β型甲状腺激素抵抗综合征

王黄曼, 单忠艳, 滕晓春

王黄曼, 单忠艳, 滕晓春. β型甲状腺激素抵抗综合征[J]. 罕见病研究, 2023, 2(3): 331-336. DOI: 10.12376/j.issn.2097-0501.2023.03.003
引用本文: 王黄曼, 单忠艳, 滕晓春. β型甲状腺激素抵抗综合征[J]. 罕见病研究, 2023, 2(3): 331-336. DOI: 10.12376/j.issn.2097-0501.2023.03.003
WANG Huangman, SHAN Zhongyan, TENG Xiaochun. The Syndromes of Resistance to Thyroid Hormone Beta[J]. Journal of Rare Diseases, 2023, 2(3): 331-336. DOI: 10.12376/j.issn.2097-0501.2023.03.003
Citation: WANG Huangman, SHAN Zhongyan, TENG Xiaochun. The Syndromes of Resistance to Thyroid Hormone Beta[J]. Journal of Rare Diseases, 2023, 2(3): 331-336. DOI: 10.12376/j.issn.2097-0501.2023.03.003

β型甲状腺激素抵抗综合征

基金项目: 

国家自然科学基金 82270831

国家自然科学基金 81970681

详细信息
    通讯作者:

    滕晓春,E-mail:tengxiaochun@126.com

  • 中图分类号: R581

The Syndromes of Resistance to Thyroid Hormone Beta

Funds: 

National Natural Science Foundation of China 82270831

National Natural Science Foundation of China 81970681

More Information
  • 摘要:

    甲状腺激素抵抗综合征(RTH)是甲状腺激素受体(TR)基因突变,导致器官对甲状腺激素(TH)的敏感性降低,TH对全身组织器官作用障碍的一种罕见综合征。THRB基因突变导致的RTH称为β型甲状腺激素抵抗综合征(RTHβ)。RTHβ主要特点是循环血中甲状腺素(T4)升高、三碘甲腺原氨酸(T3)水平正常或升高、促甲状腺激素(TSH)水平正常或轻度升高,临床上RTHβ容易被误诊为甲状腺功能亢进症,予以抗甲状腺药物、放射性131I治疗或手术治疗,进而导致TH抵抗加重,因此对该病的正确诊断非常重要。本文对RTHβ的分子机制、临床特征、诊断及治疗予以归纳并总结。

    Abstract:

    The syndrome of resistance to thyroid hormone(RTH) is a rare syndrome caused by the mutation of thyroid hormone receptor (TR) gene, which reduces the sensitivity of target organs to thyroid hormone (TH) and leads to the dysfunction of TH. Thyroid hormone resistance syndrome β (RTHβ) is caused by the mutations in the THRB gene. The main characteristics of RTHβ are increased thyroxine (T4) in the circulating blood, normal or elevated levels of triiodothyronine(T3), paired with normal or high thyroid-stimulating hormone (TSH) concentration. Clinically, it is easy to misdiagnose RTHβ as hyperthyroidism, and give anti-thyroid drugs, radioactive 131I therapy or surgery, which then leads to the aggravation of TH resistance, so the correct diagnosis of the disease is critical. In this paper, the molecular mechanism, clinical characteristics, diagnosis and treatment of RTHβ are summarized.

  • 人类有两种高度同源的甲状腺激素受体(thyroid hormone receptor,TR),分别为TRα和TRβ,分别由第17号和第3号染色体上的THRATHRB基因编码。TRα基因的受体亚型主要有TRα1和TRα2两种。TRα1表达广泛,尤其是在中枢神经系统、心肌、骨骼肌等。TRβ基因产生两种主要的受体亚型,包括TRβ1和TRβ2。TRβ1在人体组织中表达广泛,主要见于肝脏和肾脏,而TRβ2的表达主要局限于下丘脑、垂体、内耳等[1]

