*3.4.2.1 Effects due to iodine*

*Goiter - Causes and Treatment*

ICM use could lead to thyroid dysfunction, namely to hypo- and hyperthyroidism. Iodine excess-induced hypothyroidism appears when the thyroid fails to escape from the acute Wolff-Chaikoff effect. It occurs in patients with a wide variety of underlying thyroid abnormalities, including Hashimoto's thyroiditis, previously treated Graves' disease, history of thyroid lobectomy, postpartum lymphocytic thyroiditis, interferon therapy, or type 2 amiodarone-induced thyrotoxicosis [12, 39, 40]. Not only the previous thyroid disorder but also the age of the patients is a contributing factor in hypothyroidism development. A systematic review evidenced that hospitalized neonates, especially premature infants exposed to iodinated contrast media, are at increased risk for development of hypothyroidism [41]. It could be hypothesized that hypothyroidism in this case to be partially secondary to an immature thyroid gland and an exaggerated Wolff-Chaikoff effect. Older age patients are also at high risk of developing hypothyroidism after ICM

Patients with one exposure to ICM showed the highest risk of thyroid dysfunction compared with non-ICM exposure and a correlation was still found between the frequency of ICM exposure and the risk of hypothyroidism [42]. Conflicting data appear regarding to the time of onset of hypothyroidism after ICM administration: Rhee et al. [43] showed that the median time interval until the occurrence of hypothyroidism was 1 year, but Kornelius et al. [42] reported that hypothyroidism

ICM-induced hyperthyroidism rarely occurs in individuals without prior thyroid dysfunction. Previously existent thyroid diseases, such as nodular goiter, Graves' disease, and long-standing iodine deficiency followed by thyroid autonomy, were reported to be associated with a higher risk of hyperthyroidism after ICM exposure [4, 13, 24, 36, 42]. The mechanism of ICM-induced hyperthyroidism involves impairment of the acute Wolff-Chaikoff effect due to rapid iodine excess and influx into the thyroid gland. Excess iodine intake will result in transient or permanent hyperthyroidism [13, 24, 42]. Kornelius et al. [42] found in their study a 22% increased risk of hyperthyroidism after ICM administration. Older patients (between 20 and 60 years) presented a more than twofold increased risk of hyperthyroidism compared with younger patients (less than 20 years old). The number of ICM exposures did not increase the risk of hyperthyroidism. It could be hypothesized that the "stunning effect" plays a certain role in hyperthyroidism, involving a diminished absorption of excess iodine in patients with repeated iodine exposure.

Amiodarone is a class III antiarrhythmic agent, having short- and long-term actions on multiple molecular levels [44]. Its molecular structure resembles T3. However, amiodarone can alter thyroid function (inducing both hypo- and hyperthyroidism), which is due to amiodarone's high iodine content and its direct toxic effect on the thyroid follicle cells. Amiodarone is a benzofuran derivative with great lipophilicity, which is extensively distributed in adipose tissue, cardiac and skeletal muscle, liver, lung, and the thyroid. During its liver metabolization, approximately 6 mg of inorganic iodine per 200 mg of amiodarone ingested is released into the systemic circulation [45]. The average iodine content in Romanian diet is approximately 50–75 μg/day [3, 46, 47]. Thus, 6 mg of iodine markedly increases the daily iodine load. Amiodarone elimination from the body occurs with a half-life of approximately 55–100 days. The long half-life of both amiodarone and his active

exposure, as reported in a study including the Asian population [42].

may develop 2.1 years after ICM exposure.

**64**

**3.4 Amiodarone**

*3.4.1 Amiodarone pharmacology*

After chronic amiodarone administration, the thyroid dysfunctions may occur in 5–22% of the patients. Risk factors for the development of thyroid disease include not only treatment duration and cumulative amiodarone dose but also age, gender, pre-existing thyroid pathology, and associated nonthyroid conditions [51–53]. The normal autoregulation process of thyroid prevents normal individuals from becoming hyperthyroid after exposure to the high iodine content substances. When intrathyroidal iodine concentrations reach a critically high level, iodine transport and thyroid hormone synthesis are transiently inhibited until intrathyroidal iodine stores return to physiological levels (see the Wolff-Chaikoff effect). Patients with underlying thyroid pathology, however, have defects in autoregulation of iodine: for example, in autoimmune thyroid disease exists a "fail to escape" from the Wolff-Chaikoff effect. The result is the development of goiter and hypothyroidism in Hashimoto's disease. Patients with areas of autonomous function within a nodular goiter do not autoregulate iodine and the addition of more substrate may result in excessive thyroid hormone synthesis and thyrotoxicosis (see Iod-Basedow) [13, 54, 55].

