[U] How should overt drug-induced thyrotoxicosis be managed?

[U] How should overt drug-induced thyrotoxicosis be managed?

Although numerous medications may affect thyroid function or cause abnormal thyroid testing results (333), relatively few of these actually cause thyrotoxicosis. For those that do, three mechanisms are involved: (i) iodine-induced thyrotoxicosis; (ii) destructive thyroiditis; and (iii) induction of thyroid autoimmunity (GD or painless thyroiditis). More than one pathway has been identified for several medications. A summary of drugs causing thyrotoxicosis, the proposed mechanism(s), approximate timing of onset, duration, and therapeutic options is provided in Table 13.

[U1] Iodine-induced hyperthyroidism

Iodine-induced hyperthyroidism is believed to occur in patients with underlying thyroid autonomy, especially those living in areas with mild-to-moderate iodine deficiency. In one study of 788 patients undergoing cardiac angiography, none of the 27 with a suppressed TSH at baseline developed overt hyperthyroidism, and only 2 patients with no apparent risk factors became hyperthyroid (334). A retrospective study found that 7 of 28 elderly patients with hyperthyroidism had a history of recent iodine exposure (335), and a prospective study found that 2 of 73 patients developed hyperthyroidism after radiographic contrast (336). High iodine intake may also be followed by relapse of hyperthyroidism in patients with previous GD who are in remission after ATD therapy. In a small study of 10 patients, 2 had relapse of overt hyperthyroidism, and 2 developed SH after stopping high iodine intake (337).

  • RECOMMENDATION 88
    Beta-adrenergic blocking agents alone or in combination with methimazole should be used to treat overt iodine-induced hyperthyroidism. 1/+00

Iodine-induced hyperthyroidism (the Jod-Basedow phenomenon) is usually self-limited, lasting 1–18 months (335,338). Treatment includes avoidance of additional iodine and administration of beta-blockers alone or with ATDs, depending on the severity of hyperthyroidism. Radioactive iodine is not an option until the iodine load has been cleared, which may take several months depending on the length of exposure to iodine. Surgery may be used in patients allergic or resistant to antithyroid drugs.

TABLE 13. CAUSES OF DRUG-ASSOCIATED THYROTOXICOSIS

Drug

Mechanism(s)

Timing of onset following initiation of the drug

Therapy

Amiodarone

Iodine induced (type 1)

Months to Years

Supportive carea

Antithyroid drugs; perchlorateb

Surgery

Thyroiditis (type 2)

Often > 1 year

Supportive carea

Corticosteroids

Surgery

Lithium

Painless thyroiditis

Often > 1 year

Supportive carea

Antithyroid drugs

Interferon α

Painless thyroiditis; GD

Months

Supportive carea

Antithyroid drugs and/or radioactive iodine (GD only)

Interleukin-2

Painless thyroiditis; GD

Months

Supportive carea

 

 

 

Antithyroid drugs and/or radioactive iodine (GD only)

Iodinated contrast

Underlying thyroid autonomy

Weeks to months

Antithyroid drugs

Radioactive iodine, early

Destruction

1–4 weeks

Observation; if severe, administer corticosteroids

Radioactive iodine for TMNG, late

GD

3–6 months

Antithyroid drugs

Repeat radioactive iodine

Surgery

aSupportive care may include beta-adrenergic blockers during the thyrotoxic stage and levothyroxine if hypothyroidism develops.
bNot available in the United States.

Technical remarks: Dosing of MMI for iodine-induced thyrotoxicosis is 20–40mg daily, given either as a daily or twice daily dosing. There may be relative resistance to antithyroid drugs in patients with iodine-induced hyperthyroidism. Urinary iodine may be monitored to assess the rate of clearance of the iodine load.

[U2] Cytokine-induced thyrotoxicosis

  • RECOMMENDATION 89
    Patients who develop thyrotoxicosis during therapy with interferon-α or interleukin-2 should be evaluated to determine etiology (thyroiditis vs. GD) and treated accordingly. 1/+00
Interferon-α (IFN-α)- and interleukin-2-treated patients are at increased risk for developing thyrotoxicosis, especially those with pre-existing thyroid autoimmunity. Thyrotoxicosis in this setting can be due to either painless thyroiditis or GD (339). In a literature review, 69% of patients with IFN-α-associated thyrotoxicosis were deemed to have GD as the etiology (340).

