Lange Christian M, Al-Juboori Kawther, Rawitzer Josefine, Moellmann Dorothe, Schlattjan Martin, Guckenbiehl Sabrina, Willuweit Katharina, Canbay Ali, Baba Hideo A
Department of Gastroenterology and Hepatology, University Hospital and University of Duisburg-Essen, Essen, Germany.
Department of Internal Medicine II, LMU University Hospital, Munich, Germany.
Gastro Hep Adv. 2022 Apr 29;1(4):520-530. doi: 10.1016/j.gastha.2022.03.005. eCollection 2022.
Acute-on-chronic liver failure (ACLF) is associated with excessive systemic inflammation, cell death, and organ failures. Yet, little is known about the hepatic histopathology of ACLF. Here, we assessed the histopathology and regenerative capacity of the liver in ACLF with or without cirrhosis.
Liver specimens of patients with compensated cirrhosis (N = 37), acute decompensation (N = 40), and ACLF with (N = 18) or without (N = 10) cirrhosis were assessed for morphological features and the pro-regenerative Stat3 pathway.
ACLF was associated with high levels of lobular inflammation, tissue necrosis, and apoptosis. In patients with cirrhosis, the percentage of pStat3-positive hepatocytes was increasing with disease severity (3.5%/10.4%/21% for compensated cirrhosis/acute decompensation/cirrhosis-ACLF; < .001), but lower in noncirrhotic ACLF vs cirrhosis-ACLF (21% vs 13%; = .02). A distinct pattern of the expression of the proliferation marker Ki-67, a downstream effector marker of pStat3, was observed. Ki-67-positive hepatocytes were more frequent in patients with cirrhosis-ACLF compared to compensated cirrhosis or acute decompensation (4.9% vs 1.3% vs 1.8%; < .05), but much lower in cirrhosis-ACLF vs noncirrhotic ACLF (4.9% vs 13.5%; = .01). The ratio of Ki-67-positive to pStat3-positive hepatocytes was lowest in cirrhosis-ACLF and predicted 3-month transplant-free survival accurately (area under the curve = 0.95, < .00001).
Our study identifies hepatic inflammation and Stat3 activation as hallmarks of ACLF. In cirrhosis-ACLF, Stat3 activation does not appear to translate in effective liver regeneration, which is distinct from noncirrhotic ACLF.
慢加急性肝衰竭（ACLF）与全身性炎症反应过度、细胞死亡及器官功能衰竭相关。然而，关于ACLF的肝脏组织病理学情况却知之甚少。在此，我们评估了伴或不伴有肝硬化的ACLF患者肝脏的组织病理学及再生能力。
对代偿期肝硬化患者（N = 37）、急性失代偿期患者（N = 40）以及伴有（N = 18）或不伴有（N = 10）肝硬化的ACLF患者的肝脏标本进行形态学特征及促再生信号转导和转录激活因子3（Stat3）通路评估。
ACLF与小叶炎症、组织坏死及凋亡的高水平相关。在肝硬化患者中，磷酸化Stat3（pStat3）阳性肝细胞的百分比随疾病严重程度增加（代偿期肝硬化/急性失代偿期/肝硬化-ACLF分别为3.5%/10.4%/21%；P <.001），但非肝硬化ACLF患者的该比例低于肝硬化-ACLF患者（21%对13%；P =.02）。观察到增殖标志物Ki-67（pStat3的下游效应标志物）的一种独特表达模式。与代偿期肝硬化或急性失代偿期患者相比，肝硬化-ACLF患者中Ki-67阳性肝细胞更为常见（4.9%对1.3%对1.8%；P <.05），但肝硬化-ACLF患者的该比例远低于非肝硬化ACLF患者（4.9%对13.5%；P =.01）。Ki-67阳性与pStat3阳性肝细胞的比例在肝硬化-ACLF患者中最低，且能准确预测3个月无移植生存率（曲线下面积 = 0.95，P <.00001）。
我们的研究确定肝脏炎症和Stat3激活为ACLF的特征。在肝硬化-ACLF中，Stat3激活似乎并未转化为有效的肝脏再生，这与非肝硬化ACLF不同。
