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摘要：
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摘要：目的 探讨血清甲胎蛋白（alpha-fetoprotein，AFP）和三叶因子1（trefoil factor
1，TFF1）水平在原发性肝癌诊断及预后中的价值。方法 选取2015年1月至2019年1月
于海安市中医院就诊的87例原发性肝癌患者、40例病毒性肝炎患者、40例肝硬化患者
及40例健康体检者为研究对象。采用UniCel DxI 800全自动化学发光分析仪检测AFP
水平，采用酶联免疫吸附试验检测TFF1水平。根据是否复发将原发性肝癌患者分为
复发组和未复发组，比较两组不同时间点AFP和TFF1水平差异。采用受试者工作特征
（receiver operator characteristic，ROC）曲线评估AFP和TFF1对原发性肝癌的诊断价
值。采用Spearman秩相关分析各组患者血清AFP与TFF1的相关性。根据血清AFP水平
将有完整随访资料的患者分为AFP高水平组（AFP ＞ 400 μg/L)、AFP低水平组（20 μg/L ≤
AFP ＜ 400 μg/L）和AFP阴性组17例（AFP ＜ 20 μg/L）；根据TFF1诊断原发性肝癌的
截断值将患者分为TFF1高水平组（TFF1 ≥ 1.75 μg/L）和TFF1低水平组（TFF1 ＜
1.75 μg/L）。采用Kaplan-Meier法进行生存分析，采用Log-rank法分别比较3组患者的
无复发生存率。结果 原发性肝癌组患者血清AFP水平均显著高于肝硬化组、病毒性肝
炎组和健康对照组（中位数：110.45 μg/L vs 7.15 μg/L vs 3.23 μg/L vs 2.73 μg/L），差异
均有统计学意义（z值分别为-6.732、-8.270、-11.135，P均＜ 0.001）。原发性肝癌组患者
血清TFF1水平均显著高于肝硬化组、病毒性肝炎组和健康对照组（中位数：3.76 μg/L
vs 0.61 μg/L vs 0.45 μg/L vs 0.37 μg/L），差异均有统计学意义（z值分别为-4.274、
-5.313、-5.471，P均＜ 0.001）。在AFP阴性患者中，TFF1阳性率为46.15%（12/26）。
AFP、TFF1、联合检测（并联）和联合检测（串联）诊断原发性肝癌的ROC曲线下面
积分别为0.747、0.754、0.862、0.889，联合检测（并联）和联合检测（串联）的曲线
下面积均显著高于AFP和TFF1（P均＜ 0.05）。单项检测时AFP的敏感度为70.11%，
TFF1的敏感度为65.52%，联合检测（并联）可将敏感度提高至83.90%，联合检测（串
联）可将特异度提高至97.50%。健康对照组、肝硬化组、病毒性肝炎组和原发性肝癌
组患者血清AFP与TFF1均无显著相关性（rs值分别为0.130、0.064、-0.044、-0.031，P
值分别为0.216、0.483、0.811、0.875）。共76例原发性肝癌患者有完整的随访资料，
随访时间为5～13个月，中位随访期为9.6个月，随访期间27例复发。复发组与未复发
组患者术前、术后1周、术后4周和术后8周血清AFP（术前：183.47 μg/L vs 97.45 μg/L；
术后1周：25.34 μg/L vs 22.35 μg/L；术后4周：32.18 μg/L vs 26.78 μg/L；术后8周：90.57 μg/L
vs 26.54 μg/L）与TFF1（术前：5.82 μg/L vs 3.54 μg/L；术后1周：0.69 μg/L vs 0.72 μg/L；
术后4周：0.71 μg/L vs 0.84 μg/L；术后8周：1.93 μg/L vs 0.87 μg/L）水平差异均有统计
学意义（P均＜ 0.05）。复发组患者术后8周血清AFP与TFF1水平均显著高于未复发组
（z = 2.116、2.820，P = 0.024、0.005）。复发组患者术后8周血清AFP和TFF1水平均
显著高于术后1周和术后4周（P均＜ 0.05）。AFP高水平组、AFP低水平组和AFP阴性
组患者的无复发生存率分别为58.8%（17/30）、62.1%（18/29）和82.4%（14/17），
差异有统计学意义（Log-rank χ2
= 5.117，P = 0.031），AFP高水平组和AFP低水平组
无复发生存率显著低于AFP阴性组（Log-rank χ 2
= 6.289，P = 0.012；Log-rank
χ2
= 5.373，P = 0.023）。TFF1高水平组（TFF1 ≥ 1.75 μg/L）共45例，TFF1低水平
组（TFF1 ＜ 1.75 μg/L）共31例， TFF1高水平组无复发生存率显著低于TFF1低水平
组 [53.3%（24/45）vs 80.7%（25/31）]，差异有统计学意义（Log-rank χ
2
= 5.411，P =
0.020）。Cox单因素分析表明肿瘤直径、肿瘤数目、血管侵犯、AFP及TFF1水平与患
者术后无复发生存有关（P均＜ 0.05）；Cox多因素分析表明肿瘤直径≥ 5 cm（HR =
4.137，95%CI：1.352～8.573，P = 0.017）、肿瘤数目≥ 2个（HR = 3.232，95%CI：
1.395～6.447，P = 0.023）以及有血管侵犯（HR = 4.635，95%CI：1.676～9.352，P =
0.009）是患者术后无复发生存的独立危险因素。结论 血清AFP、TFF1联合检测可有效
提高原发性肝癌的诊断效能，TFF1对于AFP假阴性诊断有一定价值，两种血清肿瘤标
志物对原发性肝癌患者术后预后判断有一定临床价值。
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Abstract: Objective To investigate the value of serum alpha-fetal protein (AFP) and trilateral
factor 1 (TFF1) on the diagnosis and prognosis of primary liver cancer. Methods Total of
87 cases with primary liver cancer, 40 cases with viral hepatitis, 40 cases with liver cirrhosis and
40 cases of healthy controls in Haian Hospital of Traditional Chinese Medicine from January
2015 to January 2019 were selected. AFP level was detected by UniCel DxI 800 fully automated
chemiluminescence analyzer and TFF1 level was detected by enzyme-linked immunosorbent
assay. Receiver operator characteristic (ROC) curve was used to assess the diagnostic value
of AFP and TFF1 for primary liver cancer. Spearman rank correlation was used to analyze the
association of serum AFP and TFF1. Patients with complete follow-up data were classified into
AFP high-level group (AFP ≥ 400 μg/L), AFP low-level group (20 μg/L ≤ AFP ＜ 400 μg/L) and
AFP negative group (AFP ＜ 20 μg/L); the above patients were also classified into TFF1 highlevel group (TFF1 ≥ 1.75 μg/L) and TFF1 low-level group (TFF1 ＜ 1.75 μg/L) based on the
cut off value of TFF1 in diagnosis of primary liver cancer. Survival analysis was performed
using Kaplan-Meier method and Log-rank was used to compare the relapse-free survival
among the three groups. Results Serum AFP level of patients in primary liver cancer group
was significantly higher than those of liver cirrhosis group, viral hepatitis group and healthy
