opportunity. However, the benefits of therapy are markedly diminished when the disease is detected at the advanced cirrhosis stage. This editorial aim to highlight the current challenges in hepatitis care and the necessary steps to achieve the WHO's hepatitis elimination goals for 2030.
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Affiliation(s)
- Sudheer Marrapu
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
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Sinclair S, Shearen S, Ghobrial Y, Trad G, Abdul Basit S, Shih D, Ryan JK. Review of the Effects of Antiviral Therapy on Hepatitis B/C-Related Mortality and the Regression of Fibrosis. Viruses 2024; 16:1531. [PMID: 39459866 PMCID: PMC11512229 DOI: 10.3390/v16101531] [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: 08/16/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
Hepatitis B and Hepatitis C are viral causes of Hepatitis that lead to significant worldwide mortality and morbidity through the sequelae of fibrosis and hepatocellular carcinoma. In this review, we have summarized recent studies that have examined the effects of antiviral therapy on the regression of fibrosis and the reduction in mortalities associated with the viruses. Antiviral therapy significantly decreases mortality and induces the regression of fibrosis.
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Affiliation(s)
| | | | | | | | | | | | - John K. Ryan
- Comprehensive Digestive Institute of Nevada, Las Vegas, NV 89148, USA (S.A.B.); (D.S.)
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Albukhari M, Bagies M, Lizbeth T, Kottilil S. Fighting fire with fire: using infectious agents to treat persistent infection. Future Microbiol 2024; 19:1177-1184. [PMID: 39105632 PMCID: PMC11529199 DOI: 10.1080/17460913.2024.2363728] [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: 02/08/2024] [Accepted: 05/24/2024] [Indexed: 08/07/2024] Open
Abstract
Infectious diseases lead to significant morbidity and mortality. Often, resolution of the acute stage of the disease leads to microbial persistence, resulting in chronic debilitating disease. Management of persistent infections frequently requires lifelong therapy with antimicrobial agents. These infections could be chronic viral infections like HIV, hepatitis B or chronic bacterial persistent infections like prosthetic joint infections caused by multi-drug resistant organisms. Bacteriophages have been designed specifically to target recalcitrant bacterial infections, such as prosthetic joint infections with varying success. In this review, we describe the historic evolution of scenarios and risks associated with innovative therapy using infectious agents to treat other persistent infections.
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Affiliation(s)
- Maha Albukhari
- Department of Internal Medicine, University of Maryland Medical Center, Baltimore, MD21201, USA
| | - Maria Bagies
- Department of Internal Medicine, University of Maryland Medical Center, Baltimore, MD21201, USA
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Chen N, Sun Y, Luo P, Tang Y, Fan Y, Han L, Wang K. Association of CXCR4 gene expression and promoter methylation with chronic hepatitis B-related fibrosis/cirrhosis. Int Immunopharmacol 2024; 139:112686. [PMID: 39053226 DOI: 10.1016/j.intimp.2024.112686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 06/30/2024] [Accepted: 07/11/2024] [Indexed: 07/27/2024]
Abstract
OBJECTIVE Chronic hepatitis B (CHB) virus infection remains a major public health concern. In this study, the diagnostic capability of C-X-C chemokine receptor type 4 promoter methylation in patients with CHB-associated liver fibrosis/cirrhosis was evaluated. METHODS Two hundred participants were recruited, including 25 healthy controls (HCs), 60 patients with CHB and 115 patients with hepatitis B virus (HBV)-related liver fibrosis/LC. Researchers monitored the methylation and messenger ribonucleic acid (mRNA) levels of C-X-C chemokine receptor type 4 (CXCR4) in peripheral blood mononuclear cells (PBMCs). In addition, we utilized single cell sequencing to analyze the cell types highly expressing CXCR4 in HBV-related liver fibrosis/LC. RESULTS HBV-related fibrosis/cirrhosis patients exhibited a significant elevation in the expression level of CXCR4 mRNA in PBMCs compared to CHB ones. The CXCR4 promoter showed a significantly lower methylation level in patients with CHB-related fibrosis/cirrhosis than in patients with CHB. Additionally, the diagnostic area under the area under the curve (AUC) of methylation of the CXCR4 promoter for CHB -related liver fibrosis/LC exceeded liver stiffness measurement (LSM), aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 score (FIB-4). Furthermore, single-cell analysis demonstrated that CXCR4 expression is closely associated with Natural Killer cells(NK cells), T lymphocytes (T cells), and monocytes. CONCLUSION The low methylation of the CXCR4 promoter holds promise as a non-invasive biomarker for detecting CHB-associated liver fibrosis/LC.
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Affiliation(s)
- Nan Chen
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Yu Sun
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Pengyu Luo
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Yuna Tang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Yuchen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Liyan Han
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, PR China; Institute of Hepatology, Shandong University, Jinan 250012, PR China.
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, PR China; Institute of Hepatology, Shandong University, Jinan 250012, PR China.
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Chen S, Zhou J, Wu X, Meng T, Wang B, Liu H, Wang T, Zhao X, Zhao X, Kong Y, Ou X, Jia J, Sun Y, You H. Liver fibrosis showed a two-phase regression rate during long-term anti-HBV therapy by three-time biopsies assessments. Hepatol Int 2024; 18:904-916. [PMID: 38565833 DOI: 10.1007/s12072-024-10643-z] [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: 08/22/2023] [Accepted: 01/12/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND Evidence has proven that liver fibrosis or even cirrhosis can be reversed by anti-HBV treatment. However, the difference of fibrosis regression rates in short-term and long-term antiviral therapy remain unclear. Therefore, we aimed to identify the dynamic changes in fibrosis regression rate in patients with three-time liver biopsies during 5 years antiviral therapy. METHODS CHB patients with three times of liver biopsies (baseline, after 1.5-year and 5-year antiviral therapy) from a prospective cohort were enrolled. All patients were biopsy-proved Ishak stage ≥ 3 at baseline (n = 92). Fibrosis regression was defined as Ishak stage decreased ≥ 1 or predominantly regressive categorized by P-I-R score. RESULTS Totals of 65.2% (60/92) and 80.4% (74/92) patients attained fibrosis regression after 1.5-year and 5-year therapy, respectively. Median HBV DNA level declined from 6.5 log IU/ml (baseline) to 0 log IU/ml (1.5 years and 5 years, P < 0.001). The mean level of Ishak fibrosis stage in all patients decreased from stage 4.1 (baseline) to 3.7 (1.5 years) then 3.2 (5 years). Fibrosis regression rates were 0.27 stage/year between baseline to year 1.5 and 0.14 stage/year between year 1.5 and year 5. Furthermore, for patients who attained fibrosis regression after 5-year antiviral therapy, the two-phase regression rates were 0.39 stage/year (0 year-1.5 years) and 0.20 stage/year (1.5 years-5 years). This two-phase feature of regression rate was further confirmed by fully-quantification assessment of liver fibrosis based on SHG/TPEF. CONCLUSION During the 5 years of long-term antiviral treatment, liver fibrosis rapidly regresses in the first 1.5 years before slowing down in the following 3.5 years.
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Affiliation(s)
- Shuyan Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Jialing Zhou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xiaoning Wu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Tongtong Meng
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Bingqiong Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Hui Liu
- Department of Pathology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Tailing Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing, China
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xinyu Zhao
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing Clinical Research Institute, Beijing, China
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing Clinical Research Institute, Beijing, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Yameng Sun
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China.
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China.
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Luo J, Yuan M, Li S, Chen L, Zhou M, Li H, Bai X, Zhang Z, Zeng W, Sun X, Zhang Q, Chen Y, Zhou L. Dynamic evaluation of liver fibrosis to assess hepatocellular carcinoma risk in patients with chronic hepatitis B receiving nucleoside analogs treatment. Rev Inst Med Trop Sao Paulo 2024; 66:e27. [PMID: 38747848 PMCID: PMC11095248 DOI: 10.1590/s1678-9946202466027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/28/2024] [Indexed: 05/19/2024] Open
Abstract
Despite good hepatitis B virus (HBV) inhibition by nucleoside analogs (NAs), cases of hepatocellular carcinoma (HCC) still occur. This study proposed a non-invasive predictive model to assess HCC risk in patients with chronic hepatitis B (CHB) receiving NAs treatment. Data were obtained from a hospital-based retrospective cohort registered on the Platform of Medical Data Science Academy of Chongqing Medical University, from 2013 to 2019. A total of 501 patients under NAs treatment had their FIB-4 index updated semiannually by recalculation based on laboratory values. Patients were divided into three groups based on FIB-4 index values: < 1.45, 1.45-3.25, and ≥ 3.25. Subsequently, HCC incidence was reassessed every six months using Kaplan-Meier curves based on the updated FIB-4 index. The median follow-up time of CHB patients after receiving NAs treatment was 2.5 years. HCC incidences with FIB-4 index < 1.45, 1.45-3.25, and ≥ 3.25 were 1.18%, 1.32%, and 9.09%, respectively. Dynamic assessment showed that the percentage of patients with FIB-4 index < 1.45 significantly increased semiannually (P < 0.001), and of patients with FIB-4 index ≥ 3.25 significantly decreased (P < 0.001). HCC incidence was the highest among patients with FIB-4 index ≥ 3.25. The FIB-4 index effectively predicted HCC incidence, and its dynamic assessment could be used for regular surveillance to implement early intervention and reduce HCC risk.
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Affiliation(s)
- Jia Luo
- Chongqing Medical University, School of Public Health, Department of Epidemiology, Chongqing, China
| | - Ming Yuan
- Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Shan Li
- Chongqing Medical University, School of Public Health, Department of Epidemiology, Chongqing, China
| | - Lijuan Chen
- Chongqing Medical University, School of Public Health, Department of Epidemiology, Chongqing, China
| | - Mingsha Zhou
- Chongqing Medical University, School of Public Health, Department of Epidemiology, Chongqing, China
| | - Hailan Li
- Chongqing Medical University, School of Public Health, Department of Epidemiology, Chongqing, China
| | - Xiuyuan Bai
- Chongqing Medical University, School of Public Health, Chongqing, China
| | - Zhiyu Zhang
- Chongqing Medical University, School of Public Health, Chongqing, China
| | - Weiqi Zeng
- Chongqing Medical University, School of Public Health, Chongqing, China
| | - Xueyi Sun
- Chongqing Medical University, School of Public Health, Chongqing, China
| | - Qiongfang Zhang
- Chongqing Medical University, School of Public Health, Chongqing, China
| | - Yi Chen
- Chongqing Medical University, School of Public Health, Chongqing, China
| | - Li Zhou
- Chongqing Medical University, School of Public Health, Department of Epidemiology, Chongqing, China
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Ignat MD, Balta AAS, Barbu RE, Draganescu ML, Nechita L, Voinescu DC, Nechita A, Stefanopol IA, Busila C, Baroiu L. Antiviral Therapy of Chronic Hepatitis B Virus between Present and Future. J Clin Med 2024; 13:2055. [PMID: 38610820 PMCID: PMC11012273 DOI: 10.3390/jcm13072055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 03/31/2024] [Accepted: 03/31/2024] [Indexed: 04/14/2024] Open
Abstract
Background/Objectives: The objective of this study was to analyze the results of clinical trials regarding long-term antiviral therapies in chronic hepatitis with HBV to compare current therapeutic protocols and to analyze the results of preliminary studies with new antiviral therapies for HBV. Methods: Clinical studies and meta-analyses from PubMed, Google Scholar, and Research Gate from 2011 to 2024 were analyzed on patients undergoing chronic antiviral therapy for HBV, and a retrospective observational study performed in our clinic on a group of 76 patients undergoing chronic therapy with entecavir was presented. Also, a summary of the results of preliminary studies with various innovative antiviral molecules for HBV was performed. Results: The results of extensive clinical trials reveal that current therapies for chronic HBV are well tolerated and maintain good viral suppression if the patient is adherent to therapy. Innovative therapies aim to eliminate HBsAg and, thus, significantly shorten the duration of treatment, and the preliminary results of the studies are promising. Conclusions: Being an asymptomatic condition that requires life-long therapy, adherence to therapy is a real problem. Also, the risk of decompensation of liver cirrhosis and adenocarcinoma remains important in these patients. Future research is needed to perfect some antiviral therapy schemes that shorten the treatment period but also decrease the rate of progression towards decompensated cirrhosis and liver adenocarcinoma.
