📖Hyperthyroidism

Summary  总结

Thyrotoxicosis causes a variety of symptoms and adverse health outcomes. Hyperthyroidism refers to increased thyroid hormone synthesis and secretion, most commonly from Graves' disease or toxic nodular goitre, whereas thyroiditis (typically autoimmune, viral, or drug induced) causes thyrotoxicosis without hyperthyroidism. The diagnosis is based on suppressed serum concentrations of thyroid-stimulating hormone (TSH), accompanied by free thyroxine and total or free tri-iodothyronine concentrations, which are raised (overt hyperthyroidism) or within range (subclinical hyperthyroidism). The underlying cause is determined by clinical assessment, detection of TSH-receptor antibodies and, if necessary, radionuclide thyroid scintigraphy. Treatment options for hyperthyroidism include antithyroid drugs, radioactive iodine, and thyroidectomy, whereas thyroiditis is managed symptomatically or with glucocorticoid therapy. In Graves' disease, first-line treatment is a 12–18-month course of antithyroid drugs, whereas for goitre, radioactive iodine or surgery are preferred for toxic nodules or goitres. Evidence also supports long-term treatment with antithyroid drugs as an option for patients with Graves' disease and toxic nodular goitre.
甲状腺毒症会引起各种症状和不良健康结果。 甲状腺功能亢进症是指甲状腺激素合成和分泌增加，最常见的是 Graves 病或中毒性结节性甲状腺肿 ，而甲状腺炎 （通常是自身免疫性、病毒性或药物诱导的）会导致甲状腺毒症，但无甲状腺功能亢进症。诊断基于血清促甲状腺激素 （TSH） 浓度抑制，伴有游离甲状腺素和总或游离三碘甲状腺原氨酸浓度升高（显性甲状腺功能亢进症）或在范围内（亚临床甲状腺功能亢进症）。通过临床评估、TSH 受体抗体检测以及放射性核素甲状腺闪烁显像（如有必要）确定根本原因。甲状腺功能亢进症的治疗选择包括抗甲状腺药物、放射性碘和甲状腺切除术，而甲状腺炎则对症治疗或糖皮质激素治疗。在 Graves 病中，一线治疗是 12-18 个月的抗甲状腺药物治疗，而对于甲状腺肿，毒性结节或甲状腺肿首选放射性碘或手术治疗。证据还支持抗甲状腺药物治疗作为 Graves 病和毒性结节性甲状腺肿患者的一种选择。

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Introduction  介绍

Thyrotoxicosis is the clinical manifestation of excess thyroid hormone action at the tissue level, whereas the term hyperthyroidism refers to conditions of increased synthesis and secretion of thyroid hormone (although the terms are often used interchangeably). The two main thyroid hormones are thyroxine (T4) and tri-iodothyronine (T3). T4 has minimal biological activity and serves as a prohormone, converted to the biologically active hormone T3 by intracellular deiodination in target tissues. Under euthyroid conditions, direct thyroidal secretion of T3 accounts for only about 20% of total daily T3 production, with the remainder derived from peripheral conversion, but in hyperthyroidism the proportion can be higher because of increased intrathyroidal conversion of T4 to T3.
甲状腺毒症是组织水平甲状腺激素作用过量的临床表现，而甲状腺功能亢进症是指甲状腺激素合成和分泌增加的情况（尽管这两个术语经常互换使用）。两种主要的甲状腺激素是甲状腺素 （T4） 和三碘甲状腺原氨酸 （T3）。T4 具有最小的生物活性 ，可作为激素原 ，通过靶组织中的细胞内脱碘转化为生物活性激素 T3。在甲状腺功能正常的情况下，甲状腺直接分泌 T3 仅占每日 T3 总产量的 20% 左右，其余来自外周转化，但在甲状腺功能亢进症中，由于 T4 向 T3 的甲状腺内部转化增加，这一比例可能更高。

Overt hyperthyroidism is defined biochemically as suppressed serum concentrations of thyroid-stimulating hormone (TSH) with increased concentrations of free T4, or total or free T3. In mild cases, TSH is suppressed but free T4 and T3 concentrations are within the reference range, which is termed subclinical hyperthyroidism.¹
显性甲状腺功能亢进症在生化上定义为血清促甲状腺激素 （TSH） 浓度抑制，游离 T4 或总或游离 T3 浓度升高。在轻度病例中，TSH 受到抑制，但游离 T4 和 T3 浓度在参考范围内，这被称为亚临床甲状腺功能亢进症 。¹

Untreated hyperthyroidism can lead to serious adverse effects on multiple organ systems and, rarely, to death. Optimum treatment depends on the underlying cause, with options including antithyroid drugs, radioactive iodine treatment, and thyroidectomy.
未经治疗的甲状腺功能亢进症可对多个器官系统造成严重的不良反应 ，极少数情况下会导致死亡。最佳治疗取决于根本原因，选择包括抗甲状腺药物 、 放射性碘治疗和甲状腺切除术 。

In this Seminar we discuss the epidemiology, cause, clinical presentations and complications, diagnosis, best treatment, and shifts in treatment preference. We also focus on future directions and research priorities. Hyperthyroidism in children is not discussed in this Seminar and is reviewed elsewhere.2, 3
在本次研讨会中，我们讨论了流行病学 、原因、临床表现和并发症、诊断、最佳治疗和治疗偏好的转变。我们还关注未来的方向和研究重点。儿童甲状腺功能亢进症在本专题讲座中不作讨论，详见其他专题。2、3

Epidemiology  流行病学

The global epidemiology of thyroid disease is strongly related to population iodine status.4, 5 In iodine-sufficient regions, overt and subclinical hyperthyroidism each affect about 0·5% of the population, with a combined incidence of about 50 cases per 100 000 per year6, 7, 8 and Graves' disease accounting for most cases.⁹ In iodine-deficient areas, the prevalence of hyperthyroidism is higher: up to 10–15% for overt and subclinical hyperthyroidism combined, with toxic nodular goitre being more common than Graves' disease.10, 11, 12 Correction of iodine deficiency by public health measures can result in a transient increase in the incidence of hyperthyroidism, followed by a gradual decrease to levels recorded in iodine-sufficient regions.13, 14
甲状腺疾病的全球流行病学与人群碘状况密切相关。4， 5 在碘充足的地区，显性和亚临床甲状腺功能亢进症各影响约 0·5% 的人口，每年每 100 000 人中约有 50 例 6， 7， 8 和 Graves 病占大多数病例。⁹ 在缺碘地区，甲状腺功能亢进症的患病率更高：显性和亚临床甲状腺功能亢进症加起来高达 10-15%， 其中毒性结节性甲状腺肿比格雷夫斯病更常见。10， 11， 12 通过公共卫生措施纠正碘缺乏症可导致甲状腺功能亢进症的发病率短暂增加，然后逐渐下降到碘充足地区记录的水平。13、14

The incidence of Graves' disease in iodine-sufficient regions is 20–30 cases per 100 000 per year, with a peak in the third to fifth decades of life, and a female to male ratio of 5–6:1.9, 10, 15, 16 The incidence of toxic nodular goitre ranges from 3–6 cases per 100 000 per year in iodine-sufficient areas to 20–40 cases per 100 000 per year in iodine-deficient areas; it occurs predominantly after the age of 50 years, and is also more common in females than males.9, 10, 12
在碘充足地区，格雷夫斯病的发病率为每年每 100 000 人 20-30 例，在生命的 3 至 50 岁时达到高峰，女性与男性的比例为 5-6：1。9， 10， 15， 16毒性结节性甲状腺肿的发病率从碘充足地区每年每 100 000 人 3-6 例到碘缺乏地区每年每 100 000 人 20-40 例不等;它主要发生在 50 岁以后，女性也比男性更常见。9、10、12

Causes  原因

Causes of thyrotoxicosis can be divided into those associated with hyperthyroidism (increased synthesis and secretion of thyroid hormones by the thyroid) and those without (release of stored thyroid hormone from the gland or extrathyroidal sources of thyroid hormone). In clinical practice, Graves' disease, toxic nodular goitre, and thyroiditis are the most common conditions, with other causes of thyrotoxicosis being rare by comparison (table 1).
甲状腺毒症的原因可分为与甲状腺功能亢进症相关的原因（甲状腺合成和分泌甲状腺激素的增加）和与甲状腺功能亢进症无关的甲状腺功能亢进症（甲状腺激素的甲状腺激素分泌）。在临床实践中，Graves 病、毒性结节性甲状腺肿和甲状腺炎是最常见的疾病，相比之下，甲状腺毒症的其他原因则很少见（ 表 1）。

