Hyperthyroidism

A Review

Sun Y Lee ¹, Elizabeth N Pearce ¹

Abstract  抽象

Importance:  重要性：

Overt hyperthyroidism, defined as suppressed thyrotropin (TSH) and high triiodothyronine (T3) and/or free thyroxine (FT4) levels, affects approximately 0.2-1.4% of people worldwide. Subclinical hyperthyroidism, defined as low TSH and normal T3 and FT4 levels, affects approximately 0.7-1.4% of people worldwide. Untreated hyperthyroidism can cause cardiac arrhythmias, heart failure, osteoporosis, adverse pregnancy outcomes, and metabolic abnormalities leading to unintentional weight loss, and is associated with increased mortality.
显性甲状腺功能亢进症，定义为促甲状腺素 （TSH） 抑制和高三碘甲状腺原氨酸 （T3） 和/或游离甲状腺素 （FT4） 水平，影响全球约 0.2-1.4% 的人。亚临床甲状腺功能亢进症，定义为低 TSH 和 T3 和 FT4 水平正常，影响全球约 0.7-1.4% 的人。未经治疗的甲状腺功能亢进症可导致心律失常、心力衰竭、骨质疏松症、不良妊娠结局和代谢异常，导致意外体重减轻，并与死亡率增加有关。

Observations:  观察：

The most common cause of hyperthyroidism is Graves’ disease, with a global prevalence of 2% in women and 0.5% in men. Other causes of hyperthyroidism and thyrotoxicosis include toxic nodules and the thyrotoxic phase of thyroiditis. Common symptoms of thyrotoxicosis include anxiety, insomnia, palpitations, unintentional weight loss, diarrhea, and heat intolerance. Patients with Graves’ disease may have diffusely enlarged thyroid glands, stare, or exophthalmos on exam. Patients with toxic nodules may have symptoms from local compression of structures in the neck by the thyroid gland, such as dysphagia, orthopnea, or voice changes. Etiology can typically be established based on clinical presentation, thyroid function tests, and TSH-receptor antibody status. Thyroid scintigraphy is recommended if thyroid nodules are present, or the etiology is unclear. Thyrotoxicosis from thyroiditis may be observed or treated with supportive care. Treatment options for overt hyperthyroidism from autonomous thyroid nodules or Graves’ disease include antithyroid drugs (ATD), radioactive iodine (RAI) ablation, and surgery. Treatment for subclinical hyperthyroidism is recommended for patients at highest risk for osteoporosis and cardiovascular disease, such as those >60 years or age, or with serum TSH level < 0.1mIU/L on multiple occasions.
甲状腺功能亢进症最常见的原因是格雷夫斯病，全球女性患病率为 2%，男性为 0.5%。甲状腺功能亢进症和甲状腺毒症的其他原因包括毒性结节和甲状腺炎的甲状腺毒症期。甲状腺毒症的常见症状包括焦虑、失眠、心悸、意外体重减轻、腹泻和怕热。Graves 病患者在检查时可能有弥漫性甲状腺肿大、凝视或眼球突出。中毒结节患者可能出现甲状腺局部压迫颈部结构的症状，例如吞咽困难、端坐呼吸或声音改变。通常可以根据临床表现、甲状腺功能检查和 TSH 受体抗体状态来确定病因。如果存在甲状腺结节或病因不明，建议进行甲状腺闪烁显像。甲状腺炎引起的甲状腺毒症可以观察或接受支持性治疗。自主性甲状腺结节或 Graves 病引起的显性甲状腺功能亢进症的治疗选择包括抗甲状腺药物 （ATD）、放射性碘 （RAI） 消融和手术。对于骨质疏松症和心血管疾病风险最高的患者，例如 >60 岁或血清 TSH 水平多次< 0.1mIU/L 的患者，推荐治疗亚临床甲状腺功能亢进症。

Conclusions and Relevance:
结论和相关性：

Hyperthyroidism affects 2.5% of adults worldwide and is associated with osteoporosis, heart disease, and increased mortality. First-line treatments are antithyroid drugs, thyroid surgery, and RAI treatment. Treatment choices should be individualized and patient-centered.
甲状腺功能亢进症影响全球 2.5% 的成年人，与骨质疏松症、心脏病和死亡率增加有关。一线治疗是抗甲状腺药物、甲状腺手术和 RAI 治疗。治疗选择应个体化且以患者为中心。

Introduction  介绍

The global prevalence of hyperthyroidism in iodine-sufficient countries is estimated at 0.2-2.5%.¹ The prevalence of overt hyperthyroidism, defined as low thyroid stimulating hormone [TSH] with elevated triiodothyronine [T3] and/or free thyroxine [T4], is approximately 0.2-1.4%. The prevalence of subclinical hyperthyroidism, defined as low TSH with normal peripheral thyroid hormone, is approximately 0.7-1.4%.^1,2 Thyrotoxicosis refers to all conditions in which thyroid hormone levels are elevated, regardless of underlying mechanism.³ Thyrotoxicosis may occur due to hyperthyroidism from increased thyroid hormone production, release of preformed hormones from the thyroid gland due to inflammation, or extrathyroidal thyroid hormone availability due to excess T4 repletion, surreptitious thyroid hormone ingestion, or struma ovarii. Struma ovarii is a type of dermoid tumor of the ovary, in which thyroid tissue is the predominant component of the tumor. Untreated hyperthyroidism can cause cardiac arrhythmias, congestive heart failure, osteoporosis, adverse obstetric outcomes, and metabolic derangements such as increased resting energy expenditure and gluconeogenesis.³
在碘充足的国家，甲状腺功能亢进症的全球患病率估计为 0.2-2.5%。¹ 显性甲状腺功能亢进症的患病率约为 0.2-1.4%，定义为促甲状腺激素 [TSH] 水平低伴三碘甲状腺原氨酸 [T3] 和/或游离甲状腺素 [T4] 升高。亚临床甲状腺功能亢进症（定义为低 TSH 但外周甲状腺激素正常）的患病率约为 0.7-1.4%。^1,2 甲状腺毒症是指甲状腺激素水平升高的所有情况，无论潜在机制如何。³ 甲状腺毒症可能是由于甲状腺激素分泌增加、炎症导致甲状腺释放预先形成的激素或由于 T4 过度填充、秘密摄入甲状腺激素或卵巢口炎导致甲状腺激素外可用性引起的甲状腺功能亢进。Struma ovarii 是一种卵巢皮样肿瘤，其中甲状腺组织是肿瘤的主要成分。未经治疗的甲状腺功能亢进症可导致心律失常、充血性心力衰竭、骨质疏松症、不良产科结局和代谢紊乱，例如静息能量消耗增加和糖异生。³

This review summarizes current evidence regarding the pathophysiology, clinical presentation, and treatment of hyperthyroidism, focusing on the management of Graves’ disease and toxic nodular disease.
本综述总结了有关甲状腺功能亢进症的病理生理学、临床表现和治疗的当前证据，重点关注 Graves 病和中毒性结节病的管理。

