Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity

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• 作者：Daniel J. Antoine¹ ; ^{d.antoine@liv.ac.uk} ; Rosalind E. Jenkins¹ ; James W. Dear² ; Dominic P. Williams¹ ; Mitchell R. McGill³ ; Matthew R. Sharpe⁴ ; Darren G. Craig⁵ ; Kenneth J. Simpson⁵ ; Hartmut Jaeschke³ ; B. Kevin Park¹
• 关键词：ALF ; acute liver failure ; ALI ; acute liver injury ; ALT ; alanine aminotransferase ; APAP ; acetaminophen ; DILI ; drug-induced liver injury ; HMGB1 ; High Mobility Group Box-1 protein ; KCC ; Kings College Criteria ; K18 ; keratin-18 ; LFT ; liver function test ; NAC
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：May, 2012
• 卷：56
• 期：5
• 页码：1070-1079
• 文件大小：1483 K

摘要

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class="h4">Background & Aims

Full length keratin-18 (FL-K18) and High Mobility Group Box-1 (HMGB1) represent circulating indicators of necrosis during acetaminophen (APAP) hepatotoxicity in vivo. In addition, the caspase-cleaved fragment of K18 (cK18) and hyper-acetylated HMGB1 represent serum indicators of apoptosis and immune cell activation, respectively. The study aim was to assess their mechanistic utility to establish the balance between apoptosis, necrosis, and immune cell activation throughout the time course of clinical APAP hepatotoxicity.

class="h4">Methods

HMGB1 (total, acetylated) and K18 (apoptotic, necrotic) were identified and quantified by novel LC-MS/MS assays in APAP overdose patients (n = 78).

class="h4">Results

HMGB1 (total; 15.4 卤 1.9 ng/ml, p <0.01, acetylated; 5.4 卤 2.6 ng/ml, p <0.001), cK18 (5649.8 卤 721.0 U/L, p <0.01), and FL-K18 (54770.2 卤 6717.0 U/L, p <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, p <0.0001) and prothrombin time (R² = 0.62 and 0.71, respectively, p <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 p <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.

class="h4">Conclusions

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.