Amiodarone & Thyroid, 2016 ATA Guidelines

Amiodarone induced thyrotoxicosis could be productive or destructive, called AIT1 and AIT2 respectively. AIT1 hyperthyroidism is primarily due to excessive iodine supplied by the amiodarone, whereas AIT2 is secondary to thyroid inflammation leading to uncontrolled release of preformed hormone. Distinguishing between the two types clinically, biochemically or by imaging studies is often difficult. Common treatments are methimazole, prednisone, surgery or a combination of the three. Amiodarone could also be discontinued if approved by the heart specialist.  

In 2016, American Thyroid Association published guidelines on diagnosis and management of hyperthyroidism, including the amiodarone scenario. The publication provides great explanations and rationales on how to approach amiodarone induced thyrotoxicosis. Please read recommendations and excerpts below for more details.

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Recommendations:

  • We suggest monitoring thyroid function tests before and within the first 3 months following the initiation of amiodarone therapy, and at 3 to 6-month intervals thereafter
  • The decision to stop amiodarone in the setting of thyrotoxicosis should be determined on an individual basis in consultation with the treating cardiologist, depending on the clinical manifestations and presence or absence of effective alternative antiarrhythmic therapy.
  • In clinically stable patients with AIT, we suggest measuring thyroid function tests to identify disorders associated with iodine-induced hyperthyroidism (type 1 AIT), specifically including toxic nodular disease and previously occult graves disease.
  • Methimazole should be used to treat overt thyrotoxicosis in patients with proven underlying autonomous thyroid nodules or graves disease as the cause of AIT (type 1 disease), and corticosteroids should be used to treat patients with overt amiodarone-induced thyroiditis (type 2 disease).
  • Combined ATD and corticosteroid therapy should be used to treat patients with overt AIT who are too unstable clinically to allow a trial of monotherapy or who fail to respond to single modality therapy, or patients in whom the etiology of thyrotoxicosis cannot be unequivocally determined.
  • Patients with AIT who are unresponsive to aggressive medical therapy with methimazole and corticosteroids should undergo thyroidectomy.

Rationales from the guidelines (very USEFUL):

Background:

Amiodarone is a drug that is frequently used in the treatment of refractory atrial or ventricular tachyarrhymias. Amiodarone-induced thyrotoxicosis (AIT) occurs in up to 6% of patients taking this medication in iodine-sufficient areas of the world and in up to 10% in iodine-deficient areas, such as parts of Europe. Studies evaluating the adequacy of monitoring for adverse effects from amiodarone have shown suboptimal results.

Two distinct mechanisms have been proposed in the development of AIT, including an iodine-induced form of hyperthyroidism (type 1 AIT) due to the high iodine content of amiodarone (37% by molecular weight) and a destructive thyroiditis (type 2 AIT) due to direct toxicity of amiodarone on follicular cells. Type 1 AIT tends to occur in patients with underlying thyroid autonomy in a nodular goiter, or graves disease, whereas type 2 AIT occurs as a result of direct damage or induction of apoptosis in thyrocytes by amiodarone.

The need for amiodarone discontinuation is controversial because (i) this drug is frequently the only medication able to control cardiac arrhythmia, (ii) the effects of this fat-soluble drug may persist for many months, (iii) amiodarone may have T3-antagonistic properties at the cardiac level and inhibit T4 to T3 conversion in the heart such that withdrawal may actually aggravate cardiac manifestations of thyrotoxicosis. Deaths from ventricular fibrillation have occurred after stopping amiodarone in patients with AIT. In addition, type 2 AIT typically responds to treatment even if amiodarone therapy is continued, but continuation may lead to a more prolonged time to recovery and a higher rate of future recurrences of AIT.

Pathogenesis:

As the pathogenesis of AIT is not fully understood, the classic division of AIT into two subtypes likely represents an oversimplification. First, as discussed further below, many patients cannot be readily classified into one of the two AIT subtypes. Secondly, once classified as having type 1 or type 2 AIT, patients often fail to respond to therapy specifically directed to that subtype. Finally, findings of responsiveness in patients with type 2 AIT to measures not typically useful in destructive thyroiditis, such as perchlorate and oral cholecystographic agents, cannot be adequately explained on the basis of the current classification system, although spontaneous resolution independent of therapy is one possible explanation.

