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Studies of Thyroid Function and Immune Parameters in Patients with Hyperthyroid Graves' Disease in Remission^*

Department of Gerontology, Endocrinology, and Metabolism, Shinshu University School of Medicine (M.M., Y.K., T.A., T. Y.) Matsumoto; Japan
The Department of Medicine, Hokushin General Hospital (Y.T., T.W.) Nakano, Nagano-ken; Japan
the Department of Medicine, Nagaoka Red Cross Hospital (K.K.) Nagaoka, Niigata-ken, Japan

Address all correspondence and requests for reprints to: Takashi Yamada, M.D., Department of Gerontology, Endocrinology and Metabolism, Shinshu University, School of Medicine, 3-1-1 Asahi, Matsumoto, Japan.

The natural course of hyperthyroidism due to Graves' disease after discontinuation of antithyroid drug therapy was studied in 184 patients who had been treated with methimazole and whose thyroid function was suppressible with T₃ when methimazole was discontinued. The patients were followed after discontinuation of therapy for up to 60 months. Serum T₄, free T₄ (FT₄) and T₃ levels, TSH receptor antibody (TRab) and anti- DNA antibody titers, and the percentage of HLA-DR positive lymphocytes in peripheral blood were measured serially. TRab and anti-DNA antibody tests were positive in the majority of patients before treatment and were negative in most at the end of treatment. Twenty-three (12.5%) patients had a recurrence of their hyperthyroidism, which occurred a mean of 20 months after withdrawal of methimazole; they are designated as having overt recurrent hyperthyroidism (group A). In these patients, serum T₄, FT₄, and T₃ concentrations increased rather abruptly to markedly elevated levels in a several-month period and the TRab and anti-DNA antibody titers increased markedly at or shortly after recurrence in the majority. In 9 patients (4-1%), TRH-induced TSH secretion became totally suppressed, indicating the reappearance of thyroidal autonomy; however, the patients did not have any hyperthyroid signs and symptoms (subclinical hyperthyroidism; group B). Their serum T₄ and FT₄ concentrations fluctuated in the upper normal to slightly supranormal range, and their serum T₃ concentrations remained within the normal range throughout the follow-up period, but their TRab and anti-DNA antibody titers did not appreciably increase. Thus, the time of recurrence could not be precisely determined in group B. In the remainder (152 patients; 83.4%), serum thyroid hormone levels and TRH-induced TSH secretion remained normal, TRab and anti-DNA antibody titers remained negative, and hyperthyroidism did not recur (euthyroid remission; group C). At the time of final examination (in groups B and C) or at the time of recurrence (in group A), the percentage of HLA-DR positive peripheral lymphocytes was 17.9% in group A, 15.9% in group B, and 12.1% in group C. Retrospective analysis of the data indicated that the mean pretreatment TRab titer (percent inhibition of TSH binding) was slightly but not significantly lower in group C (37.8%) compared to those in group A (53.9%) and group B (54.8%). The 3 groups were indistinguishable by all other labaratory data both before treatment and at the time of the T₃ suppression test.

These data strongly indicate heterogeneity among patients with hyperthyroidism due to Graves' disease. Recurrence, if it occurs, can be either overt or subclinical in its expression. The degree of immunological abnormalities, such as elevated TRab and anti-DNA antibody titers and increased HLA-DR-positive lymphocyte number, paralleled the clinical course, especially in group A, suggesting their causative roles in the immune response.

^* This work was supported by a grant from Japan Educational Ministry.

Received March 23, 1987.

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