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Soluble Inflammatory Markers As Predictors of Hepatocellular Damage and Therapeutic Response in Chronic Hepatitis C

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Soluble Inflammatory Markers As Predictors of Hepatocellular Damage and Therapeutic Response in Chronic Hepatitis C BJID 2009; 13 (October) 375 Soluble Inflammatory Markers as Predictors of Hepatocellular Damage and Therapeutic Response in Chronic Hepatitis C Alexandre Sampaio Moura1, Ricardo Andrade Carmo2, Antonio Lucio Teixeira1 and Manoel Otávio da Costa Rocha1 1Postgraduate Program of Infectious Diseases and Tropical Medicine, Federal University of Minas Gerais; 2Orestes Diniz Training and Referral Center for Infectious Diseases, Belo Horizonte City Health Department; Belo Horizonte, MG, Brazil Hepatitis C is an important burden worldwide being an important cause of cirrhosis and liver cancer in different parts of the world. Host immune response, especially T helper type 1 (Th1) cell-mediated, seems to play an important role in disease progression but is also crucial for viral elimination following specific therapy. Immune activation can be evaluated using peripheral levels of different cytokines, such as different chemokines (e.g. CCL5, CXCL10) and tumor necrosis factor alpha (TNF-α), and their soluble receptors (e.g. soluble TNF-α receptors 1 (sTNF-R1) and 2 (sTNF-R2). This review article focuses on the potential use of peripheral inflammatory markers as predictors of liver histological changes and therapeutic response among patients with chronic hepatitis C. Key-Words: Hepatitis C, chemokines, tumor necrosis factor receptor, interferon-alpha, liver fibrosis. Global prevalence rates of hepatitis C virus (HCV) infection promising results in this field and will be the subject of are estimated around 2% and chronic hepatitis C (CHC) is a this review. major cause of cirrhosis and referral for liver transplant worldwide [1,2]. Soluble Inflammatory Markers of Liver Disease Severity of hepatocellular damage among CHC patients Hepatocellular damage in CHC patients is mainly a result varies and factors such as older age at infection, male gender of T-helper 1 (Th1) cell-mediated immune response [16,17] and alcohol intake are associated with greater inflammation and is a major factor for liver fibrosis progression [18]. Th1 and fibrosis [3,4]. Coinfection with HIV [5]or hepatitis B virus response is highly active in patients with chronic HCV infection [6], steatosis [7] and insulin resistance [8] are also associated and CD8+ cytotoxic T lymphocytes (CTL) has a major role in with a more rapid progression of the disease. hepatocyte destruction in their attempt to clear out infection Assessment of liver staging in HCV-infected patients is [19,20]. Estimating the intensity of immune activation through essential to establish prognosis and the requirement for assessment of soluble inflammatory markers might thus help antiviral therapy. Liver biopsy is currently the gold standard predict liver injury. for assessment of liver fibrosis but imaging techniques such as Fibroscan and panels of biochemical/hematological markers Chemokines and Liver Disease such as FibroTest or APRI (aspartate aminotransferase to Chemokines is a subgroup of small cytokines involved platelet ratio index) are gaining acceptance [9,10]. Availability with leukocyte trafficking through a process called haptotaxis of non-invasive markers of liver fibrosis is warranted due to where leukocytes move towards higher concentrations of discomfort and risks associated with liver biopsy. chemokines. This process is important for the regulation of Combined treatment with interferon and ribavirin has been leukocyte migration into sites of infection or into lymph nodes shown to interrupt fibrogenesis and even reverse liver fibrosis [21-27]. Chemokines are also involved in leukocyte activation, when there is a sustained virologic response [11]. lymphocyte differentiation, regulation of Th1/Th2 balance, Unfortunately, response rates are low, especially among angiogenesis and fibrogenesis [21-27]. genotype 1 infected patients, those at an older age or with The more than 50 identified chemokines have been advanced liver fibrosis [12-15]. Identifying appropriate classified into four subfamilies (CC, CXC, C, CX3C) according candidates for treatment is well desired due to its high cost to the position of a pair of cystein residues near their amino and potentially serious adverse effects of the currently terminus [28]. Chemokines are named according to their available therapy. subfamily followed by the letter L (for ligand) and a number The use of soluble inflammatory markers have been corresponding to their respective gene (e.g. CCL5 or CXCL10) examined over the past ten years as predictors of both [29]. Nomenclature of chemokine receptors follow similar rules, liver staging and response to therapy in CHC patients. with the letter L substituted