Methods  方法

We searched PubMed for English-language studies published from June 2013 through June 26, 2023, including the most up-to-date information for the terms “thyrotoxicosis and “hyperthyroidism.” We included randomized clinical trials (RCTs), meta-analyses, systematic reviews, and observational studies. Current practice guidelines were also reviewed. We manually searched the references of selected articles, reviews, meta-analyses, and guidelines. 2,185 papers were retrieved from the initial search. Of these, 108 were included for this review (4 randomized clinical trials, 21 systematic review or meta-analyses, 40 longitudinal prospective or retrospective observational studies, 2 cross-sectional studies, and 41 reviews). Articles were selected based on quality of the study design, recency of data, and relevance to general medical practice.
我们在 PubMed 上检索了 2013 年 6 月至 2023 年 6 月 26 日发表的英文研究，包括术语 “甲状腺毒症 和 ”甲状腺功能亢进症“ 的最新信息。我们纳入了随机临床试验 （RCTs）、meta 分析、系统评价和观察性研究。还审查了当前的实践指南。我们手动检索了所选文章、综述、meta 分析和指南的参考文献。从初始检索中检索到 2,185 篇论文。其中，108 项被纳入本综述（4 项随机临床试验、21 项系统评价或荟萃分析、40 项纵向前瞻性或回顾性观察研究、2 项横断面研究和 41 篇综述）。根据研究设计的质量、数据的新近度以及与一般医学实践的相关性来选择文章。

Pathophysiology  病理 生理

Graves disease is an autoimmune disease, in which autoantibodies directed against the thyroidal TSH receptor cause increased thyroid hormone synthesis and secretion. Graves disease is the most common cause of hyperthyroidism in iodine-replete populations, with a prevalence of 2% in women and 0.5% in men (Table 1).^1,4 Thyroid nodules with somatic activating variants in genes that regulate hormone synthesis can autonomously secrete excess thyroid hormone, referred to as toxic nodular disease. Toxic nodular disease, the second most common cause of hyperthyroidism, is more common in iodine-deplete regions, with an incidence ranging from 1.5-18 cases/100,000-person/years worldwide.^1,5,6 In early pregnancy, human chorionic gonadotrophin (hCG) stimulates the thyroidal TSH receptor, causing increased thyroid hormone synthesis. Autoimmunity (postpartum or sporadic painless thyroiditis), infection, some medications, and trauma to the thyroid can cause thyroidal inflammation and release of stored hormones into the bloodstream, causing thyrotoxicosis but not hyperthyroidism, as there is no increase in thyroid hormone synthesis (Table 1). Amiodarone causes two types of thyrotoxicosis (AIT). Type 1 AIT results from increased thyroid hormone synthesis due to the high iodine content of amiodarone acting as excess substrate for thyroid hormone production. Type 2 AIT is a destructive thyroiditis leading to release of preformed thyroid hormone from thyroid gland. As treatments differ for the two types of AIT, it is important to distinguish between them. Immune-checkpoint inhibitors are increasingly used for treatment of certain cancers, such as breast cancer, lung cancer, and melanoma. Among these, anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody and anti-programmed cell death 1 (PD-1) antibody treatment have been associated with multiple immune-related adverse endocrine effects. Thyroid dysfunction is the most common endocrine effect, and both hyperthyroidism and the thyrotoxic phase of thyroiditis have been reported after treatment with these agents.⁷Hyperthyroidism can also be caused by excess exogenous thyroid hormone ingestion. Subclinical hyperthyroidism can result from any of the etiologies that cause overt hyperthyroidism.⁸
Graves 病是一种自身免疫性疾病，其中针对甲状腺 TSH 受体的自身抗体导致甲状腺激素合成和分泌增加。格雷夫斯病是碘丰富人群甲状腺功能亢进症的最常见原因，女性患病率为 2%，男性患病率为 0.5% （ Table 1 ）。^1,4 调节激素合成的基因中具有体细胞激活变异的甲状腺结节可以自主分泌过量的甲状腺激素，称为中毒性结节病。中毒性结节病是甲状腺功能亢进症的第二大常见原因，在碘耗尽地区更为常见，全球发病率为 1.5-18 例/100,000 人/年。^1,5,6 在妊娠早期，人绒毛膜促性腺激素 （hCG） 刺激甲状腺 TSH 受体，导致甲状腺激素合成增加。自身免疫性（产后或散发性无痛性甲状腺炎）、感染、某些药物和甲状腺外伤可导致甲状腺炎症和储存的激素释放到血液中，导致甲状腺毒症而不是甲状腺功能亢进症，因为甲状腺激素合成没有增加（ Table 1 ）。胺碘酮可引起两种类型的甲状腺毒症 （AIT）。1 型 AIT 是由于胺碘酮的高碘含量作为甲状腺激素产生的过量底物，导致甲状腺激素合成增加。2 型 AIT 是一种破坏性甲状腺炎，导致甲状腺释放预先形成的甲状腺激素。由于两种 AIT 的治疗方法不同，因此区分它们很重要。免疫检查点抑制剂越来越多地用于治疗某些癌症，例如乳腺癌、肺癌和黑色素瘤。 其中，抗细胞毒性 T 淋巴细胞抗原 4 （CTLA-4） 抗体和抗程序性细胞死亡 1 （PD-1） 抗体治疗与多种免疫相关不良内分泌作用有关。甲状腺功能障碍是最常见的内分泌作用，用这些药物治疗后甲状腺功能亢进症和甲状腺炎的甲状腺毒症期都有报道。⁷ 甲状腺功能亢进症也可由过量摄入外源性甲状腺激素引起。亚临床甲状腺功能亢进症可由任何引起显性甲状腺功能亢进症的病因引起。⁸

Clinical Presentation  临床表现

Clinical manifestations of thyrotoxicosis include anxiety, insomnia,⁹ palpitations,¹⁰ weight loss from increased metabolism and energy expenditure, diarrhea or loose stools, excessive sweating, heat intolerance, and irregular menses.¹¹ Approximately 2% of older people with hyperthyroidism present with “apathetic” hyperthyroidism with minimal symptoms.^3,12 Patients with Graves’ disease or toxic nodules may report increased neck size or compressive symptoms from the enlarged thyroid gland, such as dysphagia, orthopnea, or voice changes. Thyroid pain and tenderness are present in subacute thyroiditis, which is often preceded by a viral upper respiratory infection. Subclinical hyperthyroidism is usually asymptomatic or causes symptoms similar to but milder than those of overt hyperthyroidism.
甲状腺毒症的临床表现包括焦虑、失眠、⁹ 心悸、¹⁰ 新陈代谢和能量消耗增加导致体重减轻、腹泻或稀便、出汗过多、怕热和月经不调。¹¹ 大约 2% 的老年甲状腺功能亢进症患者表现为“冷漠性”甲状腺功能亢进症，症状轻微。^3,12 患有 Graves 病或毒性结节的患者可能报告颈部增大或甲状腺肿大引起的压迫症状，例如吞咽困难、端坐呼吸或声音改变。甲状腺疼痛和压痛见于亚急性甲状腺炎，亚急性甲状腺炎通常先于病毒性上呼吸道感染。亚临床甲状腺功能亢进症通常无症状或引起的症状与显性甲状腺功能亢进症相似但较轻。

COVID-19 and hyperthyroidism
COVID-19 和甲状腺功能亢进症

During the SARS-CoV2 (COVID) pandemic, cases of Graves’ disease and subacute thyroiditis related to COVID infection or vaccination were reported, presumably due to the immunogenic nature of COVID.^13,14,15 A retrospective study reported a two-fold increase in the incidence of Graves’ disease in a Spanish hospital in 2020-2021 compared to the pre-COVID period of 2017-2019.¹⁶
在 SARS-CoV2 （COVID） 大流行期间，报告了与 COVID 感染或疫苗接种相关的格雷夫斯病和亚急性甲状腺炎病例，这可能是由于 COVID 的免疫原性。^13、14、15 一项回顾性研究报告称，与 2017-2019 年 COVID 之前的 2017-2019 年相比，2020-2021 年西班牙医院的格雷夫斯病发病率增加了两倍。¹⁶

