Thyroid needle biopsy showed diffuse epithelial hyperplasia compatible with Graves disease (Fig. thyroiditis usually runs a stable program, and only occasionally do serious changes in practical status happen.1,2)There are, however, several well documented cases of hyperthyroidism which developed spontaneously from primary hypothyroidism.3,4,5)About 40 cases are reported in the English literature5), but it is uncertain how often this unusual phenomenon occurs and what is the exact pathogenetic mechanism. Obviously, autoimmunity plays a major part6), and thyrotropin receptor antibody (TRAb) might play a particularly important role. That is, previously SB225002 nonexistent thyroid stimulating antibody (TSAb) evolves in a patient with chronic thyroiditis and stimulates remaining follicular epithelial cells to proliferate and hyperfunction, resulting in hyperthyroidism.7)On the other hand, in thyroid stimulation blocking antibody (TSBAb) connected main nongoitrous myxedema, TSBAb somehow changes to TSAb, resulting in sustained stimulation of the follicular cells causing hyperthyroidism.8) There is no doubt that TSAb causes hyperthyroidism in Graves disease.9,10)TRAb is generally not pure TSAb, but is a compound mixture of heterogeneous antibodies, differing in biological characteristics. In Graves disease, TSAb disappears and TSBAb appears with development of hypothyroidism after radioiodine therapy11,12)or even after antithyroid drug treatment.13,14,15)Moreover, once developed hypothyroidism with emergence of TSBAb reconverts to Graves hyperthyroidism with disappearance of TSBAb and reappearance of TSAb.16,17)The above findings suggest that the biological character of TRAb decides the clinical manifestations in autoimmune thyroid diseases. In this study, we serially measured thyrotropin binding inhibitory immunoglobulin (TBII), TSAb, and TSBAb when hyperthyroidism developed following main hypothyroidism, and compared the various practical TMOD3 guidelines of TRAb with medical status, to clarify the part of TRAb with this unusual phenomenon. == MATERIALS AND METHODS == == 1. Subjects == Chronic thyroiditis was diagnosed when a patient presented with diffuse goiter, elevated serum TSH level, and positive thyroid autoantibodies. Main nongoitrous myxedema was diagnosed when another patient presented with medical hypothyroidism, impalpable thyroid, low serum T4, elevated serum TSH, and decreased 24h radioactive iodine uptake. Hyperthyroid Graves disease was diagnosed clinically based on the findings of medical symptoms, diffuse goiter, elevated serum T3 and T4, decreased TSH, and improved thyroidal radioactive iodine uptake, which was not suppressed by T3 administration. Serum samples were stored in aliquot at 70C until use. IgG was prepared by means of affinity chromatography using protein A-Sepharose CL-B (Pharmacia, Sweden). == 2. Thyroid Function Test and Assay for Thyroid Autoantibodies == Twenty-four hour thyroidal radioiodine uptake was measured from the standardized method. Serum T3BU, total T3, and total T4 were measured by SB225002 commercially available RIA packages from Abbott (USA). Serum TSH was measured by SB225002 ultrasensitive immunoradiometric assay using packages from Abbott (USA), and the normal range was 0.44.1u/ml. Antimicrosomal antibody and antithyroglobulin antibody were measured by radioimmunoassay using packages from R.S.R. Ltd (UK) and ideals above 3U/ml were regarded as positive. == 3. Assay for TBII == TBII was measured as explained previously18)using commercial radioreceptor assay packages from R.S.R. Ltd (UK). TBII activity was indicated as percent inhibition of radiolabelled bTSH binding to its receptor and ideals above +15% were regarded as positive.18) == 4. Assay for TSAb and TSBAb == FRTL5 cells, generously donated by Dr. Kohn at SB225002 NIH, USA, were managed as previously explained.19)After 7 days without TSH, 300l of IgG (10mg/ml) was added to each well and incubated at 37C, in 5% CO2-95% air, for 2 hours. The cAMP released into tradition supernatant was measured by RIA (Immunonuclear, Still Water, MN, USA). TSAb activity was indicated as percent increase in cAMP production by test IgG compared to normal control IgG. Ideals above 170% were regarded as positive.19) When measuring TSBAb, IgG was incubated with or without 0.1 mU/ml bTSH. Additional procedures were the same as the TSAb assay. TSBAb activity was indicated as percent inhibition of 0.1 mU/ml bTSH induced cAMP production by test IgG compared to normal control IgG. SB225002 Ideals above 37% were considered irregular.20)In these bioassay systems, intra-assay variance was 5.07.4% and interassay variance was 17.032.5%.19) == RESULTS == == 1. Patient 1 == A 29-year-old female went to the Thyroid Medical center at Seoul National University Hospital with the chief complaint of a recently growing diffuse goiter in March 1985. No subjective symptoms were found. On exam, a diffuse goiter of moderate size (about 60gm) was the only abnormal finding. Laboratory examination showed T3RU 27.4%; T3 126ng/dl; T4 6.9g/dl; TSH 5.8u/ml; antimicrosomal antibody 80U/ml; and antithyroglobulin antibody below.
