1. 90后甲状腺结节的流行病学现状
1.1 患病率与群体特征
近年来，甲状腺结节的检出率在全球范围内呈现上升趋势，尤其在90后（指出生于1990年至1999年的人群）群体中，这一现象愈发显著。随着健康体检的普及和超声诊断技术的提高，越来越多的年轻人在常规体检中被发现患有甲状腺结节。
在患病率方面，多项研究表明，女性甲状腺结节的患病率显著高于男性。例如，有数据显示，甲状腺癌（一种常见的甲状腺结节恶性类型）在女性中的发病率是男性的三倍 1。尽管这主要针对甲状腺癌，但这种性别差异在良性甲状腺结节中也普遍存在，提示女性在甲状腺疾病易感性方面可能存在生理或内分泌方面的特异性。
年龄分布上，甲状腺结节的患病率通常随年龄增长而上升。然而，对于90后这一相对年轻的群体而言，即使在年轻阶段，甲状腺结节的检出率也已引起关注。例如，一项针对儿童、青少年和年轻成人（3-29岁）的调查显示，在有甲状腺结节的个体中，年龄和性别是重要的影响因素 2。虽然具体针对90后群体的详尽全国性体检数据尚待进一步整合分析，但现有的临床观察和局部体检中心数据显示，20-30岁年龄段的甲状腺结节检出率已不容忽视。
地域特征方面，甲状腺结节的患病率在中国不同地区存在差异。沿海地区和经济发达地区由于体检普及率高、居民健康意识强，以及可能存在的环境因素暴露差异，甲状腺结节的检出率可能相对较高。然而，目前缺乏针对90后群体全国性的、细致到地域层面的甲状腺结节患病率数据。但结合成人甲状腺疾病的流行病学研究，可以推测中国东部及沿海地区因其碘营养状态、生活方式及环境因素的特殊性，90后群体甲状腺结节的患病率可能高于内陆地区。例如，某些地区的碘摄入水平可能会对甲状腺结节的发生发展产生影响，而沿海地区的海产品消费习惯可能导致不同的碘摄入模式。
1.2 临床特点与检出方式
在90后群体中，甲状腺结节的检出主要依赖于高分辨率超声检查 3。超声因其无创、便捷、经济且能清晰显示甲状腺形态和结构特点的优势，已成为甲状腺结节诊断和评估的首选影像学方法 34。随着超声技术的不断进步，即使是亚厘米级（小于1厘米）的微小结节也能被有效发现，这在一定程度上解释了甲状腺结节检出率的升高 5。
对于90后甲状腺结节的临床特点，超声评估主要关注结节的大小、数量、内部结构、边界、回声、钙化以及血流情况 3。研究显示，甲状腺结节的大小本身与恶性风险并非线性相关，例如一项回顾性队列分析发现，小于3.0 cm的结节与大于等于3.0 cm的结节恶性几率相似 6。然而，年轻患者（如45岁以下）的结节生长速度可能更快，这意味着对于90后患者，即使是良性结节也可能在长期随访中出现显著增大 7。
结节的数量方面，90后患者可以表现为单发结节或多发结节。虽然多发结节曾被认为恶性风险较低，但目前观念认为结节数量与恶性风险无明确相关性，关键在于每个结节的超声恶性征象 4。
超声特征是评估结节良恶性的重要依据，主要包括：
- 回声：恶性结节常表现为低回声或极低回声，即比周围甲状腺组织更暗的区域 3。
- 钙化：钙化是评估甲状腺结节恶性风险的关键指标。粗大钙化可能与良性结节相关，但微小钙化（特别是点状或沙粒样钙化）是恶性结节（尤其是乳头状癌）的高度提示征象 3。
- 边界与形态：恶性结节常具有不规则或模糊的边界，形态可能呈“高大于宽”的不规则形状 3。
- 血流：彩色多普勒超声可以评估结节内部的血流情况。恶性结节往往表现为结节内部血流丰富且紊乱，而良性结节通常血流稀少或仅位于结节周边 8。
- 结构：恶性结节常呈实性结构，而良性结节可能为囊性、海绵状或囊实性 9。例如，在儿科人群中，实性结构（94.8%）和低回声（94.8%-95.7%）在恶性结节中更为常见 9。
值得注意的是，即使是良性结节也可能随时间发生形态学变化，出现一些易被误诊为恶性的超声特征，如规则的蛋壳样钙化、周边低回声晕和后方声影，因此在诊断时需结合随访图像进行综合判断 10。为了标准化甲状腺结节的超声评估和风险分层，美国甲状腺协会（ATA）和美国放射学会（ACR）等机构已推出了甲状腺影像报告与数据系统（TI-RADS），该系统通过对上述超声特征进行评分，帮助临床医生评估结节的恶性风险并指导后续处理 11。
2. 加碘盐与甲状腺结节的关联性分析
2.1 碘摄入水平与甲状腺结节的剂量效应
碘是甲状腺激素合成必需的微量元素，其摄入水平对甲状腺健康至关重要。长期以来，中国通过实施加碘盐政策有效地控制了碘缺乏病，但也引发了关于碘摄入量与甲状腺疾病（包括甲状腺结节）之间关系的新讨论，尤其是在90后这一伴随加碘盐政策成长起来的群体中。
尿碘浓度（Urinary Iodine Concentration, UIC）是评估人群碘营养状况最常用的指标。世界卫生组织（WHO）推荐的适宜尿碘中位数范围是100-199 μg/L。碘缺乏（<100 μg/L）、碘充足（100-199 μg/L）、碘超足量（200-299 μg/L）和碘过量（≥300 μg/L）被用来划分不同的碘营养状态 12。
多项研究分析了碘摄入水平与甲状腺结节患病率之间的关联，但结论并不完全一致，这反映了碘营养状况的复杂性及其对甲状腺健康影响的多样性。
碘缺乏与甲状腺结节：
在碘缺乏地区，甲状腺结节的患病率通常较高。碘缺乏会导致甲状腺代偿性增生，形成甲状腺肿和结节 13。例如，一项在中国西安地区进行的研究发现，在尿碘浓度低于100 μg/L的碘缺乏人群中，甲状腺结节的发生率在女性中高达18.5%，在男性中为12%，高于其他碘营养状态的人群 14。系统评价和荟萃分析也证实，碘缺乏（UIC < 100 μg/L）会适度增加甲状腺结节的发生风险，合并优势比为1.24（95% CI [1.16-1.33]） 12。
碘充足与甲状腺结节：
在碘充足地区，甲状腺结节的患病率相对稳定。然而，即使在碘充足的背景下，甲状腺结节的检出率仍然不低。例如，中国成都一项研究显示，在碘充足地区（中位尿碘浓度184 μg/L），甲状腺结节的患病率为16.87% 15。
碘过量与甲状腺结节：
关于碘过量与甲状腺结节的关联，研究结果存在争议。
- 部分研究显示碘过量可能增加甲状腺结节风险：
- 一项对中国9,381,032名成年人进行的全国性调查发现，饮用水中碘含量较高与甲状腺结节患病率增加呈线性相关（Pearson相关系数分别为男性0.47，女性0.40，总体0.46），居住在沿海地区的居民甲状腺结节患病率（40.1%）高于内陆居民（35.4%） 16。这提示在高碘暴露环境下，甲状腺结节可能更为普遍。
- 江西省的一项研究也指出，与碘充足人群相比，碘过量（UIC超足量或过量）个体患甲状腺结节的风险更高（OR = 3.33, 95%CI: 1.32-8.42） 17。
- 青海省的研究也发现，该地区碘营养状况普遍为碘过量，而甲状腺结节的检出率较高，其中单发结节的检出率城市高于农村（8.01% vs 4.70%），提示高碘地区可能存在甲状腺结节高发的情况 18。
- 另一些研究则未能发现明确的关联，甚至显示负相关：
加碘盐政策对90后群体的影响：
中国的全民食盐加碘政策自1990年代后期全面推行，90后群体在成长过程中普遍经历了碘营养状况从碘缺乏向碘充足甚至部分地区碘超足量的转变。这一政策的长期效应是理解90后甲状腺结节高发的关键因素之一。
- 碘营养改善与甲状腺疾病谱的演变：一项长达20年的前瞻性随访研究显示，当碘状况从碘不足转变为碘充足（中位UIC从88 μg/L增加到141.9 μg/L）时，亚临床甲状腺功能亢进、甲状腺抗体阳性率和甲状腺肿的发生密度显著下降。然而，当碘状况从碘过量转变为碘超足量（中位UIC从634 μg/L下降到266.7 μg/L）时，甲状腺结节的发生密度反而有所增加（从17.26/1000人年增加到28.25/1000人年） 20。这表明，虽然适量的碘补充对预防碘缺乏相关疾病是安全有效的，但碘摄入量的快速或长期维持在高水平可能改变甲状腺疾病的流行病学模式，可能促使甲状腺结节的发生。
- “U”形关系假说：一些研究认为碘摄入与甲状腺结节之间存在“U”形关系，即碘摄入不足和碘摄入过量都可能增加甲状腺结节的风险 12。这提示，精准的碘营养管理对于维持甲状腺健康至关重要。对于90后而言，他们在生命早期普遍接触加碘盐，若生活在碘负荷较高的地区，或因饮食习惯等导致尿碘长期处于超足量甚至过量水平，理论上可能增加甲状腺结节的风险。
总而言之，加碘盐政策的实施无疑在预防碘缺乏病方面取得了巨大成功，使得90后普遍拥有了充足的碘营养。然而，这种充足有时也伴随着碘超足量甚至过量的情况，这可能在一定程度上影响了甲状腺结节的发生率。目前研究显示，碘缺乏明确是甲状腺结节的风险因素，而碘过量与甲状腺结节的关联则更为复杂，可能存在地区差异和剂量效应，需要更深入的研究来阐明其确切作用机制。
2.2 碘过量/不足的病理机制差异
碘摄入异常（包括碘缺乏和碘过量）均可通过不同的病理机制影响甲状腺滤泡细胞的增殖、自身免疫反应以及碘代谢调控，进而促进甲状腺结节的形成，并可能影响结节的良恶性风险。
甲状腺滤泡细胞增殖与碘摄入：
- 碘缺乏： 长期碘缺乏会导致甲状腺激素合成减少，负反馈刺激垂体分泌更多的促甲状腺激素（TSH）。TSH的持续升高是甲状腺滤泡细胞增生、肥大，最终形成甲状腺肿和结节的关键驱动因素。在这种情况下，结节的形成主要是为了代偿性地提高对碘的摄取和甲状腺激素的合成能力。
- 碘过量： 虽然碘是甲状腺激素合成的必需元素，但过量的碘摄入也会对甲状腺产生抑制作用。体外研究表明，碘可以剂量依赖性地抑制大鼠甲状腺细胞（FRTL5细胞和M12细胞）的增殖，包括TSH刺激引起的增殖以及胰岛素样生长因子-I诱导的增殖 21。高碘通过激活TGFβ通路，并可能通过影响Notch/miR-19通路来抑制甲状腺滤泡细胞的过度增殖 22。然而，长期高碘也可能导致甲状腺功能紊乱，如引发或加重自身免疫性甲状腺炎，从而通过炎症和细胞损伤间接促进结节的形成。此外，过量的碘可能直接或间接引起甲状腺细胞的氧化应激和DNA损伤，从而增加细胞异常增殖的风险。
自身免疫与碘摄入（TPOAb/TgAb阳性率）：
- 碘缺乏： 长期碘缺乏被认为与甲状腺自身免疫性疾病的发生风险较低相关。例如，一项针对中国孕妇的研究发现，碘缺乏（尿碘浓度<100 μg/L）与甲状腺抗体（TPOAb/TgAb/TRAb）阳性风险增加有关（OR=1.324） 23。这表明碘缺乏可能不利于甲状腺的免疫稳态。另一项广西的流行病学调查也显示，碘缺乏人群的甲状腺抗体阳性率高于碘充足或碘过量人群 24。
- 碘过量： 碘过量与自身免疫性甲状腺炎的发生存在关联。过量的碘可能诱导或加重自身免疫反应，从而升高甲状腺过氧化物酶抗体（TPOAb）和甲状腺球蛋白抗体（TgAb）的水平。高浓度的TPOAb和TgAb是诊断自身免疫性甲状腺炎的关键指标，而自身免疫性甲状腺炎是甲状腺结节，尤其是多发结节的常见伴随疾病。一项研究表明，在BMI>30 kg/m2的肥胖个体中，血清瘦素水平与TPOAb呈显著正相关，提示肥胖相关的炎症反应也可能参与自身免疫性甲状腺炎的发生发展 25。因此，在碘过量地区，自身免疫性甲状腺炎的发生率可能上升，进而增加甲状腺结节的检出。
碘代谢调控（NIS基因表达）与结节形成：
钠/碘转运体（Sodium/Iodide Symporter, NIS）是甲状腺滤泡细胞摄取碘的关键蛋白，其功能受损是导致甲状腺结节低功能（冷结节）的重要原因 26。
- 碘缺乏对NIS的影响： 在某些甲状腺疾病状态下，如Graves病和自主功能性甲状腺结节，NIS的表达会显著上调 27。理论上，在碘缺乏状态下，甲状腺细胞可能通过调节NIS表达来应对碘摄入不足。
- 碘过量对NIS的影响： 过量的碘摄入可能抑制NIS基因的表达，从而减少碘的摄取和有机化过程。例如，雌二醇（在女性中水平较高）可以上调FRTL-5甲状腺细胞的增殖并下调NIS基因的表达 28。在高碘环境下，甲状腺滤泡细胞可能通过降低NIS的表达来避免过多的碘进入细胞，这是一种保护性机制，但长期作用下可能影响甲状腺的正常功能。
- 甲状腺结节中的NIS异常： 无论是良性还是恶性甲状腺结节，NIS的表达和细胞内定位都可能出现异常 29。在大多数低功能性（冷）甲状腺结节中，即使NIS基因表达正常，其蛋白也可能滞留在细胞内而未能有效定位于细胞膜，从而导致碘摄取功能受损 2630。在甲状腺乳头状癌中，NIS和甲状腺球蛋白（TG）mRNA的表达显著降低 31。然而，研究也发现，在碘缺乏地区形成的冷性甲状腺结节中，NIS的表达和定位可能更为正常，而在碘充足地区，NIS的表达往往较弱或缺失 32。这提示，碘营养状况可能影响结节中NIS的表达和功能，进而影响结节的生物学行为。
不同碘状态下结节良恶性风险差异：
- 碘缺乏地区： 碘缺乏地区，结节多为良性腺瘤或多结节性甲状腺肿，恶性甲状腺癌的比例相对较低，但一旦发生甲状腺癌，滤泡状癌的比例可能相对较高。
- 碘充足/过量地区： 随着碘摄入量的增加，甲状腺癌的组织学类型可能发生改变，例如乳头状癌的比例可能会增加。一项研究发现，高尿碘水平与甲状腺结节和甲状腺乳头状癌（PTC）之间存在强关联，并且高尿碘与PTC的侵袭性特征（如淋巴结转移和更高的疾病分期）显著相关，提示高尿碘可能是甲状腺恶性肿瘤的风险因素 33。该研究发现，良性甲状腺结节患者的中位尿碘（MUI）为331.33 μg/L，而PTC患者的MUI高达466.23 μg/L，两者均处于碘过量状态，且显著高于对照组的174.30 μg/L 33。然而，也有研究指出，高碘能够抑制RET/PTC3癌基因的激活，并恢复甲状腺滤泡细胞对TGFβ的响应，表明高碘在一定程度上可能具有抗癌作用 34。
- “U”形风险： 综合来看，碘摄入量与甲状腺结节的良恶性风险可能存在复杂的“U”形关系。碘摄入不足和碘摄入过量都可能增加甲状腺疾病的风险，但其引发的病理类型和机制有所不同。在90后群体中，由于普遍经历长期加碘盐政策，其碘营养状况多处于充足或超足量状态，因此需要更关注碘过量可能带来的甲状腺结节发生风险及其对良恶性转化潜在的影响。
3. 非碘因素对90后甲状腺结节的影响
除了碘摄入水平，90后甲状腺结节的高发也与多种非碘因素密切相关。这些因素包括代谢异常、不健康的生活方式、环境暴露以及遗传和自身免疫倾向等，它们可能独立或协同作用，促进甲状腺结节的形成和发展。
3.1 代谢与生活方式因素
代谢综合征（MetS）及其相关组分，如肥胖、胰岛素抵抗、高血糖、高血压和血脂异常，已被广泛认为是甲状腺结节发生发展的重要危险因素 3536。90后群体作为社会的中坚力量，面临着工作压力大、生活节奏快等问题，不良生活习惯的普遍存在使得代谢性疾病的患病率呈上升趋势，这可能进一步推动甲状腺结节的发生。
肥胖（体脂百分比、腰围）
肥胖是甲状腺结节的独立危险因素之一 3738。多项研究表明，较高的身体质量指数（BMI）、体脂百分比和腰围与甲状腺结节的发生风险呈正相关 363738。一项对希腊健康人群的研究发现，有甲状腺结节的受试者体脂含量（p=0.011）、总体脂肪百分比（p<0.001）和腰围（p=0.045）显著高于无结节者 38。另一项研究也指出，高BMI是甲状腺结节的预测因子之一 36。
肥胖促进甲状腺结节形成的机制可能涉及：
- 慢性炎症：肥胖是一种慢性炎症状态，导致系统性炎症标志物增加，如肿瘤坏死因子（TNF）和白细胞介素-6（IL-6）等细胞因子分泌增加，这些炎症因子可能促进甲状腺细胞的增殖和结节的形成 39。
- 瘦素（Leptin）：瘦素在肥胖个体中水平升高，它通过激活JAK/STAT、MAPK和PI3K/Akt等多种信号通路，在甲状腺结节和甲状腺癌的形成、增殖和侵袭中发挥关键作用 39。一项研究发现，血清瘦素水平与肥胖个体中的TPOAb显著正相关，提示肥胖相关的炎症反应可能参与自身免疫性甲状腺炎的发生发展。
- 雌激素水平异常：异常的内源性雌激素水平被认为是良性和恶性结节发展的重要因素 39。
胰岛素抵抗（HOMA-IR）与高血糖/糖尿病
胰岛素抵抗（IR）和糖尿病（特别是2型糖尿病）与甲状腺结节的发生密切相关 374041。
- 高胰岛素血症：胰岛素抵抗常伴随高胰岛素血症，升高的胰岛素水平和胰岛素样生长因子-1（IGF-1）可以促进甲状腺滤泡细胞的增殖和血管生成，从而刺激甲状腺结节的发展 39。一项研究表明，在糖尿病患者中，甲状腺结节的患病率显著高于非糖尿病患者（53.9% vs 46.7%，p<0.001） 40。
- 糖化血红蛋白（HbA1c）：HbA1c是糖尿病的诊断和血糖控制的指标。研究发现，HbA1c是甲状腺结节的独立风险因素（Exp [β] = 1.158, p < 0.001） 40。
- TSH的促有丝分裂作用：虽然TSH主要促进甲状腺细胞分化，但在胰岛素存在的条件下，TSH也具有促有丝分裂的特性，可能协同促进甲状腺结节的形成 39。
- 骨保护素（OPG）：研究发现，糖尿病患者血清OPG水平显著升高，且糖尿病大鼠甲状腺组织中的OPG表达增加，提示OPG可能参与糖尿病患者甲状腺结节的病理发生 40。
- 甲状腺血流：胰岛素抵抗还会影响甲状腺血管的分布和结构，可能通过改变血供来影响结节的生长 39。
高血压/糖尿病等代谢异常
代谢综合征的组成部分，如高血压、高甘油三酯血症和低高密度脂蛋白胆固醇，均与甲状腺结节风险增加有关 3542。一项荟萃分析指出，代谢综合征患者甲状腺结节的患病率显著高于对照组（OR 1.88, 95% CI 1.42-2.50, P < 0.0001），且与性别和年龄无关 35。即使在校正了年龄和性别后，代谢综合征组的甲状腺结节患病率仍较高 36。此外，有研究发现甲状腺结节和代谢综合征与结直肠息肉的发生也存在关联，且两者具有协同效应 43。
运动不足与饮食结构（如高糖/高脂）
不健康的生活方式，特别是运动不足和不良饮食结构，是导致肥胖和代谢综合征的关键因素，进而间接影响甲状腺结节的发生。
- 运动不足：缺乏运动是久坐生活方式的标志，与甲状腺结节大小和超声特征（如低回声和内部血流）相关 38。规律的体育锻炼有助于改善代谢健康，降低肥胖和胰岛素抵抗的风险，从而可能减少甲状腺结节的发生。
- 饮食结构：高糖和高脂肪饮食会导致体重增加、肥胖和胰岛素抵抗。例如，一项研究发现，食用高脂肪高果糖饮食的糖尿病大鼠，其甲状腺组织中的OPG表达显著增加 40。此外，研究还发现，甲状腺结节患者的牛奶摄入量显著较低 37，这可能暗示了某些营养素（如钙、维生素D）对甲状腺健康的影响。
干预策略：对于90后群体，针对代谢异常和不健康生活方式的干预可能在预防和管理甲状腺结节方面发挥作用。例如，二甲双胍（Metformin）作为一种常用的降糖药物，已被证明可以改善胰岛素抵抗，并与甲状腺结节大小、TSH水平和HOMA-IR水平的降低相关 44。这提示，通过饮食控制、增加运动以及必要的药物干预来改善代谢状况，可能有助于降低甲状腺结节的风险或延缓其进展。
总而言之，90后群体中甲状腺结节的高发，并非单一因素所致，代谢异常和不良生活方式在其中扮演了重要角色。理解这些非碘因素的作用机制，对于制定个性化的预防和管理策略具有重要意义。
3.2 环境与化学暴露因素
90后群体所处的现代社会，普遍面临着日益复杂的环境与化学物质暴露。这些环境因素，特别是空气污染物和内分泌干扰物，被认为是导致甲状腺结节甚至甲状腺癌发病率上升的重要非碘因素 4546。
环境污染物
铅：重金属铅已被证实对人体多个系统具有毒性作用，包括内分泌系统。铅暴露可能通过干扰甲状腺激素的合成、分泌和代谢，进而影响甲状腺功能。长期铅暴露可能导致甲状腺滤泡细胞损伤，增加结节形成的风险。虽然具体机制尚需深入研究，但铅可能通过氧化应激、细胞凋亡或改变基因表达等方式直接作用于甲状腺细胞。
空气颗粒物 (PM2.5/PM10)：近年来，多项研究揭示了空气污染与甲状腺疾病之间的关联。细颗粒物（PM2.5，直径小于2.5微米的颗粒物）和可吸入颗粒物（PM10，直径小于10微米的颗粒物）是主要的大气污染物，它们可以进入人体循环系统并对包括甲状腺在内的内分泌腺体产生影响。
- 甲状腺功能紊乱风险增加：长期暴露于PM2.5、PM10和二氧化氮（NO2）等空气污染物，可能显著增加甲状腺功能紊乱（包括甲状腺功能亢进和甲状腺功能减退）的风险 47。一项前瞻性研究发现，所有空气污染物都与甲状腺功能减退的风险增加显著相关，而PM2.5、PM10和NO2也与甲状腺功能亢进的风险增加显著相关 47。
- 生物学老化：空气污染暴露可能通过加速生物学老化，部分介导了甲状腺功能紊乱的风险 47。生物学年龄越大，个体发生甲状腺功能障碍的风险越高 47。
- 甲状腺结节与甲状腺癌：系统评价显示，环境空气污染，特别是臭氧（O3）和氮氧化物（NOx），与甲状腺结节和甲状腺癌的发生风险增加有关 4849。PM2.5暴露也与中国成年人甲状腺疾病的患病率增加有关，包括自身免疫性甲状腺炎和亚临床甲状腺功能减退，且PM2.5暴露与甲状腺球蛋白抗体阳性之间存在剂量反应关系 50。
- 暴露时间窗：早期生命阶段的空气污染暴露可能对儿童甲状腺功能产生不同影响。一项研究发现，妊娠早期PM2.5暴露与4岁和6岁儿童的促甲状腺激素（TSH）水平呈负相关，而儿童期PM2.5暴露则与4岁和6岁儿童的TSH升高呈正相关，并与8岁儿童的游离甲状腺素（FT4）水平呈负相关 51。这表明空气污染暴露对甲状腺功能的影响具有时间窗特异性。
- 潜在机制：空气污染物可能通过诱导氧化应激、炎症反应、内分泌干扰以及免疫系统调节异常等多种机制，直接或间接影响甲状腺细胞的增殖、分化和功能，从而促进甲状腺结节的形成和发展。
臭氧 (O3)：臭氧作为一种常见的空气污染物，与甲状腺癌和结节的风险增加有关 48。臭氧可能通过氧化应激对甲状腺细胞造成损伤。
电离辐射：虽然不是日常环境暴露的常见形式，但电离辐射是公认的甲状腺结节和甲状腺癌的风险因素 5253。切尔诺贝利核事故后的研究明确证实了儿童期碘-131暴露与甲状腺乳头状癌（PTC）之间剂量依赖性的相关性，这种关联持续数十年 54。长崎原子弹爆炸幸存者的研究也观察到实体结节（包括癌症、腺瘤等）的患病率与甲状腺辐射剂量之间存在显著的剂量反应关系 55。90后虽然未直接经历切尔诺贝利等大型核事故，但医学诊断性照射（如CT扫描）仍是小剂量电离辐射暴露的来源。电离辐射可能通过引起DNA损伤、染色体畸变和基因融合等分子机制，诱导甲状腺细胞恶性转化，并可能通过炎症反应促进甲状腺疾病的发生 56。
内分泌干扰物 (EDCs)
内分泌干扰物是指外源性物质，能够模仿或干扰内源性激素的作用，对生物体造成不利健康影响。90后群体在日常生活中广泛接触各类内分泌干扰物。
邻苯二甲酸酯 (Phthalates)：邻苯二甲酸酯是一类广泛用于塑料制品、化妆品、个人护理产品（如洗发水、香水）、食品包装和医疗器械中的增塑剂 5758。
- 甲状腺激素稳态干扰：邻苯二甲酸酯已被证实能够干扰甲状腺激素的稳态 5758。例如，邻苯二甲酸二-2-乙基己酯 (DEHP) 及其代谢物可以与甲状腺激素受体结合，影响甲状腺激素的合成、转运和代谢。一项研究发现，DEHP暴露与血脂代谢紊乱相关，而甲状腺功能改变在此关联中发挥中介作用 58。这意味着邻苯二甲酸酯可能通过影响甲状腺功能，进而影响其他代谢过程。
- 甲状腺组织损伤：动物实验表明，DEHP可以导致甲状腺组织损伤 59。例如，有研究显示，DEHP腹腔注射会导致雌性大鼠甲状腺的组织病理学改变和功能紊乱 59。
- 暴露场景：90后日常生活中，频繁使用塑料餐具、饮用塑料瓶装水、使用含邻苯二甲酸酯的化妆品和个人护理产品，都是潜在的暴露途径。
PPCPs (药品和个人护理产品)：药品和个人护理产品（Pharmaceuticals and Personal Care Products, PPCPs）也是环境中新兴的污染物。虽然直接证据较少，但其中一些成分，如某些抗菌剂、紫外线过滤剂等，可能具有内分泌干扰活性，对甲状腺功能造成影响。例如，一些含有碘的个人护理产品（如聚维酮碘漱口水）如果长期大量使用，可能导致碘过量，进而影响甲状腺功能 6061。对于90后而言，日常使用的一些护肤品、洗涤剂等可能含有这些成分。
综上所述，环境与化学暴露因素对90后甲状腺结节的发生发展具有不可忽视的影响。空气污染（PM2.5、O3、NOx）和内分泌干扰物（邻苯二甲酸酯等）可能通过诱导氧化应激、炎症反应、干扰甲状腺激素稳态以及直接损伤甲状腺细胞等多种机制，协同促进甲状腺结节的形成。由于这些暴露具有普遍性和长期性，对于90后群体而言，识别并减少这些环境风险因素的暴露，对于甲状腺健康管理具有重要意义。
3.3 遗传与自身免疫因素
遗传倾向和自身免疫机制在甲状腺结节的发生发展中扮演着重要角色，尤其对于90后这一群体，家族史和甲状腺自身抗体的检出率值得关注。
家族史
家族史是甲状腺结节，尤其是甲状腺癌的明确危险因素。约有5-10%的甲状腺癌患者存在家族史，这被称为家族性非髓样甲状腺癌（FNMTC）的范围。参考文献62的研究显示，在一组27名具有家族性非髓样甲状腺癌病史的患者中，有25名（92.6%）被诊断出甲状腺癌。虽然这些家族性病例中只有一小部分是遗传综合征的一部分，但遗传易感性在甲状腺结节和癌症的发生中是普遍存在的。
- 遗传性甲状腺癌综合征：一些罕见的遗传综合征，如家族性腺瘤性息肉病（FAP）、Cowden综合征和Carney复合体，与甲状腺结节和甲状腺癌的风险增加相关。这些综合征通常具有明确的遗传模式和特定的基因突变。
- 非综合征性家族聚集：即使没有明确的遗传综合征，具有甲状腺结节或甲状腺癌家族史的个体，其自身患病的风险也显著增加。这提示可能存在尚未明确的遗传易感基因或多基因遗传模式。对于90后而言，如果其直系亲属中有人患有甲状腺结节或甲状腺癌，他们罹患此类疾病的风险也会相应提高，这需要引起重视并在健康筛查中予以特别关注。
甲状腺自身抗体（TgAb/TPOAb阳性）
甲状腺自身抗体，主要是甲状腺球蛋白抗体（TgAb）和甲状腺过氧化物酶抗体（TPOAb），是自身免疫性甲状腺疾病（AITD）的标志物，如桥本氏甲状腺炎（HT）和格雷夫斯病（GD）63。这些抗体的存在，提示甲状腺存在自身免疫反应，而这种免疫反应与甲状腺结节的形成和性质密切相关。
- TPOAb和TgAb的检出率：在一般人群中，甲状腺抗体的阳性率较高，其中TPOAb阳性率约为5%，TgAb阳性率略低63。在甲状腺结节患者中，抗体阳性率可能更高。值得注意的是，甲状腺自身抗体阳性（特别是TPOAb）可以作为预测甲状腺癌的一个指标，尤其是在细针穿刺活检（FNAC）结果为良性的结节中，抗体阳性会增加甲状腺恶性肿瘤的风险（优势比2.16）64。
- 抗体与甲状腺癌：有研究发现，TgAb水平升高与甲状腺癌风险增加有关65，尽管这种关联在调整TSH水平后可能不再显著65。另一项研究则指出，术前TgAb水平可能与甲状腺癌的发生风险，以及淋巴结转移等不良肿瘤特征有关，但这一观点仍有争议66。
自身免疫性甲状腺炎（如桥本氏病）与结节共存的病理联系
桥本氏甲状腺炎（HT）是自身免疫性甲状腺炎最常见的形式，其特征是甲状腺被淋巴细胞浸润，导致甲状腺功能减退。HT与甲状腺结节和甲状腺癌的共存是临床上常见的现象，两者之间的病理联系复杂且备受关注。
- HT与甲状腺结节：HT患者中甲状腺结节的患病率显著高于普通人群。在儿童和青少年HT患者中，甲状腺结节的患病率可达22.4%67。HT引起的慢性炎症和免疫失调可能促进甲状腺细胞的增殖和结节形成。
- HT与甲状腺癌：越来越多的证据表明，HT与甲状腺癌（尤其是甲状腺乳头状癌，PTC）之间存在关联6368。一项对4678例甲状腺手术患者的研究发现，18.2%的甲状腺癌患者伴有HT，而无甲状腺癌的患者中HT的比例为6.74%，这表明HT与甲状腺癌的发生风险增加有关68。
- 诊断挑战：HT的存在可能给甲状腺结节的超声诊断带来挑战。HT患者的甲状腺在超声下常表现为弥漫性低回声和假结节，这可能掩盖或混淆真正的结节特征6970。因此，在HT背景下评估结节时，需要更精细的超声检查和经验。有研究探索了结合甲状腺腺体和结节本身的超声影像组学特征，以提高HT患者甲状腺结节良恶性鉴别的准确性71。
- 格雷夫斯病（GD）与结节：GD患者也可能同时出现甲状腺结节，且这些结节存在恶性风险72。一项研究显示，53%的GD患者有甲状腺结节，其中3.3%被诊断为甲状腺癌（多为微小乳头状癌）72。在GD患者中，多发结节和较大结节与甲状腺癌诊断的风险增加有关72。
对于90后群体，由于自身免疫性疾病的发病率呈上升趋势，结合遗传背景和自身抗体筛查对于早期识别高风险个体、制定个性化管理策略具有重要意义。特别是在甲状腺超声发现结节时，同时评估甲状腺自身抗体状态，有助于更全面地评估结节的性质和潜在风险。
4. 甲状腺结节对90后健康的影响及管理策略
4.1 恶性风险与临床转归
对于90后群体而言，甲状腺结节的发现不仅带来心理压力，更引发对恶性风险的担忧。虽然大多数甲状腺结节是良性的，但其恶性潜能不容忽视，尤其在年轻患者中，甲状腺癌具有独特的临床病理特征和转归。
结节恶性概率与乳头状癌比例
甲状腺结节恶性程度的评估主要通过超声检查结合细针穿刺活检（FNA）进行。FNA因其安全、简便、可靠和经济的特点，被认为是评估甲状腺结节的首选初始诊断方法，其细胞学诊断的准确率接近95% 7374。然而，FNA在儿童和青少年群体中的诊断参数存在一定的挑战。一项针对儿科人群的荟萃分析显示，FNA在儿童甲状腺结节诊断中的敏感性为94%，特异性为81% 75。另一项研究则指出，儿科甲状腺结节的恶性率似乎高于成人，并且某些Bethesda分类（用于评估FNA细胞学结果的系统）在儿童中的恶性率非常高，例如Bethesda III类（意义不明确的非典型细胞或滤泡性病变）在儿童中的恶性率可能远高于成人 76。
