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Biomarkers for the Detection and Management of Hepatocellular Carcinoma in Patients Treated with Direct-Acting Antivirals. Cancers (Basel) 2022; 14:cancers14112700. [PMID: 35681679 PMCID: PMC9179595 DOI: 10.3390/cancers14112700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Chronic Hepatitis C virus (HCV) represents the main etiological factor for hepatocellular carcinoma (HCC) in developed countries. The introduction of direct-acting antivirals (DAAs) improved the eradication of the hepatitis C virus (HCV) but not the reduction in the incidence of HCV-associated HCC. Some patients still develop HCC, even after reaching a sustained virological response (SVR). This review is a summary of pre-clinical studies that investigated predictive biomarkers for HCC occurrence and recurrence in HCV-infected patients treated with DAAs. The presented biomarkers are found dysregulated in serum or tissue at specific time points (before, during, after DAA treatment or post SVR) and correlated with HCC-predisposing conditions. Thus, this review aims to improve the management of patients developing HCV-induced HCC. Abstract Hepatocellular carcinoma (HCC) is the sixth-most common type of cancer worldwide and chronic Hepatitis C virus (HCV) represents the main etiological factor in developed countries. HCV promotes hepatocarcinogenesis through persistent liver inflammation and dysregulation of cell signaling pathways. The introduction of direct-acting antivirals (DAAs) resulted in a significant improvement in the eradication of the virus, with an expected reduction of HCC incidence. However, the risk of HCC development can persist after DAA treatment. Recent studies have investigated the potential use of molecular biomarkers that predict HCC occurrence or recurrence helping the stratification of patients under surveillance. This review aimed to summarize all pre-clinical exploration of predictive biomarkers to identify DAA-treated patients at risk for HCC development. Dysregulated microRNAs, lncRNAs, histone modifications, cytokines, proteins, and sphingolipids represent various classes of HCC risk predictors identified in two different biological sources (tissue and serum). The non-invasive serum markers can provide a more accessible means to perform clinical monitoring and predict the risk of HCC. In addition, conditions like cirrhosis, predisposing to HCC, strongly correlate with most of the molecular predictors identified, supporting the value of these molecules as possible biomarkers of HCC in DAA-treated patients.
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Glucocorticosteroids and the Risk of NAFLD in Inflammatory Bowel Disease. Can J Gastroenterol Hepatol 2022; 2022:4344905. [PMID: 35600209 PMCID: PMC9117063 DOI: 10.1155/2022/4344905] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 04/13/2022] [Indexed: 02/08/2023] Open
Abstract
Each year, the incidence of nonalcoholic fatty liver (NAFLD) disease increases. NAFLD is a chronic disease. One of the most common causes of NAFLD is an inadequate lifestyle, which is characterized by a lack or low physical activity and eating highly processed foods rich in saturated fat and salt and containing low amount of fiber. Moreover, disturbances in intestinal microbiome and the use of certain drugs may predispose to NAFLD. NAFLD is an increasingly described disease in patients with inflammatory bowel disease (IBD). Recent data also indicate a frequent coexistence of metabolic syndrome in this group of patients. Certain groups of drugs also increase the risk of developing inflammation, liver fibrosis, and cirrhosis. Particularly important in the development of NAFLD are steroids, which are used in the treatment of many diseases, for example, IBD. NAFLD is one of the most frequent parenteral manifestations of the disease in IBD patients. However, there is still insufficient information on what dose and exposure time of selected types of steroids may lead to the development of NAFLD. It is necessary to conduct further research in this direction. Therefore, patients with IBD should be constantly monitored for risk factors for the development of NAFLD.
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Seifeldein GS, Hassan EA, Imam HM, Makboul R, Idriss NK, Gaber MA, Elkady RM. Quantitative MDCT and MRI assessment of hepatic steatosis in genotype 4 chronic hepatitis C patients with fibrosis. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2021. [DOI: 10.1186/s43055-021-00590-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hepatic steatosis has been shown to worsen the course of liver disease in chronic hepatitis C (CHC) patients, and it may reduce the efficacy of antiviral therapy and accelerate disease progression. In this cross-sectional study, we aimed to evaluate the role of multidetector computed tomography and magnetic resonance imaging (MRI) in the quantitative assessment and grading of hepatic steatosis to evaluate the association between hepatic steatosis and fibrosis in Egyptian genotype 4-CHC (G4-CHC) patients.
Results
Histopathological hepatic steatosis was found in 70.3% of 155 patients. No correlation was found between the CT ratio and pathological hepatic steatosis. Proton density fat fraction, T1-fat fraction, and fat percentage correlated with histological steatosis grading (r = 0.953, p < 0.001; r = 0.380, p = 0.027 and r = 0.384, p = 0.025, respectively). An agreement between steatosis grading by histology and 1H-MRS was found in 74.2% of patients. Compared to other MRI modalities, proton density fat fraction had the highest area under the receiver operating characteristic curve (AUC), with 0.910, 0.931, and 0.975 for mild, moderate, and severe steatosis, respectively. The cutoff with the best ability to predict steatosis was > 4.95 for a proton density fat fraction (AUC = 0.958) with 95.8% sensitivity, 90% specificity, 78.5% positive predictive value, and 96.1% negative predictive value.
Conclusion
1H-MRS had good diagnostic performance in predicting hepatic steatosis in G4-CHC patients, and hence, it may offer a useful noninvasive quantitative modality for grading steatosis with clinical applicability, especially in those where a liver biopsy cannot be done.
