促甲状腺激素与心血管事件关系的研究
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摘要
研究背景
原发性甲状腺功能减低,定义为甲状腺激素水平低于正常而促甲状腺激素(Thyroid stimulating hormone, TSH)水平高于正常,已被证实与动脉粥样硬化及心血管疾病的发生风险增加相关。仅有TSH水平升高、而甲状腺激素水平正常的亚临床甲状腺功能减低(Subclinical hypothyroidism, SCH),是一种轻度的甲状腺功能减低,是否与临床不良事件相关尚不明确。有研究发现SCH与心血管疾病及相关死亡的发生风险呈显著正相关,而另外一些研究未发现两者存在显著相关。
近年来有学者进一步在甲状腺功能正常人群中观察处于正常高限的血清TSH水平与心血管危险因素及心血管疾病的关系。多项研究结果显示正常高限的TSH与高血压、高胆固醇血症、内皮功能受损、肾功能不全、代谢综合征等心血管危险因素呈显著正相关。一项前瞻性研究发现,在女性中处于正常范围的TSH水平与心血管死亡呈线性正相关。两项横断而研究发现正常高限的TSH水平与冠心病的发生呈正相关,但其他研究未发现血清TSH水平与冠心病有显著相关性。
有研究显示年龄影响SCH与冠心病的关系：对于年轻的SCH患者,冠心病的发生风险增加,而对于年老的SCH患者,冠心病的发生风险并不增加。然而,在甲状腺功能正常人群,年龄是否也影响血青TSH水平与冠心病的关系,目前尚未见相关报道。因此,本研究在甲状腺功能正常人群中观察血清TSH水平与冠心病的关系,以及年龄是否影响两者的关系。
研究目的
1、观察甲状腺功能正常者血清TSH水平与冠心病的关系；
2、观察年龄是否影响甲状腺功能正常者血.清TSH水平与冠心病的关系。
研究方法
1、研究对象：采用回顾性横断面研究的方法。选择因胸痛行冠状动脉造影者。排除标准如下：甲状腺功能异常、既往有甲状腺疾病史或因甲状腺疾病进行治疗的患者、急性或陈旧性心肌梗死、有冠状动脉成形术史、严重的心肝肾功能不全、服用影响甲状腺功能的药物。最终纳入318名受试者。
2、研究方法：记录所有受试者的性别、年龄、体重指数、有无吸烟、有无高血压、有无糖尿病、血脂、血糖、甲状腺功能、冠状动脉造影结果等信息。
3、统计分析：采用spss17.0统计学软件。所有计数资料采用均数±标准差的方法表示,计量资料采用百分比方法表示。各组间一般状况分析采用t检验、Mann-Whitney U检验或卡方检验。组间比较采用协方差分析或Logistic回归控制年龄、性别对各检测指标的影响。采用多因素Logistic回归的方法分析各变量对冠心病的影响。p<0.05认为有统计学意义。
研究结果
当对全部受试者进行分析时,未观察到冠心病者与非冠心病者的血清TSH、 T3.T4存在显著差异(TSH:1.77±0.99vs1.89±0.98mIU/L,p=0.063; T3:1.45±0.36vs1.51±0.35nmol/L, p=0.371; T4:100.06±20.49vs103.95±24.06nmol/L, p=0.233)。冠状动脉多支病变者的TSH水平与单支病变者的TSH水平无显著差别。
然后以年龄为65岁为界限进行亚组分析：
对年龄小于等于65岁者进行分析后,结果显示冠心病者的血清TSH水平显著高于非冠心病者(2.03±0.94vs1.75±0.97mIU/L,p=0.024):多因素Logistic回归分析显示血清TSH水平与冠心病的发生呈独立正相关(OR：1.512,p=0.011)；血清T3、T4水平在两组之间无显著差别；冠状动脉多支病变者的TSH水平与单支病变者的TSH水平无显著差别。
当对年龄大于65岁者进行分析后,结果显示冠心病者血清TSH水平与冠心病者比较无显著差别，血清T3、T4水平在两组之间亦无显著差别(TSH:1.66±1.0vs1.89±1.09mlU/L, T3:1.52±0.39vs1.35±0.36nmol/L, T4:101.96±18.32vs103.83±22.89nmol/L)。多因素Logistic回归分析显示血清TSH水平与冠心病的发生无显著相关(OR：1.099,p=0.767)。
结论
1、在年龄小于等于65岁的甲状腺功能正常者中,血清TSH水平升高与冠心病的发生呈显著正相关，且独立于年龄、性别、吸烟、高血压、糖尿病等传统冠心病危险因素之外。
2、在年龄大于65岁的甲状腺功能正常者中，未观察到血清TSH水平升高与冠心病的发生呈显著相关。
3、对于甲状腺功能正常者,年龄可能是影响TSH与冠心病关系的因素之一。
研究背景
亚临床甲状腺功能亢进症定义为血清促甲状腺激素水平低于正常范围,而甲状腺激素水平在正常范围。亚临床甲亢被认为是一种轻度的甲亢状态,是否导致临床不良事件发生风险增加,以及是否需要处理，一直存在争议。一些研究显示,与甲状腺功能正常人群比较,亚临床甲亢人群的房颤、高血压、骨质疏松及痴呆的发生率显著升高,但另外一些研究未证实下述结果。在关于亚临床甲亢与心血管疾病、心血管死亡及全因死亡研究方面，结论同样不一。目前没有长期的随机对照研究观察治疗亚临床甲亢是否能减少心血管事件的发生。由于亚临床甲亢发病率低,单项研究受样本量限制,易得到假阴性结果。因此,有必要汇总相关研究、扩大本量、增加统计效力,从而得到更可靠的结论。
既往有三项meta分析探讨了亚临床甲亢与心血管疾病、心血管死亡及全因死亡的关系,但其结论不一：两项meta分析结论为亚临床甲亢与心血管疾病、心血管死亡无显著相关；一项meta分析结论为亚临床甲亢显著增加全因死亡的发生风险。由于上述三项：neta分析包含的研究数量少,因此其统计效力较低,从而影响结论的可靠属于。自2008年末次meta分析发表以来,已经有11项观察亚临床甲亢与心血事件关系的队列研究发表,因此,有必要对此领域的meta分析进行更新。
研究目的
3、观察亚临床甲亢与心血管疾病的关系；
4、观察亚临床甲亢与心血管死亡的关系；
5、观察亚临床甲亢与全因死亡的关系。
研究方法
1、文献检索及纳入：全面检索在Pubmed及Embase数据库公开发表的所有观察亚临床甲亢与心血管事件或死亡(心血管死亡及全因死亡)关系的论文。符合要求的文献需满足以下标准：1)研究设计类型是队列研究(本研究所用的队列研究定义为：于研究起始时记录暴露因素,经过一定时间的随访后评价结局事件的发生情况)；2)在研究起始时检测并记录甲状腺功能；3)研究终点包括心血管疾病、心血管死亡及全因死亡的发生；4)文献中报告了相对危险度(RR)或风险比(HR)。
2.数据提取：提取的内容包括：第一位作者的姓名；发表年代；进行研究的国家；研究所纳入的受试者人数；受试者平均年龄；受试者的性别比例；亚临床甲亢的诊断标准；心血管事件的定义；亚临床甲亢的发病率；详细的研究设计方案,包括研究人群来源,研究的起始年代,研究的持续时间；研究所报告的RR或HR是否控制了年龄、性别或其他潜在的混杂因素的影响；失访率。
3、统计学分析：每项研究中控制了最多的混杂因素后得到的RR值被用来计算总的RR值及其可信区间。HR值直接换算为RR值。利用Q检验及I2计量来评价各项研究间的异质性大小。根据异质性大小选择固定效应模型或随机效应模型计算总的效应值。进行亚组分析以探讨分层因素对结果有无影响。Meta回归分析探讨异质性来源。按照逐一剔除法进行敏感性分析采用Egger's检验及Begg's检验探讨有无发表偏倚。所有数据采用STATA11.0统计学软件进行分析。P值<0.05被认为有统计学意义(除外特殊注明)。
研究结果
1.纳入研究的临床特征
共纳入17项研究。所有研究发表于2001年至2011年。大部分研究的受试者来源于社区,有5项研究的受试者的来源为因其他疾病到医院就诊的人群,亦称为特殊人群。TSH检测方法为二代或三代检测方法。大部分研究采用的TSH低限值为0.25至0.5mU/L。亚临床甲亢的发病率从1.4到14.7%不等。7项研究在随访过程中重复检测甲状腺功能,而其他10项研究仅仅在研究起始时单次检测甲状腺功能。大部分研究中的心血管事件的定义为包含各种心脏病的复合终点事件。大部分研究在统计分析时控制了传统心血管疾病危险因素的影响。一项研究的失访率为13%,其他研究的失访率均低于5%。采用Newcastle-Ottawa评分系统对各项研究进行评分,所有研究得分均在6分及以上。
2.亚临床甲亢与心血管疾病
共有11项研究观察亚临床甲亢与心血管疾病的关系。采用固定效应模型汇总所有研究的RR值后,总的RR值及其95%可信区间为1.19(95%CI：1.10-1.28),说明亚临床甲亢与心血管疾病的发生呈显著正相关；各研究间的异质性不明显(P=0.48,I2=0.0%)。仅汇总来源于社区人群的研究结果后,总的RR值为1.30(95%CI：1.16-1.47,P=0.00),结果仍具有统计学意义。
3.亚临床甲亢与心血管死亡
共有12项研究观察亚临床甲亢与心血管死亡的关系。采用随机效应模型计算总的RR值,总的RR值及可信区间为1.52(95%CI：1.08-2.13)。根据研究受试者的来源进行亚组分析,结果显示：所有来源于社区的研究汇总后的RR值及可信区间为1.26(95%CI：0.94-1.68),说明对于普通人群来说,亚临床甲亢与心血管死亡的发生无显著相关；而所有来源于医院的研究汇总后的RR值及可信区间为3.21(95%CI：1.66-6.21),说明对于合并其他疾病的人群来说,亚临床甲亢与全因死亡呈显著正相关。
4.亚临床甲亢与全因死亡
共有12项研究观察亚临床甲亢与心血管死亡的关系。采用随机效应模型计算总的RR值,总的RR值及可信区间为(RR:1.2595%CI:1.00-1.55, P=0.05)。根据研究受试者的来源进亚组分析：所有来源于社区的研究汇总后显示普通人群的亚临床甲亢与全因死亡无显著相关性(RR:1.13,95%CI:0.91-1.41,P=0.26);而所有来源于医院的研究汇总后显示合并其他疾病人群的亚临床甲亢与全因死亡呈显著正相关；RR值及可信区间为1.84(95%CI：1.05-3.25),P=0.03。
5.异质性来源的探讨
将各项研究的人群平均年龄、受试者来源、研究发表年代、研究随访时限、种族以及研究的样本量等作为可能的异质性来源纳入meta回归的变量。结果显示探讨亚临床甲亢与心血管死亡关系研究的异质性来源时,受试者人群来源具有统计学意义,提示其是各研究间异质性大的来源之一。但探讨亚临床甲亢与全因死亡关系研究的异质性来源时,上述变量均未达到统计学意义。根据各研究是否重复检测甲状腺功能及各研究人群的平均年龄进行亚组分析,结果未发生显著变化。
6.敏感性分析
对于亚临床甲亢与心血管疾病的]neta分析中,去除Robert W.Flynn等的研究后总的RR值发生轻度变化,为1.29(95%CI：1.15-1.44)。而对于亚临床甲亢与心血管死亡或全因死亡的meta分析中,剔除任一研究对研究均未产生显著影响。
7.发表偏倚检验
对于亚临床甲亢与心血管疾病、心血管死亡及全因死亡的meta分析中,采用Begg's及Egger's检验均未发现存在发表偏倚。
结论
1、亚临床甲亢显著增加普通人群的心血管疾病发生风险,且独立于传统的心血管疾病危险因素,包括年龄、体重指数、高血压、糖尿病、高胆固醇血症及吸烟等。
2、对于合并其他疾病人群,亚临床甲亢与心血管死亡及全因死亡呈显著正相关；对于普通人群,亚临床甲亢与心血管死亡及全因死亡无显著相关性。
Background
Overt hypothyroidism is known to predispose patients to cardiovascular diseases. However, controversies exist regarding whether subclinical hypothyroidism (SCH), defined as a serum thyroid stimulating hormone (TSH) concentration above the normal range with normal scrum FT4and FT3concentration, is associated with coronary artery disease (CAD) and its mortality. Some studies showed a positive association between them.But these findings were not conformed by other studies. Recently, these associations have been further investigated among individuals with normal thyroid function. High levels of TSH with the reference range were showed to be associated with hypercholesterolemia. hypertension, impaired endothelial function, arterial stiffness.metabolic syndrome and renal dysfunction. One prospective study indicated TSH levels within the reference range were positively and linearly associated with cardiovascular mortality in women and two cross-sectional studies reported that relatively high normal TSH levels within the reference range was associated with the presence of CAD, while others did not confirm these findings.
