Progression of liver fibrosis in post-transplant hepatitis C: Mechanisms, assessment and treatment  Marina Berenguer, Detlef Schuppan  Journal of Hepatology  Volume 58, Issue 5, Pages 1028-1041 (May 2013) DOI: 10.1016/j.jhep.2012.12.014 Copyright © 2012 European Association for the Study of the Liver Terms and Conditions

Fig. 1 Algorithm for disease monitoring in HCV infected liver transplant recipients. 3-MALG, algorithm combing 3 biomarkers; HAI, hepatic activity index; ALT, alanine aminotransferase; HVPG, hepatic venous pressure gradient. Journal of Hepatology 2013 58, 1028-1041DOI: (10.1016/j.jhep.2012.12.014) Copyright © 2012 European Association for the Study of the Liver Terms and Conditions

Fig. 2 Natural progression of chronic hepatitis C. This scheme includes factors that promote fibrosis progression to cirrhosis, including those that are specifically associated with rapid progression in a subgroup of patients with post-transplant hepatitis C (e.g., immunosuppression, drugs, NAFL/NASH). ECM, extracellular matrix; MMP, matrix metalloproteinase; MΦ, macrophage; T, T cell; ROS, reactive oxygen species; TIMP, tissue inhibitor of metalloproteinases; TGFβ, transforming growth factor beta. Journal of Hepatology 2013 58, 1028-1041DOI: (10.1016/j.jhep.2012.12.014) Copyright © 2012 European Association for the Study of the Liver Terms and Conditions

Fig. 3 Direct and immune-mediated fibrogenic activities of HCV. HCV replicating at high copy numbers can directly trigger (indirect) fibrogenic pathways in infected hepatocytes that lead, e.g., to release of profibrogenic TGFβ. This mechanism may be operative in conditions of extremely high viremia, as often occurs post-transplant [29,83,102]. On the other hand, the immune response to HCV may generate macrophage (M2) and T (Th2, Treg, iNKT) cell responses that are skewed towards fibrogenic cytokine production. These responses are favoured by immune suppression and other second hits, such as steatosis and especially steatohepatitis, certain medications or co-infections. Moreover, increased donor age and high-level HCV replication sensitize hepatocytes to apoptosis, which is a driver of fibrogenesis (see also Fig. 4). NKT, natural killer T cell; M2, alternatively activated macrophage; Treg, regulatory T cell. Journal of Hepatology 2013 58, 1028-1041DOI: (10.1016/j.jhep.2012.12.014) Copyright © 2012 European Association for the Study of the Liver Terms and Conditions

Fig. 4 Role of cholangiocyte and progenitor cell activation in fibrosis progression. This mechanism plays an important role in steatohepatitis, but also in more advanced fibrosis (especially F⩾2) and possibly in HCV post-transplant fibrosing cholestatic hepatitis, where massive virus replication and hepatocyte apopotosis, likely favoured by other “second hits”, such as vascular compromise, steatosis, drug toxicity, elevated donor age and generation of reactive oxygen species (ROS), e.g., due to prior ischemia reperfusion damage, drive the emergence of fibrogenic progenitor cells. These cells replicate ductal plate formation by induction of a portal fibrotic matrix via secretion of profibrogenic factors and recruitment and activation of myofibroblasts (and macrophages). On the other hand, these myofibroblasts secrete factors and provide a matrix scaffold that contributes to the maintenance and maturation of the biliary progenitor cells. bFGF, basic fibroblast growth factor; CTGF, connective tissue growth factor; ET-1, endothelin-1; HGF, hepatocyte growth factor; MCP-1, macrophage chemotactic peptide-1 (CCL-2); PDGF, platelet-derived growth factor; SHH, sonic hedgehog; TGFβ, transforming growth factor beta. Journal of Hepatology 2013 58, 1028-1041DOI: (10.1016/j.jhep.2012.12.014) Copyright © 2012 European Association for the Study of the Liver Terms and Conditions