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Heiat M, Javanbakht M, Jafari D, Poudineh M, Heydari F, Sharafi H, Alavian SM. Correlation of IL-10 and IL18 with the development of liver cirrhosis associated with hepatitis B virus infection: A systematic review. Cytokine 2025; 186:156818. [PMID: 39671883 DOI: 10.1016/j.cyto.2024.156818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/02/2024] [Accepted: 11/16/2024] [Indexed: 12/15/2024]
Abstract
BACKGROUND Patients who have been infected with the Hepatitis B virus (HBV) are susceptible to developing liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The objective of this systematic review was to comprehensively scrutinize the existing evidence concerning the association between host genetic polymorphisms and HBV-associated LC. METHODS We searched databases of PubMed, Scopus, and Web of Science for relevant articles published from building databases to 25 October 2023. RESULT We detected 104 relevant articles, relating to 84 individuals genes. Nine genes had the strong evidence of correlation, including IL-10, IL-18, IL-1B, TGF- β, TLR3, STAT4, IL-1RN, Tim3, and IFN receptors. A positive correlation was found for 33 genes but this data had not yet been replicated, 11 genes had limited or mixed evidence of a correlation, and 34 genes indicated no correlation. IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. CONCLUSION IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. It is of necessary to take into account the fundamental mechanism behind these associations and discern those that are confounded by the coexistence of other LC/HCC risk factors and response to therapy. These results are expected to guide future studies on the genetic susceptibility of HBV-related LC/HCC.
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Affiliation(s)
- Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Mohammad Javanbakht
- Nephrology and Urology Research Center, Clinical Science Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Davood Jafari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Fatemeh Heydari
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Galal ASGM, Dawood RM, Awady MKE, El-Dessouky YMM, Mahmoud MMAH, Alla MDAA. Recognition of 7 genes signature (Cirrhosis Risk Score) in the diagnosed non-responders to DAAs therapy by intra-PBMCs nested HCV RNA PCR. J Genet Eng Biotechnol 2023; 21:89. [PMID: 37646837 PMCID: PMC10468448 DOI: 10.1186/s43141-023-00544-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 08/19/2023] [Indexed: 09/01/2023]
Abstract
BACKGROUND AND AIMS Predictors of chronic HCV response to oral antiviral therapy (OAT) are related to host genetic variations. Single nucleotide polymorphisms (SNP) and alleles variations of host genes in association with hepatic fibro-cirrhotic changes have a distinct role in OAT outcomes. The current research evaluated the association of Cirrhosis-Risk-Scores (CRS) values, based on the correlation of seven genes signature-SNPs, with sonographic liver parenchymal changes in determining OAT outcomes. METHODS All study subjects (n = 54) were recruited three months after completing OAT and classified into three groups. Group I (n = 21) had negative HCV PCR, group II (n = 17) showed positive solitary intra-PBMCs HCV infection, and group III(n = 16) was serum HCV RNA PCR-positive. All study-population were subjected to examination by hepatic-ultrasound (US), FIB-4-scoring, and screening for 7 gene-signature that addressed CRS values as low, intermediate, and high depending on gene SNPs identification. RESULTS Group I showed a significant association with low CRS values compared to other groups (P < 0.001). Solitary intra- PBMCs HCV infection in group II was significantly combined with intermediate CRS values in comparison to groups I and III (P < 0.001). The high CRS values were significantly found in group III when compared to groups I and II (P < 0.01). On US imaging, low CRS values were common in normally appeared hepatic parenchyma (P < 0.001) and high CRS values were frequent in coarse-liver (P < 0.001), while bright-liver-tissues appearance was mainly detected in the intermediate CRS category (P = 0.09). On FIB-4 scoring, high CRS value were associated with hepatic fibro-cirrhosis compared to intermediate (P < 0.001) and low (P = 0.08) CRS-categories. CONCLUSION The current study concluded the association of (a) high CRS values with coarse liver in viral-RNA serologic relapse, (b) low CRS values with normal liver tissues in sustained virologic response (SVR), (c) intermediate CRS values with bright liver in solitary PBMCs relapse.
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Affiliation(s)
| | - Reham M Dawood
- Department of Microbial Biotechnology, National Research Center, Cairo, Egypt
| | - Mostafa K El Awady
- Department of Microbial Biotechnology, National Research Center, Cairo, Egypt
| | | | | | - Mohamed Darwish Ahmed Abd Alla
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Cairo, Egypt.
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3
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Xu W, Hu Q, Chen C, Li W, Li Q, Chen L. FibroScan Predicts Liver Fibrosis Progression in Chronic HBV Infection Patients with No Clear Indication for Antiviral Therapy: A Retrospective Cohort Study. Infect Drug Resist 2023; 16:1777-1785. [PMID: 37020800 PMCID: PMC10067685 DOI: 10.2147/idr.s402990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
Background and Aims Chronic hepatitis B virus (HBV) infection patients who do not fulfill the typical treatment indications should be followed up. This study aimed to evaluate the risk of liver fibrosis progression (LFP) and assess the role of noninvasive tests (NITs) of liver fibrosis in monitoring LFP in these patients. Methods A total of 116 patients with active HBV replication, persistently normal or minimally elevated alanine aminotransferase (ALT) levels, and no or mild hepatic necroinflammation or fibrosis based on liver biopsy tests at baseline and followed by a repeated liver biopsy assessment during follow-up. LFP was defined as increase in METAVIR fibrosis score by 1 score or more. Results Among 116 patients, 40 (34.5%) progressed by at least one fibrosis stage, 16 (13.8%) progressed by at least two fibrosis stages at a median follow-up interval of 27 months (IQR: 12-36). Multivariate analysis confirmed the significant association of an increase in liver stiffness measurement (LSM) value with LFP on histology (p =0.005). The AUROC of LSM value increase rate is significantly higher than that of serum-based NITs of liver fibrosis for the prediction of LFP (p < 0.05). An increase in LSM by 20% is the optimal cutoff for the prediction of LFP. Conclusion LFP is non-negligible in patients with active HBV replication, persistently normal or minimally elevated ALT, and initially no or minimal hepatic necroinflammation or fibrosis. Serial LSM tests would be more reliable in identifying LFP than serum-based NITs, and easier to obtain than serial liver biopsy tests.
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Affiliation(s)
- Wei Xu
- Department of Liver Disease, Shanghai Public Health Clinical Center, Fudan University, Shanghai, People’s Republic of China
| | - Qiankun Hu
- Department of Liver Disease, Shanghai Public Health Clinical Center, Fudan University, Shanghai, People’s Republic of China
| | - Chong Chen
- Department of Infectious Disease, Shanghai Public Health Clinical Center, Fudan University, Shanghai, People’s Republic of China
| | - Weixia Li
- Department of Infectious Disease, Shanghai Public Health Clinical Center, Fudan University, Shanghai, People’s Republic of China
| | - Qiang Li
- Department of Liver Disease, Shanghai Public Health Clinical Center, Fudan University, Shanghai, People’s Republic of China
- Correspondence: Qiang Li; Liang Chen, Email ;
| | - Liang Chen
- Department of Liver Disease, Shanghai Public Health Clinical Center, Fudan University, Shanghai, People’s Republic of China
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4
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Dawood RM, El-Meguid MA, Shousha HI, Elsayed A, Nabeel MM, Yosry A, Abdelaziz A, Salum GM. Seven gene signature explores the impact of DAAs on the appearance of hepatocellular carcinoma in HCV infected patients. Heliyon 2022; 8:e10119. [PMID: 36033258 PMCID: PMC9404272 DOI: 10.1016/j.heliyon.2022.e10119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/30/2022] [Accepted: 07/25/2022] [Indexed: 11/03/2022] Open
Abstract
UNLABELLED HCV damages the hepatocytes ending with hepatocellular carcinoma (HCC). The direct-acting antivirals (DAAs) treatment has raised hopes for reducing the incidence of HCC. However, several scientific debate regarding the impact of DAAs on the occurrence of HCC in patients with cirrhosis. We aimed to study the Cirrhosis Risk Score (CRS), several clinical factors and tumor characteristics between patients who developed HCC either with or without DAAs treatment "DAA-exposed HCC patients" and "DAA-unexposed HCC patients". METHODS CRS was assessed via genotyping by allelic discrimination assays in HCV patients who developed de novo HCC (with DAAs (DAA-exposed HCC patients, n = 50), and without DAAs treatment (DAA-unexposed HCC patients, n = 40)). APRI, FIB-4 scores, and tumor characteristics were assessed. RESULTS Around 60% and 48% of DAA-exposed HCC patients and DAA-unexposed HCC patients; respectively had high CRS scores without significant difference. DAA-exposed HCC patients showed elevated Albumin, Hemoglobin and decreased ALT, AST compared with DAA-unexposed HCC patients (P = 0.002, 0.04, <0.001 and 0.006; respectively). FIB4 and APRI didn't reach the statistical difference between the studied groups. DAA-exposed HCC patients have higher overall survival (OS) than DAA-unexposed HCC patients (median: 30 & 15 months; respectively (p = 0.019)). Moreover, no significant differences were observed between the two groups in their focal lesion characteristics. CONCLUSION All studied patients are genetically predisposed to develop HCC. Moreover, DAAs significantly improved the OS and the biochemical parameters. No differences between the two groups were detected regarding their tumor characteristics. Accordingly, the appearance of HCC after treatment is attributed to the natural course of cirrhosis.
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Affiliation(s)
- Reham M. Dawood
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
| | - Mai Abd El-Meguid
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
| | - Hend Ibrahim Shousha
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Ahmed Elsayed
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Mohamed Mahmoud Nabeel
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
| | - Ayman Yosry
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Ashraf Abdelaziz
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Ghada M. Salum
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
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[¹¹C] choline as a potential PET/CT biomarker of liver cirrhosis: A prospective pilot study. Dig Liver Dis 2021; 53:753-759. [PMID: 33272861 DOI: 10.1016/j.dld.2020.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/08/2020] [Accepted: 11/09/2020] [Indexed: 12/11/2022]
Abstract
AIM OF THE STUDY To compare [¹¹C] choline PET/CT findings between patients with cirrhosis and normal liver controls. METHODS Included 11 patients with cirrhosis and 14 controls. All underwent a dynamic [11C] choline PET/CT. The maximal standard uptake values (SUVmax), the area under the curve (AUC) and kinetic parameters (K1 and K2), clinical and laboratory data, were compared between groups. RESULTS Patients mean age was 68.4 ± 10.7 and controls, 69.7 ± 7.3 years. Mean SUVmax was higher in patients than controls (right lobe, 10.06 ± 12 vs. 6.3 ± 1.6, P = 0.011; left lobe, 8.6 ± 11.6 vs. 5.4 ± 0.9, P = 0.024; spleen 17.99 ± 27.8 vs. 13.4 ± 2.6, P = 0.027; kidney, 35.9 ± 59.5 vs. 19.3 ± 4.8, P = 0.025) and also AUC values (right lobe, 13,538 ± 20,020 vs. 8427.3 ± 1557.9, P = 0.026; left lobe 12,304 ± 18,871 vs. 6878.9 ± 1294.3, P = 0.024; spleen, 12,875 ± 17,930 vs. 8263.9 ± 1279.2, P = 0.023; kidney, 24,623 ± 36,025 vs. 13,667 ± 3873.9, P = 0.032). No difference in kinetic parameters was found. No correlations between severity of clinical signs and imaging-derived parametric data were found among patients with cirrhosis. CONCLUSIONS [11C] choline PET/CT may serve as a noninvasive biomarker for patients with cirrhosis.