## *3.4.2.2 Intrinsic drug effects*

Amiodarone inhibits peripheral deiodinase (outer ring 5′-monodeiodination of T4), thus decreasing T3 production and increasing T4 level; reverse T3 (rT3) accumulates since it is not metabolized to T2 [4, 56, 57]; amiodarone and, particularly, the metabolite DEA block T3-receptor binding to nuclear receptors [58] and decrease the expression of some thyroid hormone-related genes [59]; amiodarone may have a direct cytotoxic effect on thyroid follicular structures, which results in a destructive thyroiditis [60]. Martino et al. described marked distortion of thyroid follicle architecture, necrosis, apoptosis, inclusion bodies, lipofuscinogenesis, markedly dilated endoplasmic reticulum, and macrophage infiltration after amiodarone [19]. The role of the pre-existing autoimmune process is widely debated, due to the conflicting results of the retrospective study data [17, 18, 55]. Even if amiodarone does not induce de novo autoimmune thyroid disease, by the direct cytotoxic effect, it may cause the release of pre-existing autoantibodies and thus worsen destructive thyroiditis. In a study [61], it was described that in women the prolonged amiodarone treatment (for over 2 years) increased the antithyroid peroxidase titer.

## *3.4.3 Risk of thyrotoxicosis after amiodarone administration*

Predisposing factors for amiodarone-induced thyrotoxicosis include environmental factors such as dietary iodine (deficiency), as well as intrinsic factors such as pre-existing thyroid pathology. Depending on these factors, a great variability

exists regarding the incidence of amiodarone-induced thyroid dysfunction ranges (5–22%) [51, 52, 62, 63].

Dietary iodine intake affects an individual's risk of amiodarone-induced thyroid dysfunction: in iodine-deficient areas, amiodarone-induced thyrotoxicosis (AIT) appears to be more common than hypothyroidism [64], whereas in iodine-sufficient areas, amiodarone-induced hypothyroidism is more common than hyperthyroidism [19]. The incidence of reported AIT in different studies varies but remains within the range of 5–10% in most studies [51, 52, 63]. As was reported in a previous study from the UK, AIT appears more frequently in men than in women [65], but the time of onset of AIT is unpredictable. It can occur at almost any time throughout the course of amiodarone treatment and last for as long as 6–9 months after treatment withdrawal, almost certainly because of the drug's long half-life and associated iodine load [66]. One study illustrates the importance of the underlying thyroid status near the dietary iodine intake in relation to the risk of developing amiodarone-induced thyroid dysfunction. In Worcester, Massachusetts, an area with iodine sufficiency and a high prevalence of autoimmune thyroid disease, amiodarone was associated with a 2% rate of hyperthyroidism. In contrast, in Pisa, Italy, an area of borderline iodine intake and a high prevalence of nodular goiter, amiodarone was associated with 9.6% rate of hyperthyroidism [67].

The clinical effects of amiodarone on thyroid function in any individual are dependent upon the underlying status of that individual's thyroid gland. In euthyroid individuals receiving amiodarone, acute changes in thyroid function tests include [68, 69]:


After 3–6 months of therapy, a steady state is reached in most patients who were euthyroid at baseline:


Amiodarone may also cause destructive thyroiditis with transient thyrotoxicosis followed by hypothyroidism in patients without underlying thyroid disease [60].

Abnormal thyroid process: in patients with underlying multinodular goiter or latent Graves' disease, hyperthyroidism (increased synthesis of T4 and T3) may occur. The excess iodine from the amiodarone provides increased substrate, resulting in enhanced thyroid hormone production.

**67**

**Table 4.**

*(1994–1998 and 2001–2005).*

**Study period**

*Prevention and Treatment of Iodine-Induced Thyrotoxicosis*

*3.4.4 Clinical forms of amiodarone-induced hyperthyroidism*

Three types of AIT can be distinguished. In type 1 AIT, thyroid hormone synthesis is increased, whereas in type 2 there is an excess release of T4 and T3 from the preformed thyroid hormones, due to destructive thyroiditis. Type 3 AIT is a mixed form, existing an overlapping condition between type 1 and type 2 AIT. These types differ in their pathogenesis, clinical or paraclinical signs, and management [63]. The risk of either type increases with higher cumulative doses or reintroduction

