Amiodarone-induced thyrotoxicosis presenting as hypokalemic periodic paralysis. (Case Reports).

ABSTRACT: Thyroid disorder is a well-recognized side effect of amiodarone therapy. Thyrotoxicosis is less common than hypothyroidism. Hypokalemic periodic paralysis is one manifestation of thyrotoxicosis, and is more often seen in Oriental and Latin American men than in other demographic groups. This phenomenon, however, has not been previously described in thyrotoxicosis due to amiodarone usage. We describe a case of amiodarone-induced thyrotoxicosis in a 34-year-old man who presented with sudden lower extremity weakness, heat intolerance, and weight loss. Physical examination demonstrated fine tremors. Serum potassium level was 2.2 mEq/L on admission. Gastrointestinal and renal causes of potassium loss were excluded by history and physical examination. Further biochemical testing demonstrated abnormal thyroid function. The urinary potassium and serum bicarbonate, magnesium, and calcium levels were within normal limits. Lower extremity weakness resolved immediately after potassium replacement therapy. Methim azole therapy was initiated, and the patient was clinically euthyroid on discharge.

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THE SIDE EFFECTS OF AMIODARONE therapy include corneal deposits, photosensitivity, cutaneous hyperpigmentation, pulmonary toxicity, hepatotoxicity, peripheral neuropathy, drug interactions, thyrotoxicosis, and hypothyroidism. (1) The association between amiodarone therapy and thyrotoxicosis is well known. (2) Although there are reports of thyrotoxicosis presenting as hypokalemic periodic paralysis, it has not been described with amiodarone therapy. We report a rare case of a patient with amiodarone-induced thyrotoxicosis presenting as hypokalemic paralysis.

CASE REPORT

A 34-year-old white man presented with sudden weakness of both lower extremities. He complained of hand tremors, heat intolerance, and a 10-pound weight loss over the previous 3 months. His medical history was significant for recurrent symptomatic ventricular tachycardia. The arrhythmia was refractory to treatment with many antiarrhythmic agents and 3 radiofrequency ablations before it was eventually controlled with amiodarone therapy. He was not taking any diuretics, over-the-counter drugs, or herbal medications.

He denied chest pain, palpitations, dizziness, sweating, mood swings, loss of appetite, nausea, vomiting, or diarrhea. Physical examination revealed a heart rate of 92 beats per minute. The thyroid gland was moderately enlarged and estimated to weigh approximately 44 g (normal range, 18-20 g). There was no bruit. He was restless, with fine tremors of the fingers and hyperreflexia. There was, however, no evidence of any focal neurologic deficit, and there was no evidence of ophthalmopathy or dermopathy characteristic of Graves' disease. The admission electrocardiogram demonstrated sinus rhythm with frequent premature ventricular complexes. Cardiac monitoring showed frequent premature ventricular complexes and nonsustained ventricular tachycardia. Admission laboratory tests showed the following values: serum sodium, 133 mEq/L; potassium, 2.2 mEq/L; chloride, 109 mEq/L; bicarbonate, 24 mEq/L; creatinine, 1.1 mg/dL; and phosphorus, 3.5 mEq/L. Urine chemistry tests showed the following values: sodium, 48 mEq/L; po tassium, 16 mEq/L, and creatinine, 43 mEq/L. Urinary drug screen was negative. Intravenous potassium-replacement therapy was begun, and the weakness in the lower limbs resolved. Thyroid function tests showed the following values: thyroid stimulating hormone (TSH), <0.03 mIU/L (normal, 0.5-5.0 mIU/L); thyroxine ([T.sub.4]), 15.3 [micro]g/dL (normal, 4.0-10.5 [micro]g/dL); triiodothyronine ([T.sub.3]), 256 ng/dL (normal, 80-200 ng/dL); free thyroxine index ([FT.sub.4]I), 19.4 (normal, 4.7-10.0). He was treated with methimazole (20 mg orally, twice a day) and given amiodarone for maintenance therapy. He improved clinically, with complete resolution of symptoms. His potassium levels were normal on follow-up examination.