Table 1. Causes of thyrotoxicosis
表 1.甲状腺毒症的原因

Empty Cell	Empty Cell	Empty Cell	Alternative names  替代名称	Pathogenesis  发病机制	Clinical pointers  临床指导
Thyrotoxicosis with hyperthyroidism 甲状腺毒症伴甲状腺功能亢进症			..	Increased thyroid hormone synthesis and secretion by the thyroid 甲状腺激素合成和分泌增加	..
	Graves' disease  Graves 病		Basedow disease, diffuse toxic goitre Basedow 病，弥漫性毒性甲状腺肿	Stimulating antibodies to TSH receptor 刺激 TSH 受体抗体	Diffuse goitre, thyroid bruit (pathognomonic), ophthalmopathy 弥漫性甲状腺肿、甲状腺杂音（特异性）、眼病
	Toxic nodular goitre  毒性结节性甲状腺肿		Toxic adenoma, autonomous thyroid adenoma, Plummer's disease 毒性腺瘤、自主性甲状腺腺瘤、Plummer 病	Single or multiple autonomous adenomas, somatic activating mutations in TSH receptor 单个或多个自主腺瘤，TSH 受体体细胞激活突变	Asymmetric, irregular goitre; visible or palpable nodule(s) 不对称、不规则的甲状腺肿;可见或可触及的结节
	Gestational hyperthyroidism 妊娠期甲状腺功能亢进症		..	High values of hCG stimulating TSH receptor 高值 hCG 刺激 TSH 受体	First trimester of pregnancy, hyperemesis gravidarum, multiple pregnancy 妊娠早期、妊娠剧吐、多胎妊娠
	Gestational trophoblastic disease 妊娠滋养细胞疾病		..	As for gestational hyperthyroidism 至于妊娠期甲状腺功能亢进症	Hydatidiform mole, trophoblastic tumour 葡萄胎，滋养细胞肿瘤
	Iodine-induced hyperthyroidism 碘诱导的甲状腺功能亢进症		Jod-Basedow phenomenon  Jod-Basedow 现象	Excess iodine substrate (usually in gland with underlying autonomous function) 过量的碘底物（通常在具有潜在自主功能的腺体中）	History of excessive iodine or kelp ingestion, radiographic contrast exposure 过量摄入碘或海带、放射造影剂暴露史
	Type 1 amiodarone-induced thyrotoxicosis 1 型胺碘酮诱导的甲状腺毒症		..	As for iodine-induced hyperthyroidism 至于碘引起的甲状腺功能亢进症	Amiodarone treatment, underlying thyroid disease 胺碘酮治疗，基础甲状腺疾病
	Thyrotropinoma  促甲状腺激素瘤		TSHoma  TSHoma 餐厅	TSH secretion by pituitary adenoma 垂体腺瘤分泌 TSH	Pituitary tumour, elevated free T4 and (free) T3 with unsuppressed TSH 垂体瘤、游离 T4 和（游离）T3 升高伴 TSH 未抑制
	Thyroid hormone resistance β* 甲状腺激素抵抗 β*		..	Mutation in TRb gene TRb 基因突变	Attention deficit hyperactivity disorder, tachycardia, diffuse goitre 注意缺陷多动障碍、心动过速、弥漫性甲状腺肿
	Familial non-autoimmune hyperthyroidism 家族性非自身免疫性甲状腺功能亢进症		..	Germline activating mutation in TSH receptor TSH 受体中的种系激活突变	..
Thyrotoxicosis without hyperthyroidism 不伴甲状腺功能亢进症的甲状腺毒症			..	Increased circulating thyroid hormones without increased synthesis of thyroid hormone by the thyroid 甲状腺循环甲状腺激素增加，但甲状腺合成甲状腺激素不增加	..
	Thyroiditis  甲状腺炎		..	Inflammation leading to release of stored thyroid hormone from thyroid follicles 炎症导致储存的甲状腺激素从甲状腺滤泡中释放	..
		Lymphocytic thyroiditis  淋巴细胞性甲状腺炎	Silent thyroiditis, painless thyroiditis, autoimmune thyroiditis, includes post-partum thyroiditis 无症状甲状腺炎、无痛性甲状腺炎、自身免疫性甲状腺炎，包括产后甲状腺炎	Autoimmune thyroiditis  自身免疫性甲状腺炎	Positive TPOAb, post-partum presentation TPOAb 阳性，产后表现
		Subacute thyroiditis  亚急性甲状腺炎	De Quervain thyroiditis, granulomatous thyroiditis, viral or post-viral thyroiditis, painful thyroiditis 桡骨茎突甲状腺炎、肉芽肿性甲状腺炎、病毒性或病毒后甲状腺炎、疼痛性甲状腺炎	Viral or post-viral inflammation 病毒性或病毒后炎症	Preceding viral illness; painful, tender thyroid; negative TPOAb 既往病毒性疾病;甲状腺疼痛、触痛;阴性 TPOAb
	Other forms of thyroiditis 其他形式的甲状腺炎		..	..	..
		Drug-induced  药物诱发	..	Various  各种	..
		Traumatic  外伤 性	..	Trauma, manipulation, palpation 创伤、推拿、触诊	..
		Radiation-induced  辐射诱发	..	Radiation thyroiditis  放射性甲状腺炎	..
		Bacterial, fungal  细菌、真菌	..	Bacterial or fungal infection 细菌或真菌感染	..
	Exogenous thyroid hormone 外源性甲状腺激素		..	Excessive thyroid hormone use (iatrogenic or factitious) 过量使用甲状腺激素（医源性或做作性）	..
	Struma ovarii  Struma ovarii 卵巢		..	Ectopic thyroid hormone secretion from ovarian teratoma 卵巢畸胎瘤引起的异位甲状腺激素分泌	Pelvic mass; very rare  盆腔肿块;非常罕见

TSH=thyroid-stimulating hormone. T4=thyroxine. T3=tri-iodothyronine. TPOAb=thyroid peroxidase antibodies.
TSH=促甲状腺激素。T4=甲状腺素。T3=三碘甲状腺原氨酸。TPOAb=甲状腺过氧化物酶抗体。*

Not part of classic hyperthyroidism: mixed hyperthyroid and hypothyroid state dependent on target tissue.
不属于典型甲状腺功能亢进症：甲状腺功能亢进和甲状腺功能减退状态混合，取决于靶组织。

Graves' disease  Graves 病

Graves' disease forms part of the spectrum of autoimmune thyroid disease, with the pathogenesis involving complex interactions between genetic and environmental factors, resulting in loss of self-tolerance to thyroid antigens.17, 18 A key feature of Graves' disease pathogenesis is a Th2 immune response resulting in the production of IgG antibodies that stimulate the TSH receptor on thyrocytes, resulting in increased thyroid hormone synthesis and secretion, follicular hyperplasia, and goitre.
Graves 病是自身免疫性甲状腺疾病谱的一部分 ，其发病机制涉及遗传和环境因素之间的复杂相互作用，导致对甲状腺抗原的自身耐受性丧失。17， 18 格雷夫斯病发病机制的一个关键特征是 Th2 免疫反应，导致产生 IgG 抗体 ，刺激甲状腺细胞上的 TSH 受体，导致甲状腺激素合成和分泌增加、 滤泡增生和甲状腺肿大。

Graves' disease has a high degree of heritability, estimated at 60–80%.19, 20 Common variants in immunoregulatory genes (HLA-B, HLA-DR3, CD40, CTLA4, FCRL3, IL2RA, PTPN22) and in genes encoding thyroid autoantigens (Tg, TSHR) increase susceptibility, but much of the heritability remains unaccounted for.17, 21, 22 Smoking, iodine status, stress, pregnancy and the postpartum phase, Yersinia enterocolitica infection, and some drugs (panel) are established environmental factors, whereas other factors such as selenium status, gut microbiome, viral infection, and endocrine-disrupting chemicals can also be involved.23, 24, 25, 26, 27 Similar to other autoimmune diseases, skewed X chromosome inactivation is probably an important contributor to the female predominance.28, 29 Other epigenetic mechanisms, such as DNA methylation, provide a potential link between environmental factors, gene expression, and autoimmune thyroid disease.³⁰
Graves 病具有高度的遗传性 ，估计为 60-80%。19， 20 免疫调节基因（HLA-B、HLA-DR3、CD40、CTLA4、FCRL3、IL2RA、PTPN22）和编码甲状腺自身抗原 （Tg、TSHR） 的基因中的常见变异增加了易感性，但大部分遗传性仍未得到解释。17， 21， 22 吸烟、碘状况、压力、怀孕和产后、 小肠结肠炎耶尔森菌感染和一些药物（ 面板 ）是已确定的环境因素，而其他因素如硒状况、 肠道微生物组 、病毒感染和内分泌干扰化学物质也可能涉及。23， 24， 25， 26， 27 与其他自身免疫性疾病类似，偏斜的 X 染色体失活可能是导致女性占优势的重要因素。28， 29 其他表观遗传机制 ，如 DNA 甲基化 ，提供了环境因素、基因表达和自身免疫性甲状腺疾病之间的潜在联系。³⁰

Panel  面板

Drugs associated with thyroiditis and thyrotoxicosis
与甲状腺炎和甲状腺毒症相关的药物

• •Immune checkpoint inhibitors
  免疫检查点抑制剂
  • •PD-1 inhibitors: pembrolizumab, nivolumab, cemiplimab, dostarlimab
    PD-1 抑制剂： 帕博利珠单抗 、 纳武利尤单抗 、cemiplimab、dostarlimab
  • •PD-L1 inhibitors: atezolizumab, avelumab, durvalumab
    PD-L1 抑制剂：atezolizumab、avelumab、durvalumab
  • •CTLA-4 inhibitors: ipilumamb, tremelimumab
    CTLA-4 抑制剂：ipilumamb、tremelimumab
• •Cytokines  细胞因子
  • •Interferon-α, interleukin-2
    干扰素-α、白细胞介素-2
• •Tyrosine kinase inhibitors
  酪氨酸激酶抑制剂
  • •Sunitinib, sorafenib
    舒尼替尼 、 索拉非尼
• •Lithium  锂
• •Amiodarone  胺碘酮
  • •Type 2 amiodarone-induced thyrotoxicosis
    2 型胺碘酮诱导的甲状腺毒症
• •Alemtuzumab (also associated with Graves' disease)
  阿仑单抗 （也与 Graves 病有关）

Toxic nodular goitre  毒性结节性甲状腺肿

Thyroid nodules are common in the general population, particularly in the setting of iodine deficiency, which has a chronic stimulatory effect on the thyroid, resulting in diffuse or nodular goitre and, ultimately, thyroidal autonomy.4, 5, 11, 13 Genetic factors, female sex, and smoking also contribute to nodule development.³¹ Functional autonomy develops in about 5% of thyroid nodules, either as solitary toxic adenomas or as part of multinodular goitre. Activating mutations in the TSH receptor gene (TSHR; in up to 70% of autonomous nodules) and Gs protein α subunit (GNAS; up to 30%) cause constitutive activation of cyclic AMP or protein kinase A signalling, thereby stimulating thyroid hormone synthesis and secretion, resulting in hyperthyroidism.³¹ So-called second hit mutations in the EZH1 gene provide a further stimulus to thyrocyte proliferation in around 25% of cases.³²
甲状腺结节在普通人群中很常见，尤其是在缺碘的情况下 ，碘缺乏对甲状腺有慢性刺激作用，导致弥漫性或结节性甲状腺肿，并最终导致甲状腺自主性。4， 5， 11， 13遗传因素 、女性性别和吸烟也会导致结节的发展。³¹ 大约 5% 的甲状腺结节具有功能自主性，要么是孤立性毒性腺瘤 ，要么是多结节性甲状腺肿的一部分。TSH 受体基因 （TSHR;高达 70% 的自主结节） 和 Gs 蛋白 α亚基 （GNAS; 高达 30%） 的激活突变导致环状 AMP 或蛋白激酶 A 信号传导的组成性激活，从而刺激甲状腺激素的合成和分泌，导致甲状腺功能亢进。³¹ 在大约 25% 的病例中，EZH1 基因中所谓的二次突变进一步刺激了甲状腺细胞增殖。³²

Thyroiditis  甲状腺炎

Thyroiditis (thyroid inflammation) has many causes, including infection, autoimmunity, drugs, systemic disorders, environmental agents, and the post-partum period (table 1).³³ Thyrotoxicosis is caused by unregulated release of stored thyroid hormone resulting from inflammatory or toxic damage to thyroid follicles. Thyrotoxicosis is transient and self-limited, resolving after 1–4 months when stores of thyroid hormone have been exhausted or the inflammatory process has subsided.
甲状腺炎（甲状腺炎症）的病因很多，包括感染、自身免疫、药物、 全身性疾病 、环境因素和产后（ 表 1）。³³ 甲状腺毒症是由于甲状腺滤泡的炎症或毒性损伤导致储存的甲状腺激素释放不受控制而引起的。甲状腺毒症是短暂的和自限性的，当甲状腺激素储备耗尽或炎症过程消退时，1-4 个月后消退。

Lymphocytic thyroiditis (silent thyroiditis) is a painless, autoimmune thyroiditis that can present with thyrotoxicosis. It is part of the spectrum of autoimmune thyroid disease that encompasses post-partum thyroiditis and clinical variants of Hashimoto's disease, to which a range of names has been applied (table 1). By contrast with Graves' disease, Th1 and Th17 immune responses predominate, with lymphocytic infiltration of the thyroid, lymphoid follicle formation, and thyroid follicular atrophy. Most, but not all, affected individuals have circulating antibodies to the main autoantigens thyroid peroxidase enzyme (TPO) or thyroglobulin, or both.17, 34 Post-partum thyroiditis is a subtype, affecting about 5% of women in the first year post partum, about half of whom have thyrotoxicosis.35, 36
淋巴细胞性甲状腺炎（无症状甲状腺炎）是一种无痛性自身免疫性甲状腺炎，可表现为甲状腺毒症。它是自身免疫性甲状腺疾病谱的一部分，包括产后甲状腺炎和桥本氏病的临床变异型，已被应用了一系列名称（ 表 1）。与 Graves 病相比，Th1 和 Th17 免疫反应占主导地位，伴有甲状腺淋巴细胞浸润 、 淋巴滤泡形成和甲状腺滤泡萎缩。大多数（但不是全部）受影响的个体具有针对主要自身抗原甲状腺过氧化物酶 （TPO） 或甲状腺球蛋白或两者的循环抗体。17， 34 产后甲状腺炎是一种亚型，影响约 5% 的产后第一年妇女，其中约一半患有甲状腺毒症。35、36 元

