Correspondence *Second Floor, Institute of Biomedical Research, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

Email j.a.franklyn@bham.ac.uk

The case

A 75-year-old man experienced an anterior myocardial infarction, which was complicated by episodes of non-sustained ventricular tachycardia during the first 24 hours. An echocardiogram performed 3 months later demonstrated significant left ventricular dysfunction (ejection fraction 38%), and 24-hour ambulatory electrocardiograph monitoring revealed frequent periods of non-sustained ventricular tachycardia (<12 beats at 220/min) associated with presyncope. At that time the patient began therapy with amiodarone (200 mg by mouth daily). His symptoms resolved and he tolerated the drug without any complications. There was no personal or family history of thyroid disease.

Thyroid function tests that were performed before treatment and after 6 and 9 months revealed that the patient remained biochemically euthyroid with normal serum TSH levels. As expected, during amiodarone treatment free T₄ values were at the upper limit of the laboratory reference range (10–22 pmol/l), whereas free T₃ concentrations were at the lower limit (reference range 3.1–6.8 pmol/l; Figure 1). Thyroid autoantibodies were detected before the commencement of amiodarone therapy (thyroid peroxidase antibody concentration was 150 IU/ml, reference range 0–34 IU/ml).

Figure 1 Time course of the changes in thyroid function tests (serum levels of free T₄, free T₃ and TSH) and of the treatment with carbimazole and prednisolone in the patient described.

 

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Twelve months after commencing amiodarone therapy and 3 months after routine testing of thyroid function, the patient reported a weight loss of 4 kg during the previous 2 months without a change in appetite. He also reported an increase in the frequency of palpitations and a deterioration in exercise tolerance. On examination he seemed unwell, but was clinically euthyroid with a pulse rate of 80/min in sinus rhythm. There was no tremor of the hands and no signs of thyroid eye disease. A small non-tender goiter was evident on palpation. Thyroid function testing revealed significantly elevated free T₄ and free T₃ concentrations with an undetectable serum TSH level (<0.0 mIU/l, reference range 0.5–5.0 mIU/l). Ultrasonography of the thyroid gland revealed the presence of a small multinodular goiter; color-flow Doppler sonography studies were not performed.

The patient began treatment with carbimazole (40 mg daily), and amiodarone therapy was continued because of his underlying severe cardiac disease. Four weeks after commencing thionamide therapy his clinical state was stable, apart from further weight loss. Repeat thyroid function testing revealed no improvement, and the dose of carbimazole was increased to 60 mg daily. Four weeks later there were minimal changes in the results of thyroid function tests and the patient remained unwell with continuing weight loss and shortness of breath. Because his free T₄ and free T₃ values remained high, prednisolone 40 mg daily was added to his therapy. Addition of prednisolone was associated with a gradual reduction in thyroid hormone levels, which became normal approximately 6 months after starting glucocorticoids. The doses of prednisolone and carbimazole were first reduced, then withdrawn over the subsequent 6 months; serum TSH levels, however, continued to rise (Figure 1).

Six months after stopping thionamide therapy there was evidence of persistent hypothyroidism on thyroid function testing. Thyroxine replacement therapy was commenced and euthyroidism restored. When reviewed 12 months after commencing thyroxine therapy, the patient remained well and euthyroid whilst taking 100 g thyroxine daily in addition to amiodarone. An attempt to withdraw T₄ resulted in a rise in serum TSH level to 15 mIU/l after 1 month; permanent T₄ replacement was therefore proposed.

Discussion of diagnosis

Amiodarone treatment results in a large iodine load that exceeds normal dietary intake by approximately 250-fold (depending on the dose). This drug affects thyroid function by inhibiting the peripheral deiodination of T₄ to T₃; this inhibition typically leads to a modest increase in serum T₄ level and reduction in T₃ level in subjects who remain euthyroid. Amiodarone can also induce thyroid dysfunction; the relative proportion of subjects developing thyrotoxicosis or hypothyroidism varies according to their dietary iodine content. In iodine-replete areas, such as the UK and the USA, about 3% of those treated with amiodarone develop thyrotoxicosis,¹ whereas the prevalence is higher in iodine-deficient areas, including many parts of continental Europe.

The patient described here exhibited the typical changes in thyroid function associated with amiodarone therapy, with high-normal serum free T₄ level and low-normal free T₃ values before the development of thyrotoxicosis.² This complication, which was indicated by significant rises in T₄ and T₃ levels and suppression of the TSH level, developed rapidly more than 12 months after amiodarone exposure; it is well-recognized to develop even after amiodarone withdrawal. The major clinical features of the patient were weight loss and deterioration of the underlying cardiovascular symptoms, which are again characteristic of amiodarone-induced thyrotoxicosis (AIT).³ Some of the typical clinical features of thyrotoxicosis, such as tremor and tachycardia, were absent, probably reflecting one of the actions of amiodarone as a -adrenergic blocker.²

In view of the life-threatening nature of the patient's arrhythmia, amiodarone therapy was continued and thionamide (carbimazole) treatment was commenced.

