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亚临床甲状腺功能减退症(subclinical hypothyroidism,SCH)的定义是血液中TSH水平高于正常参考值,而游离三碘甲状腺原氨酸(free triiodothyronine,FT3)及游离甲状腺素(free thyroxine,FT4)均处于正常水平,其在成人中的发病率为4%~20%,多数SCH是由慢性淋巴细胞甲状腺炎引起的[1]。其他可能引起SCH的原因有:①甲状腺损伤(131I治疗或其他外放疗);②医源性药物(含碘化合物、碳酸锂及干扰素等)导致;③曾患有亚急性甲状腺炎、产后甲状腺炎或无痛性甲状腺炎[2]。SCH的发病率会随着年龄增长而逐渐提高,女性的发病率高于男性。虽然SCH只代表轻度的甲状腺功能减退,但由于其是一种进展性的疾病,尤其是在血浆TSH浓度大于10 mIU/L、甲状腺过氧化物酶抗体阳性的老年女性患者中,SCH更容易发展至甲状腺功能减退症(以下简称甲减)[3]。SCH的临床症状并不典型,一些患者甚至没有明显的临床症状,在一些SCH的患者中会出现焦虑、抑郁、认知和记忆功能减退等,这些症状的严重程度与疾病严重程度、病情的持续时间有关。
心血管系统是甲状腺激素(thyroid hormone,TH)发挥作用的主要靶器官,TH缺乏可导致血管外周阻力增加、收缩及舒张功能减低、心脏的前负荷降低等,进而增加心血管疾病的发病风险[3-4]。高脂血症是心血管疾病的主要风险因素之一[5-6],TH的缺乏会造成血脂水平的异常,进而增加心血管疾病的发病风险[1]。到目前为止,甲减与高脂血症的关系已经十分明确,而有关高脂血症与SCH之间的关系的研究尚不充分。既往有研究表明,在SCH患者中,血浆中TSH与总胆固醇(total cholesterol,TC)及低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)水平呈正相关[7-9]。查阅文献可知,TH替代治疗可以减小甲状腺体积,改善SCH症状,改善TH缺乏所导致的血液动力学异常[3]。但TH替代治疗是否能够改善SCH患者的血脂异常状态仍然存在争议。目前有为数不多的关于评估SCH患者使用TH治疗对血脂水平影响的随机对照试验(randomized controlled trial,RCT),但是各研究的结果之间仍然存在争议[10-17]。本研究的目的是系统地研究TH替代治疗对SCH患者血脂水平的影响。
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图 1为本研究的文献检索过程。最初检索获得相关文献共2198篇,其中2133篇因非RCT文献而被排除,经过阅读题目和摘要后57篇文献再被排除。经过仔细阅读全文,共有7篇RCT文献被纳入本研究中[10, 12-17],另外1篇RCT文献因数据不完整而被排除,文献检索筛选过程见图 1。纳入文献的研究资料见表 1。
作者 年份 患者例数 既往甲状腺相关疾病史 TH组血浆TSH水平/(mIU/L) 安慰剂组血浆TSH水平/(mIU/L) TH的初始使用剂量/μg 治疗时间/周 Cooper等[10] 1984 33 甲亢治疗后 10.8±2.2 11.1±3.2 50 48 Jaeschke等[12] 1996 31 文献中未提及 12.1±6.8 9.4±3.1 25 24 Meier等[13] 2001 63 自身免疫性甲状腺炎,甲亢治疗后及先天性SCH 14.4±1.7 11.3±1.0 25 48 Kong等[14] 2002 27 无甲状腺相关疾病病史 8.0±1.5 7.3±1.6 50 24 Razvi等[15] 2007 71 文献中未提及 5.4(3.8~15.8)a 5.3(3.7~15.9)a 100 24 Monzani等[16] 2004 45 自身免疫性甲状腺炎,高功能腺瘤及多结节性甲状腺肿治疗后 6.03(3.65~15.00)a 5.68(3.66~12.60)a 25 24 Caraccio等[17] 2002 49 自身免疫性甲状腺炎,甲亢治疗后 6.00(3.70~15.00)a 4.90(3.65~9.00)a 25 24 表中,TH:甲状腺激素;SCH:亚临床甲状腺功能减退症;a表示在该文献中,血浆TSH水平以“中位数及范围”表示,其余文献中以“均数±标准差”表示。 表 1 纳入的7篇随机对照文献的研究资料
Table 1. Characteristics of the trials included in the present meta-analysis
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本研究通过绘制偏倚风险条形图及偏倚风险概要图进行质量评估(图 2)。以Cochrane中推荐的偏倚风险评价标准对所有纳入的文献进行偏倚风险评价,图 2中A表示每条风险评价标准所占的百分比,图 2中B为偏倚风险概要图,以颜色区分风险偏倚的高低,本研究中未出现红色图例,纳入的7篇文献中有5篇文献分别有1~3条未知风险项,其余2篇文献均为偏倚低风险。因此,本研究中纳入的7篇文献方法学整体质量较好。