Assessment and Diagnosis
评估和诊断

Physical Examination  体检

Physical examination findings may vary depending on circulating thyroid hormone levels, hyperthyroidism duration, and the underlying etiology. All causes of thyrotoxicosis may cause tachycardia, systolic hypertension, a stare, lid lag (when the upper lid remains elevated on downward gaze due to activation of sympathetic tone), tremor, and proximal muscle weakness. Other signs are specific to disease etiology. Thyroid nodules (autonomous nodules) or a diffusely enlarged thyroid gland, sometimes with a bruit (Graves’ disease), may be palpable. The most common extrathyroidal Graves’ disease manifestation is orbitopathy, occurring in up to 25% of patients with Graves’ disease. This presents as conjunctival erythema, periorbital edema, lid retraction, and proptosis. Other extrathyroidal Graves’ disease manifestations include pretibial myxedema (pink or purple indurated papules, sometimes with accompanying lymphedema and elephantiasis on the anterior lower leg), which occurs in about 1.5% of patients with Graves disease, and acropachy (swelling in digits and nail clubbing) which occurs in about 0.3% of patients with Graves disease.¹⁷
体格检查结果可能因循环甲状腺激素水平、甲状腺功能亢进持续时间和潜在病因而异。甲状腺毒症的所有原因都可能导致心动过速、收缩期高血压、凝视、眼睑滞后（由于交感神经张力的激活，上眼睑向下凝视时保持抬高）、震颤和近端肌无力。其他体征是疾病病因特异性的。可触及甲状腺结节（自主结节）或弥漫性肿大的甲状腺，有时伴有杂音（Graves 病）。甲状腺外 Graves 病最常见的表现是眼眶病，发生在高达 25% 的 Graves 病患者中。表现为结膜红斑、眶周水肿、眼睑回缩和眼球突出。甲状腺外 Graves 病的其他表现包括胫前粘液性水肿（粉红色或紫色硬化丘疹，有时伴有淋巴水肿和小腿前象皮病），见于约 1.5% 的 Graves 病患者，以及见于约 0.3% 的 Graves 病患者。¹⁷

Laboratory Testing  实验室测试

Low serum TSH is the best test to detect thyroid dysfunction, and it has the highest sensitivity (92-95%) and specificity (89-85%) for the diagnosis of thyroid dysfunction.¹⁸ Thyroid hormone may circulate as T3 or as T4, a prohormone which is converted to T3 in peripheral tissues. T3 is the physiologically active form of thyroid hormone. Free T4 levels can be used to assess the degree of hyperthyroidism. T3 levels can also help establish the cause and severity of thyrotoxicosis. The total T3:T4 ratio is generally >20:1 in Graves’ disease or toxic nodules, but <20:1 in thyroiditis.³ Currently available free T3 assays are not accurate and thus total T3 levels may be preferred.³
低血清 TSH 是检测甲状腺功能障碍的最佳检测方法，对甲状腺功能障碍的诊断具有最高的敏感性 （92-95%） 和特异性 （89-85%）。¹⁸ 甲状腺激素可能以 T3 或 T4 的形式循环，T4 是一种在外周组织中转化为 T3 的激素原。T3 是甲状腺激素的生理活性形式。游离 T4 水平可用于评估甲状腺功能亢进的程度。T3 水平也有助于确定甲状腺毒症的原因和严重程度。在 Graves 病或毒性结节中，总 T3：T4 比值通常为 >20：1，但在甲状腺炎中为 <20：1。³ 目前可用的游离 T3 检测不准确，因此可能首选总 T3 水平。³

Once thyrotoxicosis is confirmed, the etiology should be ascertained (Figure 1, Table 2). The presence of TSH-receptor antibodies (TRAbs) is pathognomonic for Graves disease.¹⁹ Current guidelines recommend measuring TRAb as the initial step in differentiating Graves’ disease from other causes of thyrotoxicosis.^3,20 Two assay types are available for TRAb measurement.²¹ TRAb binding immunoassays measure both stimulating and blocking antibodies, while functional bioassays assess activity of thyroid stimulating immunoglobulin (TSI). Current 3^rd-generation TRAb assays have a high sensitivity (97.7%) and specificity (99.5%) for the diagnosis of Graves disease.²² Serum TSI concentrations correlate with the degree of extrathyroidal Graves disease manifestations.^19,21
一旦确诊甲状腺毒症，应确定病因 （ Figure 1 ， Table 2 ）。TSH 受体抗体 （TRAb） 的存在是 Graves 病的特异性诊断。¹⁹ 当前指南建议将测量 TRAb 作为区分 Graves 病与其他原因甲状腺毒症的第一步。^3,20 有两种分析类型可用于 TRAb 测量。²¹ TRAb 结合免疫测定法可测量刺激抗体和阻断抗体，而功能性生物测定法可评估促甲状腺免疫球蛋白 （TSI） 的活性。目前的第 3 代 TRAb 检测对 Graves 病的诊断具有高敏感性 （97.7%） 和特异性 （99.5%）。²² 血清 TSI 浓度与甲状腺外 Graves 病表现的程度相关。

Biotin effects on thyroid testing
生物素对甲状腺检测的影响

A false positive diagnosis of hyperthyroidism may occur due to immunoassay interference. Biotin is a soluble vitamin that is commonly used as a supplement for hair and nails. High-dose biotin intake can lead to falsely low serum TSH and high FT4 and T3 levels in immunoassays utilizing biotin-streptavidin interactions.²³ Excess biotin may also cause false positive TRAb results. When the clinical presentation is not consistent with the laboratory findings, a history regarding supplement use should be obtained. If biotin interference is suspected, biotin can be stopped for 2-7 days before repeat testing.
由于免疫测定干扰，可能会出现甲状腺功能亢进症的假阳性诊断。生物素是一种可溶性维生素，通常用作头发和指甲的补充剂。在利用生物素-链霉亲和素相互作用的免疫测定中，高剂量生物素摄入可导致假性低血清 TSH 和高 FT4 和 T3 水平。²³ 过量的生物素也可能导致 TRAb 假阳性结果。当临床表现与实验室检查结果不一致时，应询问补充剂使用史。如果怀疑生物素干扰，可以在重复检测前停用生物素 2-7 天。

Imaging Studies  影像学检查

Thyroid scintigraphy using radioactive iodine (RAI) or technetium is recommended if palpable thyroid nodules are present or if the thyrotoxicosis etiology is unclear after TRAb testing. Thyroid scintigraphy assesses activity of thyroid gland by measuring uptake of iodine or technetium. RAI uptake is diffusely increased in Graves’ disease and focally or heterogeneously increased in toxic adenoma or toxic nodules. RAI uptake is low or absent in thyroiditis, high iodine exposure, or extrathyroidal sources of thyroid hormone. In pregnancy and lactation when scintigraphy is contraindicated, thyroid ultrasound with color flow Doppler can be used. Gland vascularity is generally increased in Graves’ disease, indicating increased gland activity, but low or absent in thyroiditis, in which thyroid gland activity is not increased. A study of tests to diagnose Graves disease found the following sensitivities by test: TRAb: 93%, TSI: 94.2%, thyroid ultrasound demonstrating diffusely increased thyroid vascularity: 92.1%, and thyroid scintigraphy demonstrating diffusely increased thyroid vascularity: 95.3%.²⁴ However, the specificity of thyroid ultrasound for diagnosis of Graves’ disease was only 69.8%.
如果存在可触及的甲状腺结节，或者 TRAb 检测后甲状腺毒症病因不明，建议使用放射性碘 （RAI） 或锝进行甲状腺闪烁显像。甲状腺闪烁显像通过测量碘或锝的摄取来评估甲状腺的活动。RAI 摄取在 Graves 病中弥漫性增加，在毒性腺瘤或毒性结节中局灶性或异质性增加。在甲状腺炎、高碘暴露或甲状腺激素的甲状腺外来源中，RAI 摄取低或不存在。在妊娠和哺乳期，当禁忌闪烁显像时，可使用彩色血流多普勒甲状腺超声检查。Graves 病患者的腺体血管分布通常增加，表明腺体活动增加，但在甲状腺炎中水平较低或不存在，甲状腺活动不会增加。一项关于诊断 Graves 病的检测结果的研究发现，通过检测发现以下敏感性：TRAb：93%，TSI：94.2%，甲状腺超声显示甲状腺血管分布弥漫性增加：92.1%，甲状腺闪烁显像显示甲状腺血管分布弥漫性增加：95.3%。²⁴ 然而，甲状腺超声诊断 Graves 病的特异性仅为 69.8%。

