初始抗甲状腺药物剂量与疗效及治疗过程中低甲状腺素血症发生的相关性研究

发布时间：2018-05-30 17:59

  本文选题：Graves病 + 抗甲状腺药物　； 参考：《大连医科大学》2015年硕士论文

【摘要】：目的:抗甲状腺药物(antithyroid drug,ATD)治疗是Graves病(GD)的主要治疗方法之一,2011年ATA/AACE(American Thyroid Association/American Association of the Clinical Endocrinologists)新指南推荐,ATD治疗初始剂量为甲巯咪唑(MMI)10~20mg/d或丙硫氧嘧啶(PTU)150~450mg/d(分3次口服),但在合适的初始剂量等用药方面仍缺乏有力的询证医学支持。同时,针对GD患者在服用抗甲状腺药物治疗过程中出现低甲状腺素血症(低T4血症,hypothyroxinemia)的现象,对抗甲状腺药物治疗GD引发的低T4血症状态进行相关因素分析,进而探讨GD治疗过程中联用左旋甲状腺素(L-T4)与否对病程的影响。目前GD的治疗很不规范,具有很大的随意性,治疗过程中联用L-T4与否对病程的影响尚无定论,很多内分泌科医生在临床上往往根据其自身经验或随潮流加用或不加用L-T4。本研究通过前瞻性观察不同剂量MMI用药前及用药后疗效及其与发生低T4血症间的关系,比较使用小剂量(MMI15mg/日)、中等剂量(MMI20mg/日)和大剂量(MMI130mg/日)甲巯咪唑治疗GD的有效性和安全性,以及通过观察联用L-T4与否对GD的缓解率,为指导临床用药提供参考。实验对象与方法:选择2013年5月至2014年9月就诊于大连医科大学附属第一医院一部门诊的初发甲亢患者,依据患者临床症状、查体、甲状腺功能、促甲状腺激素受体抗体(thyrotrophin receptor antibody,TRAb)及甲状腺静态显像(ECT)检查明确诊断为GD患者,依据纳入及排除标准,共纳入146例患者。记录其性别、年龄、症状,用药前促甲状腺激素(thyroid stimulating hormone,TSH)、FT3、FT4、TRAb、TgAb、TPOAb、生化肝功、白细胞及中性粒细胞绝对数值。将146例患者中FT440pmol/L者给予MMI15mg/d,即MMI15mg组(小剂量组,n=60);ft4介于40~60pmol/l者给予mmi20mg/d,即mmi20mg组(中等剂量组,n=39);ft460pmol/l者给予mmi30mg/d,即mmi30组(大剂量组,n=47)。对治疗前合并轻度粒细胞减少(中性粒细胞数介于1.5×109/l~2.0×109/l)或存在轻度肝功能异常(alt或ast升高但未达到正常值的2.5倍)者,不论初始ft4水平如何,均给予mmi15mg/d。并按初治期、减量期、维持期规范用药,每2周随访一次,至少随访16周,治疗前后收集患者的一般资料、甲状腺功能、血常规、肝功能相关血液生化指标。数据录入采用excel2003软件,统计处理应用spss22.0软件,计量资料以均数±标准差(x±s)表示,两组间数据比较采用t检验,三组间数据比较采用方差分析,百分率比较采用x2检验,以“经atd治疗后是否出现低t4血症”为因变量,以“性别、年龄、用药前血ft4水平、trab、tgab、tpoab水平及mmi初始剂量”为自变量行多因素logistic回归分析,分别以“ft4达标所需时间”、“tsh达标所需时间”为因变量,以“性别、年龄、用药前血ft4水平、trab、tgab、tpoab水平、mmi初始剂量、是否联用l-t4”为自变量行多元线性回归分析,p0.05表示差异有统计学意义。结果:1.三组不同剂量组mmi治疗gd均能取得良好的效果,治疗后ft4均比治疗前显著下降,差异具有统计学意义(p0.01);治疗前三组组间ft4比较,mmi30mg组均高于mmi15mg组及mmi20mg组,差异有统计学意义(p0.01);治疗后三组组间ft4比较,无统计学差异(p0.05);治疗后mmi30mg组ft4下降的幅度明显大于mmi15mg组及mmi20mg组(p0.01)。三组治疗后tsh均比治疗前有上升趋势,且mmi30mg组差异具有统计学意义(p0.05)。2.以“经atd治疗后是否出现低t4血症”为因变量,以“性别、年龄、用药前血ft4水平、trab、tgab、tpoab水平及mmi初始剂量”为自变量行多因素logistic回归分析,结果显示低t4血症发生与上述指标均不相关(p0.05)。3.mmi治疗16周过程中共有65例出现低t4血症,其中联用l-t4者23例,未联用l-t4者42例,联用l-t4组ft4达标时间迟于未联用l-t4组,但差异无统计学意义(p0.05)。联用l-t4组低t4血症达标比例为65.22%,略高于不联用l-t4组52.38%,两组间比较采用x2检验,差异无统计学意义(p0.05)。4.TSH及FT4达标所需时间三组组内比较,FT4达标时间均早于TSH达标时间,且MMI15mg组差异具有统计学意义(P0.01)。TSH达标时间三组组间比较,MMI20mg组的TSH达标时间最慢,其与MMI15mg组及MMI30mg组之间均存在显著差异,差异有统计学意义(P0.05);15mg组与30mg组TSH达标时间之间无显著差异(P0.05)。而FT4达标时间三组组间比较差异无统计学意义(P0.05)。5.分别以“FT4达标所需时间”、“TSH达标所需时间”为因变量,以“性别、年龄、用药前血FT4水平、TRAb、TgAb、TPOAb水平、MMI初始剂量、是否联用L-T4”为自变量行多元线性回归分析,结果显示FT4达标所需时间及TSH达标所需时间与上述指标均不相关(P0.05)。6.三组治疗16周后共96例GD患者FT4降至正常,MMI15mg组FT4达标比例为84.62%,高于MMI20mg组及MMI30mg组,但三组间比较采用x2检验,差异无统计学意义(P0.05)。FT4降至正常时,此时TSH降至正常者16例,未完全正常者80例,其中,MMI15mg组TSH降至正常者9例,完全达标比例为20.45%,高于MMI20mg组及MMI30mg组,但三组间比较采用x2检验,无显著性差异(P0.05)。结论:1.根据初始FT4水平选择不同剂量MMI治疗,均可有效控制甲状腺功能亢进症,不同剂量组间疗效相似,其疗效与剂量无关。2.低T4血症发生与否与患者性别、年龄、用药前血FT4水平、TRAb、Tg Ab、TPOAb水平及MMI初始剂量均不相关。3.低T4血症发生时联用L-T4没有影响甲状腺功能的恢复,也没有显示出优势。
[Abstract]:Objective: antithyroid drug (ATD) is one of the main treatments for Graves disease (GD). In 2011, the new guidelines for ATA/AACE (American Thyroid Association/American Association of the) are recommended for the initial dose of methimidazole or Propyl Sulfide. 