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本研究共进行了4组荟萃分析。第1组为比较TH及安慰剂对血浆TC水平的影响差异。该组中共纳入7篇文献。各研究之间没有明显的统计学异质性(I2=42%,P=0.11),采用固定效应模型,荟萃分析结果显示TH及安慰剂在降低血浆中TC水平的程度上无明显差异(平均差:-0.18;95% CI:[-0.40,0.03];P=0.09)(图 3)。第2组为比较TH及安慰剂对血浆LDL-C水平的影响差异。该组中共纳入6篇文献。各研究之间无统计学异质性(I2=34%,P=0.18),采用固定效应模型,荟萃分析结果显示TH降低血浆中LDL-C水平的程度明显高于安慰剂(平均差:-0.23;95% CI:[-0.44,-0.33];P=0.02)(图 4)。第3组为比较TH及安慰剂对血浆甘油三酯(triglycerides,TG)水平的影响差异。该组中共纳入6篇文献。各研究之间无统计学异质性(I2=0,P=0.92),采用固定效应模型,荟萃分析结果显示TH及安慰剂在降低血浆中TG水平的程度上无明显差异(平均差:-0.02;95% CI:[-0.17,0.13];P=0.78)(图 5)。第4组为比较TH及安慰剂对血浆高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-C)水平的影响差异。该组中共纳入6篇文献。各研究之间无统计学异质性(I2=0,P=0.96),采用固定效应模型,荟萃分析结果显示TH及安慰剂在升高血浆中HDL-C水平的程度上无明显差异(平均差:-0.06;95% CI:[-0.14,0.02];P=0.14)(图 6)。
图 3 甲状腺激素及安慰剂降低亚临床甲状腺功能减退症患者血浆总胆固醇水平的差异
Figure 3. Comparison of changes in the serum total cholesterol levels of patients treated with L-thyroxine or the placebo
图 4 甲状腺激素及安慰剂降低亚临床甲状腺功能减退症患者血浆低密度脂蛋白胆固醇水平的差异
Figure 4. Comparison of changes in the serum low-density lipoprotein-cholesterol levels of patients treated with L-hyroxine or the placebo
甲状腺激素治疗亚临床甲状腺功能减退症对血脂水平影响的荟萃分析
Effect of L-thyroxine versus placebo treatment on serum lipid levels in subclinical hypothyroidism
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摘要:
目的 使用荟萃分析方法汇总随机对照试验,评估甲状腺激素对亚临床甲状腺功能减退症(SCH)患者血脂水平的影响。 方法 以“thyroxine”、“ levothyroxin”及“levothyroxine”为关键词检索了2015年7月前包括Cochrane Library、PubMed、Medline、Google Scholar及Embase等在内的数据库中有关甲状腺激素替代治疗SCH的随机对照试验文献,所有数据均为连续型变量,采用Cochrane提供的RevMan 5.2软件进行统计学分析,依据Cochrane质量评价标准进行文献质量评估。当研究间存在异质性时(I2 > 50%),采用随机效应模型进行荟萃分析;否则采用固定效应模型进行荟萃分析。 结果 最终纳入7篇随机对照试验文献,共319例患者。纳入的7篇文献方法学整体质量较好。共进行4组荟萃分析评价甲状腺激素对血脂的影响,4组研究之间无统计学异质性[总胆固醇(TC):I2=42%,P=0.11;甘油三酯(TG):I2=0,P=0.92;低密度脂蛋白胆固醇(LDL-C):I2=34%,P=0.18;高密度脂蛋白胆固醇(HDL-C):I2=0,P=0.96],均采用固定效应模型进行荟萃分析。荟萃分析结果显示,甲状腺激素及安慰剂对血浆中血脂水平的影响程度如下:TC(平均差:-0.18;95% CI:[-0.40,0.03];P=0.09)、TG(平均差:-0.02;95% CI:[-0.17,0.13];P=0.78)、LDL-C(平均差:-0.23;95% CI:[-0.44,-0.33];P=0.02)、HDL-C(平均差:-0.06; 95% CI:[-0.14,0.02];P=0.14)。 结论 对于SCH患者,在进行外源性甲状腺激素治疗后,血浆LDL-C水平得到改善,而血浆TC、TG、HDL-C水平未见明显变化。 -
关键词:
- 状腺激素类 /
- 随机对照试验 /
- Meta分析 /
- 亚临床甲状腺功能减退症 /
- 血脂