It has been reported that age influences the relationship between SCH and CAD. with increased risks for CAD in younger but not older individuals. However, few studies have explored the role of age in the link between thyroid function and CAD in euthyroid subjects so far.
Objective
1. To investigate the relationship between TSII within the reference range and CAD.
2. To investigate the modification effect of age on the relationship between TSH within
the reference range and CAD.
Methods
1. Patients who underwent coronary angiography because of chest pain were retrospectively reviewed. The exclusion criteria were as follows:Abnormal serum levels of TSH, T4or T3; History of thyroid dysfunction or under treatment with thyroid medication; Acute or past myocardial infarction; History of revascularization of coronary artery; Severe cardiac, hepatic or renal dysfunction; Medication with amiodarone, sex hormones and steroid hormones. Finally, a total of318subjects were included.
2. Information of past medications and risk factors for CAD, including smoking, hypertension, diabetes, body mass index, lipid profile, blood glucose, creatinine, thyroid hormones and coronary angiographic findings were recorded.
3. Data were represented as mean±tandard deviation. Inter-group analysis was done by using independent t test, Mann-Whitney U test and chi-square test. Analysis of covariance was performed to adjust for age and sex. Multivariate logistic regression analysis was done to determine risk factors relating to CAD. Statistical significance was set at p<0.05. All the above analyses were conducted with the use of SPSS software in version17.0.
Results
Levels of TSH, T3and T4were similar between CAD and non-CAD group (TSH:1.77±0.99vs1.89±0.98mIU/L.T3:1.45±0.36vs1.51±0.35nmol/L, T4:100.06±20.49vs103.95±24.06nmol/L, respectively) when analysis was performed among all subjects. TSH levels between the group with single-vessel CAD and multivessel CAD also did not differ significantly.
When analysis was restricted to participants younger than65years, levels of TSH were significantly higher in CAD group than in non-CAD group (2.03±0.94vs1.75±0.97mlU/L, adjusted p=0.024). Levels of T3and T4did not differ between two groups.Multiple logistic regression analysis showed elevated TSH level was an independent risk factor for CAD, with an adjusted odds ratio (OR) of1.512(95%CI:1.100-2.078, p=0.011).
Among subjects older than65years, no significant differences in TSH, T3and T4between CAD group and non-CAD group were observed (TSH:1.66±1.0vs1.89±1.09mlU/L, adjusted p=0.772; T3:1.52±0.39vs1.35±0.36nmol/L, adjusted p=0.145; T4:103.83±22.89vs101.96±18.32nmol/L, adjusted p=0.524; respectively).Multiple logistic regression analysis showed TSH level was not an independent risk factor for CAD (OR:1.099, p=0.767).
Conclusions
1. High levels of TSH within the reference range were independently associated with the presence of CAD among subjects younger than65years of age.
2. Among subjects older than65years of age, no significant relationship between high levels of TSH within the reference range and the presence of CAD was observed.
3. The findings suggested a modification effect of age on the relationship between high levels of TSH within the reference range and CAD.
Background
Subclinical hyperthyroidism, defined as a serum TSH concentration below the normal range with normal levels of thyroid hormones, is a mild form of hyperthyroidism. Whether subclinical hyperthyroidism leads to adverse clinical outcomes and should be treated remains controversial. Subclinical hyperthyroidism has been found to be associated with a higher risk of atrial fibrillation, hypertension, osteoporosis and dementia compared with euthyroid subjects in some but not all studies. Similarly, the findings from the cohort studies on the association of subclinical hyperthyroidism and cardiovascular disease (CVD), cardiovascular and all-cause mortality were also inconsistent. Lack of randomized clinical trials answering the question whether long-term health outcomes are improved by treatment of subclinical hyperthyroidism made this issue more elusive.
Several meta-analyses assessing the relationship between CVI). cardiovascular mortality and all-cause mortality have been performed previously, providing somewhat conflicting results. These meta-analyses had low power to detect this association precisely with availability of only a small number of studies. Since the latest meta-analysis had been performed, a total of eleven new large prospective studies on this issue have been published. Now data is sufficient to update the meta-analysis.
Objective
1. To investigate the relationship between subclinical hyperthyroidism and cardiovascular diseases.
2. To investigate the relationship between subclinical hyperthyroidism and cardiovascular mortality.
3. To investigate the relationship between subclinical hyperthyroidism and all-cause mortality.
Methods
1. Search strategy and Study selection. PubMed and Embase database were searched for relevant studies assessing the association between subclinical hyperthyroidism and CVD or mortality (cardiovascular and all-cause). Studies were considered eligible if they met the following criteria:1) the study design was a cohort study (its definition was as follows:exposure is measured at baseline and the occurrence of outcomes is assessed after a certain time span of follow-up);2) thyroid function was measured at baseline;3) the outcome of interest was CVD, cardiovascular or all-cause mortality; and4) relative risk (RR) or hazard ratio (HR) and the corresponding95%confidence interval (CI)(or data to calculate them) were reported.
2. Data extraction. The following data were abstracted:the first author's name; the publication year; the country of origin; the number, mean age, and sex of the participants; the definition of subclinical hyperthyroidism and cardiovascular events, based on the information as provided in the primary studies; the prevalence of subclinical hyperthyroidism; the study design details, including population source, starting year of study, and study duration; whether the reported RR or HR was adjusted for potential confounders; and losses to follow-up.
3. Statistical analyses. The study-specific maximally adjusted RR or HR was used to compute a summary RR and its95%CI. HRs were directly considered as RRs. Heterogeneity across studies was tested by using the Q and I2statistic. The combined risk estimates were computed using either fixed-effects models or random-effects models with the presence of heterogeneity. A subgroup analysis was conducted to explore the potential effect modification of variables on outcomes. Meta-regression was used to explore possible contributors to heterogeneity. We also investigated the influence of a single study on the overall risk estimate by omitting1study in each turn. Potential publication bias was assessed by Egger's test and Begg's test to evaluate publication bias. All analyses were performed using STATA version11.0. A P value<0.05was considered statistically significant, except where otherwise specified.
Results
1. Study characteristics and Quality assessment. The characteristics of17cohort studies were included. These studies were published between2001and2011. The mean length of follow-up ranged from2to20years. In most studies participants were recruited from communities and participants of five studies derived from convenience sample. All studies used second or third generation method for TSH assay. Most studies had a TSH cutoff value of0.25to0.5mU/L with normal FT4level. The prevalence of subclinical hyperthyroidism ranged from1.4%to14.7%. Seven studies repeatedly measured thyroid functions over follow-up and the others made single baseline measurements. Most studies defined cardiovascular events as a combined endpoint. All outcome assessments were from medical record and hospital database. Most studies adjusted for a group of conventional risk factors for CVD. Losses to follow-up were lower than5%in most studies. The Newcastle-Ottawa Scale was adopted for quality assessment and all studies scored6or higher.
2. Subclinical hyperthyroidism and risk of CVD.Eleven eligible studies on the association between subclinical hyperthyroidism and CVD were pooled. The summary RR from the fixed-effects model was1.19(95%CI:1.10to1.28) with no evidence of heterogeneity (P=0.48,I2-=0.0%). When only combining studies from community sample the summary RR was1.30(95%CI:1.16to1.47.P=0.00).
3. Subclinical hyperthyroidism and risk of cardiovascular mortality. Twelve eligible studies on the association between subclinical hyperthyroidism and cardiovascular mortality were combined. The summary RR for cardiovascular mortality was1.52(95%CI:1.08to2.13) with a moderate degree of heterogeneity (P=0.084,I2=38.5%). Sub-analysis by sample source showed that the summary RR was1.26(95%CI:0.94to 1.68) when restricting to studies from community sample and3.21(95%CI:1.66to6.21) when restricting to those from convenience sample.
4. Subclinical hyperthyroidism and risk of All-cause mortality. Twelve studies were pooled to calculate the overall RR for all-cause mortality. A borderline significant association was observed when combining all studies (RR:1.2595%CI:1.00to1.55, P=0.05) with presence of heterogeneity (P=0.03,I2=48.0%). Significant difference between subclinical hyperthyroidism and reference group disappeared when combining studies from community samples (RR:1.13[95%CI:0.91to1.41]; P=0.26) but existed when pooling those from convenience samples (RR:1.84[95%CI:1.05to3.25]; P=0.03).
5. Exploration of the sources of heterogeneity. Exploratory univariate meta-regression was performed with age, sample source, publication year, length of follow-up, ethnicity and sample size as the potential sources of between-study heterogeneity. Sample source was a key contributor to the heterogeneity among studies on the association between subclinical hyperthyroidism and cardiovascular mortality. None of variables abovementioned was identified as a potentially important source of between-study heterogeneity in combining RRs for total mortality. Stratified analysis by assessment of thyroid function (repeated or not) and mean age barely changed the results among studies from community sample.
6. Sensitivity analysis. Omission of the study by Robert W. Flynnhad moderate influence on the combined RRs of subclinical hyperthyroidism for risk of CVD, changing the summary RR to1.29(95%CI:1.15to1.44). No evidence of any individual study having excessive influence on the pooled effect in combining risk estimates of subclinical hyperthyroidism for cardiovascular mortality or all-cause mortality was observed.
7. Publication bias. The Begg's funnel plot and Egger s regression test did not indicate evidence of publication bias.
Conclusions
1. Subclinical hyperthyroidism was associated with an increased risk of CVD for general individuals, independent of conventional CVD risk factors, including age, diabetes, hypertension, smoking, BMI and hypercholesterolemia et al.
2. Subclinical hyperthyroidism was associated with an increased risk of cardiovascular and all-cause mortality only for sick individuals, but not for general individuals.
