Effect of T-lymphocyte phenotype on immune status in chronic hepatitis B virus infection and its application value

Zhao JinHua; Li JunFeng; Mao XiaoRong

doi:10.3969/j.issn.1001-5256.2020.05.014

Volume 36 Issue 5

May 2020

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Article Navigation > Journal of Clinical Hepatology > 2020 > 36(5): 1019-1023

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Effect of T-lymphocyte phenotype on immune status in chronic hepatitis B virus infection and its application value

DOI: 10.3969/j.issn.1001-5256.2020.05.014

The First Clinical Medical College,Lanzhou University

Research funding:

Received Date: 2019-12-16
Published Date: 2020-05-20

Abstract

Abstract

Objective To investigate the association between T-lymphocyte phenotype and immune status in chronic hepatitis B(CHB)and its application value.Methods A total of 77 CHB patients who attended The First Hospital of Lanzhou University from January 2015 to May 2019 were enrolled, and according to the status of HBeAg and the serum levels of alanine aminotransferase(ALT), HBsAg, and HBV DNA, they were divided into immune tolerance group and non-immune tolerance group. The laboratory results of T-lymphocyte phenotype, HBV serological test, HBV DNA load, routine blood test, and liver function were obtained, and aspartate aminotransferase-to-platelet ratio index(APRI) and fibrosis-4(FIB-4) were calculated. Thettest was used for comparison of normally distributed continuous data between two groups; and the Mann-WhitneyUtest was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between groups. Spearman correlation analysis was used to test the correlation effect between the two variables. The diagnostic efficacy of Treg, CD8+PD-1+T lymphocyte percentage and CD8+CD45 RO+T lymphocyte percentage were evaluated by AUC.Results Compared with the non-immune tolerance group, the immune tolerance group had significantly higher percentages of Treg and CD8+PD-1+T cells(U= 12. 0 and 59. 0,P< 0. 001,P= 0 013) and significantly lower percentages of CD3+CD8+T cells and CD8+CD45 RO+T cells(U= 50. 0 and 38. 5, bothP< 0. 05). Compared with the high HBV DNA load group, the low HBV DNA load group had significantly lower percentages of Treg and CD8+PD-1+T cells(U= 178 5 and 255.0,P= 0. 003 and 0. 018) and significantly higher percentages of CD3+T cells and CD8+CD45 RO+T cells(U= 104. 0 and1495,P= 0. 033 and 0. 025). APRI was negatively correlated with the percentage of Treg(r=-0. 379,P= 0. 013), and FIB-4 was negatively correlated with the percentages of CD3+CD4+, CD3+CD8+, CD4+CD45 RO+, and CD8+CD45 RO+T cells(r=-0. 259,-0. 275,-0. 233, and-0. 229,P= 0. 023, 0. 016, 0. 041, and 0. 045). Treg, CD8+PD-1+T cells, and CD8+CD45 RO+T cellshad an area under the ROC curve of 0. 793(95% confidence interval [CI]: 0. 651-0. 936), 0. 802(95% CI: 0. 678-0. 927), and0. 816(95% CI: 0. 706-0. 927), respectively, in evaluating immune status.Conclusion There are various T-lymphocyte phenotypesin patients with chronic HBV infection, and different T lymphocytes have different abilities to eliminate HBV. Detection of T-lymphocytephenotype helps to understand the immune status and adjust the immune function in CHB patients and can provide a reference for the func-tional cure of CHB patients.
- hepatitis B,chronic,
- T-lymphocyte subsets,
- immunity,cellular