control group (median: 110.45 μg/L vs 7.15 μg/L vs 3.23 μg/L vs 2.73 μg/L), respectively,
the differences were statistically significant (z = -6.732, -8.270, -11.135; all P ＜ 0.001). The
serum TFF1 level of patients in primary liver cancer group was significantly higher than those in
liver cirrhosis group, viral hepatitis group and healthy control group (median: 3.76 μg/L vs 0.61 μg/L vs
0.45 μg/L vs 0.37 μg/L), respectively, the differences were statistically significant (z = -4.274,
-5.313, -5.471; all P ＜ 0.001). The positive rate of TFF1 in patients with AFP negative was
46.15% (12/26). The area under ROC curve of AFP, TFF1, joint detection (in parallel) and
joint detection (in series) were 0.747, 0.754, 0.862 and 0.889, respectively. The area under
ROC curve of joint detection (parallel) and joint detection (series) were significantly higher
than those of AFP and TFF1 (all P ＜ 0.05). The sensitivity of AFP and TFF1 were 70.11%
and 65.52%, respectively, while joint detection (in parallel) could increase the sensitivity to
83.90%, and joint detection (in series) could increase the specificity to 97.50%. There were no
association between serum AFP and TFF1 in healthy control group, liver cirrhosis group, viral
hepatitis group and primary liver cancer group, respectively (rs = 0.130, 0.064, -0.044, -0.031;
P = 0.216, 0.483, 0.811, 0.875). A total of 76 patients had complete follow-up data, the followup period was 5～13 months (median time 9.6 months). Total of 27 cases relapsed during
the follow-up period. There were significant differences in serum AFP (before operation:
183.47 μg/L vs 97.45 μg/L; 1 week after operation: 25.34 μg/L vs 22.35 μg/L; 4 weeks after
operation: 32.18 μg/L vs 26.78 μg/L; 8 weeks after operation: 90.57 μg/L vs 26.54 μg/L) and
TFF1 (before operation: 5.82 μg/L vs 3.54 μg/L; 1 week after operation: 0.69 μg/L vs 0.72 μg/L;
4 weeks after operation: 0.71 μg/L vs 0.84 μg/L; 8 weeks after operation: 1.93 μg/L vs 0.87 μg/L)
levels of patients in relapsed group and non-relapsed group before operation, 1 week after
operation, 4 weeks after operation and 8 weeks after operation (all P ＜ 0.05). Both serum
AFP and TFF1 levels of patients in relapsed group were significantly higher than those in nonrelapsed group 8 weeks after operation. Serum AFP and TFF1 levels of patients in relapsed
group 8 weeks after operation were significantly higher than those of 1 week and 4 weeks
after operation (all P ＜ 0.05). The relapse free survive rate of patients in AFP high-level
group, AFP low-level group and AFP negative group were 58.8% (17/30), 62.1% (18/29) and
82.4% (14/17), respectively, the difference was statistically significant (Log-rank χ
2
= 5.117,
P = 0.031). The relapse free survive rate of patients in AFP high-level group and AFP lowlevel group were significantly lower than that in AFP negative group (Log-rank χ2
= 6.289,
P = 0.012; Log-rank χ
2
= 5.373, P = 0.023). The relapse free survive rate of patients in TFF1
high-level group was significantly lower than that in TFF1 low-level group [53.3%(24/45) vs
80.7%(25/31)], the difference was statistically significant (Log-rank χ
2
= 5.411, P = 0.020).
Cox univariate analysis showed that tumor diameter, tumor number, vascular invasion, AFP
and TFF1 were related to postoperative relapse free survival (all P ＜ 0.05); multivariate
analysis showed that tumor diameter ≥ 5 cm (HR = 4.137, 95%CI: 1.352～8.573, P = 0.017),
tumors number ≥ 2 (HR = 3.232, 95%CI: 1.395～6.447, P = 0.023) and vascular invasion
(HR = 4.635, 95%CI: 1.676～9.352, P = 0.009) were independent risk factors affecting
postoperative relapse free survival. Conclusions The combined detection of serum AFP and
TFF1 can effectively improve the diagnostic efficacy of primary liver cancer. TFF1 is valuable
in the diagnosis of false AFP negative, and the two serum tumor markers have a certain
clinical value on the prognosis of postoperative primary liver cancer patients.
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