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Affiliation(s)
- Mariana Daniela Ignat
- Doctoral School of Biomedical Sciences, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.D.I.); (R.E.B.)
| | | | - Raisa Eloise Barbu
- Doctoral School of Biomedical Sciences, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.D.I.); (R.E.B.)
| | - Miruna Luminita Draganescu
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.L.D.); (L.N.); (D.C.V.); (A.N.); (C.B.); (L.B.)
- ‘Sf. Cuv. Parascheva’ Clinical Hospital of Infectious Diseases, 800179 Galati, Romania
| | - Luiza Nechita
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.L.D.); (L.N.); (D.C.V.); (A.N.); (C.B.); (L.B.)
- ‘Sf. Apostol Andrei’ Clinical Emergency County Hospital, 800578 Galati, Romania
| | - Doina Carina Voinescu
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.L.D.); (L.N.); (D.C.V.); (A.N.); (C.B.); (L.B.)
- ‘Sf. Apostol Andrei’ Clinical Emergency County Hospital, 800578 Galati, Romania
| | - Aurel Nechita
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.L.D.); (L.N.); (D.C.V.); (A.N.); (C.B.); (L.B.)
- ‘Sf. Ioan’ Clinical Hospital for Children, 800487 Galati, Romania;
| | - Ioana Anca Stefanopol
- ‘Sf. Ioan’ Clinical Hospital for Children, 800487 Galati, Romania;
- Clinical Surgical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania
| | - Camelia Busila
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.L.D.); (L.N.); (D.C.V.); (A.N.); (C.B.); (L.B.)
- ‘Sf. Ioan’ Clinical Hospital for Children, 800487 Galati, Romania;
| | - Liliana Baroiu
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.L.D.); (L.N.); (D.C.V.); (A.N.); (C.B.); (L.B.)
- ‘Sf. Cuv. Parascheva’ Clinical Hospital of Infectious Diseases, 800179 Galati, Romania
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Sun Y, Chen W, Chen S, Wu X, Zhang X, Zhang L, Zhao H, Xu M, Chen Y, Piao H, Li P, Li L, Jiang W, Li X, Xing H, Liu X, Zhang Y, Wang B, Zhou J, Meng T, Zhao X, Shao C, Kong Y, Zhao X, Ou X, Liu C, Jia J, You H. Regression of Liver Fibrosis in Patients on Hepatitis B Therapy Is Associated With Decreased Liver-Related Events. Clin Gastroenterol Hepatol 2024; 22:591-601.e3. [PMID: 38040276 DOI: 10.1016/j.cgh.2023.11.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 11/09/2023] [Accepted: 11/16/2023] [Indexed: 12/03/2023]
Abstract
BACKGROUND & AIMS Liver fibrosis in patients with chronic hepatitis B can regress with successful antiviral therapy. However, the long-term clinical benefits of fibrosis regression have not been fully elucidated. This study investigated the association between biopsy-proven fibrosis regression by predominantly progressive, indeterminate, and predominantly regressive (P-I-R) score and liver-related events (LREs) in chronic hepatitis B patients. METHODS Patients with on-treatment liver biopsy and significant fibrosis/cirrhosis (Ishak stage ≥3) were included in this analysis. Fibrosis regression was evaluated according to the P-I-R score of the Beijing Classification. LREs were defined as decompensations, hepatocellular carcinoma, liver transplantation, or death. The Cox proportional hazards model was used to determine associations of fibrosis regression with LREs. RESULTS A total of 733 patients with Ishak stages 3/4 (n = 456; 62.2%) and cirrhosis (Ishak stages 5/6; n = 277; 37.8%) by on-treatment liver biopsy were enrolled. According to the P-I-R score, fibrosis regression, indeterminate, and progression were observed in 314 (42.8%), 230 (31.4%), and 189 (25.8%) patients, respectively. The 7-year cumulative incidence of LREs was 4.1%, 8.7%, and 18.1% in regression, indeterminate, and progression, respectively (log-rank, P < .001). Compared with patients with fibrosis progression, those with fibrosis regression had a lower risk of LREs (adjusted hazard ratio, 0.40; 95% CI, 0.16-0.99; P = .047), followed by the indeterminate group (adjusted hazard ratio, 0.86; 95% CI, 0.40-1.85; P = .691). Notably, this favorable association also was observed in patients with cirrhosis or low platelet counts (<150 × 109/L). CONCLUSIONS Antiviral therapy-induced liver fibrosis regression assessed by P-I-R score is associated with reduced LREs. This shows the utility of histologic fibrosis regression assessed by on-treatment P-I-R score as a surrogate endpoint for clinical events in patients with hepatitis B virus-related fibrosis or early cirrhosis.
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Affiliation(s)
- Yameng Sun
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Wei Chen
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shuyan Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xiaoning Wu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xinxin Zhang
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lingyi Zhang
- Department of Hepatology, Second Hospital, Lanzhou University, Lanzhou, China
| | - Hong Zhao
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Mingyi Xu
- Department of Gastroenterology and Hepatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongpeng Chen
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Hongxin Piao
- Infectious Department, Affiliated Hospital of Yanbian University, Yanji, Jilin, China
| | - Ping Li
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Lei Li
- Department of Gastroenterology and Hepatology, Beijing You-an Hospital, Capital Medical University, Beijing, China
| | - Wei Jiang
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaodong Li
- Hepatic Disease Institute, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Huichun Xing
- Department of Hepatology, Division 3, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xudong Liu
- Department of Liver Diseases, Ruikang Hospital, Guangxi Traditional Chinese Medicine University, Nanning, China
| | - Yuxi Zhang
- Department of Infectious Diseases, Ningxia People's Hospital, Yinchuan, China
| | - Bingqiong Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Jialing Zhou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Tongtong Meng
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Chen Shao
- Department of Pathology, Beijing You-an Hospital, Capital Medical University, Beijing, China
| | - Yuanyuan Kong
- Clinical Epidemiology and Evidence-based Medicine Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xinyu Zhao
- Clinical Epidemiology and Evidence-based Medicine Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Chenghai Liu
- Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China.
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China.
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Jeng WJ, Chien RN, Chen YC, Lin CL, Wu CY, Liu YC, Peng CW, Su CW, Hsu CE, Liaw YF. Hepatocellular carcinoma reduced, HBsAg loss increased, and survival improved after finite therapy in hepatitis B patients with cirrhosis. Hepatology 2024; 79:690-703. [PMID: 37625144 DOI: 10.1097/hep.0000000000000575] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023]
Abstract
BACKGROUND AND AIMS Long-term nucleos(t)ide analog (Nuc) treatment can reduce HCC in patients with HBV-related liver cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in HBeAg-negative patients with HBV-LC who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. APPROACH AND RESULTS From 2 centers, 494 HBeAg-negative patients with HBV-LC who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, HBsAg loss, liver-related mortality/transplantation, and overall survival rates were compared between 2 groups with 1:1 propensity score matching of sex, treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end of therapy in finite group or 3-year on-therapy in continuous groups. During a median follow-up of 6.2 (3.4-8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/y and 10-y 15.7% vs. 26.8%, respectively; log-rank test, p <0.0001). The finite group showed greater HBsAg decline/year (-0.116 vs. -0.095 log 10 IU/mL, p =0.0026) and 7.6 times higher 10-year incidence of HBsAg loss (22.7% vs. 3%, p <0.0001). Multivariate Cox regression showed finite therapy an independent factor for HBsAg loss (adjusted HR: 11.79) but protective against HCC (adjusted HR: 0.593), liver-related mortality/transplantation (adjusted HR: 0.312), and overall mortality (adjusted HR: 0.382). CONCLUSIONS Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss, and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Yi-Cheng Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Chih-Lang Lin
- College of Medicine, Chang Gung University, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Keelung Branch, Taiwan
| | - Chia-Ying Wu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Yen-Chun Liu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Chien-Wei Peng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Chung-Wei Su
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Cheng-Er Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
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11
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Jung CY, Jung HY, Kim HW, Ryu GW, Lee JI, Ahn SH, Kim SU, Kim BS. Fibrotic Burden in Patients With Hepatitis B Virus-Related Cirrhosis Is Independently Associated With Poorer Kidney Outcomes. J Infect Dis 2024; 229:108-116. [PMID: 37470458 DOI: 10.1093/infdis/jiad273] [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: 03/30/2023] [Revised: 07/06/2023] [Accepted: 07/18/2023] [Indexed: 07/21/2023] Open
Abstract
BACKGROUND We investigated whether higher fibrotic burden was independently associated with poorer kidney outcomes in patients with hepatitis B virus (HBV)-related cirrhosis. METHODS A total of 1691 patients with radiologically diagnosed HBV-related cirrhosis but without baseline chronic kidney disease (CKD) who underwent transient elastography (TE) between March 2012 and August 2018 were selected. The study outcome was the composite of development of incident CKD, defined as the occurrence of estimated glomerular filtration rate (eGFR) <60 mL/minute/1.73 m2 or proteinuria (≥1+ on dipstick test) on 2 consecutive measurements during follow-up, 50% decline in eGFR or onset of end-stage kidney disease (initiation of chronic dialysis), or all-cause mortality. RESULTS The mean age was 53.4 years and 1030 (60.9%) patients were male. During 8379 person-years of follow-up (median 5.2 years), 60 (3.5%) patients experienced study outcomes. When stratified according to TE-defined fibrotic burden, multivariable Cox models revealed that risk of poorer kidney outcomes was 2.77-fold (95% confidence interval, 1.16-6.63; P < .001) higher in patients with liver stiffness range indicating cirrhosis (≥11.7 kPa), compared to those without significant liver fibrosis (<7.9 kPa). These associations remained significant even after adjusting for vigorous confounders. CONCLUSIONS Higher fibrotic burden assessed using TE was independently associated with poorer kidney outcomes in patients with HBV-related cirrhosis.