在年轻患者中，甲状腺结节的恶性风险存在争议。一项对6391名患者（20-95岁）的回顾性研究显示，甲状腺结节的患病率随年龄增长而增加，但新发现结节的恶性风险却随年龄增长而降低。在该研究中，最年轻的队列（20-30岁）患者的甲状腺癌发病率为22.9%，而最年长的队列（>70岁）为12.6% 77。这意味着，虽然年轻人发生甲状腺结节的比例相对较低，但一旦发现结节，其恶性程度的可能性相对更高。
在组织学类型上，甲状腺乳头状癌（Papillary Thyroid Carcinoma, PTC）是儿童和年轻人中最常见的甲状腺癌类型。几乎所有在年轻患者中发现的恶性肿瘤都是分化良好的甲状腺癌，其中PTC是主要的亚型 77。PTC的变异型也可能存在，其中一些变异型具有更高的侵袭性潜力 78。
年轻患者（<30岁）结节的侵袭性特征与淋巴结转移风险
年轻患者甲状腺癌的一个显著特点是其侵袭性行为，尤其体现在淋巴结转移方面。多项研究表明，儿童和年轻成人（特别是30岁以下）的甲状腺乳头状癌患者，淋巴结转移的风险显著高于年龄较大的患者 7980。
- 一项基于SEER数据库（1988-2015年，59330名PTC患者）的分析显示，淋巴结转移的总体发生率为26.11%，且随着年龄的减小而增加。与30岁以上组相比，0-10岁组、11-20岁组和21-30岁组的淋巴结转移校正优势比（OR）分别为7.19、3.45和2.28 79。这意味着90后群体（21-30岁）相比年长者，淋巴结转移的风险高出2倍以上。
- 年龄减小还与总阳性淋巴结数量增加、淋巴结比率增加以及侧颈淋巴结病变风险增加相关 79。
- 在甲状腺微小乳头状癌（PTMC，指直径≤1 cm的PTC）中，虽然其通常预后良好，但年轻患者（每增加10岁，中央淋巴结转移和侧颈淋巴结转移的优势比分别下降0.760和0.838）仍是淋巴结转移的高风险因素 81。此外，男性、肿瘤大小>0.5 cm、多发性、双侧性以及甲状腺外侵犯（ETE）也是淋巴结转移的独立预测因子 81。
尽管年轻患者的甲状腺癌可能表现出更高的淋巴结转移率，但通常认为年轻PTC患者的预后相对较好。这可能是因为年轻患者的甲状腺癌通常是分化良好的乳头状癌，并且他们对治疗的反应更好。然而，即使转移风险高，年轻患者往往能通过积极的手术治疗（包括淋巴结清扫）和术后放射性碘治疗获得较好的长期生存率 80。
总的来说，对于90后群体发现的甲状腺结节，虽然绝大多数是良性的，但考虑到其相对较高的恶性概率和甲状腺癌的侵袭性特征（特别是淋巴结转移倾向），临床上应采取更为积极的评估和管理策略。精确的诊断和个体化的治疗方案对于改善年轻甲状腺癌患者的预后至关重要。
4.2 个性化筛查与干预建议
针对90后群体甲状腺结节的流行病学特征、多因素成因及恶性风险特点，制定个性化的筛查与干预建议至关重要。这不仅能提高早期诊断率，还能避免过度诊断和不必要的治疗，同时优化医疗资源配置。
基于多因素风险模型的超声筛查策略
90后人群的甲状腺结节筛查应结合其多因素风险评估，而非简单地进行普查。高风险人群应接受更频繁、更精细的超声筛查。
高风险人群识别：
- 肥胖及代谢综合征患者：BMI过高、胰岛素抵抗、糖尿病、高血压等代谢异常的90后，其甲状腺结节患病率及恶性风险可能增高。应建议此类人群进行定期的甲状腺超声检查，并关注结节的生长速度和超声特征变化。
- 甲状腺疾病家族史者：直系亲属（父母、兄弟姐妹）有甲状腺结节或甲状腺癌病史的90后，应视为高风险群体。此类人群除了超声检查外，还应评估甲状腺自身抗体，以筛查自身免疫性甲状腺疾病。
- 高碘摄入地区居民：虽然我国整体碘营养状况充足，但在部分地区或由于特定饮食习惯（如过量摄入富碘食物或保健品），90后个体可能存在长期高碘暴露。这类人群应结合尿碘检测，评估碘摄入水平，并定期进行甲状腺超声检查，尤其关注结节的发生与发展。
- 环境/化学暴露高风险者：长期暴露于空气污染物（如PM2.5）、电离辐射或特定内分泌干扰物（如邻苯二甲酸酯）的90后，也应纳入重点筛查范畴。
- 甲状腺自身抗体阳性者：即使甲状腺功能正常，TPOAb或TgAb阳性的90后，其发生甲状腺结节及并发自身免疫性甲状腺炎的风险较高，建议定期超声监测。
超声筛查频率与监测重点：
- 基础筛查：对于一般低风险的90后，可参照成人指南，在常规健康体检中进行甲状腺超声检查。对于首次检出的良性结节，通常建议在6-18个月后进行首次随访超声，此后根据结节的稳定性和患者风险因素调整随访间隔。
- 高风险人群的强化监测：高风险90后建议缩短随访间隔，例如每6-12个月进行一次甲状腺超声检查。监测重点应包括：
良性结节的观察策略与治疗选择
绝大多数甲状腺结节（约95%）为良性8485。对于90后良性甲状腺结节的管理，应遵循“个体化、风险分层”的原则。
观察策略（Active Surveillance, AS）：
- 适应症：对于超声评估为低风险、FNA证实为良性，且无明显压迫症状（如吞咽困难、呼吸不畅、颈部疼痛）或美容困扰的结节，通常首选动态观察8485。特别是对于直径小于1cm的微小结节，如无高危特征，AS是一种安全有效的管理方式。
- 随访内容：主要通过定期超声评估结节大小和形态学变化，结合甲状腺功能检查。对于良性结节的长期随访频率，指南建议根据结节的声像图特征和患者的临床风险进行个体化调整，例如在首次随访后，可将随访间隔延长至1-2年一次。对于大多数结节，低频率的随访（low-frequency surveillance）是足够的84。
- 心理支持：甲状腺结节的发现可能导致患者出现心理困扰和睡眠障碍，尤其是在诊断和治疗过程中86。因此，在实施观察策略时，应充分告知患者结节的良性性质、恶变风险极低以及随访的重要性，提供必要的心理支持，缓解其焦虑情绪。
手术治疗：
- 适应症：手术是治疗甲状腺结节最传统也是最彻底的方式。对于90后良性结节，手术指征相对严格，主要包括：
- 结节引起明显压迫症状：如呼吸困难、吞咽障碍、声音嘶哑等，这通常是需要干预的重要指征85。
- 美容需求：巨大的甲状腺结节造成颈部外观明显隆起，影响患者生活质量，是患者选择治疗的常见原因之一87。
- 结节快速增长或出现恶性超声特征：在随访过程中，良性结节若出现快速增长或超声特征恶化，虽FNA仍为良性，但为排除假阴性或潜在恶变，可考虑手术切除。
- FNA结果不确定或可疑：对于FNA结果为不确定性（如Bethesda III或IV类）的结节，尤其在年轻患者中，恶性风险相对较高，可考虑行诊断性手术切除（如腺叶切除术）或重复FNA结合分子检测以明确诊断8889。
- 患者强烈要求切除：部分患者因担忧恶变或心理压力，即使结节为良性也强烈要求手术。
- 手术范围：对于良性结节，手术通常以腺叶切除或结节切除为主，尽量保留正常甲状腺组织，以避免术后甲状腺功能减退。
- 适应症：手术是治疗甲状腺结节最传统也是最彻底的方式。对于90后良性结节，手术指征相对严格，主要包括：
微创消融治疗（如射频消融RFA、微波消融MWA）：
- 原理与优势：射频消融（RFA）和微波消融（MWA）是近年来发展起来的微创治疗技术，通过高温使结节组织凝固坏死，达到缩小结节体积、缓解症状的目的9091。其创伤小、恢复快、不留明显瘢痕，对于90后患者尤其具有吸引力。
- 适应症：主要适用于：
- 安全性：RFA/MWA的并发症发生率低，主要为轻微疼痛、术区水肿等。严重并发症如喉返神经损伤、甲状旁腺损伤等发生率极低9092。此外，有研究表明RFA不会诱导良性甲状腺结节发生肿瘤性病变或对邻近正常甲状腺组织造成损伤93。
- 局限性：消融治疗通常不适用于恶性结节（除非某些特殊情况下的姑息治疗），且对于伴有钙化较多、位置深或靠近危险结构的结节，消融治疗可能存在技术挑战。
综上所述，90后甲状腺结节的筛查与管理应强调个性化和风险分层。对于高风险人群，应加强超声监测频率和内容；对于检出的良性结节，应优先考虑动态观察，在有明确指征时选择手术或微创消融治疗。在整个管理过程中，充分医患沟通，提供科学的健康教育和心理支持，对于提高患者依从性、改善预后至关重要。
5. 争议与未来研究方向
5.1 加碘盐政策的长期效应争议
中国的全民食盐加碘（Universal Salt Iodization, USI）政策自20世纪90年代中期全面推行以来，在消除碘缺乏病方面取得了举世瞩目的成就。然而，伴随碘营养状况从普遍缺乏转向充足甚至部分地区过量，加碘盐政策对甲状腺结节等甲状腺疾病长期效应的争议也日益凸显，尤其对于90后这一在USI政策下成长起来的特殊群体，其碘暴露与甲状腺结节的关联呈现出更为复杂的特殊性。
当前碘摄入与结节关系的矛盾结论
关于碘摄入水平与甲状腺结节患病率之间的关系，现有研究呈现出一定的矛盾性，主要体现在以下几个方面：
碘缺乏地区结节患病率升高是共识：多数研究一致认为，在碘缺乏地区，由于甲状腺的代偿性增生，甲状腺结节（特别是甲状腺肿性结节）的患病率显著升高 94。这充分肯定了USI政策在防治碘缺乏病方面的积极作用。
碘过量与结节风险的争议：
- 支持碘过量增加结节风险的研究：一些研究表明，碘过量与甲状腺结节的患病率增加呈正相关。例如，一项对中国全国范围内的成年人调查显示，饮用水中碘含量升高与甲状腺结节患病率增加呈线性相关 16。另一项来自江西省的研究也发现，碘过量（尿碘超足量或过量）个体患甲状腺结节的风险高于碘充足人群 94。这些研究指出，长期高碘暴露可能导致甲状腺细胞功能紊乱，促进结节的形成。甚至有研究发现，高尿碘水平与甲状腺乳头状癌的侵袭性特征（如淋巴结转移）显著相关，提示碘过量可能是甲状腺恶性肿瘤的风险因素 94。
- 支持碘过量降低结节风险或无显著关联的研究：然而，也有研究得出相反或不确定的结论。例如，一项对中国成年人的横断面研究发现，当尿碘浓度低于527 μg/L时，尿碘浓度与甲状腺结节呈负相关，即在此范围内碘浓度升高，结节风险反而下降 94。最新的系统评价和荟萃分析也指出，碘超足量和碘过量与甲状腺结节风险之间没有显著的、一致的关联 94。甚至有动物实验表明，高碘能够抑制某些癌基因的激活，并在一定程度上具有抗癌作用 94。
- “U”形关系假说：为了解释这些矛盾，一些学者提出了碘摄入与甲状腺疾病风险的“U”形关系假说，即碘摄入不足和碘摄入过量都可能增加甲状腺疾病的风险，而适宜的碘摄入量才能维持甲状腺健康 94。
90后作为政策实施后成长的一代，其碘暴露与结节关联的特殊性
90后群体具有其独特的碘暴露历史和生理特点，这使得他们成为研究USI政策长期效应的关键人群：
生命全程高碘暴露：与上一代人可能经历碘缺乏、碘充足、再到碘超足量的复杂转变不同，绝大多数90后个体自出生起就生活在普遍加碘盐的环境中，他们的甲状腺可能从胚胎期、儿童期到成年期都处于相对较高的碘负荷状态。这种长期的、持续的碘暴露对其甲状腺生理功能和病理过程可能产生不同于以往的累积效应。
碘营养状态的动态变化：尽管USI政策保证了碘的普遍供应，但90后个体实际的碘摄入水平仍受多种因素影响，如不同地区加碘盐的含碘量差异、居民膳食结构（海产品摄入）、饮用水中碘含量、以及是否存在碘营养强化食品或补充剂的摄入等。例如，中国沿海地区居民的甲状腺结节患病率高于内陆地区，部分原因可能与沿海居民的饮食习惯（如高海产品摄入）导致碘摄入量相对较高有关 16。这种动态且个体化的碘营养状态，使得简单地将90后归为“高碘暴露”群体可能过于笼统。
与其他风险因素的协同作用：90后甲状腺结节的高发，并非单一由碘摄入引起，而是碘暴露与其他非碘因素（如代谢紊乱、环境污染、遗传易感性、自身免疫等）复杂交互作用的结果。例如，有研究发现，在肥胖和碘过量的背景下，甲状腺疾病的风险可能更高。这意味着，单纯探讨碘与结节的线性关系可能无法完全解释90后甲状腺结节的流行病学特征。
诊断技术进步的影响：90后成长过程中，超声诊断技术飞速发展并普及。高分辨率超声能够检出以往难以发现的微小结节，这在一定程度上解释了甲状腺结节检出率的升高。因此，需要区分是“真正发病率的升高”还是“检出率的升高”。对于90后而言，更多的“微小结节”被检出，如何判断这些结节的临床意义，也增加了诊断与治疗的复杂性。
综上所述，USI政策对90后甲状腺结节的长期效应是一个复杂且充满争议的议题。未来的研究需要更深入地关注90后群体的碘暴露谱、碘营养状态与甲状腺结节发生、发展和恶性转归之间的剂量-反应关系，并充分考虑与其他非碘因素的协同作用，以期为90后甲状腺结节的精准防控提供更科学的依据。
5.2 多因素交互作用的机制探索
鉴于90后甲状腺结节的高发具有多因素、复杂性的特点，未来的研究方向应着重于探索这些因素之间的交互作用机制，而不仅仅是单一因素的影响。特别是碘摄入与代谢、环境因素以及表观遗传学机制在结节发生发展中的协同作用，将是深入理解其病因学并开发更有效干预策略的关键。
碘摄入与代谢、环境因素的协同效应（如碘过量+肥胖）
以往的研究倾向于独立分析碘摄入或环境因素对甲状腺结节的影响，但人体是一个复杂的系统，各种内外环境因素往往协同作用。未来的研究应将这些因素整合起来，探索其交互效应：
碘过量与代谢紊乱的协同效应：
- 肥胖与胰岛素抵抗：肥胖和胰岛素抵抗已被证实是甲状腺结节的重要非碘危险因素。有证据表明，在碘过量背景下，肥胖个体甲状腺疾病的风险可能更高。例如，肥胖与胰岛素抵抗导致的高胰岛素血症和高瘦素血症，本身就促进甲状腺细胞增殖。当这种促增殖环境与碘过量导致的氧化应激或自身免疫激活相结合时，可能加速甲状腺结节的形成和进展。未来的研究可以深入探讨高碘环境下肥胖个体甲状腺滤泡细胞的信号通路（如PI3K/Akt、MAPK通路）如何被协同激活，以及这种协同作用如何影响结节的良恶性转化。
- 脂肪因子与碘代谢：脂肪细胞分泌的脂肪因子（如瘦素、脂联素）不仅影响全身代谢，也可能直接作用于甲状腺细胞。在碘过量的情况下，这些脂肪因子如何影响甲状腺细胞对碘的摄取、有机化和甲状腺激素合成，以及是否通过改变NIS（钠/碘转运体）的表达或功能来影响结节发生，都是值得探索的方向。
环境污染物与碘摄入的交互作用：
- 空气污染物与甲状腺炎症/氧化应激：长期暴露于PM2.5、重金属等环境污染物会诱导甲状腺细胞的氧化应激和炎症反应。这些损伤在碘过量或碘不足的背景下可能会被放大或改变其作用模式。例如，碘过量本身也能引起氧化应激，当与空气污染物叠加时，对甲状腺细胞的损伤可能更加严重。研究可关注污染物暴露如何影响甲状腺对碘的敏感性，以及在不同碘状态下，污染物诱导的DNA损伤和炎症反应是否更易导致甲状腺结节的发生和恶性转化。
- 内分泌干扰物与甲状腺激素稳态：邻苯二甲酸酯等内分泌干扰物能够干扰甲状腺激素的合成和代谢。在碘摄入不足或过量的情况下，这些干扰物对甲状腺功能的扰动可能更为显著。未来的研究应评估不同碘摄入水平下，EDCs如何影响甲状腺激素受体功能、NIS表达以及甲状腺细胞增殖，从而促进结节形成。
表观遗传（DNA甲基化）在结节发生中的中介作用
表观遗传学，特别是DNA甲基化，在甲状腺结节的发生、发展和良恶性鉴别中扮演着越来越重要的角色。DNA甲基化是指DNA序列上特定碱基（通常是胞嘧啶）的甲基化修饰，不改变DNA序列，但能影响基因表达。在90后甲状腺结节的研究中，表观遗传学机制可能是连接疾病发生的关键环节。
DNA甲基化模式的改变：
- 恶性结节的特异性甲基化标志物：大量研究已经发现，甲状腺肿瘤（特别是甲状腺乳头状癌, PTC）与良性甲状腺结节之间存在显著的DNA甲基化模式差异 9596。例如，HYAL1基因的超甲基化与PTC相关，尤其在女性患者中更为明显 97。RASGEF1C基因的低甲基化被认为是PTC的良好诊断生物标志物，尤其在年轻患者和BRAF V600E突变阳性的PTC中表现出更高的诊断效能 98。此外，PTEN和DAPK等抑癌基因的异常高甲基化与PTC的发生密切相关，并可作为鉴别良恶性结节的生物标志物 99。这些研究提示，DNA甲基化可以作为区分良恶性甲状腺结节的潜在标志物。
- 细胞游离DNA（cfDNA）甲基化：利用血浆中的细胞游离DNA进行甲基化检测，是一种无创诊断甲状腺癌的潜在方法 100。研究表明，cfDNA甲基化标志物，例如一个包含6个标志物的ThyMet分类器，在区分PTC和良性结节方面表现出良好的特异性，并与超声诊断结合后能进一步提高诊断准确性 100。此外，基于DNA甲基化的免疫反应特征（MeIS）也展示了诊断细胞学不确定甲状腺结节的潜力 101。
- 器官氯农药（OCPs）与表观遗传改变：研究发现，器官氯农药（OCPs）暴露与甲状腺肿瘤的发生发展密切相关，并能引起表观遗传学改变。例如，OCPs能够显著增加TSHR基因启动子的高甲基化和降低P16基因的甲基化，同时影响组蛋白乙酰化水平，从而促进甲状腺乳头状癌的进展 102。这表明环境化学暴露可以通过表观遗传途径影响甲状腺结节的发生。
表观遗传在多因素交互中的中介作用：
- 环境暴露诱导的甲基化改变：环境因素（如污染物、饮食模式、生活方式）可能通过影响DNA甲基化酶（DNMTs）和去甲基化酶（TETs）的活性，导致基因组范围内的甲基化模式改变。这些改变可能发生在关键的甲状腺功能相关基因或抑癌基因上，从而促进结节的形成或恶性转化。
- 遗传背景与表观遗传易感性：个体遗传背景可能影响其对环境因素诱导的表观遗传改变的易感性。例如，某些基因多态性可能使个体更容易发生与碘代谢相关的甲基化异常。
- 整合多组学数据：未来的研究应整合基因组学、转录组学和表观基因组学（如DNA甲基化、组蛋白修饰）等多组学数据，构建多因素交互作用下的甲状腺结节发生发展模型。通过高通量测序技术，可以全面分析90后甲状腺结节患者的甲基化图谱，识别与特定风险因素（如高碘、肥胖、环境暴露）相关的特异性甲基化特征，并进一步阐明这些表观遗传改变如何调控甲状腺细胞的增殖、分化和凋亡，最终导致结节的发生。
通过深入探索上述多因素交互作用及其表观遗传中介机制，将有助于我们更全面地理解90后甲状腺结节高发的复杂病因，为开发更精准的风险评估模型、早期诊断生物标志物以及个性化的干预策略提供科学依据。
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参考文献
1Sex Differences in Papillary Thyroid Cancer.PubMed
Lindsay F Remer, Christina I Lee, Omar Picado, et al.
J Surg Res. 2022 Mar;271:163-170. doi: 10.1016/j.jss.2021.11.004. Epub 2021 Dec 16.
BACKGROUND: Papillary thyroid cancer (PTC) is three times more common in women than men. However, PTC in men appears to be associated with poorer outcomes than in women. This study compares the clinical presentation and pathologic features of men and women with PTC. MATERIALS AND METHODS: A retrospective review of prospectively collected data for patients with PTC who underwent fine needle aspiration (FNA) of a solitary thyroid nodule and thyroidectomy at a single institution was performed. Factors including age, ultrasound features, FNA results, extent of surgical operation and final histopathology were compared between male and female patients. Descriptive statistics using chi-square and t-test statistics compared outcomes by sex. RESULTS: Of the 851 patients with PTC, 158 (19%) were men and 693 (81%) were women. Mean age and standard deviation (SD) of patients was 48 (± 14) years, and most were of Hispanic origin (69%). Men had a significantly higher rate of radiation exposure relative to women, respectively (8% vs. 2%, P<0.01). There were no ultrasonographic or FNA cytologic differences among sexes. Men had more aggressive pathologic features including lymphovascular invasion (LVI) (47% vs. 34%, P<0.01) and positive lymph nodes (LN) (36% vs. 27%, P<0.05) compared to women. Thyroid lobectomy with isthmusectomy was more commonly performed among men compared to women (24% vs. 13%, P<0.01). CONCLUSION: Men with PTC have higher rates of radiation exposure associated with more aggressive disease with LVI and LN involvement on final histopathology compared to women. Total thyroidectomy with possible central neck dissection should further be considered when counseling men with PTC.
2Potential implications of thyroid autoantibodies in children, adolescents, and young adults with thyroid nodules in Japan: The Fukushima Health Management Survey.PubMed
Rina Tazaki, Yurie Kobashi, Nana Nakahata, et al.
Endocr J. 2024 Dec 2;71(12):1145-1155. doi: 10.1507/endocrj.EJ24-0293. Epub 2024 Sep 20.
There have been no systematic epidemiological evaluations of the relationship between thyroid autoimmunity and the clinical background of young patients with thyroid nodules. We aimed to clarify the clinical features associated with thyroglobulin or thyroperoxidase antibodies (thyroid autoantibodies [Tabs]) in children and young adults with nodules. We performed a cross-sectional study using data from 3,018 participants of 3-29 years of age with nodules, including thyroid cancer, from the Fukushima Health Management Survey. After stratification of the data for body mass index (BMI) and the bilateral width and thickness of the area (BWTAR) as indicators of thyroid volume for age, sex, body surface area (BSA), and sex-adjusted standard deviation score (SDS), trend analyses were performed. A logistic regression analysis was performed using tab-positivity as an objective variable. The overall prevalence of tab-positivity is 13.9%. It was high in females (17%), participants with diffuse goiter (DG) (19.2%), and those with papillary thyroid carcinoma (PTC) (12.8%). The age- and sex-adjusted odds ratios (95% confidence intervals) for BMI-SDS, BWTAR-SDS, presence of DG, diagnosis of PTC, and TSH concentrations were 0.962 (0.863-1.073), 1.263 (1.171-1.361), 7.357 (4.816-11.239), 2.787 (1.965-4.014), and 1.403 (1.257-1.564), respectively. Tab positivity was independently associated with a large thyroid, the presence of DG, the presence of PTC, and a high TSH concentration in patients with nodules. Based on the systematic epidemiologic evidence shown in young patients, Tab positivity might complement ultrasonography for the assessment of the thyroid function and identification of malignancy in younger patients with asymptomatic thyroid nodules.
3Thyroid Ultrasound: Diffuse and Nodular Disease.PubMed
Lauren F Alexander, Neema J Patel, Melanie P Caserta, et al.
Radiol Clin North Am. 2020 Nov;58(6):1041-1057. doi: 10.1016/j.rcl.2020.07.003. Epub 2020 Sep 17.
Thyroid ultrasound with gray-scale and color Doppler is the most helpful imaging modality to differentiate normal thyroid parenchyma from diffuse or nodular thyroid disease by evaluating glandular size, echogenicity, echotexture, margins, and vascularity. The various causes of diffuse thyroid disease often have overlapping sonographic imaging features. Thyroid nodules may be hyperplastic or neoplastic, with most due to benign hyperplastic changes in architecture and benign follicular adenomas; only a small percentage are malignant. A systematic approach to nodule morphology that includes evaluation of composition, echogenicity, margin, shape, and any echogenic foci can guide decision to biopsy or follow nodules.
