FGF19在妊娠期肝内胆汁淤积症患者血清中的表达水平及相关因素分析

doi:10.3877/cma.j.issn.2095-3259.2023.04.011

目的

探讨成纤维细胞生长因子19(fibroblast growth factor 19，FGF19)在妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy, ICP)患者血清中的表达水平，并分析其相关因素。

方法

采用前瞻性研究方法收集2021年1月至2022年1月在中山大学附属第三医院产检并住院分娩的25例ICP患者及25例健康孕妇的空腹血清，使用酶联免疫吸附法测定FGF19浓度，全自动生化分析仪检测肝功能指标，同时登记并随访研究对象的临床资料及妊娠结局。采用t检验、Wilcoxon秩和检验、χ²检验、Spearman相关等进行统计分析，比较两组血清FGF19水平的差异，分析其相关影响因素。

结果

ICP患者的血清FGF19水平的平均值为116.43 pg/ml，中位数为87.17 pg/ml，明显低于对照组的234.93 pg/ml和176.67 pg/ml，两组间差异具有统计学意义(P<0.05)。ICP患者血清FGF19水平与总胆汁酸浓度呈负相关(r＝－0.472，P＝0.017)，而健康孕妇两个指标间无相关(P>0.05)。血清FGF19水平与ALT、AST、TBil、入组孕周、年龄、孕前BMI、入院BMI均无相关。与健康孕妇比较，ICP患者的血清AST水平较高、孕前BMI较低、分娩孕周更早，两组间差异有统计学意义(P<0.05)。

结论

ICP患者血清FGF19水平下降，且与总胆汁酸浓度呈负相关，今后ICP的研究方向可关注FGF19因子上下游通路的激活状态。

关键词: 妊娠, 胆汁淤积，肝内, 胆汁酸类, 成纤维细胞生长因子19

Objective

In this study, we aimed to investigate the serum FGF19 levels in intrahepatic cholestasis of pregnancy (ICP) and its relative factors.

Methods

This prospective clinical study was conducted at the Department of Obstetrics, the Third Affiliated Hospital of Sun Yat-sen University. 25 women whose pregnancies were complicated with ICP and 25 healthy pregnant women without ICP were recruited for the study group. The fasting blood samples for the FGF19 analyses were prospectively collected. The serum FGF19 concentrations were measured using an enzyme-linked immunosorbent assay, and the serological indicators including ALT, AST, TBA, and TBil were detected by an automatic biochemical analyzer.The patient characteristics, including maternal age, gestational age at the time of diagnosis and delivery, body mass index (BMI), and perinatal outcome were followed up and recorded. Student′s text, Wilcoxon rank sum test, Chi-square test and the Spearman′s rank coefficient of correlation were used for statistical analysis. The differences in serum FGF19 levels between the two groups were compared and the relative factors were analyzed.

Results

The mean and median levels of maternal serum FGF19 in the ICP cases were 116.43 pg/ml and 87.17 pg/ml, which were significantly lower than in the control group(234.93 pg/ml and 176.67 pg/ml) (P<0.05). A significantly negative correlation was between maternal serum FGF19 levels and maternal serum total bile acid levels in ICP patients (r=-0.472, P=0.017), but there was no correlation between the two indexes in healthy pregnant women (P>0.05). There was no correlation between serum FGF19 levels and serum ALT concentrations, serum AST concentrations, serum TBil concentrations, maternal age, gestational age of at the time of diagnosis, or BMI. Compared with healthy pregnant women, the ICP cases have higher serum AST levels, lower preconception BMI and earlier delivery (P<0.05).

Conclusions

The serum FGF19 levels decreased in ICP patients and were negatively correlated with the serum total bile acid concentrations. FGF19 may be used as an auxiliary diagnostic factor for ICP.