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Affiliation(s)
- Chan-Young Jung
- Department of Internal Medicine, Yonsei University College of Medicine
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine
| | - Hui-Yun Jung
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Hyung Woo Kim
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Geun Woo Ryu
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Jung Il Lee
- Division of Gastroenterology, Gangnam Severance Hospital
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Beom Seok Kim
- Department of Internal Medicine, Yonsei University College of Medicine
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12
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Zhong Y, Hang L, Wang F, Shen B, Shen C, Xue Y, Jia H, Wang L, Yuan H. Herpetetrone nanosuspensions enhance drug solubility and bioavailability to improve anti-hepatic fibrosis effects. J Microencapsul 2023; 40:587-598. [PMID: 37733492 DOI: 10.1080/02652048.2023.2258974] [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: 11/20/2022] [Accepted: 09/08/2023] [Indexed: 09/23/2023]
Abstract
The aim of this study was to enhance the dissolution rate and oral bioavailability of herpetetrone (HPT) by preparing nanosuspensions (NSs) and evaluate the changes in its anti-hepatic fibrosis effect. Herpetetrone nanosuspension (HPT-NS) was prepared using the ultrasound-precipitation technique, and characterised on the basis of mean diameter, zeta potential (ZP), encapsulation efficiency percent (EE%), scanning electron microscopy (SEM), and X-ray powder diffraction (XRPD). In addition, the pharmacokinetics and anti-hepatic fibrosis activity were evaluated. HPT-NS prepared with the optimised formulation was found to be spherical with mean diameter of 177.48 ± 6.13 nm, polydispersity index (PDI) of 0.108 ± 0.002 and ZP of -17.28 ± 2.02 mV. The EE (m/m, %) was 83.25 ± 0.27. XRPD analyses confirmed that the amorphous state of HPT in HPT-NS remained unchanged. The dissolution rate of HPT-NS was significantly higher than that of HPT coarse suspensions (HPT-CSs). Following oral administration, Cmax and AUC0-t of HPT-NS showed a significant increase (p < 0.05). In vitro, HPT inhibited the proliferation of HSC-T6 cells and induced apoptosis by up-regulating the expression of Bax proteins and down-regulating the expression of Bcl-2 and TGF-β1 proteins. Compared with HPT-CS, HPT-NS exhibited a more pronounced anti-fibrotic effect. HPT-NS, as a new drug formulation designed to improve the solubility and bioavailability of the drug, shows promising potential in enhancing the anti-liver fibrosis effect.
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Affiliation(s)
- Yuji Zhong
- Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
- School of Medicine, Huaqiao University, Quanzhou, China
| | - Lingyu Hang
- Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
| | - Fang Wang
- Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
- School of Medicine, Huaqiao University, Quanzhou, China
| | - Baode Shen
- Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
| | - Chengying Shen
- Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
| | - Yuye Xue
- Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
| | - Haiqiang Jia
- Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
- School of Medicine, Huaqiao University, Quanzhou, China
| | - Liqiang Wang
- School of Medicine, Huaqiao University, Quanzhou, China
| | - Hailong Yuan
- Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
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14
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Kumar R, Kumar S, Prakash SS. Compensated liver cirrhosis: Natural course and disease-modifying strategies. World J Methodol 2023; 13:179-193. [PMID: 37771878 PMCID: PMC10523240 DOI: 10.5662/wjm.v13.i4.179] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/05/2023] [Accepted: 06/27/2023] [Indexed: 09/20/2023] Open
Abstract
Compensated liver cirrhosis (CLC) is defined as cirrhosis with one or more decompensating events, such as ascites, variceal haemorrhage, or hepatic encephalopathy. Patients with CLC are largely asymptomatic with preserved hepatic function. The transition from CLC to decompensated cirrhosis occurs as a result of a complex interaction between multiple predisposing and precipitating factors. The first decompensation event in CLC patients is considered a significant turning point in the progression of cirrhosis, as it signals a drastic decline in median survival rates from 10-12 years to only 1-2 years. Furthermore, early cirrhosis has the potential to regress as liver fibrosis is a dynamic condition. With the advent of effective non-invasive tools for detecting hepatic fibrosis, more and more patients with CLC are currently being recognised. This offers clinicians a unique opportunity to properly manage such patients in order to achieve cirrhosis regression or, at the very least, prevent its progression. There are numerous emerging approaches for preventing or delaying decompensation in CLC patients. A growing body of evidence indicates that treating the underlying cause can lead to cirrhosis regression, and the use of non-selective beta-blockers can prevent decompensation by lowering portal hypertension. Additionally, addressing various cofactors (such as obesity, diabetes, dyslipidaemia, and alcoholism) and precipitating factors (such as infection, viral hepatitis, and hepatotoxic drugs) that have a detrimental impact on the natural course of cirrhosis may benefit patients with CLC. However, high-quality data must be generated through well-designed and adequately powered randomised clinical trials to validate these disease-modifying techniques for CLC patients. This article discussed the natural history of CLC, risk factors for its progression, and therapeutic approaches that could alter the trajectory of CLC evolution and improve outcomes.
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Affiliation(s)
- Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Sudhir Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Sabbu Surya Prakash
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
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15
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Cho H, Lee YB, Ha Y, Chon YE, Kim MN, Lee JH, Park H, Rim KS, Hwang SG. Changes in liver stiffness values assessed using transient elastography in chronic hepatitis B patients treated with tenofovir disoproxil fumarate: a prospective observational study. BMC Gastroenterol 2023; 23:210. [PMID: 37322445 DOI: 10.1186/s12876-023-02846-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 06/06/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND/AIMS Regression of liver fibrosis during antiviral therapy in chronic hepatitis B (CHB) patients has been demonstrated, but data on the influence of long-term treatment with tenofovir disoproxil fumarate (TDF) on liver stiffness (LS) measured by transient elastography are scarce. We aimed to investigate the changes in LS values during the 144-week TDF therapy in treatment-naïve CHB patients. METHODS This prospective observational study was conducted from April 2015 to July 2020 at CHA Bundang Medical Center. Laboratory tests and LS measurements were performed at baseline and repeated at weeks 12, 24, 48, 96, and 144. A significant decline in LS was defined as ≥ 30% decrease in LS value at week 96 from baseline. RESULTS A total of 48 treatment-naïve CHB patients initiating TDF therapy were screened, and 36 patients were included in the final analysis (median age, 46 [interquartile range, 34.5-55.8] years; 19 men [52.8%]). During TDF therapy, the median LS values decreased from 13.8 kPa at baseline to 8.7 kPa, 6.5 kPa, and 6.4 kPa at weeks 48, 96, and 144, respectively (all P < 0.001). At week 96, virological and biochemical responses were achieved in 34 (94.4%) patients and 20 (76.9%) patients, respectively. Moreover, 21 of 36 (58.3%) patients showed a significant decline in LS value. A higher baseline LS value was a single independent predictor for the reduction in LS value at week 96 from baseline (P < 0.001). CONCLUSIONS During the 144-week TDF therapy, LS values declined significantly in treatment-naïve CHB patients.
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Affiliation(s)
- Heejin Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
| | - Yeonjung Ha
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Young Eun Chon
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Mi Na Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Joo Ho Lee
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Hana Park
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
- Health Screening and Promotion Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyu Sung Rim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
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16
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Gao V, Long MT, Singh SR, Kim Y, Zhang X, Rogers G, Jacques PF, Levy D, Ma J. A Healthy Diet is Associated with a Lower Risk of Hepatic Fibrosis. J Nutr 2023; 153:1587-1596. [PMID: 37023964 PMCID: PMC10273161 DOI: 10.1016/j.tjnut.2023.03.038] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/13/2023] [Accepted: 03/31/2023] [Indexed: 04/07/2023] Open
Abstract
BACKGROUND Higher diet quality is associated with a lower risk of NAFLD. OBJECTIVES We examined the relationship between diet quality and hepatic fibrosis. METHODS We analyzed cross-sectional associations between 3 a priori diet quality scores-the Dietary Approaches to Stop Hypertension (DASH) score, the Alternative Healthy Eating Index (AHEI), and a modified Mediterranean-style Diet Score (MDS)-and hepatic fat [controlled attenuation parameter (CAP)] and fibrosis [liver stiffness measurement (LSM)] measured by vibration-controlled transient elastography (VCTE) in 2532 Framingham Heart Study (FHS) participants and 3295 participants of the National Health and Nutrition Examination Survey (NHANES). RESULTS Higher diet quality scores were associated with lower LSM in both FHS and NHANES after adjustment for demographic and lifestyle factors. Additional adjustment for CAP or BMI attenuated the observed associations. Association strength was similar across all 3 diet quality scores. Fixed-effect meta-analysis demonstrated that, under CAP-adjusted models, the LSM decreases associated with 1-SD increase of the DASH, AHEI, and MDS scores were 2% (95% CI: 0.7%, 3.3%; P = 0.002), 2% (95% CI: 0.7%, 3.3%; P = 0.003), and 1.7% (95% CI: 0.7%, 2.6%; P = 0.001), respectively, whereas in the meta-analysis of BMI-adjusted models, LSM reductions associated with 1-SD increase of the DASH, AHEI, and MDS scores were 2.2% (95% CI: -0.1%, 2.2%; P = 0.07), 1.5% (95% CI: 0.3%, 2.7%; P = 0.02), and 0.9 (95% CI: -0.1%, 1.9%; P = 0.07), respectively. CONCLUSIONS We demonstrated associations of higher diet quality with favorable hepatic fat and fibrosis measures. Our data suggest that a healthy diet may reduce the likelihood of obesity and hepatic steatosis as well as the progression of steatosis to fibrosis.
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Affiliation(s)
- Vincent Gao
- Emory College of Arts and Sciences, Emory University, Atlanta, GA, United States
| | - Michelle T Long
- Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, MA, United States
| | - Shridhar R Singh
- Department of Ophthalmology and Visual Sciences, UMass Chan Medical School, Worcester, MA, United States
| | - Youjin Kim
- Division of Nutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, United States
| | - Xuehong Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Gail Rogers
- Epidemiology, Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, MA, United States
| | - Paul F Jacques
- Nutritional Epidemiology, Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, MA, United States
| | - Daniel Levy
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, and the Framingham Heart Study, Framingham, MA, United States
| | - Jiantao Ma
- Division of Nutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, United States.
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17
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Burdette D, Hyrina A, Song Z, Beran RK, Cheung T, Gilmore S, Kobayashi T, Li L, Liu Y, Niedziela-Majka A, Medley J, Mehra U, Morganelli P, Novikov N, Niu C, Tam D, Tang J, Wang J, Yue Q, Fletcher SP, Holdorf MM, Delaney WE, Feierbach B, Lazerwith S. Characterization of a Novel Capsid Assembly Modulator for the Treatment of Chronic Hepatitis B Virus Infection. Antimicrob Agents Chemother 2023; 67:e0134822. [PMID: 36519892 PMCID: PMC9872672 DOI: 10.1128/aac.01348-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 11/10/2022] [Indexed: 12/23/2022] Open
Abstract
The standard of care for the treatment of chronic hepatitis B (CHB) is typically lifelong treatment with nucleos(t)ide analogs (NAs), which suppress viral replication and provide long-term clinical benefits. However, infectious virus can still be detected in patients who are virally suppressed on NA therapy, which may contribute to the failure of these agents to cure most CHB patients. Accordingly, new antiviral treatment options are being developed to enhance the suppression of hepatitis B virus (HBV) replication in combination with NAs ("antiviral intensification"). Here, we describe GS-SBA-1, a capsid assembly modulator (CAM) belonging to class CAM-E, that demonstrates potent inhibition of extracellular HBV DNA in vitro (EC50 [50% effective concentration] = 19 nM) in HBV-infected primary human hepatocytes (PHHs) as well as in vivo in an HBV-infected immunodeficient mouse model. GS-SBA-1 has comparable activities across HBV genotypes and nucleos(t)ide-resistant mutants in HBV-infected PHHs. In addition, GS-SBA-1 demonstrated in vitro additivity in combination with tenofovir alafenamide (TAF). The administration of GS-SBA-1 to PHHs at the time of infection prevents covalently closed circular DNA (cccDNA) formation and, hence, decreases HBV RNA and antigen levels (EC50 = 80 to 200 nM). Furthermore, GS-SBA-1 prevents the production of extracellular HBV RNA-containing viral particles in vitro. Collectively, these data demonstrate that GS-SBA-1 is a potent CAM that has the potential to enhance viral suppression in combination with an NA.
