幽门螺杆菌感染对非酒精性脂肪性肝病及其相关结直肠息肉的影响研究

doi:10.12114/j.issn.1007-9572.2021.00.549

摘要/Abstract

摘要： 背景　目前，非酒精性脂肪性肝病（NAFLD）已成为全球最常见的慢性肝病，有研究表明幽门螺杆菌（H.pylori）感染与NAFLD的发生发展相关，但尚存争议。目的　探讨H.pylori感染对NAFLD及其相关结直肠息肉的影响。方法　选取2018年12月至2020年5月在昆明医科大学第二附属医院经腹部B超检查诊断为NAFLD的118例患者为研究对象，根据是否感染H.pylori将其分为NAFLD合并H.pylori感染组及NAFLD不合并H.pylori感染组。收集两组患者人口学资料、肝纤维化和脂肪肝检测、结肠镜检查、血液生化检测结果。根据FibroTouch检测结果分别将NAFLD患者的脂肪衰减程度和肝脏硬度分为轻、中、重度。结果　118例NAFLD患者中H.pylori阳性62例（NAFLD合并H.pylori感染组），H.pylori阴性56例（NAFLD不合并H.pylori感染组）。NAFLD合并H.pylori感染组体质指数（BMI）、受控衰减参数（CAP）、E值、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、谷氨酰转肽酶（GGT）、总胆红素（TBiL）、直接胆红素（DBiL）、总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白（LDL）、三酰甘油葡萄糖指数（TyG）、白细胞计数（WBC）、中性粒细胞计数/淋巴细胞计数（NLR）、降钙素原（PCT）、白介素6（IL-6）、C反应蛋白（CRP）、NAFLD纤维化评分（NFS评分）、AST和血小板计数比率指数（APRI）高于NAFLD不合并H.pylori感染组（P<0.05）。NAFLD合并H.pylori感染组脂肪衰减程度、肝脏硬度差于NAFLD不合并H.pylori感染组（P<0.05）。118例NAFLD患者中75例（NAFLD合并H.pylori感染组37例，NAFLD不合并H.pylori感染组38例）行结肠镜检查，结果示存在结直肠息肉者51例，其中NAFLD合并H.pylori阳性组26例。NAFLD合并H.pylori感染组中多个息肉、息肉直径≥1 cm发生率高于NAFLD不合并H.pylori感染组（P<0.05）。75例行结肠镜检查患者中共41例进行病理检查。NAFLD合并H.pylori感染组中腺瘤性息肉发生率、上皮内瘤变发生率高于NAFLD不合并H.pylori感染组（P<0.05）。多因素Logistic回归分析结果显示，H.pylori阳性是NAFLD患者结直肠息肉数量〔OR=7.547，95%CI（1.467，38.827）〕、息肉病理〔OR=8.500，95%CI（1.574，45.916）〕、上皮内瘤变〔OR=4.571，95%CI（1.218，17.157）〕的影响因素（P<0.05）。结论　H.pylori感染可加重NAFLD患者肥胖、高血压、糖尿病、肝功能障碍、血脂紊乱、炎性反应、肝纤维化程度、脂肪衰减程度，此外，H.pylori感染还是NAFLD患者结直肠息肉数量、息肉病理、上皮内瘤变的影响因素。

