新型血清纤维化标志物在IgG4相关性疾病诊断评价中的临床价值

doi:10.16150/j.1671-2870.2019.03.016

摘要/Abstract

摘要：

目的： 寻找血清中对IgG4相关性疾病（IgG4-related disease, IgG4-RD）诊断有临床价值的新型血清学标志物,并探讨其与器官受累间的相关性及对糖皮质激素治疗的反应。方法： 收集本院2015年1月至2019年1月收治的未经治疗的IgG4-RD患者共72例,通过酶联免疫吸附法测定其血清生长分化因子15（growth differentiation factor 15, GDF-15）、CC趋化因子配体2（CC chemokine ligand 2, CCL2）、透明质酸、Ⅲ型胶原氨基末端前肽（amino-terminal propeptide of type Ⅲ procollagen, PⅢNP）和金属蛋白酶-1组织抑制物（tissue inhibitor of metalloproteinases, TIMP-1）浓度,并以TIMP-1、PⅢNP、透明质酸浓度为基础计算增强肝纤维化（enhanced liver fibrosis, ELF）评分,评估这些标志物在反映IgG4-RD患者组织纤维化程度及器官受累范围方面的价值。结果： 与50例健康对照者相比,IgG4-RD患者血清中GDF-15、CCL2、透明质酸、PⅢNP和TIMP-1的浓度显著升高,其平均浓度分别为1 121 pg/mL、398 pg/mL、87.2 ng/mL、26.1 ng/mL和211 ng/mL;IgG4-RD患者的ELF评分也明显升高（11.2分）。其中,GDF-15取临界值为666 pg/mL时,在区分健康对照者与IgG4-RD患者上的能力最为显著（曲线下面积0.92,灵敏度77.8%,特异度100%）。13例患者接受糖皮质激素治疗后行影像学检查均表现出受累器官的好转迹象,其血清IgG4浓度均出现了下降,中位浓度为91 mg/dL（P=0.000 5）,但其血清GDF-15、CCL2、TIMP-1浓度却出现了上升。结论： 新型血清纤维化标志物GDF-15对IgG4-RD的诊断有较好的临床价值,但其不能反映IgG4-RD患者器官受累的范围和数目,也不能作为糖皮质激素治疗后疾病转归的观察指标。

Abstract:

Objective: To explore serological biomarkers which can be used for diagnosing IgG4-related diseases (IgG4-RD) and to analyze its correlation with involvement of IgG4-RD and patients' response to corticosteroid therapy. Methods: Seventy-two patients with untreated IgG4-RD from January 2015 to January 2019 were enrolled. The serum concentrations of growth differentiation factor 15 (GDF-15), CC chemokine ligand 2 (CCL2), hyaluronic acid (HA), amino-terminal propeptide of type Ⅲ procollagen (PⅢNP), and tissue inhibitor of metalloproteinases 1 (TIMP-1) were measured by enzyme-linked immunosorbent assay. The enhanced liver fibrosis (ELF) score was calculated from the TIMP-1, PⅢNP and HA values. The value of these biomarkers in reflecting the degree of tissue fibrosis and extent of organ involvement was assessed. Results: Compared with healthy controls, patients with IgG4-RD had significantly elevated serum concentrati-ons of GDF-15, HA, PⅢNP, and TIMP-1; the average concentrations of CCL2, HA, PⅢNP and TIMP-1 were 1 121 pg/mL, 398 pg/mL, 87.2 ng/mL and 211 ng/mL, respectively. The ELF score of IgG4-RD patients was also significantly elevated (11.2). Among them, serum GDF-15 of 666 pg/mL distinguished most efficiently patients with IgG4-RD from healthy controls (area under ROC 0.92, sensitivity 77.8%, specificity 100%). Conclusions: New-type serological biomarker GDF-15 and CCL2 have substantial clinical value in diagnosis of IgG4-RD but can not reflect the severity of organ involvement and degree of fibrosis, or cannot be served as criteria of outcome of corticosteroid treatment.

Key words: IgG4-related disease, Fibrosis, Growth differentiation factor 15, CC chemokine ligand 2

中图分类号:

R539.3

周鑫昀, 陈惠, 沈立松. 新型血清纤维化标志物在IgG4相关性疾病诊断评价中的临床价值[J]. 诊断学理论与实践, 2019, 18(03): 329-333.

ZHOU Xinyun, CHEN Hui, SHEN Lisong. Value of new-type serum fibrosis-related biomarkers level in diagnosing IgG4-related disease[J]. Journal of Diagnostics Concepts & Practice, 2019, 18(03): 329-333.

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参考文献 19

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项目	中位数（四分位数间距）
年龄（岁）	64（57~74）
性别（男/女）	51（70.8%）/21（29.2%）
病程持续时间（月）	10（4~33）
实验室数据
总IgG（mg/dL）	1 885（1 380~2 460）
IgG4（mg/dL）	457（260~705）
IgG4≥135 mg/dL的比例	68/72（94.4%）
IgE（U/mL）	408（125~774）
C₃（mg/dL）	78.9（69.6~101.9）
C₄（mg/dL）	20.8（13.3~29.2）
sIL-2R（U/mL）	788（485~1 123）

指标	IgG4-RD（n=72）	健康对照组（n=50）	P值
GDF-15（pg/mL）	1 121（645~2033）	286（133~325）	<0.000 1
CCL2（pg/mL）	398（231~475）	309（207~350）	0.014 0
TIMP-1（ng/mL）	211（138~279）	135（103~159）	<0.000 1
HA（ng/mL）	87.2（46.3~132）	20.9（10.8~41.7）	<0.000 1
PⅢNP（ng/mL）	26.1（13.6~50.1）	5.2（0.7~19.9）	<0.000 1
ELF评分（分）	11.2（8.8~13.9）	6.6（4.1~8.9）	<0.000 1

项目	Spearman相关系数	P值
GDF-15	0.08	0.490 0
CCL2	0.04	0.770 0
TIMP-1	0.09	0.450 0
HA	0.16	0.160 0
PⅢNP	-0.16	0.190 0
ELF评分	-0.05	0.850 0
总IgG	0.50	0.000 3
IgG4	0.68	<0.000 1
C₃	-0.31	0.016 0
C₄	-0.47	0.003 7
sIL-2R	0.55	<0.000 1

参数	治疗前	治疗后	P值
IgG4（mg/dL）	248（191~504）	91（59~163）	0.000 5
GDF-15（pg/mL）	989（571~1537）	1 158（872~1743）	0.034 0
CCL2（pg/mL）	310（248~392）	359（297~434）	0.033 0
TIMP-1（ng/mL）	220（172~245）	246（207~280）	0.019 0
HA（ng/mL）	70.6（51.4~86.6）	70.8（55.4~91.0）	0.970 0
PⅢNP（ng/mL）	20.4（5.7~76.8）	35.6（28.2~57.4）	0.860 0
ELF评分	10.3（9.4~10.9）	10.8（10.5~11.4）	0.250 0