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Affiliation(s)
| | | | - Zhijuan Song
- Gilead Sciences, Inc., Foster City, California, USA
| | | | - Tara Cheung
- Gilead Sciences, Inc., Foster City, California, USA
| | | | | | - Li Li
- Gilead Sciences, Inc., Foster City, California, USA
| | - Yang Liu
- Gilead Sciences, Inc., Foster City, California, USA
| | | | | | | | | | | | - Congrong Niu
- Gilead Sciences, Inc., Foster City, California, USA
| | - Danny Tam
- Gilead Sciences, Inc., Foster City, California, USA
| | | | | | - Qin Yue
- Gilead Sciences, Inc., Foster City, California, USA
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18
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Jung CY, Kim HW, Lee JI, Lee HW, Ahn SH, Kim SU, Kim BS. Similar risk of kidney function decline between tenofovir alafenamide and besifovir dipivoxil maleate in chronic hepatitis B. Liver Int 2022; 42:2408-2417. [PMID: 35943853 DOI: 10.1111/liv.15388] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 07/03/2022] [Accepted: 08/08/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Although tenofovir alafenamide (TAF) and besifovir dipivoxil maleate (BSV) are potent antiviral agents in the treatment of chronic hepatitis B (CHB) infection, their renal safety profiles have not been previously compared. This study compared the risk of kidney function decline among patients with treatment-naïve CHB treated with TAF or BSV. METHODS This multicenter, retrospective, longitudinal cohort study included 556 patients with treatment-naïve CHB treated with TAF (n = 366) or BSV (n = 190) between November 2017 and August 2021. The primary outcome was chronic kidney disease (CKD) progression, defined as an increase in CKD stage by at least one stage for at least three consecutive months. RESULTS 1:1 Propensity score matching yielded 154 patients in each treatment group. The mean estimated glomerular filtration rate (eGFR) was 100.4 vs. 100.3 ml/min/1.73 m2 in the TAF and BSV groups respectively. A total of 25 patients developed a progression in CKD stage ≥1, of which 13 and 12 patients were from the TAF and BSV treated groups respectively (3.1 vs. 3.3 per 1000 person-years; p = .751). The unadjusted hazard ratio for risk of progression in CKD stage ≥1 of the BSV group (vs. the TAF group) was 1.13 (95% confidence interval, 0.50-2.58; p = .758). This association persisted even after adjusting for potential confounders. Virological, serological and biochemical responses were also similar between the two treatment groups (all p > .05). CONCLUSIONS TAF and BSV showed a similar risk of kidney function decline in patients with treatment-naïve CHB. Further prospective randomized studies are warranted for validation.
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Affiliation(s)
- Chan-Young Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyung Woo Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jung Il Lee
- Division of Gastroenterology, Gangnam Severance Hospital, Seoul, Republic of Korea
| | - Hyun Woong Lee
- Division of Gastroenterology, Gangnam Severance Hospital, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.,Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.,Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Beom Seok Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
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Older Age and High α-Fetoprotein Predict Higher Risk of Hepatocellular Carcinoma in Chronic Hepatitis-B-Related Cirrhotic Patients Receiving Long-Term Nucleos(t)ide Analogue Therapy. Diagnostics (Basel) 2022; 12:diagnostics12092085. [PMID: 36140487 PMCID: PMC9497657 DOI: 10.3390/diagnostics12092085] [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: 07/18/2022] [Revised: 08/22/2022] [Accepted: 08/25/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Nucleos(t)ide analogues (NUCs) were proved to reduce hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) patients, but data were limited on their efficacy in cirrhotic CHB patients. Methods: A total of 447 cirrhotic CHB patients treated with tenofovir/entecavir were retrospectively analyzed and divided into HCC (n = 48) and non-HCC (n = 399) groups. The median follow-up period was 62.1 months. Results: A total of 48 patients (10.7%) developed HCC during surveillance. The annual incidence rate of HCC was 2.04 per 100 person-years. The cumulative incidence of HCC was 0.9%, 9.8%, and 22.1% at 1, 5, and 10 years, respectively. Significant predictors for HCC identified using a multiple Cox regression analysis were age ≥50 years (hazard ratio (HR): 2.34) and α-fetoprotein (AFP) ≥8 ng/mL (HR: 2.05). The incidence rate of HCC was 8.67-fold higher in patients with age ≥50 years and AFP ≥8 ng/mL (3.14 per 100 person-years) than those with age <50 years and AFP <8 ng/mL (0.36 per 100 person-years). Conclusions: Cirrhotic CHB patients with age <50 years and AFP <8 ng/mL had the lowest annual incidence of HCC. However, those with age ≥50 years or/and AFP ≥8 ng/mL had a significantly higher risk for HCC development and warrant a careful surveillance schedule.
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20
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Orr CE, Wang PL, Chen L, Wang T. Features of fibrosis regression abound in “non-cirrhotic” patients with resected hepatocellular carcinoma. PLoS One 2022; 17:e0267474. [PMID: 35552548 PMCID: PMC9098014 DOI: 10.1371/journal.pone.0267474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 04/08/2022] [Indexed: 11/18/2022] Open
Abstract
Cirrhosis is a major risk factor for developing hepatocellular carcinoma (HCC). However, many surgically resected HCCs are presumably non-cirrhotic. The dynamic nature of chronic liver disease leads to periods of hepatic repair and fibrosis regression. We hypothesize that most resected HCCs, including those from non-cirrhotic patients, exhibit features of fibrosis regression in their background liver, suggesting previously more advanced liver disease. We reviewed the histology of 37 HCC resections performed between 2005–2020, including 30 from non-cirrhotic patients. The non-neoplastic liver was evaluated for features of liver disease and of the hepatic repair complex (HRC). CD34 immunohistochemistry was performed as a marker of sinusoidal capillarization. CD34 staining was evaluated manually and also by a digital image classifier algorithm. Overall, 28 cases (76%) had a high number of fibrosis regression and hepatic repair features (≥4 out of 8 features). Amongst the 30 non-cirrhotic patients, 21 (70%) showed a high number of repair features. Relative CD34 expression was increased in cases with a high number (≥4) of HRC features versus a low number (≤3) of features (p = 0.019). High HRC cases were more likely to exhibit nodular circumferential CD34 staining (p = 0.019). Our findings suggest that most resected HCC from non-cirrhotic patients display features of fibrosis regression in their background liver. Thus many, if not most, HCC patients who are “non-cirrhotic” may in fact have regressed cirrhosis. This finding reinforces that patients with regressed cirrhosis continue to be at high risk for HCC.
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Affiliation(s)
- Christine E. Orr
- Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada
| | - Peter L. Wang
- Department of Medicine, Division of Gastroenterology, Queen’s University, Kingston, Ontario, Canada
| | - Lina Chen
- Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - Tao Wang
- Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada
- * E-mail:
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21
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Jung CY, Kim HW, Ahn SH, Kim SU, Kim BS. Higher risk of kidney function decline with entecavir than tenofovir alafenamide in patients with chronic hepatitis B. Liver Int 2022; 42:1017-1026. [PMID: 35220649 DOI: 10.1111/liv.15208] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 01/03/2022] [Accepted: 02/16/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Entecavir (ETV) and tenofovir alafenamide (TAF) are the preferred agents in patients with predisposing factors for nephrotoxicity, but no studies to date have directly compared the renal safety of the two antiviral agents. Hence, we compared the risk of kidney function decline among patients with treatment-naïve chronic hepatitis B (CHB) treated with ETV or TAF. METHODS This study included 1988 patients with treatment-naïve CHB who were treated with ETV (n = 1839) or TAF (n = 149) between 2007 and 2020 for ETV and between 2017 and 2020 for TAF. The primary outcome was chronic kidney disease (CKD) progression, defined as an increase in CKD stage by at least one stage for at least three consecutive months. RESULTS A 1:1 propensity score match yielded 149 patients in each treatment group. The mean estimated glomerular filtration rate (eGFR) was 100.6 ml/min/1.73 m2 vs. 101.3 ml/min/1.73 m2 in the ETV and TAF groups respectively. A total of 61 patients developed a progression in CKD stage ≥ 1, of which 47 and 14 patients were from the ETV- and TAF-treated groups respectively (19.9 vs. 5.1 per 1000 person-years; p < .001). The risk of progression in CKD stage ≥1 was significantly higher in patients treated with ETV, even when adjusted for potential confounders (adjusted hazard ratio 4.05; 95% CI 2.14-7.68; p < .001). CONCLUSIONS ETV was associated with a higher risk of kidney function decline than TAF in patients with treatment-naïve CHB. Therefore, further prospective randomized studies are needed.
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Affiliation(s)
- Chan-Young Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyung Woo Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.,Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.,Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Beom Seok Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
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22
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Recent Advancements in Antifibrotic Therapies for Regression of Liver Fibrosis. Cells 2022; 11:cells11091500. [PMID: 35563807 PMCID: PMC9104939 DOI: 10.3390/cells11091500] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/21/2022] [Accepted: 04/26/2022] [Indexed: 11/18/2022] Open
Abstract
Cirrhosis is a severe form of liver fibrosis that results in the irreversible replacement of liver tissue with scar tissue in the liver. Environmental toxicity, infections, metabolic causes, or other genetic factors including autoimmune hepatitis can lead to chronic liver injury and can result in inflammation and fibrosis. This activates myofibroblasts to secrete ECM proteins, resulting in the formation of fibrous scars on the liver. Fibrosis regression is possible through the removal of pathophysiological causes as well as the elimination of activated myofibroblasts, resulting in the reabsorption of the scar tissue. To date, a wide range of antifibrotic therapies has been tried and tested, with varying degrees of success. These therapies include the use of growth factors, cytokines, miRNAs, monoclonal antibodies, stem-cell-based approaches, and other approaches that target the ECM. The positive results of preclinical and clinical studies raise the prospect of a viable alternative to liver transplantation in the near future. The present review provides a synopsis of recent antifibrotic treatment modalities for the treatment of liver cirrhosis, as well as a brief summary of clinical trials that have been conducted to date.
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23
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Pan Y, Tan WF, Yang MQ, Li JY, Geller DA. The therapeutic potential of exosomes derived from different cell sources in liver diseases. Am J Physiol Gastrointest Liver Physiol 2022; 322:G397-G404. [PMID: 35107032 PMCID: PMC8917924 DOI: 10.1152/ajpgi.00054.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Exosomes are small nanovesicles with a size of approximately 40-120 nm that are secreted from cells. They are involved in the regulation of cell homeostasis and mediate intercellular communication. In addition, they carry proteins, nucleic acids, and lipids that regulate the biological activity of receptor cells. Recent studies have shown that exosomes perform important functions in liver diseases. This review will focus on liver diseases (drug-induced liver injury, hepatic ischemia-reperfusion injury, liver fibrosis, acute liver failure, and hepatocellular carcinoma) and summarize the therapeutic potential of exosomes from different cell sources in liver disease.
