【作者】 刘璐；

【导师】 赵家军； 高聆；

【作者基本信息】 山东大学 ， 内科学（内分泌与代谢病）（专业学位）， 2018， 博士

【摘要】 研究背景:亚临床甲状腺功能减退症(subclinical hypothyroidism,SCH),简称亚临床甲减,被认为是甲状腺功能衰退的早期阶段,表现为血清促甲状腺激素(thyroid stimulating hormone,TSH)水平升高,而游离甲状腺素(free thyroxine,FT4)水平正常。近年来,亚临床甲减的患病率呈上升趋势,其全球范围内的患病率为4%～10%;在老年尤其女性群体中更多见,在60岁以上妇女中可以达到20%,是最常见的甲状腺功能异常性疾病。亚临床甲减虽无明显临床症状,但具有多种潜在危害:可引起心脏功能异常,是缺血性心脏病的独立危险因素;而且每年约有2%-5%的亚临床甲减患者进展为临床甲减。因此防治亚临床甲减是国际内分泌学界医生面临的一项重要任务。左甲状腺素(levothyroxine,LT4)是治疗甲状腺功能减退症的首选药物。但目前对于亚临床甲减是否需要治疗,以及治疗的目标经历了长期的论证与争议。2012年美国临床内分泌医师协会联合美国甲状腺协会颁布的《成人甲状腺功能减退症诊疗指南》(Clinical Practice Guidelines for Hypothyroidism in Adults:Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association)提出,TSH≥10 mU/L的重度亚临床甲减患者应给甲状腺激素补充治疗;而对TSH水平介于正常参考值范围高限与10mU/L之间的轻度亚临床甲减患者,由于目前尚缺乏足够的前瞻性干预研究证据,指南并未明确这部分患者是否应积极给予甲状腺激素补充治疗。同时,该指南指出,“甲状腺激素补充治疗能否给亚临床甲减患者带来心脏获益”这一命题是未来研究的重要领域之一。众所周知,高胆固醇血症是心血管疾病发生和发展的重要危险因素,降低血清胆固醇水平可有效降低心血管疾病的发病率及死亡率。近年来,许多观察性研究显示亚临床甲减与高胆固醇血症之间有密切关系;我们课题组的前期临床研究也发现血清TSH水平与血脂水平正相关,并且在进一步校正包括血清甲状腺激素、肥胖、年龄等混杂因素后,这种相关性依然存在。而且,关于亚临床甲减与心血管疾病的关系的队列研究结果提示,高胆固醇血症可能是亚临床甲减导致的心血管疾病风险增加的重要中间环节之一。因此,在探讨“甲状腺激素补充治疗能否给亚临床甲减患者带来心血管获益”这一问题时,首先应明确,甲状腺激素补充治疗可否改善亚临床甲减患者的血清胆固醇水平。既往曾有干预性研究探讨该问题,但未能得到一致结论;而且由于样本量均较小,这些研究未能在不同TSH或血脂水平的人群中进行亚组分析,从而不能回答LT4补充治疗对血清胆固醇水平的影响在基线TSH或胆固醇水平水平不同的患者中是否有所差异。相对较小的样本量和不一致的结论可能是这些研究没有提供足够有力的证据来指导临床实践的原因。因此,还需要大样本的临床随机对照试验来进一步完善LT4补充治疗对血脂的影响的研究。近年来亚临床甲减与非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)的关系越来越引起学者的重视。已有横断面及前瞻性病例对照研究提示亚临床甲减是NAFLD发病的独立危险因素;我们课题组的前期基础研究也发现TSH可通过影响甘油三酯(triglyceride,TG)从头合成相关基因的表达直接调控肝脏TG的合成,从而参与NAFLD的发病。那么通过补充LT4,使亚临床甲减患者的血清TSH恢复至正常水平,是否可以改善NAFLD呢?迄今为止,尚无干预性研究关注这一问题。研究目的:本研究遵循循证医学原则,运用临床流行病学的方法,通过规范化的临床随机对照试验,观察LT4补充治疗对亚临床甲减患者的血清胆固醇水平的影响。并进一步对该随机对照试验进行事后分析(post hoc analysis),探索LT4补充治疗是否可以改善亚临床甲减患者NAFLD的患病情况。本研究旨在探索LT4补充治疗对亚临床甲减患者血清胆固醇水平及NAFLD的影响,从上述两个方面观察LT4补充治疗是否可以给亚临床甲减患者带来脂代谢相关获益,从而为亚临床甲减的治疗提供参考依据。研究方法:1.研究设计和研究对象本研究基于一项为期15个月的前瞻性、开放性、随机、对照、单中心试验。研究对象来自山东省宁阳县,经过严格的纳入排除标准,共有415例亚临床甲减患者纳入试验。该临床随机对照试验设计流程及内容在临床研究注册网站(ClinicalTrials.gov)注册(注册码:NCT01848171)。2.随机分组根据美国临床内分泌医师协会和美国甲状腺协会协同制定的甲减诊疗指南的要求,对所有的重度亚临床甲减患者(n = 37)全部给予LT4补充治疗;利用随机分组软件采用完全随机化的方法将轻度亚临床甲减患者以1.5:1的比例随机分为给予LT4补充治疗的干预组(n = 215)和不施加干预的对照组(n= 163)。3.研究终点研究的第一部分通过该临床随机对照试验,观察LT4补充治疗对亚临床甲减患者的血清胆固醇水平的影响,观察的主要结局指标是随访结束时血清TC浓度较基线水平的变化;次要结局指标是随访期间其他胆固醇指标,包括LDL和高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL)水平的变化。研究的第二部分通过对该临床随机对照试验进行事后分析,探索LT4补充治疗对亚临床甲减患者中NAFLD的影响,观察的主要结局指标是随访期间受试者NAFLD的患病率的变化;次要结局指标是血清肝功能酶学的变化。4.资料获取所有受试者均在试验开始及结束时完成下述检查:(1)通过标准化调查问卷记录受试者信息包括:人口统计学特征(年龄、性别、民族等)、疾病史、用药及手术史、家族史、生活方式等。(2)通过体格检查获取身高、体重、腰围、血压等资料;经腹部超声检查协助NAFLD的诊断。(3)采空腹血,采用电化学发光法定量检测TSH,FT4,3-碘甲状腺原氨酸(free triiodothyronine,FT3);采用贝克曼化学分析仪AU5800系统检测血脂谱、肝酶(血清丙氨酸氨基转移酶,ALT;和天门冬氨酸氨基转移酶,AST)。上述血清学检测的批内差异和批间差异均控制在5%以下。5.统计分析采用SPSS 22.0软件进行统计分析。连续变量根据其是否符合正态分布采用均数±标准差或中位数(四分位数间距)进行描述,分类变量采用计数(百分数)进行描述。组间连续变量的比较采用独立样本t检验(Student’s t检验)或Mann-Whitney U检验;组内基线及随访结束时连续变量的比较采用配对t检验(paired-samples t-test)或Wilcoxon Paired Rank检验。分类变量差异的比较采用卡方检验(Chi-squared test)。双侧P值小于0.05认为有统计学意义。结果:1-1 LT4补充治疗可降低SCH患者的血清TC和LDL水平重度亚临床甲减患者经15个月的LT4补充治疗后,血清TC(P = 0.004)和LDL(P = 0.016)水平均较基线时显著下降。在轻度亚临床甲减患者中,干预组与对照组血清TC均较基线时显著下降,但干预组降低的幅度显著大于对照组(-6.35 ± 12.88%vs-1.66± 16.61%,P = 0.003);而对于血清 LDL 的水平,干预组血清 LDL(from 3.34±0.81 mmo/L to 3.25 ± 0.84 mmo/L,P = 0.023)较基线时显著下降,而对照组无显著变化(P =0.072)。1-2无论轻度SCH患者基线血清TSH水平的高低,LT4补充治疗均可显著降低血清TC水平将轻度亚甲减患者根据基线TSH水平分层分为3个亚组(亚组1,4.2 mIU/L≤TSH<5mIU/L;亚组 2,5mIU/L≤TSH<7mIU/L;亚组 3,7mIU/L≤TSH<10mIU/L),分别分析受试者在随访期内血清TC和LDL的变化。