    甲状腺激素抵抗综合征(thyroid hormone resistance syndrome,RTH)是由于TR的基因突变,引起靶器官对甲状腺激素的敏感性降低,导致甲状腺激素对全身组织器官作用障碍的一种罕见综合征。THRA基因突变导致的RTH称为α型甲状腺激素抵抗综合征(thyroid hormone resistance syndrome α,RTHα),THRB基因突变导致的RTH称为β型甲状腺激素抵抗综合征(thyroid hormone resistance syndrome β,RTHβ)。RTHβ主要特点是循环血中甲状腺素(thyroxine, T4)升高、三碘甲腺原氨酸(triiodothyronine, T3)正常或升高、促甲状腺激素(thyroid stimulating hormone,TSH)正常或轻度升高[2],临床上易将RTHβ误诊为甲状腺功能亢进症(以下简称甲亢),予以抗甲状腺药物、放射性131I治疗或手术治疗,进而导致甲状腺激素抵抗加重,因此对该病的正确诊断非常重要。本文对RTHβ的分子机制、临床特征、诊断及治疗予以归纳并总结。

    甲状腺激素主要通过核受体起作用,TR是类固醇核受体超家族转录因子的一员,调节下游基因在各种组织中的表达。TR优先与视黄醇X受体(retinoid X receptor,RXR)结合,形成异源二聚体,然后与靶基因启动子区域的DNA序列——甲状腺激素反应元件(thyroid hormone responsive elements,TREs)结合。TR也可形成同源二聚体与靶基因上的TRE结合。在T3不存在的情况下,TR形成同二聚体或异二聚体形式以招募共抑制因子,如视黄酸和甲状腺受体的沉默调节介质(silencing mediator for retinoid and thyroid hormone receptors,SMRT)、核受体的协同抑制因子(the nuclear receptor corepressor,NCoR),在这种状态下,基因转录被抑制或“沉默”。当T3存在时,T3与TR结合,SMRT或NCoR等转录抑制因子与TR解离。与此同时,共刺激因子会被招募如类固醇受体协同激活因子1(steroid receptor coactivator-1,SRC-1)、CREB结合蛋白(cAMP-response element binding protein,CBP)和CBP相关因子(P300/CBP-related factor,pCAF)[3-4],介导T3对靶基因的转录作用。

    RTHβ患者的受体突变位点位于配体结合域,导致其与T3结合能力下降,除此之外,这种天然的突变也可能损害核受体和转录辅助因子之间的相互作用[2]。RTHβ杂合子突变不仅导致突变受体本身的结合功能受损,也能抑制另外一条野生型受体的作用,即优势负性抑制作用[5-6]

    临床表现、生化检查、L-T3抑制试验、TRH兴奋试验符合RTHβ,但TRβ的基因未检测到突变,称为非TRβ突变的甲状腺激素抵抗,即non-TRβ RTH[7]。目前国际上报道805个RTHβ家系,236种突变位点。THRB基因突变位点多位于核受体配体结合区和铰链区[8]。突变类型包括点突变、碱基缺失或插入引起的框移突变,其中点突变最为常见。80%的病例有家族史,绝大部分为常染色体显性遗传,极少数为常染色体隐性遗传[9-10]。有5个家系近亲结婚,后代中有纯合子突变者,临床症状较杂合子突变者严重[9-12]

    RTHβ患者的临床表型异质性较大,这可能与TRβ突变类型、突变位点及TRβ的辅助调节因子均有关[2, 13]。RTHβ杂合突变患者通常没有甲状腺毒症或甲状腺功能减退症的特征性临床症状或体征。如果有,这些症状也呈轻微、非持续性。RTHβ患者接受131I治疗或甲状腺切除术后常会出现甲状腺功能减退症症状,如乏力、便秘、记忆力下降等。RTHβ纯合突变临床症状明显,通常伴有听力障碍、生长发育迟滞、骨成熟延迟、学习障碍等[9-12]。RTHβ的临床表现如下。

    甲状腺肿最常见,66%~95%的RTHβ患者可见此临床表现。甲状腺肿绝大多数是弥漫性的,但在手术后复发的患者中,多出现结节性改变和不对称性肿大。RTHβ患者循环血中TSH生物活性增强可能与甲状腺的肿大相关。

