**4. Prevention and treatment of iodine-induced thyrotoxicosis**

Preventing therapy for iodine-induced hyperthyroidism is not generally recommended. However, older patients with known multinodular goiter and/or subclinical hyperthyroidism should be told of the risk for iodine-induced hyperthyroidism, and alternatives to contrast-enhanced CT scanning should be considered when appropriate (e.g., noncontrast CT, magnetic resonance imaging). Iodine-induced hyperthyroidism is particularly important in geriatric patients for several reasons: (1) the prevalence of thyroid nodular disease is higher in older patients than in younger patients, (2) the hyperthyroidism may be more difficult to detect clinically, (3) apathetic hyperthyroidism often being present, and (4) older adults more often have underlying heart disease [21]. In high-risk patients (older, history of multinodular goiter with autonomy), treatment with a thioamide or perchlorate prior to the administration of an iodine load may blunt or prevent the induction of hyperthyroidism [82, 83]. However, there are insufficient randomized trial data to support the use of thioamides or perchlorate. Routine measurement of thyroid function tests (TSH, and if low, free T4 and T3) in older patients after exposure to iodinated radiographic contrast agents is favored by some experts, particularly since the symptoms of hyperthyroidism in older adults may be atypical [84–86].

Iodine-induced hyperthyroidism (iodine content supplements and dietary nutrients, ICM, type 1 AIT) is usually self-limited (lasting 1–18 months) if the source of iodine is discontinued. The American Thyroid Association (ATA) [87] and European Thyroid Association (ETA) recommendations [40] as initial therapy for patients with iodine-induced hyperthyroidism are discontinuation of iodine (except for amiodarone, which could be continued in type 2 AIT), avoidance of further exposure, and administration of a beta-adrenergic antagonist drug (assuming there

**69**

*Prevention and Treatment of Iodine-Induced Thyrotoxicosis*

are no contraindications to its use) to minimize the manifestations of the overactive thyroid. Thyroid tests (TSH, free T4, total T3) should be measured initially at 4- to 6-week interval and then less frequently (TSH and free T4 every 3 months) depending upon the results of prior testing. Beta blockers can be tapered and discontinued

Due to the lack of sufficient evidence, there is no consensus regarding the decision to continue or stop amiodarone in patients with type 1 AIT. The decision should be individualized taking into account the risks of patients and taken jointly by cardiologists and endocrinologist [40]. Amiodarone should be continued in critically ill patients with life-threatening cardiac disorders [88]. When deciding whether to discontinue amiodarone, the following should be considered: amiodarone may be necessary to control a life-threatening arrhythmia; since the half-life of elimination from the body is prolonged, there is no immediate benefit to stopping amiodarone; amiodarone appears to ameliorate hyperthyroidism by blocking T4 to T3 conversion, beta-adrenergic receptors, and possibly T3 receptors. Stopping amiodarone might actually exacerbate hyperthyroid symptoms and signs.

In case of amiodarone withdrawal, after the restoration of euthyroidism and normalization of urinary iodine excretion (generally 6–12 months), radioactive iodine (RAI) therapy can be performed. Recombinant human TSH (rhTSH) administration increases the sensibility of the thyroid gland to RAI therapy. If RAI administration is contraindicated, total thyroidectomy should be considered for definitive treatment of the underlying thyroid disease [40]. In the absence of the thyroid gland, amiodarone reintroduction, when necessary, could be safe. In the case of the thyroid gland is conserved, the recurrence rate of type 1 AIT after amiodarone reintroduction is 9% [89]. As ETA suggested, emergency thyroidectomy in severe cardiac patients may be required not only in type 1 but also in all types of AIT. Prior to thyroid surgery, plasmapheresis is able to remove the excess of thyroid hormones [40]. It was reported in a study, including seven patients with AIT, that iopanoic acid short-course adminis-

tration prior surgery permitted a safe and uneventful thyroidectomy [90].

Thioamides (thiamazole, carbimazole, propylthiouracil) are effective in older patients with underlying heart disease having severe and prolonged (>1 month) hyperthyroid symptoms, except the emergency situations. All thioamides are blocking thyroid hormones synthesis, propylthiouracil having an additional inhibiting effect on T4–T3 transformation. ATA recommended, the starting dose of thiamazole, to be 10–20 mg once daily because of its long duration of action, allowing for once-daily dosing, more rapid efficacy, and lower incidence of side effects [87]. ETA recommended very high daily doses of the drug (40–60 mg/day of thiamazole) for a more extended time, considering that in type 1 AIT the iodine-enriched thyroid gland of patients is less responsive to thioamides [40]. Carbimazole, the prodrug of thiamazole, is an alternative choice of treatment, available in some European countries, but not in Romania. Due to the teratogenicity of thiamazole, propylthiouracil (not currently available in Romania) can be used in the first trimester of pregnancy [68]. To increase the sensitivity and response of the thyroid gland to thioamides, potassium or sodium perchlorate (not available in Romania) has been used. Perchlorate reduces thyroid iodine uptake by sodium/iodide symporter inhibiting action and discharge iodine from the thyroid, but toxic effects are limiting its use. To minimize the nephro- and medullotoxicity of the drug, doses not exceeding 4 × 250 mg/day and a shorter period than 4–6 weeks were used [40, 87, 91]. Thyroid function should be assessed after 4 weeks by measurement of serum TSH, free T4, and T3. The dose of thiamazole is then tapered with the goal of maintaining a euthyroid state. Thereafter, thyroid function tests (TSH, free T4) should be measured every 3 months. Many patients with underlying autonomous nodular thyroid disease are able to taper and discontinue thiamazole within 6–12 months. In