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Dawood RM, Salum GM, El-Meguid MA, Elsayed A, Yosry A, Abdelaziz A, Shousha HI, Nabeel MM, El Awady MK. Development of a gene signature for predicting cirrhosis risk score of chronic liver disease associated with HCV infection in Egyptians. Microb Pathog 2021; 153:104805. [PMID: 33609649 DOI: 10.1016/j.micpath.2021.104805] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Complex diseases such as fibrosis are likely polygenic. Lately, cirrhosis risk score (CRS) clearly discriminated Chronic HCV patients with high-risk versus those with low-risk for cirrhosis better than clinical factors. METHODS Herein, the CRS was assessed via genotyping by allelic discrimination assays in 243 HCV Egyptian patients categorized into 164 patients didn't develop HCC (93 mild, 71 advanced fibrosis); and 79 patients developed HCC. APRI and FIB-4 scores were calculated, compared with CRS and correlated with degree of fibrosis progression. RESULTS Median of the three CRS, APRI and FIB-4 scores were significantly elevated in late fibrotic and HCC patients (p < 0.001); however CRS displayed proper discrimination (mild fibrosis (0.59; 0.4-0.75), advanced fibrosis (0.75; 0.7-0.86) and HCC (0.73; 0.57-0.77); (p < 0.001)). The ROC analysis of CRS score displayed modest accuracy to discriminate between mild and advanced fibrotic patient; AUC was 0.73; p < 0.0001), while AUC was only 0.57 (p = 0.05) for the discrimination between HCC and no HCC. Moreover, the combination of CRS, APRI and FIB4 lessened the power of correlation (AUC, 0.63 (p < 0.0001)) in fibrosis prognosis. In HCC prognosis, the combination of CRS, APRI and FIB4 in HCC patients showed modest accuracy with AUC, 0.59 (p = 0.0001). CONCLUSION The diagnostic accuracy of FIB-4 for predicting liver fibrosis was nearly identical to that of CRS, however the strength of CRS score stemmed from that it is built on 7 SNPs host genetic factor. Our study validates non invasive algorithms for fibrosis prognosis purposes which may aid in decision making for therapeutic intervention.
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Affiliation(s)
- Reham M Dawood
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt.
| | - Ghada M Salum
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
| | - Mai Abd El-Meguid
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
| | - Ahmed Elsayed
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Ayman Yosry
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Ashraf Abdelaziz
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Hend Ibrahim Shousha
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Mohamed Mahmoud Nabeel
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Mostafa K El Awady
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
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Resino S, Fernández-Rodríguez A, Pineda-Tenor D, Gómez-Moreno AZ, Sánchez-Ruano JJ, Artaza-Varasa T, Muñoz-Gómez MJ, Virseda-Berdices A, Martín-Vicente M, Martínez I, Jiménez-Sousa MA. TRPM5 rs886277 Polymorphism Predicts Hepatic Fibrosis Progression in Non-Cirrhotic HCV-Infected Patients. J Clin Med 2021; 10:483. [PMID: 33525598 PMCID: PMC7865714 DOI: 10.3390/jcm10030483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/23/2021] [Accepted: 01/25/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND TRPM5 (transient receptor potential cation channel subfamily M member 5) rs886277 polymorphism has been related to liver cirrhosis from different etiologies. The present study investigates the association of TRPM5 rs886277 polymorphism with liver fibrosis progression and cirrhosis development in chronic hepatitis C (CHC) patients. METHODS We conducted a retrospective study of 208 non-cirrhotic patients with CHC, who had at least two liver stiffness measurements (LSM) with a separation of 12 months (baseline LSM (LSM1) and the last LSM (LSM2)). Two outcome variables were considered: (1) LSM2/LSM1 ratio; (2) cirrhosis progression (F4; LSM ≥ 12.5 kPa). DNA genotyping was done at the CeGen using a MassARRAY platform. RESULTS The follow-up time was similar irrespective of the rs886277 genotype (46.4 months in TT genotype, 46.4 months in CT genotype, and 49.2 months in CC genotype; p = 0.649). The highest LSM increases were found in patients with CC genotype compared with TT and CT genotypes (p = 0.044 and p = 0.038, respectively). The cirrhosis progression was higher in patients with CC genotype than TT genotype (p = 0.033). Thus, the rs886277 C allele was associated with higher cirrhosis progression (adjusted odds ratio (aOR) = 2.64; p = 0.014). Moreover, rs886277 CC genotype was also related to higher values of LSM2/LSM1 ratio (adjusted arithmetic mean ratio a(AMR) = 1.31; p = 0.001) and cirrhosis progression (aOR = 4.33; p = 0.027). CONCLUSIONS TRPM5 rs886277 polymorphism was associated with liver fibrosis progression and cirrhosis development among hepatitis C virus (HCV)-infected patients. Specifically, the rs886277 C allele and CC genotype were risk factors for advancing liver fibrosis and cirrhosis compared to the rs886277 T allele and CT/TT genotype, respectively.
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Affiliation(s)
- Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28222 Majadahonda, Spain; (A.F.-R.); (M.J.M.-G.); (A.V.-B.); (M.M.-V.); (I.M.); (M.A.J.-S.)
| | - Amanda Fernández-Rodríguez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28222 Majadahonda, Spain; (A.F.-R.); (M.J.M.-G.); (A.V.-B.); (M.M.-V.); (I.M.); (M.A.J.-S.)
| | - Daniel Pineda-Tenor
- Servicio de Laboratorio Clínico, Hospital de Antequera, 29200 Málaga, Spain;
| | - Ana Zaida Gómez-Moreno
- Servicio de Digestivo, Hospital Virgen de la Salud, 45004 Toledo, Spain; (A.Z.G.-M.); (J.J.S.-R.); (T.A.-V.)
| | - Juan José Sánchez-Ruano
- Servicio de Digestivo, Hospital Virgen de la Salud, 45004 Toledo, Spain; (A.Z.G.-M.); (J.J.S.-R.); (T.A.-V.)
| | - Tomas Artaza-Varasa
- Servicio de Digestivo, Hospital Virgen de la Salud, 45004 Toledo, Spain; (A.Z.G.-M.); (J.J.S.-R.); (T.A.-V.)
| | - María José Muñoz-Gómez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28222 Majadahonda, Spain; (A.F.-R.); (M.J.M.-G.); (A.V.-B.); (M.M.-V.); (I.M.); (M.A.J.-S.)
| | - Ana Virseda-Berdices
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28222 Majadahonda, Spain; (A.F.-R.); (M.J.M.-G.); (A.V.-B.); (M.M.-V.); (I.M.); (M.A.J.-S.)
| | - María Martín-Vicente
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28222 Majadahonda, Spain; (A.F.-R.); (M.J.M.-G.); (A.V.-B.); (M.M.-V.); (I.M.); (M.A.J.-S.)
| | - Isidoro Martínez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28222 Majadahonda, Spain; (A.F.-R.); (M.J.M.-G.); (A.V.-B.); (M.M.-V.); (I.M.); (M.A.J.-S.)
| | - María A. Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28222 Majadahonda, Spain; (A.F.-R.); (M.J.M.-G.); (A.V.-B.); (M.M.-V.); (I.M.); (M.A.J.-S.)
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Connolly JC, Lim JK. Non-invasive Fibrosis Assessment of Patients with Hepatitis C: Application of Society Guidelines to Clinical Practice. CURRENT HEPATOLOGY REPORTS 2019; 18:249-258. [DOI: 10.1007/s11901-019-00471-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis. Sci Rep 2018; 8:17905. [PMID: 30559459 PMCID: PMC6297163 DOI: 10.1038/s41598-018-36037-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 10/27/2018] [Indexed: 02/07/2023] Open
Abstract
Extracellular matrix (ECM) deposition and resultant scar play a major role in the pathogenesis and progression of liver fibrosis. Identifying core regulators of ECM deposition may lead to urgently needed diagnostic and therapetic strategies for the disease. The transcription factor Sex determining region Y box 9 (SOX9) is actively involved in scar formation and its prevalence in patients with liver fibrosis predicts progression. In this study, transcriptomic approaches of Sox9-abrogated myofibroblasts identified >30% of genes regulated by SOX9 relate to the ECM. Further scrutiny of these data identified a panel of highly expressed ECM proteins, including Osteopontin (OPN), Osteoactivin (GPNMB), Fibronectin (FN1), Osteonectin (SPARC) and Vimentin (VIM) as SOX9 targets amenable to assay in patient serum. In vivo all SOX-regulated targets were increased in human disease and mouse models of fibrosis and decreased following Sox9-loss in mice with parenchymal and biliary fibrosis. In patient serum samples, SOX9-regulated ECM proteins were altered in response to fibrosis severity, whereas comparison with established clinical biomarkers demonstrated superiority for OPN and VIM at detecting early stages of fibrosis. These data support SOX9 in the mechanisms underlying fibrosis and highlight SOX9 and its downstream targets as new measures to stratify patients with liver fibrosis.
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Athwal VS, Pritchett J, Llewellyn J, Martin K, Camacho E, Raza SM, Phythian-Adams A, Birchall LJ, Mullan AF, Su K, Pearmain L, Dolman G, Zaitoun AM, Friedman SL, MacDonald A, Irving WL, Guha IN, Hanley NA, Piper Hanley K. SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis. EMBO Mol Med 2018; 9:1696-1710. [PMID: 29109128 PMCID: PMC5709769 DOI: 10.15252/emmm.201707860] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Fibrosis and organ failure is a common endpoint for many chronic liver diseases. Much is known about the upstream inflammatory mechanisms provoking fibrosis and downstream potential for tissue remodeling. However, less is known about the transcriptional regulation in vivo governing fibrotic matrix deposition by liver myofibroblasts. This gap in understanding has hampered molecular predictions of disease severity and clinical progression and restricted targets for antifibrotic drug development. In this study, we show the prevalence of SOX9 in biopsies from patients with chronic liver disease correlated with fibrosis severity and accurately predicted disease progression toward cirrhosis. Inactivation of Sox9 in mice protected against both parenchymal and biliary fibrosis, and improved liver function and ameliorated chronic inflammation. SOX9 was downstream of mechanosignaling factor, YAP1. These data demonstrate a role for SOX9 in liver fibrosis and open the way for the transcription factor and its dependent pathways as new diagnostic, prognostic, and therapeutic targets in patients with liver fibrosis.
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Affiliation(s)
- Varinder S Athwal
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,Research & Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - James Pritchett
- School of Healthcare Science, Manchester Metropolitan University, Manchester, UK
| | - Jessica Llewellyn
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Katherine Martin
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,Research & Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Elizabeth Camacho
- Centre for Health Economics, Institute of Population Health, Faculty of Medical & Human Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Sayyid Ma Raza
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,Research & Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Alexander Phythian-Adams
- Manchester Centre for Collaborative Inflammation Research, Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - Lindsay J Birchall
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,Research & Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Aoibheann F Mullan
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,Research & Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Kim Su
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,Research & Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Laurence Pearmain
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,Research & Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Grace Dolman
- Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Abed M Zaitoun
- Department of Cellular Pathology, Nottingham Digestive Diseases Centre and National Institute of Health Research Biomedical Research Unit in Gastroenterology and Liver Disease, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Andrew MacDonald
- Manchester Centre for Collaborative Inflammation Research, Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - William L Irving
- Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.,School of Life Sciences, Nottingham Digestive Diseases Centre and National Institute of Health Research Biomedical Research Unit in Gastroenterology and Liver Disease, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Indra N Guha
- Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Neil A Hanley
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,Research & Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Karen Piper Hanley
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK .,Research & Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
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11
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Walker AJ, Peacock CJ, Pedergnana V, STOP‐HCV Consortium, Irving WL. Host genetic factors associated with hepatocellular carcinoma in patients with hepatitis C virus infection: A systematic review. J Viral Hepat 2018; 25:442-456. [PMID: 29397014 PMCID: PMC6321980 DOI: 10.1111/jvh.12871] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 01/02/2018] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV)-infected patients are at risk of developing hepatocellular carcinoma (HCC). Individuals at heightened risk could be targeted by intensive follow-up surveillance. We have conducted a systematic review of the literature to identify host genetic predisposition to HCC in HCV-infected patients. A comprehensive search of Medline and Embase databases was performed, and the strength of evidence of associations for each gene on development of HCC was evaluated. We identified 166 relevant studies, relating to 137 different genes, or combinations thereof. Seventeen genes were classified as having "good" evidence of an association, a significant association was observed for 37 genes but this finding had not yet been replicated, 56 genes had mixed or limited evidence of an association, and 27 genes showed no association. IFNL3/4, TNF-α and PNPLA3 genes had the most evidence of an association. There was, however, considerable heterogeneity in study design and data quality. In conclusion, we identified a number of genes with evidence of association with HCC, but also a need for more standardized approaches to address this clinically critical question. It is important to consider the underlying mechanism of these relationships and which are confounded by the presence of other HCC risk factors and response to therapy. We also identified many genes where the evidence of association is contradictory or requires replication, as well as a number where associations have been studied but no evidence found. These findings should help to direct future studies on host genetic predisposition to HCC in HCV-infected patients.