Subacute thyroiditis is characterised by thyroidal pain, preceded or accompanied by fever and systemic inflammatory symptoms. It is thought to be caused by viral infection of the thyroid or a postviral inflammatory state in genetically predisposed individuals (particularly HLA-B35 and HLA-B67 status), resulting in granulomatous change, giant cell formation, and a mixed monocytic and lymphocytic interfollicular infiltrate.³³ It has an incidence of 2–5 cases per 100 000 per year, and a female to male ratio of 3–7:1.12, 37 Findings from epidemiological and virological studies have implicated several viruses including mumps, echoviruses, coxsackie viruses, and SARS-CoV-2.27, 38, 39, 40, 41 Despite many case reports of subacute thyroiditis after COVID-19 vaccination,⁴² a population-based study of 2·3 million vaccine recipients noted no increased risk of thyroiditis in the 56 days after vaccination compared with the pre-exposure period, suggesting that the association could be coincidental.⁴³
亚急性甲状腺炎的特征是甲状腺疼痛，之前或伴有发热和全身炎症症状。它被认为是由甲状腺病毒感染或遗传易感个体的病毒后炎症状态（尤其是 HLA-B35 和 HLA-B67 状态）引起的，导致肉芽肿性变化、巨细胞形成以及单核细胞和淋巴细胞滤泡间混合浸润。³³ 它的发病率为每年每 100 000 人 2-5 例，男女比例为 3-7：1。12， 37 流行病学和病毒学研究的结果涉及多种病毒，包括流行性腮腺炎、 埃可病毒 、 柯萨奇病毒和 SARS-CoV-2。27， 38， 39， 40， 41 尽管 COVID-19 疫苗接种后亚急性甲状腺炎的病例报告很多，⁴² 但一项针对 2·30 万疫苗接种者的人群研究指出，与接种疫苗相比，接种疫苗后 56 天内患甲状腺炎的风险没有增加暴露前期，表明这种关联可能是巧合。⁴³

Several drugs can cause thyroiditis (panel). Checkpoint inhibitor immunotherapy is now standard of care for many cancers: thyroiditis occurs in about 10% of treated patients,44, 45 with higher rates in those with pre-existing thyroid autoimmunity.46, 47 Thyroiditis is more common with programmed cell death-1 (PD-1) inhibitors or combination therapy than with programmed cell death-1 ligand-1 (PD-L1) inhibitor or cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor monotherapy.⁴⁸ Thyrotoxicosis occurs in 3–5% of patients treated with interferon-α.⁴⁹
几种药物可引起甲状腺炎（ 面板 ）。检查点抑制剂免疫疗法现在是许多癌症的标准治疗：甲状腺炎发生在大约 10% 的接受治疗患者中，44， 45 在预先存在甲状腺自身免疫的患者中发生率更高。46， 47 与程序性细胞死亡-1 配体-1 （PD-L1） 抑制剂或细胞毒性 T 淋巴细胞抗原-4 （CTLA-4） 抑制剂单药治疗相比，程序性细胞死亡-1 （PD-1） 抑制剂或联合治疗更常见甲状腺炎。⁴⁸ 3-5% 的干扰素-α治疗患者发生甲状腺毒症。⁴⁹

Clinical presentation and complications
临床表现和并发症

The usual clinical presentation of hyperthyroidism signifies the hypermetabolic effects of thyroid hormone excess at the cellular level, as well as enhanced β-adrenergic activity. For reasons that remain uncertain, signs and symptoms of hyperthyroidism vary greatly among patients and are only roughly linked to circulating thyroid hormone concentrations.⁵⁰ Some patients have several complaints that seem out of proportion to their apparent modest biochemical hyperthyroidism, whereas others are oligosymptomatic despite very high serum hormone concentrations. Age is one factor, with older individuals often having few hyperthyroid symptoms.⁵¹ Although this finding might relate to milder disease seen in older adults, the index of suspicion for hyperthyroidism should be heightened in older people with unexplained weight loss, atrial fibrillation or atrial flutter, palpitations, altered mood, and other non-specific complaints.⁵²
甲状腺功能亢进症的常见临床表现是指甲状腺激素过多在细胞水平上的代谢亢进作用，以及β-肾上腺素能活性增强。由于仍不确定的原因，甲状腺功能亢进症的体征和症状因患者而异，仅与循环甲状腺激素浓度大致相关。⁵⁰ 一些患者有一些抱怨，这些抱怨似乎与他们明显的适度生化甲状腺功能亢进不成比例，而另一些患者尽管血清激素浓度非常高，但仍有轻微症状。年龄是一个因素，老年人通常很少有甲状腺功能亢进症状。⁵¹ 尽管这一发现可能与老年人中较轻的疾病有关，但在出现不明原因体重减轻、 心房颤动或心房扑动 、 心悸、 情绪改变和其他非特异性主诉的老年人中，应提高对甲状腺功能亢进症的怀疑指数。⁵²

Table 2 shows both typical and unusual symptoms and signs of hyperthyroidism. Patients with Graves' disease have additional findings that are highly specific to this condition and are diagnostically helpful (table 2). The most prevalent is thyroid eye disease, also known as Graves' ophthalmopathy or orbitopathy, with an overall prevalence of 25–40%⁵³ among patients with Graves' hyperthyroidism. Other findings in patients with Graves' hyperthyroidism are less frequent and include thyroid dermopathy (pretibial myxedema), thyroid acropachy (clubbing of the nails), and other autoimmune disorders such as thymic enlargement, splenomegaly, alopecia, vitiligo, pernicious anaemia, and urticaria.
表 2 显示了甲状腺功能亢进症的典型和不常见症状和体征。Graves 病患者还有其他针对该病的高度特异性表现，对诊断有帮助（ 表 2）。最普遍的是甲状腺眼病 ，也称为 Graves 眼病或眼眶病，Graves 甲状腺功能亢进症患者的总体患病率为 25-40%53。Graves 甲状腺功能亢进症患者的其他发现较少见，包括甲状腺皮肤病 （胫前粘液性水肿）、甲状腺杵状指癣（指甲杵状指）和其他自身免疫性疾病，例如胸腺肿大、 脾肿大 、 脱发 、 白癜风 、 恶性贫血和荨麻疹 。

Table 2. Signs and symptoms of hyperthyroidism, by system
表 2.甲状腺功能亢进症的体征和症状 ，按系统

Empty Cell	Symptoms* 症状 *	Signs* 标志 *
General  常规	Nervousness, insomnia, fatigue 紧张、失眠、疲劳	Anxiety, restlessness  焦虑、不安
Skin  皮肤	Diaphoresis, thinning hair 出汗、头发稀疏	Warm, moist skin, onycholysis, alopecia†, acropachy†, urticaria*, vitiligo* 皮肤温暖、潮湿、甲剥离、脱发 †、戵状 †、荨麻疹 *、白癜风 *
Eyes  眼睛	Dry eye, eye protrusion, diplopia, photophobia 干眼症、突出眼球、复视、畏光	Proptosis†, conjunctival injection†, chemosis†, decreased visual acuity†, lid lag† 眼睑下垂 †、结膜充血 †、水肿 †、视力下降 †、眼睑滞后 †
Neck  脖子	Anterior neck swelling, dysphagia 颈前肿胀、吞咽困难	Goitre  甲状腺肿
Cardiovascular  心血管	Palpitations, dyspnoea on exertion, chest pain 心悸、劳力性呼吸困难、胸痛	Tachycardia, tachyarrhythmia, congestive heart failure‡ 心动过速、快速性心律失常、充血性心力衰竭 ‡
Gastrointestinal  胃肠	Hyperdefecation, diarrhoea 排便过多、腹泻	Abnormal liver function tests 肝功能检查异常
Metabolic  新陈代谢的	Hyperphagia, weight loss, heat sensitivity 食欲亢进、体重减轻、热敏感	Cachexia, fever‡ 恶病质、发热 ‡
Neuromuscular  神经肌肉的	Muscle weakness, paralysis§ 肌肉无力、瘫痪 §	Hyper-reflexia, proximal muscle weakness, muscle wasting, hypokalaemic periodic paralysis§ 反射亢进、近端肌无力、肌肉萎缩、低钾血症性周期性麻痹 §
Skeletal  骨骼的	..	Low bone mass and fractures, hypercalcaemia, hypercalciuria 低骨量和骨折、高钙血症、高钙尿症
Neurological  神经学上的	Tremor  震颤	Tremor, stupor‡, coma‡, choreoathetosis§ 震颤、木僵 、 昏迷、舞蹈手足徐动症 §
Reproductive/sexual  生殖/性	Oligo-amenorrhoea, decreased fertility in women, decreased libido in men 少闭经、女性生育能力下降、男性下降	Gynecomastia  男性乳房发育症
Haemopoietic  造血	..	Leukopenia†, normochromic normocytic anaemia, splenomegaly†, thymic enlargement† 白细胞减少 †、正色素性正细胞性贫血、脾肿大 †、胸腺肿大 †
Psychiatric/cognitive  精神病学/认知学	Emotional lability, poor concentration, irritability 情绪不稳定、注意力不集中、易怒	Depression, psychosis, irrational behaviour 抑郁、精神病、非理性行为

*

Signs and symptoms of hyperthyroidism are less specific or might be absent in patients of older age.
甲状腺功能亢进症的体征和症状在老年患者中特异性较低或可能不存在。†

Findings seen in Graves' disease.
在 Graves 病中发现。‡

Findings seen in thyroid storm.
在甲状腺危象中可见。§

References for rare findings are provided in the appendix.
附录中提供了罕见发现的参考文献。

Thyroid storm, a severe exacerbation of hyperthyroidism associated with decompensation in one or more organ systems, occurs in up to 0·2% of patients with thyrotoxicosis54, 55 and has a mortality rate of up to 10–17% in people older than 60 years.⁵⁶ Thyroid storm is a combination of signs and symptoms characterised by many of the following: fever, altered mental status, gastrointestinal and hepatic dysfunction, tachycardia with atrial arrhythmias, and congestive heart failure, often with a precipitating event such as infection, surgery, or childbirth. It rarely is the initial presentation of hyperthyroidism.
甲状腺危象是甲状腺功能亢进症的严重恶化，与一个或多个器官系统失代偿有关，发生在高达 0·2% 的甲状腺毒症患者中 54， 55，在 60 岁以上的人群中死亡率高达 10-17%。⁵⁶甲状腺危象是体征和症状的组合，其特征是以下许多方面：发热、精神状态改变、胃肠道和肝脏功能障碍 、 心动过速伴房性心律失常和充血性心力衰竭 ，通常伴有感染、手术或分娩等诱发事件.它很少是甲状腺功能亢进症的首发表现。