在对照组中,不论基线TSH水平的高低,血清TC和LDL水平均无显著变化。而在接受LT4补充治疗的干预组中,上述3个亚组人群血清TC均显著下降(下降的幅度分别为0.41 mmol/L、0.41 mmol/L和0.42 mmol/L,P 均<0.001。);在 5 mIU/L≤TSH<7 mIU/L 组,血清 LDL 也显著下降(from 3.34 ± 0.82 mmol/L to 3.22 ± 0.85 mmol/L,P = 0.033。)。1-3基线LDL水平升高的情况下,LT4补充治疗对轻度SCH患者LDL的改善作用更加明显根据基线LDL的水平将轻度亚临床甲减患者分为LDL正常组(LDL<4.1 mmol/L)和LDL升高组(LDL ≥ 4.1 mmol/L)。在基线LDL正常组,随访结束时干预组(P = 0.474)和对照组(P = 0.312)的血清LDL水平较基线时均无显著变化;在基线LDL升高组,干预组血清 LDL 从 4.55 ± 0.46 mmol/L 显著下降至 4.07 ± 0.82 mmol/L(P<0.001),而对照组血清LDL无显著变化(P = 0.075)。而无论基线血清LDL水平正常还是升高,干预组血清TC均显著下降,而对照组血清TC无显著变化。2-1在重度SCH患者中,LT4补充治疗可改善NAFLD重度亚临床甲减患者经过15个月的LT4补充治疗后,NAFLD的患病率从48.5%显著降低至24.2%(P = 0.041);并且血清AST水平从26.12 ± 5.83 IU/L显著下降至20.52± 6.69 IU/L(P<0.001),2-2在轻度SCH患者中,LT4补充治疗对NAFLD无显著影响随访15个月后,干预组和对照组中NAFLD的患病率较基线时均无显著下降。随访结束时干预组血清ALT水平较基线时有较明显的下降(19.09 ± 9.00 IU/L to 17.95 ±7.71 IU/L,P = 0.087),而对照组血清ALT水平在随访期内保持相对恒定;两组人群血清AST的变化无显著差异。2-3在合并血脂异常的轻度SCH患者中,LT4补充治疗可改善NAFLD在合并血脂异常的轻度亚临床甲减患者中,接受LT4干预治疗15个月后,NAFLD的患病率从54.3%下降至40.5%(P = 0.035),血清ALT水平从19.93 ± 10.60(IU/L)下降至18.07 ± 8.27(IU/L)(P = 0.043);而未接受LT4干预治疗的患者,NAFLD的患病率和血清ALT水平均无显著变化(P均>0.05)。结论:1.LT4补充治疗显著降低亚临床甲减患者,包括轻度亚临床甲减患者的血清TC和LDL水平。2.在轻度亚临床甲减患者中,不论血清TSH水平或血清LDL水平的高低,LT4补充治疗均可改善血脂。3.在重度亚临床甲减患者,以及合并血脂异常的轻度亚临床甲减患者中,LT4补充治疗可改善NAFLD。研究背景:随着各国经济的高速发展和生活水平的提高,糖尿病(diabetes mellitus,DM)已成为第三大慢性非传染性疾病,严重威胁人类健康。根据国际糖尿病联盟(International Diabetes Federation,IDF)提供的数据,2017年全球范围内糖尿病的患病人数为4.25亿;而如果目前的糖尿病的增长速率无法得到遏制,到2045年这一数字将增加48%达6.29亿。糖尿病不仅使患者本人遭受肉体和精神上的痛苦,还给国家和地区带来了沉重的社会经济负担:2017年全球范围内因糖尿病带来的健康相关支出高7230亿美元。近年来,在内分泌学者的不懈努力下,在延缓糖尿病并发症的发生、降低致残致死率方面取得巨大进展。但是面对糖尿病带来的如此巨大的社会经济负担,预防糖尿病的发生、控制糖尿病患病人数的增长成为更加经济有效的应对策略。既往已有学者分别在不同的人群中开展了多项关于糖尿病危险因素的前瞻性队列研究,证实了年龄、肥胖、高血压、以及传统的胆固醇指标,包括较高的低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL)和较低的高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL)等均与糖尿病的发病显著相关。近年来,另一项简单易得的胆固醇指标:非高密度脂蛋白胆固醇(non-high-density lipoprotein cholesterol,non-HDL)逐渐引起临床医师的重视:一项在746例2型糖尿病患者中实施的前瞻性队列研究显示,non-HDL是心血管疾病发生的独立危险因素,且non-HDL预测心血管疾病发病的能力显著超出LDL;另一项病例对照研究显示,在36岁以下的年轻人中,血清non-HDL水平每增加10mg/dl,心肌梗死的患病风险增加34%,判别分析显示non-HDL是所有心肌梗死危险因素(包括年龄、性别、BMI、高血压、糖尿病、吸烟、总胆固醇(total cholesterol,TC)、LDL、甘油三酯(triglycerides,TG))中最强的指示因子。上述研究均提示non-HDL水平是比LDL更有效的预测心血管疾病发病的指标。2013年由美国心脏病学院和美国心脏病协会的实践指南工作小组联合颁布的调脂治疗指南推荐non-HDL作为LDL达标后的次要胆固醇控制指标。然而,non-HDL对糖尿病发病的影响,尚未得到充分的论证。一项在540位无糖尿病的加拿大原住居民中实施的前瞻性队列研究比较了各项血脂指标预测糖尿病发病的能力,研究显示在校正年龄、性别、血压、身体质量指数(body mass index,BMI)等混杂因素后,non-HDL是糖尿病发病的独立危险因素。随后,一项回顾性研究也发现了 non-HDL在预测糖耐量正常(normal glucose tolerance,NGT)人群发生糖尿病的风险中的优势作用。与之相反地,一项在8,405例非糖尿病人群中进行的6年随访研究显示,不论在男性(OR,1.14;95%CI,0.95-1.37,P = 0.15)还是女性(OR,1.01;95%CI,0.86-1.19,P = 0.86)中non-HDL与糖尿病的发生并无显著关系。可以看到,目前关于non-HDL与糖尿病发病关系的研究还存在许多不足:首先,研究入选人群的不一致性,即部分研究未明确区分糖耐量正常和糖尿病前期人群,将处于不同的基础糖代谢状态的人群混为一谈可能会对研究结果造成影响。其次,为了更早地预防糖尿病的发病,有必要以糖尿病的发病风险为指标来找出胆固醇水平的适宜切点值,从而为通过及早改变不良的生活方式或药物干预来控制血脂,进而预防糖尿病的发生提供科学的依据。而目前尚未见前瞻性研究报道non-HDL预测糖尿病发病的临界值。综上所述,为了探讨non-HDL与糖尿病的关系,我们在糖耐量正常的人群中设计实施了一项前瞻性队列研究,验证血清胆固醇指标与糖尿病发生风险的关系;探讨在使用胆固醇指标预测糖尿病发病时,血清non-HDL与传统的胆固醇指标:总胆固醇(total cholesterol,TC)、LDL和HDL相比,是否可以更好地预测糖尿病的发病;并用该前瞻性队列数据计算各个胆固醇指标预测糖尿病发病的适宜切点值。从而为识别糖尿病的危险因素提供一个新的角度,为通过改变不良的生活方式或药物干预控制血脂水平进而预防糖尿病的发生提供更多的科学依据。研究目的:1.验证血清胆固醇指标与糖尿病发生风险之间的关系2.探讨血清non-HDL是否可以比传统的胆固醇指标更好地预测糖尿病的发病3.寻找各个胆固醇指标预测糖尿病发病的适宜切点值研究方法:1.研究设计及研究对象研究对象来自一项在中国大陆的25个社区开展的全国性、多中心流行病学调查项目:“中国2型糖尿病患者恶性肿瘤发生风险的流行病学研究”。我们选择了来自其中1个社区(山东省宁阳县)的人群,在排除不符合标准的人群后,共有3,653例糖耐量正常的个体纳入本研究。3年后,我们对这些研究对象进行随访调查,其中43例死亡,443例失访,最终有1,025名男性和1,805名女性完成了 3年随访并最终纳入分析。2.