Hyperthyroidism with amiodarone

The major clinical use for potassium perchlorate is to block thyroidal reuptake of 1 in patients with iodide-induced hyperthyroidism (eg, amiodarone-induced hyperthyroidism). However, potassium perchlorate is rarely used clinically because it is associated with aplastic anemia. 

Color-flow Doppler sonography can be of use in distinguishing the two types, because type 1 is associated with increased vascularity and type 2 is not. In a retrospective study of 24 patients with amiodarone-induced hyperthyroidism in an iodine-replete environment, 13 had little or no vascularity, of whom seven were prednisolone-responsive of 11 patients with increased vascularity, four responded to antithyroid drugs alone and only one of seven responded to prednisolone (37). Euthyroidism was achieved twice as rapidly in patients with low vascularity than in those with increased vascularity. Thus, responsiveness to prednisolone was not consistently predicted by lack of vascularity, but the presence of flow appeared to correlate with non-responsiveness to prednisolone. 

Despite the fact that she was clinically euthyroid, the authors suggested that this patient had amiodarone-induced hyperthyroidism. However, amiodarone inhibits the peripheral conversion of thyroxine to triiodothyronine it can therefore increase the serum thyroxine and suppress the serum TSH, as in this case. On the other hand, the reduced uptake by the thyroid gland is consistent with type 2 amiodarone-induced hyperthyroidism. The authors did not report the serum concentrations of free thyroxine and triiodothyronine. 

In five patients who presented in Tasmania during 1 year, all of whom were taking amiodarone 200 mg/day, serum TSH was undetectable and the free thyroxine and triiodothyronine concentrations were raised (46). In one case there was a low titer of TSH receptor antibodies and in another a high titer of antithyroid peroxidase antibodies. In all cases the hyperthyroidism was severe and occurred after at least 2 years of treatment with amiodarone. In one of two patients in whom it was measured the serum concentration of interleukin-6 was raised, as has been previously shown (SEDA-19, 193). In two cases the hyperthyroidism was refractory to treatment with propylthiouracil, lithium, and dexamethasone in these cases thyroidectomy was required. Two patients responded to propylthiouracil, lithium, and dexamethasone, and one responded to carbimazole. 

The management of hyperthyroidism due to amiodarone has been reviewed in the light of the practices of 101 European endocrinologists (60). Most (82%) treat type I amiodarone-induced hyperthyroidism with thionamides, either alone (51%) or in combination with potassium perchlorate (31%) the preferred treatment for type II hyperthyroidism is a glucocorticoid (46%). Some initially treat all cases, before the type has been established, with a combination of thionamides and glucocorticoids. After restoration of normal thyroid function, 34% recommend ablative therapy in type I hyperthyroidism and only 8% in type II. If amiodarone therapy needs to be restarted, 65% recommend prophylactic thyroid ablation in type I hyperthyroidism and 70% recommend a wait-and-see strategy in type II. 

The use of local anesthesia for total thyroidectomy in patients with amiodarone-induced hyperthyroidism and cardiac impairment has been reviewed in the context of six patients (74). 

Reichert LJ, de Rooy HA. Treatment of amiodarone induced hyperthyroidism with potassium perchlorate and methimazole during amiodarone treatment. BMJ 1989 298(6687) 1547-8. 

A Methimazole has a longer TV2 than PTU and can be dosed once daily PTU requires three to four daily doses, which may affect compliance. PTU does not cause pretibial myxedema rather Graves hyperthyroidism leads to pretibial myxedema. Methimazole does not interact with amiodarone however, amiodarone can affect thyroid function, leading to both hypo- and hyperthyroidism. PTU therapy may result in spontaneous remission, but patients typically require therapy for many years (1 to 15 years). 

Chronic therapy with amiodarone has been associated with pulmonary interstitial pneumonitis/alveolitis, hypersensitivity pneumonitis, and pulmonary fibrosis fatalities have resulted. Other side effects include elevated liver function tests, worsening of arrhythmias, onset of new arrhythmias, fatigue, tremor, involuntary movements, dizziness, paresthesias, difficulty in walking, hypothyroidism, hyperthyroidism, nausea, vomiting, constipation, anorexia, corneal... 