4Thyroid nodules.PubMed
Geanina Popoveniuc, Jacqueline Jonklaas
Med Clin North Am. 2012 Mar;96(2):329-49. doi: 10.1016/j.mcna.2012.02.002.
Thyroid nodules are common entities, clinically important primarily because of their malignant potential. Serum thyrotropin and thyroid ultrasonography are pivotal in evaluating thyroid nodules. Fine-needle aspiration biopsy is the most accurate tool for diagnosing malignancy and selecting candidates for surgery. An approach to the initial evaluation and management of single nodules, functioning nodules, multinodular glands, incidental nodules, and cysts is discussed, as are therapeutic interventions for benign nodules. Thyroid cancer discovered during pregnancy is also discussed.
5Temporal Trends in Thyroid Nodule Size on Ultrasonography: A Systematic Review and Meta-Analysis.PubMed
Hayley Mann, Natalia Arroyo, Vivian Hsiao, et al.
JAMA Otolaryngol Head Neck Surg. 2025 Jan 1;151(1):47-55. doi: 10.1001/jamaoto.2024.3623.
IMPORTANCE: In recent years, concern has grown around the overdetection of thyroid cancer. Changes to thyroid nodule risk stratification systems and guidelines were made to improve diagnostic yield. It is not known how these advancements have affected the size of thyroid nodules reported on ultrasonography over time. OBJECTIVE: To evaluate change in reported nodule size since 1990, particularly between studies of thyroid ultrasonography obtained for diagnostic vs screening purposes. STUDY SELECTION: The systematic review included original research studies that reported thyroid nodule size in adults undergoing their first thyroid ultrasonography. Excluded studies were those that included patients with known thyroid disease, prior thyroid ultrasonography, nodules identified through other imaging modalities, and/or that had constraints on nodule size and/or characteristics. DATA SOURCES: PubMed, SCOPUS, CENTRAL, and CINAHL were reviewed from January 1990 to March 2021. Study characteristics, patient demographic characteristics, nodule size, and ultrasonography techniques were independently extracted by multiple observers. MAIN OUTCOMES AND MEASURES: The size of thyroid nodules reported via ultrasonography over time. Mixed-effects meta-regression models were used to evaluate mean nodule size (1) overall, (2) in studies that used ultrasonography diagnostically, and (3) in studies that used ultrasonography for screening. RESULTS: A total of 11 963 patients were included; the mean (SD) age was 47.6 (5.2) years. A total of 1097 studies were identified; of these, 395 full-text articles were assessed, and 18 studies met inclusion criteria. All were done at academic institutions. Altogether, these studies had 11 963 patients who underwent a first thyroid ultrasonography. Reported mean nodule size increased 0.52 mm each year from 1990 to 2021 (95% CI, 0.2-0.81). Diagnostic subgroup mean nodule size increased 0.57 mm each year from 1990 to 2021 (95% CI, 0.21-0.93). Screening subgroup mean nodule size decreased by 0.23 mm each year up to 2012 (95% CI, -0.40 to -0.07). CONCLUSIONS: The results of this systematic review and meta-analysis suggest that thyroid nodule size reported on diagnostic ultrasonography has increased over time in conjunction with changes in risk stratification systems, nodule guidelines, and radiology practice patterns. Conversely, a decrease in size reported in asymptomatic, ultrasonography-screened populations was observed. Findings from screening studies show that subcentimeter nodules are prevalent and easily identified with ultrasonography, but clinical relevance is questionable. Altogether, these results may provide insight into how ultrasonography guidelines and practice patterns have changed thyroid nodule reporting over time and can inform future guidelines and policies associated with thyroid nodule management.
6Association between thyroid nodule size and malignancy rate.PubMed
M Jinih, F Faisal, K Abdalla, et al.
Ann R Coll Surg Engl. 2020 Jan;102(1):43-48. doi: 10.1308/rcsann.2019.0156. Epub 2019 Dec 23.
INTRODUCTION: The diagnostic performance of ultrasound-fine needle aspiration to identify thyroid nodules harbouring malignancy remains variable. The aim of this study was to determine thyroid nodule size and cytological classification as predictors of malignancy risk. MATERIALS AND METHODS: We conducted a retrospective cohort analysis at an academic hospital involving 499 consecutive patients who underwent thyroid surgery between 2004 and 2015. RESULTS: A total of 503 thyroid nodules (499 patients, 84% female; mean age 50.8 years, standard deviation, SD, 15.4 years) were analysed. Of these, 19.5% were malignant. The mean (± SD) nodule size was 3.28 ± 1.63 cm and 3.27 ± 1.54 cm for benign and malignant nodules, respectively. The odds of malignancy for thyroid nodules less than 3.0 cm was similar to those for nodules of 3.0 cm or greater (0.26 compared with 0.29; =0.77). Overall, the sensitivity and specificity of fine-needle aspiration in this cohort were 71.4% and 100%, respectively. The overall false negative rate was 5.4%. When the cut-off of 3.0 cm was used, the false negative rate in thyroid nodules less than 3.0 cm was 0% compared with 7.0% in nodules of 3.0 cm or greater. Thus, class (<0.01) but not nodule size (=0.49), was associated with higher malignancy risk. CONCLUSIONS: Our results suggest that thyroid nodule size did not accurately predict the risk of thyroid malignancy irrespective of fine-needle aspiration cytology. Routine diagnostic thyroid lobectomy solely owing to thyroid nodule size of 3.0 cm or greater is currently not justified.
7Changes in the Volume and Diameter of Benign Thyroid Nodules: A 10-Year Follow-Up Study.PubMed
Murat Faik Erdoğan, Adile Begüm Bahçecioğlu, Fatma Avcı Merdin, et al.
Thyroid. 2025 Jan;35(1):31-40. doi: 10.1089/thy.2024.0405. Epub 2024 Dec 18.
The incidence of asymptomatic thyroid nodules has risen enormously, with > 90% being benign. Despite limited long-term data, significant nodule growth (SNG) is common. Guidelines recommend cytology reevaluation if SNG occurs. Our study aimed to identify the rate and factors associated with SNG, compare diameter and volume-based assessments, and examine the association between SNG and malignancy risk over the long term (10 years). The retrospective cohort study, conducted at Ankara University, School of Medicine, Department of Endocrinology and Metabolism, included 732 nodules from 376 euthyroid patients, all monitored over a 10-year period by the same experienced sonographer, with evaluations at baseline, 5th and 10th years. The nodules were cytologically benign and/or sonographically in the low-to-intermediate risk category. Size changes at the 5th and 10th years were considered significant if there was a 20% or 2 mm increment in two diameters according to diameter-based criterion (DBC) or 50% increment in volume-based criterion (VBC) designed by the ellipsoid formula. Generalized linear mixed-effects models were used to account for the clustered data structure and analyze factors affecting nodule growth. Nodule growth was the dependent variable, while sex, age at diagnosis, initial TSH level, total nodule count, nodule volume, echogenicity, and localization were independent variables. At the 5th and 10th years, SNG frequencies were higher when calculated using VBC [27.7% ( = 203) and 44% ( = 321), respectively] compared with DBC [19.1% ( = 140) and 35% ( = 256), respectively], with the differences being statistically significant (McNemar test, < 0.01). Factors associated with SNG included being younger than 45 years of age (VBC OR = 1.704, CI = 1.227-2.366, = 0.002; DBC OR = 1.913, CI = 1.379-2.656, < 0.001), having higher number of nodules (VBC: OR = 1.171, CI = 1.061-1.291, = 0.002; DBC: OR = 1.147, CI = 1.040-1.265, = 0.006), and having smaller nodule volume (VBC: OR = 0.870, CI = 0.806-0.940, < 0.001; DBC: OR = 0.912, CI = 0.850-0.978, = 0.010). Thyroid cancer was diagnosed in four original nodules (0.5%), whereas the malignancy rate in biopsies performed was 1.4% ( = 4). In long-term follow-ups of sonographically and/or cytologically benign thyroid nodules, SNG is not rare. Growth is more likely in younger patients, those with higher number of nodules and smaller nodules. In the follow-up of nodule size, VBCs yield augmented results compared with DBCs. However, malignancy is quite rare in growing nodules. Therefore, adopting flexible long-term follow-up protocols appears to be practical for benign nodular thyroid disease.
8Imaging the thyroid in children.PubMed
Jérôme Clerc
Best Pract Res Clin Endocrinol Metab. 2014 Mar;28(2):203-20. doi: 10.1016/j.beem.2013.04.011. Epub 2013 May 28.
Color Doppler Ultrasounds (CDU) and Thyroid Scanning (TS) have much improved in recent years and offer a likely diagnosis of the disorder and its main subtypes. This especially applies when diagnosing permanent or transient causes of congenital hypothyroidism (CH), where dual imaging has proven to be more informative than single scanning. Though both isotopes have acceptable performances, the use of (123)I appears more advisable, since it more accurately identifies the various aetiologies of CH and probably has better dosimetric characteristics than (99m)Tc. Detailed dual imaging patterns are presented in connection with most of the underlying mechanisms explaining CH, thyroid dysgenesis (75%) and dyshormonogenesis (20%). Imaging of thyroid autoimmunity, of immunogenic thyrotoxicosis and of thyroid autonomy, is helped by CDU but most often requires a quantified (123)I-TS (molecular imaging). We finally show the interest of CDU to sort suspicious nodule and present the new TIRADS scoring system.
9Diagnostic performance of adult-based thyroid imaging reporting and data systems in pediatric thyroid carcinoma: a retrospective study.PubMed
Wanying Li, Yiyan Du, Yao Wei, et al.
BMC Med Imaging. 2024 Nov 15;24(1):311. doi: 10.1186/s12880-024-01496-x.
BACKGROUND: Thyroid nodules diagnosed in children pose a greater risk of malignancy compared to those in adults. However, there is no ultrasound thyroid nodule evaluation system aimed at children. The objective of this research is to assess the diagnostic performance of the adult-based American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS) and Chinese Thyroid Imaging Reporting and Data System (C-TIRADS) in pediatric thyroid carcinoma. METHODS: The preoperative ultrasound images of 177 thyroid lesions in 136 pediatric patients aged 18 or younger who underwent thyroid surgery or fine needle aspiration (FNA) at our center from July 2017 to July 2022 were reviewed. The sonographic characteristics of pediatric thyroid carcinoma were compared and analyzed in contrast to benign nodules. All the nodules were evaluated by the ACR-TIRADS and the C-TIRADS respectively. RESULTS: Ultrasound features such as solid composition (94.8%), hypoechogenicity or marked hypoechogenicity (94.8-95.7%) and microcalcification (78.3-84.3%) were more common in pediatric malignant nodules (P-values < 0.05). The areas under receiver operating characteristic curves (AUC) of the ACR-TIRADS and the C-TIRADS in diagnosing pediatric thyroid carcinoma were 0.903-0.906, 0.907-0.909 (P-value > 0.05). The interobserver agreement of both the ACR-TIRADS and the C-TIRADS was strong (weighted Kappa > 0.90). CONCLUSIONS: Both the C-TIRADS and the ACR-TIRADS owned great diagnostic performance and strong interobserver agreement in diagnosing pediatric thyroid carcinoma. However, a more complete and specific ultrasound evaluation system for pediatric thyroid nodules is still needed.
10Mummified Thyroid Syndrome.PubMed
Alexis Lacout, Carole Chevenet, Pierre-Yves Marcy
AJR Am J Roentgenol. 2016 Apr;206(4):837-45. doi: 10.2214/AJR.15.15267.
OBJECTIVE: The purpose of this article is to highlight the various sonographic characteristics that should help to differentiate a restructured benign collapsed thyroid nodule from histologically proven thyroid carcinoma by different imaging means, including Doppler sonography, and fine-needle aspiration cytologic analysis. CONCLUSION: Benign thyroid nodules may display morphologic changes over time, which can have misleading sonographic features suggestive of malignancy. Precise knowledge of certain sonographic imaging features, such as regular eggshell calcifications, peripheral hypoechoic or hypoechoic rim, posterior shadowing, and absence of intranodular vascularization, and meticulous comparison with previous images showing thyroid nodule shrinkage over time are useful for reaching the correct final diagnosis. Fine-needle aspiration cytologic assessment of such initially suspicious thyroid nodules and sonographic follow-up contribute to establishing the final diagnosis of benign thyroid findings. Knowledge of the elements described should help to identify the so-called mummified thyroid nodule and avert surgical excision.
11Diagnosis and Evaluation of Thyroid Nodules-the Clinician's Perspective.PubMed
Rajasree Nambron, Richard Rosenthal, Deepti Bahl
Radiol Clin North Am. 2020 Nov;58(6):1009-1018. doi: 10.1016/j.rcl.2020.07.007. Epub 2020 Sep 17.
Thyroid nodules are a common clinical problem encountered in an endocrine practice. More and more thyroid nodules are now being detected on unrelated imaging studies, leading to an increased diagnosis of low-risk thyroid cancers. There is therefore a greater emphasis on risk assessment based on clinical and sonographic features to avoid morbidity secondary to unnecessary therapy. Molecular diagnostics are also being widely used to further characterize indeterminate nodules. The American Thyroid Association and American College of Radiology-Thyroid Imaging Reporting and Data System guidelines are the most commonly used in clinical practice for risk assessment.
12The myth of iodine: A systematic review and meta-analysis on the relationship between iodine and thyroid nodule.PubMed
Willy Gräfe, Sandy Scheibe, Josy Schwarz, et al.
J Endocrinol Invest. 2025 Aug;48(8):1693-1706. doi: 10.1007/s40618-025-02606-4. Epub 2025 May 28.
BACKGROUND: Iodine is an essential trace element for thyroid hormone synthesis, and its role in thyroid health has been widely studied. While iodine deficiency is recognized as a risk factor for goiter, its association with thyroid nodules remains controversial. The aim of this systematic review and meta-analysis was to evaluate the relationship between iodine intake and the development of thyroid nodules. METHODS: A systematic literature search was conducted in Medline (via PubMed), the Cochrane Library, and guideline registries (AWMF, GIN) for studies published between 2012 and 2023. Inclusion criteria focused on studies examining the association between iodine intake and thyroid nodule. Systematic review has been conducted whereas study quality was assessed using the checklists of Critical Appraisal Skills Programme (CASP). A meta-analysis was performed for studies reporting odds ratios based on WHO-defined iodine categories. RESULTS: A total of 31 studies were included. Most studies (n = 23) were cross-sectional, limiting causal conclusions. The most used method for assessing iodine intake was urinary iodine concentration (UIC), though measurement approaches varied. N = 10 studies compared median UIC between groups with and without thyroid nodules, with n = 8 reporting significant differences. However, the iodine levels in both groups often remained within the WHO-defined adequate iodine range. N = 8 studies examined odds ratios for iodine intake and thyroid nodule risk, with n = 5 identifying iodine deficiency (< 100 μg/L) as a significant risk factor. However, results for more than adequate (> 200 μg/L) and excessive iodine intake (> 300 μg/L) were inconsistent. N = 3 studies suggested a U-shaped relationship between iodine and thyroid nodule prevalence, but meta-analysis findings did not confirm this hypothesis. The pooled odds ratio for iodine deficiency was 1.24 (95% CI [1.16-1.33], I = 0.00), while more than adequate and excessive iodine intake showed no significant association. CONCLUSION: This systematic review and meta-analysis indicate that iodine deficiency increases moderately the risk of developing thyroid nodules, while more than adequate and excessive iodine intake does not show a consistent effect. However, the heterogeneity of study results and the predominance of cross-sectional designs limit definitive conclusions. Further prospective studies are needed to clarify the causal relationship between iodine intake and thyroid nodules.
13Iodine deficiency.PubMed
Michael B Zimmermann
Endocr Rev. 2009 Jun;30(4):376-408. doi: 10.1210/er.2009-0011. Epub 2009 May 21.
Iodine deficiency has multiple adverse effects in humans, termed iodine deficiency disorders, due to inadequate thyroid hormone production. Globally, it is estimated that 2 billion individuals have an insufficient iodine intake, and South Asia and sub-Saharan Africa are particularly affected. However, about 50% of Europe remains mildly iodine deficient, and iodine intakes in other industrialized countries, including the United States and Australia, have fallen in recent years. Iodine deficiency during pregnancy and infancy may impair growth and neurodevelopment of the offspring and increase infant mortality. Deficiency during childhood reduces somatic growth and cognitive and motor function. Assessment methods include urinary iodine concentration, goiter, newborn TSH, and blood thyroglobulin. But assessment of iodine status in pregnancy is difficult, and it remains unclear whether iodine intakes are sufficient in this group, leading to calls for iodine supplementation during pregnancy in several industrialized countries. In most countries, the best strategy to control iodine deficiency in populations is carefully monitored universal salt iodization, one of the most cost-effective ways to contribute to economic and social development. Achieving optimal iodine intakes from iodized salt (in the range of 150-250 microg/d for adults) may minimize the amount of thyroid dysfunction in populations. Ensuring adequate iodine status during parenteral nutrition has become important, particularly in preterm infants, as the use of povidone-iodine disinfectants has declined. Introduction of iodized salt to regions of chronic iodine deficiency may transiently increase the incidence of thyroid disorders, but overall, the relatively small risks of iodine excess are far outweighed by the substantial risks of iodine deficiency.
14Relationship Between Urinary Iodine Concentration and the Prevalence of Thyroid Nodules and Subclinical Hypothyroidism.PubMed
Huachao Zhu, Pu Chen, Xi Ding, et al.
Horm Metab Res. 2024 May;56(5):368-372. doi: 10.1055/a-2258-8258. Epub 2024 Mar 6.
The aim of the study was to investigate the iodine intake in the resident population in Xi'an and analyze the relationship between iodine nutritional status and the prevalence of subclinical hypothyroidism and thyroid nodules (TNs). A total of 2507 people were enrolled in Xi'an. Venous serum thyroid stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb), urinary iodine concentration (UIC), and thyroid ultrasonography were collected. Patients with abnormal TSH were checked for free thyroxine (FT4) and triiodothyronine (FT3). Adults in Xi'an had median UICs of 220.80 μg/L and 178.56 μg/l, respectively. A sum of 16.78% of people had subclinical hypothyroidism. Both iodine excess and iodine deficit increased the frequency of subclinical hypothyroidism. The lowest was around 15.09% in females with urine iodine levels between 200 and 299 μg/l. With a rate of 10.69%, the lowest prevalence range for males was 100-199 μg/l. In Xi'an, 11.37% of people have TNs. In comparison to other UIC categories, TN occurrences were higher in females (18.5%) and males (12%) when UIC were below 100 μg/l. In conclusion, iodine intake was sufficient in the Xi'an area, while the adults' UIC remains slightly higher than the criteria. Iodine excess or deficiency can lead to an increase in the prevalence of subclinical hypothyroidism. Patients with iodine deficiency are more likely to develop TNs.
15Iodine nutrition and thyroid diseases in Chengdu, China: an epidemiological study.PubMed
Y R Yan, Y Liu, H Huang, et al.
QJM. 2015 May;108(5):379-85. doi: 10.1093/qjmed/hcu216. Epub 2014 Oct 21.
OBJECTIVE: To assess the iodine nutritional status and investigate the prevalence of thyroid diseases in a community population in Chengdu, China. METHODS: Eighty school-age children were randomly selected for measurements of urinary iodine concentration. A total of 1500 residents over the age of 18 who had lived in Chengdu for more than 5 years were selected by stratified cluster sampling. Serum thyroid hormone concentrations and thyroid autoantibodies were measured, and thyroid ultrasonography was performed. RESULTS: The median urine iodine concentration was 184 µg/l in school-age children. The prevalence of clinical hyperthyroidism, subclinical hyperthyroidism, clinical hypothyroidism and subclinical hypothyroidism was 0.97%, 1.95%, 0.90% and 5.55%, respectively. The prevalence of thyroid autoantibodies and thyroid nodules was 15.82% and 16.87%, respectively. The prevalence of clinical hyper- and hypothyroidism was greater in females than in males (P < 0.05). The prevalence of subclinical hyper- and hypothyroidism, thyroid nodules and thyroid autoantibodies increased significantly with age (P < 0.05). The rate of new abnormal TSH was 9.37%, and the average serum Thyroid Stimulating Hormone (TSH) concentrations increased with age. When TSH >0.71 mU/l, the prevalence of positive TPOAb and/or TgAb increased significantly with rising concentrations of TSH (P < 0.05); however, the prevalence of thyroid nodules did not increase with escalating concentrations of TSH (P = 0.09). CONCLUSION: Subclinical thyroid diseases, especially subclinical hypothyroidism and thyroid nodules, are common in an iodine sufficient area. Females and the elderly might benefit from routine screening for thyroid diseases, followed by appropriate detection and treatment.
16Prevalence of thyroid nodules and its association with water iodine among Chinese men and women.PubMed
Yu Zhu, Mingkun Tong, Yingying Wang, et al.
Environ Res. 2022 Sep;212(Pt B):113270. doi: 10.1016/j.envres.2022.113270. Epub 2022 Apr 21.
BACKGROUND: Because of the large change in iodine nutrition and other lifestyle in China, there is concern that thyroid nodules (TNs) may become epidemic. However, few data are currently available on the national prevalence of TNs. In addition, whether excess iodine in drinking water is associated with an increased risk of TNs, following universal salt iodization, has been less studied. We aim to estimate a national prevalence of TNs and its association with drinking water iodine. METHODS: We conducted a national survey of 9,381,032 adults, aged 18 years or older, from 30 provinces and municipalities in China, who underwent a thyroid ultrasound test from January 2018 to December 2018. Crude and standardized prevalence of TNs were estimated. We further evaluated the ecological association between province- or city-specific iodine levels in drinking water and the prevalence of TNs using linear regression. RESULTS: The age-standardized prevalence of TNs in men, women, and both sexes were 29.8%, 44.7%, and 37.1%, respectively. The prevalence increased with age from 22.7% (18-30 years) to 71.5% (≥70 years), and body mass index from 26.1% (<18.5 kg/m2) to 40.8% (≥28 kg/m2). Participants living in the eastern, northern, and northeastern regions had a higher prevalence of TNs (ranged from 38.7% to 43.7%) than those in other regions (ranged from 30.1% to 35.5%). The coastal residents (40.1%) had a higher prevalence of TNs than those in inlanders (35.4%). Higher levels of iodine in drinking water were linearly associated with increased prevalence of TNs, with Pearson correlation coefficients of 0.47 (P < 0.01) in men, 0.40 (P = 0.03) in women, and 0.46 (P = 0.01) in overall participants. CONCLUSION: This was a nationwide prevalence study of TNs in China, showing that TNs were common health problems, and increased concentration of iodine in drinking water was associated with a higher prevalence of TNs.
17Iodine status and its association with prevalence of thyroid diseases in adults from Jiangxi Province, China.PubMed
Di-En Yan, Lei Hu, Yun-Feng Shen, et al.
Endocrine. 2023 Nov;82(2):335-342. doi: 10.1007/s12020-023-03413-8. Epub 2023 Jun 12.
BACKGROUND: Iodine is an essential element for the biosynthesis of thyroid-stimulating hormone (TSH). Both excessive and deficient iodine are major risk factors for thyroid diseases, including thyroid dysfunction, thyroid nodules, and thyroid autoimmunity (TAI). This study aimed to elucidate the relationship between iodine status and the prevalence of thyroid diseases through a national cross-sectional epidemiological survey in Jiangxi province (China). METHODS: This population-based, cross-sectional study enrolled 2636 Chinese local inhabitants who aged over 18 years old from April to August in 2015. Physical examination was performed and biochemical indices, urinary iodine concentration (UIC), and TSH level were measured. The Chi-square test, nonparametric test, and 4 multivariate logistic regression models adjusted for risk factors were applied to analysis. Spearman correlation coefficients were calculated to investigate the relationship between iodine intake level and the prevalence of thyroid diseases. RESULTS: The median UIC was 176.4 μg/L, and a significant difference was found in median UIC between men (182.45 μg/L) and women (169.25 μg/L) (P = 0.03). Among these study subjects, 14.4%, 44.5%, 26.1%, and 15.0% had deficient, adequate, more than adequate, and excessive iodine concentrations, respectively. The prevalence rates of hyperthyroidism, subclinical hyperthyroidism, hypothyroidism, subclinical hypothyroidism, thyroid nodules, and TAI were 0.91%, 0.57%, 0.34% and 7.89%, 9.45%, and 12.7%, respectively. Significant differences were found in iodine status, waist circumstance, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), TSH, thyroid nodules, and TAI between men and women (P < 0.05). Compared with those with adequate UIC, subjects with excessive UIC had higher prevalence rates of thyroid dysfunction (odds ratio (OR) = 1.74, 95% confidence interval (CI): 1.40-2.54) and thyroid nodules (OR = 3.33, 95%CI 1.32-8.42). In addition, subjects with deficient and excessive UIC were at the higher risk of TAI compared with those with adequate UIC (OR = 1.68, 95%CI: 1.19-2.60; OR = 1.52, 95%CI: 1.04-2.96, respectively). UIC was positively correlated with the prevalence rates of thyroid nodules (r = -0.44, P < 0.01) and TAI (r = -0.055, P < 0.01). On the contrary, UIC was negatively correlated with the risk of thyroid dysfunction (r = -0.24, P > 0.05). CONCLUSION: Adult inhabitants from Jiangxi province in the TIDE study were in the adequate iodine status. Excessive iodine status was noted as a risk factor for thyroid dysfunction and thyroid nodules. In addition, both iodine deficiency and excessive iodine were risk factors for TAI.
18Relation between iodine nutrition and thyroid diseases in Qinghai, China.PubMed
Xiaoxia Fan, Lingling Zhao, Shuqiong Wang, et al.
Front Endocrinol (Lausanne). 2023 Sep 8;14:1234482. doi: 10.3389/fendo.2023.1234482. eCollection 2023.
OBJECTIVE: To investigate the adult iodine nutrition and the prevalence of thyroid diseases in Qinghai Province, and analyze the correlation between iodine and thyroid diseases, so as to provide a basis for adjusting the salt iodization plan in Qinghai Province. METHODS: Using cluster and stratified sampling method to select 2628 permanent residents over 18 years old in Qinghai Province for questionnaire survey, physical examination, thyroid color ultrasound, and laboratory index detection. RESULTS: 1. The coverage of iodized salt in adults is 99.71%. 2. The detection rates of thyroid disorders in adults were as follows: Clinical hyperthyroidism was 1.20%, subclinical hyperthyroidism was 0.20%, clinical hypothyroidism was 1.00%, subclinical hypothyroidism was 29.20%, and the goiter was 2.10%. The percentages positivity of TPO Ab, TG Ab, goiter was 9.80%, 9.20%, 2.10%, respectively. Among them single thyroid nodule was 6.40%, multi-nodule thyroid gland was 1.80%. 3. The percentages of mild iodine deficiency, moderate iodine deficiency, Severe iodine deficiency, adequate iodine intake (AI), more than adequate iodine intake (MAI)and excessive iodine intake (EI)were 8.41%, 2.17%, 0.26%, 33.22%, 28.35%, and 27.59%, respectively. The percentages of mild, moderate and severe iodine deficiency in urban populations (7.13%, 0.87%, 0.0%) were significantly lower than those in rural populations (9.81%, 3.59%, 0.56%) (P < 0.05), and the rates of adequate, more than adequate iodine intake in urban populations (36.03%, 30.93%) were significantly higher than that in rural populations (30.14%, 25.52%). The rate of excess iodine intake was higher in rural areas (30.38%) than in urban areas (25.04%). 4. The positive rates of subclinical hypothyroidism, goiter, TPO Ab and TG Ab in female adults (35.28%, 3.39%, 13.54%, 13.94%) were higher than those in male adults (23.58%, 0.96%, 6.266%, 4.79%). The detection rate of single thyroid nodules was higher in urban (8.01%) than rural populations (4.70%), while the detection rate of hypothyroidism, subclinical hypothyroidism, and goiter (0.58%, 25.84%, 1.38%) was lower than that in rural populations (1.52%, 32.96%, 2.96%) (P<0.05). 5. There was no statistical significance in the detection rates of clinical hyperthyroidism, subclinical hypothyroidism, subclinical hypothyroidism, goiter, thyroid nodules, TPO Ab and TG Ab positive rates in different iodine nutritional status (P>0.05). The positive rate of hypothyroidism in the iodine deficiency group is higher than in other iodine nutrition groups. CONCLUSION: The nutritional status of iodine in Qinghai Province is iodine excess. Subclinical hypothyroidism was detected at a high rate. Subclinical hypothyroidism, goiter, TPO Ab, and TG Ab were more common in female than in male. The proportion of mild, moderate, and severe iodine deficiency was higher in urban areas than in rural areas. The detection rate of thyroid nodules was higher in urban than in rural areas, and that of hypothyroidism, subclinical hypothyroidism, and goiter was lower than that in rural populations. The detection rate of clinical hypothyroidism was statistically significant in different iodine nutritional states (P< 0.05).
19Association between Urinary Iodine Concentration and Thyroid Nodules in Adults: A Cross-Sectional Study in China.PubMed
Hui Sun, Hanyu Wang, Xiaolan Lian, et al.
Biomed Res Int. 2020 Dec 17;2020:4138657. doi: 10.1155/2020/4138657. eCollection 2020.
