Since amiodarone was first marketed in 1992 in Japan, the incidence of amiodarone-induced thyrotoxicosis (AIT) has been increasing [
2]. About 2–12 % of patients treated with amiodarone develop iodine-induced thyrotoxicosis, a condition sometimes extremely difficult to manage due to complex and long elimination half life of amiodarone [
3]. During amiodarone treatment, approximately 7–21 mg iodide is made available each day, releasing 50- to 100-fold excess iodine daily. Furthermore, amiodarone is distributed in several tissues from which, it is slowly released, with a terminal elimination half-life of approximately 52.6 ± 26.7 days and almost two months for its main metabolite, desethyl-amiodarone (DEA), explaining the fact that after amiodarone withdrawal, the drug remains available for a long period [
3,
4]. In peripheral tissues, amiodarone inhibits type I 5-deiodinase activity, decreasing peripheral conversion of T
4 to T
3. In addition, the drug inhibits thyroid hormone entry into peripheral tissues. Both mechanisms contribute to an increase in serum T
4 and a decrease in serum T
3 concentration in euthyroid subjects [
3,
5]. At the same time, amiodarone causes a biphasic change in serum TSH with an initial increase and a subsequent normalization of its values in patients who remain euthyroid, due to an inhibitory effect on type II 5-deiodinase activity in the pituitary [
3]. Subnormal or suppressed serum TSH could be indicative of subclinical thyrotoxicosis during chronic amiodarone treatment whereas critical non-thyroidal illness is associated with the same changes in TSH and free T
4 levels. Only a sudden decrease in serum TSH, along with high free T
4 and T
3concentrations can be useful in establishing the diagnosis of amiodarone-induced thyrotoxic crisis [
6]. Contrary to the effect on the thyroid, amiodarone can induce a hypothyroid-like state at the tissue level and particularly in the heart, related to both a reduction in the number of catecholamine levels and a decrease in the effect of T
3adrenoceptors[
3]. Two main forms of AIT have been described: type I AIT develops in an abnormal thyroid gland (nodular goiter, latent Graves' disease) due to iodine-induced true hyperthyroidism; type II AIT occurs in an apparently normal thyroid gland and is due to iodine-induced (or amiodarone -induced) destructive thyroiditis [
1,
7] In the first case, iodine load is responsible for excessive thyroid hormone synthesis and its prevalence is higher in mildly iodine deficient areas, suggesting that patients with preexisting thyroid abnormalities are unable to adapt normally to an excessive iodine intake [
8]. In the second case, patients usually have no underlying thyroid abnormalities, whereas a markedly increased serum interleukin 6 (IL-6) concentration, along with histopathologic findings demonstrating moderate to severe follicular damage, support the destructive nature of AIT type II, which seems to result from discharge of preformed thyroid hormones from disrupted follicles [
3,
8]. Useful tools in differentiating these two types include thyroid autoimmunity evaluation (positive in type I), thyroid ultrasonography (usually abnormal in type I), thyroid color flow Doppler sonography (homogeneous pattern with increased vascularity in type I and heterogeneous pattern with low vascularity in type II) and serum IL-6 levels (usually increased in type II) [
3]. Eaton et al in a retrospective audit of a large cohort of AIT patients demonstrated that CFDS was the most useful method for a rapid discrimination between type I and II AIT, whereas serum IL-6 measurement was unable to differentiate the two types of amiodarone-induced thyrotoxicosis [
9]. Nevertheless, differentiation between these two forms is not always clear-cut, and most experts believe that mixed (or indefinite) forms are probably more frequent than previously recognized (20%) [
10] and usually occur in abnormal thyroid glands but with features of destructive processes [
6]. Management of AIT remains a major challenge and is far more difficult than its diagnosis. According to Eaton, approximately 20% of cases of AIT remit spontaneously, however, in most instances specific treatment is required in order to limit the deleterious effects of thyrotoxicosis on the heart. Type I is treated with thionamides, which inhibit synthesis of new thyroid hormones, either alone or in combination with potassium perchlorate, because it limits further entry of iodine into the thyroid [
8]. Thyroidectomy represents a valid option for severe cases refractory to conventional treatment, although failure to achieve a euthyroid state before surgery may increase the surgical risk [
11]. Recently, Bogazzi et al observed that a short course of iopanoic acid prior to surgery might help to control rapidly thyrotoxicosis and reduces the risks of thyroid surgery in patients with heart disease. The former is an oral cholecystographic agent that inhibits peripheral monodeiodination of T
4 to T
3 [
12]. The preferred treatment for type II AIT is represented by glucocorticoides because it is not considered as a true form of hyperthyroidism, but rather a destructive thyroiditis caused by amiodarone and/or iodine. According to the European Thyroid Association Survey, definite treatment of thyroid disease (ablative therapy with either radioiodine or thyroidectomy) will be required in most cases of type I AIT, while most type II AIT patients will remain more easily euthyroid after control of thyrotoxicosis, because the thyroid gland is basically normal [
10].
