重组人促甲状腺激素临床应用中国专家共识（2025年版）

1. rhTSH 的研发、生物学特征及临床应用

rhTSH最早于1993年由美国健赞公司(Genzyme Corporation)利用重组DNA技术开发并生产(thyrotropin alfa)。Thyrotropin alfa氨基酸序列与垂体内源性TSH一致。rhTSH与内源性TSH的区别主要在于氨基酸残基糖基化的类型与数量。因N-乙酰氨基葡萄糖(N-acetylglucosamin, GlcNAc)和甘露糖残基的含量较高,thyrotropin alfa的糖基化水平高于内源性TSH;由于无N-乙酰半乳糖胺(N-acetylgalactosamine, GalNAc)残基,thyrotropin alfa无硫酸化修饰;同时,thyrotropin alfa末端的唾液酸化饱和度高于内源性$TSH^{[3]}$,但其半衰期较内源性TSH长10倍以上$^{[4]}$。国内2024年4月获批应用于临床的第1款rhTSH药物(人促甲状腺素注射液,研发代码SNA001)的氨基酸序列与内源性TSH一致,且其药代动力学特征与thyrotropin alfa高度一致$^{[5]}$。

美国食品药品监督管理局(Food and Drug Administration, FDA)与欧洲药品管理局(European Medicines Agency, EMA)分别于1998年与2001年正式批准 rhTSH (thyrotropin alfa)应用于DTC患者甲状腺全切除术后随访中血清甲状腺球蛋白的

检测[伴或不伴诊断性全身显像(diagnostic whole body scan, DxWBS)]。随后,EMA与FDA又分别于2005年和2007年批准 rhTSH(thyrotropin alfa)用于无远处转移的DTC患者在甲状腺全切除或近全切除术后$^{13}$I清除残余甲状腺组织的辅助治疗。中国国家药品监督管理局(National Medical Products Administration, NMPA)于2024年4月正式批准人促甲状腺素注射液用于无远处转移的DTC患者在甲状腺全切除或近全切除术后$^{13}$I清除残余甲状腺组织的辅助治疗。

DTC 患者$^{[13]}$ I 治疗前使用 rhTSH 方法: 肌肉注射, 1支 (0.9 mg) /d, 连续 2 d。满足 TSH>30 mIU/L 可进行$^{[13]}$ I 治疗, 或给予口服诊断剂量$^{[13]}$ I 治疗前 DxWBS。

DTC 患者在术后或$^{13}$I治疗后开展刺激性甲状腺球蛋白(stimulated thyroglobulin, sTg;即TSH水平>30 mIU/L时测定的Tg)检测及DxWBS使用rhTSH方法:肌肉注射,1支(0.9mg)/d,连续2d。第5天检测sTg,和(或)第3天给予口服小剂量$^{13}$I后行DxWBS$。

2. rhTSH 在 DTC $^{131}$ I 治疗中的应用

$^{13]}$I治疗是DTC患者全切除或近全切除术后综合治疗的主要措施之一,治疗目的:(1)清除手术后残留的甲状腺组织(清甲治疗);(2)清除手术后影像学检查无法证实的可能存在的微小转移或残留病灶(辅助治疗);(3)清除已证实的无法手术切除的局部或远处转移灶(清灶治疗)。

2.1 清甲治疗 循证医学证据表明,使用rhTSH与停服甲状腺激素(thyroid hormone withdrawal, THW)后$^{13]}$I清甲治疗的疗效相当,且患者的远期复发率差异无统计学意义。但THW须持续2~4周,导致患者体内甲状腺激素水平降低及甲状腺功能减退(简称甲减)症状,影响其生活质量与工作$^{[6-11]}$。使用rhTSH则无需THW,肌肉注射2次后,患者TSH能提升至30 mIU/L及以上,缩短了患者清甲治疗准备时间,同时避免甲减对生活质量的影响$^{[9-13]}$。

