慢性乙型肝炎患者发生肝细胞癌的危险因素分析

刘龙; 时克; 张群; 冉崇平; 侯杰; 张艺; 王宪波

doi:10.3969/j.issn.1001-5256.2021.07.022

慢性乙型肝炎患者发生肝细胞癌的危险因素分析

DOI: 10.3969/j.issn.1001-5256.2021.07.022

刘龙¹,
时克^{1, 2},
张群¹,
冉崇平¹,
侯杰^{1, 2},
张艺¹,
王宪波^1, ,

1.
首都医科大学附属北京地坛医院中西医结合中心，北京 100015
2.
北京中医药大学第一临床医学院，北京 100700

基金项目:

首都卫生发展科研专项 (2018-1-2172);

北京市科学技术委员会资助 (Z191100006619033);

国家中医药管理局重大疑难疾病中西医临床协作试点项目 (2018-6-4);

国家中医药管理局区域中医诊疗中心 (2019-3-18)

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：刘龙、时克负责资料分析，撰写论文；冉崇平、侯杰、张艺参与收集数据；张群负责修改论文；王宪波指导修改文章并最终定稿。

详细信息

通信作者:
王宪波，wangxianbo638@163.com

刘龙和时克对本文的贡献相同，同为第一作者

中图分类号: R512.62; R735.7
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出版历程
- 收稿日期: 2021-01-02
- 录用日期: 2021-02-10
- 出版日期: 2021-07-20

Risk factors for hepatocellular carcinoma in patients with chronic hepatitis B

Long LIU¹,
Ke SHI^{1, 2},
Qun ZHANG¹,
Chongping RAN¹,
Jie HOU^{1, 2},
Yi ZHANG¹,
Xianbo WANG^{1
, ,}

1.
Department of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
2.
The First Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100700, China

Research funding:

Capital Health Development Research Project (2018-1-2172);

Beijing Municipal Commission of Science and Technology (Z191100006619033);

National Administration of Traditional Chinese Medicine Clinical Cooperation Pilot Project of Traditional Chinese and Western Medicine for Major and Difficult Diseases (2018-6-4);

Regional TCM Diagnosis and Treatment Center of State Administration of Traditional Chinese Medicine (2019-3-18)

