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Chen S, Huang L, Chu Y, Lian J, Shao H, Wang T, Zou X, Huang H. Noninvasive diagnosis model for predicting significant liver inflammation in patients with chronic hepatitis B in the immune-tolerant phase. Sci Rep 2025; 15:3031. [PMID: 39856182 PMCID: PMC11760383 DOI: 10.1038/s41598-025-87756-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 01/21/2025] [Indexed: 01/27/2025] Open
Abstract
The presence of significant liver inflammation is an important indication for antiviral therapy in immune-tolerant (IT)phase with chronic hepatitis B(CHB) patients. This study aims to establish a non-invasive model to assess significant liver inflammation in the IT-phase of CHB patients. This multicenter retrospective study included a total of 535 IT-phase CHB patients who underwent liver biopsy, and were randomly divided into a training and a validation set. In the training cohort, the relevant indices were initially screened using univariate analysis. Then the least absolute shrinkage and selection operator and multivariable logistic regression were used to identify the significant independent risk factors and establish a predictive model. A diagnostic nomogram was constructed. Calibration curves, decision curve analysis, and receiver operating characteristic curves were utilized to evaluate the performance of the nomogram. In this study, 37.0% of the patients exhibited significant liver inflammation. Baseline characteristics revealed a median age of 35.0 years, with males accounting for 51.7% of the cohort. Age, Aspartate aminotransferase (AST), Prothrombin (PT), Albumin (ALB) and Hepatitis B virus DNA (HBV DNA) were identified as independent predictors of significant liver inflammation in the immune-tolerant phase, and a nomogram was constructed based on these indicators. The predictive model demonstrated good calibration and discrimination in both the training set and the validation set (aera under the curve (AUC) of 0.741 and 0.740, respectively). The nomogram can accurately identify significant liver inflammation in immune-tolerant phase CHB patients and facilitate the early initiation of antiviral therapy, thereby reducing the need for clinical liver biopsies.
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Affiliation(s)
- Shanshan Chen
- Emergency and Critical Care Center, Department of Emergency Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Lu Huang
- Center for General Practice Medicine, Department of Infectious Disease, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Yili Chu
- Center for General Practice Medicine, Department of Infectious Disease, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Jiangshan Lian
- State Key Laboratory of Infectious Diseases, Department of Infectious Disease, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Hui Shao
- Department of Infection, Zhejiang Taizhou Hospital Affiliated to Wenzhou Medical University, Taizhou, 317000, China
| | - Tingting Wang
- Center for General Practice Medicine, Department of Infectious Disease, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Xuehan Zou
- Center for General Practice Medicine, Department of Infectious Disease, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Haijun Huang
- Center for General Practice Medicine, Department of Infectious Disease, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China.
- , No. 158 Shangtang Road, Hangzhou City, Zhejiang Province, China.
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Nkongolo S, Mahamed D, Kuipery A, Sanchez Vasquez JD, Kim SC, Mehrotra A, Patel A, Hu C, McGilvray I, Feld JJ, Fung S, Chen D, Wallin JJ, Gaggar A, Janssen HL, Gehring AJ. Longitudinal liver sampling in patients with chronic hepatitis B starting antiviral therapy reveals hepatotoxic CD8+ T cells. J Clin Invest 2023; 133:158903. [PMID: 36594467 PMCID: PMC9797343 DOI: 10.1172/jci158903] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 10/26/2022] [Indexed: 01/04/2023] Open
Abstract
Accumulation of activated immune cells results in nonspecific hepatocyte killing in chronic hepatitis B (CHB), leading to fibrosis and cirrhosis. This study aims to understand the underlying mechanisms in humans and to define whether these are driven by widespread activation or a subpopulation of immune cells. We enrolled CHB patients with active liver damage to receive antiviral therapy and performed longitudinal liver sampling using fine-needle aspiration to investigate mechanisms of CHB pathogenesis in the human liver. Single-cell sequencing of total liver cells revealed a distinct liver-resident, polyclonal CD8+ T cell population that was enriched at baseline and displayed a highly activated immune signature during liver damage. Cytokine combinations, identified by in silico prediction of ligand-receptor interaction, induced the activated phenotype in healthy liver CD8+ T cells, resulting in nonspecific Fas ligand-mediated killing of target cells. These results define a CD8+ T cell population in the human liver that can drive pathogenesis and a key pathway involved in their function in CHB patients.
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Affiliation(s)
- Shirin Nkongolo
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Deeqa Mahamed
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Adrian Kuipery
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Juan D. Sanchez Vasquez
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | | | - Aman Mehrotra
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Anjali Patel
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Christine Hu
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Ian McGilvray
- Multi-Organ Transplant Program, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Jordan J. Feld
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Scott Fung
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Diana Chen
- Gilead Sciences, Foster City, California, USA
| | | | - Anuj Gaggar
- Gilead Sciences, Foster City, California, USA
| | - Harry L.A. Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Adam J. Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Department of Immunology, University of Toronto, Toronto, Ontario, Canada
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qHBsAg for the Identification of Liver Histological Abnormalities in HBeAg-Negative Chronic Hepatitis B Patients with Normal and Mildly Elevated ALT Levels. Can J Gastroenterol Hepatol 2022; 2022:8695196. [PMID: 35875362 PMCID: PMC9303505 DOI: 10.1155/2022/8695196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 06/09/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUNDS Noninvasive detection of histological abnormalities remains challenging in patients with HBeAg-negative chronic HBV infection with normal or mildly elevated levels of alanine aminotransferase (ALT). This study aimed to assess the utility of serum quantitative hepatitis B surface antigen (qHBsAg) in identifying significant histological lesions in this population. METHODS This is a single-center study with retrospective analysis of 392 treatment-naive patients of HBeAg-negative chronic HBV infection with normal or mildly elevated levels of ALT. RESULTS In this cohort, significant necroinflammation and fibrosis were found in 69.4% and 61.5% of patients, respectively. Patients with qHBsAg >1000 IU/mL (N = 236) had more hepatic inflammation of ≥G2 (75.4% vs. 60.9%, P < 0.01) or fibrosis ≥ S2 (66.1% vs. 54.5%, P < 0.05) compared to those without (N = 156). Serum HBsAg (cutoff point = 1000 IU/mL), aspartate aminotransferase (AST) level (cutoff point = 25 IU/L), age (cutoff point = 40 years), and HBV family history were identified as independent predictors of significant histological abnormalities in multivariate logistic analysis. CONCLUSIONS A significantly higher proportion of patients with histological abnormalities were found in patients with qHBsAg >1000 IU/mL than those without. The qHBsAg level together with age, AST, and family history of HBV infection could be used as an algorithm to help noninvasive patient selection for antiviral therapy.
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Hu Q, Wang Q, Xu W, Huang C, Tao S, Qi X, Zhang Y, Li X, Jiang X, Song J, Li Q, Chen L, Huang Y. Development and Validation of a Non-invasive Model to Predict Liver Histological Lesions in Chronic Hepatitis B Patients With Persistently Normal Alanine Aminotransferase and Detectable Viremia. Front Med (Lausanne) 2022; 9:944547. [PMID: 35911415 PMCID: PMC9326251 DOI: 10.3389/fmed.2022.944547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 06/24/2022] [Indexed: 11/13/2022] Open
Abstract
Background A critical and controversial issue is whether antiviral therapy should be recommended in chronic hepatitis B virus (HBV) infection patients with persistently normal alanine aminotransferase (PNALT) and detectable HBV DNA. The study aimed to develop a non-invasive model for predicting significant liver histological changes (SLHC), which is the histological indication for antiviral therapy in chronic hepatitis B (CHB) patients with PNALT and detectable HBV DNA. Methods 398 chronic HBV infection patients with PNALT and detectable HBV DNA who underwent liver biopsy were divided into the estimation set (n = 256) and validation set (n = 142). A multivariate logistic regression model was developed to predict SLHC in the estimation set, and the diagnostic performance was further validated in the validation set. Results 132 patients (33.2%) with PNALT and detectable HBV DNA had SLHC. Aspartate aminotransferase (AST), cholinesterase (ChE), and liver stiffness measurement (LSM) were identified as the independent predictors of SLHC. The AUROC of the SLHC index, which combined AST, ChE, and LSM, was 0.824 and 0.816 in the estimation and validation set, respectively, for the prediction of SLHC. Applying the SLHC index ≤ 0.15, the presence of SLHC could be excluded with high negative predictive value in the estimation set (93.2%) and in the validation set (90.2%). Applying the SLHC index ≥ 0.55, the presence of SLHC could be considered with high positive predictive value in the estimation set (79.2%) and in the validation set (76.5%). Conclusion The SLHC index provides a high accuracy in predicting liver histological indication for antiviral therapy in CHB patients with PNALT and detectable HBV DNA.
