Epstein-Barr virus and hepatic failure: pathogenesis, clinical manifestations, and management

Abstract

Epstein-Barr virus (EBV) infection is ubiquitous, affecting over 90% of the global population, and while typically benign, it can rarely cause acute liver failure — a life-threatening complication that is frequently fatal. This review comprehensively reviews two overlapping clinical and pathogenetic patterns of EBV-associated hepatic failure — isolated severe EBV hepatitis and EBV-triggered hemophagocytic lymphohistiocytosis (HLH) — which are best understood as ends of a clinical spectrum rather than discrete entities. In isolated EBV hepatitis, liver injury is driven by CD8-positive T cells attacking EBV-infected B cells, causing bystander hepatocyte necrosis; inflammation remains confined to the liver, and supportive care is usually sufficient. By contrast, EBV-HLH involves EBV-infected monoclonal T or natural killer cells triggering a systemic cytokine storm (including interferon-gamma, tumor necrosis factor-alpha, interleukin-6, and interleukin-18) with hemophagocytosis, requiring immediate immunosuppression. In one pediatric cohort, an EBV DNA load exceeding 100,000 copies per milliliter was associated with a more than ten-fold increase in mortality, although no universally validated cutoff has been established across age groups or sample types; T-cell EBV DNA load provides additional prognostic information. Blood purification is an experimental adjunctive strategy in refractory cases, supported by very low-certainty evidence. We also discuss risk factors, diagnostic algorithms (including EBV DNA load, HLH-2004 criteria, and histopathology), therapeutic strategies (supportive care, antiviral therapy, immunomodulation, and liver transplantation), and future research priorities. Early recognition of HLH is life-saving. This review provides a practical clinical framework for differentiating these two entities and highlights knowledge gaps for future investigation.