tients with chronic thyroiditis were treated with thyroxine and subsequently developed endoge nous hyperthyroidism. These three patients

Transcription

1 Thyroid-stimulating antibody and thyrotropin-binding inhibitory immunoglobulin activity in hypothyroid patients who subsequently developed thyrotoxicosis Hajime Tamai, Kanji Kasagi, Osamu Mizuno, Nobuyuki Kobayashi, Gen Komaki, Fumio Matsuzuka, Kanji Kuma, Junji Konishi, Lindy F. Kumagai and Shigenobu Nagataki Departments of Psychosomatic Medicine1, Faculty of Medicine, Kyushu University, Fukuoka, and Kuma Hospital2, Kobe; Department of Nuclear Medicine3, Kyoto University, School of Medicine, Kyoto; The First Department ofinternal Medicine4, Faculty of Medicine, Nagasaki University, Nagasaki, Japan, and the Department of Internal Medicine, School of Medicine3, University of California, Sacramento, California, USA Abstract. Although abnormal thyroid-stimulating and -blocking antibodies have been demonstrated in hyperthyroid and hypothyroid patients with autoimmune thyroid disorders, a direct correlation is not always observed. Thyroid-stimulating antibody, thyrotropinbinding inhibitory immunoglobulin, and thyroid-stimulating blocking antibody levels were determined in three hypothyroid patients who subsequently developed hyperthyroidism. Thyroid-stimulating antibodies levels were normal in one, elevated in another, and unmeasured in the third hypothyroid patient, but became elevated in all patients with the onset of hyperthyroidism. There was discordance, however, in one patient who had markedly elevated thyroid-stimulating antibodies and TSH-binding inhibitory immunoglobulin levels when she was hypothyroid. The data indicate that thyroidal responses to the abnormal stimulating antibodies may differ among patients with autoimmune thyroid disease. Abnormal serum immunoglobulins are associated with hyper- and hypothyroidism (1-11). TSHbinding inhibitory immunoglobulins (TBII) and thyroid-stimulating antibodies (TS-ab) are detected in about 90 of untreated Graves' disease patients. Although they are thought to play an important role in the onset of hyperthyroidism, this may not be entirely correct (12,13). Thyroid-stimulating blocking antibodies (TSB-ab) have been found in a significant number of hypothyroid patients with chronic thyroiditis (14). To complicate matters fur ther, some patients have clinical manifestations of Graves' disease and have immunological and histological signs of chronic thyroiditis. These patients have been reported as having hyperthyroidism as sociated with histological Hashimoto's thyroiditis (Hashitoxicosis) (15). Two of three hypothyroid pa tients with chronic thyroiditis were treated with thyroxine and subsequently developed endoge nous hyperthyroidism. These three patients are the subject of this study. In order to investigate whether TS-ab, TSH-binding inhibitory immunoglobulins, and TSB-ab play a pathogenetic role in the development of thyhrotoxicosis from hypothyroidism, these immunoglobulins were measured during the course of observation. Subjects and Methods Methods The 24-h thyroidal uptake of 131I (normal range, 10-35) was determined by a standard procedure. Serum T4, T3, free T4 (FT4), free T3 (FT3), and TSH were measured by commercially available RIA kits (T4 RIA kit, T3 RIA kit, TSH RIA kit, Dainabot Radioisotope Labs, Tokyo, Japan; Amerlex Free T4 RIA kit, Amerlex Free T3 RIA kit, Amersham International Ltd, Amersham, Buckingham shire, UK). Normal ranges were: T4 ( nmol/1),

