幽门螺杆菌感染联合传统危险因素预测代谢相关脂肪性肝病发生风险的价值分析
DOI: 10.3969/j.issn.1001-5256.2023.06.011
Value of Helicobacter pylori infection combined with traditional risk factors in predicting the risk of metabolic associated fatty liver disease
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摘要:
目的 研究幽门螺杆菌(HP)感染与新命名的“代谢相关脂肪性肝病(MAFLD)”之间的关系,并分析HP感染与传统危险因素对MAFLD的联合作用。 方法 对内蒙古民族大学附属医院2017年1月—2021年12月收治的350例接受碳13尿素呼气试验住院患者进行回顾性分析。按腹部超声是否确诊脂肪肝将其分为MAFLD组(n=190)和非脂肪肝组(n=160)。正态分布计量资料两组间比较采用成组t检验;非正态分布计量资料两组间比较采用Mann-Whitney U秩和检验;计数资料组间比较采用χ2检验。MAFLD的危险因素分析采用二元Logistic回归分析。 结果 与非脂肪肝组相比,MAFLD组受试者的BMI(t=8.73)、收缩压(Z=-3.67)、舒张压(Z=-3.62)、TG(Z=-8.93)、空腹血糖(Z=-9.13)、AST(Z=-2.03)、GGT(Z=-8.56)水平,以及男性(χ2=12.09)、高血压(χ2=37.91)、糖尿病(χ2=73.62)、超重/肥胖(χ2=42.82)、高甘油三酯血症(χ2=59.12)、HP感染(χ2=4.53)比例均较高,HDL-C(Z=-6.81)水平较低(P值均<0.05)。Logistic回归结果显示,空腹血糖(OR=1.255,95%CI: 1.091~1.445)、HP感染(OR=1.899,95%CI: 1.048~3.440)、高血压(OR=2.589, 95%CI: 1.468~4.567)、糖尿病(OR=2.202,95%CI: 1.123~4.315)、超重/肥胖(OR=4.571,95%CI: 2.308~9.052)、高甘油三酯血症(OR=4.187,95%CI: 2.411~7.271)是MAFLD发生的危险因素(P值均<0.05)。Logistic回归分析结果显示,联合作用后HP感染提高了糖尿病、超重/肥胖、高甘油三酯血症、高血压受试者的MAFLD发病风险(OR分别为12.267、14.005、7.911、7.364,P值均<0.05)。 结论 HP感染与MAFLD的发病风险增高有关,与传统危险因素的联合可能进一步增加MAFLD的发病风险。 Abstract:Objective To investigate the association between Helicobacter pylori (HP) infection and newly named "metabolic associated fatty liver disease (MAFLD)" and the value of HP infection combined with traditional risk factors in predicting MAFLD. Methods A retrospective analysis was performed for the clinical data of 350 patients who were admitted to Affiliated Hospital of Inner Mongolia University for the Nationalities and underwent carbon-13 urea breath test from January 2017 to December 2021, and according to whether fatty liver disease was diagnosed by abdominal ultrasound, they were divided into MAFLD group with 190 patients and non-fatty liver disease group with 160 patients. The independent-samples t test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U rank sum test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. The binary Logistic regression analysis was used to investigate the risk factors for MAFLD. Results Compared with the non-fatty liver disease group, the MAFLD group had significantly higher body mass index (t=8.73, P < 0.05), systolic blood pressure (Z=-3.67, P < 0.05), diastolic blood pressure (Z=-3.62, P < 0.05), triglyceride (Z=-8.93, P < 0.05), fasting blood glucose (Z=-9.13, P < 0.05), aspartate aminotransferase (Z=-2.03, P < 0.05), gamma-glutamyl transpeptidase (Z=-8.56, P < 0.05), proportion of male patients (χ2=12.09, P < 0.05), and proportion of patients with hypertension (χ2=37.91, P < 0.05), diabetes (χ2=73.62, P < 0.05), overweight/obesity (χ2=42.82, P < 0.05), hypertriglyceridemia (χ2=59.12, P < 0.05), or HP infection (χ2=4.53, P < 0.05), as well as a significantly lower level of high-density lipoprotein cholesterol (Z=-6.81, P < 0.05). The Logistic regression analysis showed that fasting blood glucose (odds ratio [OR]=1.255, 95% confidence interval [CI]: 1.091-1.445, P < 0.05), HP infection (OR=1.899, 95%CI: 1.048-3.440, P < 0.05), hypertension (OR=2.589, 95%CI: 1.468-4.567, P < 0.05), diabetes (OR=2.202, 95%CI: 1.123-4.315, P < 0.05), overweight/obesity (OR=4.571, 95%CI: 2.308-9.052, P < 0.05), and hypertriglyceridemia (OR=4.187, 95%CI: 2.411-7.271, P < 0.05) were risk factors for MAFLD, and it also showed that HP infection combined with traditional risk factors significantly increased the risk of MAFLD in subjects with diabetes, overweight/obesity, hypertriglyceridemia, and hypertension (OR=12.267, 14.005, 7.911, and 7.364, all P < 0.05). Conclusion HP infection is associated with an increased risk of MAFLD, and its combination with traditional risk factors may further increase the risk of MAFLD. -
Key words:
- Helicobacter Pylori /
- Non-alcoholic Fatty Liver Disease /
- Risk Factors
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非酒精性脂肪性肝病(NAFLD)是一种常见的慢性肝病,包括非酒精性脂肪肝、非酒精性脂肪性肝炎(NASH)及其相关肝纤维化和肝硬化[1],部分患者甚至进展为肝癌,现在被称为代谢相关脂肪性肝病(metabolic associated fatty liver disease,MAFLD)[2-3],随着肥胖发病率逐年增高和低龄化趋势,NAFLD成为儿童慢性肝病的常见原因[4],肝硬化的三大主要原因之一。目前MAFLD的发病机制仍不清楚,临床上亦缺乏有效的药物治疗,因此MAFLD发病机制的研究是当前的热点。
黏膜相关恒定T(mucosal associated invariant T,MAIT)淋巴细胞是一类新的天然免疫T淋巴细胞,是最丰富的TCRαβ+T淋巴细胞,以1类主要组织相容性复合体相关分子和不依赖MR1的方式快速激活MAIT淋巴细胞[5],发挥生物学功能,释放多种细胞因子,如IFNγ、TNFα、IL-17和溶细胞产物穿孔素及颗粒素分泌并脱颗粒(将CD107a暴露于细胞表面)等杀伤性细胞因子[6],迅速诱导细胞溶解和靶细胞的死亡。国外相关报道[7-9]显示MAIT淋巴细胞在成人MAFLD发病中起到减少肝脏炎症及促肝纤维化作用,但在儿童MAFLD发病中作用的研究甚少。本研究通过分析MAFLD儿童外周血MAIT淋巴细胞的变化及其与临床指标的相关性,探讨MAIT淋巴细胞在儿童MAFLD发生发展中的作用。
1. 资料与方法
1.1 研究对象
收集2022年3月—2022年5月在本院肝病中心诊治的18例MAFLD患儿(MAFLD组)的外周血标本,根据年龄匹配的20例正常儿童作为对照(对照组),其外周血标本采集于本院健康管理中心。
1.2 纳入标准
MAFLD组纳入标准:脂肪肝合并超重/肥胖、2型糖尿病和代谢功能障碍中至少一项特征[1-2]。同时排除合并甲、乙、丙、丁、戊型肝炎病毒感染,自身免疫性肝病,人类免疫缺陷病毒等病毒感染。对照组纳入标准:肝功能正常,无慢性疾病,近期无感染史等。
1.3 方法
人外周血免疫细胞的制备:留取MAFLD组和对照组儿童外周血3 mL,将PBS加入3 mL新鲜全血中,吸取稀释后的外周血缓慢加到lymphoprep表面。全血在400×g室温下离心20 min,收集第二层外周血免疫细胞并转入含有PBS的离心管中,离心机800×g室温下离心10 min。离心结束后去上清,再加入10 mL PBS,离心机400×g室温下离心5 min,清洗外周血免疫细胞以彻底去除残留的lymphoprep。
