Clinical Studies on Thyroid Dysfunction Caused by Immune Checkpoint Inhibitors in Tumor Patients
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摘要:
目的 研究恶性肿瘤患者予以免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）后发生甲状腺功能障碍（thyroiddysfunction，TD）的临床特点及相关危险因素分析。 方法 收集来自云南省第一人民医院2019年1月至2022年6月住院并行ICIs治疗后的157例肿瘤患者，根据是否发生TD分为甲状腺功能正常组以及甲状腺功能异常组。选取甲状腺功能正常组和异常组分别为58例患者，再随机抽取58例至云南省第一人民医院的健康成人体检者作为对照组，收集研究对象的性别、年龄、肿瘤及ICIs类型、用药前手术史、放化疗史等基线资料，分析患者肝肾功、血脂、甲状腺激素水平等相关指标，对3组病例的相关指标进行统计学分析，并将甲状腺功能正常组和异常组进行对照分析来测评使用ICIs引起TD的临床特征及相关危险因素。 结果 （1）在157例使用ICIs治疗的患者中，58例（36.9%）出现甲状腺功能异常，其中甲状腺功能减退症（包括亚甲减）39例，甲状腺功能亢进症（包括亚甲亢）9例，单纯相关抗体异常10例；（2）对甲状腺功能正常组、甲状腺功能异常组及对照组3组数据进行分析，结果提示3组的年龄、促甲状腺激素（thyroidstimulatinghormone，TSH ）基线水平、游离三碘甲状腺原氨酸（freetriiodothyronine，FT3）基线水平和谷草转氨酶（aspartatetransaminase，AST ）水平比较，差异均有统计学意义（P < 0.05）；甲状腺功能正常组与甲状腺功能异常组TSH基线、放疗史比较，差异均有统计学意义（P < 0.05）；（3）多元分析表明放疗史（OR=7.291，95%CI=1.579～33.663，P < 0.05）、基线TSH水平（OR=3.917，95%CI=1.697～9.038，P < 0.05）是使用ICIs治疗后肿瘤患者出现甲状腺功能异常的独立危险因素。 结论 甲状腺功能减退是肿瘤患者使用ICIs引起TD最常见的类型，患者基线TSH水平、既往存在放疗史是出现甲状腺功能异常的独立危险因素。 Abstract:Objective To investigate the clinical characteristics and risk factors of thyroid dysfunction（TD） in malignant tumor patients treated with immune checkpoint inhibitors（ICIs）. Methods A total of 157 cancer patients who were hospitalized and received ICIs treatment in the First People's Hospital of Yunnan Province from January 2019 to June 2022 were collected and divided into the normal thyroid function group and abnormal thyroid function group based on whether TD had occurred. Fifty-eight patients with the normal thyroid function and 58 patients with the abnormal thyroid function were selected, and 58 healthy adults who underwent the physical examination in our hospital were randomly selected as the control group. The baseline data on the gender, age, tumor and ICIs type, history of surgery before medication, history of radiotherapy and chemotherapy, and the related indicators of liver and kidney function, blood lipids, thyroid hormone levels and so on were collected. The relevant indicators of the three groups were statistically analyzed, and the normal thyroid function group and abnormal thyroid function group were compared to evaluate the clinical characteristics and related risk factors of TD caused by ICIs. Results 1. Among 157 patients treated with ICIs, 58 cases（36.9%） had thyroid dysfunction, including 39 cases of hypothyroidism（including subclinical hypothyroidism）, 9 cases of hyperthyroidism（including subclinical hyperthyroidism）, and 10 cases of pure related antibody abnormality. 2. The analysis of the data of the normal thyroid function group, the abnormal thyroid function group and the control group showed that the age, thyroid stimulating hormone（TSH）, and thyroid function of the three groups were significantly different. TSH） baseline level, free triiodothyronine（FT3） baseline level and aspartate transaminase（AST） baseline level were statistically different（P < 0.05）. There were significant differences in TSH baseline and radiotherapy history between the normal thyroid function group and the abnormal thyroid function group（P < 0.05）; Multivariate analysis showed that the radiotherapy history（OR=7.291, 95%CI= 1.579-33.663, P < .05）, baseline TSH level（OR=3.917, 95%CI= 1.697-9.038, P < 0.05） were the independent risk factors for thyroid dysfunction in cancer patients after ICIs treatment. Conclusion Hypothyroidism is the most common type of TD caused by ICIs in cancer patients. The baseline TSH level and the history of radiotherapy are the independent risk factors for thyroid dysfunction. -