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Affiliation(s)
- A. J. Walker
- National Institute for Health research (NIHR) Nottingham Biomedical Research CentreNottingham University Hospitals NHS TrustUniversity of NottinghamNottinghamUK,Centre for Evidence Based MedicineDepartment of Primary Care Health SciencesUniversity of OxfordOxfordUK
| | - C. J. Peacock
- National Institute for Health research (NIHR) Nottingham Biomedical Research CentreNottingham University Hospitals NHS TrustUniversity of NottinghamNottinghamUK
| | - V. Pedergnana
- Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUK
| | | | - W. L. Irving
- National Institute for Health research (NIHR) Nottingham Biomedical Research CentreNottingham University Hospitals NHS TrustUniversity of NottinghamNottinghamUK
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12
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Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 2018; 68:526-549. [PMID: 28989095 PMCID: PMC5818315 DOI: 10.1016/j.jhep.2017.09.016] [Citation(s) in RCA: 520] [Impact Index Per Article: 74.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/24/2017] [Accepted: 09/25/2017] [Indexed: 01/27/2023]
Abstract
Patients who develop chronic fibrotic liver disease, caused by viral or metabolic aetiologies, are at a high risk of developing hepatocellular carcinoma (HCC). Even after complete HCC tumour resection or ablation, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo HCC tumours, which progress into incurable, advanced-stage disease in most patients. Thus, early detection and prevention of HCC development is, in principle, the most impactful strategy to improve patient prognosis. However, a "one-size-fits-all" approach to HCC screening for early tumour detection, as recommended by clinical practice guidelines, is utilised in less than 20% of the target population, and the performance of screening modalities, including ultrasound and alpha-fetoprotein, is suboptimal. Furthermore, optimal screening strategies for emerging at-risk patient populations, such as those with chronic hepatitis C after viral cure, or those with non-cirrhotic, non-alcoholic fatty liver disease remain controversial. New HCC biomarkers and imaging modalities may improve the sensitivity and specificity of HCC detection. Clinical and molecular HCC risk scores will enable precise HCC risk prediction followed by tailoured HCC screening of individual patients, maximising cost-effectiveness and optimising allocation of limited medical resources. Several aetiology-specific and generic HCC chemoprevention strategies are evolving. Epidemiological and experimental studies have identified candidate chemoprevention targets and therapies, including statins, anti-diabetic drugs, and selective molecular targeted agents, although their clinical testing has been limited by the lengthy process of cancer development that requires long-term, costly studies. Individual HCC risk prediction is expected to overcome the challenge by enabling personalised chemoprevention, targeting high-risk patients for precision HCC prevention and substantially improving the dismal prognosis of HCC.
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Affiliation(s)
- Naoto Fujiwara
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, USA; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Japan
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, USA
| | - Nicolas Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, USA.
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13
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Prospects in non-invasive assessment of liver fibrosis: Liquid biopsy as the future gold standard? Biochim Biophys Acta Mol Basis Dis 2018; 1864:1024-1036. [PMID: 29329986 DOI: 10.1016/j.bbadis.2018.01.009] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 01/04/2018] [Accepted: 01/07/2018] [Indexed: 12/11/2022]
Abstract
Liver fibrosis is the result of persistent liver injury, and is characterized by sustained scar formation and disruption of the normal liver architecture. The extent of fibrosis is considered as an important prognostic factor for the patient outcome, as an absence of (early) treatment can lead to the development of liver cirrhosis and hepatocellular carcinoma. Till date, the most sensitive and specific way for the diagnosis and staging of liver fibrosis remains liver biopsy, an invasive diagnostic tool, which is associated with high costs and discomfort for the patient. Over time, non-invasive scoring systems have been developed, of which the measurements of serum markers and liver stiffness are validated for use in the clinic. These tools lack however the sensitivity and specificity to detect small changes in the progression or regression of both early and late stages of fibrosis. Novel non-invasive diagnostic markers with the potential to overcome these limitations have been developed, but often lack validation in large patient cohorts. In this review, we will summarize novel trends in non-invasive markers of liver fibrosis development and will discuss their (dis-)advantages for use in the clinic.
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14
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Yan Z, Wang Y. Viral and host factors associated with outcomes of hepatitis C virus infection (Review). Mol Med Rep 2017; 15:2909-2924. [PMID: 28339063 DOI: 10.3892/mmr.2017.6351] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 02/13/2017] [Indexed: 11/05/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a major health issue globally. Owing to the progress made in host genetics and HCV molecular virology, emerging data have suggested that the natural course and treatment response in patients with HCV infection are largely determined by complex host‑viral interactions. HCV genotype is the most important viral factor predicting the response to pegylated interferon‑α plus ribavirin therapy. The subtype of HCV genotype 1 is the key viral factor that predicts the efficacy of direct‑acting antiviral therapy. HCV genome heterogeneity and baseline viral load are additionally associated with the treatment response. Multiple host genetic variants localized in genes associated with the immune response have been identified as predictors of spontaneous disease course and therapy outcome in chronic HCV. However, most findings from candidate gene association studies have not been proven universal for all investigated populations and independent studies. Previous findings in independent large genome wide association studies confirmed that interferon‑λ3 gene polymorphisms are associated with spontaneous clearance and treatment responsiveness. A polymorphism of the inosine triphosphatase gene has been identified as a protective factor against ribavirin‑induced anemia and dose reductions. Another genetic variant in the patatin‑like phospholipase domain containing 3 genes is associated with hepatic steatosis and fibrosis in patients with HCV. The present review focused on the identified viral and host factors associated with outcomes of patients with HCV, and assessed the involvement of viral and host genetics in the natural history and treatment outcomes of HCV infection. This will provide novel ideas concerning personalized prevention and individualized clinical management.
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Affiliation(s)
- Zehui Yan
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
| | - Yuming Wang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
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15
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Besheer T, El-Bendary M, Elalfy H, Abd El-Maksoud M, Salah M, Zalata K, Elkashef W, Elshahawy H, Raafat D, Elemshaty W, Almashad N, Zaghloul H, El-Gilany AH, Abdel Razek AAK, Abd Elwahab M. Prediction of Fibrosis Progression Rate in Patients with Chronic Hepatitis C Genotype 4: Role of Cirrhosis Risk Score and Host Factors. J Interferon Cytokine Res 2017; 37:97-102. [PMID: 28068153 DOI: 10.1089/jir.2016.0111] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The rate of liver fibrosis progression in chronic hepatitis C (CHC) patients is highly variable and affected by different factors. This study aimed to assess the role of cirrhosis risk score (CRS) based on 7 genetic variants (7 single-nucleotide polymorphisms [SNPs]) and host factors (age and sex) in the prediction of the rate of fibrosis progression in CHC. Duration of infection was determined in 115 patients. The fibrosis progression rate (FPR) per year was calculated as the ratio between fibrosis stage and the duration of infection. SNP genotyping were performed and CRS was determined based on it. FPR was significantly elevated in patients who acquired infection at age >40 years versus those who acquired infection at 30-40 years and those who acquired infection at <30 years. Median FPR was significantly higher in males than females (0.17 vs. 0.15) with P = 0.001. CRS value ≥0.8 is predictive of patients with high risk for cirrhosis, and CRS value <0.5 is predictive of patients with low risk for cirrhosis. There was significant positive correlation between CRS and FPR (P ≤ 0.001). CRS based on 7 SNPs at cutoff value ≥0.8, age at infection >40 years, and male sex are predictors of higher FPR.
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Affiliation(s)
- Tarek Besheer
- 1 Department of Tropical Medicine, Mansoura University , Mansoura, Egypt
| | - Mahmoud El-Bendary
- 1 Department of Tropical Medicine, Mansoura University , Mansoura, Egypt
| | - Hatem Elalfy
- 1 Department of Tropical Medicine, Mansoura University , Mansoura, Egypt
| | | | - Mohamed Salah
- 1 Department of Tropical Medicine, Mansoura University , Mansoura, Egypt
| | - Khaled Zalata
- 2 Department of Pathlogy, Mansoura University , Mansoura, Egypt
| | - Wagdi Elkashef
- 2 Department of Pathlogy, Mansoura University , Mansoura, Egypt
| | - Heba Elshahawy
- 3 Department of Clinical Pathology, Mansoura University , Mansoura, Egypt
| | - Doaa Raafat
- 3 Department of Clinical Pathology, Mansoura University , Mansoura, Egypt
| | - Wafaa Elemshaty
- 3 Department of Clinical Pathology, Mansoura University , Mansoura, Egypt
| | - Noha Almashad
- 3 Department of Clinical Pathology, Mansoura University , Mansoura, Egypt
| | - Hosam Zaghloul
- 3 Department of Clinical Pathology, Mansoura University , Mansoura, Egypt
| | - Abdel-Hady El-Gilany
- 4 Department of Public Health and Preventive Medicine, Mansoura University , Mansoura, Egypt
| | | | - Mohamed Abd Elwahab
- 6 Gastroenterology Surgical Center, Mansoura Faculty of Medicine, Mansoura University , Mansoura, Egypt
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16
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Jiao J, Watt GP, Lee M, Rahbar MH, Vatcheva KP, Pan JJ, McCormick JB, Fisher-Hoch SP, Fallon MB, Beretta L. Cirrhosis and Advanced Fibrosis in Hispanics in Texas: The Dominant Contribution of Central Obesity. PLoS One 2016; 11:e0150978. [PMID: 26950933 PMCID: PMC4780836 DOI: 10.1371/journal.pone.0150978] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 02/22/2016] [Indexed: 02/07/2023] Open
Abstract
Liver cirrhosis is a leading cause of death in Hispanics and Hispanics who live in South Texas have the highest incidence of liver cancer in the United States. We aimed at determining the prevalence and associated risk factors of cirrhosis in this population. Clinical and demographic variables were extracted for 2466 participants in the community-based Cameron County Hispanic Cohort in South Texas. Aspartate transaminase to Platelet Ratio Index (APRI) was used to predict cirrhosis in Cameron County Hispanic Cohort. The prevalence of cirrhosis using APRI≥2 was 0.94%, which is nearly 4-fold higher than the national prevalence. Using APRI≥1, the overall prevalence of cirrhosis/advanced fibrosis was 3.54%. In both analyses, highest prevalence was observed in males, specifically in the 25-34 age group. Risk factors independently associated with APRI≥2 and APRI≥1 included hepatitis C, diabetes and central obesity with a remarkable population attributable fraction of 52.5% and 65.3% from central obesity, respectively. Excess alcohol consumption was also independently associated with APRI≥2. The presence of patatin-like phospholipase domain-containing-3 gene variants was independently associated with APRI≥1 in participants >50 years old. Males with both central obesity and excess alcohol consumption presented with cirrhosis/advanced fibrosis at a young age. Alarmingly high prevalence of cirrhosis and advanced fibrosis was identified in Hispanics in South Texas, affecting young males in particular. Central obesity was identified as the major risk factor. Public health efforts are urgently needed to increase awareness and diagnosis of advanced liver fibrosis in Hispanics.
