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Circulating matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as serum markers of fibrosis in patients with chronic hepatitis C. Relationship to interferon response
Abstract
The imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) is considered to be an important determinant of extracellular matrix deposition and breakdown. We measured serum MMP-1, MMP-2, TIMP-1 and TIMP-2 levels using the respective one-step sandwich enzyme immunoassays in 98 patients with chronic hepatitis C treated with interferon beta to examine their clinical significance for assessment of liver histology and to determine whether they can be useful as predictors of the interferon response.
Serum TIMP-1 levels showed a positive correlation with the degree of fibrosis (r(s)=0.30, p= 0.004). Serum MMP-2 levels revealed positive relationships with the degree of periportal necrosis (r(s)= 0.32, p=0.002), the degree of fibrosis (r(s)=0.26, p= 0.01) and total score of histological activity index (r(s)=0.24, p=0.02). Serum MMP-2 levels were significantly higher in patients with no response than in those with sustained and transient response (p<0.01 and p<0.05, respectively), while serum MMP-1 levels did not differ among the three groups. Compared with the levels in sustained responders, the total amounts of serum TIMP-1 were significantly lower in transient responders and non-responders (p<0.01 and p<0.001, respectively). As for serum TIMP-2 levels, a significant decrease was found in transient responders and non-responders (p<0.01). The ratios of serum MMP-2 to TIMP-1 levels were significantly higher in transient responders and non-responders than in sustained responders (p<0.001, respectively) even when HCV RNA levels were low in patients with HCV genome subtype 1b or when the HCV genome subtype was 2a or 2b. Sustained response was never found in type 1b patients with ratios of serum MMP-2 to TIMP-1 levels of over 6.0. In logistic multivariate regression analysis, the ratios of serum MMP-2 to TIMP-1 level (p=0.0001), HCV genome subtype (p=0.005) and serum TIMP-2 level (p=0.03) were the independent predictors for sustained response, while serum MMP-2 level (p=0.0006) was the only predictor for no response.
Serum MMP-2 and TIMP-1 levels might be useful for estimating the degree of liver fibrosis. The ratio of serum MMP-2 to TIMP-1 levels may serve as a new predictor of interferon response in patients with chronic hepatitis C.
... Therefore, proteolysis of ECM is the final result between proteolytic and inhibitory activities [39,40]. Recent studies have shown that the over-expression of MMP-2 is generally associated with chronic liver disease [41] and with a poor prognosis or shorter survival in patients with HCC treated with TACE, while elevated serum TIMP-2 levels have been disclosed in patients with chronic hepatitis C with special reference to interferon treatment [42]. Under physiological conditions, TIMP-2 is capable of inhibiting the active form of MMP-2 as MMP-2/TIMP-2 is present at a stoichiometric ratio of 1:1, while in tumors with a poor prognosis the ratios of serum MMP-2 to TIMP-2 (MMPs/TIMPs) are higher. ...
... With regard to TIMP-2, which is known to be a specific inhibitor of MMP-2, the figure that emerges from this study is that its concentrations increase significantly after treatment with TACE, acting in the opposite way to the concentrations of MMP-2 and AFP. Some authors have considered in their studies the MMP-2/TIMP-2 ratio, such as an interesting study by Kasahara et al. that investigated the role of circulating MMP-2 and TIMP-2 as predictors of interferon response in patients with chronic hepatitis, suggesting that the ratio of serum MMP-2/TIMP-1 could serve as a predictor of interferon response [42]. Similar results were reported by Giannelli et al. who found a close correlation between tissue and serum levels of TIMP-2, suggesting that MMP-2/TIMP-2 imbalance could represent an important prognostic factor in patients with HCC [44]. ...
... On the other hand, the lower serum concentration of TIMP-2 at baseline is further confirmation of the worse clinical outcome and unfavorable response to loco-regional treatment considering the inhibitory role of TIMP vs MMP-2. These data confirm the results of the above studies by authors who have examined the role of MMP-2/TIMP-2 ratio in the carcinogenesis of hepatocellular carcinoma [44,42]. In addition, our study found a very significant correlation between higher serum levels of MMP-2 at baseline in the subgroup of patients who were HBV and HCV positive and an inversely significant correlation between serum AFP levels and circulating TIMP-2, suggesting that the clinical trend of AFP in patients with HCC is comparable to that of MMP-2 as a prognostic biomarker. ...
Background and aims:
Trans-hepatic arterial chemo-embolization is the most commonly used treatment for unresectable hepatocellular carcinoma. The prognostic impact of tumor biomarkers has not therefore been evaluated in this treatment. Imbalance between matrix metalloproteinase-2 and tissue inhibitor metalloproteinase-2 is considered to play an important role in extracellular matrix remodeling and degradation. Higher serum levels of MMP-2 have been shown to predict a poor prognosis and shorter overall survival in HCC after TACE. The objective of this study was to evaluate the serum levels of MMP-2 and TIMP-2 in HCC patients before and after TACE to evaluate their clinical significance and usefulness as prognostic biomarkers.
Methods:
MMP-2 and TIMP-2 levels were measured by ELISA in 75 HCC patients and 30 healthy controls. Sera MMP-2 and TIMP-2 were correlated with clinico-pathological features.
Results:
The mean serum MMP-2 and TIMP-2 levels of HCC patients before TACE were 1700±71ng/mL and 89±45ng/mL respectively, significantly higher than that of the control group: 771±60ng/mL (p<0.0001, t-test) and 25.7±20ng/mL respectively (p<0.0001, t-test). A significant decrease of MMP-2 levels after 1 and 3months compared to baseline time was observed (p<0.0001), while with TIMP-2 a gradual increase in serum before and after TACE (p<0.01) was detected. No significant correlation between serum MMP-2 levels and other clinico-pathological features was observed. Patients with serum MMP-2 >1500ng/mL (median value) had worse overall and recurrence-free survival compared with those with serum MMP-2 levels <1500ng/mL before treatment.
Conclusion:
Higher serum MMP-2 levels and MMP-2/TIMP-2 ratio could predict poor prognosis after TACE, suggesting prognostic role of these biomarkers in HCC.
... We also studied matrix metalloproteinase-2 (MMP-2) (72 kD, type IV collagenase or gelatinase), one of the gene families of zinc enzymes capable of degrading type IV collagen (9). The serum level of MMP-2 is thought to be useful for estimating the degree of liver fibrosis in both humans (10) and rats (11). Moreover, T cells and macrophages secrete the gelatinases MMP-2 and -9, after beta 1 integrin-or VCAM-1-dependent stimulation by cytokines and inflammatory mediators (9). ...
... In the present study, we attempted to analyze the mechanism of hepatocellular injury during AH and CH from the aspect of another adhesion molecule, VCAM-1, and its ligand VLA-4. In addition, we studied the serum level of MMP-2 because it is thought to be a marker of hepatic fibrosis (10) and because the release of MMP-2 may be mediated by VLA-4-positive cells (12). ...
... The interaction between these VLA-4-positive Kupffer cells and VCAM-1-positive sinusoidal lining cells may be involved in chronic liver disease progression. We also examined the serum level of MMP-2, a kind of liver fibrosis marker (10). T cells and macrophages secrete the gelatinases MMP-2 and -9, after beta 1 integrin-or VCAM-1-dependent stimulation by cytokines and inflammatory mediators (9). ...
To clarify the role of adhesion molecule in liver cell injury.
The serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), and the expression of VCAM-1 and its ligand, very late activation antigen-4 (VLA-4), were examined in patients with various liver diseases. In addition, the presence of matrix metalloproteinase-2 (MMP-2) was investigated because the release of MMP-2 is thought to be mediated by VLA-4-positive cells. sVCAM-1 and MMP-2 were measured by ELISA assay, and VCAM-1 and VLA-4 were studied by immuno-histological methods.
In acute hepatitis (AH) patients, the serum level of sVCAM-1 was significantly elevated compared with that in other cohorts. VCAM-1 was expressed on sinusoidal lining cells but not on hepatocytes. In patients with chronic liver disease, sVCAM-1 levels rose in concert with the progression of chronic hepatitis (CH), and VCAM-1 was also expressed. VLA-4 was detected in both mononuclear cells and Kupffer cells in AH livers, but mainly in Kupffer cells in patients with CH. In AH patients, MMP-2 levels were similar to those in control subjects, but in CH and liver cirrhosis patients, MMP-2 level was elevated in association with CH progression.
The immune response through the VCAM-1 and VLA-4 pathways is important in hepatocyte injury, especially in AH patients, to attach VLA-4-positive mononuclear cells to VCAM-1-positive sinusoidal lining cells. The distribution of VLA-4-positive cells differs between AH and CH patients. VLA-4-positive Kupffer cells in chronic liver diseases might be involved in the progression of CH, perhaps through the mechanism of upregulation of MMP-2 production.
... The other mechanism-the decrease in MMP activity-is mainly due to the overexpression of their endogenous inhibitors (TIMPs) [14]. TIMP1 has been reported to be upregulated in serum and liver during the progression of hepatic fibrosis in human as well as animal models [30][31][32]. Kasahara et al. determined that serum TIMP1 was positively correlated with the degree of liver fibrosis in patients with chronic hepatitis C [31], whereas Prystupa et al. showed that the activities of MMP2, MMP8, and MMP9 in serum might be markers of progression of human alcoholic liver disease [16]. Here, we determined that the HFC diet exacerbated serum TIMP1 elevation and, thus, further reduced MMP (MMP2, MMP8, and MMP9) activity in hypertensive SHRs when compared with that in the normotensive WKY strain. ...
... TIMP1 has been reported to be upregulated in serum and liver during the progression of hepatic fibrosis in human as well as animal models [30][31][32]. Kasahara et al. determined that serum TIMP1 was positively correlated with the degree of liver fibrosis in patients with chronic hepatitis C [31], whereas Prystupa et al. showed that the activities of MMP2, MMP8, and MMP9 in serum might be markers of progression of human alcoholic liver disease [16]. Here, we determined that the HFC diet exacerbated serum TIMP1 elevation and, thus, further reduced MMP (MMP2, MMP8, and MMP9) activity in hypertensive SHRs when compared with that in the normotensive WKY strain. ...