3 times of oral administration), but there is still a lack of strong evidence medical support in the appropriate initial dose. At the same time, the phenomenon of hypothyroidemia (hypothyroidemia, hypothyroxinemia) in the treatment of antithyroid drugs for GD patients and the related factors of the hypothyroidism caused by the treatment of thyroid drugs for GD induced by GD are carried out. The effect of combined use of levothyroxine (L-T4) on the course of disease during the treatment of GD is discussed. At present, the treatment of GD is not standardized and has great randomness. There is no definite conclusion on the influence of combined use of L-T4 on the course of disease in the treatment process. Many department of endocrinology doctors often use or do not add to their own experience or trend according to their own experience. The effect of different doses of MMI before and after drug use and its relationship with low T4 were prospectively observed. The efficacy and safety of small dose (MMI15mg/ day), medium dose (MMI20mg/ day) and large dose (MMI130mg/ day) methimazole in the treatment of GD were compared, and the remission of GD was observed by observing the combined use of L-T4 to the GD. Rate, to provide reference for guiding clinical medication. Experimental subjects and methods: selected patients with primary hyperthyroidism in an outpatient department of the First Affiliated Hospital of Dalian Medical University from May 2013 to September 2014. According to the clinical symptoms, examination, thyroid function, thyroid stimulating hormone receptor antibody (thyrotrophin receptor antibody, TRAb) and thyroid gland The static imaging (ECT) examination was clearly diagnosed as GD patients. According to the inclusion and exclusion criteria, 146 patients were included. The sex, age, symptoms, thyroid stimulating hormone (thyroid stimulating hormone, TSH), FT3, FT4, TRAb, TgAb, TgAb, TPOAb, biochemical liver work, and the absolute values of leukocyte and neutrophils were recorded in 146 patients. MMI15mg/d, MMI15mg group (small dose group, n=60), FT4 between 40~60pmol/l and mmi20mg group (medium dose group, n=39); ft460pmol/l was given to mmi30mg/d, that is, mmi30 group (large dose group, n=47). Mild granulocytic reduction (neutrophilic granulocyte count was 1.5 * * * * *) before treatment or mild liver function difference before treatment. Often (ALT or ast increased but not 2.5 times the normal value), regardless of the initial FT4 level, all of them were given mmi15mg/d. and according to the initial treatment period, the reduction period and the maintenance period, followed up every 2 weeks for at least 16 weeks. The general data of the patients, the thyroid gland function, blood routine, and the blood biochemical indexes related to liver function were collected before and after treatment. Using Excel2003 software, statistical processing and application of spss22.0 software, the measurement data were expressed with mean + standard deviation (x + s). The data of the two groups were compared with t test. The data of the three groups were compared by variance analysis, and the percentage was compared with x2 test. The result was "whether there was low T4 after ATD treatment" as the dependent variable and "sex, age, and blood ft before medication". The 4 level, TRAb, TGAb, TPOAb level and the initial dose of MMI "multiple factor Logistic regression analysis of the independent variables, respectively," the time required for the FT4 standard "," the time required for the TSH standard "as the dependent variable, with" sex, age, blood FT4 level before medication, TRAb, TGAb, TPOAb water level, MMI initial dose, whether or not to use "as the independent variable linear multivariate linear Regression analysis, P0.05 showed that the difference was statistically significant. Results: 1. three groups of different doses of MMI treatment GD can achieve good results, after treatment, FT4 was