海军军医大学学报  2024, Vol. 45 Issue (8): 973-980   PDF    
甘油三酯葡萄糖指数及其衍生指标对瘦型代谢相关脂肪性肝病的预测价值
董旭1, 葛宇2, 王超群3, 许明晓1, 陈怡1, 陈琳4     
1. 海军军医大学(第二军医大学)第一附属医院感染科, 上海 200433;
2. 海军军医大学(第二军医大学)第一附属医院超声诊断科, 上海 200433;
3. 海军军医大学(第二军医大学)第一附属医院内分泌科, 上海 200433;
4. 海军军医大学(第二军医大学)第一附属医院健康管理中心, 上海 200433
摘要: 目的 探讨甘油三酯葡萄糖指数(TyG)及其衍生指标TyG-BMI、TyG-丙氨酸转氨酶(ALT)与瘦型代谢相关脂肪性肝病(MAFLD)患病风险的相关性。方法 选择2023年7-12月在我院健康管理中心进行年度健康体检并诊断为瘦型MAFLD的207例患者及100名瘦型健康对照为研究对象,比较两组血脂、血糖、肝功能、TyG、TyG-BMI、TyG-ALT等,采用单因素和多因素logistic回归模型分析影响瘦型MAFLD的因素。将所有研究对象按照TyG及其衍生指标四分位数分为4个亚组(Q1~Q4),观察各亚组瘦型MAFLD的患病率。绘制TyG、TyG-BMI、TyG-ALT预测瘦型MAFLD的ROC曲线,评估各指标的预测效能。结果 纳入的8 764例体检者中MAFLD患者2 350例(26.8%),其中瘦型207例(8.8%,207/2 350)。与瘦型健康对照组相比,瘦型MAFLD组患者的年龄大、男性多见、BMI高,空腹血糖、总胆固醇、甘油三酯、低密度脂蛋白胆固醇、ALT、天冬氨酸转氨酶、γ-谷氨酰转肽酶、碱性磷酸酶、总胆红素、TyG、TyG-BMI与TyG-ALT均升高,高密度脂蛋白胆固醇降低(均P<0.01)。logistic回归分析显示,年龄、男性、ALT水平升高是瘦型MAFLD患病的独立危险因素。TyG的Q4亚组瘦型MAFLD的患病率为34.3%(71/207),高于Q1亚组(10.6%,22/207)及Q2亚组(24.2%,50/207),差异均有统计学意义(均P<0.05);TyG-BMI的Q4亚组和TyG-ALT的Q4亚组瘦型MAFLD的患病率均高于其Q1、Q2、Q3亚组[35.3%(73/207)vs 8.2%(17/207)、24.6%(51/207)、31.9%(66/207),33.8%(70/207)vs 14.0%(29/207)、23.2%(48/207)、29.0%(60/207)],差异均有统计学意义(均P<0.05)。TyG-BMI预测瘦型MAFLD的AUC值为0.869 0(95% CI 0.825 5~0.912 6,P<0.001),高于TyG[AUC=0.818 8(95% CI 0.768 0~0.869 6,P<0.001)]和TyG-ALT[AUC=0.772 5(95% CI 0.718 7~0.826 2,P<0.001)]。结论 TyG、TyG-BMI与TyG-ALT均与瘦型MAFLD相关,三者对瘦型MAFLD具有一定的预测价值;TyG及其衍生指标计算简易且价格低廉,可用于对瘦型MAFLD的临床初步评估。
关键词: 代谢相关脂肪性肝病    瘦型    甘油三酯葡萄糖指数    体重指数    丙氨酸转氨酶    
Predictive value of triglyceride-glucose index and its derivatives for lean metabolic associated fatty liver disease
DONG Xu1, GE Yu2, WANG Chaoqun3, XU Mingxiao1, CHEN Yi1, CHEN Lin4     
1. Department of Infectious Diseases, The First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China;
2. Department of Ultrasound, The First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China;
3. Department of Endocrinology, The First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China;
4. Health Management Center, The First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China
Abstract: Objective To explore the correlations between triglyceride glucose index (TyG) and its derivatives TyG-body mass index (BMI) and TyG-alanine transaminase (ALT) with the risk of lean metabolic associated fatty liver disease (MAFLD). Methods A total of 207 patients diagnosed with lean MAFLD and 100 lean healthy controls who received annual health examination in Health Management Center of our hospital from Jul. to Dec. 2023 were enrolled. Plasma lipids, blood glucose, liver function, TyG, TyG-BMI and TyG-ALT were compared between the 2 groups. The influencing factors of lean MAFLD were analyzed by univariate and multivariate logistic regression models. All subjects were divided into 4 subgroups (Q1-Q4) according to the quartile of TyG and its derivatives, and the prevalence of lean MAFLD in each subgroup was observed. The receiver operating characteristic (ROC) curves of TyG, TyG-BMI and TyG-ALT for lean MAFLD were plotted to evaluate the prediction efficiency. Results Of the 8 764 health examination cases included, 2 350 (26.8%) had MAFLD, of which 207 were lean MAFLD (8.8%, 207/2 350). Compared with the lean healthy controls, the patients in the lean MAFLD group were older, with more male and high BMI, and their fasting blood glucose, total cholesterol, triglyceride, low density lipoprotein-cholesterol, ALT, aspartate transaminase, γ-glutamyl transpeptidase, alkaline phosphatase, total bilirubin, TyG, TyG-BMI and TyG-ALT were significantly increased, while high density lipoprotein-cholesterol was significantly decreased (all P < 0.01). Logistic regression analysis showed that age, male, and elevated ALT level were independent risk factors for lean MAFLD. The prevalence of lean MAFLD in the Q4 subgroup of TyG was significantly higher than that in the Q1 and Q2 subgroups (34.3% [71/207] vs 10.6% [22/207] and 24.2% [50/207], both P < 0.05). The prevalence rates of lean MAFLD in the Q4 subgroup of TyG-BMI and the Q4 subgroup of TyG-ALT were significantly higher than those in the corresponding Q1, Q2, and Q3 subgroups (35.3% [73/207] vs 8.2% [17/207], 24.6% [51/207], and 31.9% [66/207]; 33.8% [70/207] vs 14.0% [29/207], 23.2% [48/207], and 29.0% [60/207]; all P < 0.05). The area under curve (AUC) of TyG-BMI in predicting lean MAFLD was 0.869 0 (95% confidence interval [CI] 0.825 5-0.912 6, P < 0.001), which was higher than that of TyG (AUC=0.818 8 [95% CI 0.768 0-0.869 6, P < 0.001]) and TyG-ALT (AUC=0.772 5 [95% CI 0.718 7-0.826 2, P < 0.001]). Conclusion TyG, TyG-BMI, and TyG-ALT are associated with lean MAFLD, and have predictive value for lean MAFLD. TyG and its derivatives are easy to calculate and cheap, and can be used for preliminary clinical assessment of lean MAFLD.
Key words: metabolic associated fatty liver disease    lean type    triglyceride-glucose index    body mass index    alanine transaminase    

