非酒精性脂肪性肝病肝纤维化进展中胃肠激素的变化水平

朱沪敏; 刘旭东; 黄露; 李品桦; 吴铁雄; 庞华珍

doi:10.3969/j.issn.1001-5256.2021.10.021

非酒精性脂肪性肝病肝纤维化进展中胃肠激素的变化水平

DOI: 10.3969/j.issn.1001-5256.2021.10.021

1.
广西中医药大学研究生学院，南宁 530000
2.
广西中医药大学附属瑞康医院肝病科，南宁 530000

基金项目:

广西科技攻关项目 (GK AB18221009);

广西一流学科建设课题 (2019XK139);

广西中医药大学岐黄工程高层次人才团队培育项目 (2021007)

详细信息

通信作者:
刘旭东，lxdlhx@163.com

中图分类号: R575.5
计量
- 文章访问数: 412
- HTML全文浏览量: 86
- PDF下载量: 30
- 被引次数: 0
出版历程
- 收稿日期: 2021-03-02
- 录用日期: 2021-03-23
- 出版日期: 2021-10-20

Expression levels of gastrointestinal hormones in the progression of liver fibrosis in patients with nonalcoholic fatty liver disease

1.
Graduate School, Guangxi University of Chinese Medicine, Nanning 530000, China
2.
Department of Hepatology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530000, China

Research funding:

Guangxi Key Science and Technology Program (GK AB18221009);

Guangxi First-class Discipline Construction Project (2019XK139);

Project of High-level Talent Team Cultivation in Qihuang Program of Guangxi University of Chinese Medicine (2021007)