资料获取所有受试者在基线时及3年随访结束时均完成全面的资料采集,包括调查问卷、体格检查、血液标本采集及检测、口服葡萄糖耐量试验(oral glucose tolerance test,OGTT)等。上述检查均由经统一、标准化培训,并考核合格的有医学背景的调查人员完成,以尽量减少资料采集过程中由于判定标准或调查方法不同所造成的信息偏倚。3.研究指标根据世界卫生组织1999年制定的糖尿病诊断标准(World Health Organization(WHO)1999 criteria):糖耐量正常定义为空腹血糖(fasting plasma glucose,FPG)<6.1 mmol/L且2小时血糖(2-hour plasma glucose,2hPG)<7.8 mmol/L;糖尿病定义为空腹血糖≥7.0 mmol/L和/或2hPG≥ 11.1 mmol/L,或自述既往有明确的糖尿病病史;符合以下任一条件者诊断为糖尿病前期:① 6.1 mmol/L ≤ FPG<7.0 mmol/L 并且 2hPG<1 1.1mmol/L;② FPG<7.0 mmol/L 并且 7.8 mmol/L ≤ 2hPG<11.1 mmol/L。4.统计分析采用SPSS 22.0软件进行统计分析。由于糖尿病的发病风险在男性和女性之间差异显著,我们在不同性别人群中分别分析了血清胆固醇指标与糖尿病发病风险的关系。糖尿病的发病风险采用Logistic回归模型进行分析;利用受试者工作特征(Receiver Operating Characteristic,ROC)曲线分析法分析基线时不同的胆固醇指标对3年随访结束时糖尿病发病风险的预测作用;计算约登指数(Youden index,sensitivity + specificity-1),取约登指数取值最大时所对应的胆固醇指标的取值作为该胆固醇指标预测糖尿病发病的适宜切点值(optimal cut-off points)。结果:1.在女性中,糖尿病的发病风险随TC、LDL及non-HDL水平的升高而逐渐增加分别根据不同的血清胆固醇指标的四分位数将研究人群分为4组。在女性研究对象中,糖尿病的三年累积发病率随血清TC(from Quartile 1 to Quartile 4:3.5%,4.3%,5.9%,7.7%)、LDL(from Quartile 1 to Quartile 4:2.5%,5.3%,6.4%,7.3%)、non-HDL(from Quartile 1 to Quartile 4:3.2%,4.1%,5.7%,8.4%)水平的升高逐渐增加。在多因素 Logistics回归模型中,在校正混杂因素后,糖尿病的发生风险随血清TC、LDL、non-HDL的升高呈剂量依赖性的增加:血清non-HDL>4.11 mmol/L组(Quartile 4)的糖尿病发病风险是血清 non-HDL<2.83 mmol/L 组(Quartile 1)的 2.4 倍(OR,2.39;95%CI,1.22-4.68,P = 0.011)。而在男性研究对象中,血清 TC(P = 0.750)、LDL(P = 0.222)、HDL(P =0.774)、non-HDL(P = 0.451)均与糖尿病的发病风险无独立相关关系。2.在女性中,与TC和LDL相比,non-HDL对糖尿病发病的影响更大在女性中,non-HDL对糖尿病发病的影响比TC和LDL更大:血清non-HDL每增加一个标准差(standard deviation,SD),糖尿病的发病风险增加43%(OR,1.43;95%CI,1.14-1.79;P = 0.002);而TC和LDL每增加一个SD,糖尿病的发病风险增加分别增加33%(95%CI,1.06-1.67;P = 0.015)和 30%(95%CI,1.04-1.64;P = 0.024)。3.各胆固醇指标预测糖尿病发病的适宜切点值在全体女性研究对象中,TC、LDL和non-HDL预测糖尿病发病适宜切点值分别为为5.25mmol/L、2.95mmol/L和3.48mmol/L。在不同的肥胖程度的女性研究人群中,随着肥胖程度的增加,non-HDL预测糖尿病发病的适宜切点值逐渐升高:在超重组和肥胖组女性中,non-HDL预测糖尿病发病的适宜切点值分别为3.39mmo/L(灵敏度为0.73,特异度为0.51)和3.51mmo/L(灵敏度为0.83,特异度为0.50)。结论:1.在糖耐量正常的女性中,血清non-HDL水平与糖尿病发病风险显著正相关。2.在糖耐量正常的女性中,与TC和LDL相比,non-HDL对糖尿病发病的影响更大。3.随肥胖程度的增加,non-HDL预测糖尿病发病的适宜切点值逐渐升高。更多还原

【Abstract】 Background:Hypothyroidism is one of the most common endocrine disorders with low metabolic syndrome as the main manifestation.Depending on the severity of the disease,hypothyroidism is classified into overt hypothyroidism and subclinical hypothyroidism(SCH).SCH is an early manifestation of thyroid underactivity,which is characterized by elevated serum thyroid-stimulating hormone(TSH)levels,whereas serum-free thyroxine(FT4)levels within the normal range.According to the extent of elevation of TSH,SCH can be further defined as significant SCH(TSH ≥ 10.0 mIU/L)and mild SCH(TSH<10.0 mIU/L).Recent years,with the introduction of a hypersensitive assay method of TSH and FT4,the prevalence of SCH is progressively increasing.The worldwide prevalence of SCH was estimated ranging from 4%to 10%.In women over the age of 60,the prevalence of SCH is high to 20%.Previous studies have demonstrated that SCH can cause cardiac dysfunction,and is an independent risk factor for ischemic heart disease.In addition,about 2%-5%of SCH patients might progress to overt hypothyroidism.Therefore,prevention and treatment of SCH is an important task faced by endocrinologists.Levothyroxine(LT4)is the recommended medication for the treatment of SCH.However,the questions about whether SCH need positive LT4 supplement,as well as the target for treatment,have gone through a long period of argument.The most recent Clinical Practice Guidelines for Hypothyroidism in