应用流式细胞仪检测MAIT细胞,根据标准方案使用以下抗体:CD183(CXCR3)、CD279(PD-1), CD186(CXCR6)、CD3、TCRVα7.2、CD8、CD69、CD161、CD107a、CD196 (CCR6)、CD4和穿孔素抗体进行染色,上流式细胞仪(三激光八色流式细胞分析仪,型号:FacsCantoll,产地:美国)进行分析。外周血中MAIT细胞定义为CD3+CD161+TCRVα7.2+细胞。
收集MAFLD组和对照组儿童血常规及肝功能结果,使用瞬时弹性成像检测MAFLD组患儿的肝纤维化和脂肪含量,儿童MAFLD肝纤维化最佳临界值为6.65 kPa[10],区分有无脂肪变性的脂肪肝参数最佳临界值为222.5 dB/m[11]。
1.4 统计学方法
采用SPSS 23.0软件进行统计学分析。符合正态分布的计量资料以x±s表示,两组间比较采用独立样本t检验;非正态分布的计量资料以M(P25~P75)表示,两组间比较采用Mann-Whitney U检验。MAFLD组患儿外周血MAIT淋巴细胞频率与肝损伤、肝脏脂肪含量和纤维化相关性分析应用Spearman相关分析法。P<0.05为差异具有统计学意义。
2. 结果
2.1 一般资料
MAFLD组18例患儿年龄波动在6.17~13.08岁,对照组20例儿童年龄波动在5.83~13.00岁。MAFLD组的中性粒细胞、ALT、AST水平高于对照组(P值均<0.05)(表 1)。MAFLD组患儿肝纤维化弹性值为5.55(4.18~7.13)kPa,脂肪肝参数为(253.85±16.40) dB/m。
表 1 两组患儿临床资料比较Table 1. The comparation of clinical data between the two groups指标 MAFLD组(n=18) 对照组(n=20) 统计值 P值 男/女(例) 10/8 11/9 年龄(岁) 10.65(8.44~11.87) 9.00(7.40~11.25) Z=-1.083 0.279 ALT(U/L) 37.30(25.08~157.53) 13.65(11.75~17.00) Z=-4.474 <0.001 AST(U/L) 29.95(26.08~62.70) 20.95(18.90~24.23) Z=-3.304 0.001 WBC(×109/L) 7.31±2.56 7.00±1.50 t=0.937 0.355 中性粒细胞(×109/L) 4.47(3.36~5.18) 3.62(2.77~3.97) Z=-2.222 0.026 淋巴细胞(×109/L) 2.76(2.38~3.11) 2.44(1.82~2.91) Z=-1.608 0.112 2.2 儿童外周血MAIT淋巴细胞频率比较
与对照组相比,MAFLD组患儿外周血MAIT淋巴细胞占CD3+T淋巴细胞的比例明显升高(P<0.001),CD4+CD8-MAIT淋巴细胞、CD4+CD8+MAIT淋巴细胞所占MAIT淋巴细胞比例明显升高,CD4-CD8+MAIT淋巴细胞所占MAIT淋巴细胞比例降低(P值均<0.001),CD4-CD8-MAIT淋巴细胞所占MAIT淋巴细胞比例无变化(P>0.05)(表 2)。
表 2 两组患儿外周血MAIT淋巴细胞及各亚组MAIT淋巴细胞频率比较Table 2. The comparation of the peripheral blood MAIT lymphocytes and subtypes between the two groups指标 MAFLD组(n=18) 对照组(n=20) Z值 P值 MAIT淋巴细胞(%) 2.98(1.83~5.99) 0.29(0.09~0.69) -4.765 <0.001 CD4+CD8-MAIT淋巴细胞(%) 13.75(3.28~30.33) 0.38(0~1.55) -3.703 <0.001 CD4-CD8-MAIT淋巴细胞(%) 26.45(1.03~47.03) 31.25(24.05~50.33) 0.254 >0.05 CD4-CD8+MAIT淋巴细胞(%) 9.20(1.16~16.80) 43.65(29.65~64.98) -3.876 <0.001 CD4+CD8+MAIT淋巴细胞(%) 25.65(14.78~84.95) 9.36(6.04~22.45) -2.675 <0.001 2.3 外周血MAIT淋巴细胞表型和功能的差异
与对照组相比,MAFLD组患儿外周血表达PD-1、CD69、CD107α、CXCR3、CXCR6和CCR6的MAIT淋巴细胞比例均明显升高(P值均<0.05)(表 3)。
表 3 两组患儿外周血MAIT淋巴细胞表型和功能的差异Table 3. Differences in phenotype and function of peripheral blood MAIT lymphocytes between the two groups指标 MAFLD组(n=18) 对照组(n=20) Z值 P值 PD-1(%) 21.80(8.38~51.70) 4.43(2.07~11.29) -3.334 0.001 CD69(%) 56.00(28.93~68.35) 18.90(13.23~31.18) -2.646 0.008 穿孔素(%) 9.32(4.53~18.80) 4.16(1.35~9.53) -1.827 0.068 CD107α(%) 45.20(26.03~59.03) 10.95(6.80~17.18) -3.172 0.002 CXCR3(%) 87.35(80.08~96.03) 44.80(32.93~53.00) -4.678 <0.001 CXCR6(%) 30.40(8.24~54.90) 6.02(3.27~21.58) -2.939 0.003 CCR6(%) 26.80(13.03~77.70) 4.94(3.32~17.13) -2.749 0.006 2.4 MAFLD组患儿外周血MAIT淋巴细胞频率与肝脏炎症、脂肪含量和纤维化程度的关系
