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Systemic inflammation has been linked to its pathogenesis and outcome, but the identifiable triggers are absent. Recently, extracellular histones, especially H4, have been recognized as important mediators of cell damage in various inflammatory conditions. This study aimed to investigate whether extracellular histones have clinical implications in patients with hepatitis B virus (<jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content>)\u2010related <jats:styled-content style=\"fixed-case\">ACLF<\/jats:styled-content>. One hundred and twelve patients with <jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content>\u2010related <jats:styled-content style=\"fixed-case\">ACLF<\/jats:styled-content>, 90 patients with chronic hepatitis B, 88 patients with <jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content>\u2010related liver cirrhosis and 40 healthy volunteers were entered into this study. Plasma histone H4 levels, cytokine profile and clinical data were obtained. Besides, patient's sera were incubated overnight with human L02 hepatocytes or monocytic U937 cells in the presence or absence of antihistone H4 antibody, and cellular damage and cytokine production were evaluated. We found that plasma histone H4 levels were greatly increased in patients with <jats:styled-content style=\"fixed-case\">ACLF<\/jats:styled-content> as compared with chronic hepatitis B, liver cirrhosis and healthy control subjects and were significantly associated with disease severity, systemic inflammation and outcome. Notably, <jats:styled-content style=\"fixed-case\">ACLF<\/jats:styled-content> patients' sera incubation decreased cultured L02 cell integrity and induced profound cytokine production in the supernatant of U937 cells. Antihistone H4 antibody treatment abrogated these adverse effects, thus confirming a cause\u2010effect relationship between extracellular histones and organ injury\/dysfunction. The data support the hypothesis that the increased extracellular histone levels in <jats:styled-content style=\"fixed-case\">ACLF<\/jats:styled-content> patients may aggravate disease severity by inducing cellular injury and systemic inflammation. Histone\u2010targeted therapies may have potentially interventional value in clinical practice.<\/jats:p>","DOI":"10.1111\/jvh.12612","type":"journal-article","created":{"date-parts":[[2016,9,23]],"date-time":"2016-09-23T11:23:43Z","timestamp":1474629823000},"page":"59-67","source":"Crossref","is-referenced-by-count":20,"title":["Patients with <scp>HBV<\/scp>\u2010related acute\u2010on\u2010chronic liver failure have increased concentrations of extracellular histones aggravating cellular damage and systemic inflammation"],"prefix":"10.1111","volume":"24","author":[{"given":"X.","family":"Li","sequence":"first","affiliation":[{"name":"Beijing You\u2010An Hospital Capital Medical University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Gou","sequence":"additional","affiliation":[{"name":"Beijing You\u2010An Hospital Capital Medical University  Beijing 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