摘要

摘要: 目的探讨非酒精性脂肪性肝病(NAFLD)肝纤维化进展中胃肠激素水平的变化，为消化系统功能损伤提供依据。方法选取2018年10月—2020年6月在广西中医药大学附属瑞康医院门诊就诊及病房住院治疗的NAFLD患者326例，采用FibroTouch进行肝脏弹性值(LSM)检测，按照有无肝纤维化分为无肝纤维化组(A组，LSM＜7.3 kPa，n=161)和肝纤维化组(B组，LSM≥7.3 kPa，n=165)。根据不同纤维化程度，进一步分为F0~1组(LSM＜7.3 kPa)、F2组(7.3 kPa≤LSM＜9.7 kPa)、F2~3组(9.7 kPa≤LSM＜12.4 kPa)、F3~4组(12.4 kPa≤LSM＜17.5 kPa)、F4组(LSM≥17.5 kPa)。收集患者的年龄、性别、肝功能指标、胃肠激素指标。计量资料符合正态分布组间比较采用独立样本t检验和单因素方差分析；不符合正态分布组间比较采用非参数Mann-Whitney U检验和Kruskal-Wallis H检验。应用Spearman分析LSM值与肝功能指标的相关性。结果 A组与B组患者肝功能、胃肠激素指标比较，ALT(Z=-3.778, P＜0.001)、AST(Z=-3.320, P=0.001)、GGT(Z=-3.040, P=0.002)、CCK(t=-2.944, P=0.003)、LPS(Z=-2.317, P=0.020)差异均有统计学意义。F0~1组(n=161)、F2组(n=89)、F2~3组(n=46)、F3~4组(n=16)、F4组(n=14) 5组间ALT(χ²=23.113, P＜0.001)、AST(χ²=23.415, P＜0.001)、ALP(χ²=15.962, P=0.003)、GGT(χ²=20.172, P＜0.001)、CCK(F=2.687, P=0.031)比较差异均有统计学意义。LSM值与DBil、ALT、AST、ALP、GGT呈正相关 (r值分别为0.128、0.266、0.225、0.137、0.213，P值均＜0.05)。结论 NAFLD肝纤维化进展能够影响胆囊收缩功能及胃肠功能，检测NAFLD肝纤维化患者血清CCK、LPS水平对胆囊收缩功能及胃肠功能相关的消化系统疾病的早诊早治有重要的临床价值。
- 非酒精性脂肪性肝病 /
- 肝硬化 /
- 胃肠激素类
Abstract: Objective To investigate the changes in gastrointestinal hormones during the progression of liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD), and to provide a basis for digestive function impairment. Methods A prospective analysis was performed for 326 patients with NAFLD who attended the outpatient service and were hospitalized and treated in Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine from October 2018 to June 2020, and FibroTouch was used to measure liver stiffness measurement (LSM). According to the presence or absence of liver fibrosis, they were divided into non-liver fibrosis group (group A, 161 patients with LSM < 7.3 kPa) and liver fibrosis group (group B, 165 patients with LSM ≥7.3 kPa). According to the fibrosis degree, the patients were further divided into F0-1 group (LSM < 7.3 kPa), F2 group (7.3 kPa ≤LSM < 9.7 kPa), F2-3 group (9.7 kPa ≤LSM < 12.4 kPa), F3-4 group (12.4 kPa ≤LSM < 17.5 kPa), and F4 group (LSM ≥17.5 kPa). Related data were collected, including age, sex, liver function parameters, and gastrointestinal hormones. The independent samples t-test and the one-way analysis of variance were used for comparison of normally distributed continuous data between groups, and the nonparametric Mann-Whitney U test and the Kruskal-Wallis H test were used for comparison of non-normally distributed continuous data between groups. A Spearman correlation analysis was used to investigate the correlation between LSM and liver function parameters. Results Comparison of liver function and gastrointestinal hormones showed that there were significant differences between groups A and B in alanine aminotransferase (ALT) (Z=-3.778, P < 0.001), aspartate aminotransferase (AST) (Z=-3.320, P=0.001), gamma-glutamyl transpeptidase (GGT) (Z=-3.040, P=0.002), cholecystokinin (CCK) (t=-2.944, P=0.003), and lipopolysaccharide (LPS) (Z=-2.317, P=0.020). There were significant differences in ALT (χ²=23.113, P < 0.001), AST (χ²=23.415, P < 0.001), ALP (χ²=15.962, P=0.003), GGT (χ²=20.172, P < 0.001), and CCK (F=2.687, P=0.031) between the F0-1 group with 161 patients, the F2 group with 89 patients, the F2-3 group with 46 patients, the F3-4 group with 16 patients, and the F4 group with 14 patients. LSM was positively correlated with direct bilirubin, ALT, AST, alkaline phosphatase, and GGT (r=0.128, 0.266, 0.225, 0.137, and 0.213, all P < 0.05). Conclusion Liver fibrosis progression in NAFLD can affect gallbladder contraction function and gastrointestinal function, and measurement of the serum levels of CCK and LPS has an important clinical value in the early diagnosis and treatment of digestive diseases related to gallbladder contraction function and gastrointe stinal function in NAFLD patients with liver fibrosis.
- Non-Alcoholic Fatty Liver Disease /
- Liver Cirrhosis /
- Gastrointestinal Hormones