代谢相关脂肪性肝病(metabolic associated fatty liver disease,MAFLD)是常见的慢性肝脏疾病之一,既往称为非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)[1]。随着经济发展及生活方式的转变,MAFLD的全球患病率急剧上升,影响着世界上约1/3的成年人[2],目前其已取代乙型肝炎成为我国慢性肝病的主要原因,过去20年我国成人MAFLD患病率达29.6%,男性(34.8%)高于女性(23.5%)[3],如未重视并及时防治,容易向肝纤维化、肝硬化甚至肝癌进展。一般认为MAFLD发生在肥胖人群中,但在瘦型人群中也存在部分MAFLD患者,中国的瘦型MAFLD患病率约为9%,在确诊的MAFLD人群中瘦型患者约占19.2%[4]。meta分析显示,瘦型MAFLD患者的全因死亡风险比非瘦型患者显著升高(RR=1.39)[5],因此体检时应注意早期预测瘦型MAFLD的发病并启动干预策略。

胰岛素抵抗被认为是MAFLD发病的主要机制之一[6],检测胰岛素抵抗的金标准是高胰岛素-正葡萄糖钳夹技术[7],但该技术操作复杂、价格昂贵、耗时较长。甘油三酯葡萄糖指数(triglyceride-glucose index,TyG)结合了血清甘油三酯(triglyceride,TG)和空腹血糖(fasting blood glucose,FBG),可反映机体的代谢状态,并且与胰岛素抵抗高度相关[8-9],其衍生的TyG-BMI在TyG基础上纳入BMI,比单独TyG能更准确地反映胰岛素抵抗程度[10];Taheri等[11]首次将TyG与丙氨酸转氨酶(alanine transaminase,ALT)结合形成了新指标TyG-ALT,用于评价MAFLD。既往有研究报道TyG、TyG-BMI及TyG-ALT与MAFLD之间存在相关性[10-13],本研究旨在探讨TyG及其衍生指标预测瘦型MAFLD的价值,以期为早期诊治MAFLD提供更便捷的指标。