Thyrotoxicosis Treatment
甲状腺毒症治疗

Untreated overt thyrotoxicosis, especially in older individuals, may cause osteoporosis and atrial fibrillation and, rarely, high-output heart failure,¹⁰ from the effect of excess thyroid hormone on the thyroid hormone receptors present in bone and heart. Atrial fibrillation is present in 10-25% of patients with thyrotoxicosis, with higher risks in men and those aged >65 years.¹⁰ Treatment should be patient-centered and individualized, taking into account age, comorbidities, severity of hyperthyroidism, likelihood of remission, plans for pregnancy, available surgical expertise, and patient preferences.²⁵ Treatment choices should be informed by understanding the underlying etiology. In patients with Graves disease, treatment should focus on controlling hyperthyroidism with anticipated eventual remission of Graves disease, while causes of hyperthyroidism due to toxic nodular disease require indefinite treatment if antithyroid drugs are used because this does not remit (Figure 2). Symptomatic patients with all forms of thyrotoxicosis may benefit from initiation of beta blockers, which decreases heart rate and improves hyperadrenergic symptoms,²⁶ but is relatively contraindicated in patients with bronchospastic disease. Beta blockade is typically the only therapy required in thyrotoxicosis due to thyroiditis, as this disorder is self-limited and there is no indication for antithyroid drug therapy in the absence of increased thyroid hormone synthesis.³ Most patients with overt hyperthyroidism from autonomous thyroid nodules or Graves’ disease will require treatment with antithyroid drugs (ATD), radioactive iodine ablation, or surgery. U.S costs, excluding visits and testing, have been estimated as $300-400 for ATDs, $4000-5000 for radioactive iodine, and $30,000-40,000 for surgery.²⁷ However, assessments of the most cost-effective treatment modality have varied in different settings.^28-30 Practice patterns in the U.S. have shifted to prioritize ATD rather than radioactive iodine treatment as the initial treatment modality, which is more in line with practices in other regions.^31,32
未经治疗的显性甲状腺毒症，尤其是老年人，可能会导致骨质疏松症和心房颤动，罕见情况下，由于甲状腺激素过量对骨骼和心脏中存在的甲状腺激素受体的影响，可能会导致高输出量性心力衰竭，¹⁰。心房颤动见于 10-25% 的甲状腺毒症患者，男性和 >65 岁患者的风险更高。¹⁰ 治疗应以患者为中心，个体化，同时考虑到年龄、合并症、甲状腺功能亢进的严重程度、缓解的可能性、怀孕计划、可用的手术专业知识和患者意愿。²⁵ 应通过了解潜在病因来告知治疗选择。在 Graves 病患者中，治疗应侧重于控制甲状腺功能亢进症，并预期 Graves 病最终缓解，而如果使用抗甲状腺药物，则由毒性结节性疾病引起的甲状腺功能亢进症的原因需要无限期治疗，因为这不会缓解 （ Figure 2 ）。患有各种形式甲状腺毒症的有症状患者可能受益于开始使用 β 受体阻滞剂，这种药物可降低心率并改善肾上腺素能亢进症状，²⁶ 但支气管痉挛性疾病患者相对禁忌。β 受体阻滞剂通常是甲状腺炎引起的甲状腺毒症唯一需要的治疗，因为这种疾病是自限性的，在没有甲状腺激素合成增加的情况下，没有抗甲状腺药物治疗的指征。³ 大多数由自主性甲状腺结节或 Graves 病引起的显性甲状腺功能亢进症患者需要抗甲状腺药物 （ATD）、放射性碘消融术或手术治疗。 美国的费用（不包括就诊和检测）估计为 ATD 为 300-400 美元，放射性碘为 4000-5000 美元，手术为 30,000-40,000 美元。²⁷ 然而，对最具成本效益的治疗方式的评估在不同的环境中有所不同。^28-30 岁美国的实践模式已转变为优先考虑 ATD 而不是放射性碘治疗作为初始治疗方式，这与其他地区的做法更一致。

Antithyroid drugs  抗甲状腺药物

Thionamides (methimazole [MMI], carbimazole, which is metabolized to MMI, and propylthiouracil [PTU)) decrease thyroid hormone synthesis and secretion and can restore euthyroidism in patients with hyperthyroidism. MMI is the first-line agent for people who are not within the first trimester of pregnancy. The starting MMI dose for Graves’ disease can be based on severity: 5-10 mg/day for FT4 concentrations 1.0-1.5 times the upper limit of normal, 10-20 mg/day for FT4 1.5-2.0 times the upper limit of normal, and 30-40 mg/day for FT4 2-3 times the upper limit of normal.³ Thyroid function tests should be monitored every 4-8 weeks after treatment initiation, and MMI can often be titrated down to a maintenance dose of 5-10 mg/day as hyperthyroidism improves. High-dose MMI in combination with levothyroxine (a “block and replace” regimen) is not recommended for routine use in Graves’ disease patients, because the high ATD doses required may increase the likelihood of toxicity and a clear benefit has not been established.³³ In patients with autonomous thyroid nodules , MMI dose requirements are typically ≤10 mg/day, and thyroid function tests should be monitored every 3 months at least initially. In both Graves’ disease and toxic nodular disease, thyroid function tests may need to be monitored every 2-4 months, especially after initiation of ATDs, as dose adjustment is frequently needed.
硫烟酰胺类药物（甲巯咪唑 [MMI]、代谢为 MMI 的卡比马唑和丙硫氧嘧啶 [PTU]）可减少甲状腺激素的合成和分泌，并可以恢复甲状腺功能亢进症患者的甲状腺功能正常。MMI 是非怀孕前三个月人群的一线药物。格雷夫斯病的起始 MMI 剂量可以基于严重程度：FT4 浓度为正常上限的 5-10 毫克/天 1.0-1.5，FT4 为 10-20 毫克/天，为正常上限的 1.5-2.0 倍，FT4 为 30-40 毫克/天正常上限的 2-3 倍。³ 治疗开始后应每 4-8 周监测一次甲状腺功能检查，随着甲状腺功能亢进症的改善，MMI 通常可以滴定至 5-10 mg/天的维持剂量。不建议将高剂量 MMI 联合左旋甲状腺素（一种“阻断和替代”方案）用于 Graves 病患者的常规使用，因为所需的高 ATD 剂量可能会增加毒性的可能性，并且尚未确定明确的益处。³³ 在自主性甲状腺结节患者中，MMI 剂量要求通常为 ≤10 毫克/天，至少在最初应每 3 个月监测一次甲状腺功能检查。在 Graves 病和中毒性结节病中，可能需要每 2-4 个月监测一次甲状腺功能检查，尤其是在开始 ATD 后，因为经常需要调整剂量。