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Affiliation(s)
- Jingjing Jiao
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Gordon P. Watt
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, Texas, United States of America
| | - MinJae Lee
- Department of Internal Medicine, Division of Clinical and Translational Sciences, The University of Texas Medical School at Houston, Houston, Texas, United States of America
- Biostatistics/Epidemiology/Research Design (BERD) Core, Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America
| | - Mohammad H. Rahbar
- Department of Internal Medicine, Division of Clinical and Translational Sciences, The University of Texas Medical School at Houston, Houston, Texas, United States of America
- Biostatistics/Epidemiology/Research Design (BERD) Core, Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America
- The University of Texas School of Public Health at Houston, Houston, Texas, United States of America
| | - Kristina P. Vatcheva
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, Texas, United States of America
| | - Jen-Jung Pan
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Medical School at Houston, Houston, Texas, United States of America
| | - Joseph B. McCormick
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, Texas, United States of America
| | - Susan P. Fisher-Hoch
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, Texas, United States of America
| | - Michael B. Fallon
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Medical School at Houston, Houston, Texas, United States of America
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
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17
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Eslam M, Hashem AM, Romero-Gomez M, Berg T, Dore GJ, Mangia A, Chan HLY, Irving WL, Sheridan D, Abate ML, Adams LA, Weltman M, Bugianesi E, Spengler U, Shaker O, Fischer J, Mollison L, Cheng W, Nattermann J, Riordan S, Miele L, Kelaeng KS, Ampuero J, Ahlenstiel G, McLeod D, Powell E, Liddle C, Douglas MW, Booth DR, George J. FibroGENE: A gene-based model for staging liver fibrosis. J Hepatol 2016; 64:390-398. [PMID: 26592354 DOI: 10.1016/j.jhep.2015.11.008] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 11/02/2015] [Accepted: 11/09/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The extent of liver fibrosis predicts long-term outcomes, and hence impacts management and therapy. We developed a non-invasive algorithm to stage fibrosis using non-parametric, machine learning methods designed for predictive modeling, and incorporated an invariant genetic marker of liver fibrosis risk. METHODS Of 4277 patients with chronic liver disease, 1992 with chronic hepatitis C (derivation cohort) were analyzed to develop the model, and subsequently validated in an independent cohort of 1242 patients. The model was assessed in cohorts with chronic hepatitis B (CHB) (n=555) and non-alcoholic fatty liver disease (NAFLD) (n=488). Model performance was compared to FIB-4 and APRI, and also to the NAFLD fibrosis score (NFS) and Forns' index, in those with NAFLD. RESULTS Significant fibrosis (⩾F2) was similar in the derivation (48.4%) and validation (47.4%) cohorts. The FibroGENE-DT yielded the area under the receiver operating characteristic curve (AUROCs) of 0.87, 0.85 and 0.804 for the prediction of fast fibrosis progression, cirrhosis and significant fibrosis risk, respectively, with comparable results in the validation cohort. The model performed well in NAFLD and CHB with AUROCs of 0.791, and 0.726, respectively. The negative predictive value to exclude cirrhosis was>0.96 in all three liver diseases. The AUROC of the FibroGENE-DT performed better than FIB-4, APRI, and NFS and Forns' index in most comparisons. CONCLUSION A non-invasive decision tree model can predict liver fibrosis risk and aid decision making.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia
| | - Ahmed M Hashem
- Department of Systems and Biomedical Engineering, Faculty of Engineering, Minia University, Minia, Egypt
| | - Manuel Romero-Gomez
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla, Spain
| | - Thomas Berg
- Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charite, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Germany; Department of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Gregory J Dore
- Kirby Institute, The University of New South Wales, Sydney, NSW, Australia; St Vincent's Hospital, Sydney, NSW, Australia
| | - Alessandra Mangia
- Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy
| | - Henry Lik Yuen Chan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - William L Irving
- NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, United Kingdom
| | - David Sheridan
- Liver Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute of Translational and Stratified Medicine, Plymouth University, United Kingdom
| | - Maria Lorena Abate
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
| | - Leon A Adams
- School of Medicine and Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, WA, Australia
| | - Martin Weltman
- Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Olfat Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Janett Fischer
- Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charite, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Germany
| | - Lindsay Mollison
- School of Medicine and Pharmacology, Fremantle Hospital, UWA, Fremantle, WA, Australia
| | - Wendy Cheng
- Department of Gastroenterology & Hepatology, Royal Perth Hospital, WA, Australia
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Stephen Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, NSW, Australia
| | - Luca Miele
- Department of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Kebitsaone Simon Kelaeng
- Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia
| | - Javier Ampuero
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla, Spain
| | - Golo Ahlenstiel
- Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia
| | - Duncan McLeod
- Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, Australia
| | - Elizabeth Powell
- Princess Alexandra Hospital, Department of Gastroenterology and Hepatology, Woolloongabba, QLD, Australia; The University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Christopher Liddle
- Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia
| | - Mark W Douglas
- Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia
| | - David R Booth
- Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia.
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18
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Boccaccio V, Russo ML, Carbone M, Bruno S. Treatment discontinuation with peg-interferon: what to consider. Expert Rev Clin Pharmacol 2015; 8:761-8. [PMID: 26437265 DOI: 10.1586/17512433.2015.1090872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Eradication of chronic hepatitis C virus infection improves the outcome of both liver and extrahepatic-related diseases and interferon-based regimens represented, for years, the standard of care to achieve this goal. Several baseline and on-treatment predictors of response, associated with a lower chance to achieve sustained virological response after interferon-based treatment, were developed. In the past few years, the advent of direct acting antivirals has dramatically modified the landscape of antiviral therapy, leading to an evolution from interferon-based to interferon-free therapies. This review will focus on the usefulness of futility stopping rules that allow the discontinuation of therapy in patients with a reduced chance to obtain sustained virological response if treated with interferon-containing regimens.
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Affiliation(s)
- Vincenzo Boccaccio
- a 1 Internal Medicine and Hepatology Unit, Humanitas Research Hospital , Rozzano, Italy
| | - Maria Luisa Russo
- a 1 Internal Medicine and Hepatology Unit, Humanitas Research Hospital , Rozzano, Italy
| | - Marco Carbone
- a 1 Internal Medicine and Hepatology Unit, Humanitas Research Hospital , Rozzano, Italy
| | - Savino Bruno
- a 1 Internal Medicine and Hepatology Unit, Humanitas Research Hospital , Rozzano, Italy.,b 2 Department of Internal Medicine, Humanitas University Medicine , Rozzano, Italy
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19
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Rüeger S, Bochud PY, Dufour JF, Müllhaupt B, Semela D, Heim MH, Moradpour D, Cerny A, Malinverni R, Booth DR, Suppiah V, George J, Argiro L, Halfon P, Bourlière M, Talal AH, Jacobson IM, Patin E, Nalpas B, Poynard T, Pol S, Abel L, Kutalik Z, Negro F. Impact of common risk factors of fibrosis progression in chronic hepatitis C. Gut 2015; 64:1605-15. [PMID: 25214320 DOI: 10.1136/gutjnl-2014-306997] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 08/22/2014] [Indexed: 12/15/2022]
Abstract
OBJECTIVE The natural course of chronic hepatitis C varies widely. To improve the profiling of patients at risk of developing advanced liver disease, we assessed the relative contribution of factors for liver fibrosis progression in hepatitis C. DESIGN We analysed 1461 patients with chronic hepatitis C with an estimated date of infection and at least one liver biopsy. Risk factors for accelerated fibrosis progression rate (FPR), defined as ≥ 0.13 Metavir fibrosis units per year, were identified by logistic regression. Examined factors included age at infection, sex, route of infection, HCV genotype, body mass index (BMI), significant alcohol drinking (≥ 20 g/day for ≥ 5 years), HIV coinfection and diabetes. In a subgroup of 575 patients, we assessed the impact of single nucleotide polymorphisms previously associated with fibrosis progression in genome-wide association studies. Results were expressed as attributable fraction (AF) of risk for accelerated FPR. RESULTS Age at infection (AF 28.7%), sex (AF 8.2%), route of infection (AF 16.5%) and HCV genotype (AF 7.9%) contributed to accelerated FPR in the Swiss Hepatitis C Cohort Study, whereas significant alcohol drinking, anti-HIV, diabetes and BMI did not. In genotyped patients, variants at rs9380516 (TULP1), rs738409 (PNPLA3), rs4374383 (MERTK) (AF 19.2%) and rs910049 (major histocompatibility complex region) significantly added to the risk of accelerated FPR. Results were replicated in three additional independent cohorts, and a meta-analysis confirmed the role of age at infection, sex, route of infection, HCV genotype, rs738409, rs4374383 and rs910049 in accelerating FPR. CONCLUSIONS Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.
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Affiliation(s)
- S Rüeger
- Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland Institute of Social and Preventive Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - P-Y Bochud
- Infectious Diseases Service, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - J-F Dufour
- Department of Hepatology, University of Berne, Berne, Switzerland
| | - B Müllhaupt
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
| | - D Semela
- Department of Gastroenterology, Canton Hospital St Gallen, St Gallen, Switzerland
| | - M H Heim
- Department of Gastroenterology and Hepatology, University Hospital of Basel, Basel, Switzerland
| | - D Moradpour
- Department of Gastroenterology and Hepatology, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - A Cerny
- Epatologia, Clinica Moncucco, Lugano, Switzerland
| | | | - D R Booth
- Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia
| | - V Suppiah
- Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney and University of Sydney Medical Foundation, Sydney, Australia
| | - J George
- Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney and University of Sydney Medical Foundation, Sydney, Australia
| | - L Argiro
- Laboratoire d'Immunologie et de Génétique des Maladies Parasitaires, INSERM-UMR 906/Université de la Méditerranée, Marseilles, France
| | - P Halfon
- Laboratoire Alphabio, Hôpital Ambroise Paré, Marseilles, France
| | - M Bourlière
- Service d'Hépato-gastroentérologie, Hôpital Saint-Joseph, Marseilles, France
| | - A H Talal
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, USA
| | - I M Jacobson
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, USA
| | - E Patin
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, U980, Imagine Institute, Paris, France University Paris Descartes, Paris, France
| | - B Nalpas
- University Paris Descartes, Paris, France Département d'Hépatologie, INSERM Unité 1016, Groupe Hospitalier Cochin-Hôtel Dieu-Broca, Paris, France
| | - T Poynard
- Université Pierre et Marie Curie, Service d'Hépato-gastroentérologie, Hôpital Pitié-Salpêtrière (AP-HP), Paris, France
| | - S Pol
- University Paris Descartes, Paris, France Département d'Hépatologie, INSERM Unité 1016, Groupe Hospitalier Cochin-Hôtel Dieu-Broca, Paris, France
| | - L Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, U980, Imagine Institute, Paris, France University Paris Descartes, Paris, France St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
| | - Z Kutalik
- Institute of Social and Preventive Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - F Negro
- Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland Department of Gastroenterology and Hepatology, University Hospitals of Geneva, Geneva, Switzerland
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Coppola N, Pisaturo M, Sagnelli C, Onorato L, Sagnelli E. Role of genetic polymorphisms in hepatitis C virus chronic infection. World J Clin Cases 2015; 3:807-822. [PMID: 26380828 PMCID: PMC4568530 DOI: 10.12998/wjcc.v3.i9.807] [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: 07/27/2014] [Revised: 12/09/2014] [Accepted: 06/08/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To analyze the host genetics factors influencing the clinical course and the response to antiviral treatment in patients with chronic hepatitis C (CHC).