BACKGROUND: Associations between iodine intake and thyroid nodules (TNs) were not consistent. We aimed to illustrate the relationship between urinary iodine concentration (UIC) and TNs. METHODS: A total of 12,698 participants were enrolled in analysis. All of the participants filled out questionnaires and underwent physical examinations, laboratory tests, and thyroid ultrasonography. UIC, serum thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb) were measured in the central laboratory. RESULTS: The prevalence of TNs was 16.00%, and the median UIC was 206.1 g/L. TNs and UIC were negatively related when UIC was less than 527 g/L (adjusted OR = 0.87; 95% CI, 0.80, 0.94), and the relationship between UIC and TNs was not statistically significant when UIC was greater than 527 g/L (adjusted OR = 1.25; 95% CI, 0.98, 1.60). In women, UIC was negatively associated with risk for TNs (adjusted OR 0.95; 95% CI, 0.91, 0.99). CONCLUSION: The relationship between TNs and UIC differed between men and women. The risk of TNs decreased with the elevation of UIC in men when UIC was lower than 527 g/L, while UIC and the presence of TNs were negatively correlated in women. In the future, cohort studies or other studies that can explain causality must be conducted to explore the relationship between iodine status and TNs.
20Changing Iodine Status and the Incidence of Thyroid Disease in Mainland China: A Prospective 20-Year Follow-Up Study.PubMed
Zhongyan Shan, Yushu Li, Yongze Li, et al.
Thyroid. 2023 Jul;33(7):858-866. doi: 10.1089/thy.2022.0505. Epub 2023 May 26.
We aimed to assess the long-term effects of the transition in iodine status on the incidence of thyroid disorders over 20 years of follow-up. The original prospective cohort study, started in 1999 ( = 3761), classified three regions in north China based on iodine status (insufficient iodine, more than adequate iodine, and excessive iodine, respectively) for 5 years. Subsequently, participants were followed for up to another 15 years to assess the long-term effects of shifts to adequate iodine on the incidence of thyroid disorders. Panshan transitioned from insufficient to adequate iodine, and Huanghua transitioned from excessive to more than adequate iodine. Both regions were compared with Zhangwu, in which iodine status changed from more than adequate to adequate iodine (from 214 to 167.2 μg/L). A cluster sampling method was used to select participants in the three regions. Participants completed questionnaires and underwent thyroid ultrasonography. Urinary iodine concentrations (UICs), serum thyroid hormone concentration, and thyroid antibodies were measured. When the iodine status changed from insufficient to adequate (with the median UIC increasing from 88 to 141.9 μg/L), the incidence density of subclinical hyperthyroidism, positive thyroperoxidase antibody, positive thyroglobulin antibody (TgAb), and goiter decreased significantly ( < 0.05 for all). Additionally, the cumulative incidence of subclinical hypothyroidism was significantly lower compared with the region where the iodine status changed from being more than adequate to adequate (1.9% vs. 6.0%, < 0.001). When the iodine status changed from excessive to more than adequate (median UIC from 634 to 266.7 μg/L), a significant decrease in the incidence density of subclinical hyperthyroidism, positive thyroid antibodies, positive TgAb, and goiter ( < 0.05 for all) were also found. However, an increase in thyroid nodule incidence density (17.26 vs. 28.25 per 1000 person-years, < 0.001) was seen. The incidence of thyroid disorders (except for thyroid nodules) stabilized or decreased among adults in the three communities from year 5 to year 15 of follow-up. Appropriate iodine fortification is safe and effective over the long term. Restoring urinary iodine to appropriate levels reduces population risk for thyroid disorders.
21Iodine inhibits the proliferation of rat thyroid cells in culture.PubMed
D Tramontano, B M Veneziani, A Lombardi, et al.
Endocrinology. 1989 Aug;125(2):984-92. doi: 10.1210/endo-125-2-984.
We have explored the mechanisms whereby iodine inhibits thyroid growth using as models both the FRTL5 line of rat thyroid follicular cells that require TSH for growth and the M12 line of mutant cells that grow in the absence of TSH. Between 0.01-1.0 mM, NaI produced a dose-dependent inhibition of TSH stimulation of [3H]thymidine incorporation and replication in FRTL5 cells as well as spontaneous growth in M12 cells. Iodide also inhibited the cAMP-dependent growth of FRTL5 cells induced by forskolin and (Bu)2cAMP, as well as the cAMP-independent mitogenesis induced by insulin-like growth factor-I. The effect of iodide to inhibit both TSH- and insulin-like growth factor-I-stimulated growth in FRTL5 cells was abolished by concomitant culture with methimazole, and no iodide inhibition of growth was observed in L6 myoblasts and BRL 30E hepatocytes. Exposure of cells to iodide under conditions that resulted in inhibition of TSH-stimulated growth did not significantly alter the ability of TSH to increase the intracellular cAMP concentration, nor did iodide alter two responses to TSH in FRTL5 cells that depend upon an increase in cAMP concentration: down-regulation of TSH receptor and cytoskeletal reorganization. We conclude that iodide exerts its inhibitory action on the growth of thyroid cells at multiple loci related to both the cAMP-dependent and cAMP-independent pathways of mitogenic regulation.
22High iodine blocks a Notch/miR-19 loop activated by the BRAF(V600E) oncoprotein and restores the response to TGFβ in thyroid follicular cells.PubMed
Cesar Seigi Fuziwara, Edna Teruko Kimura
Thyroid. 2014 Mar;24(3):453-62. doi: 10.1089/thy.2013.0398. Epub 2014 Jan 29.
BACKGROUND: Excess iodine inhibits thyroid follicular cell proliferation associated with TGFβ pathway activation, although thyroid cancers are frequently refractory to TGFβ signaling. The TGFβ pathway is predicted to be regulated by miR-17-92 cluster microRNAs. MicroRNAs are small noncoding RNAs that inhibit target mRNA translation and have emerged as potent modulators of tumorigenesis. Although the BRAF(V600E) mutation is the most prevalent alteration in thyroid cancer, the impact of iodine intake on BRAF-mediated oncogenesis remains unclear. Therefore, the aim of this study was to investigate the influence of high iodine on miR-17-92 transcriptional regulation and expression in thyroid cells expressing activated BRAF. METHODS: Rat thyroid follicular cells that conditionally express BRAF(V600E) under doxycycline stimulation (PC-BRAF(V600E)-6) were derived from the PCCl3 line. These cells were treated with doxycycline for two days, in the absence or presence of 10 μM sodium iodide. The thyroid cancer cell lines BCPAP and KTC2 were also analyzed. Expression of the miR-17-92 cluster and Notch1 was analyzed by quantitative polymerase chain reaction, and expression of these genes was modulated by anti-miR or anti-Notch1 siRNAs transfection. Protein expression was assessed by Western blot. Luciferase assays were used to quantify Smad4 3'-UTR/miR-19 interaction and Notch signaling activation. TGFβ responsiveness was evaluated by cell cycle analysis of TGFβ-treated cells. RESULTS: High iodine blocked BRAF(V600E)-induced upregulation of miR-17-92, including miR-19a/b. miR-17-92 promoter region analysis revealed a putative binding site for Hes1, a transcription factor responsive to Notch signaling. Notch-1 overexpression resulted in miR-19 upregulation in normal thyroid cells, while Notch-1 knockdown blocked BRAF-induced miR-19 expression. Moreover, in anaplastic thyroid cancer cells, Notch-1 knockdown reduced miR-19. Expression of BRAF(V600E) decreased Smad4 protein in normal thyroid cells. Smad4 was validated as a miR-19 target by luciferase assays, which revealed reduced luminescence associated with miR-19 interaction in Smad4 3'-UTR. Iodine treatment restored Smad4 levels in BRAF-activated cells, resulting in enhanced G1-cell cycle arrest in response to TGFβ. Moreover, this effect was mimicked in papillary thyroid cancer cells treated with anti-miR-19. CONCLUSION: High iodine abrogates BRAF(V600E)-induced activation of miR-19, a newly identified Smad4 regulator, through Notch pathway inhibition and restores responsiveness to TGFβ signaling. Our results indicate that iodine exerts protective effects in thyroid cells, attenuating acute BRAF oncogene-mediated microRNA deregulation.
23Iodine nutrition status and thyroid autoimmunity during pregnancy: a cross-sectional study of 4635 pregnant women.PubMed
Xiao Chen, Chunfeng Wu, Zhengyuan Wang, et al.
Nutr J. 2022 Jan 29;21(1):7. doi: 10.1186/s12937-022-00760-6.
BACKGROUND: Pregnant women in Shanghai have long been at risk for mild iodine deficiency. Because thyroid autoimmunity in pregnant women can lead to premature birth and miscarriage as well as neurodevelopmental deficits in the fetus, the aim of this study was to explore the association of iodine nutrition status with thyroid antibodies during pregnancy. METHODS: A pregnancy-birth cohort was conducted including 4635 pregnant women in Shanghai, China. The eligible participants underwent a face-to-face interview and completed questionnaire surveys to collect baseline information and diet intake. Spot urine samples were collected to test urine iodine. Thyroid antibodies including thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and thyrotrophic antibodies (TRAb) were tested. Single-factor analysis and logistic regression were used to evaluate the association between iodine status and thyroid autoimmunity during pregnancy. RESULTS: The median urinary iodine excretion level in the sample was 138.14 μg/L (interquartile range [IQR] 80.90-219.00 μg/L). Among all the subjects, 25.9% consumed non-iodized salt, 54.5% had iodine deficiency, and 31.0% had thyroid autoimmunity. The proportion of patients with iodine deficiency was significantly higher among those who consumed non-iodized salt (36.9% vs. 33.1%; p = 0.04). After adjusting for age, educational status, former smoker status, former drinker status, first pregnancy, and previous thyroid disease, non-iodized salt (odds ratio [OR] = 1.394 [confidence interval, CI, 1.165-1.562]; p = 0.003), iodine-rich food (OR = 0.681 [CI 0.585-0.793]; p = 0.003), iodized nutritional supplements (OR = 0.427 [CI 0.347-0.526]; p = 0.003), were found to be individually associated with thyroid autoimmunity in all participants. The results of the multivariable restricted cubic spline regression analysis showed a non-linear relationship between the continuous change in iodine intake and thyroid autoimmunity (p = 0.019). Participants with iodine deficiency (urinary iodine concentration, UIC,< 100 μg/L) had an increased risk of testing positive for thyroid antibodies (TPOAb/TgAb/TRAb[+]; OR = 1.324 [CI 1.125-1.559]; p < 0.001). Moreover, this associated existed even after removing participants with previous thyroid disease. CONCLUSION: Inadequate iodine nutrition in pregnant women is an independent risk factor for thyroid autoimmunity in Shanghai. It's important to maintain the adequate iodine status in pregnant women.
24Epidemiological survey of the status of iodine nutrition and thyroid diseases in Guangxi, China.PubMed
Li-Heng Meng, Cui-Hong Chen, Ying Liu, et al.
J Trace Elem Med Biol. 2022 Mar;70:126918. doi: 10.1016/j.jtemb.2021.126918. Epub 2021 Dec 22.
OBJECTIVE: To survey the status of iodine nutrition and the prevalence of thyroid diseases in Guangxi, China, and to explore the risk factors for positive thyroid antibody. METHODS: We used the multistage stratified cluster random sampling method to select a total of 2488 subjects from an urban and a rural location. All the subjects completed a questionnaire survey, blood and urine samples were also collected, and B-mode thyroid ultrasound was used to determine thyroid function and detect thyroid antibodies. RESULTS: 1) The median level of urinary iodine was 148.53 μg/L in school-age children in Guangxi, China. 2) The prevalence rates for thyroid diseases were as follows: hyperthyroidism, 0.89 %; subclinical hyperthyroidism, 1.05 %; hypothyroidism, 0.69 %; and subclinical hypothyroidism, 8.87 %. The rates of thyroid antibody positivity were as follows: thyroid peroxidase antibody (TPOAb), 13.60 %; thyroglobulin antibody (TGAb), 13.60 %; thyroid antibodies, 18.2 %; and thyroid nodules, 16.94 %. 3) The rate of TPOAb positivity was significantly higher in women aged 18-29, 30-39, 40-49, or 60-69 years than in men in the same age groups (P < 0.05), and the TGAb positivity rate was significantly higher in women than in men of the same age group (P < 0.05). 4) The rate of thyroid antibody positivity was significantly higher in individuals with iodine deficiency than in individuals with adequate iodine (21.6 % vs 18.4 %) or excess iodine (21.6 % vs 15.5 %) (both P < 0.05). 5) The female sex and a family history of thyroid diseases were the major risk factors for thyroid antibody positivity (odds ratio [OR] 3.010, P <0.05; OR 2.486, P <0.05). CONCLUSION: The overall level of iodine is adequate in Guangxi, China; this level should be maintained to prevent the thyroid diseases related with iodine deficiency or excess of iodine. Female sex and a family history of thyroid diseases are independent risk factors for thyroid antibody positivity.
25Study of the relationship between thyroid autoimmunity, obesity and serum leptin level in a sample of Egyptian individuals.PubMed
Salma S Hassan, Salwa S Hosny, Khaled M Makboul, et al.
Egypt J Immunol. 2024 Oct;31(4):136-144.
Obesity is a worldwide health problem, and its prevalence is increasing steadily all over the globe. Leptin, mainly produced by adipocytes, was identified to modulate the immune system, as well as contributing to increased production of thyroid peroxidase antibodies (TPO-Ab) and thyroglobulin antibody (TG-Ab). Autoimmune thyroiditis, mainly Hashimoto's thyroiditis, is believed to be the main cause of hypothyroidism in iodine sufficient regions, (TPO-Ab) and (TG-Ab) are the hallmarks of this disease. This study aimed to assess the relationship between thyroid autoimmunity, obesity and serum leptin level in a sample of Egyptian individuals. This study was a case control study which included 60 participants, recruited from the outpatient of the Internal Medicine Clinic at Ain Shams University Hospitals, during the period from February 2022 to October 2022. They were divided into two groups: Group 1 included 30 participants, have Residual hematopoiesis is an important prognostic factor of immunosuppressive therapy in severe aplastic anemia (BMI) >30 kg/m2, and Group 2 included 30 participants, have BMI (18.5-25 kg/m2). We detected serum leptin, thyroid profile and thyroid antibodies using the enzyme linked immunosorbent assay and other immunoassays. Serum levels of leptin, thyroid-stimulating hormone (TSH) and glycated hemoglobin (HbA1c) were statistically significantly higher in group 1 than in group 2 (p=0.0001 for all). Also, there was a statistically significant positive correlation between leptin level and Anti-TPO in group 1 (p=0.002). In addition, in group 1, there was a statistically significant positive correlation between serum leptin level and TSH (p=0.0001). In conclusion, there is a relationship between thyroid autoimmunity and serum leptin level in obese subjects.
26The importance of sodium/iodide symporter (NIS) for thyroid cancer management.PubMed
Denise P Carvalho, Andrea C F Ferreira
Arq Bras Endocrinol Metabol. 2007 Jul;51(5):672-82. doi: 10.1590/s0004-27302007000500004.
The thyroid gland has the ability to uptake and concentrate iodide, which is a fundamental step in thyroid hormone biosynthesis. Radioiodine has been used as a diagnostic and therapeutic tool for several years. However, the studies related to the mechanisms of iodide transport were only possible after the cloning of the gene that encodes the sodium/iodide symporter (NIS). The studies about the regulation of NIS expression and the possibility of gene therapy with the aim of transferring NIS gene to cells that normally do not express the symporter have also become possible. In the majority of hypofunctioning thyroid nodules, both benign and malignant, NIS gene expression is maintained, but NIS protein is retained in the intracellular compartment. The expression of NIS in non-thyroid tumoral cells in vivo has been possible through the transfer of NIS gene under the control of tissue-specific promoters. Apart from its therapeutic use, NIS has also been used for the localization of metastases by scintigraphy or PET-scan with 124I. In conclusion, NIS gene cloning led to an important development in the field of thyroid pathophysiology, and has also been fundamental to extend the use of radioiodine for the management of non-thyroid tumors.
27Analysis of human sodium/iodide symporter, thyroid transcription factor-1, and paired-box-protein-8 gene expression in benign thyroid diseases.PubMed
W Joba, C Spitzweg, K Schriever, et al.
Thyroid. 1999 May;9(5):455-66. doi: 10.1089/thy.1999.9.455.
The ability to concentrate iodide, a fundamental property of normally functioning thyroid tissue, is altered in various thyroid diseases. Given the critical role of the Na+/I- symporter (NIS) in controlling iodide access to the thyroid gland, altered expression of NIS may be responsible, at least in part, for an enhanced or diminished capacity to concentrate iodide. In this study, we used Northern blot analysis, a newly established quantitative polymerase chain reaction (PCR) assay and in addition hNIS-directed immunohistochemical analysis to assess the levels of hNIS mRNA and protein expression in various localized and diffuse benign thyroid abnormalities, including Graves' disease (GD), scintigraphically cold solitary benign thyroid nodule (CBTN), nontoxic multinodular goiter (NMNG), solitary autonomously functioning thyroid nodule (AFTN), and mild diffuse iodine deficiency goiter (IDG). In addition, in view of the recent identification of putative binding sites for the transcription factors thyroid transcription factor-1 (TTF-1) and human paired-box-protein-8 (Pax-8) in the human NIS gene promoter, we used reverse transcriptase-polymerase chain reaction (RT-PCR) to assess in these same samples the levels of TTF-1 and Pax-8 gene expression. Northern blot analysis revealed high levels of hNIS gene expression in thyroid specimens derived from patients with GD and AFTN. In contrast, levels of hNIS mRNA expression were moderate in NMNG, low in diffuse IDG, and very low in CBTN. Quantitative RT-PCR analysis of hNIS mRNA transcripts revealed variable but generally low levels of hNIS gene expression in IDG and NMNG, and undetectable or very low levels of hNIS mRNA in all scintigraphically CBTN studied. In contrast, markedly elevated levels of hNIS mRNA transcripts were detected in active GD (up to 17-fold) and AFTN (up to 25-fold). Immunohistochemical analysis revealed abundant hNIS protein expression by thyroid follicular cells in GD, moderate and heterogeneous levels in NMNG, and very low levels in CBTN. hNIS mRNA levels were correlated with TTF-1 and Pax-8 gene expression in GD and, to a lesser degree, in AFTN, NMNG, and IDG, but not in CBTN. In general, hNIS gene expression was more closely correlated with TTF-1 as compared to Pax-8 gene expression. In conclusion, the abundance of hNIS mRNA and protein expression in a broad range of benign thyroid pathologies correlated well with their functional state as assessed by thyroid scintigraphy. In addition to TTF-1 and Pax-8, other transcription factors and enhancer elements may contribute to regulation of NIS gene promoter activity.
28Estradiol increases proliferation and down-regulates the sodium/iodide symporter gene in FRTL-5 cells.PubMed
T W Furlanetto, L Q Nguyen, J L Jameson
Endocrinology. 1999 Dec;140(12):5705-11. doi: 10.1210/endo.140.12.7197.
Goiter (increased thyroid gland size) is more prevalent in women than men, even in areas where iodine levels in the diet are sufficient. We investigated a possible role of estrogen on thyroid follicular cell growth using rat FRTL-5 thyroid follicular cells as a model. Estrogen receptor-alpha (ERalpha) messenger RNA was present in FRTL-5 cells using a RT-PCR assay and was confirmed by Western blot analysis. An estrogen-responsive reporter gene was transfected into FRTL-5 cells to test the functionality of the endogenous ERs. Estradiol increased the activity of the reporter gene, and the antagonist, ICI182780, inhibited ER-dependent transcription. To extend this analysis, we examined the effect of estradiol on FRTL-5 cell growth. Estradiol increased FRTL-5 cell growth in a time- and concentration-dependent manner in either the absence or presence of TSH. Because iodine is known to inhibit thyroid cell growth, the effect of estradiol on the expression of the sodium/iodide symporter (NIS) was assessed as a potential target of estrogen action. Estradiol blocked TSH-induced NIS expression, and treatment of cells with estradiol and ICI182780 restored TSH-induced NIS expression to normal levels. These data demonstrate that FRTL-5 cells contain functional ERs that enhance cell growth and inhibit expression of the NIS. The demonstration of a direct effect of estradiol on thyroid follicular cells raises the possibility that it may play a role in the sexually dimorphic prevalence of goiter.
29Sodium/iodide symporter mRNA expression in cold thyroid nodules.PubMed
R Paschke, S Neumann
Exp Clin Endocrinol Diabetes. 2001;109(1):45-6. doi: 10.1055/s-2001-11013.
Clinical and experimental data suggest a low thyroid hormone synthesis in cold thyroid nodules (CTN). Therefore, the Na(+)/I(-)-symporter (NIS) as the first step in the thyroid hormone synthesis could be a possible candidate gene in the pathogenesis of CTNs. A reduction of NIS transcripts in CTNs compared to samples of normal thyroid tissues with large inter-individual variations ranging from 2- to 700-fold reductions was observed with real-time RT-PCR. Therefore, the aim of our investigations was to perform an intra-individual comparison of NIS expression in CTNs. Moreover, we used direct detection of NIS mRNA by RNase protection assay (RPA). We investigated 14 patients with one CTN for NIS mRNA expression. NIS mRNA transcripts from nodule and surrounding tissue were examined by RPA. A significantly reduced NIS expression was detected in 86% of the CTNs compared to their corresponding surrounding tissue. The level of NIS expression was decreased to more than 65% in 10 CTNs (72% of the nodules). Two of the 14 nodules showed a decrease of NIS mRNA expression of 42%, and 32%, while no significant differences could be detected in 2 cold nodules. Compared to other studies the intra-individual comparison of NIS mRNA expression revealed a much lower variation of reduced NIS expression in CTNs. Further studies should try to identify molecular factors like post-transcriptional modifications or alterations in iodide organification which are likely to be involved in the pathogenesis of CTNs.
30Benign nonfunctioning thyroid adenomas are characterized by a defective targeting to cell membrane or a reduced expression of the sodium iodide symporter protein.PubMed
Massimo Tonacchera, Paolo Viacava, Patrizia Agretti, et al.
J Clin Endocrinol Metab. 2002 Jan;87(1):352-7. doi: 10.1210/jcem.87.1.8173.
Nodular thyroid disease is the most common endocrine disorder. Nonfunctioning thyroid nodules are identified by their low radioiodide uptake compared with the normal extranodular tissue, which, at thyroid scintiscan, produces the typical picture of a cold thyroid nodule. Previous in vitro studies demonstrated that the majority of nonfunctioning thyroid nodules have a specific defect in iodide transport that accounts for their failure to accumulate radioactive iodide in vivo. A defect in the expression or structure of the sodium iodide symporter (NIS) gene has been hypothesized as a possible cause of the impaired iodide trapping in nonfunctioning thyroid nodules. We studied 22 patients who were submitted to surgery for a solitary nonfunctioning thyroid nodule that originated in an otherwise normal gland. Thyroid scintigraphy was performed at 1, 2, 3, 4, 6, and 24 h after the oral administration of a tracer dose of 131I (iodine). All patients showed absence of 131I uptake in the nodule, with normal uptake in the extranodular tissue and in the contralateral thyroid lobe. Eight patients with toxic adenomas who underwent lobectomy were also included in the study. We first studied the expression of human NIS (hNIS) protein by immunohistochemistry in paraffin-embedded tissue sections using a specific anti-hNIS monoclonal antibody. Subsequently, we searched for somatic mutations of hNIS gene in nonfunctioning thyroid nodules. The level of hNIS expression was determined in both the nodules and the normal tissue from the same thyroid gland. In all functioning thyroid nodules (toxic adenomas), a high expression of hNIS protein was detected with respect to normal surrounding tissue. Similar to the normal thyroid tissue, follicular cells of toxic thyroid adenomas showed an exclusive expression of hNIS protein at the cell membrane. Fifty-four percent of benign nonfunctioning thyroid nodules overexpressed hNIS protein compared with the normal surrounding tissue, but in these nodules the hNIS protein failed to target the cell membrane, being mostly localized inside the cytoplasm. hNIS protein was not detected by immunohistochemistry in 46% of nonfunctioning nodules, whereas it was expressed in the surrounding unaffected thyroid tissue. Direct sequencing of the hNIS gene in all of the nonfunctioning nodules did not reveal major genetic alterations. A silent polymorphism (GCC/GCG codon 544, exon 13) was found in one nodule. In conclusion, the results obtained in this study show that two mechanisms contribute to the reduced radioiodide uptake typical of benign nonfunctioning thyroid nodules: 1) reduced expression of the hNIS protein, and 2) defective targeting of hNIS to the cell membrane.
31Expression of the sodium iodide symporter and thyroglobulin genes are reduced in papillary thyroid cancer.PubMed
M D Ringel, J Anderson, S L Souza, et al.
Mod Pathol. 2001 Apr;14(4):289-96. doi: 10.1038/modpathol.3880305.
Altered expression of the gene encoding the sodium iodine symporter (NIS) may be an important factor that leads to the reduced iodine accumulation characteristic of most benign and malignant thyroid nodules. Both up- and down-regulation of NIS gene expression have been reported in thyroid cancer using several different methods. The goal of the present study was to accurately identify alterations in NIS gene expression in benign and malignant thyroid nodules using an accurate real-time quantitative RT-PCR assay system. Total RNA was prepared from 18 benign thyroid nodules, 20 papillary thyroid cancers, and 23 normal thyroid samples from 38 subjects. Quantitative RT-PCR was used to measure NIS and thyroglobulin (TG) mRNA expression in normal thyroid tissue and in each nodular tissue sample. Papillary thyroid cancer samples had significantly lower NIS mRNA expression (72 +/- 41 picogram equivalents [pg Eq]), than did benign nodules (829 +/- 385 pg Eq), or normal tissues (1907 +/- 868 pg Eq, P = 0.04). Most important, in the paired samples, NIS gene expression was decreased in each papillary thyroid cancer compared with normal tissue (69% median decrease; range, 40-96%; P = .013). Eleven of the 12 benign nodules also demonstrated lower NIS gene expression than the normal tissue (49% decrease; range, 2-96%; P = .04). Analysis of the paired samples demonstrated that Tg mRNA expression was significantly lower in each of the thyroid cancer samples than in corresponding normal tissue (759 +/- 245 pg Eq vs. 1854 +/- 542 pg Eq, P = .03). We have demonstrated a significant decrement in NIS gene expression in all papillary thyroid cancers and in over 90% of benign nodules examined compared with adjacent normal thyroid tissue, using a highly accurate quantitative RT-PCR technique. Similarly, thyroid cancers demonstrated significantly lower TG mRNA expression than corresponding normal thyroid. Reduced NIS expression may be an important factor in the impairment of iodine-concentrating ability of neoplastic thyroid tissues.
32hNIS protein in thyroid: the iodine supply influences its expression and localization.PubMed
Angela Scipioni, Elisabetta Ferretti, Giuseppe Soda, et al.
Thyroid. 2007 Jul;17(7):613-8. doi: 10.1089/thy.2007.0064.
OBJECTIVE: Nonfunctioning thyroid nodules (NFTNs) display a diminished iodide-concentrating ability, owing to defective expression and cell membrane targeting of the sodium-iodide symporter (NIS). Since NIS expression is primarily modulated by thyroid iodine content in vitro and in animal models, we attempted to determine whether iodine supply influences the expression and localization of human NIS (hNIS) in NFTNs. DESIGN: Using immunohistochemistry, we analyzed cold hyperplastic nodules and nonnodular thyroid samples (controls) from patients living in iodine-sufficient (n = 19) or severely iodine-deficient (n = 15) areas. MAIN OUTCOME: Nodules from the iodine-sufficient area exhibited weak or absent hNIS immunostaining whereas almost all nodules from the iodine-deficient area were hNIS positive. Heterogeneous hNIS staining was common among the iodine-deficient samples (p = 0.028). hNIS was localized on membrane in all nodular samples from the iodine-deficient area and in less than 40% in the iodine-sufficient area. CONCLUSIONS: hNIS is adequately expressed and appropriately localized in NFTNs cell membrane from iodine-deficient areas and its expression in vivo is modulated by iodine supply.
33Strong association of high urinary iodine with thyroid nodule and papillary thyroid cancer.PubMed
Fang Wang, Yangang Wang, Luan Wang, et al.
Tumour Biol. 2014 Nov;35(11):11375-9. doi: 10.1007/s13277-014-2397-8. Epub 2014 Aug 15.
This study demonstrates a strong association of high urinary iodine with thyroid nodules and papillary thyroid cancer as well as aggressive cancer features, suggesting that high urinary iodine is a risk factor for thyroid cancer. The risk of high iodine intake for thyroid cancer has been suggested but not established. The objective of the study was to evaluate the relationship between urine iodine levels and thyroid nodule and thyroid cancer. We preoperatively tested fasting urine iodine in 154 thyroid nodule patients and correlated the results with pathological diagnoses and compared with 306 subjects as normal control. The median urine iodine (MUI) was 331.33 μg/L in patients with benign thyroid nodules versus 466.23 μg/L in patients with papillary thyroid cancer (PTC) (P=0.003), both of which were in the excessive iodine state and higher than the MUI of 174.30 μg/L in the control group (P < 0.001), which was in the sufficient iodine state. Excessive iodine state (MUI>300 μg/L) was seen in 62.75% of patients with benign thyroid nodules and 66.99% of patients with PTC, both of which were significantly higher than the iodine excessive rate of 19.93% in the control group (P<0.001). Moreover, MUI in patients with PTC with lymph node metastasis was significantly higher than that of PTC patients without lymph node metastasis (P<0.001). Urine iodine of thyroid cancer patients with stage III and IV disease was significantly higher than that of patients with stage I and II diseases (P<0.001). Multivariable analyses showed that, like sand calcification of thyroid nodule and TSH, urine iodine was an independent risk factor for PTC. These data demonstrate a significant association between high urinary iodine and benign and malignant thyroid nodules and PTC aggressiveness, supporting high urinary iodine as a risk factor for thyroid malignancy. Further studies are warranted to confirm these findings.