原发性甲状腺功能减低,定义为甲状腺激素水平低于正常而促甲状腺激素(Thyroid stimulating hormone, TSH)水平高于正常,已被证实与动脉粥样硬化及心血管疾病的发生风险增加相关。仅有TSH水平升高、而甲状腺激素水平正常的亚临床甲状腺功能减低(Subclinical hypothyroidism, SCH),是一种轻度的甲状腺功能减低,是否与临床不良事件相关尚不明确。有研究发现SCH与心血管疾病及相关死亡的发生风险呈显著正相关,而另外一些研究未发现两者存在显著相关。
近年来有学者进一步在甲状腺功能正常人群中观察处于正常高限的血清TSH水平与心血管危险因素及心血管疾病的关系。多项研究结果显示正常高限的TSH与高血压、高胆固醇血症、内皮功能受损、肾功能不全、代谢综合征等心血管危险因素呈显著正相关。一项前瞻性研究发现,在女性中处于正常范围的TSH水平与心血管死亡呈线性正相关。两项横断而研究发现正常高限的TSH水平与冠心病的发生呈正相关,但其他研究未发现血清TSH水平与冠心病有显著相关性。
有研究显示年龄影响SCH与冠心病的关系：对于年轻的SCH患者,冠心病的发生风险增加,而对于年老的SCH患者,冠心病的发生风险并不增加。然而,在甲状腺功能正常人群,年龄是否也影响血青TSH水平与冠心病的关系,目前尚未见相关报道。因此,本研究在甲状腺功能正常人群中观察血清TSH水平与冠心病的关系,以及年龄是否影响两者的关系。
研究目的
1、观察甲状腺功能正常者血清TSH水平与冠心病的关系；
2、观察年龄是否影响甲状腺功能正常者血.清TSH水平与冠心病的关系。
研究方法
1、研究对象：采用回顾性横断面研究的方法。选择因胸痛行冠状动脉造影者。排除标准如下：甲状腺功能异常、既往有甲状腺疾病史或因甲状腺疾病进行治疗的患者、急性或陈旧性心肌梗死、有冠状动脉成形术史、严重的心肝肾功能不全、服用影响甲状腺功能的药物。最终纳入318名受试者。
2、研究方法：记录所有受试者的性别、年龄、体重指数、有无吸烟、有无高血压、有无糖尿病、血脂、血糖、甲状腺功能、冠状动脉造影结果等信息。
3、统计分析：采用spss17.0统计学软件。所有计数资料采用均数±标准差的方法表示,计量资料采用百分比方法表示。各组间一般状况分析采用t检验、Mann-Whitney U检验或卡方检验。组间比较采用协方差分析或Logistic回归控制年龄、性别对各检测指标的影响。采用多因素Logistic回归的方法分析各变量对冠心病的影响。p<0.05认为有统计学意义。
研究结果
当对全部受试者进行分析时,未观察到冠心病者与非冠心病者的血清TSH、 T3.T4存在显著差异(TSH:1.77±0.99vs1.89±0.98mIU/L,p=0.063; T3:1.45±0.36vs1.51±0.35nmol/L, p=0.371; T4:100.06±20.49vs103.95±24.06nmol/L, p=0.233)。冠状动脉多支病变者的TSH水平与单支病变者的TSH水平无显著差别。
然后以年龄为65岁为界限进行亚组分析：
对年龄小于等于65岁者进行分析后,结果显示冠心病者的血清TSH水平显著高于非冠心病者(2.03±0.94vs1.75±0.97mIU/L,p=0.024):多因素Logistic回归分析显示血清TSH水平与冠心病的发生呈独立正相关(OR：1.512,p=0.011)；血清T3、T4水平在两组之间无显著差别；冠状动脉多支病变者的TSH水平与单支病变者的TSH水平无显著差别。
当对年龄大于65岁者进行分析后,结果显示冠心病者血清TSH水平与冠心病者比较无显著差别，血清T3、T4水平在两组之间亦无显著差别(TSH:1.66±1.0vs1.89±1.09mlU/L, T3:1.52±0.39vs1.35±0.36nmol/L, T4:101.96±18.32vs103.83±22.89nmol/L)。多因素Logistic回归分析显示血清TSH水平与冠心病的发生无显著相关(OR：1.099,p=0.767)。
结论
1、在年龄小于等于65岁的甲状腺功能正常者中,血清TSH水平升高与冠心病的发生呈显著正相关，且独立于年龄、性别、吸烟、高血压、糖尿病等传统冠心病危险因素之外。
2、在年龄大于65岁的甲状腺功能正常者中，未观察到血清TSH水平升高与冠心病的发生呈显著相关。
3、对于甲状腺功能正常者,年龄可能是影响TSH与冠心病关系的因素之一。
研究背景
亚临床甲状腺功能亢进症定义为血清促甲状腺激素水平低于正常范围,而甲状腺激素水平在正常范围。亚临床甲亢被认为是一种轻度的甲亢状态,是否导致临床不良事件发生风险增加,以及是否需要处理，一直存在争议。一些研究显示,与甲状腺功能正常人群比较,亚临床甲亢人群的房颤、高血压、骨质疏松及痴呆的发生率显著升高,但另外一些研究未证实下述结果。在关于亚临床甲亢与心血管疾病、心血管死亡及全因死亡研究方面，结论同样不一。目前没有长期的随机对照研究观察治疗亚临床甲亢是否能减少心血管事件的发生。由于亚临床甲亢发病率低,单项研究受样本量限制,易得到假阴性结果。因此,有必要汇总相关研究、扩大本量、增加统计效力,从而得到更可靠的结论。
既往有三项meta分析探讨了亚临床甲亢与心血管疾病、心血管死亡及全因死亡的关系,但其结论不一：两项meta分析结论为亚临床甲亢与心血管疾病、心血管死亡无显著相关；一项meta分析结论为亚临床甲亢显著增加全因死亡的发生风险。由于上述三项：neta分析包含的研究数量少,因此其统计效力较低,从而影响结论的可靠属于。自2008年末次meta分析发表以来,已经有11项观察亚临床甲亢与心血事件关系的队列研究发表,因此,有必要对此领域的meta分析进行更新。
研究目的
3、观察亚临床甲亢与心血管疾病的关系；
4、观察亚临床甲亢与心血管死亡的关系；
5、观察亚临床甲亢与全因死亡的关系。
研究方法
1、文献检索及纳入：全面检索在Pubmed及Embase数据库公开发表的所有观察亚临床甲亢与心血管事件或死亡(心血管死亡及全因死亡)关系的论文。符合要求的文献需满足以下标准：1)研究设计类型是队列研究(本研究所用的队列研究定义为：于研究起始时记录暴露因素,经过一定时间的随访后评价结局事件的发生情况)；2)在研究起始时检测并记录甲状腺功能；3)研究终点包括心血管疾病、心血管死亡及全因死亡的发生；4)文献中报告了相对危险度(RR)或风险比(HR)。
2.数据提取：提取的内容包括：第一位作者的姓名；发表年代；进行研究的国家；研究所纳入的受试者人数；受试者平均年龄；受试者的性别比例；亚临床甲亢的诊断标准；心血管事件的定义；亚临床甲亢的发病率；详细的研究设计方案,包括研究人群来源,研究的起始年代,研究的持续时间；研究所报告的RR或HR是否控制了年龄、性别或其他潜在的混杂因素的影响；失访率。
3、统计学分析：每项研究中控制了最多的混杂因素后得到的RR值被用来计算总的RR值及其可信区间。HR值直接换算为RR值。利用Q检验及I2计量来评价各项研究间的异质性大小。根据异质性大小选择固定效应模型或随机效应模型计算总的效应值。进行亚组分析以探讨分层因素对结果有无影响。Meta回归分析探讨异质性来源。按照逐一剔除法进行敏感性分析采用Egger's检验及Begg's检验探讨有无发表偏倚。所有数据采用STATA11.0统计学软件进行分析。P值<0.05被认为有统计学意义(除外特殊注明)。
研究结果
1.纳入研究的临床特征
共纳入17项研究。所有研究发表于2001年至2011年。大部分研究的受试者来源于社区,有5项研究的受试者的来源为因其他疾病到医院就诊的人群,亦称为特殊人群。TSH检测方法为二代或三代检测方法。大部分研究采用的TSH低限值为0.25至0.5mU/L。亚临床甲亢的发病率从1.4到14.7%不等。7项研究在随访过程中重复检测甲状腺功能,而其他10项研究仅仅在研究起始时单次检测甲状腺功能。大部分研究中的心血管事件的定义为包含各种心脏病的复合终点事件。大部分研究在统计分析时控制了传统心血管疾病危险因素的影响。一项研究的失访率为13%,其他研究的失访率均低于5%。采用Newcastle-Ottawa评分系统对各项研究进行评分,所有研究得分均在6分及以上。
2.亚临床甲亢与心血管疾病
共有11项研究观察亚临床甲亢与心血管疾病的关系。采用固定效应模型汇总所有研究的RR值后,总的RR值及其95%可信区间为1.19(95%CI：1.10-1.28),说明亚临床甲亢与心血管疾病的发生呈显著正相关；各研究间的异质性不明显(P=0.48,I2=0.0%)。仅汇总来源于社区人群的研究结果后,总的RR值为1.30(95%CI：1.16-1.47,P=0.00),结果仍具有统计学意义。
3.亚临床甲亢与心血管死亡
共有12项研究观察亚临床甲亢与心血管死亡的关系。采用随机效应模型计算总的RR值,总的RR值及可信区间为1.52(95%CI：1.08-2.13)。根据研究受试者的来源进行亚组分析,结果显示：所有来源于社区的研究汇总后的RR值及可信区间为1.26(95%CI：0.94-1.68),说明对于普通人群来说,亚临床甲亢与心血管死亡的发生无显著相关；而所有来源于医院的研究汇总后的RR值及可信区间为3.21(95%CI：1.66-6.21),说明对于合并其他疾病的人群来说,亚临床甲亢与全因死亡呈显著正相关。
4.亚临床甲亢与全因死亡
共有12项研究观察亚临床甲亢与心血管死亡的关系。采用随机效应模型计算总的RR值,总的RR值及可信区间为(RR:1.2595%CI:1.00-1.55, P=0.05)。根据研究受试者的来源进亚组分析：所有来源于社区的研究汇总后显示普通人群的亚临床甲亢与全因死亡无显著相关性(RR:1.13,95%CI:0.91-1.41,P=0.26);而所有来源于医院的研究汇总后显示合并其他疾病人群的亚临床甲亢与全因死亡呈显著正相关；RR值及可信区间为1.84(95%CI：1.05-3.25),P=0.03。
5.异质性来源的探讨
将各项研究的人群平均年龄、受试者来源、研究发表年代、研究随访时限、种族以及研究的样本量等作为可能的异质性来源纳入meta回归的变量。结果显示探讨亚临床甲亢与心血管死亡关系研究的异质性来源时,受试者人群来源具有统计学意义,提示其是各研究间异质性大的来源之一。但探讨亚临床甲亢与全因死亡关系研究的异质性来源时,上述变量均未达到统计学意义。根据各研究是否重复检测甲状腺功能及各研究人群的平均年龄进行亚组分析,结果未发生显著变化。
6.敏感性分析
对于亚临床甲亢与心血管疾病的]neta分析中,去除Robert W.Flynn等的研究后总的RR值发生轻度变化,为1.29(95%CI：1.15-1.44)。而对于亚临床甲亢与心血管死亡或全因死亡的meta分析中,剔除任一研究对研究均未产生显著影响。
7.发表偏倚检验
对于亚临床甲亢与心血管疾病、心血管死亡及全因死亡的meta分析中,采用Begg's及Egger's检验均未发现存在发表偏倚。
结论
1、亚临床甲亢显著增加普通人群的心血管疾病发生风险,且独立于传统的心血管疾病危险因素,包括年龄、体重指数、高血压、糖尿病、高胆固醇血症及吸烟等。
2、对于合并其他疾病人群,亚临床甲亢与心血管死亡及全因死亡呈显著正相关；对于普通人群,亚临床甲亢与心血管死亡及全因死亡无显著相关性。
Background
Overt hypothyroidism is known to predispose patients to cardiovascular diseases. However, controversies exist regarding whether subclinical hypothyroidism (SCH), defined as a serum thyroid stimulating hormone (TSH) concentration above the normal range with normal scrum FT4and FT3concentration, is associated with coronary artery disease (CAD) and its mortality. Some studies showed a positive association between them.But these findings were not conformed by other studies. Recently, these associations have been further investigated among individuals with normal thyroid function. High levels of TSH with the reference range were showed to be associated with hypercholesterolemia. hypertension, impaired endothelial function, arterial stiffness.metabolic syndrome and renal dysfunction. One prospective study indicated TSH levels within the reference range were positively and linearly associated with cardiovascular mortality in women and two cross-sectional studies reported that relatively high normal TSH levels within the reference range was associated with the presence of CAD, while others did not confirm these findings.
It has been reported that age influences the relationship between SCH and CAD. with increased risks for CAD in younger but not older individuals. However, few studies have explored the role of age in the link between thyroid function and CAD in euthyroid subjects so far.
Objective
1. To investigate the relationship between TSII within the reference range and CAD.
2. To investigate the modification effect of age on the relationship between TSH within
the reference range and CAD.
Methods
1. Patients who underwent coronary angiography because of chest pain were retrospectively reviewed. The exclusion criteria were as follows:Abnormal serum levels of TSH, T4or T3; History of thyroid dysfunction or under treatment with thyroid medication; Acute or past myocardial infarction; History of revascularization of coronary artery; Severe cardiac, hepatic or renal dysfunction; Medication with amiodarone, sex hormones and steroid hormones. Finally, a total of318subjects were included.
2. Information of past medications and risk factors for CAD, including smoking, hypertension, diabetes, body mass index, lipid profile, blood glucose, creatinine, thyroid hormones and coronary angiographic findings were recorded.
3. Data were represented as mean±tandard deviation. Inter-group analysis was done by using independent t test, Mann-Whitney U test and chi-square test. Analysis of covariance was performed to adjust for age and sex. Multivariate logistic regression analysis was done to determine risk factors relating to CAD. Statistical significance was set at p<0.05. All the above analyses were conducted with the use of SPSS software in version17.0.
Results
Levels of TSH, T3and T4were similar between CAD and non-CAD group (TSH:1.77±0.99vs1.89±0.98mIU/L.T3:1.45±0.36vs1.51±0.35nmol/L, T4:100.06±20.49vs103.95±24.06nmol/L, respectively) when analysis was performed among all subjects. TSH levels between the group with single-vessel CAD and multivessel CAD also did not differ significantly.
When analysis was restricted to participants younger than65years, levels of TSH were significantly higher in CAD group than in non-CAD group (2.03±0.94vs1.75±0.97mlU/L, adjusted p=0.024). Levels of T3and T4did not differ between two groups.Multiple logistic regression analysis showed elevated TSH level was an independent risk factor for CAD, with an adjusted odds ratio (OR) of1.512(95%CI:1.100-2.078, p=0.011).