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Chaudhari R, Fouda S, Sainu A, Pappachan JM. Metabolic complications of hepatitis C virus infection. World J Gastroenterol 2021; 27:1267-1282. [PMID: 33833481 PMCID: PMC8015302 DOI: 10.3748/wjg.v27.i13.1267] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 02/10/2021] [Accepted: 03/12/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a systemic disease that is implicated in multiple extrahepatic organ dysfunction contributing to its protean manifestations. HCV is associated with diverse extrahepatic disorders including atherosclerosis, glucose and lipid metabolic disturbances, alterations in the iron metabolic pathways, and lymphoproliferative diseases over and above the traditional liver manifestations of cirrhosis and hepatocellular carcinoma. The orchestration between HCV major proteins and the liver-muscle-adipose axis, poses a major burden on the global health of human body organs, if not adequately addressed. The close and inseparable associations between chronic HCV infection, metabolic disease, and cardiovascular disorders are specifically important considering the increasing prevalence of obesity and metabolic syndrome, and their economic burden to patients, the healthcare systems, and society. Cellular and molecular mechanisms governing the interplay of these organs and tissues in health and disease are therefore of significant interest. The coexistence of metabolic disorders and chronic hepatitis C infection also enhances the progression to liver fibrosis and hepatocellular carcinoma. The presence of metabolic disorders is believed to influence the chronicity and virulence of HCV leading to liver disease progression. This comprehensive review highlights current knowledge on the metabolic manifestations of hepatitis C and the potential pathways in which these metabolic changes can influence the natural history of the disease.
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Affiliation(s)
- Rahul Chaudhari
- Department of Medicine, Pennsylvania Hospital of the University of Pennsylvania, Pennsylvania, PA 19104, United States
| | - Sherouk Fouda
- School of Health and Biomedical Sciences, RMIT University, Melbourne VIC 3000, Australia
| | - Ashik Sainu
- Department of Gastroenterology and Hepatology, Aster Oman Hospital, Al Ghubra, Muscat OM 133, Oman
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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The Safety of The Directly Acting Antiviral Treatment For Hepatitis C Virus According To The Egyptian National Program Protocol In Patients With Midrange Ejection Fraction. Glob Heart 2021; 16:3. [PMID: 33598383 PMCID: PMC7792459 DOI: 10.5334/gh.906] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background The Egyptian National Committee of Viral Hepatitis program is the leading national hepatitis C virus (HCV) management program globally. However, limited data is available about the effect of the new directly acting antiviral agents on the cardiovascular system. Objectives Our study aimed to assess the safety of the relatively new directly acting antiviral agents approved by the National Health Committee in Egypt to treat patients infected with hepatitis C virus who have midrange left ventricular ejection fraction. Methods This multicenter study included 400 successive patients with an ejection fraction (40-49%) from May 2017 to December 2019. We classified them into two groups: Group I (Child A), who received Sofosbuvir and Daclatasvir for twelve weeks, and Group II (Child B), who received Sofosbuvir, Daclatasvir, and Ribavirin for twelve weeks. Patients were evaluated for their symptoms, ejection fraction, brain natriuretic peptide, lipid profile, fasting blood glucose, fasting insulin, Homeostatic Model Assessment of Insulin Resistance levels, and Holter monitoring (just before the start of treatment and within three days after completing therapy). Results We found New York Heart Association Class, ejection fraction, brain natriuretic peptide, premature ventricular contractions burden, as well as highest and lowest heart rate did not show a statistically significant difference in both groups after treatment. The treatment did not cause bradycardia or non-sustained ventricular tachycardia. Fasting blood glucose and fasting insulin levels declined, with improved insulin resistance after treatment in both groups. Both low and high-density lipoprotein cholesterol increased after treatment in Group II. Conclusions Both regimens of directly acting antiviral agents used in Egypt to treat chronic hepatitis C virus infection are safe in patients with New York Heart Association Class I and II with midrange left ventricular ejection fraction (40-49%). There are beneficial metabolic changes following HCV clearance as an improvement of insulin resistance.
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Emmanuel B, El-Kamary SS, Magder LS, Stafford KA, Charurat ME, Chairez C, McLaughlin M, Hadigan C, Prokunina-Olsson L, O'Brien TR, Masur H, Kottilil S. Metabolic Changes in Chronic Hepatitis C Patients Who Carry IFNL4-ΔG and Achieve Sustained Virologic Response With Direct-Acting Antiviral Therapy. J Infect Dis 2020; 221:102-109. [PMID: 31504644 DOI: 10.1093/infdis/jiz435] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 08/21/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Clearance of hepatitis C virus (HCV) results in rapid changes in metabolic parameters early in direct-acting antiviral (DAA) therapy. Long-term changes after sustained virologic response (SVR) remain unknown. METHODS We investigated longitudinal changes in metabolic and inflammatory outcomes in chronic hepatitis C (CHC) patients: low-density lipoprotein (LDL), high-density lipoprotein, triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) using a general linear model for repeated measurements at 5 clinical time points and by human immunodeficiency virus (HIV) coinfection and IFNL4 genotype. RESULTS The mean LDL increased markedly during DAA therapy (pre-DAA, 86.6 to DAA, 107.4 mg/dL; P < .0001), but then it decreased to 97.7 mg/dL by post-SVR year 1 (P < .001 compared with DAA; P = .0013 compared with SVR). In patients who carry the IFNL4-ΔG allele, mean LDL increased during treatment, then decreased at post-SVR year 1; however, in patients with TT/TT, genotype did not change during and after DAA treatment. The mean ALT and AST normalized rapidly between pre-DAA and DAA, whereas only mean ALT continued to decrease until post-SVR. Metabolic and inflammatory outcomes were similar by HIV-coinfection status. CONCLUSIONS Changes in LDL among CHC patients who achieved SVR differed by IFNL4 genotype, which implicates the interferon-λ4 protein in metabolic changes observed in HCV-infected patients.
