Department of Gastroenterology, Hepatology, and Endocrinology, the Institute of Pathology, Hannover Medical School, Hannover, Germany.
Crit Care Med. 2012 May;40(5):1499-505. doi: 10.1097/CCM.0b013e318241e34e.
Angiopoietin-2, an antagonistic ligand of the endothelial Tie2 receptor, has been identified as a gatekeeper of endothelial activation. We examined whether the release of Angiopoietin-2 correlates with surrogates of organ dysfunction and outcome in patients with acute liver failure.
Retrospective clinical and immunohistological study.
Intensive care unit of a university hospital.
Thirty-seven patients with acute liver failure and 20 healthy control subjects.
None.
Angiopoietin-2 levels were measured in sera from 37 patients with acute liver failure on admission and from 20 healthy control subjects. Median age of patients with acute liver failure was 34 yrs, 29 were female, and 21 developed encephalopathy grade 3 or greater. Nine patients survived to day 28 without transplantation, five died without transplantation, and 23 received a transplant. Median (interquartile range) Angiopoietin-2 serum concentrations steadily increased across the following groups: healthy control subjects (1.4 [0.9-1.7] ng/mL), patients with transplant-free recovery (10.0 [4.7-12.1] ng/mL), and patients who reached the composite end point of death or emergency liver transplantation (16.8 [11.3-39.5] ng/mL). Angiopoietin-2 release correlated strongly with surrogate markers of organ dysfunction and disease severity measures (lactate, platelet count, Sequential Organ Failure Assessment score, and Simplified Acute Physiology Score III). Angiopoietin-2 levels were higher in patients with acute kidney injury and patients on mechanical ventilation. Furthermore, Angiopoietin-2 levels were closely associated with Bilirubin-Lactate-Etiology score but not with other liver-specific markers. Unadjusted and adjusted Cox's proportional hazards analyses identified Angiopoietin-2 as a predictor of the composite end point of death or transplantation. Finally, immunohistological studies showed that Angiopoietin-2 protein was upregulated in acute liver failure explants compared with matched liver biopsies obtained at baseline.
Collectively, our data show that circulating Angiopoietin-2, which potentially originates from the injured liver, correlates with several features of multiple organ dysfunction syndrome and independently predicts outcome. Tie2 agonists may have potential as an endothelium-targeted therapy to ameliorate multiple organ dysfunction syndrome and improve outcome in acute liver failure.
血管生成素-2（Angiopoietin-2）是内皮 Tie2 受体的拮抗配体，已被确定为内皮激活的守门员。我们研究了急性肝衰竭患者中 Angiopoietin-2 的释放是否与器官功能障碍和预后的替代指标相关。
回顾性临床和免疫组织化学研究。
一所大学医院的重症监护病房。
37 例急性肝衰竭患者和 20 名健康对照者。
无。
急性肝衰竭患者入院时和 20 名健康对照者血清中 Angiopoietin-2 水平。急性肝衰竭患者的中位年龄为 34 岁，29 例为女性，21 例发生 3 级或更高级别的脑病。9 例患者在无移植的情况下存活至 28 天，5 例无移植死亡，23 例接受移植。中位数（四分位距）Angiopoietin-2 血清浓度在以下各组中逐渐升高：健康对照组（1.4[0.9-1.7]ng/mL）、无移植恢复患者（10.0[4.7-12.1]ng/mL）和达到死亡或紧急肝移植复合终点的患者（16.8[11.3-39.5]ng/mL）。Angiopoietin-2 的释放与器官功能障碍和疾病严重程度的替代标志物（乳酸、血小板计数、序贯器官衰竭评估评分和简化急性生理学评分 3 分）密切相关。急性肾损伤患者和机械通气患者的 Angiopoietin-2 水平较高。此外，Angiopoietin-2 水平与胆红素-乳酸-病因评分密切相关，但与其他肝脏特异性标志物无关。未调整和调整后的 Cox 比例风险分析将 Angiopoietin-2 确定为死亡或移植复合终点的预测因子。最后，免疫组织化学研究表明，与基线时获得的匹配肝活检相比，急性肝衰竭标本中 Angiopoietin-2 蛋白上调。
总的来说，我们的数据表明，循环 Angiopoietin-2 可能来源于受损的肝脏，与多种器官功能障碍综合征的多个特征相关，并独立预测预后。Tie2 激动剂可能具有作为内皮靶向治疗的潜力，以改善多器官功能障碍综合征并改善急性肝衰竭的预后。
