Dirchwolf Melisa, Podhorzer Ariel, Marino Monica, Shulman Carolina, Cartier Mariano, Zunino Moira, Paz Silvia, Muñoz Alberto, Bocassi Andrea, Gimenez Juan, Di Pietro Lucía, Romero Gustavo, Fainboim Hugo, Fainboim Leonardo
Hepatopatías Infecciosas, Hospital Francisco J. Muñiz, Buenos Aires 1282, Argentina.
Instituto de Inmunología, Genética y Metabolismo (INIGEM-CONICET), Hospital de Clínicas "José de San Martín", Universidad de Buenos Aires, 1120, Argentina.
Cytokine. 2016 Jan;77:14-25. doi: 10.1016/j.cyto.2015.10.006. Epub 2015 Oct 23.
BACKGROUND/OBJECTIVES: Cirrhosis associated immune dysfunction has been proposed to switch from a pro-inflammatory phenotype in stable cirrhosis to an immunodeficient one in patients with decompensated cirrhosis and acute-on-chronic liver failure. The aim of the present study was to compare serum cytokine levels between healthy patients, stable cirrhosis, and decompensated cirrhotic patients with and without development of acute-on-chronic liver failure (ACLF); and to explore whether any of the measured cytokines is associated with cirrhosis severity and prognosis in ACLF patients.
Patients were enrolled from October 2013 to May 2014 in two hospitals located in Buenos Aires. Cirrhotic patients with an acute decompensating event were enrolled accordingly to the development of ACLF defined by the CANONIC study group. There were two control groups: healthy subjects (n=14) and stable cirrhotic patients (n=14). Demographic, clinical and biochemical data were obtained. Seventeen cytokines were measured using Bio-Plex Pro Human Cytokine 17-plex Assay.
Of the 49 decompensated cirrhotic patients enrolled, 18 (36.7%) developed ACLF. Leukocyte count, MELD score at admission, Clif-SOFA at admission and day 7 were significantly higher in the ACLF group (p=0.046, p<0.001, p<0.001, p<0.001 respectively) as well as short-term mortality (p<0.001) compared to stable and decompensated cirrhotic patients. In comparison with healthy controls, stable cirrhotic and decompensated cirrhotic patients showed increased levels of pro-inflammatory and anti-inflammatory cytokines: IL-6, IL-7, IL-8, IL-10, IL 12, and TNF-α. Decompensated cirrhotic patients with the development of ACLF showed a significant decrease of IL-7, IL-10, IL-12, TNF-α, MCP-1 and IFN-γ, but a sustained response of IL-6 and IL-8. When evaluating cirrhosis severity, IL-6 and IL-8 correlated positively with MELD score, whereas only IL-6 correlated positively with Clif-SOFA score at day 7; IL-2 correlated negatively with Clif-SOFA at admission. In comparison with all scores, leukocyte count showed positive correlation and IFN-γ negative correlation with disease severity. When evaluating survival, only MELD and Clif-SOFA scores had a significant association with mortality.
Pro-inflammatory cytokines and chemo-attractant elements are increased in cirrhosis in comparison with healthy subjects, and display higher values concomitantly with cirrhosis progression. However, in acute-on-chronic liver failure an opposite cytokine pattern that can be resumed as a combination of immune paresis and excessive inflammatory response was observed. Several pro-inflammatory cytokines (IL-2, IL-6, IL-8 and IFN-γ) showed correlation with disease severity; their utility as prognostic biomarkers needs to be further studied.
背景/目的：已有研究提出，肝硬化相关免疫功能障碍会从稳定期肝硬化的促炎表型转变为失代偿期肝硬化和慢加急性肝衰竭患者的免疫缺陷表型。本研究旨在比较健康患者、稳定期肝硬化患者以及伴有或不伴有慢加急性肝衰竭（ACLF）的失代偿期肝硬化患者的血清细胞因子水平；并探讨所检测的细胞因子是否与ACLF患者的肝硬化严重程度及预后相关。
2013年10月至2014年5月期间，在布宜诺斯艾利斯的两家医院招募患者。根据CANONIC研究组定义的ACLF发生情况，纳入有急性失代偿事件的肝硬化患者。设有两个对照组：健康受试者（n = 14）和稳定期肝硬化患者（n = 14）。获取人口统计学、临床和生化数据。使用Bio-Plex Pro人细胞因子17项检测法测定17种细胞因子。
在纳入的49例失代偿期肝硬化患者中，18例（36.7%）发生了ACLF。与稳定期和失代偿期肝硬化患者相比，ACLF组的白细胞计数、入院时的终末期肝病模型（MELD）评分、入院时及第7天的慢性肝衰竭序贯器官衰竭评估（Clif-SOFA）评分均显著更高（分别为p = 0.046、p < 0.001、p < 0.001、p < 0.001），短期死亡率也更高（p < 0.001）。与健康对照组相比，稳定期肝硬化患者和失代偿期肝硬化患者的促炎和抗炎细胞因子水平均升高：白细胞介素-6（IL-6）、IL-7、IL-8、IL-10、IL-12和肿瘤坏死因子-α（TNF-α）。发生ACLF的失代偿期肝硬化患者的IL-7、IL-10、IL-12、TNF-α、单核细胞趋化蛋白-1（MCP-1）和干扰素-γ（IFN-γ）显著降低，但IL-6和IL-8持续反应。在评估肝硬化严重程度时，IL-6和IL-8与MELD评分呈正相关，而仅IL-6与第7天的Clif-SOFA评分呈正相关；IL-2与入院时的Clif-SOFA呈负相关。与所有评分相比，白细胞计数与疾病严重程度呈正相关，IFN-γ与疾病严重程度呈负相关。在评估生存率时，只有MELD和Clif-SOFA评分与死亡率有显著关联。
与健康受试者相比，肝硬化患者的促炎细胞因子和趋化因子增加，且随着肝硬化进展呈现更高水平。然而，在慢加急性肝衰竭中，观察到一种相反的细胞因子模式，可归结为免疫麻痹和过度炎症反应的组合。几种促炎细胞因子（IL-2、IL-6、IL-8和IFN-γ）与疾病严重程度相关；其作为预后生物标志物的效用有待进一步研究。
