Elevated level of circulating histones in acute-on-chronic liver failure patients and mice with conA-induced acute liver injury

Background: Hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) is characterized by a systematic inflammatory response and immunity disorder. Histones are extracellular damage-associated molecular pattern (DAMP) molecules that modulate the inflammatory response in a wide range of diseases; however, their clinical significance in HBV-related ACLF remains elusive. Objective: We aimed to elucidate the relationship between the expression of circulating histones and disease severity in ACLF patients. Method: We measured the histone mRNA expression in the peripheral blood mononuclear cells (PBMCs) of ACLF patients. We also measured serum histones and other inflammatory cytokines in both ACLF patients and ConA-induced liver injury/failure mice. Results: Circulating histone levels were significantly higher in ACLF patients than chronic hepatitis B patients and healthy volunteers (P<0.05 and P<0.001, respectively). No significant difference in HIST2H4A mRNA expression was observed between groups. Serum histone levels closely correlated with serological markers and cytokine levels, including total bilirubin (TBIL), international normalized ratio (INR), model for end-stage liver disease (MELD), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6). A negative correlation was found between circulating histones and the prognosis of ACLF patients. Conclusion: Excessive circulating histones may play a crucial role in the systemic inflammation associated with ACLF and represent a potential therapeutic target.