Diagnosis:

Several methods have been examined to distinguish type 1 from type 2 AIT, but with the possible exception of color flow Doppler study (CFDS), most are considered unreliable. For example, the T3-to-T4 ratio, which tends to be higher in patients with autonomous thyroid glands than in those with destructive thyroiditis, is not helpful in this instance because of amiodarone-associated inhibition of T4 monodeiodination. Further, features historically used to distinguish the subtypes, such as antibodies against thyroid peroxidase and the presence of thyroid nodules in patients with type 1 AIT, may actually occur with both subtypes, given the prevalence of these abnormalities in the general population. Interleukin-6 levels and RAIU values, once promoted as useful for distinguishing between subtypes, actually overlap extensively between the two subtypes and are therefore also not useful. Several modern series of patients with AIT make no attempt to classify patients into type 1 or type 2 disease.

Several studies have shown that increased vascularity on CFDS may be seen in patients with type 1, but not type 2 AIT. Two studies showed a clear separation into type 1 and type 2 AIT, allowing successful application of targeted therapy. However, CFDS is not universally useful. Recently, sestamibi uptake by the thyroid, which is diminished with thyroiditis, has been applied for distinguishing AIT subtypes with preliminarily promising results.

Onset of thyrotoxicosis:

A recent retrospective report including 200 AIT patients found that the onset of thyrotoxicosis was significantly earlier in type 1 (median 3.5 months, range 1–61 months) than type 2 (median 30 months, range 1–95 months; p < 0.001). Since 80% of type 1 patients in this study had autonomous thyroid nodules or TMNG, it is not unexpected that iodine-induced thyrotoxicosis occurred early in the course of amiodarone therapy. However, based on these data, a patient with late onset of AIT in whom GD has been excluded is more likely to have type 2 AIT. Another observation reported in this study is the development of AIT following amiodarone discontinuation. Nineteen percent of patients developed AIT a mean of 5.5 months after the drug was stopped, 36 of whom had type 2 AIT.

Monotherapy:

Patients who are clinically stable and have definite evidence supporting a distinct subtype of overt AIT may be tried on appropriate monotherapy. When identified with certainty, type 1 AIT is best treated with methimazole to prevent new hormone synthesis and rarely with added potassium perchlorate (250 mg four times daily; not available in the United States). Type 2 AIT is better treated with anti-inflammatory therapy such as prednisone, with improvement occasionally seen as early as 1 week, and usually within a few weeks. As noted above, some patients with mild type 2 AIT (approximately 20%) resolve spontaneously without stopping amiodarone or administering corticosteroids.

Sequential therapy:

Most series of patients with AIT contain cases in which sequential therapy for both subtypes was required before resolution of AIT occurred. These patients are frequently referred to as having “mixed” types of AIT. Patients are often reclassified retrospectively from type 1 to type 2 AIT based on a positive response to corticosteroid therapy or after an outcome of permanent hypothyroidism, both of which would be unlikely in iodine-induced thyrotoxicosis. Patients recovering from apparent type 2 AIT should be monitored for permanent hypothyroidism, which appears to occur more often with AIT than with subacute thyroiditis.

Combined Therapy:

Importantly, individuals with moderate thyrotoxicosis and compromised cardiac status should be considered for initial combined therapy rather than sequential empiric therapy. Some centers recommend starting combined therapy with ATDs and corticosteroids at the time of initial AIT diagnosis, and between 16%-25% of surveyed thyroidologists prefer combination ATD and corticosteroid therapy for patients with apparent type 2 AIT. A rapid response to combined corticosteroid and ATD therapy is believed to favor type 2 AIT and allows a reduction in ATDs, although some patients with type 2 AIT have a prolonged course, particularly those with larger thyroids or worse thyrotoxicosis at the time of diagnosis.

Technical remarks: The suggested starting dose of methimazole in this setting is 40 mg once daily until the patient is euthyroid (generally 3–6 months). If high doses of MMI continue to be required, splitting the dose may be more effective. The suggested dose of corticosteroids in this setting is equivalent to 40 mg prednisone given once daily for 2–4 weeks, followed by a gradual taper over 2–3 months, based on the patient's clinical response.

Surgery:

Patients with AIT who fail to respond to medical therapy should be offered thyroidectomy before they become excessively debilitated from inadequately controlled thyrotoxicosis. The patient should be counseled that while thyroidectomy in this setting carries with it significant morbidity and a high mortality rate (9%), delay or deferral of surgery imparts an even higher risk of death. Thyroidectomy done under regional anesthesia when available may be preferred for very ill patients. Several surgical series involving patients with AIT have now been published, with generally favorable results. Patients in whom amiodarone was stopped during an episode of AIT should be considered for definitive therapy with RAI or surgery in order to facilitate reintroduction of amiodarone without concerns about recurrent AIT.