血浆胆汁酸在肝肿瘤中的差异分析及应用价值

贾茹; 张平平; 袁苑; 胡义扬; 冯琴

doi:10.12449/JCH241018

血浆胆汁酸在肝肿瘤中的差异分析及应用价值

DOI: 10.12449/JCH241018

贾茹^1a,
张平平^1a,
袁苑^2a,
胡义扬^{2b, 3, 4},
冯琴^{1b, 2b, 3, 4, , ,}

1a.
上海中医药大学附属曙光医院肿瘤科，上海 201203
1b.
上海中医药大学附属曙光医院科技实验中心，上海 201203
2a.
上海中医药大学中西医结合学院，上海 201203
2b.
上海中医药大学肝病研究所，上海 201203
3.
上海市中医临床重点实验室，上海 201203
4.
肝肾疾病病证教育部重点实验室，上海 201203

基金项目:

国家自然科学基金 (82104619);

上海市卫健委卫生行业临床研究专项 (20214Y0455);

上海中医药大学预算内项目 (2021LK105)

伦理学声明：本研究方案经由上海中医药大学附属曙光医院伦理委员会审批，批号：2020-831-38-01。

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：贾茹负责实验设计，样本采集，数据分析及论文撰写；张平平、袁苑负责样本采集及数据分析；胡义扬负责指导实验设计；冯琴负责指导实验设计及论文撰写并最终定稿。

详细信息

通信作者:
冯琴， fengqin@shutcm.edu.cn （ORCID： 0000-0002-4641-1636）

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出版历程
- 收稿日期: 2024-01-24
- 录用日期: 2024-04-15
- 出版日期: 2024-10-25

Differences and application value of plasma bile acids in tumors of the liver

Ru JIA^1a,
Pingping ZHANG^1a,
Yuan YUAN^2a,
Yiyang HU^{2b, 3, 4},
Qin FENG^{1b, 2b, 3, 4
, ,
,}

1a.
Department of Oncology，Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine，Shanghai 201203，China
1b.
Technical Experimental Center，Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine，Shanghai 201203，China
2a.
School of Integrative Medicine，Shanghai University of Traditional Chinese Medicine，Shanghai 201203，China
2b.
Institute of Liver Diseases，Shanghai University of Traditional Chinese Medicine，Shanghai 201203，China
3.
Shanghai Key Laboratory of Traditional Chinese Medicine，Shanghai 201203，China
4.
Key Laboratory of Liver and Kidney Diseases，Ministry of Education，Shanghai 201203，China

Research funding:

National Natural Science Foundation of China (82104619);

Shanghai Municipal Health Commission Health Industry Clinical Research Project (20214Y0455);

Project under Budget of Shanghai University of Traditional Chinese Medicine (2021LK105)

More Information

Corresponding author: FENG Qin， fengqin@shutcm.edu.cn （ORCID： 0000-0002-4641-1636）

