Studies of Thyroid Function in Health and Disease

已知或怀疑有甲状腺异常的任何年龄的受试者都被积极招募到这一自然病史方案中。所研究的疾病可以广泛地定义为甲状腺机能亢进或甲状腺功能减退状态和实验室异常。 甲亢状态包括但不限于伴有或不伴有甲状腺外表现的Graves病；亚急性甲状腺炎；静止性甲状腺炎；单个或多个功能亢进的甲状腺结节；碘诱导的甲亢；偷偷给药甲状腺激素；滋养细胞肿瘤；由产生促甲状腺激素的垂体瘤或非肿瘤性原因引起的促甲状腺激素的“不适当”分泌，即对甲状腺激素作用的抵抗。 甲状腺功能低下包括由于发育不全、自身免疫或医源性原因导致的原发性甲状腺功能衰竭；继发性(或垂体)甲状腺功能减退症，通常由非促甲状腺原发肿瘤引起，如生长激素(GH)分泌肿瘤或催乳素瘤；第三(或下丘脑)甲状腺功能减退症，通常由下丘脑激素释放激素(TRH)缺乏引起，原因不明或继发于脑垂体瘤；生物不活跃的促甲状腺激素(TSH)，要么与下丘脑激素内源性异常有关，要么继发于脑垂体瘤(通常与促甲状腺激素(TSH)分子糖基化模式异常有关)；全身性甲状腺激素抵抗(RTH)，这是一种已被证明是由于TH受体异常引起的疾病。 此外，还研究了导致甲状腺功能测试异常的条件或状态，包括非甲状腺疾病；导致正常甲状腺功能亢进或高三碘甲状腺原氨酸血症的血清TH结合蛋白异常；甲状腺激素结合球蛋白(TBG)遗传缺陷；TSH或其他甲状腺激素检测中的抗体干扰。最近，反射质谱仪被用来进一步诊断这组患者中的甲状腺功能障碍，从而能够比较质谱仪和标准免疫分析在诊断甲状腺疾病方面的诊断准确性。 碱尿症是一种常染色体隐性遗传病，由HGD基因的致病变异引起。HGD酶的缺乏会导致组织中同种异构酸(HGA)的沉积，导致严重的骨关节病和心脏瓣膜退行性变。虽然HGD对酪氨酸的分解代谢至关重要，为甲状腺激素的合成提供了基础，但碱尿症中甲状腺功能障碍的发生率尚不清楚。因此，我们评估了尿酸尿症患者的甲状腺结构和功能。在第三转诊中心进行了一项单中心队列研究，包括尿蛋白尿患者，在2000年2月1日至2018年12月31日期间进行了中位数93个月(四分位数范围，48-150个月)的随访。尿白蛋白尿的诊断依据是临床表现和尿HGA水平升高。共有130名患者被考虑参加。与普通人群相比，患有尿酸尿症的成年人甲状腺功能障碍的患病率。用免疫测定法测定促甲状腺激素和游离甲状腺激素水平，并在每个患者中重复中位数3次(四分位数范围，2-22次)。对一部分参与者的颈部超声扫描进行了分析。用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而行甲状腺切除术。研究队列包括125名患者；中位年龄为45岁(四分位数范围为35-51岁)。男性居多(7257.6%)。原发性甲状腺功能亢进症的患病率为0.8%(1例患者)，与普通人群的0.5%相似(差值0.003；95%可信区间-0.001至0.04；P=.88)。原发性甲状腺功能减退症的患病率为16.0%(20/125)，显著高于普通人群的3.7%(差值0.12；95%可信区间0.10~0.24；P&lt；.001)。女性比男性更有可能患有原发性甲状腺功能减退症(优势比，10.99；95%可信区间，3.13-38.66；P&lt；.001)。具有TPO抗体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(优势比，7.36；95%可信区间，1.89-28.62；P=0.004)。在本研究中，甲状腺结节的患病率(29/49 59.2%)与普通人群(68%)(差值，0.088；95%可信区间，-0.44~0.73；P=0.20)或癌症(7%对5%；差值，0.01；95%可信区间，-0.01~0.17；P=.86)无显著差异。 在这项研究中注意到的原发性甲状腺功能减退症在尿酸尿症患者中的高患病率表明，应该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.