HTML全文

表 1 5组间肝功能及胃肠激素指标比较

指标	F0~1组(n=161)	F2组(n=89)	F2~3组(n=46)	F3~4组(n=16)	F4组(n=14)	统计值	P值
TBil(μmol/L)	11.10(8.00~16.00)	10.70(8.25~14.25)	11.00(7.23~14.90)	12.60(7.43~14.35)	12.60(8.10~26.20)	χ²=1.940	0.773
DBil(μmol/L)	3.10(2.40~4.55)	3.30(2.50~4.30)	3.80(2.88~4.53)	3.80(2.88~4.63)	4.10(3.38~11.75)	χ²=8.739	0.068
IBil(μmol/L)	7.90(5.30~11.45)	7.60(5.50~9.65)	7.55(4.20~11.05)	8.75(5.25~9.45)	7.85(4.58~10.15)	χ²=1.863	0.761
TP(g/L)	73.49±6.16	74.24±5.51	72.29±6.73	74.62±6.21	72.49±10.90	F=0.939	0.441
Alb(g/L)	44.27±4.34	43.89±3.78	44.00±6.46	44.24±3.81	39.54±8.02	F=3.249	0.012
Glb(g/L)	29.30(26.10~31.95)	30.70(27.30~32.75)	29.15(26.38~32.20)	30.10(28.25~35.45)	29.65(26.00~37.78)	χ²=5.464	0.243
ALT(U/L)	25.00(16.50~35.00)	28.00(19.50~45.00)	44.50(23.00~90.00)	31.00(18.25~56.50)	47.50(34.50~76.75)	χ²=23.113	＜0.001
AST(U/L)	22.00(16.50~28.00)	23.00(18.00~32.50)	29.50(23.00~47.50)	26.50(16.50~40.25)	41.00(19.25~70.25)	χ²=23.415	＜0.001
ALP(U/L)	68.00(56.00~80.50)	66.00(57.00~78.50)	77.00(59.75~85.25)	70.50(58.25~102.50)	88.00(69.50~129.00)	χ²=15.962	0.003
GGT(U/L)	34.00(24.00~55.00)	38.00(27.00~57.00)	50.00(35.00~76.00)	37.50(33.00~50.00)	73.00(42.50~224.25)	χ²=20.172	＜0.001
CCK(ng/mL)	49.91±26.19	60.36±25.43	57.16±23.35	56.32±24.68	50.39±26.36	F=2.687	0.031
DAO(U/L)	9.74±2.10	9.42±2.81	9.81±2.64	8.91±2.15	9.18±2.14	F=0.787	0.534
D-LA(mmol/L)	25.59±10.95	23.81±8.61	25.10±12.15	23.21±7.52	25.66±8.97	F=0.557	0.694
G-17(pg/mL)	17.27(13.24~21.71)	17.77(14.10~22.39)	17.56(11.32~21.71)	20.97(13.25~23.13)	18.21(12.36~22.25)	χ²=2.650	0.618
LPS(EU/mL)	463.68(317.24~587.17)	412.40(222.89~533.94)	387.26(212.48~529.82)	411.17(124.25~598.58)	474.39(360.81~626.83)	χ²=7.922	0.094
MTL(pg/mL)	182.75(111.76~256.14)	170.36(110.37~245.35)	169.01(116.54~206.94)	206.01(145.96~243.70)	155.40(104.97~197.02)	χ²=3.819	0.431

下载: 导出CSV

表 2 两组间肝功能指标、胃肠激素指标比较

指标	A组(n=161)	B组(n=165)	统计值	P值
肝功能
TBil(μmol/L)	11.10(8.00~16.00)	10.90(8.15~14.50)	Z=-0.671	0.502
DBil(μmol/L)	3.10(2.40~4.55)	3.50(2.60~4.40)	Z=-1.905	0.057
IBil(μmol/L)	7.90(5.30~11.45)	7.60(5.10~9.65)	Z=-1.358	0.174
TP(g/L)	73.49±6.16	73.58±6.52	t=-0.137	0.891
Alb(g/L)	44.27±4.34	43.58±5.20	t=1.296	0.196
Glb(g/L)	29.30(26.10~31.95)	30.10(27.10~32.70)	Z=-1.677	0.093
ALT(U/L)	25.00(16.50~35.00)	32.00(21.00~57.50)	Z=-3.778	＜0.001
AST(U/L)	22.00(16.50~28.00)	26.00(19.00~36.00)	Z=-3.320	0.001
ALP(U/L)	68.00(56.00~80.50)	69.00(58.50~85.00)	Z=-1.587	0.113
GGT(U/L)	34.00(24.00~55.00)	41.00(29.50~64.50)	Z=-3.040	0.002
胃肠激素
CCK(ng/mL)	49.91±26.19	58.23±24.81	t=-2.944	0.003
DAO(U/L)	9.74±2.10	9.46±2.65	t=1.074	0.284
D-LA(mmol/L)	25.59±10.95	24.26±9.61	t=1.159	0.247
G-17(pg/mL)	17.27(13.24~21.71)	18.31(12.99~22.17)	Z=-0.428	0.668
LPS(EU/mL)	463.68(317.24~587.17)	412.40(222.89~547.73)	Z=-2.317	0.020
MTL(pg/mL)	182.75(111.76~256.14)	171.44(116.49~240.04)	Z=-1.068	0.286

