Studies of Thyroid Function in Health and Disease

健康和疾病中的甲状腺功能研究

• 批准号: 10255335
• 负责人: Joanna Klubo-Gwiezdzinska
• 金额: $ 11.69万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10255335
• 关键词: Adult; Age; Alkaptonuria; Antibodies; Autoimmunity; Binding Proteins; Biological; Biological Assay; Blood; Board Certification; Body Composition; Catabolism; Clinical; Cohort Studies; Deposition; Diagnosis; Diagnostic Procedure; Differentiation and Growth; Discipline of Nuclear Medicine; Disease; Endocrine; Endocrinology; Energy Metabolism; Enrollment; Enzymes; Etiology; Failure; Family history of; Functional disorder; General Population; Genes; Genetic; Graves' Disease; Health; Heart Valves; High Prevalence; Homogentisic Acid; Hyperthyroidism; Hyperthyroxinemia; Hypothalamic Hormones; Hypothalamic structure; Hypothyroidism; Iatrogenesis; Immunoassay; Institutes; Iodide Peroxidase; Iodides; Laboratories; Laboratory Study; Logistic Regressions; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Measures; Metabolism; Natural History; Neck; Odds Ratio; Participant; Pathogenicity; Patients; Pattern; Physical Examination; Pituitary Gland; Pituitary Neoplasms; Population; Prevalence; Prolactinoma; Protocols documentation; Public Health; Radioactive Iodine; Recording of previous events; Recruitment Activity; Reflex action; Reporting; Resistance; Scanning; Secondary to; Serum; Signs and Symptoms; Somatotropin; Spectrophotometry; Structure; Subacute thyroiditis; Technetium; Testing; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyroid Nodule; Thyroid Stimulating Hormone Secreting Pituitary Gland Adenoma; Thyroidectomy; Thyroiditis; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Thyroxine-Binding Globulin; Time; Tissues; Training; Training Programs; Trophoblastic Neoplasms; Tyrosine; United States National Institutes of Health; Urine; Variant; Woman; X-Ray Computed Tomography; base; biomedical referral center; cell growth; cohort; diagnostic accuracy; follow-up; glycosylation; imaging study; men; patient screening; receptor; research study; screening; sex; tumor; uptake

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.

已知或疑似甲状腺异常的任何年龄的受试者都被积极招募到该自然史方案中。 研究的疾病可广义地定义为甲状腺功能亢进或甲状腺功能减退状态以及实验室异常。 甲状腺功能亢进状态包括但不限于伴有或不伴有甲状腺外表现的格雷夫斯病；亚急性甲状腺炎;无症状甲状腺炎;单个或多个甲状腺功能亢进结节；碘引起的甲状腺功能亢进；秘密施用甲状腺激素；滋养细胞肿瘤；由产生 TSH 的垂体肿瘤或非肿瘤原因（即垂体对甲状腺激素作用的抵抗）引起的 TSH“不适当”分泌。 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，通常由非促甲状腺来源的垂体肿瘤引起，例如生长激素（GH）分泌肿瘤或催乳素瘤；三级（或下丘脑）甲状腺功能减退症，通常由下丘脑激素促甲状腺素释放激素（TRH）缺乏引起，病因不明或继发于垂体肿瘤；生物无活性 TSH，与下丘脑激素的内源性异常有关或继发于垂体肿瘤（通常与 TSH 分子的异常糖基化模式有关）； 对甲状腺激素 (RTH) 的普遍抵抗，这种疾病已被证明是由于 TH 受体异常引起的。 此外，还研究了导致甲状腺功能测试异常的病症或状态，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素血症； 甲状腺素结合球蛋白（TBG）遗传缺陷； 抗体干扰 TSH 或其他甲状腺激素测定。最近，反射质谱法被用来进一步诊断这组患者的甲状腺功能障碍，从而可以比较质谱法和标准免疫分析在诊断甲状腺疾病时的诊断准确性。 黑酸尿症是一种由 HGD 基因致病性变异引起的常染色体隐性遗传病。 HGD 酶的缺乏会导致黑黑酸 (HGA) 的组织沉积，导致严重的骨关​​节病和心脏瓣膜变性。虽然 HGD 对于酪氨酸的分解代谢至关重要，而酪氨酸是甲状腺激素合成的基础，但黑酸尿症中甲状腺功能障碍的患病率尚不清楚。因此，我们评估了黑酸尿症患者的甲状腺结构和功能。一项在三级转诊中心进行的单中心队列研究，纳入了 2000 年 2 月 1 日至 2018 年 12 月 31 日期间中位随访 93 个月（四分位距，48-150）个月的黑酸尿症患者。临床表现和尿液 HGA 水平升高。共有 130 名患者被考虑参与。与一般人群相比，黑酸尿症成人甲状腺功能障碍的患病率。通过免疫测定法测量促甲状腺素和游离甲状腺素水平，并在每个患者中重复中位数3次（四分位距，2-22）次。对一部分参与者的颈部超声扫描进行了分析。 Logistic 回归用于测试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液 HGA 水平的关联。 在 130 名患者中，有 5 名因甲状腺切除术导致甲状腺功能减退而被排除。研究队列由 125 名患者组成；中位年龄为 45 岁（四分位距，35-51）岁。大多数患者是男性（72 57.6%）。原发性甲状腺功能亢进症的患病率为 0.8%（125 名患者中的 1 名），与普通人群中观察到的 0.5% 相似（差异，0.003；95% CI，-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%（125 名患者中的 20 名），显着高于一般人群报告的 3.7%（差异，0.12；95% CI，0.10-0.24；P < .001）。女性比男性更有可能患有原发性甲状腺功能减退症（比值比，10.99；95% CI，3.13-38.66；P < .001）。具有 TPO 抗体的患者比没有 TPO 抗体的患者患原发性甲状腺功能减退症的可能性更高（比值比，7.36；95% CI，1.89-28.62；P = .004）。本研究中患者（49 名患者中的 29 名，59.2%）与一般人群（68%）相比，甲状腺结节的患病率没有显着差异（差异，0.088；95% CI，-0.44 至 0.73；P = .20）或癌症（7% vs 5%；差异，0.01；95% CI，-0.01 至 0.17；P = .86）。 本研究中发现黑酸尿症患者原发性甲状腺功能减退症的患病率很高，这表明应考虑并优先考虑对该人群进行系列筛查。