肝硬化患者肠黏膜通透性改变与肝功能分级的关系研究

doi:10.3760/cma.j.issn.1007-1245.2023.01.023

摘要/Abstract

摘要：

目的　探讨肝硬化患者肠黏膜通透性改变与肝功能分级的关系。方法　以2020年11月至2022年4月经郑州市第六人民医院医学检验科收治肝硬化患者96例为观察组，按Child-Pugh肝功能分级分为A组（35例）、B组（43例）、C组（18例）3个亚组；同期选择无肝硬化的健康体检者40例为对照组。A组男25例、女10例，年龄（55.01±8.71）岁；B组男30例、女13例，年龄（55.19±8.76）岁；C组男14例、女4例，年龄（55.34±8.81）岁；对照组男27例、女13例，年龄（54.52±8.56）岁。收集粪便标本，通过细菌培养测定肠道主要菌群变化，测定肠黏膜通透性指标［D-乳酸（D-LAC）、内毒素（ETX）及二胺氧化酶（DAO）］。Pearson相关性分析分析肠黏膜通透性指标之间的相关性，Spearman相关性分析分析肠黏膜通透性指标与Child-Pugh肝功能分级的相关性，并使用受试者工作特征曲线（ROC）分析肠黏膜通透性指标的预测价值。计量资料采用F检验、独立样本t检验，计数资料采用χ²检验。结果　A、B、C组肠杆菌［（8.61±0.42）lgCFU/g、（8.95±0.39）lgCFU/g、（9.22±0.56）lgCFU/g］、肠球菌数目［（7.75±0.46）lgCFU/g、（8.42±0.87）lgCFU/g、（9.28±0.63）lgCFU/g］均高于对照组［（8.12±0.68）lgCFU/g、（7.18±0.71）lgCFU/g］，乳杆菌［（9.08±0.63）lgCFU/g、（8.60±0.48）lgCFU/g、（8.04±0.76）lgCFU/g］、双歧杆菌数目［（9.15±0.58）lgCFU/g、（8.54±0.61）lgCFU/g、（7.96±0.82）lgCFU/g］均低于对照组［（9.85±1.01）lgCFU/g、（9.97±0.96）lgCFU/g］，差异均有统计学意义（均P<0.05）。随Child-Pugh肝功能分级提高，肠杆菌、肠球菌数目呈上升趋势，乳杆菌、双歧杆菌数目呈下降趋势，差异均有统计学意义（均P<0.05）。A、B、C组D-LAC［（5.83±2.63）mg/L、（8.75±3.27）mg/L、（10.16±3.58）mg/L］、ETX［（10.53±4.36）U/L、（12.67±5.12）U/L、（23.08±9.37）U/L］、DAO水平［（34.06±10.36）U/L、（40.12±11.72）U/L、（43.07±14.20）U/L］均高于对照组［（3.92±2.27）mg/L、（3.72±2.51）U/L、（3.65±1.63）U/L］，差异均有统计学意义（均P<0.05）。B、C组D-LAC、DAO水平均高于A组（均P<0.05），但B、C组间比较差异均无统计学意义（均P>0.05）；C组ETX水平均高于A、B组（均P<0.05），但A、B组间比较差异无统计学意义（P>0.05）。经Pearson相关性分析显示，D-LAC与ETX、DAO呈正相关（r=0.595、0.489，均P<0.05）；ETX与DAO呈正相关（r=0.353，P<0.05）；经Spearman相关性分析显示，D-LAC、ETX、DAO与Child-Pugh肝功能分级呈正相关（r=0.468、0.470、0.236，均P<0.05）。经ROC分析显示，D-LAC预测Child-Pugh肝功能分级的诊断价值最高，曲线下面积（AUC）为0.772，最佳截断值为6.60 mg/L，灵敏度、特异度分别为78.69%、65.71%。结论　肝硬化患者因肠道菌群紊乱、肠黏膜通透性改变导致肠道微生态失调可使病情加重，不利于预后。通过无创、可靠且实用肠黏膜通透性指标监测有助于为肝硬化患者诊疗提供重要指导。

关键词:

肝硬化, , 肠黏膜通透性, 肝功能分级

Abstract:

