尿液有机酸类代谢物对妊娠期肝内胆汁淤积症的临床预测价值

doi:10.3969/j.issn.1004-583X.2025.06.007

摘要/Abstract

摘要：

目的通过对妊娠期女性尿液样本进行靶向代谢组学分析,探究孕妇尿液中有机酸类代谢物的改变对妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)的临床预测价值。方法收集无锡市妇幼保健院10例ICP孕产妇作为观察组,同期选取无妊娠期合并症的正常孕产妇10例作为对照组,收集其一般资料并对两组尿液进行靶向代谢组学研究。采用Student’s t检验法分析两组代谢物变化中的差异并根据变化倍数进行了初步筛选。绘制受试者工作特征曲线,分析经过初步筛选的有机酸类代谢物的诊断性能,筛选出高诊断性能的代谢物。采用Pearson相关分析ICP患者尿液中7种有机酸代谢物水平与肝功能指标及新生儿出生体重的相关性。结果观察组孕妇尿液中油酸、亚油酸等18种代谢物与对照组的差异有统计学意义(P<0.05)。其中,12种代谢物的曲线下面积>0.8,显示12种代谢物具有良好的敏感度和特异度。AUC>0.9的7种代谢物(壬酸、癸二酸、油酸、亚油酸、棕榈酸、3-羟基丙酸和L-苯丙氨酸)展现出更理想的预测性能,与肝功能指标(总胆汁酸、天门冬氨酸氨基转移酶、丙氨酸氨基转移酶)中的部分指标呈相关性(P<0.05);壬酸和3-羟基丙酸与新生儿出生体重呈相关性(P<0.05)。结论孕妇尿液中的壬酸、癸二酸在ICP患者中表达上调;油酸、亚油酸、棕榈酸、3-羟基丙酸和L-苯丙氨酸在ICP患者中表达下调。这7种有机酸类代谢物对ICP的发生有重要预测价值。

关键词: 胆汁淤积, 肝内, 靶向代谢组学, 尿液有机酸类代谢物, 临床预测价值

Abstract:

Objective To identify the role of organic acid metabolites in the prediction of intrahepatic cholestasis of pregnancy (ICP) by performing targeted metabolomic analysis of urine samples from pregnant women. Methods A total of 10 pregnant women with ICP from Wuxi Maternity and Child Health Care Hospital were selected as the observation group and 10 healthy pregnant women as the control group. Their general information was collected. Targeted metabolomics studies were carried out on the urine of both groups. Differences in metabolites between the two groups were examined using the Student's t-test, and preliminary screening was performed based on the fold change. The receiver operating characteristic curve was drawn to analyze the diagnostic performance of the initially screened organic acid metabolites and screen out metabolites with high diagnostic performance. Pearson correlation was performed to analyze the correlation of the urine levels of seven organic acid metabolites with liver function indexes and the newborn weight in ICP patients.Results A total of 18 metabolites, such as oleic acid, and linoleic acid in the urine of the observation group significantly differed from those in the control group (P<0.05). The area under the curve (AUC) of 12 metabolites in distinguishing ICP among pregnant women was larger than 0.8, showing good sensitivity and specificity. The AUC of 7 metabolites (nonanoic acid, sebacic acid, oleic acid, linoleic acid, palmitic acid, 3-hydroxypropionic acid, and L-phenylalanine) was larger than 0.9, showing more significant differences between the observation group and the control group and more desirable predictive abilities. The seven metabolites were correlated with some indexes of liver function (total bile acids, aspartate aminotransferase, alanine aminotransferase)(P<0.05). Nonanoic acid and 3-hydroxypropionic acid were correlated with the newborn weight (P<0.05). Conclusion The expression levels of nonanoic acid and sebacic acid in the urine are upregulated in pregnant women with ICP, while those of oleic acid, linoleic acid, palmitic acid, 3-hydroxypropionic acid, and L-phenylalanine are downregulated. These seven metabolites have important clinical predictive value for ICP patients.

Key words: cholestasis, intrahepatic, targeted metabolomics, urine organic acid metabolites, clinical predictive value

中图分类号:

R575

尤怡澜, 陈玲燕, 缪可言, 倪珞航, 张岩, 肖建平. 尿液有机酸类代谢物对妊娠期肝内胆汁淤积症的临床预测价值[J]. 临床荟萃, 2025, 40(6): 519-526.