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Affiliation(s)
- Yun Pan
- 1Colorectal Cancer Center, Tenth People’s Hospital of Tongji University, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Wei-Feng Tan
- 2Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Mu-Qing Yang
- 3Department of General Surgery, Tenth People’s Hospital of Tongji University, Tongji University, Shanghai, People’s Republic of China
| | - Ji-Yu Li
- 3Department of General Surgery, Tenth People’s Hospital of Tongji University, Tongji University, Shanghai, People’s Republic of China
| | - David A. Geller
- 4Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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24
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Wang FD, Zhou J, Chen EQ. Molecular Mechanisms and Potential New Therapeutic Drugs for Liver Fibrosis. Front Pharmacol 2022; 13:787748. [PMID: 35222022 PMCID: PMC8874120 DOI: 10.3389/fphar.2022.787748] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/17/2022] [Indexed: 12/11/2022] Open
Abstract
Liver fibrosis is the pathological process of excessive extracellular matrix deposition after liver injury and is a precursor to cirrhosis, hepatocellular carcinoma (HCC). It is essentially a wound healing response to liver tissue damage. Numerous studies have shown that hepatic stellate cells play a critical role in this process, with various cells, cytokines, and signaling pathways engaged. Currently, the treatment targeting etiology is considered the most effective measure to prevent and treat liver fibrosis, but reversal fibrosis by elimination of the causative agent often occurs too slowly or too rarely to avoid life-threatening complications, especially in advanced fibrosis. Liver transplantation is the only treatment option in the end-stage, leaving us with an urgent need for new therapies. An in-depth understanding of the mechanisms of liver fibrosis could identify new targets for the treatment. Most of the drugs targeting critical cells and cytokines in the pathogenesis of liver fibrosis are still in pre-clinical trials and there are hardly any definitive anti-fibrotic chemical or biological drugs available for clinical use. In this review, we will summarize the pathogenesis of liver fibrosis, focusing on the role of key cells, associated mechanisms, and signaling pathways, and summarize various therapeutic measures or drugs that have been trialed in clinical practice or are in the research stage.
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25
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Kim TH, Kim M, Yim HJ, Suh SJ, Jung YK, Seo YS, Um SH, Lee JI, Lee SH, Kim SG, Kim IH, Kim HS, Cho EY, Kim TY, Hwang SG. Telbivudine Plus Adefovir Versus Lamivudine Plus Adefovir for Lamivudine-Resistant Chronic Hepatitis B: TeSLA Randomized Trial. HEPATITIS MONTHLY 2022; 21. [DOI: 10.5812/hepatmon.121627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Background: In countries with unavailable tenofovir, a combination of lamivudine (LMV) and adefovir (ADV) is recommended for the treatment of LMV-resistant chronic hepatitis B (CHB). Considering that telbivudine (L-dT) was demonstrated to be superior to LMV in previous studies, L-dT and ADV combination therapy is expected to show better antiviral efficacy than the combination of LMV and ADV in patients with LMV-resistant CHB. Methods: This was a prospective randomized multicenter study. The primary endpoint was Hepatitis B Virus (HBV) DNA reduction after 52 weeks of treatment. The secondary endpoints were HBV DNA undetectability, hepatitis B e antigen seroconversion, the incidence of virological and biochemical breakthroughs, and safety during the study period. Results: A total of 43 LMV-resistant CHB patients were enrolled. Twenty-one were treated with LMV + ADV and 22 with L-dT + ADV. After 52 weeks of antiviral treatment, the HBV DNA reduction showed no significant intergroup difference (-4.54 ± 1.23 log IU/mL in the LMV + ADV group, -4.24 ± 1.46 log IU/mL in the L-dT + ADV group, P = 0.475). There were no significant intergroup differences in HBV DNA undetectability rates, mean HBV DNA level, or hepatitis B e antigen seroconversion rate at 13, 26, 39, and 52 weeks of treatment. In terms of safety, the mean creatine phosphokinase level was significantly higher in the L-dT + ADV group. Conclusions: In the treatment of LMV-resistant CHB, the combination of L-dT and ADV did not show any clinical benefit compared to the combination of LMV and ADV.
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26
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Russo FP, Zanetto A, Pinto E, Battistella S, Penzo B, Burra P, Farinati F. Hepatocellular Carcinoma in Chronic Viral Hepatitis: Where Do We Stand? Int J Mol Sci 2022; 23:500. [PMID: 35008926 PMCID: PMC8745141 DOI: 10.3390/ijms23010500] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/28/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in "high-risk" patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient's risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC.
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Affiliation(s)
| | | | | | | | | | | | - Fabio Farinati
- Gastroenterology/Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy; (F.P.R.); (A.Z.); (E.P.); (S.B.); (B.P.); (P.B.)
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27
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Caligiuri A, Gentilini A, Pastore M, Gitto S, Marra F. Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression. Cells 2021; 10:cells10102759. [PMID: 34685739 PMCID: PMC8534788 DOI: 10.3390/cells10102759] [Citation(s) in RCA: 136] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.
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28
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Gane EJ, Kim HJ, Visvanathan K, Kim YJ, Nguyen AH, Wallin JJ, Chen DY, McDonald C, Arora P, Tan SK, Gaggar A, Roberts SK, Lim YS. Safety, Pharmacokinetics, and Pharmacodynamics of the Oral TLR8 Agonist Selgantolimod in Chronic Hepatitis B. Hepatology 2021; 74:1737-1749. [PMID: 33704806 DOI: 10.1002/hep.31795] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 02/04/2021] [Accepted: 02/22/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS In patients with chronic hepatitis B (CHB) infection, activation of toll-like receptor 8 may induce antiviral immunity and drive functional cure. Selgantolimod, a toll-like receptor 8 agonist, was evaluated in patients with CHB who were virally suppressed on oral antiviral treatment or viremic and not on oral antiviral treatment. APPROACH AND RESULTS In this phase 1b study, patients were randomized 4:1 to receive either selgantolimod or placebo once weekly. Virally suppressed patients received either 1.5 mg (for 2 weeks) or 3 mg (for 2 weeks or 4 weeks). Viremic patients received 3 mg for 2 weeks. The primary endpoint was safety, as assessed by adverse events (AEs), laboratory abnormalities, and vital sign examination. Pharmacokinetic and pharmacodynamic parameters were assessed by plasma analysis. A total of 38 patients (28 virally suppressed, 10 viremic) were enrolled from six sites in Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in severity. The most common AEs were headache (32%), nausea (24%), and dizziness (13%). With a half-life of 5 hours, no accumulation of selgantolimod was observed with multiple dosing. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40 and IL-1RA, which are important for the expansion and activity of multiple T- cell subsets and innate immunity. CONCLUSION Selgantolimod was safe and well-tolerated in virally suppressed and viremic patients with CHB and elicited cytokine responses consistent with target engagement. Further studies with longer durations of selgantolimod treatment are required to evaluate efficacy.
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Affiliation(s)
- Edward J Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | | | - Kumar Visvanathan
- St. Vincent's Hospital Melbourne and University of Melbourne, Fitzroy, VIC, Australia
| | - Yoon Jun Kim
- Seoul National University Hospital, Seoul, South Korea
| | | | | | | | | | | | | | | | - Stuart K Roberts
- Alfred Hospital and Monash University, Melbourne, VIC, Australia
| | - Young-Suk Lim
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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29
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Yoshikawa M, Kudo K, Harada T, Harashima K, Suzuki J, Ogawa K, Fujiwara T, Nishida M, Sato R, Shirai T, Bito Y. Quantitative Susceptibility Mapping versus R2*-based Histogram Analysis for Evaluating Liver Fibrosis: Preliminary Results. Magn Reson Med Sci 2021; 21:609-622. [PMID: 34483224 DOI: 10.2463/mrms.mp.2020-0175] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
PURPOSE The staging of liver fibrosis is clinically important, and a less invasive method is preferred. Quantitative susceptibility mapping (QSM) has shown a great potential in estimating liver fibrosis in addition to R2* relaxometry. However, few studies have compared QSM analysis and liver fibrosis. We aimed to evaluate the feasibility of estimating liver fibrosis by using QSM and R2*-based histogram analyses by comparing it with ultrasound-based transient elastography and the stage of histologic fibrosis. METHODS Fourteen patients with liver disease were enrolled. Data sets of multi-echo gradient echo sequence with breath-holding were acquired on a 3-Tesla scanner. QSM and R2* were reconstructed by water-fat separation method, and ROIs were analyzed for these images. Quantitative parameters with histogram features (mean, variance, skewness, kurtosis, and 1st, 10th, 50th, 90th, and 99th percentiles) were extracted. These data were compared with the elasticity measured by ultrasound transient elastography and histological stage of liver fibrosis (F0 to F4, based on the new Inuyama classification) determined by biopsy or hepatectomy. The correlation of histogram parameters with intrahepatic elasticity and histologically confirmed fibrosis stage was examined. Texture parameters were compared between subgroups divided according to fibrosis stage. Receiver operating characteristic (ROC) analysis was also performed. P < 0.05 indicated statistical significance. RESULTS The six histogram parameters of both QSM and R2*were significantly correlated with intrahepatic elasticity. In particular, three parameters (variance, percentiles [90th and 99th]) of QSM showed high correlation (r = 0.818-0.844), whereas R2* parameters showed a moderate correlation with elasticity. Four parameters of QSM were significantly correlated with fibrosis stage (ρ = 0.637-0.723) and differentiated F2-4 from F0-1 fibrosis and F3-4 from F0-2 fibrosis with areas under the ROC curve of > 0.8, but those of R2* did not. CONCLUSION QSM may serve as a promising surrogate indicator in detecting liver fibrosis.