METHODS: We conducted an electronic search on the PubMed and MEDLINE (2000-2014) databases and Cochrane library (2000-2014). A total of 73 articles were retrieved and their data were extensively evaluated and discussed by the authors and then analyzed in this review article.
RESULTS: Several studies associated polymorphisms in the interleukin 28B gene on chromosome 19 (19q13.13) with a spontaneous viral clearance in acute hepatitis C and with the response to pegylated interferon (Peg-IFN)-based treatment in chronic hepatitis C patients. Other investigations demonstrated that inosine triphosphate pyrophosphatase genetic variants protect hepatitis C virus-genotype-1 CHC patients from ribavirin-induced anemia, and other studies that a polymorphism in the patatin-like phospholipase domain-containing protein 3 was associated with hepatic steatosis in CHC patients. Although not conclusive, some investigations suggested that the vitamin D-associated polymorphisms play an important role in the achievement of sustained virologic response in CHC patients treated with Peg-IFN-based antiviral therapy. Several other polymorphisms have been investigated to ascertain their possible impact on the natural history and on the response to treatment in patients with CHC, but the data are preliminary and warrant confirmation.
CONCLUSION: Several genetic polymorphisms seem to influence the clinical course and the response to antiviral treatment in patients with CHC, suggesting individualized follow up and treatment strategies.
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Carulli L. Telomere shortening as genetic risk factor of liver cirrhosis. World J Gastroenterol 2015; 21:379-383. [PMID: 25593453 PMCID: PMC4292269 DOI: 10.3748/wjg.v21.i2.379] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 11/04/2014] [Accepted: 12/01/2014] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis is the main complication of chronic liver disease, leads to progressive liver function impairment and is the main risk factor for the development of liver cancer. Liver failure at endstage cirrhosis is associated with increased mortality with liver transplantation as the only possible treatment at this stage. The pathogenesis of liver cirrhosis is not completely elucidated. Although the common factors leading to liver injury, such as viral hepatitis, alcohol consume or fatty liver disease can be identified in the majority of patients a small percentage of patients have no apparent risk factors. Moreover given the same risk factors, some patients progress to cirrhosis whereas others have a benign course, the reason remains unclear. In order to develop new diagnostic and therapeutic tools, it is s essential to understand the pathogenesis of cirrhosis. The identification of genetic risk factors associated with cirrhosis is one of the possible approach to achieve these goal. In the past years several studies have supported the role of telomere shortening and cirrhosis. In the recent year several studies on the relation between several single nucleotide polymorphism (SNPs) and cirrhosis have been published; it has been proposed also a cirrhosis risk score based on seven SNPs. Also epidemiological studies on identical twins and in different ethnic groups have been supporting the importance of the role of genetic risk factors. Finally in the very recent years it has been suggested that telomere shortening may represent a genetic risk factor for the development of cirrhosis.
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Wu YJ, Xu MY, Lu LG. Clinical Advances in Fibrosis Progression of Chronic Hepatitis B and C. J Clin Transl Hepatol 2014; 2:222-7. [PMID: 26357628 PMCID: PMC4521239 DOI: 10.14218/jcth.2014.00029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 12/02/2014] [Accepted: 12/03/2014] [Indexed: 12/15/2022] Open
Abstract
Chronic liver diseases, such as chronic hepatitis B (CHB) and chronic hepatitis C (CHC), are characterized by the presence of liver fibrosis, which may ultimately lead to cirrhosis. The progression of fibrosis is associated with various factors. Here, we review recent advances in the study of factors related to the progression rate of CHB- and CHC-induced fibrosis. Identification of these factors and establishment of a scoring system for cirrhosis risk are particularly important for predicting cirrhosis development, planning individualized treatment, and preventing fibrosis progression.
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Affiliation(s)
| | | | - Lun-Gen Lu
- Correspondence to: Lun-Gen Lu, Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, No. 100 Haining Road, Haikou District, Shanghai 200080, China. Tel: +86-021-63240090, Fax: + 86-21-63241377. E-mail:
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Hoshida Y, Fuchs BC, Bardeesy N, Baumert TF, Chung RT. Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma. J Hepatol 2014; 61:S79-90. [PMID: 25443348 PMCID: PMC4435677 DOI: 10.1016/j.jhep.2014.07.010] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 07/03/2014] [Accepted: 07/10/2014] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) is one of the major aetiologic agents that causes hepatocellular carcinoma (HCC) by generating an inflammatory, fibrogenic, and carcinogenic tissue microenvironment in the liver. HCV-induced HCC is a rational target for cancer preventive intervention because of the clear-cut high-risk condition, cirrhosis, associated with high cancer incidence (1% to 7% per year). Studies have elucidated direct and indirect carcinogenic effects of HCV, which have in turn led to the identification of candidate HCC chemoprevention targets. Selective molecular targeted agents may enable personalized strategies for HCC chemoprevention. In addition, multiple experimental and epidemiological studies suggest the potential value of generic drugs or dietary supplements targeting inflammation, oxidant stress, or metabolic derangements as possible HCC chemopreventive agents. While the successful use of highly effective direct-acting antiviral agents will make important inroads into reducing long-term HCC risk, there will remain an important role for HCC chemoprevention even after viral cure, given the persistence of HCC risk in persons with advanced HCV fibrosis, as shown in recent studies. The successful development of cancer preventive therapies will be more challenging compared to cancer therapeutics because of the requirement for larger and longer clinical trials and the need for a safer toxicity profile given its use as a preventive agent. Molecular biomarkers to selectively identify high-risk population could help mitigate these challenges. Genome-wide, unbiased molecular characterization, high-throughput drug/gene screening, experimental model-based functional analysis, and systems-level in silico modelling are expected to complement each other to facilitate discovery of new HCC chemoprevention targets and therapies.
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Affiliation(s)
- Yujin Hoshida
- Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, United States.
| | - Bryan C Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, United States
| | - Nabeel Bardeesy
- Cancer Center, Massachusetts General Hospital, Harvard Medical School, United States
| | - Thomas F Baumert
- INSERM Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, and Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, France; Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, United States
| | - Raymond T Chung
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, United States.
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Abstract
BACKGROUND Cirrhosis is diagnosed in patients of all ages and is the end result of many different diseases. The aim of this study was to characterize clinical and ethnic features of adult patients who were admitted to the hospital at different (young/old) ages and examine associations between age and ethnicity within these groups. METHODS In this retrospective analysis of a diverse cohort of 2017 patients with a clinical diagnosis of cirrhosis between January 2001 and December 2011, we focused on age, ethnicity, and outcome of patients with cirrhosis. RESULTS We identified 219 patients younger than the age of 40 years, including 87 (11%) of 802 white, 31 (6%) of 550 African American, and 89 (16%) of 550 Hispanic patients (P < 0.001). Ethnicity and causes of cirrhosis were found to have a significant correlation with age. Overall, Hispanic and white patients together were more than twice as likely to be diagnosed with cirrhosis at an age younger than 40 years compared with African American patients (P < 0.001). Autoimmune hepatitis caused cirrhosis at a younger age regardless of ethnicity (P < 0.001), whereas cryptogenic/nonalcoholic fatty liver disease/nonalcoholic steatohepatitis was more likely identified at an older age (P = 0.008). African American patients with cirrhosis due to either alcohol or hepatitis C virus were older than Hispanic (P < 0.001 and P = 0.003, respectively) and white patients (P < 0.001 and P < 0.001, respectively) at presentation. Finally, younger patients admitted with cirrhosis had a higher in-hospital mortality rate (P < 0.001). CONCLUSIONS The data suggest an association between ethnicity and age of cirrhosis diagnosis, both overall and in patients with certain cirrhosis etiologies. This work raises the possibility of an ethnic and/or genetic basis for cirrhosis.
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Affiliation(s)
- Krishna C. Sajja
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center and Parkland Memorial Hospital, Dallas, TX, USA
| | - Desh P. Mohan
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center and Parkland Memorial Hospital, Dallas, TX, USA
| | - Don C. Rockey
- Department of Internal Medicine, Medical University of South Carolina, Charleston, SC, USA
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Molecular mechanism and treatment of viral hepatitis-related liver fibrosis. Int J Mol Sci 2014; 15:10578-604. [PMID: 24927147 PMCID: PMC4100170 DOI: 10.3390/ijms150610578] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Revised: 06/09/2014] [Accepted: 06/09/2014] [Indexed: 02/07/2023] Open
Abstract
Hepatic fibrosis is a wound-healing response to various chronic stimuli, including viral hepatitis B or C infection. Activated myofibroblasts, predominantly derived from the hepatic stellate cells (HSCs), regulate the balance between matrix metalloproteinases and their tissue inhibitors to maintain extracellular matrix homeostasis. Transforming growth factor-β and platelet-derived growth factor are classic profibrogenic signals that activate HSC proliferation. In addition, proinflammatory cytokines and chemokines coordinate macrophages, T cells, NK/NKT cells, and liver sinusoidal endothelial cells in complex fibrogenic and regression processes. In addition, fibrogenesis involves angiogenesis, metabolic reprogramming, autophagy, microRNA, and epigenetic regulations. Hepatic inflammation is the driving force behind liver fibrosis; however, host single nucleotide polymorphisms and viral factors, including the genotype, viral load, viral mutation, and viral proteins, have been associated with fibrosis progression. Eliminating the underlying etiology is the most crucial antifibrotic therapy. Growing evidence has indicated that persistent viral suppression with antiviral therapy can result in fibrosis regression, reduced liver disease progression, decreased hepatocellular carcinoma, and improved chances of survival. Preclinical studies and clinical trials are currently examining several investigational agents that target key fibrogenic pathways; the results are promising and shed light on this debilitating illness.
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Abstract
Liver fibrosis is the final common pathway for almost all causes of chronic liver injury. Liver fibrosis is now known to be a dynamic process having significant potential for resolution. Therefore, fibrosis prediction is an essential part of the assessment and management of patients with chronic liver disease. As such, there is strong demand for reliable liver biomarkers that provide insight into disease etiology, diagnosis, therapy, and prognosis in lieu of more invasive approaches such as liver biopsy. Current diagnostic strategies range from use of serum biomarkers to more advanced imaging techniques including transient elastography and magnetic resonance imaging. In addition to these modalities, there are other approaches including the use of novel, but yet to be validated, biomarkers. In this chapter, we discuss the biomarkers of liver fibrosis including the use of invasive and noninvasive biomarkers and disease-specific biomarkers in various chronic liver diseases.
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Real LM, Caruz A, Rivero-Juarez A, Soriano V, Neukam K, Rivero A, Cifuentes C, Mira JA, Macías J, Pineda JA. A polymorphism linked to RRAS, SCAF1, IRF3 and BCL2L12 genes is associated with cirrhosis in hepatitis C virus carriers. Liver Int 2014; 34:558-66. [PMID: 24131527 DOI: 10.1111/liv.12330] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 09/06/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Host genetic factors could play a primary role in determining risk for cirrhosis development in HCV-infected patients. The aims of this study were to discover new genetic variants associated with this trait and to replicate some associations formerly reported. METHODS Three hundred and thirty-seven HCV carriers with available data about liver fibrosis status, who initiated treatment with pegylated interferon plus ribavirin, were included. Of them, 77 (22.85%) were cirrhotic. One hundred and forty-four SNPs from 40 genes related to cholesterol metabolism/transport, sustained viral response to HCV therapy, liver fibrosis, or immune response, were genotyped in all samples. Plink software was used to perform univariate association analyses. The results obtained were adjusted by other parameters related to cirrhosis using multivariate logistic regression models. RESULTS Only the SNP rs12104272, linked to RRAS, SCAF1, IRF3 and BCL2L12 genes, was associated with cirrhosis. It was observed a higher proportion of rs12104272 A allele carriers in the non-cirrhotic group (60.63%) than in the cirrhotic group (38.15%) (adjusted OR = 0.36, 95% CI = 0.180-0.746, P = 0.006). This effect was stronger in the background of rs12979860 CC genotype of IL28B (adjusted OR = 0.069, 95% CI = 0.014-0.349, P = 0.001). CONCLUSION The rs12104272 SNP could have clinical value to select those individuals at lower risk for cirrhosis development.