For patients with Graves’ disease, ATD treatment can be discontinued after 12-18 months if serum TSH has normalized and the TRAb is no longer positive.³ TRAb titers typically decline over the course of treatment and resolve in 70-80% by 18 months of therapy.³⁴ Overall, reported remission rates (euthyroidism a year following ATD discontinuation) after an initial 12-18 months of ATD therapy are 30-50%,^35-37 although the likelihood is much lower (0-20%) if TRAb remains positive.^3,38 The likelihood of remission may increase with longer duration of ATD treatment, with remission rates up to 80-85% reported in selected patients after >5 years of treatment.^37,39 Individuals <40 years of age, with higher thyroid hormone levels at baseline, with higher baseline TRAb titers, and with larger goiters are less likely to attain remission.^36,40 Hyperthyroidism recurrence is most likely in the first 6 months following ATD discontinuation, especially if the TRAb level remains elevated. In Graves’ disease, patients who do not achieve remission after 12-18 months, or in those whose hyperthyroidism remits and then recurs, definitive therapy with radioactive iodine or thyroidectomy should be considered.³ However, MMI has been shown to be safe and effective for as long as 24 years.^41,42 TRAb titers can be assessed every 1-2 years, and thyroid function testing every 4-6 months, in patients on long-term ATD treatment.³
对于 Graves 病患者，如果血清 TSH 恢复正常且 TRAb 不再阳性，则可以在 12-18 个月后停止 ATD 治疗。³ TRAb 滴度通常在治疗过程中下降，并在治疗 18 个月时在 70-80% 内消退。³⁴ 总体而言，在 ATD 治疗的最初 12-18 个月后，报告的缓解率（ATD 停药后一年的甲状腺功能正常）为 30-50%，^35-37，但如果 TRAb 保持阳性，可能性要低得多 （0-20%）。^3,38ATD 治疗持续时间的延长可能会增加缓解的可能性，据报道，在治疗 >5 年后，特定患者的缓解率高达 80-85%。^37,39 元<40 岁、基线时甲状腺激素水平较高、基线 TRAb 滴度较高且甲状腺肿较大的个体不太可能达到缓解。^36,40 元甲状腺功能亢进症最有可能在 ATD 停药后的前 6 个月内复发，尤其是当 TRAb 水平仍然升高时。在 Graves 病中，12-18 个月后未达到缓解的患者，或甲状腺功能亢进症缓解后复发的患者，应考虑放射性碘或甲状腺切除术的确定性治疗。³ 然而，MMI 已被证明是安全有效的，长达 24 年。^41,42 元对于长期接受 ATD 治疗的患者，可以每 1-2 年评估一次 TRAb 滴度，每 4-6 个月进行一次甲状腺功能检测。³

Patients should be carefully counseled about potential adverse effects of ATDs before treatment initiation. Overall, adverse effects are reported in approximately 13% of patients.⁴³ The most frequent adverse effect is pruritis and/or rash (occurring in 6% on MMI and 3% on PTU), which can typically be managed with antihistamines.^3,43 Successful desensitization protocols have been described for patients with MMI allergy.⁴⁴ Rare side effects include agranulocytosis, which occurs in 0.2-0.5% of patients and most frequently in the first 90 days after treatment initiation.^45,46 Rare cases of fulminant hepatic failure resulting in death or need for liver transplant have been reported with PTU use.⁴⁷ Both ATDs can cause hepatitis, and hepatic injury is reported in approximately 2.7% of patients on PTU and 0.4% on MMI.⁴³ Risk of liver injury is highest in the first 90 days after ATD initiation.⁴⁸ Baseline complete blood count (CBC) and liver function testing (LFT) is recommended prior to initiating ATD treatment, although it is unclear whether there is any benefit of ongoing CBC or LFT monitoring in patients treated with anti-thyroid drugs.³ Uncontrolled hyperthyroidism is also associated with at least one abnormal liver function test in 55% of patients at baseline, with results normalizing in the majority of patients after initiation of ATD treatment, even when baseline transaminases are five times the upper limit of normal.⁴⁹ Antineutrophil cytoplasmic antibody-associated small-vessel vasculitis has been reported in up to 3% of ATD-treated patients, with the risk being three-fold higher with PTU than with MMI and increasing with duration of use.⁵⁰ Pancreatitis is newly listed as an adverse MMI effect in Europe, although data for this are conflicting. The absolute risk over the initial 18 months of therapy appears to be <0.4%.^51,52
在治疗开始前，应仔细告知患者 ATD 的潜在不良反应。 总体而言，约 13% 的患者报告了不良反应。⁴³ 最常见的不良反应是瘙痒和/或皮疹（MMI 组为 6%，PTU 组为 3%），通常可以使用抗组胺药来控制。^3,43 已经描述了 MMI 过敏患者的成功脱敏方案。⁴⁴ 罕见的副作用包括粒细胞缺乏症，发生在 0.2-0.5% 的患者中，最常见于治疗开始后的前 90 天。^45,46 元据报道，使用 PTU 会导致死亡或需要肝移植的罕见暴发性肝衰竭病例。⁴⁷ 两种 ATD 均可引起肝炎，据报道，大约 2.7% 的 PTU 患者和 0.4% 的 MMI 患者出现肝损伤。⁴³ ATD 开始后的前 90 天内肝损伤风险最高。⁴⁸ 建议在开始 ATD 治疗之前进行基线全血细胞计数 （CBC） 和肝功能检测 （LFT），但尚不清楚持续的 CBC 或 LFT 监测是否对接受抗甲状腺药物治疗的患者有任何益处。³ 未控制的甲状腺功能亢进症也与 55% 基线时患者至少一次肝功能检查异常有关，大多数患者在开始 ATD 治疗后结果恢复正常，即使基线转氨酶是正常上限的五倍。⁴⁹ 据报道，高达 3% 的 ATD 治疗患者患有抗中性粒细胞胞浆抗体相关的小血管炎，PTU 的风险是 MMI 的三倍，并且随着使用时间的延长而增加。⁵⁰ 胰腺炎在欧洲被新列为 MMI 不良反应，尽管这方面的数据相互矛盾。 最初 18 个月治疗的绝对风险似乎为 <0.4%。^51,52 元

Radioactive iodine treatment
放射性碘处理

RAI treatment cures hyperthyroidism in more than 90% of patients with Graves’ disease or autonomous thyroid nodules.^32,53 Factors associated with persistent hyperthyroidism after RAI treatment in Graves’ disease include male sex, prior ATD therapy, treatment >6 months after GD diagnosis, elevated FT4 level, larger thyroid volume, and higher RAI uptake.⁵⁴ Beta blockade and pre-treatment MMI are recommended in older patients and those at particularly high risk of cardiovascular events in case of transiently worsening hyperthyroidism following RAI treatment.³ If employed, MMI should be stopped 2-7 days prior to treatment and may be re-started 3-7 days post-therapy.^3,55 The goal of therapy in Graves’ disease is rendering a patient hypothyroid, while in toxic nodular goiter, the goal is merely to alleviate hyperthyroidism. The eventual likelihood of developing hypothyroidism after RAI treatment for autonomous thyroid nodules is dependent on the administered activity but may be up to 60%.^56,57 Following RAI, thyroid function tests should be measured every 4-6 weeks for 6 months, or until the patient has become hypothyroid and is stable on thyroid hormone replacement. If hyperthyroidism persists after 6 months, repeat RAI dosing is recommended.³
RAI 治疗可治愈超过 90% 的 Graves 病或自主甲状腺结节患者的甲状腺功能亢进症。^32,53 元与 Graves 病 RAI 治疗后持续性甲状腺功能亢进相关的因素包括男性、既往 ATD 治疗、GD 诊断后 6 个月治疗 >、FT4 水平升高、甲状腺体积较大和 RAI 摄取增加。⁵⁴ 如果 RAI 治疗后甲状腺功能亢进症一过性恶化，建议老年患者和心血管事件风险特别高的患者使用 β 受体阻滞剂和治疗前 MMI。³ 如果使用，应在治疗前 2-7 天停止 MMI，并可在治疗后 3-7 天重新开始。^3,55Graves 病的治疗目标是使患者甲状腺功能减退，而毒性结节性甲状腺肿的治疗目标只是缓解甲状腺功能亢进。自主甲状腺结节的 RAI 治疗后发生甲状腺功能减退症的最终可能性取决于给药活性，但可能高达 60%。^56,57 元 RAI 后，应每 4-6 周测量一次甲状腺功能检查，持续 6 个月，或直到患者出现甲状腺功能减退且甲状腺激素替代治疗稳定。如果甲状腺功能亢进症在 6 个月后持续存在，建议重复 RAI 给药。³