by the letter R (for receptor) (e.g. Different chemokines, tumor necrosis factor-α (TNF-α) CCR5, CXCR3). It is important to note that receptors are and TNF-α soluble receptors (sTNF-R) have been showing subfamily specific but usually binds more than one type of Received on 7 May 2009; revised 13 July 2009. chemokine [29]. Address for correspondence: Dr. Alexandre Sampaio Moura. R. Santa The two most important chemokine subfamilies are CXC Rita Durão, 41/503. Belo Horizonte – MG, Brazil. Zip code: 30140- [two cysteines separated by another amino acid (X)] and CC 110. (two adjacent cysteines). In chronic infections, CC chemokines The Brazilian Journal of Infectious Diseases 2009;13(5):375-382. are more involved with monocyte attraction whereas CXC © 2009 by The Brazilian Journal of Infectious Diseases and Contexto seems to be more important in directing migration of activated Publishing. All rights reserved. T lymphocytes into sites of inflammation [21,30]. www.bjid.com.br 376 Soluble Inflammatory Markers in Hepatitis C BJID 2009; 13 (October) As Th1 response is particularly involved in hepatocellular damage in CHC patients. CXCL10 has been widely studied in damage of CHC patients, there is special interest on CHC and is among the most promising soluble inflammatory chemokines responsible for the recruitment of Th1 cells into markers of liver inflammation and fibrosis. the liver. The most important of these chemokines are CCL2 In HCV infected liver, CXCL10 is produced by lymphoid (Monocyte Chemotactic Protein-1, MCP-1), CCL3 cells, hepatocytes and endothelial cells in response to (Macrophagic Inflammatory Protein 1 alpha, MIP-1 alpha), interferon-gamma, tumor necrosis factor-alpha (TNF-α) and CCL4 (Macrophagic Inflammatory Protein 1 beta, MIP-1beta), to HCV proteins such as NS5A and core [41-43]. Besides CCL5 (Regulated upon Activation, Normal T Cell Expressed attracting monocytes and T cells, CXCL 10 also plays a role in and Secreted, RANTES), CXCL9 (Monokine Induced by IFN- fibrogenesis. Hepatic stellate cells (HSC), the main cell gamma, MIG) and CXCL10 (Interferon-gamma Inducible involved in liver fibrogenesis[44], express CXCR3 and has Protein, IP-10). The above mentioned CCL chemokines bind been shown to migrate following a gradient of CXCL10 [45]. to CCR5 receptors while those CXCL chemokines bind to The association between circulating CXCL10 levels and CXCR3 [31]. HCV infection was initially demonstrated in 1997 [42] in a In the liver, chemokines are mainly produced by activated study that showed increased serum CXCL10 levels among monocytes, Kupffer cells, endothelial cells and hepatocytes CHC patients as compared to healthy volunteers. Further [32,33]. In accordance with the predominance of Th1 driven studies showed that besides being elevated [38], peripheral immune response, endothelial cells within portal tracts of HCV (either serum or plasmatic) CXCL10 levels showed a dose- infected livers secrete CCL3, CCL4 and CCL5 and infiltrating response association with liver inflammation and fibrosis lymphocytes express high levels of CCR5 [34]. In fact, there is [46,47]. greater expression of CCR5 and also of CXCR3 on liver Other chemokines have been studied in relation to liver lymphocytes as compared to circulating lymphocytes in histological changes in CHC patients. Intrahepatic expression patients with cirrhosis attributed to hepatitis C [34]. of CXCL9, a chemokine that binds to the same receptor of Expression of these chemokines receptors in liver CXCL10 and has similar functions, is also increased in CHC lymphocytes has also been associated with hepatocellular patients compared to a control group and correlates with liver damage. In a recent study, Larrubia et al. showed that the inflammation [34,48]. Peripheral levels of CXCL9 were also majority of CTL cells infiltrating the liver expressed a CCR5high/ significantly elevated among CHC patients compared to CXCR3high phenotype which was associated with porto- healthy control subjects [38,46]. periportal and lobular inflammatory activity [35]. In accordance Peripheral levels of other chemokines from CXC subfamily, with these findings, mutations resulting in a less functional such as CXCL8 (Interleukin-8, IL-8) and CXCL11 (Interferon- CCR5 were associated with less hepatic inflammation in gamma Inducible Protein-9, IP-9) are also increased among findings of two previous studies [36,37]. patients with CHC [38,48]. CXCL8 expression is stimulated by Although relevant to the understanding of the mechanisms the presence of intracellular HCV non-structural proteins (e.g. of liver inflammation in CHC, evaluation of chemokine NS5A) [49] and besides acting as a proinflammatory receptors profile and/or intrahepatic chemokines levels is chemokine, CXCL8 exerts a proviral effect through technically difficult to be made and cannot be widely used. inhibition of interferon antiviral activity [50-52]. Some However,
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