J. Endocrinol. Invest. 15.· 853-855,1992

CASE REPORT

Subclinical hypothyroidism, overt thyrotoxicosis and subclinical hypothyroidism: The subsequent phases of thyroid function in a patient chronically treated with amiodarone 1 R. Minelli 2 , E. Gardini 2 , L. Bianconi, M. Salvi, and E. Roti Centro per 10 Studio, Prevenzione, Diagnosi e Cura delle Tireopatie, Cattedra di Endocrinologia, Universita di Parma, Parma, Italy ABSTRACT. In a patient chronically treated with amiodarone, subclinical iodine-induced hypothyroidism occurred as a result of excess iodine released fram the amiodarone moleeule. The patient was maintained on amiodarone and developed thyrotoxicosis as a result of a destructive process into the thyroid follicles. Amiodarone was withdrawn and methylprednisolone and methimazole treatment was

started with resolution of the thyrotoxic phase. Months later, off therapy, the patient developed subclinical hypothyroidism. This is the first description of hypo- and hyperthyroidism in the same patient caused by amiodarone therapy. This unusual observation suggests that patients treated with amiodarone are at risk to develop hyperthyroidism even if they show laboratory findings consistent with hypothyroidism.

INTRODUCTION Amiodarone, a benzofuranic derivative containing 37.2% iodine (75 mg of iodine per 200 mg tablet), affects the metabolism of thyroid hormones. Patients chronically treated with amiodarone present abnormal thyroid function tests, but their metabolic state is of euthyroidism. In some patients amiodarone therapy may induce hyper-or hypothyroidism (1). It has been reported that, in general, hyperthyroidism occurs more frequently in patients with low iodine intake whereas hypothyroidism is prevalent in those with high iodine intake (2). We report a patient who developed subclinical hypothyroidism, severe thyrotoxicosis and then subclinical hypothyroidism as results of amiodarone therapy.

since two years before, was evaluated for thyroid function on September 1988, Serum total T4, total T3 and TSH concentrations were measured by ELiSA with enzymun-test T4, enzymun-test T3 and enzymun-test TSH provided by Boehringer Mannheim GMbH Diagnostica (Milan, Italy). Normal ranges: T4 64,3-141,6 nmol/l; T3 0.99-2.45 nmol/l; TSH 0.3-3,6 mUll Serum antithyroglobulin (AbTg) and antimicrosomal (AbM) antibodies were measured by RIA with materials provided by ARES-Serono (Milan, Italy). Values higher than 50 U/ml are considered positive, At that time serum T4 concentration was 108.1 nmol/l, T3 1,01 nmol/l and TSH 5,1 mUll; serum AbTg and AbM antibodies were absent. Thyroid gland was not palpable. Seven and 20 months later serum TSH concentrations were 5,0 and 4.7 mUll, respectively, The patient was clinically weil and he was diagnosed to have subclinical iodineinduced hypothyroidism, Amiodarone therapy was continued and l-thyroxine substitution therapy was not considered necessary, In December 1990 the patient began to complain of weight loss, palpitations, heat intolerance, tremor and excessive sweating. In February 1991 serum T4 concentration was 211,1 nmol/l, T3 4,57 nmol/l and TSH undetectable low, Serum AbTg and AbM were absent. Thyroid gland was enlarged, irregular and slightly painful. Fine needle biopsy was performed and the cytological examination revealed

CASE REPORT E.l. a 62 year old man, treated with amiodarone for paroxysmal supraventricular tachycardia episodes Key-words. Amiodarone, hypothyroidism, thyrotoxicosis. Correspondence Dr. Elio Roti Cattedra di Endocrinologia, Universita di Parma, Via Gramsci 14,43100 Parma, Italy. 'Thls work was supported in part by Grants 89.04244.04, 90.01540.CT04, 91.00316.CT04 from Consiglio Nazionale delle Ricerche (Rome); Grant "Patologia dei la Tlrolde: Indagine dei Fattori Etiopatogenetici" Ministero Pubblica Istruzione 40% (Rome, Italy); Grant Ricerca Finalizzata Reglone Emilia-Romagna 1988-1990 2Reclpients 01 a lollowship Irom Associazione Volontaria Promozlone Ricerca Tumori (A.VO.PRO.Rl.T.), Parma, Italy. Received April 2,1992; accepted October 5, 1992