RAI may cause or exacerbate eye disease in Graves’ patients, particularly in people who smoke cigarettes or in those with very high TRAb titers. To prevent this, pretreatment with prednisone 0.3-0.5 mg/kg/day, tapered over 3 months, should be used in people who smoke cigarettes, those with high TRAb levels, or those with preexisting thyroid eye disease.⁵⁸ Whether or not RAI treatment for hyperthyroidism is associated with increased long-term risk for future malignancies is unclear, with a recent meta-analysis of 12 studies involving 479,452 people with hyperthyroidism showing no significant association of exposure to RAI therapy with cancer risk, compared to nonexposure (59). However, overall, a linear dose-response association was identified between RAI therapy and mortality due to breast cancer and other solid tumor cancers.⁵⁹
RAI 可能导致或加重 Graves 患者的眼病，尤其是吸烟者或 TRAb 滴度非常高的患者。为了防止这种情况，对于吸烟者、TRAb 水平高的人或先前患有甲状腺眼病的人，应使用泼尼松 0.3-0.5 mg/kg/天进行预处理，在 3 个月内逐渐减量。⁵⁸ 甲状腺功能亢进症的 RAI 治疗是否与未来恶性肿瘤的长期风险增加相关尚不清楚，最近对涉及 479,452 名甲状腺功能亢进症患者的 12 项研究的荟萃分析显示，与不暴露相比，暴露于 RAI 治疗与癌症风险没有显着关联 （59）。然而，总体而言，RAI 治疗与乳腺癌和其他实体瘤癌症的死亡率之间存在线性剂量反应关联。⁵⁹ 元

Thyroid Surgery  甲状腺手术

Thyroidectomy is indicated for patients with hyperthyroidism who have local compressive symptoms from a large goiter, suspicious or malignant thyroid nodules, or moderate to severe Graves ophthalmopathy. Thyroidectomy should be the first-line treatment if concurrent thyroid malignancy is confirmed or suspected.³ In patients with Graves disease, total thyroidectomy is associated with a lower risk for recurrent hyperthyroidism than subtotal thyroidectomy and is the preferred operation.^3,60 In individuals with toxic adenoma, thyroid lobectomy may be preferred over RAI when rapid resolution is preferred, for cosmesis, or if there are local compressive symptoms from a large thyroid gland.⁶¹ Total thyroidectomy rapidly cures hyperthyroidism from Graves disease or toxic multinodular goiter but results in a lifelong need for thyroid hormone replacement. Potential surgical complications include damage to the recurrent laryngeal nerves, hematoma, and hypoparathyroidism,⁶² with higher complication rates for surgeons who have performed relatively few procedures, compared to more experienced surgeons (6.4% vs. 4.1%; P <0.0001).⁶³ Pre-treatment with ATD lowers risk for thyroid storm at the time of surgery.⁶¹ Preoperative treatment with high-dose iodine (such as saturated solution of potassium iodide [SSKI] or Lugol’s solution) of Graves’ disease patients decreases thyroid vascularity and thus operative blood loss, although it may not change risks of postoperative complications.⁶⁴ Calcium and/or vitamin D supplementation pre-operatively may decrease risk for postoperative hypocalcemia.⁶⁵
甲状腺切除术适用于甲状腺功能亢进症患者，这些患者因大甲状腺肿、可疑或恶性甲状腺结节或中度至重度 Graves 眼病而出现局部压迫症状。如果确诊或怀疑并发甲状腺恶性肿瘤，应将甲状腺切除术作为一线治疗。³ 在 Graves 病患者中，甲状腺全切除术与甲状腺功能亢进症复发风险相比，是首选手术。^3,60 元对于毒性腺瘤患者，当首选快速消退、美观或甲状腺大出现局部压迫症状时，甲状腺叶切除术可能优于 RAI。⁶¹ 全甲状腺切除术可迅速治愈 Graves 病或毒性多结节性甲状腺肿引起的甲状腺功能亢进症，但会导致终生需要甲状腺激素替代治疗。潜在的手术并发症包括喉返神经损伤、血肿和甲状旁腺功能减退症，⁶² 与更有经验的外科医生相比，手术相对较少的外科医生的并发症发生率更高（6.4% 对 4.1%;P <0.0001）。⁶³ ATD 预处理可降低手术时甲状腺危象的风险。⁶¹ 格雷夫斯病患者的术前使用高剂量碘（如碘化钾饱和溶液 [SSKI] 或 Lugol 溶液）进行治疗可减少甲状腺血管分布，从而减少手术失血，尽管它可能不会改变术后并发症的风险。⁶⁴ 术前补充钙和/或维生素 D 可降低术后低钙血症的风险。⁶⁵

Novel treatments  新疗法

In selected centers, radiofrequency ablation, which induces necrosis of thyroid tissue using heat energy, is a minimally invasive alternative to surgery or radioactive iodine for the treatment of toxic nodules. This procedure reduces nodule volume by 52%-86% and normalizes thyroid function in 61.7% (95% CI: 48.7%-74.7%).⁶⁶ Guidelines recommend restricting this technique to younger patients with small nodules, although it may be considered in those with larger toxic multinodular goiters who are not candidates for surgery or RAI treatment.⁶⁷ Novel Graves’ disease therapies are currently under investigation, including small molecules, biologies, and immunomodulatory peptides with specific effects at the TSH receptor.⁶⁸
在选定的中心，射频消融术利用热能诱导甲状腺组织坏死，是治疗毒性结节的手术或放射性碘的微创替代方法。该程序将结节体积减少 52%-86%，并使 61.7% 的甲状腺功能恢复正常 （95% CI： 48.7%-74.7%）。⁶⁶ 指南建议将这种技术仅限于患有小结节的年轻患者，尽管可以考虑用于那些不适合手术或 RAI 治疗的较大毒性多结节性甲状腺肿患者。⁶⁷ 种新型 Graves 病疗法目前正在研究中，包括小分子、生物学和对 TSH 受体具有特异性作用的免疫调节肽。⁶⁸

