What is hepatitis due to infectious mononucleosis?

Hepatitis Due to Infectious Mononucleosis

Hepatitis due to infectious mononucleosis is liver inflammation caused by Epstein-Barr virus (EBV) infection, characterized by elevated transaminases that typically remain mild and self-limiting, though rarely can progress to severe hepatitis with jaundice. 1

Clinical Definition and Pathophysiology

Hepatitis in infectious mononucleosis represents liver involvement during primary EBV infection, where the virus infects lymphocytes (particularly T cells in severe cases) that infiltrate the liver, rather than directly infecting hepatocytes. 2

Key Characteristics:

• Typical presentation: Self-limited liver function abnormalities with transaminase elevations less than 5-fold the upper limit of normal in most cases 3
• Severe presentation: Rarely, transaminases can exceed 10 times normal levels, with jaundice developing in uncommon cases 3, 4
• Cellular mechanism: In severe hepatitis, CD3+, CD4+, and CD8+ T cells harbor most of the EBV DNA, whereas B cells are predominantly infected in milder cases without jaundice 2
• Histologic findings: Liver biopsy demonstrates EBV-infected lymphocytes infiltrating the liver tissue, not direct hepatocyte infection 2, 4

Clinical Presentation

Hepatitis in infectious mononucleosis occurs most prominently in adolescents and young adults, with liver involvement becoming increasingly apparent as the age of primary infection increases in developed countries. 5

Associated Features:

• Classic triad: Fever, pharyngitis, and lymphadenopathy accompany the hepatitis 1, 4
• Physical findings: Hepatosplenomegaly and tender hepatomegaly are common, with gallbladder wall thickening on imaging potentially predicting significant liver involvement 6, 4
• Laboratory findings: Atypical lymphocytosis on peripheral blood smear is characteristic 1, 4
• Subclinical presentation: Some patients present with predominantly hepatic manifestations and minimal physical symptoms, particularly in adult populations 5

Diagnostic Approach

Diagnosis requires serologic confirmation of acute EBV infection combined with elevated transaminases, using VCA IgM antibodies as the primary marker of recent infection. 1

Serologic Testing:

• Acute infection pattern: Positive VCA IgM (with or without VCA IgG) in the absence of EBNA antibodies indicates recent primary EBV infection 1, 7
• Heterophile antibodies: Monospot or heterophile tests become detectable between days 6-10 after symptom onset, though false-negative results occur in approximately 10% of patients, especially children under 10 years 1
• Timing considerations: EBNA antibodies develop 1-2 months after primary infection; their presence indicates infection occurred more than 6 weeks prior 1

Molecular and Histologic Confirmation:

• EBV DNA detection: Real-time PCR can detect EBV DNA in peripheral blood, with higher viral loads correlating with severe hepatitis 3, 2
• Liver biopsy: Shows lymphocytic infiltration with EBV-positive lymphocytes (confirmed by in situ hybridization for EBER), not infected hepatocytes 2, 4
• Cross-reactivity caveat: Serological assays may lack specificity due to antigenic cross-reactivity with other herpes viruses, requiring molecular confirmation in atypical cases 3

Clinical Course and Prognosis

The hepatitis is typically self-limiting with full recovery expected through conservative management alone, even in cases with markedly elevated transaminases or jaundice. 6

Important Clinical Patterns:

• Multiple peaks: Transaminases may show multiple elevation peaks corresponding with clinical deterioration over several weeks, but this does not indicate need for antiviral or immunosuppressive therapy 6
• Peak values: Alanine transaminase can reach levels as high as 1,795 U/L and total bilirubin up to 154 µmol/L in severe cases, yet still resolve with conservative management 6
• Duration: Prolonged hepatitis can persist for 11 weeks or more before complete resolution 6

Management Approach

Conservative management is recommended for immunocompetent patients, as there is no strong evidence supporting antiviral or immunosuppressive therapy for EBV-associated hepatitis. 6

Key Management Principles:

• Supportive care: Conservative management with monitoring is the standard approach 6
• Antiviral therapy: Aciclovir does not ameliorate the course of infectious mononucleosis in otherwise healthy individuals 1
• Immunosuppression: Not indicated for hepatitis in immunocompetent patients, even with multiple transaminase peaks 6
• Monitoring: Serial liver function tests and clinical assessment until resolution 6

Differential Diagnosis Considerations

Hepatitis due to infectious mononucleosis can be clinically and biochemically indistinguishable from acute hepatitis caused by hepatotropic viruses (hepatitis A-E), requiring specific EBV testing for definitive diagnosis. 3

Conditions to Exclude:

• Other viral causes: CMV, adenovirus, HIV, hepatitis A-E viruses, and Toxoplasma gondii can cause mononucleosis-like illness with hepatitis 1, 3
• Concurrent infections: Hepatitis A can occur concomitantly with EBV infectious mononucleosis 4
• False-positive heterophile tests: Can occur in leukemia, pancreatic carcinoma, viral hepatitis, and CMV infection 1