DISCUSSION

Amiodarone is an effective antiarrhythmic drug, but it can cause severe adverse effects, including thyroid dysfunction; hypothyroidism develops in 6% and thyrotoxicosis in 12% to 15% of patients. (1) Amiodarone-induced thyrotoxicosis is prevalent in populations with low iodine intake, whereas hypothyroidism occurs in people in areas with high iodine intake. (2) Unlike hypothyroidism, which is rare after the first 18 months of therapy, thyrotoxicosis can occur at any time throughout the duration of treatment. (3) Overt thyroid dysfunction, either amiodarone-induced thyrotoxicosis or amiodarone-induced hypothyroidism, occurring in 14% to 18% of patients receiving long-term treatment, may develop both in apparently normal thyroid glands and in glands with preexisting abnormalities. Thyrotoxicosis can be due to excess-iodine-induced thyroid hormone synthesis (type I) or to amiodaronerelated destructive thyroiditis (type II), although mixed forms often occur. (4) The iodine content of amiodarone may induce excessi ve synthesis of thyroid hormone. The other pathogenic mechanisms include disturbance of thyroid iodine autoregulation and immunologic (induction of thyroid antibodies). (3)

The diagnosis of amiodarone-induced thyrotoxicosis is difficult to make, since classic symptoms of thyrotoxicosis are usually absent because of its rapid onset. In addition, many patients undergoing long-term amiodarone treatment have abnormal thyroid-function tests, despite being euthyroid. (5) The diagnosis of amiodarone-induced thyrotoxicosis is made on the basis of the constellation of clinical signs and symptoms of thyrotoxic state, decreased TSH level, and increased levels of [T.sub.4], [FT.sub.4]I, and sometimes [T.sub.3]. (5)

The clinical clues leading to diagnosis of amiodarone-induced thyrotoxicosis in our patient were hand tremors, heat intolerance, nervousness, unexplained weight loss, and hyperreflexia. The diagnosis was confirmed on the basis of his clinical presentation, decreased TSH level, and elevated levels of [T.sub.4], [T.sub.3] and [FT.sub.4]I. An unusual feature of our patient's presentation was that he had symptoms suggestive of thyrotoxicosis at the time of presentation with the paralysis. This is in contrast to the observations made by Magsino and Ryan, (6) who comment that overt findings of thyrotoxicosis are rarely present with the initial paralytic attack.

Thyrotoxic periodic paralysis is a thyroid-related disorder that is manifested as recurrent episodes of hypokalemia and muscle weakness lasting from hours to days. The periodic paralysis has been associated with thyrotoxicosis from various etiologies. (7) The diagnosis of hypokalemic periodic paralysis was based on sudden muscle weakness, low serum potassium level, and immediate resolution of muscle weakness after potassium replacement therapy. Thyrotoxic periodic paralysis is characterized by a rapid fall in serum potassium level during the acute attack (6) (as was seen in our patient). During acute episodes, the muscle membrane remains depolarized, although the contractile mechanism remains functional. (8,9)

Since amiodarone has a prolonged half-life, treatment of amiodarone-induced thyrotoxicosis is more prolonged than other forms of iodine-induced thyrotoxicosis. Discontinuation of amiodarone therapy in patients such as ours, with amiodarone-induced thyrotoxicosis, is often difficult, since it is the only effective treatment for the underlying life-threatening arrhythmia. In addition, worsening of thyrotoxicosis and cardiac status have been described after sudden withdrawal of amiodarone therapy. (10) Continuation of treatment with amiodarone does not alter the basic approach to the medical management of thyrotoxicosis, but it reduces the chances of a successful outcome. In type I thyrotoxicosis, the effectiveness of treatment with antithyroid drugs and radioiodine is reduced by the persistently raised thyroidal and circulating iodide levels. (11) Spontaneous remission of type II thyrotoxicosis (but not type I) can occur despite continued treatment. (12) There are reports that treatment with antithyroid drugs, maintained until TSH concentrations recover, can be associated with a permanent cure. (13,14)

The combination of treatment with methimazole, which decreases thyroidal synthesis of [T.sub.4] and [T.sub.3], and potassium perchlorate, which inhibits the entry of iodide into the gland, has been shown to rapidly control amiodarone-induced thyrotoxicosis. Radioactive iodine is not a recommended therapy, since a high plasma iodide concentration suppresses the radioactive iodine uptake by the thyroid. (15) Surgery is sometimes the only antithyroid treatment that permits continued therapy with amiodarone. (16) Methimazole alone was used to treat the amiodarone-induced thyrotoxicosis in our patient because of the potential toxicity from long-term treatment with perchlorate. (15)