The distribution of AIT by type (1 or 2) varies by geographical region. This is thought to be primarily due to differences in dietary iodine intake. In iodinedeficient regions, as some geographical zones were in Romania before universal salt iodization [3], AIT occurs in approximately 10–12% of patients with type 1 AIT usually predominating [64, 67]. However, the distribution of cases by type may be changing, as illustrated in a report of 215 consecutive patients with AIT seen at a single institution in Italy over 26 years [71]. In 1980 compared with 2006, 2 of 6 (40%) versus 12 of 14 (86%) of new AIT cases were type 2. Possible explanations for this observation include improved dietary iodine intake in the region and the avoidance of amiodarone use in case of previously diagnosed thyroid disease. Our unpublished data from a study conducted in a single institute (Endocrinology Clinic, Târgu Mureș, Romania) in two different periods, which included 5 years, similarly show a moderate increase of type 2 AIT after the introduction of universal

salt iodization (governmental decision no. 586/5 June 2002; see **Table 4**).

scan despite the daily ingestion of 6 mg or more bioavailable iodine [77, 78].

1994–1998 4/7 (57%) 1/7 (14%) 2/7 (29%) 2001–2005 17/38 (45%) 9/38(24%) 12/38 (31%)

*Distribution of AIT types in patients of the Endocrinology Clinic, Târgu Mureș, Romania, in two study periods* 

**Type 1 AIT/total patients Type 2 AIT/total patients Type 3 AIT/total patients**

Clinical signs of AIT are classical thyrotoxicosis symptoms such as unexplained weight loss, proximal myopathy, restlessness, heat intolerance, low-grade fever, or exacerbation of tachyarrhythmia, heart failure, or angina pectoris; however, the adrenergic manifestations of amiodarone-induced hyperthyroidism are often masked because its distinct antiadrenergic properties and impairment of conversion of T4 to T3 [68, 72]. Patients with amiodarone-induced hyperthyroidism have a threefold higher rate of major adverse cardiovascular events (mostly ventricular arrhythmias) compared with euthyroid controls [73]. The presence of severe left ventricular dysfunction, especially in older patients with AIT, may be associated with increased mortality [74]. Differentiating the two types of AIT is critical since therapy differs. However, the distinction may be difficult using clinical criteria, partly because some patients may have a mixture of both mechanisms, presenting the type 3 (type 1 + type 2) AIT. Thyroid function tests (TSH, T4 and T3 plasma levels) do not help to distinguish type 1 AIT (hyperthyroidism) from type 2 AIT (transient thyrotoxicosis). Type 1 AIT appears usually early after amiodarone introduction (3–20 months after exposure) [19, 66, 71]. It is characterized by hyperfunctional thyroid tissue with elevated blood flow on color Doppler [75, 76]. Furthermore, the enlarged or nodular thyroid tissue fixes either on 24-hour 123I-scan or on 99 mTc-SestaMIBI radio isotope

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

of amiodarone [53, 70].

*Goiter - Causes and Treatment*

(5–22%) [51, 52, 62, 63].

hyperthyroidism [67].

month of therapy.

include [68, 69]:

therapy.

euthyroid at baseline:

exists regarding the incidence of amiodarone-induced thyroid dysfunction ranges

Dietary iodine intake affects an individual's risk of amiodarone-induced thyroid dysfunction: in iodine-deficient areas, amiodarone-induced thyrotoxicosis (AIT) appears to be more common than hypothyroidism [64], whereas in iodine-sufficient areas, amiodarone-induced hypothyroidism is more common than hyperthyroidism [19]. The incidence of reported AIT in different studies varies but remains within the range of 5–10% in most studies [51, 52, 63]. As was reported in a previous study from the UK, AIT appears more frequently in men than in women [65], but the time of onset of AIT is unpredictable. It can occur at almost any time throughout the course of amiodarone treatment and last for as long as 6–9 months after treatment withdrawal, almost certainly because of the drug's long half-life and associated iodine load [66]. One study illustrates the importance of the underlying thyroid status near the dietary iodine intake in relation to the risk of developing amiodarone-induced thyroid dysfunction. In Worcester, Massachusetts, an area with iodine sufficiency and a high prevalence of autoimmune thyroid disease, amiodarone was associated with a 2% rate of hyperthyroidism. In contrast, in Pisa, Italy, an area of borderline iodine intake and a high prevalence of nodular goiter, amiodarone was associated with 9.6% rate of

The clinical effects of amiodarone on thyroid function in any individual are dependent upon the underlying status of that individual's thyroid gland. In euthyroid individuals receiving amiodarone, acute changes in thyroid function tests

• Serum total T4 and free T4 concentrations rise by 20–40% during the first

• Serum T3 concentrations decrease by up to 30% within the first few weeks of

• Serum rT3 concentrations increase by 20% soon after the initiation of therapy.