Untreated hyperthyroidism is associated with various adverse outcomes, especially in older individuals. In one population-based study, the standardised mortality ratio was 1·14 (95% CI 1·04–1·24, p=0·002) compared with the general population.⁵⁷ Cardiovascular adverse events are most important, especially atrial fibrillation leading to heart failure and embolic stroke.⁵⁸ Such events are more likely to occur in older patients with comorbidities including cardiovascular disease, hypertension, diabetes, and valvular heart disease.⁵⁸ Fractures are more common, especially in postmenopausal women with hyperthyroidism, than in the general population, probably because of increased bone turnover.59, 60 Overall quality of life is diminished in individuals with untreated hyperthyroidism,⁶¹ especially if they have concomitant Graves' ophthalmopathy.⁶²
未经治疗的甲状腺功能亢进症与各种不良结局相关，尤其是在老年人中。在一项基于人群的研究中， 与一般人群相比， 标准化死亡率为 1·14（95% CI 1·04–1·24，p=0·002）。⁵⁷ 心血管不良事件是最重要的，尤其是导致心力衰竭和栓塞性卒中的心房颤动。⁵⁸ 此类事件更可能发生在患有心血管疾病、高血压、糖尿病和瓣膜性心脏病等合并症的老年患者中。⁵⁸ 骨折比一般人群更常见，尤其是在患有甲状腺功能亢进症的绝经后妇女中 ，这可能是因为骨转换增加。59， 60 未经治疗的甲状腺功能亢进症患者的总体生活质量会降低，⁶¹ 特别是如果他们同时患有 Graves 眼病。⁶²

Diagnosis of thyrotoxicosis
甲状腺毒症的诊断

Overt thyrotoxicosis is characterised by increased serum concentrations of free T4 and total or free T3, and suppressed serum TSH, usually less than 0·01 mU/L. Some patients have so-called T3 thyrotoxicosis, in which free T4 concentrations are within range but T3 values are raised. This occurrence is common in patients with milder disease or early in the course of disease. In subclinical hyperthyroidism, thyroid hormone values are within range but TSH is suppressed.¹ Measurement of the free fraction of T4 is preferred over the measurement of total T4, because it reflects the freely available hormone, which is unbound to proteins and ready to enter tissues. Because of limitations of current free T3 assays, either total or free T3 can be measured.
显性甲状腺毒症的特征是血清游离 T4 和总或游离 T3 浓度升高，血清 TSH 抑制，通常低于 0·01 mU/L。一些患者患有所谓的 T3 甲状腺毒症，其中游离 T4 浓度在范围内，但 T3 值升高。这种情况常见于病情较轻的患者或病程早期。在亚临床甲状腺功能亢进症中，甲状腺激素值在范围内，但 TSH 受到抑制。¹ T4 游离分数的测量优于总 T4 的测量，因为它反映了自由可用的激素，该激素未与蛋白质结合并准备进入组织。由于当前游离 T3 测定的局限性，可以测量总 T3 或游离 T3。

In patients suspected of having Graves' disease, particularly when they do not have Graves' ophthalmopathy or other pathognomonic physical findings, measurement of antibodies to the TSH receptor (TRAb) is a key diagnostic. TRAb can be measured with immunoassays that simultaneously detect two categories of functional TRAb—ie, thyroid stimulating antibodies and thyroid blocking antibodies, which sometimes co-exist in patients with Graves' disease (figure). These immunoassays do not differentiate between thyroid stimulating and thyroid blocking antibodies. For approximately 5 years, novel automated bridge-based binding assays have become commercially available to more selectively, but not exclusively,⁶³ measure thyroid stimulating antibodies.⁶⁴ Either assay method provides excellent diagnostic sensitivity and specificity.⁶⁵
对于疑似 Graves 病的患者，特别是当他们没有 Graves 眼病或其他特异性体格检查结果时，TSH 受体 （TRAb） 抗体的检测是一项关键的诊断。TRAb 可以用免疫测定法来测量，免疫测定法可同时检测两类功能性 TRAb，即促甲状腺抗体和甲状腺阻断抗体 ，它们有时在 Graves 病患者中共存（ 图 ）。这些免疫测定法不区分促甲状腺抗体和甲状腺阻断抗体 。大约 5 年来，新型基于桥的自动结合测定已上市，以更具选择性地（但不限于 ）⁶³ 测量促甲状腺抗体 。⁶⁴ 两种检测方法均具有出色的诊断敏感性和特异性。⁶⁵

In patients in whom the cause of thyrotoxicosis is not readily apparent, scintigraphy and radioisotope uptake are useful to determine the cause. Radioisotopes of iodine (¹²³I and ¹³¹I) or ⁹⁹-technetium are administered and subsequently detected in the thyroid gland by planar imaging. In Graves' disease, diffuse accumulation of the radiotracer throughout the gland is seen with raised or high to normal uptake, whereas uptake is usually very low or absent in thyroiditis. Tracer uptake is reduced in patients with iodine-induced hyperthyroidism because of competition for uptake with the administered radiotracer. In patients with toxic nodular goitre, scintigraphy can disclose areas of hyperfunction and hypofunction within the thyroid gland (so-called hot and cold nodules).
对于甲状腺毒症病因不明显的患者， 闪烁显像和放射性同位素摄取有助于确定病因。施用碘 （¹²³I 和 ¹³¹I） 或 ⁹⁹-锝的放射性同位素，随后通过平面成像在甲状腺中检测。在 Graves 病中，放射性示踪剂在整个腺体中的弥漫性积累表现为摄取升高或升高至正常水平，而甲状腺炎的摄取通常非常低或不存在。碘诱导的甲状腺功能亢进症患者的示踪剂摄取减少，因为与施用的放射性示踪剂竞争摄取。在毒性结节性甲状腺肿患者中，闪烁显像可以揭示甲状腺内功能亢进和功能减退的区域（所谓的冷热结节）。

Thyroid ultrasound is indicated to define thyroid nodules that are detected on physical examination or on scintigraphy. In some centres, assessment of thyroidal vascularity by ultrasound with colour flow Doppler is used in preference to thyroid scintigraphy to differentiate between Graves' disease and other causes of thyrotoxicosis. Thyroidal blood flow is increased in Graves' disease, but is normal or low in various forms of thyroiditis, including silent and post-partum thyroiditis⁶⁶ and amiodarone-induced thyroiditis.⁶⁷
甲状腺超声用于确定在体格检查或闪烁显像中检测到的甲状腺结节。在一些中心，通过彩色血流多普勒超声评估甲状腺血管分布 ，而不是甲状腺闪烁显像 ，以区分 Graves 病和甲状腺毒症的其他原因。Graves 病患者的甲状腺血流量增加，但各种形式的甲状腺炎患者甲状腺血流量正常或降低，包括无症状和产后甲状腺炎 ⁶⁶ 和胺碘酮诱导的甲状腺炎。⁶⁷

Laboratory diagnosis of thyrotoxicosis is usually straightforward, but there are circumstances in which results cause diagnostic confusion. Analytical interference from circulating heterophilic antibodies can affect TSH measurements resulting in discordant thyroid function tests (eg, increased thyroid hormones with unsuppressed TSH). In assays using streptavidin-biotin detection systems, ingestion of biotin supplements by patients can cause concomitantly falsely raised thyroid hormone concentrations and falsely suppressed TSH, leading to the erroneous diagnosis of thyrotoxicosis.⁶⁸ Some patients have spuriously increased immunoreactive free T4 concentrations because of variant thyroid hormone binding proteins (familial dysalbuminaemic hyperthyroxinaemia),69, 70 and in rare cases patients with thyroid autoimmunity might have circulating autoantibodies to T4 or T3 causing analytical interference.⁷¹ Although serum TSH is always subnormal in primary hyperthyroidism, two rare conditions present with normal or raised serum concentrations of thyroid hormone and unsuppressed serum TSH: TSH-secreting pituitary tumours causing central thyrotoxicosis, and resistance to thyroid hormone β, caused by mutations in the thyroid hormone receptor β.72, 73 Several common clinical entities are associated with subnormal serum TSH but normal or low concentrations of thyroid hormones, including severe non-thyroidal illness, central hypothyroidism, and high-dose glucocorticoid therapy. Suppressed TSH with normal free T4 and T3 can also be seen in early pregnancy.74, 75 Ethnic differences can also be important; up to 8% of healthy African Americans have serum TSH concentrations below the reference range lower limit of 0·45 mU/L compared with White Americans.⁷⁶ Whether genetic predisposition or environmental factors explain these differences is still unclear.
甲状腺毒症的实验室诊断通常很简单，但在某些情况下，结果会导致诊断混淆。循环嗜异性抗体的分析干扰会影响 TSH 测量，导致甲状腺功能检查不一致（例如，甲状腺激素增加但 TSH 未抑制）。在使用链霉亲和素-生物素检测系统的检测中，患者摄入生物素补充剂可导致甲状腺激素浓度假性升高和 TSH 假性抑制，从而导致甲状腺毒症的错误诊断。⁶⁸ 由于甲状腺激素结合蛋白变异（家族性白蛋白不良血症性高甲状腺素血症），一些患者出现免疫反应性游离 T4 浓度虚假增加，69、70 在极少数情况下，甲状腺自身免疫患者可能具有针对 T4 或 T3 的循环自身抗体，从而引起分析干扰。⁷¹ 尽管原发性甲状腺功能亢进症的血清 TSH 总是低于正常水平，但血清甲状腺激素浓度正常或升高且血清 TSH 未受到抑制，两种罕见的情况：分泌 TSH 的垂体瘤引起中枢性甲状腺毒症，以及由甲状腺激素受体β 突变引起的甲状腺激素β抵抗。72， 73 几种常见的临床实体与血清 TSH 低于正常但甲状腺激素浓度正常或低浓度有关，包括严重的非甲状腺疾病、中枢性甲状腺功能减退症和大剂量糖皮质激素治疗。 TSH 抑制伴游离 T4 和 T3 正常也可见于妊娠早期 。74， 75 种族差异也很重要 ; 与美国白人相比，高达 8% 的健康非裔美国人的血清 TSH 浓度低于 0·45 mU/L 的参考范围下限。⁷⁶遗传易感性或环境因素是否解释了这些差异仍不清楚。

