ABSTRACT
There are few indications for ordering a RAIU or a thyroid scan in a primary care setting. In suspected hyperthyroidism, a sensitive thyrotropin assay should be the initial test ordered. If the thyrotropin level is low or suppressed, and the diagnosis of thyroiditis vs Graves' hyperthyroidism is not clear, a RAIU test is appropriate. In the case of a euthyroid nodular goiter, fine-needle aspiration is the most accurate initial test to evaluate for malignancy. The primary indication for a scan in the case of a euthyroid nodular goiter is a low or suppressed thyrotropin level, because malignancy is rare in a hot nodule. If thyroid cancer or congenital hypothyroidism is encountered, referral to an endocrinologist is probably the most expedient and cost-effective way to proceed.
Subject(s)
Iodine Radioisotopes , Thyroid Diseases/diagnostic imaging , Humans , Radionuclide ImagingABSTRACT
CONTEXT: Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of variable tissue hyporesponsiveness to thyroid hormone (TH). OBJECTIVE: We report a newborn who presented with severe RTH (Mkar) with serum TSH 1500 mU/liter and free T(3) greater than 50 pm (normal 3.1-9.4) and free T(4) 25.3 pm (normal 12-22). We hypothesized that the RTH was due to reduced ligand binding and/or abnormal interaction with nuclear cofactors. DESIGN: These were prospective in vivo and in vitro studies. SETTING: The study was conducted at a tertiary care university hospital. PATIENTS: Patients included a newborn child and two other subjects with RTH. INTERVENTION: The effect of various TH-lowering agents in the subject with RTH was studied. In vitro studies including EMSA and mammalian two-hybrid assay as well as in vitro transfection studies were conducted. MAIN OUTCOME MEASURES: Sequencing of the TH receptor (TR)beta and in vitro measurements of receptor-cofactor interaction were measured. RESULTS: Sequencing of the TRbeta demonstrated a de novo heterozygous mutation, 1590_1591insT, resulting in a frameshift producing a mutant TRbeta (mutTR)-beta with a 28-amino acid (aa) nonsense sequence and 2-amino acid carboxyl-terminal extension. The Mkar mutation was evaluated in comparison to three other TRbeta frameshift mutations in the carboxyl terminus. EMSA demonstrated that the Mkar mutTRbeta1 had impaired ability to recruit nuclear receptor corepressor but intact association with silencing mediator of retinoid and thyroid receptor (SMRT). CONCLUSION: Our data suggest that alterations in codons 436-453 in helix 11 result in significantly diminished association with nuclear receptor corepressor but not SMRT. This novel mutTRbeta demonstrates nuclear corepressor specificity that results in severe predominantly pituitary RTH due to impaired release of SMRT.
Subject(s)
Frameshift Mutation/genetics , Frameshift Mutation/physiology , Nuclear Proteins/metabolism , Pituitary Gland/physiopathology , Repressor Proteins/metabolism , Thyroid Hormone Receptors beta/genetics , Thyroid Hormone Resistance Syndrome/genetics , Thyroid Hormone Resistance Syndrome/physiopathology , Amino Acid Sequence , Child , DNA-Binding Proteins/genetics , Electrophoretic Mobility Shift Assay , Fibroblasts/metabolism , Genes, Reporter/genetics , Histone Acetyltransferases , Humans , Infant, Newborn , Male , Molecular Sequence Data , Nuclear Receptor Co-Repressor 1 , Nuclear Receptor Co-Repressor 2 , Nuclear Receptor Coactivator 1 , Plasmids/genetics , Repressor Proteins/genetics , Transcription Factors/metabolism , TransfectionABSTRACT
Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of reduced tissue responsiveness to thyroid hormone (TH) usually due to mutations in the TH receptor beta gene (TRbeta). We studied pituitary and peripheral tissue responses to graded doses of liothyronine (L-T3) in 5 affected members (2 children and 3 adults) of a family with RTH due to the common TRbeta mutation P453T. Overall, the 5 subjects studied exhibited suppressed thyrotropin response to thyrotropin-releasing hormone of 51% +/- 8%, 12.1% +/- 1.5%, and 6.3% +/- 3% of the 100% baseline on 50, 100, and 200 microg/dL L-T3, respectively. This degree of suppression was greater than that observed in subjects with RTH due to other TRbeta mutations, indicating less resistance. Compared with normal subjects, however, the family described here demonstrated less suppression by L-T3, compatible with their RTH, although of a mild magnitude. The 2 children with RTH demonstrated less L-T3-mediated suppression of prolactin and cholesterol than the adults. Patients often receive thyroid ablative therapy before the diagnosis of RTH and are left with variable degrees of hypothyroidism. Our results demonstrate that graded doses of L-T3 can be used to evaluate RTH patients, even under the condition of limited thyroid reserve, when results are compared with their baseline. We demonstrate that RTH patients can be evaluated either on or off thyroid hormone and still be distinguished from hypothyroid subjects without RTH.