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Affiliation(s)
- Luis M Real
- Unidad de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain; Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain
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Prediction of hepatic fibrosis in patients coinfected with HIV and hepatitis C virus based on genetic markers. J Acquir Immune Defic Syndr 2014; 64:434-42. [PMID: 23797694 DOI: 10.1097/qai.0b013e3182a06eb6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To assess the ability of the cirrhosis risk score (CRS) to predict liver fibrosis progression in HIV/hepatitis C virus (HCV)-coinfected patients. DESIGN Retrospective follow-up study. METHODS Based on a minimum follow-up time of 10 years with HCV infection, 190 HIV/HCV-coinfected patients were classified according to their METAVIR score: (1) 25 nonprogressor patients who did not develop fibrosis (F0) and (2) 165 progressor patients who developed fibrosis (F ≥ 1). Seven polymorphisms of CRS signature and IL28B genotype were performed using the GoldenGate assay. The CRS signature was calculated by naive Bayes formula as previously described. RESULTS Nonprogressors had CRS values significantly lower than progressors (0.61 versus 0.67; P = 0.043). Among the progressors, we observed similar CRS values through all the fibrosis stages (F1/F2/F3/F4). The percentage of patients with CRS > 0.70 (high risk of developing fibrosis) was higher in progressors than in nonprogressors; but the percentages with values between 0.50 and 0.70 (intermediate risk) and <0.50 (low risk) were quite similar for each of the fibrosis stages (P = 0.047). The area under the receiver-operating characteristic curve of CRS for discriminating nonprogressor versus progressor was 0.625 (P = 0.043). When clinical variables were considered (age at HCV infection, intravenous drug use, gender, IL28B, and HCV genotype), the area under the receiver-operating characteristic curve of CRS improved up to 0.739 (P < 0.001). CONCLUSIONS CRS itself seems not to be a good marker for identifying HIV/HCV-coinfected patients who are at high risk of developing liver fibrosis. However, CRS score coupled with clinical factors might help to distinguish between nonprogressors and progressors patients.
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Ramakrishna G, Rastogi A, Trehanpati N, Sen B, Khosla R, Sarin SK. From cirrhosis to hepatocellular carcinoma: new molecular insights on inflammation and cellular senescence. Liver Cancer 2013; 2:367-83. [PMID: 24400224 PMCID: PMC3881319 DOI: 10.1159/000343852] [Citation(s) in RCA: 161] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Sequential progression from chronic liver disease to fibrosis and to cirrhosis culminates in neoplasia in hepatocellular carcinoma (HCC). The preneoplastic setting of the cirrhotic background provides a conducive environment for cellular transformation. The role of classical inflammation in cirrhosis is widely known, but the exact mechanism linking inflammation and cancer remains elusive. Recent studies have elucidated roles for NF-κB, STAT3 and JNK as possible missing links. In addition, the "inflammasome" (a multiprotein complex and sensor of cellular damage) is a recently identified player in this field. The hallmarks of cirrhosis include necroinflammation, deposition of extracellular matrix and shortening of telomeres, leading to senescence and regeneration. Additionally, the accumulation of genetic/epigenetic changes propels atypical cells toward a malignant phenotype. This review provides recent information on the classical inflammatory pathway, together with a spotlight on inflammasomes and the immunomodulatory role of cellular senescence during the progression from cirrhosis to HCC. Moreover, lacunae in the current knowledge were identified and key questions raised on whether the observed adaptive responses are beneficial or detrimental to tissue homeostasis in a complex organ like liver.
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Affiliation(s)
- Gayatri Ramakrishna
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nirupama Trehanpati
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Bijoya Sen
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ritu Khosla
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India,*Shiv K. Sarin, MD, DM, Department of Hepatology, Institute of Liver and Biliary Sciences, D1, Vasant Kunj, New Delhi 110070 (India), Tel. +91 11 2670 6700, E-Mail
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Peng L, Guo J, Zhang Z, Liu L, Cao Y, Shi H, Wang J, Wang J, Friedman SL, Sninsky JJ. A candidate gene study for the association of host single nucleotide polymorphisms with liver cirrhosis risk in chinese hepatitis B patients. Genet Test Mol Biomarkers 2013; 17:681-6. [PMID: 23844940 DOI: 10.1089/gtmb.2013.0058] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND AND AIMS Recently, genetic association studies have linked a number of single nucleotide polymorphisms (SNPs) with liver fibrosis risk of hepatitis C. The present study was designed to validate the association of emerging SNPs with development of liver cirrhosis and chronicity in a Chinese population infected with hepatitis B virus (HBV). METHODS 714 Chinese subjects with persistent HBV infection (429 with evident liver cirrhosis and 285 without cirrhosis clinically or pathologically) and 280 subjects with spontaneous HBV clearance were studied. Six SNPs in five candidate genes were detected with the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) method. The distribution of each polymorphism was compared between the age-matched cirrhotic and noncirrhotic subjects, and between subjects with persistent infection and spontaneous HBV clearance. RESULTS The rs2679757 polymorphism of antizyme inhibitor 1 (AZIN1) gene was associated with the risk of cirrhosis (odds ratio [OR] for GG+AG versus AA=1.47, 95% confidence interval [CI]=1.08-2.01, p=0.01). So was rs886277 in the transient receptor potential cation channel subfamily M, member 5 (TRPM5) gene (OR for CC versus CT+TT=1.63, 95% CI=1.20-2.22, p=0.002). The frequencies of these two SNPs were also associated with the severity of decompensated cirrhosis based on the Child-Pugh classification. Genotype frequencies of other SNPs were not different between the cirrhotic and noncirrhotic groups. No SNPs were associated with the outcome of spontaneous HBV clearance. CONCLUSIONS AZIN1 rs2679757 and TRPM5 rs886277 are associated with the risk of HBV-related liver cirrhosis in Chinese. The emerging SNPs warrant further clinical validation in other cohorts or ethnic groups, and could lead to mechanistic studies to reveal their contributions to fibrosis progression.
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Affiliation(s)
- Lijun Peng
- Division of Digestive Diseases, Department of Internal Medicine, Zhong Shan Hospital, Shanghai Medical College, Fu Dan University, Shanghai, China
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Berenguer M, Schuppan D. Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment. J Hepatol 2013; 58:1028-41. [PMID: 23262248 DOI: 10.1016/j.jhep.2012.12.014] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 12/10/2012] [Accepted: 12/10/2012] [Indexed: 12/12/2022]
Abstract
Liver fibrosis results from an excessive wound healing response in most chronic liver diseases, such as hepatitis C. Despite great advances in antiviral therapy in recent years, progressive liver fibrosis remains a major problem for patients with recurrent hepatitis C after liver transplantation. Liver biopsy remains a central tool in the management of HCV-positive liver transplant recipients, but reliable non-invasive methods for the assessment of liver fibrosis, such as ultrasound elastography, are increasingly being incorporated in the management of post-transplant patients, helping predict prognosis, guide treatment decisions, and stratify patients for emerging antifibrotic therapies. In this manuscript, we will review the natural history as well as tools to monitor fibrosis progression in the HCV-positive liver transplant recipient, the mechanisms underlying rapid fibrosis progression in up to 30% of these patients, the effect of antiviral therapies and highlight promising antifibrotic approaches.
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Affiliation(s)
- Marina Berenguer
- University Valencia, Dept. of Medicine, Hepatology & Liver Transplantation Unit, La Fe Hospital and CIBEREHD, National Network Center for Hepatology and Gastroenterology Research, Instituto de Salud Carlos III, Spain.
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Hoshida Y, Villanueva A, Sangiovanni A, Sole M, Hur C, Andersson KL, Chung RT, Gould J, Kojima K, Gupta S, Taylor B, Crenshaw A, Gabriel S, Minguez B, Iavarone M, Friedman SL, Colombo M, Llovet JM, Golub TR. Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology 2013; 144:1024-30. [PMID: 23333348 PMCID: PMC3633736 DOI: 10.1053/j.gastro.2013.01.021] [Citation(s) in RCA: 184] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Revised: 01/10/2013] [Accepted: 01/13/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Cirrhosis affects 1% to 2% of the world population and is the major risk factor for hepatocellular carcinoma (HCC). Hepatitis C cirrhosis-related HCC is the most rapidly increasing cause of cancer death in the United States. Noninvasive methods have been developed to identify patients with asymptomatic early-stage cirrhosis, increasing the burden of HCC surveillance, but biomarkers are needed to identify patients with cirrhosis who are most in need of surveillance. We investigated whether a liver-derived 186-gene signature previously associated with outcomes of patients with HCC is prognostic for patients with newly diagnosed cirrhosis but without HCC. METHODS We performed gene expression profile analysis of formalin-fixed needle biopsy specimens from the livers of 216 patients with hepatitis C-related early-stage (Child-Pugh class A) cirrhosis who were prospectively followed up for a median of 10 years at an Italian center. We evaluated whether the 186-gene signature was associated with death, progression of cirrhosis, and development of HCC. RESULTS Fifty-five (25%), 101 (47%), and 60 (28%) patients were classified as having poor-, intermediate-, and good-prognosis signatures, respectively. In multivariable Cox regression modeling, the poor-prognosis signature was significantly associated with death (P = .004), progression to advanced cirrhosis (P < .001), and development of HCC (P = .009). The 10-year rates of survival were 63%, 74%, and 85% and the annual incidence of HCC was 5.8%, 2.2%, and 1.5% for patients with poor-, intermediate-, and good-prognosis signatures, respectively. CONCLUSIONS A 186-gene signature used to predict outcomes of patients with HCC is also associated with outcomes of patients with hepatitis C-related early-stage cirrhosis. This signature might be used to identify patients with cirrhosis in most need of surveillance and strategies to prevent the development of HCC.
