Long-Term Obeticholic Acid Therapy Improves Histological Endpoints in Patients With Primary Biliary Cholangitis
Long-Term Obeticholic Acid Therapy Improves Histological Endpoints in Patients With Primary Biliary Cholangitis
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DOI：
10.1016/j.cgh.2019.09.050
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发表时间：
2020-05-01
影响因子：
12.6
通讯作者：
Bedossa, Pierre
中科院分区：
文献类型：
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作者：
Bowlus, Christopher L.;Pockros, Paul J.;Bedossa, Pierre
背景与目的：原发性胆管炎是一种以胆管破坏为特征的自身免疫性疾病，可进展为肝硬变。在PBC乙酰胆酸(OCA)国际疗效研究(POISE)中进行了一项肝活检亚研究，以确定OCA对PBC患者肝脏损伤和纤维化的长期影响。POISE是一项3期、双盲、安慰剂对照的随机试验，为期5年，开放标签延长5年，每天评估5-10 mg OCA对熊去氧胆酸不耐受或无反应的患者。方法：在双盲期登记时和OCA治疗3年后，从17名患者的肝脏活检标本中收集。组织学评估由两位病理学家以盲法、随机方式进行，以确定OCA对纤维化和其他组织学参数的影响。结果：从入选到治疗3年，大多数患者的纤维化(71%)、胆管丢失(76%)、胆管减少(82%)、导管反应(82%)、交界性肝炎(100%)和小叶性肝炎(94%)得到改善或稳定。在3年的时间里，我们发现胶原面积比(中位数，-2.1；第一个四分位数，-4.6，第三个四分位数，-0.3；P=.013)，胶原纤维密度(中位数，-0.8；第一个四分位数，-2.5；第三个四分位数，0；P=.021)，胶原网状指数(中位数，-0.1；第一个四分位数，-0.3；第三个四分位数，0；P=.008)，和纤维化综合评分(中位数，-1.0；第一个四分位数为-2.5；第三个四分位数为-0.5；P=0.002)。结论：POISE研究数据的子分析表明，PBC患者长期接受OCA治疗与疾病特征的改善或稳定有关，包括导管损伤、纤维化和胶原形态计量特征
BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is an autoimmune disease characterized by bile duct destruction that can progress to cirrhosis. A liver biopsy substudy was conducted in the PBC obeticholic acid (OCA) International Study of Efficacy (POISE) to determine the long-term effects of OCA on liver damage and fibrosis in patients with PBC. POISE is a phase 3, double-blind, placebo-controlled, randomized trial with a 5-year open-label extension that evaluated 5 to 10 mg OCA daily in patients who were intolerant or unresponsive to ursodeoxycholic acid.METHODS: Liver biopsy specimens were collected from 17 patients at time of enrollment in the double-blind phase and after 3 years of OCA treatment. Histologic evaluations were performed by 2 pathologists in a blinded, randomized fashion to determine the effects of OCA on fibrosis and other histologic parameters. Collagen morphometry assessments were performed by automated second harmonic generation and 2-photon excitation microscopy to observe quantitative measures of fibrosis.RESULTS: From the time of enrollment until 3 years of treatment, most patients had improvements or stabilization in fibrosis (71%), bile duct loss (76%), ductopenia (82%), ductular reaction (82%), interface hepatitis (100%), and lobular hepatitis (94%). Over the 3-year period, we found significant reductions in collagen area ratio (median, -2.1; first quartile, -4.6, third quartile, -0.3; P = .013), collagen fiber density (median, -0.8; first quartile, -2.5; third quartile, 0; P = .021), collagen reticulation index (median, -0.1; first quartile, -0.3; third quartile, 0; P = .008), and fibrosis composite score (median, -1.0; first quartile, -2.5; third quartile, -0.5; P = .002).CONCLUSIONS: A subanalysis of data from the POISE study showed that long-term OCA treatment in patients with PBC is associated with improvements or stabilization of disease features, including ductular injury, fibrosis, and collagen morphometry feature