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Affiliation(s)
- Benjamin Emmanuel
- Division of Clinical Care and Research, Institute of Human Virology, Baltimore, Maryland
| | | | | | - Kristen A Stafford
- Division of Clinical Care and Research, Institute of Human Virology, Baltimore, Maryland.,Department of Epidemiology and Public Health, Baltimore, Maryland
| | - Man E Charurat
- Department of Epidemiology and Prevention, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Cheryl Chairez
- National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
| | - Mary McLaughlin
- National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
| | - Colleen Hadigan
- National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
| | | | - Thomas R O'Brien
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Henry Masur
- Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, Baltimore, Maryland
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Shen F, Mi YQ, Xu L, Liu YG, Wang XY, Pan Q, Zhang RN, Hu XQ, Xu LM, Fan JG. Moderate to severe hepatic steatosis leads to overestimation of liver stiffness measurement in chronic hepatitis B patients without significant fibrosis. Aliment Pharmacol Ther 2019; 50:93-102. [PMID: 31094016 DOI: 10.1111/apt.15298] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 11/29/2018] [Accepted: 04/19/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Liver stiffness measurement (LSM) by transient elastography is a noninvasive method for the diagnosis of hepatic fibrosis. The impact of hepatic steatosis on LSM remains to be explored. AIM To determine whether LSM is affected by hepatic steatosis in patients with chronic hepatitis B (CHB). METHODS Consecutive patients with biopsy-proven CHB were prospectively enrolled. Hepatic steatosis was classified by pathology as none (S0, <5%), mild (S1, 5%-33%), and moderate-severe (S2-3, >33%), and quantitatively by controlled attenuation parameter (CAP) as CAP S0 (≤247 dB/m), CAP S1 (248-267 dB/m) and CAP S2-3 (≥268 dB/m). Liver fibrosis was assessed by METAVIR classification and noninvasively by LSM. RESULTS The prevalence of non-alcoholic fatty liver disease (n = 223) in CHB patients (n = 593) was 37.6%. Forty-eight belonged to S2-3 and 127 belonged to CAP S2-3. In patients without significant fibrosis (F0-1), the median LSM (kPa) was 7.4 in S2-3 and 7.1 in CAP S2-3, which was significantly higher than that in S0/S1 (P = 0.005) and CAP S0/S1 (P = 0.003). No significant difference was found in significant fibrosis (F2-4). For LSM identifying significant fibrosis (F2-4), the negative predictive value was higher in CHB patients with CAP ≥ 268 compared to those with CAP < 268 (0.81 vs 0.73); the positive predictive value was lower in CAP ≥ 268 than its counterpart (0.65 vs 0.76). CONCLUSIONS Moderate-severe steatosis increased the LSM value in CHB patients without significant fibrosis. A CAP ≥ 268 did not affect LSM for ruling out, but it slightly affected LSM for ruling in significant fibrosis. TRIAL REGISTRATION ChiCTR-DDT-13003983.
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Affiliation(s)
- Feng Shen
- Department of Gastroenterology, Center for Fatty Liver, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yu-Qiang Mi
- Research Institute of Liver Diseases, Tianjin Second People's Hospital, Tianjin, China
| | - Liang Xu
- Research Institute of Liver Diseases, Tianjin Second People's Hospital, Tianjin, China
| | - Yong-Gang Liu
- Research Institute of Liver Diseases, Tianjin Second People's Hospital, Tianjin, China
| | - Xiao-Ying Wang
- Department of Pathology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qin Pan
- Department of Gastroenterology, Center for Fatty Liver, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Rui-Nan Zhang
- Department of Gastroenterology, Center for Fatty Liver, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xi-Qi Hu
- Department of Pathology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Lei-Ming Xu
- Department of Gastroenterology, Center for Fatty Liver, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Center for Fatty Liver, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
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8
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Llibre A, Shimakawa Y, Mottez E, Ainsworth S, Buivan TP, Firth R, Harrison E, Rosenberg AR, Meritet JF, Fontanet A, Castan P, Madejón A, Laverick M, Glass A, Viana R, Pol S, McClure CP, Irving WL, Miele G, Albert ML, Duffy D. Development and clinical validation of the Genedrive point-of-care test for qualitative detection of hepatitis C virus. Gut 2018; 67:2017-2024. [PMID: 29615488 PMCID: PMC6176522 DOI: 10.1136/gutjnl-2017-315783] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 03/09/2018] [Accepted: 03/14/2018] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. DESIGN We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case-control study comparing results with those obtained with the Abbott RealTime HCV test. RESULTS The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. CONCLUSION We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions. TRIAL REGISTRATION NUMBER NCT02992184 .