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Affiliation(s)
- Qiankun Hu
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Qianqian Wang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Wei Xu
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Chenlu Huang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Shuai Tao
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xun Qi
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yi Zhang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xinyan Li
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xuhua Jiang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Jie Song
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Qiang Li
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- Qiang Li,
| | - Liang Chen
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- Liang Chen,
| | - Yuxian Huang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- *Correspondence: Yuxian Huang,
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Liu J, Wang J, Yan X, Xue R, Zhan J, Jiang S, Geng Y, Liu Y, Mao M, Xia J, Yin S, Tong X, Chen Y, Ding W, Huang R, Wu C. Presence of Liver Inflammation in Asian Patients With Chronic Hepatitis B With Normal ALT and Detectable HBV DNA in Absence of Liver Fibrosis. Hepatol Commun 2021; 6:855-866. [PMID: 34783181 PMCID: PMC8948668 DOI: 10.1002/hep4.1859] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 10/16/2021] [Accepted: 10/26/2021] [Indexed: 02/06/2023] Open
Abstract
Liver biopsies are recommended to exclude significant liver inflammation in patients with chronic hepatitis B (CHB) with elevated HBV DNA but without other indications for antiviral treatment. We aimed to investigate the proportions and determinants of significant inflammation in Asian patients with CHB with detectable HBV DNA. We conducted a cross‐sectional study that retrospectively included 581 patients with CHB with detectable HBV DNA who had undergone liver biopsy. Liver inflammation and fibrosis were staged by Scheuer’s classification. Significant inflammation and significant fibrosis were defined as G ≥ 2 and S ≥ 2, respectively. There were 179 (30.8%) patients with alanine aminotransferase (ALT) < 1 × upper limit of normal (ULN), 205 (35.3%) patients with ALT 1‐2 × ULN, and 197 (33.9%) patients with ALT > 2 × ULN. A total of 397 (68.3%) patients had significant inflammation, and 340 (58.5%) patients had significant fibrosis. Significant inflammation was found in 85% of patients with significant fibrosis and in 44.8% of patients without significant fibrosis. Furthermore, 28.7% of patients with CHB with detectable HBV DNA and normal ALT in the absence of significant fibrosis had significant inflammation. Moderate HBV DNA (5‐7 log10 IU/mL) was a risk factor for significant inflammation (odds ratio [OR] 6.929, 95% confidence interval [CI] 2.830‐16.966, P < 0.001) in patients with CHB with detectable HBV DNA, especially for patients with detectable HBV DNA and normal ALT in the absence of significant fibrosis (adjusted OR 13.161, 95% CI 1.026‐168.889, P = 0.048). Conclusion: A high proportion of CHB patients with detectable HBV DNA and normal ALT in the absence of significant fibrosis have significant liver inflammation. Liver biopsies are recommended to evaluate liver inflammation in such patients, especially for those with moderate HBV DNA.
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Affiliation(s)
- Jiacheng Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Ruifei Xue
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jie Zhan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Suling Jiang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Geng
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yilin Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Minxin Mao
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Yuxin Chen
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.,Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Weimao Ding
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
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Chen S, Huang H. Clinical Non-invasive Model to Predict Liver Inflammation in Chronic Hepatitis B With Alanine Aminotransferase ≤ 2 Upper Limit of Normal. Front Med (Lausanne) 2021; 8:661725. [PMID: 34150800 PMCID: PMC8206479 DOI: 10.3389/fmed.2021.661725] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/10/2021] [Indexed: 12/17/2022] Open
Abstract
Background and Aim: Liver biopsy remains the gold standard for evaluating liver histology. However, it has certain limitations, and many patients refuse it. Non-invasive methods of liver evaluation are thus attracting considerable interest. In this study, we sought predictors of liver inflammation in chronic hepatitis B (CHB) patients with alanine aminotransferase (ALT) levels ≤ 2-fold the upper limit of normal (ULN); these may guide decisions on whether to commence antiviral therapy. Methods: We retrospectively analyzed 720 patients with CHB who underwent liver biopsy and whose ALT levels were ≤2 ULN. The patients were randomly divided into a training and validation set. We used univariate and multivariate regression analyses of data from the training set to construct a model that predicted significant (grade ≥2) liver inflammation, and validated the model employing the validation set. Results: Aspartate aminotransferase (AST) level, prothrombin time (PT), glutamyl transpeptidase (GGT) level, and anti-hepatitis B virus core antibody (anti-HBC) level were independent predictors of significant liver inflammation in CHB patients with ALT levels ≤ 2 ULN. A model featuring these four parameters afforded areas under the ROC curve of 0.767 and 0.714 for the training and validation sets. The model was more predictive than were the individual factors. Conclusion: AST, GGT, anti-HBC, and PT reflect significant liver inflammation among CHB patients with ALT levels ≤ 2 ULN. Their combination indicates whether antiviral therapy is required.
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Affiliation(s)
- Shanshan Chen
- Department of Infectious Disease, Zhejiang Provincial People's Hospital and People's Hospital Affiliated of Hangzhou Medical College, Hangzhou, China.,Graduate School of Clinical Medicine, Bengbu Medical College, Bengbu, China
| | - Haijun Huang
- Department of Infectious Disease, Zhejiang Provincial People's Hospital and People's Hospital Affiliated of Hangzhou Medical College, Hangzhou, China
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Significant histological changes and satisfying antiviral efficacy in chronic hepatitis B virus infection patients with normal alanine aminotransferase. Antiviral therapy decision in chronic HBV patients with normal ALT. Clin Res Hepatol Gastroenterol 2021; 45:101463. [PMID: 32571749 DOI: 10.1016/j.clinre.2020.05.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 05/06/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS A proportion of chronic hepatitis B virus (HBV) infection patients with normal alanine aminotransferase (ALT) should start antiviral therapy based on liver biopsy. We aim to evaluate the proportion of such patients, find noninvasive methods for identifying and then evaluate antiviral efficacy. METHODS 253 chronic HBV infection patients with normal ALT were analyzed at baseline and 57 patients with histological indication for antiviral therapy (Histology activity index ≥5 and/or Ishak fibrosis score ≥3) and 140 patients with elevated ALT received entecavir therapy and were followed-up to 78 weeks with a second liver biopsy in this multi-center study. RESULTS 127 (50.2%) of 253 patients with normal ALT fulfilled histological indication for antiviral therapy. Aspartate aminotransferase (P=0.049), anti-hepatitis B virus core antibody (P=0.001) and liver stiffness measurement (P=0.000) were independent variables for identifying histological indication for antiviral therapy. A noninvasive model (AAF) performed best among independent variables and other noninvasive models with area under the operating characteristic curve of 0.887. Antiviral efficacy showed that 38 (66.7%) of 57 patients had undetectable HBV DNA. 12 (41.4%) of 29 patients who were hepatitis B e antigen (HBeAg)-positive at baseline achieved HBeAg loss and 3 (10.3%) achieved HBeAg seroconversion. 25 (43.9%) of 57 patients achieved histological response. Moreover, 57 patients with normal ALT had a similar antiviral therapy efficacy with 140 patients with elevated ALT (P>0.1) except proportion of inflammation improvement and histological response (P=0.005, P=0.049). CONCLUSIONS Half of chronic HBV patients with normal ALT should start antiviral therapy based on liver biopsy. A noninvasive model could be used as a reliable tool for antiviral therapy decision. Patients with normal or elevated ALT had a similar antiviral efficacy.
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Chen S, Huang H, Huang W. A noninvasive model to predict liver histology for antiviral therapy decision in chronic hepatitis B with alanine aminotransferase < 2 upper limit of normal. BMC Gastroenterol 2021; 21:4. [PMID: 33407146 PMCID: PMC7788863 DOI: 10.1186/s12876-020-01576-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 12/08/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND At present, most assessments of liver fibrosis staging mainly focus on non-invasive diagnostic methods. This study aims to construct a noninvasive model to predict liver histology for antiviral therapy in chronic hepatitis B (CHB) with alanine aminotransferase (ALT) < 2 times upper limit of normal (ULN). METHODS We retrospectively analyzed 577 patients with CHB who received liver biopsy and whose ALT was less than 2 ULN. Then they were randomly divided into a training group and a validation group. Through logistic regression analysis, a novel predictive model was constructed in the training group to predict significant changes in liver histology [necro-inflammatory activity grade (G) ≥ 2 or fibrosis stage (S) ≥ 2] and then validated in the validation group. RESULTS If liver biopsy showed moderate or severe inflammation or significant fibrosis, antiviral treatment was recommended. Aspartate aminotransferase (AST), anti-hepatitis B virus core antibody (anti-HBC) and glutamine transpeptidase (GGT) were identified as independent predictors for antiviral therapy, with area under the ROC curve (AUROC) of 0.649, 0.647 and 0.616, respectively. Our novel model index, which combined AST, anti- HBC and GGT with AUROC of 0.700 and 0.742 in training set and validation set. CONCLUSIONS This study established a noninvasive model to predict liver histology for antiviral treatment decision in patients with CHB with ALT < 2 ULN, which can reduce the clinical needs of liver biopsy.