A meta-analysis found that 46% of patients with positive pretreatment thyroid peroxidase antibodies (TPO Ab) developed thyroid dysfunction after IFN-α therapy for hepatitis C infection, compared to only 5% of those with negative antibodies (341).

[U3] Amiodarone-induced thyrotoxicosis

  • RECOMMENDATION 90
    We suggest monitoring thyroid function tests before and at 1 and 3 months following the initiation of amiodarone therapy, and at 3–6 month intervals thereafter. 2/+00

Amiodarone is a drug 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 (18,342,343) and in up to 10% in iodine-deficient areas, such as parts of Europe (344).

  • RECOMMENDATION 91
    We suggest testing to distinguish type 1 (iodine-induced) from type 2 (thyroiditis) varieties of amiodarone-induced thyrotoxicosis. 1/+00

Two basic mechanisms have been identified in the development of AIT, including an iodine-induced form of hyperthyroidism (type 1 AIT, or goitrous AIT) due to the high iodine content of amiodarone (37% by molecular weight), and type 2 AIT, which is a destructive thyroiditis. Type 1 AIT tends to occur in patients with underlying thyroid autonomy in a nodular goiter, but the term is also used when amiodarone use is associated with GD, whereas type 2 AIT is due to a direct destructive effect of amiodarone on thyrocytes. RAIU is occasionally measurable in type 1 AIT (particularly in regions of iodine deficiency), but not in type 2 AIT. Increased vascular flow on color-flow Doppler ultrasound study may be seen in patients with type 1 AIT, but not type 2 AIT. Measurement of serum interleukin-6 levels does not reliably distinguish between the two types of AIT (345). The distinction between type 1 AIT and type 2 AIT is not always clear, and some patients have elements of both types (18).

  • RECOMMENDATION 92
    The decision to stop amiodarone in the setting of thyrotoxicosis should be determined on an individual basis in consultation with a cardiologist, based on the presence or absence of effective alternative antiarrhythmic therapy. 1/+00

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, and (iii) amiodarone may have T3-antagonistic properties at the cardiac level and inhibit T4 to T3 conversion, such that withdrawal may actually aggravate cardiac manifestations of thyrotoxicosis (18,342). In addition, type 2 AIT typically resolves even if amiodarone therapy is continued.

  • RECOMMENDATION 93
    Methimazole should be used to treat type 1 amiodarone-induced thyrotoxicosis and corticosteroids should be used to treat type 2 amiodarone-induced thyrotoxicosis. 1/+00
     
  • RECOMMENDATION 94
    Combined antithyroid drug and anti-inflammatory therapy should be used to treat patients with overt amiodarone- induced thyrotoxicosis who fail to respond to single modality therapy, and patients in whom the type of disease cannot be unequivocally determined. 1/+00

Type 1 AIT is best treated with MMI (40mg daily) to prevent new hormone synthesis and, rarely, with added potassium perchlorate (250mg four times daily; not available in the United States) (346). Type 2 AIT is better treated with antiinflammatory therapy such as prednisone (40mg daily) with improvement occasionally seen as early as 1 week, and usually within a few weeks (346).

In one study, 20 patients with AIT, including both type 1 and type 2 subtypes, were treated with perchlorate for 1 month to inhibit thyroid iodide transport, resulting in euthyroidism in 12 patients (7 with type 1 AIT and 5 with type 2 AIT). Corticosteroids were then given to the eight nonresponders, and euthyroidism was achieved in all after an average of approximately 6 weeks (347). When a clear distinction between type 1 AIT and type 2 AIT is not possible, a combination of prednisone and methimazole should be used until the patient has stabilized, at which time the drugs may be individually tapered. Thyroidectomy may be required in patients who prove refractory to medical therapy (348).

Technical remarks: The suggested starting dose of MMI in this setting is 40mg 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 40mg prednisone given once daily for 2–4 weeks, followed by a gradual taper over 2–3 months, based on the patient's clinical response.

  • RECOMMENDATION 95
    Patients with amiodarone-induced thyrotoxicosis who are unresponsive to aggressive medical therapy with methimazole and corticosteroids should undergo thyroidectomy. 1/+00

Technical remarks: 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 (348). Thyroidectomy done under regional anesthesia when available may be preferred (18,349).