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Affiliation(s)
- Alba Llibre
- Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France
- Inserm U1223, Institut Pasteur, Paris, France
| | - Yusuke Shimakawa
- Unité d’Epidémiologie des Maladies Emergentes, Institut Pasteur, Paris, France
| | - Estelle Mottez
- Centre for Translational Research, Institut Pasteur, Paris, France
- INSERM UMS20, Institut Pasteur, Paris, France
| | | | - Tan-Phuc Buivan
- Centre for Translational Research, Institut Pasteur, Paris, France
- INSERM UMS20, Institut Pasteur, Paris, France
| | | | | | - Arielle R Rosenberg
- Université Paris Descartes, EA4474 "Hepatitis C Virology", AP-HP, Hôpital Cochin, Service de Virologie, Paris, France
| | - Jean-François Meritet
- Université Paris Descartes, EA4474 "Hepatitis C Virology", AP-HP, Hôpital Cochin, Service de Virologie, Paris, France
| | - Arnaud Fontanet
- Unité d’Epidémiologie des Maladies Emergentes, Institut Pasteur, Paris, France
- PACRI Unit, Conservatoire National des Arts et Métiers, Paris, France
| | | | - Antonio Madejón
- Liver Unit, Hospital Universitario La Paz, CIBERehd, IdiPAZ, Madrid, Spain
| | | | | | | | - Stanislas Pol
- Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France
- Inserm U1223, Institut Pasteur, Paris, France
- Centre for Translational Research, Institut Pasteur, Paris, France
- Université Paris Descartes, EA4474 "Hepatitis C Virology", AP-HP, Hôpital Cochin, Service de Virologie, Paris, France
| | - C Patrick McClure
- Gastrointestinal and Liver Disorders Theme, NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | - William Lucien Irving
- Gastrointestinal and Liver Disorders Theme, NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | | | - Matthew L Albert
- Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France
- Inserm U1223, Institut Pasteur, Paris, France
- Centre for Translational Research, Institut Pasteur, Paris, France
- Department of Cancer Immunology, Genentech Inc, San Francisco, California, USA
| | - Darragh Duffy
- Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France
- Inserm U1223, Institut Pasteur, Paris, France
- Centre for Translational Research, Institut Pasteur, Paris, France
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Recent Advances in the Pathogenesis of Hepatitis C Virus-Related Non-Alcoholic Fatty Liver Disease and Its Impact on Patients Cured of Hepatitis C. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s11901-017-0370-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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The benefit of statins in chronic hepatitis C patients: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2017; 29:759-766. [PMID: 28240613 DOI: 10.1097/meg.0000000000000867] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Besides regulating lipid metabolism, statins have garnered considerable interest because of their antiviral and antineoplastic properties. The potential benefit of statins using in chronic hepatitis C (CHC) patients is not well described. This meta-analysis was carried out to quantitatively assess the efficacy of statins in improving the therapeutic effect and prognosis of patients with CHC. PATIENTS AND METHODS We searched electronic databases for relevant studies comparing the course of benefit in CHC patients with statins versus without statins. Risk estimates were pooled to assess the association of statins use with sustained virological response and the prognosis of CHC patients. RESULTS Twenty-three studies fulfilled the inclusion criteria. Meta-analysis of 16 homogeneous studies showed that the sustained virological response rate increased by 31% [relative risk (RR)=1.31; 95% confidence interval (CI): 1.23-1.39] in 12 791 CHC patients with statins as an adjuvant under the general antiviral therapy compared with those without this adjuvant therapy. Moreover, meta-analysis of seven studies suggested that statins was beneficial on several specific poor outcomes of CHC patients (RR=0.49; 95% CI: 0.42-0.56). CHC patients with statin use were found to be inversely associated with a 55% reduced risk of hepatocellular carcinoma (RR=0.45; 95% CI: 0.36-0.57) and 53% reduced risk of cirrhosis (RR=0.47; 95% CI: 0.33-0.67) as well as 44% reduced risk of mortality (RR=0.56; 95% CI: 0.46-0.69). However, significant heterogeneity and publication bias were present in some of our analyses. CONCLUSION Beneficial effects of statins use were found in the therapy and the prognosis of CHC patients. Further prospective studies are still needed to confirm these benefits.
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Zhang Y, Meng T, Zuo L, Bei Y, Zhang Q, Su Z, Huang Y, Pang J, Xiang Q, Yang H. Xyloketal B Attenuates Fatty Acid-Induced Lipid Accumulation via the SREBP-1c Pathway in NAFLD Models. Mar Drugs 2017; 15:md15060163. [PMID: 28587208 PMCID: PMC5484113 DOI: 10.3390/md15060163] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 05/27/2017] [Accepted: 06/01/2017] [Indexed: 01/08/2023] Open
Abstract
The goal of this study was to examine the effects of xyloketal B on nonalcoholic fatty liver disease (NAFLD) and to explore the molecular mechanisms underlying its effects in both in vivo and in vitro models. We discovered an association between xyloketal B and the sterol regulatory element-binding protein-1c (SREBP-1c) signaling pathway, which is related to lipid metabolism. Mice were dosed with xyloketal B (5, 10 and 20 mg/kg/d) and atorvastatin (15 mg/kg/d) via intraperitoneal injection once daily for 40 days after being fed a high fat diet plus 10% high fructose liquid (HFD+HFL) for 8 weeks. Xyloketal B significantly improved HFD+HFL-induced hepatic histological lesions and attenuated lipid and glucose accumulation in the blood as well as lipid accumulation in the liver. Xyloketal B increased the expression of CPT1A, and decreased the expression of SREBP-1c and its downstream targeting enzymes such as ACC1, ACL, and FAS. Xyloketal B also significantly reduced lipid accumulation in HepG2 cells treated with free fatty acids (FFAs). These data suggested that xyloketal B has lipid-lowering effects via the SREBP-1c pathway that regulate lipid metabolism. Thus, targeting SREBP-1c activation with xyloketal B may be a promising novel approach for NAFLD treatment.
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Affiliation(s)
- Youying Zhang
- Institute of Biomedicine & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China.
- Department of Pharmacy, Jinan University, Guangzhou 510632, China.
| | - Tian Meng
- Institute of Biomedicine & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China.
- Department of Pharmacy, Jinan University, Guangzhou 510632, China.
| | - Ling Zuo
- Institute of Biomedicine & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China.
- Department of Pharmacy, Jinan University, Guangzhou 510632, China.
| | - Yu Bei
- Institute of Biomedicine & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China.
- Department of Pharmacy, Jinan University, Guangzhou 510632, China.
| | - Qihao Zhang
- Institute of Biomedicine & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China.
| | - Zhijian Su
- Institute of Biomedicine & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China.
| | - Yadong Huang
- Institute of Biomedicine & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China.
| | - Jiyan Pang
- School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China.
| | - Qi Xiang
- Institute of Biomedicine & Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China.
- Department of Pharmacy, Jinan University, Guangzhou 510632, China.
| | - Hongtu Yang
- Department of Pharmacy, Jinan University, Guangzhou 510632, China.
- The People's Hospital of Shenzhen City, Shenzhen 518020, China.
