Vesterhus Mette, Nielsen Mette Juul, Hov Johannes Roksund, Saffioti Francesca, Manon-Jensen Tina, Leeming Diana Julie, Moum Bjørn, Boberg Kirsten Muri, Pinzani Massimo, Karlsen Tom Hemming, Karsdal Morten Asser, Thorburn Douglas
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway.
JHEP Rep. 2020 Sep 3;3(1):100178. doi: 10.1016/j.jhepr.2020.100178. eCollection 2021 Feb.
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are phenotypically distinct autoimmune liver diseases that progress to cirrhosis and liver failure; however, their histological fibrosis distribution differs. We investigated the extracellular matrix (ECM) profiles of patients with PSC, PBC, and AIH to establish whether the diseases display differential patterns of ECM turnover.
Serum samples were retrospectively collected from the UK (test cohort; PSC n = 78; PBC n = 74; AIH n = 58) and Norway (validation cohort; PSC n = 138; PBC n = 28; AIH n = 27). Patients with ulcerative colitis without liver disease (n = 194) served as controls. We assessed specific serological biomarkers of ECM turnover: type III and V collagen formation (PRO-C3, PRO-C5), degradation of type III and IV collagen (C3M, C4M), biglycan (BGM) and citrullinated vimentin (VICM).
Most of the ECM markers showed elevated serum levels in PBC compared with PSC or AIH ( <0.01). PRO-C3 correlated well with liver stiffness and showed the most striking differences between advanced and non-advanced liver disease; several of the other ECM markers were also associated with stage. PRO-C3 and other ECM markers were inversely associated with ursodeoxycholic acid treatment response in PBC and remission in AIH. All ECM remodelling markers were significantly elevated ( <0.05) in patients with PSC, PBC, or AIH compared with ulcerative colitis.
In this first study comparing ECM turnover in autoimmune liver diseases, we found increased ECM turnover in PBC compared with either PSC or AIH. The study indicates that ECM remodelling is different in PSC, PBC, and AIH, suggesting differing opportunities for therapeutic intervention.
The level of scarring is linked to prognosis in autoimmune liver diseases such as primary sclerosing cholangitis, primary biliary cholangitis, and autoimmune hepatitis; hence, the scarring process is a possible target for novel therapy. Investigating the scarring process using highly specific technology, we show that the scarring process is different between the 3 autoimmune liver diseases, and this may have important implications for the development of medical treatment.
原发性硬化性胆管炎（PSC）、原发性胆汁性胆管炎（PBC）和自身免疫性肝炎（AIH）是表型不同的自身免疫性肝病，可进展为肝硬化和肝衰竭；然而，它们的组织学纤维化分布有所不同。我们研究了PSC、PBC和AIH患者的细胞外基质（ECM）特征，以确定这些疾病是否表现出不同的ECM周转模式。
回顾性收集来自英国（测试队列；PSC患者78例；PBC患者74例；AIH患者58例）和挪威（验证队列；PSC患者138例；PBC患者28例；AIH患者27例）的血清样本。无肝病的溃疡性结肠炎患者（194例）作为对照。我们评估了ECM周转的特定血清生物标志物：III型和V型胶原形成（PRO-C3、PRO-C5）、III型和IV型胶原降解（C3M、C4M）、双糖链蛋白聚糖（BGM）和瓜氨酸化波形蛋白（VICM）。
与PSC或AIH相比，大多数ECM标志物在PBC患者血清中水平升高（<0.01）。PRO-C3与肝脏硬度相关性良好，在晚期和非晚期肝病之间显示出最显著差异；其他几种ECM标志物也与疾病分期相关。PRO-C3和其他ECM标志物与PBC患者的熊去氧胆酸治疗反应及AIH患者的缓解呈负相关。与溃疡性结肠炎患者相比，PSC、PBC或AIH患者的所有ECM重塑标志物均显著升高（<0.05）。
在这项比较自身免疫性肝病中ECM周转的首次研究中，我们发现与PSC或AIH相比，PBC患者的ECM周转增加。该研究表明，PSC、PBC和AIH中的ECM重塑不同，提示治疗干预的机会不同。
在原发性硬化性胆管炎、原发性胆汁性胆管炎和自身免疫性肝炎等自身免疫性肝病中，瘢痕形成水平与预后相关；因此，瘢痕形成过程可能是新疗法的靶点。利用高度特异性技术研究瘢痕形成过程，我们发现这三种自身免疫性肝病的瘢痕形成过程不同，这可能对医学治疗的发展具有重要意义。