You Yilan, Chen Lingyan, Miao Keyan, Ni Luohang, Zhang Yan, Xiao Jianping. Clinical predictive value of urine organic acid metabolites in intrahepatic cholestasis of pregnancy[J]. Clinical Focus, 2025, 40(6): 519-526.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://lchc.magtechjournal.com/CN/10.3969/j.issn.1004-583X.2025.06.007

https://lchc.magtechjournal.com/CN/Y2025/V40/I6/519

图/表 8

参考文献 25

[1]	Majsterek M, Wierzchowska-Opoka M, Makosz I, et al. Bile acids in intrahepatic cholestasis of pregnancy[J]. Diagnostics (Basel), 2022, 12(11).
[2]	中华医学会妇产科学分会产科学组, 中华医学会围产医学分会. 妊娠期肝内胆汁淤积症临床诊治和管理指南(2024版)[J]. 中华妇产科杂志, 2024, 59(2): 97-107.
[3]	Manzotti C, Casazza G, Stimac T, et al. Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy[J]. Cochrane Database Syst Rev, 2019, 7(7): Cd012546.
[4]	Xiao J, Li Z, Song Y, et al. Molecular pathogenesis of intrahepatic cholestasis of pregnancy[J]. Can J Gastroenterol Hepatol, 2021, 2021: 6679322.
[5]	Qiu C, Enquobahrie DA, Frederick IO, et al. Early pregnancy urinary biomarkers of fatty acid and carbohydrate metabolism in pregnancies complicated by gestational diabetes[J]. Diabetes Res Clin Pract, 2014, 104(3): 393-400.
[6]	Straub RH. The memory of the fatty acid system[J]. Prog Lipid Res, 2020, 79: 101049.
[7]	Cao XY, Li MY, Shao CX, et al. Fatty Acid Metabolism Disruptions: A subtle yet critical factor in adverse pregnancy outcomes[J]. Int J Biol Sci, 2024, 20(15): 6018-6037.
[8]	Li M, Xu C, Shi J, et al. Fatty acids promote fatty liver disease via the dysregulation of 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway[J]. Gut, 2018, 67(12): 2169-2180. doi: 10.1136/gutjnl-2017-313778 pmid: 28877979
[9]	中华医学会妇产科学分会产科学组. 妊娠期肝内胆汁淤积症诊疗指南(2015)[J]. 临床肝胆病杂志, 2015, 31(10): 1575-1578.
[10]	胡翠芳, 朱大伟, 李力. 妊娠期肝内胆汁淤积症的研究进展[J]. 中国实用妇科与产科杂志, 2021, 37(2): 248-252.
[11]	Gao XX, Ye MY, Liu Y, et al. Prevalence and risk factors of intrahepatic cholestasis of pregnancy in a Chinese population[J]. Sci Rep, 2020, 10(1): 16307.
[12]	Puljic A, Kim E, Page J, et al. The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age[J]. Am J Obstet Gynecol, 2015, 212(5): 667.
[13]	Arafa A, Dong JY. Association between intrahepatic cholestasis of pregnancy and risk of gestational diabetes and preeclampsia: A systematic review and meta-analysis[J]. Hypertens Pregnancy, 2020, 39(3): 354-360. doi: 10.1080/10641955.2020.1758939 pmid: 32326772
[14]	Avsar HA, Atlıhan U, Ata C, et al. Intrahepatic cholestasis of pregnancy and its association with preeclampsia and gestational diabetes: A retrospective analysis[J]. Arch Gynecol Obstet, 2024, 310(1): 221-227. doi: 10.1007/s00404-024-07507-0 pmid: 38625544
[15]	Chen Y, Zhang H, Ning W, et al. The impact of intrahepatic cholestasis on pregnancy outcomes: A retrospective cohort study[J]. BMC Gastroenterol, 2023, 23(1): 16.
[16]	龚燕, 龚杰. 妊娠期肝内胆汁淤积症的致病因素和药物治疗进展[J]. 肝脏, 2022, 27(2): 247-9+254.
[17]	施秋洁. 常用肝功能项目在妊娠期肝内胆汁淤积症中的变化及临床意义[J]. 系统医学, 2022, 7(3): 13-16.
[18]	Piccinin E, Cariello M, De Santis S, et al. Role of oleic acid in the gut-liver axis: From diet to the regulation of its synthesis via stearoyl-coa desaturase 1 (SCD1)[J]. Nutrients, 2019, 11(10).
[19]	Sales-Campos H, Souza PR, Peghini BC, et al. An overview of the modulatory effects of oleic acid in health and disease[J]. Mini Rev Med Chem, 2013, 13(2): 201-210. pmid: 23278117
[20]	Szczuko M, Kikut J, Komorniak N, et al. The role of arachidonic and linoleic acid derivatives in pathological pregnancies and the human reproduction process[J]. Int J Mol Sci, 2020, 21(24):9628.
[21]	Shrestha N, Holland OJ, Kent NL, et al. Maternal high linoleic acid alters placental fatty acid composition[J]. Nutrients, 2020, 12(8):2183.
[22]	Dong R, Ye N, Zhao S, et al. Studies on novel diagnostic and predictive biomarkers of intrahepatic cholestasis of pregnancy through metabolomics and proteomics[J]. Front Immunol, 2021, 12: 733225.
[23]	Ennis MA, Rasmussen BF, Lim K, et al. Dietary phenylalanine requirements during early and late gestation in healthy pregnant women[J]. Am J Clin Nutr, 2020, 111(2): 351-359. doi: 10.1093/ajcn/nqz288 pmid: 31758682
[24]	Tessari P, Vettore M, Millioni R, et al. Effect of liver cirrhosis on phenylalanine and tyrosine metabolism[J]. Curr Opin Clin Nutr Metab Care, 2010, 13(1): 81-86.
[25]	Wilson KA, Han Y, Zhang M, et al. Inter-relations between 3-hydroxypropionate and propionate metabolism in rat liver: Relevance to disorders of propionyl-CoA metabolism[J]. Am J Physiol Endocrinol Metab, 2017, 313(4): E413-428.

