**3.6.2.1 Transforming growth factor-**β**1 (TGF-**β**1)**

As a multifunctional polypeptide with fibrogenic, an anti-inflammatory and antiproliferative property, TGF-β1 is considered to play a pivotal role in the hepatic fibrogenesis strongly upregulating the production and deposition of ECM-components [10, 17, 62]. Similarly to the natural setting of HCV-infection, functionally relevant polymorphisms of TGF-β1 at codon 25 are associated with the rapid development of HCV-induced graft fibrosis.

Fig. 4. Genotype distribution (TGF-β1) within maximal fibrosis stages

C-allele of the TGF-β1-gene (codon 25) has been identified as marker for graft fibrosis development and was observed significantly less frequently in advanced fibrosis stages compared to lower ones (fig. 4; p=0.001) [63].

#### **3.6.2.2 Interleukine-28B (IL-28B)**

According to numerous studies, genetic variants of IL-28B seem to be significantly involved in the pathogenesis of HCV-related graft inflammation and antiviral therapy response [60, 64, 65]. IL-28B-gene encodes an antiviral protein - IFN-λ with antiviral properties in response to IFN-α, and is upregulated by peripheral blood mononuclear cells and hepatocytes during HCV-infection [40, 66-68]. Recently, a significant association of IL-28Bgenotype distribution was observed with the median grade of inflammation (p<0.001), mean levels of aminotransferases (ALT: p=0.001, AST: p=0.003; fig.5), median pre-treatment viremia level within 1 year after LT (p=0.046) and interferon-based antiviral therapy failure (p<0.001). IL-28B polymorphism (rs8099917) seems to influence the degree of graft inflammation at biochemical and histological levels [64].

Fig. 5. Levels of aminotransferases according to IL-28B-genotypes

Among successfully treated patients G-allele was significantly less frequent and GGgenotype was not present at all [64]. G-allele might serve as a marker for graft inflammation and as predictor for unfavorable antiviral therapy outcome in HCV-re-infected LTpopulation [60, 64].

The identification of non-invasive inflammation and fibrosis markers might help to differentiate re-infected patients with stable graft function without significant inflammation or fibrosis progression from patients at risk for short-term graft damage and define the indication for antiviral treatment.

#### **3.7 Organ allocation system**

Methodological changes in the principals of graft allocation may affect the course of HCVassociated graft disease. Since December 2006 liver graft allocation has been carried out according to MELD-score, which primarily assesses the impairment of liver function and secondarily reflects the extent of kidney damage. Some evidence arises about the negative impact of the current allocation system regarding survival, rate of re-transplantation, fibrosis progression and success of antiviral treatment. Therefore, the MELD-score, as an apparently reasonable attempt to improve the procedure of organ distribution, must undergo a critical analysis in future.