1 资料和方法 1.1 研究对象

选择2023年7-12月在海军军医大学(第二军医大学)第一附属医院健康管理中心进行年度健康体检的人群为研究对象。纳入标准:完成腹部超声及血常规、血生化等检查。排除标准:(1)合并病毒性肝炎、自身免疫性肝病等基础疾病;(2)患有原发性肝癌、肝血管瘤、巨大肝囊肿等重大肝脏疾病;(3)近1年有过量饮酒史,即男性每周饮酒量超过140 g,女性每周饮酒量超过70 g;(4)近1个月服用过降脂或降糖药物;(5)重要数据不全。选择同期行健康体检的身体健康、BMI<23 kg/m2、超声未检出脂肪肝的100名成年人作为瘦型健康对照组。本研究获得海军军医大学(第二军医大学)第一附属医院伦理委员会审批(CHEC2021-151)。

1.2 诊断标准

MAFLD的诊断符合亚太肝脏研究协会(Asian Pacific Association for the Study of the Liver,APASL)MAFLD的诊断和管理临床实践指南[14],在明确肝脏脂肪变性的基础上同时合并超重、肥胖、2型糖尿病或代谢功能障碍即可诊断MAFLD。其中肝脏脂肪变性的诊断依赖于影像学检查,主要是腹部超声,诊断依据NAFLD防治指南(2018年更新版)[15]:(1)肝脏近场回声弥漫性增强并强于肾脏;(2)肝内管道结构显示不清;(3)肝脏远场回声逐渐衰减,具备其中2项即可诊断为弥漫性脂肪肝。瘦型的诊断符合美国胃肠病学协会(American Gastroenterological Association,AGA)的建议,即BMI<25 kg/m2(非亚裔)或BMI<23 kg/m2(亚裔)[16]

1.3 研究方法

所有体检人群的血检验结果均为禁食至少8 h后抽取静脉血测得。通过健康管理中心电子信息系统收集纳入者的临床资料,包括基本情况(年龄、性别、身高、体重)、肝功能[ALT、天冬氨酸转氨酶(aspartate transaminase,AST)、碱性磷酸酶(alkaline phosphatase,ALP)、γ-谷氨酰转肽酶(γ-glutamyl transpeptidase,γ-GT)、总胆红素(total bilirubin,TBil)]、血脂[总胆固醇(total cholesterol,TC)、TG、低密度脂蛋白胆固醇(low density lipoprotein-cholesterol,LDL-C)、高密度脂蛋白胆固醇(high density lipoprotein-cholesterol,HDL-C)]、FBG、腹部超声检查结果。以上实验室检查及腹部超声检查均在我院完成,其中腹部超声检查均由经验丰富的高年资医生完成。根据公式计算BMI、TyG、TyG-BMI、TyG-ALT、血浆致动脉粥样硬化指数(atherogenic index of plasma,AIP)、LDL-C/HDL-C和γ-GT/HDL-C:BMI=体重(kg)/身高(m)2;TyG=ln[TG(mg/L)×FBG(mg/L)/2],其中TG 1 mg/L=1.13 μmol/L,FBG1 mg/L=5.56 μmol/L[8];TyG-BMI=TyG×BMI;TyG-ALT=TyG×ALT;AIP=lg[TG(mg/L)/HDL-C(mmol/L)];LDL-C/HDL-C=LDL-C(mmol/L)/HDL-C(mmol/L);γ-GT/HDL-C=γ-GT(U/L)/HDL-C(mmol/L)。

1.4 统计学处理

使用SPSS 26.0及GraphPad Prism 10.0软件对数据进行统计学处理。对计量资料行正态性与方差齐性检验,若符合正态分布以x±s表示,组间比较采用独立样本t检验;若为偏态分布以中位数(下四分位数,上四分位数)表示,组间比较采用Mann-Whitney U检验;计数资料以例数和百分数表示,组间比较采用χ2检验或Fisher确切概率法。采用二元logistic回归模型分析TyG、TyG-BMI及TyG-ALT与瘦型MAFLD患病风险的相关性,绘制ROC曲线探讨TyG、TyG-BMI及TyG-ALT对瘦型MAFLD的预测价值,AUC值的比较采用Z检验。检验水准(α)为0.05。

2 结果 2.1 一般情况

纳入的8 764例参加年度健康体检的人群中MAFLD患者2 350例(26.8%),其中瘦型MAFLD患者207例,在确诊的MAFLD人群中占8.8%。瘦型MAFLD患者中男109例(52.7%)、女98例(47.3%),年龄为24~73岁。