Treatment  治疗

Relief of thyrotoxic symptoms (irrespective of cause) can be achieved by β-adrenergic blocker therapy. The non-selective β-blocker propranolol has long been used (10–40 mg given three to four times a day), but longer acting, selective β-1 blockers such as atenolol and metoprolol are also effective. The preferred choice of therapy in thyrotoxicosis with hyperthyroidism depends on the underlying pathophysiology, but the most common options are antithyroid drugs, radioactive iodine, and thyroidectomy. In patients with toxic adenoma or multinodular goitre, radioactive iodine treatment and surgery have been the preferred options. However, studies have shown that long-term, low-dose treatment with antithyroid drugs is effective, especially in older patients or those who are poor candidates for radioactive iodine treatment or surgery.⁷⁷ In Graves' disease, all three treatment options are effective, but antithyroid drugs may be the patient-preferred approach.⁷⁸ A cohort study of 1186 patients with Graves' disease followed up for up to 10 years after treatment with radioactive iodine reported lower quality of life than did those who had received antithyroid drugs or surgery,⁷⁹ whereas findings from an earlier, smaller randomised controlled trial showed no difference.⁸⁰ Clinicians in Europe and the Asia-Pacific region generally prefer antithyroid drugs as first-line treatment.81, 82 In the USA, treatment choices have shifted in favour of antithyroid drugs over radioactive iodine in the past two decades.⁸³ Emerging evidence of the efficacy and safety of long-term administration of antithyroid drugs in patients with Graves' disease might also contribute to future treatment preferences.⁸⁴ During the COVID-19 pandemic, non-urgent surgery and radioactive iodine treatment were curtailed in many countries, leading to a further shift towards the use of antithyroid drugs. Table 3 shows the mode of action, contraindications, and major side-effects for antithyroid drugs, radioactive iodine, and thyroidectomy.
甲状腺毒症症状（无论原因如何）可通过 β-肾上腺素能阻滞剂治疗实现。非选择性 β 受体阻滞剂普萘洛尔长期以来一直使用（10-40 毫克，每天 3 至 4 次），但长效选择性 β-1 阻滞剂（如阿替洛尔和美托洛尔）也有效。甲状腺毒症伴甲状腺功能亢进症的首选治疗选择取决于潜在的病理生理学，但最常见的选择是抗甲状腺药物、放射性碘和甲状腺切除术。对于毒性腺瘤或多结节性甲状腺肿患者，放射性碘治疗和手术一直是首选方案。 然而，研究表明，长期、低剂量的抗甲状腺药物治疗是有效的，尤其是对于老年患者或不适合放射性碘治疗或手术的患者。⁷⁷ 在 Graves 病中，所有三种治疗方案都是有效的，但抗甲状腺药物可能是患者首选的方法。⁷⁸ 一项对 1186 名 Graves 病患者进行的队列研究在接受放射性碘治疗后随访长达 10 年，报告称其生活质量低于接受抗甲状腺药物或手术的患者，⁷⁹ 而早期、规模较小的随机对照试验的结果显示没有差异。⁸⁰ 欧洲和亚太地区的临床医生通常更喜欢将抗甲状腺药物作为一线治疗。81， 82 在美国，在过去的二十年里，治疗选择已经转向抗甲状腺药物而不是放射性碘。⁸³ 新出现的证据表明 Graves 病患者长期服用抗甲状腺药物的有效性和安全性，也可能有助于未来的治疗偏好。⁸⁴ 在 COVID-19 大流行期间，许多国家减少了非紧急手术和放射性碘治疗，导致进一步转向使用抗甲状腺药物。 表 3 显示了抗甲状腺药物、放射性碘和甲状腺切除术的作用方式、禁忌症和主要副作用。

Table 3. Treatments for thyrotoxicosis with hyperthyroidism
表 3.甲状腺毒症伴甲状腺功能亢进症的治疗

Empty Cell	Mode of action  作用方式	Usual starting dose  通常的起始剂量	Contraindications  禁忌	Advantages  优势	Disadvantages  弊	Adverse events
Antithyroid drugs (methimazole, carbimazole, and propylthiouracil) 抗甲状腺药物（甲巯咪唑、卡比马唑和丙硫氧嘧啶）	Inhibition of thyroid hormone synthesis by preventing iodination and coupling of tyrosine residues. Propylthiouracil additionally decreases T4 to T3 conversion by inhibiting type 1 deiodinase. 通过防止酪氨酸残基的碘化和偶联来抑制甲状腺激素合成。丙硫氧嘧啶还通过抑制 1 型脱碘酶来降低 T4 到 T3 的转化。	Methimazole*: 10–30 mg, once a day. Carbimazole: 15–40 mg, once a day. Propylthiouracil: 100–400 mg, 2–3 times a day. 甲巯咪唑 *：10-30 毫克，每天一次。卡比马唑：15-40 毫克，每天一次。丙硫氧嘧啶：100-400 毫克，每天 2-3 次。	Previous major adverse reactions to antithyroid drugs. Severe liver disease. Propylthiouracil preferred in first trimester of pregnancy. 以前对抗甲状腺药物的主要不良反应。严重的肝病。丙硫氧嘧啶优先用于妊娠早期。	No radiation exposure. No adverse effect on Graves' orbitopathy. No risk of surgery or anaesthesia. No hospitalisation required. Use during pregnancy and breastfeeding possible. Low risk of subsequent hypothyroidism. Chance of remission. 无辐射暴露。对 Graves 眼眶病无不良影响。没有手术或麻醉的风险。无需住院治疗。可以在怀孕和哺乳期间使用。随后发生甲状腺功能减退症的风险较低。缓解的机会。	High relapse rate (about 50% after one course). Long-term compliance. Long therapy duration. 复发率高（一个疗程后约 50%）。长期合规。治疗持续时间长。	Minor pruritus (<5%). Gastrointestinal distress (<1%). Major agranulocytosis (<0·5%). Hepatotoxicity (<0·1%). Vasculitis (<0·1%). Pancreatitis.†
Radioactive iodine  放射性碘	Radiation-induced thyrocyte destruction. 辐射诱导的甲状腺细胞破坏。	Fixed radioiodine activity of 185, 370, or 555 MBq. Calculated radioiodine activity based on thyroid gland weight and percentage update on scintigraphy. 固定放射性碘活度为 185、370 或 555 MBq。根据甲状腺重量和闪烁显像的百分比更新计算放射性碘活度。	Pregnancy and breastfeeding. Short-term planning to conceive or father a child. Severe thyroid eye disease. 怀孕和母乳喂养。怀孕或生育孩子的短期计划。严重的甲状腺眼病。	High cure rate. No risk of surgery or anaesthesia. Moderate costs compared with surgery (especially fixed-activity radioactive iodine therapy). 固化率高。没有手术或麻醉的风险。与手术（尤其是固定活性放射性碘治疗）相比，费用适中。	Risk factor for exacerbating hyperthyroidism, Graves' orbitopathy. Slow control of hyperthyroidism. Frequent permanent hypothyroidism. Avoid pregnancy 6–12 months after radioactive iodine. Radiation exposure. Need for pre-treatment with antithyroid drugs. Relief of hyperthyroidism not achieved in about 10% of patients. 加剧甲状腺功能亢进症的危险因素，Graves 眼眶病。甲状腺功能亢进症控制缓慢。频繁的永久性甲状腺功能减退症。避免在放射性碘后 6-12 个月怀孕。辐射暴露。需要用抗甲状腺药物进行预处理。约 10% 的患者未缓解甲状腺功能亢进症。	Exacerbation or development of Graves' orbitopathy (15–30%). Radiation thyroiditis. Increased risk of solid-cancer mortality.†
Thyroidectomy  甲状腺 切除 术	Removal of the thyroid gland. 切除甲状腺。	Total thyroidectomy (preferred). Subtotal thyroidectomy (in specific cases). 甲状腺全切除术（首选）。甲状腺次全切除术（在特定病例中）。	Frail or elderly patients with serious comorbidities. Pregnancy.†‡ 虚弱或老年患者有严重合并症。怀孕。†‡	Rapid control of hyperthyroidism. Definitive treatment. Possible in severe thyroid eye disease. No radiation exposure. Preferred in patients with coexisting compressive symptoms, (suspect) thyroid malignancy, and hyperparathyroidism. 甲状腺功能亢进症的快速控制。确定性治疗。可能在严重的甲状腺眼病中。无辐射暴露。对于同时存在压迫症状、（疑似）甲状腺恶性肿瘤和甲状旁腺功能亢进症的患者，首选该药。	High-volume surgeons not always available. Surgery-related risks and hospitalisation. Permanent hypothyroidism. Need for pre-treatment with antithyroid drugs or potassium/Lugol's iodine. Cosmetic burden (permanent scar).§ High costs. 大手术医生并不总是可用。手术相关风险和住院治疗。永久性甲状腺功能减退症。需要用抗甲状腺药物或钾/Lugol 碘进行预处理。美容负担（永久性疤痕）。§ 成本高。	Bleeding or haematoma. Laryngeal nerve injury (1–2%). Hypoparathyroidism related hypocalcaemia (1–2%). Anaesthesia complications.

*

Initial dose for hyperthyroidism control. In titration therapy methimazole is typically administered at a dose of 2·5–10 mg per day.
甲状腺功能亢进症控制的初始剂量。在滴定疗法中，甲巯咪唑通常以每天 2·5-10 mg 的剂量给药。†

Adverse events suggested but not confirmed because of conflicting evidence.
提示不良事件，但由于证据相互矛盾而未得到证实。‡

With the exception of second trimester pregnancy, which is a contraindication.
妊娠中期除外，这是禁忌证。§

Scarless thyroidectomy is available in some centres.
一些中心提供无疤痕甲状腺切除术。

Antithyroid drugs  抗甲状腺药物

The thionamide antithyroid drugs include propylthiouracil, carbimazole, and its metabolite methimazole. Carbimazole and methimazole are generally preferred over propylthiouracil because of superior efficacy and tolerability, and because their longer duration of action allows once daily oral administration rather than twice or thrice daily as for propylthiouracil.83, 85 Patients with newly diagnosed Graves' hyperthyroidism can be treated for 12–18 months with carbimazole and methimazole according to American and European guidelines,78, 86 after which they can be discontinued if TSH serum is normal and TRAb is negative. In case of persistent high TRAb on treatment or relapse after treatment withdrawal, patients can choose carbimazole and methimazole for a further 12 months (or longer), or opt for definitive treatment with radioactive iodine or thyroidectomy. A disadvantage of antithyroid drugs is high relapse rates (about 50%) after a single course, especially in the first 6 months after withdrawal.84, 87, 88 However, in a longitudinal study of 128 patients with recurrent Graves' disease, over 75% of those who received a second course of treatment with antithyroid drugs had long-term remission.⁸⁹ Evidence shows that long-term (5–10 years) or perhaps even lifelong treatment with low-dose carbimazole and methimazole is a safe and an effective option.84, 90
硫脲酰胺类抗甲状腺药物包括丙硫氧嘧啶 、 卡比马唑及其代谢物甲巯咪唑。卡比马唑和甲巯咪唑通常优于丙硫氧嘧啶，因为丙硫氧嘧啶具有更好的疗效和耐受性 ，而且它们的作用持续时间较长，允许每天口服一次 ，而不是像丙硫氧嘧啶那样每天两次或三次。83， 85 新诊断的格雷夫斯甲状腺功能亢进症患者可以根据美国和欧洲指南使用卡比马唑和甲巯咪唑治疗 12-18 个月，78， 86 之后如果 TSH 血清正常且 TRAb 阴性，则可以停药。如果治疗期间 TRAb 持续升高或停止治疗后复发，患者可以选择卡比马唑和甲巯咪唑再持续 12 个月（或更长时间），或选择放射性碘或甲状腺切除术的根治性治疗。 抗甲状腺药物的缺点是单疗程后复发率高（约 50%），尤其是在停药后的前 6 个月。84， 87， 88 然而，在一项对 128 名复发性 Graves 病患者的纵向研究中，接受第二个疗程抗甲状腺药物治疗的患者中有超过 75% 的患者实现了长期缓解。⁸⁹ 有证据表明，使用低剂量卡比马唑和甲巯咪唑进行长期（5-10 年）甚至终身治疗是一种安全有效的选择。84、90 元