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

Subclinical hyperthyroidism may resolve spontaneously and progresses to overt hyperthyroidism in approximately 8% of patients at 1 year, and 26% by 5 year follow-up..⁶⁹ Progression to overt hyperthyroidism is more common in people with undetectable serum TSH at baseline and in those with toxic multinodular goiter.^69,70 Black Americans have lower mean TSH levels compared to White Americans and a slightly low serum TSH level may be normal in Black Americans, compared to White Americans.³ Still, subclinical hyperthyroidism is associated with increased risks of atrial fibrillationheart failure, total mortality, cardiovascular mortality, and coronary heart disease events.^71,72 Cardiovascular mortality and atrial fibrillation risks are increased when the serum TSH is <0.1 mlU/L compared to 0.1-0.44 mIU/L.⁷⁰ Thyroid hormone enhances both osteoblast and osteoclast action, and excess thyroid hormone leads to increased bone resorption.⁷³ Serum TSH ≤0.1mIu/L has been associated with 3-4-fold increased hip and spinal fracture risks, especially in postmenopausal women (Absolute rates not provided).⁷⁴ Subclinical hyperthyroidism has been associated with a 36% increased hip fracture risk, 28% increased risk of any fracture, and 16% increased non-spine fracture risk compared to euthyroidism, as well as low bone density in both men and women.⁷⁵ No placebo-controlled randomized clinical trials have assessed the effects of treatment for subclinical hyperthyroidism. In small and uncontrolled studies, treatment with ATD⁷⁶ and RAI⁷⁷ has been reported to improve stability of bone density in postmenopausal women. A randomized clinical trial comparing the effects of RAI therapy to 60 months’ treatment with ATD in 83 adults with subclinical hyperthyroidism age ≥65 years with baseline serum TSH <0.1 mlU/L found that by the end of the study, 66% of the RAI-treated patients were hypothyroid and 34% remained euthyroid, while 6% ATD-treated patients spontaneously developed hypothyroidism and the other 94% remained euthyroid.⁷⁸ Results of bone density and echocardiography were not different between the treatment groups, there were no treatment-associated significant adverse events, and there was no significant difference in treatment costs.
亚临床甲状腺功能亢进症可能会自发消退，并在 1 年时在大约 8% 的患者中发展为明显的甲状腺功能亢进症，在 5 年随访时为 26%。⁶⁹ 进展为显性甲状腺功能亢进症在基线时血清 TSH 检测不到的人群和毒性多结节性甲状腺肿的人群中更为常见。^69,70 元与美国白人相比，美国黑人的平均 TSH 水平较低，与美国白人相比，美国黑人的血清 TSH 水平略低可能是正常的。³ 尽管如此，亚临床甲状腺功能亢进症与心房颤动心力衰竭、总死亡率、心血管死亡率和冠心病事件的风险增加有关。^71,72 元当血清 TSH 为 <0.1 mlU/L 时，与 0.1-0.44 mIU/L 相比，心血管死亡率和心房颤动风险增加。⁷⁰ 甲状腺激素增强成骨细胞和破骨细胞的作用，过量的甲状腺激素导致骨吸收增加。⁷³ 血清 TSH ≤0.1mIu/L 与髋部和脊柱骨折风险增加 3-4 倍相关，尤其是在绝经后妇女中（未提供绝对比率）。⁷⁴ 与甲状腺功能正常相比，亚临床甲状腺功能亢进症与髋部骨折风险增加 36%、任何骨折风险增加 28% 和非脊柱骨折风险增加 16% 以及男性和女性的低骨密度有关。⁷⁵ 没有安慰剂对照的随机临床试验评估治疗亚临床甲状腺功能亢进症的效果。 在小型和非对照研究中，据报道 ATD⁷⁶ 和 RAI⁷⁷ 治疗可改善绝经后妇女骨密度的稳定性。一项随机临床试验在 83 名年龄为 ≥65 岁且基线血清 TSH <0.1 mlU/L 的亚临床甲状腺功能亢进症成人中比较了 RAI 治疗与 60 个月的 ATD 治疗效果，发现到研究结束时，66% 的 RAI 治疗患者甲状腺功能减退，34% 的患者保持甲状腺功能正常，而 6% 的 ATD 治疗患者自发发展为甲状腺功能减退症，其他 94% 的患者保持甲状腺功能正常。⁷⁸ 治疗组之间骨密度和超声心动图结果无差异，无治疗相关显著不良事件，治疗费用无显著差异。

The U.S. Preventive Services Task Force currently recommends against testing or treatment for subclinical hyperthyroidism.⁷⁹ However, other U.S. and European guidelines recommend treatment for subclinical hyperthyroidism when identified in patients over 65 years of age (or in those ≤65 years old with symptoms, osteoporosis, or heart disease) when the serum TSH is consistently <0.1 mlU/L.^3,80 Therapy can be considered in those groups when the TSH is persistently in the 0.1-0.4 mlU/L range, but it should be avoided in asymptomatic patients age <65 in the absence of osteoporosis or heart disease. It is also important to consider the possibility of exogenous subclinical hyperthyroidism from excess T4 repletion for hypothyroidism or thyrotoxicosis factitia.
美国预防服务工作组 （U.S. Preventive Services Task Force） 目前建议不要对亚临床甲状腺功能亢进症进行检测或治疗。⁷⁹ 然而，其他美国和欧洲指南建议，当血清 TSH 始终为 <0.1 mlU/L 时（或有症状、骨质疏松症或心脏病的 ≤65 岁患者）发现亚临床甲状腺功能亢进症时，可以考虑治疗 TSH 持续在 0.1-0.4 mlU/L 范围内， 但在没有骨质疏松症或心脏病的情况下，年龄 <65 的无症状患者应避免使用。考虑甲状腺功能减退症或人为甲状腺毒症的 T4 过量补充导致外源性亚临床甲状腺功能亢进症的可能性也很重要。

Pregnancy and lactation  怀孕和哺乳期

Gestational transient thyrotoxicosis, in which thyroid hormone production increases because of thyroid stimulation by elevated hCG levels, affects approximately 2-11% of pregnancies and is associated with hyperemesis gravidarum.⁸¹ This condition does not require ATD treatment and it is not associated with adverse obstetric outcomes⁸²; it can simply be monitored with serial thyroid function testing and it resolves spontaneously as maternal hCG levels decline.^83,84 All other forms of overt hyperthyroidism in pregnancy require treatment to reduce risks for outcomes including preeclampsia, low birth weight, miscarriage, and preterm delivery.⁸⁵ Both ATDs are teratogenic, but congenital anomalies are milder and risk lower for PTU than for MMI. PTU-associated anomalies include facial or neck cysts and urinary tract abnormalities, while those associated with MMI include aplasia cutis, esophageal atresia, abdominal wall defects, and ventricular septal defects. In a meta-analysis of 16 cohorts that included 5,367,601 people, the adjusted relative risk for MMI compared to controls was 1.28 (95% CI 1.06-1.54) and that for PTU was 1.16 (95% CI 1.08-1.25) [AU- please provide absolute rates- or say “absolute rates not provided” if that is correct].⁸⁶ Therefore, PTU is preferred in the first trimester of pregnancy.^83,84 Because ATDs cross the placenta and have more pronounced effects on fetal than on maternal thyroid function, the lowest ATD dose necessary should be used to maintain the maternal FT4 level at or just above the upper reference limit.⁸⁴ ATDs are secreted in breast milk at low levels, but doses up to 20 mg/d of MMI and 450 mg/day of PTU are considered safe in lactation and do not require thyroid function monitoring of the breastfed infant.⁸³ RAI treatment is contraindicated in pregnancy and lactation.⁸⁴ It should be deferred until a minimum of 3 months after breastfeeding is completed, to allow for lactation- induced mammary tissue changes to resolve, avoiding radiation exposure which could damage breast tissue.^84,87 If needed, thyroidectomy in pregnancy is safest in the second trimester.⁶¹
妊娠短暂性甲状腺毒症，其中甲状腺激素的产生由于 hCG 水平升高刺激甲状腺而增加，影响大约 2-11% 的妊娠，并与妊娠剧吐有关。⁸¹ 这种情况不需要 ATD 治疗，并且与不良产科结局无关 ⁸²;它可以简单地通过连续的甲状腺功能测试进行监测，并且随着母体 hCG 水平的下降而自发消退。^83,84 元妊娠期所有其他形式的显性甲状腺功能亢进症都需要治疗，以降低包括子痫前期、低出生体重、流产和早产在内的结局风险。⁸⁵ 两种 ATD 都是致畸性的，但先天性异常 PTU 比 MMI 更轻微，风险更低。PTU 相关异常包括面部或颈部囊肿和尿路异常，而与 MMI 相关的异常包括皮肤再生障碍、食管闭锁、腹壁缺损和室间隔缺损。 在一项对 16 个队列（包括 5,367,601 人）的荟萃分析中，与对照组相比，调整后的 MMI 相对风险为 1.28 （95% CI 1.06-1.54），PTU 的调整后相对风险为 1.16 （95% CI 1.08-1.25） [AU- 请提供绝对率 - 如果正确，请说“未提供绝对率”]。⁸⁶ 因此，PTU 是怀孕前三个月的首选。^83,84 元由于 ATD 穿过胎盘，对胎儿的影响比对母体甲状腺功能的影响更明显，因此应使用所需的最低 ATD 剂量以将母体 FT4 水平维持在或略高于参考上限。⁸⁴ 种 ATD 在母乳中分泌水平较低，但高达 20 mg/d 的 MMI 和 450 mg/天的 PTU 剂量被认为在哺乳期是安全的，不需要对母乳喂养的婴儿进行甲状腺功能监测。⁸³ RAI 治疗禁用于妊娠期和哺乳期。⁸⁴ 应推迟到母乳喂养完成后至少 3 个月，以便解决哺乳期引起的乳腺组织变化，避免可能损伤乳腺组织的辐射暴露。^84,87 元如果需要，妊娠中期的妊娠期甲状腺切除术是最安全的。⁶¹

