Lam Simon, Singh Ruchi, Dillman Jonathan R, Trout Andrew T, Serai Suraj D, Sharma Divya, Sheridan Rachel, Su Weizhe, Fei Lin, Karns Rebekah, Haramija Marija M, Ridgway Ged, Goldfinger Marc, Squires James E, Denson Lee A, Hyams Jeffery S, Miethke Alexander G
Division of Gastroenterology, Hepatology and Nutrition Cincinnati Children's Hospital Medical Center Cincinnati OH USA.
Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH USA.
Hepatol Commun. 2020 Sep 24;4(11):1680-1693. doi: 10.1002/hep4.1589. eCollection 2020 Nov.
In autoimmune liver disease (AILD), including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and overlap syndrome of AIH and PSC (ASC), the presence of biliary injury portends a worse prognosis. We studied serum matrix metalloproteinase 7 (sMMP7) as a biomarker for pediatric sclerosing cholangitis (SC). We prospectively enrolled 54 children (median age, 16 years) with AILD (AIH, n = 26; ASC, n = 16; and PSC, n = 12) at our center. The sMMP7 concentrations were higher in patients with SC compared to those without cholangiopathy ( < 0.001). An sMMP7 concentration >23.7 ng/mL had a sensitivity and specificity of 79% and 96%, respectively, and outperformed alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) in segregating patients with SC. Serum concentrations correlated with liver gene expression levels for ( = 0.70; < 0.001). Using immunofluorescence, MMP7 was localized primarily to the cholangiocytes of patients with SC. In 46 subjects with liver biopsy available for blinded review, elevation in sMMP7 concentrations segregated with the presence of lymphocytic and neutrophilic cholangitis and periductal fibrosis and correlated with Ishak, Ludwig, and Nakanuma scoring systems. Liver stiffness measured by magnetic resonance elastography also correlated with sMMP7 concentrations ( = 0.56; < 0.01). Using magnetic resonance cholangiopancreatography plus (MRCP+), sMMP7 in 34 patients correlated with the number of biliary dilatations ( = 0.54; < 0.01) and strictures ( = 0.56; < 0.01). MMP7 as a marker of biliary injury was validated in an independent cohort of children with ulcerative colitis. Higher sMMP7 concentrations also correlated with a history of SC-related complication. : MMP7 is a promising biomarker for pediatric SC that diagnostically outperforms ALP and GGT. sMMP7 may directly reflect biliary injury and fibrosis, the main drivers of disease progression in SC.
在自身免疫性肝病（AILD）中，包括自身免疫性肝炎（AIH）、原发性硬化性胆管炎（PSC）以及AIH和PSC的重叠综合征（ASC），胆汁损伤的存在预示着预后更差。我们研究了血清基质金属蛋白酶7（sMMP7）作为儿童硬化性胆管炎（SC）的生物标志物。我们前瞻性地纳入了本中心54名患有AILD的儿童（中位年龄16岁）（AIH 26例；ASC 16例；PSC 12例）。与无胆管病变的患者相比，SC患者的sMMP7浓度更高（<0.001）。sMMP7浓度>23.7 ng/mL时，敏感性和特异性分别为79%和96%，在区分SC患者方面优于碱性磷酸酶（ALP）和γ-谷氨酰转移酶（GGT）。血清浓度与肝基因表达水平相关（=0.70；<0.001）。通过免疫荧光法，MMP7主要定位于SC患者的胆管细胞。在46名有肝活检可供盲法评估的受试者中，sMMP7浓度升高与淋巴细胞性和中性粒细胞性胆管炎及导管周围纤维化的存在相关，并与Ishak、Ludwig和Nakanuma评分系统相关。通过磁共振弹性成像测量的肝脏硬度也与sMMP7浓度相关（=0.56；<0.01）。在34例患者中，使用磁共振胰胆管造影增强（MRCP+），sMMP7与胆管扩张数量（=0.54；<0.01）和狭窄数量（=0.56；<0.01）相关。MMP7作为胆汁损伤的标志物在一组独立的溃疡性结肠炎儿童队列中得到验证。较高的sMMP7浓度也与SC相关并发症的病史相关。结论：MMP7是一种有前景的儿童SC生物标志物，在诊断方面优于ALP和GGT。sMMP7可能直接反映胆汁损伤和纤维化，这是SC疾病进展的主要驱动因素。
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