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12
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Nirei K, Matsumura H, Kumakawa M, Matsumoto N, Nakamura H, Yamagami H, Matsuoka S, Moriyama M. Steatosis influences the clinical profiles and long-term outcomes of interferon-treated chronic hepatitis C and liver cirrhosis patients. Int J Med Sci 2017; 14:45-52. [PMID: 28138308 PMCID: PMC5278658 DOI: 10.7150/ijms.17202] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 11/01/2016] [Indexed: 12/30/2022] Open
Abstract
Objective: This study aimed to assess the relationship between steatosis and long-term outcomes of patients with chronic hepatitis C (CH) and liver cirrhosis (LC). Patients and methods: The study population included 282 subjects with CH or LC who underwent liver biopsy at our institute. All patients achieved a sustained virological response (SVR) to interferon (IFN). Clinical characteristics, including age, gender and body mass index (BMI), were compared. The liver biopsy specimens of all patients were examined and scores were assigned to indicate the severity of each of the following features: inflammatory cell infiltration in the periportal, parenchymal and portal areas; F (fibrosis) stage; portal sclerotic change; perivenular fibrosis; pericellular fibrosis; bile duct damage; hepatic steatosis. Results: Of the 282 patients, 112 (39.7%) were free of steatosis. The other 170 patients (60.3%) had steatosis. The blood biochemical parameters of the patients with hepatic steatosis were significantly poorer than those of patients free of steatosis. Inflammatory cell infiltration and F stage were both significantly more severe in patients with than in those without steatosis. The incidences of hepatocellular carcinoma differed significantly between the two groups. However, the incidences of hepatocellular carcinoma did not differ significantly between the groups with BMI above and below 25. Conclusion: We consider hepatic steatosis to potentially affect the blood biochemical parameters and clinical profiles of Japanese patients with CH due to hepatitis virus type C. Patients with this form of CH showed favorable clinical responses to IFN. Furthermore, fibrosis and steatosis appear to affect the long-term outcomes of these patients. However, BMI alone cannot be used to predict HCC development.
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Affiliation(s)
- Kazushige Nirei
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Hiroshi Matsumura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Mariko Kumakawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Hitomi Nakamura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Hiroaki Yamagami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
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Pedersen MR, Patel A, Backstedt D, Choi M, Seetharam AB. Genotype specific peripheral lipid profile changes with hepatitis C therapy. World J Gastroenterol 2016; 22:10226-10231. [PMID: 28028371 PMCID: PMC5155182 DOI: 10.3748/wjg.v22.i46.10226] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 09/27/2016] [Accepted: 10/27/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate magnitude/direction of changes in peripheral lipid profiles in patients undergoing direct acting therapy for hepatitis C by genotype.
METHODS Mono-infected patients with hepatitis C were treated with guideline-based DAAs at a university-based liver clinic. Patient characteristics and laboratory values were collected before and after the treatment period. Baseline demographics included age, ethnicity, hypertension, diabetes, hyperlipidemia, treatment regimen, and fibrosis stage. Total cholesterol (TCHOL), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG), and liver function tests were measured prior to treatment and ETR. Changes in lipid and liver function were evaluated by subgroups with respect to genotype. Mean differences were calculated for each lipid profile and liver function component (direction/magnitude). The mean differences in lipid profiles were then compared between genotypes for differences in direction/magnitude. Lipid profile and liver function changes were evaluated with Levene’s test and student’s t test. Mean differences in lipid profiles were compared between genotypes using ANOVA, post hoc analysis via the Bonferroni correction or Dunnett T3.
RESULTS Three hundred and seventy five patients enrolled with 321 (85.6%) achieving sustained-viral response at 12 wk. 72.3% were genotype 1 (GT1), 18.1% genotype 2 (GT2), 9.7% genotype 3 (GT3). Baseline demographics were similar. Significant change in lipid profiles were seen with GT1 and GT3 (ΔGT1, p and ΔGT3, p), with TCHOL increasing (+5.3, P = 0.005 and +16.1, P < 0.001), HDL increasing (+12.5, P < 0.001 and +7.9, P = 0.038), LDL increasing (+7.4, P = 0.058 and +12.5, P < 0.001), and TG decreasing (-5.9, P = 0.044 and -9.80 P = 0.067). Among genotypes (ΔGT1 v. ΔGT2 v. ΔGT3, ANOVA), significant mean differences were seen with TCHOL (+5.3 v. +0.1 v. +16.1, P = 0.017) and HDL (+12.3 v. +2 v. +7.9, P = 0.040). Post-hoc, GT3 was associated with a greater increase in TCHOL than GT1 and GT2 (P = 0.028 and P = 0.019).
CONCLUSION Successful DAA therapy results in increases in TCHOL, LDL, and HDL and decrease in TG, particularly in GT1/GT3. Changes are most pronounced in GT3.
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Yair-Sabag S, Nussinson E, Ben-Assuli O, Shibli F, Shahbari A, Zelber-Sagi S. Retrospective study of the associations between hepatitis C virus infection and metabolic factors. World J Hepatol 2016; 8:1269-1278. [PMID: 27843537 PMCID: PMC5084056 DOI: 10.4254/wjh.v8.i30.1269] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Revised: 07/18/2016] [Accepted: 09/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the bidirectional association between metabolic syndrome (MS) components and antiviral treatment response for chronic hepatitis C virus (HCV) infection.
METHODS This retrospective cohort study included 119 HCV + patients treated with pegylated-interferon-α and ribavirin. Metabolic characteristics and laboratory data were collected from medical records. Differences in baseline clinical and demographic risk factors between responders and non-responders were assessed using independent samples t-tests or χ2 tests. The effects of sustained viral response (SVR) to antiviral treatment on de novo impairments in MS components, including impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM), were assessed using univariable and multivariable logistic regression analysis, while the effect of MS components on SVR was assessed using univariable logistic regression analysis.