Hypertension is an important risk factor for nonalcoholic steatohepatitis. We have previously demonstrated that hypertensive rats fed a high fat and cholesterol (HFC) diet incurred a more severe hepatic inflammatory response and fibrosis. Here we investigated the role of hypertension in NASH by comparing HFC-induced hepatic fibrogenesis between spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto counterpart. Compared to the counterpart, the HFC diet led to stronger aggregation of CD68-positive macrophages in SHRs. HFC feeding also resulted in significantly higher upregulation of the fibrosis-related gene alpha-smooth muscle actin in SHR. The HFC diet induced higher overexpression of serum tissue inhibitor of metalloproteinase-1 (TIMP1) and greater suppression of matrix metalloproteinase-2 (MMP2):TIMP1, MMP8:TIMP1, and MMP9:TIMP1 ratios, as a proxy of the activities of these MMPs in SHR. Administration of the antihypertensive agent hydralazine to SHRs significantly ameliorated HFC-induced liver fibrosis; it suppressed the aggregation of CD68-positive macrophages and the upregulation of platelet-derived growth factor receptor beta, and collagen, type 1, alpha-1 chain. In conclusion, a hypertensive environment exacerbated the hepatic fibrogenetic effects of the HFC diet; while the effects were partially reversed by the antihypertensive agent hydralazine. Our data suggest that antihypertensive drugs hold promise for treating NASH exacerbated by hypertension.
... There is not much data currently available about the change in these parameters in response to therapy to compare our results with. Kasahara et al. 19 have reported that serum levels of MMP-2 was a predictor for no response and the MMP-2 to TIMP-1 ratio in serum might be used to predict response to IFN in HCV patients. 19 Our results have confirmed the findings of their study. ...
... Kasahara et al. 19 have reported that serum levels of MMP-2 was a predictor for no response and the MMP-2 to TIMP-1 ratio in serum might be used to predict response to IFN in HCV patients. 19 Our results have confirmed the findings of their study. ...
Background: Egypt has the highest prevalence of hepatitis C virus worldwide. Monitoring hepatitis C-infected patients for hepatocellular carcinoma development is an important clinical issue to diagnose these patients during the potentially curable early-stage of disease. This study aims to evaluate the role of N-terminal procollagen III, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-1, alpha-fetoprotein, and conventional liver function tests as predictors of hepatocellular carcinoma development upon long-term follow-up of non-responding hepatitis C virus patients. Methods: The study included 850 treatment-naïve hepatitis C virus genotype 4a adult patients; after treatment, 360 achieved sustained viral response while 490 did not. Non-responding patients had a 5-year rate for hepatocarcinogenesis of 8.4% and a 10-year rate of 27.5%. N-terminal procollagen III, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-1, alpha-fetoprotein, and conventional liver function tests were evaluated in all patients before and after treatment, and after hepatocellular carcinoma development. The study also included a group of 50 hepatocellular carcinoma patients who were negative for hepatitis C and hepatitis B viruses, and a group of 50 healthy subjects as controls. Results: The non-responders had significantly higher age, stage, grade, viral load, alanine aminotransferase, and aspartate aminotransferase than responders. Also N-terminal procollagen III, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-1, and alpha-fetoprotein were significantly higher in non-responders; after treatment they decreased in responders. In non-responders they remained higher than the control. The most significant risk factors for hepatocellular carcinoma development in non-responding hepatitis C virus patients were male gender and increased age, stage, grade, aspartate aminotransferase, N-terminal procollagen III, and tissue inhibitor of matrix metalloproteinase-1. Patients with viral-hepatocellular carcinoma were of significantly lower age, higher grade, stage, γ-glutamyl-transferase, N-terminal procollagen III, and matrix metalloproteinase-2 than non-viral hepatocellular carcinoma patients. Percent positive N-terminal procollagen III, tissue inhibitor of matrix metalloproteinase-1, and alpha-fetoprotein were significantly higher in viral hepatocellular carcinoma patients. Conclusion: Data suggest that high N-terminal procollagen III and tissue inhibitor of matrix metalloproteinase-1levels after treatment might be particularly important as markers of hepatitis C virus-non-responding patients who are at higher risk of developing hepatocellular carcinoma, especially in older males with high stage and grade liver disease. However, studies of larger scale are needed to verify this suggestion. © 2018, Shiraz University of Medical Sciences. All rights reserved.
... The following year, in 1997, Kasahara et al. investigated about the clinical role of the MMP-2/TIMP-2 ratio to predict the interferon response in 98 patients with chronic C hepatitis finding that serum MMP-2 was significantly higher in non-responders patients vs sustained and transient responders patients to interferon therapy (p < 0.01 and p < 0.05 respectively), TIMP1 and TIMP2 serum were significantly lower in non-responders and in transient responders (p < 0.01 and 0.001 respectively), the MMP-2/TIMP-1 ratio was significantly higher in transient and non responding patients compared to responding patients; the authors suggested that this ratio can predict interferon response in patients with chronic hepatitis C (Kasahara et al., 1997). ...
... Patients Pathology Sample Assay System Results Hayasaka et al. (1996) 145 HCC, Chronic Hepatitis, Liver Cirrhosis Plasma ELISA Significantly Higher Plasma MMP-9 levels in HCC respect to those Control Ggroup Kasahara et al. (1997) The mean MMP-2and MMP-9 serum levels were slightly increase in chronic hepatitis HBV pts respect to healthy subjects; a significant inverse correlation between AFP and the ratio of MMP-9/MMP-2 was find: higher AFP levels in patients corresponded to low ratios of MMP-9/MMP-2 ...
... MMPs are involved in degrading ECM, while TIMPs prevent their fibrolytic action [15] . The imbalance between MMPs and TIMPs is considered to be an important determinant of ECM deposition and breakdown [19,29] . In this observational one-point study, we evaluated the status of TIMP-1 and TIMP-2 among patients of NAFLD and compared these levels with obese and control patients. ...
... Markers including MMP-2, TIMP-1, HA, PIIINP, MMP-1 and MMP-9 were significantly related with fibrosis. Kasahara et al. [29] measured serum MMP-1, MMP-2, TIMP-1 and TIMP-2 levels among patients with chronic hepatitis C treated with interferon beta. There was a positive correlation between the degree of fibrosis and serum TIMP-1 levels; serum MMP-2 was positively correlated with the degree of periportal necrosis, degree of fibrosis. ...
Non-alcoholic fatty liver disease is a spectrum of clinical conditions, including simple steatosis and non-alcoholic steatohepatitis (NASH). The aim of the study is to evaluate the tissue inhibitors of metalloproteinase-1 and 2 (TIMPs) as noninvasive predictors of NASH.
Three groups were included in the study. Obese patients (n = 30) with normal liver enzymes were included in group I and obese patients (n = 30) with elevated liver enzymes with liver biopsy-based diagnosis of NASH were included in group II. Age-matched subjects (n = 30) formed the control as group III. The lipid profile, liver enzyme levels and levels of TIMPs were compared among all the patients and subjects.
Comparison of groups I and II showed significantly elevated levels of TIMP-1 and TIMP-2 in group II as compared to group I (p < 0.05). Similarly, comparison between groups II and III showed significantly increased levels of TIMP-1 and TIMP-2 in group II as compared to group III (p < 0.05). TIMP-1 (sensitivity 96.7%, specificity 100%) and TIMP-2 (sensitivity 93.3%, specificity 100%) showed high accuracy in NASH diagnosis.
TIMP-1 and TIMP-2 may be considered noninvasive markers for the diagnosis of NASH.
© 2015 S. Karger AG, Basel.
... We observed an association between MMP-2 and TIMP-2 levels and LF ‡ 2 assessed by TE in the univariate analysis al- though this disappeared in the multivariate one where other variables such as ddI, male gender, older age and HCV load had a higher statistical weight. Our results regarding MMP-2 in LF ‡ 2 agree with previous ones [17,34,37]. Ours is the first report of an association between serum TIMP-2 levels and LF ‡ 2. MMP-2 and TIMP-2 levels in combination with TE and APRI, Forns, and FIB-4 indexes might help predict LF ‡ 2 in HIV-HCV-coinfected patients instead of liver biopsy. ...
... Ours is the first report of an association between serum TIMP-2 levels and LF ‡ 2. MMP-2 and TIMP-2 levels in combination with TE and APRI, Forns, and FIB-4 indexes might help predict LF ‡ 2 in HIV-HCV-coinfected patients instead of liver biopsy. No association between LF ‡ 2 and serum TIMP-1 or MMP-1 was observed in our series as others did [16,34,35,37]. Differences among the different ELISA microarrays used might account for the different results reported. ...
The role of exposure to antiretrovirals (ARV) and serum matrix metalloproteases (MMPs) on liver fibrosis (LF) progression in human immunodeficiency virus (HIV) mono or HIV- hepatitis C virus (HCV) coinfection is unclear. Thus, 213 Caucasian adult HIV-infected patients were studied, 111 of whom had HCV-coinfection and 68 were HCV-monoinfected. Patients with ethanol consumption >50 g/day, hepatitis B coinfection, non-infective liver diseases or HAART adherence <75% were excluded. LF was assessed by transient elastometry (TE, Fibroscan). Serum levels of MMPs (MMP -1,-2,-3,-8,-9,-10 and -13) and their tissue inhibitors (TIMP-1,-2 and -4) were measured by ELISA microarrays. Associations with LF were statistically analysed. Protease inhibitors, usually administered to patients with advanced LF were excluded from the analysis. Increased LF was significantly associated with d4T (P = 0.006) and didanosine (ddI) use (P = 0.007), months on d4T (P = 0.001) and on ARV (P = 0.025), duration of HIV (P < 0.0001) and HCV infections (P < 0.0001), higher HIV (P = 0.03) and HCV loads (P < 0.0001), presence of lipodystrophy (P = 0.02), male gender (P = 0.02), older age (P = 0.04), low nadir (P = 0.02) and current CD4(+) T-cells (P < 0.0001), low gain of CD4(+) T-cells after HAART (P = 0.01) and higher MMP-2 (P = 0.02) and TIMP-2 serum levels (P = 0.02). By logistic regression the only variables significantly associated with increased LF were: use of ddI (OR 8.77, 95% CI: 2.36-32.26; P = 0.005), male gender (OR 7.75, 95% CI: 2.33-25.64, P = 0.0008), HCV viral load (in log) (OR 3.53, 95% CI: 2.16-5.77; P < 0.0001) and age (in years) (OR 1.21, 95% CI: 1.09-1.34, P = 0.0003). We conclude that only higher HCV viral load, older age, male gender, and use of ddI associated independently with increased LF in our study.