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the presence of large masses of colloid and hystiocytes but granulomatous cells were absent. Respiratory virus titers were negative and erythrocyte sedimentation rate was normal. A diagnosis of amiodarone associated thyrotoxicosis was done and we hypothized that the pathogenesis of the thyrotoxicosis was related to a destructive process into the thyroid follicles. Amiodarone was withdrawn and the patient was treated with methylprednisolone 16 mg/day beginning March 1991. In June 1991 the clinical conditions of the patient were partially ameliorated and signs of steroid excess were present even if methylprednisolone was reduced to 8 mg/day 3 weeks before. Serum T4 concentration was 155.7 nmol/l, T3 was 3.50 nmol/l and TSH undetectable. Thyroid gland was not palpable. Methylprednisolone was continued, 8 mg/day, and methimazole (MMI) was added at the dose of 15 mg/day. Three weeks later serum T4 was 101.7 nmol/l, T3 2.18 nmol/l and TSH 0.1 mUll. The patient was continued on MMI 15 mg/day and 4 mg/day of methylprednisolone; the latter drug was withdrawn 2 weeks later; in July 1991 MMI was increased to 20 mg/day until August 1991 and then was reduced to 10 mg/day and kept at the same dose until September 1991. At that time serum T4 concentration was 57.9 nmol/l, serum T3 0.93 nmol/l and TSH >33 mUll. Signs of hypothyroidism were present and thyroid gland appeared normal. MMI was discontinued. In January 1992 the patient was clinically weil, thyroid gland was not palpable and serum T4 concentration was 93.9 nmol/l, T3 1.27 nmol/l and TSH 6.0 mUll. In May 1992, eight months after MMI therapy

withdrawal, serum T4 concentrations was 78.1 nmol/l, T3 1.56 nmol/l and TSH 4.3 mUll (Fig. 1). DISCUSSION Amiodarone, an iodine-containing drug is a potent inhibitor of 5' deiodination of thyroxine and reverse T3 causing decreased serum T3 and increased T4 and rT3 concentrations, whereas serum TSH iso in general, in the normal range (1-3). These hormone changes are accompanied by a metabolie state of euthyroidism. The metabolie course of this patient on chronic amiodarone treatment is interesting since he went through aperiod of subclinical hypothyroidism, overt thyrotoxicosis and then subclinical hypothyroidism. The occurrence of hypothyroidism in patients treated with amiodarone has been attributed to the release of iodine from the moleeule of amiodarone (1-3). Approximately 6 mg of free iodine are realesed each day from 200 mg of amiodarone (1). Excess iodine may induce hypothyroidism as a result of an absent escape phenomenon from the Inhibitory effect of iodine on intrathyroid iodine organification (Wolff-Chaikoff effect) (4). lodine-induced hypothyroidism occurs frequently in euthyroid subjects with autoimmune thyroid disease such as Hashimoto's (5), postpartum thyroiditis (6), in patients previously treated with 131 1 or thyroidectomy for Graves' disease (7) and in euthyroid patients, who long before had subacute thyroiditis (8). The patient described did not have any previous thyroid disease and serum AbTg and AbM were absent suggesting that the condition of subclinlcal

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Figure 1 - Serum T4, T3 and TSII concentrations in a patient who developed subc/inical iodine-induced hypothyroidism and thyrotoxicosis during chronic amiodarone therapy Normal ranges. T4 643-1416 nmollL. T30.992.45 nmollL TSH 0..3-3.6 mUlL