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Affiliation(s)
- Yujin Hoshida
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Augusto Villanueva
- HCC Translational Research Laboratory, Barcelona Clinic Liver Cancer Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer Centro de Investigaciones en Red de Enfermedades Hepáticas y Digestivas, Hosptial Clínic Barcelona, Barcelona, Spain
| | - Angelo Sangiovanni
- Department of Medicine, 1 Division of Gastroenterology, Fondazione IRCCS Maggiore Hospital, Università degli Studi di Milano, Milan, Italy
| | - Manel Sole
- Department of Pathology, Barcelona Clinic Liver Cancer Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer Centro de Investigaciones en Red de Enfermedades Hepáticas y Digestivas, Hosptial Clínic Barcelona, Barcelona, Spain
| | - Chin Hur
- Massachusetts General Hospital, Boston, MA
| | | | | | - Joshua Gould
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA
| | - Kensuke Kojima
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Supriya Gupta
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA
| | - Bradley Taylor
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA
| | - Andrew Crenshaw
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA
| | - Stacey Gabriel
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA
| | - Beatriz Minguez
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Massimo Iavarone
- Department of Medicine, 1 Division of Gastroenterology, Fondazione IRCCS Maggiore Hospital, Università degli Studi di Milano, Milan, Italy
| | - Scott L. Friedman
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Massimo Colombo
- Department of Medicine, 1 Division of Gastroenterology, Fondazione IRCCS Maggiore Hospital, Università degli Studi di Milano, Milan, Italy
| | - Josep M. Llovet
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
- HCC Translational Research Laboratory, Barcelona Clinic Liver Cancer Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer Centro de Investigaciones en Red de Enfermedades Hepáticas y Digestivas, Hosptial Clínic Barcelona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
| | - Todd R. Golub
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA
- Children’s Hospital, Harvard Medical School, Boston, MA
- Howard Hughes Medical Institute
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Genetic variants of STAT-4 affect the development of graft fibrosis after liver transplantation for HCV-induced liver disease. Transplantation 2013. [PMID: 23202532 DOI: 10.1097/tp.0b013e318277e2f6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) reinfection after liver transplantation may lead to recirrhosis and seems to be influenced by genetic factors. The aim of our study was to evaluate the role of STAT-4-polymorphisms in the development of HCV-related graft disease based on protocol biopsies. METHODS One hundred sixty transplant patients with HCV recurrence were genotyped for STAT-4 (rs7574865) by polymerase chain reaction. Fibrosis stages were determined based on Desmet and Scheuer classification. SPSS was used for the statistical analysis of genotype distribution and of time to the development of advanced fibrosis among the genotypes. RESULTS During a comparable observation period of 86.2 months (P=0.654), 65 patients (46.5%) developed advanced fibrosis. Advanced fibrosis was observed significantly more frequent in patients (n=34) with at least one T-allele (53.1 vs. 32.3%; P=0.013) compared with homozygotes for G-allele (n=31). Significant differences in the duration of advanced fibrosis development were detected between patients with at least one T-allele compared with G-allele (34.4 vs. 49.0 months; P=0.022). No impact was observed regarding the outcome of interferon-based antiviral treatment (P=0.297) and the occurrence of acute cellular rejection (P=0.365). CONCLUSION Present results indicate a possible impact of genetic confounders in the recipient on graft fibrogenesis, thus explaining significantly different graft behavior observed after transplantation for HCV-associated liver disease. STAT-4-T-allele is identified as fibrogenic factor and seems to have a negative impact on HCV-induced fibrosis development.
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Cartón JA, Collazos J, de la Fuente B, Asensi V. Course of liver fibrosis in HIV-hepatitis C virus-coinfected patients depending on the response to hepatitis C therapy. AIDS Res Hum Retroviruses 2013; 29:215-22. [PMID: 22734850 DOI: 10.1089/aid.2012.0108] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
To evaluate the course of liver fibrosis, 328 HIV-hepatitis C virus (HCV)-coinfected patients (210 HCV treated and 118 HCV untreated) were followed-up for 38-42 months. Liver fibrosis was assessed by biopsy or elastometry at baseline and by elastometry afterward, in addition to other noninvasive indexes. A combined liver stiffness stage (LSS) was established and evaluated over time. Eighty patients had sustained virological response (SVR) and 130 had treatment failure (TF) after a standard course of peginterferon-ribavirin therapy. LSS decreased significantly in all fibrosis indexes during HCV therapy in treated patients, but the improvement persisted only in those with SVR. At the end of study, median elastometry values suffered variations of -29%, -5.0%, and +15.4% in SVR, TF, and untreated patients, respectively. Likewise, LSS worsened in 2.5%, 33.1%, and 39% of these groups, respectively: [OR (95% CI) 19.3 (4.4-119), p<0.001] for TF vs. SVR; [24.9 (5.6-154), p<0.001] for no therapy vs. SVR; and [1.29 (0.74-2.3), p=0.40] for no therapy vs. TF. LSS improved in 53.8%, 19.2%, and 5.9% of these groups, respectively: [4.88 (2.51-9.53), p<0.001] for SVR vs. TF; 18.4 (7.17-49.4), p<0.001 for SVR vs. no therapy; and 3.78 (1.47-10.1), p=0.003 for TF vs. no therapy. Independent predictive factors of LSS improvement or worsening were as follows: alcohol abuse [OR (95% CI) 0.48 (0.20-0.99), p=0.047] and [2.45 (1.19-5.03), p=0.016], respectively; SVR [27.7 (6.41-168), p<0.001] and [0.15 (0.07-0.31), p<0.001], respectively; and lower baseline CD4 counts [1.92 (1.08-3.45), p=0.026] and [0.31 (0.15-0.63), p=0.001], respectively. SVR was usually associated with regression of noninvasive liver fibrosis markers, whereas TF and HCV-untreated patients experienced poorer outcomes.
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Affiliation(s)
- José-Antonio Cartón
- Internal Medicine (Infectious Diseases), Hospital Universitario Central de Asturias, Oviedo University School of Medicine, Oviedo, Spain
| | - Julio Collazos
- Infectious Diseases Unit, Hospital de Galdácano, Galdácano (Vizcaya), Spain
| | - Belén de la Fuente
- Internal Medicine (Infectious Diseases), Hospital de Cabueñes, Gijón; Spain
| | - Víctor Asensi
- Internal Medicine (Infectious Diseases), Hospital Universitario Central de Asturias, Oviedo University School of Medicine, Oviedo, Spain
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Affiliation(s)
- Yujin Hoshida
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY
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Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for Fibrotic Diseases: Nearing the Starting Line. Sci Transl Med 2013; 5:167sr1. [DOI: 10.1126/scitranslmed.3004700] [Citation(s) in RCA: 480] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Holmes JA, Thompson AJ, Adams LA. Biomarkers of Fibrosis and Fibrosis Progression in Chronic Hepatitis C. CURRENT HEPATITIS REPORTS 2012; 11:231-242. [DOI: 10.1007/s11901-012-0148-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Rau M, Baur K, Geier A. Host genetic variants in the pathogenesis of hepatitis C. Viruses 2012; 4:3281-302. [PMID: 23342360 PMCID: PMC3528266 DOI: 10.3390/v4123281] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 11/17/2012] [Accepted: 11/17/2012] [Indexed: 02/06/2023] Open
Abstract
Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA) were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR) and ABCB11 (bile salt export pump). Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment.
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Affiliation(s)
- Monika Rau
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacherstraße 6, 97080 Würzburg, Germany;
| | - Katharina Baur
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland;
| | - Andreas Geier
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacherstraße 6, 97080 Würzburg, Germany;
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland;
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Estrabaud E, Vidaud M, Marcellin P, Asselah T. Genomics and HCV infection: progression of fibrosis and treatment response. J Hepatol 2012; 57:1110-25. [PMID: 22659520 DOI: 10.1016/j.jhep.2012.05.016] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Revised: 05/11/2012] [Accepted: 05/14/2012] [Indexed: 12/20/2022]
Abstract
HCV infection is a global health problem that affects 170 million people worldwide. The severity of the disease varies from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma (HCC). Recently, the standard of care for genotype 1 patients has greatly improved with the addition of protease inhibitors (telaprevir or boceprevir) to pegylated interferon (PegIFN) and ribavirin (RBV). The prediction of fibrosis progression and the response to antiviral treatment are two major issues in the management of patients with chronic hepatitis C. Differential expression of mRNAs was first analyzed for both progression of fibrosis and treatment response. Specific polymorphisms, associated with either fibrosis or viral response, were identified thanks to major improvements in genome scanning technologies. Since 2009, several independent genome wide association studies (GWAS) have reported an association between genetic polymorphisms within the IL-28B promoter and both natural and treatment-induced clearance in genotype 1 infected patients. These different studies showed the strong association and the importance of IL-28B polymorphisms in the treatment response. Combining the different genetic factors could improve their predictive value and help identify patients at a high risk of progression of fibrosis as well as those with a lower chance of responding to treatment. The aim of this review was to discuss the genomic factors (mRNAs, miRNAs, and SNPs) and HCV infection with clinical implications for either progression of fibrosis or treatment response. Recent findings on the IL-28B polymorphism and its application in clinical practice will also be discussed.
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Affiliation(s)
- Emilie Estrabaud
- INSERM, UMR773, Team Viral hepatitis, Centre de Recherche Bichat Beaujon, BP 416, F-75018 Paris, France.
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Doyle JS, Hellard ME, Thompson AJ. The role of viral and host genetics in natural history and treatment of chronic HCV infection. Best Pract Res Clin Gastroenterol 2012. [PMID: 23199501 DOI: 10.1016/j.bpg.2012.09.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Understanding of the natural history and treatment responsiveness of chronic hepatitis C virus (HCV) infection has evolved rapidly in recent years. Advances in HCV molecular virology and host genetics can now better predict spontaneous clearance and treatment outcomes. HCV genotype is the most important viral factor predicting interferon-α treatment responsiveness; HCV-1 subtype is emerging as a key determinant of the efficacy of direct acting antiviral therapy. Genome-wide association studies have recently identified several clinically important host determinants of the outcomes of peginterferon-α and ribavirin treatment outcome: IL28B polymorphism is associated with spontaneous clearance and treatment responsiveness; ITPA polymorphism protects against ribavirin-induced anaemia and dose reductions; genetic determinants of liver fibrosis progression rate have been proposed. In this review, we evaluate the role of viral and host genetics in the natural history and treatment outcomes of chronic HCV infection, and consider how this knowledge might help individualize clinical management in the era of DAA therapy.
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Affiliation(s)
- Joseph S Doyle
- Centre for Population Health, Burnet Institute, 85 Commercial Road, Melbourne, VIC 3004, Australia.
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Abstract
Hepatitis C virus (HCV) infection remains a major global health burden. Hepatitis C causes significant liver-related morbidity and mortality due to hepatic decompensation and development of hepatocellular carcinoma. In addition, extra-hepatic manifestations of hepatitis C are frequent. There is a very large interindividual variability in the natural history of both acute and chronic hepatitis C which can be explained in part by a combination of various host, viral and environmental factors. Successful antiviral treatment can prevent short- and long-term complications of HCV infection in many patients. Still, the relative contribution of distinct risk factors for disease progression in different phases of HCV infection needs to be better defined. Personalized treatment approaches for HCV infection should consider individual risk profiles to avoid both under- and over-treatment - which will remain important also in upcoming era of interferon-free treatment of hepatitis C.
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Affiliation(s)
- Benjamin Maasoumy
- Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany
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Predicting cirrhosis and clinical outcomes in patients with advanced chronic hepatitis C with a panel of genetic markers (CRS7). Pharmacogenet Genomics 2012; 21:851-60. [PMID: 21946897 DOI: 10.1097/fpc.0b013e32834c3e74] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
OBJECTIVES Genetic factors may play a role in fibrosis progression in patients with chronic hepatitis C (CHC). A cirrhosis risk score (CRS7) with seven single nucleotide polymorphisms was previously shown to correlate with cirrhosis in patients with CHC. This study aimed to assess the validity of CRS7 as a marker of fibrosis progression and cirrhosis and as a predictor of clinical outcomes in patients with CHC. METHODS A total of 938 patients (677 Caucasians, 165 African-Americans, and 96 Hispanic/Other) in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial were studied. CRS7 was categorized a priori as high risk (n=440), medium risk (n=310), or low risk (n=188). Patients were assessed for four possible outcomes: fibrosis progression, cirrhosis, clinical outcomes [decompensation or hepatocellular carcinoma (HCC)], or HCC alone. RESULTS Twenty-nine percent (142/493) developed an increase in fibrosis score by greater than or equal to 2 points on follow-up biopsies, 58% had cirrhosis on one or more biopsies, 35% developed at least one clinical outcome, and 13% developed HCC. CRS7 (trend test) was associated with risk for fibrosis progression (P=0.04) with adjusted hazard ratio of 1.27 (95% confidence interval: 1.01-1.58) and with cirrhosis (P=0.05) with adjusted odds ratio of 1.19 (1.00-1.41). Rates of HCC and clinical outcomes were increased in patients with higher CRS7 scores, but were not statistically significant (P=0.12 clinical outcomes, and P=0.07 HCC). A single nucleotide polymorphism in AZIN1 was significantly associated with fibrosis progression. CONCLUSION CRS7 was validated as a predictor of fibrosis progression and cirrhosis among Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, who all had advanced fibrosis. CRS7 was not predictive of clinical outcome.