... From June 1989 to September 1995, a total of 1,142 patients, who had had elevated ALT levels (at least double the upper limit of the normal range for at least 6 months) and who had been histologically proven to have chronic hepatitis with or without Child grade A liver cirrhosis, were treated with interferon in six trials using different treatment schedules. [9][10][11][15][16][17] Almost all of the chronic hepatitis C patients treated with interferon at the participating institutions were included in these trials. Patients with positive hepatitis B surface antigen or other forms of liver disease (such as alcoholic liver disease and autoimmune liver disease) were excluded from the interferon treatment trials. ...
... 15 Another group of 132 cases was randomly assigned to receive either 6 or 10 MU of recombinant interferon alfa-2b (Intron A; Schering-Plough or Yamanouchi Pharmaceutical Co., Tokyo, Japan) intramuscularly every day for the first 2 weeks and then three times a week for the following 22 weeks. 16 A third group of 132 patients were treated with 6 MU of natural beta interferon (Toray Industries or Daiichi Pharmaceutical Co., Tokyo, Japan) by intravenous injection ranging from 252 to 264 MU. 17 This total amount of interferon beta is the ordinary dosage for treatment of chronic hepatitis C patients in Japan. A fourth group of 56 patients received 28-or 52-week courses of natural interferon alfa. ...
To elucidate the risk factors for liver carcinogenesis and to examine the incidence of hepatocellular carcinoma (HCC) after interferon therapy, 1,022 chronic hepatitis C patients treated with interferon were followed by ultrasonography for 13 to 97 months (median 36 months). Sustained response with prolonged alanine aminotransferase normalization was found in 313 patients, transient response with alanine aminotransferase relapse after therapy in 304, and no response in 405. Forty-six developed HCC, of whom 5 were sustained responders, 9 were transient responders, and 32 were nonresponders. The cumulative incidence of HCC in transient responders was almost equal to that in sustained responders, and it was significantly higher in nonresponders than in sustained and transient responders (P = .0009). The seventh-year cumulative incidence rates of HCC in sustained responders, transient responders, and nonresponders were estimated to be 4.3%, 4.7%, and 26.1%, respectively. However, there was no significant difference in the cumulative incidence of HCC between patients with HCV subtype 1 and 2 (P = .14). Cox regression analysis showed that the risk of HCC development was not elevated in transient responders compared with sustained responders, but that the risk was 7.90-fold higher in nonresponders than in sustained responders (P = .008). Patients ≥55 years of age had a significantly higher risk ratio (4.65) than did those under 55 years of age (P = .006). The risk of HCC development in men was 4.35 times higher than the risk in women (P = .02). However, the degree of fibrosis was not a significant risk factor for the development of HCC (risk ratio, 3.16; P = .052). These results suggest that patients in the high-risk group of HCC after interferon therapy were those who showed no response, those who were older, and those who were male, and that such patients should be carefully followed using ultrasonography.
... Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are interesting new diagnostic tools in oncology, liver diseases, and rheumatoid arthritis (1)(2)(3)(4)(5). However, the preanalytical issue of their determination in blood was only recently shown (6). ...
... These results are of special interest because MMP-2, MMP-9, and TIMP-2 were measured both in serum and in plasma samples, and different data were presented (1)(2)(3)(4)(5)(7)(8)(9). To assess these discrepancies, several reasons have to be considered. ...
... observaron que MMP-2 también se puede emplear para detectar la cirrosis con gran eficacia en pacientes con VHC crónica, con mayor valor diagnóstico que el AH o TIMP-1 [135]. Además, se ha propuesto la relación MMP-2/TIMP-1 como un indicador de respuesta a tratamiento con inferón-γ en pacientes con CHC, habiendo sido descrita una mayor reducción de dicha relación en los pacientes con buena respuesta, frente a los que no respondieron o no recibieron tratamiento [136]. Munsterman y col. ...
Resumen
La fibrosis hepática se desarrolla como respuesta a la presencia de daño hepático crónico de diferentes etiologías, provocando un desequilibrio entre la síntesis y degeneración de la matriz extracelular y la desregulación de diversos mecanismos fisiológicos. En los estadios iniciales de las patologías crónicas, el hígado posee una elevada capacidad de regeneración, por lo que la detección temprana de la fibrosis hepática resulta esencial. En este contexto, es preciso contar con herramientas sencillas y económicas que permitan detectar la fibrosis hepática en sus fases iniciales. Para evaluar la fibrosis hepática, se han propuesto multitud de biomarcadores séricos no invasivos, tanto directos, como el ácido hialurónico o las metaloproteasas, como indirectos. Así mismo, se han desarrollado diversas fórmulas que combinan dichos biomarcadores junto con parámetros demográficos, como el índice FIB-4, el índice de fibrosis en la enfermedad de hígado graso no alcohólico (NFS, por sus siglas en inglés), la prueba ELF o el score de fibrosis Hepamet (HFS, por sus siglas en inglés). En el presente manuscrito, realizamos una revisión crítica del valor diagnóstico y pronóstico de los diferentes biomarcadores séricos y fórmulas actualmente existentes.
... Also, Boeker et al., reported that MMP-2 can be used to detect cirrhosis with high efficacy in patients with chronic HCV, and that performed better than HA or TIMP-1 [135]. Furthermore, the MMP-2/TIMP-1 ratio was proposed as an indicator of Interferon-γ treatment response in CHC patients, describing a greater decrease in ratio levels in responders compared to no-responders or not treated patients [136]. In addition, Munsterman et al. described higher levels of TIMP-1 and TIMP-2 in severe fibrosis than in mild or no fibrosis in MASLD patients, and also that MMP-9 was the only ECM component correlated with inflammation severity [137]. ...
Liver fibrosis is the result of chronic liver injury of different etiologies produced by an imbalance between the synthesis and degeneration of the extracellular matrix and dysregulation of physiological mechanisms. Liver has a high regenerative capacity in the early stage of chronic diseases so a prompt liver fibrosis detection is important. Consequently, an easy and economic tool that could identify patients with liver fibrosis at the initial stages is needed. To achieve this, many non-invasive serum direct, such as hyaluronic acid or metalloproteases, and indirect biomarkers have been proposed to evaluate liver fibrosis. Also, there have been developed formulas that combine these biomarkers, some of them also introduce clinical and/or demographic parameters, like FIB-4, non-alcoholic fatty liver disease fibrosis score (NFS), enhance liver fibrosis (ELF) or Hepamet fibrosis score (HFS). In this manuscript we critically reviewed different serum biomarkers and formulas for their utility in the diagnosis and progression of liver fibrosis.
... 1.10.13.2 Serum hyaluronan, type HI procollagen peptide and MMP-2 have been shown to reflect the degree of liver fibrosis and reflect response to therapy in patients with hepatitis C virus infection (Guechot et al. 1995;Suou et al. 1995;Kasahara et al. 1997). Serum TIMP-1 level G-om patients with acute viral hepatitis, cirrhosis, alcoholic hepatitis, and alcoholic cirrhosis has been shown to be significantly elevated compared to controls (Ueno et al. 1996). ...
p>The aim of this study was to determine the effect of TIMP-1 and TIMP-2 on HSC survival and determine whether this effect was through effects on inhibition of MMP activity. In vivo studies of experimental liver fibrosis demonstrated a correlation between resolution of fibrosis, falling, TIMP-1 mRNA, loss of HSC and transient increase in collagenolytic activity. This data suggested that TIMP-1 was likely to have an effect promoting HSC survival. In vitro studies of culture activated HSC demonstrated that neither TIMP-1 nor TIMP-2 regulated HSC proliferation suggesting that the pro survival effect was likely to be via inhibition of apoptosis. Incubation with TIMP-1 or TIMP-2 significantly reduced apoptosis of HSC induced by a number of stimuli in a dose-dependent manner. Neutralising antibodies to TIMP-1 and TIMP-2 increased HSC apoptosis compared non-immune IgG control. Whilst both a synthetic selective inhibitor of MMP-2 and a broad spectrum synthetic MMP inhibitor reduced HSC apoptosis, a non-functional mutated TIMP-1 (T2G mutant) had no effect indicating that the inhibition of apoptosis by TIMP-1 was via inhibition of MMP activity. MMP-2 like TIMP-1 is expressed by activated HSC. Addition of recombinant active MMP-2 to HSC resulted in significantly enhanced apoptosis and was associated with cleavage of N-cadherin which could be reduced by co-incubation with recombinant TIMP-1 but not by the non-functional T2G mutant TIMP-1. Furthermore, selective MMP-2 inhibitors protected N-cadherin from cleavage. Active MMP-2 cleaves intact N-cadherin into similar sized fragments in vitro. Blockade of N-cadherin binding with blocking antibody or HAVDI blocking peptide promoted HSC apoptosis, suggesting N-cadherin is a potential target mechanism for the regulation of survival and apoptosis of HSC via active MMP-2 mediated cleavage. Finally, to determine if effects on apoptosis by TIMP-1 were through changes in cell-matrix interactions, HSC plated onto a mutated collagen that is resistant to degradation by MMP-2 were more resistant to apoptosis induced by active MMP-2 than HSCs plated onto normal wild type collagen-1.</p
... The authors therefore concluded that the ratio of serum MMP-2/TIMP-1 levels may act as a new predictor for interferon response in patients with chronic hepatitis C patients. 27 Our study also showed a consistent reduction in the pattern of MMP-2/TIMP-1 and MMP-9/ TIMP-1 in active cases at all levels, which is suggestive of the increase in TIMP-1 expression and secretion. In the MMP-2/TIMP-2 ratio, a consistent pattern of decrease in the order of active, inactive, and controls conveys the fact that MMP-2 expression and secretion increases as the disease progresses, which is in agreement with previous studies. ...
