We report a patient who underwent, over a mere 3-year period, three successive cycles of oscillation from hypo to hyper-thyroidism and back to hypothyroidism. This unusual sequence of events originated in a rare passage of primary hypothyroidism to hyper-thyroidism. The hyperthyroidism seemed typical of the autoimmune subgroup of toxic multinodular goitre. Stimulating and blocking TSH receptor antibody activities were measured (by cAMP functional bioassays using cultured human thyrocytes) during the course of the fluctuating phases of hypo and hyper-thyroidism. Measurement of such antibody activities revealed the coexistence of both stimulatory and blocking types of antibody in several serum samples from the patient. Throughout the whole course of alterations in thyroid function, thyroid stimulating antibodies were present. This was not the case with thyrotrophin receptor antibodies exhibiting TSH antagonist activity which seemed to appear and disappear. Monitoring such activity indicated that the emergence of blocking antibody seems to herald the onset of hypothyroidism.
The aim of this study was to examine whether at least a subgroup of patients with toxic multinodular goiter may have autoimmune thyroid disease. Thyroid-stimulating immunoglobulin (TSI) activity, measured by a sensitive bioassay employing cultured human thyroid cells, was determined in patients with toxic multinodular goiter and other thyroid disorders. All patients with active Graves' disease (n = 47) had detectable serum TSI activity, whereas TSI was undetectable in patients with thyroid disease not believed to be of autoimmune origin: toxic adenoma (n = 13), cold nodule (n = 5), and nontoxic goiter (n = 19), with a single exception in the latter group. Toxic multinodular goiter (n = 26) was diagnosed based on clinical and laboratory evidence of hyperthyroidism associated with a multinodular goiter on palpation and scintiscan. The toxic multinodular goiter group was then subclassified according to scintiscan pattern (type A, diffuse but uneven distribution of technetium uptake; type B, multiple discrete nodules of varying size and function). All but 1 of the 11 TSI-positive toxic multinodular goiter patients had a type A scintiscan pattern. The patients with the type A scintiscan pattern were younger and more often had elevated antithyroid antibody titers, ophthalmopathy, and concurrent development of goiter and hyperthyroidism (rather than long-standing goiter preceding hyperthyroidism) compared to the type B patients. Thus, a subgroup of patients with clinically defined toxic multinodular goiter (type A) probably have autoimmune hyperthyroidism (a variant of Graves' disease), while in another subgroup (type B) hyperthyroidism is not related to an autoimmune etiology (a variant of toxic adenoma).
The prevalence and characteristics of TSH receptor blocking activity were examined in patients with different thyroid disorders. Studies were also performed on the in-vitro synthesis and immunoregulation of the blocking antibody. Blocking activity was tested by measuring the inhibition of TSH-stimulated cAMP production of cultured human thyroid cells by patient immunoglobulin (Ig) preparations. The following patients were investigated (number of cases in parentheses): Hashimoto's thyroiditis (33); primary myxoedema (17); euthyroid ophthalmopathy (8); active Graves' disease (19); cold nodule (5); non-toxic goitre (14); toxic adenoma (8); toxic multinodular goitre (9) and 22 normal controls. TSH receptor blocking activity was only detected in primary hypothyroidism with the following characteristics: (i) Such activity was present in only 16% of the patients (both goitrous, i.e. Hashimoto's thyroiditis, and non-goitrous, i.e. primary myxoedema), and in three patients with previously active Graves' hyperthyroidism who had become hypothyroid. (ii) Blocking activity seems to be associated with the Ig fraction of serum as indicated by protein A adsorption. (iii) The block-positive samples did not bind 125I-TSH, which seems to rule out an antibody directed against TSH. (iv) The specificity of the blocking activity seems to be directed towards the TSH-(thyroid stimulating immunoglobulin, TSI) receptor-mediated cAMP response since no inhibition of prostaglandin E1-stimulated cAMP production was found. Moreover, all cases in which an inhibitory effect was demonstrated towards TSH also exhibited blocking of TSI-stimulated cAMP, with a high correlation between the degree of inhibition of the TSH to that of the TSI response (r = 0.89, P less than 0.001, n = 11). The blocking activity may contribute to the pathogenesis of some cases of primary hypothyroid autoimmune thyroiditis, both goitrous and non-goitrous, as well as in the evolution of hyper- to hypothyroidism. By culturing peripheral blood lymphocytes, as well as B/T lymphocyte co-cultures isolated from three patients with blocking activity present in serum, the in-vitro synthesis of the blocking antibody was demonstrated for the first time. Moreover, in-vitro secretion of the antibody by patients B lymphocytes, as well as T cell regulation of autoantibody production, were also shown.
Surgical management of multinodular goiter (MNG) poses an ongoing dilemma between radical resection with its associated complications and partial resection, which carries the risk of recurrence and increased morbidity and difficulty for rethyroidectomy. This study was designed to evaluate the recurrence rate and need for reoperation in a carefully selected population of MNG patients, after nontotal thyroidectomy. The study addressed a highly selected population of patients who were treated and thoroughly evaluated at one surgical department for several years. We analyzed the recurrence rate of MNG in 124 patients. The follow-up duration extended from 6 to 516 months (mean 93 months). The general recurrence rate for all nontotal bilateral thyroidectomies was 21% (21/100 patients), increasing from 13.4% to 60% according to the extent of resection. The average time for recurrence was 105 months (8.75 years). Among the patients with recurrent MNG, only 4 (4% of the patients with nontotal bilateral thyroidectomy) required secondary surgical interventions with no resultant morbidity. In our series of very highly selected patients, the recurrence rate for nontotal thyroidectomy was high (21%); however, the need for secondary surgical intervention was low (4%). Thus nontotal thyroidectomy for MNG is legitimate. However, we suggest that the surgical procedure of choice be tailored according to the severity of the disease and the patient's general condition.
Apparently complex modulatory effects of alpha‐interferon (α ‐IFN), tumor necrosis factor (TNF), and epidermal growth factor (EGF) have been found in neoplastic human thyroid cells, which could possibly affect the final outcome in neoplastic disease. This was achieved by examining the influence of α‐IFN, TNF, and EGF alone and in combination, on human leukocyte antigen‐DR (DR) antigen expression and viability of neoplastic and non‐neoplastic human thyroid cells in culture. α‐IFN‐induced DR antigen expression on non‐neoplastic human thyroid cells, whereas TNF‐α or EGF alone were ineffective. The addition of the same TNF‐α concentrations (10 to 100 ng/ml) to α‐IFN enhanced the expression of DR antigens compared with the effect of α‐IFN alone. However, EGF inhibited α‐IFN‐induced DR on the same cells and at the same concentrations (10 to 500 ng/ml) at which the growth factor alone was ineffective. In contrast to the common pattern of cytokine effects on DR expression of all nonmalignant thyroid cell lines, neoplastic thyroid cell lines showed divergent responses to α‐IFN, TNF‐α, and EGF. In three malignant thyroid cell lines that were DR negative (follicular carcinoma WRO 82‐1 and NRO 87‐1 cell lines, and anaplastic carcinoma ARO 81‐1), DR antigen could be induced by α‐IFN and enhanced by TNF‐α, whereas EGF was ineffective. In a fourth cell line (an anaplastic carcinoma SW1736) α‐IFN, TNF‐α, and EGF alone were capable of inducing DR, and a combination of either TNF‐α and EGF with α‐IFN potentiated DR induction. In a fifth neoplastic cell line (papillary carcinoma, NPA) that constitutively expressed surface DR, its expression was inhibited by both α‐IFN and TNF‐α and was not affected by EGF.
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