The initial dose of antithyroid drug required depends on the severity of hyperthyroidism and size of thyroid gland.⁹¹ After initial control, which can take 1–3 months, depending on the starting dose, antithyroid drugs can be titrated to the lowest dose needed to maintain euthyroidism. Alternatively, especially in difficult to control disease, a so-called block and replace regimen can be used in which antithyroid drugs are given in a high dose to fully block thyroid function accompanied by levothyroxine replacement to avoid hypothyroidism.78, 86 Thyroid function should be checked 4–6 weeks after starting treatment, with dose titration based on serum T4 and T3 concentrations, because serum TSH can remain suppressed for several months.⁸⁶ Overtreatment resulting in hypothyroidism should be avoided, particularly in Graves' disease, because it can provoke or exacerbate thyroid eye disease.⁹² Once patients achieve biochemical euthyroidism, follow-up intervals can be extended to 2–4 months.
所需的抗甲状腺药物的初始剂量取决于甲状腺功能亢进症的严重程度和甲状腺的大小。⁹¹ 初始控制可能需要 1-3 个月，具体取决于起始剂量，在初始控制后，抗甲状腺药物可以滴定至维持甲状腺功能正常所需的最低剂量。或者，特别是在难以控制的疾病中，可以使用所谓的阻断和替代方案，其中大剂量给予抗甲状腺药物以完全阻断甲状腺功能 ，同时补充左旋甲状腺素以避免甲状腺功能减退。78， 86 应在开始治疗后 4-6 周检查甲状腺功能，并根据血清 T4 和 T3 浓度进行剂量调整 ，因为血清 TSH 可以保持抑制数月。⁸⁶ 应避免导致甲状腺功能减退症的过度治疗，尤其是在 Graves 病中，因为它会引发或加剧甲状腺眼病。⁹² 一旦患者达到生化甲状腺功能正常，随访间隔可以延长至 2-4 个月。

Minor side-effects occur in about 5% of patients, including pruritus and gastrointestinal distress (table 3). Major side-effects of antithyroid drugs are rare. There is some evidence that serious side-effects are dose related with carbimazole and methimazole, which has not been reported for propylthiouracil.⁹³ Agranulocytosis occurs in less than 0·5% of patients, typically within the first 3 months of treatment, and can present with fever or sore throat, or both. Patients should be alerted for the occurrence of these symptoms and, if agranulocytosis is confirmed, antithyroid drugs should be discontinued permanently. Hepatoxicity, cholestatic or hepatocellular, occurs in less than 0·1% of patients, and is generally more severe with propylthiouracil than with carbimazole and methimazole, particularly in children and in the first 3 months of therapy,⁸⁵ with cases of fatal liver failure reported. For that reason, propylthiouracil received a so-called black box warning from the US Food and Drug Administration, recommending use only in specific circumstances. Finally, in 2020, the European Medicines Agency issued a warning of increased risk of acute pancreatitis in patients given carbimazole and methimazole, although evidence for this effect is conflicting.94, 95, 96
约 5% 的患者会出现轻微的副作用，包括瘙痒和胃肠道不适 （ 表 3）。抗甲状腺药物的主要副作用很少见。有一些证据表明，严重的副作用与卡比马唑和甲巯咪唑的剂量有关，而丙硫氧嘧啶尚未报道。⁹³ 粒细胞缺乏症发生在不到 0·5% 的患者中，通常在治疗的前 3 个月内，可表现为发热或喉咙痛，或两者兼而有之。应提醒患者这些症状的发生，如果确诊粒细胞缺乏症，应永久停用抗甲状腺药物。肝毒性，胆汁淤积或肝细胞性，发生在不到 0·1% 的患者中，丙硫氧嘧啶通常比卡比马唑和甲巯咪唑更严重，特别是在儿童和治疗的前 3 个月，⁸⁵ 报告了致命性肝衰竭病例。出于这个原因，丙硫氧嘧啶收到了美国食品和药物管理局的所谓黑框警告，建议仅在特定情况下使用。最后，在 2020 年，欧洲药品管理局 （European Medicines Agency） 发出警告，称服用卡比马唑和甲巯咪唑的患者患急性胰腺炎的风险增加，尽管这种影响的证据相互矛盾。 票价：94、95、96 元

Radioactive iodine therapy
放射性碘治疗

Radioactive iodine is first-line treatment in many cases of toxic adenoma and toxic multinodular goitre, especially for older patients with comorbidities incurring higher surgery risk. It can be administered either as a fixed activity or calculated activity on the basis of thyroid size and the 24 h radioiodine uptake. In the first weeks after treatment, T4 and T3 concentrations can transiently increase, but ultimately hypothyroidism occurs in 50–85% of treated patients with Graves' disease⁹⁷ and is more common with high administered radioactive iodine activities. Relief of hyperthyroidism after radioactive iodine therapy is not achieved in roughly 10% of patients after initial treatment and depends on the underlying cause.⁹⁸ Radioactive iodine can be administered as a definitive treatment option, but the effects are not immediate. It can reduce goitre volume up to 60% in multinodular goitre, depending on the initial size.⁹⁸ Carbimazole and methimazole or β blockers are typically prescribed before radioactive iodine to control hyperthyroidism and reduce risk for post-treatment exacerbation, especially in older patients and those with severe hyperthyroidism. They should be stopped at least 3–7 days before ¹³¹iodine administration and may be restarted 3–7 days later and continued until euthyroidism occurs.⁹⁹
放射性碘是许多毒性腺瘤和毒性多结节性甲状腺肿病例的一线治疗，尤其是对于患有手术风险较高合并症的老年患者。它可以作为固定活性或根据甲状腺大小和 24 小时放射性碘摄取的计算活性给药。在治疗后的最初几周内，T4 和 T3 浓度可短暂增加，但最终 50-85% 的格雷夫斯病治疗患者会出现甲状腺功能减退^{症 97}，并且在放射性碘活性高的情况下更常见。大约 10% 的患者在初始治疗后没有达到放射性碘治疗后甲状腺功能亢进症的缓解，这取决于根本原因。⁹⁸ 放射性碘可以作为确定性的治疗选择，但效果不是立竿见影的。它可以将多结节性甲状腺肿的甲状腺肿体积减少多达 60%，具体取决于初始大小。⁹⁸ 卡比马唑和甲巯咪唑或β阻滞剂通常在放射性碘之前开具，以控制甲状腺功能亢进症并降低治疗后恶化的风险，尤其是在老年患者和严重甲状腺功能亢进症患者中。它们应在 ¹³¹ 碘给药前至少 3-7 天停止，并且可以在 3-7 天后重新开始并持续使用，直到出现甲状腺功能正常。⁹⁹

Side-effects include neck tenderness and development or worsening of pre-existing thyroid eye disease, especially in people who smoke.100, 101 Therefore, radioactive iodine is contraindicated in patients with Graves' disease with severe orbitopathy, and glucocorticoid prophylaxis is recommended in those with mild orbitopathy or judged at risk of de-novo thyroid eye disease (those who smoke, with severe or unstable hyperthyroidism, and with high serum TRAb) when receiving radioactive iodine.¹⁰⁰ Untreated hypothyroidism after radioactive iodine should be avoided since this treatment can elicit or worsen thyroid eye disease. Other contraindications to radioactive iodine therapy include pregnancy (or pregnancy planned in the next 6 months), breastfeeding,⁸⁶ and inability to adhere to radiation safety precautions. Finally, although findings from several studies showed no difference in cancer incidence or mortality with radioactive iodine in general or between fixed and calculated radioiodine activity regimens,102, 103 some evidence suggests a dose-dependent positive association between RAI and solid cancer mortality;¹⁰⁴ however, findings are controversial.
副作用包括颈部压痛和先前存在的甲状腺眼病的发展或恶化，尤其是在吸烟者中。100， 101 因此，放射性碘禁用于有严重眼眶病的 Graves 病患者，建议轻度眼病患者或判断有新发甲状腺眼病风险的患者（吸烟、严重或不稳定的甲状腺功能亢进症患者以及血清 TRAb 高的患者）在接受放射性碘治疗时进行糖皮质激素预防。¹⁰⁰ 应避免放射性碘后未经治疗的甲状腺功能减退症，因为这种治疗会诱发或加重甲状腺眼病。放射性碘治疗的其他禁忌症包括怀孕（或计划在未来 6 个月内怀孕）、母乳喂养 ⁸⁶ 和无法遵守辐射安全预防措施。最后，尽管几项研究的结果表明，一般放射性碘或固定放射性碘活性方案与计算放射性碘活性方案之间的癌症发病率或死亡率没有差异，102， 103 一些证据表明 RAI 与实体癌死亡率之间存在剂量依赖性正相关;¹⁰⁴ 然而，研究结果存在争议。

Thyroidectomy  甲状腺 切除 术

Thyroidectomy can be regarded as first-line treatment for toxic nodular goitre and as definitive treatment for Graves' disease, particularly when other treatments are ineffective, not tolerated, or contraindicated (eg, radioactive iodine therapy in severe orbitopathy); in patients with (suspected) malignant nodules, large goitres, or concurrent primary hyperparathyroidism; or when thyroidectomy is the patient's preference. For Graves' disease, total thyroidectomy is generally more effective than subtotal thyroidectomy, with equal rates of complications, and therefore preferred. Antithyroid drugs should be used to achieve euthyroidism before surgery and replaced by levothyroxine treatment postoperatively. Pretreatment with Lugol's iodine or potassium iodide decreases intraoperative blood loss for patients with Graves' disease and is recommended in clinical practice guidelines.78, 86 For toxic nodular goitre, hemithyroidectomy or total thyroidectomy might be appropriate depending on the number and distribution of thyroid nodules. Surgical complications are infrequent (1–2%), particularly when undertaken by high-volume thyroid surgeons (ie, those doing >25–50 thyroidectomies per year).105, 106, 107 Complications include postoperative bleeding, hypocalcaemia (usually transient) due to hypoparathyroidism, and recurrent laryngeal nerve injury, with a risk for each of around 1%.
甲状腺切除术可被视为毒性结节性甲状腺肿的一线治疗和 Graves 病的确定性治疗，特别是当其他治疗无效、不能耐受或有禁忌证时（例如，严重眼眶病的放射性碘治疗）;在患有（疑似）恶性结节、大甲状腺肿或并发原发性甲状旁腺功能亢进症的患者中;或者当患者更喜欢甲状腺切除术时。对于 Graves 病，甲状腺全切除术通常比甲状腺次全切除术更有效，并发症发生率相同，因此首选。手术前应使用抗甲状腺药物达到甲状腺功能正常，术后用左旋甲状腺素治疗替代。使用 Lugol 碘或碘化钾进行预处理可减少 Graves 病患者的术中失血量，并在临床实践指南中推荐使用。78， 86 对于毒性结节性甲状腺肿，根据甲状腺结节的数量和分布，半甲状腺切除术或全甲状腺切除术可能是合适的。 手术并发症很少见 （1-2%），尤其是由大容量甲状腺外科医生（即每年进行 >25-50 次甲状腺切除术的人）进行手术时。105， 106， 107 并发症包括术后出血 、 甲状旁腺功能减退症引起的低钙血症 （通常是短暂的） 和喉返神经损伤 ，每种风险约为 1%。

