The Open Microbiology Journal




ISSN: 1874-2858 ― Volume 13, 2019

Plasma Levels of Matrix Metalloproteinase (MMP)-2, MMP-9 and Tumor Necrosis Factor-α in Chronic Hepatitis C Virus Patients



Mohamed S Abdel-Latif*
Department of Medical Laboratory Technology, Faculty of Allied Medical Science, Pharos University in Alexandria, Egypt

Abstract

Background:

In chronic HCV infection, pathological accumulation of the extracellular matrix is the main feature of liver fibrosis; that indicates the imbalanced rate of increased matrix synthesis to decreased breakdown of connective tissue proteins. Matrix metalloproteinases (MMPs) play a crucial role in remodeling of extracellular matrix. It is known that expression of MMPs is regulated by Tumor necrosis factor (TNF)-α. Also, levels of TNF-α in liver and serum are increased in chronic HCV patient. Accordingly, this study aimed to correlate the plasma levels of MMP-2, MMP-9 and TNF-α in chronic HCV patients with the pathogenesis of the liver.

Methods:

The current study was conducted on 15 fibrotic liver cases with detectable HCV RNA, 10 HCV cirrhotic liver cases, and 15 control subjects of matched age and sex. Plasma MMP-2, MMP-9 and TNF-α were measured by ELISA.

Results:

Data revealed that the MMP2, MMP9 and TNF-α levels showed a significant elevation in chronic HCV patients compared to control group (p= 0.001). But, no significant correlation was observed in levels of MMP-2, MMP-9, and TNF-α between fibrotic and cirrhotic cases.

Conclusions:

MMP-2, MMP-9 and TNF-α showed high reproducibility to differentiate chronic HCV patients from control group. On the contrary, MMP-2, MMP-9 and TNF-α were not able to differentiate fibrotic from cirrhotic liver cases. Thus, MMP-2, MMP-9 and TNF-α could not be correlated with the progression of liver disease. Rather they could be used as prognostic markers of liver fibrosis.

Keywords: Metalloproteinase (MMP)-9, MMP-2, TNF-α, liver firbrosis, HCV.


Article Information


Identifiers and Pagination:

Year: 2015
Volume: 9
First Page: 136
Last Page: 140
Publisher Id: TOMICROJ-9-136
DOI: 10.2174/1874285801509010136

Article History:

Received Date: 15/12/2014
Revision Received Date: 27/2/2015
Acceptance Date: 2/3/2015
Electronic publication date: 31/8/2015
Collection year: 2015

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© Mohamed S. Abdel-Latif; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the (https://creativecommons.org/licenses/by/4.0/legalcode), which permits unrestricted, noncommercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Department of Medical Laboratory Technology, Faculty of Allied Medical Science, Pharos University in Alexandria, Egypt; Tel: +(203) 3877640; Fax: +(203) 3830249; E-mail: mohamed.abdellatif@pua.edu.eg




INTRODUCTION

Chronic HCV patients are susceptible to hepatic inflammation, developing liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Such a case does not depend on virus genotype or viral load [1Craxì A, Pawlotsky JM, Wedemeyer H, et al. EASL Clinical Practice Guidelines: management of hepatitis C virus infection J Hepatol 2011; 55(2): 245-64.
[http://dx.doi.org/10.1016/j.jhep.2011.02.023] [PMID: 21371579]
].

