胸腺素β4的高甲基化预示着慢性乙型肝炎急性肝衰竭患者的预后不良。
Hypermethylation of thymosin β4 predicts a poor prognosis for patients with acute-on-chronic hepatitis B liver failure.
作者信息
Wang He, Yin Yan-Ping, Wang Zhen-Li, Qian Yu, Fan Yu-Chen, Liu Hui-Hui, Wang Kai
机构信息
Department of Hepatology, Qilu Hospital of Shandong University, #107 Wenhuaxi Road, Jinan 250012, China; Department of Hepatology, Qingdao Sixth People's Hospital, Qingdao 266000, China.
Department of Gastroenterology, Yantaishan Hospital, Yantai 264000, China.
出版信息
Hepatobiliary Pancreat Dis Int. 2023 Aug;22(4):373-382. doi: 10.1016/j.hbpd.2022.08.005. Epub 2022 Aug 19.
BACKGROUND
It has been demonstrated that thymosin β4 (Tβ4) could inflect the severity of acute-on-chronic hepatitis B liver failure (ACHBLF), but the relationship between its methylation status and the prognosis of liver failure is not clear. This study aimed to determine Tβ4 promoter methylation status in patients with ACHBLF and to evaluate its prognostic value.
METHODS
The study recruited 115 patients with ACHBLF, 80 with acute-on-chronic hepatitis B pre-liver failure (pre-ACHBLF), and 86 with chronic hepatitis B (CHB). In addition, there were 36 healthy controls (HCs) from the Department of Hepatology, Qilu Hospital of Shandong University. The 115 patients with ACHBLF were divided into three subgroups: 33 with early stage ACHBLF (E-ACHBLF), 42 with mid-stage ACHBLF (M-ACHBLF), and 40 with advanced stage ACHBLF (A-ACHBLF). Tβ4 promoter methylation status in peripheral blood mononuclear cells (PBMCs) was measured by methylation-specific polymerase chain reaction, and mRNA was detected by quantitative real-time polymerase chain reaction.
RESULTS
Methylation frequency of Tβ4 was significantly higher in patients with ACHBLF than in those with pre-ACHBLF, CHB or HCs. However, expression of Tβ4 mRNA showed the opposite trend. In patients with ACHBLF, Tβ4 promoter methylation status correlated negatively with mRNA levels. The 3-month mortality of ACHBLF in the methylated group was significantly higher than that in the unmethylated group. Also, Tβ4 promoter methylation frequency was lower in survivors than in non-survivors. When used to predict the 1-, 2-, and 3-month incidence of ACHBLF, Tβ4 methylation status was better than the model for end-stage liver disease (MELD) score. The predictive value of Tβ4 methylation was higher than that of MELD score for the mortality of patients with E-ACHBLF and M-ACHBLF, but not for A-ACHBLF.
CONCLUSIONS
Tβ4 methylation might be an important early marker for predicting disease incidence and prognosis in patients with ACHBLF.
背景
已证实胸腺素β4（Tβ4）可影响慢性乙型肝炎急性肝衰竭（ACHBLF）的严重程度，但其甲基化状态与肝衰竭预后的关系尚不清楚。本研究旨在确定ACHBLF患者中Tβ4启动子甲基化状态并评估其预后价值。
方法
本研究纳入115例ACHBLF患者、80例慢性乙型肝炎前期肝衰竭（pre-ACHBLF）患者及86例慢性乙型肝炎（CHB）患者。此外，选取山东大学齐鲁医院肝病科的36名健康对照（HC）。115例ACHBLF患者分为三个亚组：33例早期ACHBLF（E-ACHBLF）、42例中期ACHBLF（M-ACHBLF）和40例晚期ACHBLF（A-ACHBLF）。采用甲基化特异性聚合酶链反应检测外周血单个核细胞（PBMC）中Tβ4启动子甲基化状态，采用定量实时聚合酶链反应检测mRNA。
结果
ACHBLF患者Tβ4甲基化频率显著高于pre-ACHBLF、CHB患者或HC。然而，Tβ4 mRNA表达呈现相反趋势。在ACHBLF患者中，Tβ启动子甲基化状态与mRNA水平呈负相关。甲基化组ACHBLF患者3个月死亡率显著高于未甲基化组。此外，幸存者Tβ4启动子甲基化频率低于非幸存者。当用于预测ACHBLF患者1、2和3个月发病率时，Tβ4甲基化状态优于终末期肝病模型（MELD）评分。Tβ4甲基化对E-ACHBLF和M-ACHBLF患者死亡率的预测价值高于MELD评分，但对A-ACHBLF患者则不然。
结论
Tβ4甲基化可能是预测ACHBLF患者疾病发生率和预后的重要早期标志物。
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