Chronic Epstein-Barr virus-related hepatitis in immunocompetent patients

Abstract

Aim: To investigate reactivated Epstein-Barr virus (EBV) infection as a cause for chronic hepatitis.

Methods: Patients with occasionally established elevated serum aminotransferases were studied. HIV, HBV and HCV-infections were excluded as well as any other immunosuppressive factors, metabolic or toxic disorders. EBV viral capsid antigen (VCA) IgG and IgM, EA-R and EA-D IgG and Epstein-Barr nuclear antigen (EBNA) were measured using IFA kits. Immunophenotyping of whole blood was performed by multicolor flow cytometry. CD8(+) T cell responses to EBV and PHA were determined according to the intracellular expression of IFN-gamma.

Results: The mean alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGTP) values exceeded twice the upper normal limit, AST/ALT ratio < 1. Serology tests showed reactivated EBV infection in all patients. Absolute number and percentages of T, B and NK cells were within the reference ranges. Fine subset analysis, in comparison to EBV(+) healthy carriers, revealed a significant decrease of naive T cells (P < 0.001), accompanied by increased percentage of CD45RA(-) (P < 0.0001), and terminally differentiated CD28(-)CD27(-)CD8(+) T cells (P < 0.01). Moderately elevated numbers of CD38 molecules on CD8(+) T cells (P < 0.05) proposed a low viral burden. A significantly increased percentage of CD8(+) T cells expressing IFN-gamma in response to EBV and PHA stimulation was registered in patients, as compared to controls (P < 0.05). Liver biopsy specimens from 5 patients revealed nonspecific features of low-grade hepatitis.

Conclusion: Chronic hepatitis might be a manifestation of chronic EBV infection in the lack of detectable immune deficiency; the expansion of CD28(-)CD27(-) and increase of functional EBV-specific CD8(+) T cells being the only surrogate markers of viral activity.

Figure 1

Significant differences detected between patients and control group by immunophenotyping. Patients were characterized by a decreased absolute number of naive CCCR7⁺CD45RA⁺CD4⁺ (A) and CD8⁺ (C) T cells, increased absolute number of memory CD45RA^-CD4⁺ (B) and CD8⁺ (D)T cells, increased absolute number of effector CD28^-CD27^-CD8⁺ T cells (E), as well as by increased percentage of IFNγ⁺CD69⁺CD8⁺ T cells after stimulation with EBV peptide GLCTMVL (F) and with PHA (G). Box-and-whiskers indicate the 25-75 percentile and min-max values for each group. Mean values are designated on all plots by a horizontal line. Man-Witney. P values are indicated for each comparison.

Figure 2

Liver biopsy, showing lymphocyte infiltrate within the lobule and some hepatocyte injury, with mild steatosis displayed in some cells.