However, these same characteristics make lithium a useful adjunct in the treatment of hyperthyroidism with i l. A 39-year-old woman with Graves disease who may have developed thyrotoxicosis secondary to treatment with amiodarone, an iodine-rich medication [92 ]. She was administered lithium 900mg/day for 12 days to increase uptake. When this was combined with two doses of 0.9 mg of recombinant human thyroid stimulating hormone (rhTSH), there was a fivefold increase in uptake [92 ]. In a retrospective study of 204 hyperthyroid patients (n = 163 Graves disease, n = 26 toxic multinodular goiter, and n=15 solitary toxic thyroid adenoma), 103 patients received alone (median dose 558 MBq) and 101 received 1 with lithium (median... 

Jonckheer MH, Blockx P, Kawers R and Wyffels W. 1973. Hyperthyroidism as a possible complication of treatment of ischemic heart disease with amiodarone. Acta Cardiol (Bruxelles) 28, 192-200. 

I think Dr. Jonckheer is correct. However, if you take 100 patients with iodine-induced hyperthyroidism, at least in the US, I would guess that 95 % of them have a suppressed radioactive iodine uptake. As a matter of fact, in a joint study with Dr. Pinchera on iodine-induced thyrotoxicosis in patients treated with amiodarone, we showed that the condition could be associated with normal or elevated uptakes. Those cases represent, however, a minority. The majority of patients with Jod-Basedow in the US will have an elevated urinary iodine excretion and a low radioactive iodine uptake. 

The perchlorate ion of potassium perchlorate, KCIO4, is a competitive inhibitor of thyroidal 1 transport via the Sodium Iodide Symporter (NIS).This drug can cause fatal aplastic anemia and gastric ulcers and is now rarely used. If administered with careful supervision, in limited low doses and for only brief periods, serious toxic effects can be avoided. The compound is especially effective in treating iodine-induced hyperthyroidism, which may occur, for example, in patients treated with the antiar-rhythmic compound amiodarone. Perchlorate ion can also be used in a diagnostic test of 1 incorporation into Tg, the so-called perchlorate discharge test. 

Inhibition of thyroid hormone synthesis or release with the induction of hypothyroidism (or occasionally hyperthyroidism) Iodides (including amiodarone), lithium, aminoglutethimide, thioamides, ethionamide... 

Induction of autoimmune thyroid disease with hypothyroidism or hyperthyroidism Interferon-a, interleukin-2, interferon-B, lithium, amiodarone... 

Apart from its effects on thyroid function tests, amiodarone is also associated with both functional hyperthyroidism and hypothyroidism, in up to 6% of patients. The frequency of thyroid disease in patients taking amiodarone has been retrospectively studied in 90 patients taking amiodarone 200 mg/day for a mean duration of 33 months (35). Hypothyroidism occurred in five patients and hyperthyroidism in 11. Hyperthyroidism became more frequent with time and was associated with recurrent supraventricular dysrhythmias in four of the 11 patients. 

Amiodarone causes two different varieties of hyperthyroidism (SEDA-23, 199), one by the effects of excess iodine in those with latent disease (so-called type 1 hyperthyroidism), the other through a destructive thyroiditis in a previously normal gland (so-called type 2 hyperthyroidism). The two varieties can be distinguished... 

There has been a retrospective study of the frequency of amiodarone-associated thyroid dysfunction in adults with congenital heart disease (41). Of 92 patients who had taken amiodarone for at least 6 months (mean age 35, range 18-60 years), 36% developed thyroid dysfunction— 19 became hyperthyroid and 14 hypothyroid. The mean dosage was 194 (100-300) mg/day, and the median duration of therapy was 3 (0.5-15) years. Female sex (OR = 3) and unoperated or palliated cyanotic congenital heart disease (OR = 7) were significant susceptibility factors for thyroid dysfunction. The risk was also dose-related. Although the authors conceded that they may have over-estimated the... 

In contrast, it has been suggested that men are more susceptible to hyperthyroidism due to amiodarone (42). Of 122 600 patients in 12 practices in the West Midlands in the UK, 142 men and 74 women were taking amiodarone and 27 (12.5%) had thyroid disease. Of those, 11 men (7.7%) and 4 women (5.4%) had hypothyroidism, a nonsignificant difference however, 12 men (8.5%) had hyperthyroidism compared with no women. This difference is particularly striking because hyperthyroidism is usually more common in women. 

