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Zheng S, Xue C, Li S, Qi W, Zao X, Li X, Wang W, Liu Q, Cao X, Zhang P, Ye Y. Research Progress of Chinese Medicine in the Regulation of Liver Fibrosis-Related Signaling Pathways. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:1693-1728. [PMID: 39343991 DOI: 10.1142/s0192415x24500666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Liver fibrosis is a common complication of chronic liver disease, significantly affecting patients' quality of life and potentially leading to cirrhosis and hepatocellular carcinoma. Despite advancements in modern medicine, the treatment of liver fibrosis remains limited and challenging. Thus, identifying new therapeutic strategies is of great clinical importance. Signaling pathways related to liver fibrosis play a crucial regulatory role in immune response and inflammation. Aberrant activation of specific pathways, such as the NF-κB signaling pathway, results in the overexpression of genes associated with liver inflammation and fibrosis, thereby promoting the progression of liver fibrosis. Chinese medicine offers unique potential advantages as a therapeutic approach. Recent studies have increasingly demonstrated that certain Chinese medicines can effectively treat liver fibrosis by regulating relevant signaling pathways. The active ingredients in these medicines can inhibit hepatic inflammatory responses and fibrotic processes by interfering with these pathways, thus reducing the severity of liver fibrosis. This paper aims to investigate the mechanisms of Chinese medicine in treating liver fibrosis and its modulation of related signaling pathways. Additionally, it discusses the prospects of the clinical application of these treatments and provides valuable references for further research and clinical practice.
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Affiliation(s)
- Shihao Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Chengyuan Xue
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Size Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Wenying Qi
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine Beijing, P. R. China
| | - Xiaoke Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Wei Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Qiyao Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Xu Cao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Peng Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Yongan Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P. R. China
- Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P. R. China
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Jeng WJ, Chien RN, Chen YC, Lin CL, Wu CY, Liu YC, Peng CW, Su CW, Hsu CE, Liaw YF. Hepatocellular carcinoma reduced, HBsAg loss increased, and survival improved after finite therapy in hepatitis B patients with cirrhosis. Hepatology 2024; 79:690-703. [PMID: 37625144 DOI: 10.1097/hep.0000000000000575] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023]
Abstract
BACKGROUND AND AIMS Long-term nucleos(t)ide analog (Nuc) treatment can reduce HCC in patients with HBV-related liver cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in HBeAg-negative patients with HBV-LC who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. APPROACH AND RESULTS From 2 centers, 494 HBeAg-negative patients with HBV-LC who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, HBsAg loss, liver-related mortality/transplantation, and overall survival rates were compared between 2 groups with 1:1 propensity score matching of sex, treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end of therapy in finite group or 3-year on-therapy in continuous groups. During a median follow-up of 6.2 (3.4-8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/y and 10-y 15.7% vs. 26.8%, respectively; log-rank test, p <0.0001). The finite group showed greater HBsAg decline/year (-0.116 vs. -0.095 log 10 IU/mL, p =0.0026) and 7.6 times higher 10-year incidence of HBsAg loss (22.7% vs. 3%, p <0.0001). Multivariate Cox regression showed finite therapy an independent factor for HBsAg loss (adjusted HR: 11.79) but protective against HCC (adjusted HR: 0.593), liver-related mortality/transplantation (adjusted HR: 0.312), and overall mortality (adjusted HR: 0.382). CONCLUSIONS Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss, and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Yi-Cheng Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Chih-Lang Lin
- College of Medicine, Chang Gung University, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Keelung Branch, Taiwan
| | - Chia-Ying Wu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Yen-Chun Liu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Chien-Wei Peng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Chung-Wei Su
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Cheng-Er Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
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Liaw YF, Jeng WJ, Chien RN. Reply: Benefits of stopping therapy in patients with cirrhotic hepatitis B, true effect, or residual confounding? Hepatology 2024; 79:E97-E98. [PMID: 37862454 DOI: 10.1097/hep.0000000000000641] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 10/22/2023]
Affiliation(s)
- Yun-Fan Liaw
- Department of Medicine, College of Medicine, Chang Gung University, Taipei, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan
| | - Wen-Juei Jeng
- Department of Medicine, College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Department of Medicine, College of Medicine, Chang Gung University, Taipei, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
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Cogliati B, Yashaswini CN, Wang S, Sia D, Friedman SL. Friend or foe? The elusive role of hepatic stellate cells in liver cancer. Nat Rev Gastroenterol Hepatol 2023; 20:647-661. [PMID: 37550577 PMCID: PMC10671228 DOI: 10.1038/s41575-023-00821-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/06/2023] [Indexed: 08/09/2023]
Abstract
Liver fibrosis is a substantial risk factor for the development and progression of liver cancer, which includes hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Studies utilizing cell fate mapping and single-cell transcriptomics techniques have identified quiescent perisinusoidal hepatic stellate cells (HSCs) as the primary source of activated collagen-producing HSCs and liver cancer-associated fibroblasts (CAFs) in HCC and liver metastasis, complemented in iCCA by contributions from portal fibroblasts. At the same time, integrative computational analysis of single-cell, single-nucleus and spatial RNA sequencing data have revealed marked heterogeneity among HSCs and CAFs, with distinct subpopulations displaying unique gene expression signatures and functions. Some of these subpopulations have divergent roles in promoting or inhibiting liver fibrogenesis and carcinogenesis. In this Review, we discuss the dual roles of HSC subpopulations in liver fibrogenesis and their contribution to liver cancer promotion, progression and metastasis. We review the transcriptomic and functional similarities between HSC and CAF subpopulations, highlighting the pathways that either promote or prevent fibrosis and cancer, and the immunological landscape from which these pathways emerge. Insights from ongoing studies will yield novel strategies for developing biomarkers, assessing prognosis and generating new therapies for both HCC and iCCA prevention and treatment.
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Affiliation(s)
- Bruno Cogliati
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, SP, Brazil
| | | | - Shuang Wang
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daniela Sia
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Abubakr S, Hazem NM, Sherif RN, Elhawary AA, Botros KG. Correlation between SDF-1α, CD34 positive hematopoietic stem cells and CXCR4 expression with liver fibrosis in CCl4 rat model. BMC Gastroenterol 2023; 23:323. [PMID: 37730560 PMCID: PMC10512633 DOI: 10.1186/s12876-023-02932-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 08/25/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND One of the most frequent disorders is liver fibrosis. An improved understanding of the different events during the process of liver fibrosis & its reversibility could be helpful in its staging and in finding potential therapeutic agents. AIM The goal of this research was to evaluate the relationship among CD34 + HPSCs, SDF-1α, and CXCR4 receptor expression with the percentage of the area of hepatic fibrosis. MATERIALS AND METHODS Thirty-six male Sprague-Dawley rats were separated into the control group, liver injury group & spontaneous reversion group. The liver injury was induced by using 2 ml/kg CCl4 twice a week. Flow cytometric examination of CD34 + cells in the blood & liver was performed. Bone marrow & liver samples were taken for evaluation of the SDF-1α mRNA by PCR. Liver specimens were stained for histopathological and CXCR4 immuno-expression evaluation. RESULTS In the liver injury group, the hepatic enzymes, fibrosis area percentage, CXCR4 receptor expression in the liver, CD34 + cells in the blood and bone marrow & the level SDF-1α in the liver and its concentration gradient were statistically significantly elevated with the progression of the liver fibrosis. On the contrary, SDF-1α in the bone marrow was statistically significantly reduced with the development of liver fibrosis. During the spontaneous reversion group, all the studied parameters apart from SDF-1α in the bone marrow were statistically substantially decreased compared with the liver injury group. We found a statistically substantial positive correlation between fibrosis area and all of the following: liver enzymes, CXCR4 receptor expression in the liver, CD34 + cells in the blood and liver, and SDF- 1α in the liver and its concentration gradient. In conclusion, in CCl4 rat model, the fibrosis area is significantly correlated with many parameters in the blood, bone marrow, and liver, which can be used during the process of follow-up during the therapeutic interventions.
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Affiliation(s)
- Sara Abubakr
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Noha M Hazem
- Medical Biochemistry and Molecular Biology Department, Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Algomhoria Street, Mansoura, 35516, Egypt.
- Pathological Sciences Department, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia.
| | - R N Sherif
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Adel Abdelmohdy Elhawary
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Kamal G Botros
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Liaw YF. Perspectives on current controversial issues in the management of chronic HBV infection. J Gastroenterol 2022; 57:828-837. [PMID: 36053366 DOI: 10.1007/s00535-022-01918-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/18/2022] [Indexed: 02/04/2023]
Abstract
Clinical and basic research in the past decades has achieved consensus in the understanding of chronic hepatitis B virus (HBV) infection and the management of chronic hepatitis B and HBV-cirrhosis. However, debatable challenges to the existing consensus in the concept and/or definitions have emerged. These include (1). alanine aminotransferase upper limit of normal: traditional laboratory-defined vs fixed; (2). nomenclature for phases of chronic HBV infection: classical vs EASL proposal; (3). indication of antiviral therapy: to treat patients vs to treat HBV; (4). finite vs indefinite long-term antiviral therapy: A. finite therapy in HBV-cirrhosis; B. retreatment decision: biochemical markers vs HBsAg/ALT kinetics. The pros and cons of these controversial issues were reviewed, assessed, and discussed in depth based on relevant lines of scientific evidence, intended to clarify or solve these controversial issues.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199, Tung Hwa North Road, Taipei, 105, Taiwan.
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Li YG, Yu ZJ, Li A, Ren ZG. Gut microbiota alteration and modulation in hepatitis B virus-related fibrosis and complications: Molecular mechanisms and therapeutic inventions. World J Gastroenterol 2022; 28:3555-3572. [PMID: 36161048 PMCID: PMC9372803 DOI: 10.3748/wjg.v28.i28.3555] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/06/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) has posed a threat to public health, mainly resulting in liver damage. With long-term accumulation of extracellular matrix, patients with chronic hepatitis B are at high risk of developing into liver fibrosis and cirrhosis and even life-threatening hepatic carcinoma. The occurrence of complications such as spontaneous bacterial peritonitis and hepatic encephalopathy greatly increases disability and mortality. With deeper understanding of the bidirectional interaction between the liver and the gut (gut-liver axis), there is a growing consensus that the human health closely relates to the gut microbiota. Supported by animal and human studies, the gut microbiota alters as the HBV-related liver fibrosis initials and progresses, characterized as the decrease of the ratio between “good” and “potentially pathogenic” microbes. When the primary disease is controlled via antiviral treatment, the gut microbiota dysfunction tends to be improved. Conversely, the recovery of gut microbiota can promote the regression of liver fibrosis. Therapeutic strategies targeted on gut microbiota (rifaximin, probiotics, engineered probiotics and fecal microbiota transplantation) have been applied to animal models and patients, obtaining satisfactory results.