Among subjects older than65years, no significant differences in TSH, T3and T4between CAD group and non-CAD group were observed (TSH:1.66±1.0vs1.89±1.09mlU/L, adjusted p=0.772; T3:1.52±0.39vs1.35±0.36nmol/L, adjusted p=0.145; T4:103.83±22.89vs101.96±18.32nmol/L, adjusted p=0.524; respectively).Multiple logistic regression analysis showed TSH level was not an independent risk factor for CAD (OR:1.099, p=0.767).
Conclusions
1. High levels of TSH within the reference range were independently associated with the presence of CAD among subjects younger than65years of age.
2. Among subjects older than65years of age, no significant relationship between high levels of TSH within the reference range and the presence of CAD was observed.
3. The findings suggested a modification effect of age on the relationship between high levels of TSH within the reference range and CAD.
Background
Subclinical hyperthyroidism, defined as a serum TSH concentration below the normal range with normal levels of thyroid hormones, is a mild form of hyperthyroidism. Whether subclinical hyperthyroidism leads to adverse clinical outcomes and should be treated remains controversial. Subclinical hyperthyroidism has been found to be associated with a higher risk of atrial fibrillation, hypertension, osteoporosis and dementia compared with euthyroid subjects in some but not all studies. Similarly, the findings from the cohort studies on the association of subclinical hyperthyroidism and cardiovascular disease (CVD), cardiovascular and all-cause mortality were also inconsistent. Lack of randomized clinical trials answering the question whether long-term health outcomes are improved by treatment of subclinical hyperthyroidism made this issue more elusive.
Several meta-analyses assessing the relationship between CVI). cardiovascular mortality and all-cause mortality have been performed previously, providing somewhat conflicting results. These meta-analyses had low power to detect this association precisely with availability of only a small number of studies. Since the latest meta-analysis had been performed, a total of eleven new large prospective studies on this issue have been published. Now data is sufficient to update the meta-analysis.
Objective
1. To investigate the relationship between subclinical hyperthyroidism and cardiovascular diseases.
2. To investigate the relationship between subclinical hyperthyroidism and cardiovascular mortality.
3. To investigate the relationship between subclinical hyperthyroidism and all-cause mortality.
Methods
1. Search strategy and Study selection. PubMed and Embase database were searched for relevant studies assessing the association between subclinical hyperthyroidism and CVD or mortality (cardiovascular and all-cause). Studies were considered eligible if they met the following criteria:1) the study design was a cohort study (its definition was as follows:exposure is measured at baseline and the occurrence of outcomes is assessed after a certain time span of follow-up);2) thyroid function was measured at baseline;3) the outcome of interest was CVD, cardiovascular or all-cause mortality; and4) relative risk (RR) or hazard ratio (HR) and the corresponding95%confidence interval (CI)(or data to calculate them) were reported.
2. Data extraction. The following data were abstracted:the first author's name; the publication year; the country of origin; the number, mean age, and sex of the participants; the definition of subclinical hyperthyroidism and cardiovascular events, based on the information as provided in the primary studies; the prevalence of subclinical hyperthyroidism; the study design details, including population source, starting year of study, and study duration; whether the reported RR or HR was adjusted for potential confounders; and losses to follow-up.
3. Statistical analyses. The study-specific maximally adjusted RR or HR was used to compute a summary RR and its95%CI. HRs were directly considered as RRs. Heterogeneity across studies was tested by using the Q and I2statistic. The combined risk estimates were computed using either fixed-effects models or random-effects models with the presence of heterogeneity. A subgroup analysis was conducted to explore the potential effect modification of variables on outcomes. Meta-regression was used to explore possible contributors to heterogeneity. We also investigated the influence of a single study on the overall risk estimate by omitting1study in each turn. Potential publication bias was assessed by Egger's test and Begg's test to evaluate publication bias. All analyses were performed using STATA version11.0. A P value<0.05was considered statistically significant, except where otherwise specified.
Results
1. Study characteristics and Quality assessment. The characteristics of17cohort studies were included. These studies were published between2001and2011. The mean length of follow-up ranged from2to20years. In most studies participants were recruited from communities and participants of five studies derived from convenience sample. All studies used second or third generation method for TSH assay. Most studies had a TSH cutoff value of0.25to0.5mU/L with normal FT4level. The prevalence of subclinical hyperthyroidism ranged from1.4%to14.7%. Seven studies repeatedly measured thyroid functions over follow-up and the others made single baseline measurements. Most studies defined cardiovascular events as a combined endpoint. All outcome assessments were from medical record and hospital database. Most studies adjusted for a group of conventional risk factors for CVD. Losses to follow-up were lower than5%in most studies. The Newcastle-Ottawa Scale was adopted for quality assessment and all studies scored6or higher.
2. Subclinical hyperthyroidism and risk of CVD.Eleven eligible studies on the association between subclinical hyperthyroidism and CVD were pooled. The summary RR from the fixed-effects model was1.19(95%CI:1.10to1.28) with no evidence of heterogeneity (P=0.48,I2-=0.0%). When only combining studies from community sample the summary RR was1.30(95%CI:1.16to1.47.P=0.00).
3. Subclinical hyperthyroidism and risk of cardiovascular mortality. Twelve eligible studies on the association between subclinical hyperthyroidism and cardiovascular mortality were combined. The summary RR for cardiovascular mortality was1.52(95%CI:1.08to2.13) with a moderate degree of heterogeneity (P=0.084,I2=38.5%). Sub-analysis by sample source showed that the summary RR was1.26(95%CI:0.94to 1.68) when restricting to studies from community sample and3.21(95%CI:1.66to6.21) when restricting to those from convenience sample.
4. Subclinical hyperthyroidism and risk of All-cause mortality. Twelve studies were pooled to calculate the overall RR for all-cause mortality. A borderline significant association was observed when combining all studies (RR:1.2595%CI:1.00to1.55, P=0.05) with presence of heterogeneity (P=0.03,I2=48.0%). Significant difference between subclinical hyperthyroidism and reference group disappeared when combining studies from community samples (RR:1.13[95%CI:0.91to1.41]; P=0.26) but existed when pooling those from convenience samples (RR:1.84[95%CI:1.05to3.25]; P=0.03).
5. Exploration of the sources of heterogeneity. Exploratory univariate meta-regression was performed with age, sample source, publication year, length of follow-up, ethnicity and sample size as the potential sources of between-study heterogeneity. Sample source was a key contributor to the heterogeneity among studies on the association between subclinical hyperthyroidism and cardiovascular mortality. None of variables abovementioned was identified as a potentially important source of between-study heterogeneity in combining RRs for total mortality. Stratified analysis by assessment of thyroid function (repeated or not) and mean age barely changed the results among studies from community sample.
6. Sensitivity analysis. Omission of the study by Robert W. Flynnhad moderate influence on the combined RRs of subclinical hyperthyroidism for risk of CVD, changing the summary RR to1.29(95%CI:1.15to1.44). No evidence of any individual study having excessive influence on the pooled effect in combining risk estimates of subclinical hyperthyroidism for cardiovascular mortality or all-cause mortality was observed.
7. Publication bias. The Begg's funnel plot and Egger s regression test did not indicate evidence of publication bias.
Conclusions
1. Subclinical hyperthyroidism was associated with an increased risk of CVD for general individuals, independent of conventional CVD risk factors, including age, diabetes, hypertension, smoking, BMI and hypercholesterolemia et al.
2. Subclinical hyperthyroidism was associated with an increased risk of cardiovascular and all-cause mortality only for sick individuals, but not for general individuals.
引文
1. Chakera AJ, Pearce SH, Vaidya B. Treatment for primary hypothyroidism:current approaches and future possibilities. Drug Des Devel Ther.2012;6:1-11.
2. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab. 2003;88(6):2438-2444.
3. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Intern Med.2000;160(4):526-534.
4. Luboshitzky R, Aviv A, Herer P, et al. Risk factors for cardiovascular disease in women with subclinical hypothyroidism. Thyroid.2002;12(5):421-425.
5. Liu D, Jiang F, Shan Z, et al. A cross-sectional survey of relationship between serum TSH level and blood pressure. J Hum Hypertens.2010;24(2):134-138.
6. Danese MD, Ladenson PW, Meinert CL, et al. Clinical review 115:effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure:a quantitative review of the literature. J Clin Endocrinol Metab.2000;85(9):2993-3001.
7. Maratou E, Hadjidakis DJ, Kollias A, et al. Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol.2009;160(5):785-790.
8. Knudsen N, Laurberg P, Rasmussen LB, et al. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. J Clin Endocrinol Metab.2005;90(7):4019-4024.
9. Owen PJ, Sabit R, Lazarus JH. Thyroid disease and vascular function. Thyroid. 2007;17(6):519-524.
10. Lindeman RD, Romero LJ, Schade DS, et al. Impact of subclinical hypothyroidism on serum total homocysteine concentrations, the prevalence of coronary heart disease (CHD), and CHD risk factors in the New Mexico Elder Health Survey. Thyroid. 2003;13(6):595-600.
11. Wang CY, Chang TC, Chen MF. Associations between subclinical thyroid disease and metabolic syndrome. Endocr J.2012.
12. Imaizumi M, Akahoshi M, Ichimaru S, et al. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab.2004;89(7):3365-3370.
13. Walsh JP, Bremner AP, Bulsara MK, et aI. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med. 2005;l65(2l):2467-2472.
14. Tseng FY, Lin WY, Lin CC, et al. Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults. J Am Coll Cardiol. 2012;60(8):730-737.
15. Iervasi G, Molinaro S, Landi P, et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med. 2007; 167(14): 1526-1532.
16. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006;295(9):1033-1041.
17. Rodondi N, Newman AB, Vittinghoff E, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005;165(21):2460-2466.
18. Boekholdt SM, Titan SM, Wiersinga WM, et al. Initial thyroid status and cardiovascular risk factors: the EPIC-lNorfolk prospective population study. Clin Endocrinol (Oxf)-2010;72(3):404-410.
19. Asvold BO, Bjoro T, INilsen Tl, et al. Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study. Arch Intern Med. 2008;168(8):855-860.
20. Miura S, litaka M, Suzuki S, et al. Decrease in serum levels of thyroid hormone in patients with coronary heart disease. Endoer.Jl. 1996;43(6):657-663.
21. Yun KH, Jeong MH, Oh SK, et al. Relationship of thyroid stimulating hormone with coronary atherosclerosis in angina patients, Int J Cardiol. 2007;I22(1):56-60.
22. Auer J, Berent R, Weber T, et al. Thyroid function is associated with presence and severity of coronary atherosclerosis. Clin Cardiol. 2003;26(12):569-573.
23. Coceani M, Iervasi G, Pingitorc A, et al. Thyroid hormone and coronary artery disease: from clinical correlations to prognostic implications. Clin Cardiol. 2(K)9;32(7):38()-385.
24.康慨,程飞,张敏,等.正常值范围内的甲状腺激素对冠心病的影响.临床荟萃.2010；25(10)：885－887.
25. Peters A, Ehlers M, Blank B, et al. Excess triiodothyronine as a risk factor of coronary events. Arch Intern Med. 2000; 160(13): 1993-1999.
26. Jung CH, Rhee EJ, Shin HS, et al. Higher serum free thyroxine levels are associated with coronary artery disease. Endocr J.2008;55(5):819-826.
27. Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003;13(1):3-126.
28. Brabant G, Beck-Peccoz P, Jarzab B, et al. Is there a need to redefine the upper normal limit of TSH? Eur J Endocrinol.2006;154(5):633-637.
29. Waise A, Price HC. The upper limit of the reference range for thyroid-stimulating hormone should not be confused with a cut-off to define subclinical hypothyroidism. Ann Clin Biochem.2009;46(Pt 2):93-98.
30. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab.2005;90(9):5483-5488.
31. Razvi S, Shakoor A, Vanderpump M, et al. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease:a metaanalysis. J Clin Endocrinol Metab.2008;93(8):2998-3007.
32. Bassett JH, Williams GR. Critical role of the hypothalamic-pituitary-thyroid axis in bone. Bone.2008;43(3):418-426.
33. Zhang W, Tian LM, Han Y, et al. Presence of thyrotropin receptor in hepatocytes:not a case of illegitimate transcription. J Cell Mol Med.2009; 13(11-12):4636-4642.