In the liver, pathological accumulation of the extracellular matrix (ECM) is the main feature of fibrogenesis; that indicates the imbalanced rate of increased matrix synthesis to decreased breakdown of connective tissue proteins which is regulated by the matrix metalloproteinases (MMPs). Apparently, MMPs play a central role in remodeling of extracellular matrix and are involved in fibrogenesis and carcinogenesis [2Friedman SL. Liver fibrosis -- from bench to bedside J Hepatol 2003; 38(Suppl. 1): S38-53.
[http://dx.doi.org/10.1016/S0168-8278(02)00429-4] [PMID: 12591185]
]. Remodeling of ECM is associated with regulation of different levels of MMPs, which is mediated by regulated MMPs gene expression, activation of MMPs, and tissue inhibitor of metalloproteinases (TIMPs) [3Henderson NC, Iredale JP. Liver fibrosis: cellular mechanisms of progression and resolution Clin Sci 2007; 112(5): 265-80.
[http://dx.doi.org/10.1042/CS20060242] [PMID: 17261089]
]. Recently, it has been shown that the increased levels of hepatic gelatinases, such as MMP-2 and MMP-9, are associated with the fibrotic index in chronic HCV patients and with progression and recurrence of HCC [4Lichtinghagen R, Michels D, Haberkorn CI, et al. Matrix metalloproteinase (MMP)-2, MMP-7, and tissue inhibitor of metalloproteinase-1 are closely related to the fibroproliferative process in the liver during chronic hepatitis C J Hepatol 2001; 34(2): 239-47.
[http://dx.doi.org/10.1016/S0168-8278(00)00037-4] [PMID: 11281552]
, 5Théret N, Musso O, Turlin B, et al. Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas Hepatology 2001; 34(1): 82-8.
[http://dx.doi.org/10.1053/jhep.2001.25758] [PMID: 11431737]
].

HCV infection stimulates the production of inflammatory cytokines and chemokines; also enhances the enrollment of inflammatory cells to the liver, that resulting in hepatic inflammation and chronic hepatitis [6Losikoff PT, Self AA, Gregory SH. Dendritic cells, regulatory T cells and the pathogenesis of chronic hepatitis C Virulence 2012; 3(7): 610-20.
[http://dx.doi.org/10.4161/viru.21823] [PMID: 23076334]
-8Coquillard G, Patterson BK. Determination of hepatitis C virus-infected, monocyte lineage reservoirs in individuals with or without HIV coinfection J Infect Dis 2009; 200(6): 947-54.
[http://dx.doi.org/10.1086/605476] [PMID: 19678757]
].

In addition, levels of tumor necrosis factor (TNF)-α are known to be increased in liver and serum of chronic HCV patients [9Larrea E, Garcia N, Qian C, Civeira MP, Prieto J. Tumor necrosis factor α gene expression and the response to interferon in chronic hepatitis C Hepatology 1996; 23(2): 210-7.
[PMID: 8591843]
, 10Nelson DR, Lim HL, Marousis CG, et al. Activation of tumor necrosis factor-alpha system in chronic hepatitis C virus infection Dig Dis Sci 1997; 42(12): 2487-94.
[http://dx.doi.org/10.1023/A:1018804426724] [PMID: 9440625]
]. Subsequently, TNF-α elevation, which may interfere with insulin signaling, could be the key molecule of processes like inflammation, steatosis, and fibrosis in chronic HCV patients [11Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links Cell 2012; 148(5): 852-71.
[http://dx.doi.org/10.1016/j.cell.2012.02.017] [PMID: 22385956]
].

The aim of this study was to correlate the plasma levels of MMP-2, MMP-9 and TNF-α in chronic HCV patients with the pathogenesis of liver.

SUBJECTS AND METHODS

Subjects

This study was conducted on 25 patients with chronic HCV infection and 15 healthy individuals of matched age and sex. Patients and healthy individuals were recruited from the Gastro-enterology department, Medical Research Institute, Alexandria University, and divided into three groups. Group one (fibrotic liver cases) included 15 patients with detectable HCV RNA who were referred to the hepatology unit having liver fibrosis as evaluated by liver biopsy. Group two (cirrhotic liver cases) included 10 patients with established liver cirrhosis as diagnosed by clinical, laboratory, and sonographic data. All were selected to have advanced degree of liver fibrosis as detected histopathologically using the Metavir scoring system (F1-F4). Group three (control = F0) included 15 healthy individuals with normal liver function tests, normal complete blood picture, no HCV and/or HBV infection, and normal abdominal ultrasound examination.

Group one and two met the following inclusion criteria: no diabetes mellitus, no co- infection with HBV, no evidence of hepatocellular carcinoma and no schistosomiasis. Also, they were seropositive for antibodies to HCV genotype 4 as detected by ELISA technique and HCV genotyping, positive for HCV RNA by PCR and did not receive any interferon therapy. Ethical approval for the study was obtained from the local ethical committee of the Medical Research Institute.