RESULTS Of the 119 patients, 80 (67%) developed SVR over the average 54 ± 13 mo follow-up. The cumulative risks for de novo T2DM and IFG were 5.07- (95%CI: 1.261-20.4, P = 0.022) and 3.87-fold higher (95%CI: 1.484-10.15, P = 0.006), respectively for non-responders than responders, when adjusted for the baseline risk factors age, sex, HCV genotype, high viral load, and steatosis. Post-treatment triglyceride levels were significantly lower in non-responders than in responders (OR = 0.27; 95%CI: 0.069-0.962, P = 0.044). Age and HCV genotype 3 were significantly different between responders and non-responders, and MS components were not significantly associated with SVR. Steatosis tended to attenuate SVR (OR = 0.596; 95%CI: 0.331-1.073, P = 0.08).
CONCLUSION SVR was associated with lower de novo T2DM and IFG incidence and higher triglyceride levels. Patients infected with HCV should undergo T2DM screening and antidiabetic treatment.
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15
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Abstract
The diagnostics of diffuse liver disease traditionally rely on liver biopsies and histopathological analysis of tissue specimens. However, a liver biopsy is invasive and carries some non-negligible risks, especially for patients with decreased liver function and those requiring repeated follow-up examinations. Over the last decades, magnetic resonance imaging (MRI) has developed into a valuable tool for the non-invasive characterization of focal liver lesions and diseases of the bile ducts. Recently, several MRI methods have been developed and clinically evaluated that also allow the diagnostics and staging of diffuse liver diseases, e.g. non-alcoholic fatty liver disease, hepatitis, hepatic fibrosis, liver cirrhosis, hemochromatosis and hemosiderosis. The sequelae of diffuse liver diseases, such as a decreased liver functional reserve or portal hypertension, can also be detected and quantified by modern MRI methods. This article provides the reader with the basic principles of functional MRI of the liver and discusses the importance in a clinical context.
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16
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Prime time for 25-hydroxycholestrol treatment against inflammation and viral infections? Int J Cardiol 2016; 208:107-8. [DOI: 10.1016/j.ijcard.2016.01.210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 01/22/2016] [Indexed: 11/23/2022]
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Kralj D, Jukić LV, Stojsavljević S, Duvnjak M, Smolić M, Čurčić IB. Hepatitis C Virus, Insulin Resistance, and Steatosis. J Clin Transl Hepatol 2016; 4:66-75. [PMID: 27047774 PMCID: PMC4807145 DOI: 10.14218/jcth.2015.00051] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 02/15/2016] [Accepted: 02/16/2016] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide. Liver steatosis is a common finding in many hepatic and extrahepatic disorders, the most common being metabolic syndrome (MS). Over time, it has been shown that the frequent coexistence of these two conditions is not coincidental, since many epidemiological, clinical, and experimental studies have indicated HCV to be strongly associated with liver steatosis and numerous metabolic derangements. Here, we present an overview of publications that provide clinical evidence of the metabolic effects of HCV and summarize the available data on the pathogenetic mechanisms of this association. It has been shown that HCV infection can induce insulin resistance (IR) in the liver and peripheral tissues through multiple mechanisms. Substantial research has suggested that HCV interferes with insulin signaling both directly and indirectly, inducing the production of several proinflammatory cytokines. HCV replication, assembly, and release from hepatocytes require close interactions with lipid droplets and host lipoproteins. This modulation of lipid metabolism in host cells can induce hepatic steatosis, which is more pronounced in patients with HCV genotype 3. The risk of steatosis depends on several viral factors (including genotype, viral load, and gene mutations) and host features (visceral obesity, type 2 diabetes mellitus, genetic predisposition, medication use, and alcohol consumption). HCV-related IR and steatosis have been shown to have a remarkable clinical impact on the prognosis of HCV infection and quality of life, due to their association with resistance to antiviral therapy, progression of hepatic fibrosis, and development of hepatocellular carcinoma. Finally, HCV-induced IR, oxidative stress, and changes in lipid and iron metabolism lead to glucose intolerance, arterial hypertension, hyperuricemia, and atherosclerosis, resulting in increased cardiovascular mortality.
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Affiliation(s)
- Dominik Kralj
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Lucija Virović Jukić
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Sanja Stojsavljević
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Marko Duvnjak
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Martina Smolić
- Department of Pharmacology, Faculty of Medicine, University of Osijek, Osijek, Croatia
| | - Ines Bilić Čurčić
- Department of Pharmacology, Faculty of Medicine, University of Osijek, Department of Endocrinology and metabolism disorders, University Hospital Center, Osijek, Osijek, Croatia
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18
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Mastro TD, Morrison CS, Hamilton CD. Determining the Incidence of Hepatitis C Virus Infection in Populations: An Important Tool for Epidemic Control. J Infect Dis 2016; 214:339-40. [DOI: 10.1093/infdis/jiw006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 01/04/2016] [Indexed: 11/12/2022] Open
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19
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Martinello M, Dore GJ. Editorial Commentary: Interferon-free Hepatitis C Treatment Efficacy From Clinical Trials Will Translate to “Real World” Outcomes. Clin Infect Dis 2016; 62:927-8. [DOI: 10.1093/cid/civ1227] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 12/22/2015] [Indexed: 11/14/2022] Open
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20
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Li C, Nie SP, Zhu KX, Ding Q, Li C, Xiong T, Xie MY. Lactobacillus plantarum NCU116 improves liver function, oxidative stress and lipid metabolism in rats with high fat diet induced non-alcoholic fatty liver disease. Food Funct 2015; 5:3216-23. [PMID: 25317840 DOI: 10.1039/c4fo00549j] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The effect of Lactobacillus plantarum NCU116 on liver function, oxidative stress and lipid metabolism in rats with high fat diet induced non-alcoholic fatty liver disease (NAFLD) was studied. The rats were divided into four groups: the normal diet (ND) group; the high fat diet (HFD) group; and HFD plus L. plantarum NCU116 as two doses (NCU116-L, 10(8) CFU mL(-1); NCU116-H, 10(9) CFU mL(-1)) groups. Treatment of L. plantarum NCU116 for 5 weeks was found to restore liver function and oxidative stress in rats with NAFLD, and decrease the levels of fat accumulation in the liver. In addition, the bacterium significantly reduced endotoxin and proinflammatory cytokines, and regulated bacterial flora in the colon and the expression of lipid metabolism in the liver. These results suggest that possible underlying mechanisms for the beneficial effect of L. plantarum NCU116 on NAFLD may include two pathways of downregulating lipogenesis and upregulating lipolysis and fatty acid oxidation related gene expression.