Special circumstances  特殊情况

Subclinical hyperthyroidism
亚临床甲状腺功能亢进症

Roughly between a third and a quarter of patients with subclinical hyperthyroidism have a serum TSH less than 0·1 mU/L, which is regarded as more severe subclinical hyperthyroidism.86, 108 In patients with serum TSH between 0·1 mU/L and 0·4 mU/L (mild subclinical hyperthyroidism), TSH concentrations normalise during follow-up in 20–30% of individuals over 4·5–5 years. In patients with a TSH concentration less than 0·1 mU/L, thyroid dysfunction usually persists or progresses to overt hyperthyroidism.109, 110 In addition to the risk of developing overt hyperthyroidism, older patients with subclinical hyperthyroidism have increased risks of cardiovascular disease (atrial fibrillation, heart failure, coronary heart disease, and stroke), bone loss, fractures, and dementia.¹ This risk has led to clinical practice recommendations to treat severe and possibly mild subclinical hyperthyroidism in people older than 65 years, despite little high-quality evidence of therapeutic benefits. When treatment is started, the goal is to normalise serum TSH concentrations.86, 108 Similar to overt hyperthyroidism, treatment depends on the underlying condition, comorbidities, and patient preference.
大约三分之一到四分之一的亚临床甲状腺功能亢进症患者的血清 TSH 低于 0·1 mU/L，这被认为是更严重的亚临床甲状腺功能亢进症 。86， 108 在血清 TSH 在 0·1 mU/L 和 0·4 mU/L 之间（轻度亚临床甲状腺功能亢进症）的患者中，20-30% 的个体在 4·5-5 年的随访期间 TSH 浓度恢复正常。在 TSH 浓度低于 0·1 mU/L 的患者中， 甲状腺功能障碍通常会持续存在或发展为明显的甲状腺功能亢进症。109， 110 除了发生显性甲状腺功能亢进症的风险外，患有亚临床甲状腺功能亢进症的老年患者患心血管疾病（心房颤动、心力衰竭、 冠心病和中风）、 骨质流失 、骨折和痴呆的风险增加。¹ 这种风险导致临床实践建议治疗 65 岁以上人群的严重和可能轻度的亚临床甲状腺功能亢进症，尽管几乎没有高质量的治疗益处证据。治疗开始时，目标是使血清 TSH 浓度恢复正常。86， 108 与显性甲状腺功能亢进症类似，治疗取决于基础疾病、合并症和患者意愿。

Hyperthyroidism in pregnancy
妊娠期甲状腺功能亢进症

During a normal pregnancy, pronounced changes in thyroid physiology occur. The pregnancy hormone human chorionic gonadotropin (hCG, which is a weak agonist of the TSH receptor), stimulates thyroid hormone secretion leading to higher circulating T4 concentrations and a concomitant decrease in serum TSH. Therefore, pregnancy-specific TSH reference ranges are required to diagnose thyroid dysfunction in pregnant women.⁷⁵ Gestational hyperthyroidism due to very high concentrations of hCG occurs in about 1–3% of pregnancies; it is usually transient and does not require treatment.¹¹¹ In about half of cases, gestational hyperthyroidism is associated with hyperemesis gravidarum. De-novo pathological hyperthyroidism during pregnancy (mainly due to Graves' disease and toxic nodules) is much less common, with a frequency of about 0·2%.¹¹²
在正常怀孕期间，甲状腺生理机能发生明显变化。妊娠激素人绒毛膜促性腺激素 （hCG，它是 TSH 受体的弱激动剂） 刺激甲状腺激素分泌 ，导致循环 T4 浓度升高，同时血清 TSH 降低。因此，需要妊娠特异性 TSH 参考范围来诊断孕妇的甲状腺功能障碍。⁷⁵ 由于非常高浓度的 hCG 导致的妊娠期甲状腺功能亢进症发生在大约 1-3% 的怀孕中;它通常是短暂的，不需要治疗。¹¹¹ 在大约一半的病例中，妊娠甲状腺功能亢进症与妊娠剧吐有关。妊娠期新发病理性甲状腺功能亢进症（主要是由于 Graves 病和毒性结节）不太常见，频率约为 0·2%。¹¹² 元

Overt hyperthyroidism during pregnancy is associated with adverse pregnancy and neonatal outcomes, including increased risk of miscarriage, stillbirth, pre-eclampsia, pre-term birth, and low birthweight.¹¹¹ Most published studies do not have data for treatment, but available evidence suggests that cautious treatment of hyperthyroidism during pregnancy improves outcomes,¹¹³ and that women who receive adequate antenatal care do not have increased risks.¹¹⁴ Excessive maternal thyroid hormones could affect fetal development,¹¹⁵ and overt hyperthyroidism during pregnancy should be treated. However, antithyroid drug treatment in early pregnancy, especially in weeks 5–11, carries a small risk of teratogenic side-effects with differences in pattern and severity generally in favour of propylthiouracil over carbimazole and methimazole.¹¹⁶ Ideally, women with hyperthyroidism planning pregnancy would receive definitive therapy before pregnancy. In case of de-novo pathological hyperthyroidism during pregnancy, the lowest effective dose of antithyroid drug should be used (as monotherapy rather than so-called block and replace), with frequent monitoring of mother and fetus, and propylthiouracil preferred to carbimazole and methimazole during the first trimester. A more detailed discussion on the treatment of hyperthyroidism in pregnancy is available elsewhere.36, 111
妊娠期显性甲状腺功能亢进与不良妊娠和新生儿结局相关，包括流产、 死产 、先兆子痫、早产和低出生体重的风险增加。¹¹¹ 大多数已发表的研究没有治疗数据，但现有证据表明，怀孕期间谨慎治疗甲状腺功能亢进症可改善结局，¹¹³ 并且接受适当产前保健的妇女不会增加风险。¹¹⁴ 母体甲状腺激素过多会影响胎儿发育 ，¹¹⁵ 怀孕期间明显的甲状腺功能亢进症应予以治疗。然而， 妊娠早期的抗甲状腺药物治疗 ，尤其是第 5-11 周的抗甲状腺药物治疗，具有较小的致畸副作用风险，模式和严重程度的差异通常有利于丙硫氧嘧啶而不是卡比马唑和甲巯咪唑 。¹¹⁶ 理想情况下，计划怀孕的甲状腺功能亢进症妇女会在怀孕前接受确定性治疗。在妊娠期间新发病理性甲状腺功能亢进症的情况下，应使用最低有效剂量的抗甲状腺药物（作为单一疗法而不是所谓的阻断和替代疗法），并经常监测母亲和胎儿，丙硫氧嘧啶优于卡比马唑和甲巯咪唑在妊娠早期。关于妊娠期甲状腺功能亢进症治疗的更详细讨论详见其他专题。36、111 元

Thyroiditis  甲状腺炎

Thyrotoxicosis caused by thyroiditis is usually transient and self-limiting, regardless of cause, and often no treatment is required. β blockers provide symptomatic relief, but antithyroid drugs are ineffective and not indicated. For subacute painful thyroiditis, first-line treatment is a non-steroidal anti-inflammatory drug (NSAID), with glucocorticoid treatment used if symptoms are severe or the patient does not respond to NSAID. Prednisolone or prednisone 30–40 mg daily for 1–2 weeks followed by dose tapering is widely used,86, 117 although lower initial doses (15–20 mg) can be effective.117, 118
甲状腺炎引起的甲状腺毒症通常是一过性的和自限性的，与病因无关，通常不需要治疗。β阻滞剂可缓解症状，但抗甲状腺药物无效且无需使用。对于亚急性疼痛性甲状腺炎，一线治疗是非甾体抗炎药 （NSAID），如果症状严重或患者对 NSAID 无反应，则使用糖皮质激素治疗。泼尼松龙或泼尼松每天 30-40 毫克，持续 1-2 周，然后逐渐减少剂量，86,117 尽管较低的初始剂量（15-20 毫克）可能有效。117、118 元

Thyrotoxicosis is often followed by hypothyroidism, which can be transient or permanent. In subacute thyroiditis, most patients recover normal thyroid function, whereas in lymphocytic thyroiditis (including post partum), hypothyroidism can be long lasting (eg, 6–12 months) or permanent in 10–40% of cases.³⁵ Levothyroxine replacement is indicated if hypothyroidism is severe or symptomatic, with consideration of a trial of withdrawal of therapy after 6–12 months. Thyroiditis caused by checkpoint inhibitor immunotherapy is followed by permanent hypothyroidism in most cases.44, 119
甲状腺毒症之后通常伴有甲状腺功能减退症，这可能是短暂的或永久性的。在亚急性甲状腺炎中，大多数患者的甲状腺功能恢复正常 ，而在淋巴细胞性甲状腺炎 （包括产后）中，甲状腺功能减退症可以是长期的（例如，6-12 个月）或 10-40% 的病例是永久性的。³⁵ 如果甲状腺功能减退症严重或有症状，则需替代左旋甲状腺素 ，并考虑在 6-12 个月后尝试停止治疗。大多数病例中，由检查点抑制剂免疫疗法引起的甲状腺炎后会出现永久性甲状腺功能减退症。44、119 元

Iodine-induced hyperthyroidism
碘诱导的甲状腺功能亢进症

Excessive iodine intake can cause hyperthyroidism. It occurs mainly in patients with pre-existing thyroid disease (autonomous thyroid nodules or latent Graves' disease) as a result of the Jod-Basedow phenomenon (thyroid hormone hypersecretion in response to excess iodine substrate), but can occur in individuals with no evidence of underlying thyroid disease. Nowadays, iodine-induced hyperthyroidism occurs most often after exposure to iodinated radiographic contrast¹²⁰ or treatment with the iodine-containing antiarrhythmic drug amiodarone, but it has also been described after ingestion of kelp, high-dose iodine supplements, topical disinfectant use, and food contamination. Amiodarone-induced thyrotoxicosis can be due to the Jod-Basedow phenomenon, called type 1 amiodarone-induced thyrotoxicosis, but more commonly it is due to drug-induced thyroiditis, termed type 2 amiodarone-induced thyrotoxicosis.¹²¹ Typically, type 1 amiodarone-induced thyrotoxicosis presents after only a few months to 1 year of therapy in previously euthyroid patients who have thyroid nodules or latent Graves' disease. By contrast, type 2 amiodarone-induced thyrotoxicosis usually develops several years after drug therapy was initiated. It is characterised clinically by a non-tender, non-enlarged thyroid gland, with absence of thyroid nodules or evidence of thyroid autoimmunity, and low parenchymal blood flow on thyroid sonography. It can be difficult to distinguish between the two types on clinical grounds, and both forms can coexist.
过量摄入碘会导致甲状腺功能亢进症。它主要发生在由于 Jod-Basedow 现象（甲状腺激素分泌过多对过量的碘底物做出反应）而患有甲状腺疾病（自主甲状腺结节或潜伏性 Graves 病）的患者中，但也可能发生在没有潜在甲状腺疾病证据的个体中。如今，碘诱导的甲状腺功能亢进症最常发生在暴露于碘放射造影剂 ¹²⁰ 或用含碘的抗心律失常药物胺碘酮治疗后，但也描述了在摄入海带 、高剂量碘补充剂、局部使用消毒剂和食物污染后。胺碘酮诱导的甲状腺毒症可能是由于 Jod-Basedow 现象引起的，称为 1 型胺碘酮诱导的甲状腺毒症，但更常见的是由于药物诱导的甲状腺炎，称为 2 型胺碘酮诱导的甲状腺毒症。¹²¹ 通常，1 型胺碘酮诱导的甲状腺毒症在治疗几个月到 1 年后出现，见于既往甲状腺功能正常且患有甲状腺结节或潜伏性 Graves 病的患者。相比之下，2 型胺碘酮诱导的甲状腺毒症通常在药物治疗开始数年后发生。其临床特征为甲状腺无触痛、不肿大，无甲状腺结节或甲状腺自身免疫证据，甲状腺超声显示实质血流低。根据临床原因可能很难区分这两种类型，两种形式可以共存。