All individuals, after obtaining an informed consent, were subjected to routine laboratory investigation, ultrasound examination and percutaneous ultrasound-assisted needle liver biopsy; similarly, as described in our previously published data [12Abdel-Latif MS, Almahal EK, Ragab NM, Omar MF, Afifi MS. Cellular fibronectin expression in chronic hepatitis C virus patients Scand J Infect Dis 2014; 46(7): 508-14.
[http://dx.doi.org/10.3109/00365548.2014.907499] [PMID: 24832854]
].

Assessment of Plasma MMP-2, MMP-9 and TNF-α Levels

Enzyme linked immune-sorbent assay (ELISA) kits (RayBio® Human, USA) were used to evaluate plasma levels of MMP-2, MMP-9 and TNF-α according to manufacturer recommendation.

Statistical Analysis

Data obtained in the present study were statistically evaluated using SPSS version 15 (SPSS Inc., Chicago, IL, USA.). Numerical data were expressed as mean ± SD and the analyses were considered statistically significant at a two-sided P≤0.05. Receiver operating characteristic (ROC) analysis was performed to determine the diagnostic significance of MMP-2, MMP-9 and TNF-α. ROC curve was plotted to analyze recommended cut-off values for MMP-2, MMP-9 and TNF-α; also to differentiate between F1–F4 and F0. The area under the ROC curve (AUC) denotes the diagnostic performance of the marker. Agreement of this cut-off value for MMP-2, MMP-9 and TNF-α was expressed in sensitivity, specificity, positive predictive value, negative predictive value and accuracy. Significance of the test results is quoted as two-tailed probabilities, using student t-test.

RESULTS

Results that obtained from routine laboratory investigation, ultrasound examination and percutaneous ultrasound-assisted needle liver biopsy were clearly shown in our previously published study [12Abdel-Latif MS, Almahal EK, Ragab NM, Omar MF, Afifi MS. Cellular fibronectin expression in chronic hepatitis C virus patients Scand J Infect Dis 2014; 46(7): 508-14.
[http://dx.doi.org/10.3109/00365548.2014.907499] [PMID: 24832854]
].

MMP-2, MMP-9 and TNF-α levels were measured in all plasma samples, from control subjects and chronic HCV patients, using ELISA technique.

Assessment of Plasma MMP-2

Plasma levels of MMP-2 in group three (control subjects) ranged from 0.24 – 0.46 ng/mL with mean value of 0.34 ± 0.07 ng/mL. In chronic HCV patients (group one and group two), plasma levels of MMP-2 ranged from 0.41 – 1.65 ng/mL with mean value of 0.80 ± 0.35 ng/mL. Mean level of plasma MMP-2 was significantly higher in chronic HCV patients when compared to the control group, (p<0.001). Consequently, a positive significant correlation of MMP-2 levels was observed for discriminating chronic HCV patients (Metavir score F1-F4, as revealed by liver biopsy) from control group (F0) (Fig. 1a). On the contrary, levels of MMP-2 in fibrotic and that in cirrhotic cases were not significantly correlated (p=0.166; data not shown). Therefore, MMP-2 could not be used in differentiating fibrotic cases (F1-F3) from cirrhotic cases (F4).

Fig. (1)

The distribution values of (a) MMP-2, (b) MMP-9 and (c) TNF-α levels around the cut-off. F1-F4 = chronic HCV patients, and F0 = healthy control, according to Metavir score.



Fig. (2)

ROC curve of MMP-2, MMP-9 and TNF-α levels for discriminating: (a) chronic HCV patients (F1-F4) from healthy control (F0), and (b) fibrotic cases (F1-F3) from cirrhotic cases (F4).



Table 1

Sensitivity, specificity and accuracy for TNF-α, MMP-2 and MMP-9 in control (F0) and chronic HCV patients (F1-F4).




Table 2

Sensitivity, specificity and accuracy for TNF-α, MMP-2 and MMP-9 in fibrotic cases (F1-F3) and cirrhotic cases (F4).