下载: 导出CSV

参考文献(28)

[1]	HUBER Y, GALLE PR, SCHATTENBERG JM. What is the (right) target for non-alcoholic fatty liver disease (NAFLD)?[J]. Z Gastroenterol, 2020, 58(1): 68-73. DOI: 10.1055/a-1068-3981.
[2]	STINE JG, WENTWORTH BJ, ZIMMET A, et al. Systematic review with meta-analysis: Risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases[J]. Aliment Pharmacol Ther, 2018, 48(7): 696-703. DOI: 10.1111/apt.14937.
[3]	MACALUSO FS, MAIDA M, PETTA S. Genetic background in nonalcoholic fatty liver disease: A comprehensive review[J]. World J Gastroenterol, 2015, 21(39): 11088-11111. DOI: 10.3748/wjg.v21.i39.11088.
[4]	Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Gastroenterology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. Consensus on the diagnosis and therapy of hepatic fibrosis(2019)[J]. J Clin Hepatol, 2019, 35(10): 2163- 2172. DOI: 10.3969/j.issn.1001-5256.2019.10.007. 中华医学会肝病学分会, 中华医学会消化病学分会, 中华医学会感染病学分会. 肝纤维化诊断及治疗共识(2019年)[J]. 临床肝胆病杂志, 2019, 35(10): 2163-2172. DOI: 10.3969/j.issn.1001-5256.2019.10.007.
[5]	National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical Association, Fatty Liver Expert Committee, Chinese Medical Doctor Association. Guidelines of prevention and treatment for nonalcoholic fatty liver disease: A 2018 update[J]. J Clin Hepatol, 2018, 34(5): 947-957. DOI: 10.3969/j.issn.1001-5256.2018.05.007. 中华医学会肝病学分会脂肪肝和酒精性肝病学组, 中国医师协会脂肪性肝病专家委员会. 非酒精性脂肪性肝病防治指南(2018年更新版)[J]. 临床肝胆病杂志, 2018, 34(5): 947-957. DOI: 10.3969/j.issn.1001-5256.2018.05.007.
[6]	HAGSTRÖM H, NASR P, EKSTEDT M, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD[J]. J Hepatol, 2017, 67(6): 1265-1273. DOI: 10.1016/j.jhep.2017.07.027.
[7]	ARCHER S, DAVIES K. Biological basis of child health 9: Development of the liver and clinical features of childhood liver disease[J]. Nurs Child Young People, 2021. DOI: 10.7748/ncyp.2021.e1258.[Online ahead of print]
[8]	WANG SK, CHEN DH. The serum levels and their clinical significance of retinol-binding protein and several liver function index in different types of liver disease[J]. Chin J Health Lab Technol, 2017, 27(8): 1065-1067. https://www.cnki.com.cn/Article/CJFDTOTAL-ZWJZ201708001.htm 王胜奎, 陈戴红. 常见肝脏疾病患者血清视黄醇结合蛋白表达水平及部分肝功能指标联合检测的临床意义[J]. 中国卫生检验杂志, 2017, 27(8): 1065-1067. https://www.cnki.com.cn/Article/CJFDTOTAL-ZWJZ201708001.htm
[9]	HAN L, WEN QS. Relationship between serum uric acid and non-alcoholic fatty liver disease in male adults[J]. Chin J Integr Trad West Med Dig, 2015, 23(7): 496-500. DOI: 10.3969/j.issn.1671-038X.2015.07.13. 韩琳, 温巧生. 血清尿酸与男性非酒精性脂肪肝的相关性研究[J]. 中国中西医结合消化杂志, 2015, 23(7): 496-500. DOI: 10.3969/j.issn.1671-038X.2015.07.13.