Background:
The study aimed to look at alterations in expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) and their potential use as biomarkers in the pathogensis of SLE.
Methods:
SLE patients (n = 41) and healthy controls (n = 50) were recruited. Quantitative RT-PCR/ELISA assays were performed for expression of MMP and TIMP mRNA in whole blood and PBMC; and corresponding serum protein levels. Intracellular levels of MMP-2 and MMP-9 proteins were analysed by flow cytometry.
Results:
Based on SLEDAI scores patients were grouped into active (SLEDAI ≥ 10) and inactive cases (SLEDAI < 10). In active cases, MMP-2 expression significantly increased and TIMP-2 expression was decreased (p < 0.0001) both at serum secretion (p = 0.0003) and mRNA (p < 0.0001) levels as compared to inactive cases. MMP-9 and TIMP-1 showed significantly reduced serum secretion and mRNA expression (p < 0.0001) in active cases as compared to inactive cases. Intracellular concentration of MMP-9 was reported to be higher in neutrophils, while MMP-2 was mainly found in lymphocytes of SLE patients as compared to controls. MMP/TIMP ratio profile was altered as SLE disease progresses.
Interpretation & conclusions:
Findings suggest disturbed MMP and TIMP levels have a role in the pathogenesis of SLE.
... We also observed significantly higher MMP-2 levels and MMP-2:TIMP-1 ratios in HIV+ individuals with CD4 + T lymphocyte counts < 350 cells/mm 3 , indicative of ongoing ECM remodeling [27]. While high MMP-2 and TIMP-1 levels have been associated with severity of liver fibrosis, [28,29] in this cohort levels did not differ by viral hepatitis co-infection status (data not shown).While we did not observe an association between circulating LOXL2 levels and circulating CD4 + T lymphocyte counts, the circulating CD4 + cells pool is derived from a number of tissues that may not be affected/equally affected by fibrosis, preventing a strong correlation. ...
Background: Incomplete immune reconstitution may occur despite successful antiretroviral therapy (ART). Gut-associated lymphoid tissue (GALT) fibrosis may contribute via local CD4+ T lymphocyte depletion, intestinal barrier disruption, microbial translocation, and immune activation.
Methods: In a cross-sectional analysis, we measured circulating fibrosis biomarker levels on cryopreserved plasma from adult HIV-infected (HIV+) SCOPE study participants on suppressive ART who also had fibrosis quantification on recto-sigmoid biopsies. Relationships among biomarker levels, clinical and demographic variables, GALT lymphoid aggregate (LA) collagen deposition, and LA CD4+ T lymphocyte density were analyzed using simple regression. Biomarker levels were also compared to levels in HIV+ viremic SCOPE participants and a convenience sample of HIV-uninfected (HIV-) samples.
Results: HIV+ aviremic participants (n=39) were 92% male and 41% non-white, with median age 48 years, CD4+ T lymphocyte count 277 cells/mm3, and 17 years since HIV diagnosis. Most biomarkers were lower in HIV− (n=36) vs HIV+ aviremic individuals, although CXCL4 levels were higher. HIV+ viremic individuals (N=18) had higher median TGF-ß3, CIC-C1Q, and TIMP-1 (P
... TIMP-1 and -2 appear to follow a similar pattern (18). It has been reported that changes to circulating levels of MMPs and TIMPs are indicative of changes at the tissue level (15). An investigation into the serum MMP and TIMP antigenicity response to downhill running in humans revealed small but significant changes in levels of MMP-9, TIMP-1 and -2, and the MMP-2/TIMP-2 complex after the run; no change was observed in serum MMP-2 levels (17). ...
... There is a good correlation between serum and hepatic levels of TIMP-1 in a range of liver diseases (Murawak et al., 1997) and encouraging studies on the role of plasma TIMP-1, as a non-invasive marker of histological damage in alcoholic liver disease, hepatitis C , Kasahara et al., 1997 and other chronic liver diseases (Murawaki et al.,1993). Li et al. (1992) studied 44 alcoholics versus eight controls. ...
... Several biochemical indicators have been reported as potential noninvasive serum/plasma markers of fibroproliferation. Among them, the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been shown by several groups to correlate in some way with the development of cirrhosis, the extent of toxic damage to the liver in alcoholic liver disease and the inflammatory activity in patients with chronic viral hepatitis (Kasahara et al. 1997;Walsh et al. 1999;B€ oker et al. 2000). Until present, 28 extracellular MMPs classes have been presented as inflammatory markers, which play a role in tissue degradation by physiological and pathological mechanisms. ...
The aim of this study is to predict potential hepatocellular damage by determining total antioxidant status (TAS) and matrix metalloproteinases (MMPs) 2 and 9 levels of different groups of dental surgery patients who are asymptomatic (normal ALT, AST records). Patients were divided into five groups according to the anamnesis (to be diagnosed formerly as HCV infection or not), microbiological (positive-Anti-HCV antibodies and HCV-RNA positive or negative) and biochemical test results. Except for the control group, serum Anti HCV antibody levels and line immunoassay tests were found positive in all groups. HCV-RNAs were found positive only in group 3 whom were formerly diagnosed with HCV infection, not under medical treatment and in group 5 under medical treatment (<2X10(5) IU/mL). Statistical analyses were performed using one way multifactorial ANOVA (MANOVA) at the statistical significance level of 5% and was confirmed that the changes in biochemical markers had significant effects on subjects who had been in different groups. Following multiple comparisons, significant groups' differences were obtained in all biochemical markers. In conclusion, to determine not only TAS levels but also the MMPs and evaluate those together may be noninvasive biomarkers for predicting the inflammation in liver and approaching the prognosis of HCV infection. This article is protected by copyright. All rights reserved.
... As widely recognized, the excess synthesis and deposition of extracellular matrix (ECM) that is mainly directed by the induction of cytokine release, is mostly associated with the increased severity of liver disease [92,93] . As a result, the matrix metalloproteinase (MMPs) including, MMP-1, -2, -3, -8, -9, -12, -13 and -14, become inactive and fail to remove excess ECM [94][95][96] , and subsequently disturb the balance between fibrogenesis and fibrolysis in the liver [97][98][99][100] , an evidence for the development of liver fibrosis. ...
Hepatitis C virus (HCV) infects more than 170 million people worldwide, and thereby becomes a series global health challenge. Chronic infection with HCV is considered one of the major causes of end-stage liver disease including cirrhosis and hepatocellular carcinoma. Although the multiple functions of the HCV proteins and their impacts on the modulation of the intracellular signaling transduction processes, the drive of carcinogenesis during the infection with HCV, is thought to result from the interactions of viral proteins with host cell proteins. Thus, the induction of mutator phenotype, in liver, by the expression of HCV proteins provides a key mechanism for the development of HCV-associated hepatocellular carcinoma (HCC). HCC is considered one of the most common malignancies worldwide with increasing incidence during the past decades. In many countries, the trend of HCC is attributed to several liver diseases including HCV infection. However, the development of HCC is very complicated and results mainly from the imbalance between tumor suppressor genes and oncogenes, as well as from the alteration of cellular factors leading to a genomic instability. Besides the poor prognosis of HCC patients, this type of tumor is quite resistance to the available therapies. Thus, understanding the molecular mechanisms, which are implicated in the development of HCC during the course of HCV infection, may help to design a general therapeutic protocol for the treatment and/or the prevention of this malignancy. This review summarizes the current knowledge of the molecular mechanisms, which are involved in the development of HCV-associated HCC and the possible therapeutic strategies.
... In agreement with our results, Kasahara et al and Walsh et al found that serum levels of MMP-2 were elevated in patients than in controls [33,34]. On the other hand, Boeker et al [35] and Mueawaki et al [36] reported that serum MMP-2 concentrations were not altered in chronic liver disease. ...
Background: The need for repetition of liver biopsy, especially in assessing the degree of fibrosis and follow-up of treatment protocols, justifies an intensive search for non-invasive alternatives. We attempted to investigate the clinical usefulness of serum fibrogenesis markers in pediatric chronic liver diseases.
Methods: We measured serum levels of TGF-β1, collagen IV, laminin, MMP-2 and EGF-R, in 50 children with chronic liver disease (HBV, HCV and Bilharziasis) and 30 healthy controls, and determined their relationship to frequently used liver function tests and liver biopsy findings in patients.
Results: TGF-β1, collagen IV, laminin and MMP-2, but not EGF-R, were significantly higher in patients than in controls (P < 0.01). None of these markers correlated with the histological fibrosis stage, whereas laminin correlated with necroinflammatory activity (P < 0.01). TGF-β1, collagen IV, laminin and MMP-2 had the ability to discriminate patients with significant fibrosis, while only collagen IV and laminin were able to discriminate those with cirrhosis. Among these markers, collagen IV had the best predictive accuracy for significant fibrosis (AUROC 0.94; PPV 91.5%) and cirrhosis (AUROC 0.85; PPV 80%).
Conclusions: In conclusion, these markers may be useful in reducing but not replacing the need for liver biopsy in the monitoring of disease progression and treatment effectiveness and might be an inseparable part of assessment of chronic hepatopathies.
... MMP expression is enhanced in various tissues during inflammation, fibrosis and sclerosis. Increased serum levels of MMP-1 and MMP-3 in rheumatoid arthritis [16], MMP-1, MMP-8, and MMP-9 in cystic fibrosis [17], MMP-9 in chronic obstructive pulmonary disease [18], MMP-2, MMP-9, and TIMP-1 in acute coronary syndrome [19], MMP-9 and TIMP-1 in aortic sclerosis [20], MMP-2 in liver cirrhosis [21], MMP-2 and TIMP-1 in hepatic fibrosis [22], and MMP-2 in chronic kidney disease [23, 24] suggest a relationship between MMP levels and pathology of tissue injury. ...