Assessment of Plasma MMP-9

Plasma levels of MMP-9 in group three (control subjects) ranged from 2.61 – 3.05 ng/mL with mean value of 2.97 ± 0.13 ng/mL. In chronic HCV patients (group one and group two), plasma levels of MMP-9 ranged from 3.20 – 3.37 ng/mL with mean value of 3.27 ± 0.04 ng/mL. Mean level of plasma MMP-9 was significantly higher in chronic HCV patients when compared to the control group, (p<0.001). Consequently, a positive significant correlation of MMP-9 levels was observed for discriminating chronic HCV patients (Metavir score F1-F4, as revealed by liver biopsy) from control group (F0) (Fig. 1b). On the contrary, levels of MMP-9 in fibrotic and that in cirrhotic cases were not significantly correlated (p=0.157; data not shown). Therefore, MMP-9 could not be used in differentiating fibrotic cases (F1-F3) from cirrhotic cases (F4).

Assessment of Plasma TNF-α

Plasma levels of TNF-α in group three (control subjects) ranged from 0.14 – 0.17 pg/mL with mean value of 0.15 ± 0.01 pg/mL. In chronic HCV patients (group one and group two), plasma levels of TNF-α ranged from 0.32 – 0.43 pg/mL with mean value of 0.36 ± 0.03 pg/mL. Mean level of plasma TNF-α was significantly higher in chronic HCV patients when compared to the control group, (p<0.001). Consequently, a positive significant correlation of TNF-α levels was observed for discriminating chronic HCV patients (Metavir score F1-F4, as revealed by liver biopsy) from control group (F0) (Fig. 1c). On the contrary, levels of TNF-α in fibrotic and that in cirrhotic cases were not significantly correlated (p=0.760; data not shown). Therefore, TNF-α could not be used in differentiating fibrotic cases (F1-F3) from cirrhotic cases (F4).

ROC curve analysis was performed to determine the diagnostic significance of MMP-2 and MMP-9 compared to TNF-α (Fig. (2a), Table 1). The sensitivity, specificity, and accuracy of MMP-2, MMP-9 and TNF-α for discriminating control group (F0) from chronic HCV patients (F1-F4) were 100% each. The area under ROC curve (AUC) was 1.000 each (p<0.001). However, the closer the AUC value of one, the better the overall diagnostic performance of the test. On the other hand MMP-2, MMP-9 and TNF-α were failed to discriminate fibrotic cases (group one, F1-F3) from cirrhotic cases (group two, F4) (Fig. (2b), Table 2).

DISCUSSION

In liver diseases, determining the stage of fibrosis is of great importance for improved diagnosis, prognosis and administration of the effective therapy [13Grigorescu M. Noninvasive biochemical markers of liver fibrosis J Gastrointestin Liver Dis 2006; 15(2): 149-59.
[PMID: 16802010]
].

The potential role of MMP-2 for prognosis of liver fibrosis remains unclear, due to contradictory data was reported in different studies [14Walsh KM, Timms P, Campbell S, MacSween RN, Morris AJ. Plasma levels of matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases -1 and -2 (TIMP-1 and TIMP-2) as noninvasive markers of liver disease in chronic hepatitis C: comparison using ROC analysis Dig Dis Sci 1999; 44(3): 624-30.
[http://dx.doi.org/10.1023/A:1026630129025] [PMID: 10080160]
, 15Murawaki Y, Ikuta Y, Idobe Y, Kawasaki H. Serum matrix metalloproteinase-1 in patients with chronic viral hepatitis J Gastroenterol Hepatol 1999; 14(2): 138-45.
[http://dx.doi.org/10.1046/j.1440-1746.1999.01821.x] [PMID: 10029294]
]. On the contrary, it has been shown that MMP-9 has a great value in the diagnosis of hepatocellular carcinoma; However, a study showed that MMP-9 levels were not significantly correlated to the fibrotic index of the liver in chronic HCV patients [16Hayasaka A, Suzuki N, Fujimoto N, et al. Elevated plasma levels of matrix metalloproteinase-9 (92-kd type IV collagenase/gelatinase B) in hepatocellular carcinoma Hepatology 1996; 24(5): 1058-62.
[http://dx.doi.org/10.1002/hep.510240513] [PMID: 8903375]
, 17Badra G, Lotfy M, El-Refaie A, et al. Significance of serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in chronic hepatitis C patients Acta Microbiol Immunol Hung 2010; 57(1): 29-42.
[http://dx.doi.org/10.1556/AMicr.57.2010.1.3] [PMID: 20350877]
].