CD4+CD8+MAIT淋巴细胞和CD107α阳性MAIT淋巴细胞比例与ALT呈负相关(P值均<0.05);MAIT淋巴细胞、CD4+CD8-MAIT淋巴细胞、CD4-CD8+MAIT淋巴细胞比例与ALT无相关性(P值均>0.05);MAIT淋巴细胞、CD4+CD8-MAIT淋巴细胞、CD4-CD8+MAIT淋巴细胞、CD4+CD8+MAIT淋巴细胞和CD107α阳性MAIT淋巴细胞比例与AST、瞬时弹性成像中脂肪肝参数以及弹性值均无相关性(P值均>0.05)(表 4)。
表 4 MAFLD组患儿外周血MAIT细胞频率与肝脏炎症、脂肪含量和纤维化程度相关性分析Table 4. Correlation analysis between the frequency of MAIT lymphocytes in peripheral blood and the degree of liver inflammation, fat content, and fibrosis in children with MAFLD项目 ALT AST 弹性值 脂肪肝参数 MAIT淋巴细胞 r值 0.041 -1.050 0.064 0.112 P值 0.871 0.677 0.801 0.660 CD4+CD8-MAIT淋巴细胞 r值 -0.305 -0.330 -0.303 -0.272 P值 0.218 0.181 0.221 0.275 CD4-CD8+MAIT淋巴细胞 r值 0.140 -0.130 -0.047 0.228 P值 0.580 0.606 0.854 0.363 CD4+CD8+MAIT淋巴细胞 r值 -0.474 -0.436 -0.347 -0.115 P值 0.047 0.071 0.158 0.650 CD107α阳性MAIT淋巴细胞 r值 -0.550 -0.334 -0.201 -0.168 P值 0.018 0.176 0.432 0.504 3. 讨论
MAIT细胞与代谢功能障碍的发展有关, 肥胖儿童外周血MAIT细胞频率高于非肥胖儿童[12],其频率随着肥胖人群年龄的增长而下降,糖尿病和肥胖成人外周血MAIT细胞频率降低[13-15],肥胖成人和儿童中的高IL-17+表型在胰岛素抵抗发展中发挥着重要作用[12, 16]。目前MAIT淋巴细胞在MAFLD发病中作用机制的研究主要集中在成人,研究发现,MAFLD患者中循环MAIT淋巴细胞频率降低[7-9, 17],伴随着CXCR6表达的增加,而肝脏中MAIT淋巴细胞数量则明显增加,与MAFLD活动评分呈正相关[8]。本研究发现,MAFLD患儿外周血MAIT淋巴细胞频率明显升高的同时伴有趋化因子CCR6、CXCR6、CXCR3表达的增加,表明MAFLD患儿外周血MAIT淋巴细胞亦具有更强的迁移至肝脏的倾向[8],MAFLD患者外周血MAIT淋巴细胞频率的变化亦有着随着年龄增长而有下降的趋势,而这种下降的趋势可能与其迁移至肝脏有关。MAIT淋巴细胞可分为DP(CD4+CD8+)MAIT淋巴细胞、CD4+CD8-(CD4+)MAIT淋巴细胞、CD4-CD8+(CD8+)MAIT淋巴细胞和CD4-CD8-(DN)MAIT淋巴细胞。本研究发现健康儿童中以CD4-CD8-MAIT淋巴细胞和CD8+MAIT淋巴细胞为主[18],而MAFLD组患儿中以CD4-CD8-MAIT淋巴细胞和CD4+CD8+MAIT淋巴细胞为主,且与对照组相比,MAFLD组患儿CD4+MAIT淋巴细胞和CD4+CD8+MAIT淋巴细胞所占MAIT细胞比率升高,CD8+MAIT淋巴细胞所占MAIT淋巴细胞比率降低。
MAIT淋巴细胞在MAFLD中的作用为保护还是促进作用,与其所处疾病阶段有关。MAFLD成人患者中,外周血MAIT淋巴细胞降低的同时伴随着功能的改变,高表达CD69、PD-1及IL-4的产生增加,而IFNγ和TNFα的产生减少等。在蛋氨酸胆碱缺乏诱导的NASH模型中,MAIT细胞在肝脏中富集,并通过产生IL-4和IL-10以及诱导抗炎M2巨噬细胞来保护肝脏炎症[8]。随着病情的进展,肝内MAIT淋巴细胞的频率下降,在肝硬化和肝细胞癌的进展中起到促进作用[7, 17, 19]。本研究发现,MAFLD患儿外周血MAIT淋巴细胞水平明显升高的同时,伴有CD69、PD-1及CD107表达的增加,提示MAIT淋巴细胞被激活并功能性耗竭的同时,伴随着细胞毒性能力的增加。进一步研究显示CD4+CD8+MAIT淋巴细胞、CD107阳性MAIT淋巴细胞比例与ALT水平呈负相关,说明MAFLD患儿外周血MAIT细胞在肝脏炎症中具有保护作用,与文献[8]报道一致。
综上所述,MAIT淋巴细胞比例在MAFLD患儿外周血中明显升高,并在肝脏炎症中起着保护作用。本研究的局限性在于样本量偏少,进展期肝纤维化患儿病例数少,未检测肝脏组织MAIT淋巴细胞数量和其功能改变,MAIT淋巴细胞在儿童MAFLD发病中确切的免疫学机制及作用尚待进一步明确。
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表 1 MAFLD组与非脂肪肝组临床资料比较结果
Table 1. Comparison of clinical data between MAFLD and non-fatty liver groups