After 3–6 months of therapy, a steady state is reached in most patients who were

• Serum total T4, free T4, and rT3 concentrations remain slightly elevated or in

Amiodarone may also cause destructive thyroiditis with transient thyrotoxicosis followed by hypothyroidism in patients without underlying thyroid disease [60]. Abnormal thyroid process: in patients with underlying multinodular goiter or latent Graves' disease, hyperthyroidism (increased synthesis of T4 and T3) may occur. The excess iodine from the amiodarone provides increased substrate, result-

• Serum TSH concentration usually rises slightly after the initiation of

treatment and may exceed the upper limit of normal.

• Serum T3 concentrations remain in the low normal range.

• Serum TSH concentration normalizes.

ing in enhanced thyroid hormone production.

the upper normal range.

**66**

#### *3.4.4 Clinical forms of amiodarone-induced hyperthyroidism*

Three types of AIT can be distinguished. In type 1 AIT, thyroid hormone synthesis is increased, whereas in type 2 there is an excess release of T4 and T3 from the preformed thyroid hormones, due to destructive thyroiditis. Type 3 AIT is a mixed form, existing an overlapping condition between type 1 and type 2 AIT. These types differ in their pathogenesis, clinical or paraclinical signs, and management [63].

The risk of either type increases with higher cumulative doses or reintroduction of amiodarone [53, 70].

The distribution of AIT by type (1 or 2) varies by geographical region. This is thought to be primarily due to differences in dietary iodine intake. In iodinedeficient regions, as some geographical zones were in Romania before universal salt iodization [3], AIT occurs in approximately 10–12% of patients with type 1 AIT usually predominating [64, 67]. However, the distribution of cases by type may be changing, as illustrated in a report of 215 consecutive patients with AIT seen at a single institution in Italy over 26 years [71]. In 1980 compared with 2006, 2 of 6 (40%) versus 12 of 14 (86%) of new AIT cases were type 2. Possible explanations for this observation include improved dietary iodine intake in the region and the avoidance of amiodarone use in case of previously diagnosed thyroid disease. Our unpublished data from a study conducted in a single institute (Endocrinology Clinic, Târgu Mureș, Romania) in two different periods, which included 5 years, similarly show a moderate increase of type 2 AIT after the introduction of universal salt iodization (governmental decision no. 586/5 June 2002; see **Table 4**).

Clinical signs of AIT are classical thyrotoxicosis symptoms such as unexplained weight loss, proximal myopathy, restlessness, heat intolerance, low-grade fever, or exacerbation of tachyarrhythmia, heart failure, or angina pectoris; however, the adrenergic manifestations of amiodarone-induced hyperthyroidism are often masked because its distinct antiadrenergic properties and impairment of conversion of T4 to T3 [68, 72]. Patients with amiodarone-induced hyperthyroidism have a threefold higher rate of major adverse cardiovascular events (mostly ventricular arrhythmias) compared with euthyroid controls [73]. The presence of severe left ventricular dysfunction, especially in older patients with AIT, may be associated with increased mortality [74].

Differentiating the two types of AIT is critical since therapy differs. However, the distinction may be difficult using clinical criteria, partly because some patients may have a mixture of both mechanisms, presenting the type 3 (type 1 + type 2) AIT. Thyroid function tests (TSH, T4 and T3 plasma levels) do not help to distinguish type 1 AIT (hyperthyroidism) from type 2 AIT (transient thyrotoxicosis).

Type 1 AIT appears usually early after amiodarone introduction (3–20 months after exposure) [19, 66, 71]. It is characterized by hyperfunctional thyroid tissue with elevated blood flow on color Doppler [75, 76]. Furthermore, the enlarged or nodular thyroid tissue fixes either on 24-hour 123I-scan or on 99 mTc-SestaMIBI radio isotope scan despite the daily ingestion of 6 mg or more bioavailable iodine [77, 78].


**Table 4.**

*Distribution of AIT types in patients of the Endocrinology Clinic, Târgu Mureș, Romania, in two study periods (1994–1998 and 2001–2005).*


#### **Table 5.**

*Characteristics of type 1 and type 2 amiodarone-induced thyrotoxicosis (AIT—amiodarone-induced 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 AIT are presented in **Table 5**.

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].