Also, TNF-α appears to play a key role in the necroinflammatory processes occurring in the liver of chronic HCV patients. An independent association has been noted between hepatic inflammatory activity and the level of TNF-mRNA. A positive significant correlation has been shown between serum TNF-α levels and the severity of hepatic inflammation in some but not all cases [18Zylberberg H, Rimaniol AC, Pol S, et al. Soluble tumor necrosis factor receptors in chronic hepatitis C: a correlation with histological fibrosis and activity J Hepatol 1999; 30(2): 185-91.
[http://dx.doi.org/10.1016/S0168-8278(99)80060-9] [PMID: 10068094]
].

The present study was designated to correlate the levels of MMP-2, MMP-9 and TNF-α with the pathogenesis of chronic liver diseases (CLD) caused by HCV, it also aimed at using them as possible non-invasive serum markers for liver fibrosis. Accordingly, we measured the levels of MMP2, MMP9 and TNF-α in 40 cases (25 chronic HCV patients and 15 healthy control subjects).

Demographic and clinical laboratory data of the studied cases were in accordance with the natural history of HCV [12Abdel-Latif MS, Almahal EK, Ragab NM, Omar MF, Afifi MS. Cellular fibronectin expression in chronic hepatitis C virus patients Scand J Infect Dis 2014; 46(7): 508-14.
[http://dx.doi.org/10.3109/00365548.2014.907499] [PMID: 24832854]
].

MMP2, MMP9 and TNF-α showed a significant elevation in patients with liver fibrosis (F1–F4) compared to control group (p=0.001). Area under ROC curve for MMP2, MMP9 and TNF-α, to discriminate chronic HCV patients (F1–F4) from control group (F0), was 1.000 each (p=0.001). Recently, it has been shown that serum MMP2 concentrations were significantly higher in stage F2-F4 patients compared to controls [19Liang B, Li Y, Zhao A, Xie F, Guo Z. Clinical utility of serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 concentrations in the assessment of liver fibrosis due to chronic hepatitis B J Int Med Res 2012; 40(2): 631-9.
[http://dx.doi.org/10.1177/147323001204000225] [PMID: 22613424]
]. Area under ROC curve was 0.770; which is in accordance with our obtained data.

Meanwhile, obtained results showed that, there was no significant correlation between the METAVIR score and levels of MMP2, MMP9 and TNF-α (P values: 0.166, 0.157 and 0.760; respectively) in fibrotic cases and cirrhotic cases. The area under the ROC curve of MMP2, MMP9 and TNF-α for discriminating fibrotic cases (F1-F3) from cirrhotic cases (F4) were 0.667, 0.670 and 0.537 respectively. In such a manner, obtained data were in agreement with other studies that reported this insignificant correlation [20Kuyvenhoven JP, van Hoek B, Blom E, et al. Assessment of the clinical significance of serum matrix metalloproteinases MMP-2 and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma Thromb Haemost 2003; 89(4): 718-25.
[PMID: 12669127]
-22Reif S, Somech R, Brazovski E, et al. Matrix metalloproteinases 2 and 9 are markers of inflammation but not of the degree of fibrosis in chronic hepatitis C Digestion 2005; 71(2): 124-30.
[http://dx.doi.org/10.1159/000084626] [PMID: 15785038]
].

According to current data, MMP-9 mean serum levels were significantly higher in chronic HCV patients than in controls (p<0.05), which comes in agreement with what has been published [22Reif S, Somech R, Brazovski E, et al. Matrix metalloproteinases 2 and 9 are markers of inflammation but not of the degree of fibrosis in chronic hepatitis C Digestion 2005; 71(2): 124-30.
[http://dx.doi.org/10.1159/000084626] [PMID: 15785038]
]. But others reported that serum MMP-9 was significantly lower in patients with chronic HCV than in controls [21Leroy V, Monier F, Bottari S, et al. Circulating matrix metalloproteinases 1, 2, 9 and their inhibitors TIMP-1 and TIMP-2 as serum markers of liver fibrosis in patients with chronic hepatitis C: comparison with PIIINP and hyaluronic acid Am J Gastroenterol 2004; 99(2): 271-9.
[http://dx.doi.org/10.1111/j.1572-0241.2004.04055.x] [PMID: 15046217]
]. This variability in results may be related to differences in study populations, type and severity of CLD and difference in assay systems.