Thyroid Storm  甲状腺风暴

Thyroid storm consists of severe uncontrolled hyperthyroidism and is characterized by multi-organ system failure and a mortality rate of 3.6-17%.^88,89 Presenting symptoms may include fever, tachycardia, heart failure, atrial fibrillation, and various central nervous system abnormalities. Thyroid storm may be precipitated by surgery, amiodarone use, or discontinuation of antithyroid drugs.^89,90 Diagnostic criteria have been published by Burch and Wartofsky⁹¹ and by the Japanese Thyroid Association.⁹² Management is aimed at rapidly reducing circulating T3 levels using antithyroid drugs, glucocorticoids, beta blockade, inorganic iodide, and cholestyramine.³ Although both ATDs decrease thyroid hormone synthesis, U.S. guidelines recommend PTU for patients with thyroid storm since PTU, but not MMI, blocks T4 to T3 conversion.³ However, a recent comparative effectiveness study found no difference in in-hospital mortality, costs, adverse events, or duration of organ support in those treated with PTU compared to MMI.⁹³ In addition to lowering serum T3 levels, patients should be treated in the intensive care unit and any precipitating illness should be addressed.³ Plasmapheresis to lower circulating T3 levels may be considered in refractory⁹⁴
甲状腺危象包括严重的不受控制的甲状腺功能亢进症，其特征是多器官系统衰竭，死亡率为 3.6-17%。^88,89 元主要症状可能包括发热、心动过速、心力衰竭、心房颤动和各种中枢神经系统异常。甲状腺危象可能由手术、胺碘酮使用或抗甲状腺药物停药诱发。^89,90 元 Burch 和 Wartofsky⁹¹ 以及日本甲状腺协会已发布诊断标准。⁹² 管理旨在使用抗甲状腺药物、糖皮质激素、β 受体阻滞剂、无机碘化物和消胆胺快速降低循环 T3 水平。³ 尽管两种 ATD 都会减少甲状腺激素合成，但美国指南建议甲状腺危象患者使用 PTU，因为 PTU 而不是 MMI 会阻断 T4 到 T3 的转化。³ 然而，最近的一项比较有效性研究发现，与 MMI 相比，接受 PTU 治疗的患者在院内死亡率、成本、不良事件或器官支持持续时间方面没有差异。⁹³ 除了降低血清 T3 水平外，患者还应在重症监护病房接受治疗，并应解决任何诱发疾病。³ 难治性可考虑血浆置换以降低循环 T3 水平 ⁹⁴

Prognosis  预后

Compared to euthyroidism, overt hyperthyroidism is associated with a 35-400% increase in all-cause mortality, varying according to the acuity and severity of hyperthyroidism, and a 20% increase in cardiovascular mortality .^95,96 The exact mechanism is not clear, but increased mortality risks of hyperthyroidism are thought to be related to increased risks of endothelial damage and hypercoagulability. Mortality is associated with the cumulative duration of time spent hyperthyroid, regardless of the treatment modality employed.^97,98 A network meta-analysis that included three retrospective Graves’ disease cohorts concluded that while all three major treatment modalities were associated with lower risks for congestive heart failure and arrhythmia, surgery was associated with greater benefit than ATD or RAI.⁹⁹ Similarly, a registry study of 10,992 people that compared mortality after treatment for hyperthyroidism concluded that all-cause mortality was lower following surgery than after RAI treatment (absolute rates not provided). ¹⁰⁰ A registry-based study reported that all-cause and cardiovascular mortality risk may be higher among patients treated for toxic multinodular goiter compared to those treated for Graves’ disease.¹⁰¹
与甲状腺功能正常相比，显性甲状腺功能亢进与全因死亡率增加 35-400% 相关，根据甲状腺功能亢进症的严重程度和严重程度而变化，心血管死亡率增加 20%。^95,96 元确切的机制尚不清楚，但甲状腺功能亢进症的死亡风险增加被认为与内皮损伤和高凝状态风险增加有关。死亡率与甲状腺功能亢进的累积持续时间相关，与采用何种治疗方式无关。^97,98 元一项包括 3 个回顾性 Graves 病队列的网络荟萃分析得出结论，虽然所有三种主要治疗方式都与充血性心力衰竭和心律失常风险较低相关，但手术比 ATD 或 RAI 获益更大。⁹⁹ 同样，一项对 10,992 人进行的登记研究比较了甲状腺功能亢进症治疗后的死亡率，得出的结论是，手术后的全因死亡率低于 RAI 治疗后（未提供绝对死亡率）。¹⁰⁰ 一项基于登记的研究报告称，与 Graves 病治疗的患者相比，接受毒性多结节性甲状腺肿治疗的患者的全因和心血管死亡风险可能更高。¹⁰¹ 元

Limitations  局限性

This review has several limitations. First, some relevant papers may have been missed. Second, a formal literature quality assessment was not performed. Third, management of nonthyroidal aspects of Graves’ disease, such as orbitopathy and dermatopathy, was not covered.
本综述有几个局限性。首先，可能遗漏了一些相关论文。其次，未进行正式的文献质量评估。第三，未涵盖 Graves 病的非甲状腺方面的管理，例如眼眶病和皮肤病。

Conclusion  结论

Hyperthyroidism affects 2.5% of adults worldwide and is associated with osteoporosis, heart disease, and increased mortality. First-line treatments are antithyroid drugs, thyroid surgery, and RAI treatment. Treatment choices should be individualized and patient-centered.
甲状腺功能亢进症影响全球 2.5% 的成年人，与骨质疏松症、心脏病和死亡率增加有关。一线治疗是抗甲状腺药物、甲状腺手术和 RAI 治疗。治疗选择应个体化且以患者为中心。