摘要

摘要: 目的探究慢性乙型肝炎(CHB)患者发生肝细胞癌(HCC)的危险因素。方法收集2013年1月—2015年6月北京地坛医院确诊的CHB且随访超过3年的患者，共1239例。其中非肝硬化患者1108例，肝硬化患者131例。收集患者的一般资料及实验室检查指标并计算APRI、FIB-4及mFZB-4评分。符合正态分布的计量资料2组间比较采用t检验；非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。影响HCC发生的独立危险因素采用Cox回归分析。采用受试者工作特征曲线下面积(AUC)比较3种评分对CHB患者发生HCC的预测能力，采用DeLong检验对各个评分的AUC进行比较。通过拟合优度检验分析mFIB-4评分校准能力。使用Kalplan-Merier法对HCC发生进行分析，log-rank法进行比较。结果中位随访时间为4.6年，37例(3.0%)患者发生HCC。多因素Cox回归分析显示，年龄(HR=1.046，95%CI：1.018~1.074，P=0.001)、ALT (HR=0.995，95%CI：0.992~0.999，P=0.008)、AST (HR=0.994，95%CI：0.990~0.998，P=0.020)和PLT (HR=0.988，95%CI：0.981~0.994，P=0.001)是影响HCC发生的独立危险因素。mFIB-4、FIB-4、APRI评分的AUC分别为0.771、0.658、0.676，其中mFIB-4评分的AUC大于FIB-4评分(Z=5.629, P＜0.000 1)及APRI评分(Z=4.243, P＜0.000 1)。与mFIB-4＜2.68的患者相比，mFIB-4 ≥2.68的患者HCC发生风险更高(Z=37.840, P＜0.000 1)。结论年龄、ALT、AST和PLT是CHB患者发生HCC的独立危险因素。与FIB-4，APRI评分相比，mFIB-4评分对CHB患者发生HCC的预测价值更高。mFIB-4 ≥2.68的CHB患者是发生HCC的高危人群。
- 慢性乙型肝炎 /
- 癌，肝细胞 /
- 危险因素 /
- 肝纤维化评分
Abstract: Objective To investigate the risk factors for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Methods A total of 1239 patients who were diagnosed with CHB in Beijing Ditan Hospital from January 2013 to June 2015 and were followed up for more than 3 years were enrolled, among whom 1108 had no liver cirrhosis and 131 had liver cirrhosis. General information and laboratory markers were collected. The chi-square test was used for comparison of categorical data between groups, and the t-test or the Mann-Whitney U test was used for comparison of continuous data between groups. The t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test for comparison of categorical data between two groups. A multivariate Cox regression analysis was used to identify the independent risk factors for HCC. The area under the ROC curve (AUC) was used to compare the ability of fibrosis-4 (FIB-4), modified FIB-4 (mFIB-4), and aspartate aminotransferase-to-platelet ratio index (APRI) scores to predict the development of HCC, and the DeLong test was used for comparison of AUC. Goodness of fit was used to evaluate the calibration ability of mFIB-4 score. The Kaplan-Meier method was used to analyze the development of HCC, and the log-rank test was used for comparison. Results The median follow-up time was 4.6 years, and of all patients, 37 (3.0%) developed HCC. The multivariate Cox regression analysis showed that age (hazard ratio [HR]=1.046, 95% confidence interval [CI]: 1.018-1.074, P=0.001), alanine aminotransferase (ALT) (HR=0.995, 95%CI: 0.992-0.999, P=0.008), aspartate aminotransferase (AST) (HR=0.994, 95%CI: 0.990-0.998, P=0.020), and platelet count (PLT) (HR=0.988, 95%CI: 0.981-0.994, P=0.001) were independent risk factors for HCC in CHB patients. The mFIB-4, FIB-4, and APRI scores had an AUC of 0.771, 0.658, and 0.676, respectively, and mFIB-4 score had a significantly higher AUC than FIB-4 score (Z=5.629, P < 0.000 1) and APRI score (Z=4.243, P < 0.000 1). Compared with the patients with mFIB-4 < 2.68, the patients with mFIB-4 ≥2.68 had a significantly higher risk of HCC (Z=37.840, P < 0.000 1). Conclusion Age, ALT, AST, and PLT are independent risk factors for HCC in CHB patients. Compared with FIB-4 and APRI scores, mFIB-4 s core has a higher value in predicting HCC in CHB patients. The patients with mFIB-4 ≥2.68 are the high-risk population of HCC.
- Chronic Hepatitis B /
- Carcinoma, Hepatocellular /
- Risk Factors /
- Liver Fibrosis Score