Objective　To investigate the relationship between change of intestinal mucosal permeability and liver function classification in patients with liver cirrhosis. Methods　A total of 96 patients with liver cirrhosis who were treated in Clinical Laboratory, The Sixth People's Hospital of Zhengzhou from November 2020 to April 2022 were selected as an observation group, and were divided into three subgroups, group A, B, and C (35, 43, and 18 cases), according to the Child-Pugh liver function classification. During the same period, 40 healthy controls without liver cirrhosis were selected as a control group. Group A included 25 males and 10 females, aged (55.01±8.71) years; group B included 30 males and 13 females, aged (55.19±8.76) years; group C included 14 males and 4 females, aged (55.34±8.81) years; the control group included 27 males and 13 females, aged (54.52±8.56) years. The fecal sample was collected, the changes of main intestinal flora were determined by bacterial culture, and the intestinal mucosal permeability indexes [D-lactic acid (D-LAC), endotoxin (ETX), and diamine oxidase (DAO)] were determined. Pearson correlation analysis was used to analyze the correlations among intestinal mucosal permeability indexes, Spearman correlation analysis was used to analyze the correlations between intestinal mucosal permeability indexes and Child-Pugh liver function classification, and the receiver operating characteristic curve (ROC) was used to analyze the predictive values of intestinal mucosal permeability indexes. F test and independent-sample t test were used for the measurement data and χ² test was used for the count data. Results　The numbers of enterobacterium [(8.61±0.42) lgCFU/g, (8.95±0.39) lgCFU/g, and (9.22±0.56) lgCFU/g] and enterococcus [(7.75±0.46) lgCFU/g, (8.42±0.87) lgCFU/g, and (9.28±0.63) lgCFU/g] in group A, B, and C were all higher than those in the control group [(8.12±0.68) lgCFU/g and (7.18±0.71) lgCFU/g], and the numbers of Lactobacillus [(9.08±0.63) lgCFU/g, (8.60±0.48) lgCFU/g, and (8.04±0.76) lgCFU/g] and bifidobacterium [(9.15±0.58) lgCFU/g, (8.54±0.61) lgCFU/g, and (7.96±0.82) lgCFU/g] were lower than those in the control group [(9.85±1.01) lgCFU/g and (9.97±0.96) lgCFU/g], with statistically significant differences (all P<0.05). With the increase of Child-Pugh liver function classification, the numbers of enterobacterium and enterococcus showed an upward trend, while the numbers of Lactobacillus and bifidobacterium showed a downward trend, with statistically significant differences (all P<0.05). The levels of D-LAC [(5.83±2.63) mg/L, (8.75±3.27) mg/L, and (10.16±3.58) mg/L], ETX [(10.53±4.36) U/L, (12.67±5.12) U/L, and (23.08±9.37) U/L], and DAO [(34.06±10.36) U/L, (40.12±11.72) U/L, and (43.07±14.20) U/L] in group A, B, and C were higher than those in the control group [(3.92±2.27) mg/L, (3.72±2.51) U/L, and (3.65±1.63) U/L], with statistically significant differences (all P<0.05). The levels of D-LAC and DAO in group B and C were higher than those in group A (all P<0.05), but there were no statistically significant differences between group B and C (both P>0.05). The level of ETX in group C was higher than those in group A and B (both P<0.05), but there was no statistically significant difference between group A and B (P>0.05). Pearson correlation analysis showed that D-LAC was positively correlated with ETX and DAO (r=0.595 and 0.489; both P<0.05), and ETX was positively correlated with DAO (r=0.353, P<0.05). Spearman correlation analysis showed that D-LAC, ETX, and DAO were positively correlated with Child-Pugh liver function classification (r=0.468, 0.470, and 0.236; all P<0.05). ROC analysis showed that D-LAC had the highest diagnostic value in predicting Child-Pugh liver function classification, the area under the curve (AUC) was 0.772, the optimal cut-off value was 6.60 mg/L, and the sensitivity and specificity were 78.69% and 65.71%, respectively. Conclusions　The intestinal microecological imbalance caused by intestinal flora disturbance and intestinal mucosal permeability changes in patients with liver cirrhosis can aggravate the disease and is not conducive to the prognosis. Non-invasive, reliable, and practical monitoring on intestinal mucosal permeability indicators helps to provide important guidance for the diagnosis and treatment of patients with liver cirrhosis.

Key words:

Liver cirrhosis, Intestinal mucosal permeability, Liver function classification

王丽张瑞.

肝硬化患者肠黏膜通透性改变与肝功能分级的关系研究 [J]. 国际医药卫生导报, 2023, 29(1): 105-.

Wang Li, Zhang Rui.

Study on the relationship between change of intestinal mucosal permeability and liver function classification in patients with liver cirrhosis [J]. International Medicine and Health Guidance News, 2023, 29(1): 105-.