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Affiliation(s)
- Yao-Guang Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zu-Jiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Ang Li
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhi-Gang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, Shandong Province, China
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Current Trend in Antiviral Therapy for Chronic Hepatitis B. Viruses 2022; 14:v14020434. [PMID: 35216027 PMCID: PMC8877417 DOI: 10.3390/v14020434] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/13/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
Since active hepatitis B virus (HBV) replication is the key driver of hepatic necroinflammation and disease progression, the treatment aim of chronic hepatitis B (CHB) is to suppress HBV replication permanently to prevent hepatic decompensation, liver cirrhosis and/or hepatocellular carcinoma and prolong survival. Currently, pegylated interferon (Peg-IFN), entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line drugs of choice. Peg-IFN therapy has been used rarely due to its subcutaneous injection and significant side effect profile. Once daily oral ETV, TDF and TAF can suppress HBV DNA profoundly but have no direct action on cccDNA of the HBV-infected hepatocytes, hence continuing long-term therapy is usually needed to maintain HBV suppression, but the ultimate goal of HBsAg loss was rarely achieved (10 year 2%). In addition, long-term NUC therapy comes with several concerns such as increasing cost, medication adherence and loss-to-follow-up. Studies, mainly from Taiwan, have shown that finite NUCs therapy of two to three years in HBeAg-negative patients is feasible, safe and has a great benefit of much increasing HBsAg loss rate up to 30%/5 year. These have led an emerging paradigm shift to finite NUC therapy in HBeAg-negative patients globally. However, off-NUC relapse with hepatitis B flares may occur and have a risk of decompensation or even life-threatening outcomes. Therefore, proper monitoring, assessment, and retreatment decisions are crucial to ensure safety. Ideally, retreatment should be not too late to ensure safety and also not too early to allow further immune response for further HBsAg decline toward HBsAg loss. Assessment using combined HBsAg/ALT kinetics during hepatitis flare is better than biochemical markers alone to make a right retreatment decision. The strategy of finite NUC therapy has set a benchmark of high HBsAg loss rate to be achieved by the new anti-HBV drugs which are under preclinical or early phase study.
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Yang L, Bi L, Jin L, Wang Y, Li Y, Li Z, He W, Cui H, Miao J, Wang L. Geniposide Ameliorates Liver Fibrosis Through Reducing Oxidative Stress and Inflammatory Respose, Inhibiting Apoptosis and Modulating Overall Metabolism. Front Pharmacol 2021; 12:772635. [PMID: 34899328 PMCID: PMC8651620 DOI: 10.3389/fphar.2021.772635] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/05/2021] [Indexed: 12/15/2022] Open
Abstract
Liver fibrosis is a progressive liver damage condition caused by various factors and may progress toward liver cirrhosis, and even hepatocellular carcinoma. Many studies have found that the disfunction in metabolism could contribute to the development of liver fibrosis. Geniposide, derived from Gardenia jasminoides J. Ellis, has been demonstrated with therapeutic effects on liver fibrosis. However, the exact molecular mechanisms of such liver-protection remain largely unknown. The aim of this study was to explored the effect of geniposide on metabolic regulations in liver fibrosis. We used carbon tetrachloride (CCl4) to construct a mouse model of liver fibrosis and subsequently administered geniposide treatment. Therapeutic effects of geniposide on liver fibrosis were accessed through measuring the levels of hepatic enzymes in serum and the pathological changes in liver. We also investigated the effects of geniposide on inflammatory response, oxidative stress and apoptosis in liver. Furthermore, serum untargeted metabolomics were used to explore the metabolic regulatory mechanisms behind geniposide on liver fibrosis. Our results demonstrated that geniposide could reduce the levels of hepatic enzymes in serum and ameliorate the pathological changes in liver fibrosis mice. Geniposide enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased methane dicarboxylic aldehyde (MDA) levels in liver. Geniposide treatment also decreased the levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-a) in liver tissue homogenate. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining demonstrated that geniposide could reduce the apoptosis of hepatocytes. Geniposide increased the protein expression of B-cell lymphoma-2 (Bcl-2) and downregulated the protein expression of Bcl-2 Associated X (Bax), cleaved-Caspase 3, and cleaved-Caspase 9. Serum untargeted metabolomics analysis demonstrated that geniposide treatment improved the metabolic disorders including glycerophospholipid metabolism, arginine and proline metabolism, and arachidonic acid (AA) metabolism. In conclusion, our study demonstrated the protective effects of geniposide on liver fibrosis. We found that geniposide could treat liver fibrosis by inhibiting oxidative stress, reducing inflammatory response and apoptosis in the liver, and modulating glycerophospholipid, and arginine, proline, and AA metabolism processes.
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Affiliation(s)
- Lu Yang
- Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Tianjin Second People's Hospital, Tianjin, China
| | - Liping Bi
- Tianjin Second People's Hospital, Tianjin, China
| | - Lulu Jin
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuming Wang
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuting Li
- Tianjin University of Traditional Chinese Medicine, Tianjin, China.,First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zixuan Li
- Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, China
| | - Wenju He
- Tianjin First Central Hospital, Tianjin, China
| | - Huantian Cui
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Jing Miao
- Tianjin Second People's Hospital, Tianjin, China
| | - Li Wang
- Tianjin Second People's Hospital, Tianjin, China
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10
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Abstract
Antiviral therapy has greatly improved the survival and reduced the incidence of adverse liver events such as hepatic decompensation and hepatocellular carcinoma in chronic hepatitis B patients with cirrhosis (hepatitis B virus [HBV]-cirrhosis). However, hepatitis B surface antigen loss, regarded as the ultimate goal of therapy or functional cure, was rarely achieved during long-term indefinite nucleos(t)ide analogues (Nuc) treatment. Emerging issues such as medication adherence and loss-to-follow-up may lead to increased risk of hepatic decompensation, even catastrophic life-threatening events. Studies have shown that finite therapy is feasible and reasonably safe, even in patients with HBV-cirrhosis. This review critically assesses the scientific evidence of the pros and cons for finite Nuc therapy in HBV-cirrhosis and proposes how to stop Nuc therapy and monitor the off-therapy patients. It also proposes the perspective and unsolved issues to be investigated in the future.
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Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan
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11
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Rockey DC, Friedman SL. Fibrosis Regression After Eradication of Hepatitis C Virus: From Bench to Bedside. Gastroenterology 2021; 160:1502-1520.e1. [PMID: 33529675 PMCID: PMC8601597 DOI: 10.1053/j.gastro.2020.09.065] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/01/2020] [Accepted: 09/06/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection and its complications have been the major cause of cirrhosis and its complications for several decades in the Western world. Until recently, treatment for HCV with interferon-based regimens was associated with moderate success but was difficult to tolerate. More recently, however, an arsenal of novel and highly effective direct-acting antiviral (DAA) drugs has transformed the landscape by curing HCV in a broad range of patients, including those with established advanced fibrosis, cirrhosis, comorbidities, and even those with complications of cirrhosis. Fibrosis is a dynamic process comprising both extracellular matrix deposition, as well as its degradation. With almost universal sustained virologic response (SVR) (ie, elimination of HCV), it is timely to explore whether HCV eradication can reverse fibrosis and cirrhosis. Indeed, fibrosis in several types of liver disease is reversible, including HCV. However, we do not know with certainty in whom fibrosis regression can be expected after HCV elimination, how quickly it occurs, and whether antifibrotic therapies will be indicated in those with persistent cirrhosis. This review summarizes the evidence for reversibility of fibrosis and cirrhosis after HCV eradication, its impact on clinical outcomes, and therapeutic prospects for directly promoting fibrosis regression in patients whose fibrosis persists after SVR.
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Affiliation(s)
- Don C Rockey
- The Medical University of South Carolina, Charleston, South Carolina.
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York
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12
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Cheng G, Dai M, Xiao T, Fu T, Han H, Wang Y, Wang W, Ding H, Yu J. Quantitative evaluation of liver fibrosis based on ultrasound radio frequency signals: An animal experimental study. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2021; 199:105875. [PMID: 33340924 DOI: 10.1016/j.cmpb.2020.105875] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 11/17/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND Chronic liver disease is an important cause of liver failure and death worldwide, and liver fibrosis is a common pathological process of most chronic liver diseases. There still lacks a useful tool for evaluating liver fibrosis progression precisely and non-invasively. The purpose of this study was to explore the use of ultrasound radio frequency (RF) signals combined with deep learning approach to evaluate the degree of liver fibrosis quantitatively. METHODS In this study, by extracting the output of deep learning models as a prediction value, a quantitative liver fibrosis prediction method was achieved based on the bidirectional long short-term memory (Bi-LSTM) network to analyze radio frequency (RF) signals. The dataset consisted of 160 sets of ultrasound RF signals of rat livers, including five fibrosis stages 0-4, upon pathological diagnosis. In total, 150 sets of RF signals were used to train four deep learning classification models, the output of which contained quantitative information. In each training stage of the four models, a large number of signal segments were extracted from the 150 sets and divided randomly into training and validation sets in a ratio of 80:20. Ten sets of RF data using the gold standard of quantitative fibrosis parameter (q-FP) of liver tissues were left for independent testing. To validate the proposed method, correlation analysis was carried out between q-FP and the quantitative prediction results based on the independent test data. RESULTS The accuracy of the four deep learning networks using the training and validation data was above 0.83 and 0.80, and the corresponding areas under the receiver operating characteristic curves were higher than 0.95 and 0.93, respectively. For the quantitative analysis in the independent test set, the determination coefficient, R2, of the linear regression analysis between the quantitative prediction results and q-FP was above 0.93. liver fibrosis is a common pathological process of most chronic liver diseases. CONCLUSIONS This study indicates that a prediction system based on ultrasound RF signals and a deep learning approach is promising for realizing quantitative and visualized diagnosis of liver fibrosis, which would be of great value in monitoring liver fibrosis non-invasively.
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Affiliation(s)
- Guangwen Cheng
- Department of Ultrasound, Huashan Hospital, Fudan University, No. 12 Urumqi Middle Road, Shanghai 200040, China
| | - Meng Dai
- Department of Electronic Engineering, Fudan University, No. 220, Handan Road, Shanghai 200433, China
| | - Tianlei Xiao
- Department of Electronic Engineering, Fudan University, No. 220, Handan Road, Shanghai 200433, China
| | - Tiantian Fu
- Department of Ultrasound, Huashan Hospital, Fudan University, No. 12 Urumqi Middle Road, Shanghai 200040, China; Department of Ultrasound, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China; Shanghai Institute of Medical Imaging, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China
| | - Hong Han
- Department of Ultrasound, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China
| | - Yuanyuan Wang
- Department of Electronic Engineering, Fudan University, No. 220, Handan Road, Shanghai 200433, China
| | - Wenping Wang
- Department of Ultrasound, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China
| | - Hong Ding
- Department of Ultrasound, Huashan Hospital, Fudan University, No. 12 Urumqi Middle Road, Shanghai 200040, China.
| | - Jinhua Yu
- Department of Electronic Engineering, Fudan University, No. 220, Handan Road, Shanghai 200433, China.
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13
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Wang C, Zhang X, Ling Q, Zheng S, Xu X. A model integrating donor gene polymorphisms predicts fibrosis after liver transplantation. Aging (Albany NY) 2020; 13:1264-1275. [PMID: 33291080 PMCID: PMC7835018 DOI: 10.18632/aging.202302] [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: 07/16/2020] [Accepted: 09/21/2020] [Indexed: 01/10/2023]
Abstract
Post-transplant liver fibrosis (PTLF) is a common and severe complication in liver recipients. In this study, we assessed the impact of donor liver genetics on the development of PTLF. A total of 232 patients undergoing liver transplantation were included. Twenty-two single nucleotide polymorphisms (SNPs) associated with liver fibrosis were analyzed. Univariate analysis revealed seven donor SNPs to be associated with PTLF. In a multivariate analysis, independent risk factors of PTLF were genetic variation of donor GRP78 rs430397 (OR = 8.99, p = 0.003), GSTP1 rs1695 (OR = 0.13, p = 0.021), miRNA-196a rs12304647 (OR = 16.01, p =0.001), and TNF-α rs1800630 (OR = 79.78, p = 0.001); blood tacrolimus levels at maintenance > 7 ng/ml (OR =7.48, p <0.001); and post-transplant diabetes mellitus (OR = 7.50, p = 0.001). A predictive model that included donor SNPs showed better prognostic ability for PTLF than a model with only clinical parameters (AUROC: 0.863 vs 0.707, P < 0.001). Given that donor gene SNPs are associated with an increased risk of PTLF, this model integrated with donor gene polymorphisms may help clinicians predict PTLF.