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Affiliation(s)
- Shanshan Chen
- Department of Infectious Disease, Zhejiang Provincial People's Hospital, Hangzhou, 310014, Zhejiang, China
- Graduate School of Clinical Medicine, Bengbu Medical College, BengbuAnhui, 233000, China
| | - Haijun Huang
- Department of Infectious Disease, Zhejiang Provincial People's Hospital, Hangzhou, 310014, Zhejiang, China.
| | - Wei Huang
- Department of Digestive Disease, Zhejiang Provincial People's Hospital, Hangzhou, 310014, Zhejiang, China
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KAAN D, TOPRAK G, YAY A, BAŞKOL G, ERTEKİN T, ÜLGER H. Karaciğer Fibrozis Modellerinde Sık Kullanılan Kimyasal Ajanların Farklı Doz ve Zaman Dilimindeki Etkilerinin Belirlenmesi. ACTA MEDICA ALANYA 2020. [DOI: 10.30565/medalanya.775667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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10
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Landerer S, Kalthoff S, Paulusch S, Strassburg CP. UDP-glucuronosyltransferase polymorphisms affect diethylnitrosamine-induced carcinogenesis in humanized transgenic mice. Cancer Sci 2020; 111:4266-4275. [PMID: 32860300 PMCID: PMC7648041 DOI: 10.1111/cas.14635] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/18/2020] [Accepted: 08/23/2020] [Indexed: 12/13/2022] Open
Abstract
UDP‐glucuronosyltransferase (UGT) 1A enzymes detoxify a broad array of exogenous compounds including environmental toxins and carcinogens. Case‐control studies identified genetic variations in UGT1A genes leading to reduced glucuronidation activity, which were associated with hepatocellular carcinoma (HCC) formation and progression. The aim of the study was therefore to examine the direct effect of common UGT1A polymorphisms (SNPs) on HCC development and outcome in a diethylnitrosamine (DEN)‐induced mouse model. Therefore, a single intraperitoneal DEN injection (20 mg/kg) was administered to 15‐day‐old htgUGT1A‐WT and htgUGT1A‐SNP mice (containing a human haplotype of 10 common UGT1A SNPs) either receiving water or coffee cotreatment for the following 39 weeks. After this time, tumor incidence, size (>1 mm), histology, liver‐body ratio, serum aminotransferase activities, and UGT1A regulation and activity levels were determined. In DEN‐treated htgUGT1A‐SNP mice, a markedly higher number of tumors with a bigger cumulative diameter were detected. The relative liver weight and aminotransferase activity levels were also significantly higher in mice carrying UGT1A SNPs. After coffee + DEN cotreatment, susceptibility for tumor development and growth considerably decreased in both mouse lines, but was still higher in htgUGT1A‐SNP mice. In conclusion, our study provides experimental evidence for the protective role of UGT1A enzymes in neoplastic transformation. These data confirm case‐control studies implicating impaired UGT1A‐mediated carcinogen detoxification as a risk factor for individual cancer disposition. Coffee treatment, which is able to activate UGT1A expression and activity, reduced HCC development and provides an explanation for the protective properties of coffee on liver diseases including liver cancer.
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Affiliation(s)
- Steffen Landerer
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Sandra Kalthoff
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Stefan Paulusch
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
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Wei M, Xu Z, Pan X, Zhang X, Liu L, Yang B, Chen Y. Serum GP73 - An Additional Biochemical Marker for Liver Inflammation in Chronic HBV Infected Patients with Normal or Slightly Raised ALT. Sci Rep 2019; 9:1170. [PMID: 30718535 PMCID: PMC6362062 DOI: 10.1038/s41598-018-36480-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 11/21/2018] [Indexed: 12/24/2022] Open
Abstract
This study aimed to assess the feasibility of GP73 as a diagnostic marker for liver inflammation and fibrosis in chronic HBV patients with normal or slightly raised ALT (<2 ULN) and to develop models based on GP73 and other biochemical parameters to improve diagnostic accuracy. Serum GP73 levels were analyzed in 220 chronic HBV patients with normal or slightly raised ALT who underwent liver biopsy. The results showed that the area under the receiver operating characteristic (ROC) curve (AUC) was 0.806 for predicting significant liver inflammation (≥G2), while it was 0.742 for predicting significant fibrosis (≥S2). These results suggest that GP73 has higher diagnostic value for liver inflammation than liver fibrosis. Combining GP73, AST and ALB, as a diagnostic model for predicting significant liver inflammation, resulted in superior diagnostic performance over GP73 alone (AUC value increased from 0.806 to 0.854, z = 2.299, P = 0.021). By applying this diagnostic model, over 80% of chronic HBV patients with normal or slightly raised ALT will be correctly identified and hence avoid delay in diagnosis and treatment. In conclusion, GP73 would be an additional serum marker for predicting liver inflammation and fibrosis in chronic HBV patients with normal or slightly raised ALT.
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Affiliation(s)
- Meijuan Wei
- Clinical Liver Center, The 910th Hospital of the People's Liberation Army, Quanzhou, 362000, China.,Clinical Liver Center, Decheng hospital of Quanzhou/Affiliated of Huaqiao University, Quanzhou, 362000, China
| | - Zhengju Xu
- Clinical Liver Center, The 910th Hospital of the People's Liberation Army, Quanzhou, 362000, China.
| | - Xingnan Pan
- Clinical Liver Center, Decheng hospital of Quanzhou/Affiliated of Huaqiao University, Quanzhou, 362000, China
| | - Xiaoman Zhang
- Clinical Liver Center, The 910th Hospital of the People's Liberation Army, Quanzhou, 362000, China
| | - LiGuan Liu
- Clinical Liver Center, The 910th Hospital of the People's Liberation Army, Quanzhou, 362000, China
| | - Bishuang Yang
- Clinical Liver Center, The 910th Hospital of the People's Liberation Army, Quanzhou, 362000, China
| | - Yuxia Chen
- Clinical Liver Center, Decheng hospital of Quanzhou/Affiliated of Huaqiao University, Quanzhou, 362000, China
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12
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Wu Z, Dong X, Wang G, Zhao H. Clinical noninvasive markers for antiviral therapy decision in chronic hepatitis B with alanine aminotransferase less than two times upper limit of normal. J Viral Hepat 2019; 26:287-296. [PMID: 30380162 DOI: 10.1111/jvh.13030] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 10/01/2018] [Accepted: 10/04/2018] [Indexed: 12/12/2022]
Abstract
Liver biopsy is the reference method for antiviral therapy decision-making in chronic hepatitis B (CHB) when alanine aminotransferase (ALT) is less than two times of upper limit of normal (<2ULN). Our aim was to explore noninvasive markers for antiviral therapy decision in CHB with ALT <2ULN. A total of 452 treatment-naïve CHB patients with ALT < 2ULN who had undergone liver biopsy were analysed in this prospective multi-centre study. If liver biopsy showed moderate or severe inflammation (histology activity index ≥ 5) or significant fibrosis (Ishak fibrosis score ≥ 3), antiviral treatment was recommended. We analysed data using univariate and multivariate analyses and receiver operating characteristic curves (ROC). Two hundred and sixty-nine (59.5%) of 452 cases with ALT < 2ULN had moderate, severe or significant inflammation. Aspartate aminotransferase (AST) (P = 0.03), anti-hepatitis B virus core antibody (anti-HBc) (P = 0.003) and liver stiffness measurement (LSM) (P = 0.000) were independent variables for antiviral therapy decision-making, with area under the ROC curve (AUROC) of 0.718, 0.703 and 0.819, respectively. Our novel AAF index, which combined AST, anti-HBc and LSM, showed better performance with AUROC of 0.876, 0.877 and 0.876 in estimation, validation and total set. Finally, 247 (54.6%) of 452 patients could avoid liver biopsy based on AAF index. Furthermore, performances of 23 noninvasive models were unsatisfactory for antiviral therapy decision with AUROC < 0.800, which were inferior to AAF index. In conclusion, AST, anti-HBc and LSM were related to antiviral therapy decision-making among CHB patients with ALT < 2ULN. Thus, the novel AAF index was a more reliable noninvasive model for antiviral therapy decision-making.
