Public Release Type:
Journal
Publication Year: 2014
Authors:
Lee WM,
Balko JA,
Dubin PH,
Gottfried M
Studies:
Hepatitis B Research Network
Background: Hepatitis B virus (HBV)-related liver injury is immune-mediated. The 1% of acute HBV infection evolving to acute liver failure (ALF) is presumed to result from over-exuberant immune responses. Arginase (ARG) is a non-antigen dependent immuno-modulator that inhibits HBV specific CD8 T-cells, by depleting arginine necessary for T-cell-hepatocyte attachment. ARG released from within damaged hepatocytes may provide increased modulatory effect, thus limiting further hepatocyte injury. We hypothesized that ARG might be driving the evolution to ALF, if values of ARG were lower than expected in ALF patients, suggesting a muted immune response in this setting. Methods: Serum levels of ARG-1 isotype were measured using a sandwich type ELISA employing HRP-labeled antibody in 107 HBV patients with different phenotypes: HBVALF (non-immunosuppressed), acute HBV with recovery, chronic hep B (with and without flares of activity), and, as controls, 20 acetaminophen-related ALF, 10 chronic hepatitis C and 10 healthy subjects. Results: Healthy controls had median ARG of 5 ng/mL, chronic HBV and HCV ~25-30 ng/mL (Table), while acute HBV, HBV flares and HBV-ALF median levels were 89.2, 78.4 and 69.5 ng/mL, respectively, markedly lower than APAP median level of 968 ng/mL. HBV-ALF ARG levels were actually lower than acute or flare HBV despite comparable aminotransferase levels. Particularly low values for ARG were found in those who died of HBV-ALF (median 30.4 ng/ mL; n=5). For chronic HBV phenotypes with relatively low AST values there was poor correlation of AST with ARG (Spearman rho); only flare or APAP patients showed strong correlations (rho >0.75). Summary/Conclusions: Despite massive hepatocyte necrosis, low ARG levels characterize HBV-ALF and, to a lesser extent, acute HBV patients, supporting the postulate of ARG-driven immunomodulation in hepatitis B. A genetically mediated alteration in ARG protein might account for the low levels observed. Further understanding of the significance of ARG levels in these settings will require mechanistic or genomic studies.