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Affiliation(s)
- Chao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Xueyou Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qi Ling
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
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14
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Recompensation of Decompensated Hepatitis B Cirrhosis: Current Status and Challenges. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9609731. [PMID: 33029534 PMCID: PMC7527887 DOI: 10.1155/2020/9609731] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 09/07/2020] [Accepted: 09/15/2020] [Indexed: 02/07/2023]
Abstract
Liver-function decompensation or hepatocellular carcinoma (HCC) gradually appears after chronic hepatitis B progresses to cirrhosis. Effective antiviral treatment can significantly improve the long-term prognosis of decompensated patients, and some patients present recompensation of decompensated hepatitis B cirrhosis. At present, there are limited research data on the recompensation of decompensated hepatitis B cirrhosis. There is still controversy regarding the evaluation time, evaluation indicators, influencing factors, and long-term prognosis of recompensation.
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15
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Li D, Zhu M, Zhou C, Liu X. Effect of Liuweiwuling tablet on biochemical and virological parameters, and quality of life in patients with hepatitis B virus-related cirrhosis: A protocol for a systematic review and meta-analysis. Medicine (Baltimore) 2020; 99:e22065. [PMID: 32925741 PMCID: PMC7489732 DOI: 10.1097/md.0000000000022065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liuweiwuling (LWWL) tablet, a kind of plant-derived traditional Chinese medicine preparation, has been widely applied as a promising adjunctive drug for hepatitis B virus-related cirrhosis (HBVC). However, its exact clinical efficacy and safety is still not well investigated. In this study, we aimed to summarize the efficacy of LWWL tablet on biochemical and virological parameters, and quality of life (QoL) in patients with HBVC through the meta-analysis. METHODS All available randomized controlled trials and high-quality prospective cohort studies that investigated the efficacy and safety of LWWL for patients with HBVC were searched from the following electronic databases: PubMed, Medline, Cochrane Library, Google Scholar, Web of Science, Excerpt Medica Database, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, China Scientific Journal Database, and Wanfang Database. Papers in Chinese or English published from January 2000 to August 2020 will be included without any restrictions.Study selection and data extraction will be performed independently by 2 authors. The clinical outcomes including biochemical (liver function and fibrosis indexes) and virological parameters, QoL, immune function and adverse events, were systematically evaluated. Review Manager 5.3 and Stata 14.0 were used for data synthesis, sensitivity analysis, meta regression, subgroup analysis, and risk of bias assessment. RESULTS The results of this study will be published in a peer-reviewed journal, and provide a helpful evidence for clinicians to formulate the best postoperative adjuvant treatment strategy for HBVC patients. CONCLUSION Our study will draw an objective conclusion of the efficacy of LWWL on biochemical and virological parameters, and QoL in patients with HBVC. INPLASY REGISTRATION NUMBER INPLASY202080010.
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Affiliation(s)
- Ding Li
- Department of Clinical Laboratory
| | - Min Zhu
- Department of Clinical Laboratory
| | - Changhui Zhou
- Department of Central Laboratory, Liaocheng People's Hospital, Liaocheng, Shandong Province, P.R. China
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16
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Kim DH, Beckett JD, Nagpal V, Seman-Senderos MA, Gould RA, Creamer TJ, MacFarlane EG, Chen Y, Bedja D, Butcher JT, Mitzner W, Rouf R, Hata S, Warren DS, Dietz HC. Calpain 9 as a therapeutic target in TGFβ-induced mesenchymal transition and fibrosis. Sci Transl Med 2020; 11:11/501/eaau2814. [PMID: 31316008 DOI: 10.1126/scitranslmed.aau2814] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 01/14/2019] [Accepted: 06/05/2019] [Indexed: 12/26/2022]
Abstract
Fibrosis is a common pathologic outcome of chronic disease resulting in the replacement of normal tissue parenchyma with a collagen-rich extracellular matrix produced by myofibroblasts. Although the progenitor cell types and cellular programs giving rise to myofibroblasts through mesenchymal transition can vary between tissues and diseases, their contribution to fibrosis initiation, maintenance, and progression is thought to be pervasive. Here, we showed that the ability of transforming growth factor-β (TGFβ) to efficiently induce myofibroblast differentiation of cultured epithelial cells, endothelial cells, or quiescent fibroblasts is dependent on the induced expression and activity of dimeric calpains, a family of non-lysosomal cysteine proteases that regulate a variety of cellular events through posttranslational modification of diverse substrates. siRNA-based gene silencing demonstrated that TGFβ-induced mesenchymal transition of a murine breast epithelial cell line was dependent on induction of expression of calpain 9 (CAPN9), an isoform previously thought to be restricted to the gastrointestinal tract. Mice lacking functional CAPN9 owing to biallelic targeting of Capn9 were viable and fertile but showed overt protection from bleomycin-induced lung fibrosis, carbon tetrachloride-induced liver fibrosis, and angiotensin II-induced cardiac fibrosis and dysfunction. A predicted loss-of-function allele of CAPN9 is common in Southeast Asia, with the frequency of homozygosity matching the prediction of Hardy-Weinberg equilibrium. Together with the highly spatially restricted pattern of CAPN9 expression under physiologic circumstances and the heartiness of the murine knockout, these data provide a strong signature for tolerance of therapeutic strategies for fibrosis aimed at CAPN9 antagonism.
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Affiliation(s)
- David H Kim
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Cellular and Molecular Medicine Program, School of Medicine, Baltimore, MD 21205, USA
| | - James D Beckett
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Varun Nagpal
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Manuel A Seman-Senderos
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Cellular and Molecular Medicine Program, School of Medicine, Baltimore, MD 21205, USA
| | - Russell A Gould
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Tyler J Creamer
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Elena Gallo MacFarlane
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Yichun Chen
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Djahida Bedja
- Department of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jonathan T Butcher
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Wayne Mitzner
- Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Rosanne Rouf
- Department of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Shoji Hata
- Department of Advanced Science for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Daniel S Warren
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Harry C Dietz
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. .,Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
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17
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Cheng M, Feng X, Wang L, Yang Y, Ma L, Wang B. Nucleoside analogs assisted with Chinese compound prescription in treating hepatic fibrosis of chronic hepatitis B patients: A protocol of systematic review and meta-analysis. Medicine (Baltimore) 2020; 99:e21032. [PMID: 32629728 PMCID: PMC7337550 DOI: 10.1097/md.0000000000021032] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 06/02/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Chronic hepatitis B is often complicated with different degrees of hepatic fibrosis, which affects the quality of life. Nucleoside analogs are recommended by almost all guidelines in the world for the treatment of chronic hepatitis B. At present, there is no specific and effective chemical and biological agents for hepatic fibrosis. In China, Chinese compound prescription combined with nucleoside analogs have been used to treat hepatic fibrosis of chronic hepatitis B patients in more and more cases, and good results have been achieved. Several Chinese compound prescriptions that have been made into proprietary Chinese medicine for the convenience of use. This article aims to systematically evaluate the efficacy and safety of Chinese medicine compounds assisting nucleoside analogs in the treatment of hepatic fibrosis in chronic hepatitis B patients. METHOD The following databases will be searched from their inception to September 2019: PubMed, EMBASE, EBSCOhost, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical literature Database (CBM), VIP Database, Wanfang Database. Languages are limited to Chinese and English. The study includes randomized controlled trials using Chinese compound prescription combined with entecavir and Chinese compound prescription combined with tenofovir disoproxil fumarate to treat hepatic fibrosis of chronic hepatitis B patients. The primary outcomes including effective rate and biochemical parameters (levels of hyaluronic acid, laminin, pre-type-III collagen and type IV collagen will be tested. Additional outcomes include liver function indexes (levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin) and levels of hepatitis B virus DNA. Stata14.0 software will be used for meta-analysis. RESULT The efficacy and safety of Chinese compound prescriptions assisting nucleoside analogs for hepatic fibrosis of chronic hepatitis B patients will be assessed from the effective rate, biochemical parameters, liver function indexes, and levels of hepatitis B virus DNA. CONCLUSION The conclusion of this study will be used to evaluate the efficacy and safety of Chinese compound prescriptions assisting nucleoside analogs in the treatment of hepatic fibrosis of chronic hepatitis B patients, as well as the adjuvant effectiveness of Chinese compound prescriptions in combined therapy. PROSPERO REGISTRATION NUMBER CRD42020156859.
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Affiliation(s)
- Maoyuan Cheng
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine
| | - Xianrong Feng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Long Wang
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine
| | - Yu Yang
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine
| | - Li Ma
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine
| | - Baojia Wang
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine
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18
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Xu LM, Liu P. Guidelines for diagnosis and treatment of hepatic fibrosis with integrated traditional Chinese and Western medicine (2019 edition). JOURNAL OF INTEGRATIVE MEDICINE 2020; 18:203-213. [PMID: 32331978 DOI: 10.1016/j.joim.2020.03.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 09/25/2019] [Indexed: 12/16/2022]
Abstract
In 2006, the Hepatology Committee of Chinese Association of Integrative Medicine issued the "Guidelines for the Prevention and Treatment of Liver Fibrosis with Integrated Traditional Chinese and Western Medicine." In recent years, the fields of Chinese medicine, Western medicine, and integrative medicine have made rapid advances in basic and clinical research into chronic liver disease, and accumulated new evidence for the prevention and treatment of hepatic fibrosis. Therefore, in order to meet clinical needs, liver disease experts of integrated traditional Chinese and Western medicine were united to revise the previous guidelines in order to help physicians make correct and reasonable decisions in the diagnosis and treatment of hepatic fibrosis.
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Affiliation(s)
- Lie-Ming Xu
- Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Ping Liu
- Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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19
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Zhang T, Yang Y, Wang B, Zheng X, Wang L, Feng X, Li G, Shi J, Cao N. Meta-analysis of influences of Biejiajian Pill combined with entecavir on serum liver fibrosis markers of compensatory period of hepatitis b cirrhosis: Protocol of systematic review and meta-analysis. Medicine (Baltimore) 2019; 98:e18458. [PMID: 31861022 PMCID: PMC6940166 DOI: 10.1097/md.0000000000018458] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 11/18/2019] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Chronic viral hepatitis b and its related complications have caused serious harm to human health and become a worldwide public health problem. Hepatitis b cirrhosis is one of the most common complications in Asia. Traditional Chinese medicine combined with antiviral therapy has become the first choice for clinical treatment of hepatitis b Cirrhosis. Biejia Pill is an effective prescription of traditional Chinese medicine in treating Compensatory period of cirrhosis, and there are more and more clinical reports about its validity in treating Compensatory period of cirrhosis. Therefore, we designed this study protocol to evaluate the adjuvant role of Biejia Pill in the treatment of Compensatory period of cirrhosis. METHOD Electronic Databases, PubMed, EMBASE database, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang, Chinese Scientific Journals Database (VIP) and China Biology Medicine disc, (CBM), will be systematically searched from inception to July 2019. Randomized controlled trials (RCTs) on Biejiajian Pill combined with Entecavir and Entecavir alone against Compensatory period of hepatitis b cirrhosis will be included; inclusion and exclusion criteria will be used to screen the trials. liver fibrosis biomarkers including ECM or its metabolites (serum hyaluronic acid (HA), laminin (LN), procollagen type III (PC-III), and type IV collagen (IV-C)) will be measured as primary outcomes. Liver function, including alanine aminotransferase (ALT) and aspartarte aminotransferase (AST), and improvement of related clinical symptoms will be measured as secondary outcomes. RevMan5 software will be used for literature quality evaluation and data synthesis and analysis. RESULT To evaluate the efficacy and safety of Biejiajian Pill in combination therapy by observing the outcomes of serum liver fibrosis markers, adverse reactions and liver function. CONCLUSION This study protocol will be used to evaluate the efficacy and safety of Biejia Pill in combination with entecavir in the treatment of Compensatory period of hepatitis b cirrhosis, as well as the adjuvant treatment of Biejia Pill in combination.PROSPERO registration number: CRD42019135402.