Adults(2012,Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association)recommended that significant SCH patients should be given thyroid hormone replacement therapy.Although the majority of SCH patients are categorized as mild SCH,there were no clearly defined therapeutic recommendations due to the limited evidence from prospective,interventional studies.At the same time,this guideline stated out the issue that whether or not SCH patients could get cardiac benefit from LT4 treatment should be involved in the areas of future research.As we all know,hypercholesterolemia is an important risk factor for the occurrence and development of cardiovascular diseases.Lowering serum cholesterol levels can effectively reduce the morbidity and mortality of cardiovascular disease.Recent years,SCH has been shown to be associated with hypercholesterolemia.Our previous clinical study also found that serum TSH level was positively correlated with serum cholesterol levels,even after adjusted for other confounding factors.Moreover,hypercholesterolemia might be one of the important intermediate links for increased risk of cardiovascular disease induced by SCH.Therefore,when discussing the question of whether LT4 supplementation can bring cardiac benefit to patients with SCH,it should be clear first whether LT4 supplementation can improve serum cholesterol levels in SCH patients.There have been interventional studies explored this issue,but no consensus has been reached.Moreover,due to the small sample size,these studies failed to perform subgroup analyses in patients with different TSH or lipid levels,and could not answer the question that whether the effect of LT4 supplementation on serum cholesterol levels varied in patients with different basal serum TSH or cholesterol levels.The relatively small sample size and inconsistent conclusions may be the reason that why these studies did not provide enough strong evidence to guide clinical practice.Therefore,a large-sample,randomized,controlled trial was still necessary.In recent years,the relationship between SCH and non-alcoholic fatty liver disease(NAFLD)has attracted more and more attention.Both cross-sectional and prospective case-control studies have suggested that SCH is an independent risk factor for NAFLD.Our previous study also found that TSH can regulate hepatic triglycerides metabolism by affecting the expression of triglyceride de novo synthesis genes.Then,does the treatment of SCH patients to normalize elevated serum TSH levels via appropriate LT4 supplementation yield any benefits on NAFLD?No interventional study focusing on this issue is currently available.Objectives:We conducted a standardized clinical randomized controlled trial to observe the effect of LT4 supplementation on serum cholesterol levels in SCH patients.We further did a post hoc analysis of this randomized controlled trial to explore the effect of LT4 supplementation on NAFLD in SCH patients.The purpose of this study was to explore whether the LT4 supplementation therapy can bring lipid metabolism-related benefits to SCH patients from the above two perspectives,and thus to provide a reference for the management of SCH.Methods:1.Study Design and ParticipantsThis study was based on an open-label,randomized,controlled trial.37 significant and 378 mild SCH patients recruited from Ningyang County,Shandong Province were enrolled in the trial.The trial was registered at ClinicalTrials.gov(NCT01848171).2.RandomizationAccording