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h4 class="
h4">Background & Ai
ms
h4>Full lengt
h keratin-18 (FL-K18) and Hig
h Mobility Group Box-1 (HMGB1) represent circulating indicators of necrosis during aceta
minop
hen (APAP)
hepatotoxicity
m>in vivo.m> In addition, t
he caspase-cleaved frag
ment of K18 (cK18) and
hyper-acetylated HMGB1 represent seru
m indicators of apoptosis and i
mmune cell activation, respectively. T
he study ai
m was to assess t
heir
mec
hanistic utility to establis
h t
he balance between apoptosis, necrosis, and i
mmune cell activation t
hroug
hout t
he ti
me course of clinical APAP
hepatotoxicity.<
h4 class="
h4">Met
hods
h4>
HMGB1 (total, acetylated) and K18 (apoptotic, necrotic) were identified and quantified by novel LC-MS/MS assays in APAP overdose patients (n = 78).<h4 class="h4">Resultsh4>
HMGB1 (total; 15.4 卤 1.9 ng/ml, m>pm> <0.01, acetylated; 5.4 卤 2.6 ng/ml, m>pm> <0.001), cK18 (5649.8 卤 721.0 U/L, m>pm> <0.01), and FL-K18 (54770.2 卤 6717.0 U/L, m>pm> <0.005) were elevated in the sera of APAP overdose patients with liver injury compared to overdose patients without liver injury and healthy volunteers. HMGB1 and FL-K18 correlated with alanine aminotransferase (ALT) activity (R2 = 0.60 and 0.58, respectively, m>pm> <0.0001) and prothrombin time (R2 = 0.62 and 0.71, respectively, m>pm> <0.0001). Increased total and acetylated HMGB1 and FL-K18 were associated with worse prognosis (King鈥檚 College Criteria) or patients that died/required liver transplant compared to spontaneous survivors (all m>pm> <0.05-0.001), a finding not reflected by ALT and supported by ROC analysis. Acetylated HMGB1 was a better predictor of outcome than the other markers of cell death.<h4 class="h4">Conclusionsh4>
K18 and HMGB1 represent blood-based tools to investigate the cell death balance clinical APAP hepatotoxicity. Activation of the immune response was seen later in the time course as shown by the distinct profile of acetylated HMGB1 and was associated with worse outcome.