Key words: Pregnancy, Cholestasis, intrahepatic, Bile acid, Fibroblast growth factor 19

表1 两组患者临床资料的比较

组别	例数	年龄(岁，±s)	入组孕周(周，±s)	孕前BMI(kg/m²，±s)	入院BMI(kg/m²，±s)
ICP组	25	29.24±4.54	30.59±9.27	19.75±1.39	24.78±2.26
对照组	25	30.28±4.52	32.75±8.40	21.02±2.41	25.67±2.39
t值		0.811	0.862	2.283	1.351
P值		0.421	0.393	0.027	0.183
组别	例数	分娩孕周(周，±s)	早产[例(%)]	剖宫产[例(%)]	羊水粪染[例(%)]	新生儿出生体重(g，±s)
ICP组	25	38.43±2.21	3(12)	9(36)	5(20)	3051.20±530.56
对照组	25	39.40±0.88	0	12(48)	3(12)	3230.00±367.42
统计值		t＝2.046	－	χ²＝0.762	χ²＝2.095	t＝1.385
P值		0.049	0.235^a	0.683	0.553	0.172

表1 两组患者临床资料的比较

组别	例数	年龄(岁，±s)	入组孕周(周，±s)	孕前BMI(kg/m²，±s)	入院BMI(kg/m²，±s)
ICP组	25	29.24±4.54	30.59±9.27	19.75±1.39	24.78±2.26
对照组	25	30.28±4.52	32.75±8.40	21.02±2.41	25.67±2.39
t值		0.811	0.862	2.283	1.351
P值		0.421	0.393	0.027	0.183
组别	例数	分娩孕周(周，±s)	早产[例(%)]	剖宫产[例(%)]	羊水粪染[例(%)]	新生儿出生体重(g，±s)
ICP组	25	38.43±2.21	3(12)	9(36)	5(20)	3051.20±530.56
对照组	25	39.40±0.88	0	12(48)	3(12)	3230.00±367.42
统计值		t＝2.046	－	χ²＝0.762	χ²＝2.095	t＝1.385
P值		0.049	0.235^a	0.683	0.553	0.172

表2 两组患者生化指标的比较

组别	例数	TBA[μmol/L, M(P₂₅，P₇₅)]	AST[U/L, M(P₂₅，P₇₅)]	ALT[U/L, M(P₂₅，P₇₅)]	TBil[μmol/L, M(P₂₅，P₇₅)]
ICP组	25	17.8(14.30，25.30)	19.0(15.50，23.50)	12.0(9.50，24.50)	4.4(3.55，6.70)
对照组	25	2.5(1.40，4.55)	16.0(14.00，17.50)	8.5(11.00，14.00)	4.4(3.55，6.70)
Z值		－6.065	－2.229	－1.304	－0.575
P值		<0.001	0.026	0.192	0.565

表2 两组患者生化指标的比较

组别	例数	TBA[μmol/L, M(P₂₅，P₇₅)]	AST[U/L, M(P₂₅，P₇₅)]	ALT[U/L, M(P₂₅，P₇₅)]	TBil[μmol/L, M(P₂₅，P₇₅)]
ICP组	25	17.8(14.30，25.30)	19.0(15.50，23.50)	12.0(9.50，24.50)	4.4(3.55，6.70)
对照组	25	2.5(1.40，4.55)	16.0(14.00，17.50)	8.5(11.00，14.00)	4.4(3.55，6.70)
Z值		－6.065	－2.229	－1.304	－0.575
P值		<0.001	0.026	0.192	0.565

表3 患者FGF19与生化指标、临床资料的相关性分析结果

类别	相关系数	P值
TBA(未分组)	－0.397	0.004
TBA(健康对照组)	－0.010	0.964
TBA(ICP患者组)	－0.472	0.017
ALT	－0.077	0.593
AST	－0.066	0.650
TBil	－0.081	0.600
入组孕周	0.138	0.338
年龄	－0.112	0.440
孕前BMI	0.166	0.249
入院BMI	0.046	0.751

表3 患者FGF19与生化指标、临床资料的相关性分析结果

类别	相关系数	P值
TBA(未分组)	－0.397	0.004
TBA(健康对照组)	－0.010	0.964
TBA(ICP患者组)	－0.472	0.017
ALT	－0.077	0.593
AST	－0.066	0.650
TBil	－0.081	0.600
入组孕周	0.138	0.338
年龄	－0.112	0.440
孕前BMI	0.166	0.249
入院BMI	0.046	0.751

