循环中微小RNA-122水平升高与急性呼吸窘迫综合征的死亡率及急性肝损伤相关。

Increased circulating microRNA-122 is associated with mortality and acute liver injury in the acute respiratory distress syndrome.

作者信息

Rahmel Tim, Rump Katharina, Adamzik Michael, Peters Jürgen, Frey Ulrich H

机构信息

Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892, Bochum, Germany.

Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum Essen, D-45122, Essen, Germany.

出版信息

BMC Anesthesiol. 2018 Jun 23;18(1):75. doi: 10.1186/s12871-018-0541-5.

BACKGROUND

Acute liver injury in patients with ARDS decreases survival but early stages may be easily missed due to the lack of sufficient biomarkers signalling its onset. Accordingly, we tested in ARDS patients the hypotheses that microRNA-122, the foremost liver-related microRNA (miR), 1) is an sensitive and specific early predictor for potential liver injury and 2) analysed its impact on 30-day-survival.

METHODS

We collected clinical data and analysed blood samples from 119 ARDS patients within the first 24 h of ICU admission and from 20 patients undergoing elective abdominal non-liver surgery serving as controls. Total circulating miR was isolated from serum and relative miR-122 expression was measured (using specific probes and spiked-in miR-54), as were liver function and 30-day survival. Acute liver injury was defined as a total bilirubin concentration ≥ 3.0 mg/dl, an ALT activity ≥350 U/l, and an INR ≥2.0.

RESULTS

30-day survival of the entire ARDS-cohort was 69% but differed between patients with normal liver function (77%) and acute liver injury (19% p < 0.001). miR-122 expression was 20fold higher in non-survivors (95%-CI 0.0149-0.0768; p = 0.001) and almost 4fold greater in survivors (95%-CI: 0.0037-0.0122; p = 0.005) compared to controls (95%-CI 0.0008-0.0034) and correlated with markers of liver cell integrity/function [ALT (p < 0.001, r = 0.495), AST (p < 0.001, r = 0.537), total bilirubin (p = 0.025, r = 0.206), INR (p = 0.001, r = 0.308), and GLDH (p < 0.001, r = 0.489)]. miR-122 serum expression discriminated survivors and non-survivors (AUC: 0.78) better than total bilirubin concentration (AUC: 0.66). Multivariable Cox-regression analysis revealed both acute liver injury (HR 7.6, 95%-CI 2.9-19.8, p < 0.001) and miR-122 (HR 4.4, 95%-CI 1.2-16.1, p = 0.02) as independent prognostic factors for 30-day mortality.

CONCLUSIONS

Increased miR-122 serum expression is an early and independent risk factor for 30-day mortality in ARDS patients and potentially reveal an acute liver injury earlier than the conventional markers of liver cell integrity.

背景

急性呼吸窘迫综合征（ARDS）患者发生急性肝损伤会降低生存率，但由于缺乏足够的生物标志物提示其发病，早期阶段可能容易被忽视。因此，我们在ARDS患者中检验了以下假设：即肝脏相关的首要微小RNA（miR）——微小RNA-122，1）是潜在肝损伤的敏感且特异的早期预测指标；2）分析其对30天生存率的影响。

方法

我们收集了119例ARDS患者入住重症监护病房（ICU）后24小时内的临床资料并分析其血样，同时收集了20例接受择期腹部非肝脏手术患者作为对照。从血清中分离出总的循环miR，测量相对微小RNA-122的表达水平（使用特异性探针和掺入的miR-54），同时检测肝功能和30天生存率。急性肝损伤定义为总胆红素浓度≥3.0mg/dl、丙氨酸转氨酶（ALT）活性≥350U/l以及国际标准化比值（INR）≥2.0。

结果

整个ARDS队列的30天生存率为69%，但肝功能正常的患者（77%）和急性肝损伤患者（19%，p<0.001）之间存在差异。与对照组（95%置信区间0.0008 - 0.0034）相比，非幸存者的微小RNA-122表达水平高20倍（95%置信区间0.0149 - 0.0768；p = 0.001），幸存者的表达水平高近4倍（95%置信区间：0.0037 - 0.0122；p = 0.005），且与肝细胞完整性/功能标志物相关[ALT（p<0.001，r = 0.495）、天冬氨酸转氨酶（AST）（p<0.001，r = 0.537）、总胆红素（p = 0.025，r = 0.206）、INR（p = 0.001，r = 0.308）和谷氨酸脱氢酶（GLDH）（p<0.001，r = 0.489）]。微小RNA-122血清表达水平对幸存者和非幸存者的区分能力（曲线下面积[AUC]：0.78）优于总胆红素浓度（AUC：0.66）。多变量Cox回归分析显示，急性肝损伤（风险比[HR] 7.6，95%置信区间2.9 - 19.8，p<0.001）和微小RNA-122（HR 4.4，95%置信区间1.2 - 16.1，p = 0.02）均为30天死亡率的独立预后因素。