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Affiliation(s)
- Zhao Wu
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, Beijing, China
| | - Xiaoqin Dong
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, Beijing, China
| | - Guiqiang Wang
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, Beijing, China.,The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China.,Peking University International Hospital, Beijing, China
| | - Hong Zhao
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, Beijing, China.,Peking University International Hospital, Beijing, China
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13
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Liao Y, Gong J, Zhou W, Dong H, Liang J, Luo M, Hu B. Serum liver fibrosis markers discriminate significant liver inflammation in chronic hepatitis B patients with normal or near-normal alanine aminotransferase. J Med Virol 2018; 91:642-649. [PMID: 30537157 DOI: 10.1002/jmv.25364] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 11/18/2018] [Indexed: 12/30/2022]
Abstract
Chronic liver inflammation caused by chronic hepatitis B virus (CHB) infection leads to liver cirrhosis and hepatocellular carcinoma. Recently, the role of alanine aminotransferase (ALT) as a predictor of liver inflammation has been questioned. The aim of this study was to investigate the utility of noninvasive fibrosis markers including hyaluronic acid (HA), collagen type IV (CIV), N-terminal propeptide of type III procollagen (PIIINP), and laminin (LN) in identifying significant liver inflammation in patients with CHB, especially in patients with normal or near-normal ALT. A total of 242 CHB patients who underwent liver biopsy were enrolled. The serum levels of ALT, aspartate aminotransferase, HA, CIV, PIIINP, and LN were quantified and the relationship between histological staging and serum markers was systematically analyzed. Serum CIV, PIIINP, HA, and LN levels increased significantly along with the increasing severity of liver inflammation. Multivariate analysis showed that CIV and LN were independently associated with significant inflammation. CIV, PIIINP, HA, and LN levels were found to have high diagnostic values for predicting significant inflammation in patients with CHB (area under the curve, AUC = 0.807, 0.795, 0.767, and 0.703, respectively). The combined index for the identification of significant inflammation, including CIV, PIIINP, HA, and LN levels, significantly improved diagnostic performance (AUC = 0.851). Moreover, the combined index also achieved excellent diagnostic accuracy (AUC = 0.861) in patients with CHB with normal or near-normal ALT. In conclusion, the combined index may be a strong indicator for discriminating significant liver inflammation, especially in patients with CHB with normal or near-normal ALT.
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Affiliation(s)
- Yuan Liao
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jiao Gong
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Wenying Zhou
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Huimin Dong
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jiayin Liang
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Minqi Luo
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Bo Hu
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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14
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Liao R, Li DW, Du CY, Li M. Combined Preoperative ALBI and FIB-4 Is Associated with Recurrence of Hepatocellular Carcinoma After Curative Hepatectomy. J Gastrointest Surg 2018; 22:1679-1687. [PMID: 29777455 DOI: 10.1007/s11605-018-3810-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 05/07/2018] [Indexed: 01/31/2023]
Abstract
BACKGROUND AND PURPOSE Chronic inflammatory response is a risk factor for hepatocarcinogenesis and recurrence. This study aimed to develop a nomogram incorporating the combined albumin-bilirubin (ALBI) and fibrosis-4 (FIB-4) scores and the peritumoral inflammation score (PIS) to predict postoperative recurrence-free survival (RFS) of hepatocellular carcinoma (HCC). METHODS The prognostic roles of preoperative ALBI and FIB-4 scores for HCC recurrence were investigated, and a nomogram was developed. The predictive ability of the nomogram was compared with the American Joint Commission on Cancer (AJCC) and Barcelona Clinic Liver Cancer (BCLC) staging systems for HCC. Necroinflammatory activity in the peritumoral liver tissues was evaluated by hematoxylin and eosin (H&E) staining. RESULTS Combined ALBI and FIB-4 was associated with PIS in the training and validation cohorts (r = 0.342 and 0.473, both P < 0.001), and all of the scores exhibited predictive value for RFS of HCC. The independent predictive factors of RFS such as AFP, tumor number, tumor size, microvascular invasion, PIS, and combined ALBI and FIB-4 were included in the corresponding nomogram. In the training cohort, the C-index of the RFS nomogram was 0.722. ROC analyses showed that the RFS nomogram had a larger AUC (0.739) than the AJCC and BCLC staging systems. These results were verified by the validation cohort. CONCLUSIONS The proposed nomogram incorporating PIS and combined ALBI and FIB-4 was associated with recurrence for HCC following curative hepatectomy.
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Affiliation(s)
- Rui Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Chongqing, 400016, China
| | - De-Wei Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Chongqing, 400016, China
| | - Cheng-You Du
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Chongqing, 400016, China.
| | - Ming Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Chongqing, 400016, China
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15
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Wang J, Xia J, Zhang R, Yan X, Yang Y, Zhao X, Chang H, Wang G, Chen G, Liu Y, Chen Y, Jia B, Zhang Z, Ding W, Huang R, Wu C. A novel index using routine clinical parameters for predicting significant liver inflammation in chronic hepatitis B. J Viral Hepat 2018; 25:1151-1160. [PMID: 29741221 DOI: 10.1111/jvh.12925] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 04/20/2018] [Indexed: 12/14/2022]
Abstract
Identifying the degree of liver inflammation is critical for therapeutic judgement of patients with chronic hepatitis B (CHB). However, we lack indexes which can accurately predict significant liver inflammation in patients with CHB. This study aimed to develop a simple predictive index for liver inflammation in CHB using routine clinical parameters. A total of 519 patients with CHB who underwent liver biopsy were enrolled and randomly divided into training (n = 346) and validation cohorts (n = 173). Based on routine clinical parameters, gamma-glutamyl transpeptidase (GGT; P = 0.031) and platelets (PLT; P < 0.001) were identified as independent predictors of significant inflammation by multivariable analysis in the training cohort. Accordingly, the GGT to PLT ratio (GPR) was developed to amplify the opposing effects for predicting liver inflammation. In the training cohort, the AUCs of GPR in predicting significant inflammation were 0.791 (95% CI: 0.742-0.839), 0.783 (95% CI: 0.717-0.849) and 0.791 (95% CI: 0.716-0.867) in the entire patients with CHB, HBeAg-positive CHB patients and HBeAg-negative CHB patients, respectively. The diagnostic performance of GPR for significant inflammation was significantly superior to that of alanine aminotransferase (ALT), aspartate transaminase (AST) and GGT in all patients with CHB and HBeAg-positive CHB patients, but was comparable with ALT, AST and GGT in HBeAg-negative CHB patients. In the validation cohort, the diagnostic performance of GPR in assessing significant liver inflammation was also superior to other indexes in all patients with CHB and HBeAg-positive CHB patients, but was comparable with GGT in HBeAg-negative CHB patients. Thus, GPR can be a novel and simple index for predicting significant liver inflammation in CHB, especially for HBeAg-positive CHB.
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Affiliation(s)
- J Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - J Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - R Zhang
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - X Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Y Yang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - X Zhao
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - H Chang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - G Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - G Chen
- Department of Infectious Diseases, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, China
| | - Y Liu
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Y Chen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - B Jia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Z Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - W Ding
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - R Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - C Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
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16
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Xu Z, Shen J, Pan X, Wei M, Liu L, Wei K, Liu L, Yang H, Huang J. Predictive value of serum Golgi protein 73 for prominent hepatic necroinflammation in chronic HBV infection. J Med Virol 2018; 90:1053-1062. [PMID: 29424455 DOI: 10.1002/jmv.25045] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 01/25/2018] [Indexed: 12/17/2022]
Abstract
As a noninvasive marker, serum alanine aminotransferase (ALT) has limitations, because a large proportion of patients chronically infected with hepatitis B virus (HBV) suffer from severe hepatic necroinflammation, but have normal or mildly elevated ALT. In the present study, we aimed to investigate the potential value of serum Golgi protein 73 (GP73) in predicting significant hepatic necroinflamation among chronic HBV infected patients. A cohort of 497 chronic HBV infected patients was retrospectively recruited. Liver biopsy was performed in all patients and serum GP73 levels were measured by enzyme-linked immunosorbent assay. Serum GP73 increased in parallel with the increase in hepatic necroinflammatory activity grade (r = 0.682) and the stage of liver fibrosis (r = 0.539). The positive correlation of serum GP73 with the degree of hepatic necroinflammatory activity was statistically significant, while serum GP73 with the stage of liver fibrosis was weaker than that with hepatic necroinflammation. Furthermore, serum GP73 levels were significantly greater in patients with normal or mildly elevated ALT and significant hepatic necroinflammation (≥G2) than in patients with minimal to mild hepatic necroinflammation. The sensitivity and specificity of GP73 for the diagnosis of G2 hepatic necroinflammation was 42.35% and 95.0%, respectively, at a cut-off value of 88.38 ng/mL. When the cut-off value was set at 124.76 ng/mL, the sensitivity and specificity of GP73 for the diagnosis of G3 hepatic necroinflammation was 55.56% and 97.29%, respectively. These findings indicate that GP73 holds promise as an important candidate for diagnosing significant hepatic necroinflammation.
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Affiliation(s)
- Zhengju Xu
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Jiankun Shen
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Xingnan Pan
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Meijuan Wei
- Central Laboratory of Clinical Hepatology, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Liguan Liu
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Kaipeng Wei
- Central Laboratory of Clinical Hepatology, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Lifei Liu
- Department of Pathology, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Huanwen Yang
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Jinfa Huang
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
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17
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Cheng JL, Wang XL, Yang SG, Zhao H, Wu JJ, Li LJ. Non-ALT biomarkers for markedly abnormal liver histology among Chinese persistently normal alanine aminotransferase-chronic hepatitis B patients. World J Gastroenterol 2017; 23:2802-2810. [PMID: 28487618 PMCID: PMC5403760 DOI: 10.3748/wjg.v23.i15.2802] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 01/12/2017] [Accepted: 02/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine incidence and clinical biomarkers of marked necroinflammation and fibrosis characteristics among chronic hepatitis B (CHB) patients with persistently normal alanine aminotransferase (PNALT).
METHODS Liver biopsy was performed on 115 CHB patients with PNALT. Necroinflammation and fibrosis were graded by the Knodell histologic activity index and the Ishak fibrosis score, respectively. Correlations between the available clinical parameters and necroinflammation and fibrosis were analysed.