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Abstract
While preclinical development of potential anti-fibrotics is far advanced, with numerous pharmacological targets and promising agents, almost none has entered clinical validation. Reasons are manifold, including the usually slow progression of liver fibrosis, requiring high numbers of well-stratified patients undergoing long-term treatment when conventional liver biopsy based parameters or hard liver-related endpoints are used. Importantly, there is a notorious lack of sensitive and specific surrogate markers or imaging technologies for liver fibrosis progression or regression that would permit a rapid clinical screening for potential anti-fibrotics. Nonetheless, in view of an urgent need for anti-fibrotics that positively impact morbidity and mortality from chronic liver diseases, the field is now moving more quickly towards clinical translation. This development is driven by thoughtful preclinical validation, a better study design and improved surrogate readouts using currently available methodologies. Moreover, upcoming novel biomarkers and imaging technologies will soon permit a more exact and efficient assessment of fibrosis progression and regression.
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Müllenbach R, Weber SN, Krawczyk M, Zimmer V, Sarrazin C, Lammert F, Grünhage F. A frequent variant in the human bile salt export pump gene ABCB11 is associated with hepatitis C virus infection, but not liver stiffness in a German population. BMC Gastroenterol 2012; 12:63. [PMID: 22681771 PMCID: PMC3457846 DOI: 10.1186/1471-230x-12-63] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Accepted: 05/17/2012] [Indexed: 12/13/2022] Open
Abstract
Background The human ATP-binding cassette, subfamily B, member 11 (ABCB11) gene encodes the bile salt export pump, which is exclusively expressed at the canalicular membrane of hepatocytes. A frequent variant in the coding region, c.1331 T > C, leading to the amino acid exchange p.V444A, has been associated with altered serum bile salt levels in healthy individuals and predisposes homozygous carriers of the [C] allele for obstetric cholestasis. Recently, elevated bile salt levels were shown to be significantly associated with rates and risk of cirrhosis in patients with chronic hepatitis C virus (HCV) infection treated with pegylated interferon-α2 and ribavirin, suggesting a potential role for bile salt levels in HCV treatment outcomes and in the fibrogenic evolution of HCV-related liver disease. The aim of this study was to investigate a possible association of ABCB11 c.1331 T > C with hepatitis C virus (HCV) infection and fibrosis stages as assessed by non-invasive transient elastography in a German cohort of patients. Methods ABCB11 c.1331 T > C genotype was determined by allelic discrimination assay in 649 HCV infected cases and 413 controls. Overall, 444 cases were staged for fibrotic progression by measurement of liver stiffness. Results Homo- or heterozygous presence of the frequent [C] allele was associated with HCV positivity (OR = 1.41, CI = 1.02 - 1.95, p = 0.037). No association was detectable between the ABCB11 c.1331 T > C genotype and increased liver stiffness. Conclusions Our data confirm that homozygous presence of the major [C] allele of ABCB11 c.1331 T > C is a genetic susceptibility factor for HCV infection, but not for liver fibrosis.
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Affiliation(s)
- Roman Müllenbach
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
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Fontana RJ, Litman HJ, Dienstag JL, Bonkovsky HL, Su G, Sterling RK, Lok AS. YKL-40 genetic polymorphisms and the risk of liver disease progression in patients with advanced fibrosis due to chronic hepatitis C. Liver Int 2012; 32:665-74. [PMID: 22103814 PMCID: PMC3299849 DOI: 10.1111/j.1478-3231.2011.02686.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Accepted: 10/21/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS The aim of this study was to explore the association of a functional YKL-40 promoter polymorphism (rs4950928) with baseline disease stage, response to antiviral therapy and risk of liver disease progression in a group of patients with chronic hepatitis C (CHC). METHODS YKL-40 promoter polymorphisms were determined in 456 Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial patients with bridging fibrosis or cirrhosis entering a prerandomization lead-in peginterferon/ribavirin 24-week treatment phase and in 462 patients followed for a mean of 3.8 years after randomization to maintenance peginterferon or observation. RESULTS Mean patient age was 49.5 years, 70.4% were men and 71.2% were Caucasian. The 17% frequency of the YKL-40 minor allele (T) was similar to that reported in the general population. YKL-40 genotype was associated significantly with baseline serum YKL-40 levels but was not associated with the likelihood of a virological response following 24-48 weeks of peginterferon/ribavirin therapy. Serum YKL-40 levels remained significantly lower during follow-up in the randomized TT homozygotes compared with CT heterozygotes and CC homozygotes (P < 0.001). Despite this association, YKL-40 genotype was not associated with the risk of clinical or histological liver disease progression. CONCLUSIONS A reduced frequency of the protective YKL-40 promoter polymorphism was not observed in the HALT-C Trial patient population. The absence of an association between YKL-40 promoter polymorphisms and baseline liver disease severity as well as with the risk of liver disease progression over time suggests that this polymorphism is not associated with disease progression in CHC patients with established fibrosis.
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Affiliation(s)
- Robert J. Fontana
- Department of Internal Medicine, University of Michigan Medical School, Michigan, USA
| | | | - Jules L. Dienstag
- Gastrointestinal unit (Medical Services), Massachusetts General Hospital and the Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Herbert L. Bonkovsky
- Departments of Medicine and Molecular and Structural Biology and the Liver-Biliary-Pancreatic center, University of Connecticut Health Center, Connecticut, USA
| | - Grace Su
- Department of Internal Medicine, University of Michigan Medical School, Michigan, USA
| | - Richard K. Sterling
- Hepatology Section, Virginia Commonwealth University Medical Center, Virginia, USA
| | - Anna S. Lok
- Department of Internal Medicine, University of Michigan Medical School, Michigan, USA
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Rocco A, de Nucci G, Valente G, Compare D, D'Arienzo A, Cimino L, Perri F, Nardone G. 13C-aminopyrine breath test accurately predicts long-term outcome of chronic hepatitis C. J Hepatol 2012; 56:782-7. [PMID: 22173159 DOI: 10.1016/j.jhep.2011.10.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Revised: 10/04/2011] [Accepted: 10/10/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Although numerous non-invasive tests are currently available to explore liver function and disease activity in patients with HCV-related chronic diseases, none of these indicate the likelihood of disease progression in the individual patient. We aimed at assessing the prognostic ability of (13)C(2)-aminopyrine breath test ((13)C-ABT) in the prediction of liver fibrosis progression in patients with HCV chronic hepatitis who prospectively entered a long-term follow-up. METHODS Fifty patients with HCV-related chronic disease who underwent paired liver biopsy (at baseline and after a mean period of 86 months) were included in the study. (13)C-ABT was carried out at baseline and every 3 years. Histological progression was defined as increase of at least 2 fibrosis units according to Ishak score. RESULTS Fourteen patients progressed of at least 2 fibrosis units during the follow-up. These patients were more frequently infected with a HCV-1b genotype and had, at baseline, a significantly older age, higher BMI, AST levels, and AST to platelet ratio index (APRI). (13)C-ABT was altered in 57% of cases at baseline and in 100% of the cases at 3-year follow-up. In the univariate analysis, age (p=0.005), BMI (p=0.006), platelet count (p=0.03), AST (p=0.012) and ALT (p=0.04) levels, APRI (p=0.03), and baseline (13)C-ABT results (p<0.0001) were all independently associated with progression of liver fibrosis. By Cox's multiple regression analysis, the (13)C-ABT was the only covariate that significantly predicted liver fibrosis progression (HR 6.7; 95% CI 2.3-20.1; p<0.001). CONCLUSIONS (13)C-ABT accurately predicts the risk of disease progression in patients with HCV-related chronic hepatitis.
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Affiliation(s)
- Alba Rocco
- Department of Clinical and Experimental Medicine, Gastroenterology Unit, University of Naples Federico II, Naples, Italy
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Hoshida Y, Fuchs BC, Tanabe KK. Genomic risk of hepatitis C-related hepatocellular carcinoma. J Hepatol 2012; 56:729-30. [PMID: 21963516 DOI: 10.1016/j.jhep.2011.08.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Revised: 07/29/2011] [Accepted: 08/01/2011] [Indexed: 12/22/2022]
Abstract
To identify the genetic susceptibility factor(s) for hepatitis C virus-induced hepatocellular carcinoma (HCV-induced HCC), we conducted a genome-wide association study using 432,703 autosomal SNPs in 721 individuals with HCV-induced HCC (cases) and 2890 HCV-negative controls of Japanese origin. Eight SNPs that showed possible association (P <1 10(⁻5)) in the genome-wide association study were further genotyped in 673 cases and 2596 controls. We found a previously unidentified locus in the 50 flanking region of MICA on 6p21.33 (rs2596542, P(combined) = 4.21 10(⁻13), odds ratio = 1.39) to be strongly associated with HCV induced HCC. Subsequent analyses using individuals with chronic hepatitis C (CHC) indicated that this SNP is not associated with CHC susceptibility (P = 0.61) but is significantly associated with progression from CHC to HCC (P = 3.13 10(⁻8)). We also found that the risk allele of rs2596542 was associated with lower soluble MICA protein levels in individuals with HCV-induced HCC (P = 1.38 10(⁻13)).
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Affiliation(s)
- Yujin Hoshida
- Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
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Asselah T, De Muynck S, Broët P, Masliah-Planchon J, Blanluet M, Bièche I, Lapalus M, Martinot-Peignoux M, Lada O, Estrabaud E, Zhang Q, El Ray A, Vidaud D, Ripault MP, Boyer N, Bedossa P, Valla D, Vidaud M, Marcellin P. IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C. J Hepatol 2012; 56:527-32. [PMID: 21951981 DOI: 10.1016/j.jhep.2011.09.008] [Citation(s) in RCA: 146] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Revised: 08/24/2011] [Accepted: 09/02/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Polymorphisms in the region of the interleukin (IL)28B gene have been associated with pegylated-interferon (PEG-IFN) and ribavirin treatment response mainly in genotype 1 HCV infections. However, there are few data on HCV genotype 4 (HCV-4) infection. We evaluated, in a unique well-characterized cohort of HCV-4 patients, the association of IL28B polymorphism with response to treatment or liver disease severity. METHODS This study included 164 HCV-4 patients from different ethnic groups (Egyptian, European, and Sub-Saharan African). Among these patients, 82 were studied for response and 160 for disease severity. Free DNA extracted from all the 164 patient's serum samples was analyzed by direct sequencing of the SNP rs12979860 of IL28B. Genetic and bio-clinical features from patients having sustained virological response (43 SVR patients) and from those who did not respond to treatment or had a relapse after the end of the treatment (39 NR patients) were compared. IL28B polymorphism was compared between the 78 patients with mild fibrosis (Metavir score F0-F1) and the 82 with advanced fibrosis (F2-F4). RESULTS Our data showed a better treatment response rate of the C allele of the IL28B gene SNP rs12979860 (p=0.0008). The response rates were 81.8%, 46.5%, and 29.4% for genotype CC, CT, and TT, respectively. No significant relationship was found between rs12979860 and the severity of the disease. CONCLUSIONS The SNP rs12979860 is strongly associated with SVR in patients infected with HCV-4, but not with liver disease severity. Analysis of IL28B genotype might be used to guide treatment for these patients.
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Affiliation(s)
- Tarik Asselah
- Hepatology Department, AP-HP, University Paris Diderot 7 and INSERM U773, CRB3, Beaujon Hospital, Clichy, France.
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