... Indeed, in previous studies in HCV monoinfection, TIMP-1 levels alone had high sensitivity, but relatively low specificity [27][28][29]. However, previous studies on MMP-2 in HCV monoinfection also yielded conflicting results, with some studies finding MMP-2 useful in predicting fibrosis [28,30] and other studies showing low diagnostic utility [27,29]. The reason for these contradictory results is not clear. ...
Noninvasive tests that can be used in place of liver biopsy to diagnose fibrosis have major limitations. They either leave a significant proportion of patients without a definitive diagnosis or produce inaccurate results. Moreover, the performance of these tests is lower in HIV/hepatitis C virus (HCV) coinfection. Against this background, we examined the utility of serum matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 1 (TIMP-1) measurements in combination with routine clinical data to predict fibrosis in HIV/HCV-coinfected patients.
Patients with a liver biopsy who had not received anti-HCV therapy were included in the study. A model including variables independently associated with fibrosis was constructed. Diagnostic accuracy was determined by measuring the area under the receiver operating characteristic curve (AUROC). Positive (PPV) and negative (NPV) predictive values were calculated.
Ninety patients were included in the study. Aspartate aminotransferase (AST), platelet count and MMP-2 were predictors of significant fibrosis (F≥2) and cirrhosis (F4). A score constructed using these variables yielded an AUROC of 0.76 for F≥2 and 0.88 for F4. Score cut-offs detected (value ≥3.5) and excluded (value ≤1.5) F≥2 with a PPV of 87% and an NPV of 88%. Thirty-one patients (34%) were correctly diagnosed using these cut-offs, with four (13%) incorrect classifications. Cirrhosis was excluded with a certainty of 98% and diagnosed with a probability of 83%. Two (17%) of 12 patients were misclassified as having cirrhosis. The AST to platelet count index and MMP-2 levels were sequentially applied to detect F≥2. Forty-one patients (46%) were identified with this approach, with six (15%) misclassifications.
MMP-2 levels can be used in combination with AST and platelet count to aid the diagnosis of liver fibrosis in HIV/HCV-coinfected patients.
... Matrix degradation regulates the development of fibrosis (Bataller and Brenner, 2005), and collagen degradation occurs as a consequence of changes in the balance of the matrix-degrading metalloproteinases (MMPs) and their specific tissue inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) (Kasahara et al., 1997). Then we examined the expression of MMP-2, MMP-13, TIMP-1, and TIMP-2 by quantitative real time RT-PCR in WT and A 1 AR(Ϫ/Ϫ) mice. ...
Mice lacking A(1) adenosine receptors (A(1)AR) were thought to be protected from developing fatty liver; however, the contribution of A(1)AR to hepatic fibrosis has not been explored. Here we found that the expression of A(1)AR was decreased in fibrotic liver induced by chronic carbon tetrachloride (CCl(4)) but increased in that induced by bile duct ligation (BDL). Therefore, we examined whether A(1)AR contributes to hepatic fibrosis in CCl(4) and BDL animal models using A(1)AR knockout mice. Compared with wild-type (WT) mice, hepatic fibrosis resulting from chronic CCl(4) exposure was attenuated in A(1)AR(-/-) mice with markedly decreased collagen deposition and reduced hepatic stellate cell activation, whereas bile duct-ligated A(1)AR(-/-) mice displayed a significant increase in hepatic fibrosis. Hepatocyte damage was reduced in A(1)AR(-/-) mice after a single injection of CCl(4), with down-regulation of CYP2E1 and UCP2 gene expression in livers, which resulted in impaired liver sensitivity to CCl(4). However, BDL caused severe bile infarcts in livers of A(1)AR(-/-) mice, with significantly elevated levels of bile acid compared with those in WT mice. CCl(4) and BDL resulted in different expression patterns of genes involved in fibrogenesis in A(1)AR(-/-) mice. These results indicate that A(1)AR participates in the pathogenesis of hepatic fibrosis with a complex mechanism, and the effect of targeting adenosine and its receptors in the prevention of hepatic fibrosis should be cautiously evaluated.
... En la regulación extracelular de la actividad de las MMPs las moléculas más importantes son los inhibidores tisulares de las metaloproteinasas (TIMPs) (90,101). Diversos estudios, tanto a nivel experimental como en muestras de pacientes con HC, han demostrado la relación entre el aumento de la expresión y la activación de diferentes MMPs y la progresión de la fibrosis hepática en la HC por el VHC (102)(103)(104) La carcinogénesis se entiende como un proceso con múltiples etapas que se van acumulando hasta llegar al tumor maligno y su diseminación. En el caso del CHC el daño hepático crónico por diferentes causas produce inflamación, muerte celular, regeneración celular y cirrosis, daño del ADN, displasia y finalmente CHC (106). ...
La Ciclooxigenasa 2 (COX-2) ha sido implicada en múltiples procesos patológicos como inflamación, fibrogénesis y carcinogénesis. Los objetivos de este trabajo de Tesis Doctoral han sido valorar el patrón de expresión de la COX-2 en la infección crónica por el virus C (VHC) y su relación con la expresión de las metaloproteinasas (MMPs) en pacientes con infección crónica por el VHC.Se han estudiado 51 pacientes, 32 con una infección crónica por VHC, 9 con hepatopatía alcohólica y 10 pacientes como grupo control. Western Blot, RT-PCR, ELISA e inmunohistoquímica se utilizaron para estudiar el patrón de expresión de COX-2, MMP-2 y MMP-9 en muestras de tejido hepático.El análisis de la COX-2 en muestras hepáticas de pacientes con infección crónica por el VHC demostró un incremento progresivo de sus niveles de expresión intrahepática en relación con la gravedad de la lesión histológica y que se acompañó de un aumento de la concentración intrahepática de prostaglandinas. En el estudio inmunohistoquímico se observó que la COX-2 se expresaba en el citoplasma de hepatocitos en la hepatitis crónica grave y cirrosis hepática (CH) por el VHC. El patrón de expresión intrahepático de la COX-2 fue similar en la CH vírica y alcohólica. El nivel de expresión intrahepático de las MMP-2 y MMP-9, y la actividad intrahepática de MMP-9, estaban significativamente aumentados en relación a la progresión de la lesión hepática y de forma paralela al patrón de expresión intrahepático de la COX-2. Se determinó una asociación de los niveles de expresión intrahepática de la COX-2 con el estadio de fibrosis hepática. Los resultados indican que la COX-2 juega un importante papel en la fibrogénesis y, probablemente, en la carcinogénesis hepática, en la infección crónica por el VHC.
... (38;39) In accordance to increased production of MMPs in liver tissue samples, serum MMP-2, and also TIMP-1 and TIMP-2 concentrations, were markedly increased in patients with liver cirrhosis, and showed a good correlation with the degree of liver fibrosis. (39)(40)(41)(42)(43) However, in one study no correlation was observed between plasma MMP-2 and both liver fibrosis and grade of inflammation in patients with chronic hepatitis C. (44) Kupffer cells can influence stellate cells through the secretion of MMP-9.(15) MMP-9 can activate latent transforming growth factor-beta, which is the dominant stimulus to ECM production by stellate cells. ...
... Basal MMP concentrations were also assessed at baseline, after 4 weeks, and upon the completion of the exercise training programs. In addition to the acute changes in MMP concentrations, recent data suggests that circulating MMPs play an integral role in growth factor bioavailability, capillary growth, cytokine regulation, and atherosclerotic plaque disruption (Coppock et al. 2004;Fowlkes et al. 1995Fowlkes et al. , 2004Hashimoto et al. 2002;Kai et al. 1998;Kasahara et al. 1997;Roberts et al. 2006;Tayebjee et al. 2005). Previously,Roberts et al. (2006)examined the eVects of a three week exercise intervention on circulating MMP-9 concentrations in obese men diagnosed with metabolic syndrome. ...
Matrix metalloproteases (MMPs) in the circulation are thought to modulate the activation of growth factors, cytokines, and angiogenesis, facilitating physiological adaptations to exercise training. The purpose of this work was to characterize serum MMP-1, MMP-2, MMP-3, and MMP-9 concentrations pre- and post-eight weeks of exercise training. We tested the hypothesis that exercise training would influence serum MMP concentrations in response to an acute resistance exercise test (ARET). Participants were randomized into an 8-week training program (5 days per week) that emphasized callisthenic (CT, N = 8) or resistance (RT, N = 8) exercise. Serum MMP concentrations (MMP-1, -2, -3, -9) were assessed in men (N = 16) in response to an acute bout of high-intensity resistance exercise (six sets of 10-RM squats with 2-min inter-set rest periods) both before and after 8 weeks of training. Training resulted in a temporal shift in the peak MMP-1 concentration from post-ARET to mid-ARET in both groups. Post-training, MMP-9 concentrations were increased immediately after the ARET in the CT group as compared to pre-training ARET concentrations. RT did not alter MMP-3 and -9 concentrations. These data suggest that the mode of exercise training influences the MMP response to an acute bout of exercise, revealing a possible role of MMPs in initiating training-specific adaptations.
... While there was no difference in the MMP-2 concentrations of patients with haemochromatosis with fibrosis and control subjects, there was a significant correlation between serum MMP-2 and the degree of fibrosis. A similar correlation between serum MMP-2 and fibrosis has recently been described in patients with chronic hepatitis C. 36 An increase in MMP-2 mRNA with increasing fibrosis has been shown in other fibrotic liver diseases, 30 and increased MMP-2 may play a role in the perpetuation of fibrogenesis in iron overload. ...
Altered matrix degradation contributes to fibrosis in some liver diseases but the role of matrix degradation in fibrogenesis associated with genetic haemochromatosis has not previously been addressed.
To measure serum concentrations of tissue inhibitor of metalloproteinase 1 (TIMP-1) and matrix metalloproteinases (MMP), MMP-1, MMP-2, and MMP-3 in patients with haemochromatosis and control subjects.
Forty patients with haemochromatosis and 19 healthy control subjects. Ten of the 40 patients were studied before and after venesection therapy.
Serum levels of TIMP-1, MMP-1, MMP-2, and MMP-3 were measured by enzyme immunoassay and correlated to hepatic iron concentration and degree of histological fibrosis.