临床指标 MAFLD组(n=190) 非脂肪肝组(n=160) 统计值 P值 性别[例(%)] χ2=12.09 0.001 女 87(45.8) 103(64.4) 男 103(54.2) 57(35.6) 年龄(岁) 57(48~64) 58(49~64) Z=-0.60 0.550 BMI(kg/m2) 26.64±3.31 23.67±3.01 t=8.73 <0.001 收缩压(mmHg) 136.00(125.00~149.00) 128.00(114.25~142.75) Z=-3.67 <0.001 舒张压(mmHg) 86(77~93) 80(72~88) Z=-3.62 <0.001 TG(mmol/L) 2.26(1.54~3.60) 1.30(0.98~1.72) Z=-8.93 <0.001 LDL-C(mmol/L) 2.87(2.36~3.52) 2.91(2.43~3.56) Z=-0.76 0.450 胆固醇(mmol/L) 5.05(4.43~5.76) 5.02(4.42~5.65) Z=-0.74 0.460 HDL-C(mmol/L) 1.09(0.90~1.30) 1.33(1.11~1.51) Z=-6.81 <0.001 空腹血糖(mmol/L) 6.74(5.47~9.37) 5.08(4.66~5.75) Z=-9.13 <0.001 ALT(U/L) 20.15(14.80~32.38) 15.25(12.00~20.10) Z=-5.87 <0.001 AST(U/L) 18.20(14.48~24.13) 17.45(14.33~20.60) Z=-2.03 0.040 GGT(U/L) 35.90(25.08~52.90) 19.20(14.80~26.60) Z=-8.56 <0.001 超重/肥胖[例(%)] 166(87.4) 90(56.3) χ2=42.82 <0.001 高甘油三酯血症[例(%)] 127(66.8) 41(25.6) χ2=59.12 <0.001 高血压[例(%)] 116(61.1) 45(28.1) χ2=37.91 <0.001 HP感染[例(%)] 74(38.9) 45(28.1) χ2=4.53 0.033 糖尿病[例(%)] 125(65.8) 32(20.0) χ2=73.62 <0.001 表 2 MAFLD患者中HP阳性组与阴性组的其他相关疾病的分布特征
Table 2. Distribution characteristics of other related diseases in HP positive and negative groups in MAFLD group
其他相关疾病 HP阴性组(n=115) HP阳性组(n=75) χ2值 P值 高血压[例(%)] 71(61.2) 45(60.8) 0.003 0.956 糖尿病[例(%)] 71(61.2) 54(73.0) 2.779 0.096 高TG(≥1.7 mmol/L)[例(%)] 83(71.6) 44(59.5) 2.981 0.084 高LDL-C(≥3.4 mmol/L)[例(%)] 31(26.7) 25(33.8) 1.083 0.298 低HDL-C(<1.0 mmol/L)[例(%)] 45(38.8) 28(37.8) 0.017 0.895 高TC(≥5.2 mmol/L)[例(%)] 53(45.7) 36(48.6) 0.580 0.446 高ALT(≥40 U/L)[例(%)] 16(13.8) 11(14.9) 0.043 0.837 高AST(≥40 U/L)[例(%)] 3(2.6) 3(4.1) 0.318 0.573 高GGT(≥50 U/L)[例(%)] 34(29.3) 19(25.7) 0.297 0.586 表 3 MAFLD的危险因素多因素分析
Table 3. Multivariate analysis of risk factors for MALD
项目 B值 OR 95%CI P值 HP感染 0.641 1.899 1.048~3.440 0.035 超重/肥胖 1.520 4.571 2.308~9.052 <0.001 高血压 0.951 2.589 1.468~4.567 0.001 糖尿病 0.789 2.202 1.123~4.315 0.022 高甘油三酯血症 1.432 4.187 2.411~7.271 <0.001 空腹血糖 0.227 1.255 1.091~1.445 0.002 表 4 HP感染和传统危险因素对MAFLD的患病风险分析结果
Table 4. Risk analysis of HP infection and traditional risk factors for MAFLD
项目 例数 B值 OR(95%CI) P值 糖尿病+HP感染 糖尿病(-)HP(-) 137 1.000 糖尿病(-)HP(+) 56 0.127 1.136(0.591~2.181) 0.702 糖尿病(+)HP(-) 94 1.842 6.311(3.498~11.387) <0.001 糖尿病(+)HP(+) 63 2.507 12.267(5.564~27.045) <0.001 超重/肥胖+HP感染 超重/肥胖(-)HP(-) 56 1.000 超重/肥胖(-)HP(+) 38 1.225 3.406(1.297~8.942) 0.013 超重/肥胖(+)HP(-) 175 2.106 8.217(3.785~17.840) <0.001 超重/肥胖(+)HP(+) 81 2.639 14.005(5.897~33.263) <0.001 高血压+HP感染 高血压(-)HP(-) 126 1.000 高血压(-)HP(+) 63 0.429 1.535(0.83~2.840) 0.172 高血压(+)HP(-) 105 1.324 3.759(2.174~6.499) <0.001 高血压(+)HP(+) 56 1.997 7.364(3.467~15.640) <0.001 高甘油三酯血症+HP感染 高甘油三酯血症(-)HP(-) 122 1.000 高甘油三酯血症(-)HP(+) 60 0.992 2.697(1.415~5.139) 0.003 高甘油三酯血症(+)HP(-) 109 2.153 8.610(4.750~15.604) <0.001 高甘油三酯血症(+)HP(+) 59 2.068 7.911(3.893~16.078) <0.001 -