34. Abe E, Marians RC, Yu W, et al. TSH is a negative regulator of skeletal remodeling. Cell. 2003; 115(2):151-162.
35. Tian L, Song Y, Xing M, et al. A novel role for thyroid-stimulating hormone:up-regulation of hepatic 3-hydroxy-3-methyl-glutaryl-cocnzyme A reductase expression through the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-responsive element binding protein pathway. Hepatology. 2010;52(4):1401-1409.
36. Antunes TT, Gagnon A, Chen B, et al. Interleukin-6 release from human abdominal adipose cells is regulated by thyroid-stimulating hormone:effect of adipocyte differentiation and anatomic depot. Am J Physiol Endocrinol Metab. 2006;290(6):E1140-1144.
37. Menendez C, Baldelli R, Camina JP, et al. TSH stimulates leptin secretion by a direct effect on adipocytes. J Endocrinol. 2003; 176(1):7-12.
38. Santini F, Galli G, Maffei M, et al. Acute exogenous TSH administration stimulates leptin secretion in vivo. Eur J Endocrinol. 2010;163(l):63-67.
39. Balzan S, Nicolini G, Forini F, et al. Presence of a functional TSH receptor on human erythrocytes. Biomed Pharmacother. 2007;61(8):463-467.
40. Sellitti DF, Akamizu T, Doi SQ, et al. Renal expression of two 'thyroid-specific' genes: thyrotropin receptor and thyroglobulin. Exp Nephrol. 2000;8(4-5):235-243.
41. Sun MT, Hsiao FC, Su SC, et al. Thyrotropin as an independent factor of renal function and chronic kidney disease in normoglycemic cuthyroid adults. Endocr Res. 2012;37(3):110-116.
42. Hase H, Ando T, Eldeiry L, et al. TNFalpha mediates the skeletal effects of thyroid-stimulating hormone. Proc Natl Acad Sci U S A. 2006; 103(34): 12849-12854.
43. Bagriacik El), Klein JR. The thyrotropin (thyroid-stimulating hormone) receptor is expressed on murine dendritic cells and on a subset of CD45RBhigh lymph node T cells: functional role for thyroid-stimulating hormone during immune activation.J Immunol. 2000;164(12):6I58-6165.
44. Lu M, Lin RV. TSH stimulates adipogenesis in mouse embryonic stem cells. J Endocrinol. 2008; 196(1): 159-169.
45.宋秀霞,姜涛,姚晓爱,等.急性心肌梗死忠者甲状腺激素水平与冠状动脉病变严重程度相关性研究.中国循环杂志.2012；27(1)(173)：21-2-4.
46.王冬莲,卢先本,何小帆,等.甲状腺激素水平与冠心病严重程度的相关性研究.心脑血管病防治.2009；9(1)：9-10.
47. Hyland KA, Arnold AM, Lee JS, et al. Persistent Subclinical Hypothyroidism and Cardiovascular Risk in the Elderly: The Cardiovascular Health Study. J Clin Endocrinol Metab. 2012.
48. Waring AC, Arnold AIM, Newman AB, et al. Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study.J Clin Endocrinol Metab.2012;97(11):3944-3950.
49. Waring AC, Harrison S, Samuels MH, et al. Thyroid function and mortality in older men: a prospective study. J Clin Endocrinol Metab.2012;97(3):862-870.
50. Gussekloo J, van Exel E, de Craen AJ, et al. Thyroid status, disability and cognitive function, and survival in old age. JAMA.2004;292(21):2591-2599.
51. Ochs N, Auer R, Bauer DC, et al. Meta-analysis:subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med.2008;148(11):832-845.
52. Razvi S, Weaver JU, Butler TJ, et al. Levothyroxine Treatment of Subclinical Hypothyroidism, Fatal and Nonfatal Cardiovascular Events, and Mortality. Arch Intern Med.2012.
53. Mariotti S, Franceschi C, Cossarizza A, et al. The aging thyroid. Endoer Rev. 1995;16(6):686-715.
54. Bremner AP, Feddema P, Leedman PJ, et al. Age-related changes in thyroid function:a longitudinal study of a community-based cohort. J Clin Endocrinol Metab. 2012;97(5):1554-1562.
55. Wang F, Tan Y, Wang C, et al. Thyroid-stimulating hormone levels within the reference range are associated with serum lipid profiles independent of thyroid hormones. J Clin Endocrinol Metab.2012;97(8):2724-2731.
56. Wanjia X, Chenggang W, Aihong W, et al. A high normal TSH level is associated with an atherogenic lipid profile in euthyroid non-smokers with newly diagnosed asymptomatic coronary heart disease. Lipids Health Dis.2012; 11:44.
57. Xu C, Yang X, Liu W, et al. Thyroid stimulating hormone, independent of thyroid hormone, can elevate the serum total cholesterol level in patients with coronary heart disease:a cross-sectional design. Nutr Metab (Lond).2012;9(1):44.
58. Gumieniak O, Perlstein TS, Hopkins PN, et al. Thyroid function and blood pressure homeostasis in euthyroid subjects. J Clin Endocrinol Metab.2004;89(7):3455-3461.
59. Asvold BO, Bjoro T, Nilsen TI, et al. Association between blood pressure and serum thyroid-stimulating hormone concentration within the reference range:a population-based study. J Clin Endocrinol Metab.2007;92(3):841-845.
60. Ittermann T, Thamm M, Wallasehofski H, et al. Scrum thyroid-stimulating hormone levels are associated with blood pressure in children and adolescents.J Clin Endocrinol Metab. 2012;97(3):828-834.
61. Volzke H, Alte D, Dorr M, et al. The association between subclinical hyperthyroidism and blood pressure in a population-based study. J Hypertens. 2006;24(10):1947-1953.
62. Walsh JP, Bremncr AP, Bulsara MK, et al. Subclinical thyroid dysfunction and blood pressure: a community-based study. Clin Endocrinol (Oxf). 2006;65(4):486-491.
63. Dardano A, Ghiadoni L, Plantinga Y, et al. Recombinant human thyrotropin reduces endothelium-depcndent vasodilation in patients monitored for differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2006;9I(10):4175-4I78.
64. Napoli R, Biondi B, Guardasole V, et al. Enhancement of vascular endothelial function by recombinant human thyrotropin. J Clin Endocrinol Metab. 2008;93(5):1959-1963.
65. Napoli R, Apuzzi V, Bosso G, et al. Recombinant human thyrotropin enhances endothelial-mediated vasodilation of conduit arteries. J Clin Endocrinol Metab. 2009;94(3):1012-1016.
66. Volzke H, Robinson DM, Spielhagen T, et al. Are serum thyrotropin levels within the reference range associated with endothelial function? Eur Heart J. 2009;30(2):217-224.
67. Takamura N, Akilzhanova A, Hayashida N, et al. Thyroid function is associated with carotid intima-media thickness in euthyroid subjects. Atherosclerosis. 2009;204(2):e77-81.
68. Lambrinoudaki I, Armeni E, Rizos D, et al. High normal thyroid-stimulating hormone is associated with arterial stiffness in healthy postmenopausal women. J Hypertens. 20I2;30(3):592-599.
69. Tatar E, Sezis Demirci M, Kircelli F, et al. The association between thyroid hormones and arterial stiffness in peritoneal dialysis patients, Int Urol Nephrol. 2012;44(2):601-606.
70. Ruhla S, Weickert MO, Arafat AM, et al. A high normal TSH is associated with the metabolic syndrome. Clin Endocrinol (Oxf).2010;72(5):696-701.
71. Park SB, Choi HC, Joo NS. The relation of thyroid function to components of the metabolic syndrome in Korean men and women. .1 Korean Med Sci. 2011;26(4):540-545.
72. Lai Y, Wang J, Jiang F, et al. The relationship between serum thyrotropin and components of metabolic syndrome. Endocr J.2011;58(1):23-30.
73. Papanicolaou DA. Euthyroid Sick Syndrome and the role of cytokines. Rev Endocr Metab Disord.2000;1(1-2):43-48.
1. Haentjens P, Van Meerhaeghe A, Poppe K, et al. Subclinical thyroid dysfunction and mortality:an estimate of relative and absolute excess all-cause mortality based on time-to-event data from cohort studies. Eur J Endocrinol.2008; 159(3):329-341.
2. Gussekloo J, van Exel E, de Craen AJ, et al. Thyroid status, disability and cognitive function, and survival in old age. JAMA.2004;292(21):2591-2599.
3. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994):National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab.2002;87(2):489-499.
4. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Intern Med.2000;160(4):526-534.
5. Laurberg P, Pedersen KM, Hreidarsson A, et al. Iodine intake and the pattern of thyroid disorders:a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark. J Clin Endocrinol Metab.1998;83(3):765-769.
6. Laurberg P, Cerqueira C, Ovesen L, et al. Iodine intake as a determinant of thyroid disorders in populations. Best Pract Res Clin Endocrinol Metab.2010;24(1):13-27.
7. Somwaru LL, Arnold AM, Joshi N, et al. High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over. J Clin Endocrinol Metab.2009;94(4):1342-1345.
8. Gammage MD, Parle JV, Holder RL, et al. Association between serum free thyroxine concentration and atrial fibrillation. Arch Intern Med.2007;167(9):928-934.
9. Walsh JP, Bremner AP, Bulsara MK, et al. Subclinical thyroid dysfunction and blood pressure:a community-based study. Clin Endocrinol (Oxf).2006;65(4):486-49l.
10. Kim DJ, Khang YH, Koh JM, et al. Low normal TSH levels are associated with low bone mineral density in healthy postmenopausal women. Clin Endocrinol (Oxf)-2006;64(1):86-90.
11. Bensenor IM, Lotufo PA, Menezes PR, et al. Subclinical hyperthyroidism and dementia:the Sao Paulo Ageing & amp; Health Study (SPAH). BMC Public Health.2010; 10:298.
12. Volzke H, Alte D, Dorr M, et al. The association between subclinical hyperthyroidism and blood pressure in a population-based study. J Hypertens.2006;24(10):1947-1953.
13. van der Deure WM, Uitterlinden AG, Hofman A, et al. Effects of serum TSH and FT4 levels and the TSHR-Asp727Glu polymorphism on bone:the Rotterdam Study. Clin Endocrinol (Oxf).2008;68(2):175-181.
14. Bell RJ, Rivera-Woll L, Davison SL, et al. Well-being, health-related quality of life and cardiovascular disease risk profile in women with subclinical thyroid disease-a community-based study. Clin Endocrinol (Oxf)-2007;66(4):548-556.
15. Parle JV, Maisonneuve P, Sheppard MC, et al. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result:a 10-year cohort study. Lancet.2001;358(9285):861-865.
16. Walsh JP, Bremner AP, Bulsara MK, et al. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med.2005;165(21):2467-2472.
17. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA.2006;295(9):1033-1041.
18. Bauer DC, Rodondi N, Stone KL, et al. Thyroid hormone use, hyperthyroidism and mortality in older women. Am J Med.2007;120(4):343-349.
19. Iervasi G, Molinaro S, Landi P, et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med.2007; 167(14):1526-1532.
20. Radacsi A, Kovacs G, Bernard W, et al. Mortality rate of chronically ill geriatric patients with subnormal serum thyrotropin concentration:a 2-yr follow-up study. Endocrine. 2003;21(2):133-136.
21. Rodondi N, Bauer DC, Cappola AR, et al. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study..1 Am Coll Cardiol. 2008;52(14):l 152-1159.
22. Flynn RW, Bonellie SR, Jung RT, et al. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab.2010;95(l):186-193.
23.Ittermann T. Haring R, Sauer S, et al. Decreased serum TSH levels are not associated with mortality in the adult northeast German population. Eur J Endocrinol.2010;162(3):579-585.
24. Sgarbi JA, Matsumura LK, Kasamatsu TS, et al. Subclinical thyroid dysfunctions are independent risk factors for mortality in a 7.5-year follow-up:the Japanese-Brazilian thyroid study. Eur J Endocrinol.2010;162(3):569-577.
25. Kalra S, Williams A, Whitaker R, et al. Subclinical thyroid dysfunction does not affect one-year mortality in elderly patients after hip fracture:a prospective longitudinal study. Injury.2010;41 (4):385-387.
26. Boekholdt SM, Titan SM, Wiersinga WM, et al. Initial thyroid status and cardiovascular risk factors:the EPIC-Norfolk prospective population study. Clin Endocrinol (Oxf). 2010;72(3):404-410.
27. Vadiveloo T, Donnan PT, Cochrane L, et al. The Thyroid Epidemiology, Audit, and Research Study (TEARS):morbidity in patients with endogenous subclinical hyperthyroidism. J Clin Endocrinol Metab.2011;96(5):1344-1351.