Serum TIMP-1 was increased in patients with haemochromatosis compared with controls (163 (30) versus 123 (28) ng/ml, p < 0.0002). Mean serum TIMP-1 concentration of patients with haemochromatosis without fibrosis was significantly higher than in controls (153 (16) versus 123 (28) ng/ml, p = 0.03). Serum TIMP-1 concentration correlated with both hepatic iron concentration and hepatic iron index (r = 0.42, p < 0.01; r = 0.42, p < 0.01). Serum MMP-2 concentrations correlated with increasing degree of fibrosis in patients with haemochromatosis (r = 0.38, p = 0.01). The mean MMP-1: TIMP-1, MMP-2:TIMP-1 and age/sex matched MMP-3:TIMP-1 ratios were significantly lower in patients with haemochromatosis than controls (0.11 (0.06) versus 0.2 (0.14), p = 0.02; 3.32 (0.9) versus 3.91 (0.81), p = 0.05; and 0.26 (0.12) versus 0.47 (0.27), p = 0.007, respectively). Following venesection, MMP-2 and MMP-3 concentrations increased by 11% (p = 0.03) and 19% (p = 0.03), respectively.
This study provides the first evidence of an alteration in matrix degradation in haemochromatosis that may be a contributing factor to hepatic fibrogenesis in this disease.
... Following their initial identification, circulating gelatinase levels in humans have been correlated to rheumatoid arthritis (12,13), glomerulonephritis (14), hepatitis (15), and cancer (16)(17)(18). Increased plasma MMP-2 activity has also been associated with placental remodeling in late pregnancy (19). ...
Three constitutive gelatinases in human plasma were identified and characterized relative to known matrix metalloproteinase (MMP) gelatinases: MMP-2 (fibroblast 72-kDa) and MMP-9 (neutrophil 92-, 130-, and 225-kDa). Substrate gel electrophoresis (gelatin zymography) revealed an apparent Mw of 78-, 82-, and 89-kDa for these gelatinases. Densitometry revealed that MMP-9 and MMP-2 were highly calcium sensitive requiring 50-150 microM and 500 microM calcium for half-maximal activity, respectively. Of the new gelatinases, only the 89-kDa form demonstrated slight calcium activation. The three gelatinases were unaffected by known MMP inhibitors: EDTA (5 mM), 1,10-phenanthroline (2 mM), and pepstatin (18 microM). Serine and thiol protease inhibitors (leupeptin, aprotinin, PMSF, TLCK, TPCK, antichymostatin, antipain) were also ineffective. Solution-phase IEF revealed that the 78- and 82-kDa forms focused at neutral pI 6.72-7.95 whereas the 89-kDa focused at an acidic pI 4.89-5.18 (similar to neutrophil and fibroblast forms). The data indicate that these gelatinases are not MMPs or partially activated MMPs. Their role in normal and pathological conditions is not known.
Aim:
The aim of the present study is to investigate the effect of long-term zinc supplementation, which is important for the activation of various enzymes that contribute to antioxidant and antifibrotic activities, on the improvement of serum fibrotic markers in patients with autoimmune hepatitis (AIH).
Methods:
A total of 38 patients with AIH under regular treatment at our hospital who provided their consent for being treated with polaprezinc (75 mg twice daily) were included and classified into 2 groups: the patients with zinc elevation (n = 27) and the patients without zinc elevation (n = 11). Serum biomarker of fibrosis, protein expression levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were evaluated.
Results:
A significant difference was found between the variability of serum procollagen type Ⅲ and collagen type Ⅳ-7S between the 2 groups before and after zinc administration for more than 24 months (p = 0.043 and p = 0.049). In the patients with zinc elevation, no significant changes were found in collagenase (MMP-1 and MMP-13) before and after zinc administration, whereas a significant increase in the expression of gelatinase (MMP-2 and MMP-9) was found after administration (p = 0.021 and p = 0.005). As for the relative ratio of MMPs to TIMPs, only MMP-9 to TIMP-1 showed a significant increase (p = 0.004).
Conclusions:
Long-term treatment with polaprezinc has been demonstrated to safely improve serum fibrosis indices through increases in MMP-2/-9 and MMP-9/TIMP-1 and is expected to be well combined with direct antifibrotic therapies such as molecularly targeted agents.
Background and aims
Disturbances in matrix metalloproteinases (MMPs) and corresponding tissue inhibitors (TIMPs) contribute to hepatitis C virus (HCV)-induced fibrosis. This study aimed to determine MMP-9/TIMP-1 levels in addition to MMP-2 and -9 activities; correlating with the improvement of liver fibrosis in patients under direct-acting antiviral (DAA) therapy.
Methods
Clinical and laboratory follow-up were performed before treatment and after 12 weeks post-treatment, referred as sustained viral response (SVR). We evaluated liver function including non-invasive fibrosis measurements; MMP activity by zymography; and MMP-9/TIMP-1 complex, inflammatory and pro-fibrogenic mediators by immunoenzymatic assays.
Results
Cohort included 33 patients (59.5 ± 9.3 years, 60.6% females) whose reached SVR and 11 control-paired subjects (42.5 ± 15 years, 54.5% females). Before treatment, HCV patients presented higher MMP-9/TIMP-1 levels (P < 0.05) when compared to controls, and the highest values were observed in patients with fibrosis (P < 0.05). In addition, MMP-9/TIMP-1 levels were significantly reduced after DAA therapy (P < 0.0001) and were associated with profibrogenic biomarkers. No differences were observed for MMP-2 and -9 activities; however, these biomarkers were significantly associated with inflammatory mediators.
Conclusion
Our data suggest that MMP-9/TIMP-1 complex can be a promising biomarker of active fibrogenesis, being able to identify the interruption of fibrosis progression after HCV eradication.
In Japan, the incidence of hepatocellular carcinoma (HCC) has been increasing over the last 30 years, and epidemiological surveys have shown that as a causative agent, hepatitis C virus (HCV) is more common than hepatitis B virus (HBV). Chronic hepatitis C has been demonstrated to evolve to cirrhosis and HCC [1–3]. The HCC occurrence rate in cirrhotic patients with anti-HCV has been reported to increase steadily with a yearly incidence of 1.4%–7% [4–6]. Thus, a majority of cases with chronic HCV infection progress slowly to liver cirrhosis and HCC.
During fibrogenesis, the quantity, proportion, and composition of matrix proteins in the liver change due to the activation of hepatic stellate cells (HSCs) resulting in excessive accumulation of fibrous tissue. The exact mechanisms of these changes are not fully known. In this study, we postulated that IL-18 may upregulate matrix metalloproteinase-2 (MMP-2) and its tissue inhibitor (TIMP-1) in such proportions that will encourage fibrogenesis. To test this hypothesis we estimated the serum concentrations of IL-18, MMP-2, TIMP-1 in 56 patients with chronic hepatitis C virus (HCV), 28 patients with hepatitis B virus (HBV), 16 patients with non-alcoholic steatohepatitis (NASH) and 100 healthy controls using commercially available ELISA kits. The METAVIR activity and fibrosis scores of the liver biopsies from the patients were determined histologically. We found that IL-18 concentrations were significantly higher among HCV, HBV, and NASH patients than in healthy controls. We also found that IL-18 increased progressively from patients with no fibrosis (397.46 ± 73.54 pg/mL) to patients with cirrhosis (1384.11 ± 526.60 pg/mL). Although IL-18 is associated with minimal production of MMP-2 throughout the period of fibrosis from 199.48 ± 18.62 ng/mL at F0 to 225.25 ± 14.75 ng/mL at F4, it is associated with two-fold increase of TIMP-1 from 225.25 ± 14.75 ng/mL to 500.77 ± 30.50 ng/mL. We suggested that the high concentration of TIMP-1 inhibits the relatively low concentration of MMP-2 thus promoting the continuous deposition of collagen fibers in the liver. We concluded that IL-18 and TIMP-1 may be more important than MMP-2 in hepatic fibrogenesis. © 2012 Olusi et al, publisher and licensee Dove Medical Press Ltd.
Background
Airway inflammation and remodeling of extracellular matrix are important features of asthma. Matrix metalloproteinases (MMPs) are group of enzymes expressed in the airways with their inhibitor (tissue inhibitor of MMPs (TIMP) and they are the key responsible for extra cellular matrix (ECM) degradation.Objective
To clarify the role of MMP-9 and TIMP-1 in asthma exacerbation and airway remodeling.Subjects and methodsThe study included 3 groups, group “A” included 22 patients with stable asthma group “B” included 18 patients during asthma exacerbation and group “C” of 18 healthy volunteer served as control. All groups were matching age and sex. Levels of MMP-9 and TIMP-1 were measured in the induced sputum of the 3 groups. Serum IgE skin prick test and PEFR were assessed.ResultsMMP-9, TIMP-1 and MMP-9/TIMP-1 ratio increased in both A and B groups in comparison to control (P < 0.001). During exacerbation MMP-9 and MMP-9/TIMP-1 ratio showed significant increase for both but TIMP-1 did not show significant change when compared to stable asthmatics. There was significant negative correlation between PEFR and MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio.ConclusionMMP-9 and TIMP-1 play an important role in pathophysiology of asthma exacerbation and airway remodeling. Clearly, a greater understanding of the pathogenesis of asthma is critical to the development of better therapeutic modalities.