significantly lower than before treatment, the difference was statistically significant (P0.01); before the treatment of three groups of FT4, mmi30mg group was higher than the mmi15mg group and mmi20mg group, the difference was statistically significant (P0.01); After treatment, there was no significant difference in FT4 between the three groups (P0.05), and the decrease of FT4 in group mmi30mg was significantly greater than that in group mmi15mg and mmi20mg (P0.01). The TSH in the three groups had a higher trend than before the treatment, and the difference in the mmi30mg group was statistically significant (P0.05).2.. "Sex, age, blood FT4 level, TRAb, TGAb, TPOAb level and initial dose of MMI" were analyzed by multiple factor Logistic regression analysis of the independent variable. The results showed that there were 65 cases of low T4 anemia in the 16 week process of.3.mmi treatment of low T4 (P0.05), of which 23 cases were combined with L-T4, 42 cases were not combined with L-T4. The standard time of FT4 in group T4 was later than that of the non combined L-T4 group, but the difference was not statistically significant (P0.05). The proportion of the low T4 anemia in the L-T4 group was 65.22%, slightly higher than that of the non combined L-T4 group. The two groups were compared with the x2 test. The difference was not statistically significant (P0.05) in the three groups of.4.TSH and FT4. Time, and the difference in group MMI15mg was statistically significant (P0.01).TSH standard time between three groups, MMI20mg group TSH standard time was the slowest, and there was significant difference between group MMI15mg and MMI30mg group, the difference was statistically significant (P0.05); 15mg group and 30mg group TSH time between the standard time no significant difference (P0.05) and three groups of time standard time. There was no statistically significant difference between the groups (P0.05).5. as "time required for the standard of FT4" and "time required for the standard of TSH" as the dependent variable. "Sex, age, FT4 level of blood before medication, TRAb, TgAb, TPOAb level, MMI initial dose, or not with L-T4" was a multivariate linear regression analysis, and the results showed the time required for FT4 and T. The time required for the SH standard was not related to the above index (P0.05).6. three groups after 16 weeks of treatment, 96 cases of GD patients were reduced to normal FT4, MMI15mg group FT4 standard ratio was 84.62%, higher than the MMI20mg group and MMI30mg group, but the three groups were compared to x2 test, the difference was not statistically significant (P0.05) to normal, this time to 16 cases, not complete. 80 cases were normal, among which, 9 cases of MMI15mg group TSH were reduced to normal, the proportion of complete standard was 20.45%, higher than that of group MMI20mg and MMI30mg, but x2 test was used in the three groups, and there was no significant difference (P0.05). Conclusion: 1. according to the initial FT4 level, the choice of different doses of MMI therapy can effectively control the hyperthyroidism, the effect of different dosage groups is effective. Similarly, the efficacy and dose independent.2. hypothyroidemia was associated with patients' sex, age, blood FT4 levels, TRAb, Tg Ab, TPOAb level and initial dose of MMI, which did not affect the recovery of thyroid function, and did not show advantages.
【学位授予单位】：大连医科大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R581.1

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