**3. Major sources of increased iodine exposure: iodine supplementation, dietary iodine, iodine-containing contrast media, amiodarone, and the clinical forms of amiodarone-induced thyrotoxicosis**

#### **3.1 Iodine supplementation**

The assessment of iodine deficiency can be accomplished by assessing the prevalence and severity of goiter, by testing the excretion of iodine in urine, and by determining hormonal levels (e.g., TSH, FT4). When used alone, neither of these are sufficiently sensitive and specific to measure iodine deficiency of a population, but urinary iodine remains the index of choice in the monitoring of iodine supplementation programmes. The most successful method of intervention for iodine deficiency control is salt iodization, iodine being added to salt as potassium iodide (KI), potassium iodate (KIO3), or sodium iodide (NaI). Due to the high prevalence of hypertension and cardiovascular diseases, many countries proposed to promote the reduction of salt intake to 5 g/day (<2 g of sodium), so complementary measures are needed in order to tackle iodine deficiency [20]. But iodine also binds to fatty acids, so iodine oil can also be given orally or intravenously to severely iodine-deficient patients in the short term. Nascent iodine is like the precursor form of iodine, which converts into thyroid hormones. The human body can recognize and assimilate this form more easily than potassium salt. Lugol's solution is a widely used commercial iodine source, which contains elemental iodine and potassium iodide also. If someone consumes high quantities of iodine-rich foods (e.g., marine food, kelp), the use of iodized salt or iodinated water may increase iodine levels above the safe upper level as recommended by WHO. Individuals, who consume large amounts of seaweed regularly, are also exposed to the risk of iodine-induced hyperthyroidism [21, 22]. Several reports are available describing diet-induced thyrotoxicosis in patients consuming seaweed-containing foods or beverages [23]. Risk factors for iodineinduced hyperthyroidism include nontoxic or diffuse nodular goiter, latent Graves' disease, and long-standing iodine deficiency [24].

#### **3.2 Dietary supplements**

Most dietary supplements, as well as food and water, contains iodine as salts: sodium iodide, sodium iodate, potassium iodide, and potassium iodate. Different solid dosage forms of potassium iodide are available, but around 20% is assimilated from inorganic forms of iodine into the body [25]. Iodine is also present in most multivitamin/mineral supplements. Some case reports described that previously


#### **Table 1.**

*Commercially available nutritional supplements with iodine content exceeding the daily intake recommended by WHO (RDA—recommended daily allowances).*

euthyroid patients taking nutritional supplements developed iodine-induced hyperthyroidism [26–28]. The iodine content of dietary supplements shows high variability; some supplements may contain up to 160-fold of the recommended daily intake (**Table 1**). Short-term increase of basal and poststimulation TSH was described even in euthyroid patients administering dietary supplements with kelp [29, 30].

#### **3.3 Iodine-containing contrast media**

Iodinated contrast media (ICM) is given for computed tomography (CT), angiography, myelography, and arthrogram. The route of administration could be systemic as i.v, i.a., oral, rectal, and local. The pharmacokinetics of all currently available ICMs is similar. The half-life of ICM in normal renal function subjects is approximately 2 hours. Thus, approximately 20 hours are required for the total excretion of the administered ICM [31]. Referring to their iodine content and osmolarity, the contrast media are divided into ionic ICM with high osmolarity (1500–2000 mOsm/kg) or nonionic ICM with low and iso-osmolarity (600–1000 mOsm/kg). A list of iodinated contrast agents available in Romania and their molecular properties can be found in **Table 2**.

The safety profile of the systemic administered nonionic low- or iso-osmolar contrast currently in use is 5- to 10-fold better than the ionic high-osmolar agents [32, 33]. The ratio of iodine atoms to the number of contrast particles in lowosmolar solution is higher than compared with high osmolar ICM and hence have a greater concentration of iodine than the high osmolar [32]. In both low and high osmolar ICM, the iodine content is far greater than the recommended daily allowance. Patients generally are given 50 and 100 mL of contrast per CT scan; however, it is essential to know that not all CT scans require contrast media administration (see **Table 3**) [31, 33–35].