国内外权威指南$^{[14-19]}$均推荐将 rhTSH用于

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DTC$^{131}$I 清甲治疗前准备。2023年由英国甲状腺协会(British Thyroid Association, BTA)等多学会发布的指南强烈推荐,对于$T_{1-3}$、$N_0/N_1/N_x$、$M_0$并R0切除的DTC患者,在清甲前准备时使用rhTSH[14]。2023年,由中华医学会内分泌学分会、中华医学会外科学分会甲状腺及代谢外科学组、中国抗癌协会头颈肿瘤专业委员会、中华医学会核医学分会、中国抗癌协会甲状腺癌专业委员会、中国医师协会外科医师分会甲状腺外科医师委员会、中华医学会超声医学分会联合修订的《甲状腺结节和分化型甲状腺癌诊治指南(第二版)》[15]也强推荐,对于低、中危DTC患者,使用rhTSH用于$^{131}$I治疗前准备。2022版欧洲甲状腺协会(European Thyroid Association, ETA)共识推荐,将rhTSH作为$^{131}$I治疗前的优选准备方案$^{[16]}$,充分肯定rhTSH的临床诊疗价值。2025版美国甲状腺学会(American Thyroid Association, ATA)成人DTC患者管理指南[20]则明确指出,进行$^{131}$I清甲治疗前准备时,rhTSH优于THW(强推荐,高确定性证据)。因此,rhTSH可作为优选方案,用于DTC患者$^{[131]}$I清甲治疗前准备。

推荐意见1: DTC 患者全切除或近全切除术后$^{131}$I 清甲治疗前准备，推荐使用 rhTSH。

2.2 辅助治疗[13]I辅助治疗的目的是清除中、高危DTC患者术后可能存在的微小残留病灶,从而延长疾病特异性生存期(disease-specific survival, DSS)和降低复发率[21]。

多项回顾性临床研究[22-24]结果显示,对于$^{131}$I辅助治疗,使用rhTSH与THW进行治疗前准备时的初始治疗疗效及患者远期预后均相当。一项纳入586例中危和高危复发风险 DTC患者的回顾性临床研究[25]发现, rhTSH组患者的术后首次$^{131}$I治疗疗效满意(excellent response, ER)率优于THW组(39.4% vs 30%, P=0.03)。2024年一项荟萃分析[26]结果显示,对于中危和高危复发风险 DTC患者(包括远处转移患者), rhTSH是一种$^{131}$I治疗前准备的实用性选择。2020年,来自欧洲的一个多学科专家小组建议,将rhTSH作为低中复发风险患者[13]I治疗前准备的优选[27]。$^{131}$I清甲治疗与辅助治疗常有重叠,且难于区分。清甲治疗

的同时有辅助治疗的作用,辅助治疗本身也有清甲作用。2025版 ATA成人 DTC 患者管理指南[20]推荐,在进行131I辅助治疗前准备时,使用 rhTSH优于THW(强推荐,高确定性证据)。

推荐意见2: DTC 患者全切除或近全切除术后$^{131}$I辅助治疗前准备，推荐使用 rhTSH。

2.3 清洁治疗 2010年EMA更新了thyrotropin alfa适应证:没有远处转移证据的全切除或近全切除术后分化良好的甲状腺癌。因此,rhTSH可用于局部晚期肿瘤(TNM $T_4$期)或局部淋巴结转移(TNM $N_{1a}/N_{1b}$期)患者$^{[13]}$I辅助治疗前准备$^{[28]}$。

TSH抑制治疗的理论基础是TSH对DTC细胞有促增殖作用。有研究对比了$^{13]}$I治疗前使用rhTSH与THW后血清TSH水平的曲线下面积(area under the curve, AUC),发现THW组血清TSH的AUC是rhTSH组的4.6倍$^{[29]}$。由于促使TSH上升过程缓慢、耗时较长,THW促使DTC转移并导致其增长的风险增高$^{[30]}$。另有研究$^{[31-33]}$显示,血管内皮生长因子(vascular endothelial growth factor, VEGF)对DTC转移的发生发展有促进作用,且DTC患者血清VEGF水平与TSH正相关,但短期使用rhTSH不会提高转移性DTC患者血清中的VEGF水平。

2022年,美国核医学和分子影像学会和欧洲核医学协会(Society of Nuclear Medicine and Molecular Imaging/European Association of Nuclear Medicine, SNMMI/EANM) DTC核医学评估和治疗指南[34]建议,在有转移灶的情况下,根据个体化选择,可以在适应外应用 rhTSH。2023年,由BTA等学会发布的指南[14]也推荐,可在131I清灶治疗前使用rhTSH进行准备。2025版ATA成人DTC患者管理指南[20]推荐,对于远处转移的DTC患者,在进行清灶治疗前准备时,可选用THW或rhTSH(有条件推荐,低确定性证据)。