2.2 瘦型MAFLD患者与瘦型健康对照者的临床资料对比

与瘦型健康对照组相比,瘦型MAFLD组患者的年龄大、男性多见、BMI高,FBG、TC、TG、LDL-C、ALT、AST、γ-GT、ALP、TBil、AIP、LDL-C/HDL-C、γ-GT/HDL-C、TyG、TyG-BMI、TyG-ALT均升高,HDL-C降低(均P<0.01)。见表 1

表 1 瘦型MAFLD患者与瘦型健康对照者的临床资料比较 Tab 1 Comparison of clinical data between lean MAFLD patients and lean healthy controls

2.3 瘦型MAFLD的危险因素

单因素和多因素logistic回归分析显示,年龄大、男性、ALT水平升高是瘦型MAFLD的独立危险因素(均P<0.01)。见表 2

表 2 瘦型MAFLD影响因素的logistic回归分析 Tab 2 Logistic regression analysis of influencing factors of lean MAFLD

2.4 TyG、TyG-BMI、TyG-ALT各四分位组瘦型MAFLD患病率比较

将所有研究对象按照TyG、TyG-BMI、TyG-ALT四分位数分为Q1~Q4亚组,观察各亚组瘦型MAFLD的患病率。结果显示随着TyG、TyG-BMI、TyG-ALT的升高瘦型MAFLD的患病率升高。TyG的Q4亚组瘦型MAFLD的患病率高于Q1及Q2亚组,差异均有统计学意义(均P<0.05);TyG-BMI的Q4亚组、TyG-ALT的Q4亚组瘦型MAFLD的患病率均高于其Q1、Q2及Q3亚组,差异均有统计学意义(均P<0.05)。见表 3

表 3 不同TyG、TyG-BMI、TyG-ALT亚组的瘦型MAFLD患病率比较 Tab 3 Comparison of prevalence of lean MAFLD in different TyG, TyG-BMI and TyG-ALT subgroups 

2.5 TyG及其衍生指标对瘦型MAFLD的预测作用及与其他预测指标的比较

ROC曲线分析结果显示,TyG-BMI预测瘦型MAFLD的价值高于TyG和TyG-ALT(均P<0.05)。同时对TyG及其衍生指标与AIP、LDL-C/HDL-C、γ-GT/HDL-C的预测效能进行了比较,结果仍为TyG-BMI的预测效能最佳(均P<0.05)。见表 4

表 4 TyG及其衍生指标与AIP、LDL-C/HDL-C、γ-GT/HDL-C对瘦型MAFLD的预测价值 Tab 4 Prediction value of TyG and its derivatives, AIP, LDL-C/HDL-C, and γ-GT/HDL-C on lean MAFLD

3 讨论

NAFLD是在没有大量乙醇摄入的情况下,排除病毒、药物等其他危险因素后,肝细胞中脂质过度堆积超过体重的5%而导致的一种慢性肝脏疾病[17]。目前其发病机制仍不明确,多数学者比较认可的是“二次打击”学说,认为第一重打击是肥胖、高脂饮食和胰岛素抵抗,胰岛素抵抗引起细胞内TG的合成与转运功能紊乱,使脂类在肝脏细胞的细胞质内过度聚集,而后触发机体氧化应激反应,导致肝细胞内产生慢性炎症[18]。而程序性细胞死亡如焦亡、坏死性凋亡、铁死亡等与炎症和氧化应激高度相关[19]。随着对疾病认识的加深,众多国际专家小组倡议以MAFLD取代原命名,并将代谢紊乱明确为MAFLD的主要病因[1, 20]。MAFLD好发于肥胖人群,但临床实践中很多BMI正常甚至偏低的人群也存在MAFLD,即瘦型MAFLD,本研究中检出MAFLD患病率为26.8%,其中瘦型MAFLD在确诊的MAFLD中占8.8%。研究显示,瘦型MAFLD患者的全因死亡风险比非瘦型患者更高[5]。与肥胖型相比,瘦型MAFLD患者的心血管疾病风险增加,具有更高的动脉粥样硬化性心血管疾病患病率[21-22],并且瘦型MAFLD患者的消化系统癌症和肥胖相关癌症的风险也增加[23]。而对于肝脏本身的转归,有研究显示瘦型MAFLD患者的终末期肝病如肝硬化、肝功能衰竭、肝细胞癌的发生风险显著增加(HR=2.69)[24],Nabi等[25]进一步证实了瘦型MAFLD患者的进展性肝纤维化发生率(3.7% vs 1.7%,P<0.01)及肝病相关死亡风险(HR=5.84)均显著增加。基于以上结果,早期诊断MAFLD并对其进行病情评估非常重要,但目前临床上大多数瘦型MAFLD患者无特异性临床表现,早期甚至中期血清学指标也未见明显异常。