[1] MAK LY, YUEN MF, SETO WK. Letter regarding "A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement"[J]. J Hepatol, 2020, 73(6): 1573-1574. DOI: 10.1016/j.jhep.2020.07.008. [2] ESLAM M, SANYAL AJ, GEORGE J, et al. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease[J]. Gastroenterology, 2020, 158(7): 1999-2014. e1. DOI: 10.1053/j.gastro.2019.11.312. [3] ESLAM M, SARIN SK, WONG VW, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease[J]. Hepatol Int, 2020, 14(6): 889-919. DOI: 10.1007/s12072-020-10094-2. [4] DOULBERIS M, PIERRE NT, MANZINI G, et al. Helicobacter pylori-related metabolic parameters and premalignant gastric mucosa histological lesions in swiss bariatric patients[J]. Microorganisms, 2021, 9(7): 1361. DOI: 10.3390/microorganisms9071361. [5] ABENAVOLI L, MILIC N, MASARONE M, et al. Association between non-alcoholic fatty liver disease, insulin resistance and Helicobacter pylori[J]. Med Hypotheses, 2013, 81(5): 913-915. DOI: 10.1016/j.mehy.2013.08.011. [6] ZHANG S, LIU XH, WANG G, et al. Population differences of metabolic associated fatty liver disease and nonalcoholic fatty liver disease based on a community elderly population[J]. J Clin Hepatol, 2022, 38(3): 547-552. DOI: 10.3969/j.issn.1001-5256.2022.03.011.张爽, 刘晓慧, 王罡, 等. 基于社区老人群比较代谢相关脂肪性肝病与非酒精性脂肪性肝病的人群差异[J]. 临床肝胆病杂志, 2022, 38(3): 547-552. DOI: 10.3969/j.issn.1001-5256.2022.03.011. [7] TANG DM, CHASCSA DM, CHOU JY, et al. Helicobacter pylori infection is strongly associated with metabolic syndrome, and weakly associated with non-alcoholic fatty liver disease, in a US Hispanic population[J]. GastroHep, 2019, 1(6): 325-331. DOI: 10.1002/ygh2.375. [8] HEYDARI K, YOUSEFI M, ALIZADEH-NAVAEI R, et al. Helicobacter pylori infection and non-alcoholic fatty liver disease: A systematic review and meta-analysis[J]. Turk J Gastroenterol, 2022, 33(3): 171-181. DOI: 10.5152/tjg.2022.21467. [9] LIN S, HUANG J, WANG M, et al. Comparison of MAFLD and NAFLD diagnostic criteria in real world[J]. Liver Int, 2020, 40(9): 2082-2089. DOI: 10.1111/liv.14548. [10] CHOI JM, PARK HE, HAN YM, et al. Non-alcoholic/metabolic-associated fatty liver disease and helicobacter pylori additively increase the risk of arterial stiffness[J]. Front Med (Lausanne), 2022, 9: 844954. DOI: 10.3389/fmed.2022.844954. [11] WEI L, DING HG. Relationship between Helicobacter pylori infection and nonalcoholic fatty liver disease: What should we expect from a meta-analysis?