[10]	LIU WY, GAO XZ. Analysis of the value of serum pepsinogen, gastrin-17, and Helicobacter pylori antibody detection in screening gastric cancer risk groups[J/CD]. Chin J Gastrointest Endosc(Electronic Edition), 2021, 8(1): 37-41. DOI: 10.3877/cma.j.issn.2095-7157.2021.01.007. 刘炜钰, 高孝忠. 血清胃蛋白酶原、胃泌素-17、幽门螺杆菌抗体检测在筛查胃癌风险人群中的价值分析[J/CD]. 中华胃肠内镜电子杂志, 2021, 8(1): 37-41. DOI: 10.3877/cma.j.issn.2095-7157.2021.01.007.
[11]	CHAI CH, LI LQ, CHEN P, et al. Detection and clinical analysis of fasting serum gastrin in patients with various liver diseases[J]. J Zunyi Med Coll, 1995, 18(3): 190-192. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYYB199503013.htm 柴朝会, 李良庆, 陈萍, 等. 各型肝病患者空腹血清胃泌素检测与临床分析[J]. 遵义医学院学报, 1995, 18(3): 190-192. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYYB199503013.htm
[12]	WILLIAMS RL. Textbook of endocrinology[M]. 6th ed. Philadelphia: Saunders, 1981: 704-705.
[13]	SVENBERG T, NILSSON I, SAMUELSON K, et al. Studies on the causal relationship between gall-bladder emptying and motilin release in man[J]. Acta Chir Scand Suppl, 1984, 520: 59-61.
[14]	QIN J, ZHOU SZ, ZHANG YJ. Analysis of related factors of liver cirrhosis on gastrointestinal motility[J]. Hubei J Prevent Med, 2001, 12: 47-48. https://www.cnki.com.cn/Article/CJFDTOTAL-FBYF2001S1043.htm 秦俊, 周韶璋, 张一洁. 肝硬化对胃肠动力学影响的相关因素分析[J]. 湖北预防医学杂志, 2001, 12: 47-48. https://www.cnki.com.cn/Article/CJFDTOTAL-FBYF2001S1043.htm
[15]	CHEN Q, CHEN J, QU CY. Research progress on the relationship between leptin, cholecystokinin and alcoholic fatty liver[J]. Chin Primary Health Care, 2008, 22(3): 92-93. DOI: 10.3969/j.issn.1001-568X.2008.03.044. 陈青, 陈吉, 曲春燕. 瘦素、胆囊收缩素与酒精性脂肪肝关系的研究进展[J]. 中国初级卫生保健, 2008, 22(3): 92-93. DOI: 10.3969/j.issn.1001-568X.2008.03.044.
[16]	SMITH SM, ENG RH, BUCCINI F. Use of D-lactic acid measurements in the diagnosis of bacterial infections[J]. J Infect Dis, 1986, 154(4): 658-664. DOI: 10.1093/infdis/154.4.658.
[17]	JIN X, LI YM, YU CH, et al. Changes of intestinal permeability during the formation of nonalcoholic steatohepatitis in rats[J]. Chin J Dig, 2006, 28(8): 547-548. DOI: 10.3760/j.issn:0254-1432.2006.08.013. 金希, 厉有名, 虞朝辉, 等. 大鼠非酒精性脂肪性肝炎形成过程中肠道通透性的变化[J]. 中华消化杂志, 2006, 28(8): 547-548. DOI: 10.3760/j.issn:0254-1432.2006.08.013.
[18]	SHEN Z, CEN L, CHEN X, et al. Increased risk of low bone mineral density in patients with non-alcoholic fatty liver disease: A cohort study[J]. Eur J Endocrinol, 2020, 182(2): 157-164. DOI: 10.1530/EJE-19-0699.
[19]	KEMPIŃSKI R, ŁUKAWSKA A, KRZYŻANOWSKI F, et al. Clinical outcomes of non-alcoholic fatty liver disease: Polish-case control study[J]. Adv Clin Exp Med, 2019, 28(12): 1615-1620. DOI: 10.17219/acem/106173.
