Hepatitis C is often complicated by the development of cirrhosis and hepatocellular carcinoma. In Europe, the prevalence of hepatitis C virus (HCV) infection is approximately 1.5%. If a HCV infection is not treated or ineffectively treated, hepatocellular function may deteriorate progressively Citation[1]. For patients with end-stage disease, liver transplantation (LT) is currently the treatment of choice Citation[2]. The course of hepatitis C in a graft after LT is usually more severe than the course of hepatitis C in nontransplant patients Citation[2]. Recurrent hepatitis C in a liver graft is an important determinant of morbidity and mortality in patients following (LT; clinical presentation varies from minor symptoms in a clinically stable patient to rapid loss of graft function, leading to stage 3–4 fibrosis after 1 year and consecutive graft failure. Pegylated IFN-α2a (pegIFN-α2a) and ribavirin (RBV) treatment for up to 1.5 years is the current standard regimen in HCV-positive patients. A sustained virological response (i.e., the patient is serum-negative for HCV by PCR 6 months after the cessation of therapy) occurs in approximately 30–40% of patients with genotype 1 and in 80% of patients with genotype 2 or 3. However, antiviral treatments after LT are limited due to severe side effects. In addition, response rates, varying between 30 and 40%, are substantially lower in all HCV-positive patients Citation[3]. Relevant risk factors for the development of graft failure include high levels of viremia in the early post-transplant period, HCV genotype 1b, multiple episodes of rejection, the immunosuppressive regimen applied and the donor’s age (18–24 years). However, appreciable variations in graft inflammation and fibrosis, susceptibility to HCV infection, spontaneous viral clearance and antiviral therapy response suggest the existence of endogenous factors that influence the evolution of graft disease after LT. In several trials, the maximum capacity for producing different cytokines in response to appropriate stimulation has been shown to vary between individuals. Genetic polymorphisms of enzyme systems, cytokines and growth factors, which are involved in the mediation of immunomodulation, inflammation, extracellular matrix turnover and antioxidative stress, may explain the substantial differences in the severity of graft damage between individuals. Recently, notable associations between IL-28B gene single-nucleotide polymorphisms (SNPs) and spontaneous clearance of HCV and favorable responses to standard antiviral therapy (pegIFN–RBV) for HCV infection have been demonstrated in several trials Citation[4], and they suggest the influence of multiple genes in nontransplant patients. The IL-28B gene encodes the antiviral protein IFN-κ, which exhibits antiviral properties in response to IFN-α. IFN-κ is upregulated by peripheral blood mononuclear cells and hepatocytes during infection with HCV Citation[5]. Published data suggest that its nucleotide substitution lowers the cytokine expression of IL-28B and thereby reduces its antiviral potential in comparison with the T allele. However, considerations about the role of IL-28B variants in histological and biochemical severity of HCV recurrence, occurrence of acute cellular rejection and antiviral treatment success are promising. As there are similarities between the reinfection of a graft with HCV after LT and the natural course of infection with HCV, it is postulated that genetic variants of IL-28B (T/G, rs8099917) might play a role in the development of HCV-related graft disease and its response to treatment.
There are a few studies that have analyzed the association of distinct genetic variations to the progression of liver fibrosis after LT Citation[6–10]. However, all studies conducted had relatively small patient numbers.
Three recent studies have analyzed a higher number of HCV-infected patients and have provided follow-up data for at least 5 years Citation[11–13]. The first of these studies assessed the importance of a nonsynonymous TLR4 SNP (D299G) on graft survival following LT. In this mixed cohort of liver transplant recipients (55% with HCV infection) TLR4 D299G was associated with graft failure during follow-up. Interestingly, only the recipient, but not the donor TLR4 genotype, was responsible for this association. Notably, a TLR4 SNP (T399I, rs4986791), which cosegregates with the D299G variant, is incorporated into the CRS, which has been identified by a genome-wide association study Citation[14].
