益生菌在食管胃静脉曲张破裂出血初级预防中的作用

张群; 牛帅帅; 王宪波

doi:10.3969/j.issn.1001-5256.2021.02.017

益生菌在食管胃静脉曲张破裂出血初级预防中的作用

DOI: 10.3969/j.issn.1001-5256.2021.02.017

首都医科大学附属北京地坛医院中西医结合中心，北京 100015

基金项目:

北京市科学技术委员会资助 (Z191100006619033);

首都卫生发展科研专项 (首发2018-1-2172);

国家中医药管理局区域中医(肝病)诊疗中心建设项目 (2019-3-18);

国家中医药管理局重大疑难疾病中西医临床协作试点项目 (2018-6-4)

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突，特此声明。

作者贡献声明：王宪波负责课题设计；张群、牛帅帅参与数据收集，数据分析；张群负责论文撰写及修改；王宪波负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

作者简介:
张群(1991—)，女，主要从事中西医结合肝病方面的研究

通信作者:
王宪波，wangxianbo638@163.com

中图分类号: R575.2
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出版历程
- 收稿日期: 2020-08-10
- 录用日期: 2020-09-01
- 出版日期: 2021-02-20

Role of probiotics in primary prevention of esophagogastric variceal bleeding

Department of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China

摘要

摘要: 目的探讨益生菌对肝硬化食管胃静脉曲张患者1年内出血风险的影响。方法选取2008年2月—2017年2月于首都医科大学附属北京地坛医院住院且随访时间超过1年的肝硬化食管胃静脉曲张患者692例，其中346例患者在1年的随访期内接受了益生菌治疗(益生菌组)队列，随后采用1:1倾向评分的方法通过校正Child-Pugh分级、静脉曲张分度、红色征为其匹配346例未接受益生菌治疗的患者(非益生菌组)。所有入选患者均按照指南推荐的初级预防策略进行管理，而益生菌队列则在此基础上辅助了益生菌治疗，观察两个队列1年内静脉曲张出血发生率的差异。计量资料两组间比较采用t检验或Mann-Whitney U检验；计数资料两组间比较采用χ²检验；食管胃静脉曲张破裂出血影响因素的筛选采用向后的Cox单因素和多因素回归分析；Kaplan-Meier对两个队列EVB的累积发生率进行分析，并用log-rank进行比较。结果益生菌治疗是肝硬化食管胃静脉曲张破裂出血的独立保护因子(校正危险比=0.510，95%CI：0.299~0.870，P=0.013)。共61例患者在1年的随访期内发生了EVB事件，其中益生菌组23例，非益生菌组38例, 益生菌组1年内EVB的累积发生率明显低于非益生菌组(6.6% vs 11.0%，χ²=4.045，P=0.042)，且益生菌组基线时至发生出血的中位时间晚于非益生菌组[137.0(85.0~258.0)d vs 123.0(72.5~206.5)d, Z=-1.101, P=0.271]。结论益生菌能有效降低肝硬化食管胃静脉曲张患者1年内出血事件的发生率，并有延缓出血事件发生时间的趋势。
- 肝硬化 /
- 食管和胃静脉曲张 /
- 乳杆菌属
Abstract: Objective To investigate the effect of probiotics on the risk of esophagogastric variceal bleeding (EVB) within 1 year in cirrhotic patients with gastroesophageal varices. Methods A retrospective analysis was performed for the clinical data of 692 cirrhotic patients with gastroesophageal varices who were hospitalized in Beijing Ditan Hospital, Capital Medical University, from February 2008 to February 2017 and were followed up for more than 1 year. Among these patients, 346 patients who received probiotics during the 1-year follow-up were enrolled as probiotics cohort (probiotics group), and then, by using the 1:1 propensity score method, 346 patients who did not receive probiotics treatment were enrolled as non-probiotics group after adjustment for Child-Pugh class, degree of varices, and red color sign. All patients were managed according to the primary prevention strategy recommended by related guidelines, and in addition, the patients in the probiotics group were given probiotic therapy. The incidence rate of EVB within 1 year was compared between the two groups. The t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. Univariate and multivariate backward Cox regression analyses were used to screen out the influencing factors for EVB. The Kaplan-Meier analysis was used to investigate the cumulative incidence rate of EVB in both groups, and the log-rank test was used for comparison. Results Probiotic therapy was an independent protective factor against EVB in cirrhotic patients (adjusted hazard ratio=0.510, 95% confidence interval: 0.299-0.870, P=0.013). A total of 61 patients experienced EVB during the 1-year follow-up, with 23 patients in the probiotics group and 38 in the non-probiotics group, and the probiotics group had a significantly lower cumulative incidence rate of EVB within 1 year than the non-probiotics group (6.6% vs 11.0%, χ²=4.045, P=0.042). The probiotics group had a significantly longer median time from baseline to the occurrence of EVB than the non-probiotics group [137.0 (85.0-258.0) days vs 123.0(72.5-206.5) days, Z=-1.101, P=0.271]. Conclusion Probiotics can effectively reduce the incidence rate of EVB within 1 year in cirrhotic patients with gastroesophageal varices, with a tendency to delay the occurrence of bleeding events.
- Liver Cirrhosis /
- Esophageal and Gastric Varices /
- Lactobacillus

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图 1 两组1年EVB累积发生率Kaplan-Meier分析曲线

