血清巨噬细胞极化相关因子与多房棘球蚴病肝纤维化的相关性分析

鄂维建; 芦永良; 祁秉民; 庞明泉; 王志鑫; 张灵强; 樊海宁

doi:10.3969/j.issn.1001-5256.2021.12.017

血清巨噬细胞极化相关因子与多房棘球蚴病肝纤维化的相关性分析

DOI: 10.3969/j.issn.1001-5256.2021.12.017

a.
青海大学附属医院检验科，西宁 810001
b.
青海大学附属医院肝胆胰外科，西宁 810001

基金项目:

国家自然科学基金 (81960576);

青海省科技计划项目 (2018-ZJ-757)

详细信息

通信作者:
芦永良，625196237@qq.com

中图分类号: R575.2
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出版历程
- 收稿日期: 2021-05-10
- 录用日期: 2021-07-23
- 出版日期: 2021-12-20

Association between serum macrophage polarization-related factors and liver fibrosis in echinococcosis multilocularis

a.
Department of Clinical Laboratory, The Affiliated Hospital of Qinghai University, Xining 810001, China
b.
Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qinghai University, Xining 810001, China

Research funding:

National Natural Science Foundation of China (81960576);

Qinghai Province Science and Technology Plan Project (2018-ZJ-757)

摘要

摘要: 目的探究血清巨噬细胞极化相关因子与多房棘球蚴病(AE)患者肝纤维化的关系。方法选择2018年9月—2020年10月青海大学附属医院肝胆胰外科AE患者120例，另外选取33例健康对照者作为正常对照组。比较2组受试者间及不同肝纤维化程度患者IL-6、IL-10、TNFα、TGFβ1水平。符合正态分布的计量资料2组间比较采用独立样本t检验；不符合正态分布的计量资料组间比较采用Mann-Whitney U检验或Kruskal-Wallis H检验。计数资料组间比较采用χ²检验。采用单因素及多因素logistic回归分析法分析血清巨噬细胞极化相关因子与AE患者肝纤维化的关系，采用受试者工作特征曲线(ROC曲线)分析血清学检查对AE患者肝纤维化的诊断价值。采用Spearman法分析各指标与HAI评分和Metavir分期的相关性。结果与正常对照组比较，AE组血清IL-6[(13.97(9.64~23.62)pg/mL vs 1.30(0.35~2.71)pg/mL，Z=-5.980，P＜0.001]、TNFα[2.26(1.65~4.13)pg/mL vs 1.40 (1.04~2.10)pg/mL，Z=-3.114，P＜0.01]、TGFβ1[3.64(2.71~5.72)pg/mL vs 2.91(2.20~3.35)pg/mL，Z=-2.594，P＜0.05] 水平均显著升高。且血清IL-6、TNFα水平升高是肝AE患者发生肝纤维化的独立危险因素[HR(95%CI)：2.721(1.730~4.280)、3.527(1.158~10.747)，P值均＜0.05]。经ROC曲线分析，包虫抗体IgG联合血清IL-6、TNFα对于肝纤维化的诊断敏感度和特异度分别为88.4%和95.8%，曲线下面积为0.951(95%CI：0.937~0.964)，均高于IL-6、TNFα、包虫抗体IgG的单独诊断(Z值分别为-3.458、-4.011、2.379，P值均＜0.05)。经Spearman分析，血清IL-6、TNFα、TGFβ水平与HAI评分(r值分别为0.560、0.644、0.465，P值均＜0.001)、Metavir纤维化评分(r值分别为0.530、0.758、0.567，P值均＜0.001)均呈正相关性，而血清IL-10与HAI评分(r=-0.232，P=0.011)和Metavir纤维化评分(r=-0.288，P=0.001)则呈负相关性。结论肝AE患者普遍存在巨噬细胞极化状态，且巨噬细胞极化相关因子IL-6、TNFα、TGFβ1水平与肝纤维化发生和进展有关，对于预测肝纤维化可提供一定的参考信息。
- 棘球蚴病, 肝 /
- 肝硬化 /
- 巨噬细胞 /
- 白细胞介素类 /
- 肿瘤坏死因子α /
- 转化生长因子β
Abstract: Objective To investigate the association between serum macrophage polarization-related factors and liver fibrosis in patients with alveolar echinococcosis (AE). Methods A total of 120 patients with AE who attended Department of Hepatobiliary and Pancreatic Surgery in The Affiliated Hospital of Qinghai University from September 2018 to October 2020 were enrolled as AE group, and 33 healthy controls were enrolled as normal control group. The two groups and the patients with varying degrees of liver fibrosis were compared in terms of the levels of interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1). Comparison of normally distributed continuous