to the guideline for hypothyroidism cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association,significant SCH patients were all treated with LT4(Euthyrox,50 μg per tablet,Merck Serono,Darmstadt,Germany).Mild SCH patients were randomized in a 1.5:1 fashion to LT4 supplement therapy or no treatment.3.Study endpointsIn the Part Ⅰ,we focused on the effect of LT4 supplement therapy on serum cholesterol levels through this randomized controlled trial.The primary outcome measure was the change in serum TC concentration;secondary outcome measures were other cholesterol indices,including changes in LDL and high-density lipoprotein cholesterol(HDL)levels during follow-up.In the Part Ⅱ,we explored the effect of LT4 supplement therapy on NAFLD in patients with SCH.The primary outcome was the prevalence of NAFLD.Secondary outcome were changes in serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels.4.Data CollectionBlood samples were drawn after an overnight fast for at least 10 hours.Chemiluminescent methods(Cobas E601;Roche)were used to quantitate thyroid function based FT3,FT4,and TSH levels.The serum lipid profile was determined using the ARCHITECT ci16200 Integrated System(Abbott).Non-HDL was calculated by subtracting HDL from total cholesterol.The intraassay and interassay coefficients of variation were always below 5%for all of the above parameters.Liver ultrasound was performed to assist the diagnosis of NAFLD.5.Statistical analysisQuantitative data are expressed as the mean 士 standard deviation or median(interquartile range)according to their distributions,and categorical data are presented as a number(percentage).Comparisons of variables among the groups were performed using one-way AN OVA,independent Student’s t-test.or the Mann-Whitney U test.A paired-samples t-test or Wilcoxon paired rank test was used for within-group comparisons(baseline and end-of-study variables in each group).Differences in categorical data were evaluated by chi-squared test.All statistical analyses were performed using SPSS version 22.0 for Windows(Chicago,IL,USA).Results:1-1 LT4 supplementation reduces serum TC and LDL levels in patients with SCHAfter LT4 treatment,significant SCH patients experienced significant decrease in serum TC(P = 0.004)and LDL(P = 0.016)levels.In addition,patients in mild SCH-LT4 group experienced a larger extent of reduction serum TC than that in the control group(P = 0.003).However,for serum LDL levels,Serum LDL decreased in mild SCH-LT4 group(P = 0.023),but was quite stable in the control group(P = 0.072).1-2 Effect of LT4 supplement on serum TC level was similar in mild SCH patients,regardless of the baseline TSH levelWhen stratify mild SCH patients according to TSH levels into three subgroups(i.e.,4.2 mIU/L≤TSH<5 mIU/L,5 mIU/L ≤ TSH<7 mIU/L,7 mIU/L≤ TSH<10 mIU/L)little change in serum TC level was observed in the control group.However,after the LT4 supplementation,serum TC levels decreased by 0.41 mmol/L,0.41 mmol/L,and 0.42 mmol/L(all P<0.001),respectively,in the three intervention subgroups defined above.In the 5 mlU/L≤TSH<7 mlU/L group,serum LDL also significantly decreased in the intervention subgroup(P = 0.033).1-3 The effect of LT4 supplement therapy on LDL was more pronounced in mild SCH patients with elevated basal LDLIn mild SCH patients with normal basal LDL(LDL<4.1 mmol/L),there were no significant changes in serum LDL levels