Also, it has been shown that TNF-α, is significantly higher in cirrhotic patients compared to chronic HCV patients with no or mild fibrosis [23Andersen ES, Ruhwald M, Moessner B, et al. Twelve potential fibrosis markers to differentiate mild liver fibrosis from cirrhosis in patients infected with chronic hepatitis C genotype 1 Eur J Clin Microbiol Infect Dis 2011; 30(6): 761-6.
[http://dx.doi.org/10.1007/s10096-010-1149-y] [PMID: 21229279]
]. On the contrary, current data revealed that TNF-α level is significantly higher in both fibrotic and cirrhotic cases than in healthy control subjects.

In conclusion, MMP2, MMP9 and TNF-α showed high reproducibility to differentiate patients with liver fibrosis (F1–F4) from control group. But, MMP2, MMP9 and TNF-α were not able to differentiate fibrotic liver cases (F1–F3) from cirrhotic liver cases (F4). Thus current results suggested that MMP2, MMP9 and TNF-α could be considered as potential markers of inflammation but not of the degree of liver fibrosis in chronic HCV patients.

CONFLICT OF INTEREST

The author confirms that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Author would like to acknowledge Prof. Dr. Samia M. El-Sharkawy for the appreciated cooperation.

Ethical approval: This study was approved by the local ethics committee of the Medical Research Institute.

