TIPE2 mRNA Level in PBMCs Serves as a Novel Biomarker for Predicting Short-Term Mortality of Acute-on-Chronic Hepatitis B Liver Failure A Prospective Single-Center Study

摘要

It remains difficult to accurately predicate short-term mortality of acute-on-chronic hepatitis B liver failure (ACHBLF). Tumor necrosis factor--induced protein 8-like 2 (TIPE2) is a novel identified negative regulator of immune response and we have previously demonstrated TIPE2 play an essential role in the pathogenesis of ACHBLF. We therefore aimed to evaluate the diagnosis value of TIPE2 mRNA in peripheral blood mononuclear cells (PBMCs) for predicting 3-month mortality of ACHBLF patients.This prospective study consisted of 108 ACHBLF patients from March 2009 to May 2013 as training cohort and 63 ACHBLF patients from June 2013 to December 2014 as validation cohort. Forty-two patients with chronic hepatitis B (CHB) and 22 healthy volunteers were also included as controls. The mRNA level of TIPE2 in PBMCs was determined using quantitative real-time polymerase chain reaction. Univariate analysis and Cox proportional hazard regression analysis were performed to identify independent risk factors to 3-month mortality. Area under the receptor operating characteristic curve (AUROC) was performed to assess diagnostic value of TIPE2 mRNA in training and validation cohort.The level of TIPE2 mRNA was significantly higher in ACHBLF patients (median (interquartile): 6.5 [3.7, 9.6]) compared with CHB (2.3 [1.6, 3.7]) and healthy controls (0.4 [0.3, 0.6]; both P<0.05). Cox proportional hazards regression analyses showed 5 independent risk factors associated with 3-month mortality of ACHBLF: white blood cells (HR=1.058, 95% CI: 1.023-1.095), spontaneous bacterial peritonitis (HR=2.541, 95% CI: 1.378-4.686), hepatic encephalopathy (HR=1.848, 95% CI: 1.028-3.321), model for end-stage liver diseases (MELD) score (HR=1.062, 95% CI: 1.009-1.118), and TIPE2 mRNA (HR=1.081, 95% CI: 1.009-1.159). An optimal cut-off point 6.54 of TIPE2 mRNA showed sensitivity of 74.63%, specificity of 90.24%, positive predictive value of 92.5%, and negative predictive value of 67.3% for predicting 3-month mortality in training cohort. Furthermore, TIPE2 mRNA plus MELD performed better than MELD alone for predicting 3-month mortality in training (AUROC, 0.853 vs 0.722, P<0.05) and validation cohort (AUROC, 0.909 vs 0.717, P<0.001).TIPE2 mRNA level might be a novel biomarker in predicting 3-month mortality of ACHBLF. Combination of TIPE2 mRNA and MELD would improve the diagnostic value of MELD alone in predicting 3-month mortality of patients with ACHBLF.