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Affiliation(s)
- Masato Yoshikawa
- Department of Diagnostic Imaging, Hokkaido University Graduate School of Medicine
| | - Kohsuke Kudo
- Department of Diagnostic Imaging, Hokkaido University Graduate School of Medicine.,Global Center for Biomedical Science and Engineering, Hokkaido University Faculty of Medicine
| | - Taisuke Harada
- Center for Cause of Death Investigation, Hokkaido University Faculty of Medicine.,Department of Diagnostic and Interventional Radiology, Hokkaido University Hospital
| | - Kazutaka Harashima
- Department of Diagnostic and Interventional Radiology, Hokkaido University Hospital
| | - Jun Suzuki
- Department of Radiation Oncology, Hakodate Municipal Hospital
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine
| | - Taro Fujiwara
- Department of Radiology, Division of Medical Imaging and Technology, Hokkaido University Hospital
| | - Mutsumi Nishida
- Diagnostic Center for Sonography, Hokkaido University Hospital
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30
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Yoshino K, Taura K, Iwaisako K, Masano Y, Uemoto Y, Kimura Y, Nam NH, Nishino H, Ikeno Y, Okuda Y, Nishio T, Yamamoto G, Seo S, Uemoto S. Novel mouse model for cholestasis-induced liver fibrosis resolution by cholecystojejunostomy. J Gastroenterol Hepatol 2021; 36:2493-2500. [PMID: 33448457 DOI: 10.1111/jgh.15406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 01/04/2021] [Accepted: 01/09/2021] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIM Studies on the resolution of liver fibrosis are becoming more important in this era of etiologic eradication. In contrast to the extensive research on the recovery of liver fibrosis induced by hepatotoxic injuries, regression of cholestatic liver fibrosis has been insufficiently examined owing to the limited availability of animal models. METHODS We examined our novel recanalization mice model of biliary obstruction, involving anastomosis between the gallbladder and jejunum (G-J anastomosis) by invagination. Transgenic mice expressing green fluorescent protein (GFP) under the collagen 1(α)1 promoter underwent G-J anastomosis 14 days after bile duct ligation (BDL) and were sacrificed 14 days later. RESULTS Transaminase and total bilirubin levels decreased to almost normal values on day 14 after G-J anastomosis. G-J anastomosis resulted in dramatic reversal of liver fibrosis induced by BDL. Activated portal fibroblasts (PFs) double-positive for GFP and Thy-1 on immunofluorescence in the liver of BDL-injured mice became less noticeable following G-J anastomosis. Messenger RNA expression of markers for activated PFs in the liver was downregulated after anastomosis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were induced by BDL. After anastomosis, expressions of MMP-3, 8 as well as hepatocyte growth factor were further upregulated, whereas those of TIMP-1 and TIMP-3 were markedly downregulated. CONCLUSIONS Our established G-J anastomosis model is associated with fibrosis resolution and reduced PF activation through reopening of bile duct obstruction and will be valuable for studying the recovery process of cholestatic liver fibrosis.
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Affiliation(s)
- Kenji Yoshino
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kojiro Taura
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Keiko Iwaisako
- Faculity of Life and Medical Sciences, Department of Medical Life Systems, Doshisha University, Kyoto, Japan
| | - Yuki Masano
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yusuke Uemoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yusuke Kimura
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Nguyen Hai Nam
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroto Nishino
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshinobu Ikeno
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yukihiro Okuda
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takahiro Nishio
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Gen Yamamoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Satoru Seo
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
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31
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Tadokoro T, Morishita A, Masaki T. Diagnosis and Therapeutic Management of Liver Fibrosis by MicroRNA. Int J Mol Sci 2021; 22:8139. [PMID: 34360904 PMCID: PMC8347497 DOI: 10.3390/ijms22158139] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 02/07/2023] Open
Abstract
Remarkable progress has been made in the treatment and control of hepatitis B and C viral infections. However, fundamental treatments for diseases in which liver fibrosis is a key factor, such as cirrhosis, alcoholic/nonalcoholic steatohepatitis, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, are still under development and remain an unmet medical need. To solve this problem, it is essential to elucidate the pathogenesis of liver fibrosis in detail from a molecular and cellular perspective and to develop targeted therapeutic agents based on this information. Recently, microRNAs (miRNAs), functional RNAs of 22 nucleotides, have been shown to be involved in the pathogenesis of liver fibrosis. In addition, extracellular vesicles called "exosomes" have been attracting attention, and research is being conducted to establish noninvasive and extremely sensitive biomarkers using miRNAs in exosomes. In this review, we summarize miRNAs directly involved in liver fibrosis, miRNAs associated with diseases leading to liver fibrosis, and miRNAs related to complications of cirrhosis. We will also discuss the efficacy of each miRNA as a biomarker of liver fibrosis and pathology, and its potential application as a therapeutic agent.
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Affiliation(s)
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (T.T.); (T.M.)
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32
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Fujita K, Masaki T. Serum Biomarkers of Liver Fibrosis Staging in the Era of the Concept "Compensated Advanced Chronic Liver Disease". J Clin Med 2021; 10:3340. [PMID: 34362121 PMCID: PMC8347037 DOI: 10.3390/jcm10153340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/12/2021] [Accepted: 07/25/2021] [Indexed: 12/12/2022] Open
Abstract
Non-invasive indexes of liver fibrosis based on blood examinations have been developed for decades, partially replacing liver biopsy examinations. Recently, the concept of liver cirrhosis was revised and converted to "compensated advanced chronic liver diseases" since the Baveno VI consensus statement in 2015. The term "compensated advanced chronic liver diseases" was established based on the premise that serum biomarkers were not able to differentiate cirrhosis from severe fibrosis. The difficulty to histologically distinguish cirrhosis from severe fibrosis had been pointed out in 1977, when the definition and nomenclatures of cirrhosis had been determined by the World Health Organization. That was decades before serum biomarkers available at present were investigated. Though we are accustomed to differentiating the fibrosis stage as stage 1, 2, 3 (severe fibrosis), and 4 (cirrhosis), differentiation of cirrhosis from severe fibrosis is difficult even by histopathological examination. The current review will provide readers a framework to revise how to apply serum biomarkers on liver fibrosis staging in an era of the concept of "compensated advanced chronic liver disease".
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Affiliation(s)
- Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita District, Kagawa 761-0793, Japan;
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Yang X, Shu B, Zhou Y, Li Z, He C. Ppic modulates CCl 4-induced liver fibrosis and TGF-β-caused mouse hepatic stellate cell activation and regulated by miR-137-3p. Toxicol Lett 2021; 350:52-61. [PMID: 34224798 DOI: 10.1016/j.toxlet.2021.06.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 06/10/2021] [Accepted: 06/30/2021] [Indexed: 11/28/2022]
Abstract
Hepatic stellate cell activation, characterized by hyperproliferation and increased release of collagens, is a critical event during the initiation and development of hepatic fibrosis. The deregulated genes among different expression profiles based on online datasets were analyzed, attempting to identify novel potential biomarkers and treatment targets for hepatic fibrosis. The abnormal upregulation of mouse peptidylprolyl isomerase C (Ppic) within the CCl4-caused hepatic fibrosis model in mice was identified according to bioinformatics and experimental analyses. The knockdown of Ppic in the CCl4-caused liver fibrosis murine model significantly improved CCl4-caused liver damage, decreased the fibrotic area, reduced ECM deposition, and reduced the hydroxyproline levels. The knockdown of Ppic in TGF-β-stimulated mouse hepatic stellate cells inhibited cell proliferation and decreased ECM levels. Through direct targeting, miR-137-3p negatively regulated Ppic expression. Contrastingly to Ppic knockdown, miR-137-3p inhibition further promoted cell proliferation and boosted ECM levels; the effects of miR-137-3p inhibition could be partially reversed by Ppic knockdown. Altogether, mmu-miR-137-3p directly targets Ppic and forms a regulatory axis with Ppic, modulating CCl4-caused hepatic fibrosis in mice and TGF-β-caused mouse hepatic stellate cell activation.
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Affiliation(s)
- Xin Yang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Bo Shu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Yingxia Zhou
- Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Zhuan Li
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Hunan Normal University School of Medicine, Changsha, Hunan, 410013, China; Department of Pharmacy, Hunan Normal University School of Medicine, Changsha, Hunan, 410013, China
| | - Chao He
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
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Yoshiji H, Nagoshi S, Akahane T, Asaoka Y, Ueno Y, Ogawa K, Kawaguchi T, Kurosaki M, Sakaida I, Shimizu M, Taniai M, Terai S, Nishikawa H, Hiasa Y, Hidaka H, Miwa H, Chayama K, Enomoto N, Shimosegawa T, Takehara T, Koike K. Evidence-based clinical practice guidelines for Liver Cirrhosis 2020. J Gastroenterol 2021; 56:593-619. [PMID: 34231046 PMCID: PMC8280040 DOI: 10.1007/s00535-021-01788-x] [Citation(s) in RCA: 189] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 02/07/2023]
Abstract
The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.
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Affiliation(s)
- Hitoshi Yoshiji
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.
- Department of Gastroenterology, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
| | - Sumiko Nagoshi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takemi Akahane
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshinari Asaoka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshiyuki Ueno
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Koji Ogawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takumi Kawaguchi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masayuki Kurosaki
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Isao Sakaida
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masahito Shimizu
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Makiko Taniai
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Shuji Terai
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroki Nishikawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoichi Hiasa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hisashi Hidaka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuaki Chayama
- The Japan Society of Hepatology, Kashiwaya 2 Building 5F, 3-28-10 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tetsuo Takehara
- The Japan Society of Hepatology, Kashiwaya 2 Building 5F, 3-28-10 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis", The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
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Yoshiji H, Nagoshi S, Akahane T, Asaoka Y, Ueno Y, Ogawa K, Kawaguchi T, Kurosaki M, Sakaida I, Shimizu M, Taniai M, Terai S, Nishikawa H, Hiasa Y, Hidaka H, Miwa H, Chayama K, Enomoto N, Shimosegawa T, Takehara T, Koike K. Evidence-based clinical practice guidelines for liver cirrhosis 2020. Hepatol Res 2021; 51:725-749. [PMID: 34231046 DOI: 10.1111/hepr.13678] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022]
Abstract
The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.
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Affiliation(s)
- Hitoshi Yoshiji
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan.,Department of Gastroenterology, Nara Medical University, Nara, Japan
| | - Sumiko Nagoshi
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Takemi Akahane
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Yoshinari Asaoka
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Yoshiyuki Ueno
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Koji Ogawa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Takumi Kawaguchi
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Masayuki Kurosaki
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Isao Sakaida
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Masahito Shimizu
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Makiko Taniai
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Shuji Terai
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Hiroki Nishikawa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Yoichi Hiasa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Hisashi Hidaka
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | | | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
| | | | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the Evidence-Based Clinical Practice Guidelines for Liver Cirrhosis, The Japanese Society of Gastroenterology/the Japan Society of hepatology, Tokyo, Japan
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Abstract
It has been reported that liver fibrosis could be reversed after eliminating liver injuries. This article systematically summarizes the evidence of fibrosis regression based on histology, liver stiffness, and serum biomarkers, and discusses several clinically relevant challenges. Evidence from liver biopsy has been regarded as the gold standard in the assessment of fibrosis regression. Semi-quantitative staging and grading systems are traditionally and routinely used to define regression. Recently, the predominantly regressive, indeterminate, and predominantly progressive score was proposed, based on the regressive features from "hepatic repair complex", to provide additional information regarding the quality of fibrosis. For non-invasive assessment, although liver stiffness and serum biomarkers could be applied to reflect the dynamic changes of liver fibrosis, other confounding factors such as liver inflammation have to be considered. In conclusion, both histology and non-invasive methods can provide evidence regarding fibrosis regression. The predictive value of fibrosis regression in long-term prognosis warrants further investigation.