Background/Aim: Non invasive diagnosis of hepatic fibrosis has become the focus because of the limited biopsy, especially in the screening of hepatic fibrosis. Matrix metalloproteinases (MMPs) are thought to play an essential role in liver injury associated with tissue remodeling. The present study aims to investigate levels of two major collagen-degrading enzymes, matrix metalloproteinase (MMP-1& MMP-2) in children with viral and parasitic liver diseases. Methods: Serum samples from 75 children with chronic hepatitis B (n = 12), hepatitis C (n = 22), Bilharziasis (n = 34), and healthy children (n = 30) were collected for measuring the levels of MMP-1 and MMP-2 using ELISA technique. Liver function tests were measured using auto-analyzer. Abdominal ulltrasonography was also done. Results: The results of this study showed a significant increase in MMP-1 level in children with Bilharziasis, whereas serum MMP-2 level was significantly increased in children with hepatitis B and C. Serum MMP-1 and MMP-2 levels were correlated with liver function indices and liver biopsy scores. MMP-1 level showed negative correlation with ALT (r= -0.274, P< 0.05), AST (r= -0.343, P< 0.01) ALP (r = -0.322,P<0.05), total bilirubin (r= -0.357, P< 0.01), GGT(r= -0.244, P<0.05). Significant positive correlation was obtained with ALT/AST ratio (r=0.250, P ≤ 0.05), serum albumin (r=0.249, P< 0.05), and prothrombin concentration (r= 0.236, P< 0.05). Level of MMP-2 showed positive correlation with ALP(r= 0.249, P<0.05). According to the severity of liver disease, levels of MMP-1 showed significant decrease whereas MMP-2 showed significant increase. The sensitivity level of MMP-1 was 0, 0 & 76.5 % and of MMP-2 was 50, 48.3 & 61.8 % for HBV, HCV and Bilharzial respectively at specificity 100% for both markers. Conclusion: Since serum MMP S activities were significantly varied according to the cause as well as the stage of liver fibrosis, an individual profile of these parameters might serve as an easy accessing serum marker to monitor the progression of liver disease.
To explore the relationships between serum concentrations of tissue inhibitor of metalloproteinase-2 (TIMP-2) and matrix metalloproteinase-2 (MMP-2), and severity of liver fibrosis in chronic hepatitis B.
A total of 101 patients with hepatitis B and 54 healthy control subjects were consecutively enrolled. Serum MMP-2 and TIMP-2 were quantified by enzyme-linked immunosorbent assay.
Serum MMP-2 concentrations in patients with stage F2 - F4 fibrosis were significantly higher than in patients with stage F0 - F1 fibrosis and control subjects, but no significant difference was found between patients with stage F0 - F1 fibrosis and control subjects. Significant differences in serum TIMP-2 concentrations were found between patients with stages F2 - F4 and F0 - F1 fibrosis, and between stages F0 - F1 fibrosis and healthy control subjects. Areas under the receiver operating characteristic curves of serum TIMP-2 and MMP-2 for predicting clinically significant fibrosis (stage F2 - F4) were 0.899 and 0.770, respectively.
Serum TIMP-2 and MMP-2 assessment may represent a valuable noninvasive diagnostic test for liver fibrosis in hepatitis B.
Hepatitis C virus (HCV) causes chronic hepatitis C (CH-C) and is epidemiologically linked with the occurrence of hepatocellular carcinoma (HCC). To elucidate the comprehensive gene expression profiles of CH-C and HCC, serial analysis of gene expression (SAGE) libraries were made from CH-C and HCC tissues of a patient, and compared with a reported SAGE library of a normal liver (NL). Scatter plots of the distribution of tags from the HCC library exhibited the existence of many differentially expressed genes compared with those from the CH-C and NL libraries. Up-regulation of IFN-gamma inducible genes and oxidative stress-inducible genes were identified in both the CH-C and HCC libraries, and some unpublished new genes were specifically up- or down-regulated in the HCC library. This genome-wide scanning study discloses the molecular portraits of CH-C and HCC, and provides novel candidate genes that should help clarify the mechanism of hepatocarcinogenesis in the chronically HCV-infected liver.
There are still some limitations of these marker panels to be considered. First, the design of every study differed in population characteristic, patient selection, significant fibrosis prevalence, blood test inclusion, biochemical measurement and liver histological assessment, resulted in various panels with different markers and parameters. The agreement among these indexes is poor and validation study is needed to choose a proper panel and cutoff value for clinical use. Second, none of the studies controlled for degree of necro-inflammatory activity, most of the panels include markers likely to reflect or be affected by inflammation in the liver, which is much more mobile than fibrosis stage. Third, the formulae are easy to fail because many markers included will be influenced by extrahepatic diseases or conditions such as inflammation, haemolysis, cholestasis, hypercholesterolaemia and renal failure. Finally, few of the studies include treated patients. It is not clear whether these indexes are suitable for assessing treatment response. However, a few studies by Poynard et al suggested that Fibrotest could also be used as surrogate markers of the histological impact of treatments in patients infected by HCV and HBV 53, 54.
Liver disease in patients with chronic hepatitis C virus (HCV) infection has an accelerated course in the presence of human immunodeficiency virus (HIV) coinfection. Some data suggest that HIV suppression achieved with highly active antiretroviral therapy (HAART) ameliorates HCV-related liver disease progression. The aim of this study was to test if there is overexpression of serum markers of liver inflammation and fibrosis in HIV-HCV-coinfected patients and if the effect is counteracted by HAART. In a pilot, cross-sectional, and comparative study serum markers of liver inflammation (CK-18 and HGF) and fibrosis (HGF, MMP-2, and TIMP-1) were measured via ELISA in HIV-infected patients off and on HAART, HCV monoinfected, HIV-HCV coinfected off and on HAART, and controls (10 per group). HIV-HCV-coinfected off HAART patients with low CD4 counts had higher levels of M30, HGF, and MMP-2 than HIV-HCV-coinfected on HAART. HCV coinfection predicted higher levels of MMP-2 [B 65.82 (95% CI 3.86-127.78); p = 0.04], HGF [B 520.22 (95% CI 123.65-916.78); p = 0.01] and M30 [B 128.02 (95%CI 16.39-239.64); p = 0.03]. HAART use was a predictor of lower levels of MMP2 [B -83.18 (95%CI (-146.8) - (-19.52)); p = 0.01] and M30 [B -112.9 (95% CI (-221.3) - (-4.52)); p = 0.04]. Other factors analyzed including alcohol intake ware not associated with the studied markers. In conclusion, serum markers of hepatic inflammation and fibrosis are overexpressed in HIV-HCV-coinfected patients with advanced immunosuppression, while HAART has a "protective" effect.
Fibrogenesis is a typical reaction of the liver to injury. In the case of overstimulation of fibrogenesis clinically significant fibrosis and, eventually, cirrhosis occur. Treatment of liver cirrhosis is limited, therefore it is important to screen and monitor patients at risk of cirrhosis. Noninvasive parameters are ideal for this purpose due to their risk profile and repeatability.
Systematic review of literature.
Among large number of proposed biomarkers, there is a distinct difference between two groups or classes. Class I biomarkers are associated with the process of fibrogenesis, their presence in the serum is the result of the increased turnover of extracellular matrix. Class II biomarkers and their combinations are mostly markers of liver function or structural damage. We have identified 27 Class I and 13 Class II biomarkers that have been proposed in the literature. We have evaluated in detail those which reached limited clinical application.
General clinical acceptance of these biomarkers is low because of various drawbacks. Simple and readily available biomarkers have low accuracy in predicting liver fibrosis and more advanced markers have low cost-benefit ratio. Therefore liver biopsy remains the "gold standard" for diagnosis of fibrosis. However potential noninvasive alternatives exist and their implementation could be valuable.
Liver fibrosis (LF), where the chronic HCV infection is a major cause, is a characteristic of chronic liver diseases. LF results from chronic damage to the liver in conjunction with the accumulation of ECM proteins. Matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs) are thought to play an essential role in the hepatic lesions. The available data concerning the circulating levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in chronic hepatitis C are not conclusive. Therefore, the present study was designed to seek the relationship between serum MMP-9, and TIMP-1 to liver status in chronic liver disease in fifty patients divided into three groups (chronic hepatitis, liver cirrhosis and hepatocellular carcinoma). MMP-9 and TIMP-1 were analyzed by the enzyme linked immunosorbent assay (ELISA). The results showed that the lowest serum level of MMP-9 was found in chronic hepatitis patients compared to the control ( P < 0.05). Serum MMP-9 is decreasing during progression of chronic hepatitis to cirrhosis showing the least level in the cirrhotic group. Serum TIMP-1 was significantly higher in the cirrhotic group compared to chronic hepatitis ( P < 0.05) and controls ( P < 0.001). MMP-9 was negatively correlated to both TIMP-1 and the histological severity in chronic hepatitis. There was a positive correlation between TIMP-1 and the degree of fibrosis (r = 0.73, P < 0.001). Lastly, there was a statistically significant increase of MMP-9 ( P < 0.001) and TIMP-1 ( P < 0.05) in HCC patients compared with the other groups. In conclusion, these findings raise the possibility of using serum TIMP-1 as a non-invasive assay in liver fibrosis. Further, the altered balance between circulating MMP-9 and TIMP-1 during HCV infection may play an important role in aggravating liver injury progression in chronic liver diseases.
Auteursnaam op omslag: Johan Kuyvenhoven. Proefschrift Universiteit Leiden. Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.
Background:
Chronic transplant nephropathy remains the major cause of graft loss after the first year post transplant, with the exception of death with functioning graft. The histological hallmark of chronic kidney rejection is progressive fibrosis in which extracellular matrix turnover plays an important role. This turnover is regulated by several systems of connective tissue proteases, the matrix metalloproteinases family being one of them. Every metalloproteinase exerts a different function over extracellular matrix proteins and can contribute to the pathogenesis of several diseases, such as rheumatoid arthritis and glomerulonephritis. The role of metalloproteinases in the pathogenesis of chronic transplant nephropathy and in kidney transplantation has not yet been addressed.
Methods:
We measured the serum levels of proMMP-1, proMMP-2 and proMMP-3 by ELISA in 40 patients with chronic transplant nephropathy, 30 with acute rejection, 30 with stable graft function for a time equivalent to chronic transplant nephropathy, 30 with stable graft function for a time equivalent to acute rejection, and 30 healthy age-paired blood donors.
Results:
Serum proMMP-2 and proMMP-3 were significantly higher in patients with chronic transplant nephropathy than in patients with acute rejection, stable graft function and healthy donors. The most striking finding was the significant positive correlation observed between serum levels of proMMP-3 and serum creatinine, and between circulating levels of proMMP-2 and proteinuria. Serum concentration of proMMP-1 was increased in patients with acute rejection compared with those with stable graft function and healthy donors.
