Studies of Thyroid Function in Health and Disease

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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.