Human Herpesvirus 6 in Acute Liver Failure: Leading Role, Supporting Actor or Innocent Bystander? A Case Series, Narrative Review and Management Algorithm Proposal

In recent years, an increasing number of acute liver failure (ALF) cases have been attributed to HHV-6, although its pathogenic role remains debated. In the absence of standardised diagnostic criteria, HHV-6 is likely underrecognized as a potential etiologic agent. We report three cases of liver injury with confirmed HHV-6 replication; each showing a markedly different degree of viral involvement. A narrative review of all previously reported cases of HHV-6-induced hepatitis in immunocompetent adults was conducted. Based on the available evidence, an algorithm was designed for the management of HHV-6-associated liver injury. Twenty cases were included, showing a predominance of young women (80%), fever as the most consistent symptom (75%), and a notable association (30%) with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Overall, 65% of patients met ALF criteria, and mortality reached 30%. Blood RT-PCR was the most frequently used diagnostic tool (70%), while liver biopsy was performed in 35% of cases. Antiviral therapy was administered in 45% of patients and corticosteroids in 40%, mainly due to coexisting DRESS syndrome or initial suspicion of autoimmune hepatitis. Notably, 25% of patients underwent liver transplantation. The proposed algorithm offers a structured approach to managing HHV-6 in patients with ALF and emphasises the importance of considering it in the differential diagnosis. HHV-6 should be considered in cases of ALF, particularly in young febrile women without an identified aetiology and in patients with concomitant DRESS syndrome. Further studies are needed to validate diagnostic criteria and guide treatment strategies.