Comparative Analysis of Liver Injury-Associated Cytokines in Acute Hepatitis A and B

Abstract

Purpose: Acute hepatitis A (AHA) and acute hepatitis B (AHB) are caused by an acute infection of the hepatitis A virus and the hepatitis B virus, respectively. In both AHA and AHB, liver injury is known to be mediated by immune cells and cytokines. In this study, we measured serum levels of various cytokines and T-cell cytotoxic proteins in patients with AHA or AHB to identify liver injury-associated cytokines.

Materials and methods: Forty-six patients with AHA, 16 patients with AHB, and 14 healthy adults were enrolled in the study. Serum levels of 17 cytokines and T-cell cytotoxic proteins were measured by enzyme-linked immunosorbent assays or cytometric bead arrays and analyzed for correlation with serum alanine aminotransferase (ALT) levels.

Results: Interleukin (IL)-18, IL-8, CXCL9, and CXCL10 were significantly elevated in both AHA and AHB. IL-6, IL-22, granzyme B, and soluble Fas ligand (sFasL) were elevated in AHA but not in AHB. In both AHA and AHB, the serum level of CXCL10 significantly correlated with the peak ALT level. Additionally, the serum level of granzyme B in AHA and the serum level of sFasL in AHB correlated with the peak ALT level.

Conclusion: We identified cytokines and T-cell cytotoxic proteins associated with liver injury in AHA and AHB. These findings deepen the existing understanding of immunological mechanisms responsible for liver injury in acute viral hepatitis.

Keywords: Hepatitis A virus; chemokines; cytokines; hepatitis B virus; liver injury.

Fig. 1. Serum levels of cytokines, chemokines, and T-cell cytotoxic proteins in AHA and AHB. The data represent the serum proteins that were elevated in patients with AHA or AHB compared to healthy controls. Horizontal lines indicate mean values; n=46 for AHA, n=16 for AHB, and n=14 for healthy controls. p values are presented as *p<0.01 or ^†p<0.001, based on the unpaired Student's t-test. IL, interleukin; AHA, acute hepatitis A; AHB, acute hepatitis B.

Fig. 2. Correlation between the serum levels of CXCR3 chemokines and the degree of liver injury. Serum concentrations of CXCL10 (A) and CXCL9 (B) correlated to peak ALT levels in samples drawn from patients with AHA (left) or AHB (right). Correlation coefficients (r) are based on Pearson (AHA) or Spearman (AHB) analyses. p values <0.05 are considered statistically significant. AHA, acute hepatitis A; AHB, acute hepatitis B; ALT, alanine aminotransferase.

Fig. 3. Correlation between the serum levels of cytokines or T-cell cytotoxic proteins and the degree of liver injury. Serum concentrations of granzyme B (left), sFasL (center), or IL-18 (right) correlated to peak ALT levels (A and B) or peak total bilirubin levels (C and D) in samples drawn from patients with AHA (A and C) or AHB (B and D). Correlation coefficients (r) are based on Pearson (AHA) or Spearman (AHB) analyses. p values<0.05 are considered statistically significant. n.s., non-significant; sFasL, soluble Fas ligand; IL, interleukin; AHA, acute hepatitis A; AHB, acute hepatitis B; ALT, alanine aminotransferase.