*DOI: http://dx.doi.org/10.5772/intechopen.89615*

after thyroid tests return to normal.

#### *Prevention and Treatment of Iodine-Induced Thyrotoxicosis DOI: http://dx.doi.org/10.5772/intechopen.89615*

*Goiter - Causes and Treatment*

AIT are presented in **Table 5**.

Radio iodine uptake (I123-Scan)/

SestaMIBI-Scan

**Table 5.**

*thyrotoxicosis).*

Type 2 AIT is a destructive thyroiditis which onset time is after 20–30 months of amiodarone introduction. It appears in patients with apparently normal thyroid morphology and is due to the massive release of thyroid hormones. The mechanism is similar to that of subacute thyroiditis, but the thyrotoxicosis is usually less severe and could spontaneously resolve in some cases [79]. The features of the two types of

Pathophysiology Iodine overload Destruction/inflammation

vascularity

*Characteristics of type 1 and type 2 amiodarone-induced thyrotoxicosis (AIT—amiodarone-induced* 

Pre-existing thyroid disease Yes No

Color flow Doppler Increased or

Ultrasound findings Goiter/nodule(s) Normal

**Type 1 AIT Type 2 AIT**

Normal or increased Absent

Reduced or absent vascularity

However, interpretations of color flow Doppler sonogram in amiodarone-associated hyperthyroidism require an experienced sonographer, and other markers for differential diagnosis were also sought. In two studies, serum interleukin-6 concentrations were higher in patients with type 2 AIT [80, 81]. In a third study, interleukin-6 concentrations were not useful for distinguishing type 1 from type 2 AIT [76].

Preventing therapy for iodine-induced hyperthyroidism is not generally recommended. However, older patients with known multinodular goiter and/or subclinical hyperthyroidism should be told of the risk for iodine-induced hyperthyroidism, and alternatives to contrast-enhanced CT scanning should be considered when appropriate (e.g., noncontrast CT, magnetic resonance imaging). Iodine-induced hyperthyroidism is particularly important in geriatric patients for several reasons: (1) the prevalence of thyroid nodular disease is higher in older patients than in younger patients, (2) the hyperthyroidism may be more difficult to detect clinically, (3) apathetic hyperthyroidism often being present, and (4) older adults more often have underlying heart disease [21]. In high-risk patients (older, history of multinodular goiter with autonomy), treatment with a thioamide or perchlorate prior to the administration of an iodine load may blunt or prevent the induction of hyperthyroidism [82, 83]. However, there are insufficient randomized trial data to support the use of thioamides or perchlorate. Routine measurement of thyroid function tests (TSH, and if low, free T4 and T3) in older patients after exposure to iodinated radiographic contrast agents is favored by some experts, particularly since

**4. Prevention and treatment of iodine-induced thyrotoxicosis**

the symptoms of hyperthyroidism in older adults may be atypical [84–86]. Iodine-induced hyperthyroidism (iodine content supplements and dietary nutrients, ICM, type 1 AIT) is usually self-limited (lasting 1–18 months) if the source of iodine is discontinued. The American Thyroid Association (ATA) [87] and European Thyroid Association (ETA) recommendations [40] as initial therapy for patients with iodine-induced hyperthyroidism are discontinuation of iodine (except for amiodarone, which could be continued in type 2 AIT), avoidance of further exposure, and administration of a beta-adrenergic antagonist drug (assuming there

**68**

are no contraindications to its use) to minimize the manifestations of the overactive thyroid. Thyroid tests (TSH, free T4, total T3) should be measured initially at 4- to 6-week interval and then less frequently (TSH and free T4 every 3 months) depending upon the results of prior testing. Beta blockers can be tapered and discontinued after thyroid tests return to normal.

Due to the lack of sufficient evidence, there is no consensus regarding the decision to continue or stop amiodarone in patients with type 1 AIT. The decision should be individualized taking into account the risks of patients and taken jointly by cardiologists and endocrinologist [40]. Amiodarone should be continued in critically ill patients with life-threatening cardiac disorders [88]. When deciding whether to discontinue amiodarone, the following should be considered: amiodarone may be necessary to control a life-threatening arrhythmia; since the half-life of elimination from the body is prolonged, there is no immediate benefit to stopping amiodarone; amiodarone appears to ameliorate hyperthyroidism by blocking T4 to T3 conversion, beta-adrenergic receptors, and possibly T3 receptors. Stopping amiodarone might actually exacerbate hyperthyroid symptoms and signs.

