The Epstein-Barr virus (EBV) has an important and multifaceted role in liver pathology. As a member of the herpes virus family, EBV establishes a persistent infection in more than 90% of adults. Besides acute hepatitis during primary infection, many clinical syndromes of interest for the hepatologist are associated with EBV infection. The role of EBV in the evolution of chronic hepatitis from hepatotropic viruses is considered. Chronic EBV-associated hepatitis is suspected in immunocompetent adults with compatible serology, suggestive histology and detection of the viral genome in the liver and/or increase of specific circulating cytotoxic T-lymphocytes. EBV is the main cause of post-transplant lymphoproliferative disorders which occur in up to 30% of cases. EBV-driven lymphoproliferative diseases are also recognized in non-immunocompromised patients and liver is involved in up to a third of the cases. Directly implicated in the pathogenesis of different tumors, EBV has a disputable role in hepatocellular carcinoma carcinogenesis. Further research is required in order to establish or reject the role of EBV in human liver cancer. This paper attempts to discuss the range of EBV-associated chronic liver diseases in immunocompetent patients, from mild, self-limiting mononuclear hepatitis to liver cancer.

• Epstein-Barr virus
• Chronic hepatitis
• Liver disease
• Chronic active Epstein-Barr virus
• Post-transplant lymphoproliferative disorder
• Infectious mononucleosis

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-γ.

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-γ 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.

• Chronic hepatitis
• Epstein-Barr
• Epstein-Barr virus-specific CD8⁺ T cell

• Adult
• CD28 Antigens/blood
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/pathology
• Case-Control Studies
• Epstein-Barr Virus Infections/blood
• Epstein-Barr Virus Infections/complications
• Epstein-Barr Virus Infections/immunology
• Epstein-Barr Virus Infections/pathology
• Female
• Hepatitis, Chronic/blood
• Hepatitis, Chronic/etiology
• Hepatitis, Chronic/pathology
• Hepatitis, Chronic/virology
• Herpesvirus 4, Human/immunology
• Humans
• Immunocompromised Host/immunology
• Leukocyte Common Antigens/blood
• Liver/immunology
• Liver/pathology
• Liver/virology
• Male
• Middle Aged
• T-Lymphocytes/immunology
• T-Lymphocytes/pathology
• Transaminases/blood
• Tumor Necrosis Factor Receptor Superfamily, Member 7/blood