References

[1] Craxì A, Pawlotsky JM, Wedemeyer H, et al. EASL Clinical Practice Guidelines: management of hepatitis C virus infection J Hepatol 2011; 55(2): 245-64.
[http://dx.doi.org/10.1016/j.jhep.2011.02.023] [PMID: 21371579]
[2] Friedman SL. Liver fibrosis -- from bench to bedside J Hepatol 2003; 38(Suppl. 1): S38-53.
[http://dx.doi.org/10.1016/S0168-8278(02)00429-4] [PMID: 12591185]
[3] Henderson NC, Iredale JP. Liver fibrosis: cellular mechanisms of progression and resolution Clin Sci 2007; 112(5): 265-80.
[http://dx.doi.org/10.1042/CS20060242] [PMID: 17261089]
[4] Lichtinghagen R, Michels D, Haberkorn CI, et al. Matrix metalloproteinase (MMP)-2, MMP-7, and tissue inhibitor of metalloproteinase-1 are closely related to the fibroproliferative process in the liver during chronic hepatitis C J Hepatol 2001; 34(2): 239-47.
[http://dx.doi.org/10.1016/S0168-8278(00)00037-4] [PMID: 11281552]
[5] Théret N, Musso O, Turlin B, et al. Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas Hepatology 2001; 34(1): 82-8.
[http://dx.doi.org/10.1053/jhep.2001.25758] [PMID: 11431737]
[6] Losikoff PT, Self AA, Gregory SH. Dendritic cells, regulatory T cells and the pathogenesis of chronic hepatitis C Virulence 2012; 3(7): 610-20.
[http://dx.doi.org/10.4161/viru.21823] [PMID: 23076334]
[7] Dolganiuc A, Norkina O, Kodys K, et al. Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection Gastroenterology 2007; 133(5): 1627-36.
[http://dx.doi.org/10.1053/j.gastro.2007.08.003] [PMID: 17916356]
[8] Coquillard G, Patterson BK. Determination of hepatitis C virus-infected, monocyte lineage reservoirs in individuals with or without HIV coinfection J Infect Dis 2009; 200(6): 947-54.
[http://dx.doi.org/10.1086/605476] [PMID: 19678757]
[9] Larrea E, Garcia N, Qian C, Civeira MP, Prieto J. Tumor necrosis factor α gene expression and the response to interferon in chronic hepatitis C Hepatology 1996; 23(2): 210-7.
[PMID: 8591843]
[10] Nelson DR, Lim HL, Marousis CG, et al. Activation of tumor necrosis factor-alpha system in chronic hepatitis C virus infection Dig Dis Sci 1997; 42(12): 2487-94.
[http://dx.doi.org/10.1023/A:1018804426724] [PMID: 9440625]
[11] Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links Cell 2012; 148(5): 852-71.
[http://dx.doi.org/10.1016/j.cell.2012.02.017] [PMID: 22385956]
[12] Abdel-Latif MS, Almahal EK, Ragab NM, Omar MF, Afifi MS. Cellular fibronectin expression in chronic hepatitis C virus patients Scand J Infect Dis 2014; 46(7): 508-14.
[http://dx.doi.org/10.3109/00365548.2014.907499] [PMID: 24832854]
[13] Grigorescu M. Noninvasive biochemical markers of liver fibrosis J Gastrointestin Liver Dis 2006; 15(2): 149-59.
[PMID: 16802010]
[14] Walsh KM, Timms P, Campbell S, MacSween RN, Morris AJ. Plasma levels of matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases -1 and -2 (TIMP-1 and TIMP-2) as noninvasive markers of liver disease in chronic hepatitis C: comparison using ROC analysis Dig Dis Sci 1999; 44(3): 624-30.
[http://dx.doi.org/10.1023/A:1026630129025] [PMID: 10080160]
[15] Murawaki Y, Ikuta Y, Idobe Y, Kawasaki H. Serum matrix metalloproteinase-1 in patients with chronic viral hepatitis J Gastroenterol Hepatol 1999; 14(2): 138-45.
[http://dx.doi.org/10.1046/j.1440-1746.1999.01821.x] [PMID: 10029294]
[16] Hayasaka A, Suzuki N, Fujimoto N, et al. Elevated plasma levels of matrix metalloproteinase-9 (92-kd type IV collagenase/gelatinase B) in hepatocellular carcinoma Hepatology 1996; 24(5): 1058-62.
[http://dx.doi.org/10.1002/hep.510240513] [PMID: 8903375]
[17] Badra G, Lotfy M, El-Refaie A, et al. Significance of serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in chronic hepatitis C patients Acta Microbiol Immunol Hung 2010; 57(1): 29-42.
[http://dx.doi.org/10.1556/AMicr.57.2010.1.3] [PMID: 20350877]
[18] Zylberberg H, Rimaniol AC, Pol S, et al. Soluble tumor necrosis factor receptors in chronic hepatitis C: a correlation with histological fibrosis and activity J Hepatol 1999; 30(2): 185-91.
[http://dx.doi.org/10.1016/S0168-8278(99)80060-9] [PMID: 10068094]
[19] Liang B, Li Y, Zhao A, Xie F, Guo Z. Clinical utility of serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 concentrations in the assessment of liver fibrosis due to chronic hepatitis B J Int Med Res 2012; 40(2): 631-9.
[http://dx.doi.org/10.1177/147323001204000225] [PMID: 22613424]
[20] Kuyvenhoven JP, van Hoek B, Blom E, et al. Assessment of the clinical significance of serum matrix metalloproteinases MMP-2 and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma Thromb Haemost 2003; 89(4): 718-25.
[PMID: 12669127]
[21] Leroy V, Monier F, Bottari S, et al. Circulating matrix metalloproteinases 1, 2, 9 and their inhibitors TIMP-1 and TIMP-2 as serum markers of liver fibrosis in patients with chronic hepatitis C: comparison with PIIINP and hyaluronic acid Am J Gastroenterol 2004; 99(2): 271-9.
[http://dx.doi.org/10.1111/j.1572-0241.2004.04055.x] [PMID: 15046217]
[22] Reif S, Somech R, Brazovski E, et al. Matrix metalloproteinases 2 and 9 are markers of inflammation but not of the degree of fibrosis in chronic hepatitis C Digestion 2005; 71(2): 124-30.
[http://dx.doi.org/10.1159/000084626] [PMID: 15785038]
[23] Andersen ES, Ruhwald M, Moessner B, et al. Twelve potential fibrosis markers to differentiate mild liver fibrosis from cirrhosis in patients infected with chronic hepatitis C genotype 1 Eur J Clin Microbiol Infect Dis 2011; 30(6): 761-6.
[http://dx.doi.org/10.1007/s10096-010-1149-y] [PMID: 21229279]

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"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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