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Güzelbulut F, Gökçen P, Can G, Adalı G, Değirmenci Saltürk AG, Bahadır Ö, Özdil K, Doğanay HL. Validation of the HCC-RESCUE score to predict hepatocellular carcinoma risk in Caucasian chronic hepatitis B patients under entecavir or tenofovir therapy. J Viral Hepat 2021; 28:826-836. [PMID: 33586270 DOI: 10.1111/jvh.13485] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/12/2021] [Accepted: 01/29/2021] [Indexed: 02/06/2023]
Abstract
The HCC-RESCUE score was developed to predict hepatocellular carcinoma (HCC) risk in Korean chronic hepatitis B (CHB) patients under entecavir therapy. We aimed to validate the HCC-RESCUE score to predict HCC risk in Caucasian CHB patients under entecavir or tenofovir therapy and to compare the predictive performance of the HCC-RESCUE score with those of the CAMD, PAGE-B and modified PAGE-B (mPAGE-B) scores. The study included 647 nucleos(t)ide analogue-naive noncirrhotic and compensated/decompensated cirrhotic patients who had received entecavir or tenofovir for ≥6 months and did not develop HCC during the first 6 months of therapy. Patients with HCC-RESCUE scores ≤64, 65-84 and ≥85 points were classified into low-, intermediate- and high-risk groups, respectively. The AUROCs of the HCC-RESCUE, CAMD, PAGE-B and mPAGE-B scores to predict HCC risk at 5 years were 0.875, 0.870, 0.866 and 0.880, and those at 10 years were 0.862, 0.845, 0.841 and 0.862, respectively (both p > .05). Cumulative HCC incidences at 5 years were 0.0%, 10.5% and 15.8%, and those at 10 years were 1.4%, 15.5% and 24.9%, respectively, in the low-, intermediate- and high-risk groups based on the HCC-RESCUE score (both log rank p < .001). In the entecavir versus tenofovir cohorts, the AUROCs of the HCC-RESCUE score to predict HCC risk at 5 and 10 years were 0.831 versus 0.898 and 0.803 versus 0.910, respectively (both p > .05). The HCC-RESCUE score accurately predicted HCC risk in Caucasian CHB patients under entecavir or tenofovir therapy. A substantial proportion of patients can be dropped from HCC surveillance by using the HCC-RESCUE score.
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Affiliation(s)
- Fatih Güzelbulut
- Department of Gastroenterology, Haydarpaşa Numune Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Pınar Gökçen
- Department of Gastroenterology, Ümraniye Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Güray Can
- Faculty of Medicine, Department of Gastroenterology, Abant Izzet Baysal University, Bolu, Turkey
| | - Gupse Adalı
- Department of Gastroenterology, Ümraniye Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Ayça Gökçen Değirmenci Saltürk
- Department of Gastroenterology, Haydarpaşa Numune Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Özgür Bahadır
- Department of Gastroenterology, Haydarpaşa Numune Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Kamil Özdil
- Department of Gastroenterology, Ümraniye Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Hamdi Levent Doğanay
- Department of Gastroenterology, Ümraniye Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
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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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Abayli B, Abaylı C, Gencdal G. Histopathological evaluation of long-term tenofovir disoproxil fumarate treatment in patients with hepatitis be antigen-negative chronic hepatitis B. World J Gastrointest Pharmacol Ther 2021; 12:32-39. [PMID: 33815864 PMCID: PMC8008959 DOI: 10.4292/wjgpt.v12.i2.32] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/10/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis B virus is a universal health problem. There are approximately 250 million people living with hepatitis B worldwide, and approximately 600000 of these people die every year due to the virus.
AIM To compare the pretreatment and post-treatment histopathological results of patients with hepatitis be antigen (HBeAg)-negative chronic hepatitis B (CHB) who had been receiving tenofovir disoproxil fumarate (TDF) treatment at our clinic for at least 5 years.
METHODS Patients with HBeAg-negative CHB who were being treated with TDF (245 mg/d) were included in the study. Liver biopsies of patients before TDF treatment and liver biopsies after 5 years of TDF treatment were retrospectively compared.
RESULTS A total of 50 HBeAg-negative CHB patients were included in the study (mean age: 47.9 ± 10.4 years, men: 27.54%). Histological improvement was observed in 78% (39) of the patients after 5 years of treatment. After the 5 years of treatment, the mean Ishak score of the patients was 1.3 ± 1.3, and the mean histologic activity index score was 4.1 ± 2.8. A 1.53 point reduction in Ishak fibrosis score was detected after long-term TDF treatment.
CONCLUSION Liver biopsies after 5 years of TDF treatment revealed a significant histological response and a regression of the necroinflammatory score compared to pretreatment liver biopsies. To better understand the effects of antiviral treatments on the improvement of liver histology, long-term studies involving larger numbers of patients are needed.
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Affiliation(s)
| | | | - Genco Gencdal
- Department of Gastroenterology, Hepatology and Liver Transplantation, Koc University, School of Medicine, İstanbul 34300, Turkey
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Li J, Zhang D, Zhang X. The Occurrence of rtA194T Mutant After Long-Term Lamivudine Monotherapy Remains Sensitive to Tenofovir Disoproxil Fumarate: A Case Report. Infect Drug Resist 2021; 14:1013-1017. [PMID: 33758517 PMCID: PMC7979339 DOI: 10.2147/idr.s295060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/03/2021] [Indexed: 01/11/2023] Open
Abstract
Tenofovir disoproxil fumarate (TDF) is recommended as first-line agents in chronic hepatitis B (CHB) patients for its high antiviral effects and high barrier to resistance. It is controversial whether the rtA194T mutation truly confers resistance against TDF. We present here a 62-year-old CHB patient who occurred rtL180M, rtM204V and rtA194T mutants after lamivudine (LAM) monotherapy for 9 years. TDF was introduced in replacement of LAM and led to Hepatitis B Virus (HBV) DNA undetectable in 1 month, maintained in the follow up of 52 weeks. These observations suggest that rtA194T mutation emerges under LAM monotherapy and remains sensitive to TDF.
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Affiliation(s)
- Jing Li
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Donghua Zhang
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xinxin Zhang
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Sino-French Research Centre for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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41
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BATTISTELLA S, LYNCH EN, GAMBATO M, ZANETTO A, PELLONE M, SHALABY S, SCIARRONE SS, FERRARESE A, GERMANI G, SENZOLO M, BURRA P, RUSSO FP. Hepatocellular carcinoma risk in patients with HBV-related liver disease receiving antiviral therapy. Minerva Gastroenterol (Torino) 2021; 67:38-49. [DOI: 10.23736/s2724-5985.20.02791-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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42
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Fraquelli M, Fanetti I, Costantino A. Elastography After Treatment and During Follow-Up. ELASTOGRAPHY OF THE LIVER AND BEYOND 2021:119-141. [DOI: 10.1007/978-3-030-74132-7_9] [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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43
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Dong Y, Li M, Zhu S, Gao X, Zhao P. De novo combination antiviral therapy in e antigen-negative chronic hepatitis B virus-infected paediatric patients with advanced fibrosis. J Viral Hepat 2020; 27:1338-1343. [PMID: 32810891 DOI: 10.1111/jvh.13372] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/10/2020] [Accepted: 08/11/2020] [Indexed: 01/04/2023]
Abstract
To date, studies that focus on treatment of e antigen-negative chronic hepatitis B virus-infected children with advanced fibrosis are extremely limited. This puts these patients at risk of rapid disease progression. Our study aimed to investigate the efficacy of combination antiviral therapy in this population. We prospectively enrolled treatment-naı̈ve paediatric patients between 1 year and 12 years of age who had e antigen-negative chronic hepatitis B and histologically proven advanced fibrosis. All patients received de novo combination therapy with lamivudine (LAM) and interferon-α (IFN) for 12 months and then were clinically followed up. The main outcome measure was rate of serum hepatitis B surface antigen (HBsAg) loss at month 12 of treatment. A total of 14 paediatric patients were enrolled, including 9 boys and 5 girls. All patients achieved undetectable HBV DNA levels at month 9 of treatment. A total of 5 patients (35.7%) achieved HBsAg loss at month 12 and finally developed HBsAg seroconversion. Four patients who did not clear HBsAg underwent second liver biopsy, and histological evaluation revealed significant improvements in all of them. As a serum fibrosis marker, aspartate aminotransferase-to-platelet ratio index after 12-month treatment in the 14 patients showed a significant improvement compared with that at baseline (P = .0021). No serious adverse events were observed during the study. Combination antiviral therapy is beneficial to e antigen-negative chronic hepatitis B virus-infected paediatric patients with advanced fibrosis. Further studies with larger cohorts are required.
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Affiliation(s)
- Yi Dong
- The Fifth Medical Center (formerly Beijing 302 Hospital), Chinese PLA General Hospital, Beijing, China
| | - Meina Li
- Department of Health Service, Second Military Medical University, Shanghai, China
| | - Shishu Zhu
- The Fifth Medical Center (formerly Beijing 302 Hospital), Chinese PLA General Hospital, Beijing, China
| | - Xue Gao
- The Fifth Medical Center (formerly Beijing 302 Hospital), Chinese PLA General Hospital, Beijing, China
| | - Pan Zhao
- The Fifth Medical Center (formerly Beijing 302 Hospital), Chinese PLA General Hospital, Beijing, China
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44
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Damiris K, Tafesh ZH, Pyrsopoulos N. Efficacy and safety of anti-hepatic fibrosis drugs. World J Gastroenterol 2020; 26:6304-6321. [PMID: 33244194 PMCID: PMC7656211 DOI: 10.3748/wjg.v26.i41.6304] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/30/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Recent progress in our understanding of the pathways linked to progression from hepatic insult to cirrhosis has led to numerous novel therapies being investigated as potential cures and inhibitors of hepatic fibrogenesis. Liver cirrhosis is the final result of prolonged fibrosis, which is an intimate balance between fibrogenesis and fibrinolysis. A number of these complex mechanisms are shared across the various etiologies of liver disease. Thankfully, investigation has yielded some promising results in regard to reversal of fibrosis, particularly the indirect benefits associated with antiviral therapy for the treatment of hepatitis B and C and the farnesoid receptor agonist for the treatment of primary biliary cholangitis and metabolic associated fatty liver disease. A majority of current clinical research is focused on targeting metabolic associated fatty liver disease and its progression to metabolic steatohepatitis and ultimately cirrhosis, with some hope of potential standardized therapeutics in the near future. With our ever-evolving understanding of the underlying pathophysiology, these therapeutics focus on either controlling the primary disease (the initial trigger of fibrogenesis), interrupting receptor ligand interactions and other intracellular communications, inhibiting fibrogenesis, or even promoting resolution of fibrosis. It is imperative to thoroughly test these potential therapies with the rigorous standards of clinical therapeutic trials in order to ensure the highest standards of patient safety. In this article we will briefly review the key pathophysiological pathways that lead to liver fibrosis and present current clinical and experimental evidence that has shown reversibility of liver fibrosis and cirrhosis, while commenting on therapeutic safety.
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Affiliation(s)
- Konstantinos Damiris
- Department of Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States
| | - Zaid H Tafesh
- Medicine-Gastroenterology and Hepatology, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Medicine-Gastroenterology and Hepatology, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States
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45
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Chon YE, Jung KS, Ha Y, Kim MN, Lee JH, Hwang SG, Ahn SH, Kim DY, Han KH, Park JY. High body mass index hinders fibrosis improvement in patients receiving long-term tenofovir therapy in hepatitis B virus-related cirrhosis. J Viral Hepat 2020; 27:1119-1126. [PMID: 32558181 DOI: 10.1111/jvh.13345] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 04/26/2020] [Accepted: 05/25/2020] [Indexed: 12/12/2022]
Abstract
Long-term suppression of hepatitis B virus with tenofovir (TDF) induces fibrosis regression, and repeated liver stiffness (LS) measurement can indicate the improvement of fibrosis. We aimed to investigate predictors for LS improvement assessed by changes in patients receiving long-term TDF therapy in chronic hepatitis B (CHB) with liver cirrhosis. CHB patients with histologically proven liver cirrhosis who received TDF as the first-line therapy from 2012 to 2015 were recruited. LS and controlled attenuation parameter (CAP) measurements were repeated at baseline and 3 years after therapy. Liver stiffness improvement was defined as a drop of LS value ≥30% from the baseline. A total of 131 patients were enrolled (mean age 51.4% and male 64.9%). After 3 years of TDF therapy, the mean LS value significantly improved (from 14.7 to 8.6 kPa, P < .001), and 96 (73.3%) patients have achieved LS improvement. Predictors associated with improvement of LS were low body mass index (BMI), HBeAg positivity, and low CAP value at baseline. In multivariate analysis, low BMI was a single factor independently associated with LS improvement (odds ratio 0.680, 95% CI 0.560-0.825, P < .001). Patients with BMI < 23.5, had a 1.96 times more chance of achieving LS improvement compared to those with BMI ≥ 23.5 (90.1% vs. 46.0%, P = .001). High BMI was a single significant factor hindering the fibrosis improvement in patients receiving long-term TDF therapy in CHB with liver cirrhosis. Life style modification and BMI reduction should be encouraged to enhance fibrosis improvement.