组别	例数	年龄(岁)		体质指数(kg/m²)	TBA(μmol/L)		AST(IU/L)		ALT(IU/L)		ALP(IU/L)
对照组	10	33.3±5.6		26.9±3.3	3.6±2.2		18.8±5.6		11.7±7.1		167.7±84.2
观察组	10	31.4±4.2		26.6±3.0	61.8±40.7		57.6±38		91.8±67.9		227.4±47.4
t值		0.944		0.271	4.940		3.501		3.561		2.140
P值		0.356		0.789	0.000		0.002		0.002		0.047
组别	发病孕天(d)		分娩孕天(d)			孕次(次)		产次(次)		新生儿出生体重(g)
对照组	-		273.3±2.6			2.6±1.3		0.8±0.6		3430.0±455.4
观察组	215.6±55.9		256.8±8.2			3.1±1.6		0.9±0.8		2827.1±435.3
t值			6.668			0.849		0.573		3.068
P值			0.000			0.406		0.573		0.006

组别	例数	年龄(岁)		体质指数(kg/m²)	TBA(μmol/L)		AST(IU/L)		ALT(IU/L)		ALP(IU/L)
对照组	10	33.3±5.6		26.9±3.3	3.6±2.2		18.8±5.6		11.7±7.1		167.7±84.2
观察组	10	31.4±4.2		26.6±3.0	61.8±40.7		57.6±38		91.8±67.9		227.4±47.4
t值		0.944		0.271	4.940		3.501		3.561		2.140
P值		0.356		0.789	0.000		0.002		0.002		0.047
组别	发病孕天(d)		分娩孕天(d)			孕次(次)		产次(次)		新生儿出生体重(g)
对照组	-		273.3±2.6			2.6±1.3		0.8±0.6		3430.0±455.4
观察组	215.6±55.9		256.8±8.2			3.1±1.6		0.9±0.8		2827.1±435.3
t值			6.668			0.849		0.573		3.068
P值			0.000			0.406		0.573		0.006

