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甲胎蛋白和甲胎蛋白异质体比率（AFP-L3%）对HBV相关早期肝细胞癌的诊断效能分析
DOI: 10.3969/j.issn.1001-5256.2023.11.014
伦理学声明：本研究方案于2023年1月11日经由中山大学附属第三医院伦理委员会审批，批号：Ⅱ2022-008-01。所有患者均知情同意。
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：唐宇雁负责课题设计，收集数据，资料分析，撰写论文；谢仕斌负责课题设计，修改论文；朱建芸负责拟定写作思路，指导撰写文章并最后定稿。
Diagnostic efficacy of alpha-fetoprotein and alpha-fetoprotein L3% in hepatitis B virus-related early-stage hepatocellular carcinoma
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摘要:
目的 探讨甲胎蛋白（AFP）、AFP异质体L3（AFP-L3）在HBV相关早期肝细胞癌（HCC）中的诊断效能及最佳截断值。 方法 纳入2019年1月—2022年7月在中山大学附属第三医院就诊的首次诊断且尚未治疗的HBV相关HCC患者（HCC组）共1 080例（其中中国肝癌分期Ⅰa～Ⅱa期肝癌620例），346例慢性乙型肝炎患者（CHB组）和293例HBV相关肝硬化患者（LC组）为对照组，分析AFP和AFP-L3%筛查HBV相关早期HCC的诊断效能，包括灵敏度、特异度、受试者工作特征曲线下面积（AUC）等。偏态分布的计量资料两组间比较采用Mann-Whitney U检验，多组间比较采用Kruskal-Wallis H检验，进一步两两比较采用Bonferroni法。 结果 HCC组AFP、AFP-L3%水平显著高于CHB组和LC组（H分别为542.479、418.974，P值均<0.001）。在早期HCC中，AFP和AFP-L3%最佳截断值分别为8.7 ng/mL和5%，AFP单用时AUC最高，为0.816，灵敏度和特异度分别为66.9%、85.1%；联合使用AFP-L3%与单用AFP的AUC无明显差异（Z=0.609，P=0.543），但均显著高于单用AFP-L3%（AFP vs AFP-L3%：Z=8.173，P<0.001；AFP+AFP-L3% vs AFP-L3%：Z=8.802，P<0.001）。 结论 AFP对HBV相关早期HCC有较好的诊断价值，并且优于AFP-L3%，为了提高早期HCC的检出率，应该下调AFP的筛查截断值。 Abstract:Objective To investigate the diagnostic efficacy and optimal cut-off values of alpha-fetoprotein （AFP） and alpha-fetoprotein variant L3 （AFP-L3） in hepatitis B virus （HBV）-related early-stage hepatocellular carcinoma （HCC）. Methods A total of 1 080 patients with HBV-related HCC （HBV-HCC） who were diagnosed for the first time and not yet treated in The Third Affiliated Hospital of Sun Yat-Sen University from January 2019 to July 2022 were enrolled as HCC group in the study， among whom there were 620 patients with CNLC Ⅰa-Ⅱa HCC， and in addition， 346 patients with HBV-related chronic hepatitis B （CHB group） and 293 patients with HBV-related liver cirrhosis （LC group） were enrolled as controls. The diagnostic efficacy of AFP and AFP-L3% in screening for HBV-related early-stage HCC was analyzed， including sensitivity， specificity， and the area under the ROC curve （AUC）. The Mann-Whitney U test was used for comparison of continuous data with skewed distribution between two groups； the Kruskal-Wallis H test was used for comparison between multiple groups， and the Bonferroni method was used for further comparison between two groups. Results The HCC group had significantly higher levels of AFP and AFP-L3% than the CHB group and the LC group （H=542.479 and 418.974， both P<0.001）. In early-stage HCC， AFP and AFP-L3% had an optimal cut-off value of 8.7 ng/mL and 5%， respectively， and AFP alone had the largest AUC of 0.816， with a sensitivity of 66.9% and a specificity of 85.1%. There was no significant difference in AUC between AFP-L3%+AFP and AFP alone （Z=0.609， P=0.543）， but both AFP-L3%+AFP and AFP alone had a significantly larger AUC than AFP-L3% alone （AFP vs AFP-L3%： Z=8.173， P<0.001； AFP+AFP-L3% vs AFP-L3%： Z=8.802， P<0.001）. Conclusion AFP has a good value and is superior to AFP-L3% in the diagnosis of HBV-related early-stage HCC， and the screening cut-off value of AFP should be lowered in order to improve the detection rate of early-stage HCC. -
Key words:
- Hepatitis B virus /
- Liver Cirrhosis /
- Carcinoma， Hepatocellular /
- alpha-Fetoproteins /
- Diagnosis
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图 1 AFP、AFP-L3%单独及联合诊断总体HCC的ROC曲线
Figure 1. ROC curve of AFP， AFP-L3% alone and combined about the diagnosis of total HCC
图 2 AFP、AFP-L3%单独及联合诊断早期HCC的ROC曲线
