A 7-gene signature of the recipient predicts the progression of fibrosis after liver transplantation for hepatitis C virus infection

Abstract

Fibrosis recurrence after liver transplantation (LT) for hepatitis C virus (HCV) is a universal event and strongly determines a patient's prognosis. The recipient risk factors for fibrosis recurrence are still poorly defined. Here we assess a genetic risk score as a predictor of fibrosis after LT. The cirrhosis risk score (CRS), which comprises allele variants in 7 genes (adaptorrelated protein complex 3 S2, aquaporin 2, antizyme inhibitor 1, degenerative spermatocyte homolog 1 lipid desaturase, syntaxin binding protein 5-like, toll-like receptor 4, and transient receptor potential cation channel M5), was calculated for 137 patients who underwent LT for HCV infection and experienced HCV reinfection of the graft. The patients were stratified into 3 CRS categories: <0.5, 0.5 to 0.7, and >0.7. All patients underwent protocol biopsy after LT (median follow-up ¼ 5 years), and liver fibrosis was assessed according to the Desmet and Scheuer score. The data were analyzed with univariate and multivariate analyses. The results showed that the highest CRS category was strongly associated with the presence of F2 or F3 fibrosis in protocol biopsy samples 1, 3, and 5 years after LT (P ¼ 0.006, P ¼ 0.001, and P ¼ 0.02, respectively). Overall, 75.0% of the patients with a CRS > 0.7 developed at least F2 fibrosis, whereas 51.5% developed F3 fibrosis during follow-up. The predictive value of the CRS for fibrosis progression was independent of known clinical risk factors, including the age of the donor, the sex of the recipient, and the occurrence of acute rejection. A Kaplan-Meier analysis confirmed the prognostic value of the CRS with respect to the recurrence of severe liver fibrosis in HCV-infected patients after LT (log rank ¼ 6.23, P ¼ 0.03). In conclusion, the genetic signature of the recipient predicts the likelihood of severe liver fibrosis in the graft after HCV recurrence. The CRS might help with early clinical decision making (eg, the selection of patients for antiviral therapy after LT).

Prognostic model of rapid hepatic fibrosis progression in men with chronic hepatitis C

“…The rate of hepatic fibrosis progression is the main characteristic of the patient since the patients with the rapid progression of fibrosis to cirrhosis are the first candidates for antiviral therapy of chronic hepatitis C. Along with universally recognized risk factors that have an influence on the rate of hepatic fibrosis progression, significant role belongs to genetic markers. Comparison of genetic studies with clinical materials demonstrated the existence of a significant effect of the genetic polymorphism on this process in patients with chronic hepatitis C, however, the analysis of the complex impact of clinical data and genetic polymorphism was carried out in only a few works [2,13,17,[20][21][22][23].…”

TLR4 stresses the liver: Figure 1

“…Importantly, in murine models of liver fibrosis the expression of TLR4 on hepatic stellate cells appears to be functionally more relevant than its expression on KCs 4. In line with these data in mice, human genetic studies have also provided strong evidence for a link between TLR4 and the risk of developing severe hepatitis C virus-induced liver fibrosis before and after liver transplantation 7 8. While most of the latter studies have focused on liver fibrosis as the main outcome measure, the role of TLR signalling in other types of liver diseases—for example, alcoholic and non-alcoholic fatty liver, is less well defined 9 10…”

Association of Genetic Variants With Rapid Fibrosis

“…Limited other studies have focused on other gene regions. Evidence from a single study links recipients with higher cirrhosis risk scores to progression post-LT (30). On the other hand, a separate locus strongly predictive of cirrhosis—PNPLA3—had no significant association with progression after HCV-related LT (31).…”