组别	例数	油酸			亚油酸		棕榈酸	壬酸		癸二酸		草酸
对照组	10	488.35±155.97			195.68±114.64		1113.22±674.54	104.62±57.66		815.26±114.26		6542.63±3682.01
观察组	10	309.53±56.15			74.40±25.78		467.21±460.79	1260.79±405.67		159.98±67.91		10372.78±3894.39
变化倍数 (观察组/对照组)		0.634			0.380		0.420	1.546		0.380		1.585
P值		0.003			0.004		0.022	0.045		0.039		0.036
组别	L-苯丙氨酸		3-羟基丙酸			柠檬酸			乙醇酸		L-苹果酸		尿嘧啶
对照组	2467.92±985.14		47372.17±20851.61			141568.05±70636.63			61405.95±29008.71		2442.89±1682.24		3950.87±1648.88
观察组	1128.04±604.12		15732.55±10120.39			66582.48±32340.82			29776.15±22874.65		1034.51±967.84		1793.62±1123.919
变化倍数 (观察组/对照组)	0.457		0.332			0.470			0.485		0.423		0.454
P值	0.002		<0.001			0.007			0.014		0.034		0.003
组别	L-4-羟脯氨酸			顺式乌头酸			琥珀酸	DL-焦谷氨酸			3-(4-羟基苯基)乳酸			尿黑酸
对照组	2802.90±1870.56			98772.97±53695.87			1804.07±838.35	72246.58±38762.87			582.55±249.04			120.45±88.21
观察组	1360.91±747.21			49167.89±38805.84			913.76±747.21	37181.64±27278.68			298.92±206.05			46.54±35.95
变化倍数 (观察组/对照组)	0.486			0.498			0.506	0.515			0.513			0.386
P值	0.036			0.029			0.022	0.031			0.012			0.024

组别	例数	油酸			亚油酸		棕榈酸	壬酸		癸二酸		草酸
对照组	10	488.35±155.97			195.68±114.64		1113.22±674.54	104.62±57.66		815.26±114.26		6542.63±3682.01
观察组	10	309.53±56.15			74.40±25.78		467.21±460.79	1260.79±405.67		159.98±67.91		10372.78±3894.39
变化倍数 (观察组/对照组)		0.634			0.380		0.420	1.546		0.380		1.585
P值		0.003			0.004		0.022	0.045		0.039		0.036
组别	L-苯丙氨酸		3-羟基丙酸			柠檬酸			乙醇酸		L-苹果酸		尿嘧啶
对照组	2467.92±985.14		47372.17±20851.61			141568.05±70636.63			61405.95±29008.71		2442.89±1682.24		3950.87±1648.88
观察组	1128.04±604.12		15732.55±10120.39			66582.48±32340.82			29776.15±22874.65		1034.51±967.84		1793.62±1123.919
变化倍数 (观察组/对照组)	0.457		0.332			0.470			0.485		0.423		0.454
P值	0.002		<0.001			0.007			0.014		0.034		0.003
组别	L-4-羟脯氨酸			顺式乌头酸			琥珀酸	DL-焦谷氨酸			3-(4-羟基苯基)乳酸			尿黑酸
对照组	2802.90±1870.56			98772.97±53695.87			1804.07±838.35	72246.58±38762.87			582.55±249.04			120.45±88.21
观察组	1360.91±747.21			49167.89±38805.84			913.76±747.21	37181.64±27278.68			298.92±206.05			46.54±35.95
变化倍数 (观察组/对照组)	0.486			0.498			0.506	0.515			0.513			0.386
P值	0.036			0.029			0.022	0.031			0.012			0.024

影响因素	TBA		AST		ALT		ALP
影响因素	r值	P值	r值	P值	r值	P值	r值	P值
壬酸	0.827	0.000	0.728	0.000	0.713	0.000	0.371	0.107
癸二酸	0.369	0.110	0.532	0.016	0.357	0.122	0.289	0.217
油酸	-0.542	0.014	-0.571	0.009	-0.522	0.018	-0.216	0.361
亚油酸	-0.489	0.029	-0.443	0.050	-0.426	0.061	-0.117	0.622
棕榈酸	-0.527	0.017	-0.409	0.074	-0.443	0.050	-0.097	0.686
3-羟基丙酸	-0.605	0.005	-0.440	0.052	-0.427	0.061	-0.174	0.462
L-苯丙氨酸	-0.576	0.008	-0.472	0.036	-0.485	0.030	-0.074	0.755