Abstract:Objective Subclinical hypothyroidism is a common disease. However, whether L-thyroxine replacement treatment can affect serum lipids in cases of subclinical hypothyroidism remains controversial. The objective of this meta-analysis was to assess the effect of L-thyroxine therapy on serum lipid levels of patients with subclinical hypothyroidism. Methods Literature dated until July 2015 was retrieved from the Cochrane Library, PubMed, Medline, Google Scholar, and Embase searching for the keywords "hyroxine", "levothyroxin" and "levothyroxine". All randomized controlled trials(RCTs) to determine the effects of L-thyroxine replacement on serum lipid levels were included in this study. After screening, the eligible RCTs were included in this meta-analysis. Statistical analyses were performed by the Review Manager 5.2 software. All the assessed outcomes were continuous data. Results A total of 7 RCTs involving 319 patients were included. The overall methodological quality of the RCTs was good. Results showed that the serum low density lipoprotein-cholesterol(LDL-C) level significantly decreased after L-thyroxine treatment [mean difference(MD):-0.23; 95% CI: [-0.44, -0.03]; P=0.02]. Meanwhile, changes in the total cholesterol(MD: -0.18; 95% CI: [-0.40, 0.03]; P=0.09), triglyceride(MD: -0.02; 95% CI: [-0.17, 0.13]; P=0.78), and high density lipoprotein-cholesterol(MD: -0.06; 95% CI: [-0.14, 0.02]; P=0.14) levels were not significant. Conclusions All available RCT evidence on the effect of L-thyroxine on serum lipid levels in subclinical hypothyroidism revealed a significant improvement in the serum LDL-C levels. However, the serum TC, TG, and HDL-C levels did not significantly change. -
表 1 纳入的7篇随机对照文献的研究资料
Table 1. Characteristics of the trials included in the present meta-analysis
作者 年份 患者例数 既往甲状腺相关疾病史 TH组血浆TSH水平/(mIU/L) 安慰剂组血浆TSH水平/(mIU/L) TH的初始使用剂量/μg 治疗时间/周 Cooper等[10] 1984 33 甲亢治疗后 10.8±2.2 11.1±3.2 50 48 Jaeschke等[12] 1996 31 文献中未提及 12.1±6.8 9.4±3.1 25 24 Meier等[13] 2001 63 自身免疫性甲状腺炎,甲亢治疗后及先天性SCH 14.4±1.7 11.3±1.0 25 48 Kong等[14] 2002 27 无甲状腺相关疾病病史 8.0±1.5 7.3±1.6 50 24 Razvi等[15] 2007 71 文献中未提及 5.4(3.8~15.8)a 5.3(3.7~15.9)a 100 24 Monzani等[16] 2004 45 自身免疫性甲状腺炎,高功能腺瘤及多结节性甲状腺肿治疗后 6.03(3.65~15.00)a 5.68(3.66~12.60)a 25 24 Caraccio等[17] 2002 49 自身免疫性甲状腺炎,甲亢治疗后 6.00(3.70~15.00)a 4.90(3.65~9.00)a 25 24 表中,TH:甲状腺激素;SCH:亚临床甲状腺功能减退症;a表示在该文献中,血浆TSH水平以“中位数及范围”表示,其余文献中以“均数±标准差”表示。 -
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