In case of amiodarone withdrawal, after the restoration of euthyroidism and normalization of urinary iodine excretion (generally 6–12 months), radioactive iodine (RAI) therapy can be performed. Recombinant human TSH (rhTSH) administration increases the sensibility of the thyroid gland to RAI therapy. If RAI administration is contraindicated, total thyroidectomy should be considered for definitive treatment of the underlying thyroid disease [40]. In the absence of the thyroid gland, amiodarone reintroduction, when necessary, could be safe. In the case of the thyroid gland is conserved, the recurrence rate of type 1 AIT after amiodarone reintroduction is 9% [89]. As ETA suggested, emergency thyroidectomy in severe cardiac patients may be required not only in type 1 but also in all types of AIT. Prior to thyroid surgery, plasmapheresis is able to remove the excess of thyroid hormones [40]. It was reported in a study, including seven patients with AIT, that iopanoic acid short-course administration prior surgery permitted a safe and uneventful thyroidectomy [90].

Thioamides (thiamazole, carbimazole, propylthiouracil) are effective in older patients with underlying heart disease having severe and prolonged (>1 month) hyperthyroid symptoms, except the emergency situations. All thioamides are blocking thyroid hormones synthesis, propylthiouracil having an additional inhibiting effect on T4–T3 transformation. ATA recommended, the starting dose of thiamazole, to be 10–20 mg once daily because of its long duration of action, allowing for once-daily dosing, more rapid efficacy, and lower incidence of side effects [87]. ETA recommended very high daily doses of the drug (40–60 mg/day of thiamazole) for a more extended time, considering that in type 1 AIT the iodine-enriched thyroid gland of patients is less responsive to thioamides [40]. Carbimazole, the prodrug of thiamazole, is an alternative choice of treatment, available in some European countries, but not in Romania. Due to the teratogenicity of thiamazole, propylthiouracil (not currently available in Romania) can be used in the first trimester of pregnancy [68]. To increase the sensitivity and response of the thyroid gland to thioamides, potassium or sodium perchlorate (not available in Romania) has been used. Perchlorate reduces thyroid iodine uptake by sodium/iodide symporter inhibiting action and discharge iodine from the thyroid, but toxic effects are limiting its use. To minimize the nephro- and medullotoxicity of the drug, doses not exceeding 4 × 250 mg/day and a shorter period than 4–6 weeks were used [40, 87, 91]. Thyroid function should be assessed after 4 weeks by measurement of serum TSH, free T4, and T3. The dose of thiamazole is then tapered with the goal of maintaining a euthyroid state. Thereafter, thyroid function tests (TSH, free T4) should be measured every 3 months. Many patients with underlying autonomous nodular thyroid disease are able to taper and discontinue thiamazole within 6–12 months. In

case of thioamide allergy, lithium is used to control the hyperthyroidism temporarily [91, 92], but it has a narrow therapeutic range, produces nephrotoxicity, and its efficacy is not well documented. Therefore, it is not recommended by ETA for the type 1 AIT treatment [40]. However, it was reported that lithium-associated rhTSH administration increases RAI sensibility of the thyroid follicles in AIT [93].

After resolution of the acute episode of iodine-induced hyperthyroidism, treatment of the underlying thyroid disease should be addressed. For patients with underlying Graves' disease, treatment options include continuing thiamazole, radioiodine ablation, or surgery. Patients with underlying autonomous adenoma or multinodular goiter who return to euthyroidism after discontinuation of iodine do not necessarily require definitive treatment. However, these patients are at risk for recurrent hyperthyroidism if given iodine again.

Type 2 AIT generally is self-limited and amiodarone is not necessary to discontinue. When the efficacy of non-thioamide type antithyroid drugs to restore euthyroid state was compared, the best results were obtained with 30 mg oral prednisone therapy. The rate of achievement of euthyroid state was 100% when glucocorticoids were used versus 71% obtained after perchlorate administration [94]. ETA recommendation, for this reason, is oral glucocorticoids as the first-line treatment for type 2 AIT. In patients in whom a mixed form of AIT is suspected, thioamides together with glucocorticoids should be given initially, or glucocorticoids should be added after a period of 4–6 weeks of inadequate response [40]. In addition, it must be noted that i.v. administration of glucocorticoids (hydrocortisone, dexamethasone) has crucial benefits (inhibiting T4 transformation to T3) in thyroid storm and preoperative management of any type of thyrotoxicosis [91]. It was reported that glucocorticoid therapy (oral prednisone) restored the normal thyroid function and shrink goiter, preventing surgery, in a patient diagnosed with iodine containing supplement-induced hyperthyroidism [95].