Effects of amiodarone on thyroid function

hypothyroidism during amiodarone therapy was due to the absent escape from the acute inhibitory effect of iodine. Continuing amiodarone therapy, he developed overt thyrotoxicosis. Amiodarone induced thyrotoxicosis has been observed in subjects residing in endemie goiter area and in those with latent thyraid disorders such as Graves' disease and autonomous thyroid function (1,2). Recently, cases of amiodarone-induced thyratoxicosis whose pathogenesis was related to a destructive process in thyroid follicles have been described (9-14). The rapid appearance of thyrotoxicosis, after aperiod of subclinical hypothyroidism, the cytological examination, the clinical course of the disease and the appearance of increased serum TSH concentrations, following the thyrotoxicosis period, suggest that this patient had a destructive form of amiodarone associated hyperthyroidism. This is the first description of a patient who during amiodarone therapy developed subclinical iodine-induced hypothyroidism, overt thyrotoxicosis and finally, off amiodarone therapy, subclinical hypothyroidism. We do not think that the patient had borderline elevated serum TSH concentrations before amiodarone therapy because he did not have any clinical and laboratory evidence of autoimmune thyroid disease. Furthermore if the patient had increased serum TSH concentrations before amiodarone treatment, he would have showed markedly increased serum TSH concentrations during amiodarone treatment as observed in patients affected by other thyroid diseases administered with iodine (5-8). This unusual case suggests that patients treated with amiodarone are at risk to develop hyperthyroidism even if they show mildly elevated serum TSH concentrations. Therefore, careful monitoring of the patients is always required and thyroid hormone administration for subclinical hypothyroidism in amiodarone treated patients may be detrimental if the eventual appearance of thyrotoxicosis is not readily recognized.

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REFERENCES

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1. Lombardi A, Martino E., Braverman L.E. Amiodarone and the thyroid. Thyroid Today 13: 1, 1990. 2. Martino E., Safran M., Aghini-Lombardi F., Rajatanavin K., Lenziardi M., Fay M., Pacchiarotti A, Aronin N., Macchia E., Haffajee C., Udoguardi L, Love J, Bigalli A, Baschieri L, Pinchera A, Braverman L.E.

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Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann. Intern. Med. 101: 28,1984. Kennedy R.L, Griffiths H., Gray TA Amiodarone and the thyroid. Clin. Chem. 35: 1882, 1989. Wolff J., Chaikoff I.L. Plasma inorganic iodide as homeostatic regulator of thyroid function. J. Biol. Chem. 174: 555,1948. Braverman L.E., Ingbar S.H., Vagenakis AG., Adams L., Maloof F. Enhanced susceptibility to iodide myxedema in patients with Hashimoto's disease. J. Clin. Endocrinol. Metab. 32: 515,1971. Roti E., Minelli R., Gardini E, Bianconi L., Neri T, Gavaruzzi G., Ugolotti G., Salvo D., Braverman L.E. Impaired intrathyroidal iodine organification and iodine-induced hypothyroidism in euthyroid women with a previous episode of postpartum thyroiditis. J. Clin. Endocrinol. Metab. 73: 958, 1991. Braverman L.E., Woeber KA, Ingbar S.H. The induction of myxedema by iodide in patients euthyroid after radioiodine or surgical treatment of diffuse toxic goiter. N. Engl. J. Med. 281: 816,1969. Roti E, Minelli R, Gardini E., Bianconi L., Braverman L.E. lodine-induced hypothyroidism in euthyroid subjects with a previous episode of subacute thyroiditis. J. Clin. Endocrinol. Metab. 70 1581,1990. Roti E., Minelli R, Gardini E., Bianconi L., Braverman L.E. Thyrotoxicosis followed by hypothyroidism in patients treated with amiodarone: a possible consequence of a destructive process in the thyroid. Arch. Intern. Med, in press. Miaskiewicz SL., Amico J.A., Follansbee WP., Levey G.S. Amiodarone-associated thyrotoxicosis masquerading as painful thyroiditis. Ann. Intern. Med. 107: 118, 1987. GUdbJornsson B, Kristinsson A., Geirsson G., Hreidarsson A Painful autoimmune thyroiditis occurring on amiodarone therapy. Acta Med. Scand. 221 219,1987. Leung W.H., Pun K.K., Lau C.P., Wong C.K., Wang C. Amiodarone-induced thyroiditis. Am. Heart. J. 118: 848,1989. Lambert M., Unger J., Oe Nayer P., Brohet C, Gangji O. Amiodarone-induced thyrotoxicosis suggestive of thyroid damage. J. Endocrinol. Invest. 13: 527,1990. Smyrk TC., Goellner J.R., Brennan MD., Carney J.A. Pathology of the thyroid in amiodarone-associated thyrotoxicosis. Am. J. Surg. Pathol. 11: 197,1987.

Subclinical hypothyroidism, overt thyrotoxicosis and subclinical hypothyroidism: the subsequent phases of thyroid function in a patient chronically treated with amiodarone.

In a patient chronically treated with amiodarone, subclinical iodine-induced hypothyroidism occurred as a result of excess iodine released from the am...
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