    窦性心动过速也很常见,大约80%的RTHβ患者伴有心悸和静息性心动过速,30%的RTHβ患者伴有心肌收缩力增强、二尖瓣脱垂和舒张功能障碍。RTHβ老年患者易出现心房颤动。RTHβ患者也可能发生全身血管的抵抗和动脉硬化[14-15]

    中枢神经系统的主要表现为儿童时期注意缺陷多动障碍(attention deficit hyperactive disorder,ADHD)、抑郁状态、学习障碍、智力发育迟缓。虽然30%患者有轻微的智力障碍(IQ<85),但显著的智力障碍(IQ<60)相对较少(3%)[2]。RTHβ合并ADHD的患者与仅有ADHD患者比较显示,前者的非语言性智商和学术成就较低[16]。单纯ADHD与RTH患者的多动症表现均随着年龄增长有缓解趋势。

    在儿童期,RTHβ患者生长迟缓,并且骨骼成熟延迟,身高低于第5百分位数的患者有18%,骨龄延迟大于2倍标准差的患者有29%[17]。然而,尽管存在这些异常,在成年后患者的最终身高不受影响[18]

    目前,对于RTHβ是否会合并TSH瘤还未得出统一结论。以下证据支持RTHβ可能与TSH瘤有关:①促甲状腺激素分泌的负反馈调节机制受到TRβ基因突变的损害,这可能是垂体增生或垂体TSH瘤形成的潜在原因。这在转基因小鼠研究中得到证实,TRβ(PV/PV)突变小鼠出现了垂体TSH大腺瘤[19]。1993年日本学者报道一例TSH分泌不当综合征患者,发现垂体微腺瘤,病理证实是TSH瘤,垂体瘤切除后,仍表现为TSH分泌不当综合征,推测是合并RTHβ,很遗憾当时并未做基因测定[20]。2015年,国内中国医科大学报道了一例RTHβ的散发病例,突变位点为P453T,TSH明显升高伴垂体微腺瘤,后经手术病理证实为TSH瘤,并行垂体瘤切除术。术后甲状腺肿明显减小,TSH降至正常范围[21]。②垂体TRHB体细胞突变可能与垂体TSH瘤的发生有关。目前报道了两例TSH瘤患者存在TRHB体细胞突变[22-23],一例TSH瘤患者存在TRHATRHB基因体细胞缺失,一例TSH瘤患者垂体体细胞发现新的TRβ亚型(TRβ4)可能参与TSH瘤形成[24-25]。③在不适当的抗甲状腺药物治疗或手术治疗下,RTHβ患者循环TSH水平上升,刺激垂体增生,使用适量的甲状腺素替代治疗后,垂体增生消退[26]

    血清总T4(TT4)、游离T4(FT4)水平升高, 总T3(TT3)、游离T3(FT3)水平升高或正常, TSH轻度升高或正常。血清T3/T4比值接近正常人,但低于GD患者[2]。反T3(rT3)往往升高、血清甲状腺球蛋白水平偏高[13]。纯合突变血清甲状腺激素水平更高,是杂合突变患者的2.5~6倍[9, 10-12]。性激素结合球蛋白、甘油三酯、胆固醇、碱性磷酸酶、肌酸激酶、血清铁蛋白、骨钙素是甲状腺激素作用于外周组织的指标,这些指标通常无异常。RTHβ患者甲状腺放射性核素扫描时核素显像增强,131I摄取率增强。

    目前RTHβ最直接明确的诊断方法是基因诊断,但TRH兴奋实验、L-T3抑制试验或TRH兴奋实验联合L-T3抑制试验对于未发现突变的疑似RTHβ患者仍然十分重要。基因检测的阴性结果并不能排除疑似RTHβ的诊断。

    典型的甲亢患者血清TSH往往是最早发生变化的指标,被明显抑制,应用第3代TSH检测试剂盒检测,TSH值小于0.01 mIU/mL,随后才出现血清FT3、FT4均升高。甲亢患者如果FT3、FT4均升高,而TSH不被抑制,要考虑其他原因导致FT3、FT4升高。鉴别诊断包括甲状腺素结合球蛋白增多症、甲状腺激素自身抗体的干扰、家族性白蛋白异常高甲状腺素血症[27]、TSH瘤和RTHα(表 1)。