表 1 ICIs治疗患者的基本情况[（$\bar x \pm s $）/n（%）]
Table 1. Basic information of patients treated with ICIs [（$\bar x \pm s $）/n（%）]
基本项目 数值 年龄（岁） 56.34±0.96 性别 男 107（68.2） 女 50（31.8） 肿瘤类型 肺癌 77（49.0） 淋巴瘤 11（7.0） 肝癌 16（10.2） 食管癌 14（8.9） 结直肠癌 8（5.1） 泌尿系恶性肿瘤 5（3.2） 鼻咽癌 5（3.2） 其他恶性肿瘤 21（13.4） 药物种类 卡瑞丽珠单抗 56（35.7） 信迪利单抗 40（25.5） 替雷利珠单抗 44（28.0） 特瑞普利单抗 7（4.5） 帕博利珠单抗 8（5.1） 度伐利尤单抗 2（1.3） 临床分型 甲减 19（12.1） 亚甲减 20（12.7） 甲亢 7（4.5） 亚甲亢 2（1.3） 单纯抗体异常 10（6.4） 
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表 2 3组患者临床资料分析[n（%）/（$ \bar x \pm s$）/M（P25，P75）]
Table 2. The clinical data of the three groups were analyzed [n（%）/（$\bar x \pm s $）/M（P25，P75）]
项目 对照组（n=58） 甲功正常组（n=58） 甲功异常组（n=58） x2/F/H P 性别 7.310 0.120 男 30（51.7） 42（72.4） 36（62.1） 女 28（48.3） 16（27.6） 22（37.9） 年龄（岁） 40.00（33.75，47.25）&# 58.50（51.00，65.25） 57.00（50.00，66.00） 62.183 < 0.001* TSH基线（mIU/L） 2.25（1.65，2.81）& 1.41（1.03，2.16）# 2.33（1.67，3.19） 16.238 < 0.001* FT3基线（pmol/L） 5.07±0.51&# 4.41±0.77 4.34±0.82 16.818 < 0.001* G（mmol/L） 5.10（4.88，5.40） 5.20（4.75，5.70） 5.10（4.70，6.10） 0.321 0.852 FT4基线（pmol/L） 16.18±1.76 15.51±3.20 15.61±3.04 3.271 0.374 AST（U/L） 20.00（18.00，23.00）# 23.00（17.75，27.25） 25.5（18.75，35.00） 11.525 0.003* ALT（U/L） 18.50（14.00，27.50） 19.50（13.00，28.00） 20.50（13.00，31.88） 0.192 0.908 TC（mmol/L） 5.18（4.53，5.71） 4.41（3.67，5.47） 5.17（3.90，5.75） 4.976 0.083 TG（mmol/L） 1.41（0.92，2.23） 1.28（0.94，1.70） 1.46（1.06，2.25） 1.167 0.558 BUN（mmol/L） 5.05（4.30，5.80） 4.60（3.80，6.23） 5.10（3.80，6.23） 1.027 0.598 CR（μmol/L） 67.00（55.75，78.00） 69.00（59.00，79.00） 67.50（59.00，85.00） 1.023 0.599 与甲功正常组比较，&P < 0.05；与甲功异常组比较，#P < 0.05；*P < 0.05。
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表 3 甲功正常组与甲功异常组资料分析[n（%）]
Table 3. Data analysis of the normal thyroid function group and the abnormal thyroid function group[n（%）]
项目 甲功正常组（n=45） 甲功异常组（n=45） χ2 P 病程 ≥1 a 26（44.8） 31（53.4） 0.863 0.353 < 1 a 32（55.2） 27（46.6） 手术史（有） 23（39.7） 35（43.1） 1.142 0.706 化疗史（有） 44（75.9） 43（74.1） 0.046 0.830 放疗史（有） 10（17.2） 23（39.7） 7.157 0.007* *P < 0.05。
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表 4 甲状腺功能异常危险因素的多因素分析结果
Table 4. Results of multivariate analysis of risk factors for thyroid dysfunction
项目 B SE Wald χ2 OR 95%CI P 性别（男） 0.554 0.681 0.661 1.740 0.458～6.612 0.416 年龄 –0.056 0.032 3.060 0.946 0.888～2.147 0.080 病程（≥1a） –0.623 0.708 0.775 0.536 0.134～2.147 0.379 手术史（有） 0.130 0.629 0.042 1.138 0.332～3.907 0.837 化疗史（有） –0.654 0.739 0.783 0.520 0.122～2.214 0.376 放疗史（有） 1.987 0.781 6.478 7.291 1.579～33.663 0.011* TSH基线 1.365 0.427 10.238 3.917 1.697～9.038 0.001* FT4基线 0.033 0.104 0.098 1.033 0.842～1.267 0.755 FT3基线 –0.556 0.495 1.262 0.574 0.217～1.513 0.261 *P < 0.05。
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