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Affiliation(s)
| | - Yu Yang
- Chengdu University of Traditional Chinese Medicine
| | - Baojia Wang
- Chengdu University of Traditional Chinese Medicine
| | - Xiuli Zheng
- Chengdu University of Traditional Chinese Medicine
| | - Long Wang
- Chengdu University of Traditional Chinese Medicine
| | - Xianrong Feng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan
| | - Guiyu Li
- Chengdu University of Traditional Chinese Medicine
| | - Jinyu Shi
- Chengdu University of Traditional Chinese Medicine
| | - Ning Cao
- Shaanxi University of Traditional Chinese Medicine, Xianyang, Shaanxi province, China
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20
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Soufi M, Otake Y, Hori M, Moriguchi K, Imai Y, Sawai Y, Ota T, Tomiyama N, Sato Y. Liver shape analysis using partial least squares regression-based statistical shape model: application for understanding and staging of liver fibrosis. Int J Comput Assist Radiol Surg 2019; 14:2083-2093. [PMID: 31705418 DOI: 10.1007/s11548-019-02084-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 10/21/2019] [Indexed: 12/14/2022]
Abstract
PURPOSE Liver shape variations have been considered as feasible indicators of liver fibrosis. However, current statistical shape models (SSM) based on principal component analysis represent gross shape variations without considering the association with the fibrosis stage. Therefore, we aimed at the application of a statistical shape modelling approach using partial least squares regression (PLSR), which explicitly uses the stage as supervised information, for understanding the shape variations associated with the stage as well as predicting it in contrast-enhanced MR images. METHODS Contrast-enhanced MR images of 51 patients with fibrosis stages F0/1 (n = 18), F2 (n = 15), F3 (n = 7) and F4 (n = 11) were used. The livers were manually segmented from the images. An SSM was constructed using PLSR, by which shape variation modes (scores) that were explicitly associated with the reference pathological fibrosis stage were derived. The stage was predicted using a support vector machine (SVM) based on the PLSR scores. The performance was assessed using the area under receiver operating characteristic curve (AUC). RESULTS In addition to commonly known shape variations, such as enlargement of left lobe and shrinkage of right lobe, our model represented detailed variations, such as enlargement of caudate lobe and the posterior part of right lobe, and shrinkage in the anterior part of right lobe. These variations qualitatively agreed with localized volumetric variations reported in clinical studies. The accuracy (AUC) at classifications F0/1 versus F2‒4 (significant fibrosis), F0‒2 versus F3‒4 and F0‒3 versus F4 (cirrhosis) were 0.90 ± 0.03, 0.80 ± 0.05 and 0.82 ± 0.05, respectively. CONCLUSIONS The proposed approach offered an explicit representation of commonly known as well as detailed shape variations associated with liver fibrosis stage. Thus, the application of PLSR-based SSM is feasible for understanding the shape variations associated with the liver fibrosis stage and predicting it.
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Affiliation(s)
- Mazen Soufi
- Division of Information Science, Nara Institute of Science and Technology, 8916-5, Takayama-cho, Ikoma, Nara, 630-0192, Japan
| | - Yoshito Otake
- Division of Information Science, Nara Institute of Science and Technology, 8916-5, Takayama-cho, Ikoma, Nara, 630-0192, Japan
| | - Masatoshi Hori
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kazuya Moriguchi
- Division of Information Science, Nara Institute of Science and Technology, 8916-5, Takayama-cho, Ikoma, Nara, 630-0192, Japan
| | - Yasuharu Imai
- Department of Gastroenterology, Ikeda Municipal Hospital, 3-1-18, Jonan, Ikeda, Osaka, 563-8510, Japan
| | - Yoshiyuki Sawai
- Department of Gastroenterology, Ikeda Municipal Hospital, 3-1-18, Jonan, Ikeda, Osaka, 563-8510, Japan
| | - Takashi Ota
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Noriyuki Tomiyama
- Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, D1, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yoshinobu Sato
- Division of Information Science, Nara Institute of Science and Technology, 8916-5, Takayama-cho, Ikoma, Nara, 630-0192, Japan.
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21
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Serum Mac-2-binding protein (M2BPGi) as a marker of chronological liver fibrosis in biliary atresia patients with cirrhosis. Pediatr Surg Int 2019; 35:1065-1070. [PMID: 31392502 DOI: 10.1007/s00383-019-04535-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/01/2019] [Indexed: 12/15/2022]
Abstract
PURPOSE Biliary atresia (BA) is characterized by progressive liver fibrosis, but it is difficult to assess the progression after the patient develops cirrhosis. Mac-2-binding protein glycosylation isomer (M2BPGi) is a new marker for hepatic fibrosis. We examined the chronological changes in M2BPGi levels in BA patients with cirrhosis. METHODS Patients with cirrhosis were selected from among pediatric BA patients who had their native livers. Serum M2BPGi levels and Child-Pugh classification were evaluated. A total of 11 pediatric BA patients with cirrhosis were recruited. RESULTS Initial M2BPGi level after diagnosis of liver cirrhosis based on liver biopsy was on average 3.4, and the most recent M2BPGi level under observation was on average 4.3. The follow-up period from the initial M2BPGi measurement averaged 22.6 months. The ratio of the initial and most recent values (M2BPGi ratio) was on average 1.3 (0.5-2.4). Three cases with improved fibrosis (M2BPGi ratio < 1.0) remained in Child A, as did six cases (1.0 ≤ M2BPGi ratio < 2.0), but two cases with marked fibrosis progression (2.0 ≤ M2BPGi ratio) advanced to decompensated cirrhosis Child B. CONCLUSION M2BPGi is useful as a prognostic factor for BA patients with liver cirrhosis. In addition, fibrosis improved even after the development of cirrhosis.
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22
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Qian X, Zheng S, Wang L, Yao M, Guan G, Wen X, Zhang L, Xu Q, Chen X, Zhao J, Duan Z, Lu F. Exploring the Diagnostic Potential of Serum Golgi Protein 73 for Hepatic Necroinflammation and Fibrosis in Chronic HCV Infection with Different Stages of Liver Injuries. DISEASE MARKERS 2019; 2019:3862024. [PMID: 31636735 PMCID: PMC6766121 DOI: 10.1155/2019/3862024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Accepted: 06/26/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM Serum Golgi protein 73 (GP73) is a promising alternative biomarker of chronic liver diseases, but most data are from patients with HBV infection rather than HCV. MATERIALS AND METHODS Two independent cohorts of chronic hepatitis C (CHC) patients from the 5th Medical Centre of the Chinese PLA General Hospital (n = 174) and Beijing Youan Hospital (n = 120) with different histories of HCV infection were enrolled. The correlations between serum GP73 and other biochemical indices, as well as its correlations with different stages of liver disease progression, were investigated. The receiver operating characteristic (ROC) curve was employed to evaluate the diagnostic potential of serum GP73 for liver necroinflammation and fibrosis, and comparisons of the diagnostic efficiency with traditional indices of hepatic liver injuries were further investigated. RESULTS Levels of serum GP73 were found significantly elevated in patients with moderate to severe inflammatory grade (G ≥ 2) and/or with advanced fibrotic stages (F ≥ 3) in both cohorts (P < 0.05, respectively), as compared to those with a normal or mild liver lesion. Further ROC analysis demonstrated that serum GP73 was comparable to serum ALT and AST in diagnosing the liver necroinflammation grade at G ≥ 2, but its diagnostic values for advanced fibrosis (F ≥ 3) and cirrhosis (F = 4) were limited when compared to APRI and FIB-4, and FIB-4 exhibited the best performance. Notably, an obvious elevation of serum GP73 was observed after patients received PEG-IFN and ribavirin treatment. CONCLUSIONS Serum GP73 is an important biomarker in evaluating and monitoring the disease progression including liver necroinflammation and fibrosis in patients with chronic HCV infection, but the value is limited for diagnosing advanced fibrosis and cirrhosis in comparison with APRI and FIB-4.
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Affiliation(s)
- Xiangjun Qian
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Sujun Zheng
- Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Leijie Wang
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Mingjie Yao
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Guiwen Guan
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Xiajie Wen
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Ling Zhang
- Department of Hepatopancreatobiliary Surgery, Henan Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou 450008, China
| | - Qiang Xu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Xiangmei Chen
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Jingmin Zhao
- Department of Pathology and Hepatology, the 5th Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
| | - Zhongping Duan
- Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Fengmin Lu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
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Abstract
Systemic sclerosis (SSc) is a severe autoimmune disease that is characterized by vascular abnormalities, immunological alterations and fibrosis of the skin and internal organs. The results of genetic studies in patients with SSc have revealed statistically significant genetic associations with disease manifestations and progression. Nevertheless, genetic susceptibility to SSc is moderate, and the functional consequences of genetic associations remain only partially characterized. A current hypothesis is that, in genetically susceptible individuals, epigenetic modifications constitute the driving force for disease initiation. As epigenetic alterations can occur years before fibrosis appears, these changes could represent a potential link between inflammation and tissue fibrosis. Epigenetics is a fast-growing discipline, and a considerable number of important epigenetic studies in SSc have been published in the past few years that span histone post-translational modifications, DNA methylation, microRNAs and long non-coding RNAs. This Review describes the latest insights into genetic and epigenetic contributions to the pathogenesis of SSc and aims to provide an improved understanding of the molecular pathways that link inflammation and fibrosis. This knowledge will be of paramount importance for the development of medicines that are effective in treating or even reversing tissue fibrosis.
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Hsieh YH, Huang HC, Chang CC, Chuang CL, Lee FY, Hsu SJ, Huang YH, Hou MC, Lee SD. Nucleos(t)ide Analogs Do Not Independently Influence Hepatic Fibrosis and Portal Hypertension beyond Viral Suppression in CBDL-Induced Cirrhotic Rat. J Pharmacol Exp Ther 2018; 367:260-266. [PMID: 30194095 DOI: 10.1124/jpet.118.250431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Accepted: 08/07/2018] [Indexed: 11/22/2022] Open
Abstract
Chronic hepatitis is the major cause of liver cirrhosis and portal hypertension. Several factors affect portal pressure, including liver fibrosis, splanchnic vasodilatation, and pathologic angiogenesis. Nucleos(t)ide analogs (NUCs), the oral antiviral agents, effectively attenuate chronic hepatitis B-related liver cirrhosis and portal hypertension via viral suppression and alleviation of hepatitis. On the other hand, NUCs affect tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and nitric oxide, which participate in fibrogenesis, vasodilatation, and angiogenesis. However, whether NUCs independently influence liver fibrosis and portal hypertension beyond viral suppression is unknown. This study thus aimed to evaluate the influences of three frequently used NUCs in rats with nonviral cirrhosis. Male Sprague-Dawley rats received common bile duct ligation (CBDL) to induce cholestatic cirrhosis and portal hypertension. The rats were randomly allocated into four groups, treated by mouth with lamivudine (30 mg/kg per day), entecavir (0.09 mg/kg per day), tenofovir (50 mg/kg per day), or distilled water (vehicle control) from the 15th day after CBDL. On the 29th day, liver cirrhosis- and portal hypertension-related parameters were evaluated. The results showed that chronic NUCs treatment did not affect hemodynamic parameters, plasma TNF-α concentration, and hepatic fibrogenesis protein expressions in rats with nonviral cirrhosis. Though the mesenteric VEGF receptor 2 phosphorylation was downregulated in NUCs-treated groups, the splanchnic angiogenesis was not influenced. In conclusion, lamivudine, entecavir, and tenofovir had no additional effects on liver cirrhosis and portal hypertension in rats with nonviral cirrhosis.