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随着经济水平的发展和膳食结构的改变，我国2型糖尿病(T2DM)的患病率一直处于上升趋势，流行病学调查显示我国18岁及以上成年人中T2DM的患病率已达11.2%^[1]。非酒精性脂肪性肝病(NAFLD)是肝细胞内脂质的过度沉积^[2]，T2DM与NAFLD的关系已得到充分认可。T2DM合并NAFLD的全球患病率为55.5%^[3]，对于T2DM合并NAFLD的预测具有重要的意义。肥胖和胰岛素抵抗(IR)是T2DM合并NAFLD的危险因素^[4]。BMI是判断肥胖的常用指标，甘油三酯葡萄糖乘积指数(triglyceride-glucose index，TyG)可反应体内的IR。因此，本研究通过回顾性分析中国医科大学附属盛京医院T2DM合并NAFLD患者的临床资料，探讨TyG联合BMI对T2DM合并NAFLD的预测价值。

1. 资料与方法

1.1 研究对象

收集2020年5月—2021年7月经本院诊治为T2DM患者的临床资料，T2DM的诊断符合《中国2型糖尿病防治指南(2020年版)》^[5]，按照有无NAFLD分为T2DM合并NAFLD组和单纯T2DM组，NAFLD的诊断符合《非酒精性脂肪性肝病防治指南(2018更新版)》^[6]。

排除标准：(1)年龄＜18岁或＞65岁的患者；(2)1型糖尿病及其他类型糖尿病患者，2型糖尿病并发酮症酸中毒或高渗昏迷等急性并发症的患者；(3)酒精性肝病、病毒性肝炎、药物性肝损伤、自身免疫性肝病、遗传代谢性肝病等其他肝病患者；(4)恶性肿瘤患者；(5)近3个月口服保肝药物的患者。

1.2 研究指标

1.2.1 一般资料测量

(1) 测量患者的身高和晨起体质量，计算BMI；(2)测量晨起静息状态下右上臂收缩压及舒张压。

1.2.2 生化指标检测

清晨空腹采肘静脉血，采用日立7600全自动生化分析仪检测AST、ALT、GGT、TBil、IBil、DBil、TG、TC、HDL-C、LDL-C、空腹血糖(FBG)、糖化血红蛋白(HbA1c)。计算TyG指数，TyG=ln[TG(mg/dL)× FBG(mg/dL)/2]。

1.2.3 肝脏彩超检测

使用TOSHIBA Aplio500彩色多普勒超声于空腹状态下检查肝脏，NAFLD表现包括肝脏近场回声增强、肝内管道结构显示不清、远场回声衰减等特征。

1.3 统计学方法

采用SPSS 25.0统计学软件进行分析。符合正态分布的计量资料以x±s表示，两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以M(P₂₅~P₇₅)表示，两组间比较采用Mann-Whitney U检验；计数资料两组间比较采用χ²检验。采用logistic回归分析TyG及BMI与T2DM合并NAFLD的关系；绘制受试者工作特征曲线(ROC曲线)评价TyG、BMI及TyG联合BMI对T2DM合并NAFLD的预测效能，测量曲线下面积(AUC)，根据约登指数最大原则确定最佳截断点，并计算敏感度、特异度、阳性预测值、阴性预测值，采用Kappa系数分析预测结果的一致性程度。P＜0.05为差异有统计学意义。

2. 结果

2.1 一般资料

共纳入T2DM患者349例。T2DM合并NAFLD组213例，其中男139例，女74例，年龄21~65岁，平均(45.59±12.53) 岁；单纯T2DM组136例，其中男95例，女41例，年龄19~64岁，平均(43.82±12.95)岁。两组的年龄(t=1.265)、性别(χ²=0.793)差异均无统计学意义(P值均＞0.05)。

2.2 两组BMI、血压及生化指标的比较

T2DM合并NAFLD组的BMI、舒张压、FBG、HbA1c、ALT、AST、GGT、TG、TC、LDL-C、TyG均高于单纯T2DM组(P值均＜0.05)，T2DM合并NAFLD组的HDL-C低于单纯T2DM组(P＜0.05)，两组在收缩压、TBil、DBil、IBil间的差异均无统计学意义(P值均＞0.05)(表 1)。

