Review

Epstein-Barr virus (EBV) is ubiquitous across the world, and most infected individuals are seropositive for EBV by the time they are young adults. The primary EBV infection is usually asymptomatic but sometimes causes infectious mononucleosis (IM). Hepatobiliary problems are very common, particularly mild hepatic involvement (in 80%–90% of cases), which present as asymptomatic and self-limited elevation of transaminases, typically to 2–3 times above the upper limit of normal.¹

Recently, Hara and colleagues have suggested that pathogenic mechanisms can explain the hepatic involvement of EBV.² These authors studied peripheral blood mononuclear cells from 4 patients with severe EBV hepatitis and jaundice, and found that EBV mainly infected T cells, whereas EBV mainly infected B cells in patients with IM. T lymphocytes express fewer viral antigens than B cells and, therefore, exhibit greater immune evasion, which might explain the severity of some EBV cases with hepatic involvement. In the study by Hara and colleagues, the liver was biopsied in 3 patients with severe hepatitis, and spotty necrosis of the liver parenchyma with destruction of the limiting plate was found. Interestingly, in situ hybridization assays showed that lymphocytes, not hepatocytes, were infected, and it was confirmed that these were CD8+ T cells. Animal studies have suggested that activated CD8+ T cells are selectively trapped in normal livers, primarily through intracellular adhesion molecule 1 (ICAM-1), which is expressed in the sinusoidal endothelium and Kupffer cells.^3,4 These findings suggests that EBV-infected cells and activated CD8+ T cells may undergo uncontrolled clonal expansion, accumulating in the liver and causing hepatocellular injury through interferon-gamma, tumor necrosis factor alfa, and Fas ligand.⁵

LoSavio and Te describe 2 clinical cases in older adults, in whom mild cholestatic hepatitis led to a diagnosis of acute EBV infection despite atypical presentations.⁶ This is an interesting problem in this growing age group.⁷ In the first case, a 73-year-old woman with many medical problems presented with confusion, fever, and abnormal gamma-glutamyl transferase activity, and later developed hyperbilirubinemia and elevated alkaline phosphatase levels. After extensive testing and despite the absence of heterophilic antibodies (a common finding in this age group), the presence of EBV viral capsid immunoglobulin M antibodies led to the diagnosis of EBV. The patient's disease progression was good and required no specific therapy. In the second case, a 59-year-old woman presented with malaise, occasional fevers, bradylalia, hyponatremia, and abnormal liver enzyme activities, and subsequently developed hyperbilirubinemia and lower extremity pain with abnormal reflexes. A diagnosis of acute EBV infection complicated with encephalomyelitis and cholestatic hepatitis was established. Again, in terms of liver involvement, her disease progression was good and required no specific therapy.

In these cases, the diagnosis of cholestatic hepatitis due to EBV was established based on clinical suspicion and associated findings related to multiorgan involvement. Cholestatic hepatitis due to acute EBV infection in the elderly is rare, and it is usually difficult to diagnose because similar responses in liver function tests are common in other infectious and noninfectious processes.⁸ We recommend a two-step diagnostic algorithm when EBV hepatitis is suspected, as shown in Table 1 (based on data from Petrova and associates⁹ and Drebber and associates¹⁰).

Table 1.

Two-Step Diagnostic Algorithm for Hepatitis Secondary to Epstein-Barr Virus Infection

Confirmation Step Altered liver function tests – AST and ALT Serological evidence of EBV activity – Viral capsid antigen IgM – Viral capsid antigen IgG Histopathological changes – Sinusoidal lymphocytic infiltration Viral genome identified in liver tissue by PCR

Exclusion Step Alcohol consumption >40 mL per day Diabetes or impaired glucose tolerance Body mass index <18 kg/m2 or >26 kg/m2 Dyslipidemia Impaired thyroid function tests Gluten enteropathy Prior confirmed chronic liver disease Autoimmune hepatitis, primary biliary cirrhosis Viral hepatitis B or C Hereditary hemochromatosis or iron overload Wilson disease Hepatotoxic drug use in the past 12 months Hereditary muscular disorder

AST

aspartate aminotransferase

ALT

alanine aminotransferase

IgM

immunoglobulin M

IgG

immunoglobulin G

PCR

polymerase chain reaction.

Medical therapy for EBV cholestatic hepatitis is restricted to supportive measures in most cases.¹¹ However, (Continued on page 126) the severity and duration of some cases has led to different interventions, from antiviral agents to Molecular Adsorbents Recirculation System (MARS) therapy¹² and orthotopic liver transplantation.¹³

Finally, we believe that hepatic involvement in EBV infection is a field that requires systematic clinical research to define diagnostic and therapeutic guidelines. In the meantime, highly comprehensive clinical accuracy and judicious use of therapeutic options is the most useful and secure approach.