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Affiliation(s)
- Chuan Li
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China.
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21
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Zhang Q, Zhang HM, Qi WQ, Zhang YG, Zhao P, Jiao J, Wang JB, Zhang CY. 3.0T 1H magnetic resonance spectroscopy for assessment of steatosis in patients with chronic hepatitis C. World J Gastroenterol 2015; 21:6736-6744. [PMID: 26074712 PMCID: PMC4458784 DOI: 10.3748/wjg.v21.i21.6736] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Revised: 01/09/2015] [Accepted: 02/13/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the utility of 1H magnetic resonance spectroscopy (1H MRS) as a noninvasive test for steatosis in patients infected with hepatitis C virus.
METHODS: Ninety patients with chronic hepatitis C and pathology data underwent 3.0T 1H MRS, and the results of MRS and pathological analysis were compared.
RESULTS: This group of patients included 26 people with mild fatty liver (28.89%), 16 people with moderate fatty liver (17.78%), 18 people with severe fatty liver (20.0%), and 30 people without fatty liver (33.33%). The water peak was near 4.7 parts per million (ppm), and the lipid peak was near 1.3 ppm. Analysis of variance revealed that differences in the lipid peak, the area under the lipid peak, ratio of the lipid peak to the water peak, and ratio of the area under the lipid peak to the area under the water peak were statistically significant among the groups. Specifically, as the severity of fatty liver increased, the value of each index increased correspondingly. In the pairwise comparisons, the mean lipid peak, area under the lipid peak, ratio of the lipid peak to the water peak, and ratio of the area under the lipid peak to the area under the water peak were significantly different between the no fatty liver and moderate fatty liver groups, whereas no differences were noted between the severe fatty liver group and the mild or moderate fatty liver group. Area under the ROC curve (AUC) of area ratio in lipid and water and ratio in lipid and water in the no fatty liver group to mild fatty liver group, mild fatty liver group to moderate fatty liver group, and moderate fatty liver disease group to severe fatty liver group, were 0.705, 0.900, and 0.975, respectively.
CONCLUSION: 1H MRS is a noninvasive technique that can be used to provide information on the effect of liver steatosis on hepatic metabolic processes. This study indicates that the 1H MRS can be used as an indicator of steatosis in patients with chronic hepatitis C.
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22
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Chen JH, Peng DQ. Is 25-hydroxycholesterol the interplay of statins and inflammation? Int J Cardiol 2015; 184:255-256. [DOI: 10.1016/j.ijcard.2015.02.047] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 02/21/2015] [Indexed: 11/29/2022]
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23
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Meissner EG, Lee YJ, Osinusi A, Sims Z, Qin J, Sturdevant D, McHutchison J, Subramanian M, Sampson M, Naggie S, Patel K, Remaley AT, Masur H, Kottilil S. Effect of sofosbuvir and ribavirin treatment on peripheral and hepatic lipid metabolism in chronic hepatitis C virus, genotype 1-infected patients. Hepatology 2015; 61:790-801. [PMID: 25203718 PMCID: PMC4340816 DOI: 10.1002/hep.27424] [Citation(s) in RCA: 119] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 09/03/2014] [Indexed: 12/23/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral replication. Chronic HCV infection is associated with altered metabolism, including dyslipidemia and insulin resistance (IR), which contributes to disease progression and influences response to therapy. To further understand the impact of HCV infection on host metabolism, we examined changes in serum lipid profiles and intrahepatic expression of lipid-related genes during interferon (IFN)-free treatment of chronic HCV, genotype 1 infection with sofosbuvir and ribavirin (RBV), and explored associations with treatment outcome. Serum lipids (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TGs]) and hemoglobin A1C (HbA1C) were measured during treatment, while gene expression of lipid-related genes was assessed using paired pre- and end-of-treatment (EOT) liver biopsies from 8 patients (n=7 sustained virologic response [SVR]; n=1 relapse) and unpaired EOT liver biopsies from 25 patients (n=17 SVR; n=8 relapse). Serum LDL concentration and particle size increased early in therapy, whereas TG concentration and very-low-density lipoprotein particle size decreased concomitantly, irrespective of treatment outcome. Whereas LDL increased in patients regardless of treatment outcome, average LDL concentration was lower at baseline and post-treatment in patients who relapsed. Analysis of paired liver biopsies revealed altered expression of genes associated with lipid transport, assembly, and signaling. In unpaired EOT liver biopsies, intrahepatic expression of fatty acid metabolism and lipid transport genes was lower in patients who experienced treatment relapse. CONCLUSION Clearance of HCV using an IFN-free antiviral regimen results in rapid changes in peripheral and intrahepatic metabolic pathways, implicating a direct effect of HCV replication on lipid homeostasis.