Nevertheless, in view of diagnostic difficulties, experts suggest initially treatment of all cases of AIT with a combination of thionamides and glucocorticoids, whereas patients unresponsive to medical therapy can be managed with thyroidectomy [
10,
13,
14]. In a recent retrospective study of 28 cases with AIT, Osman et al found that amiodarone withdrawn had no adverse influence on response to treatment of amiodarone-induced thyrotoxicosis while there were no differences in overall outcome between types I and II of AIT [
15]. In the present case, despite the fact that serum IL-6 levels were not measured, we supposed that the patient had a dramatic clinical manifestation of amiodarone-induced thyrotoxicosis type II, as thyroid autoantibodies and thyroid ultrasonography examination were indicative of destructive thyroiditis and there was no previous history of thyroid disease. At the same time, the region of Thrace, Greece is considered a geographic area with high iodine intake, making more unlike the diagnosis of AIT type I.
However, due to the severity of thyrotoxicosis, an aggressive combination pharmacological therapy (beta-blockers, thionamides plus glucocorticoides) was started, which proved to be temporally effective. Despite the moderate decrease in active hormone levels and the initial amelioration of clinical status, the patient experienced a new rapid deterioration, refractory to further intensive medical therapy, after performing a percutaneous tracheotomy. This procedure aimed at aiding liberation from mechanical ventilation, as the patient experienced difficulties in weaning, probably because of pre-existing interstitial fibrosis that increases significantly respiratory system elastance and usually demands the administration of neuromuscular blockers, in order to achieve effective ventilation. Their combination with high doses of glucocorticoids can decrease muscle strength and affect negatively the weaning outcome [
16,
17]. Interstitial fibrosis develops in 0.5–15% of patients with chronic amiodarone treatment and if severe enough, is the least likely abnormality to resolve. Pulmonary toxicity is usually attributed to direct cytotoxic damage and an indirect immune reaction due to an amiodarone-induced inhibition of phospholipase A. The last effect can result in an accumulation of phospholipids within lysosomes in the lungs [
18]. Patients in whom acute respiratory distress syndrome (ARDS) [
19] develops have the highest mortality. However, early discontinuation of amiodarone therapy can improve pulmonary function [
18]. Since this case seemed to respond promptly to initial treatment, we did not consider emergency thyroid surgery as an alternative. However, after recurrence of thyrotoxicosis following percutaneous tracheotomy, thyroidectomy seemed the only valid option, despite a non-euthyroid state of the patient [
13]. Unfortunately, we never thought of giving him a short course of iopanoic acid, aiming at reducing thyrotoxic symptoms before emergency surgery and the patient never responded to conventional medical therapy. At the same time, we think that a definitive treatment, along with percutaneous tracheotomy should have been scheduled in the first place, due to his severe concomitant respiratory disease.