    表  1  高甲状腺素血症鉴别诊断
    Table  1.  Differential diagnosis of hyperthyroxinemia
    疾病名称 临床表现 FT4 FT3 TSH rT3 TT4 TT3 基因缺陷 其他
    RTHβ 甲状腺肿、窦性心动过速、轻微神经认知功能障碍 ↑或N ↑或N ↑或N THRB 甲状腺摄碘率升高;L-T3抑制试验:TSH部分抑制
    RTHα 神经认知功能障碍、身材矮小、骨发育延迟、心率缓慢、巨颅症、便秘、贫血 ↑或N N ↑或N THRA
    TSH瘤 甲状腺毒症 ↑或N α-GSU↑、α-GSU/TSH↑;MRI影像学存在占位病变、TRH兴奋试验阴性、L-T3抑制试验TSH不被抑制
    TBG增多症 N N N TBG的基因拷贝数异常 血清TBG↑
    FDH ↑或N ↑或N N ↑或N ALB 化学发光免疫分析法检测FT3或FT4假性升高、平衡透析或超滤后检测FT3、FT4水平正常
    THAAb干扰 ↑或N ↑或N N N ↑或N ↑或N THAAb阳性
    RTHβ:β型甲状腺激素抵抗综合征;RTHα:α型甲状腺激素抵抗综合征;TBG:甲状腺素结合球蛋白;THAAb:甲状腺激素自身抗体;FDH:家族性白蛋白异常高甲状腺素血症;TSH:促甲状腺激素;FT4:游离T4;FT3:游离T3;rT3:反T3;TT4:总T4;TT3:总T3;α-GSU:血清糖蛋白激素α亚单位;TRH:促甲状腺激素释放激素;N:正常;↑:升高;↓:下降
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    在大多数情况下,RTHβ患者不需治疗,因全身性甲状腺激素抵抗通过循环血液中高水平的甲状腺激素来代偿。抗甲状腺药物、手术或131I治疗可降低甲状腺激素水平、血清TSH水平升高,可刺激甲状腺增生,增加垂体TSH细胞增生,甚至可能加重甲状腺激素抵抗,所以在RTHβ患者中尽量不要使用[2, 26]。在少数情况下,当RTHβ患者有严重的甲亢性心力衰竭时,甲状腺手术后给予甲状腺激素替代治疗,可减少甲状腺激素对心脏的影响[28]

    对于儿童生长发育迟缓和成人严重高胆固醇血症的患者,这些患者具有显著的甲状腺激素抵抗,可用超生理剂量的L-T4或L-T3进行治疗[2],定期监测甲状腺激素作用的指标也很重要,如性激素结合球蛋白、心率等。甲状腺激素治疗儿童RTHβ应特别注意骨代谢、生长和神经发育的指标。过度使用甲状腺激素往往会引起心脏副作用或过度分解代谢[2, 28]

    有明显的甲亢症状和TSH严重抵抗的患者应用肾上腺素β受体阻滞剂也是一个有效的选择。对于高代谢状态明显的患者,多巴胺能药物或生长抑素类药物可抑制垂体TSH的分泌,能有效缓解症状[29-30]。但也有研究表明多巴胺能药物或生长抑素类药物在长期使用此类药物的RTHβ患者中可能出现逃逸现象[31]

    甲亢症状明显的患者通常表现为心动过速、多汗、明显的甲状腺肿和ADHD,甲状腺激素类似物3,5,3′-三碘甲腺原氨酸(Triac) 也可用于治疗这些患者。与T3相比,Triac具有更强的TRβ亲和力、活性和效力。在体内,Triac主要作用于垂体而非外周组织发挥拟甲状腺激素作用,从而使TSH和甲状腺激素水平降低,进而改善高代谢状态[32-33]。这种药物已证明在成人和儿童患者中均有益[31-35]。常用剂量为每日1.4~2.8 mg,有文献报道一日两次给药可抑制TSH分泌[36]。对于Triac治疗无效果的患者,也可选择右旋甲状腺素进行治疗[37-38]