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Affiliation(s)
- Young Eun Chon
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Hospital, Seongnam, Korea
| | - Kyu Sik Jung
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Yeonjung Ha
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Hospital, Seongnam, Korea
| | - Mi Na Kim
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Hospital, Seongnam, Korea
| | - Joo Ho Lee
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Hospital, Seongnam, Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.,CHA Bundang Liver Center, CHA Bundang Hospital, Seongnam, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
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46
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Kumada T, Toyoda H, Tada T, Yasuda S, Tanaka J. Changes in Background Liver Function in Patients with Hepatocellular Carcinoma over 30 Years: Comparison of Child-Pugh Classification and Albumin Bilirubin Grade. Liver Cancer 2020; 9:518-528. [PMID: 33083278 PMCID: PMC7548913 DOI: 10.1159/000507933] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 04/11/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Background liver function in patients with hepatocellular carcinoma (HCC) has improved remarkably with advances in various treatments. Recently, the Child-Pugh classification (CPC) system has been recognized as limited in its ability to assess patients with good hepatic reserve. We compared the albumin-bilirubin (ALBI) grade, which is suitable for a more detailed evaluation of patients with good liver function, with CPC over a 30-year period. METHODS A total of 2,347 patients were analyzed. Patients were stratified by year of diagnosis into 6 groups: Group A (1990-1994, n = 376), Group B (1995-1999, n = 434), Group C (2000-2004, n = 438), Group D (2005-2009, n = 444), Group E (2010-2014, n = 392), and Group F (2015-2018, n = 263). We compared ALBI grade and CPC across the groups. RESULTS The prevalence of patients with CPC A at diagnosis increased throughout the study period, reaching nearly 80% in Groups E and F (p < 0.001). By contrast, the percentage of patients with ALBI grade 1 disease remained approximately 50% in Groups E and F (p < 0.001). Modified ALBI (mALBI) grade 2a corresponds to patients with CPC A who have poor hepatic function. There were significant survival differences between patients with mALBI grade 1 versus 2a, 1 versus 2b, and 2a versus 2b disease, respectively (p < 0.0001), in patients with CPC A. CONCLUSIONS CPC is not suitable for assessing patients with recently diagnosed HCC and good remnant hepatic function. In such patients with HCC, the prognosis can be stratified by ALBI grade rather than CPC.
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Affiliation(s)
- Takashi Kumada
- Department of Nursing, Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Toshifumi Tada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
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47
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Mohammed Abdul MK, Snyder HS, Chunduru M, Lee SMK, Satapathy SK. Hepatitis C Virus in the Elderly in the Direct-Acting Antiviral Era: from Diagnosis to Cure. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2020; 12:296-309. [PMID: 32837340 PMCID: PMC7418288 DOI: 10.1007/s40506-020-00231-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose of review Hepatitis C (HCV) is the most common cause of viral hepatitis in elderly individuals. This patient population previously experienced suboptimal outcomes with interferon-based regimens. Unfortunately, patients aged 65 years and older were underrepresented in phase 2 and 3 clinical trials with newer direct acting antiviral (DAA) therapies. Since the advent of second-generation DAA in 2013, numerous robust real-world experiences highlighting the efficacy and safety of DAA in the elderly have been published. This review article summarizes the cascade of care for hepatitis C from diagnosis to cure from an evidence-based perspective of the aging population. Recent finding In a large study from the Veterans Affairs Healthcare System, the overall sustained virologic response (SVR) of 15,884 patients treated with DAA regimens was 91.2%. These newer therapies remained highly effective in the subset of patients aged 65 years and older with SVR rates above 90%. A Spanish National Registry reported outcomes in patients ≥ 65 years old treated for HCV with oral DAA regimens over a 2-year period. The overall SVR was 94% in the study of 1252 subjects. Summary Current real-world data imply DAA treatment regimens remain highly effective and safe in elderly patients when compared to the general population.
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Affiliation(s)
| | - Heather S Snyder
- Department of Pharmacy, Methodist University Hospital, Memphis, TN USA
| | - Mythili Chunduru
- Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH USA
| | - Susan M K Lee
- Department of Internal Medicine, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Division of Hepatology, Northwell Health, 400 Community Drive, Manhasset, NY 11030 USA
| | - Sanjaya K Satapathy
- Department of Internal Medicine, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Division of Hepatology, Northwell Health, 400 Community Drive, Manhasset, NY 11030 USA.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 400 Community Drive, Manhasset, NY 11030 USA
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48
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Arteel GE, Naba A. The liver matrisome - looking beyond collagens. JHEP Rep 2020; 2:100115. [PMID: 32637906 PMCID: PMC7330160 DOI: 10.1016/j.jhepr.2020.100115] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/17/2020] [Accepted: 03/22/2020] [Indexed: 02/07/2023] Open
Abstract
The extracellular matrix (ECM) is a diverse microenvironment that maintains bidirectional communication with surrounding cells to regulate cell and tissue homeostasis. The classical definition of the ECM has more recently been extended to include non-fibrillar proteins that either interact or are structurally affiliated with the ECM, termed the 'matrisome.' In addition to providing the structure and architectural support for cells and tissue, the matrisome serves as a reservoir for growth factors and cytokines, as well as a signaling hub via which cells can communicate with their environment and vice-versa. The matrisome is a master regulator of tissue homeostasis and organ function, which can dynamically and appropriately respond to any stress or injury. Failure to properly regulate these responses can lead to changes in the matrisome that are maladaptive. Hepatic fibrosis is a canonical example of ECM dyshomeostasis, leading to accumulation of predominantly collagenous ECM; indeed, hepatic fibrosis is considered almost synonymous with collagen accumulation. However, the qualitative and quantitative alterations of the hepatic matrisome during fibrosis are much more diverse than simple accumulation of collagens and occur long before fibrosis is histologically detected. A deeper understanding of the hepatic matrisome and its response to injury could yield new mechanistic insights into disease progression and regression, as well as potentially identify new biomarkers for both. In this review, we discuss the role of the ECM in liver diseases and look at new "omic" approaches to study this compartment.
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Key Words
- AUROC, area under the receiver operating characteristic curve
- CCl4, carbon tetrachloride
- ECM
- ECM, extracellular matrix
- Extracellular matrix
- Fibrosis
- HCC, hepatocellular carcinoma
- Liver disease
- MMP, matrix metalloproteinase
- NAFLD, non-alcoholic fatty liver disease
- NPV, negative predictive value
- POSTN, periostin
- PPV, positive predictive values
- Proteomics
- Regeneration
- TGFβ, transforming growth factor beta
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Affiliation(s)
- Gavin E. Arteel
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, Pittsburgh, PA, USA
| | - Alexandra Naba
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
- University of Illinois Cancer Center, Chicago, IL, USA
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49
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Matsuda M, Seki E. The liver fibrosis niche: Novel insights into the interplay between fibrosis-composing mesenchymal cells, immune cells, endothelial cells, and extracellular matrix. Food Chem Toxicol 2020; 143:111556. [PMID: 32640349 DOI: 10.1016/j.fct.2020.111556] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 06/22/2020] [Accepted: 06/24/2020] [Indexed: 12/11/2022]
Abstract
Liver fibrosis is a hepatic wound-healing response caused by chronic liver diseases that include viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis, and cholestatic liver disease. Liver fibrosis eventually progresses to cirrhosis that is histologically characterized by an abnormal liver architecture that includes distortion of liver parenchyma, formation of regenerative nodules, and a massive accumulation of extracellular matrix (ECM). Despite intensive investigations into the underlying mechanisms of liver fibrosis, developments of anti-fibrotic therapies for liver fibrosis are still unsatisfactory. Recent novel experimental approaches, such as single-cell RNA sequencing and proteomics, have revealed the heterogeneity of ECM-producing cells (mesenchymal cells) and ECM-regulating cells (immune cells and endothelial cells). These approaches have accelerated the identification of fibrosis-specific subpopulations among these cell types. The ECM also consists of heterogenous components. Their production, degradation, deposition, and remodeling are dynamically regulated in liver fibrosis, further affecting the functions of cells responsible for fibrosis. These cellular and ECM elements cooperatively form a unique microenvironment: a fibrotic niche. Understanding the complex interplay between these elements could lead to a better understanding of underlying fibrosis mechanisms and to the development of effective therapies.
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Affiliation(s)
- Michitaka Matsuda
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - Ekihiro Seki
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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50
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Li C, Chen Y, Yuan X, He L, Li X, Huang S, Hou S, Liang J. Vitexin ameliorates chronic stress plub high fat diet-induced nonalcoholic fatty liver disease by inhibiting inflammation. Eur J Pharmacol 2020; 882:173264. [PMID: 32544504 DOI: 10.1016/j.ejphar.2020.173264] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 06/03/2020] [Accepted: 06/08/2020] [Indexed: 12/11/2022]
Abstract
Evidences showed that chronic stress (CS) can aggravate the situation of nonalcoholic fatty liver disease (NAFLD). Vitexin is one of the major components in hawthorn, which is widely used to reduce blood lipid. This study was aimed to explore the therapeutic effects and potential mechanisms of vitexin on chronic stress mice with high-fat diet (CSHFD). The results showed that 5-week vitexin administration (40 mg/kg, i.g.) could obviously reduce hepatic fat deposition, alleviate lipid metabolism, and inhibit liver inflammation in CSHFD mice. In addition, vitexin significantly reduced hepatic macrophage infiltration, obviously down-regulated the mRNA and protein expressions of hepatic SREBP-1c, FAS, ACC. Moreover, we also found that vitexin treatment could significantly inhibit the expressions of TLR4/NF-κB signaling in CSHFD mice. This results suggested that vitexin could ameliorate chronic stress combined with high-fat diet induced NAFLD, and its mechanisms is closely related to inhibit TLR4/NF-κB signaling and reduce fatty acid synthesis proteins.
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Affiliation(s)
- Chujie Li
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangzhou, 510006, PR China
| | - Yonger Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
| | - Xin Yuan
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangzhou, 510006, PR China
| | - Lian He
- Guangdong Food and Drug Vocational College, Guangzhou, 510520, Guangdong, PR China
| | - Xiaojun Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
| | - Song Huang
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangzhou, 510006, PR China
| | - Shaozhen Hou
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangzhou, 510006, PR China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China.
| | - Jian Liang
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangzhou, 510006, PR China.
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