外部验证REAL-B评分对抗病毒治疗的慢性乙型肝炎患者肝细胞癌发生风险的预测价值

吴雪; 楚伟可; 周辉; 牛斌; 张鹏; 冯婧; 宓余强; 李萍

doi:10.3969/j.issn.1001-5256.2022.08.010

外部验证REAL-B评分对抗病毒治疗的慢性乙型肝炎患者肝细胞癌发生风险的预测价值

DOI: 10.3969/j.issn.1001-5256.2022.08.010

吴雪¹,
楚伟可¹,
周辉¹,
牛斌¹,
张鹏¹,
冯婧¹,
宓余强²,
李萍^2, , ,

1.
天津医科大学, 第二人民医院临床学院, 天津 300070
2.
天津市第二人民医院, 天津市肝病医学研究所, 天津 300192

基金项目:

中国肝炎防治基金会王宝恩肝纤维化研究基金 (2021038)

伦理学声明：本研究方案2019年12月25日经由天津市第二人民医院伦理委员会审批，批号：〔2019〕58号。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：吴雪参与采集、分析数据及起草文章内容；楚伟可、周辉、牛斌、张鹏及冯婧参与数据收集及分析；宓余强、李萍参与文章思路设计，指导文章撰写并最后定稿。

详细信息

通信作者:
李萍, tjlplxg@163.com

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出版历程
- 收稿日期: 2021-12-19
- 录用日期: 2022-01-20
- 出版日期: 2022-08-20

Value of external validation of REAL-B score in predicting the risk of hepatocellular carcinoma in chronic hepatitis B patients treated by antiviral therapy

Xue WU¹,
Weike CHU¹,
Hui ZHOU¹,
Bin NIU¹,
Peng ZHANG¹,
Jing FENG¹,
Yuqiang MI²,
Ping LI^{2
, ,
,}

1.
Clinical College of The Second People's Hospital, Tianjin Medical University, Tianjin 300070, China
2.
Tianjin Hepatopathy Research Institute, Tianjin Second People's Hospital, Tianjin 300192, China

Research funding:

Wang Bao'en Liver Fibrosis Research Fund of China Hepatitis Prevention foundation (2021038)

More Information

Corresponding author: LI Ping, tjlplxg@163.com(ORCID: 0000-0001-9930-6429)