[J]. Medicine (Baltimore), 2021, 100(31): e26706. DOI: 10.1097/MD.0000000000026706. [12] JIANG T, CHEN X, XIA C, et al. Association between Helicobacter pylori infection and non-alcoholic fatty liver disease in North Chinese: a cross-sectional study[J]. Sci Rep, 2019, 9(1): 4874. DOI: 10.1038/s41598-019-41371-2. [13] 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. [14] 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. [15] MOHAMMADIFARD M, SAREMI Z, RASTGOO M, et al. Relevance between Helicobacter pylori Infection and non-alcoholic fatty liver disease in Birjand, Iran[J]. J Med Life, 2019, 12(2): 168-172. DOI: 10.25122/jml-2019-0012. [16] CHENG DD, HE C, AI HH, et al. The possible role of helicobacter pylori infection in non-alcoholic fatty liver disease[J]. Front Microbiol, 2017, 8: 743. DOI: 10.3389/fmicb.2017.00743. [17] BOECKMANS J, ROMBAUT M, DEMUYSER T, et al. Infections at the nexus of metabolic-associated fatty liver disease[J]. Arch Toxicol, 2021, 95(7): 2235-2253. DOI: 10.1007/s00204-021-03069-1. [18] OKUSHIN K, TSUTSUMI T, IKEUCHI K, et al. Helicobacter pylori infection and liver diseases: Epidemiology and insights into pathogenesis[J]. World J Gastroenterol, 2018, 24(32): 3617-3625. DOI: 10.3748/wjg.v24.i32.3617. [19] LEE CH, LUI DT, LAM KS. Non-alcoholic fatty liver disease and type 2 diabetes: An update[J]. J Diabetes Investig, 2022, 13(6): 930-940. DOI: 10.1111/jdi.13756. [20] KANWAL S, GHAFFAR T, AAMIR AH, et al. Frequency of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus and its associated risk factors[J]. Pak J Med Sci, 2021, 37(5): 1335-1341. DOI: 10.12669/pjms.37.5.4211. [21] MA HL, QUAN L, JIANG S. Analysis of clinical characteristics and risk factors in patients with nonal-coholic fatty liver disease complicated with type 2 diabetes mellitus[J]. China Med Herald, 2022, 19(21): 70-73, 82. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202221016.htm马海林, 权莉, 蒋升. 非酒精性脂肪性肝病合并2型糖尿病患者的临床特征及危险因素分析[J]. 中国医药导报, 2022, 19(21): 70-73, 82. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202221016.htm [22] KAYA E, YILMAZ Y. Metabolic-associated Fatty Liver Disease (MAFLD): A multi-systemic disease beyond the liver[J]. J Clin Transl Hepatol, 2022, 10(2): 329-338. DOI: 10.14218/JCTH.2021.00178. [23] HAN L, ZHANG Y, YUE C, et al. Preliminary study on risk factors for morbidity of nonalcoholic fatty liver disease in high-income male population[J]. J Healthc Eng, 2022, 