TyG涵盖TG和FBG 2个指标,与引起MAFLD的脂代谢、糖代谢紊乱相关,2008年Simental-Mendía等[26]首次提出其可作为反映胰岛素抵抗的指标,由其衍生出的TyG-BMI于2016年被首次提出[27],该指数加入BMI这一数据,BMI升高可反映出饮食、运动等生活方式不健康导致的体重变化,而肥胖是MAFLD发生及发展的重要因素。本研究表明在瘦型患者中,BMI也与MAFLD密切相关。ALT不仅是传统的肝细胞损伤标志物,同时也与肝脏脂肪含量显著相关,可作为肝脏脂质水平的标志物[28],2022年Taheri等[11]首次提出TyG-ALT的概念并在伊朗人群中发现其与MAFLD风险存在关联。本研究结果显示,瘦型MAFLD患者若为男性,BMI越高越容易出现糖脂代谢紊乱,且TyG及其衍生指标均明显升高,考虑可能是由于饮食不健康、运动量不足导致机体能量过剩,同时胰岛素抵抗抑制脂肪组织分解、增加肝内脂肪生成[29]。当TyG、TyG-BMI、TyG-ALT升高,瘦型MAFLD的患病率都随之升高。但本研究中TyG及其衍生指标并非瘦型MAFLD的独立危险因素,既往对TyG与MAFLD的相关性研究针对的是整体MAFLD人群,以肥胖型为主,并发现TyG或其衍生指标与MAFLD发生风险呈正相关,是MAFLD的独立危险因素[10-11],但本研究的对象特指瘦型,而瘦型患者代谢紊乱及组织学病变相对较轻[30],因此虽然瘦型MAFLD患者的TyG及其衍生指标较瘦型健康对照人群高,但并不是MAFLD的独立危险因素。ROC曲线分析显示TyG及其衍生指标对瘦型MAFLD有较好的预测价值,其中TyG-BMI最佳,以179.949为最佳截断值时TyG-BMI预测瘦型MAFLD的灵敏度和特异度分别为77.3%和82.0%。既往也有关于瘦型NAFLD预测指标的研究,如AIP(即TG/HDL-C比值的常用对数)、LDL-C/HDL-C、γ-GT/HDL-C等,Li等[31]研究发现随着AIP的增高新发NAFLD逐渐增加。Zou等[32]发现LDL-C/HDL-C是血脂正常的非肥胖人群中NAFLD的独立预测因子。一项中国人群的大型纵向队列研究表明,γ-GT/HDL-C与非肥胖人群NAFLD的发生风险呈线性正相关,但在预测NAFLD方面,γ-GT/HDL-C并不比单独的γ-GT和BMI有显著优势[33]。本研究结果表明,与之前研究的早筛模型比较,TyG-BMI的预测效能更高。

综上所述,BMI正常甚至低于正常的人群也有发生MAFLD的风险,TyG及其衍生指数TyG-BMI、TyG-ALT作为一类简单的、能够反映机体糖脂代谢情况的指标,它们的高水平状态均与瘦型MAFLD发生风险升高相关,并对瘦型MAFLD具有一定的预测价值,其中TyG-BMI的预测价值最高,当其大于179.949时应注意警惕瘦型MAFLD发生;同时其价格低廉、检测方便,在各级医疗机构均可开展,监测TyG及其衍生指标可为瘦型MAFLD的早期防治提供新思路。

本研究仍存在一些局限性:(1)研究设计为单中心研究,作为军队三甲医院,纳入的体检人群多为军队人员,对其他职业人群覆盖不够全面,职业特性使受试者的运动量高于普通地方人员,故瘦型MAFLD的检出率较其他报道[4]低;(2)仅分析体检时基线情况,为横断面研究,缺乏随访数据,且生活习惯、吸烟情况等数据缺失,未来可尝试使用孟德尔随机化分析等新的方法从遗传学角度进一步分析瘦型MAFLD的危险因素[34];(3)本研究MAFLD的诊断依赖于超声检查,但由于腹部超声对轻度脂肪变性(即肝脂肪含量为5%~30%)的诊断灵敏度欠佳[35],因此可能会漏诊一些早期瘦型MAFLD患者,而且由于MAFLD的诊断标准在国内的指南中尚未更新,部分参考既往NAFLD的指南,这种差异可能导致一定程度的偏倚;(4)有部分研究将TyG与腰围、臀围、腰高比等数据联合并探究它们在MAFLD预测中的应用[36],而本研究数据不全,无法完善此类衍生指数。今后将进一步扩大受试者人群、开展多中心队列研究,以进一步证实TyG及其衍生指数的应用价值。

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