参考文献

[1] 张洪林,律正严,李海蓉. 滋阴活血汤恩替卡韦治疗代偿期乙型肝炎肝硬化的临床效果[J]. 国际医药卫生导报,2017,23(7):1065-1067. DOI:10.3760/cma.j.issn.1007-1245. 2017.07.046.
[2] Ginès P, Krag A, Abraldes JG, et al. Liver cirrhosis[J].Lancet,2021,398(10308):1359-1376. DOI:10.1016/S0140- 6736(21)01374-X.
[3] Lee NY, Suk KT. The role of the gut microbiome in liver cirrhosis treatment[J]. Int J Mol Sci,2020,22(1):199. DOI:10.3390/ijms22010199.
[4] Suk KT, Kim DJ. Gut microbiota: novel therapeutic target for nonalcoholic fatty liver disease[J]. Expert Rev Gastroenterol Hepatol,2019,13(3):193-204. DOI:10.1080/17474124.2019.1569513.
[5] GBD 2017 Cirrhosis Collaborators. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017[J]. Lancet Gastroenterol Hepatol,2020,5(3):245-266. DOI:10.1016/S2468-1253(19)30349-8.
[6] 张露,范志芳,刘殿武,等.1990－2016年中国乙型肝炎引起的肝硬化及其他慢性肝病疾病负担变化趋势分析[J].中华流行病学杂志,2020,41(2):173-177. DOI:10.3760/cma.j.issn.0254-6450.2020.02.007.
[7] Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: pathophysiological basis for therapy[J]. J Hepatol,2020,72(3):558-577. DOI:10.1016/j.jhep.2019. 10.003.
[8] Huang W, Kong D. The intestinal microbiota as a therapeutic target in the treatment of NAFLD and ALD[J]. Biomed Pharmacother,2021,135:111235. DOI:10.1016/j.biopha.2021.111235.
[9] Hu H, Lin A, Kong M, et al. Intestinal microbiome and NAFLD: molecular insights and therapeutic perspectives[J]. J Gastroenterol,2020,55(2):142-158. DOI:10.1007/s00535-019-01649-8.
[10] Chen J, Vitetta L. Gut microbiota metabolites in NAFLD pathogenesis and therapeutic implications[J]. Int J Mol Sci,2020,21(15):5214. DOI:10.3390/ijms21155214.
[11] 唐源淋,陈烨. 肠道菌群失衡与肝硬化分级及预后的关系[J]. 现代消化及介入诊疗,2019,24(1):11-15. DOI:10.3969/j.issn.1672-2159.2019.01.004.
[12] 唐源淋,陈烨. 定量分析肠道菌群失衡与肝硬化病情的关系[J]. 胃肠病学,2020,25(4):199-203. DOI:10.3969/j.issn.1008-7125.2020.04.002.
[13] 中华医学会肝病学分会. 肝硬化诊治指南[J]. 临床肝胆病杂志,2019,35(11):2408-2425. DOI:10.3969/j.issn.1001- 5256.2019.11.006.
[14] Aron-Wisnewsky J, Warmbrunn MV, Nieuwdorp M, et al. Nonalcoholic fatty liver disease: modulating gut microbiota to improve severity?[J]. Gastroenterology,2020,158(7):1881-1898. DOI:10.1053/j.gastro.2020. 01.049.
[15] Chen J, Thomsen M, Vitetta L. Interaction of gut microbiota with dysregulation of bile acids in the pathogenesis of nonalcoholic fatty liver disease and potential therapeutic implications of probiotics[J]. J Cell Biochem,2019,120(3):2713-2720. DOI:10.1002/jcb. 27635.
[16] Safari Z, Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD)[J]. Cell Mol Life Sci,2019,76(8):1541-1558. DOI:10.1007/s00018- 019-03011-w.
[17] Philips CA, Augustine P. Gut barrier and microbiota in cirrhosis[J]. J Clin Exp Hepatol,2022,12(2):625-638. DOI:10.1016/j.jceh.2021.08.027.
[18] 魏凯艳,黄胡萍,林爱萍,等. 肝硬化患者肠道菌群的初步分析及肠型分析[J]. 胃肠病学和肝病学杂志,2022,31(2):158-164. DOI:10.3969/j.issn.1006-5709.2022.02.008.
[19] 李玉珍,孙元培,廉晓晓,等. 不同病因肝硬化患者肠道菌群变化研究[J]. 中西医结合肝病杂志,2022,32(4):306-310. DOI:10.3969/j.issn.1005-0264.2022.04.006.
[20] 张雯,彭琼. 乙肝肝硬化患者肠道菌群与肝功能及血清炎症因子水平的关系[J]. 现代消化及介入诊疗,2020,25(2):158-162. DOI:10.3969/j.issn.1672-2159.2020.02.006.
[21] Dubinkina VB, Tyakht AV, Odintsova VY, et al. Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease[J]. Microbiome,2017,5(1):141. DOI:10.1186/s40168-017-0359-2.
[22] 张红霞,蔡王锋,李燕妮,等. 肠屏障在自身免疫性肝炎发病中的作用[J]. 中华消化杂志,2020,40(1):9-15. DOI:10.3760/cma.j.issn.0254-1432.2020.01.003.
[23] 陈瑶,向正国,李科军,等. 肝硬化患者肝功能分级与其肠道微生态的相关性研究[J]. 广西医科大学学报,2017,34(7):1006-1009. DOI:10.16190/j.cnki.45-1211/r.2017.07.014.
[24] 戚励,裴冬梅,杨惠,等. 恩替卡韦联合美常安对乙型肝炎肝硬化患者肠道菌群及肠黏膜通透性的影响[J]. 实用临床医药杂志,2020,24(6):61-65. DOI:10.7619/jcmp.202006017.
[25] 廉晓晓,孙元培,郭晓霞. 肝硬化患者肠道黏膜通透性与预后的相关性研究[J]. 中华肝脏病杂志,2020,28(1):58-63. DOI:10.3760/cma.j.issn.1007-3418.2020.01.014.