RESULTS Marked necroinflammation (Knodell activity index ≥ 7) and fibrosis (Ishak fibrosis score ≥ 3) were found in 36.5% and 15.5% of CHB patients with PNALT, respectively. Following a univariate logistic regression analysis, multiple logistic regression analysis indicated that aspartate transaminase (AST) (AUROC = 0.852, cut-off value = 22.5 U/L) serves as an independent predictor of notable liver inflammation, while platelet (PLT) count (AUROC = 0.905, cut-off value = 171.5 ×109/mL) and gamma-glutamyl transpeptidase (GGT) (AUROC = 0.909, cut-off value = 21.5 U/L) level serve as independent predictors of notable liver fibrosis.
CONCLUSION A considerable proportion of marked histological abnormalities existed in our cohort, who will benefit from optimal therapeutic strategies administered according to predictive indication by AST, PLT and GGT levels.
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18
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Hong MZ, Ye L, Jin LX, Ren YD, Yu XF, Liu XB, Zhang RM, Fang K, Pan JS. Noninvasive scoring system for significant inflammation related to chronic hepatitis B. Sci Rep 2017; 7:43752. [PMID: 28281521 PMCID: PMC5345042 DOI: 10.1038/srep43752] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 01/26/2017] [Indexed: 01/10/2023] Open
Abstract
Although a liver stiffness measurement-based model can precisely predict significant intrahepatic inflammation, transient elastography is not commonly available in a primary care center. Additionally, high body mass index and bilirubinemia have notable effects on the accuracy of transient elastography. The present study aimed to create a noninvasive scoring system for the prediction of intrahepatic inflammatory activity related to chronic hepatitis B, without the aid of transient elastography. A total of 396 patients with chronic hepatitis B were enrolled in the present study. Liver biopsies were performed, liver histology was scored using the Scheuer scoring system, and serum markers and liver function were investigated. Inflammatory activity scoring models were constructed for both hepatitis B envelope antigen (+) and hepatitis B envelope antigen (-) patients. The sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve were 86.00%, 84.80%, 62.32%, 95.39%, and 0.9219, respectively, in the hepatitis B envelope antigen (+) group and 91.89%, 89.86%, 70.83%, 97.64%, and 0.9691, respectively, in the hepatitis B envelope antigen (-) group. Significant inflammation related to chronic hepatitis B can be predicted with satisfactory accuracy by using our logistic regression-based scoring system.
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Affiliation(s)
- Mei-Zhu Hong
- Department of Traditional Chinese Medicine, Zhongshan Hospital Xiamen University, Xiamen, 361004 Fujian, China
| | - Linglong Ye
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, New Taipei City, 24205 Taiwan
| | - Li-Xin Jin
- Department of Gastroenterology, People’s Hospital of Rizhao, Rizhao, 276800 Shandong, China
| | - Yan-Dan Ren
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, 361004 Fujian, China
| | - Xiao-Fang Yu
- Hepatology Unit and Department of Infectious Diseases, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361001 Fujian, China
| | - Xiao-Bin Liu
- Department of Infectious Diseases, the First Affiliated Hospital of Xiamen University, Xiamen, 361004 Fujian, China
| | - Ru-Mian Zhang
- Hepatology Unit and Department of Infectious Diseases, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361001 Fujian, China
| | - Kuangnan Fang
- Department of Statistics, School of Economics, Xiamen University, Xiamen, 361002 Fujian, China
| | - Jin-Shui Pan
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, 361004 Fujian, China
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19
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Li Q, Li W, Huang Y, Chen L. The gamma-glutamyl transpeptidase-to-platelet ratio predicts liver fibrosis and cirrhosis in HBeAg-positive chronic HBV infection patients with high HBV DNA and normal or mildly elevated alanine transaminase levels in China. J Viral Hepat 2016; 23:912-919. [PMID: 27375134 DOI: 10.1111/jvh.12563] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Accepted: 05/03/2016] [Indexed: 02/07/2023]
Abstract
The gamma-glutamyl transpeptidase-to-platelet ratio (GPR) is a new serum diagnostic model, which is reported to be more accurate than aspartate transaminase-to-platelet ratio index (APRI) and fibrosis index based on the four factors (Fib-4) for the diagnosis of significant fibrosis and cirrhosis in chronic HBV infection (CHBVI) patients in West Africa. To evaluate the performance of the GPR model for the diagnosis of liver fibrosis and cirrhosis in HBeAg-positive CHBVI patients with high HBV DNA (≥5 log10 copies/mL) and normal or mildly elevated alanine transaminase (ALT) (≤2 times upper limit of normal (ULN)) in China. A total of 1521 consecutive CHBVI patients who underwent liver biopsies and routine laboratory tests were retrospectively screened. Of these patients, 401 treatment naïve HBeAg-positive patients with HBV DNA≥5 log10 copies/mL and ALT≤2 ULN were included. The METAVIR scoring system was adopted as the pathological diagnosis standard of liver fibrosis. Using liver histology as a gold standard, the performances of GPR, APRI, and Fib-4 for the diagnosis of liver fibrosis and cirrhosis were evaluated and compared by receiver operating characteristic (ROC) curves and the area under the ROC curves (AUROCs). Of 401 patients, 121 (30.2%), 49 (12.2%) and 17 (4.2%) were classified as having significant fibrosis (≥F2), severe fibrosis (≥F3) and cirrhosis (=F4), respectively. After estimating the AUROC to predict significant fibrosis, the performance of GPR (AUROC=0.66, 95% CI 0.60-0.72) was higher than APRI (AUROC=0.58, 95% CI 0.52-0.64, P=.002) and Fib-4 scores (AUROC=0.54, 95% CI 0.47-0.60, P<.001). After estimating the AUROC to predict severe fibrosis, the performance of GPR (AUROC=0.71, 95% CI 0.63-0.80) was also higher than APRI (AUROC=0.65, 95% CI 0.56-0.73, P=.003) and Fib-4 scores (AUROC=0.67, 95% CI 0.58-0.75, P=.001). After estimating the AUROC to predict cirrhosis, the performance of GPR (AUROC=0.73, 95% CI 0.56-0.88) was higher than APRI (AUROC=0.69, 95% CI 0.54-0.83, P=.041) and Fib-4 scores (AUROC=0.69, 95% CI 0.55-0.82, P=.012) too. The GPR is a new serum model for the diagnosis of liver fibrosis and cirrhosis and shows obvious advantages in Chinese HBeAg-positive patients with HBV DNA≥5 log10 copies/mL and ALT≤2 ULN compared with APRI and Fib-4, thus warranting its widespread use for this specific population.
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Affiliation(s)
- Q Li
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - W Li
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Y Huang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
| | - L Chen
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
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20
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Ebrahimi H, Naderian M, Sohrabpour AA. New Concepts on Pathogenesis and Diagnosis of Liver Fibrosis; A Review Article. Middle East J Dig Dis 2016; 8:166-178. [PMID: 27698966 PMCID: PMC5045669 DOI: 10.15171/mejdd.2016.29] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Liver fibrosis is a potentially reversible response to hepatic insults, triggered by different chronic diseases most importantly viral hepatitis, alcoholic, and nonalcoholic fatty liver disease. In the course of the chronic liver disease, hepatic fibrogenesis may develop, which is attributed to various types of cells, molecules, and pathways. Activated hepatic stellate cell (HSC), the primary source of extracellular matrix (ECM), is fundamental in pathophysiology of fibrogenesis, and thus is the most attractable target for reversing liver fibrosis. Although, liver biopsy has long been considered as the gold standard for diagnosis and staging of hepatic fibrosis, assessing progression and regression by biopsy is hampered by its limitations. We provide recent views on noninvasive approaches including serum biomarkers and radiologic techniques.
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Affiliation(s)
- Hedyeh Ebrahimi
- Liver and Pancreaticobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Naderian
- Liver and Pancreaticobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Sohrabpour
- Assistant Professor, Liver and Pancreaticobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Diktas H, Karacaer Z, Özturk II, Cicek H. Comparison of relationship between histopathological, serological and biochemical parameters in patients with chronic hepatitis B infection. Postgrad Med J 2016; 92:693-696. [PMID: 27170311 DOI: 10.1136/postgradmedj-2016-134069] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 04/18/2016] [Accepted: 04/24/2016] [Indexed: 12/23/2022]
Abstract
OBJECTIVE To demonstrate the relationship between liver histology, alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and hepatitis B virus (HBV) DNA levels based on hepatitis B e antigen (HBeAg) seropositivity status in naive patients with chronic hepatitis B (CHB). MATERIALS AND METHOD Naive patients with CHB admitted to our hospital between January 2012 and April 2014 were evaluated retrospectively. The patients were allocated into one of two groups based on HBeAg-seropositivity status. RESULTS Two hundred and fourteen patients were enrolled in the study. Of these 214 patients, 103 (48.1%) were HBeAg-positive and 111 (51.9%) were HBeAg-negative. In the HBeAg-positive group, positive correlations were found between histologic activity index (HAI) scores and ALT (t=3.3, r=0.31, p=0.001), AST (t=2.8, r=0.27, p=0.005) and HBV DNA load (t=2.5, r=0.24, p=0.014). Additionally, in this group, fibrosis scores had positive correlations with ALT (t=3.3, r=0.32, p=0.001) and AST (t=2.7, r=0.26, p=0.008). In the HBeAg-negative group, positive correlations were found between HAI scores and ALT (t=3, r=0. 28, p=0.003), AST (t=3, r=0. 28, p=0.003) and HBV DNA (t=5.3, r=0. 45, p=0). In this same group, fibrosis scores had a positive correlation with HBV DNA (t=2.2, r=0. 21, p=0.024). Multivariate logistic regression analysis showed a positive relationship between fibrosis and ALT in the HBeAg-positive group and a positive relationship between fibrosis and HBV DNA load in the HBeAg-negative group. CONCLUSIONS This study showed that HBV DNA load is an independent predictive factor for evaluating HAI and fibrosis in the HBeAg-negative group. Also, ALT is an independent predictive factor for evaluating fibrosis in the HBeAg-positive group.