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图 1 各评分ROC曲线及mFIB-4评分校准直方图

下载: 全尺寸图片幻灯片

图 2 不同mFIB-4评分患者肝癌发生情况

下载: 全尺寸图片幻灯片

表 1 患者基线特征

指标	全部患者(n=1239)	非肝硬化组(n=1108)	肝硬化组(n=131)	统计值	P值
年龄(岁)	39.4±11.8	38.3±11.5	48.3±10.8	t=9.506	＜0.001
男/女(例)	912/327	809/299	103/28	χ²=2.228	0.522
HCC家族史[例(%)]	74 (6.0)	61 (5.5)	13 (9.9)	χ²=3.997	0.046
饮酒史[例(%)]	285 (23.0)	280 (25.3)	28 (21.4)	χ²=0.234	0.628
高血压[例(%)]	107 (8.6)	87 (7.9)	20 (15.3)	χ²=12.621	＜0.001
糖尿病[例(%)]	87 (7.0)	66 (6.0)	21 (16.0)	χ²=12.425	＜0.001
ALT(U/L)	112.4 (39.9~403.3)	129.0(44.7~442.3)	44.6 (27.3~106.2)	Z=-5.010	＜0.001
AST(U/L)	62.0 (30.8~191.1)	67.4 (32.3~204.0)	34.6 (26.2~85.3)	Z=-3.541	＜0.001
TBil(μmol/L)	16.1 (11.3~27.6)	15.9 (11.1~27.3)	18.6(13.4~29.0)	Z=-0.337	0.736
Alb(g/L)	30.6(27.5~33.9)	41.5(37.8~45.4)	39.5(35.9~42.8)	Z=-3.256	0.003
GGT(U/L)	59.7 (27.3~124.1)	61.0 (27.1~126.8)	50.6 (28.0~110.9)	Z=-0.706	0.480
WBC(×10⁹/L)	5.1 (4.2~6.1)	5.1 (4.2~6.2)	4.7 (3.1~5.7)	Z=-2.882	0.004
PLT(×10⁹/L)	153.0(115.5~197.5)	160.6(122.0~200.1)	100.6(76.0~129.0)	Z=-9.572	0.001
BUN(mmol/L)	4.4 (3.5~5.4)	4.4 (3.7~5.3)	4.9 (4.2~5.9)	Z=0.271	0.786
Cr(μmoI/L)	68.7 (59.0~77.0)	68.3 (58.8~77.0)	70.0 (59.8~77.0)	Z=-0.002	0.998
PT(s)	12.2 (11.5~13.1)	12.1 (11.4~13.0)	12.7 (11.7~14.1)	Z=2.922	0.004
INR	1.0 (0.9~1.1)	1.1 (1.0~1.1)	1.1 (1.0~1.2)	Z=-0.195	0.846
AFP(ng/ml)	5.7 (2.6~25.9)	5.6 (2.9~24.9)	6.5 (3.3~29.4)	Z=-0.634	0.405
HBV DNA(log₁₀拷贝/ml)	5.5 (3.3~7.1)	5.7 (3.5~7.1)	3.9 (2.7~6.1)	Z=-5.374	0.001
mFIB-4	1.6(0.8~2.9)	1.5(0.8~2.5)	3.6(2.3~7.3)	Z=10.827	＜0.001
FIB-4	1.6 (0.9~3.3)	1.5 (0.8~3.1)	3.2 (1.8~5.4)	Z=3.194	0.001
APRI	1.5(1.1~2.2)	1.5(1.1~2.1)	2.1(1.5~2.8)	Z=5.124	＜0.001
抗病毒治疗[例(%)]
恩替卡韦	1239(100.0)	1108(100.0)	131(100.0)
之前服用抗病毒药物	312(25.2)	86(6.9)	226(18.3)
聚乙二醇化干扰素	35(2.8)	35(2.8)	0

下载: 导出CSV

表 2 CHB患者发生HCC风险的单因素分析

因素	HR(95%CI)	P值
年龄	1.067(0.041~1.094)	＜0.001
男性	1.361(0.658~2.823)	0.407
HCC家族史	1.443(0.444~4.720)	0.540
饮酒史	1.222(0.591~2.525)	0.588
高血压	1.270(0.454~3.555)	0.660
糖尿病	0.374(0.051~2.734)	0.332
ALT	0.994(0.990~0.998)	0.003
AST	0.994(0.989~0.999)	0.014
TBil	0.984(0.966~1.003)	0.102
Alb	0.966(0.923~1.011)	0.139
GGT	0.996(0.991~1.001)	0.183
WBC	0.978(0.840~1.139)	0.978
PLT	0.984(0.978~0.990)	＜0.001
BUN	1.004(0.991~1.018)	0.530
Cr	1.009(0.999~1.019)	0.054
PT	1.049(0.938~1.114)	0.400
INR	0.991(0.803~1.222)	0.935
AFP	0.997(0.991~1.003)	0.361
HBV DNA	0.827(0.699~1.078)	0.271

下载: 导出CSV

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