34High iodine concentration attenuates RET/PTC3 oncogene activation in thyroid follicular cells.PubMed
Ana Paula Zen Petisco Fiore, Cesar Seigi Fuziwara, Edna Teruko Kimura
Thyroid. 2009 Nov;19(11):1249-56. doi: 10.1089/thy.2008.0408.
BACKGROUND: Papillary thyroid carcinoma (PTC) is frequently associated with a RET gene rearrangement that generates a RET/PTC oncogene. RET/PTC is a fusion of the tyrosine kinase domain of RET to the 5' portion of a different gene. This fusion results in a constitutively active MAPK pathway, which plays a key role in PTC development. The RET/PTC3 fusion is primarily associated with radiation-related PTC. Epidemiological studies show a lower incidence of PTC in radiation-exposed regions that are associated with an iodine-rich diet. Since the influence of excess iodine on the development of thyroid cancer is still unclear, the aim of this study is to evaluate the effect of high iodine concentrations on RET/PTC3-activated thyroid cells. METHODS: PTC3-5 cells, a rat thyroid cell lineage harboring doxycycline-inducible RET/PTC3, were treated with 10(-3) M NaI. Cell growth was analyzed by cell counting and the MTT assay. The expression and phosphorylation state of MAPK pathway-related (Braf, Erk, pErk, and pRet) and thyroid-specific (natrium-iodide symporter [Nis] and thyroid-stimulating hormone receptor [Tshr]) proteins were analyzed by Western blotting. Thyroid-specific gene expression was further analyzed by quantitative reverse transcription (RT)-polymerase chain reaction. RESULTS: A significant inhibition of proliferation was observed, along with no significant variation in cell death rate, in the iodine-treated cells. Further, iodine treatment attenuated the loss of Nis and Tshr gene and protein expression induced by RET/PTC3 oncogene induction. Finally, iodine treatment reduced Ret and Erk phosphorylation, without altering Braf and Erk expression. CONCLUSION: Our results indicate an antioncogenic role for excess iodine during thyroid oncogenic activation. These findings contribute to a better understanding of the effect of iodine on thyroid follicular cells, particularly how it may play a protective role during RET/PTC3 oncogene activation.
35Correlation Between Thyroid Nodules and Metabolic Syndrome: A Systematic Review and Meta-Analysis.PubMed
Chenyu Zhang, Xiaotong Gao, Yutong Han, et al.
Front Endocrinol (Lausanne). 2021 Sep 16;12:730279. doi: 10.3389/fendo.2021.730279. eCollection 2021.
OBJECTIVE: Thyroid nodules (TNs) are a common thyroid disorder that can be caused by many factors. Several studies have investigated the relationship between TNs and metabolic syndrome (MetS), but the role of sex and age remains controversial. The purpose of this paper was to analyze published data from all relevant studies to reliably estimate the relationship between TNs and MetS. METHODS: Thirteen articles were included in this study; articles were identified by searching for publications until July 2021 in PubMed, EMBASE, the Cochrane Library and the Web of Science. The outcomes are presented as the summary odds ratio (OR) and 95% confidence interval (CI) and the pooled prevalence and 95% CI. RESULTS: The TNs prevalence was significantly higher in MetS patients than in controls (OR 1.88, 95% CI 1.42-2.50, P < 0.0001) and was independent of sex (male: OR 1.53, 95% CI 1.20-1.94, P = 0.0006; female: OR 1.90, 95% CI 1.54-2.33, P < 0.00001; combined: OR 2.06, 95% CI 1.31-3.25, P = 0.002) and age (< 40 years old: OR 1.62, 95% CI 1.39-1.89, P < 0.0001; 40~50 years old: OR 2.14, 95% CI 1.49-3.08, P < 0.0001;50~60 years old: OR 1.50, 95% CI 1.08-2.07, P = 0. 01; 60 years old: OR 1.70, 95% CI 1.36-2.14, P < 0.00001); the pooled TNs prevalence in MetS patients was 45% (95% CI 36-54%). However, it has not yet been considered that MetS is related to TNs in people with iodine deficiency (OR 3.14, 95% CI 0.92-10.73, P = 0.07). CONCLUSION: The meta-analysis results showed a strong correlation between TNs and MetS. Both male and female patients with MetS had an increased TNs prevalence. In addition, the prevalence was independent of age. However, MetS is not considered to be associated with TNs in iodine-deficient populations.
36Relationship between metabolic syndrome and thyroid nodules in healthy Koreans.PubMed
Juyoung Shin, Min-Hee Kim, Kun-Ho Yoon, et al.
Korean J Intern Med. 2016 Jan;31(1):98-105. doi: 10.3904/kjim.2016.31.1.98. Epub 2015 Dec 28.
BACKGROUND/AIMS: This study evaluated the relationship between thyroid nodules and metabolic syndrome (MS) and its components in apparently healthy Koreans. METHODS: We reviewed the records of 3,298 subjects with no noticeable symptoms who underwent thyroid ultrasound imaging as part of a routine check-up between July 2009 and June 2010; of these, 1,308 were excluded based upon predefined criteria. Among the remaining 1,990 patients, we examined the association between MS and its components and the incidence of thyroid nodules. RESULTS: Of the 1,990 subjects included in this study, 38.4% (n = 764) had thyroid nodules and 12.7% (n = 253) had MS. Female sex, older age, higher body mass index, larger waist circumference, higher glycated hemoglobin level, lower thyroid stimulating hormone level, and presence of MS were all closely related with the presence of thyroid nodules (all p < 0.05). Furthermore, the relevant number of MS components showed a positive linear correlation with the occurrence of thyroid nodules (p < 0.001). Evidence of MS alone was not independently associated with thyroid nodules after adjusting for sex and age in a multivariate binary logistic regression analysis; however, glycated hemoglobin for females and waist circumference for males, as well as both age and thyroid stimulating hormone for all patients, were identified as independent predictors for the existence of thyroid nodules (all p < 0.05). CONCLUSIONS: This study suggests a positive relationship between the components of MS and thyroid nodules in an ostensibly healthy Korean population. Our data support the idea that the recent increase in thyroid nodules is partly due to increases in both MS and obesity.
37Association of obesity and diabetes with thyroid nodules.PubMed
Silvio Buscemi, Fatima Maria Massenti, Sonya Vasto, et al.
Endocrine. 2018 May;60(2):339-347. doi: 10.1007/s12020-017-1394-2. Epub 2017 Aug 23.
AIM: There are conflicting data concerning the possibility that obesity and diabetes raise the risk of thyroid nodules. The incidence of thyroid nodules is increasing, as is that of obesity and diabetes; therefore, understanding whether these metabolic and nutritional disorders influence nodular thyroid disease is important for organizing prevention strategies. This study investigated the association between thyroid nodules, obesity, diabetes, and dietary habits. MATERIALS AND METHODS: A cohort of randomly selected adults (455 males, 746 females; age: 18-90 years) living in Palermo (Italy), a mild iodine deficiency area, was cross-sectionally investigated. Participants underwent high-resolution ultrasonographic evaluation of the thyroid, and answered a food frequency questionnaire. Laboratory blood measurements were obtained in 587 participants. RESULTS AND DISCUSSION: Thyroid nodules were detected in 475 (39.5%) participants. The number of thyroid nodules was correlated with age (r = 0.19; P < 0.001), gender (r = 0.08; P = 0.005), and body mass index (r = 0.07; P = 0.02). No significant correlation was observed between the number of nodules and glycated hemoglobin, serum insulin concentrations, and homeostasis model assessment of insulin resistance. Age-adjusted and gender-adjusted prevalence of both overweight/obesity and type 2 diabetes of each group of participants divided according to the number of nodules significantly increased with the number of nodules (P < 0.05 in both cases). The group of participants with nodules exhibited a significantly lower age-adjusted and gender-adjusted habitual intake of milk (P = 0.02). Multivariate regression analysis showed that age, gender, body mass index, diabetes, and habitual consumption of milk were independently correlated with presence of thyroid nodules. CONCLUSION: This study seems to indicate that an association exists between obesity, diabetes, and thyroid nodules.
38Association between lifestyle and anthropometric parameters and thyroid nodule features.PubMed
Grigorios Panagiotou, Despina Komninou, Panagiotis Anagnostis, et al.
Endocrine. 2017 Jun;56(3):560-567. doi: 10.1007/s12020-017-1285-6. Epub 2017 Apr 8.
PURPOSE: Thyroid nodularity has been associated with obesity, but data regarding associations of body composition parameters with specific ultrasound features of thyroid nodules are lacking. The aim of the present study was to assess associations between thyroid nodule ultrasound characteristics, lifestyle, and anthropometric parameters. SUBJECTS AND METHODS: This was a cross-sectional study in the general apparently healthy population of Northern Greece. Thyroid ultrasound data together with medical history, demographic, and anthropometric characteristics were individually recorded. Body composition was evaluated using bioelectrical impedance. RESULTS: Three hundred and six subjects [215 females (70.3%), aged 20-83 years] were included. Ultrasound revealed one or more thyroid nodules in 168 subjects (54.9%). Subjects with thyroid nodules were more frequently females (p = 0.033), older (p < 0.001) and had higher fat mass (p = 0.011), total body fat percentage (p < 0.001) and waist circumference (p = 0.045) than subjects without nodules. In logistic regression analyses, age and female gender were the only independent predictors of presence of thyroid nodules, as well as specific sonographic features. Additionally, total body fat percentage was positively correlated with nodule size (rho = 0.210, p = 0.006) and was the only independent predictor of hypoechoic thyroid nodule(s) and peripheral vascularity, while lack of exercise was predictive of internal vascularity. CONCLUSIONS: Body fat accumulation and lack of exercise, used as surrogate markers of sedentary lifestyle, influence thyroid nodule size and could predict some ultrasonographic characteristics, like hypoechoicity and internal vascularity. Therefore, routine thyroid examination of obese patients and promotion of active lifestyle may be warranted to prevent thyroid nodule formation and possibly progression to malignancy.
39Thyroid Nodules and Obesity.PubMed
Elpida Demetriou, Maria Fokou, Savvas Frangos, et al.
Life (Basel). 2023 May 31;13(6):1292. doi: 10.3390/life13061292.
A widely discussed topic in the pathophysiology of thyroid nodules is the role of obesity, a state that leads to increased systemic inflammatory markers. Leptin plays a vital role in forming thyroid nodules and cancer through several mechanisms. Together with chronic inflammation, there is an augmentation in the secretion of tumor necrosis factor (TNF) and the cytokine interleukin 6 (IL-6), which contributed to cancer development, progression and metastasis. In addition, leptin exerts a modulatory action in the growth, proliferation and invasion of thyroid carcinoma cell lines via activating various signal pathways, such as Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) and/or phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt). Through several proposed mechanisms, aberrant endogenous estrogen levels have been suggested to play a vital role in the development of both benign and malignant nodules. Metabolic syndrome triggers the development of thyroid nodules by stimulating thyroid proliferation and angiogenesis due to hyperinsulinemia, hyperglycemia and dyslipidemia. Insulin resistance influences the distribution and structure of the thyroid blood vessels. Insulin growth factor 1 (IGF-1) and insulin affect the regulation of the expression of thyroid genes and the proliferation and differentiation of thyroid cells. TSH can promote the differentiation of pre-adipocytes to mature adipocytes but also, in the presence of insulin, TSH possesses mitogenic properties. This review aims to summarize the underlying mechanisms explaining the role of obesity in the pathophysiology of thyroid nodules and discuss potential clinical implications.
40OPG is associated with thyroid nodule development in type 2 diabetes.PubMed
Dazhi Huang, Yixin Niu, Weiwei Zhang, et al.
J Clin Lab Anal. 2022 Sep;36(9):e24615. doi: 10.1002/jcla.24615. Epub 2022 Jul 23.
BACKGROUND: Thyroid nodule prevalence is increasing lately, especially in diabetes, but the mechanism of which is not clear. In this study, we investigated if osteoprotegerin (OPG) is involved in the pathogenesis of thyroid nodules in diabetes. METHODS: A total of 7568 individuals with detailed information and ultrasound examination results were studied for the prevalence of thyroid nodules. Among them, 1883 were with type 2 diabetes and 5685 were non-diabetic. Then, 1120 individuals were randomly selected for the measurement of OPG. Diabetic rats were made by feeding a high-fat-high-fructose diet for 28 weeks. Rats fed with a normal diet were as controls. Fresh thyroid tissues were obtained and fixed, dehydrated, and embedded in paraffin for hematoxylin-eosin staining and observing pathological changes. qPCR and western blot were used to detect OPG expression in rat thyroid tissues. RESULTS: We found that HbA1c is an independent risk factor for thyroid nodules (Exp [β] = 1.158, p < 0.001). The prevalence of thyroid nodules in type 2 diabetes was higher than that in non-diabetes (53.9% vs. 46.7%, p < 0.001). Serum OPG levels were significantly elevated in the diabetes group than in the non-diabetes group (3160.17 pg/ml vs. 2819.39 pg/ml, p < 0.01). The expression of OPG increased significantly in the thyroid tissues of diabetic rats. CONCLUSION: Osteoprotegerin may be associated with thyroid nodule development in diabetes.
41Insulin resistance factors associated with differentiated thyroid carcinoma and malignant cytology: serum thyroxine as an associated factor.PubMed
Lina Guzikauskas Celescuekci, Mariana Pereira Pinto, Ilka Mara Borges Botelho, et al.
Ann Med. 2025 Dec;57(1):2530697. doi: 10.1080/07853890.2025.2530697. Epub 2025 Jul 15.
BACKGROUND: Factors related to cardiovascular risk and insulin sensitivity seem to be related to the increase in the number of thyroid cancer (TC) diagnosis, but there is a lack of studies to corroborate these hypotheses. METHODS: This observational and cross-sectional study evaluated ultrasonographic, clinical, cytological and anatomopathological characteristics of thyroid nodules (TN) related with factors indicative of cardiovascular risk (CVR), serum lipids, and glucose profiles through medical records, and interviews during routine medical consultation. RESULTS: The study included 160 TN patients, 85.53% women, 41.3% with obesity, 24.18% with type 2 Diabetes Mellitus, 63.4% with arterial hypertension, 9.15% with previous CVR, 38.16% with dyslipidemia. 38.5% had Papillary TC, 8.5% Follicular TC. Regarding cytology categories (Bethesda,B), 34.64% BII, 8.5% BIII, 11.11% BIV, 26.8% BV, 8.5% BVI. Microcalcifications were associated with higher Framingham and ASCVD CVR Scores, fasting glucose and glycated hemoglobin. BII TN had lower fasting glucose; BIII greater glycated hemoglobin; and BIV higher both CVR scores. Framingham Score was lower in papillary TC, abdominal waist was lower in follicular TC. Higher FT4 increased 4.7 times the chance of malignant cytology. Higher HDL was an associated factor for malignant cytology (OR = 1.064) and higher FT4 for Differentiated TC (OR = 7.409). CONCLUSION: TN with greater malignant potential on ultrasound and cytology were associated with greater CVR and altered glucose metabolism. Larger goiters and multiple nodules were related to factors indicative of insulin resistance. Malignant cytology was related to hormonal factors that induce greater cell replication, such as thyroxine and insulin resistance.
42Relationship between metabolic syndrome and nodular thyroid diseases.PubMed
Seher Kir, Yusuf Aydin, Hulya Coskun
Scand J Clin Lab Invest. 2018 Feb-Apr;78(1-2):6-10. doi: 10.1080/00365513.2017.1402363. Epub 2017 Nov 16.
Nodular thyroid diseases are common in Turkey. Insulin resistance (IR) is considered as the most important component of metabolic syndrome (MetS), and it is thought to directly affect thyroid diseases, together with other components of MetS. The aim of this study was to evaluate potential factors associated with thyroid nodularity. This study was part of the prospective MELEN study. In total, randomly selected 2233 subjects were evaluated. A euthyroid subgroup of participants (n = 1432) was selected and 421 of them had MetS. Both goitres and multinodular goitres (MNGs) were significantly more common in the MetS (+) group (p < .001). Older age was the only factor that significantly affected the presence of a nodular goitre (NG) (p < .001). The presence of a MNG was associated with older age (p < .001), systolic blood pressure level (p < .008) and MetS (p < .001). There was no difference in the thyroid volume or presence of nodular thyroid diseases between the IR (+) and (-) groups. Both the thyroid volume and the presence of MNGs were significantly associated with MetS, independent of thyroid-stimulating hormone (TSH) and IR. We suggest that the individual components of MetS may influence thyroid nodularity to some degree and that together they exert a cumulative effect on the thyroid gland. As a result, in the absence of MetS, we further suggest that IR alone does not explain the increase in thyroid volume and thyroid nodule formation.
43Presence of Metabolic Syndrome and Thyroid Nodules in Subjects with Colorectal Polyps.PubMed
Yue Yu, Jiansheng Wu
Med Sci Monit. 2021 Feb 1;27:e927935. doi: 10.12659/MSM.927935.
BACKGROUND Thyroid nodules (TNs) and metabolic syndrome (MS) have been individually associated with colorectal polyps. However, the potential joint relationship between them in relation to colorectal polyps has not been fully evaluated. This study aimed to validate the association of TNs/MS and colorectal polyps/adenomas and to determine the risk of colonic polyps in patients with TNs/MS. MATERIAL AND METHODS A retrospective study was conducted on patients undergoing routine health checks in the First Affiliated Hospital of Wenzhou Medical University from July 2014 to August 2017. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for colorectal polyps/adenomas after adjusting for confounding factors. Then patients were divided into 4 groups according to whether they had TNs or MS. Relative excess risks of interaction, attributable proportion, and synergy index were used to determine the additive interaction of TNs and MS on colorectal polyps/adenomas. RESULTS A total of 4514 eligible patients were included in this study. TNs and MS were confirmed to be independent risk factors for colorectal polyps/adenomas. Compared with the group of TNs(-)/MS(-), the odds ratios of TNs(+)/MS(+) in colorectal polyps (odds ratio [OR]: 3.031, 95% confidence interval [CI]: 2.262-4.062, P<0.05) or adenomas (OR: 2.894, 95% CI: 2.099-3.990, P<0.05) were significantly increased, and there was an interactive additive effect between TNs and MS. CONCLUSIONS TNs and MS have an associative and superimposing effect on the increased occurrence of colorectal adenomas. Colonoscopy screening should be advocated for patients with both of these diseases.
44Role of Metformin in the Treatment of Patients with Thyroid Nodules and Insulin Resistance: A Systematic Review and Meta-Analysis.PubMed
Xiaowei He, Dan Wu, Cuining Hu, et al.
Thyroid. 2019 Mar;29(3):359-367. doi: 10.1089/thy.2017.0707. Epub 2019 Feb 1.
BACKGROUND: Metformin is the most-prescribed oral medication to lower blood glucose worldwide. Some data suggest that metformin may have a role in the treatment of patients with thyroid nodules, but contrasting results are reported in different settings. This study explores and critically reevaluates the knowledge on this topic. METHODS: A literature search identified 250 records. Studies evaluating the size of thyroid nodules before and after metformin treatment were included. Assessed outcomes were the size of thyroid nodules, thyrotropin (TSH) level, thyroid gland volume, and insulin resistance index (HOMA-IR). After screening and full-text assessment, five studies were included in the systematic review. Random-effects meta-analyses of the standardized mean difference (SMD) were performed for the four outcomes of interest. Heterogeneity was estimated using I, and the quality of evidence was assessed for each outcome using the Grading of Recommendations Assessment, Development, and Evaluation guidelines. RESULTS: A total of 189 patients were included in the final analysis. After metformin treatment, a slight but significant reduction in thyroid nodule size was found in four studies, which included a total of 167 patients (SMD 0.46 [confidence interval (CI) 0.00-0.93]; p = 0.05). Similarly, in four studies reporting on a total of 146 patients, significant reductions in TSH level (SMD 0.30 [CI 0.07-0.53]; p = 0.01) and HOMA-IR level (SMD 0.90 [CI 0.12-1.67]; p = 0.02) were reported after treatment with metformin. In two studies, which included 114 patients, no change in thyroid gland volume was discovered after treatment with metformin (SMD 0.21 [CI -0.05 to 0.47]; p = 0.11). Quality of evidence was generally assessed as low or very low. CONCLUSIONS: Metformin induces reductions in thyroid nodule size and TSH and HOMA-IR levels in patients with thyroid nodules and insulin resistance. In contrast, no change in thyroid gland volumes was found. Whether metformin treatment for thyroid nodules has clinical significance remains to be demonstrated.
45The changing incidence of thyroid cancer.PubMed
Cari M Kitahara, Julie A Sosa
Nat Rev Endocrinol. 2016 Nov;12(11):646-653. doi: 10.1038/nrendo.2016.110. Epub 2016 Jul 15.
During the past few decades, the incidence of thyroid cancer has increased substantially in many countries, including the USA. The rise in incidence seems to be attributable both to the growing use of diagnostic imaging and fine-needle aspiration biopsy, which has led to enhanced detection and diagnosis of subclinical thyroid cancers, and environmental factors. The latest American Thyroid Association (ATA) practice guidelines for the management of adult patients with thyroid nodules and differentiated thyroid cancer differ substantially from the previous ATA guidelines published in 2009. Specifically, the problems of overdiagnosis and overtreatment of a disease that is typically indolent, where treatment-related morbidity might not be justified by a survival benefit, now seem to be acknowledged. As few modifiable risk factors for thyroid cancer have been established, the specific environmental factors that have contributed to the rising incidence of thyroid cancer remain speculative. However, the findings of several large, well-designed epidemiological studies have provided new information about exposures (such as obesity) that might influence the development of thyroid cancer. In this Review, we describe the changing incidence of thyroid cancer, suggest potential explanations for these trends, emphasize the implications for patients and highlight ongoing and potential strategies to combat this growing clinical and public health issue.
46Evolving Understanding of the Epidemiology of Thyroid Cancer.PubMed
Carolyn Dacey Seib, Julie Ann Sosa
Endocrinol Metab Clin North Am. 2019 Mar;48(1):23-35. doi: 10.1016/j.ecl.2018.10.002. Epub 2018 Dec 23.
The incidence of thyroid cancer worldwide has increased significantly over the past 3 decades, due predominantly to an increase in papillary thyroid cancer. Although most of these cancers are small and localized, population-based studies have documented a significant increase in thyroid cancers of all sizes and stages, in addition to incidence-based mortality for papillary thyroid cancer. This suggests that the increasing incidence of thyroid cancer is due in large part to increasing surveillance and overdiagnosis, but that there also appears to be a true increase in new cases of thyroid cancer.
47Air pollution exposure, accelerated biological aging, and increased thyroid dysfunction risk: Evidence from a nationwide prospective study.PubMed
Ruyi Liang, Lieyang Fan, Xuefeng Lai, et al.
Environ Int. 2024 Jun;188:108773. doi: 10.1016/j.envint.2024.108773. Epub 2024 May 25.
BACKGROUND: Long-term air pollution exposure is a major health concern, yet its associations with thyroid dysfunction (hyperthyroidism and hypothyroidism) and biological aging remain unclear. We aimed to determine the association of long-term air pollution exposure with thyroid dysfunction and to investigate the potential roles of biological aging. METHODS: A prospective cohort study was conducted on 432,340 participants with available data on air pollutants including particulate matter (PM, PM, and PM), nitrogen dioxide (NO), and nitric oxide (NO) from the UK Biobank. An air pollution score was calculated using principal component analysis to reflect joint exposure to these pollutants. Biological aging was assessed using the Klemera-Doubal method biological age and the phenotypic age algorithms. The associations of individual and joint air pollutants with thyroid dysfunction were estimated using the Cox proportional hazards regression model. The roles of biological aging were explored using interaction and mediation analyses. RESULTS: During a median follow-up of 12.41 years, 1,721 (0.40 %) and 9,296 (2.15 %) participants developed hyperthyroidism and hypothyroidism, respectively. All air pollutants were observed to be significantly associated with an increased risk of incident hypothyroidism, while PM, PM, and NO were observed to be significantly associated with an increased risk of incident hyperthyroidism. The hazard ratios (HRs) for hyperthyroidism and hypothyroidism were 1.15 (95 % confidence interval: 1.00-1.32) and 1.15 (1.08-1.22) for individuals in the highest quartile compared with those in the lowest quartile of air pollution score, respectively. Additionally, we noticed that individuals with higher pollutant levels and biologically older generally had a higher risk of incident thyroid dysfunction. Moreover, accelerated biological aging partially mediated 1.9 %-9.4 % of air pollution-associated thyroid dysfunction. CONCLUSIONS: Despite the possible underestimation of incident thyroid dysfunction, long-term air pollution exposure may increase the risk of incident thyroid dysfunction, particularly in biologically older participants, with biological aging potentially involved in the mechanisms.
48Association Between Environmental Air Pollution and Thyroid Cancer and Nodules: A Systematic Review.PubMed
Varun Vohra, Lekha V Yesantharao, Rachel Stemme, et al.
Thyroid. 2024 Dec;34(12):1451-1464. doi: 10.1089/thy.2024.0317. Epub 2024 Nov 18.
The global incidence of thyroid cancer has increased over the past several decades. While this increase is partially due to increased detection, environmental pollutants have also emerged as a possible contributing factor. Our goal was to perform a systematic review to assess the relationship between environmental air pollution and thyroid cancer. Systematic literature search was performed using PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus databases for original articles published prior to March 2024, investigating outdoor air pollution and thyroid cancer/nodules (PROSPERO CRD42024517624). Inclusion criteria included quantitative reporting of pollutant levels and effect size. Specific pollutants included ozone (O), particulate matter less than 2.5 (PM) or 10 microns in diameter (PM), sulfur dioxide (SO), nitric oxides (NO), carbon monoxide (CO), and polyaromatic hydrocarbons (PAHs). Study design, sample size, pollution assessment method, covariates, and strength/direction of associations between pollutants and thyroid cancer/nodule detection were extracted, and descriptive synthesis was utilized to summarize pertinent findings. Risk of bias was assessed using the National Heart, Lung, and Blood Institute quality assessment tool. Of 1294 identified studies, 11 met inclusion criteria. Over 6 million patients from diverse regions were represented across studies. Pollutants studied included O in 5 studies; PM, PM, SO, and NO in 3 studies; unspecified PM and CO in 2 studies; and PAHs in 1 study. Primary outcome was thyroid cancer diagnosis among 9 studies and thyroid nodule detection in 2. All studies examining NO and O reported increased risks ranging from 1.03 to 1.5-fold and 1.1 to 1.3-fold, respectively. Both studies assessing PM reported 1.18 to 1.23-fold increased odds of thyroid cancer diagnosis, and the magnitude of association increased with increasing duration or concentration of PM Inconsistent results were observed for levels of CO, PM, and SO. While an emerging body of literature suggests a potential association between air pollution and thyroid cancer, the quality of evidence is limited by study design constraints, variability in exposure assessment, and inconsistent adjustment for potential confounding factors. The heterogeneity in study designs and methodologies present challenges in interpreting results, underscoring the need for standardized approaches in future research.
49Association between air pollutants, thyroid disorders, and thyroid hormone levels: a scoping review of epidemiological evidence.PubMed
Kaijie Yang, Guofeng Zhang, Yongze Li
Front Endocrinol (Lausanne). 2024 Oct 8;15:1398272. doi: 10.3389/fendo.2024.1398272. eCollection 2024.
BACKGROUND: Over the past two decades, the incidence of thyroid disorders has been steadily increasing. There is evidence to suggest that air pollution may be one of the etiological factors of thyroid diseases. This comprehensive review aimed to examine the evidence related to air pollutants and thyroid disorders and thyroid hormones levels from an epidemiological perspective. METHODS: The scoping review adopted a systematic approach to search for, identify, and include peer-reviewed articles published in English. We performed a comprehensive search of three databases-PubMed, Embase, and Web of Science to identify relevant literature on the relationship between air pollution [particulate matter, nitrogen oxide, carbon monoxide (CO), ozone (O), sulfur dioxide (SO)] exposure and thyroid disorders, including hypothyroidism, congenital hypothyroidism (CH), thyroid nodules, thyroid cancer, autoimmune thyroid diseases, as well as thyroid hormone levels, such as thyroid-stimulating hormone (TSH), free triiodothyronine (FT), and free thyroxine (FT). Articles published until August 1, 2023, were included. RESULTS: A total of 3,373 studies were retrieved, and among them, 25 studies covering eight different air pollutants were relevant. The most frequently studied air pollutants in this review included fine particulate matter (with fine particulate matter (PM), n=21; inhalable particles (PM), n=10; PM, n=1) and nitrogen oxides (with NO, n=13; NOx, n=3). The thyroid disorders and thyroid hormone levels most commonly associated with evidence of air pollution exposure were hypothyroidism (n=7) and TSH (n=12). CONCLUSIONS: Despite variations in study designs and exposure assessments, the findings consistently highlight the substantial health risks that air pollution, particularly PM, poses to thyroid health, especially among vulnerable populations. Given that our study was limited to epidemiological investigations and the increasing prevalence of toxic substances in the environment, there is an urgent need for further research to elucidate the mechanisms by which these pollutants disrupt thyroid function and contribute to the development of thyroid diseases.