2 Table I. Thyroid function tests and TSH-binding inhibitory immunoglobulin (TBII), TS-ab and TSB-ab in Patient No. 1. Dates T nmol/1 TSH mu/1 FT FT Tg-ab Mi-ab 'i-uptake TS-ab TBII TSB-ab Sept 6, 82 Mar 17, 86 Dec 22, 86 Apr 8, 87 Apr 20, >0.05 < " M T3 ( nmol/1), FT4 ( ), FT3 ( ), and TSH ( mu/1) (16). Antithyroglobulin (Tg-ab) and antimicrosomal (Mi-ab) antibodies were mea sured by the tanned cell hemagglutination technique using commercially available kits (Thyroid Test and Microsome Test, respectively, Fujizoki Pharmaceutical Co, Japan). Antibody titres below were judged as negative in both tests (17). TBII activities were deter mined by using commercially available RIA kits by Southgate et al. (18) with a minor modification (19). The normal range determined for 53 normal subjects was 11.9 to TS-ab activities were measured using a method previously described by Kasagi et al. (20). The normal range in this assay was 55.0 to TSB-ab activities were determined by a method previously de scribed by Konishi et al. (14). The blocking activity in 16 normal samples was 40 to +40 (17). Patient No. I A 45-year-old woman noticed a goitre in March She was unaware of any symptoms suggestive of either hyperor hypothyroidism. She noted a feeling of»fullness«in her throat and was seen at the Kuma Hospital in Septem ber She had no previous history of thyroid disease and had not been taking any drugs or excessively iodiderich foods such as seaweed. She was clinically and bio chemically euthyroid. However, 3'A years later, in March 1986, she had symptoms of mild hypothyroidism such as constipation and loss of hair. Her serum TSH at that time was 10.4 mu/1. We could not get any thyroid tissue in the subclinical hypothyroid phase. She was treated with L-T4 (50ug/day) and, subsequently, her TS-ab andtbii titres gradually increased above the normal range. In Decem ber 1986 she had palpitations and tremor with serum T4 concentration in the high normal range and increased TS-ab. L-T4 therapy was discontinued. Four months later she developed clinical hyperthyroidism with elevated thy roid hormones. Thyroid needle biopsy at that time re vealed epithelial hyperplasia with papillary projection of follicular epithelium (Table 1, Fig. 1). Patient No. 2 A 41-year-old woman noticed a goitre in July She was asymptomatic and was not examined until August Table 2. Thyroid function tests and TSH-binding inhibitory immunoglobulin (TBII), TS-ab and TSB-ab in Patient No. 2. Dates T nmol/1 TSH mu/1 FT T nmol /l Tg-ab Mi-ab '1-uptake TS-ab TBII TSB-ab <0.5 < , , a 41.9b a, b: before and after T3 suppression test.

3 Fig. 1. Thyroid needle biopsy of Patient No. 1. Enlarged lymphocyte infiltration, suggesting Graves' disease. follicles with She took no drugs or iodide. Her initial thyroid function tests revealed subclinical hypothyroidism. A needle biopsy was refused as was L-T4 treatment. She became mildly hyperthyroid in January 1985, but her thyroid functions returned to within normal ranges about three months later without medication (Table 2). She de veloped clinical and biochemical hyperthyroidism, and was papillary hyperplasia of follicular T3 non-suppressible in July (20 mg/day). epithelium She was and treated with methimazole Patient No. 3 A 22-year-old man was seen because of cold intolerance in January His thyroid was not palpable at that time. Serum T4, T3, and TSH concentrations were 7.7 nmol/1, Table 3. Thyroid function tests and TSH-binding inhibitory immunoglobulin (TBII), TS-ab and TSB-ab in T nmol /l TSH mu/1 FT FT <1.5 < >36.9 Tg-ab Mi-ab 'i-uptake TS-ab Patient No. 3. TBII TSB-ab '

4 0.61 nmol/1, and mu/1, respectively, and Tg-ab and Mi-ab were markedly increased. While being treated with T4, 100 ug/day, for 6V2 years, his goitre gradually in creased in size with free T4 and TS-ab titres becoming elevated. The T4 was decreased to 50 ug/day, but serum T4 and T3 levels remained elevated. In August 1986, serum T4, FT4, and FT3 levels were significantly in creased, whereas serum TSH was suppressed. T4 admini stration was discontinued. His diffuse goitre became larger (about 50 g), and his thyroid function tests indi cated hyperthyroidism (Table 3). The was patient treated with methimazole, 30 mg/day. Results Figs. 2, 3, and 4 show the changes in TS-ab, TBII, and TSB-ab during the observation period. When Patient No. 1 developed subclinical hypothyroidism, TS-ab and TSB-ab activities were negative. Her values of TS-ab and TBII gradually increased. Both TS-ab and TBII were strongly positive in Patient No. 2, even though she showed subclinical hypothyroidism. However, her thyroid hormone levels and 131I-uptake value were elevated five months later. At that time the activities of both TS-ab and TBII continued at strongly positive levels. Although Patient No. 3 had severe hypothyroid ism, no serum from 1977 was available for tesing, so we were unable to check the activities of TS-ab, Ö c 100-? 12 ó Fig. 3. Changes in serum concentration of T4, TSH and in ab normal antibodies in Patient No. 2 during follow-up. J. indicates the time when the patient became hyperthyroid. D-D: TS-ab, - : TBII, A-A: TSB-ab, 9-9: T4, O-O: TSH. For abbreviations, see legend to Fig. 2. TBII, or TSB-ab. TS-ab and TBII levels increased at the onset of thyrotoxicosis. Discussion The majority of patients who develop hypothyroidism owing to chronic thyroiditis remain perma nently hypothyroid. Yet, occasionally some patients 300p 9 15r W 3 E 5 v r 10Or # 500 I 10 '82.9 ' '87.4 Fig. 2. Changes in serum concentration of T4, TSH and in ab normal antibodies in Patient No. 1 during follow-up. J, indicates the time when the patient became hyperthyroid. D-D: Thyroid-stimulating antibodies (TS-ab), - : TSH-binding inhibitory immunoglobulin (TBII), A-A: Thyroid-stimulating blocking antibod ies (TSB-ab), - : T4, O-O: TSH r a«50r = 0 (0 m I- 0 '77.1 ^8ÏÏÎP' '82.8 '86.8 ' I a co 0 I- Fig- 4. Changes in serum concentration of T4, TSH and in ab normal antibodies in Patient No. 3 during follow-up. j indicates the time when the patient became hyperthyroid. D---D: TS-ab, - : TBII, A-A: TSB-ab, 9-9: T4, O-O: TSH. For abbreviations, see legend to Fig. 2.

