Further studies on thyroid growth-stimulating immunoglobulins in euthyroid nonendemic goiter

Sixty-two consecutive patients with sporadic euthyroid goiter (57 women and 5 men) from noniodine-deficient areas, including 15 patients with diffuse goiter, 39 patients with multinodular goiter, and 8 patients with a single nodule, were studied for the presence of serum thyroid growth-stimulating immunoglobulins (TGI) by the ultrasensitive cytochemical bioassay based on DNA cytophotometry (Feulgen-cytochemical bioassay). Using strictly specified conditions, 43 patients (67%) were positive. Values tended to be high in diffuse goiter, nodular goiters reccuring after partial thyroidectomy, and those with recent growth. Thirty-seven individual immunoglobulin (Ig)-rich fractions obtained by ammonium-sulfate precipitation from 20 normal subjects, 13 atrophic thyroiditis patients, and 4 dyshormonogenetic goiter patients were tested similarly, and only 3 gave positive growth assays. These results lend further support to our concept that a majority of patients with sporadic nontoxic simple goiters have a variant of thyroid autoimmune diseases separate from lymphocytic thyroiditis. With regard to assays thought to reflect activities of TSH receptor antibodies, none of 20 tested Ig preparations stimulated thyroid cAMP production. The TSH binding inhibition assay gave weak positive activity, but failed to correlate with either TGI or TSH unresponsiveness to TRH. These findings suggest that sporadic goiter TGI is not directed to the TSH-binding site. Dose-response studies performed with Igs of patients with nontoxic goiters and with human TSH standard and goitrous hyperthyroid Graves Igs as controls all revealed bell-shaped responses. Similar maximal values were reached regardless of the growth stimulus applied. However, approximately 10 times more Ig was needed to reach maximal responsiveness in sporadic goiter than in goitrous Graves' disease (i.e. 125-500 micrograms vs. 15-125 micrograms Ig/ml culture fluid). The optimal dose of human TSH ranged from 0.01-1.0 microU/ml. The assays in the present series of the 62 consecutive patients with nontoxic diffuse or nodular goiter were all carried out with a fixed amount of 125 micrograms Ig/ml and considering a value above 5% of cells in the S-phase as a positive assay. Some Ig preparations negative for TGI at this concentration may contain TGI when tested using other doses, and these are a prerequisite to assess the potency of growth antibodies in individual patients.