50Association Between Long-Term Exposure to Environmental Fine Particulate Matter and the Prevalence of Thyroid Disorders: A National Cross-Sectional Study in China.PubMed
Kaijie Yang, Cihang Lu, Kang Chen, et al.
Thyroid. 2024 Sep;34(9):1094-1104. doi: 10.1089/thy.2024.0286. Epub 2024 Aug 30.
Exposure to particles with an aerodynamic diameter of ≤2.5 μm (PM) is associated with the occurrence of thyroid dysfunction among pregnant women and neonates, but it is not known if this association occurs in the general population. We aimed to determine the association of prolonged exposure to PM with the prevalence of thyroid disorders among adults in China. A nationally representative cross-sectional study of thyroid disorders, iodine status, and diabetes status was carried out in all 31 provinces across China from 2015 to 2017. In total, 73,900 adults aged 18 years and older were included. Serum concentrations of thyroid hormones, thyrotropin, and thyroid antibodies and the urine iodine concentration were measured. The environmental concentration of PM for each participant's residential address at a spatial resolution of 1 × 1 km was estimated. The average long-term exposure to PM at residential addresses was 66.41 μg/m, ranging from 17.58 μg/m to 120.40 μg/m. Compared with that of individuals with lower exposure levels, the prevalence of thyroid diseases such as autoimmune thyroiditis and subclinical hypothyroidism was greater in those with PM concentrations within the third quartile range (60.18 to 73.78 μg/m). Compared with those in the first quartile (17.58 to 46.38 μg/m), participants in the highest PM quartile (73.78 to 120.40 μg/m) presented an increased risk of overt hypothyroidism (OR 1.23 [CI 0.94-1.61]), subclinical hypothyroidism (1.10 [1.01-1.21]), autoimmune thyroiditis (1.09 [1.00-1.18]), and thyroglobulin antibody positivity (1.17 [1.07-1.29]). However, there was no association between PM exposure and overt hyperthyroidism, subclinical hyperthyroidism, Graves' disease, or thyroid peroxidase antibody positivity ( > 0.05). Each 10 μg/m³ increase in the PM concentration was associated with an increased risk of overt hypothyroidism (OR 1.05 [1.00-1.11]), subclinical hypothyroidism (1.02 [1.00-1.03]), and thyroglobulin antibody positivity (1.02 [1.00-1.04]). Furthermore, a nearly linear exposure-response relationship was observed between long-term PM exposure and thyroglobulin antibody positivity. PM exposure was associated with thyroid disorders among Chinese adults. A dose-response relationship between PM exposure and autoimmune thyroiditis, as well as thyroglobulin antibody positivity, was also observed.
51Early life air pollution exposures and thyroid function in children: A prospective cohort study.PubMed
You Joung Heo, Yun Jeong Lee, Soon Tae Kim, et al.
Environ Pollut. 2024 Dec 15;363(Pt 1):125092. doi: 10.1016/j.envpol.2024.125092. Epub 2024 Oct 9.
Studies on early life ambient air pollution exposures and childhood thyroid function are scarce. This study aimed to evaluate the relationships between early life fine particulate matter (≤2.5 μm; PM) and nitrogen dioxide (NO) exposures and thyroid function in children. We measured the levels of thyrotropin, triiodothyronine, and free thyroxine in children (n = 684) residing in a rural Korean area at age 2, 4, 6, or 8 years from 2012 to 2020 in the Environment and Development of Children cohort. The relationship between residential average exposure levels of PM and NO during pregnancy and 1-year average levels before visit and thyroid function during childhood were analyzed. Inverse association between increases of 10 μg/m in PM during the first trimester and thyrotropin levels at aged 4 (β, -0.12; 95% CI: -0.22, -0.02) and 6 years (β, -0.16; 95% CI: -0.26, -0.06) were observed. No association was found between PM exposure during the second and third trimester and childhood TSH levels. Childhood PM exposure was positively associated with thyrotropin rise at aged 4 (β, 0.2; 95% CI: 0.06, 0.35) and 6 years (β, 0.16; 95% CI: 0.02, 0.29) and inversely related with free thyroxine levels at aged 8 years (β, -0.04; 95% CI: -0.07, -0.01). No relationship between NO exposure and thyroid function was found. In conclusion, association between PM exposure and childhood thyrotropin levels varied depending on exposure timing. Early gestational exposure showed an inverse relationship, whereas childhood exposure were positively associated with childhood thyrotropin levels. The long-term effects of early life air pollution exposure and underlying mechanisms should be investigated in future studies.
52Pathomorphology of thyroid gland lesions associated with radiation exposure: the Chernobyl experience and review of the literature.PubMed
Y E Nikiforov, D R Gnepp
Adv Anat Pathol. 1999 Mar;6(2):78-91. doi: 10.1097/00125480-199903000-00002.
The common sources of ionizing radiation exposure to the thyroid gland in humans are accidental environmental exposure and medical, therapeutic, or diagnostic irradiation. Radiation often induces notable histologic changes in the thyroid tissue and is a well-established risk factor for benign and malignant thyroid tumors. In this paper, we review the acute and chronic histologic changes in the thyroid gland subjected to irradiation, and characterize benign thyroid nodules and malignant tumors arising after exposure, with particular emphasis on thyroid lesions in the population exposed to ionizing radiation as a result of the Chernobyl nuclear accident.
53Occupation and thyroid cancer.PubMed
Briseis Aschebrook-Kilfoy, Mary H Ward, Curt T Della Valle, et al.
Occup Environ Med. 2014 May;71(5):366-80. doi: 10.1136/oemed-2013-101929. Epub 2014 Mar 6.
Numerous occupational and environmental exposures have been shown to disrupt thyroid hormones, but much less is known about their relationships with thyroid cancer. Here we review the epidemiology studies of occupations and occupational exposures and thyroid cancer incidence to provide insight into preventable risk factors for thyroid cancer. The published literature was searched using the Web of Knowledge database for all articles through August 2013 that had in their text 'occupation' 'job' 'employment' or 'work' and 'thyroid cancer'. After excluding 10 mortality studies and 4 studies with less than 5 exposed incident cases, we summarised the findings of 30 articles that examined thyroid cancer incidence in relation to occupations or occupational exposure. The studies were grouped by exposure/occupation category, study design and exposure assessment approach. Where available, gender-stratified results are reported. The most studied (19 of 30 studies) and the most consistent associations were observed for radiation-exposed workers and healthcare occupations. Suggestive, but inconsistent, associations were observed in studies of pesticide-exposed workers and agricultural occupations. Findings for other exposures and occupation groups were largely null. The majority of studies had few exposed cases and assessed exposure based on occupation or industry category, self-report, or generic (population-based) job exposure matrices. The suggestive, but inconsistent findings for many of the occupational exposures reviewed here indicate that more studies with larger numbers of cases and better exposure assessment are necessary, particularly for exposures known to disrupt thyroid homeostasis.
54Somatic health effects of Chernobyl: 30 years on.PubMed
Maureen Hatch, Elisabeth Cardis
Eur J Epidemiol. 2017 Dec;32(12):1047-1054. doi: 10.1007/s10654-017-0303-6. Epub 2017 Sep 19.
2016 marked the 30th anniversary of the Chernobyl Nuclear Power Plant accident. We and others wrote reviews for the 25th anniversary. Since then, additional papers have appeared and it seems timely to highlight lessons learned. To present, not a systematic review, but a commentary drawing attention to notable findings. We include not only recent reports and updates on previous results, but key findings from prior Chernobyl studies. The dose-dependent increase in Papillary Thyroid Cancer (PTC) following childhood I-131 exposure in Ukraine and Belarus has now been shown to persist for decades. Studies of post-Chernobyl PTCs have produced novel information on chromosomal rearrangements and gene fusions, critical to understanding molecular mechanisms. Studies of clean-up workers/liquidators suggest dose-related increases of thyroid cancer and hematological malignancies in adults. They also report increases in cardiovascular and cerebrovascular disease. If confirmed, these would have significant public health and radiation protection implications. The lens opacities following low to moderate doses found earlier are also a concern, particularly among interventional radiologists who may receive substantial lens doses. Finally, there is some, inconsistent, evidence for genetic effects among offspring of exposed persons. Further efforts, including improved dosimetry, collection of information on other risk factors, and continued follow-up/monitoring of established cohorts, could contribute importantly to further understand effects of low doses and dose-rates of radiation, particularly in young people, and ensure that appropriate public health and radiation protection systems are in place. This will require multinational collaborations and long-term funding.
55Thyroid diseases among atomic bomb survivors in Nagasaki.PubMed
S Nagataki, Y Shibata, S Inoue, et al.
JAMA. 1994 Aug 3;272(5):364-70.
OBJECTIVE: To elucidate the current thyroid disease status for the Nagasaki Adult Health Study cohort of the Radiation Effects Research Foundation. DESIGN: Survey study. SETTING: Nagasaki, Japan. PARTICIPANTS: Cohort members of the Nagasaki Adult Health Study who received biennial health examinations from October 1984 to April 1987 (n = 2856). A total of 2587 subjects remained after exclusion of persons exposed in Hiroshima or in utero and those who were not in Nagasaki at the time of the bombing. Thyroid radiation dose by the dosimetry system established in 1986 was available for 1978 of the 2587 subjects. MAIN OUTCOME MEASURES: Thyroid diseases were diagnosed using uniform procedures including ultrasonic scanning. The relationship of the prevalence of each thyroid disease with thyroid radiation dose, sex, and age was analyzed using logistic models. RESULTS: A significant dose-response relationship was observed for solid nodules, which include cancer, adenoma, adenomatous goiter, and nodules without histological diagnosis, and for antibody-positive spontaneous hypothyroidism (autoimmune hypothyroidism) but not for other diseases. The prevalence of solid nodules showed a monotonic dose-response relationship, yet that of autoimmune hypothyroidism displayed a concave dose-response relationship reaching a maximum (+/- SE) level of 0.7 +/- 0.2 Sv. CONCLUSIONS: The present study confirmed the results of previous studies by showing a significant increase in solid nodules with dose to the thyroid and demonstrated for the first time a significant increase in autoimmune disease among atomic bomb survivors. A concave dose-response relationship indicates the necessity for further studies on the effects of relatively low doses of radiation on thyroid disease.
56Radiation-induced inflammation and autoimmune diseases.PubMed
Rasoul Yahyapour, Peyman Amini, Saeed Rezapour, et al.
Mil Med Res. 2018 Mar 20;5(1):9. doi: 10.1186/s40779-018-0156-7.
Currently, ionizing radiation (IR) plays a key role in the agricultural and medical industry, while accidental exposure resulting from leakage of radioactive sources or radiological terrorism is a serious concern. Exposure to IR has various detrimental effects on normal tissues. Although an increased risk of carcinogenesis is the best-known long-term consequence of IR, evidence has shown that other diseases, particularly diseases related to inflammation, are common disorders among irradiated people. Autoimmune disorders are among the various types of immune diseases that have been investigated among exposed people. Thyroid diseases and diabetes are two autoimmune diseases potentially induced by IR. However, the precise mechanisms of IR-induced thyroid diseases and diabetes remain to be elucidated, and several studies have shown that chronic increased levels of inflammatory cytokines after exposure play a pivotal role. Thus, cytokines, including interleukin-1(IL-1), tumor necrosis factor (TNF-α) and interferon gamma (IFN-γ), play a key role in chronic oxidative damage following exposure to IR. Additionally, these cytokines change the secretion of insulin and thyroid-stimulating hormone(TSH). It is likely that the management of inflammation and oxidative damage is one of the best strategies for the amelioration of these diseases after a radiological or nuclear disaster. In the present study, we reviewed the evidence of radiation-induced diabetes and thyroid diseases, as well as the potential roles of inflammatory responses. In addition, we proposed that the mitigation of inflammatory and oxidative damage markers after exposure to IR may reduce the incidence of these diseases among individuals exposed to radiation.
57Phthalates Induced Neurotoxicity: A Mechanistic Approach.PubMed
Kajal Gaur, Yasir Hasan Siddique
Cent Nerv Syst Agents Med Chem. 2024 Dec 3. doi: 10.2174/0118715249332874241113030902.
Phthalates play a significant role as plastic modifying additives in everyday items like plastics, pesticides, paints, and cosmetics. This review explores the relationship between phthalates and neurotoxicity and sheds light on the potential risks these ubiquitous chemicals pose to neurological health. The review elucidates the diverse neurotoxic effects of phthalates exposure, spanning developmental neurotoxicity, neuropathy, neurodegenerative diseases, and neurobehavioral toxicity. Mechanistic insights reveal the pathways through which phthalates induce cellular damage, including oxidative stress, disruption of calcium signalling, alteration in lipid metabolism, and interference with thyroid hormone homeostasis. Moreover, the review discusses regulatory measures aimed at restricting phthalate usage and highlights the imperative for further research and awareness to safeguard public health against the neurotoxic effects of phthalates.
58Mediation effects of thyroid function in the associations between phthalate exposure and lipid metabolism in adults.PubMed
Han-Bin Huang, Po-Keng Cheng, Chi-Ying Siao, et al.
Environ Health. 2022 Jul 1;21(1):61. doi: 10.1186/s12940-022-00873-9.
Phthalates are a group of industrial chemicals widely used in everyday products including cosmetics, food packaging and containers, plastics, and building materials. Previous studies have indicated that urinary phthalate metabolites are associated with metabolic effects including those on lipid metabolism, but the results are mixed. Furthermore, whether thyroid function mediates the association between phthalate exposure and lipid metabolism remains unclear. In the present study, we explored whether changes in thyroid function markers mediate the associations between phthalate exposure and lipid metabolism indicators in Taiwanese adults. The cross-sectional data were obtained from the Taiwan Environmental Survey for Toxicants conducted in 2013. Levels of 11 urinary phthalate metabolites, levels of 5 thyroid hormones, and 8 indicators of lipid metabolism were assessed in 222 Taiwanese adults. The relationships of urinary phthalate metabolite levels with serum thyroid hormone levels and lipid metabolism indicators were explored using multiple regression models. Mediation analysis was conducted to evaluate the role of thyroid function in the association between phthalate exposure and lipid metabolism. The metabolite of di(- 2-ethylhexyl) phthalate (∑DEHPm) exhibited a significant positive association with the lipid metabolite indicator of high-density lipoprotein cholesterol (HDL-C; β = 0.059, 95% confidence interval [CI] = 0.009, 0.109) in adults, and the thyroid function indicator thyroxine (T) had a significant negative association with the metabolite ∑DEHPm (β = - 0.059, 95% CI = - 0.101, - 0.016) and a significant negative association with HDL-C (β = - 0.284, 95% CI = - 0.440, - 0.128). The T indirect effect was 0.015 (95% CI = - 0.0087, 0.05), and the mediation effect was 32.2%. Our results support the assumption that exposure to phthalates influences the homeostasis of lipid metabolism by interfering with thyroid function.
59Endocrine-disruptor endpoints in the ovary and thyroid of adult female rats exposed to realistic doses of di-(2-ethylhexyl) phthalate.PubMed
Amel Jebara, Asma Beltifa, Guissepa Di Bella, et al.
J Water Health. 2022 Aug;20(8):1256-1267. doi: 10.2166/wh.2022.140.
Di-(2-ethylhexyl) phthalate (DEHP) is the world's most widely used polyvinyl chloride (PVC) plasticizer and is used in virtually every category of flexible PVC. In fact, DEHP is extensively used in food cosmetics and medical packaging. It has become a serious problem in recent years. DEHP can be absorbed into the human body through the air, food, water, and skin. The current study involved intraperitoneal injection of DEHP dissolved in corn oil once daily for 21 consecutive days to investigate the effects of DEHP on the thyroid and the reproductive system in female rats. Results show that ovarian hormones (progesterone and estrogen) decreased significantly in the rats treated with DEHP compared to control. This result is supported by the alteration of folliculogenesis, the decrease of the follicles viability, and the apoptosis of the granulosa cells observed on histological sections of ovary and thyroid in female rats exposed to low doses of DEHP. Histopathological study revealed that DEHP could damage thyroid tissue and disrupt these functions. We also observed cellular damage, particularly in the liver cells, and a significant increase in biochemical parameters such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared to the control group.
60Povidone-iodine-induced transient triiodothyronine thyrotoxicosis in a Japanese patient with prolonged habitual gargling: A case report and literature review.PubMed
Ryuji Suzuki, Seiji Suzuki
Medicine (Baltimore). 2023 Aug 25;102(34):e34631. doi: 10.1097/MD.0000000000034631.
RATIONALE: Iodine-induced hyperthyroidism and triiodothyronine (T3) thyrotoxicosis in patients who routinely gargle with povidone-iodine (PVP-I) gargling solution are rare in Japan. PATIENT CONCERNS: A 50-year-old man presented to our hospital for a close examination of an enlarged thyroid, which was noted during a complete health checkup. The thyroid was slightly enlarged with no palpable nodules. He had an increased appetite but no weight gain. He had been routinely gargling with PVP-I gargling solution 4 times daily for >10 years. He had no history of thyroid disease. DIAGNOSES: Test results revealed suppressed thyroid-stimulating hormone, normal free thyroxine, and increased free triiodothyronine levels, leading to the diagnosis of T3 thyrotoxicosis. INTERVENTIONS: The patient agreed to stop gargling with PVP-I gargle solution. OUTCOMES: The free triiodothyronine and thyroid-stimulating hormone levels returned to normal at 18 and 21 weeks, respectively, after discontinuation of PVP-I gargling. After an improvement in thyroid function, he gained 5 kg in 1 year. LESSONS: To our knowledge, this is the first case report that describes PVP-I gargle-induced T3 thyrotoxicosis in a healthy individual without thyroid disease. In Japan, which is an iodine-sufficient country, considering the possibility of high-dose iodine intake-induced thyrotoxicosis due to long-term PVP-I gargling or other causes is necessary, even in individuals with no history of thyroid disease.
61Thyroid function in nurses: the influence of povidone-iodine hand washing and gargling.PubMed
Keigo Nobukuni, Shin Kawahara
Dermatology. 2002;204 Suppl 1:99-102. doi: 10.1159/000057735.
The effect of povidone-iodine (PVP-I) hand washing and gargling on thyroid function was assessed. In 16 nurses using PVP-I products and 16 control subjects, serum inorganic iodine levels and thyroid functions were investigated. The status of PVP-I use was also surveyed in the nurses. Clinical symptoms considered to be attributable to thyroid dysfunctions were seen in none of the subjects, nor was a goiter observed in any of the subjects. In nurses, serum inorganic iodine levels were slightly increased as compared to those in the control subjects, although the difference was not significant. The iodine incorporated during working hours of nurses appears to be attributable to gargling rather than to hand washing. The long-term use of PVP-I for gargling should be avoided by (1) people with a high risk of developing thyroid dysfunction due to the excessive intake of iodine, (2) pregnant women and (3) breast-feeding mothers.
62Reliability of fine-needle aspiration in patients with familial nonmedullary thyroid cancer.PubMed
M R Vriens, U Sabanci, H D Epstein, et al.
Thyroid. 1999 Oct;9(10):1011-6. doi: 10.1089/thy.1999.9.1011.
In this case-control study we describe how often thyroid cancers and occult cancers are diagnosed or not diagnosed by fine-needle aspiration (FNA) in patients with thyroid nodules and a family history of nonmedullary thyroid cancers (FNMTC). Our hypothesis is that patients with thyroid nodules and a family history of FNMTC seem to be similar to patients with thyroid nodules and a history of exposure to low-dose therapeutic radiation. Both have been reported to have multifocal thyroid neoplasms and malignant tumors are common. Cytological examination may therefore be less accurate. From 1979 to 1996, 27 patients from 24 families with FNMTC were examined histologically after a preoperative cytological examination in all of them. A positive cytology examination was defined when biopsy documented thyroid cancer. It was interpreted as a false-negative study when a benign diagnosis was made and thyroid cancer was present anywhere within the thyroid, including in areas sampled or not sampled by FNA and not palpable preoperatively. A randomized control group, matched for age and gender, contained 27 patients with papillary thyroid cancer without familial disease. In our study group, 25 patients were treated with total thyroidectomy, including 7 with neck dissection, and 2 by thyroid lobectomy. At final histological examination 17 of 27 patients (63%) in this study group had multiple nodules and 25 of 27 (92.6%) had thyroid cancer. Thyroid cancer was diagnosed by FNA in 22 of 25 patients (88%), with 3 (12%) false-negative biopsies due to sampling errors (thyroid cancer not in the index nodule), versus 1 (3.7%) false-negative biopsy in the control group. Two patients in the study group with benign nodules were accurately diagnosed. In patients with false-negative biopsies and a history of FNMTC, the cancer was situated in one or more small nodules. Only one cancer was occult (< 1.0 cm). One-third of the patients in our study group (33%) had a history of radiation; 44% of the irradiated group had a single nodule; 56% had multiple nodules. In the control group, 9 of 27 patients (33%) also had a history of radiation; 33% of the irradiated group had a single nodule, 67% had multiple nodules. In conclusion, the reliability of FNA in patients with FNMTC appears to be less accurate than it is for other patients because of the high incidence of multifocal thyroid cancer and coexistence of benign nodules. Patients with thyroid nodules and a family history of thyroid cancer are more likely to have thyroid cancer and because they also have more coexistent benign nodules, they must be followed closely or treated with total or near-total thyroidectomy.
63Autoimmune thyroid disorders.PubMed
Alessandro Antonelli, Silvia Martina Ferrari, Alda Corrado, et al.
Autoimmun Rev. 2015 Feb;14(2):174-80. doi: 10.1016/j.autrev.2014.10.016. Epub 2014 Oct 25.
Autoimmune thyroid diseases (AITD) result from a dysregulation of the immune system leading to an immune attack on the thyroid. AITD are T cell-mediated organ-specific autoimmune disorders. The prevalence of AITD is estimated to be 5%; however, the prevalence of antithyroid antibodies may be even higher. The AITD comprise two main clinical presentations: Graves' disease (GD) and Hashimoto's thyroiditis (HT), both characterized by lymphocytic infiltration of the thyroid parenchyma. The clinical hallmarks of GD and HT are thyrotoxicosis and hypothyroidism, respectively. The mechanisms that trigger the autoimmune attack to the thyroid are still under investigation. Epidemiological data suggest an interaction among genetic susceptibility and environmental triggers as the key factor leading to the breakdown of tolerance and the development of disease. Recent studies have shown the importance of cytokines and chemokines in the pathogenesis of AT and GD. In thyroid tissue, recruited T helper 1 (Th1) lymphocytes may be responsible for enhanced IFN-γ and TNF-α production, which in turn stimulates CXCL10 (the prototype of the IFN-γ-inducible Th1 chemokines) secretion from the thyroid cells, therefore creating an amplification feedback loop, initiating and perpetuating the autoimmune process. Associations exist between AITD and other organ specific (polyglandular autoimmune syndromes), or systemic autoimmune disorders (Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, cryoglobulinemia, sarcoidosis, psoriatic arthritis). Moreover, several studies have shown an association of AITD and papillary thyroid cancer. These data suggest that AITD patients should be accurately monitored for thyroid dysfunctions, the appearance of thyroid nodules, and other autoimmune disorders.
64Anti-thyroid antibodies as a predictor of thyroid cancer.PubMed
Sze Ling Wong, Simon Grodski, Meei J Yeung, et al.
ANZ J Surg. 2015 Nov;85(11):849-53. doi: 10.1111/ans.12453. Epub 2013 Dec 3.
BACKGROUND: Recent literature has suggested an association between autoimmune thyroiditis and papillary thyroid cancer. The aims of this study were to evaluate if positive thyroid antibodies are associated with thyroid carcinoma and to examine the role of thyroid antibodies in the management of thyroid nodules. METHODS: This is a database study of all patients undergoing thyroidectomy with recorded preoperative thyroid antibodies (autoantibodies to thyroglobulin and/or thyroid peroxidase) levels from 2010 to 2012. We analysed preoperative thyroid antibody levels, fine needle aspiration cytology (FNAC) results, type of thyroid surgery and final histopathology. RESULTS: There were 960 patients who underwent thyroidectomy with recorded preoperative thyroid antibodies. Of 960 patients, 784 had preoperative FNAC of thyroid nodules. Final histopathology showed 758 benign and 202 malignant cases. As expected, there was a strong association between raised thyroid antibodies and lymphocytic thyroiditis on histology (P = 0.0001) (two-sided probability). Overall, positive thyroid antibodies were not found to be a predictor of thyroid carcinoma (P = 0.161) (two-sided probability). However, in patients with benign FNAC, positive thyroid antibodies increased the risk of thyroid malignancy (odds ratio 2.16; 95% confidence interval 1.11 to 4.21, P = 0.027) (two-sided probability). CONCLUSION: Patients with positive thyroid antibodies have a greater risk of malignancy in those with benign FNAC. We recommend routine thyroid antibody assessment in addition to FNAC as part of the assessment of thyroid nodules.
65Thyroid Hormones, Autoantibodies, Ultrasonography, and Clinical Parameters for Predicting Thyroid Cancer.PubMed
Lin-Zheng He, Tian-Shu Zeng, Lin Pu, et al.
Int J Endocrinol. 2016;2016:8215834. doi: 10.1155/2016/8215834. Epub 2016 May 19.
Our objective was to evaluate thyroid nodule malignancy prediction using thyroid function tests, autoantibodies, ultrasonographic imaging, and clinical data. We conducted a retrospective cohort study in 1400 patients with nodular thyroid disease (NTD). The thyroid stimulating hormone (TSH) concentration was significantly higher in patients with differentiated thyroid cancer (DTC) versus benign thyroid nodular disease (BTND) (p = 0.004). The receiver operating characteristic curve of TSH showed an AUC of 0.58 (95% CI 0.53-0.62, p = 0.001), sensitivity of 74%, and specificity of 57% at a cut-off of 1.59 mIU/L. There was an incremental increase in TSH concentration along with the increasing tumor size (p < 0.001). Thyroglobulin antibody (TgAb) concentration was associated with an increased risk of malignancy (p = 0.029), but this association was lost when the effect of TSH was taken into account (p = 0.11). Thyroid ultrasonographic characteristics, including fewer than three nodules, hypoechoic appearance, solid component, poorly defined margin, intranodular or peripheral-intranodular flow, and punctate calcification, can be used to predict the risk of thyroid cancer. In conclusion, our study suggests that preoperative serum TSH concentration, age, and ultrasonographic features can be used to predict the risk of malignancy in patients with NTD.
66Clinical implications of anti-thyroglobulin antibody measurement before surgery in thyroid cancer.PubMed
Kwanhoon Jo, Dong-Jun Lim
Korean J Intern Med. 2018 Nov;33(6):1050-1057. doi: 10.3904/kjim.2018.289. Epub 2018 Oct 30.
Thyroglobulin antibody (TgAb) is a class G immunoglobulin and a conventional marker for thyroid autoimmunity. From a clinical perspective, TgAb is less useful than thyroid peroxidase antibodies for predicting thyroid dysfunction. However, TgAb is found more frequently in differentiated thyroid cancer (DTC) and can interfere with thyroglobulin (Tg) measurements, which are used to monitor the recurrence or persistence of DTC. Recent studies suggested a small but consistent role for preoperative TgAb in predicting DTC in thyroid nodules, and in reflecting adverse tumor characteristics or prognosis, including lymph node metastasis, but this is still controversial. Postoperative TgAb can serve as a biomarker for remnant thyroid tissue, so follow-up measures of TgAb are useful for predicting cancer recurrence in DTC patients. Since high serum TgAb levels may also affect the fine needle aspiration washout Tg levels from suspicious lymph nodes of DTC patients, it is important to use caution when interpreting the washout Tg levels in patients who are positive for TgAb.
67Thyroid nodules and cancer in children and adolescents affected by Hashimoto's thyroiditis.PubMed
Ji Hye Won, Ji Ye Lee, Hyun Sook Hong, et al.
Br J Radiol. 2018 Jul;91(1087):20180014. doi: 10.1259/bjr.20180014. Epub 2018 Apr 9.
OBJECTIVE: To investigate the rates of thyroid nodules and cancer in pediatric cases of Hashimoto's thyroiditis (HT) in Korea. METHODS: We retrospectively reviewed 89 pediatric and adolescent patients (age, 3-18.0 years) with HT who underwent thyroid ultrasonography (US) at our institution from February 2006 to July 2016. The diagnosis of HT was based on the presence of thyroid autoantibodies. The presence of any thyroid nodules with US and cytopathologic features was analyzed. The malignancy rate was also determined. RESULTS: Thyroid nodules were in 20 of the 89 patients (22.4%). Eight of these 20 patients (40%) had colloid cysts, two (10%) had nodular hyperplasia, one (5%) had follicular adenoma, and two (10%) had lymphocytic thyroiditis. Seven of the 89 patients (7.9%) were confirmed to have a malignancy, all of which were papillary thyroid carcinoma (PTC); of those, five patients had diffuse sclerosing variant PTC, and two had conventional PTC on pathology. CONCLUSION: The prevalence of thyroid nodules in children and adolescents with HT was 22.4%. The malignancy rate of children with HT was 7.9%. The malignancy rate among thyroid nodules was 35%, which is higher than the 26% rate generally reported for children with nodules. Therefore, using thyroid US to survey known or suspected thyroid nodules might be helpful in children and adolescents with HT and may provide further useful diagnostic information. Advances in knowledge: Thyroid US could help to assess HT patients who have known or suspected thyroid nodules.