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Affiliation(s)
- Yu-Hsin Hsieh
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Hui-Chun Huang
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Ching-Chih Chang
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Chiao-Lin Chuang
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Fa-Yauh Lee
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Shao-Jung Hsu
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Shou-Dong Lee
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
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Platelets' increase is associated with improvement of liver fibrosis in entecavir-treated chronic hepatitis B patients with significant liver fibrosis. Hepatol Int 2018; 12:237-243. [PMID: 29700765 DOI: 10.1007/s12072-018-9864-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 04/03/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Reduction of platelet count is often observed in chronic hepatitis B (CHB) patients with significant liver fibrosis. In this cohort study, we investigated whether platelets' increase after entecavir (ETV) therapy was associated with the improvement of liver fibrosis. METHODS We collected the data of a cohort 82 CHB patients with paired liver biopsies before and after 78-week ETV therapy, and assessed the platelets' change following the treatment and further investigated the associated clinical factors with platelets' change. RESULTS Platelet count increased after treatment, which occurred mainly in patients with low baseline level of platelet count (< 200 × 109/L) or with significant fibrosis (Ishak ≥ 3). Regression analysis showed that baseline platelet count was the main factor associated with post-treatment increase of platelets (β = - 0.215, p = 0.015). In patients with significant fibrosis, correlation and linear regression analysis revealed that post-treatment platelets' increase was correlated with improvement of liver fibrosis assessed by reduction of quantitative collagen percentage area (r = 0.392, p = 0.006) (β = 2.449, p = 0.035), but no correlation between changes in platelet counts and Ishak fibrosis score. Receiver operating curve analysis showed an increase of 12.5 × 109/L in platelet count could identify improvement of liver fibrosis (AUC = 0.70). CONCLUSION Platelets' increase after ETV therapy was associated to the improvement of liver fibrosis with reduction of collagen percentage area in CHB patients with significant fibrosis.
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Nagaoki Y, Aikata H, Daijyo K, Teraoka Y, Honda F, Nakamura Y, Hatooka M, Morio K, Fujino H, Nakahara T, Kawaoka T, Miki D, Tsuge M, Hiramatsu A, Imamura M, Kawakami Y, Ochi H, Chayama K. Risk factors for exacerbation of gastroesophageal varices and portosystemic encephalopathy during treatment with nucleos(t)ide analogs for hepatitis B virus-related cirrhosis. Hepatol Res 2018; 48:264-274. [PMID: 29114970 DOI: 10.1111/hepr.12996] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 10/11/2017] [Accepted: 11/03/2017] [Indexed: 12/18/2022]
Abstract
AIM The aim of this study was to determine the risk factors for worsening of gastroesophageal varices (GEVs) and development of portosystemic encephalopathy in patients with hepatitis B virus (HBV)-related cirrhosis during nucleos(t)ide analog (NA) treatment. METHODS One hundred and thirty-seven patients with HBV-related cirrhosis were enrolled in this retrospective cohort study. Findings of portal hemodynamics with computed tomography, liver function, and endoscopic examinations during NA treatment were assessed. RESULTS Among 137 patients, feeding vessels for GEVs (left gastric vein, posterior gastric vein, and short gastric vein) were present in 56 (41%) patients, and extrahepatic portosystemic shunt (paraesophageal vein, paraumbilicul vein, and splenorenal shunt) were present in 36 (26%) patients at the start of NA treatment. Although NA treatment was successful, significant improvements were not observed in portosystemic collateral vessels 3 years after NA treatment and GEVs were exacerbated in 48 (35%) patients. The cumulative 5- and 10-year exacerbation rate of GEVs was 27% and 50%, respectively. By multivariate analysis, the existence of feeding vessels for GEVs at the start of NA treatment was the independent predictive factor for the exacerbation of GEVs (P < 0.001). Eight patients who had extrahepatic portosystemic shunt at the start of NA treatment developed portosystemic encephalopathy during follow-up. The 3- and 5-year incidence of that was 5% and 8%, respectively. CONCLUSIONS The presence of portosystemic collateral vessels at the start of NA treatment increases the risk of GEVs worsening and development of portosystemic encephalopathy in patients with HBV-related cirrhosis, despite improvement of liver function and success in reducing viral loads with NA treatment.
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Affiliation(s)
- Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Kana Daijyo
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Fumi Honda
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuki Nakamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Masahiro Hatooka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
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Quantitative assessment of liver fibrosis (qFibrosis) reveals precise outcomes in Ishak "stable" patients on anti-HBV therapy. Sci Rep 2018; 8:2989. [PMID: 29445243 PMCID: PMC5813020 DOI: 10.1038/s41598-018-21179-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 01/29/2018] [Indexed: 12/16/2022] Open
Abstract
Current widely used semiquantitative histological assessment methods are insensitive to identify subtle changes of liver fibrosis. Therefore, to precisely assess therapeutic efficacy on chronic hepatitis B (CHB), we explored the utility of qFibrosis (a fully-quantitative morphometric method employing second harmonic generation/two photon excitation fluorescence) in liver fibrosis evaluation. Fibrosis changes were evaluated by Ishak fibrosis scoring and qFibrosis in CHB patients with paired liver biopsies before and after 78 weeks' antiviral therapy. A total of 162 patients with qualified paired biopsies were enrolled. Ishak fibrosis scoring revealed that 42.6% (69/162) of the patients achieved fibrosis regression (≥1-point decrease), 51.9% (84/162) remained stable, and 5.5% (9/162) showed progression (≥1-point increase). qFibrosis showed similar trends in the groups of regression and progression patients as evaluated by Ishak. However, in Ishak stable patients, qFibrosis revealed hitherto undetected changes, allowing for further subcategorization into regression ("Regression by qFibrosis"; 40/84, 47.6%), stable (29/84, 34.5%), and progression ("Progression by qFibrosis"; 15/84, 17.9%) groups. These newly fine-tuned categories were supported by changes of morphological parameters of fibrosis, collagen percentage area, and liver stiffness measurements. In conclusion, qFibrosis can be used to quantitatively identify subtle changes of liver fibrosis in CHB patients after antiviral therapy.
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Abstract
Fibrosis is the excessive accumulation of extracellular matrix that often occurs as a wound healing response to repeated or chronic tissue injury, and may lead to the disruption of organ architecture and loss of function. Although fibrosis was previously thought to be irreversible, recent evidence indicates that certain circumstances permit the resolution of fibrosis when the underlying causes of injury are eradicated. The mechanism of fibrosis resolution encompasses degradation of the fibrotic extracellular matrix as well as elimination of fibrogenic myofibroblasts through their adaptation of various cell fates, including apoptosis, senescence, dedifferentiation, and reprogramming. In this Review, we discuss the present knowledge and gaps in our understanding of how matrix degradation is regulated and how myofibroblast cell fates can be manipulated, areas that may identify potential therapeutic approaches for fibrosis.
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Feig JL, Mediero A, Corciulo C, Liu H, Zhang J, Perez-Aso M, Picard L, Wilder T, Cronstein B. The antiviral drug tenofovir, an inhibitor of Pannexin-1-mediated ATP release, prevents liver and skin fibrosis by downregulating adenosine levels in the liver and skin. PLoS One 2017; 12:e0188135. [PMID: 29145453 PMCID: PMC5690602 DOI: 10.1371/journal.pone.0188135] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 11/01/2017] [Indexed: 12/14/2022] Open
Abstract
Background Fibrosing diseases are a leading cause of morbidity and mortality worldwide and, therefore, there is a need for safe and effective antifibrotic therapies. Adenosine, generated extracellularly by the dephosphorylation of adenine nucleotides, ligates specific receptors which play a critical role in development of hepatic and dermal fibrosis. Results of recent clinical trials indicate that tenofovir, a widely used antiviral agent, reverses hepatic fibrosis/cirrhosis in patients with chronic hepatitis B infection. Belonging to the class of acyclic nucleoside phosphonates, tenofovir is an analogue of AMP. We tested the hypothesis that tenofovir has direct antifibrotic effects in vivo by interfering with adenosine pathways of fibrosis using two distinct models of adenosine and A2AR-mediated fibrosis. Methods Thioacetamide (100mg/kg IP)-treated mice were treated with vehicle, or tenofovir (75mg/kg, SubQ) (n = 5–10). Bleomycin (0.25U, SubQ)-treated mice were treated with vehicle or tenofovir (75mg/kg, IP) (n = 5–10). Adenosine levels were determined by HPLC, and ATP release was quantitated as luciferase-dependent bioluminescence. Skin breaking strength was analysed and H&E and picrosirus red-stained slides were imaged. Pannexin-1expression was knocked down following retroviral-mediated expression of of Pannexin-1-specific or scrambled siRNA. Results Treatment of mice with tenofovir diminished adenosine release from the skin of bleomycin-treated mice and the liver of thioacetamide-treated mice, models of diffuse skin fibrosis and hepatic cirrhosis, respectively. More importantly, tenofovir treatment diminished skin and liver fibrosis in these models. Tenofovir diminished extracellular adenosine concentrations by inhibiting, in a dose-dependent fashion, cellular ATP release but not in cells lacking Pannexin-1. Conclusions These studies suggest that tenofovir, a widely used antiviral agent, could be useful in the treatment of fibrosing diseases.
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Affiliation(s)
- Jessica L. Feig
- Division of Translational Medicine, Department of Medicine, NYU-Langone Medical Center, New York, New York, United States of America
| | - Aranzazu Mediero
- Division of Translational Medicine, Department of Medicine, NYU-Langone Medical Center, New York, New York, United States of America
- Bone and Joint Research Unit, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain
| | - Carmen Corciulo
- Division of Translational Medicine, Department of Medicine, NYU-Langone Medical Center, New York, New York, United States of America
| | - Hailing Liu
- Division of Translational Medicine, Department of Medicine, NYU-Langone Medical Center, New York, New York, United States of America
| | - Jin Zhang
- Division of Translational Medicine, Department of Medicine, NYU-Langone Medical Center, New York, New York, United States of America
- Department of Immunology and Rheumatology, LiHuili Hospital, Medical School of Ningbo University, Ningbo, China
| | - Miguel Perez-Aso
- Division of Translational Medicine, Department of Medicine, NYU-Langone Medical Center, New York, New York, United States of America
| | - Laura Picard
- Division of Translational Medicine, Department of Medicine, NYU-Langone Medical Center, New York, New York, United States of America
| | - Tuere Wilder
- Division of Translational Medicine, Department of Medicine, NYU-Langone Medical Center, New York, New York, United States of America
| | - Bruce Cronstein
- Division of Translational Medicine, Department of Medicine, NYU-Langone Medical Center, New York, New York, United States of America
- * E-mail:
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Jung YK, Yim HJ. Reversal of liver cirrhosis: current evidence and expectations. Korean J Intern Med 2017; 32:213-228. [PMID: 28171717 PMCID: PMC5339475 DOI: 10.3904/kjim.2016.268] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 12/23/2016] [Indexed: 02/06/2023] Open
Abstract
In the past, liver cirrhosis was considered an irreversible phenomenon. However, many experimental data have provided evidence of the reversibility of liver fibrosis. Moreover, multiple clinical studies have also shown regression of fibrosis and reversal of cirrhosis on repeated biopsy samples. As various etiologies are associated with liver fibrosis via integrated signaling pathways, a comprehensive understanding of the pathobiology of hepatic fibrogenesis is critical for improving clinical outcomes. Hepatic stellate cells play a central role in hepatic fibrogenesis upon their activation from a quiescent state. Collagen and other extracellular material components from activated hepatic stellate cells are deposited on, and damage, the liver parenchyma and vascular structures. Hence, inactivation of hepatic stellate cells can lead to enhancement of fibrolytic activity and could be a potential target of antifibrotic therapy. In this regard, continued efforts have been made to develop better treatments for underlying liver diseases and antifibrotic agents in multiple clinical and therapeutic trials; the best results may be expected with the integration of such evidence. In this article, we present the underlying mechanisms of fibrosis, current experimental and clinical evidence of the reversibility of liver fibrosis/cirrhosis, and new agents with therapeutic potential for liver fibrosis.