CONCLUSION

Hypokalemic periodic paralysis is an uncommon feature of thyrotoxicosis, and has not been previously reported in amiodarone-induced thyrotoxicosis. Discontinuation of amiodarone treatment in patients who develop thyrotoxicosis is often difficult, since it may be the only effective treatment for the underlying life-threatening arrhythmia. Surgery may be the only antithyroid treatment that permits continued therapy with amiodarone. However, methimazole, has been shown to rapidly control amiodarone-induced thyrotoxicosis, as is illustrated by our case.

References

(1.) Harris L, McKenna WJ, Rowland E, et al: Side effects of long-term amiodarone therapy. Circulation 1983;67:45-51

(2.) Harjai KJ, Licata AA: Amiodarone-induced hyperthyroidism. Pacing Clin Electrophysiol 1996;19:1548-1554

(3.) Trip MD, Wiersinga W, Plomp TA: Incidence, predictability and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism. Am J Med 1991;91:507-511

(4.) Nademanee K, Piwonka RW, Singh BN, et al: Amiodarone and thyroid function. Ping Candiovasc Dis 1989;31:427-437

(5.) Bogazzi F, Bartalena L, Gasped M, et al: The various effects of amiodarone on thyroid function. Thyroid 2001;11:511-519

(6.) Magsino CH Jr, Ryan AJ Jr: Thyrotoxic periodic paralysis. South Med J 2000; 93:996-1003

(7.) Amico JA, Richardson V, Alpert B, et al: Clinical and chemical assessment of thyroid function during therapy with amiodarone. Arch Intern Med 1984; 144:487-490

(8.) Riggs JE: The periodic paralyses. Neurol Clin 1988; 6:485-498

(9.) Engel AG, Lambert EH: Calcium activation of electrically inexcitable muscle fibres in primary hypokalemic periodic paralysis. Neurology 1969; 19:851-858

(10.) Rudel R, Lehmann-Horn F, Ricker K, et al: Hypokalemic periodic paralysis: in vitro investigation of muscle fibre parameters. Muscle Nerve 1984; 7:110-120

(11.) Newman GM, Price A, Davies DW, et al: Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy. Heart 1998;79:121-127

(12.) Wiersinga W: Amiodarone and the thyroid. Handbook of Experimental Pharmacology. Pharmacotherapeutics of the Thyroid Gland. Weetman AP, Grossman A (eds). Heidelberg, Springer-Verlag, 1997, Vol 128, pp 225-287

(13.) Martino E, Aghini-Lombardi F, Mariotti S, et al: Amiodarone: a common source of iodine-induced thyrotoxicosis Horm Res 1987; 26:158-171

(14.) Brousolle C, Ducottet X, Martin C, et al: Rapid effectiveness of prednisone and thionamides combined therapy in severe amiodarone iodine-induced thyrotoxicosis. Comparison of two groups of patients with apparently normal thyroid glands. J Endocrinol Invest 1989; 12:37-42

(15.) Martino E, Aghini-Lombardi F, Mariotti S, et al: Treatment of amiodarone-associated thyrotoxicosis by simultaneous administration of potassium perchlorate and methimazole. J Endocrinol Invest 1986; 9:201-207

(16.) Brennan MD, van Heerden JA, Carney JA: Amiodarone-associated thyrotoxicosis (AAT): experience with surgical management. Surgery 1987; 102:1062-1067

RELATED ARTICLE: KEY POINTS

* Hypokalemic periodic paralysis is an uncommon feature of thyrotoxicosis, and has not previously been reported with amiodarone-induced thyrotoxicosis.

* Discontinuation of amiodarone therapy in patients who develop thyrotoxicosis is often difficult, and surgery has thus far been the major treatment modality for this condition.

* Methimazole can rapidly control amiodarone-induced thyrotoxicosis.

From the Department of Internal Medicine, University of North Dakota School of Medicine; and the Department of Medicine, Veterans Affairs Medical Center, Fargo, ND.

Reprint requests to Sandeep T. Laroia, MD, Department of Internal Medicine, University of North Dakota School of Medicine, 1919 Elm St N, Fargo, ND 58102.