The second genetic locus that seems of importance in fibrosis progression after LT is the IL28B gene region. A SNP in this locus (rs12979860) has been shown to be associated with the development of at least F2 fibrosis in the graft 1 year after transplantation in 154 HCV-infected recipients Citation[12]. Again, as for the TLR4 SNP, only the recipient genotype but not the donor genotype, was predictive of fibrosis progression. The importance of the IL28B genotype was initially identified by genome-wide association studies in order to assess risk factors for therapy response and spontaneous clearance of HCV infection, however, has also been applied as an indicator for histological severity of HCV-induced liver disease. The previously published data on the association of the IL-28B gene polymorphism with the HCV-related outcome after LT have been confirmed by Eurich et al., who showed significant correlations between the IL-28B genotype distribution and grade of inflammation of the graft, levels of aminotransferases, viremia and treatment failure of antiviral interferon based therapy Citation[13]. The retrospective evaluation showed that the G allele was identified as a better marker of severe serum biochemical and histological indices of graft infection than the T allele. Furthermore, there was a strong association between the G allele and a lack of response to antiviral treatment. These data parallel several independent studies of the natural history of HCV infection that have found a significant association between two IL-28B SNPs (rs8099917 and rs12979860) and the response to antiviral treatment and spontaneous viral clearance Citation[5,15]. Nevertheless, the risk of therapy failure in the unfavorable phenotype group was much higher in patients after LT compared with the nontransplant group. This can be explained by an unrecognized mechanism by which immunosuppression interacts with IL-28B actions. However, other immunological factors such as HLA diversity between recipient and donor may contribute here. Thus, it might be interesting to combine the IL28B genotype with other associated markers, to further increase the predictive power of the polymorphism.
What clinical implications might be drawn from the results of the current studies? Severity of hepatitis C is limiting for a number of patients suffering from recurrent disease after LT. Prediction of fibrosis progression and response to antiviral therapy could markedly improve the outcome in this patient population. The clinical use of genetics in complex diseases, such as HCV recurrence after LT, has been hampered by difficulties in establishing markers that are robustly associated with a clinical phenotype.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Iadonato SP, Katze MG. Genomics: hepatitis C virus gets personal. Nature461, 357–358 (2009).
- Neumann UP, Berg T, Bahra M et al. Long-term outcome of liver transplants for chronic hepatitis C: a 10-year follow-up. Transplantation77, 226–231 (2004).
- Schmidt SC, Bahra M, Bayraktar S et al. Antiviral treatment of patients with recurrent hepatitis C after liver transplantation with pegylated interferon. Dig. Dis. Sci.55, 2063–2069 (2010).
- Suppiah V, Moldovan M, Ahlenstiel G et al. IL28b is associated with response to chronic hepatitis C interferon-α and ribavirin therapy. Nat. Genet.41, 1100–1104 (2009).
- Tanaka Y, Nishida N, Sugiyama M et al. Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat. Genet.41, 1105–1109 (2009).
- Falleti E, Fabris C, Toniutto P et al. Genetic polymorphisms of inflammatory cytokines and liver fibrosis progression due to recurrent hepatitis C. J. Interferon Cytokine Res.27, 239–246 (2007).
- Toniutto P, Fabris C, Falleti E et al. Methylenetetrahydrofolate reductase C677T polymorphism and liver fibrosis progression in patients with recurrent hepatitis C. Liver Int.28, 257–263 (2008).
- Fabris C, Toniutto P, Bitetto D et al. Low fibrosis progression of recurrent hepatitis C in apolipoprotein E ε4 carriers: relationship with the blood lipid profile. Liver Int.25, 1128–1135 (2005).
- Ben-Ari Z, Pappo O, Druzd T et al. Role of cytokine gene polymorphism and hepatic transforming growth factor β1 expression in recurrent hepatitis C after liver transplantation. Cytokine27, 7–14 (2007).
- Ben-Ari Z, Tambur AR, Pappo O et al. Platelet-derived growth factor gene polymorphism in recurrent hepatitis C infection after liver transplantation. Transplantation81, 392–397 (2006).
- Dhillon N, Walsh L, Kruger B et al. A single nucleotide polymorphism of Toll-like receptor 4 identifies the risk of developing graft failure after liver transplantation. J. Hepatol.53, 67–72 (2010).
- Charlton MR, Thompson A, Veldt BJ et al. Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection. Hepatology53, 317–324 (2011).
- Eurich D, Boas-Knoop S, Ruehl M et al. Relationship between the interleukin-28b gene polymorphism and the histological severity of hepatitis C virus-induced graft inflammation and the response to antiviral therapy after liver transplantation. Liver Transplant.17, 289–298 (2011).
- Manolio TA. Genomewide association studies and assessment of the risk of disease. N. Engl. J. Med.363, 166–176 (2010).
- Rauch A, Kutalik Z, Descombes P et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology138, 1338–1345 (2010).