Thyrotropin Receptor Antibody Activities Significantly Correlate with the Outcome of Radioiodine (131I) Therapy for Hyperthyroid Graves' Disease.
KAZURO KAISENOBUKO KAISEKatsumi YoshidaHiroshi FukazawaK. MoriMakiko YamamotoTOSHIRO SAKURADAShintaro SaitoKAORU YOSHINAGA
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Abstract:
The outcome of 131I therapy for 109 patients with Graves' disease was analysed according to pretreatment laboratory data including thyrotropin receptor antibody (TRAb) activities. Forty-five percent of patients became euthyroid, and 13% of patients became hypothyroid within one year after 131I therapy. Forty-two percent of patients remained hyperthyroid one year after 131I therapy. Pretreatment values for serum T4, T3, and the estimated weight of the thyroid were significantly higher in the hyperthyroid group. The mean for the TRAb index of the hyperthyroid group was significantly higher than that of the euthyroid group. Life table analysis revealed a significant effect of the TRAb index on the rate of hyperthyroidism after 3 months or later. These results appear to suggest that the TRAb index is one of the factors which influence the outcome of 131I therapy for Graves' disease.Keywords:
Radioiodine therapy
Thyrotropin receptor
Background and Objectives: Graves disease complicates 0.2% of pregnancies. Maternal thyrotoxicosis increases morbidity in both fetus and mother. The main objective of this study was to evaluate the clinical outcomes in neonates born to mother with Graves disease at birth and first postnatal month and correlate maternal and neonatal Thyrotropin receptor antibody (TRAb) levels and outcomes. This is the first study in India studying the neonatal outcomes in large cohort of pregnant women with Graves disease. Methods: The study was conducted in a 3000 bedded tertiary care centre in South Tamilnadu over a period of two years. 46 pregnant women with Graves disease who were TRAb positive at third trimester were evaluated with serial thyroid function tests (TFTs). Neonates born to these mothers were evaluated for signs of hyperthyroidism, hypothyroidism, and adverse effect of antithyroid drugs. TFTs and TRAb levels were measured at day 3 of postnatal life and after one month. TFTS and TRAb levels were measured using electro chemiluminescenceimmunoassay (ECLIA) by Roche cobas e411. Results: Out of 46 TRAb positive pregnant women 22 (47%) had TRAb levels more than 3 times in the 3 rd trimester and all neonates born to these mothers were TRAb positive (100%). Five women had very high TRAb levels (>10 times), among which 4 (80%) presented with thyroid storm andwereassociatedadverse pregnancy outcomes, 3 had intrauterine death, 1 had abortionand1 with still birth. Of the 41 (89%) women who delivered, 6 were preterm delivery (14%). Out of 41 neonates, 19 (46%) were TRAb positive at day3 of life. TRAb levels normalized by 3-6 months (Mean -150 days) in all neonates. One fetus hadfetal thyrotoxicosis diagnosed by goitre and fetal tachycardiain antenatal ultrasound which improved with treatment in the mother. Out of 19 Trab positive neonates, 4 neonates (21%) had transient neonatal thyrotoxicosis. However, all were asymptomatic, did not require treatment and spontaneously became euthyroid with negative TRAbtitres by3-6 months.5 neonates (26%) had transient hypothyroidismpossibly because of TRAb induced blocking antibodies requiring thyroxine therapyfor 6 months. Thyroxine was stopped onceTRAbtitres became negative. 2 neonates (10%) had transient central hypothyroidism because of transient suppression of pituitary axis by high maternal thyroid hormone levels requiring thyroxine therapyand the axis recovered by 6 months. 1 neonate developed bilateral cleft lip and palate probably due to inadvertent use of high dose of antithyroid drugs in I trimester. Also 5 neonates developed transient drug induced hypothyroidism which resolved by 15 days of life. Conclusion: More than 3 times the TRAb levels in mother wastransmitted to the infants, which was transient and spontaneously resolved by 3-6 months. Few TRAb positive infants (57%) was associated with transient neonatal thyrotoxicosis, transient neonatal hypothyroidism and transient central hypothyroisim which may require followup and close observation. Uncontrolled hyperthyroidism with high TRAb (>10 times)) were associated with poor pregnancy outcomes and all had fetal demise. Thus TRAb levels in mother may predict pregnancy outcomes and in newborn help in vigilant interpretation of abnormal TFTs and helpto avoid inadvertent Thyroxine/ antithyroid drugs.
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Graves disease, a common organ-specific autoimmune disease affecting humans, differs from all other autoimmune diseases in being associated with target organ hyperfunction rather than organ damage. Clinical thyrotoxicosis is directly caused by autoantibodies that activate the thyrotropin receptor (TSHR). The etiology of Graves disease is multifactorial, with nongenetic factors playing an important role. Of the latter, there is the intriguing possibility that the molecular structure of the target antigen contributes to the development of thyroid-stimulatory autoantibodies (TSAb’s). Among the glycoprotein hormone receptors, only the TSHR undergoes intramolecular cleavage into disulfide-linked subunits with consequent shedding of some of the extracellular, autoantibody-binding A subunits. Functional autoantibodies do not arise to the noncleaving glycoprotein hormone receptors. Recently, TSAb’s were found to preferentially recognize shed, rather than attached, A subunits. Here we use a new adenovirus-mediated animal model of Graves disease to show that goiter and hyperthyroidism occur to a much greater extent when the adenovirus expresses the free A subunit as opposed to a genetically modified TSHR that cleaves minimally into subunits. These data show that shed A subunits induce or amplify the immune response leading to hyperthyroidism and provide new insight into the etiology of Graves disease.