    与甲亢女性患者相反,尽管RTHβ患者甲状腺激素水平升高,但并未增加早产、死产或子痫前期风险。然而,RTHβ女性的早期流产率明显高于RTHβ男性的配偶或未有突变的一级亲属。RTHβ女性流产的胎儿是无基因突变胎儿,而不是有基因突变的胎儿,表明流产的发生是由于胎儿暴露于宫内高甲状腺激素水平所致[39]。此外,RTHβ母亲没有患病的后代更易出现低体重,而患病后代的突变TRβ反而避免了高甲状腺激素的毒性作用。因此RTHβ孕妇如果怀有正常胎儿,母体FT4水平最好控制在高于正常上限20%之下,但也有病例报告显示,FT4水平控制在高于正常上限50%之下也不会导致新生儿低体重儿和TSH抑制[40-41]

    目前尚无胎儿RTHβ的治疗方案。甲状腺激素对神经系统发育至关重要,特别是在婴幼儿时期。因此RTHβ婴儿的任何甲状腺激素缺乏的迹象(如骨发育延迟、生长迟缓、TSH升高)都要考虑进行甲状腺激素治疗。是否接受治疗也可参照未接受治疗的RTHβ家庭成员患者的情况来确定[39]。对神经运动参数的长期监测有助于了解早期干预的效果。

    RTHβ是一种罕见的内分泌疾病,许多临床医生对其认识不足,误将其诊断为甲亢,很多患者接受131I或手术治疗,导致其甲状腺激素抵抗症状加重,需要应用超大剂量的甲状腺激素维持甲状腺功能正常,导致心脏和骨代谢障碍,患者的生活质量和预期寿命受到严重影响。因此,有必要加强对RTHβ的认识,以避免误诊误治,改善患者的预后。

    作者贡献:王黄曼负责文献检索、分析;单忠艳、滕晓春共同参与综述选题、文献检索、分析与论文撰写。
    利益冲突:所有作者均声明不存在利益冲突。
  • 表  1   高甲状腺素血症鉴别诊断

    Table  1   Differential diagnosis of hyperthyroxinemia

    疾病名称 临床表现 FT4 FT3 TSH rT3 TT4 TT3 基因缺陷 其他
    RTHβ 甲状腺肿、窦性心动过速、轻微神经认知功能障碍 ↑或N ↑或N ↑或N THRB 甲状腺摄碘率升高;L-T3抑制试验:TSH部分抑制
    RTHα 神经认知功能障碍、身材矮小、骨发育延迟、心率缓慢、巨颅症、便秘、贫血 ↑或N N ↑或N THRA
    TSH瘤 甲状腺毒症 ↑或N α-GSU↑、α-GSU/TSH↑;MRI影像学存在占位病变、TRH兴奋试验阴性、L-T3抑制试验TSH不被抑制
    TBG增多症 N N N TBG的基因拷贝数异常 血清TBG↑
    FDH ↑或N ↑或N N ↑或N ALB 化学发光免疫分析法检测FT3或FT4假性升高、平衡透析或超滤后检测FT3、FT4水平正常
    THAAb干扰 ↑或N ↑或N N N ↑或N ↑或N THAAb阳性
    RTHβ:β型甲状腺激素抵抗综合征;RTHα:α型甲状腺激素抵抗综合征;TBG:甲状腺素结合球蛋白;THAAb:甲状腺激素自身抗体;FDH:家族性白蛋白异常高甲状腺素血症;TSH:促甲状腺激素;FT4:游离T4;FT3:游离T3;rT3:反T3;TT4:总T4;TT3:总T3;α-GSU:血清糖蛋白激素α亚单位;TRH:促甲状腺激素释放激素;N:正常;↑:升高;↓:下降
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    1. 于浩,郭孛,裴京,童慧昕,李钰婕,梁琳琅. 垂体促甲状腺激素腺瘤的诊疗策略. 解放军医学杂志. 2024(11): 1251-1258 . 百度学术

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  • 收稿日期:  2023-06-14
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