Studies of Thyroid Function in Health and Disease

本自然史方案积极招募已知或疑似甲状腺异常的任何年龄的受试者。 所研究的疾病可以广义地定义为甲状腺功能亢进或甲状腺功能减退状态和实验室异常。 甲状腺功能亢进状态包括但不限于伴或不伴甲状腺外表现的Graves病;亚急性甲状腺炎;无症状甲状腺炎;单个或多个功能亢进甲状腺结节;碘诱导的甲状腺功能亢进;甲状腺激素的超敏给药;滋养层肿瘤;由产生TSH的垂体瘤或非肿瘤原因引起的TSH“不适当”分泌，即垂体抵抗甲状腺激素的作用。 甲状腺功能减退状态包括由于发育不全、自身免疫或医源性原因引起的原发性甲状腺功能衰竭;（或垂体）甲状腺功能减退，通常由非促甲状腺激素来源的垂体肿瘤引起，如生长激素（GH）分泌肿瘤或泌乳素瘤;叔（或下丘脑）甲状腺功能减退，通常由下丘脑激素促甲状腺激素释放激素（TRH）缺乏引起，病因不明或继发于垂体瘤;无生物活性的TSH，与下丘脑激素的内源性异常有关或继发于垂体瘤（通常与TSH分子的异常糖基化模式有关）;对甲状腺激素（RTH）的全身性抵抗，这是一种已被证明是由于TH受体异常引起的疾病。 此外，研究了导致甲状腺功能异常的条件或状态，包括非甲状腺疾病;血清TH结合蛋白异常导致甲状腺功能正常的高甲状腺素血症或高三碘甲状腺原氨酸血症;甲状腺素结合球蛋白（TBG）的遗传缺陷; TSH或其他甲状腺激素测定中的抗体干扰。最近，反射质量分光光度法被用于进一步诊断该患者队列中的甲状腺功能障碍，从而能够比较质量分光光度法和标准免疫测定法在诊断甲状腺疾病中的诊断准确性。 尿白蛋白是一种常染色体隐性遗传疾病，由HGD基因的致病性变异引起。HGD酶的缺乏导致尿黑酸（HGA）的组织沉积，引起严重的骨关节病和心脏瓣膜变性。尽管HGD对酪氨酸的分解代谢至关重要，而酪氨酸的分解代谢为甲状腺激素的合成提供了基础，但尿黑酸症中甲状腺功能障碍的患病率尚不清楚。因此，我们评估黑酸尿症患者的甲状腺结构和功能。在三级转诊中心进行了一项单中心队列研究，纳入了2000年2月1日至2018年12月31日期间随访中位时间为93个月（四分位距，48-150）的黑酸尿患者。黑尿症的诊断是基于临床表现和尿HGA水平升高。共考虑130例患者参与研究。与普通人群相比，黑酸尿症成人甲状腺功能障碍的患病率。促甲状腺激素和游离甲状腺素水平通过免疫测定法测定，并在每位患者中重复测定，中位数为3次（四分位数间距，2-22）。颈部超声扫描在一个子集的参与者进行了分析。Logistic回归分析甲状腺功能障碍与年龄、性别、甲状腺过氧化物酶（TPO）抗体、血清酪氨酸水平和尿HGA水平的关系。 130例患者中，5例因甲状腺功能减退症行甲状腺切除术而排除。研究队列包括125例患者;中位年龄为45岁（四分位距，35-51）。大多数患者为男性（72 57.6%）。原发性甲状腺功能亢进症的患病率为0.8%（1/125例患者），与一般人群中观察到的0.5%相似（差异，0.003; 95% CI，-0.001至0.04; P = 0.88）。原发性甲状腺功能减退症的患病率为16.0%（125例患者中有20例），显著高于一般人群报告的3.7%（差异为0.12; 95%CI为0.10-0.24; P <0.001）。女性比男性更容易患原发性甲状腺功能减退症（比值比，10.99; 95%CI，3.13-38.66; P <0.001）。TPO抗体阳性的患者发生原发性甲状腺功能减退的可能性高于无TPO抗体的患者（比值比，7.36; 95%CI，1.89-28.62; P = .004）。本研究中患者之间甲状腺结节的患病率无显著差异（29/49 59.2%）vs一般人群（68%）（差异，0.088; 95% CI，-0.44至0.73; P = 0.20）或癌症（7% vs 5%;差异，0.01; 95% CI，-0.01至0.17; P = 0.86）。 本研究中黑尿症患者原发性甲状腺功能减退症的高患病率表明，应考虑并优先考虑在这一人群中进行系列筛查。

Subjects of any age with known or suspected thyroid abnormalities are actively recruited to this natural history protocol. The disorders studied can be broadly defined as hyper- or hypothyroid states and laboratory abnormalities. Hyperthyroid states include but are not restricted to Graves' disease with or without extrathyroidal manifestations; subacute thyroiditis; silent thyroiditis; single or multiple hyperfunctioning thyroid nodules; iodide-induced hyperthyroidism; surreptitious administration of thyroid hormone; trophoblastic neoplasms; "inappropriate" secretion of TSH arising from TSH- producing pituitary tumors or from a non-neoplastic cause, i.e. pituitary resistance to the action of thyroid hormone. Hypothyroid states include primary thyroid failure due to agenesis, autoimmunity or iatrogenic causes; secondary (or pituitary) hypothyroidism, usually resulting from tumors of the pituitary of non-thyrotropic origin such, as growth hormone (GH)-secreting tumors or prolactinomas; tertiary (or hypothalamic) hypothyroidism, usually resulting from a deficiency in the hypothalamic hormone thyrotropin-releasing hormone (TRH), either of unknown etiology or secondary to a pituitary tumor; bio-inactive TSH, either relating to an endogenous abnormality of hypothalamic hormones or secondary to pituitary tumors (and usually related to abnormal glycosylation patterns of the TSH molecule); generalized resistance to thyroid hormone (RTH), a disease which has been shown to be due to abnormalities in the TH receptor. Additionally, conditions or states that result in