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A rare find of a mummified child from the 16th century AD, in Korea, with relatively preserved organs, enabled a search for ancient hepatitis B virus (aHBV) DNA sequences from laparoscopic-derived liver biopsies. Analysis of the complete aHBV genome (3,215 base pairs) revealed a unique HBV genotype C2 (HBV/C2) sequence commonly spread in Southeast Asia, which probably represents an HBV that infected the Joseon Dynasty population in Korea. Comparison of the aHBV sequences with contemporary HBV/C2 DNA sequences revealed distinctive differences along four open reading frames. Genetic diversity between contemporary and recovered aHBV/C2 DNA may be the result of immunologic, environmental, and/or pharmacologic pressures. The calculated time of most recent common ancestor suggests that the Korean HBV sequence origin dates back at least 3,000 years and possibly as long as 100,000 years. This isolate most likely represents the earliest human HBV sequence that colonized Southeast Asia by human migration. Conclusion: This study describes the complete sequence of the oldest HBV isolate and the most ancient full viral genome known so far. (HEPATOLOGY 2012;56:1671–1680)

Hepatic fibrosis associated with inflammatory cell infiltration is a prominent feature of persistent infection by hepatitis B virus (HBV) and hepatitis C virus (HCV). The hepatic stellate cell (HSC) has assumed a central role in this response after its activation by inflammatory cytokines and mediators.1–5 The cell-mediated immune response after viral hepatitis reflects the activity of CD4+ helper T and CD8+ cytotoxic T lymphocytes. CD4+ T cells are activated through the interaction of major histocompatibility complex (MHC)-II with antigen-presenting cells, Kupffer cells, dendritic cells, and macrophages. CD8+ T cells are MHC-I restricted and are a major mechanism of cytotoxic clearance of infected cells.6 CD4+ T cells secrete cytokines such as tumor necrosis factor alpha, interferon gamma (IFN-γ), and interleukin 2. These cytokines are responsible for the activation of macrophages, Kupffer cells, and natural killer (NK) cells, leading to phagocytosis and nonspecific lysis of infected cells. Viral clearance during HCV infection is made possible through vigorous HCV-specific CD4+ and CD8+ T cell responses.7 It is thought that CD4+ T cell activation and priming are required for CD8+ T cells’ ability to achieve viral clearance through cytotoxic effects.8,9 These processes can also lead to activation of HSCs in response to injury, which in the absence of viral clearance is followed by matrix deposition, fibrosis, and eventually cirrhosis.10,11 HCV-specific CD4 activity is correlated with histological fibrosis and portal tract inflammation.12–14 A role of HSCs in the inflammatory response to viral infection has been established based on their capacity to present antigen and modulate lymphocyte behavior.15,16 Although lymphocytes directly interact with HSCs by adhesion,14 the pathways mediating interaction of lymphocytes and HSCs are not well understood. Moreover, HSC are phagocytic based on their internalization of latex particles, bacteria16 as well as apoptotic bodies.17 In murine models, fibrosis is mainly mediated by direct activation of HSCs by CD8 lymphocytes,18 and adoptively transferred CD8 cells are fibrogenic in naive mice. In addition, NK cells display anti-fibrotic activity by killing activated HSCs that have lost the self-recognition marker, MHC class I.19–21 In this study, we have investigated the morphological and functional interactions between human HSCs and lymphocyte subsets. Our results indicate that HSCs not only physically interact with lymphocytes but may contribute to lymphocyte clearance by cellular ingestion.

Liver diseases and regeneration are associated with hemodynamic changes denoting pathological alterations. Determining and monitoring physiological and pathological liver changes is essential for diagnostic and therapeutic objectives. Our aim was to determine the feasibility of functional magnetic resonance imaging (fMRI) during hypercapnia and hyperoxia for monitoring liver pathology. Liver fMRI images were acquired in rodents following acute bleeding, partial hepatectomy, and fibrosis. Results were quantitated and confirmed by histology. Changes induced by hyperoxia and hypercapnia following hemorrhage significantly correlated with the percentage of blood loss, reflecting lower liver perfusion and diminished vessel responsiveness to gas saturation. Hepatectomy resulted in an early decline in signal intensity changes due to hyperoxia, suggesting a decrease in liver perfusion and blood content. Following hepatectomy, signal intensity changes due to hypercapnia increased, signifying a change in liver perfusion from a mainly portal to a more arterial source. Two weeks after induction of fibrosis, signal intensity changes due to hypercapnia became much lower and those due to hyperoxia were much higher than those in normal livers, reflecting the increased perfusion due to the inflammatory process as confirmed by histologic analysis. With fibrosis progression, signal intensity changes induced by hypercapnia and hyperoxia were gradually attenuated, indicating structural and functional alterations of the liver vasculature during fibrosis. Conclusion: In various liver pathologies, fMRI response to hypercapnia and hyperoxia is sensitive to changes in liver hemodynamic status involved in hepatic damage or recovery; thus, this technique may offer an additional noninvasive diagnostic tool for evaluation and follow-up of liver diseases by means of examining perfusion-related alterations. (HEPATOLOGY 2008.)

Evaluation of needle biopsies and extensive clinicopathological correlation play an important role in the determination of liver allograft dysfunction occurring more than 1 year after transplantation. Interpretation of these biopsies can be quite difficult because of the high incidence of recurrent diseases that show histopathological, clinical, and serological features that overlap with each other and with rejection. Also, more than one insult can contribute to allograft injury. In an attempt to enable centers to compare and pool results, improve therapy, and better understand pathophysiological disease mechanisms, the Banff Working Group on Liver Allograft Pathology herein proposes a set of consensus criteria for the most common and problematic causes of late liver allograft dysfunction, including late-onset acute and chronic rejection, recurrent and new-onset viral and autoimmune hepatitis, biliary strictures, and recurrent primary biliary cirrhosis and primary sclerosing cholangitis. A discussion of differential diagnosis is also presented.