Adebayo Danielle, Morabito Vincenzo, Andreola Fausto, Pieri Giulia, Luong Tu-Vin, Dhillon Amar, Mookerjee Rajeshwar, Jalan Rajiv
Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK.
Sheila Sherlock, Liver Center and UCL, Institute of Liver and Digestive Health, Royal Free Hospital, London, UK.
Liver Int. 2015 Dec;35(12):2564-74. doi: 10.1111/liv.12850. Epub 2015 May 11.
BACKGROUND & AIMS: Mortality of patients who develop acute-on-chronic liver failure (ACLF) is unacceptably high but the predominant mode of cell death is unknown. The aim of this study was to evaluate whether plasma levels of caspase-cleaved cytokeratin M30 (marker of apoptosis) and uncleaved cytokeratin M65 (marker of total cell death) are altered in ACLF patients and relate this to liver histology.
Twenty-seven patients with acute decompensation of liver disease were divided into two groups: no-ACLF (n = 11) or ACLF (n-16). Healthy controls (n = 8) and acute liver failure (ALF) patients (n = 10) were also enrolled. Cell death was assessed in plasma using an ELISA kit (M30 and M65). Simultaneous biopsy samples were analysed for M30 and caspase-3 staining.
Plasma M30 value was significantly elevated in ACLF patients compared with healthy volunteers (P = 0.0001), it was also significantly higher in ACLF patients compared with no-ACLF patients (P = 0.002). M65 levels were higher in ALF compared with ACLF patients (P = 0.002) but the apoptotic index defined by M30/M65 ratio was significantly higher in ACLF patients. Patients with extra-hepatic failure had higher M30 levels compared with patients without organ failure (P = 0.03). M30 staining in liver was more marked in the patients with ACLF and was observed in all the patients that died.
The results of this study suggest that hepatocyte apoptosis is the predominant mode of cell death in ACLF, which can be identified in the peripheral blood. Further studies are required to validate our findings and to determine whether M30 can be used as a biomarker of apoptosis or as a target for therapy.
发生慢加急性肝衰竭（ACLF）的患者死亡率高得令人难以接受，但其主要的细胞死亡方式尚不清楚。本研究旨在评估ACLF患者血浆中半胱天冬酶切割的细胞角蛋白M30（凋亡标志物）和未切割的细胞角蛋白M65（总细胞死亡标志物）水平是否发生改变，并将其与肝脏组织学相关联。
27例急性失代偿性肝病患者分为两组：非ACLF组（n = 11）和ACLF组（n = 16）。还纳入了健康对照者（n = 8）和急性肝衰竭（ALF）患者（n = 10）。使用酶联免疫吸附测定试剂盒（M30和M65）评估血浆中的细胞死亡情况。同时对活检样本进行M30和半胱天冬酶-3染色分析。
与健康志愿者相比，ACLF患者的血浆M30值显著升高（P = 0.0001），与非ACLF患者相比也显著更高（P = 0.002）。与ACLF患者相比，ALF患者的M65水平更高（P = 0.002），但ACLF患者中由M30/M65比值定义的凋亡指数显著更高。与无器官衰竭的患者相比，有肝外衰竭的患者M30水平更高（P = 0.03）。ACLF患者肝脏中的M30染色更明显，且在所有死亡患者中均有观察到。
本研究结果表明，肝细胞凋亡是ACLF中主要的细胞死亡方式，在外周血中即可识别。需要进一步研究来验证我们的发现，并确定M30是否可作为凋亡的生物标志物或治疗靶点。