during the study both in the intervention subgroup and in the control group.In mild SCH patients with elevated basal LDL level(LDL>4.1 mmol/L),serum LDL significantly decreased 4.55 ± 0.46 mmol/L to 4.07 ± 0.82 mmol/L(P<0.001)in the intervention group,while did not change significantly in the control group(P = 0.075).Regardless of the basal serum LDL level,serum TC decreased significantly in the two intervention subgroups defined above,while there was no significant change in the control group.2-1 In significant SCH patients,LT4 supplementation may ameliorate NAFLDIn the significant SCH group,the prevalence of NAFLD was reduced from 48.5%to 24.2%(P = 0.041)during the course of the study.Meanwhile,significant SCH patients experienced a decrease of 5.61 IU/L in serum AST(P<0.001)and a moderate but not statistically significant decrease in serum ALT-2-2 In mild SCH patients,LT4 supplementation could not ameliorate NAFLDIn mild SCH patients,there was no significant change in the prevalence of NAFLD in both the mild SCH-LT4 group and the mild SCH-Control group(P>0.05 for both).Patients in the mild SCH=LT4 group showed a marginally significant reduction in serum ALT from 19.09 IU/L to 17.95 IU/L(P,= 0.087),whereas serum ALT in the mild SCH-Control group was quite stable in the study.2-3 In mild SCH patients combined with dyslipidemia,LT4 supplementation might ameliorate NAFLDMild SCH patients with dyslipidemia who received LT4 treatment experienced decreases in the prevalence of NAFLD and serum ALT levels(P<0.05 for both).In contrast,these parameters remained comparably stable in patients who were not treated.Conclusion:1.LT4 supplementation reduces serum TC and LDL levels in patients with SCH2.Effect of LT4 supplementation on serum cholesterol level was similar in mild SCH patients,regardless of the baseline TSH or LDL level3.LT4 supplement therapy improves NAFLD in significant SCH patients,as well as in mild SCH patients combined with dyslipidemia.Background:With the rapid development in economy and changes in lifestyle,diabetes mellitus has become the third largest chronic non-communicable disease,seriously threatening humans’health.According to the data provided by the International Diabetes Federation(IDF),in 2017,there were 425 million people worldwide suffering from diabetes.Meanwhile,health-related expenditures due to diabetes were 723 billion dollars.In face of the unprecedented growth in the number of people with diabetes worldwide,preventing the onset of diabetes is indispensable in disposing the burden of diabetes.It has been well established that traditional cholesterol indexes,including higher low-density lipoprotein cholesterol(LDL)and lower high-density lipoprotein cholesterol(HDL)are important risk factors for diabetes.Recent years,non-high-density lipoprotein cholesterol(non-HDL)has been proved to be a more potent predictor of cardiovascular disease incidence than LDL:A prospective cohort study in 746 patients with type 2 diabetes showed that non-HDL is an independent risk factor for incident cardiovascular disease.In addition,a case-control study reported that for young people under the age of 36,non-HDL was the strongest indicator of myocardial infarction compared with other traditional risk factors.The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults:A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines recommended non-HDL as the secondary monitoring target