Patients with beta-thalassemia major have an increased risk of primary hypothyroidism. In 23 patients with beta-thalassemia amiodarone was associated with a high risk of overt hypothyroidism (33 versus 3% in controls) (43). This occurred at up to 3 months after starting amiodarone. The risk of subclinical hypothyroidism was similar in the two groups. In one case overt hypothyroidism resolved spontaneously after withdrawal, but the other patients were given thyroxine. After 21-47 months of treatment three patients developed thyrotoxicosis, with remission after withdrawal. There were no cases of hyperthyroidism in the controls. The authors proposed that patients with beta-thalassemia may be more susceptible to iodine-induced hypothyroidism, related to an underlying defect in iodine in the thyroid, perhaps associated with an effect of iron overload. 

A 62-year-old man took amiodarone for 2 years and developed hyperthyroidism carbimazole 40 mg/day, prednisolone, lithium, and colestyramine were ineffective and he died with hepatic encephalopathy and multiorgan failure. 

In three other cases reported in the same paper, severe hyperthyroidism responded severally to treatment with carbimazole, carbimazole plus lithium, or propylthiouracil. In one case amiodarone therapy was restarted after prophylactic subtotal thyroidectomy. 

The treatment of amiodarone-induced hyperthyroidism is difficult. It often does not respond to conventional therapy with carbimazole, methimazole, or radio-iodine. However, corticosteroids and the combination of methimazole with potassium perchlorate have been reported to be effective (52), even if amiodarone is continued (53). Other regimens that have been used include combinations of corticosteroids with carbimazole (54), corticosteroids and benzylthiouracil (55), or propylthiouracil (SEDA-15, 170). Potassium perchlorate has also been used (SEDA-21, 199). Other forms of treatment that have been successful have been plasma exchange and in very severe cases subtotal thyroidectomy (56) or total thyroidectomy (SEDA-15,170 SEDA-17, 220 57). 

It has been suggested that potassium perchlorate should be used in the treatment of type 1 hyperthyroidism and glucocorticoids in the treatment of type 2 (SEDA-21, 199). Since hypothyroidism due to amiodarone tends to occur in areas in which there is sufficient iodine in the diet, it has been hypothesized that an iodinated organic inhibitor of hormone synthesis is formed and that the formation of this inhibitor is inhibited by perchlorate to a greater extent than thyroid hormone iodination is inhibited, since the iodinated lipids that are thought to be inhibitors require about 10 times more iodide than the hormone. However, there is a high risk of recurrence after treatment with potassium perchlorate, and it can cause serious adverse effects (SED-13,1281). 

When five patients with type 2 amiodarone-induced hyperthyroidism were treated with a combination of an oral cholecystographic agent (sodium ipodate or sodium iopanoate, which are rich in iodine and potent inhibitors of 5 -deiodinase) plus a thionamide (propylthiouracil or methimazole) after amiodarone withdrawal, all improved substantially within a few days and became euthyroid or... 

Thyroid function tests were measured before and after treatment of amiodarone-induced hyperthyroidism (n = 12) and the response to combined antithyroid and glucocorticoid treatment (n = 11) was recorded (61). One patient had type 1 hyperthyroidism, nine had type 2, and two probably had a mixed form. Six patients had diffuse hypoechoic goiters. The median time to euthyroidism (defined as a normal free T3 concentration) with a thionamide + prednisolone (starting dose 20-75 mg/day) was... 

A 40 year-old patient with severe amiodarone-induced hyperthyroidism after heart transplantation did not respond to high doses of antithyroid drugs combined with glucocorticoids (62). A low dose of lithium carbonate resulted in normalization of thyroid function. 

Prevention of recurrence of amiodarone-induced hyperthyroidism has been successfully attempted with 131I in 18 patients, in 16 of whom amiodarone was reintroduced (65) the same authors reported the first 15 of these patients in two separate papers (66,67). The... 

Mackie GC, Shulkin BL. Amiodarone-induced hyperthyroidism in a patient with functioning papillary carcinoma of the thyroid and extensive hepatic metastases. Thyroid 2005 15(12) 1337-40. 

The observation that Canada, with ample nutritional iodine, has a relatively high rate of lithium-related hypothyroidism compared with relatively low rates in iodine-deficient countries such as Italy, Spain, and Germany led to the suggestion that ambient iodine may play a role in the genesis of this condition (270). This is reminiscent of the association of amiodarone with hypothyroidism or hyperthyroidism in iodine-replete and iodine-deficient areas respectively (SEDA-10,148). 

In euthyroid subjects with normal glands an excess of iodide from any source can cause goitre (with or without hyperthyroidism), e.g. use of iodide-containing cough medicines, iodine-containing radio-contrast media, amiodarone, seaweed eaters. 

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