28. Schultz M, Kistorp C, Raymond I, et al. Cardiovascular events in thyroid disease:a population based, prospective study. Horm Metab Res.2011;43(9):653-659.
29. Molinaro S, Iervasi G, Lorenzoni V, et al. Persistence of mortality risk in patients with acute cardiac diseases and mild thyroid dysfunction. Am J Med Sci.2012;343(1):65-70.
30. de Jongh RT, Lips P, van Schoor NM, et al. Endogenous subclinical thyroid disorders, physical and cognitive function, depression, and mortality in older individuals. Eur J Endocrinol.2011; 165(4):545-554.
31. Dawson J. QTJ, Walters M.R., Lees K.R. Subclinical disorders of thyroid function and risk ofcardiovascular events following suspected transient ischemic attack; A cohort study. Stroke.2011; 42:3 (e348).(3):e348.
32. Ochs N, Auer R, Bauer DC, et al. Meta-analysis:subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med.2008; 148(11):832-845.
33. Singh S, Duggal J, Molnar J, et al. Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all-cause mortality:a meta-analysis. Int J Cardiol. 2008;125(l):41-48.
34. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology:a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA.2000;283(15):2008-2012.
35. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.
36. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177-188.
37. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ.1997;315(7109):629-634.
38. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics.1994;50(4):1088-1101.
39. Goldman MB, Monson RR, Maloof F. Cancer mortality in women with thyroid disease. Cancer Res.1990;50(8):2283-2289.
40. Bossoni S, Cossi S, Marengoni A, et al. The negative role of subclinical thyrotoxicosis on the outcome of hospitalized geriatric patients. J Endocrinol Invest.2002;25(10 Suppl):64-65.
41. Davis PJ, Davis FB. Hyperthyroidism in patients over the age of 60 years. Clinical features in 85 patients. Medicine (Baltimore).1974;53(3):161-181.
42. Friberg L, Drvota V, Bjelak All, et al. Association between increased levels of reverse triiodothyronine and mortality after acute myocardial infarction. Am J Med. 2001; 111 (9):699-703.
43. Kaptein EM, Weiner JM, Robinson WJ, et al. Relationship of altered thyroid hormone indices to survival in nonthyroidal illnesses. Clin Endocrinol (Oxf).1982; 16(6):565-574.
44. Nyirenda MJ, Clark DN, Finlayson AR. et al. Thyroid disease and increased cardiovascular risk. Thyroid.2005; 15(7):718-724.
45. Peters A, Ehlers M, Blank B, et al. Excess triiodothyronine as a risk factor of coronary events. Arch Intern Med.2000; 160(13):1993-1999.
46. Alevizaki M, Synetou M, Xynos K, et al. Low triiodothyronine:a strong predictor of outcome in acute stroke patients. Eur J Clin Invest.2007;37(8):651-657.
47. Enia G, Panuccio V, Cutrupi S, et al. Subclinical hypothyroidism is linked to micro-inflammation and predicts death in continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant.2007;22(2):538-544.
48. Carrero JJ, Qureshi AR, Axelsson J, et al. Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med.2007;262(6):690-701.
49. Westerink J, van der Graaf Y, Faber DR, et al. Relation between thyroid-stimulating hormone and the occurrence of cardiovascular events and mortality in patients with manifest vascular diseases. Eur J Prev Cardiol.2012;19(4):864-873.
50. Flynn RW, Macdonald TM, Jung RT, et al. Mortality and vascular outcomes in patients treated for thyroid dysfunction. J Clin Endocrinol Metab.2006;91(6):2159-2164.
51. Razvi S, Weaver JU, Vanderpump MP, et al. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism:reanalysis of the Whickham Survey cohort. J Clin Endocrinol Metab.2010;95(4):1734-1740.
52. Pearce EN, Yang Q, Benjamin EJ, et al. Thyroid function and left ventricular structure and function in the Framingham Heart Study. Thyroid.2010;20(4):369-373.
53. Park YJ, Lee YJ, Choi SI, et al. Impact of subclinical hypothyroidism on the coronary artery disease in apparently healthy subjects. Eur J Endocrinol.2011; 165(1):115-121.
54. McQuade C, Skugor M, Brennan DM, et al. Hypothyroidism and moderate subclinical hypothyroidism are associated with increased all-cause mortality independent of coronary heart disease risk factors:a PreCIS database study. Thyroid.2011;21(8):837-843.
55. Ceresini G, Lauretani F, Maggio M, et al. Thyroid function abnormalities and cognitive impairment in elderly people:results of the Invecchiare in Chianti study. J Am Geriatr Soc. 2009;57(1):89-93.
56. Dorr M, lttermann T, Aumann N, et al. Subclinical hyperthyroidism is not associated with progression of cardiac mass and development of left ventricular hypertrophy in middle-aged and older subjects:results from a 5-year follow-up. Clin Endocrinol (Oxf). 2010;73(6):821-826.
57. van den Beld AW, Visser TJ, Feelders RA, et al. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab. 2005;90(12):6403-6409.
58. Singer RB. Mortality in a complete 4-year follow up of 85-year-old residents of Leiden, classified by serum level of thyrotropin and thyroxine. J Insur Med.2006;38(I):14-19.
59. Wells GA SB, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa, Ontario:Ottawa Health Research Institute, University of Ottawa; Available at:http://www.ohri.ca/prougratns/elinical_epidemiology/oxford.htm.
60. Klein I, Danzi S. Thyroid disease and the heart. Circulation.2007;116(15):1725-1735.
61. Sgarbi JA, Villaca FG, Garbeline B, et al. The effects of early antithyroid therapy for endogenous subclinical hyperthyroidism in clinical and heart abnormalities. J Clin Endocrinol Metab.2003;88(4):1672-1677.
62. Biondi B, Palmieri EA, Fazio S, et al. Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab.2000;85(12):4701-4705.
63. Petretta M, Bonaduce D, Spinelli L, et al. Cardiovascular haemodynamics and cardiac autonomic control in patients with subclinical and overt hyperthyroidism. Eur J Endocrinol. 2001;145(6):691-696.
64. Selmer C, Olesen JB, Hansen ML, et al. The spectrum of thyroid disease and risk of new onset atrial fibrillation:a large population cohort study. BMJ.2012;345:e7895.
65. Erem C. Blood coagulation, fibrinolytic activity and lipid profile in subclinical thyroid disease:subclinical hyperthyroidism increases plasma factor X activity. Clin Endocrinol (Oxf).2006;64(3):323-329.
66. Coban E, Aydemir M. Levels of plasma fibrinogen and D-dimer in subjects with subclinical hyperthyroidism. Med Sci Monit.2008:14(1):CR42-46.
67. Coban E, Aydemir M. Yazicioglu G. et al. Endotbelial dysfunction in subjects with subclinical hyperthyroidism. J Endocrinol Invest.2006:29(3):197-200.
68. Maratou E, Hadjidakis DJ, Peppa M, et al. Studies of insulin resistance in patients with clinical and subclinical hyperthyroidism. Eur J Endocrinol.2010; 163(4):625-630.
69. Meyerovitch J, Rotman-Pikielny P, Sherf M, et al. Serum thyrotropin measurements in the community:five-year follow-up in a large network of primary care physicians. Arch Intern Med.2007;167(14):1533-1538.
70. Diez JJ, Iglesias P. An analysis of the natural course of subclinical hyperthyroidism. Am J Med Sci.2009;337(4):225-232.
71. Rosario PW. The natural history of subclinical hyperthyroidism in patients below the age of 65 years. Clin Endocrinol (Oxf).2008;68(3):491-492.
72. Rosario PW. Natural history of subclinical hyperthyroidism in elderly patients with TSH between 0.1 and 0.4 mIU/1:a prospective study. Clin Endocrinol (Oxf).2010;72(5):685-688.
73. Schouten BJ, Brownlie BE, Frampton CM, et al. Subclinical thyrotoxicosis in an outpatient population-predictors of outcome. Clin Endocrinol (Oxf).2011;74(2):257-261.
74. Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat Med.2002;21 (11):1559-1573.
75. Fazio S, Biondi B, Carella C, et al. Diastolic dysfunction in patients on thyroid-stimulating hormone suppressive therapy with levothyroxine:beneficial effect of beta-blockade. J Clin Endocrinol Metab.1995;80(7):2222-2226.
76. Biondi B, Fazio S, Cuocolo A, et al. Impaired cardiac reserve and exercise capacity in patients receiving long-term thyrotropin suppressive therapy with levothyroxine. J Clin Endocrinol Metab.1996;81(12):4224-4228.
77. Faber J, Wiinberg N, Schifter S, et al. Haemodynamic changes following treatment of subclinical and overt hyperthyroidism. Eur J Endocrinol.2001; 145(4):391-396.
78. Kung AW, Yeung SS. Prevention of bone loss induced by thyroxine suppressive therapy in postmenopausal women:the effect of calcium and calcitonin. J Clin Endocrinol Metab. 1996;81(3):1232-1236.
79. Schneider DL, Barrett-Connor EL, Morton DJ. Thyroid hormone use and bone mineral density in elderly women. Effects of estrogen. JAMA.1994;271(16):1245-1249.
80. Rosen HN, Moses AC, Garber J, et al. Randomized trial of pamidronate in patients with thyroid cancer:bone density is not reduced by suppressive doses of thyroxine, but is increased by cyclic intravenous pamidronate. J Clin Endocrinol Metab. 1998;83(7):2324-2330.
81. Faber J, Jensen IW, Petersen L, et al. Normalization of serum thyrotrophin by means of radioiodine treatment in subclinical hyperthyroidism:effect on bone loss in postmenopausal women. Clin Endocrinol (Oxf).1998;48(3):285-290.
82. Mudde AH, Houben AJ, Nieuwenhuijzen Kruseman AC. Bone metabolism during anti-thyroid drug treatment of endogenous subclinical hyperthyroidism. Clin Endocrinol (Oxf).1994;41(4):421-424.
83. Yonem O, Dokmetas HS, Aslan SM, et al. Is antithyroid treatment really relevant for young patients with subclinical hyperthyroidism? Endocr J.2002;49(3):307-314.
84. Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med.2006;25(20):3443-3457.
2. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab. 2003;88(6):2438-2444.
3. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Intern Med.2000;160(4):526-534.
4. Luboshitzky R, Aviv A, Herer P, et al. Risk factors for cardiovascular disease in women with subclinical hypothyroidism. Thyroid.2002;12(5):421-425.
5. Liu D, Jiang F, Shan Z, et al. A cross-sectional survey of relationship between serum TSH level and blood pressure. J Hum Hypertens.2010;24(2):134-138.
6. Danese MD, Ladenson PW, Meinert CL, et al. Clinical review 115:effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure:a quantitative review of the literature. J Clin Endocrinol Metab.2000;85(9):2993-3001.
7. Maratou E, Hadjidakis DJ, Kollias A, et al. Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol.2009;160(5):785-790.
8. Knudsen N, Laurberg P, Rasmussen LB, et al. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. J Clin Endocrinol Metab.2005;90(7):4019-4024.
9. Owen PJ, Sabit R, Lazarus JH. Thyroid disease and vascular function. Thyroid. 2007;17(6):519-524.
10. Lindeman RD, Romero LJ, Schade DS, et al. Impact of subclinical hypothyroidism on serum total homocysteine concentrations, the prevalence of coronary heart disease (CHD), and CHD risk factors in the New Mexico Elder Health Survey. Thyroid. 2003;13(6):595-600.
11. Wang CY, Chang TC, Chen MF. Associations between subclinical thyroid disease and metabolic syndrome. Endocr J.2012.
12. Imaizumi M, Akahoshi M, Ichimaru S, et al. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab.2004;89(7):3365-3370.
13. Walsh JP, Bremner AP, Bulsara MK, et aI. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med. 2005;l65(2l):2467-2472.
14. Tseng FY, Lin WY, Lin CC, et al. Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults. J Am Coll Cardiol. 2012;60(8):730-737.
15. Iervasi G, Molinaro S, Landi P, et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med. 2007; 167(14): 1526-1532.
16. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006;295(9):1033-1041.
17. Rodondi N, Newman AB, Vittinghoff E, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005;165(21):2460-2466.
18. Boekholdt SM, Titan SM, Wiersinga WM, et al. Initial thyroid status and cardiovascular risk factors: the EPIC-lNorfolk prospective population study. Clin Endocrinol (Oxf)-2010;72(3):404-410.
19. Asvold BO, Bjoro T, INilsen Tl, et al. Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study. Arch Intern Med. 2008;168(8):855-860.