摘要

摘要: 目的分析原发性肝癌与转移性肝癌患者血浆胆汁酸水平及其与临床指标的相关性，并评估其联合AFP对于原发性肝癌的诊断价值。方法纳入2020年8月—2021年9月于上海中医药大学附属曙光医院就诊且具有组织病理学及影像学明确的75例原发性肝癌患者及79例转移性肝癌患者，采集外周血并分别分离血清及血浆，比色法及色谱法检测生化指标，电化学发光免疫分析法检测肿瘤标志物水平，高效液相色谱-串联质谱法检测胆汁酸含量。符合正态分布的计量资料两组间比较采用成组t检验，不符合正态分布的计量资料两组间比较采用Mann-Whitney U检验。相关性检验采用Spearman相关分析。临床诊断效能采用受试者工作特征曲线（ROC曲线）评估。结果原发性肝癌组患者TC、TG、LDL-C及载脂蛋白（Apo）B显著低于转移性肝癌组患者，差异均具有统计学意义（U值分别为1 598、1 255、909、889，P值均<0.05）。原发性肝癌组患者AFP显著高于转移性肝癌组患者，癌胚抗原（CEA）显著低于转移性肝癌组患者，差异均具有统计学意义（U值分别为1 873、926，P值均<0.05）。原发性肝癌组患者总胆汁酸（TBA）、胆酸（CA）、鹅脱氧胆酸（CDCA）、熊脱氧胆酸（UDCA）、牛磺胆酸（TCA）、牛磺鹅脱氧胆酸（TCDCA）、甘氨胆酸（GCA）、甘氨鹅脱氧胆酸（GCDCA）、牛磺熊脱氧胆酸（TUDCA）、甘氨熊脱氧胆酸（GUDCA）均显著高于转移性肝癌患者，脱氧胆酸（DCA）显著低于转移性肝癌患者，差异均具有统计学意义（P值均<0.05）。总人群中TBA、CDCA、GCA、GCDCA、GUDCA、TCA、TCDCA及TUDCA含量与AFP水平呈显著正相关（P值均<0.05）。原发性肝癌患者中GCA、TCA、TCDCA及TUDCA含量与AFP水平呈显著正相关（P值均<0.05）。AFP+TCA+GCA+TCDCA联合检测的AUC为0.822（95%CI：0.746～0.898，P<0.000 1），效能最高。结论原发性肝癌与转移性肝癌患者血浆胆汁酸含量具有显著差异，差异性胆汁酸与肝损伤及AFP升高密切相关，联合AFP对原发性肝癌具有更优的临床诊断价值。
- 胆汁酸类和盐类 /
- 肝肿瘤 /
- 肿瘤转移
Abstract: Objective To investigate the levels of plasma bile acids （BA） in patients with primary liver cancer （PLC） or metastatic liver cancer （MLC） and their correlation with clinical indicators， as well as the value of plasma BAs combined with alpha-fetoprotein （AFP） in the diagnosis of PLC. Methods This study was conducted among 75 patients with PLC and 79 patients with MLC who attended Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from August 2020 to September 2021 and had a confirmed diagnosis based on histopathological and imaging findings. Peripheral blood samples were collected from all patients， and serum and plasma were separated. Colorimetry and chromatography were used to measure biochemical parameters； electrochemiluminescence immunoassay was used to measure the levels of tumor markers； liquid chromatography-tandem mass spectrometry was used to measure the content of BA. The t-test was used for comparison of normally distributed continuous data， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data； the Spearman’s coefficient was used for correlation analysis； the receiver operating characteristic （ROC） curve was used to evaluate clinical diagnostic efficacy. Results The PLC group had significantly lower levels of total cholesterol， triglyceride， low-density lipoprotein cholesterol， and apolipoprotein B than the MLC group （U=1 598， 1 255， 909， and 889， all P<0.05）. Compared with the MLC group， the PLC group had a significantly higher level of AFP and a significantly lower level of carcinoembryonic antigen （U=1 873 and 926， both P<0.05）. Compared with the MLC group， the PLC group had significantly higher levels of TBA， CA， CDCA， UDCA， TCA， TCDCA， GCA， GCDCA， TUDCA， and GUDCA and a significantly lower level of DCA （all P<0.05）. In the total population， the levels of TBA， CDCA， GCA， GCDCA， GUDCA， TCA， TCDCA， and TUDCA were significantly positively correlated with the level of AFP （all P<0.05）. In the patients with PLC， the levels of GCA， TCA， TCDCA， and TUDCA were significantly positively correlated with the level of AFP （all P<0.05）. Combined measurement of AFP+TCA+GCA+TCDCA had an area under the ROC curve of 0.822 （95% confidence interval： 0.746‍ ‍—‍ ‍0.898， P<0.000 1）， suggesting that it had the highest diagnostic efficacy. Conclusion There are significant differences in the levels of plasma BA between the patients with PLC and those with MLC， and the differentially expressed BAs are closely associated with liver function impairment and the increase in AFP. BAs combined with AFP has a better clinical value in the diagnosis of PLC.
- Bile Acids and Salts /
- Liver Neoplasms /
- Neoplasm Metastasis

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图 1 总人群中血浆胆汁酸含量与临床指标的相关性分析

Figure 1. Correlation analysis of plasma BA and clinical markers in all liver cancer patients

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图 2 原发性肝癌人群中血浆胆汁酸含量与临床指标的相关性分析

Figure 2. Correlation analysis of plasma BA and clinical markers in primary liver cancer patients

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图 3 AFP联合血浆胆汁酸区别原发性肝癌的ROC曲线分析

Figure 3. ROC curves of AFP combined with plasma BA for detection of primary liver cancer

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表 1 两组患者生化指标比较

Table 1. Comparison of levels of laboratory tests between patients with primary liver cancer or metastatic liver cancer