Figure 2. ROC curve of AFP， AFP-L3% alone and combined about diagnosis of CNLC early stage HCC
表 1 3组患者临床基线特点及AFP、AFP-L3、AFP-L3%的比较
Table 1. Comparison of clinical baseline characteristics and distribution of AFP， AFP-L3 and AFP-L3% in three groups
项目 CHB组（n=346） LC组（n=293） HCC组（n=1 080） 统计值 P值 年龄（岁） 43.0（34.8～50.0） 52.0（45.0～59.0） 55.5（48.0～63.0） H=248.327 <0.001 男/女（例） 249/97 236/57 969/111 χ2=67.783 <0.001 HBeAg阳性1）［例（%）］ 86/333（25.8） 47/283（16.6） 229/1 068（21.4） χ2=20.143 <0.001 HBV DNA≥100 IU/mL1）［例（%）］ 110/341（32.3） 68/290（23.4） 569/1 029（55.3） χ2=136.770 <0.001 ALT（U/L） 24.0（18.0～30.0） 25.0（19.0～31.0） 33.0（24.0～51.0） H=208.268 <0.001 Child-Pugh分级（A/B/C，例） 333/13/0 183/86/24 848/195/37 χ2=115.502 <0.001 AFP（ng/mL） 3.2（2.4～4.7） 3.9（2.4～7.2） 25.8（6.7～176.6） H=542.497 <0.001 AFP-L3（ng/mL） 0.6（0.6～0.6） 0.6（0.6～0.6） 2.7（0.6～23.4） H=456.749 <0.001 AFP-L3（%） 5.0（5.0～5.0） 5.0（5.0～5.0） 9.0（5.0～14.2） H=418.974 <0.001 注：1）部分指标的观察例数有缺失，原因为部分患者住院期间未能完善相关检查。 
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表 2 对照组与早期HCC组AFP、AFP-L3、AFP-L3%水平比较
Table 2. Comparison of AFP， AFP-L3 and AFP-L3% levels between the control group and the early stage HCC
项目 对照组（n=639） 早期HCC组（n=620） Z值 P值 AFP（ng/mL） 3.5（2.4～5.9） 18.7（5.5～121.4） -19.381 <0.001 AFP-L3（ng/mL） 0.6（0.6～0.6） 1.9（0.6～14.7） -18.352 <0.001 AFP-L3（%） 5.0（5.0～5.0） 8.0（5.0～13.1） -17.475 <0.001
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表 3 ALT正常对照组与ALT正常HCC组的AFP、AFP-L3、AFP-L3%水平比较
Table 3. Comparison of AFP， AFP-L3 and AFP-L3% levels between the control group with normal ALT and the HCC group with normal ALT
项目 ALT正常对照组（n=597） ALT正常HCC组（n=598） Z值 P值 AFP（ng/mL） 3.4（2.4～5.7） 19.6（5.2～162.4） -18.654 <0.001 AFP-L3（ng/mL） 0.6（0.6～0.6） 2.3（0.6～23.5） -18.512 <0.001 AFP-L3（%） 5.0（5.0～5.0） 8.7（5.0～14.2） -17.816 <0.001
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表 4 不同ALT水平的HCC组的AFP、AFP-L3、AFP-L3%水平比较
Table 4. Comparison of AFP， AFP-L3 and AFP-L3% levels among HCC groups with different ALT levels
项目 ALT正常HCC组（n=598） ALT升高HCC组（n=482） Z值 P值 AFP（ng/mL） 19.6（5.2～162.4） 32.7（9.1～190.4） -2.961 0.003 AFP-L3（ng/mL） 2.3（0.6～23.5） 3.2（0.6～22.8） -1.854 0.064 AFP-L3（%） 8.7（5.0～14.2） 9.4（5.0～14.2） -1.499 0.134
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表 5 AFP、AFP-L3%在总体HCC中的诊断效能分析
Table 5. Analysis of the diagnostic efficacy of AFP and AFP-L3% in overall HCC
指标 AUC（95%CI） 截断值 敏感度（%） 特异度（%） 约登指数 阳性预测值（%） 阴性预测值（%） AFP（ng/mL） 0.834（0.815～0.853） 8.5 70.4 85.0 0.554 88.8 62.9 AFP-L3%（%） 0.766（0.748～0.785） 5.0 62.4 88.4 0.508 90.1 58.2 AFP+AFP-L3% 0.833（0.814～0.852） NA 71.1 84.5 0.556 88.6 63.4 注：NA，无确切截断值。
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表 6 AFP、AFP-L3%在早期HCC中的诊断性能及截断值比较
Table 6. Diagnostic performance analysis of AFP and AFP-L3% in early stage HCC and comparison of different cut-off points
项目 截断值 敏感度（%） 特异度（%） 阳性预测值 （%） 阴性预测值 （%） Kappa值 AUC（95%CI） AFP（ng/mL） 8.7 66.9 85.1 81.4 72.6 0.522 0.816（0.792～0.839） 20 48.5 94.5 89.6 65.4 0.434 200 20.2 99.2 96.2 56.2 0.196 400 11.6 99.5 96.0 53.7 0.113 AFP-L3%（%） 5 58.1 88.4 82.9 68.5 0.467 0.741（0.718～0.764） 10 40.3 93.4 85.6 61.7 0.340 15 17.9 99.2 95.7 55.5 0.173 AFP+AFP-L3% AFP 8.7+AFP-L3% 5 67.7 84.7 81.1 73.0 0.525 0.814（0.790～0.838） AFP 20+AFP-L3% 10 56.9 90.6 85.5 68.4 0.478 AFP 20+AFP-L3% 15 51.5 94.1 89.4 66.6 0.458 AFP 200+AFP-L3% 10 46.3 93.0 86.4 64.1 0.395 AFP 200+AFP-L3% 15 29.4 98.6 95.3 59.0 0.282 AFP 400+AFP-L3% 10 43.5 93.1 86.0 63.0 0.369 AFP 400+AFP-L3% 15 24.2 98.9 95.5 57.4 0.234
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