5 become euthyroid or develop hyperthyroidism. These changes in thyroidal status may be associated with alterations in the levels of abnormal circulat ing serum immunoglobulins such as those which stimulate or block thyroid activity. Kasagi et al. (21) and Takeda et al. (22) studied TBII, TS-ab, and TSB-ab activity in hypothyroid patients who developed hyperthyroidism (23,24). Although TSB-ab was negative when the patient described by Kasagi et al. was hypothyroid, both TBII and TS-ab activities increased above normal when she became hyperthyroid. Incidentally, she became hypothyroid two months post-partum which may be similar to the patients described by Amino et al. (25) who developed postpartum hy perthyroidism. When the patient described by Takeda et al. (22) became hyperthyroid, the ele vated, TSB-ab activity during her hypothyroidism disappeared, and TS-ab activity was significantly increased. A direct correlation between levels of thyroidstimulating or -blocking antibody activities and thy roidal status was not observed in all of our patients. In Patient No. 2, for example, TS-ab and TBII activities were markedly elevated and TSB-ab was normal when she was minimally hypothyroid, with an elevated TSH of 11.0 mu/1. As TSB-ab was normal, needle biopsy of the thyroid gland would have been of interest in order to determine whether the patient had signs of autoimmune thy roiditis which could balance the stimulating anti bodies, but a needle biopsy was refused. This pa tient also had fluctuations in serum T4 and T3 levels, and TS-ab activities during the year before she became clinically hyperthyroid. The increase in TS-ab in Patients No. 1 and 3 correlated with the As to Patient No. onset of clinical hyperthyroidism. 1, her levels of Mi-ab decreased within one year after administration of T4, whereafter she devel oped thyrotoxicosis. Tamai et al. (26) found ele vated TS-ab activities in approximately 60 of Graves' disease patients previously treated with antithyroidal drugs who eventually became hy pothyroid after discontinuing drug therapy. Those patients may resemble Patient No. 2 in this study. It would be of interest to do a follow-up study to see whether they have had recurrence of active Graves' disease. It is evident from these data that, not only do the levels of thyroid-stimulating antibodies fluctuate in individual patients, but there may be discordance between the levels and thyroidal status. It seems that there may be different thyroidal responses to the antibodies, or that other factors as yet unknown may be stimulating or blocking thyroidal activity. References 1. Teng CS, Yeung RTT. Changes in thyroid-stimu lating antibody activity in Graves' disease treated with antithyroid drug and its relationship to relapse: a prospective study. J Clin Endocrinol Metab 1980; 50: Teng CS, Yeung RTT, Khoo RKK, Alagaratnam TT. A prospective study of the changes in thyrotropin binding inhibitory immunoglobulins in Graves' dis ease treated by subtotal thyroidectomy or radioactive iodine. J Clin Endocrinol Metab 1980;50: Steel NR, Weightman DR, Taylor JJ, Kendal-Taylor P. Blocking activity to action of thyroid stimulating hormone in serum from patients with primary hy pothyroidism. Br Med J 1984;288: Arikawa K, Ichikawa Y, Yoshida T, et al. Blocking type antithyrotropin receptor antibody in patients with nongoitrous hypothyroidism: its incidence and characteristics of action. J Clin Endocrinol Metab 1985;60: Tanaka H, Yamauchi K, Takagi S, et al. Pathophysiological role of thyroid blocking antibody in pa tients with primary hypothyroidism. Endocrinol Jpn 1987;34: Cho BY, Shong YK, Lee HK, Koh C-S, Min HK. Inhibition of thyrotropin-stimulated adenylate cyclase activation and growth of rat thyroid cells, FRTL-5. by immunoglobulin G from patients with primary myxedema: comparison with activities of thyrotropin-binding inhibitor immunoglobulins. Acta Endocrinol (Copenh) 1989;120: Kraiem Z, Lahat N, Glaser B, Baron E, Sadeh O, Sheinfeld M. Thyrotropin receptor blocking anti bodies: incidence, characterization and in-vitro syn thesis. Clin Endocrinol (Oxf) 1987;27: Tamaki H, Amino N, Iwatani Y, Miyai K. Improve ment of infiltrative ophthalmopathy in parallel with decrease of thyroid-stimulating antibody (TSAb) ac tivity in two patients with hypothyroid Graves' dis ease. J Endocrinol Invest 1989;12: Yoshikawa N, Nishikawa M, Horimoto M, Uno C, Taniguchi N, Inada M. Activity of thyroid stimulat ing antibody and thyroid stimulation blocking anti body determined by radioiodine uptake into FRTL-5 cells. Endocrinol Jpn 1989;36: Tamaki H, Amino N, Aozawa M, et al. Effective method for prediction of transient hypothyroidism in neonates born to mothers with chronic thyroiditis. AmJ Perinatol 1989;6: Amino N. Autoimmunity and hypothyroidism. Baillieres Clin Endocrinol Metab 1988;2:

6 12. Zakarija M, Mckenzie JM. Pregnancy-associated changes in the thyroid-stimulating antibody of Gra ves' disease and the relationship to neonatal hy perthyroidism. J Clin Endocrinol Metab 1983;57: Kasagi K, Iida Y, Konishi J, et al. Paired determina tion of thyroid-stimulating and TSH-binding inhib itory activities in patients with Graves' disease during antithyroid drug treatment. Acta Endocrinol (Copenh) 1986;111: KonishiJ, Iida Y, Kasagi K, et al. Primary myxedema with thyrotropin-binding inhibitor immunoglobu lins: clinical and laboratory findings in 15 patients. Ann Int Med 1985;103: Fatourechi V, McConahey WM, Woolner LB. Hy perthyroidism associated with histologie Hashimoto's thyroiditis. Mayo Clin Proc 1971;46: Tamai H, Uno H, Hirota Y, et al. Immunogenetics of Hashimoto's and Graves' diseases. J Clin Endocrinol Metab 1985;60: Tamai H, Hirota Y, Kasagi K, et al. The mechanism of spontaneous hypothyroidism in patients with Gra ves' disease after antithyroid drug treatment. J Clin Endocrinol Metab 1987;64: Southgate K, Creagh F, Teece M, Kingswood C, Smith BR. A receptor assay for the measurement of TSH receptor antibodies in unextracted serum. Clin Endocrinol (Oxf) 1984;20: Konishi J, Kasagi K, Iida Y, et al. Optimization and clinical assessment of radioreceptor assay for thyro tropin-binding inhibitor immunoglobulins. Endocri nol Jpn 1987;34: Kasagi K, Konishi J, Iida Y, et al. A sensitive and practical assay for thyroid-stimulating antibodies using FRTL-5 thyroid cells. Acta Endocrinol (Copenh) 1987;115: Kasagi K, Konishi J, Iida Y, Mori T, Torizuka K. Changes in thyroid-stimulating and TSH-binding in hibitory activities in a patient who developed hyperthyroidism due to Graves' disease following pri mary hypothyroidism. Clin Endocrinol (Oxf) 1986; 25: Takeda K, Takamatsu T, Kasagi K, et al. Develop ment of hyperthyroidism following primary hy pothyroidism: A case report with changes in thyroidrelated antibodies. Clin Endocrinol (Oxf) 1988; 28: Miyauchi A, Amino N, Tamaki H, Kuma K. Coex istence of thyroid-stimulating and thyroid-blocking antibodies in a patient with Graves' disease who had transient hypothyroidism. Am J Med 1988;85: Volpé R, Ehrlich R, Steiner G. Graves' disease in pregnancy years after hypothyroidism with recur rent passive-transfer neonatal Graves' disease in off spring. Am J Med 1984;77: Amino N, Iwatani Y, Tamaki H, et al. Postpartum autoimmune thyroid syndromes. In: Walfish PG, Wall JR, Volpé R, eds. Autoimmunity and the thy roid. Toronto: Academic Press, 1985: Tamai H, Kasagi K, Takaichi Y, et al. Development of spontaneous hypothyroidism in patients with Graves' disease treated with antithyroidal drugs: clinical immunological and histological findings in 26 patients. J Clin Endocrinol Metab 1989;69: Received July 10th, Accepted Januar 4th, Dr Hajime Tamai, Department of Psychosomatic Medicine, Faculty of Medicine, Kyushu University, Maidashi, Higashi-ku, Fukuoka812, Japan.