AIT has been classified into two types. Type I is iodine-induced hyperthyroidism, which develops in those with underlying thyroid disease, type II is amiodarone-induced destructive thyroiditis. Type I AIT typically occurs in those with underlying autoimmune thyroid disease (suggested by the presence of thyroid autoantibodies, as in the patient described, although amiodarone-induced hypothyroidism is more common in such patients) and is frequently found in association with non-toxic nodular goiter (also evident in this patient). In contrast, type II AIT occurs in those without any underlying thyroid disease and is characterized by thyroid cell damage, inflammatory cell infiltration and fibrosis, as revealed by histopathological examination.⁴

The clinical presentation is similar in both types of AIT. We previously compared 14 cases of possible type I AIT with 14 cases of type II and found that women were over-represented in type I cases, reflecting the higher prevalence of thyroid disease in women.⁵ Other features including age, symptom duration, biochemical severity, cumulative amiodarone dose and duration of therapy were, however, not different in the two groups,⁵ although other studies have reported lower cumulative amiodarone doses in type I cases.⁶

Experience in the UK and the USA has demonstrated low 24-hour radioiodine uptake in both types of AIT,^{7, 8} as would be predicted from the huge iodine load associated with amiodarone ingestion. On the other hand, studies performed in continental Europe have surprisingly suggested that some patients with type I AIT can have normal or high radioiodine uptake despite receiving amiodarone therapy.⁹

Other ways proposed to differentiate between type I and type II cases include measurement of serum interleukin-6 level (reported to be high in type II AIT because of the associated inflammatory process), but this test has not been found to be consistently useful.^{6, 8} Another test, which holds considerably more promise, is color-flow Doppler ultrasonography. Its use is based on the assumption that type I cases exhibit increased blood flow typical of hyperthyroidism, a feature that is absent in cases of destructive thyroiditis. This test has been reported in both the UK and Italy to aid the distinction of type I from type II cases.^{6, 10} It is very likely, however, that 'mixed' cases with features of both subtypes of AIT commonly occur, as thyroid experts increasingly recognize the difficulty in distinguishing the two types.¹¹

Treatment and management

It is important to differentiate true hyperthyroidism from destructive thyroiditis because their treatments differ. Iodine-induced hyperthyroidism responds to treatment with thionamide drugs that are typically given in doses larger than usual, because of the large intrathyroidal stores of iodine resulting from amiodarone therapy. Potassium perchlorate, which acts as an inhibitor of iodine trapping, has also been reported to be useful.² We have reported that thionamide therapy is highly effective in AIT patients despite the continuation of amiodarone treatment; when given as the sole therapeutic agent, it was associated with good outcome in 22 out of 23 cases.⁵ Owing to the cardiovascular morbidity and mortality associated with hyperthyroidism in general,¹² especially if serious comorbidities are present, radioiodine represents the therapy of choice. In AIT, however, this therapy is ineffective and, therefore, contra-indicated because of the high level of circulating iodine associated with amiodarone therapy.

Consideration of radioiodine treatment often prompts the question of whether amiodarone therapy should be withdrawn in order to allow definitive treatment. In the short-term management of patients with AIT this question is of limited relevance, as stopping amiodarone treatment has little effect on thyroid function because of the long (approximately 50 days) half-life of this fat-soluble drug. As in the case described here, the severity of the underlying cardiac condition often precludes amiodarone withdrawal, although this option (as well as substitution of alternative antiarrhythmics) should be discussed with the managing cardiologist. A period off amiodarone of at least 6 months is typically required before radioiodine uptake into the thyroid is sufficient to make radioiodine therapy feasible. A relatively novel therapeutic consideration is ablation of the thyroid gland with radioiodine in those who have experienced an episode of AIT and stopped amiodarone, in order to allow later reintroduction of the drug for recurrent arrhythmias.¹³ The risk of recurrent AIT, however, is as yet poorly defined.

For patients with amiodarone-induced destructive thyroiditis, glucocorticoid therapy is considered to be the treatment of choice and is again reported to be effective when amiodarone is continued. Prednisone doses of 40–60 mg are often recommended and result in improvement of the symptoms, sometimes within a week.⁷ A recent study from Italy has indicated that the median time to restoration of euthyroidism with glucocorticoids in cases of type II AIT is 30 days, although this period might be much longer in those with higher free T₄ concentrations and larger thyroid gland size,¹⁴ as in the case reported here.

Because of the inherent difficulty in distinguishing type I from type II cases of AIT, and because some cases seem to respond only to therapy with both thionamides and glucocorticoids, one suggested approach is to add the 'second' therapy if the first has not worked after a period of several weeks to months. A suggested alternative is commencement of both treatment modalities at the time of diagnosis of AIT.^{7, 8} The latter approach has particular merit if the patient has significant or rapidly developing symptoms and signs of thyroid hormone excess. If the patient responds to therapy very rapidly (within 1–2 weeks), it is likely that they have a destructive thyroiditis and thionamides can be withdrawn; a relatively small proportion of such patients become permanently hypothyroid and require long-term T₄ replacement. A few patients respond to neither treatment, and various adjunctive therapies have been described in case reports or small series. These therapies include lithium, radiographic contrast agents¹⁵ and total thyroidectomy (sometimes under local anesthetic). Surgery represents an important therapeutic option in those with drug-resistant AIT.⁷

Conclusions

This case outlines the clinical course of a patient with severe underlying cardiac disease requiring amiodarone treatment, who developed AIT. Some of the clinical and immunological features (e.g. the presence of goiter and thyroid antibodies) suggested the diagnosis of amiodarone-induced hyperthyroidism. The patient failed to respond to thionamide therapy, but the addition of glucocorticoids led to a clinical and biochemical remission. He became hypothyroid after withdrawal of antithyroid and glucocorticoid treatment, consistent with an amiodarone-induced destructive thyroiditis. The patient displayed features suggestive of both type I and type II AIT, as indicated by clinical findings, but treatment response and outcome suggested this was predominantly a destructive thyroiditis. The case illustrates some of the diagnostic and therapeutic dilemmas associated with this condition.

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Subject areas under which this article appears: Thyroid gland | Therapy (pharmacotherapy, radiotherapy, nutrition, alternative)