Conclusions:
Serum proMMP-2 and proMMP-3 reflect the changes of glomerular and interstitial extracellular matrix in chronic transplant nephropathy, suggesting that they could play a role in the pathogenesis of this condition. Acute rejection is associated with increased levels of proMMP-1, which could be a reflection of the stimulation induced by a number of inflammatory cytokines produced in such a process.
BACKGROUND & AIMS:: Biomarkers are being developed as alternatives to liver biopsy for predicting liver fibrosis in patients with chronic hepatitis C (CHC). Hepascore utilizes non-invasive serum markers and has been validated in Australian and European populations for predicting different degrees of fibrosis. This study validated this test in a US population. METHODS:: Patients with chronic hepatitis C virus infection were assigned to training (n=203) or validation (n=188) sets. Liver fibrosis was staged according to the METAVIR scoring system. The Hepascore algorithm utilizes data on age, sex, as well as total bilirubin, gamma-glutamyl transferase, alpha2-macroglobulin and hyaluronic acid levels. RESULTS:: The ability of Hepascore to predict significant fibrosis (F2-4) as determined by the area under the ROC was similar in training (0.83) and validation sets (0.81) and was comparable to results seen in previous studies. A cutoff score of =0.55 was best for predicting significant fibrosis with a sensitivity and specificity of 82% and 65%, and positive and negative predictive values of 70% and 78%. When compared with two simple indices FIB-4 (age, platelets, AST and ALT) and APRI (AST and platelets), Hepascore performed better at excluding advanced fibrosis using a low cutoff score but worse at predicting fibrosis using a high cutoff score. An algorithm using Hepascore followed by FIB-4 or APRI, spared 103 of 391 individuals a liver biopsy missing advanced fibrosis in only 1 patient. CONCLUSION:: Hepascore accurately predicted likelihood of developing fibrosis and could alleviate the need for liver biopsy in a subset of patients.
A non-endoscopic abrasive panesophageal method of detecting malignant cells is described. This method showed a high specificity and an acceptable sensitivity as compared with endoscopic abrasive guided cytology, and is suitable for screening patients at risk of developing esophageal malignancy, and in the follow-up of patients who have undergone radical surgery.
Serum levels of tissue inhibitor of metalloproteinases-2 (TIMP2) and of precursor form of matrix metalloproteinase-2 (proMMP2) were determined in patients with chronic hepatitis and hepatocellular carcinoma by a one-step sandwich enzyme immunoassay. Serum levels of TIMP2 and proMMP2 were significantly higher in patients with chronic liver disease, than in normal controls. Serum levels of TIMP2 showed a weak negative correlation with the serum albumin level and prothrombin time (PT). Serum levels of proMMP2 in patients with chronic hepatitis were strongly correlated with those of type IV collagen and were negatively correlated with PT and serum albumin levels. Serum proMMP2 levels were also significantly correlated with histological stages. These data indicate that serum levels of proMMP2 might be useful in the follow-up of patients with chronic hepatitis.
Asthma presents a variable clinical response to corticosteroids (CS). Because CS more likely act on inflammation than on tissue remodeling, the presence of bronchial structural changes in certain asthmatics may explain their limited clinical response to CS. Matrix metalloproteinase-9 (MMP-9) and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), are, respectively, involved in tissue inflammatory processes and fibrogenic processes. Previous reports have suggested that MMP-9:TIMP-1 ratio may reflect the balance between these two processes in various diseases. This study evaluated the relation of this ratio and the response to CS in severe asthma. Twenty asthmatics with low baseline FEV1 (59 +/- 4% predicted) and >/= 30 % increase with beta2-agonist were recruited. Serum MMP-9 and TIMP-1 levels were measured and correlated with response to an oral CS trial (methylprenisolone 40 mg/d for 14 d). With oral CS, FEV1 changes (DeltaFEV1) ranged from -15 to +43%. The DeltaFEV1 closely correlated with the MMP-9:TIMP-1 ratios (rho = 0. 79, p = 0.0006). In conclusion, serum MMP-9: TIMP-1 ratio could predict the response of oral CS therapy in asthma. The low MMP-9:TIMP-1 ratio observed in subjects with little or no FEV1 improvement with CS supports the hypothesis that, in these asthmatic subjects, bronchial fibrogenesis predominates over inflammation.
As chronic liver disease progresses, an imbalance occurs between synthesis and breakdown of extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are involved in degrading ECM while tissue inhibitors of metalloproteinases (TIMPs) prevent their fibrolytic action. We determined if plasma levels of MMP-2, TIMP-1 and TIMP-2 are related to liver histology in patients with chronic hepatitis C. Plasma MMP-2, TIMP-1 and TIMP-2 levels were measured in 43 patients with chronic hepatitis C. Plasma levels of MMP-2, TIMP-1 and TIMP-2 and serum ALT were correlated with liver biopsy score and specificity and sensitivity of the assays in detecting advanced liver disease were calculated from ROC analysis. Plasma TIMP-1 was significantly correlated with histological activity index (r = 0.45), portal inflammation (r = 0.48), periportal necrosis (r = 0.34) and focal necrosis (r = 0.38). Plasma TIMP-2 was significantly correlated with fibrosis (r = 0.43) and confluent necrosis (r = 0.41). Using ROC analysis both TIMP-1 and TIMP-2 had significant diagnostic ability in detecting advanced liver disease (Area under the curve 0.73 for both, p 0.015 and 0.036 respectively). A normal plasma TIMP-1 excluded advanced liver disease. Neither plasma MMP-2 or serum ALT were related to fibrosis or to histological activity index. With increased severity of liver disease in chronic hepatitis C there is increased plasma levels of TIMPs -1 and -2. Plasma TIMP-1 and TIMP-2 are sensitive and to a lesser extent specific in detecting advanced liver disease in chronic hepatitis C and could be used in preference to serum ALT.
Tissue inhibitors of metalloproteinases (TIMPs) are involved in liver fibrosis through impaired matrix degradation. Previous studies showed that the serum level of TIMP-1 was increased in patients with chronic liver disease, reflecting the liver TIMP-1 level, and that it is useful for assessing liver fibrosis. An enzyme immunoassay for TIMP-2 is now available. In this study, we examined the clinical usefulness of this serum TIMP-2 test for liver fibrosis in patients with chronic liver disease, in comparison with the serum TIMP-1 test. The serum TIMP-2 concentration was 61 +/- 13 ng/ml in healthy controls (n = 32), and 18% higher in the group of chronic active hepatitis (CAH) patients (n = 34), 64% higher in the liver cirrhosis (LC) group (n = 33) and 44% higher in the hepatocellular carcinoma (HCC) group (n = 61), and similar to the control level in the chronic persistent hepatitis (CPH) group (n = 23). In contrast, the serum TIMP-1 concentration was 155 +/- 17 ng/ml in the healthy controls, 18% higher in CPH, 35% in CAH, 63% higher in LC and 92% higher in HCC. The serum TIMP-2 level was related to the histological degrees of both periportal necrosis and liver fibrosis, as well as to the serum TIMP-1 level. However, the relationships for TIMP-2 were weaker compared to those of serum TIMP-1. These results suggest that compared to the serum TIMP-1 level, changes in the serum TIMP-2 level in chronic liver disease are less liver-specific, and the serum TIMP-2 level is less useful in the assessment of liver fibrosis in chronic liver disease.
gement to cirrhosis, while the activity grades do not necessarily show linear correlation. The main risk factor associated with the progression of fibrosis is the age of infection. Other strongly associated factors are alcohol consumption and male sex. The median estimated duration of infection for progression to cirrhosis is shown to be from 20 to 30 years. 3‐5 When blood transfusion is the cause of the infection, the interval from its administration to the diagnosis of HCC is reported to be 30 years. 5 A cohort study of Japanese patients with chronic hepatitis C has shown that the average annual incidence of HCC is 1.3%‐3.2%. 6‐8 The incidence of HCC is lower in patients with mild fibrosis than in those with advanced fibrosis. Thus, the occurrence of HCC is strongly related to advanced liver fibrosis and the presence of liver cirrhosis. Indeed, the animal incidence of HCC in Japanese cirrhotic patients infected with HCV is 5%‐7%. 7
Matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs) are thought to play an essential role in liver injury associated with tissue remodeling. However, their distinct expression profile in different liver repair models still remains to be established. Hepatic expression of collagenase (MMP-13), gelatinases A and B (MMP-2, -9), stromelysin-1 and -2 (MMP-3, -10), membrane-type MMP-1 (MMP-14), and TIMP-1 and -2 was studied following single and repeated CCl4-mediated injury and after partial hepatectomy. Expression was analyzed by reverse transcription-PCR (RT-PCR), northern blot analysis, zymography, and immunohistochemistry. Following a single toxic liver injury, MMPs and TIMPs were induced in a distinct time frame in that expression of most MMPs was induced during the early phase of liver injury, was maximal during the inflammatory reaction, and was diminished in the recovery phase. In contrast, TIMP and MMP-2 steady state mRNA levels remained constant in the early phase, were strongly induced during tissue inflammation, and remained increased until the recovery phase. Interestingly, hepatic TNF-alpha expression paralleled the MMP induction profile, while the increase of TGF-beta1 expression mapped to the increase of TIMPs. Chronic liver injury was accompanied by an increase in the steady state mRNA levels of MMP-2 and TIMPs, while other MMPs remained more or less unchanged or were diminished. Partial hepatectomy was followed by a dramatic increase of MMP-14 and to a lesser extent also of TIMP-1 expression; other MMPs and TIMPs were not significantly induced. Liver injury is accompanied by profound changes in hepatic MMP/TIMP expression, the latter being critically dependent on the type of injury. Single toxic injury resulting in complete restoration was characterized by a sequential induction of MMPs and TIMPs suggesting initial matrix breakdown and matrix restoration thereafter. Chronic liver injury leading to fibrosis displays overall diminished matrix degradation mainly through TIMP induction, while liver regeneration induced by partial hepatectomy caused an induction of MMP-14 and TIMP-1 only, which might be unrelated to matrix turnover but connected to pericellular fibrinolysis or fibrolysis required for hepatocellular replication.
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