摘要

摘要: 目的探究肝细胞癌(HCC)预测模型REAL-B评分对抗病毒治疗的慢性乙型肝炎患者HCC风险的预测性能，并与mPAGE-B、aMAP、PAGE-B评分进行比较。方法回顾性收集2013年1月—2015年12月天津市第二人民医院1160例接受1年以上恩替卡韦(ETV)或替诺福韦(TDF)治疗的慢性乙型肝炎患者的临床资料，并记录肝癌事件的发生。通过受试者工作特征曲线下面积(AUC)评估REAL-B、mPAGE-B、aMAP、PAGE-B评分对HCC的预测性能。采用Kaplan-Meier方法评估不同时间点HCC累积发生率，并通过log-rank检验比较不同评分分组间肝癌发生的差异。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2组间比较采用Mann-Whitney U检验；计数资料2组间比较采用χ²检验。结果 1160例慢性乙型肝炎患者中，有108 (9.8%)例患者在中位随访5.3(5.0~6.3)年内进展为HCC。REAL-B评分预测5年内HCC发生的AUC及其95%CI为0.848 (0.816~0.880)，其次为aMAP评分[0.823(0.786~0.860)]、mPAGE-B评分[0.822(0.788~0.857)]和PAGE-B评分[0.780(0.736~0.824)]。在REAL-B评分低危组(0~3分)中，5年内肝癌累积发生率为0.8%, 低于中危组(4~7分)11.8%和高危组(8~13分)35.6%(P < 0.05)。REAL-B评分低危组中，3年和5年发生HCC的阴性预测值分别为100%和99.67%。结论 REAL-B评分准确地预测了接受抗病毒治疗的慢性乙型肝炎患者HCC风险，并在抗病毒治疗3年中的预测价值优于其他风险模型。
- 乙型肝炎, 慢性 /
- 癌, 肝细胞 /
- 危险因素
Abstract: Objective To investigate the value of the hepatocellular carcinoma (HCC) risk model REAL-B score in predicting the risk of HCC in chronic hepatitis B (CHB) patients receiving antiviral therapy in comparison with mPAGE-B, aMAP and PAGE-B scores. Methods A retrospective analysis was performed for the clinical data of 1160 CHB patients who received entecavir or tenofovir treatment for more than 1 year from January 2013 to December 2015 in Tianjin Second Peolple's Hospital, and the events of HCC were recorded. The area under the ROC curve (AUC) was used to evaluate the value of REAL-B, mPAGE-B, aMAP, and PAGE-B scores in predicting HCC. The Kaplan-Meier method was used to evaluate the cumulative incidence rate of HCC at different time points, and the log-rank test was used to compare the incidence rate of HCC between the groups with different scores. The independent samples t-test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. Results Among the 1160 CHB patients, 108 (9.8%) progressed to HCC within a median follow-up time of 5.3 (5.0-6.3) years. REAL-B score had an AUC of 0.848 (95% confidence interval [CI]: 0.816-0.880) in predicting the onset of HCC within 5 years, followed by aMAP score (AUC=0.823, 95% CI: 0.786-0.860), mPAGE-B score (AUC=0.822, 95%CI: 0.788-0.857), and PAGE-B scores (AUC=0.780, 95%CI: 0.736-0.824). The 5-year cumulative incidence rate of HCC was 0.8% in the low-risk group (with a REAL-B score of 0-3 points), which was significantly lower than the incidence rate of 11.8% in the medium-risk group (with a REAL-B score of 4-7 points) and 35.6% with the high-risk group (with a REAL-B score of 8-13 points) (P < 0.05). In the low-risk group, REAL-B score had a negative predictive value of 100% and 99.67%, respectively, in predicting HCC within 3 and 5 years. Conclusion REAL-B score accurately predicts the risk of HCC in CHB patients receiving antiviral therapy, with a better predictive value than the other risk models within 3 years of antiviral therapy.
- Hepatitis B, Chronic /
- Carcinoma, Hepatocellular /
- Risk Factors

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图 1 各HCC风险评分分组中肝癌累积发生率

Figure 1. Cumulative incidence of HCC in different risk scores

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表 1 1160例慢性乙型肝炎患者基本特征

Table 1. Basic characteristics of 1160 patients with chronic hepatitis B

项目	总体(n=1160)	非HCC组(n=1052)	HCC组(n=108)	统计值	P值¹⁾
年龄(岁)	45.8±12.9	44.5±12.5	58.2±8.9	t=-11.047	＜0.001
男性[例(%)]	764 (65.9)	686(65.2)	78(72.2)	χ²=2.143	0.143
肝硬化[例(%)]	283(24.4)	217(20.6)	66(61.1)	χ²=87.031	＜0.001
糖尿病[例(%)]	302(26.0)	262(24.9)	40(37.0)	χ²=7.486	0.006
高血压[例(%)]	126(10.9)	100(9.5)	26(24.1)	χ²=21.470	＜0.001
饮酒[例(%)]	88(8.3)	72(6.8)	16(14.8)	χ²=8.876	0.003
肝癌家族史[例(%)]	122(10.5)	111(10.6)	11(10.2)	χ²=0.014	0.906
HBeAg阳性[例(%)]	621(53.5)	578(54.9)	43(39.9)	χ²=9.011	0.003
ALT (U/L)	36.0(22.0~72.0)	36.2(22.6~76.0)	32.3(21.8~49.8)	Z=-1.939	0.052
AST(U/L)	32.2(22.0~55.7)	32(22.0~55.8)	34.3(26.0~55.7)	Z=-1.740	0.082
TBil (mg/dL)	0.9(0.7~1.3)	0.9(0.7~1.3)	1.1(0.8~1.5)	Z=-3.318	0.001
Alb (g/L)	42.0±6.5	42.3±6.4	39.1±6.6	t=-4.632	＜0.001
PLT (×10⁹/L)	156.0(107.0~204.0)	162.0(114.0~210.0)	99.0(69.0~153.0)	Z=-7.015	＜0.001
HBV DNA(log₁₀ IU/mL)	4.5±2.3	4.6±2.3	4.7±1.8	t=1.392	0.164
AFP(ng/mL)	4.2(2.5~8.5)	3.1(2.5~7.1)	4.7(2.5~13.6)	Z=-1.694	0.009
NLR	1.7(1.2~2.4)	1.6(1.2~2.3)	2.0(1.5~3.2)	Z=-3.915	＜0.001
随访时间(年)	5.3(5.0~6.2)	5.3(5.1~6.2)	2.9(2.0~4.9)	Z=-11.386	＜0.001
抗病毒治疗[例(%)]				χ²=0.032	0.859
ETV	1036(89.3)	939(89.3)	97(8.4)
TDF	124(10.7)	113(10.7)	11(10.2)
REAL-B评分	4.3±2.3	4.0±2.1	6.9±1.6	t=-13.441	＜0.001
mPAGE-B评分	10.0±3.9	9.6±3.8	14.0±2.6	t=-11.882	＜0.001
aMAP评分	52.9±9.0	51.9±8.7	62.3±6.7	t=-12.058	＜0.001
PAGE-B评分	13.2±5.4	12.7±5.3	18.0±4.2	t=-9.948	＜0.001
注：REAL-B评分，由男性、年龄、基线时肝硬化、饮酒、糖尿病、PLT和AFP构成；PAGE-B评分，由年龄、男性、PLT构成；mPAGE-B评分，由年龄、性别、PLT、Alb构成；aMAP评分，由年龄、男性、白蛋白-胆红素、PLT构成。

