Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, United Kingdom.
European Foundation for the study of Chronic Liver Failure (EF-CLIF), Barcelona, Spain.
Hepatology. 2018 Mar;67(3):989-1002. doi: 10.1002/hep.29581. Epub 2018 Jan 24.
The aims of this study were to determine the role of cell death in patients with cirrhosis and acute decompensation (AD) and acute on chronic liver failure (ACLF) using plasma-based biomarkers. The patients studied were part of the CANONIC (CLIF Acute-on-Chronic Liver Failure in Cirrhosis) study (N = 337; AD, 258; ACLF, 79); additional cohorts included healthy volunteers, stable patients with cirrhosis, and a group of 16 AD patients for histological studies. Caspase-cleaved keratin 18 (cK18) and keratin 18 (K18), which reflect apoptotic and total cell death, respectively, and cK18:K18 ratio (apoptotic index) were measured in plasma by enzyme-linked immunosorbent assay. The concentrations of cK18 and K18 increased and the cK18:K18 ratio decreased with increasing severity of AD and ACLF (P < 0.001, respectively). Alcohol etiology, no previous decompensation, and alcohol abuse were associated with increased cell death markers whereas underlying infection was not. Close correlation was observed between the cell death markers and, markers of systemic inflammation, hepatic failure, alanine aminotransferase, and bilirubin, but not with markers of extrahepatic organ injury. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining confirmed evidence of greater hepatic cell death in patients with ACLF as opposed to AD. Inclusion of cK18 and K18 improved the performance of the CLIF-C AD score in prediction of progression from AD to ACLF (P < 0.05).
Cell death, likely hepatic, is an important feature of AD and ACLF and its magnitude correlates with clinical severity. Nonapoptotic forms of cell death predominate with increasing severity of AD and ACLF. The data suggests that ACLF is a heterogeneous entity and shows that the importance of cell death in its pathophysiology is dependent on predisposing factors, precipitating illness, response to injury, and type of organ failure. (Hepatology 2018;67:989-1002).
本研究旨在使用基于血浆的生物标志物，确定肝硬化伴急性失代偿（AD）和慢加急性肝衰竭（ACLF）患者细胞死亡的作用。本研究的患者来自 CANONIC（CLIF 肝硬化急性慢性肝衰竭）研究（N=337；AD 患者 258 例，ACLF 患者 79 例）；另外还包括健康志愿者、稳定期肝硬化患者和 16 例 AD 患者的组织学研究组。采用酶联免疫吸附试验检测血浆中半胱氨酸天冬氨酸蛋白酶切割角蛋白 18（cK18）和角蛋白 18（K18），分别反映凋亡和总细胞死亡，cK18：K18 比值（凋亡指数）。随着 AD 和 ACLF 严重程度的增加，cK18 和 K18 的浓度增加，cK18：K18 比值降低（分别为 P<0.001）。酒精病因、无既往失代偿和酒精滥用与细胞死亡标志物的增加相关，而潜在感染则没有相关性。细胞死亡标志物与全身炎症标志物、肝衰竭、丙氨酸氨基转移酶和胆红素密切相关，但与肝外器官损伤标志物无关。末端脱氧核苷酸转移酶 dUTP 缺口末端标记染色证实 ACLF 患者的肝实质细胞死亡程度大于 AD。cK18 和 K18 的纳入提高了 CLIF-C AD 评分对 AD 向 ACLF 进展的预测性能（P<0.05）。
细胞死亡（可能为肝源性）是 AD 和 ACLF 的重要特征，其程度与临床严重程度相关。随着 AD 和 ACLF 严重程度的增加，非凋亡性细胞死亡形式占主导地位。这些数据表明 ACLF 是一种异质性实体，并表明细胞死亡在其病理生理学中的重要性取决于易患因素、诱发疾病、对损伤的反应和器官衰竭的类型。（Hepatology 2018；67：989-1002）。