表 1 两组一般资料的比较

Table 1. Comparison of general data between two groups

指标	T2DM合并NAFLD组(n=213)	单纯T2DM组(n=136)	统计值	P值
BMI(kg/m²)	26.33(24.52~29.37)	23.23(21.92~25.39)	Z=-9.044	＜0.001
收缩压(mmHg)	130.00(120.00~140.00)	130.00(120.00~140.00)	Z=-1.729	0.084
舒张压(mmHg)	80.00(80.00~90.00)	80.00(75.00~84.00)	Z=-3.251	0.001
FBG(mmol/L)	9.85(8.20~12.29)	7.96(6.36~9.68)	Z=-6.126	＜0.001
HbA1c(%)	8.90(7.45~10.25)	7.35(6.50~9.05)	Z=-5.075	＜0.001
ALT(U/L)	31.00(22.00~44.00)	21.00(13.00~26.00)	Z=-7.820	＜0.001
AST(U/L)	22.00(17.00~29.00)	18.00(15.00~21.00)	Z=-5.447	＜0.001
GGT(U/L)	36.00(24.00~56.00)	18.00(13.00~25.25)	Z=-9.402	＜0.001
TBil(μmol/L)	10.25(8.30~13.40)	10.40(7.80~13.20)	Z=-0.098	0.922
DBil(μmol/L)	3.20(2.50~4.18)	3.30(2.53~4.38)	Z=-1.129	0.259
IBil(μmol/L)	7.25(5.40~9.20)	7.05(5.25~9.00)	Z=-0.226	0.821
TG(mmol/L)	2.42(1.74~3.63)	1.07(0.81~1.50)	Z=-11.831	＜0.001
TC(mmol/L)	5.04(4.28~5.96)	4.21(3.86~4.70)	Z=-7.188	＜0.001
HDL-C(mmol/L)	1.02(0.88~1.25)	1.16(1.02~1.37)	Z=-4.897	＜0.001
LDL-C(mmol/L)	3.28(2.63~3.97)	2.87(2.63~3.87)	Z=-4.042	＜0.001
TyG	9.98±0.79	8.87±0.61	t=13.832	＜0.001

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2.3 TyG、BMI与T2DM合并NAFLD的logistic回归分析

以是否合并NAFLD为因变量，TyG和BMI为自变量纳入logistic回归方程，提示TyG和BMI为T2DM合并NAFLD的危险因素。校正单因素分析具有统计学差异的舒张压、FBG、HbA1c、ALT、AST、GGT、TG、TC、LDL-C、HDL-C后，仍具有统计学意义，表示TyG和BMI均为T2DM合并NAFLD的独立危险因素(表 2)。

表 2 TyG、BMI与T2DM合并NAFLD的logistic回归分析

Table 2. Logistic regression analysis of TyG, BMI in T2DM combined with NAFLD

指标	β值	标准误	Wald值	OR值	95%CI	P值
校正前BMI	0.392	0.051	59.377	1.479	1.339~1.634	＜0.001
校正前TyG	2.439	0.269	82.237	11.459	6.764~19.411	＜0.001
校正后BMI	0.314	0.071	19.390	1.369	1.191~1.575	＜0.001
校正后TyG	1.874	0.633	8.766	6.513	1.884~22.517	0.003

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2.4 TyG、BMI及TyG联合BMI对T2DM合并NAFLD的预测价值

根据ROC曲线结果可见，TyG和BMI预测T2DM合并NAFLD的最佳截断点分别为9.41、24.22，TyG预测的AUC、特异度、敏感度、阳性预测值、阴性预测值均高于BMI，二者联合可以进一步提高预测效能。Kappa系数显示TyG联合BMI预测T2DM合并NAFLD具有更好的一致性(图 1，表 3)。

图 1 TyG、BMI及TyG联合BMI预测T2DM合并NAFLD的ROC曲线

Figure 1. ROC curve of TyG, BMI and TyG combined with BMI for predicting T2DM combined with NAFLD