abnormal thyroid function tests are studied including non-thyroidal illness; abnormalities of serum TH binding proteins leading to euthyroid hyperthyroxinemia or hypertriiodothyronemia; genetic deficiency of thyroxine-binding globulin (TBG); antibody interference in TSH or other thyroid hormone assays. Recently, reflex mass spectrophotometry is utilized to further diagnose the thyroid dysfunction in this cohort of patients, thus enabling comparison of diagnostic accuracy between the mass spectrophotometry and standard immunoassays in diagnosing thyroid disorders. Alkaptonuria is an autosomal recessive disorder caused by pathogenic variants in the HGD gene. Deficiency of the HGD enzyme leads to tissue deposition of homogentisic acid (HGA), causing severe osteoarthropathies and cardiac valve degeneration. Although HGD is vital for the catabolism of tyrosine, which provides the basis for thyroid hormone synthesis, the prevalence of thyroid dysfunction in alkaptonuria is unknown. Therefore, we assessed thyroid structure and function in patients with alkaptonuria. A single-center cohort study was conducted in a tertiary referral center including patients with alkaptonuria followed up for a median of 93 (interquartile range, 48-150) months between February 1, 2000, and December 31, 2018. The alkaptonuria diagnosis was based on clinical presentation and elevated urine HGA levels. A total of 130 patients were considered for participation. Prevalence of thyroid dysfunction in adults with alkaptonuria compared with the general population. Thyrotropin and free thyroxine levels were measured by immunoassay and repeated in each patient a median of 3 (interquartile range, 2-22) times. Neck ultrasonographic scans were analyzed in a subset of participants. Logistic regression was used to test the association of thyroid dysfunction with age, sex, thyroid peroxidase (TPO) antibodies, serum tyrosine levels, and urine HGA levels. Of the 130 patients, 5 were excluded owing to thyroidectomy as the cause of hypothyroidism. The study cohort consisted of 125 patients; the median age was 45 (interquartile range, 35-51) years. Most of the patients were men (72 57.6%). The prevalence of primary hyperthyroidism was 0.8% (1 of 125 patients), similar to 0.5% observed in the general population (difference, 0.003; 95% CI, -0.001 to 0.04; P = .88). The prevalence of primary hypothyroidism was 16.0% (20 of 125 patients), which is significantly higher than 3.7% reported in the general population (difference, 0.12; 95% CI, 0.10-0.24; P < .001). Women were more likely to have primary hypothyroidism than men (odds ratio, 10.99; 95% CI, 3.13-38.66; P < .001). Patients with TPO antibodies had a higher likelihood of primary hypothyroidism than those without TPO antibodies (odds ratio, 7.36; 95% CI, 1.89-28.62; P = .004). There was no significant difference in the prevalence of thyroid nodules between patients in this study (29 of 49 59.2%) vs the general population (68%) (difference, 0.088; 95% CI, -0.44 to 0.73; P = .20) or of cancer (7% vs 5%; difference, 0.01; 95% CI, -0.01 to 0.17; P = .86). The high prevalence of primary hypothyroidism noted in patients with alkaptonuria in this study suggests that serial screening in this population should be considered and prioritized.