2022: 9331284. DOI: 10.1155/2022/9331284. [24] LI H, GUO M, AN Z, et al. Prevalence and risk factors of metabolic associated fatty liver disease in Xinxiang, China[J]. Int J Environ Res Public Health, 2020, 17(6): 1818. DOI: 10.3390/ijerph17061818. [25] CHEN YL, LI H, LI S, et al. Prevalence of and risk factors for metabolic associated fatty liver disease in an urban population in China: a cross-sectional comparative study[J]. BMC Gastroenterol, 2021, 21(1): 212. DOI: 10.1186/s12876-021-01782-w. [26] LIU Y, LI D, LIU Y, et al. Association between helicobacter pylori infection and non-alcoholic fatty liver disease, hepatic adipose deposition and stiffness in southwest China[J]. Front Med (Lausanne), 2021, 8: 764472. DOI: 10.3389/fmed.2021.764472. [27] SIDDIQUI B, KAMRAN M, TIKMANI SS, et al. Frequency and risk factors of non-alcoholic fatty liver disease in Helicobacter pylori-infected dyspeptic patients: A cross-sectional study[J]. SAGE Open Med, 2021, 9: 20503121211025421. DOI: 10.1177/20503121211025421. [28] BAEG MK, YOON SK, KO SH, 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. [29] KIM TJ, LEE H, KANG M, et al. Helicobacter pylori is associated with dyslipidemia but not with other risk factors of cardiovascular disease[J]. Sci Rep, 2016, 6: 38015. DOI: 10.1038/srep38015. [30] SUMIDA Y, KANEMASA K, IMAI S, et al. Helicobacter pylori infection might have a potential role in hepatocyte ballooning in nonalcoholic fatty liver disease[J]. J Gastroenterol, 2015, 50(9): 996-1004. DOI: 10.1007/s00535-015-1039-2. [31] GOO MJ, KI MR, LEE HR, et al. Helicobacter pylori promotes hepatic fibrosis in the animal model[J]. Lab Invest, 2009, 89(11): 1291-1303. DOI: 10.1038/labinvest.2009.90. [32] YU LY, HU KC, LIU CJ, et al. Helicobacter pylori infection combined with non-alcoholic fatty liver disease increase the risk of atherosclerosis: Focus in carotid artery plaque[J]. Medicine (Baltimore), 2019, 98(9): e14672. DOI: 10.1097/MD.0000000000014672. [33] 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. [34] JAMALI R, MOFID A, VAHEDI H, et al. The effect of helicobacter pylori eradication on liver fat content in subjects with non-alcoholic Fatty liver disease: a randomized open-label clinical trial[J]. Hepat Mon, 2013, 13(12): e14679. DOI: 10.5812/hepatmon.14679. [35] YU YY, TONG YL, WU LY, et al. Helicobacter pylori infection eradication for nonalcoholic fatty liver disease: a randomized controlled trial[J]. Sci Rep, 2022, 12(1): 19530. DOI: 10.1038/s41598-022-23746-0. -