data between two groups was made by the independent samples t-test, while comparison of non-normally distributed continuous data was made by the Mann-Whitney U test or Kruskal-Wallis H test. Comparison of categorical data between groups was made by the chi-square test. Univariate and multivariate logistic regression analyses were used to investigate the association between serum macrophage polarization-related factors and liver fibrosis in patients with AE, and the receiver operating characteristic (ROC) curve was used to analyze the value of serological examination in the diagnosis of liver fibrosis in patients with AE. A Spearman correlation analysis was used to analyze the correlation of each index with HAI score and Metavir score. Results Compared with the normal control group, the AE group had significant increases in the serum levels of IL-6 [13.97 (9.64-23.62) pg/mL vs 1.30 (0.35-2.71) pg/mL, Z=-5.980, P < 0.001], TNF-α [2.26 (1.65-4.13) pg/mL vs 1.40 (1.04-2.10) pg/mL, Z=-3.114, P < 0.01], and TGF-β1 [3.64(2.71-5.72) pg/mL vs 2.91(2.20-3.35) pg/mL, Z=-2.594, P < 0.05], and increases in the serum levels of IL-6 (hazard ratio [HR]=2.721, 95% confidence interval [CI]: 1.730-4.280, P < 0.05) and TNF-α(HR=3.527, 95%CI: 1.158-10.747, P < 0.05) were independent risk factors for the onset of liver fibrosis in AE patients. The ROC curve analysis showed that hydatid IgG combined with the serum levels of IL-6 and TNF-α had a sensitivity of 88.4%, a specificity of 95.8%, and an area under the ROC curve of 0.951(95%CI: 0.937-0.964) in the diagnosis of liver fibrosis, which were significantly higher than those of IL-6, TNF-α, or hydatid IgG alone (Z=-3.458, -4.011, and 2.379, all P < 0.05). The Spearman analysis showed that the serum levels of IL-6, TNF-α, and TGF-β1 were positively correlated with HAI score (r=0.560, 0.644, and 0.465, all P < 0.001) and Metavir fibrosis score (r=0.530, 0.758, and 0.567, all P < 0.001), and the serum level of IL-10 was negatively correlated with HAI score (r=-0.232, P=0.011) and Metavir fibrosis score (r=-0.288, P=0.001). Conclusion Macrophage polarization is often observed in patients with hepatic AE, and the levels of the macrophage polarization-related factors IL-6, TNF-α, and TGF-β1 are associated with the development and progression of liver fibrosis, which can provide certain reference information for predicting the onset of liver fibrosis.
- Echinococcosis, Hepatic /
- Liver Cirrhosis /
- Macrophages /
- Interleukins /
- Tumor Necrosis Factor-alpha /
- Transforming Growth Factor beta

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图 1 肝AE患者肝脏病变的HE染色结果(×200)

注：a，距病灶中心＞2 cm的正常肝组织；b，距病灶中心≤2 cm的肝组织。

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图 2 肝AE患者肝脏病变的Masson染色结果(×200)