[1]	Hobson S, Gandhi S, Sobel M. Intrahepatic cholestasis of pregnancy[J]．CMAJ，2022，194(48)：E1650.
[2]	Girling J, Knight CL, Chappell L, et al. Intrahepatic cholestasis of pregnancy: green-top guideline No. 43 June 2022[J]. BJOG，2022，129(13)：e95-114.
[3]	Sarker M, Zamudio AR, DeBolt C, et al. Beyond stillbirth: association of intrahepatic cholestasis of pregnancy severity and adverse outcomes[J]. Am J Obstet Gynecol，2022，227(3)：517.e1-517.e7.
[4]	Bertolini A, Fiorotto R, Strazzabosco M. Bile acids and their receptors: modulators and therapeutic targets in liver inflammation[J]. Semin Immunopathol，2022，44(4)：547-564.
[5]	Borup C, Wildt S, Rumessen J, et al. Biochemical diagnosis of bile acid diarrhea: prospective comparison with the 75seleno-taurohomocholic acid test[J]. Am J Gastroenterol，2020，115(12)：2086-2094.
[6]	刘雅丽，柳涛，赵旭，等. 酒精性肝病中基于胆汁酸的调控机制及潜在治疗靶点[J]. 中国医学前沿杂志(电子版)，2023，15(2)：58-64.
[7]	Tayyar AT, Tayyar A, Kozali S, et al. Evaluation of FGF-19 and β-klotho as biomarkers in patients with intrahepatic cholestasis of pregnancy[J]. Arch Med Sci，2019，15(1)：113-119.
[8]	黄丽莉，夏可辉，唐荣，等. FGF-19和β-Klotho在妊娠期肝内胆汁淤积症患者血清中的表达及其临床意义[J]. 医学临床研究，2023，40(2)：293-296.
[9]	王实，仇春波，叶黎霞. 妊娠期肝内胆汁淤积症患者血清成纤维细胞生长因子19和Klotho mRNA水平及临床意义[J]. 中国妇幼保健，2022，37(12)：2262-2265.
[10]	谢幸，孔北华，段涛. 妇产科学[M]. 9版. 北京：人民卫生出版社，2018：83-109.
[11]	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)：1-11.
[12]	Wu K, Yin B, Li S, et al. Prevalence, risk factors and adverse perinatal outcomes for Chinese women with intrahepatic cholestasis of pregnancy: a large cross-sectional retrospective study[J]. Ann Med，2022，54(1)：2966-2974.
[13]	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]. 中华妇产科杂志，2015，50(7)：481-485.
[14]	许宏辉，许倩. 妊娠期肝内胆汁淤积症胆汁酸和肝酶水平对围产结局的影响[J]. 江苏医药，2016，42(11)：1298-1300.
[15]	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.
[16]	Marschall HU, Wikström Shemer E, Ludvigsson JF, et al. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study[J]. Hepatology, 2013，58(4)：1385-1391.
[17]	Wikström Shemer EA, Stephansson O, Thuresson M, et al. Intrahepatic cholestasis of pregnancy and cancer, immune-mediated and cardiovascular diseases: a population-based cohort study[J]. J Hepatol，2015，63(2)：456-461.
[18]	Monrose E, Bui A, Rosenbluth E, et al. Burden of future liver abnormalities in patients with intrahepatic cholestasis of pregnancy[J]. Am J Gastroenterol，2021，116(3)：568-575.
[19]	Majsterek M, Wierzchowska-Opoka M, Makosz I, et al. Bile acids in intrahepatic cholestasis of pregnancy[J]. Diagnostics (Basel)，2022，12(11)：1-13.
[20]	Ovadia C, Perdones-Montero A, Fan HM, et al. Ursodeoxycholic acid enriches intestinal bile salt hydrolase-expressing bacteroidetes in cholestatic pregnancy[J]. Sci Rep，2020，10(1)：1-10.
[21]	Gadaleta RM, Moschetta A. Metabolic messengers: fibroblast growth factor 15/19[J]. Nat Metab，2019，1(6)：588-594.
[22]	Perino A, Schoonjans K. Metabolic messengers: bile acids[J]. Nat Metab，2022，4(4)：416-423.
[23]	Jiao N, Baker SS, Chapa-Rodriguez A, et al. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD[J]. Gut，2018，67(10)：1881-1891.
[24]	Xiao Y, Zhou K, Lu Y, et al. Administration of antibiotics contributes to cholestasis in pediatric patients with intestinal failure via the alteration of FXR signaling[J]. Exp Mol Med，2018，50(12)：1-14.
[25]	Tang B, Tang L, Li S, et al. Gut microbiota alters host bile acid metabolism to contribute to intrahepatic cholestasis of pregnancy[J]. Nat Commun，2023，14(1)：1-17.