大量临床证据[22-25, 35-50]提示, rhTSH 用于[131] I 清洁治疗前准备安全有效, 是 THW 的良好替代方案。一项纳入 10 项临床研究共 1 929 例患者的荟萃分析[51]表明, rhTSH ($n=953$) 与 THW ($n=976$) 预处理对[131] I 治疗转移性 DTC 的有效性差异, 无统计学意义。[131] I 清洁治疗前准备方案应根据患

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者的个体情况选择，并尽量减少不良反应[26,51]。$^{13]}$ I 清洁治疗前使用 rhTSH 或 THW 对$^{13]}$ I 治疗疗效及患者远期预后的影响是否存在差异，还需要更多高质量临床研究确定。

推荐意见3: DTC 患者全切除或近全切除术后$^{131}$ I清灶治疗前准备,可考虑使用 rhTSH。

3. rhTSH在DTC术后、$^{131}$I治疗后评估及随访中的应用

对于全切除或近全切除术后的DTC患者,需经过系统的术后动态评估,以决策是否进行$^{131}$I治疗、进入随访或给予其他治疗。

3.1 rhTSH在DTC术后评估及随访中的应用 国内外权威指南[14,16-17,52-54]指出,DTC患者术后均应进行TNM分期及初始复发风险度分层,并可在术后随访过程中根据临床实际情况进行动态评估,主要评估血清学指标[如Tg、sTg、甲状腺球蛋白抗体(thyroglobulin antibody, TgAb)、TSH]及影像学检查(如颈部超声、DxWBS、CT、MRI、$^{18}$F-FDG PET/CT)结果[14,16]。DTC患者术后疗效包括ER、生化疗效不佳(biochemically incomplete response, BIR)、结构性疗效不佳(structurally incomplete response, SIR)、疗效不确切(indeterminate response, IDR)等[15]。TSH刺激可使残留甲状腺组织和(或)转移灶分泌较高水平的Tg,进而提高对结构性复发及转移的预测效能。因此,对于有中/高复发风险、疗效不确切、BIR、SIR的DTC患者,随访sTg较抑制性Tg更有助于监测病情[15]。

2025版 ATA成人 DTC 患者管理指南[20]强烈建议,在行甲状腺全切除术后6~12周,行血清sTg水平测定。虽然使用 rhTSH后 sTg的升高幅度通常低于 THW,但两者均可很好地预测疾病状态[19,52-55]。对于 THW所致的sTg>10 ng/mL或应用 rhTSH所致的sTg>5 ng/mL(rhTSH第2次注射后约 72 h), Tg或 TgAb水平持续升高,且颈部、胸部影像学及[8]F-FDG PET/CT阴性的患者,可行[13]I 经验性治疗[20]。2025版 ATA指南[20]指出,在[13]I 治疗前可行 DxWBS,以帮助指导制订治疗计划。DxWBS可用于 DTC 术后探查

甲状腺残留、可疑复发/转移灶、病灶摄碘能力及肿瘤负荷,预测[3]I治疗疗效及可能的不良反应[52,56]。研究[57-58]显示,采用rhTSH或THW后的DxWBS结果一致率为83%~88.2%。与THW相比,rhTSH显著缩短sTg检测及DxWBS等待时间,且无甲减相关不良反应;但是,由于rhTSH刺激时间相对较短,sTg的峰值水平(一般出现在rhTSH第2次注射后约72h)可能低于传统的THW[4]。

sTg测定及 DxWBS在 DTC术后动态评估中具有重要临床价值。多个指南[14,19,52]指出,进行sTg检测和 DxWBS,需要TSH>30 mIU/L以提高检出甲状腺癌复发、转移的灵敏度时,rhTSH及THW均可选用。但是,目前 sTg测定及 DxWBS检查时间点尚未达成共识。

推荐意见4: DTC 患者全切除或近全切除术后评估及随访过程中 sTg 检测前,推荐使用 rhTSH 或 THW。

推荐意见5: DTC 患者全切除或近全切除术后评估及随访过程中 DxWBS 辅助诊断前,推荐使用 rhTSH 或 THW。

3.2 rhTSH 在$^{131}$I治疗后评估及随访中的应用 DTC 患者$^{131}$I治疗后6~12个月,应依据疗效反应评估体系进行疗效评估,依据血清学指标(如 sTg)及影像学检查(如 DxWBS)结果制定后续治疗及随访方案,并根据随访结果进行动态评估$^{[17]}$。