关键词: 非酒精性脂肪性肝病, 幽门螺杆菌, 肠息肉, 影响因素分析

Abstract: Background　Non-alcoholic fatty liver disease （NAFLD） has become the most common chronic liver disease worldwide now. Studies have shown that Helicobacter pylori （H.pylori） infection is related to the development of NAFLD，but there is still controversy. Objective　To examine the association of H.pylori infection with NAFLD and related colorectal polyps. Methods　One hundred and eighteen patients diagnosed as NAFLD by transabdominal ultrasound were selected from the Second Affiliated Hospital of Kunming Medical University from December 2018 to May 2020，and were divided into NAFLD with and without H.pylori groups by H.pylori infection prevalence. Demographic data，results of liver fibrosis，fatty liver disease and biochemical tests，as well as colposcopy were collected. The severity of liver steatosis and liver stiffness measured by the FibroTouch test was divided into mild，moderate and severe. Results　Compared to NAFLD patients without H.pylori infection（n=56），those with H.pylori infection（n=62） had higher mean levels of BMI，CAP，E score，ALT，AST，GGT，TBiL，DBiL，TC，TG，LDL，TyG，WBC，NLR，PCT，IL-6，and CRP，and higher mean NFS score and APRI，as well as higher severity of liver steatosis and liver stiffness （P<0.05）.Fifty-one of the 75 cases（37 with H.pylori infection and 38 without ） undergoing colonoscopy were found with colorectal polyps，of whom 26 were H.pylori positive.Those with H.pylori infection had higher prevalence of multiple colorectal polyps or colorectal polyps with a diameter of ≥1 cm than those without （P<0.05）. A total of 41 out of 75 patients undergoing colonoscopy underwent pathological examination of polyps，and the results revealed that those with H.pylori infection had higher prevalence of adenomatous polyps and colorectal intraepithelial neoplasia than those without（P<0.05）. Multivariate logistic regression analysis showed that H.pylori infection was associated with the number of colorectal polyps〔OR=7.547，95%CI（1.467，38.827）〕，colorectal polyps pathology〔OR=8.500，95%CI（1.574，45.916）〕，and colorectal intraepithelial neoplasia〔OR=4.571，95%CI（1.218，17.157）〕in NAFLD patients （P<0.05）. Conclusion　H.pylori infection may increase BMI，and aggravate hypertension，diabetes，liver dysfunction，dyslipidemia，inflammatory response，liver fibrosis，and liver steatosis in NAFLD patients.In addition，it may be associated with the number of colorectal polyps，pathology of colorectal polyps，and colorectal intraepithelial neoplasia.

Key words: Non-alcoholic fatty liver disease, Helicobacter pylori, Intestinal polyps, Root cause analysis

杨秋瑾,郑杰,杨婧,等. 幽门螺杆菌感染对非酒精性脂肪性肝病及其相关结直肠息肉的影响研究[J]. 中国全科医学, 2021, 24(30): 3855-3862. DOI: 10.12114/j.issn.1007-9572.2021.00.549.
YANG Qiujin,ZHENG Jie,YANG Jing, et al. Association of Helicobacter Pylori Infection with Non-alcoholic Fatty Liver Disease and Related Colorectal Polyps　[J]. Chinese General Practice, 2021, 24(30): 3855-3862. DOI: 10.12114/j.issn.1007-9572.2021.00.549.