注：a，距病灶中心＞2 cm的正常肝组织；b，距病灶中心≤2 cm的肝组织。

下载: 全尺寸图片幻灯片

图 3 血清IL-6、IL-10、TNFα、TGFβ1与肝AE患者Metavir纤维化评分的关系分析

下载: 全尺寸图片幻灯片

图 4 血清IL-6、IL-10、TNFα、TGFβ1与肝AE患者HAI评分的关系分析

下载: 全尺寸图片幻灯片

表 1 AE组和正常对照组人群基线资料

指标	AE组(n=120)	正常对照组(n=33)	统计值	P值
男[例(%)]	49(40.83)	20(60.61)	χ²=4.087	0.043
年龄(岁)	39.55±12.75	45.42±15.31	t=2.240	0.026
民族[例(%)]			χ²=0.290	0.865
汉族	42(35.00)	12(36.36)
藏族	70(58.33)	18(54.55)
其他	8(6.67)	3(9.09)
职业背景[例(%)]			χ²=1.049	0.306
牧民	84(70.00)	20(60.61)
非牧民	36(30.00)	13(3.03)
血型[例(%)]			χ²=0.117	0.990
A型	51(42.50)	14(42.42)
B型	32(26.67)	9(27.27)
AB型	20(16.67)	6(18.18)
O型	17(14.17)	4(12.12)

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表 2 2组人群血清IL-6、IL-10、TNFα、TGFβ1水平分析

血清学指标	AE组(n=120)	正常对照组(n=33)	Z值	P值
IL-6(pg/mL)	13.97(9.64~23.62)	1.30(0.35~2.71)	-5.980	＜0.001
IL-10(pg/mL)	1.79(1.27~2.43)	1.70(1.50~2.14)	-1.002	0.541
TNFα(pg/mL)	2.26(1.65~4.13)	1.40(1.04~2.10)	-3.114	0.007
TGFβ1(pg/mL)	3.64(2.71~5.72)	2.91(2.20~3.35)	-2.594	0.040

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表 3 血清IL-6、IL-10、TNFα、TGFβ1与肝AE患者肝纤维化的关系分析

血清学指标	F0(n=23)	F1(n=28)	F2(n=34)	F3(n=19)	F4(n=16)	H值	P值
IL-6(pg/mL)	12.83(9.97~15.09)	8.56(6.31~13.37)	13.26(9.52~17.92)	23.70(22.88~27.89)	34.50(26.53~52.98)	50.104	＜0.001
IL-10(pg/mL)	1.80(1.48~2.83)	1.78(1.52~2.35)	1.91(1.50~2.57)	1.52(0.98~2.11)	1.70(0.89~2.35)	9.522	0.105
TNFα(pg/mL)	1.35(1.21~1.71)	1.85(1.40~2.16)	2.46(2.04~3.74)	5.06(3.43~5.96)	5.43(4.01~7.25)	70.494	＜0.001
TGFβ1(pg/mL)	2.61(2.00~2.85)	3.33(2.73~4.13)	3.77(2.97~5.86)	6.80(3.85~12.67)	5.58(3.24~11.25)	42.330	＜0.001

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表 4 单因素和多因素logistic回归分析肝AE患者发生肝纤维化的相关因素

变量	单因素分析		多因素分析
变量	HR(95%CI)	P值	HR(95%CI)	P值
IL-6	2.490(1.668~3.716)	＜0.001	2.721(1.730~4.280)	＜0.001
TNFα	2.012(1.291~3.137)	0.002	3.527(1.158~10.747)	0.027
TGFβ1	1.225(0.992~1.514)	0.060

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表 5 AE组患者血清IL-6、TNFα水平联合诊断肝纤维化的临床价值

变量	AUC	P值	敏感度	特异度	约登指数	截断值	95%CI
IL-6	0.708	＜0.001	57.9%	63.9%	0.218	15.97 pg/mL	0.669~0.747
TNFα	0.654	＜0.001	63.9%	60.6%	0.245	1.889 pg/mL	0.612~0.696
包虫抗体IgG	0.918	＜0.001	83.7%	100.0%	0.837	1	0.900~0.936
联合诊断	0.951	＜0.001	88.4%	95.8%	0.842	0.611	0.937~0.964

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