Type 1 amiodarone-induced thyrotoxicosis is treated with high doses of antithyroid drugs but thyroidectomy might be necessary in patients who do not adequately respond. Radioactive iodine treatment is usually not feasible because of the high intrathyroidal concentrations of iodine from the amiodarone, which has a half-life of 100 days.¹²¹ As with any thyroiditis, type 2 amiodarone-induced thyrotoxicosis resolves over time, and ultimately can result in transient or permanent hypothyroidism. However, its presentation can be very severe and often requires glucocorticoid therapy for several months.¹²¹ Discontinuation of amiodarone can hasten recovery from both types of amiodarone-induced thyrotoxicosis, but is not always possible because of the underlying cardiac condition.¹²² Since amiodarone is generally used in patients with severe cardiovascular disease or tachyarrhythmias, or both, amiodarone-induced thyrotoxicosis is associated with high mortality, especially in patients with underlying left ventricular dysfunction.¹²³
1 型胺碘酮诱导的甲状腺毒症用大剂量的抗甲状腺药物治疗，但对于反应不充分的患者，可能需要进行甲状腺切除术 。 放射性碘治疗通常是不可行的，因为胺碘酮的甲状腺内碘浓度很高，其半衰期为 100 天。¹²¹ 与任何甲状腺炎一样，2 型胺碘酮诱导的甲状腺毒症会随着时间的推移而消退，最终可导致短暂或永久性甲状腺功能减退症。然而，其表现可能非常严重，通常需要糖皮质激素治疗数月。¹²¹ 停用胺碘酮可以加速两种类型的胺碘酮诱导的甲状腺毒症的恢复，但由于潜在的心脏疾病，并不总是可能的。¹²² 由于胺碘酮通常用于严重心血管疾病或快速性心律失常或两者兼而有之的患者，胺碘酮诱导的甲状腺毒症与高死亡率相关，尤其是在有潜在左心室功能障碍的患者中。¹²³ 元

Future directions  未来方向

Therapeutic options for Graves' disease have remained much the same over the past 80 years. Despite improvements in delivery and safety, current treatment methods have important limitations, particularly high relapse rates after withdrawal of antithyroid drugs and hypothyroidism after radioactive iodine therapy or surgery. In the past decade, novel potential treatments for Graves' disease have emerged with different mechanisms of action: restoration of immune tolerance (immunomodulatory TSHR peptides), counteracting TSH-receptor signalling (TRAb blockers, small molecular TSHR antagonists), modulating B-cell function and activation (rituximab, iscalimab, belimumab), and inhibition of IgG recycling by neonatal Fc receptor blockade (rozanolixizumab, efgartigimod).124, 125 Published clinical studies with these treatments are small and include mainly open-label phase 1 and 2 studies.¹²⁶ Findings from large, randomised multicentre trials are awaited to confirm these promising but preliminary results.
在过去的 80 年里，格雷夫斯病的治疗选择一直基本保持不变。尽管在输送和安全性方面有所改善，但目前的治疗方法存在重大局限性，特别是抗甲状腺药物停药后的高复发率和放射性碘治疗或手术后的甲状腺功能减退症。在过去十年中，出现了 Graves 病的新型潜在治疗方法，具有不同的作用机制：恢复免疫耐受（免疫调节 TSHR 肽）、对抗 TSH 受体信号传导（TRAb 阻滞剂、小分子 TSHR 拮抗剂）、调节 B 细胞功能和激活（利妥昔单抗、伊斯卡利单抗、贝利尤单抗）以及通过新生儿 Fc 受体阻断抑制 IgG 再循环（rozanolixizumab、efgartigimod）。124， 125 已发表的关于这些治疗的临床研究规模较小，主要包括开放标签的 1 期和 2 期研究。¹²⁶ 大型随机多中心试验的结果正在等待证实这些有希望的初步结果。

Long-term treatment with a low-dose antithyroid drug is a feasible strategy to control hyperthyroidism and avoid relapse, and seems to be safe and effective in both Graves' disease and toxic nodular goitre.¹²⁷ In view of upcoming novel immunomodulating and other targeted drugs, long-term low-dose antithyroid drugs might become an appealing option in Graves' disease, while awaiting the future availability of these therapies.
长期使用低剂量抗甲状腺药物治疗是控制甲状腺功能亢进和避免复发的可行策略，并且似乎对 Graves 病和毒性结节性甲状腺肿都是安全有效的。¹²⁷ 鉴于即将到来的新型免疫调节和其他靶向药物，长期低剂量抗甲状腺药物可能成为 Graves 病的一个有吸引力的选择，同时等待这些疗法的未来可用性。

When choosing drug therapy, current guidelines advise a course of antithyroid drugs for 12–18 months in patients with Graves' disease.78, 86 However, although an initial treatment course of 12–18 months is reasonable in patients who respond quickly to treatment and who seem likely to achieve remission, studies suggest opportunities for a more individualised approach.⁸⁴ In patients with a low chance of remission upfront (eg, those who smoke or have high TRAb titres) or those for whom a relapse would be detrimental because of underlying other abnormalities (eg, patients with heart disease), providing definitive therapy or starting long-term antithyroid drug therapy from the outset might be more appropriate. Evidence suggests an increase in remission rate with every additional year of antithyroid drug therapy.87, 128
在选择药物治疗时，目前的指南建议 Graves 病患者服用 12-18 个月的抗甲状腺药物。78， 86 然而，尽管 12-18 个月的初始疗程对于对治疗反应迅速且似乎有可能达到缓解的患者来说是合理的，但研究表明有机会采用更个体化的方法。⁸⁴ 对于前期缓解机会低的患者（例如，吸烟或具有高 TRAb 滴度的患者）或由于潜在的其他异常而对复发有害的患者（例如，心脏病患者），提供确定性治疗或从一开始就开始长期抗甲状腺药物治疗可能更合适。有证据表明，抗甲状腺药物治疗每增加一年， 缓解率就会增加。87、128 元

Achieving and maintaining euthyroidism or inducing and treating hypothyroidism appear to reverse the mortality excess seen in hyperthyroidism.¹²⁹ In particular, hypothyroidism induced by radioactive iodine followed by T4 replacement reverses the increased risk of cardiovascular disease and total mortality.57, 102, 130 However, achieving euthyroidism with antithyroid drugs does not necessarily reverse the increased mortality risk,¹³¹ probably because patients are not always euthyroid while receiving antithyroid drugs and might relapse when treatment is stopped.¹⁰² The effect of long-term treatment with low-dose antithyroid drugs on risk of cardiovascular disease and mortality is yet unknown, but could be more favourable than shorter or repeated courses.
实现并维持甲状腺功能正常或诱导和治疗甲状腺功能减退似乎可以逆转甲状腺功能亢进症中的死亡率过高 。¹²⁹ 特别是，放射性碘后 T4 替代治疗诱发的甲状腺功能减退症可逆转心血管疾病和总死亡率增加的风险。57， 102， 130 然而，使用抗甲状腺药物实现甲状腺功能正常不一定能逆转增加的死亡风险，¹³¹ 可能是因为患者在接受抗甲状腺药物时并不总是甲状腺功能正常，并且在停止治疗时可能会复发。¹⁰² 长期使用低剂量抗甲状腺药物治疗对心血管疾病风险和死亡率的影响尚不清楚，但可能比较短或重复的疗程更有利。

In some patients with autonomous benign thyroid nodules, radiofrequency ablation might be an alternative to current strategies. Findings from two single-centre studies investigating radiofrequency ablation with a moving-shot technique showed normalisation of TSH in at least half of patients with a low complication rate and improvement of local cervical discomfort.132, 133 In one study a second radiofrequency ablation led to a normalisation of TSH in four of five patients.¹³³
在一些自主性良性甲状腺结节患者中， 射频消融术可能是当前策略的替代方法。两项调查移动射击技术射频消融术的单中心研究结果显示，至少有一半患者的 TSH 恢复正常，并发症发生率低，局部宫颈不适得到改善。132， 133 在一项研究中，第二次射频消融导致 5 名患者中有 4 名的 TSH 恢复正常。¹³³ 元

Patients frequently inquire about the role of dietary supplements (eg, vitamin D, selenium, and omega 3 fatty acids) for prevention or treatment of Graves' disease. Although several supplements have been investigated, data are conflicting.¹³⁴ The addition of dietary supplements or traditional medicine to current strategies to enhance efficacy or increase safety has also been studied. A meta-analysis of 17 randomised controlled trials with 1536 participants showed that tripterygium glycosides could enhance the effect of methimazole and prednisone in treatment of hyperthyroidism, without increasing side-effects.¹³⁵ A network meta-analysis showed combination of several regimens (including iodine, cholestyramine, and immunosuppressants) with methimazole to be efficacious in reducing free T3 and T4 values.¹³⁶ Two meta-analyses have been published in the same year comparing radioactive iodine with lithium to radioactive iodine alone for treatment of hyperthyroidism, but data for the effectiveness of lithium as an adjunct to radioactive iodine are inconclusive.137, 138
患者经常询问膳食补充剂（如维生素 D、硒和 omega 3 脂肪酸）对预防或治疗 Graves 病的作用。尽管已经研究了几种补充剂，但数据是相互矛盾的。¹³⁴ 还研究了在当前策略中增加膳食补充剂或传统医学以提高疗效或增加安全性。一项对 17 项随机对照试验 （涉及 1536 名参与者）的荟萃分析表明， 雷公藤糖苷可以增强甲巯咪唑和泼尼松治疗甲状腺功能亢进的效果，而不会增加副作用。¹³⁵ 一项网状荟萃分析显示，几种方案（包括碘、 考来烯胺和免疫抑制剂）与甲巯咪唑联合使用可有效降低游离 T3 和 T4 值。¹³⁶ 同年发表了两项荟萃分析，比较了放射性碘加锂与单独放射性碘治疗甲状腺功能亢进症，但锂作为放射性碘辅助治疗的有效性的数据尚无定论。137、138 元

Finally, in older patients, subclinical hyperthyroidism is more prevalent than overt hyperthyroidism. Since several individual participant meta-analyses of observational studies have shown that patients with subclinical hyperthyroidism have an increased risk of hip and other fractures, osteoporosis, cardiovascular events, and mortality, guidelines recommend treatment of subclinical hyperthyroidism with a serum TSH concentration less than 0·1 mU/L, independent of the presence of symptoms, particularly in elderly patients.1, 108 Although there is no consensus regarding treatment for patients with mild subclinical hyperthyroidism (serum TSH 0·1–0·4 mU/L), a randomised controlled trial investigating this question seems to be unlikely in the near future.
最后，在老年患者中，亚临床甲状腺功能亢进症比显性甲状腺功能亢进症更普遍。由于观察性研究的几项个体参与者荟萃分析表明，亚临床甲状腺功能亢进症患者发生髋部和其他骨折、骨质疏松症、心血管事件和死亡的风险增加，因此指南推荐治疗血清 TSH 浓度低于 0·1 mU/L 的亚临床甲状腺功能亢进症，与症状的存在无关，尤其是在老年患者中。1， 108 尽管对于轻度亚临床甲状腺功能亢进症 （血清 TSH 0·1–0·4 mU/L） 患者的治疗尚未达成共识，但调查此问题的随机对照试验似乎不太可能在不久的将来进行。