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Thymic size and density were studied in 23 untreated patients with Graves' disease and 38 control subjects using computed tomography. Both thymic size and density were higher in untreated patients with Graves' disease than in control subjects in the age-matched group. After treatment with antithyroid drugs, both thymic size and density were significantly reduced, with a concomitant decrease in thyrotropin receptor antibodies. PCR of human thymic cDNA using primers for human thyrotropin receptor amplified a fragment in a size expected for the receptor, and its nucleotide sequence was identical to human thyrotropin receptor cDNA in the thyroid. Northern blot analysis of human thymic poly(A)+ RNA demonstrated the presence of the full length form of thyrotropin receptor mRNA. Western blot analysis of human thymic membrane using anti-thyrotropin receptor peptide antibodies demonstrated a band of 100 kD that was also observed in the thyroid membrane. Immunohistochemistry of thymic tissue using mouse antihuman thyrotropin receptor monoclonal antibodies demonstrated the immunostaining of epithelial cells. These results indicate that thymic hyperplasia is apparently associated with Graves' disease and suggest that thymic thyrotropin receptor may act as an autoantigen that may be involved in the pathophysiology of development of Graves' disease.
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We compared the activities of thyroid-stimulating antibodies (TSAb) measured in cultures of human thyrocytes and the values for thyrotropin-receptor antibodies (TRAb) as measured with a commercial kit based on use of radiolabeled receptors. Sera were obtained from patients with Graves' disease before, during, and after therapy with carbimazole (1-methyl-2-thio-3-carbethoxyimidazole). We found a significant correlation between the measurements of these two antibodies in patients: before treatment (r = 0.74, p less than 0.01, n = 44), after three months of treatment (r = 0.76, p less than 0.01, n = 21), and during relapse after the drug was discontinued (r = 0.64, p less than 0.01, n = 19). In all three situations, our TSAb technique was more sensitive than the TRAb method. We conclude that, even though the TRAb technique is simpler and quicker, this commercial kit is too insensitive to replace measurement of TSAb in fresh human thyrocyte cultures for management of drug therapy of patients with Graves' disease.
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Graves disease, a common organ-specific autoimmune disease affecting humans, differs from all other autoimmune diseases in being associated with target organ hyperfunction rather than organ damage. Clinical thyrotoxicosis is directly caused by autoantibodies that activate the thyrotropin receptor (TSHR). The etiology of Graves disease is multifactorial, with nongenetic factors playing an important role. Of the latter, there is the intriguing possibility that the molecular structure of the target antigen contributes to the development of thyroid-stimulatory autoantibodies (TSAb’s). Among the glycoprotein hormone receptors, only the TSHR undergoes intramolecular cleavage into disulfide-linked subunits with consequent shedding of some of the extracellular, autoantibody-binding A subunits. Functional autoantibodies do not arise to the noncleaving glycoprotein hormone receptors. Recently, TSAb’s were found to preferentially recognize shed, rather than attached, A subunits. Here we use a new adenovirus-mediated animal model of Graves disease to show that goiter and hyperthyroidism occur to a much greater extent when the adenovirus expresses the free A subunit as opposed to a genetically modified TSHR that cleaves minimally into subunits. These data show that shed A subunits induce or amplify the immune response leading to hyperthyroidism and provide new insight into the etiology of Graves disease.
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Thyrotropin receptor
Graves' ophthalmopathy
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In 2005, in the MD PU City Hospital No. 13 of Nizhny Novgorod, a radiological department was created on the basis of a radioisotope laboratory for treating patients with Graves' disease with a radioiodine, which treats patients in the Nizhny Novgorod region and other regions of Russia. OBJECTIVE: to determine the effectiveness of radioiodine therapy in Graves disease and the dependence of the outcome on the applied 131I activities and thyrostatic therapy.В 2005 г. в МЛ ПУ Городская больница № 13 Нижнего Новгорода на базе радиоизотопной лаборатории создано радиологическое отделение для лечения радиойодом больных с болезнью Грейвса, в котором проводится лечение пациентов Нижегородской области и других регионов России. Цель исследования: определение эффективности радиойодтерапии при болезни Грейвса и зависимости исхода от примененных активностей 131I и тиреостатической терапии.
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Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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ABSTRACT One of the three principal therapies of Graves' disease is radioiodine treatment. Hypothyroidism is considered as a treatment end point of successful radioiodine treatment for Graves' disease. The radioiodine-induced hypothyroidism is mostly irreversible. Though, early recurrences can be due to treatment failure, inadequate radioiodine dose or rarely due to Marine-Lenhart syndrome. Here, we report a rare case of recurrent Graves' disease, 3 years after successful radioiodine therapy induced hypothyroidism in a 50-year-old lady.
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Rare disease
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