68Influence of Hashimoto thyroiditis on diagnosis and treatment of thyroid nodules.PubMed
Linfeng Mao, Chunmei Zheng, Shengzhao Ou, et al.
Front Endocrinol (Lausanne). 2022 Dec 23;13:1067390. doi: 10.3389/fendo.2022.1067390. eCollection 2022.
BACKGROUND: As the prevalence of Hashimoto's thyroiditis (HT) and thyroid cancer (TC) has been increasing dramatically in recent years, the association between the two diseases has been widely debated and studied. However, no consistent findings are available and the relationship remains controversial. In this study, we analyzed the influence of HT on the diagnosis and treatment of thyroid nodules and investigated the relationship between HT and TC. METHODS: From Jan 2017 to Apr 2021, 4678 patients underwent thyroid surgery were collected. Of these patients, 440 were diagnosed with HT (242 nodular goiter (NG) with HT, 198 TC with HT). These patients were grouped when appropriate and the data from these patients were statistically analyzed by using SPSS and GraphPad Prism 6. RESULTS: HT occurred in 198 of 1089 (18.2%) TC patients and 242 of 3589 (6.74%) patients without TC (=0.000). In terms of the ultrasonography features, in the NG with HT group, 33.1% (80/242) of patients had fine calcification and 45.9% (111/242) of patients whose TI-RADS classification were > Level 3. In the isolated PTC group, 32.3% (2343/7260) LN were metastasis-positive while in the NG with HT group, only 26.0% (504/1939) LN were metastasis-positive (=0.000). The proportion of PTMC was significantly higher (=0.000), while the proportion of multifocal carcinoma was significantly lower when coexisting with HT (=0.029). When comparing the data from the two groups diagnosed as PTMC coexisting with HT or not, there was no significant difference in the composition ratio of tumor number, LN metastasis, LN dissection area, regional LN metastasis and number of negative/positive LN (=0.614, =0.051, =0.139, =0.350, =1.000 and =0.333 respectively). In the MPTC group, 42.2% (872/2065) LN were metastasis-positive while in the MPTC with HT group, only 23.6% (50/212) LN were metastasis-positive (=0.000). CONCLUSIONS: Our data suggested that HT is associated with an increased risk of developing TC but may be a protective factor against PTC progression and metastasis. The coexistence of HT affects the judgment of thyroid nodules by ultrasonography.
69Ultrasonography in the diagnosis of Hashimoto's thyroiditis.PubMed
Guihua Wu, Dazhong Zou, Haiyun Cai, et al.
Front Biosci (Landmark Ed). 2016 Jun 1;21(5):1006-12. doi: 10.2741/4437.
Hashimoto's thyroiditis is a type of autoimmune thyroid disease with an increasing prevalence in past decades. Its diagnosisis mostly based on ultrasonography. Ultrasonography is a useful and essential tool to make this diagnosis based on the characteristics of the disease. In the differential diagnosis of thyroid nodules, ultrasound-guided fine-needle biopsy is an effective method to distinguish Hashimoto's thyroiditis from other thyroid disorders. One exciting and recent advance is that non-invasive ultrasound-based methods have supplemented fine-needle aspiration to diagnose Hashimoto's thyroiditis under more complex conditions. In this review, we discuss the recent advantages of ultrasonography in the diagnosis of Hashimoto's thyroiditis.
70Hashimoto's Thyroiditis.PubMed
Renata Lorini, Roberto Gastaldi, Cristina Traggiai, et al.
Pediatr Endocrinol Rev. 2003 Dec;1 Suppl 2:205-11; discussion 211.
Hashimoto's Thyroiditis (HT) is the most common cause of thyroid diseases in children and adolescents and it is also the most common cause of acquired hypothyroidism with or without goiter. The linkage between HT and some HLA genes has been reported and a genetic predisposition to thyroid autoimmunity is suggested by observations in twins. There is no direct evidence that infections cause HT in humans, while iodine and iodine containing drugs can precipitate HT in susceptible populations. There is an infiltration of lymphocytes and plasma cells between the follicles followed by their atrophy. The clinical course is variable and spontaneous remission may occur in adolescence. Goiter, menstrual disorders, short stature, constipation, nervousness and exophthalmos have been reported as the most recurrent clinical features of HT. Nevertheless we studied 33 patients with HT, 22 girls and 11 boys aged 4.9-19 years and most of them were euthyroid clinically. Hashimoto thyroiditis is often associated with type 1 diabetes and other autoimmune disorders such as coeliac disease, type 2 and type 3 polyglandular autoimmune disorders. Girls with Turner syndrome may develop HT. Patients with HT have positive antibodies to thyroglobulin and/or to thyroperoxidase in blood. Thyroid function could be normal or abnormal (overt hypothyroidism, subclinical hypothyroidism and hyperthyroidism). Abnormal ultrasound patterns may be present in patients with HT disease as diffuse hypoechogenicity and pseudonodules. L-thyroxine therapy is indicated in HT with hypothyroidism, but periodic re-evaluations are required because HT could be a self-limited disorder in some cases.
71Radiomics-based ultrasound models for thyroid nodule differentiation in Hashimoto's thyroiditis.PubMed
Mengyuan Fang, Mengjie Lei, Xuexue Chen, et al.
Front Endocrinol (Lausanne). 2023 Oct 23;14:1267886. doi: 10.3389/fendo.2023.1267886. eCollection 2023.
BACKGROUND: Previous models for differentiating benign and malignant thyroid nodules(TN) have predominantly focused on the characteristics of the nodules themselves, without considering the specific features of the thyroid gland(TG) in patients with Hashimoto's thyroiditis(HT). In this study, we analyzed the clinical and ultrasound radiomics(USR) features of TN in patients with HT and constructed a model for differentiating benign and malignant nodules specifically in this population. METHODS: We retrospectively collected clinical and ultrasound data from 227 patients with TN and concomitant HT(161 for training, 66 for testing). Two experienced sonographers delineated the TG and TN regions, and USR features were extracted using Python. Lasso regression and logistic analysis were employed to select relevant USR features and clinical data to construct the model for differentiating benign and malignant TN. The performance of the model was evaluated using area under the curve(AUC), calibration curves, and decision curve analysis(DCA). RESULTS: A total of 1,162 USR features were extracted from TN and the TG in the 227 patients with HT. Lasso regression identified 14 features, which were used to construct the TN score, TG score, and TN+TG score. Univariate analysis identified six clinical predictors: TI-RADS, echoic type, aspect ratio, boundary, calcification, and thyroid function. Multivariable analysis revealed that incorporating USR scores improved the performance of the model for differentiating benign and malignant TN in patients with HT. Specifically, the TN+TG score resulted in the highest increase in AUC(from 0.83 to 0.94) in the clinical prediction model. Calibration curves and DCA demonstrated higher accuracy and net benefit for the TN+TG+clinical model. CONCLUSION: USR features of both the TG and TN can be utilized for differentiating benign and malignant TN in patients with HT. These findings highlight the importance of considering the entire TG in the evaluation of TN in HT patients, providing valuable insights for clinical decision-making in this population.
72The role of Graves' disease in the development of thyroid nodules and thyroid cancer.PubMed
Marta Nascimento Soares, Marta Borges-Canha, Celestino Neves, et al.
Eur Thyroid J. 2023 Jul 12;12(4):e230055. doi: 10.1530/ETJ-23-0055.
AIM: The prevalence of thyroid nodules and the risk of thyroid cancer in patients with Graves' disease is uncertain. We aimed to evaluate the prevalence of thyroid nodules and cancer in patients with Graves' disease. METHODS: Retrospective observational study of adult subjects with Graves' disease (positive autoantibodies thyrotropin receptor antibodies (TRAbs)) between 2017 and 2021 at our center was done. We evaluated the prevalence of thyroid nodules and cancer in this population and characterized the predictive factors for thyroid malignancy using linear and logistic regression models. RESULTS: We evaluated a total of 539 patients with Graves' disease during a median follow-up of 3.3 years (25th-75th percentiles 1.5-5.2 years). Fifty-three percent had thyroid nodules and 18 (3.3%) were diagnosed with thyroid cancer (12 papillary microcarcinomas). All tumors were classified using TNM classification as T1, and only one had lymph node metastasis; there were no recordings of distant metastasis. Sex, age, body mass index, smoking, TSH, and TRAbs levels were not significantly different between patients with and without thyroid cancer. Patients with multiple nodules on ultrasound (OR 1.61, 95%CI 1.04-2.49) and with larger nodules (OR 2.96, 95%CI 1.08-8.14, for 10 mm increase in size) had a greater risk of thyroid cancer diagnosis. CONCLUSION: Patients with Graves' disease had a high prevalence of thyroid nodules and their nodules had a significant risk of thyroid cancer. The risk was higher in those with multiple and larger nodules. Most had low-grade papillary thyroid cancer. More studies are needed to clarify the clinical relevance of these findings.
73Fine-needle aspiration biopsy of thyroid nodules: advantages, limitations, and effect.PubMed
H Gharib
Mayo Clin Proc. 1994 Jan;69(1):44-9. doi: 10.1016/s0025-6196(12)61611-5.
BACKGROUND: The efficacy of fine-needle aspiration (FNA) biopsy and its role in the management of a nodular goiter are clearly established. The accuracy of cytologic diagnosis approaches 95%. FINDINGS: FNA biopsy is a reasonable approach to thyroid nodules; it has decreased costs substantially because it facilitates selection of patients who need to undergo surgical excision. Selecting patients for operation on the basis of results of FNA biopsy has more than doubled the yield of carcinoma. The limitations of cytologic examination, nondiagnostic results, and cellular follicular neoplasms should be remembered but need not negate continued use of FNA biopsy. Negative (benign) and positive (malignant) cytologic results are conclusive; careful clinical follow-up of benign nodules and surgical excision of malignant nodules are recommended. Nondiagnostic results are inconclusive; further evaluation by repeated FNA biopsy, ultrasound-guided biopsy, or radionuclide scanning is necessary. Suspicious cytologic results are also inconclusive and are associated with a 20% chance of malignant involvement; surgical treatment is necessary for clarification. The role of levothyroxine therapy remains uncertain and is not recommended until compelling data are available. CONCLUSION: FNA biopsy is a safe, simple, reliable, and cost-effective means of detecting benign nodules. FNA biopsy, not thyroid scanning or ultrasonography, is the preferred initial diagnostic test in all patients with thyroid nodules.
74Ultrasound-guided fine-needle aspiration biopsy of thyroid nodules and multinodular goiters.PubMed
H Jack Baskin
Endocr Pract. 2004 May-Jun;10(3):242-245. doi: 10.4158/EP.10.3.242.
OBJECTIVE: To describe various techniques for performing ultrasound-guided fine-needle aspiration (FNA) biopsy of thyroid nodules, with the intent of shortening the learning curve for physicians with interest in this new procedure. METHODS: General principles and details of biopsy techniques and equipment are reviewed, and personal experience and preferences are described. RESULTS: Real-time ultrasound guidance has technically refined the FNA biopsy technique by decreasing the number of inadequate biopsy specimens and increasing both the specificity and the sensitivity of this procedure. In addition to being cost-effective, well tolerated, and expedient, ultrasound-guided FNA biopsy has emerged as the most accurate method for evaluation of thyroid nodules. The success of the procedure depends on the experience of the person using these techniques. CONCLUSION: For provision of optimal evaluation and management of thyroid nodules, endocrinologists should develop expertise in ultrasound-guided FNA biopsy and understand its advantages over conventional FNA biopsy.
75Pediatric thyroid fine-needle aspiration cytology: a meta-analysis.PubMed
Christopher Stevens, Justin K P Lee, Mohsen Sadatsafavi, et al.
J Pediatr Surg. 2009 Nov;44(11):2184-91. doi: 10.1016/j.jpedsurg.2009.07.022.
BACKGROUND: There is conflicting evidence in the current literature regarding the use of fine-needle aspiration (FNA) biopsy in the diagnosis of a thyroid nodule in the pediatric population. There are numerous studies that look at the sensitivity and specificity of this test with varying results. A meta-analysis will provide further insight into this topic. PURPOSE: Our objective was to investigate the diagnostic parameters of FNA biopsy in the diagnosis of a thyroid nodule in the pediatric population, specifically, to determine the sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of the test in differentiating malignant vs benign tumors. MATERIAL AND METHODS: We performed a literature search of Medline, Embase, and evidence based medicine (EBM) reviews for English studies that looked at FNA biopsy in thyroid nodules in the pediatric population, in which diagnostic values were present or could be calculated and where FNA results were compared to an acceptable reference standard. Two reviewers independently selected all abstracts, and from these, studies to review. Two reviewers also independently checked diagnostic values in the studies or calculated them from data available. A meta-analysis was performed, and pooled diagnostic test values were calculated using a random-effects, bivariate meta-regression model. Studies were also assessed for quality using the quality assessment for diagnostic accuracy studies tool. RESULTS: Twelve studies were included for review. The quality of the studies in general was good. The pooled estimate of sensitivity and specificity were 94% (95% confidence interval [CI], 86%-100%) and 81% (95% CI, 72%-91%), respectively. Assuming 20% of nodules are malignant, the accuracy, PPV, and NPV were 83.6%, 55.3%, and 98.2%, respectively. CONCLUSION: This meta-analysis provides good evidence that FNA biopsy of thyroid nodules is a sensitive test in the pediatric population and may be a useful tool for excluding malignancy in young patients. Future prospective studies are needed to evaluate this further.
76Risk of malignancy for each Bethesda class in pediatric thyroid nodules.PubMed
Olov Norlén, Amanda Charlton, Leba M Sarkis, et al.
J Pediatr Surg. 2015 Jul;50(7):1147-9. doi: 10.1016/j.jpedsurg.2014.10.046. Epub 2014 Dec 6.
PURPOSE: The Bethesda classification for cytology is used to classify thyroid nodules into one of six categories, and for each category there is an implied cancer risk and also recommendation for management. Despite lack of data in children, the American thyroid association promotes the use of the same management guidelines as in adults. Our aim was to study the risk of malignancy for each Bethesda class in children with thyroid nodules. METHODOLOGY: We included all patients ≤18years of age that had underwent a thyroid fine needle aspiration (FNA) at one of two centers between January 1998 and July 2013. FNA results were reclassified according to the Bethesda criteria. Histological, repeat cytological, radiological and clinical follow-up were recorded. RESULTS: Fifty-six patients (66 nodules) underwent FNB. Mean age was 13.6 years. Numbers of nodules reported as BI-BVI were 7, 38, 11, 4, 3 and 3, respectively. Follow-up was achieved for 55 (83%) nodules. Twelve (18%) nodules were malignant by histology and revealed papillary (n=7), follicular (n=3) or insular thyroid cancer (n=2), The proportion of nodules with malignancy for BI-BVI was: 0%, 0%, 18%, 100%, 100% and 100%. CONCLUSION: The rate of malignancy in thyroid nodules in children seems to be higher than reported in adults. The Bethesda criteria seem to accurately identify benign nodules, but other categories have a very high rate of malignancy and BIII nodules pose a particular challenge.
77The Influence of Patient Age on Thyroid Nodule Formation, Multinodularity, and Thyroid Cancer Risk.PubMed
Norra Kwong, Marco Medici, Trevor E Angell, et al.
J Clin Endocrinol Metab. 2015 Dec;100(12):4434-40. doi: 10.1210/jc.2015-3100. Epub 2015 Oct 14.
INTRODUCTION: Although advancing age is known to influence the formation of thyroid nodules, the precise relationship remains unclear. Furthermore, it is uncertain whether age influences the risk that any thyroid nodule may prove cancerous. AIM: The aim was to determine the impact of patient age on nodule formation, multinodularity, and risk of thyroid malignancy. METHOD: We conducted a prospective cohort analysis of consecutive adults (ages 20-95 y) who presented for evaluation of nodular disease from 1995 to 2011. A total of 6391 patients underwent ultrasound and fine-needle aspiration of 12 115 nodules ≥ 1 cm. Patients were divided into six age groups and compared using sonographic, cytological, and histological endpoints. RESULT: The prevalence of thyroid nodular disease increases with advancing age. The mean number of nodules at presentation increased from 1.5 in the youngest cohort (age, 20-30 y) to 2.2 in the oldest cohort (age, >70 y; P < .001), demonstrating a 1.6% annual increased risk for multinodularity (odds ratio, 1.02; P < .001). In contrast, the risk of malignancy in a newly identified nodule declined with advancing age. Thyroid cancer incidence per patient was 22.9% in the youngest cohort, but 12.6% in the oldest cohort (odds ratio, 0.972; P < .001), demonstrating a 2.2% decrease per year in the relative risk of malignancy between ages 20 and 60 years, which stabilized thereafter. Despite a lower likelihood of malignancy, identified cancers in older patients demonstrated higher risk histological phenotypes. Although nearly all malignancies in younger patients were well-differentiated, older patients were more likely to have higher risk papillary thyroid carcinoma variants, poorly differentiated cancer, or anaplastic carcinoma (P < .001). CONCLUSION: With advancing age, the prevalence of clinically relevant thyroid nodules increases, whereas the risk that such nodules are malignant decreases. Nonetheless, when thyroid cancer is detected in older individuals, a higher-risk histological phenotype is more likely. These data provide insight into the clinical paradox that confronts physicians managing this common illness.
78Variants of papillary thyroid carcinoma: association with histopathological prognostic factors.PubMed
Fábio Muradás Girardi, Marinez Bizarro Barra, Cláudio Galleano Zettler
Braz J Otorhinolaryngol. 2013 Nov-Dec;79(6):738-44. doi: 10.5935/1808-8694.20130135.
UNLABELLED: Papillary carcinoma is the most common thyroid malignancy. Many variants of this tumor have been described, with different morphological and molecular characteristics. Although most cases have excellent prognosis, the relationship between tumor architecture and its biological behavior remains controversial. OBJECTIVE: To present the experience of a single center on the prevalence of thyroid papillary carcinoma variants and their relationship with other histopathological prognostic factors. METHOD: Retrospective study of all the cases submitted to thyroidectomy for papillary carcinoma in the same institution over 11 years. RESULTS: We included 517 patients, 81.9% of them were women. The average age was 47.2 years. The variants recognized to have higher aggressiveness potential corresponded to 5.6% of the sample. We found an association of tumor subtypes with greater lesion diameter, T staging, lymphovascular and gland capsule invasion. CONCLUSION: A small percentage of papillary carcinoma cases is represented by variants recognized by their greater potential for aggression. There are associations between these variants and several other histopathological factors already recognized for their prognostic value, which may, by themselves, influence the outcome of these cases.
79Association Between Age and Nodal Metastasis in Papillary Thyroid Carcinoma.PubMed
Navika Shukla, Nosayaba Osazuwa-Peters, Uchechukwu C Megwalu
Otolaryngol Head Neck Surg. 2021 Jul;165(1):43-49. doi: 10.1177/0194599820966995. Epub 2020 Oct 20.
OBJECTIVE: To determine the relationship between age and rate of lymph node metastasis, nodal burden of disease, as well as rate of lateral neck disease in papillary thyroid cancer, especially in patients aged <30 years. STUDY DESIGN: Population-based cross-sectional study. SETTING: Population-based cancer database. METHODS: Data were extracted from the SEER 18 database (Surveillance, Epidemiology, and End Results) of the National Cancer Institute. The study cohort included 59,330 patients diagnosed with papillary thyroid cancer between 1988 and 2015. Patients aged 0 to 10 years, 11 to 20 years, and 21 to 30 years old were compared with those >30 years. All analyses were adjusted for sex, race, and T classification. RESULTS: The overall rate of lymph node metastasis was 26.11%, which increased with decreasing age. Adjusted odds ratios of lymph node metastasis were 7.19 (95% CI, 3.76-13.75) for the 0- to 10-year-old group, 3.45 (95% CI, 3.08-3.87) for the 11- to 20-year-old group, and 2.28 (95% CI, 2.15-2.41) for the 21- to 30-year-old group, relative to the group >30 years old. Decreased age was also associated with increased total positive nodes, increased lymph node ratio, and increased risk of lateral neck disease. CONCLUSION: Pediatric and early young adult patients with papillary thyroid carcinoma have a greater risk of lymph node metastasis, greater burden of nodal disease, and a greater risk of lateral neck metastases.
80[Surgical and postoperative treatment of patients with carcinomas of the thyroid gland in childhood and adolescence].PubMed
A F Romanchishen, G B Thompson, A V Gostimskiĭ
Vestn Khir Im I I Grek. 2008;167(5):55-8.
Carcinoma of the thyroid gland in children and adolescents is high biological aggression with frequent involvement of the regional lymph vessels, the presence of distant metastases and invasion to the gland capsule. Surgical treatment followed by radio-iodine therapy, and if necessary with TTH-suppressive therapy allows survival of absolute majority of the patients. The application of (131)1 therapy in the postoperative period suggests the necessity of permanent observation of the patients for the early diagnosis of possible neoplasms of other localizations.
81Predictive Factors for Lymph Node Metastasis in Papillary Thyroid Microcarcinoma.PubMed
Seo Ki Kim, Inhye Park, Jung-Woo Woo, et al.
Ann Surg Oncol. 2016 Sep;23(9):2866-73. doi: 10.1245/s10434-016-5225-0. Epub 2016 Apr 13.
BACKGROUND: Because lymph node (LN) metastasis has been proven to be a predictor for locoregional recurrence (LRR) in papillary thyroid microcarcinoma (PTMC), better knowledge about the predictors for LN metastasis in PTMC is required. METHODS: We retrospectively reviewed 5656 PTMC patients who underwent total thyroidectomy and central neck dissection and/or lateral neck dissection between January 1997 and June 2015. RESULTS: Male gender (adjusted odds ratio [OR] 2.332), conventional variant (adjusted OR 4.266), tumor size >0.5 cm (adjusted OR 1.753), multiplicity (adjusted OR 1.168), bilaterality (adjusted OR 1.177), and extrathyroidal extension (ETE) (adjusted OR 1.448) were independent predictors for high prevalence of central LN metastasis (CLNM), whereas per 10-year age increment (adjusted OR 0.760) and chronic lymphocytic thyroiditis (adjusted OR 0.791) were independent predictors for low prevalence of CLNM. In addition, male gender (adjusted OR 1.489), tumor size >0.5 cm (adjusted OR 1.295), multiplicity (adjusted OR 1.801), ETE (adjusted OR 1.659), and CLNM (adjusted OR 4.359) were independent predictors for high prevalence of lateral LN metastasis (LLNM), whereas per 10-year age increment (adjusted OR 0.838) was an independent predictor for low prevalence of LLNM. There was a statistically significant difference in LRR with regard to nodal stage (p < 0.001). CONCLUSIONS: Meticulous perioperative evaluation of LN metastasis is required for PTMC patients with the above predictors.
82Thyroid nodules in children and adolescents: Investigation and management.PubMed
Jessica L Sandy, Angela Titmuss, Shihab Hameed, et al.
J Paediatr Child Health. 2022 Dec;58(12):2163-2168. doi: 10.1111/jpc.16257. Epub 2022 Nov 16.
Clinically detectable thyroid nodules are less common in children than adults. However, they are associated with an increased risk of malignancy. Therefore, thorough evaluation of paediatric thyroid nodules is necessary, and an understanding of the features associated with a higher risk of malignancy is important to guide management and referral. Thyroid cancer in children differs significantly from that seen in adults in terms of genetics, presentation, response to treatment and prognosis. Children often present with more advanced disease, but the vast majority have excellent long-term prognosis. Evaluation and management of thyroid nodules and thyroid cancer require a multidisciplinary team approach and involvement of specialists with experience in this field. This review summarises investigative pathways for thyroid nodules in children and outlines current management strategies for paediatric thyroid nodules and cancer.
83Thyroid cancer in children.PubMed
Gabriel Rivera, Humberto Lugo-Vicente
Bol Asoc Med P R. 2014;106(3):48-54.
Cancer of the thyroid gland in pediatric patients is rare and if left untreated spreads and become lethal. Thyroid nodules in pediatric patients are four times more likely being malignant than adult nodules. The incidence of thyroid cancer in children increases with age, sex, race and nodule size. Exposures to low level of head and neck irradiation at young age, cancer survivors, family history of thyroid cancer and iodine deficiency are specific risk factors to develop thyroid cancer. Thyroid cancer is subdivided into papillary, follicular and medullary thyroid cancer varying in histological characteristics. Children who present with thyroid nodules should undergo ultrasound and fine needle aspiration biopsy to evaluate malignant potential. If biopsy results are positive for malignancy best option is complete surgical resection of the thyroid gland with central lymph node dissection followed by radioactive iodine treatment. Surgeons need to take certain precaution to avoid postoperative complications like hypoparathyroidism or recurrent laryngeal nerve damage. Follow-up is essential in order to evaluate remission or recurrence. An excellent prognosis in pediatric patients is the result of such an aggressive approach that can be supported by the low complications rate and low recurrence rate following surgery.
84Contemporary Thyroid Nodule Evaluation and Management.PubMed
Giorgio Grani, Marialuisa Sponziello, Valeria Pecce, et al.
J Clin Endocrinol Metab. 2020 Sep 1;105(9):2869-83. doi: 10.1210/clinem/dgaa322.
CONTEXT: Approximately 60% of adults harbor 1 or more thyroid nodules. The possibility of cancer is the overriding concern, but only about 5% prove to be malignant. The widespread use of diagnostic imaging and improved access to health care favor the discovery of small, subclinical nodules and small papillary cancers. Overdiagnosis and overtreatment is associated with potentially excessive costs and nonnegligible morbidity for patients. EVIDENCE ACQUISITION: We conducted a PubMed search for the recent English-language articles dealing with thyroid nodule management. EVIDENCE SYNTHESIS: The initial assessment includes an evaluation of clinical risk factors and sonographic examination of the neck. Sonographic risk-stratification systems (e.g., Thyroid Imaging Reporting and Data Systems) can be used to estimate the risk of malignancy and the need for biopsy based on nodule features and size. When cytology findings are indeterminate, molecular analysis of the aspirate may obviate the need for diagnostic surgery. Many nodules will not require biopsy. These nodules and those that are cytologically benign can be managed with long-term follow-up alone. If malignancy is suspected, options include surgery (increasingly less extensive), active surveillance or, in selected cases, minimally invasive techniques. CONCLUSION: Thyroid nodule evaluation is no longer a 1-size-fits-all proposition. For most nodules, the likelihood of malignancy can be confidently estimated without resorting to cytology or molecular testing, and low-frequency surveillance is sufficient for most patients. When there are multiple options for diagnosis and/or treatment, they should be discussed with patients as frankly as possible to identify an approach that best meets their needs.
85The Diagnosis and Management of Thyroid Nodules: A Review.PubMed
Cosimo Durante, Giorgio Grani, Livia Lamartina, et al.
JAMA. 2018 Mar 6;319(9):914-924. doi: 10.1001/jama.2018.0898.
IMPORTANCE: Thyroid nodules are common, being detected in up to 65% of the general population. This is likely due to the increased use of diagnostic imaging for purposes unrelated to the thyroid. Most thyroid nodules are benign, clinically insignificant, and safely managed with a surveillance program. The main goal of initial and long-term follow-up is identification of the small subgroup of nodules that harbor a clinically significant cancer (≈10%), cause compressive symptoms (≈5%), or progress to functional disease (≈5%). OBSERVATIONS: Thyroid function testing and ultrasonographic characteristics guide the initial management of thyroid nodules. Certain ultrasound features, such as a cystic or spongiform appearance, suggest a benign process that does not require additional testing. Suspicious sonographic patterns including solid composition, hypoechogenicity, irregular margins, and microcalcifications should prompt cytological evaluation. Additional diagnostic procedures, such as molecular testing, are indicated only in selected cases, such as indeterminate cytology (≈20%-30% of all biopsies). The initial risk estimate, derived from ultrasound and, if performed, cytology report, should determine the need for treatment and the type, frequency, and length of subsequent follow-up. Management includes simple observation, local treatments, and surgery and should be based on the estimated risk of malignancy and the presence and severity of compressive symptoms. CONCLUSIONS AND RELEVANCE: Most thyroid nodules are benign. A diagnostic approach that uses ultrasound and, when indicated, fine-needle aspiration biopsy and molecular testing, facilitates a personalized, risk-based protocol that promotes high-quality care and minimizes cost and unnecessary testing.
86Psychological Distress and Sleep Disturbance Throughout Thyroid Nodule Screening, Diagnosis, and Treatment.PubMed
Ruicen Li, Genpeng Li, Yuting Wang, et al.
J Clin Endocrinol Metab. 2021 Sep 27;106(10):e4221-e4230. doi: 10.1210/clinem/dgab224.