[1]	李钱梅, 何冠南, 赵婧, 陈曦, 唐玉英, 马丽琼, 梁蓉, 袁桃, 李明星. 早孕期低危妊娠和高危妊娠胎盘微血流成像特征及预后分析[J]. 中华医学超声杂志（电子版）, 2024, 21(07): 726-732.
[2]	尹宏宇, 吴青青, 李晓菲. 颈后透明层和头臀长在妊娠11~13⁺⁶周双胎心脏畸形筛查中的价值[J]. 中华医学超声杂志（电子版）, 2024, 21(03): 251-256.
[3]	刘涵, 刘晓菲, 陈翰翰, 陈延君, 张雁. 妊娠期肉芽肿性乳腺炎一例[J]. 中华乳腺病杂志(电子版), 2024, 18(04): 253-254.
[4]	李欣, 魏艺, 张娟, 张娟娟, 凌秀凤, 赵纯, 张媔秋. 高龄女性冻胚移植周期临床妊娠结局的影响因素分析[J]. 中华妇幼临床医学杂志(电子版), 2024, 20(03): 276-283.
[5]	薛静, 孙雅楠, 朱丽丽, 李淑红. 妊娠期急性脂肪肝孕产妇诊疗及其妊娠结局[J]. 中华妇幼临床医学杂志(电子版), 2024, 20(03): 312-321.
[6]	林雪, 陈锰, 杨梅琳, 刘兴会, 周红雨. 妊娠合并重症肌无力患者的围产结局和重症肌无力病情恶化的影响因素分析[J]. 中华妇幼临床医学杂志(电子版), 2024, 20(02): 125-132.
[7]	张静, 刘畅, 华成舸. 妊娠期患者口腔诊疗进展[J]. 中华口腔医学研究杂志(电子版), 2024, 18(05): 340-344.
[8]	何俊, 易淑华, 陈婷婷, 杨玉, 李红雨, 谢飞, 何健. 妊娠并发社区获得性肺炎临床特征及降钙素原和炎症指数对其诊断意义[J]. 中华肺部疾病杂志(电子版), 2024, 17(03): 421-425.
[9]	柯彩萍, 林丽萍, 王晓怡, 李虹晔, 陈敦金. 关于双绒毛膜双羊膜囊双胎妊娠第二胎儿延迟分娩的临床研究[J]. 中华产科急救电子杂志, 2024, 13(03): 159-167.
[10]	胡淼, 杜丽丽, 张丽姿, 林琳, 张瑜亮, 古士锋, 古仲嘉, 赖思莹, 梁景英, 刘雨, 黄敏珊, 黄媛媛, 黄晴晴, 罗世君, 陈敦金. 体外受精/卵胞浆内单精子注射受孕患者胎盘植入分级及围产结局的研究[J]. 中华产科急救电子杂志, 2024, 13(03): 183-189.
[11]	赵颖, 熊钰. 妊娠合并尿路结石的诊治[J]. 中华产科急救电子杂志, 2024, 13(03): 141-145.
[12]	龚子元, 黄振宇. 妊娠期肠梗阻的诊疗策略[J]. 中华产科急救电子杂志, 2024, 13(03): 152-157.
[13]	肖露, 黄莉萍. 妊娠期急性阑尾炎[J]. 中华产科急救电子杂志, 2024, 13(03): 135-140.
[14]	马睿, 赫英东. 妊娠合并胆石症的诊断和治疗[J]. 中华产科急救电子杂志, 2024, 13(03): 146-151.
[15]	彭小蓉, 莫伟, 李琴, 吴雅琴, 李兰. 妊娠期妇女静脉血栓栓塞症预防的知信行现状及其影响因素分析[J]. 中华介入放射学电子杂志, 2024, 12(03): 274-280.

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

Serum FGF19 levels in patients with intrahepatic cholestasis of pregnancy and its relative factors

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

Serum FGF19 levels in patients with intrahepatic cholestasis of pregnancy and its relative factors