Hepatitis D and hepatocellular carcinoma

Abstract

Hepatitis D virus (HDV) is a defective circular shape single stranded HDV RNA virus with two types of viral proteins, small and large hepatitis D antigens, surrounded by hepatitis B surface antigen. Superinfection with HDV in chronic hepatitis B is associated with a more threatening form of liver disease leading to rapid progression to cirrhosis. In spite of some controversy in the epidemiological studies, HDV infection does increase the risk of hepatocellular carcinoma (HCC) compared to hepatitis B virus (HBV) monoinfection. Hepatic decompensation, rather than development of HCC, is the first usual clinical endpoint during the course of HDV infection. Oxidative stress as a result of severe necroinflammation may progress to HCC. The large hepatitis D antigen is a regulator of various cellular functions and an activator of signal transducer and activator of transcription (STAT)3 and the nuclear factor kappa B pathway. Another proposed epigenetic mechanism by which HCC may form is the aberrant silencing of tumor suppressor genes by DNA Methyltransferases. HDV antigens have also been associated with increased histone H3 acetylation of the clusterin promoter. This enhances the expression of clusterin in infected cells, increasing cell survival potential. Any contribution of HBV DNA integration with chromosomes of infected hepatocytes is not clear at this stage. The targeted inhibition of STAT3 and cyclophilin, and augmentation of peroxisome proliferator-activated receptor γ have a potential therapeutic role in HCC.

Keywords: Cirrhosis; Epigenetic processes; Hepatitis D; Hepatocellular carcinoma; Necroinflammation; Oxidative stress.

Figure 1

The influence of large hepatitis D antigen in activating oncogenic pathways. JAK: Janus kinase; SRC: Proto-oncogene tyrosine-protein kinase Src; TRADD: Tumor necrosis factor receptor type 1-associated DEATH domain protein; FADD: Fas-associated protein with death domain; TRAF2: TNF receptor associated factor 2; TNF: Tumor necrosis factor; RIP: Receptor-interacting protein; STAT3: Signal transducer and activator of transcription 3; NF-κβ: Nuclear factor kappa beta; ROS: Reactive oxygen species; MEKK: Mitogen-activated protein kinase kinase kinase (MEK kinase); PKR: Protein kinase R; IKK: IêB kinase; CBP: CREB-binding protein.