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Affiliation(s)
- Husrev Diktas
- Department of Infectious Diseases and Clinical Microbiology, Tatvan Military Hospital, Bitlis, Turkey
| | - Zehra Karacaer
- Department of Infectious Diseases and Clinical Microbiology, Etimesgut Military Hospital, Ankara, Turkey
| | - I Ilker Özturk
- Department of Infectious Diseases and Clinical Microbiology, Beytepe Military Hospital, Ankara, Turkey
| | - Huseyin Cicek
- Department of Infectious Diseases and Clinical Microbiology, Etimesgut Military Hospital, Ankara, Turkey
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Wang Y, Hao J, Liu X, Wang H, Zeng X, Yang J, Li L, Kuang X, Zhang T. The mechanism of apoliprotein A1 down-regulated by Hepatitis B virus. Lipids Health Dis 2016; 15:64. [PMID: 27015844 PMCID: PMC4807537 DOI: 10.1186/s12944-016-0232-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Accepted: 03/19/2016] [Indexed: 12/12/2022] Open
Abstract
Background Hepatitis B virus (HBV) infection correlated with the development of cirrhosis, liver failure and hepatocellular carcinoma (HCC), poses a huge health burden on the global community. However, the pathogenesis of chronic hepatitis B (CHB) remains unclear. Apolipoprotein A1 (ApoA1) mainly secreted by hepatocytes, represents the major protein component of high-density lipoprotein. ApoA1 secretion may be disrupted by HBV infection. In this study, we mainly investigated the molecular mechanism of ApoA1 down regulated by HBV for revealing the pathogenesis of CHB. Methods ApoA1 expression in livers of CHB patients as well as healthy controls were performed by Real-time PCR (RT-PCR) and Western blot. The serum ApoA1 levels were measured by Enzymed-linked immunosorbent assay (ELISA). Expression of ApoA1 mRNA and protein levels were performed by RT-PCR and Western blot in human hepatoma HepG2 cells and subline HepG2.2.15 cells. HBV expression construct, pHBV1.3 were transfected into HepG2, the changes of ApoA1 mRNA and protein expression were detected by RT-PCR and Western blot. To further study the mechanism of ApoA1 down regulation by HBV, 11 CpG islands in ApoA1 promotor were tested for DNA methylation status by MSP. HepG2.2.15 cell lines were treated with DNA methyltransferase inhibitor 5-aza-deoxycytidine (5-aza-dC), then, expression of ApoA1 mRNA and HBV particles in the supernatant, as well as ApoA1 protein levels were detected by RT-PCR and Western blot. Secretion of HBsAg and HBeAg in HepG2 cells cotransfected with pApoA1 and pHBV1.3 constructs was tested by ELISA. Meanwhile, secretion of HBsAg and HBeAg in the supernatant were quantified by ELISA in the HepG2.2.15 cells treated with 5-aza-dC plus ApoA1 siRNA. Results Expression of ApoA1 mRNA and protein levels, as well as serum ApoA1 levels in CHB patients were decreased corresponding healthy controls in vivo. In addition, the expression of ApoA1 mRNA and protein levels were down regulated in HepG2.2.15 cells correponding HepG2 cells, 11 CpG islands in ApoA1 promoter were tested for methylation status by MSP in HepG2.2.15 cells compared to HepG2 cells, while two CpG islands were found hypermethylated. Expression of ApoA1 mRNA and protein levels were increased in HepG2.2.15 cells treated with DNA methyltransferase inhibitor 5-aza-dC. Furthermore, overexpression of ApoA1 can enhance HBV expression in HepG2 cells while the inhibitory effect of 5-aza-dC on HBV expression was completely abolished by blocking 5-aza-dC-induced up-regulation of ApoA1 using RNAi. Conclusions Epigenetic silencing of ApoA1 gene expression by CpG island DNA hypermethylation induced by HBV may contribute to the pathogenesis of CHB.
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Affiliation(s)
- Yuanyuan Wang
- School of Biomedical Sciences, Chengdu Medical College, Sichuan, 610500, China
| | - Junli Hao
- School of Biomedical Sciences, Chengdu Medical College, Sichuan, 610500, China
| | - Xiaohong Liu
- School of Biomedical Sciences, Chengdu Medical College, Sichuan, 610500, China
| | - Hongxin Wang
- School of Biomedical Sciences, Chengdu Medical College, Sichuan, 610500, China
| | - Xin Zeng
- School of Biomedical Sciences, Chengdu Medical College, Sichuan, 610500, China
| | - Jing Yang
- School of Biomedical Sciences, Chengdu Medical College, Sichuan, 610500, China
| | - Lei Li
- School of Biomedical Sciences, Chengdu Medical College, Sichuan, 610500, China
| | - Xi Kuang
- Department of Pharmacology, Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Sichuan, 610041, China.
| | - Tao Zhang
- School of Biomedical Sciences, Chengdu Medical College, Sichuan, 610500, China.
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Neuman MG, Cohen LB, Nanau RM. Hyaluronic acid as a non-invasive biomarker of liver fibrosis. Clin Biochem 2015; 49:302-15. [PMID: 26188920 DOI: 10.1016/j.clinbiochem.2015.07.019] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 07/07/2015] [Accepted: 07/14/2015] [Indexed: 12/14/2022]
Abstract
UNLABELLED Chronic liver diseases may cause inflammation and progressive scarring, over time leading to irreversible hepatic damage (cirrhosis). As a result, the need to assess and closely monitor individuals for risk factors of components of matrix deposition and degradation, as well as the severity of the fibrosis using biomarkers, has been increasingly recognized. AIM Our aim is to review the use of biomarker for diagnosing and defining the severity of liver fibrosis. METHODS A systematic literature review was done using the terms "hyaluronic acid" and "liver fibrosis" as well as the name of each biomarker or algorithm known to be employed. PubMed and Google Scholar were searched, and English language articles indexed between January 2010 and October 2014 in which HA was used as a marker of liver fibrosis were retrieved, regardless of the underlying liver disease. Each author read the publications separately and the results were analyzed and discussed. RESULTS Biomarkers offer a potential prognostic or diagnostic indicator for disease manifestation, progression, or both. Serum biomarkers, including HA, have been used for many years. Emerging biomarkers such as metalloproteinases have been proposed as tools that provide valuable complementary information to that obtained from traditional biomarkers. Moreover, markers of extracellular matrix degradation provide powerful predictions of risk. In order for biomarkers to be clinically useful in accurately diagnosing and treating disorders, age-specific reference intervals that account for differences in gender and ethnic origin are a necessity. CONCLUSIONS This review attempts to provide a comprehensive analysis of the emerging risk biomarkers of liver fibrosis and to describe the clinical significance and analytical considerations of each biomarker pointing out sentinel features of disease progression.
