Herpes Simplex Virus Hepatitis: An Overlooked Cause of Acute Liver Failure Across a Broad Spectrum of Immunocompromise

BACKGROUND AND AIMS: Herpes simplex virus (HSV) infection is common worldwide, but hepatic involvement is rare. HSV hepatitis is an uncommon yet frequently catastrophic cause of acute hepatitis and acute liver failure (ALF), accounting for < 1% of ALF cases while carrying very high mortality when diagnosis and antiviral therapy are delayed. Although classically associated with profound immunosuppression and late pregnancy, HSV hepatitis is increasingly recognized in patients with less obvious or "non-traditional" forms of immune dysfunction. METHODS: We describe three cases of HSV hepatitis presenting with distinct risk profiles and clinical manifestations and review the diagnostic and therapeutic challenges associated with this condition. RESULTS: Clinical presentation was nonspecific in all cases, and mucocutaneous lesions were absent or delayed, contributing to diagnostic uncertainty. All patients exhibited marked aminotransferase elevation with relatively modest hyperbilirubinemia ("anicteric hepatitis"), frequently accompanied by cytopenias and coagulopathy. Delayed recognition was associated with rapid clinical deterioration, whereas earlier initiation of intravenous acyclovir was associated with biochemical and clinical improvement. Diagnosis was established using polymerase chain reaction-based detection of HSV DNA in blood and tissue samples. CONCLUSIONS: HSV hepatitis remains an under-recognized cause of ALF across a broad spectrum of immunocompromised and seemingly immunocompetent patients. Given the narrow therapeutic window and favourable safety profile of acyclovir, empiric intravenous antiviral therapy should be considered in patients with ALF of indeterminate aetiology while diagnostic testing is pending, particularly in high-risk clinical settings. Increased awareness of this overlooked diagnosis may improve outcomes and prevent avoidable mortality.