■原发性硬化性胆管炎(PSC)是一种病因不明的罕见胆管病变。本研究的目的是评估PSC患者胆管细胞中细胞衰老(CS)标志物的表达及其与临床病理特征和预后的相关性。
■包括35名PSC患者,至少有1个可用的肝脏采样。收集肝脏采样时的临床实验室数据。终点是无肝移植(LT)的存活,时间到LT,和生存没有LT或肝硬化代偿失调。根据Nakanuma评估组织学分级和分期。CS标记的免疫组织化学染色,p16INK4A(p16)和p21WAF1/Cip1(p21),根据天然胆管(NBD)和导管反应(DR)的阳性程度进行了三级评分。结果:NBD和DR中p16的表达与纤维化(均p≤0.001)和分期(分别为p=0.006和p<0.001)直接相关。此外,NBD中的p16与肝炎活动(HA)呈正相关(p=0.026),而DR中的p16与胆管丢失(BDL)(p=0.005)和化生肝细胞(MH)(p<0.01)直接相关。NBD和DR中p21的表达与HA直接相关(分别为p=0.004和p=0.043),纤维化(分别为p=0.006和p<0.001),阶段(p=0.006和p=0.001,分别),BDL(分别为p=0.002和p=0.03),和DR和MH(所有p≤0.004)。通过多变量分析,DR中p16的表达与分期独立相关(p=0.001),纤维化(p=0.001),和BDL(p=0.011)。NBD中p21的表达与HA独立相关(p=0.012),BDL(p=0.04),和DR(p=0.014)。最后,DR中p21的表达与无LT生存独立相关,时间到LT,和无不良结局生存期(分别为p=0.001,p=0.017和p=0.001)。
■在PSC的所有阶段都可以检测到胆管细胞衰老,并且与组织学和临床疾病的严重程度有关。可能代表一个新的预后和治疗目标。
■在这项研究中,我们表明,胆管细胞衰老(CS),先前在终末期原发性硬化性胆管炎(PSC)患者的肝脏中证实,是早期事件,在所有疾病阶段都可以检测到。此外,我们观察到CS与组织学和临床疾病严重程度以及患者预后相关.因此,我们认为CS可能是PSC新的预后工具和潜在的治疗靶点.
■协议号0034435,2020年6月8日。
UNASSIGNED: Primary sclerosing cholangitis (PSC) is a rare cholangiopathy of unknown aetiopathogenesis. The aim of this study was to evaluate cellular senescence (CS) marker expression in cholangiocytes of patients with PSC and their correlation with clinical-pathological features and prognosis.
UNASSIGNED: Thirty-five patients with PSC with at least 1 available liver sampling were included. Clinical laboratory data at the time of liver sampling were collected. The endpoints were survival without liver transplantation (LT), time to LT, and survival without LT or cirrhosis decompensation. Histological grading and staging were assessed according to Nakanuma. Immunohistochemical stains for CS markers, p16INK4A (p16) and p21WAF1/Cip1 (p21), were performed and scored by a 3-tier scale based on positivity extent in native bile duct (NBD) and ductular reaction (DR).Results: p16 expression in NBD and DR was directly correlated with fibrosis (p ≤0.001 for both) and stage (p = 0.006 and p <0.001, respectively). Moreover, p16 in NBD was positively correlated with hepatitis activity (HA) (p = 0.026), whereas p16 in DR was directly correlated with bile duct loss (BDL) (p = 0.005) and metaplastic hepatocytes (MH) (p <0.01). p21 expression in NBD and DR was directly correlated with HA (p = 0.004 and p = 0.043, respectively), fibrosis (p = 0.006 and p <0.001, respectively), stage (p = 0.006 and p = 0.001, respectively), BDL (p = 0.002 and p = 0.03, respectively), and DR and MH (p ≤0.004 for all). By multivariate analysis, p16 expression in DR was independently associated with stage (p = 0.001), fibrosis (p = 0.001), and BDL (p = 0.011). p21 expression in NBD was independently associated with HA (p = 0.012), BDL (p = 0.04), and DR (p = 0.014). Finally, p21 expression in DR was independently associated with LT-free survival, time to LT, and adverse outcome-free survival (p = 0.001, p = 0.017, and p = 0.001, respectively).
UNASSIGNED: Cholangiocyte senescence is detectable in all stages of PSC and is associated with histological and clinical disease severity, potentially representing a new prognostic and therapeutic target.
UNASSIGNED: In this study, we showed that cholangiocyte senescence (CS), previously demonstrated in liver of patients with end-stage primary sclerosing cholangitis (PSC), is an early event and is detectable in all disease stages. Moreover, we observed that CS is associated with histological and clinical disease severity and patients\' outcome. Thus, we suggest that CS may represent a new prognostic tool and a potential therapeutic target in PSC.
UNASSIGNED: Protocol number 0034435, 08/06/2020.