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Affiliation(s)
- Manuela G Neuman
- Department of Pharmacology & Toxicology, University of Toronto, CEO In Vitro Drug Safety & BioTechnology, Banting Institute, 100 College Street, Lab 217, Toronto, Ontario M5G 0A3, Canada
| | - Lawrence B Cohen
- Department of Pharmacology & Toxicology, University of Toronto, CEO In Vitro Drug Safety & BioTechnology, Banting Institute, 100 College Street, Lab 217, Toronto, Ontario M5G 0A3, Canada; Sunnybrook HSC, Department of Medicine, University of Toronto, Toronto, Canada
| | - Radu M Nanau
- Department of Pharmacology & Toxicology, University of Toronto, CEO In Vitro Drug Safety & BioTechnology, Banting Institute, 100 College Street, Lab 217, Toronto, Ontario M5G 0A3, Canada
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Park HJ, Kim HG, Wang JH, Choi MK, Han JM, Lee JS, Son CG. Comparison of TGF-β, PDGF, and CTGF in hepatic fibrosis models using DMN, CCl4, and TAA. Drug Chem Toxicol 2015; 39:111-118. [PMID: 26045230 DOI: 10.3109/01480545.2015.1052143] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 03/31/2015] [Accepted: 05/13/2015] [Indexed: 11/13/2022]
Abstract
Three chemotoxins including dimethylnitrosamine (DMN), carbon tetrachloride (CCl4), and thioacetamide (TAA) are commonly used in hepatofibrotic models. We aimed to draw characteristics of histopathology and pro-fibrogenic cytokines including TGF-β, PDGF and CTGF among three models. Rats were divided into six groups and intra-peritoneally injected with DMN (10 mg/kg, for three weeks, three consecutive days weekly), CCl4 (1.6 g/kg, for 10 weeks, twice weekly), TAA (200 mg/kg, for 12 weeks, twice weekly) or their corresponded treatment for each control group. The liver weights were decreased in DMN model, but not other models. Ascites were occurred as 3-, 2-, and 7-rats in DMN, CCl4, and TAA model, respectively. The lipid peroxidation was highest in CCl4 model, serum levels of liver enzymes were increased as similar severity. The hepatofibrotic alterations were remarkable in DMN and TAA model, but not CCl4 as evidenced by the Masson trichrome staining and hydroxyproline. The immunohistochemistry for α-SAM showed that the DMN model was most severely enhanced than other models. On the other hand, hepatic tissue levels of pro-fibrogenic cytokines including TGF-β, PDGF, and CTGF were generally increased in three models, but totally different among models or measurement resources. Especially, serum levels of three cytokines were remarkably increased by CCl4 injection and CTGF levels in both hepatic tissue and serum were highest in CCl4 group. Our results firstly demonstrated comparative study for features of morphological finding and pro-fibrogenic cytokines in serum and hepatic protein levels among three models. Above results would be a helpful reference for hepatofibrotic studies.
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Affiliation(s)
- Hye-Jung Park
- a Department of Liver and Immunology Research Center , Daejeon Oriental Hospital of Daejeon University , Republic of Korea and
| | - Hyeong-Geug Kim
- a Department of Liver and Immunology Research Center , Daejeon Oriental Hospital of Daejeon University , Republic of Korea and
| | - Jing-Hua Wang
- b Laboratory of Medical Science , Dongguk University Medical Center, Dongguk University , Republic of Korea
| | - Min-Kyung Choi
- a Department of Liver and Immunology Research Center , Daejeon Oriental Hospital of Daejeon University , Republic of Korea and
| | - Jong-Min Han
- a Department of Liver and Immunology Research Center , Daejeon Oriental Hospital of Daejeon University , Republic of Korea and
| | - Jin-Seok Lee
- a Department of Liver and Immunology Research Center , Daejeon Oriental Hospital of Daejeon University , Republic of Korea and
| | - Chang-Gue Son
- a Department of Liver and Immunology Research Center , Daejeon Oriental Hospital of Daejeon University , Republic of Korea and
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Hong MZ, Zhang RM, Chen GL, Huang WQ, Min F, Chen T, Xu JC, Pan JS. Liver stiffness measurement-based scoring system for significant inflammation related to chronic hepatitis B. PLoS One 2014; 9:e111641. [PMID: 25360742 PMCID: PMC4216134 DOI: 10.1371/journal.pone.0111641] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 09/26/2014] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVES Liver biopsy is indispensable because liver stiffness measurement alone cannot provide information on intrahepatic inflammation. However, the presence of fibrosis highly correlates with inflammation. We constructed a noninvasive model to determine significant inflammation in chronic hepatitis B patients by using liver stiffness measurement and serum markers. METHODS The training set included chronic hepatitis B patients (n = 327), and the validation set included 106 patients; liver biopsies were performed, liver histology was scored, and serum markers were investigated. All patients underwent liver stiffness measurement. RESULTS An inflammation activity scoring system for significant inflammation was constructed. In the training set, the area under the curve, sensitivity, and specificity of the fibrosis-based activity score were 0.964, 91.9%, and 90.8% in the HBeAg(+) patients and 0.978, 85.0%, and 94.0% in the HBeAg(-) patients, respectively. In the validation set, the area under the curve, sensitivity, and specificity of the fibrosis-based activity score were 0.971, 90.5%, and 92.5% in the HBeAg(+) patients and 0.977, 95.2%, and 95.8% in the HBeAg(-) patients. The liver stiffness measurement-based activity score was comparable to that of the fibrosis-based activity score in both HBeAg(+) and HBeAg(-) patients for recognizing significant inflammation (G ≥3). CONCLUSIONS Significant inflammation can be accurately predicted by this novel method. The liver stiffness measurement-based scoring system can be used without the aid of computers and provides a noninvasive alternative for the prediction of chronic hepatitis B-related significant inflammation.
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Affiliation(s)
- Mei-Zhu Hong
- Department of Infectious Diseases, Chenggong Hospital affiliated to Xiamen University (the 174th Hospital of PLA), Xiamen, Fujian, China
| | - Ru-Mian Zhang
- Hepatology Unit and Department of Infectious Diseases, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China
| | - Guo-Liang Chen
- Hepatology Unit and Department of Infectious Diseases, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China
| | - Wen-Qi Huang
- Department of Infectious Diseases, Chenggong Hospital affiliated to Xiamen University (the 174th Hospital of PLA), Xiamen, Fujian, China
| | - Feng Min
- Department of Infectious Diseases, Chenggong Hospital affiliated to Xiamen University (the 174th Hospital of PLA), Xiamen, Fujian, China
| | - Tian Chen
- Department of Infectious Diseases, Chenggong Hospital affiliated to Xiamen University (the 174th Hospital of PLA), Xiamen, Fujian, China
| | - Jin-Chao Xu
- Department of Infectious Diseases, Chenggong Hospital affiliated to Xiamen University (the 174th Hospital of PLA), Xiamen, Fujian, China
| | - Jin-Shui Pan
- Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, Fujian, China
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Jung KS, Kim JH, Kim SU, Song K, Kim BK, Park JY, Kim DY, Ahn SH, Moon DC, Song IJ, Choi GH, Park YN, Han KH. Liver stiffness value-based risk estimation of late recurrence after curative resection of hepatocellular carcinoma: development and validation of a predictive model. PLoS One 2014; 9:e99167. [PMID: 24910997 PMCID: PMC4049628 DOI: 10.1371/journal.pone.0099167] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 05/12/2014] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Preoperative liver stiffness (LS) measurement using transient elastography (TE) is useful for predicting late recurrence after curative resection of hepatocellular carcinoma (HCC). We developed and validated a novel LS value-based predictive model for late recurrence of HCC. METHODS Patients who were due to undergo curative resection of HCC between August 2006 and January 2010 were prospectively enrolled and TE was performed prior to operations by study protocol. The predictive model of late recurrence was constructed based on a multiple logistic regression model. Discrimination and calibration were used to validate the model. RESULTS Among a total of 139 patients who were finally analyzed, late recurrence occurred in 44 patients, with a median follow-up of 24.5 months (range, 12.4-68.1). We developed a predictive model for late recurrence of HCC using LS value, activity grade II-III, presence of multiple tumors, and indocyanine green retention rate at 15 min (ICG R15), which showed fairly good discrimination capability with an area under the receiver operating characteristic curve (AUROC) of 0.724 (95% confidence intervals [CIs], 0.632-0.816). In the validation, using a bootstrap method to assess discrimination, the AUROC remained largely unchanged between iterations, with an average AUROC of 0.722 (95% CIs, 0.718-0.724). When we plotted a calibration chart for predicted and observed risk of late recurrence, the predicted risk of late recurrence correlated well with observed risk, with a correlation coefficient of 0.873 (P<0.001). CONCLUSION A simple LS value-based predictive model could estimate the risk of late recurrence in patients who underwent curative resection of HCC.
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Affiliation(s)
- Kyu Sik Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Hong Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cancer Special Clinic, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Kijun Song
- Department of Biostatistics, Yonsei University College of Medicine, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cancer Special Clinic, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cancer Special Clinic, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cancer Special Clinic, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cancer Special Clinic, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Do Chang Moon
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - In Ji Song
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Gi Hong Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cancer Special Clinic, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
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Chao DT, Lim JK, Ayoub WS, Nguyen LH, Nguyen MH. Systematic review with meta-analysis: the proportion of chronic hepatitis B patients with normal alanine transaminase ≤ 40 IU/L and significant hepatic fibrosis. Aliment Pharmacol Ther 2014; 39:349-358. [PMID: 24387289 DOI: 10.1111/apt.12590] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 07/10/2013] [Accepted: 12/01/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Chronic hepatitis B (CHB) may lead to cirrhosis, hepatocellular carcinoma and premature death. Elevated alanine transaminase (ALT) levels ≥ the upper limit of normal (ULN) are a major determinant for initiating anti-viral therapy; however, ALT levels alone may not be predictive of hepatic fibrosis. AIM To determine the proportion of CHB patients with ALT ≤ 40 IU/L and liver fibrosis stage ≥ 2. Secondary goals include subgroup analysis by hepatitis B e antigen (HBeAg) status, high hepatitis B virus (HBV) DNA levels, Asian ethnicity, lower ULN of ≤ 30 IU/L (males) and 19 IU/L (females), and advanced age. METHODS Studies identified in EMBASE and MEDLINE (1/1990-6/2012) using the search criteria: "Hepatitis B"[Mesh] OR "Hepatitis B virus"[Mesh] OR "Hepatitis B, Chronic"[Mesh])) AND "Alanine Transaminase"[Mesh]) and abstracts containing the term 'hepatitis' from recent major U.S. gastroenterology and liver society meetings were considered. RESULTS Among nine studies (N = 830 patients), a significant proportion (20.7%; 95% CI: 16.2-26.0%) of CHB patients with ALT levels ≤ 40 IU/L had significant fibrosis irrespective of HBeAg status, high HBV DNA levels, ethnicity or age, although this proportion may be higher in patients older than 30-40 years old. The corresponding proportion was 27.8% even when the newer ULN of 30 IU/L (males) and 19 IU/L (females) was applied. CONCLUSIONS Approximately one fifth of CHB patients with ALT ≤ 40 IU/L may have significant hepatic fibrosis. The approach to such patients should be individualised, as further evaluation and treatment may be appropriate.