in the management of atherosclerotic cardiovascular disease risk.However,the performance of non-HDL in predicting incident diabetes,especially in comparison with routine cholesterol panels,has not been well documented.A prospective study conducted in 540 diabetes-free participants reported that non-HDL was a superior independent risk factor for type 2 diabetes than LDL or HDL in Aboriginal Canadians.Subsequently,a retrospective study further validated the superior role of non-HDL in predicting diabetes in people with normal glucose tolerance(NGT).On the contrary,there is also study that observed no solid association between non-HDL and development of diabetes.It can be seen that there are still deficiencies in the current researches about the relationship between non-HDL and diabetes.First of all,some of the studies did not clearly distinguish the basal glycemic status of the selected participants,that is either subjects with normal glucose tolerance(NGT)or pre-diabetic were involved,which might affect the results of the studies.On the other hand,for clinical practice and health promotion strategies,accurate estimate of cut-off of non-HDL to discriminate incident diabetes is necessary.What’s more,to direct precise preventive strategies,it is important to develop cut-offs according to the identification of similar risk levels across population.To the best of our knowledge,there is no longitudinal study available that estimated the threshold of non-HDL in predicting diabetes.Therefore,we conducted this prospective cohort study in people with NGT to explore the relationship between serum cholesterol indexes and incident diabetes,and to estimate the cut-offs of cholesterol parameters for discriminating incident diabetes in people with NGT.Objectives:The objective of this prospective study was to analyze the association between non-HDL and development of diabetes in comparison with traditional cholesterol indexes,and to estimate the cut-offs of cholesterol parameters for discriminating incident diabetes in people with NGT.Methods:1.Study Design and ParticipantsThe present article reports on the data from the Risk Evaluation of cAncers in Chinese diabeTic Individuals:a lONgitudinal(REACTION)study,which was a prospective observational cohort study and enrolled 259,657 Chinese(≥ 40 years of age)from 25 communities in China’s mainland between 2011 and 2012,with follow-up measurements planned 3,5 and 10 years later.In this study,baseline data were obtained from 7,068 residents of Ningyang County,Shandong Province.After exclusion,3,653 individuals with NGT were eligible for this study.At the 3-year follow-up evaluation conducted in 2014-2015,43 participants died and 443 lost to the follow-up,representing 1,025 men and 1,805 women remained in the present analysis.2.Data CollectionBlood samples were drawn after an overnight fast for at least 10 hours.Fasting total cholesterol(TC),LDL,HDL and triglyceride were measured using an auto-analyzer(ARCHITECT c16000 System,Abbott Laboratories,IL,USA).Non-HDL was calculated by subtracting HDL from TC.Participants without a known history of diabetes underwent the oral glucose tolerance test(OGTT),and plasma glucose was measured at 0 hours(FPG)and 2 hours(2hPG)by the glucose oxidase method.3.Definition of glycemic statusGlycemic status was evaluated by standardized OGTT and was defined based on the World Health Organization(WHO)1999 criteria:NGT,FPG<6.1 