参考文献

［1］YOUNOSSI Z M，KOENIG A B，ABDELATIF D，et al. Global epidemiology of nonalcoholic fatty liver disease——Meta-analytic assessment of prevalence，incidence，and outcomes［J］．Hepatology，2016，64（1）：73-84．DOI：10.1002/hep.28431.
［2］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.
［3］POLYZOS S A，KOUNTOURAS J.Novel advances in the association between Helicobacter pylori infection，metabolic syndrome，and related morbidity［J］．Helicobacter，2015，20（6）：405-409．DOI：10.1111/hel.12228.
［4］FAN N，PENG L，XIA Z，et al. Helicobacter pylori infection is not associated with non-alcoholic fatty liver disease：a cross-sectional study in China［J］．Front Microbiol，2018，9：73．DOI：10.3389/fmicb.2018.00073.
［5］OKUSHIN K，TAKAHASHI Y，YAMAMICHI N，et al. Helicobacter pylori infection is not associated with fatty liver disease including non-alcoholic fatty liver disease：a large-scale cross-sectional study in Japan［J］．BMC Gastroenterol，2015，15：25．DOI：10.1186/s12876-015-0247-9.
［6］TESTERMAN T L，MORRIS J.Beyond the stomach：an updated view of Helicobacter pylori pathogenesis，diagnosis，and treatment［J］．World J Gastroenterol，2014，20（36）：12781-12808．DOI：10.3748/wjg.v20.i36.12781.
［7］中华医学会肝脏病学分会脂肪肝和酒精性肝病学组.非酒精性脂肪性肝病诊疗指南［J］．中国肝脏病杂志：电子版，2010，2（4）：43-48.
［8］CHALASANI N，YOUNOSSI Z，LAVINE J E，et al. The diagnosis and management of non-alcoholic fatty liver disease：practice guideline by the American Gastroenterological Association，American Association for the Study of Liver Diseases，and American College of Gastroenterology［J］．Gastroenterology，2012，142（7）：1592-1609．DOI：10.1053/j.gastro.2012.04.001.
［9］SáNCHEZ-GARCíA A，RODRíGUEZ-GUTIéRREZ R，MANCILLAS-ADAME L，et al. Diagnostic accuracy of the triglyceride and glucose index for insulin resistance：a systematic review［J］．Int J Endocrinol，2020，2020：4678526．DOI：10.1155/2020/4678526.
［10］ANGULO P，HUI JM，MARCHESINI G，et al. The NAFLD fibrosis score：a noninvasive system that identifies liver fibrosis in patients with NAFLD［J］．Hepatology，2007，45（4）：846-854．DOI：10.1002/hep.21496.
［11］WAI C T，GREENSON J K，FONTANA R J，et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C［J］．Hepatology，2003，38（2）：518-526．DOI：10.1053/jhep.2003.50346.
［12］PENG Y，LI Y，HE Y，et al. The role of neutrophil to lymphocyte ratio for the assessment of liver fibrosis and cirrhosis：a systematic review［J］．Expert Rev Gastroenterol Hepatol，2018，12（5）：503-513．DOI：10.1080/17474124.2018.1463158.
［13］CHEN C，ZHANG C，WANG X，et al. Helicobacter pylori infection may increase the severity of nonalcoholic fatty liver disease via promoting liver function damage，glycometabolism，lipid metabolism，inflammatory reaction and metabolic syndrome［J］．Eur J Gastroenterol Hepatol，2020，32（7）：857-866．DOI：10.1097/meg.0000000000001601.
［14］ABDEL-RAZIK A，MOUSA N，SHABANA W，et al. Helicobacter pylori and non-alcoholic fatty liver disease：a new enigma?［J］．Helicobacter，2018，23（6）：e12537．DOI：10.1111/hel.12537.
［15］MAHARSHI V，GUPTA P，KUMAR V L，et al. Effect of Helicobacter pylori-eradication therapy on hepatic steatosis in patients with non-alcoholic fatty liver disease：a randomized-controlled pilot study［J］．Gastroenterol Rep：Oxf，2020，8（2）：104-110．DOI：10.1093/gastro/goz058.
［16］POLYZOS S A，NIKOLOPOULOS P，STOGIANNI A，et al. Effect of Helicobacter pylori eradication on hepatic steatosis，NAFLD fibrosis score and HSENSI in patients with nonalcoholic steatohepatitis：a MR imaging-based pilot open-label study［J］．Arq Gastroenterol，2014，51（3）：261-268．DOI：10.1590/s0004-28032014000300017.
［17］BAEG M K，YOON S K，KO S H，et al. Helicobacter pylori infection is not associated with nonalcoholic fatty liver disease［J］．World J Gastroenterol，2016，22（8）：2592-2600．DOI：10.3748/wjg.v22.i8.2592.
［18］ANGULO P，KLEINER D E，DAM-LARSEN S，et al. Liver fibrosis，but no other histologic features，is associated with long-term outcomes of patients with nonalcoholic fatty liver disease［J］．Gastroenterology，2015，149（2）：389-397.e10．DOI：10.1053/j.gastro.2015.04.043.
［19］EKSTEDT M，HAGSTR?M H，NASR P，et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up［J］．Hepatology，2015，61（5）：1547-1554．DOI：10.1002/hep.27368.