对于中、高危患者,$^{131}$I治疗后6~12个月可考虑行 DxWBS[52];对于接受清灶治疗的患者,治疗后6~12个月行 DxWBS有助于实时评价病灶的摄碘功能,进而评估是否再次行$^{131}$I治疗[17,52]。在$^{131}$I治疗后行疗效评估时及随访过程中,需sTg检测(如抑制性Tg水平较低不能反映疾病真实情况或抑制性Tg短期内升高)及 DxWBS时,可应用 rhTSH或 THW使TSH>30 mIU/L。应用rhTSH后,同时进行sTg检测和 DxWBS检查,可使残留甲状腺组织/颈部病灶的检出率达93%、远处转移灶的检出率达100%[55]。使用rhTSH可缩短患者准备时间,同时避免甲减对患者生活质量的影响。因此,在$^{131}$I治疗后疗效评估时及随访过程中,rhTSH也可作为一种选择。但是,由于rhTSH刺激时间相对较短,sTg的升高水平可能

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低于 THW。

推荐意见6: DTC 患者$^{131}$I治疗后评估及随访过程中 sTg 检测前,推荐使用 rhTSH 或 THW。

推荐意见7: DTC患者$^{13}$I治疗后评估及随访过程中 DxWBS辅助诊断前,推荐使用 rhTSH或 THW。

4. rhTSH 在特殊 DTC 患者中的应用

对于某些特殊患者,如垂体功能不良、肥胖患者及部分老年患者等,即使THW持续4周,体内TSH也难以高于30 mIU/L;对于合并严重基础疾病(如中枢神经系统或呼吸系统功能障碍、充血性心力衰竭、冠状动脉疾病)或精神疾病的患者,THW持续2~4周则可能导致严重并发症;此外,THW后的甲减状态会一定程度影响患者的生活质量,导致$^{[13]}$治疗延迟等。DTC患者术后THW持续2~4周,体内TSH仍无法高于30 mIU/L,且患者不愿继续THW或有明显甲减症状时,可使用rhTSH。对于这些特殊人群,rhTSH是$^{[13]}$治疗前准备的优选方案$^{[14-17]}$。

对于儿童及青少年DTC患者,一般认为血清TSH>30 mIU/L,可取得较好的$^{131}$I治疗效果。尽管应用 rhTSH 者较少,但有研究$^{[59-65]}$表明,儿童应用 rhTSH 安全有效,且中远期预后与 THW 相当。

2015版ATA指南[66]指出,对于无法产生足够内源性TSH或无法耐受严重甲减的患者,可考虑使用rhTSH(推荐级别A)。其他国内外权威指南[67-71]作了相似推荐。

对于放射性碘难治性 DTC 患者,在进行小分子靶向药物再分化等治疗后病灶摄碘功能评估时,或行 DxWBS 和$^{13}$I 治疗前,使用 rhTSH 可能更具优势$^{[72]}$。