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Affiliation(s)
- Eric G. Meissner
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Yu-Jin Lee
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Anu Osinusi
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Division of Infectious Diseases, Institute of Human Virology, University of Maryland Medical School, Baltimore, MD, USA
| | - Zayani Sims
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Jing Qin
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Dan Sturdevant
- Genomics Unit, Research Technologies Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
| | | | | | - Maureen Sampson
- Lipoprotein Metabolism Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Susanna Naggie
- Duke University, Duke Clinical Research Institute, Durham, NC, USA
| | - Keyur Patel
- Duke University, Duke Clinical Research Institute, Durham, NC, USA
| | - Alan T. Remaley
- Lipoprotein Metabolism Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Henry Masur
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Shyam Kottilil
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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24
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Camus G, Schweiger M, Herker E, Harris C, Kondratowicz AS, Tsou CL, Farese RV, Herath K, Previs SF, Roddy TP, Pinto S, Zechner R, Ott M. The hepatitis C virus core protein inhibits adipose triglyceride lipase (ATGL)-mediated lipid mobilization and enhances the ATGL interaction with comparative gene identification 58 (CGI-58) and lipid droplets. J Biol Chem 2014; 289:35770-80. [PMID: 25381252 DOI: 10.1074/jbc.m114.587816] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Liver steatosis is a common health problem associated with hepatitis C virus (HCV) and an important risk factor for the development of liver fibrosis and cancer. Steatosis is caused by triglycerides (TG) accumulating in lipid droplets (LDs), cellular organelles composed of neutral lipids surrounded by a monolayer of phospholipids. The HCV nucleocapsid core localizes to the surface of LDs and induces steatosis in cultured cells and mouse livers by decreasing intracellular TG degradation (lipolysis). Here we report that core at the surface of LDs interferes with the activity of adipose triglyceride lipase (ATGL), the key lipolytic enzyme in the first step of TG breakdown. Expressing core in livers or mouse embryonic fibroblasts of ATGL(-/-) mice no longer decreases TG degradation as observed in LDs from wild-type mice, supporting the model that core reduces lipolysis by engaging ATGL. Core must localize at LDs to inhibit lipolysis, as ex vivo TG hydrolysis is impaired in purified LDs coated with core but not when free core is added to LDs. Coimmunoprecipitation experiments revealed that core does not directly interact with the ATGL complex but, unexpectedly, increased the interaction between ATGL and its activator CGI-58 as well as the recruitment of both proteins to LDs. These data link the anti-lipolytic activity of the HCV core protein with altered ATGL binding to CGI-58 and the enhanced association of both proteins with LDs.
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Affiliation(s)
- Gregory Camus
- From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158
| | - Martina Schweiger
- From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158, Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - Eva Herker
- From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158, UCSF Liver Center, University of California, San Francisco, California 94158, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany
| | - Charles Harris
- UCSF Liver Center, University of California, San Francisco, California 94158, Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, Department of Medicine, University of California, San Francisco, California 94158, Division of Endocrinology Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Andrew S Kondratowicz
- From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158
| | - Chia-Lin Tsou
- From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158
| | - Robert V Farese
- UCSF Liver Center, University of California, San Francisco, California 94158, Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, Department of Medicine, University of California, San Francisco, California 94158, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, and
| | - Kithsiri Herath
- Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey 07065
| | - Stephen F Previs
- Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey 07065
| | - Thomas P Roddy
- Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey 07065
| | - Shirly Pinto
- Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey 07065
| | - Rudolf Zechner
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - Melanie Ott
- From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158, UCSF Liver Center, University of California, San Francisco, California 94158, Department of Medicine, University of California, San Francisco, California 94158,
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25
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Autophagy in HCV infection: keeping fat and inflammation at bay. BIOMED RESEARCH INTERNATIONAL 2014; 2014:265353. [PMID: 25162004 PMCID: PMC4138948 DOI: 10.1155/2014/265353] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 07/11/2014] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease. Viral persistence and pathogenesis rely mainly on the ability of HCV to deregulate specific host processes, including lipid metabolism and innate immunity. Recently, autophagy has emerged as a cellular pathway, playing a role in several aspects of HCV infection. This review summarizes current knowledge on the molecular mechanisms that link the HCV life cycle with autophagy machinery. In particular, we discuss the role of HCV/autophagy interaction in dysregulating inflammation and lipid homeostasis and its potential for translational applications in the treatment of HCV-infected patients.
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26
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Shahidi M, Tay ESE, Read SA, Ramezani-Moghadam M, Chayama K, George J, Douglas MW. Endocannabinoid CB1 antagonists inhibit hepatitis C virus production, providing a novel class of antiviral host-targeting agents. J Gen Virol 2014; 95:2468-2479. [PMID: 25053565 DOI: 10.1099/vir.0.067231-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Direct-acting antivirals have significantly improved treatment outcomes in chronic hepatitis C (CHC), but side effects, drug resistance and cost mean that better treatments are still needed. Lipid metabolism is closely linked with hepatitis C virus (HCV) replication, and endocannabinoids are major regulators of lipid homeostasis. The cannabinoid 1 (CB1) receptor mediates these effects in the liver. We have previously shown upregulation of CB1 receptors in the livers of patients with CHC, and in a HCV cell-culture model. Here, we investigated whether CB1 blockade inhibited HCV replication. The antiviral effect of a CB1 antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), was examined in HCV strain JFH1 cell-culture and subgenomic replicon models. The effects on the expression of genes involved in lipid metabolism were also measured. CB1 short hairpin RNA (shRNA) was used to confirm that the effects were specific for the cannabinoid receptor. Treatment with AM251 strongly inhibited HCV RNA (~70 %), viral protein (~80 %), the production of new virus particles (~70 %) and virus infectivity (~90 %). As expected, AM251 reduced the expression of pro-lipogenic genes (SREBP-1c, FASN, SCD1 and ACC1) and stimulated genes promoting lipid oxidation (CPT1 and PPARα). This effect was mediated by AMP-activated protein kinase (AMPK). Stable CB1 knockdown of cells infected with HCV showed reduced levels of HCV RNA compared with controls. Thus, reduced CB1 signalling inhibits HCV replication using either pharmacological inhibitors or CB1 shRNA. This may be due, at least in part, to reduced lipogenesis, mediated by AMPK activation. We suggest that CB1 antagonists may represent an entirely new class of drug with activity against HCV.
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Affiliation(s)
- Mahsa Shahidi
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
| | - Enoch S E Tay
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
| | - Scott A Read
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
| | - Mehdi Ramezani-Moghadam
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima-shi, Japan
| | - Jacob George
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
| | - Mark W Douglas
- Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Sydney, Australia.,Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
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