mmol/L and 2hPG<7.8 mmol/L;diabetes,FPG>7.0 mmol/L and/or 2hPG ≥11.1 mmol/L;pre-diabetes was defined as meeting either of the following two criteria:a)6.1 mmol/L≤ FPG<7.0 mmol/L and 2hPG<11.lmmol/L;b)FPG<7.0 mmol/L and 7.8 mmol/L:≤ 2hPG<11.1 mmol/L.4.Statistical analysisSPSS version 22.0 for Windows(Chicago,IL,USA)was used for statistical analyses.Multivariate Logistic regression analysis was used to estimate the odds ratios(ORs)and 95%confidence intervals(Cls)of incident diabetes according to different serum cholesterol levels.To compare the effect size of each cholesterol indexes on the development of diabetes,ORs per one SD increase in the cholesterol variables were calculated using univariate and multivariate Logistic regression analysis respectively.Receiver operating characteristic(ROC)analysis was used to compare the ability of each cholesterol index in discriminating incident diabetes.The optimal cut-off values were identified as the point at which the value of"sensitivity + specificity-1"(Youden index)was maximum.Results:1.In women,the risk of diabetes gradually increases along with increasing in TC,LDL,and non-HDL levelsThe study population was divided into 4 groups according to the quartiles of different serum cholesterol indexes.In women,incidence rate of diabetes increased significantly as the TC(from Quartile 1 to Quartile 4:3.5%,4.3%,5.9%,7.7%),,LDL(from Quartile 1 to Quartile 4:2.5%,5.3%,6.4%,7.3%),and non-HDL(from Quartile 1 to Quartile 4:3.2%,4.1%,5.7%,8.4%)increased from the first to the forth quartile.In the multivariable-adjusted model,compared with the lowest quartile,ORs of future diabetes for the higher quartiles were higher with a trend of dose-response relationship for serum TC,LDL,and non-HDL.The multivariable-adjusted ORs of incident diabetes in the highest quartile non-HDL were 2.39(95%CI,1.22-4.68;P = 0.011),higher than that of either TC(OR = 1.97;95%CI,1.04-3.76;P = 0.039)or LDL(OR = 2.32;95%CI,1.12-4.72;P = 0.012).In men,none of these four cholesterol indexes had significant linear relationship with development of diabetes.2.Non-HDL has a greater impact on the incident of diabetes than TC and LDLIn women,a one SD increment in serum non-HDL was associated with a 1.43(95%CI,1.14-1.79;P = 0.(002)fold higher risk of diabetes,while ORs for TC and LDL were 1.33(95%CI,1.06-1.67;P = 0.015)and 1.30(95%CI,1.04-1.64;P= 0.024),respectively.3.The cut-off of non-HDL for discriminating incident diabetes in people with NGTIn all female subjects,the cut-off for non-HDL with better properties for screening of incident diabetes was identified as 3.48 mmol/L(sensitivity 0.65,specificity 0.58).The discriminatory power and the optimal cut-off values of non-HDL for incident diabetes increased across BMI categories:in women with overweight(24 kg/m2<BMI<28 kg/m2)and obesity(BMI>28 kg/m2),the appropriate cut-offs of non-HDL for screening of diabetes were estimated as 3.39 mmo/L(sensitivity 0.73,specificity 0.51)and 3.51 mmo/L(sensitivity 0.83.The specificity is 0.50),respectively.Conclusion:1.Non-HDL associated with development of diabetes independent of age,BMI,blood pressure,FPG,family history of diabetes and lifestyle in women,but not in men.2.Compared with traditional cholesterol parameters,non-HDL highlighted higher risk for new-onset diabetes.3.The discriminatory power and the optimal cut-off values of non-HDL in predicting diabetes increased across BMI categories更多还原