推荐意见8:特殊DTC人群(如无法产生足够内源性TSH或无法耐受严重甲减的患者)$^{131}$治疗前准备，推荐使用rhTSH。

5 rhTSH的安全性及药物经济学

总体而言, rhTSH的安全性较好。日本一项大型上市后长期监测研究[73]发现,使用 rhTSH后,5.8%的患者(336/5822)发生药物不良反应,其

中最常见的是恶心(发生率为3.2%),而严重不良反应的发生率仅为0.2%。国产首个rhTSH药物III期临床试验(TRESON-01) [8]显示相关不良反应主要为胃肠道症状,如恶心(8.4%)、腹泻(1.9%)、呕吐(1.9%),且所有不良事件和不良反应轻微且短暂。与THW相比,rhTSH使用后,患者未出现血脂异常。与THW相比,rhTSH的使用在不影响残留甲状腺组织对$^{131}$I的摄取和$^{131}$I作用时间的同时,能缩短$^{131}$I在DTC患者体内的生物半衰期[8,74-76],原因可能在于注射rhTSH能避免甲减对肾功能的影响[77-78]。血液中$^{131}$I水平的增高,会增加造血系统[79]和其他表达NIS器官的受损风险[80]。一项前瞻性临床研究[79]发现,与THW相比,$^{131}$I治疗前准备应用rhTSH的患者发生急性涎腺炎(30% vs 58.3%)、血小板减少症或中性粒细胞减少症(7% vs 21.4%)的比例均降低。rhTSH使用后唾液腺炎发生率也较THW使用后低[81-82]。美国头颈学会发布的多学科共识声明[83]指出,$^{131}$I治疗前准备应用rhTSH较THW有助于降低唾液腺和泪腺并发症风险。THW所致的甲减症状主要包括体质量增加、疲劳、畏寒、苍白、皮肤干燥、毛发粗糙和便秘等,会影响患者的生活质量。前瞻性临床研究[6,11,59,84-85]表明,rhTSH组患者简明健康调查量表(short form-36, SF-36)、Billewicz评分或慢性病治疗功能评估(functional assessment of chronic illness therapy, FACIT)-TOI量表评估的短期生活质量优于THW组,而3个月后两组患者生活质量差异无统计学意义。

药物经济学角度,使用 rhTSH 较 THW需支付额外费用。但是,与采用 rhTSH 患者相比,采用 THW 的患者病假天数更多[86-87]、住院天数更长[88-89]。来自德国、加拿大和西班牙等的药物经济学报告[90-92]显示,rhTSH 具有高成本效益比,药品费用成本能够被其节约的其他间接成本抵消。

6 小结

大量的临床研究证据显示, DTC 患者接受$^{131}$I治疗前, 使用 rhTSH 与 THW 的诊疗效果相仿, 且安全性好, 不良反应轻微可控。与接受THW的患者相比, 接受 rhTSH 的患者$^{131}$I治疗不

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良反应发生率更低，无甲减症状、生活质量明显提升。rhTSH在保证诊治效果的同时，可缩短诊疗所需准备时间、降低诊疗过程对患者生活和工作的影响。

本共识对 rhTSH 的推荐总结

推荐意见1: DTC 患者全切除或近全切除术后$^{131}$I清甲治疗前准备，推荐使用 rhTSH。

推荐意见2: DTC 患者全切除或近全切除术后$^{131}$I辅助治疗前准备，推荐使用 rhTSH。

推荐意见3: DTC 患者全切除或近全切除术后$^{131}$ I 清洁治疗前准备, 可考虑使用 rhTSH。

推荐意见4: DTC 患者全切除或近全切除术后评估及随访过程中 sTg 检测前,推荐使用rhTSH 或 THW。

推荐意见5: DTC 患者全切除或近全切除术后评估及随访过程中 DxWBS 辅助诊断前,推荐使用 rhTSH 或 THW。

推荐意见6: DTC患者$^{131}$I治疗后评估及随访过程中 sTg检测前,推荐使用 rhTSH或 THW。

推荐意见7: DTC 患者$^{131}$I治疗后评估及随访过程中 DxWBS 辅助诊断前,推荐使用 rhTSH 或 THW。

推荐意见8:特殊DTC人群(如无法产生足够内源性TSH或无法耐受严重甲减的患者等)$^{131}$治疗前准备，推荐使用rhTSH。

伦理声明 本共识是基于现有最佳证据和专家临床经验形成的指导性意见,旨在为相关疾病的诊断、治疗与管理提供参考。医学实践具有复杂性和个体差异性,本共识不能替代临床医生的独立判断。在实际应用中,医师应结合患者的具体病情、意愿、医疗资源可获得性,以及自身的专业知识,制定最适宜的个体化诊疗方案。本共识的内容不作为任何医疗纠纷或法律诉讼的依据,共识制定者及发布不承担因应用本共识内容而产生的任何直接或间接法律责任。

利益冲突所有作者声明不存在利益冲突。

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沈晨天,顾宇参,谭辉,等.重组人促甲状腺激素临床应用中国专家共识(2025年版)[J].中国临床医学,2026,33(2):1-14.

Shen C T, Gu Y S, Tan H, et al. Chinese expert consensus on the clinical application of recombinant human thyroid-stimulating hormone (2025 edition) [J]. Chin J Clin Med, 2026, 33(2): 1-14. DOI: 10.12025/j.issn.1008-6358.2025.20260158

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