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表 3 TyG、BMI及TyG联合BMI对T2DM合并NAFLD的预测价值

Table 3. Predictive value of TyG, BMI and TyG combined BMI for T2DM combined with NAFLD

指标	最佳截断点	AUC	95%CI	敏感度(%)	特异度(%)	阳性预测值(%)	阴性预测值(%)	Kappa系数
BMI	24.22	0.787	0.740~0.834	78.9	64.0	77.36	64.23	0.416
TyG	9.41	0.875	0.839~0.911	80.3	80.1	86.36	72.19	0.592
TyG联合BMI		0.910	0.881~0.940	81.2	88.2	91.53	75.00	0.673

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3. 讨论

超声作为最常用的影像学检查方法，广泛用于临床上对于脂肪肝的诊断，但超声对于轻度脂肪肝的检出率及敏感性较低^[7]，且超声在诊断脂肪肝过程中易受操作者主观判断及患者皮下脂肪厚度、脾肾回声、肝纤维化的影响，使其有一定的局限性^[8]。因此，寻找一个简单可行的，不受操作者主观影响的无创指标，对于NAFLD的预测具有重要的临床意义。BMI包含身高和体质量，TyG包含TG和FBG，均为日常工作中最基础的指标，构成简单，应用方便，因此具有用于预测T2DM合并NAFLD的基本要求。

BMI升高反映着超重和肥胖的存在，本研究结果显示BMI是T2DM合并NAFLD的独立危险因素，原因在于：(1)超重或肥胖时出现脂肪营养不良，肝细胞则会储存多余的脂质^[9]；(2)脂肪细胞肥大、增生的过程中产生细胞因子，释放脂肪酸，在肝脏内积聚后诱发肝脏炎症反应、细胞损伤及凋亡^[10]；(3)肥胖时分泌的脂肪因子向更具脂肪及纤维生成性、炎症性的方向转移^[11]，加重肝损伤。超重或肥胖与NAFLD有着密切的关系，因此BMI可用于预测T2DM合并NAFLD的发生。

IR是T2DM和NAFLD的发病基础。TyG指数最早由Simental-Mendía于2008年提出^[12]，与评估IR金标准的高胰岛素-正葡萄糖钳夹试验显著相关^[13]，因此也被看作是IR的标志物^[14]。IR在T2DM合并NAFLD中的影响在于：(1)IR时外周组织对胰岛素的敏感性下降，胰岛素对脂解的抑制作用也减弱，导致游离脂肪酸异位沉积于肝脏中^[15-16]。(2)IR状态下的高胰岛素和高血糖上调SREBP1c和ChEBP活性，激活糖分解和脂肪生成酶，刺激肝脏脂肪的从头合成^[17]。(3)IR活化巨噬细胞，介导肝巨噬细胞和肝星状细胞关联，促进NAFLD发展为肝纤维化甚至肝癌^[18]。因此，作为IR标志物的TyG可预测T2DM中的NAFLD。

本研究结果指出TyG联合BMI对T2DM合并NAFLD的预测效能和一致性水平上高于单一指标检测，考虑在于二者联合综合了IR和肥胖对T2DM合并NAFLD的影响，所以提高了预测价值。目前对于NAFLD的筛查要求，也指出在明确NAFLD的同时应评估患者是否同时存在其他代谢综合征组分^[19]，所以，TyG联合BMI在预测NAFLD的同时，也能对肥胖、IR、血糖血脂等代谢组分的评估进行指导，因此具有较高的应用价值。

综上所述，应重视T2DM合并NAFLD的预测，TyG和BMI可作为预测T2DM合并NAFLD的指标，联合用于T2DM合并NAFLD的筛查与管理。

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Effect of T-lymphocyte phenotype on immune status in chronic hepatitis B virus infection and its application value

DOI: 10.3969/j.issn.1001-5256.2020.05.014