[20]	WASHINGTON MC, COGGESHALL J, SAYEGH AI. Cholecystokinin-33 inhibits meal size and prolongs the subsequent intermeal interval[J]. Peptides, 2011, 32(5): 971-977. DOI: 10.1016/j.peptides.2011.02.007.
[21]	CHEN D. Clinical analysis of adiposis hepatica complicated with cholecystitis in aged people[J]. Inner Mongolia J Tradit Chin Med, 2008, 40(1): 50-51. DOI: 10.3969/j.issn.1004-0951.2008.01.019. 陈东. 老年人脂肪肝并发胆囊炎的临床观察[J]. 内蒙古医学杂志, 2008, 40(1): 50-51. DOI: 10.3969/j.issn.1004-0951.2008.01.019.
[22]	KEITH JN. Bedside nutrition assessment past, present, and future: A review of the Subjective Global Assessment[J]. Nutr Clin Pract, 2008, 23(4): 410-416. DOI: 10.1177/0884533608321215.
[23]	YE YH, WANG N, TAO W. Meta-analysis of the relationship between diamine oxidase changes and gastrointestinal dysfunction in critically ill patients[J/CD]. J Clin Med Literature (Electronic Edition), 2019, 6(4): 30-32, 34. DOI: 10.3877/j.issn.2095-8242.2019.04.017. 叶云虹, 王念, 陶武. 危重患者二胺氧化酶变化与胃肠功能障碍关系的meta分析[J/CD]. 临床医药文献电子杂志, 2019, 6(4): 30-32, 34. DOI: 10.3877/j.issn.2095-8242.2019.04.017.
[24]	CHENG J, LI FL, ZHANG B, et al. Effects of high-fat diet on intestinal flora and serum LPS level in NAFLD model rats[J]. Acta Univ Med Anhui, 2017, 52(9): 1341-1345. DOI: 10.19405/j.cnki.issn1000-1492.2017.09.019. 程靖, 李枫林, 张宝, 等. 高脂饮食对NAFLD模型大鼠肠道菌群及血清LPS水平的影响[J]. 安徽医科大学学报, 2017, 52(9): 1341-1345. DOI: 10.19405/j.cnki.issn1000-1492.2017.09.019.
[25]	CANI PD, AMAR J, IGLESIAS MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance[J]. Diabetes, 2007, 56(7): 1761-1772. DOI: 10.2337/db06-1491.
[26]	GUO RX, WEI XL, SHI XM, et al. Levels of serum sdiponectin, lipopolysaccharide and matrix metalloproteinase-2 in patients with liver cirrhosis and diagnostic value[J]. Chin J Mod Med, 2020, 30(12): 100-103. DOI: 10.3969/j.issn.1005-8982.2020.12.018. 郭瑞雪, 魏新亮, 史晓盟, 等. 肝硬化患者血清脂联素、脂多糖、基质金属蛋白酶-2水平及其诊断价值[J]. 中国现代医学杂志, 2020, 30(12): 100-103. DOI: 10.3969/j.issn.1005-8982.2020.12.018.
[27]	YANG YN, WAN WQ, ZHU DD, et al. Effect of lipopolysaccharide on expression of proteins associated with cell activation and apoptosis in human hepatic stellate cell line LX-2[J]. World Chin J Dig, 2013, 21(30): 3236-3240. https://www.cnki.com.cn/Article/CJFDTOTAL-XXHB201330015.htm 杨亚楠, 万维琴, 朱丹丹, 等. 脂多糖对人肝星状细胞株LX-2活化和凋亡相关蛋白表达的影响[J]. 世界华人消化杂志, 2013, 21(30): 3236-3240. https://www.cnki.com.cn/Article/CJFDTOTAL-XXHB201330015.htm
[28]	JIA JB, WU H, YANG DR, et al. Effect of endotoxin-stimulated Kupffer cells on procollagen gene expression in hepatic stellate cells[J]. Chin J Gastroenterol, 2011, 16(8): 459-463. DOI: 10.3969/j.issn.1008-7125.2011.08.003. 贾晋斌, 吴晗, 杨东仁, 等. 内毒素刺激Kupffer细胞对肝星状细胞前胶原基因表达的影响[J]. 胃肠病学, 2011, 16(8): 459-463. DOI: 10.3969/j.issn.1008-7125.2011.08.003.