20. Miura S, litaka M, Suzuki S, et al. Decrease in serum levels of thyroid hormone in patients with coronary heart disease. Endoer.Jl. 1996;43(6):657-663.
21. Yun KH, Jeong MH, Oh SK, et al. Relationship of thyroid stimulating hormone with coronary atherosclerosis in angina patients, Int J Cardiol. 2007;I22(1):56-60.
22. Auer J, Berent R, Weber T, et al. Thyroid function is associated with presence and severity of coronary atherosclerosis. Clin Cardiol. 2003;26(12):569-573.
23. Coceani M, Iervasi G, Pingitorc A, et al. Thyroid hormone and coronary artery disease: from clinical correlations to prognostic implications. Clin Cardiol. 2(K)9;32(7):38()-385.
24.康慨,程飞,张敏,等.正常值范围内的甲状腺激素对冠心病的影响.临床荟萃.2010；25(10)：885－887.
25. Peters A, Ehlers M, Blank B, et al. Excess triiodothyronine as a risk factor of coronary events. Arch Intern Med. 2000; 160(13): 1993-1999.
26. Jung CH, Rhee EJ, Shin HS, et al. Higher serum free thyroxine levels are associated with coronary artery disease. Endocr J.2008;55(5):819-826.
27. Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003;13(1):3-126.
28. Brabant G, Beck-Peccoz P, Jarzab B, et al. Is there a need to redefine the upper normal limit of TSH? Eur J Endocrinol.2006;154(5):633-637.
29. Waise A, Price HC. The upper limit of the reference range for thyroid-stimulating hormone should not be confused with a cut-off to define subclinical hypothyroidism. Ann Clin Biochem.2009;46(Pt 2):93-98.
30. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab.2005;90(9):5483-5488.
31. Razvi S, Shakoor A, Vanderpump M, et al. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease:a metaanalysis. J Clin Endocrinol Metab.2008;93(8):2998-3007.
32. Bassett JH, Williams GR. Critical role of the hypothalamic-pituitary-thyroid axis in bone. Bone.2008;43(3):418-426.
33. Zhang W, Tian LM, Han Y, et al. Presence of thyrotropin receptor in hepatocytes:not a case of illegitimate transcription. J Cell Mol Med.2009; 13(11-12):4636-4642.
34. Abe E, Marians RC, Yu W, et al. TSH is a negative regulator of skeletal remodeling. Cell. 2003; 115(2):151-162.
35. Tian L, Song Y, Xing M, et al. A novel role for thyroid-stimulating hormone:up-regulation of hepatic 3-hydroxy-3-methyl-glutaryl-cocnzyme A reductase expression through the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-responsive element binding protein pathway. Hepatology. 2010;52(4):1401-1409.
36. Antunes TT, Gagnon A, Chen B, et al. Interleukin-6 release from human abdominal adipose cells is regulated by thyroid-stimulating hormone:effect of adipocyte differentiation and anatomic depot. Am J Physiol Endocrinol Metab. 2006;290(6):E1140-1144.
37. Menendez C, Baldelli R, Camina JP, et al. TSH stimulates leptin secretion by a direct effect on adipocytes. J Endocrinol. 2003; 176(1):7-12.
38. Santini F, Galli G, Maffei M, et al. Acute exogenous TSH administration stimulates leptin secretion in vivo. Eur J Endocrinol. 2010;163(l):63-67.
39. Balzan S, Nicolini G, Forini F, et al. Presence of a functional TSH receptor on human erythrocytes. Biomed Pharmacother. 2007;61(8):463-467.
40. Sellitti DF, Akamizu T, Doi SQ, et al. Renal expression of two 'thyroid-specific' genes: thyrotropin receptor and thyroglobulin. Exp Nephrol. 2000;8(4-5):235-243.
41. Sun MT, Hsiao FC, Su SC, et al. Thyrotropin as an independent factor of renal function and chronic kidney disease in normoglycemic cuthyroid adults. Endocr Res. 2012;37(3):110-116.
42. Hase H, Ando T, Eldeiry L, et al. TNFalpha mediates the skeletal effects of thyroid-stimulating hormone. Proc Natl Acad Sci U S A. 2006; 103(34): 12849-12854.
43. Bagriacik El), Klein JR. The thyrotropin (thyroid-stimulating hormone) receptor is expressed on murine dendritic cells and on a subset of CD45RBhigh lymph node T cells: functional role for thyroid-stimulating hormone during immune activation.J Immunol. 2000;164(12):6I58-6165.
44. Lu M, Lin RV. TSH stimulates adipogenesis in mouse embryonic stem cells. J Endocrinol. 2008; 196(1): 159-169.
45.宋秀霞,姜涛,姚晓爱,等.急性心肌梗死忠者甲状腺激素水平与冠状动脉病变严重程度相关性研究.中国循环杂志.2012；27(1)(173)：21-2-4.
46.王冬莲,卢先本,何小帆,等.甲状腺激素水平与冠心病严重程度的相关性研究.心脑血管病防治.2009；9(1)：9-10.
47. Hyland KA, Arnold AM, Lee JS, et al. Persistent Subclinical Hypothyroidism and Cardiovascular Risk in the Elderly: The Cardiovascular Health Study. J Clin Endocrinol Metab. 2012.
48. Waring AC, Arnold AIM, Newman AB, et al. Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study.J Clin Endocrinol Metab.2012;97(11):3944-3950.
49. Waring AC, Harrison S, Samuels MH, et al. Thyroid function and mortality in older men: a prospective study. J Clin Endocrinol Metab.2012;97(3):862-870.
50. Gussekloo J, van Exel E, de Craen AJ, et al. Thyroid status, disability and cognitive function, and survival in old age. JAMA.2004;292(21):2591-2599.
51. Ochs N, Auer R, Bauer DC, et al. Meta-analysis:subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med.2008;148(11):832-845.
52. Razvi S, Weaver JU, Butler TJ, et al. Levothyroxine Treatment of Subclinical Hypothyroidism, Fatal and Nonfatal Cardiovascular Events, and Mortality. Arch Intern Med.2012.
53. Mariotti S, Franceschi C, Cossarizza A, et al. The aging thyroid. Endoer Rev. 1995;16(6):686-715.
54. Bremner AP, Feddema P, Leedman PJ, et al. Age-related changes in thyroid function:a longitudinal study of a community-based cohort. J Clin Endocrinol Metab. 2012;97(5):1554-1562.
55. Wang F, Tan Y, Wang C, et al. Thyroid-stimulating hormone levels within the reference range are associated with serum lipid profiles independent of thyroid hormones. J Clin Endocrinol Metab.2012;97(8):2724-2731.
56. Wanjia X, Chenggang W, Aihong W, et al. A high normal TSH level is associated with an atherogenic lipid profile in euthyroid non-smokers with newly diagnosed asymptomatic coronary heart disease. Lipids Health Dis.2012; 11:44.
57. Xu C, Yang X, Liu W, et al. Thyroid stimulating hormone, independent of thyroid hormone, can elevate the serum total cholesterol level in patients with coronary heart disease:a cross-sectional design. Nutr Metab (Lond).2012;9(1):44.
58. Gumieniak O, Perlstein TS, Hopkins PN, et al. Thyroid function and blood pressure homeostasis in euthyroid subjects. J Clin Endocrinol Metab.2004;89(7):3455-3461.
59. Asvold BO, Bjoro T, Nilsen TI, et al. Association between blood pressure and serum thyroid-stimulating hormone concentration within the reference range:a population-based study. J Clin Endocrinol Metab.2007;92(3):841-845.
60. Ittermann T, Thamm M, Wallasehofski H, et al. Scrum thyroid-stimulating hormone levels are associated with blood pressure in children and adolescents.J Clin Endocrinol Metab. 2012;97(3):828-834.
61. Volzke H, Alte D, Dorr M, et al. The association between subclinical hyperthyroidism and blood pressure in a population-based study. J Hypertens. 2006;24(10):1947-1953.
62. Walsh JP, Bremncr AP, Bulsara MK, et al. Subclinical thyroid dysfunction and blood pressure: a community-based study. Clin Endocrinol (Oxf). 2006;65(4):486-491.
63. Dardano A, Ghiadoni L, Plantinga Y, et al. Recombinant human thyrotropin reduces endothelium-depcndent vasodilation in patients monitored for differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2006;9I(10):4175-4I78.
64. Napoli R, Biondi B, Guardasole V, et al. Enhancement of vascular endothelial function by recombinant human thyrotropin. J Clin Endocrinol Metab. 2008;93(5):1959-1963.
65. Napoli R, Apuzzi V, Bosso G, et al. Recombinant human thyrotropin enhances endothelial-mediated vasodilation of conduit arteries. J Clin Endocrinol Metab. 2009;94(3):1012-1016.
66. Volzke H, Robinson DM, Spielhagen T, et al. Are serum thyrotropin levels within the reference range associated with endothelial function? Eur Heart J. 2009;30(2):217-224.
67. Takamura N, Akilzhanova A, Hayashida N, et al. Thyroid function is associated with carotid intima-media thickness in euthyroid subjects. Atherosclerosis. 2009;204(2):e77-81.
68. Lambrinoudaki I, Armeni E, Rizos D, et al. High normal thyroid-stimulating hormone is associated with arterial stiffness in healthy postmenopausal women. J Hypertens. 20I2;30(3):592-599.
69. Tatar E, Sezis Demirci M, Kircelli F, et al. The association between thyroid hormones and arterial stiffness in peritoneal dialysis patients, Int Urol Nephrol. 2012;44(2):601-606.
70. Ruhla S, Weickert MO, Arafat AM, et al. A high normal TSH is associated with the metabolic syndrome. Clin Endocrinol (Oxf).2010;72(5):696-701.
71. Park SB, Choi HC, Joo NS. The relation of thyroid function to components of the metabolic syndrome in Korean men and women. .1 Korean Med Sci. 2011;26(4):540-545.
72. Lai Y, Wang J, Jiang F, et al. The relationship between serum thyrotropin and components of metabolic syndrome. Endocr J.2011;58(1):23-30.
73. Papanicolaou DA. Euthyroid Sick Syndrome and the role of cytokines. Rev Endocr Metab Disord.2000;1(1-2):43-48.
1. Haentjens P, Van Meerhaeghe A, Poppe K, et al. Subclinical thyroid dysfunction and mortality:an estimate of relative and absolute excess all-cause mortality based on time-to-event data from cohort studies. Eur J Endocrinol.2008; 159(3):329-341.
2. Gussekloo J, van Exel E, de Craen AJ, et al. Thyroid status, disability and cognitive function, and survival in old age. JAMA.2004;292(21):2591-2599.
3. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994):National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab.2002;87(2):489-499.
4. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Intern Med.2000;160(4):526-534.
5. Laurberg P, Pedersen KM, Hreidarsson A, et al. Iodine intake and the pattern of thyroid disorders:a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark. J Clin Endocrinol Metab.1998;83(3):765-769.
6. Laurberg P, Cerqueira C, Ovesen L, et al. Iodine intake as a determinant of thyroid disorders in populations. Best Pract Res Clin Endocrinol Metab.2010;24(1):13-27.
7. Somwaru LL, Arnold AM, Joshi N, et al. High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over. J Clin Endocrinol Metab.2009;94(4):1342-1345.
8. Gammage MD, Parle JV, Holder RL, et al. Association between serum free thyroxine concentration and atrial fibrillation. Arch Intern Med.2007;167(9):928-934.
9. Walsh JP, Bremner AP, Bulsara MK, et al. Subclinical thyroid dysfunction and blood pressure:a community-based study. Clin Endocrinol (Oxf).2006;65(4):486-49l.
10. Kim DJ, Khang YH, Koh JM, et al. Low normal TSH levels are associated with low bone mineral density in healthy postmenopausal women. Clin Endocrinol (Oxf)-2006;64(1):86-90.
11. Bensenor IM, Lotufo PA, Menezes PR, et al. Subclinical hyperthyroidism and dementia:the Sao Paulo Ageing & amp; Health Study (SPAH). BMC Public Health.2010; 10:298.
12. Volzke H, Alte D, Dorr M, et al. The association between subclinical hyperthyroidism and blood pressure in a population-based study. J Hypertens.2006;24(10):1947-1953.
13. van der Deure WM, Uitterlinden AG, Hofman A, et al. Effects of serum TSH and FT4 levels and the TSHR-Asp727Glu polymorphism on bone:the Rotterdam Study. Clin Endocrinol (Oxf).2008;68(2):175-181.