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表 2 HCC发生的危险因素分析

Table 2. Analysis of risk factors for HCC

变量	单因素分析		多因素分析
变量	HR (95%CI)	P值	HR (95%CI)	P值
年龄＞50岁	6.415(4.014~10.252)	＜0.001	4.392(2.685~7.183)	＜0.001
男性	1.362(0.894~2.075)	0.150	-	-
肝硬化	5.487(3.726~8.080)	＜0.001	3.256(2.103~5.043)	＜0.001
饮酒史	1.708(1.156~2.524)	0.007	0.792(0.448~1.401)	0.423
糖尿病	2.183(1.284~3.712)	0.004	1.427(0.920~2.213)	0.112
Alb＜40 g/L	2.011(1.375~2.942)	＜0.001	0.872(0.578~1.315)	0.513
PLT＜100×10⁹/L	3.879(2.659~5.659)	＜0.001	1.616(1.061~2.460)	0.025
AFP＞10 ng/mL	1.847(1.224~2.787)	0.003	1.585(1.022~2.458)	0.040
TBil＞2 mg/dL	1.656(0.959~2.861)	0.071	-	-

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表 3 各HCC风险评分AUC分析

Table 3. AUC of different HCC risk scores

时间	HCC风险评分	AUC	95%CI
3年	REAL-B	0.865	0.830~0.901
	mPAGE-B¹⁾	0.820	0.778~0.862
	aMAP¹⁾	0.819	0.772~0.866
	PAGE-B¹⁾	0.775	0.720~0.829
5年	REAL-B	0.848	0.816~0.880
	mPAGE-B	0.822	0.788~0.857
	aMAP	0.823	0.786~0.860
	PAGE-B¹⁾	0.780	0.736~0.824
注：与REAL-B评分比较，1)P＜0.05。

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表 4 各HCC风险评分低危组诊断性能

Table 4. Diagnostic accuracy of low risk groups in different HCC risk scores

组别	3年		5年
组别	敏感度(95%CI)	阴性预测值(95%CI)	敏感度(95%CI)	阴性预测值(95%CI)
REAL-B评分(0~3)	100%	100%	99.07% (97.22%~100%)	99.67% (98.97%~100%)
mPAGE-B评分(8)	100%	100%	100%	100%
aMAP评分(＜50)	95.31%(89.06%~100%)	99.37%(98.53%~100%)	95.37%(90.74%~99.07%)	98.94%(97.88%~99.78%)
PAGE-B评分(9)	98.44%(95.31%~100%)	99.67%(98.95%~100%)	98.15%(95.37%~100%)	99.52%(98.78%~100%)

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