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Affiliation(s)
| | - Hyung Joon Yim
- Correspondence to Hyung Joon Yim, M.D. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, Korea Tel: +82-31-412-6565 Fax: +82-31-412-5582 E-mail:
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Stoopen-Rometti M, Encinas-Escobar ER, Ramirez-Carmona CR, Wolpert-Barraza E, Kimura-Hayama E, Sosa-Lozano LA, Favila R, Kimura-Fujikami Y, Saavedra-Abril JA, Loaeza-Del Castillo A. Diagnosis and quantification of fibrosis, steatosis, and hepatic siderosis through multiparametric magnetic resonance imaging. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2017; 82:32-45. [PMID: 28089429 DOI: 10.1016/j.rgmx.2016.06.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 05/31/2016] [Accepted: 06/16/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND The presence of liver fibrosis is the common denominator in numerous chronic liver diseases that can progress to fibrosis and hepatocellular carcinoma. Most important, with respect to frequency, are viral hepatitis and non-alcoholic fatty liver disease, the prevalence of which is increasing in epidemic proportions. Liver biopsy, albeit imperfect, continues to be the criterion standard, but in many clinical situations tends to be replaced with noninvasive imaging methods. OBJECTIVES The aim of the present article was to describe our imaging department experience with magnetic resonance elastography and to analyze and discuss recently published results in gastroenterology, hepatology, and radiology from other authors in the literature, complemented with a PubMed search covering the last 10 years. RESULTS AND CONCLUSIONS Magnetic resonance elastography is an efficacious, noninvasive method with results that are concordant with liver biopsy. It is superior to ultrasound elastography because it evaluates a much greater volume of hepatic tissue and shows the often heterogeneous lesion distribution. The greatest advantage of the magnetic resonance protocol described is the fact that it quantifies fibrosis, fat content, and iron content in the same 25min examination specifically directed for that purpose, resulting in a favorable cost-benefit ratio for the patient and/or institution.
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Affiliation(s)
- M Stoopen-Rometti
- Departamento de Imagen, C.T. Scanner Lomas Altas, Ciudad de México, México.
| | - E R Encinas-Escobar
- Curso Universitario de Radiología, C.T. Scanner, Instituto Nacional de Cardiología Ignacio Chávez, Universidad Nacional Autónoma de México, Ciudad de México, México
| | | | - E Wolpert-Barraza
- Unidad de Gastroenterología y Hepatología, Clínica Lomas Altas, Ciudad de México, México
| | - E Kimura-Hayama
- Departamento de Imagen, C.T. Scanner Lomas Altas, Ciudad de México, México
| | - L A Sosa-Lozano
- Departamento de Imagen, C.T. Scanner de México, Ciudad de México, México
| | - R Favila
- General Electric Healthcare, Durango, México
| | - Y Kimura-Fujikami
- Departamento de Imagen, C.T. Scanner de México, Ciudad de México, México
| | - J A Saavedra-Abril
- Departamento de Imagen, C.T. Scanner Lomas Altas, Ciudad de México, México
| | - A Loaeza-Del Castillo
- Unidad de Gastroenterología y Hepatología, Clínica Lomas Altas, Ciudad de México, México
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Stoopen-Rometti M, Encinas-Escobar E, Ramirez-Carmona C, Wolpert-Barraza E, Kimura-Hayama E, Sosa-Lozano L, Favila R, Kimura-Fujikami Y, Saavedra-Abril J, Loaeza-del Castillo A. Diagnosis and quantification of fibrosis, steatosis, and hepatic siderosis through multiparametric magnetic resonance imaging. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2017. [DOI: 10.1016/j.rgmxen.2017.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Abstract
Great strides have been made in hepatitis B virus (HBV)-related fibrosis and cirrhosis. Available evidence indicates that HBV viral suppression causes regression of advanced fibrosis and even cirrhosis, and therefore should be attempted in all patients with advanced fibrosis and cirrhosis. The preferred agents in patients with cirrhosis are entecavir and tenofovir, primarily because the risk of breakthrough is low. HBV viral suppression leads to improved clinical outcomes even in patients with cirrhosis and complications. The risk of hepatocellular carcinoma is reduced, but not eliminated. Thus, patients with HBV cirrhosis should continue to have routine screening for hepatocellular carcinoma, even after viral suppression.
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Affiliation(s)
- Don C Rockey
- Department of Internal Medicine, The Medical University of South Carolina, 96 Jonathan Lucas Street, 803 CSB, Charleston, SC 29425, USA.
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Haldar D, Henderson NC, Hirschfield G, Newsome PN. Mesenchymal stromal cells and liver fibrosis: a complicated relationship. FASEB J 2016; 30:3905-3928. [DOI: 10.1096/fj.201600433r] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 08/15/2016] [Indexed: 12/17/2022]
Affiliation(s)
- Debashis Haldar
- National Institute for Health ResearchBirmingham Liver Biomedical Research Unit and Centre for Liver Research University of Birmingham Birmingham United Kingdom
- Liver UnitUniversity Hospital Birmingham National Health Service (NHS) Foundation Trust Birmingham United Kingdom
| | - Neil C. Henderson
- Medical Research Council (MRC) Centre for Inflammation ResearchQueens Medical Research Institute University of Edinburgh Edinburgh United Kingdom
| | - Gideon Hirschfield
- National Institute for Health ResearchBirmingham Liver Biomedical Research Unit and Centre for Liver Research University of Birmingham Birmingham United Kingdom
- Liver UnitUniversity Hospital Birmingham National Health Service (NHS) Foundation Trust Birmingham United Kingdom
| | - Philip N. Newsome
- National Institute for Health ResearchBirmingham Liver Biomedical Research Unit and Centre for Liver Research University of Birmingham Birmingham United Kingdom
- Liver UnitUniversity Hospital Birmingham National Health Service (NHS) Foundation Trust Birmingham United Kingdom
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Xu SH, Li Q, Hu YP, Ying L. Development of a model based on biochemical, real‑time tissue elastography and ultrasound data for the staging of liver fibrosis and cirrhosis in patients with chronic hepatitis B. Mol Med Rep 2016; 14:3609-19. [PMID: 27573619 PMCID: PMC5042746 DOI: 10.3892/mmr.2016.5682] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 06/22/2016] [Indexed: 12/21/2022] Open
Abstract
The liver fibrosis index (LFI), based on real‑time tissue elastography (RTE), is a method currently used to assess liver fibrosis. However, this method may not consistently distinguish between the different stages of fibrosis, which limits its accuracy. The aim of the present study was to develop novel models based on biochemical, RTE and ultrasound data for predicting significant liver fibrosis and cirrhosis. A total of 85 consecutive patients with chronic hepatitis B (CHB) were prospectively enrolled and underwent a liver biopsy and RTE. The parameters for predicting significant fibrosis and cirrhosis were determined by conducting multivariate analyses. The splenoportal index (SPI; P=0.002) and LFI (P=0.023) were confirmed as independent predictors of significant fibrosis. Using multivariate analyses for identifying parameters that predict cirrhosis, significant differences in γ‑glutamyl transferase (GGT; P=0.049), SPI (P=0.002) and LFI (P=0.001) were observed. Based on these observations, the novel model LFI‑SPI score (LSPS) was developed to predict the occurrence of significant liver fibrosis, with an area under receiver operating characteristic curves (AUROC) of 0.87. The diagnostic accuracy of the LSPS model was superior to that of the LFI (AUROC=0.76; P=0.0109), aspartate aminotransferase‑to‑platelet ratio index (APRI; AUROC=0.64; P=0.0031), fibrosis‑4 index (FIB‑4; AUROC=0.67; P=0.0044) and FibroScan (AUROC=0.68; P=0.0021) models. In addition, the LFI‑SPI‑GGT score (LSPGS) was developed for the purposes of predicting liver cirrhosis, demonstrating an AUROC value of 0.93. The accuracy of LSPGS was similar to that of FibroScan (AUROC=0.85; P=0.134), but was superior to LFI (AUROC=0.81; P=0.0113), APRI (AUROC=0.67; P<0.0001) and FIB‑4 (AUROC=0.719; P=0.0005). In conclusion, the results of the present study suggest that the use of LSPS and LSPGS may complement current methods of diagnosing significant liver fibrosis and cirrhosis in patients with CHB.
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Affiliation(s)
- Shi-Hao Xu
- Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Qiao Li
- Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yuan-Ping Hu
- Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Li Ying
- Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Kose S, Tatar B, Gül S, Pala E. The effect of long-term entecavir therapy on liver histopathology in patients with chronic viral hepatitis B. Acta Clin Belg 2016; 71:244-9. [PMID: 27075801 DOI: 10.1080/17843286.2015.1118183] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVES The aim of this study was to evaluate histopathological improvement and virological, biological and serological response rates in patients receiving long-term entecavir therapy who were followed with the diagnosis of chronic hepatitis B (CHB). MATERIALS AND METHODS Ninety-eight nucleoside(t)e-naive CHB patients who were receiving 0.5 mg/day entecavir (ETV) were included in the study. Virological, serological and biochemical test results were assessed baseline and every 12-week intervals. Liver biopsy specimens were assessed according to the modified Ishak scoring. RESULTS Forty-six CHB patients receiving ETV treatment underwent liver biopsy. The mean age of the patients was 44 ± 12.9, 26.1% of them were female. The mean duration of follow-up was 44.9 ± 10.8 months. All patients had hepatitis B virus (HBV) genotype D infection. Of 21 patients who were HBeAg positive at baseline, HBeAg loss occurred in 9 and seroconversion occurred in 5. HBsAg loss occurred in none of the patients. Serum HBV DNA levels became undetectable in 93.5% patients. Of the patients, 50% achieved ≥ 2 point improvement in HAI scores and 30.4% achieved ≥ 1 point improvement in fibrosis scores with treatment. The mean improvement in HAI and fibrosis score were 1.94 ± 1.93 and 0.11 ± 0.9 points, respectively. CONCLUSION ETV is an effective treatment in histological improvement and virological response in CHB patients. Large-scale, long-term studies are still warranted to evaluate the long-term outcomes of entecavir therapy.
