CHIP & PERSIMUNE, Department of Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen and University of Copenhagen, Copenhagen, Denmark.
Department of Internal Medicine C, Respiratory Medicine Section, Copenhagen University Hospital, Herlev-Gentofte, Denmark.
Clin Chem Lab Med. 2019 Aug 27;57(9):1422-1431. doi: 10.1515/cclm-2018-1350.
Background The prognostic impact of mild/moderate liver impairment among critically ill patients is not known. We aimed to determine whether acute liver impairment, as measured by several biomarkers, (i) is frequent, (ii) influences prognosis and (iii) to determine whether such an effect is specific for infected critically ill patients. Methods A biomarker and clinical cohort study based on a randomized controlled trial. All-cause mortality was the primary endpoint. Biomarkers hyaluronic acid (HA), bilirubin, albumin, alkaline phosphatase and the international normalized ratio (INR) were determined. Multivariable statistics were applied to estimate risk increase according to liver biomarker increase at baseline and the model was adjusted for age, APACHE II, severe sepsis/septic shock vs. milder infection, chronic alcohol abuse Charlson's co-morbidity index, cancer disease, surgical or medical patient, body mass index, sex, estimated glomerular filtration rate, mechanical ventilation and the other biomarkers. Time-to-event graphs were used. The patients were critically ill patients (n = 1096) from nine mixed medical/surgical intensive care units without known hepatobiliary disease. Results HA levels differed between infected patients (median 210.8 ng/mL [IQR: 93.2-556.6]) vs. the non-infected (median 56.8 ng/mL [IQR: 31.9-116.8], p < 0.001). Serum HA quartiles 2, 3 and 4 were independent predictors of 90-day all-cause mortality for the entire population (infected and non-infected). However, the signal was driven by the infected patients (positive interaction test, no signal in non-infected patients). Among infected patients, HA quartiles corresponded directly to the 90-day risk of dying: 1st quartile: 57/192 = 29.7%, 2nd quartile: 84/194 = 43.3%, 3rd quartile: 90/193 = 46.6%, 4th quartile: 101/192 = 52.3 %, p for trend: <0.0001. This finding was confirmed in adjusted analyses: hazard ratio vs. 1st quartile: 2nd quartile: 1.3 [0.9-1.8], p = 0.14, 3rd quartile: 1.5 [1.1-2.2], p = 0.02, 4th quartile: 1.9 [1.3-2.6], p < 0.0001). High bilirubin was also an independent predictor of mortality. Conclusions Among infected critically ill patients, subtle liver impairment, (elevated HA and bilirubin), was associated with a progressive and highly increased risk of death for the patient; this was robust to adjustment for other predictors of mortality. HA can identify patients at high risk.
目前尚不清楚危重症患者轻度/中度肝功能损害的预后影响。我们旨在确定几种生物标志物测量的急性肝损伤（i）是否频繁，（ii）是否影响预后，以及（iii）确定这种影响是否对感染性危重症患者具有特异性。
这是一项基于随机对照试验的生物标志物和临床队列研究。全因死亡率是主要终点。测定了透明质酸（HA）、胆红素、白蛋白、碱性磷酸酶和国际标准化比值（INR）等生物标志物。应用多变量统计学来估计基线时肝生物标志物增加的风险增加，并根据肝生物标志物增加调整模型年龄、APACHE II、严重脓毒症/败血症与较轻的感染、慢性酒精滥用 Charlson 合并症指数、癌症疾病、手术或内科患者、体重指数、性别、估计肾小球滤过率、机械通气和其他生物标志物。使用时间事件图。这些患者是来自 9 个混合内科/外科重症监护病房的危重症患者（n=1096），无已知的肝胆疾病。
HA 水平在感染患者（中位数 210.8 ng/mL [IQR：93.2-556.6]）与非感染患者（中位数 56.8 ng/mL [IQR：31.9-116.8]）之间存在差异（p<0.001）。血清 HA 四分位 2、3 和 4 是整个人群（感染和非感染） 90 天全因死亡率的独立预测因子。然而，该信号是由感染患者驱动的（阳性交互检验，非感染患者无信号）。在感染患者中，HA 四分位与 90 天死亡风险直接相关：第 1 四分位：57/192=29.7%，第 2 四分位：84/194=43.3%，第 3 四分位：90/193=46.6%，第 4 四分位：101/192=52.3%，趋势检验：p<0.0001。调整分析证实了这一发现：与第 1 四分位相比，第 2 四分位的风险比：1.3 [0.9-1.8]，p=0.14，第 3 四分位：1.5 [1.1-2.2]，p=0.02，第 4 四分位：1.9 [1.3-2.6]，p<0.0001）。高胆红素也是死亡率的独立预测因子。
在感染的危重症患者中，轻微的肝功能损害（HA 和胆红素升高）与患者死亡风险的逐渐和高度增加相关；这对其他死亡率预测因子的调整是稳健的。HA 可以识别高风险患者。