CONTEXT: Many controversies exist regarding screening and treatment of thyroid cancer (TC), especially papillary thyroid microcarcinoma (PTMC). OBJECTIVE: The aim of this study was to evaluate patients' psychological distress and sleep disturbance throughout thyroid nodule (TN) screening, diagnosis, and treatment. METHODS: A total of 2834 participants (1153 participants with TNs) were enrolled during the screening phase, and 1105 individuals with TNs (87 individuals with TC) were enrolled during the diagnosis phase. Of the 87 TC patients, 66 underwent immediate operation (OP), and 21 patients with PTMC opted for active surveillance (AS). Four validated scales were applied to quantify the outcome indicators at prescreening, postscreening, postdiagnosis, and posttreatment. RESULTS: Higher psychological distress and sleep disturbance were found postscreening than prescreening in subjects with TNs, but no differences in those without nodules. Compared with postscreening, higher scores of psychological distress and sleep disturbance were identified in patients with suspicious TC treated with fine needle aspiration (FNA) or with AS. Lower psychological distress and sleep disturbance were noted for patients with benign nodules than for TC patients. OP for TC, especially PTMC, did not alleviate psychological distress or sleep disturbance compared with the same parameters in patients who underwent AS. CONCLUSION: Based on the findings of impaired psychological health and sleep quality, screening for TNs in adults who show no symptoms should be performed with caution. Psychological distress and sleep disturbance should also be taken into consideration when FNA is performed for suspected TC or OP for papillary thyroid cancer, especially PTMC.
87Efficacy of microwave ablation in the treatment of large benign thyroid nodules: a multi-center study.PubMed
Yuan-Cheng Cang, Fang-Ying Fan, Yang Liu, et al.
Eur Radiol. 2024 Oct;34(10):6852-6861. doi: 10.1007/s00330-024-10614-w. Epub 2024 Mar 28.
OBJECTIVE: To evaluate the efficacy, safety, and improvement of symptoms by ultrasound-guided microwave ablation (MWA) for patients with large benign thyroid nodules (BTNs). METHODS: Eighty-seven patients with 87 BTNs (≥ 4 cm) treated with MWA between April 2015 and March 2021 were enrolled in this retrospective multicenter study, with clinical and ultrasound examinations performed at the 1st, 3rd, 6th, and 12th months. A multivariable linear mixed effects model was employed to explore the alterations in volume and volume reduction ratio (VRR), as well as the potential factors associated with VRR. RESULTS: The mean age of the 87 patients was 45.69 ± 14.21 years (range 18-76 years), and the ratio of men to women was 1:4.8. The mean volumes were much decreased at the 12th month after ablation compared to the initial volumes (p < .001). The mean VRR was 76.09% at the 12th month. The technique efficacy (VRR > 50%) was 90.80% at the 12th month. A multivariate analysis revealed that VRR was related to the initial volume (p = .015), annular flow (p = .010), and nodule composition (p = .024). The mean symptomatic score decreased from 4.40 ± 0.28 to 0.26 ± 0.06 at the 12th month (p < .001). At the same time, the mean cosmetic score decreased from 3.22 ± 0.10 to 1.31 ± 0.08 (p < .001). CONCLUSION: MWA could serve as a safe and effective therapy for large BTNs, significantly reducing the volume of BTNs and significantly improving compressive symptoms and appearance problems. CLINICAL RELEVANCE STATEMENT: Microwave ablation could serve as a safe and effective therapy for large benign thyroid nodules, leading to significant volume reduction and satisfied symptom and cosmetic alleviation period. KEY POINTS: • This multicenter study investigated the feasibility and safety of microwave ablation for large benign thyroid nodules. • After ablation, the nodule volume was significantly reduced, and patients' symptoms and appearance problems were significantly improved. • Microwave ablation is feasible for large benign thyroid nodules and has been a supplement treatment.
88Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology: A Prospective Blinded Multicenter Study.PubMed
David L Steward, Sally E Carty, Rebecca S Sippel, et al.
JAMA Oncol. 2019 Feb 1;5(2):204-212. doi: 10.1001/jamaoncol.2018.4616.
IMPORTANCE: Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients if the nodules are reliably diagnosed as benign without surgery. OBJECTIVE: To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules. DESIGN, SETTING, AND PARTICIPANTS: Prospective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules. INTERVENTIONS: A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3). MAIN OUTCOMES AND MEASURES: The primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules. RESULTS: Of the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%. CONCLUSIONS AND RELEVANCE: In this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result.
89Thyroid Nodules: Advances in Evaluation and Management.PubMed
Ravi Kant, Amanda Davis, Vipin Verma
Am Fam Physician. 2020 Sep 1;102(5):298-304.
Thyroid nodules can be detected by ultrasonography in up to 68% of the general population. They are typically benign and are often discovered incidentally. The primary goal of thyroid nodule evaluation is to determine whether it is malignant. After thyroid ultrasonography has been performed, the next step is measurement of serum thyroid-stimulating hormone. If levels are low, a radionuclide thyroid uptake scan is indicated. Hyperfunctioning nodules are rarely malignant and do not require tissue sampling. Nonfunctioning nodules and nodules in a patient with a normal or high thyroid-stimulating hormone level may require fine-needle aspiration based on ultrasound characteristics and size. Nodules with suspicious features and solid hypoechoic nodules 1 cm or larger require aspiration. The Bethesda System (categories 1 through 6) is used to classify samples. Molecular testing can be used to guide treatment when aspiration yields an indeterminate result. Molecular testing detects mutations associated with thyroid cancer and can help inform decisions about surgical excision vs. continued ultrasound monitoring. Treatment of pregnant women with nonfunctioning thyroid nodules and of children with thyroid nodules is similar to that for nonpregnant adults, with the exception of molecular testing, which has not been validated in these populations.
90Radiofrequency Ablation for Benign Thyroid Nodules: 1-Year Follow-Up in 184 Patients.PubMed
Nguyen Lam Vuong, Le Quang Dinh, Ho Tat Bang, et al.
World J Surg. 2019 Oct;43(10):2447-2453. doi: 10.1007/s00268-019-05044-5.
BACKGROUND: Benign thyroid nodules are common, and must be treated when symptomatic. Non-surgical minimally invasive modalities, including radiofrequency ablation (RFA), have been widely used with good results. The factors related to the efficacy of RFA are still debated. This study was to evaluate the safety, efficacy and related factors of RFA in the treatment of benign thyroid nodules. METHODS: A retrospective single-center study was conducted on 251 benign thyroid nodules in 184 patients treated with RFA. The procedure was performed under ultrasound (US) guidance using the trans-isthmic approach and the moving-shot technique. Clinical and US examinations were performed at 1, 3, 6, 12 months, and then at 6 month intervals. Study outcomes were volume reduction ratio (VRR) and complications. RESULTS: There were 153 women and 31 men included in the study. The mean age was 43.9 years. The median initial largest diameter and volume of nodules were 30 mm and 6.18 ml. The median length of follow-up was 12 months. Two minor complications were found. The mean VRR was 66.8; 74.3; and 81% after 3, 6, and 12 months, respectively. Initial solidity was a factor related to the efficacy: cystic nodules had higher VRR compared to solid ones. CONCLUSIONS: RFA is safe, effective and can be used as a routine treatment for benign thyroid nodules. More prospective multicenter studies with long-term follow-up are required to improve the safety and efficacy of RFA.
91Radiofrequency ablation for autonomously functioning thyroid nodules: a multicenter study.PubMed
Jin Yong Sung, Jung Hwan Baek, So Lyung Jung, et al.
Thyroid. 2015 Jan;25(1):112-7. doi: 10.1089/thy.2014.0100.
BACKGROUND: The purpose of this study is to validate the generalizability of the efficacy and safety of radiofrequency (RF) ablation for treating autonomously functioning thyroid nodules (AFTN) in a large population multicenter study. METHODS: This study included 44 patients from 5 institutions who refused or were not suitable for surgery or radioiodine therapy. Twenty-three patients were affected by a toxic nodule and 21 by a pretoxic nodule. RF ablation was performed using an 18-gauge, internally cooled electrode. Nodule volume, thyroid function, scintigraphy, symptom/cosmetic scores, and complications were evaluated before treatment and during each follow-up. RESULTS: The mean follow-up period was 19.9±12.6 months. The mean nodule volume was initially 18.5±30.1 mL and significantly decreased after treatment at 1 month (11.8±26.9 mL, p<0.001) and the last month (4.5±9.8 mL, p<0.001). Significant improvement of triiodothyronine, free thyroxine, and thyrotropin was observed at the last follow-up. Regarding scintigraphy, 35 hot nodules became cold or were normal when scanned and 9 decreased uptake, although they remained hot nodules. The mean symptom and cosmetic scores were significantly reduced at the last follow-up. No major complications were encountered. CONCLUSIONS: This multicenter study validated the efficacy and safety of RF ablation for treating AFTN; RF ablation can be considered an alternative to surgery or radioiodine therapy.
92Efficacy and Safety of Radiofrequency Ablation for Benign Thyroid Nodules: A Prospective Multicenter Study.PubMed
So Lyung Jung, Jung Hwan Baek, Jeong Hyun Lee, et al.
Korean J Radiol. 2018 Jan-Feb;19(1):167-174. doi: 10.3348/kjr.2018.19.1.167. Epub 2018 Jan 2.
OBJECTIVE: To assess the efficacy and safety of thyroid radiofrequency (RF) ablation for benign thyroid nodules by trained radiologists according to a unified protocol in a multi-center study. MATERIALS AND METHODS: From 2010 to 2011, 345 nodules from 345 patients (M:F = 43:302; mean age ± SD = 46.0 ± 12.7 years, range = 15-79) who met eligibility criteria were enrolled from five institutions. At pre-ablation, the mean volume was 14.2 ± 13.2 mL (1.1-80.8 mL). For 12 months or longer after treatment, 276 lesions, consisting of 248 solid and 28 predominantly cystic nodules, were followed. All operators performed RF ablation with a cool-tip RF system and two standard techniques (a transisthmic approach and the moving-shot technique). Volume reduction at 12 months after RF ablation (the primary outcome), therapeutic success, improvement of symptoms as well as of cosmetic problems, and complications were evaluated. Multiple linear regression analysis was applied to identify factors that were independently predictive of volume reduction. RESULTS: The mean volume reduction at 12 months was 80.3% (n = 276) and at the 24-, 36-, 48-, and 60-month follow-ups 84.3% (n = 198), 89.2% (n = 128), 91.9% (n = 57), and 95.3% (n = 6), respectively. Our therapeutic success was 97.8%. Both mean symptom and cosmetic scores showed significant improvements ( < 0.001). The rate of major complications was 1.0% (3/276). Solidity and applied energy were independent factors that predicted volume reduction. CONCLUSION: Radiofrequency ablation performed by trained radiologists from multiple institutions using a unified protocol and similar devices was effective and safe for treating benign thyroid nodules.
93Does Radiofrequency Ablation Induce Neoplastic Changes in Benign Thyroid Nodules: A Preliminary Study.PubMed
Su Min Ha, Jun Young Shin, Jung Hwan Baek, et al.
Endocrinol Metab (Seoul). 2019 Jun;34(2):169-178. doi: 10.3803/EnM.2019.34.2.169. Epub 2019 May 15.
BACKGROUND: To evaluate the clinical feasibility of radiofrequency ablation (RFA) of benign thyroid nodules along with cytomorphological alteration, and any malignant transformation through biopsy. METHODS: The data were retrospectively collected between April 2008 and June 2013 and core needle biopsy (CNB) was performed on 16 benign thyroid nodules previously treated using RFA. The parameters of the patients were compared, between the time of enrollment and the last follow-up examination, using linear mixed model statistical analysis. RESULTS: No atypical cells or neoplastic transformation were detected in the undertreated peripheral portion of treated benign nodules on the CNB specimen. RFA altered neither the thyroid capsule nor the thyroid tissue adjacent to the treated area. On histopathological examinations, we observed 81.2% acellular hyalinization, which was the most common finding. After a mean follow-up period of over 5 years, the mean volume of thyroid nodule had decreased to 6.4±4.2 mL, with a reduction rate of 81.3%±5.8% (<0.0001). CONCLUSION: RFA is a technically feasible treatment method for benign thyroid nodules, with no carcinogenic effect or tissue damage of the normal thyroid tissue adjacent to the RFA-treated zone.
94Prevalence of goiter and thyroid nodules before and after implementation of the universal salt iodization program in mainland China from 1985 to 2014: a systematic review and meta-analysis.PubMed
Wei Zhao, Cheng Han, Xiaoguang Shi, et al.
PLoS One. 2014 Oct 14;9(10):e109549. doi: 10.1371/journal.pone.0109549. eCollection 2014.
OBJECTIVES: We comprehensively estimated the prevalence of goiter and thyroid nodules (TNs) before and after the implementation of the Universal Salt Iodization (USI) program in mainland China and provided information for creating effective health policies. METHODS: PubMed, Google Scholar, CNKI, Chinese Wanfang and Chongqing VIP databases were searched for relevant studies from Jan 1985 to Feb 2014. Data from eligible citations were extracted by two independent reviewers. All analyses were performed with Stata 11.0 and SPSS 17.0. RESULTS: Eligible articles (N = 31; 4 in English and 27 in Chinese) included 52 studies (15 about goiter rates made before 1996 and 14 afterwards, and 23 about TNs). Our meta-analysis suggests a pooled prevalence for goiter before and after 1996 and for TNs of 22.8% (95% CI: 15.3%, 30.3%), 12.6% (95% CI: 9.4%, 15.8%) and 22.7% (95% CI: 18.3%, 27.0%), respectively. Egger's test of three independent categories revealed no evidence of publication bias (p = 0.101, 0.148 and 0.113, respectively). CONCLUSIONS: The prevalence of goiter was reduced by almost half after 1996 in mainland China, so the USI program was considered beneficial. However, subgroup analysis suggests that both insufficient and excess iodine may be associated with goiter. The prevalence of goiter and TNs increased significantly after 2002, suggesting a risk of excessive iodine intake. Thus, salt iodization standardizations should be set according to local conditions.
95Multi-Omics-Based Characterization of DNA Methylation Episignatures for Papillary Thyroid Cancer in a Chinese Population.PubMed
Xianhui Ruan, Feng Yang, Mengling Li, et al.
Thyroid. 2025 Jul;35(7):789-802. doi: 10.1089/thy.2024.0611. Epub 2025 May 30.
Thyroid cancer is the most common endocrine malignancy, with papillary thyroid cancer (PTC) accounting for ∼80% of all cases. DNA methylation alterations and gene expression changes in cancer, offer valuable insights into tumor biology and serve as potential clinical biomarkers. However, the functional implications of DNA methylation changes in PTC patients, particularly based on multiomics analysis in the Chinese population, remain insufficiently explored. This study aims to investigate the epigenetic signatures of thyroid cancer and identify the DNA methylation biomarkers for diagnosing PTC in Chinese patients. Thyroid cancer tissues ( = 40) and benign thyroid nodule tissues ( = 31) were collected from Chinese patients for global DNA methylation analysis. Gene expression profiles and H3K27ac modifications were also investigated to understand the impacts of epigenetic changes on gene expression. Genome-wide methylation profiling and machine learning methods were employed to differentiate PTC from control samples. Genome-wide DNA methylation maps revealed significant methylome changes in Chinese PTC tissues. By integrating our data with The Cancer Genome Atlas thyroid cancer methylation profiles, we identified unique hypomethylation patterns associated with thyroid hormone synthesis specifically in Chinese PTC patients. RNA sequencing and H3K27ac modification analysis, along with functional assays, showed that the dysregulated genes in PTC patients are critical for the proliferation, migration, and invasion of thyroid cancer. Our study provides a comprehensive view of the multi-omics-based, function-guided DNA methylation landscape for Chinese PTC patients. We identified seven functional differentially methylated regions with high sensitivity and specificity for diagnosing thyroid cancer in Chinese patients. Additionally, is highlighted as a key player in PTC pathogenesis and shows promise as a valuable biomarker for predicting patient outcomes. This research advances our understanding of DNA methylation in thyroid cancer and underscores the importance of developing population-specific diagnostic tools to improve patient outcomes. However, further validation in larger, independent cohorts is needed to confirm their diagnostic value.
96Identification of Tissue-Specific DNA Methylation Signatures for Thyroid Nodule Diagnostics.PubMed
John H Yim, Audrey H Choi, Arthur X Li, et al.
Clin Cancer Res. 2019 Jan 15;25(2):544-551. doi: 10.1158/1078-0432.CCR-18-0841. Epub 2018 Aug 9.
PURPOSE: Thyroid cancer is frequently difficult to diagnose due to an overlap of cytologic features between malignant and benign nodules. This overlap leads to unnecessary removal of the thyroid in patients without cancer. While providing some improvement over cytopathologic diagnostics, molecular methods frequently fail to provide a correct diagnosis for thyroid nodules. These approaches are based on the difference between cancer and adjacent thyroid tissue and assume that adjacent tissues are the same as benign nodules. However, in contrast to adjacent tissues, benign thyroid nodules can contain genetic alterations that can be found in cancer. For the development of a new molecular diagnostic test for thyroid cancer, we evaluated DNA methylation in 109 thyroid tissues by using genome-wide single-base resolution DNA methylation analysis. The test was validated in a retrospective cohort containing 65 thyroid nodules. RESULTS: By conducting reduced representation bisulfite sequencing in 109 thyroid specimens, we found significant differences between adjacent tissue, benign nodules, and cancer. These tissue-specific signatures are strongly linked to active enhancers and cancer-associated genes. Based on these signatures, we developed a new epigenetic approach for thyroid diagnostics. According to the validation cohort, our test has an estimated specificity of 97% [95% confidence interval (CI), 81-100], sensitivity of 100% (95% CI, 87-100), positive predictive value of 97% (95% CI, 83-100), and negative predictive value of 100% (95% CI, 86-100). CONCLUSIONS: These data show that epigenetic testing can provide outstanding diagnostic accuracy for thyroid nodules..
97DNA Methylation Status of HYAL1 in Malignant and Benign Thyroid Nodules.PubMed
Mengxia Li, Yifei Yin, Minmin Zhang, et al.
Horm Metab Res. 2023 Dec;55(12):869-875. doi: 10.1055/a-2188-0050. Epub 2023 Dec 1.
Differentiation between benign and malignant thyroid nodules has been a challenge in clinical practice. Exploring a novel biomarker to determine the malignancy of thyroid nodules has important implications. We semi-quantitatively determined the DNA methylation levels of four CpG sites located at the gene body of HYAL1 in formalin-fixed paraffin-embedded (FFPE) tissue samples from 190 early-stage papillary thyroid cancer (PTC) cases and 190 age- and gender-matched subjects with benign thyroid nodule (BTN). HYAL1 expression was evaluated by immunohistochemical (IHC) staining in another cohort of 55 PTC and 55 matched BTN cases. Covariates-adjusted odds ratios (ORs) for 10% increased methylation were calculated by binary logistic regression. A 165 bp amplicon covering four CpG sites at the second exon of HYAL1 gene was designed. After adjusted for all covariates, higher methylation level of HYAL1_CpG_3,4 in the FFPE tissue was associated with PTC (OR per 10% increased methylation=1.53, p=0.025), even with stage І PTC (OR per 10% increased methylation=1.58, p=0.021). Hypermethylation of HYAL1_CpG_3,4 had a significant association with early-stage PTC in the females (OR per 10% increased methylation=1.60, p=0.028) rather than in the males. Besides, we found the higher expression of HYAL1 protein in PTC than that in BTN patients (IHC score: 2.3 vs. 0.5, p=1.00E-06). Our study suggested altered methylation and expression of HYAL1 could be a novel and potential biomarker in distinguishing malignant and benign thyroid nodules.
98RASGEF1C methylation for the distinguishment and classification of benign and malignant thyroid tumors.PubMed
Wenkang Yu, Yifei Yin, Mengxia Li, et al.
Clin Epigenetics. 2025 Jul 14;17(1):124. doi: 10.1186/s13148-025-01931-y.
BACKGROUND: The incidence of thyroid cancer (TC) has significantly increased, highlighting the need for effective and objective approaches for the early diagnosis of TC. This study aimed to explore RASGEF1C methylation as a biomarker for papillary thyroid cancer (PTC). METHODS: Formalin-fixed paraffin-embedded samples from a total of 363 PTC and 409 benign thyroid nodules from multiple centers were analyzed. RASGEF1C methylation profiles were examined via MALDI-TOFF mass spectrometry. Statistical analysis was performed via logistic regression adjusted for covariates, nonparametric tests, and receiver operating characteristic (ROC) analysis. Additionally, 40 follicular thyroid cancer samples, 45 medullary thyroid cancer samples, and 7 anaplastic thyroid samples from three hospitals were afterward collected to compare methylation patterns across subtypes. RESULTS: Hypomethylation of RASGEF1C in PTC was observed vs. BTN (all odds ratios (ORs) ≥ 1.57, p values < 0.001). Stratification analysis revealed a more pronounced association in younger patients, especially for BRAF V600E-positive PTC patients, than in individuals with benign tumors (all ORs ≥ 1.89, p values < 0.001). ROC analysis further demonstrated the outstanding diagnostic power of RASGEF1C hypomethylation for BRAF V600E-positive PTC cases (area under the curve (AUC) = 0.93), for cases < 55 years old (AUC = 0.88), and even for patients with a tumor length ≤ 1 cm (AUC = 0.83). Moreover, we observed the lowest RASGEF1C methylation level in anaplastic thyroid carcinoma, the most aggressive subtype of TC. Our results revealed similar RASGEF1C hypomethylation between chronic lymphocytic thyroiditis and papillary thyroid cancer, whereas RASGEF1C methylation in subacute thyroiditis patients was similar to that in the other benign subtypes. CONCLUSION: Our study revealed RASGEF1C methylation as a promising biomarker for distinguishing and classifying benign and malignant thyroid tumors and even provided epigenetic evidence for the inflammatory-cancer transformation. Nevertheless, the limitation of tissue-based biomarkers should be well noted, and the development of more accessible biomarkers warrants further exploration in the future.
99Diagnostic significance of DNA methylation of PTEN and DAPK in thyroid tumors.PubMed
Feng Wei, Yun Wu, Zhaoxia Wang, et al.
Clin Endocrinol (Oxf). 2020 Aug;93(2):187-195. doi: 10.1111/cen.14192. Epub 2020 Jun 2.
OBJECTIVE: DNA Methylation of the tumour suppressor gene leading to gene silencing plays an important role in thyroid tumour development. The purpose was to determine the DNA methylation status of phosphatase and tensin homolog (PTEN) and death-associated protein kinase (DAPK) in patients with thyroid nodules and to explore whether they can be used as molecular diagnostic tools to differentiate benign and malignant thyroid nodules. DESIGN, PATIENTS AND MEASUREMENTS: Thyroid tissue and blood samples were obtained from normal healthy individuals (controls) and patients suffering from clinically diagnosed thyroid nodular disease [papillary thyroid carcinoma (PTC), adenoma and nodular goitre]. DNA methylation level, mRNA expression and protein expression of PTEN and DAPK in the thyroid tissues and peripheral blood were detected using methylation-specific PCR, semi-quantitative reverse transcription PCR and Western blot, respectively. Diagnostic sensitivity, specific and accuracy of detection were evaluated between blood and thyroid tissue. RESULTS: There was a significant increase in the level of DNA methylation of PTEN and DAPK in PTC (P < .05) compared with controls and other types of thyroid nodules. Levels of the mRNA of both PTEN and DAPK were lower in PTC in both peripheral blood and tissue samples compared with controls, while there was concomitant decrease of both PTEN and DAPK protein expression in PTC tissues (P < .05). There was no significant difference in diagnostic specificity, sensitivity and accuracy between blood sample and thyroid tissues. CONCLUSIONS: Hypermethylated status of both PTEN and DAPK in peripheral blood and tissue samples can be useful biomarkers for clinical diagnosis and, distinguishing of benign and malignant thyroid nodules.
100Cell-free DNA methylation biomarker for the diagnosis of papillary thyroid carcinoma.PubMed
Shubin Hong, Bo Lin, Minjie Xu, et al.
EBioMedicine. 2023 Apr;90:104497. doi: 10.1016/j.ebiom.2023.104497. Epub 2023 Mar 1.
BACKGROUND: Cell-free DNA (cfDNA) is being explored as biomarker for non-invasive diagnosis of cancer. We aimed to establish a cfDNA-based DNA methylation marker panel to differentially diagnose papillary thyroid carcinoma (PTC) from benign thyroid nodule (BTN). METHODS: 220 PTC- and 188 BTN patients were enrolled. Methylation markers of PTC were identified from patients' tissue and plasma by reduced representation bisulfite sequencing and methylation haplotype analyses. They were combined with PTC markers from literatures and were tested on additional PTC and BTN samples to verify PTC-detecting ability using targeted methylation sequencing. Top markers were developed into ThyMet and were tested in 113 PTC and 88 BTN cases to train and validate a PTC-plasma classifier. Integration of ThyMet and thyroid ultrasonography was explored to improve accuracy. FINDINGS: From 859 potential PTC plasma-discriminating markers that include 81 markers identified by us, the top 98 most PTC plasma-discriminating markers were selected for ThyMet. A 6-marker ThyMet classifier for PTC plasma was trained. In validation it achieved an Area Under the Curve (AUC) of 0.828, similar to thyroid ultrasonography (0.833) but at higher specificity (0.722 and 0.625 for ThyMet and ultrasonography, respectively). A combinatorial classifier by them, ThyMet-US, improved AUC to 0.923 (sensitivity = 0.957, specificity = 0.708). INTERPRETATION: The ThyMet classifier improved the specificity of differentiating PTC from BTN over ultrasonography. The combinatorial ThyMet-US classifier may be effective in preoperative diagnosis of PTC. FUNDING: This work was supported by the grants from National Natural Science Foundation of China (82072956 and 81772850).
101MeIS: DNA Methylation-Based Immune Response Signatures for Thyroid Nodule Diagnostics.PubMed
Huang Chen, Yiying Liu, Feihang Wang, et al.
J Clin Endocrinol Metab. 2024 Aug 13;109(9):2210-2219. doi: 10.1210/clinem/dgae141.
CONTEXT: Accurately distinguishing between benign thyroid nodules (BTNs) and papillary thyroid cancers (PTCs) with current conventional methods poses a significant challenge. OBJECTIVE: We identify DNA methylation markers of immune response-related genes for distinguishing BTNs and PTCs. METHODS: In this study, we analyzed a public reduced representative bisulfite sequencing dataset and revealed distinct methylation patterns associated with immune signals in PTCs and BTNs. Based on these findings, we developed a diagnostic classifier named the Methylation-based Immune Response Signature (MeIS), which was composed of 15 DNA methylation markers associated with immune response-related genes. We validated MeIS's performance in 2 independent cohorts: Z.S.'s retrospective cohort (50 PTC and 18 BTN surgery-leftover samples) and Z.S.'s preoperative cohort (31 PTC and 30 BTN fine-needle aspiration samples). RESULTS: The MeIS classifier demonstrated significant clinical promise, achieving areas under the curve of 0.96, 0.98, 0.89, and 0.90 in the training set, validation set, Z.S.'s retrospective cohort, and Z.S.'s preoperative cohort, respectively. For the cytologically indeterminate thyroid nodules, in Z.S.'s retrospective cohort, MeIS exhibited a sensitivity of 91% and a specificity of 82%; in Z.S.'s preoperative cohort, MeIS achieved a sensitivity of 84% and a specificity of 74%. Additionally, combining MeIS and BRAF V600E detection improved the detecting performance of cytologically indeterminate thyroid nodules, yielding sensitivities of 98% and 87%, and specificities of 82% and 74% in Z.S.'s retrospective cohort and Z.S.'s preoperative cohort, respectively. CONCLUSION: The 15 markers we identified can be employed to improve the diagnostic of cytologically indeterminate thyroid nodules.
102Organochlorine pesticides and epigenetic alterations in thyroid tumors.PubMed
Fouzieh Salimi, Gholamreza Asadikaram, Mohammad Reza Ashrafi, et al.
Front Endocrinol (Lausanne). 2023 Jul 25;14:1130794. doi: 10.3389/fendo.2023.1130794. eCollection 2023.
PURPOSE: Cancer incidence depends on various factors e.g., pesticide exposures which cause epigenetic alterations. The present research aimed to investigate the organochlorine pesticides (OCPs) impacts on promoter methylation of three tumor-suppressor genes and four histone modifications in thyroid nodules in 61 Papillary thyroid carcinoma (PTC) and 70 benign thyroid nodules (BTN) patients. METHODS: OCPs were measured by Gas chromatography. To identify promoter methylation of TSHR, ATM, and P16 genes, the nested-methylation-specific PCR (MSP) was utilized, and histone lysine acetylation (H3K9, H4K16, and H3K18) and lysine methylation (H4K20) were detected by performing western blot analysis. RESULTS: Further TSHR methylation and less P16 methylation were observed in PTC than in BTN. No substantial difference was detected for ATM methylation between PTC and BTN groups. Also, OCP dramatically increased the odds ratio of TSHR (OR=3.98, =0.001) and P16 (OR=5.65, <0.001) methylation while confounding variables reduced the chances of ATM methylation arising from 2,4-DDE and 4,4-DDT influence. Hypomethylation of H4K20 and hypo-acetylation of H3K9, H4K16, and H3K18 (<0.001) were observed in PTC samples than BTN. Furthermore, OCPs substantially decreased the odds ratio of H3K9 (OR=3.68, <0.001) and H4K16 (OR=6.03, <0.001) acetylation. CONCLUSION: The current research indicated that OCPs could contribute to PTC progression by TSHR promoter hypermethylation and decreased acetylation of H3K9 and H4K16. In addition, in PTC patients, assessing TSHR promoter methylation and acetylation of H3K9 and H4K16 could have predictive values.