14. Bell RJ, Rivera-Woll L, Davison SL, et al. Well-being, health-related quality of life and cardiovascular disease risk profile in women with subclinical thyroid disease-a community-based study. Clin Endocrinol (Oxf)-2007;66(4):548-556.
15. Parle JV, Maisonneuve P, Sheppard MC, et al. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result:a 10-year cohort study. Lancet.2001;358(9285):861-865.
16. Walsh JP, Bremner AP, Bulsara MK, et al. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med.2005;165(21):2467-2472.
17. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA.2006;295(9):1033-1041.
18. Bauer DC, Rodondi N, Stone KL, et al. Thyroid hormone use, hyperthyroidism and mortality in older women. Am J Med.2007;120(4):343-349.
19. Iervasi G, Molinaro S, Landi P, et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med.2007; 167(14):1526-1532.
20. Radacsi A, Kovacs G, Bernard W, et al. Mortality rate of chronically ill geriatric patients with subnormal serum thyrotropin concentration:a 2-yr follow-up study. Endocrine. 2003;21(2):133-136.
21. Rodondi N, Bauer DC, Cappola AR, et al. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study..1 Am Coll Cardiol. 2008;52(14):l 152-1159.
22. Flynn RW, Bonellie SR, Jung RT, et al. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab.2010;95(l):186-193.
23.Ittermann T. Haring R, Sauer S, et al. Decreased serum TSH levels are not associated with mortality in the adult northeast German population. Eur J Endocrinol.2010;162(3):579-585.
24. Sgarbi JA, Matsumura LK, Kasamatsu TS, et al. Subclinical thyroid dysfunctions are independent risk factors for mortality in a 7.5-year follow-up:the Japanese-Brazilian thyroid study. Eur J Endocrinol.2010;162(3):569-577.
25. Kalra S, Williams A, Whitaker R, et al. Subclinical thyroid dysfunction does not affect one-year mortality in elderly patients after hip fracture:a prospective longitudinal study. Injury.2010;41 (4):385-387.
26. Boekholdt SM, Titan SM, Wiersinga WM, et al. Initial thyroid status and cardiovascular risk factors:the EPIC-Norfolk prospective population study. Clin Endocrinol (Oxf). 2010;72(3):404-410.
27. Vadiveloo T, Donnan PT, Cochrane L, et al. The Thyroid Epidemiology, Audit, and Research Study (TEARS):morbidity in patients with endogenous subclinical hyperthyroidism. J Clin Endocrinol Metab.2011;96(5):1344-1351.
28. Schultz M, Kistorp C, Raymond I, et al. Cardiovascular events in thyroid disease:a population based, prospective study. Horm Metab Res.2011;43(9):653-659.
29. Molinaro S, Iervasi G, Lorenzoni V, et al. Persistence of mortality risk in patients with acute cardiac diseases and mild thyroid dysfunction. Am J Med Sci.2012;343(1):65-70.
30. de Jongh RT, Lips P, van Schoor NM, et al. Endogenous subclinical thyroid disorders, physical and cognitive function, depression, and mortality in older individuals. Eur J Endocrinol.2011; 165(4):545-554.
31. Dawson J. QTJ, Walters M.R., Lees K.R. Subclinical disorders of thyroid function and risk ofcardiovascular events following suspected transient ischemic attack; A cohort study. Stroke.2011; 42:3 (e348).(3):e348.
32. Ochs N, Auer R, Bauer DC, et al. Meta-analysis:subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med.2008; 148(11):832-845.
33. Singh S, Duggal J, Molnar J, et al. Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all-cause mortality:a meta-analysis. Int J Cardiol. 2008;125(l):41-48.
34. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology:a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA.2000;283(15):2008-2012.
35. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.
36. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177-188.
37. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ.1997;315(7109):629-634.
38. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics.1994;50(4):1088-1101.
39. Goldman MB, Monson RR, Maloof F. Cancer mortality in women with thyroid disease. Cancer Res.1990;50(8):2283-2289.
40. Bossoni S, Cossi S, Marengoni A, et al. The negative role of subclinical thyrotoxicosis on the outcome of hospitalized geriatric patients. J Endocrinol Invest.2002;25(10 Suppl):64-65.
41. Davis PJ, Davis FB. Hyperthyroidism in patients over the age of 60 years. Clinical features in 85 patients. Medicine (Baltimore).1974;53(3):161-181.
42. Friberg L, Drvota V, Bjelak All, et al. Association between increased levels of reverse triiodothyronine and mortality after acute myocardial infarction. Am J Med. 2001; 111 (9):699-703.
43. Kaptein EM, Weiner JM, Robinson WJ, et al. Relationship of altered thyroid hormone indices to survival in nonthyroidal illnesses. Clin Endocrinol (Oxf).1982; 16(6):565-574.
44. Nyirenda MJ, Clark DN, Finlayson AR. et al. Thyroid disease and increased cardiovascular risk. Thyroid.2005; 15(7):718-724.
45. Peters A, Ehlers M, Blank B, et al. Excess triiodothyronine as a risk factor of coronary events. Arch Intern Med.2000; 160(13):1993-1999.
46. Alevizaki M, Synetou M, Xynos K, et al. Low triiodothyronine:a strong predictor of outcome in acute stroke patients. Eur J Clin Invest.2007;37(8):651-657.
47. Enia G, Panuccio V, Cutrupi S, et al. Subclinical hypothyroidism is linked to micro-inflammation and predicts death in continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant.2007;22(2):538-544.
48. Carrero JJ, Qureshi AR, Axelsson J, et al. Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med.2007;262(6):690-701.
49. Westerink J, van der Graaf Y, Faber DR, et al. Relation between thyroid-stimulating hormone and the occurrence of cardiovascular events and mortality in patients with manifest vascular diseases. Eur J Prev Cardiol.2012;19(4):864-873.
50. Flynn RW, Macdonald TM, Jung RT, et al. Mortality and vascular outcomes in patients treated for thyroid dysfunction. J Clin Endocrinol Metab.2006;91(6):2159-2164.
51. Razvi S, Weaver JU, Vanderpump MP, et al. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism:reanalysis of the Whickham Survey cohort. J Clin Endocrinol Metab.2010;95(4):1734-1740.
52. Pearce EN, Yang Q, Benjamin EJ, et al. Thyroid function and left ventricular structure and function in the Framingham Heart Study. Thyroid.2010;20(4):369-373.
53. Park YJ, Lee YJ, Choi SI, et al. Impact of subclinical hypothyroidism on the coronary artery disease in apparently healthy subjects. Eur J Endocrinol.2011; 165(1):115-121.
54. McQuade C, Skugor M, Brennan DM, et al. Hypothyroidism and moderate subclinical hypothyroidism are associated with increased all-cause mortality independent of coronary heart disease risk factors:a PreCIS database study. Thyroid.2011;21(8):837-843.
55. Ceresini G, Lauretani F, Maggio M, et al. Thyroid function abnormalities and cognitive impairment in elderly people:results of the Invecchiare in Chianti study. J Am Geriatr Soc. 2009;57(1):89-93.
56. Dorr M, lttermann T, Aumann N, et al. Subclinical hyperthyroidism is not associated with progression of cardiac mass and development of left ventricular hypertrophy in middle-aged and older subjects:results from a 5-year follow-up. Clin Endocrinol (Oxf). 2010;73(6):821-826.
57. van den Beld AW, Visser TJ, Feelders RA, et al. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab. 2005;90(12):6403-6409.
58. Singer RB. Mortality in a complete 4-year follow up of 85-year-old residents of Leiden, classified by serum level of thyrotropin and thyroxine. J Insur Med.2006;38(I):14-19.
59. Wells GA SB, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa, Ontario:Ottawa Health Research Institute, University of Ottawa; Available at:http://www.ohri.ca/prougratns/elinical_epidemiology/oxford.htm.
60. Klein I, Danzi S. Thyroid disease and the heart. Circulation.2007;116(15):1725-1735.
61. Sgarbi JA, Villaca FG, Garbeline B, et al. The effects of early antithyroid therapy for endogenous subclinical hyperthyroidism in clinical and heart abnormalities. J Clin Endocrinol Metab.2003;88(4):1672-1677.
62. Biondi B, Palmieri EA, Fazio S, et al. Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab.2000;85(12):4701-4705.
63. Petretta M, Bonaduce D, Spinelli L, et al. Cardiovascular haemodynamics and cardiac autonomic control in patients with subclinical and overt hyperthyroidism. Eur J Endocrinol. 2001;145(6):691-696.
64. Selmer C, Olesen JB, Hansen ML, et al. The spectrum of thyroid disease and risk of new onset atrial fibrillation:a large population cohort study. BMJ.2012;345:e7895.
65. Erem C. Blood coagulation, fibrinolytic activity and lipid profile in subclinical thyroid disease:subclinical hyperthyroidism increases plasma factor X activity. Clin Endocrinol (Oxf).2006;64(3):323-329.
66. Coban E, Aydemir M. Levels of plasma fibrinogen and D-dimer in subjects with subclinical hyperthyroidism. Med Sci Monit.2008:14(1):CR42-46.
67. Coban E, Aydemir M. Yazicioglu G. et al. Endotbelial dysfunction in subjects with subclinical hyperthyroidism. J Endocrinol Invest.2006:29(3):197-200.
68. Maratou E, Hadjidakis DJ, Peppa M, et al. Studies of insulin resistance in patients with clinical and subclinical hyperthyroidism. Eur J Endocrinol.2010; 163(4):625-630.
69. Meyerovitch J, Rotman-Pikielny P, Sherf M, et al. Serum thyrotropin measurements in the community:five-year follow-up in a large network of primary care physicians. Arch Intern Med.2007;167(14):1533-1538.
70. Diez JJ, Iglesias P. An analysis of the natural course of subclinical hyperthyroidism. Am J Med Sci.2009;337(4):225-232.
71. Rosario PW. The natural history of subclinical hyperthyroidism in patients below the age of 65 years. Clin Endocrinol (Oxf).2008;68(3):491-492.
72. Rosario PW. Natural history of subclinical hyperthyroidism in elderly patients with TSH between 0.1 and 0.4 mIU/1:a prospective study. Clin Endocrinol (Oxf).2010;72(5):685-688.
73. Schouten BJ, Brownlie BE, Frampton CM, et al. Subclinical thyrotoxicosis in an outpatient population-predictors of outcome. Clin Endocrinol (Oxf).2011;74(2):257-261.
74. Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat Med.2002;21 (11):1559-1573.
75. Fazio S, Biondi B, Carella C, et al. Diastolic dysfunction in patients on thyroid-stimulating hormone suppressive therapy with levothyroxine:beneficial effect of beta-blockade. J Clin Endocrinol Metab.1995;80(7):2222-2226.
76. Biondi B, Fazio S, Cuocolo A, et al. Impaired cardiac reserve and exercise capacity in patients receiving long-term thyrotropin suppressive therapy with levothyroxine. J Clin Endocrinol Metab.1996;81(12):4224-4228.
77. Faber J, Wiinberg N, Schifter S, et al. Haemodynamic changes following treatment of subclinical and overt hyperthyroidism. Eur J Endocrinol.2001; 145(4):391-396.
78. Kung AW, Yeung SS. Prevention of bone loss induced by thyroxine suppressive therapy in postmenopausal women:the effect of calcium and calcitonin. J Clin Endocrinol Metab. 1996;81(3):1232-1236.
79. Schneider DL, Barrett-Connor EL, Morton DJ. Thyroid hormone use and bone mineral density in elderly women. Effects of estrogen. JAMA.1994;271(16):1245-1249.
80. Rosen HN, Moses AC, Garber J, et al. Randomized trial of pamidronate in patients with thyroid cancer:bone density is not reduced by suppressive doses of thyroxine, but is increased by cyclic intravenous pamidronate. J Clin Endocrinol Metab. 1998;83(7):2324-2330.
81. Faber J, Jensen IW, Petersen L, et al. Normalization of serum thyrotrophin by means of radioiodine treatment in subclinical hyperthyroidism:effect on bone loss in postmenopausal women. Clin Endocrinol (Oxf).1998;48(3):285-290.
82. Mudde AH, Houben AJ, Nieuwenhuijzen Kruseman AC. Bone metabolism during anti-thyroid drug treatment of endogenous subclinical hyperthyroidism. Clin Endocrinol (Oxf).1994;41(4):421-424.
83. Yonem O, Dokmetas HS, Aslan SM, et al. Is antithyroid treatment really relevant for young patients with subclinical hyperthyroidism? Endocr J.2002;49(3):307-314.
84. Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med.2006;25(20):3443-3457.