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图 2 两组患者出血时间间隔小提琴图

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表 1 两组患者基线特征比较

项目	所有患者 (n=692)	益生菌组 (n=346)	非益生菌组 (n=346)	统计值¹⁾	P值¹⁾
年龄(岁)	52.0 (44.0~60.0)	52.0 (44.0~60.0)	52.0 (45.0~59.0)	Z=-0.137	0.891
男/女(例)	477/215	240/106	237/109	χ²=0.061	0.805
病因(HBV/HCV/ALD/其他，例)	476/62/79/75	236/29/43/38	240/33/36/37	χ²=0.925	0.819
腹水(有/无，例)	406/286	205/141	201/145	χ²=0.095	0.757
细菌感染(有/无，例)	141/551	74/272	67/279	χ²=0.436	0.509
肝性脑病(有/无，例)	30/662	19/327	11/335	χ²=2.230	0.135
静脉曲张位置(食管/胃/同时，例)	382/25/285	191/11/144	191/14/141	χ²=0.392	0.822
静脉曲张分度(轻/中/重，例)	324/180/188	164/87/95	160/93/93	χ²=0.271	0.873
红色征(有/无，例)	228/464	109/237	119/227	χ²=0.654	0.419
ALT(U/L)	36.6 (24.4~63.6)	36.2 (25.0~62.0)	37.7 (24.1~66.7)	Z=-0.663	0.508
AST(U/L)	49.8 (33.1~82.9)	48.7 (32.1~77.0)	51.2 (34.0~90.7)	Z=-1.194	0.232
GGT(U/L)	53.3 (29.0~111.2)	52.4 (28.8~109.4)	54.0 (30.3~113.1)	Z=-0.376	0.707
TBil(μmol/L)	29.3 (18.8~46.6)	27.6 (17.4~44.8)	30.1 (19.7~49.8)	Z=-2.154	0.031
Alb(g/L)	31.9 (27.7~37.0)	32.0 (27.8~36.7)	31.8 (27.7~37.3)	Z=-0.123	0.902
WBC(×10⁹/L)	3.3 (2.6~4.5)	3.3 (2.6~4.4)	3.3 (2.5~4.6)	Z=-0.435	0.664
RBC(×10¹²/L)	3.7±0.7	3.7±0.7	3.7±0.7	t=0.236	0.813
NLR	1.9 (1.3~2.8)	1.8 (1.3~2.8)	1.9 (1.3~2.7)	Z=-0.421	0.673
Hb(g/L)	120.2 (106.4~133.6)	119.0 (105.8~133.3)	121.0 (108.0~133.7)	Z=-1.069	0.285
HCT(%)	35.1 (31.2~39.1)	34.9 (31.2~39.5)	35.5 (31.3~38.9)	Z=-0.666	0.505
PLT(×10⁹/L)	61.5 (44.0~85.0)	61.7 (45.0~88.1)	61.5 (43.3~82.9)	Z=-0.405	0.685
Cr(μmol/L)	64.0 (55.0~73.7)	64.0 (56.0~74.3)	63.6 (55.0~72.6)	Z=-1.467	0.142
Glu(mmol/L)	5.5 (4.9~6.8)	5.5 (4.9~6.8)	5.5 (4.9~7.0)	Z=-0.402	0.688
PTA(%)	66.0 (54.5~78.0)	67.0 (55.0~79.0)	64.7 (54.0~77.0)	Z=-1.213	0.225
INR	1.1 (1.1~1.4)	1.2 (1.1~1.3)	1.2 (1.1~1.4)	Z=-0.098	0.922
脾脏厚度(mm)	48.0 (42.0~55.8)	48.0 (42.0~56.0)	48.0 (42.0~55.3)	Z=-0.134	0.894
门静脉宽度(mm)	12.0 (11.0~13.0)	12.0 (11.0~13.0)	12.0 (11.0~13.0)	Z=-1.005	0.316
Child-Pugh分级(A/B/C，例)	214/345/133	105/175/66	109/170/67	χ²=0.155	0.926
初级预防
NSBB(有/无，例)	19/673	11/335	8/338	χ²=0.487	0.485
EVL(有/无，例)	86/606	45/301	41/305	χ²=0.212	0.645
注：1)益生菌组与非益生菌组进行比较。ALD，酒精性肝病；NLR，中性粒细胞淋巴细胞比值；Hb，血红蛋白；HCT，红细胞压积；Cr，肌酐；Glu，葡萄糖。

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表 2 EVB影响因素Cox回归分析

因素	单因素分析		多因素分析
因素	aHR(95%CI)	P值	aHR(95%CI)	P值
性别(女性=0;男性=1)	1.890(1.005~3.553)	0.048
病因(HBV=1;HCV=2;ALD=3;其他=4)	0.302(0.151~0.603)	0.001	0.357 (0.183~0.695)	0.002
腹水(无=0;有=1)	2.192(1.224~3.926)	0.008
静脉曲张位置(食管=1;胃=2;食管和胃=3)	1.581(1.211~2.065)	0.001
静脉曲张分度(轻度=1;中度=2;重度=3)	2.111(1.547~2.879)	＜0.001
红色征(无=0;有=1)	4.832(2.810~8.308)	＜0.001	3.997(2.260~7.071)	＜0.001
GGT	1.001(1.000~1.002)	0.013	1.001(1.001~1.002)	＜0.001
Alb	0.958(0.918~1.000)	0.049
RBC	0.628(0.446~0.883)	0.007
NLR	1.092(1.029~1.159)	0.003
Hb	0.984(0.975~0.993)	0.001	0.984(0.974~0.994)	0.001
HCT	0.950(0.919~0.981)	0.002
脾脏厚度	1.044(1.023~1.066)	＜0.001	1.034(1.011~1.058)	0.004
益生菌治疗(无=0;有=1)	0.587(0.350~0.986)	0.044	0.510(0.299~0.870)	0.013

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