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Wu FM, Earing MG, Aboulhosn JA, Johncilla ME, Singh MN, Odze RD, Ukomadu C, Gauvreau K, Landzberg MJ, Valente AM. Predictive value of biomarkers of hepatic fibrosis in adult Fontan patients. J Heart Lung Transplant 2016; 36:211-219. [PMID: 27592026 DOI: 10.1016/j.healun.2016.07.011] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 06/06/2016] [Accepted: 07/14/2016] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Hepatic fibrosis is highly prevalent in individuals with Fontan circulation. FibroSure (LabCorp, Burlington, NC) and hyaluronic acid (HA) have been validated for assessment of hepatic fibrosis in several forms of liver disease. We sought to determine whether these tests could identify Fontan patients with advanced hepatic fibrosis or cirrhosis. METHODS Subjects who had liver biopsy and FibroSure or HA testing within 6 months of biopsy were identified from the Alliance for Adult Research in Congenital Cardiology Fontan Liver Health study. Biopsy specimens were scored for degree of sinusoidal and portal fibrosis on a 3- and 5-point scale, respectively. Histologic findings were correlated with FibroSure and HA results. RESULTS The study included 27 subjects. Median age was 26.8 years (range, 17.4-59.8 years), and the median time since the Fontan surgery was 20.4 years (range, 12.0-31.3 years). FibroSure scores were elevated (>0.21) in 21 of 23 subjects (91%), and the scores for 3 (13%) suggested cirrhosis (>0.74). HA suggested cirrhosis (>46 ng/mL) in 3 of 17 subjects (18%). One subject died during the collection period. Eleven of 26 subjects (42%) had 4/5 or 5/5 portal fibrosis, consistent with cirrhosis; 17 (63%) had 3/3 sinusoidal fibrosis involving >66% of sinusoids. The FibroSure score and HA levels did not correlate with the degree of hepatic fibrosis and did not predict cirrhosis. CONCLUSIONS Abnormal biomarkers of hepatic fibrosis and specimen-proven hepatic fibrosis are common in adults with Fontan circulation. However, FibroSure and HA do not accurately predict the degree of histologic hepatic fibrosis. Further studies are needed to guide strategies for surveillance of liver disease in this population.
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Affiliation(s)
- Fred M Wu
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School; Division of Cardiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Michael G Earing
- Department of Pediatric Cardiology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jamil A Aboulhosn
- Ahmanson/University of California Los Angeles Adult Congenital Heart Disease Center, Los Angeles, California
| | | | - Michael N Singh
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School; Division of Cardiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Chinweike Ukomadu
- Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Kimberlee Gauvreau
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School
| | - Michael J Landzberg
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School; Division of Cardiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Anne Marie Valente
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School; Division of Cardiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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Liu CL, Wu CK, Shi HY, Tai WC, Liang CM, Yang SC, Wu KL, Chiu YC, Chuah SK. Medical expenses in treating acute esophageal variceal bleeding: A 15-year nationwide population-based cohort study. Medicine (Baltimore) 2016; 95:e4215. [PMID: 27428225 PMCID: PMC4956819 DOI: 10.1097/md.0000000000004215] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Acute variceal bleeding in patients with cirrhosis is related to high mortality and medical expenses. The purpose of present studies was to analyze the medical expenses in treating acute esophageal variceal bleeding among patients with cirrhosis and potential influencing clinical factors.A total of 151,863 patients with cirrhosis with International Classification of Diseases-9 codes 456.0 and 456.20 were analyzed from the Taiwan National Health Insurance Research Database from January 1, 1996 to December 31, 2010. Time intervals were divided into three phases for analysis as T1 (1996-2000), T2 (2001-2005), and T3 (2006-2010). The endpoints were prevalence, length of hospital stay, medical expenses, and mortality rate.Our results showed that more patients were <65 years (75.6%) and of male sex (78.5%). Patients were mostly from teaching hospitals (90.8%) with high hospital volume (50.9%) and high doctor service load (51.1%). The prevalence of acute esophageal variceal bleeding and mean length of hospital stay decreased over the years (P < 0.001), but the overall medical expenses increased (P < 0.001). Multiple regression analysis showed that older age, female sex, Charlson comorbidity index (CCI) score >1, patients from teaching hospitals, and medium to high or very high patient numbers were independent factors for longer hospital stay and higher medical expenses. Aged patients, female sex, increased CCI score, and low doctor service volume were independent factors for both in-hospital and 5-year mortality. Patients from teaching hospitals and medium to high or very high service volume hospitals were independent factors for in-hospital mortality, but not 5-year mortality.Medical expenses in treating acute esophageal variceal bleeding increased despite the decreased prevalence rate and length of hospital stay in Taiwan. Aged patients, female sex, patients with increased CCI score from teaching hospitals, and medium to high or very high patient numbers were the independent factors for increased medical expenses.
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Affiliation(s)
- Chueh-Ling Liu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital
| | - Cheng-Kun Wu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital
- Correspondence: Seng-Kee Chuah, and Cheng-Kun Wu, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-sung Hsiang, Kaohsiung 833, Taiwan (e-mail: and )
| | - Hon-Yi Shi
- Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung
| | - Wei-Chen Tai
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital
- Chang Gung University, College of Medicine, Taipei, Taiwan
| | - Chih-Ming Liang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital
| | - Shih-Cheng Yang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital
| | - Keng-Liang Wu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital
- Chang Gung University, College of Medicine, Taipei, Taiwan
| | - Yi-Chun Chiu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital
- Chang Gung University, College of Medicine, Taipei, Taiwan
| | - Seng-Kee Chuah
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital
- Chang Gung University, College of Medicine, Taipei, Taiwan
- Correspondence: Seng-Kee Chuah, and Cheng-Kun Wu, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-sung Hsiang, Kaohsiung 833, Taiwan (e-mail: and )
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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: 30] [Impact Index Per Article: 3.3] [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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The Effect of rhCygb on CCl4-Induced Hepatic Fibrogenesis in Rat. Sci Rep 2016; 6:23508. [PMID: 27006085 PMCID: PMC4804332 DOI: 10.1038/srep23508] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 03/08/2016] [Indexed: 12/22/2022] Open
Abstract
This study aims to investigate whether the use of recombinant human cytoglobin (rhCygb) impact on hepatic fibrogenesis caused by CCl4. SD (n = 150) rats were randomly divided into three groups of normal, CCl4 model and rhCygb groups. After model establishment, rats in rhCygb groups were administered daily with rhCygb (2 mg/kg, s.c.). Histological lesions were staged according to metavir. Serum parameters including ALT, AST, HA, LN, Col III and Col IV were determined. The liver proteins were separated by 2-DE and identified. As a result, the stage of hepatic damage and liver fibrosis in rhCygb groups were significantly milder than that in CCl4 model groups. Meanwhile, rhCygb dramatically reversed serum levels of ALT and AST, and also markedly decreased the liver fibrosis markers levels of LN, HA, Col III and Col IV. In 2-DE, 33 proteins among three groups with the same changing tendency in normal and rhCygb treated groups compared with CCl4 model group were identified. GO analysis showed that several identified proteins involved in oxidative stress pathway. The study provides new insights and data for administration of rhCygb reversing CCl4-induced liver fibrosis suggesting that rhCygb might be used in the treatment of liver fibrosis.
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Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes. J Virol 2015; 90:486-96. [PMID: 26491170 DOI: 10.1128/jvi.01263-15] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 10/14/2015] [Indexed: 01/05/2023] Open
Abstract
UNLABELLED Hepatitis B virus (HBV) infects hundreds of millions of people worldwide and causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HBV is an enveloped virus with a relaxed circular (RC) DNA genome. In the nuclei of infected human hepatocytes, conversion of RC DNA from the incoming virion or cytoplasmic mature nucleocapsid (NC) to the covalently closed circular (CCC) DNA, which serves as the template for producing all viral transcripts, is essential to establish and sustain viral replication. A prerequisite for CCC DNA formation is the uncoating (disassembly) of NCs to expose their RC DNA content for conversion to CCC DNA. We report here that in an immortalized mouse hepatocyte cell line, AML12HBV10, in which RC DNA exposure is enhanced, the exposed viral DNA could trigger an innate immune response that was able to modulate viral gene expression and replication. When viral gene expression and replication were low, the innate response initially stimulated these processes but subsequently acted to shut off viral gene expression and replication after they reached peak levels. Inhibition of viral DNA synthesis or cellular DNA sensing and innate immune signaling diminished the innate response. These results indicate that HBV DNA, when exposed in the host cell cytoplasm, can function to trigger an innate immune response that, in turn, modulates viral gene expression and replication. IMPORTANCE Chronic infection by hepatitis B virus (HBV) afflicts hundreds of millions worldwide and is sustained by the episomal covalently closed circular (CCC) DNA in the nuclei of infected hepatocytes. Release of viral genomic DNA from cytoplasmic nucleocapsids (NCs) (NC disassembly or uncoating) is a prerequisite for its conversion to CCC DNA, which can also potentially expose the viral DNA to host DNA sensors and trigger an innate immune response. We have found that in an immortalized mouse hepatocyte cell line in which efficient CCC DNA formation was associated with enhanced exposure of nucleocapsid-associated DNA, the exposed viral DNA indeed triggered host cytoplasmic DNA sensing and an innate immune response that was able to modulate HBV gene expression and replication. Thus, HBV can, under select conditions, be recognized by the host innate immune response through exposed viral DNA, which may be exploited therapeutically to clear viral persistence.
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Ding Y, Rao SX, Zhu T, Chen CZ, Li RC, Zeng MS. Liver fibrosis staging using T1 mapping on gadoxetic acid-enhanced MRI compared with DW imaging. Clin Radiol 2015; 70:1096-103. [DOI: 10.1016/j.crad.2015.04.014] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Revised: 03/24/2015] [Accepted: 04/27/2015] [Indexed: 12/21/2022]
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Pan HY, Pan HY, Chen L, Yang DH, Huang HJ, Tong YX, Chen CR, Yan J. Ten-year follow-up of hepatitis B relapse after cessation of lamivudine or telbivudine treatment in chronic hepatitis B patients. Clin Microbiol Infect 2015; 21:1123.e1-9. [PMID: 26253290 DOI: 10.1016/j.cmi.2015.07.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 07/04/2015] [Accepted: 07/24/2015] [Indexed: 12/26/2022]
Abstract
The high rate of relapse after cessation of nucleos(t)ide analogues (NUCs) treatment in chronic hepatitis B (CHB) patients leads us to reassess the feasibility for off-therapy, but long-term follow-up data are scarce. We assessed the feasibility for off-therapy by a long-term observation of relapse in response to lamivudine (LAM) and telbivudine (LdT). Eighty-six NUC-naive CHB patients, treated with LAM (n = 46) or LdT (n = 40) who reached the guidelines recommended for off-therapy, were followed for up to 10 years. Hepatitis B virus (HBV), viral serology and biochemistries were periodically determined. COX model was used to predict the risk of relapse. A total of 52.3% of patients experienced relapse within a median of 115 months (range, 61-122 months). A total of 93.3% of relapses occurred within 48 months. Relapse rates in hepatitis B e antigen (HBeAg)-positive (n = 56) and HBeAg-negative (n = 30) patients were 39.3% and 76.7%, respectively (p < 0.01). HBeAg-positive patients who achieved an early viral response (EVR), defined as undetectable HBV DNA within 6 months, had a lower relapse rate compared to non-EVR patients (21.4% vs. 59.2%, p < 0.01). EVR patients who had both lower HBV DNA (<10(6) copies/mL) at baseline and lower hepatitis B surface antigen (HBsAg) at end of treatment had a relapse rate of 10.7%. The high relapse rates in CHB patients over this 10-year follow-up make LAM or LdT off therapy infeasible in most of the cases, except in the case of HBsAg loss and/or seroconversion. HBeAg-positive patients with EVR, lower HBV DNA and HBsAg had lower relapse rates and could be good candidates for off-therapy. Long-term monitoring, especially during the first 4 years, is critical for patients off-therapy.
