Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy

Abstract

Elevated serum ferritin levels may reflect a systemic inflammatory state as well as increased iron storage, both of which may contribute to an unfavorable outcome of chronic hepatitis C (CHC). We therefore performed a comprehensive analysis of the role of serum ferritin and its genetic determinants in the pathogenesis and treatment of CHC. To this end, serum ferritin levels at baseline of therapy with pegylated interferon-alpha and ribavirin or before biopsy were correlated with clinical and histological features of chronic hepatitis C virus (HCV) infection, including necroinflammatory activity (N 5 970), fibrosis (N 5 980), steatosis (N 5 886), and response to treatment (N 5 876). The association between high serum ferritin levels (>median) and the endpoints was assessed by logistic regression. Moreover, a candidate gene as well as a genome-wide association study of serum ferritin were performed. We found that serum ferritin ! the sex-specific median was one of the strongest pretreatment predictors of treatment failure (univariate P < 0.0001, odds ratio [OR] 5 0.45, 95% confidence interval [CI] 5 0.34-0.60). This association remained highly significant in a multivariate analysis (P 5 0.0002, OR 5 0.35, 95% CI 5 0.20-0.61), with an OR comparable to that of interleukin (IL)28B genotype. When patients with the unfavorable IL28B genotypes were stratified according to high versus low ferritin levels, SVR rates differed by >30% in both HCV genotype 1-and genotype 3-infected patients (P < 0.001). Serum ferritin levels were also independently associated with severe liver fibrosis (P < 0.0001, OR 5 2.67, 95% CI 5 1.68-4.25) and steatosis (P 5 0.002, OR 5 2.29, 95% CI 5 1.35-3.91), but not with necroinflammatory activity (P 5 0.3). Genetic variations had only a limited impact on serum ferritin levels. Conclusion: In patients with CHC, elevated serum ferritin levels are independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-alpha-based therapy. (HEPATOLOGY 2012;55:1038-1047 C hronic hepatitis C (CHC) is one of the most significant infectious diseases by being a leading cause of liver-related morbidity and liver transplantation worldwide. 1,2 Triple therapy comprising the hepatitis C virus (HCV) nonstructural protein 3-4A protease inhibitors, telaprevir or boceprevir, in combination with pegylated interferon-alpha (PEG-IFN-a) and ribavirin is becoming the new standard treatment for patients infected with the difficult-tocure HCV genotype 1. 3 Recently completed phase III

The Association of Il28b Genotype with the Histological Features of Chronic Hepatitis C Is HCV Genotype Dependent

“…Interestingly, these observations mimic the findings by Rembeck et al of a trend for higher rates of liver fibrosis in IL28B CC patients with HCV-3 infection with respect to similar patients carrying the T allele [15]. In the thoroughly investigated Swiss cohort, Bochud and colleagues however failed to demonstrate any significant association between IL28B genotypes and fibrosis stage in patients HCV-3 using the rs860 SNP [16]. This could in part be explained by a direct cytoxic effect of HCV-3 strain on the liver as a consequence of its steatogenic and fibrosing activity: in HCV-3 infected patients, both a hepatic derangement of lipid metabolism and a faster progression of liver fibrosis have been demonstrated in comparison to other HCV genotypes [17,18].…”

Interferon lambda polymorphisms associate with body iron indices and hepatic expression of interferon-responsive long non-coding RNA in chronic hepatitis C

“…Additionally, genotypes in IFNL region unfavorable for disease outcome and markers of serum and hepatocyte iron overload are both associated with higher GGT activity levels and liver steatosis. Increased lipid accumulation in the liver as well as elevated activity of GGT belongs to the group of strong negative prognostic factors of progressive liver damage [29, 30]. The reciprocal interaction between immune system and body iron level has been well documented [28, 31].…”

Impact of common risk factors of fibrosis progression in chronic hepatitis C

“…Steatosis was dropped from the model due to its insignificant effect. Markers of tissue or systemic inflammation, such as liver histology activity scores16 and ferritin,17 were not included, as these were considered as surrogate markers of other factors.…”