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Affiliation(s)
- D T Chao
- Department of Internal Medicine, University of Pittsburgh Medical Center, Shadyside, Pittsburgh, PA, USA
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A novel hypothesis for an alkaline phosphatase 'rescue' mechanism in the hepatic acute phase immune response. Biochim Biophys Acta Mol Basis Dis 2013; 1832:2044-56. [PMID: 23899605 DOI: 10.1016/j.bbadis.2013.07.016] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 07/10/2013] [Accepted: 07/22/2013] [Indexed: 12/24/2022]
Abstract
The liver isoform of the enzyme alkaline phosphatase (AP) has been used classically as a serum biomarker for hepatic disease states such as hepatitis, steatosis, cirrhosis, drug-induced liver injury, and hepatocellular carcinoma. Recent studies have demonstrated a more general anti-inflammatory role for AP, as it is capable of dephosphorylating potentially deleterious molecules such as nucleotide phosphates, the pathogenic endotoxin lipopolysaccharide (LPS), and the contact clotting pathway activator polyphosphate (polyP), thereby reducing inflammation and coagulopathy systemically. Yet the mechanism underlying the observed increase in liver AP levels in circulation during inflammatory insults is largely unknown. This paper hypothesizes an immunological role for AP in the liver and the potential of this system for damping generalized inflammation along with a wide range of ancillary pathologies. Based on the provided framework, a mechanism is proposed in which AP undergoes transcytosis in hepatocytes from the canalicular membrane to the sinusoidal membrane during inflammation and the enzyme's expression is upregulated as a result. Through a tightly controlled, nucleotide-stimulated negative feedback process, AP is transported in this model as an immune complex with immunoglobulin G by the asialoglycoprotein receptor through the cell and secreted into the serum, likely using the receptor's State 1 pathway. The subsequent dephosphorylation of inflammatory stimuli by AP and uptake of the circulating immune complex by endothelial cells and macrophages may lead to decreased inflammation and coagulopathy while providing an early upstream signal for the induction of a number of anti-inflammatory gene products, including AP itself.
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Sumer S, Aktug Demir N, Kölgelier S, Cagkan Inkaya A, Arpaci A, Saltuk Demir L, Ural O. The Clinical Significance of Serum Apoptotic Cytokeratin 18 Neoepitope M30 (CK-18 M30) and Matrix Metalloproteinase 2 (MMP-2) Levels in Chronic Hepatitis B Patients with Cirrhosis. HEPATITIS MONTHLY 2013; 13:e10106. [PMID: 24032040 PMCID: PMC3768234 DOI: 10.5812/hepatmon.10106] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Revised: 04/08/2013] [Accepted: 05/25/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Serum apoptotic cytokeratine 18 neoepitope M30 (CK-18 M30) and matrix metalloproteinase 2 (MMP-2) have been popular markers for detecting liver fibrosis in recent years. CK-18 is a major intermediate filament protein in liver cells and one of the most prominent substrates of caspases during hepatocyte apoptosis. MMP-2 plays an important role in tissue remodeling and repairing processes during physiological and pathological states. OBJECTIVES The objective of this study was to investigate the significance of CK-18 M30 and MMP-2 levels for clinical use in patients with chronic hepatitis B (CHB), as well as their sensitivity in determining cirrhotic patients. PATIENTS AND METHODS This study included 189 CHB patients and 51 healthy controls. A modified Knodell scoring system was used to determine the fibrosis level in chronic hepatitis B patients. CK-18 M30 levels were determined with an M30-Apoptosense ELISA assay. MMP-2 levels were determined with the ELISA assay. RESULTS The study group consisted of 132 (69.8%) males and 57 (30.2%) females, and the control group consisted of 25 males (49.0%) and 26 females (51%). Patients' CK-18 M30 levels were higher than values of the control group (308 [1-762] vs. 168 [67-287], P=0.001). Serum MMP-2 levels were found to be statistically higher in the patient group with respect to the controls (3.0 [1.1-6.8] vs. 2.0 [1.2-3.4], P=0.001). The highest serum CK-18 M30 and MMP-2 levels were measured in patients with cirrhosis. Serum apoptotic CK-18 M30 levels positively correlated with advanced age, fibrosis stage, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (P= 0.001, 0.033, 0.001, and 0.001, respectively). Serum MMP-2 levels positively correlated with fibrosis stage, serum ALT, and AST levels (P= 0.001, 0.001, and 0.001, respectively). CONCLUSIONS Our study indicated that CK-18 M30 and MMP-2 levels were higher in CHB patients compared to healthy controls and they were in association with significant hepatic fibrosis, especially cirrhosis.
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Affiliation(s)
- Sua Sumer
- Department of Infectious Diseases and Clinical Microbiology, Selcuk University, Faculty of Medicine, Konya, Turkey
- Corresponding author: Sua Sumer, Department of Infectious Diseases and Clinical Microbiology, Selcuk University, Konya, Turkey. Tel: +90-5058746251, Fax: +90-3322412184, E-mail:
| | - Nazlim Aktug Demir
- Department of Infectious Diseases and Clinical Microbiology, Adiyaman State Hospital, Adiyaman, Turkey
| | - Servet Kölgelier
- Department of Infectious Diseases and Clinical Microbiology, Adiyaman University, Faculty of Medicine, Adiyaman, Turkey
| | - Ahmet Cagkan Inkaya
- Department of Internal Medicine, Division of Infectious Diseases, Hacettepe University, Faculty of Medicine, Ankara, Turkey
| | - Abdullah Arpaci
- Department of Biochemistry, Adiyaman University, Faculty of Medicine, Adiyaman, Turkey
| | | | - Onur Ural
- Department of Infectious Diseases and Clinical Microbiology, Selcuk University, Faculty of Medicine, Konya, Turkey
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Cardin R, Piciocchi M, Martines D, Scribano L, Petracco M, Farinati F. Effects of coffee consumption in chronic hepatitis C: a randomized controlled trial. Dig Liver Dis 2013; 45:499-504. [PMID: 23238034 DOI: 10.1016/j.dld.2012.10.021] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Revised: 10/24/2012] [Accepted: 10/30/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Coffee is associated with a reduced risk of hepatocellular carcinoma in patients with chronic C hepatitis. This prospective trial was aimed at assessing the mechanisms underlying coffee-related protective effects. METHODS Forty patients with chronic hepatitis C were randomized into two groups: the first consumed 4 cups of coffee/day for 30 days, while the second remained coffee "abstinent". At day 30, the groups were switched over for a second month. RESULTS At baseline, aspartate aminotransferase and alanine aminotransferase were lower in patients drinking 3-5 (Group B) than 0-2 cups/day (Group A) (56 ± 6 vs 74 ± 11/60 ± 3 vs 73 ± 7 U/L p=0.05/p=0.04, respectively). HCV-RNA levels were significantly higher in Group B [(6.2 ± 1.5) × 10(5)vs (3.9 ± 1.0) × 10(5)UI/mL, p=0.05]. During coffee intake, 8-hydroxydeoxyguanosine and collagen levels were significantly lower than during abstinence (15 ± 3 vs 44 ± 16 8-hydroxydeoxyguanosine/10(5)deoxyguanosine, p=0.05 and 56 ± 9 vs 86 ± 21 ng/mL, p=0.04). Telomere length was significantly higher in patients during coffee intake (0.68 ± 0.06 vs 0.48 ± 0.04 Arbitrary Units, p=0.006). Telomere length and 8-hydroxydeoxyguanosine were inversely correlated. CONCLUSION In chronic hepatitis C coffee consumption induces a reduction in oxidative damage, correlated with increased telomere length and apoptosis, with lower collagen synthesis, factors that probably mediate the protection exerted by coffee with respect to disease progression.
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Affiliation(s)
- Romilda Cardin
- Department of Surgical, Oncological and Gastroenterological Sciences, Section of Gastroenterology, Padua University, Padua, Italy
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