项目	原发性肝癌组（n=75）	转移性肝癌组（n=79）	统计值	P值
ALT（U/L）	25.00（18.00～33.00）	22.00（12.00～37.00）	U=2 375	0.177
AST（U/L）	31.00（27.25～52.00）	29.00（20.75～46.00）	U=1 933	0.063
TBil（μmol/L）	20.10（13.70～30.90）	15.85（12.63～28.80）	U=2 407	0.059
GLU（mmol/L）	5.30（4.60～6.00）	5.05（4.70～6.00）	U=2 636	0.925
HbA1c（%）	5.40（4.90～6.00）	5.50（5.10～6.00）	U=2 140	0.205
TC（mmol/L）	3.87（3.31～4.58）	4.81（4.18～5.91）	U=1 598	<0.001
TG（mmol/L）	1.04（0.88～1.38）	1.31（1.07～1.85）	U=1 255	<0.001
HDL-C（mmol/L）	1.07±0.29	1.09±0.34	t=0.243	0.867
LDL-C（mmol/L）	2.09（1.45～2.73）	3.06（2.38～4.08）	U=909	<0.001
ApoA1（g/L）	0.90（0.73～1.06）	0.93（0.81～1.14）	U=1 474	0.154
ApoB（g/L）	0.67（0.49～0.89）	0.93（0.69～1.16）	U=889	<0.001

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表 2 两组患者肿瘤标志物水平比较

Table 2. Comparison of levels of serum tumor markers between patients with primary liver cancer or metastatic liver cancer

项目	原发性肝癌组（n=75）	转移性肝癌组（n=79）	U值	P值
AFP（ng/mL）	6.45（3.16～15.74）	4.02（2.54～5.23）	1 873	<0.001
CEA（ng/mL）	3.04（2.53～5.42）	15.14（5.02～83.18）	926	<0.001
CA19-9（U/mL）	21.20（10.83～54.69）	21.36（10.22～154.38）	2 361	0.840
CA125（U/mL）	18.70（12.50～36.20）	21.20（10.55～44.63）	1 181	0.128

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表 3 两组患者血浆胆汁酸含量比较

Table 3. Comparison of concentrations of plasma BA between patients with primary liver cancer or metastatic liver cancer

项目	原发性肝癌组（n=75）	转移性肝癌组（n=79）	U值	P值
TBA（nmol/L）	11 675.7（6 098.5～33 679.9）	5 241.6（2 445.8～10 062.8）	886	<0.001
CA（nmol/L）	290.7（148.6～1 030.0）	114.0（62.8～319.0）	1 084	<0.001
CDCA（nmol/L）	2 570.0（766.4～3 040.0）	527.0（191.5～1 127.2）	750	<0.001
DCA（nmol/L）	66.9（6.9～354.0）	238.3（19.1～572.0）	1 223	0.010
UDCA（nmol/L）	199.0（109.5～572.5）	68.7（26.8～246.5）	1 039	<0.001
LCA（nmol/L）	15.7（6.3～45.6）	21.2（10.7～39.9）	1 476	0.243
TCA（nmol/L）	444.0（90.3～2 231.1）	47.2（11.3～482.2）	862	<0.001
TCDCA（nmol/L）	627.0（256.0～5 060.0）	145.0（48.7～981.9）	828	<0.001
GCA（nmol/L）	1 309.2（424.0～4 670.0）	444.6（190.5～1 400.4）	1 018	<0.001
GCDCA（nmol/L）	3 530.0（1 160.0～13 341.0）	1 149.3（388.4～3 537.4）	978	<0.001
TDCA（nmol/L）	23.6（0.0～114.0）	25.6（5.0～92.3）	1 423	0.144
TUDCA（nmol/L）	41.8（10.8～117.0）	7.3（1.9～21.5）	832	<0.001
TLCA（nmol/L）	0.9（0.2～4.0）	0.9（0.0～2.3）	1 520	0.352
GDCA（nmol/L）	119.8（5.9～609.0）	187.0（13.7～498.0）	1 586	0.570
GUDCA（nmol/L）	434.0（156.8～1 390.0）	104.0（49.9～637.1）	986	<0.001
GLCA（nmol/L）	5.2（0.6～29.0）	6.4（1.8～19.8）	1 641	0.789

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