［20］CHO Y，LIM S K，JOO S K，et al. Nonalcoholic steatohepatitis is associated with a higher risk of advanced colorectal neoplasm［J］．Liver Int，2019，39（9）：1722-1731．DOI：10.1111/liv.14163.
［21］BLACKETT J W，VERNA E C，LEBWOHL B.Increased prevalence of colorectal adenomas in patients with nonalcoholic fatty liver disease：a cross-sectional study［J］．Dig Dis，2020，38（3）：222-230．DOI：10.1159/000502684.
［22］AHN J S，SINN D H，SON H J，et al. Letter：Helicobacter pylori-related non-alcoholic fatty liver disease with concomitant metabolic syndrome as risk factor for colorectal neoplasia-authors' reply［J］．Aliment Pharmacol Ther，2017，45（4）：577-578．DOI：10.1111/apt.13911.
［23］KOUNTOURAS J，PAPAEFTHYMIOU A，DOULBERIS M，et al.
Influence of Helicobacter pylori-connected metabolic syndrome on non-alcoholic fatty liver disease and its related colorectal neoplasm high risk［J］．Liver Int，2020，40（2）：475-476．DOI：10.1111/liv.14264.
［24］WANG M，KONG W J，ZHANG J Z，et al. Association of Helicobacter pylori infection with colorectal polyps and malignancy in China［J］．World J Gastrointest Oncol，2020，12（5）：582-591．DOI：10.4251/wjgo.v12.i5.582.
［25］KAPETANAKIS N，KOUNTOURAS J，ZAVOS C，et al. Helicobacter pylori infection and colorectal carcinoma：pathologic aspects［J］．J Gastrointest Oncol，2012，3（4）：377-379．DOI：10.3978/j.issn.2078-6891.2012.041.
［26］POLYZOS S A，KOUNTOURAS J，PAPATHEODOROU A，et al. Helicobacter pylori infection in patients with nonalcoholic fatty liver disease［J］．Metabolism，2013，62（1）：121-126．DOI：10.1016/j.metabol.2012.06.007.
［27］ZELJKOVIC A，MIHAJLOVIC M，STEFANOVIC A，et al. Potential use of serum insulin-like growth factor 1 and E-cadherin as biomarkers of colorectal cancer［J］．Colorectal Dis，2020．DOI：10.1111/codi.15360.Epub ahead of print.
［28］LU C C，CHU P Y，HSIA S M，et al. Insulin induction instigates cell proliferation and metastasis in human colorectal cancer cells［J］．Int J Oncol，2017，50（2）：736-744．DOI：10.3892/ijo.2017.3844.
［29］ANDO T，ISHIKAWA T，TAKAGI T，et al. Impact of Helicobacter pylori eradication on circulating adiponectin in humans［J］．Helicobacter，2013，18（2）：158-164．DOI：10.1111/hel.12028.
［30］YAMAJI T，IWASAKI M，SASAZUKI S，et al. Interaction between adiponectin and leptin influences the risk of colorectal adenoma［J］．Cancer Res，2010，70（13）：5430-5437．DOI：10.1158/0008-5472.can-10-0178.
［31］JIANG W，WU N，WANG X，et al. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease［J］．Sci Rep，2015，5：8096．DOI：10.1038/srep08096.
［32］SI H，YANG Q，HU H，et al. Colorectal cancer occurrence and treatment based on changes in intestinal flora［J］．Semin Cancer Biol，2021，70：3-10．DOI：10.1016/j.semcancer.2020.05.004.
［33］CASTA?O-RODRíGUEZ N，MITCHELL H M，KAAKOUSH N O.NAFLD，Helicobacter species and the intestinal microbiome［J］．Best Pract Res Clin Gastroenterol，2017，31（6）：657-668．DOI：10.1016/j.bpg.2017.09.008.
［34］CHEN Y M，LIU Y，ZHOU R F，et al. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide，betaine and choline with non-alcoholic fatty liver disease in adults［J］．Sci Rep，2016，6：19076．DOI：10.1038/srep19076.
［35］NICOLETTI A，PONZIANI F R，BIOLATO M，et al. Intestinal permeability in the pathogenesis of liver damage：from non-alcoholic fatty liver disease to liver transplantation［J］．World J Gastroenterol，2019，25（33）：4814-4834．DOI：10.3748/wjg.v25.i33.4814.
［36］BERTAUX-SKEIRIK N，FENG R，SCHUMACHER M A，et al. CD44 plays a functional role in Helicobacter pylori-induced epithelial cell proliferation［J］．PLoS Pathog，2015，11（2）：e1004663．DOI：10.1371/journal.ppat.1004663.
［37］PATOURAUX S，ROUSSEAU D，BONNAFOUS S，et al. CD44 is a key player in non-alcoholic steatohepatitis［J］．J Hepatol，2017，67（2）：328-338．DOI：10.1016/j.jhep.2017.03.003.
［38］ZHANG R，QI F，SHAO S，et al. Human colorectal cancer-derived carcinoma associated fibroblasts promote CD44-mediated adhesion of colorectal cancer cells to endothelial cells by secretion of HGF［J］．Cancer Cell Int，2019，19：192．DOI：10.1186/s12935-019-0914-y.

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