Serum IL‐6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: An analysis based on gender differences

Abstract

Interleukin-6 (IL-6) may play a role in the pathogenesis of hepatocellular carcinoma (HCC). Recently, it was reported in mouse models that estrogen-mediated inhibition of IL-6 production explains the gender disparity in HCC. We conducted a retrospective cohort study to examine whether this hypothesis is applicable to human HCC. We enrolled 330 patients with chronic hepatitis C whose serum samples were collected between January 1994 and December 2002. Serum IL-6 concentrations were measured and patients were divided into three groups according to IL-6 levels: low, middle, and high. We evaluated the association between serum IL-6 levels and the risk of subsequent HCC development, including subgroup analysis on each gender. During the follow-up period (mean 9.0 yr), HCC developed in 126 patients. The incidence rates differed significantly among the three groups (p 5 0.015), increasing in accordance with serum IL-6 levels. However, unexpectedly, this tendency was significant only in female patients. In a multivariate analysis, higher serum IL-6 level was an independent risk factor for HCC development in female patients, with a hazard ratio of 1.61. Although female patients showed a weak negative correlation between serum IL-6 levels and estradiol levels, the lower risk of HCC in female patients cannot be fully explained by estrogen-mediated inhibition of IL-6 production. In conclusion, higher serum IL-6 level was an independent risk factor for HCC development in female but not male chronic hepatitis C patients. Measurement of serum IL-6 levels may provide useful information for predicting future HCC development in female chronic hepatitis C patients. ' 2009 UICC

The Value of the Cytokinome Profile

“…Since IL-8 and IL-6 concentrations correlated significantly with large tumor size (p-value < 0.05 and R > 0.83), this confirmed the clinical significance of IL-6 as a prognostic factor of cancer and, in particular, its association with the development of HCC (Łukaszewicz et al, 2007;Wong et al, 2009;Nakagawa et al, 2009). Indeed, CXCL10 levels correlated both with any tumour size and with transaminase levels suggesting that it could be used as marker of liver inflammation status and cancer progression.…”

“…However, the intra/peri-tumoral cytokines levels are often different from the serum levels (Budhu & Wang, 2006). Higher serum IL-6 level was an independent risk factor for HCC development in female but not male chronic hepatitis C patients (Nakagawa et al, 2009). IL-10 was highly expressed in HCC tumors and serum, correlating with disease progression (Budhu & Wang, 2006).…”

NF-κB and STAT3 – key players in liver inflammation and cancer

“…It is likely that genderspecific differences in IL-6 expression also affect the incidence of human HCC, as serum IL-6 is higher after menopause [50,51] and postmenopausal women display higher HCC incidence than premenopausal women [8]. Moreover, expression of IL-6 is elevated in both liver cirrhosis and HCC [52,53] and was recently found to correlate with rapid progression from viral hepatitis to HCC [54,55]. Precise mechanisms by which elevated IL-6 promotes HCC development are not known, but some of IL-6 functions are likely mediated by activation of STAT3.…”

Prevalence of Human Cytomegalovirus Infection among Human Immunodeficiency Virus Positive Women Receiving Antiretroviral Treatment at Federal Teaching Hospital Abakaliki, Ebonyi State, Nigeria

“…IL-6 levels are elevated in the serum of patients with chronic liver diseases and increase even more in patients who develop hepatocellular carcinoma [67,68]. Interestingly, high serum levels of IL-6 helped to predict the development of HCC in both hepatitis (HBV and HCV) infected patients [69].…”