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Affiliation(s)
- H-Y Pan
- Department of Infectious Diseases, Zhejiang Provincial People's Hospital, Zhejiang Chinese Medicinal University, China.
| | - H-Y Pan
- Department of Medicine, Pujiang People's Hospital, China
| | - L Chen
- Zhejiang Chinese Medicinal University, China
| | - D-H Yang
- Department of Infectious Diseases, Zhejiang Provincial People's Hospital, Zhejiang Chinese Medicinal University, China
| | - H-J Huang
- Department of Infectious Diseases, Zhejiang Provincial People's Hospital, Zhejiang Chinese Medicinal University, China
| | - Y-X Tong
- Department of Infectious Diseases, Zhejiang Provincial People's Hospital, Zhejiang Chinese Medicinal University, China
| | - C-R Chen
- Department of Internal Medicine, Hangzhou Xixi Hospital, Hangzhou, Zhejiang, China
| | - J Yan
- Department of Internal Medicine, Hangzhou Xixi Hospital, Hangzhou, Zhejiang, China
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Wu FM, Jonas MM, Opotowsky AR, Harmon A, Raza R, Ukomadu C, Landzberg MJ, Singh MN, Valente AM, Egidy Assenza G, Perez-Atayde AR. Portal and centrilobular hepatic fibrosis in Fontan circulation and clinical outcomes. J Heart Lung Transplant 2015; 34:883-91. [DOI: 10.1016/j.healun.2015.01.993] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 01/19/2015] [Accepted: 01/31/2015] [Indexed: 10/24/2022] Open
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Huang AJ, Núñez M. Outcomes in HIV/HBV-Coinfected Patients in the Tenofovir Era Are Greatly Affected by Immune Suppression. J Int Assoc Provid AIDS Care 2015; 14:360-8. [PMID: 25999329 DOI: 10.1177/2325957415586258] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES HIV-infected patients have higher mortality when coinfected with hepatitis B virus (HBV). With potent highly active antiretroviral therapy (HAART) and the use of tenofovir (TDF), outcomes may improve. Our objective was to determine the clinical and virological outcomes of a HIV/HBV-Coinfected cohort at our center since TDF became available. METHODS We retrospectively studied all HIV/HBV-Coinfected adults followed between 2002 and 2012 for ≥3 months. Outcome measurements included HBV DNA suppression, HBV e-antigen (HBeAg) and HBV surface antigen (HBsAg) clearance, cirrhosis diagnosis, development of liver complications, and overall and liver-related mortality. Predicting factors were assessed with log-rank test and logistic regression. RESULTS Median time to follow-up of the 99 patients included was 5 years. Undetectable HBV DNA and HBsAg loss were achieved by 65% and 18%, respectively. Overall and liver-related mortality rates were 4.58 and 0.91 per 100 person-years, respectively. Most patients died of causes unrelated to the liver. Four patients died from hepatocellular carcinoma (HCC) and one, hepatitis C virus (HCV) coinfected, from liver failure. Higher CD4 counts at last follow-up were associated with HBV suppression (odds ratio [OR] 1.004, 95% confidence interval [CI] 1.001-1.006, P=.007), HBeAg loss (OR 1.003, 95% CI 1-1.005, P=.02), HBsAg loss (CD4 count>700 cells/mm3, OR 3.80, 95% CI 1.06-13.58, P=.04), and survival (OR .994, 95% CI 0.990-0.997, P<.0001). HCV coinfection was associated with higher overall mortality (OR 7.74, 95% CI 1.47-40.81, P=.02). CONCLUSION Mortality was high and most often unrelated to liver disease in this HIV/HBV-Coinfected cohort treated predominantly with TDF-containing HAART. Optimal CD4 counts predicted survival and the achievement of HBV virological end points. Tenofovir prevented liver decompensation but not HCC, which was the predominant cause of liver death.
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Affiliation(s)
- Andrew J Huang
- Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Marina Núñez
- Division of Infectious Disease, Department of Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA
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Russo FP, Rodríguez-Castro K, Scribano L, Gottardo G, Vanin V, Farinati F. Role of antiviral therapy in the natural history of hepatitis B virus-related chronic liver disease. World J Hepatol 2015; 7:1097-1104. [PMID: 26052398 PMCID: PMC4450186 DOI: 10.4254/wjh.v7.i8.1097] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 10/21/2014] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a dynamic state of interactions among HBV, hepatocytes, and the host immune system. Natural history studies of chronic hepatitis B (CHB) infection have shown an association between active viral replication and adverse clinical outcomes such as cirrhosis and hepatocellular carcinoma. The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, hepatocellular carcinoma (HCC) and death. This goal can be achieved if HBV replication is suppressed in a sustained manner. The accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and of HCC, particularly in non-cirrhotic patients. However, CHB infection cannot be completely eradicated, due to the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the integration of the HBV genome into the host genome may favour oncogenesis, development of HCC and may also contribute to HBV reactivation.
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Chiang CJ, Yang YW, Chen JD, You SL, Yang HI, Lee MH, Lai MS, Chen CJ. Significant reduction in end-stage liver diseases burden through the national viral hepatitis therapy program in Taiwan. Hepatology 2015; 61:1154-62. [PMID: 25476749 DOI: 10.1002/hep.27630] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Accepted: 11/25/2014] [Indexed: 02/06/2023]
Abstract
UNLABELLED A national viral hepatitis therapy program was launched in Taiwan in October 2003. This study aimed to assess the impact of the program on reduction of end-stage liver disease (ESLD) burden. Profiles of national registries of households, cancers, and death certificates were used to derive incidence and mortality of ESLDs from 2000 to 2011. Age-gender-adjusted incidence and mortality rates of hepatocellular carcinoma (HCC) and chronic liver diseases (CLDs) and cirrhosis of adults ages 30-69 years were compared before and after launching the program using Poisson's regression models. A total of 157,570 and 61,823 patients (15%-25% of those eligible for reimbursed treatment) received therapy for chronic hepatitis B and C, respectively, by 2011. There were 42,526 CLDs and cirrhosis deaths, 47,392 HCC deaths, and 74,832 incident HCC cases occurred in 140,814,448 person-years from 2000 to 2011. Male gender and elder age were associated with a significantly increased risk of CLDs and cirrhosis and HCC. Mortality and incidence rates of ESLDs decreased continuously from 2000 to 2003 (before therapy program) through 2004-2007 to 2008-2011 in all age and gender groups. The age-gender-adjusted rate ratio (95% confidence interval; P value) in 2008-2011 was 0.78 (0.76-0.80; P < 0.001) for CLDs and cirrhosis mortality, 0.76 (0.75-0.78; P < 0.005) for HCC mortality, and 0.86 (0.85-0.88; P < 0.005) for HCC incidence using 2000-2003 as the reference period (rate ratio = 1.0). CONCLUSIONS The national viral hepatitis therapy program has significantly reduced the mortality of CLDs and cirrhosis and incidence and mortality of HCC.
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Affiliation(s)
- Chun-Ju Chiang
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Taiwan Cancer Registry, Taipei, Taiwan
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Yoon JH, Lee JM, Joo I, Lee ES, Sohn JY, Jang SK, Lee KB, Han JK, Choi BI. Hepatic fibrosis: prospective comparison of MR elastography and US shear-wave elastography for evaluation. Radiology 2014; 273:772-782. [PMID: 25007047 DOI: 10.1148/radiol.14132000] [Citation(s) in RCA: 135] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
PURPOSE To compare magnetic resonance (MR) elastography and ultrasonographic shear-wave elastography ( SWE shear-wave elastography ) for the staging of hepatic fibrosis ( HF hepatic fibrosis ) in the same individuals. MATERIALS AND METHODS This prospective study was approved by the institutional review board, and informed consent was obtained from all patients. The technical success of and reliable liver stiffness ( LS liver stiffness ) measurement rates at MR elastography and SWE shear-wave elastography were compared in 129 patients who underwent both examinations. For mutual validation, LS liver stiffness values measured at both examinations were correlated by using Pearson correlation. The diagnostic performance of the two techniques for the assessment of substantial HF hepatic fibrosis (stage ≥ F2) was compared by using nonparametric receiver operating characteristic analysis. RESULTS The technical success rates of MR elastography and SWE shear-wave elastography were 95.35% (123 of 129) and 97.67% (126 of 129), respectively (P = .51). MR elastography provided significantly more reliable LS liver stiffness measurements than did SWE shear-wave elastography (95.35% [123 of 129] vs 75.2% [97 of 129], P < .001). The two examinations showed moderate correlation (r = 0.724). In patients with HF hepatic fibrosis stages of F3 or lower, the two examinations showed moderate-to-strong correlation (r = 0.683 in normal livers, 0.754 in livers with stage F0 or F1 HF hepatic fibrosis , and 0.90 in livers with stage F2 or F3 HF hepatic fibrosis ; P < .001); however, they did not show significant correlation for stage F4 HF hepatic fibrosis (r = 0.30, P = .31). MR elastography and SWE shear-wave elastography showed similar diagnostic capability in depicting HF hepatic fibrosis of stage F2 or greater (P = .98) when LS liver stiffness measurements were reliably performed. CONCLUSION MR elastography and SWE shear-wave elastography showed moderate correlation and similar diagnostic performance in the diagnosis of HF hepatic fibrosis of stage F2 or greater; however, MR elastography yielded more reliable LS liver stiffness measurements than did SWE shear-wave elastography .
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Affiliation(s)
- Jeong Hee Yoon
- From the Departments of Radiology (J.H.Y., J.M.L., I.J., E.S.L., J.Y.S., S.K.J., J.K.H., B.I.C.) and Pathology (K.B.L.), Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea; and Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Korea (J.M.L., J.K.H., B.I.C.)
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Comparison of telbivudine efficacy in treatment-naive patients with hepatitis B virus-related compensated and decompensated cirrhosis in 96 weeks. Eur J Gastroenterol Hepatol 2014; 26:396-403. [PMID: 24569820 DOI: 10.1097/meg.0000000000000062] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Data are limited for comparison of the long-term efficacy of telbivudine (LdT) between hepatitis B virus (HBV)-related compensated and decompensated cirrhosis. The aim of this study was to compare the efficacy of LdT in treatment-naive patients with HBV-related compensated and decompensated cirrhosis in 96 weeks. PATIENTS AND METHODS We reviewed the data of 65 compensated and 62 decompensated cirrhotic patients treated with LdT for 96 weeks, and compared the difference in the related indicators before and after treatment between the groups. RESULTS Alanine aminotransferase normalized rate was significantly higher in the compensated group than in the decompensated group at weeks 12 and 24 (67.7 vs. 40.3% and 78.5 vs. 53.2%, respectively, P<0.01). Albumin level was much higher than the baseline at week 24 in the compensated group (35.1±6.2 vs. 39.9±5.1, P<0.01), but significance was observed from week 48 onwards in the decompensated group (29.8±3.7 vs. 33.7±3.8, P<0.05). The Child-Turcotte-Puge score either improved or remained steady in both groups. The HBV DNA negativity rate at week 12 (56.9 vs. 32.3%, P<0.01) was higher, whereas the drug resistance rate was lower (P>0.05), in the compensated group than in the decompensated group. The degree of esophageal varix was alleviated, including 11 (16.9%) compensated and four (6.5%) decompensated cirrhotic patients. Liver stiffness was significantly decreased in the compensated group compared with the baseline [19.1 (7.3-32.6) vs. 14.8 (7.4-32.5), P<0.01]; however, there was no statistical significance in the decompensated group compared with the baseline [30.5 (9.1-55.0) vs. 29.9 (8.4-53.2), P>0.05]. CONCLUSION Long-term LdT treatment showed superior virological, biochemical, and clinical efficacy in the compensated cirrhotic patients. Therefore, we emphasized the importance of early antiviral treatment, which may improve the prognosis of cirrhotic patients.
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