Higher doses of ICM may be required for invasive procedures such as cardiac catheterization. Typical doses for CT scans provide 2500–5000 μg of bioavailable free iodine and 15–37 g of total iodine [36]. Nonbioavailable iodine may be liberated to free iodide, particularly with increased half-times in the body (i.e., impaired kidney function) [35, 36]. After ICM administration, iodine deposits remain elevated for up to 4–8 weeks in patients with healthy thyroid. The urinary iodine excretion increased by 300–400% from baseline to peak levels after 1.1 week and normalized by 5.2 weeks following ICM administration [37].

After exposure to the iodine-containing contrast agent, the most rapid (hours to days) effect of pharmacologic doses of iodine is the Wolff-Chaikoff effect. The

**63**

**Table 3.**

*Prevention and Treatment of Iodine-Induced Thyrotoxicosis*

**Nonionic ICM Iodine content,** 

Ethiodized oil 480

Head Neoplasm, meningitis, encephalitis, focal

angiography

Cervical Cervical mass or lymphadenopathy, suspected

Cardiothoracic Heart and thoracic vessels, trauma, staging primary thoracic neoplasms

gynecologic indications

Musculoskeletal Evaluation of soft tissue masses and suspected

CT angiography Evaluating the lumen of an artery, vein, or a

active bleeding

*Indications of contrast enhancement in CT imaging.*

Abdominopelvic Virtually all other gastrointestinal,

*The iodine content of nonionic iodinated contrast media (ICM) and their molecular properties.*

neurologic deficits, skull base disorders, orbital and vision disorders, pituitary imaging, complicated sinonasal disease, seizures, cerebral

tumor or infection, abnormalities of cranial nerves X, XI, and XII, brachial plexopathy

hepatopancreaticobiliary, genitourinary,

septic arthritis or infected prostheses

pseudoaneurysm and to assess for end-organ ischemia outside the brain or lung to detect

**CT type Contrast indicated Contrast not indicated**

Iobitridol 300, 350 Low Iodixanol 270, 320 Low Iohexol 240, 300, 350 Low Iomeprol 300, 350, 400 Low Iopamidol 300, 370 Low Iopromide 300, 370 Low Ioversol 240, 300, 320, 350 Low

**mg/mL**

**Osmolarity**

Head trauma, acute stroke, intracranial hemorrhage

Trauma unless arterial injury is a possibility or the mechanism of injury is

Coronary calcium scoring, pulmonary parenchymal evaluation lymph node

Colonography, renal stone evaluation, extraparenchymal

Extremities and spine

Monitoring a known aneurysm for growth or for detection of a hematoma

penetrating

evaluation

lymphoma

mechanism for this acute effect is partially explained by the generation of iodolactones, iodoaldehydes, and/or iodolipids, which inhibit thyroid peroxidase activity, necessary for thyroid hormone synthesis [37]. The decrease of thyroglobulin proteolysis resulting in reduced thyroid hormone secretion also may be contributing to the ICM-induced Wolff-Chaikoff effect. The diminished serum T4 and T3 concentrations temporarily increased the serum concentrations of TSH, in some cases above the normal range. The phenomenon is transient in euthyroid adult patients and does not typically determine permanent hypothyroidism [38].

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

**Watersoluble, nephrotropic X-ray contrast media**

**Non-watersoluble**

**Table 2.**

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


#### **Table 2.**

*Goiter - Causes and Treatment*

Survival shield X-2, Detoxadine®

(nascent iodine)

**Table 1.**

euthyroid patients taking nutritional supplements developed iodine-induced hyperthyroidism [26–28]. The iodine content of dietary supplements shows high variability; some supplements may contain up to 160-fold of the recommended daily intake (**Table 1**). Short-term increase of basal and poststimulation TSH was described even

*Commercially available nutritional supplements with iodine content exceeding the daily intake recommended* 

**serving (μg)**

3000

1950 1300

**% RDA iodine per serving (%)**

16667, 8333, 4167, 2000

in euthyroid patients administering dietary supplements with kelp [29, 30].

**Nutritional supplement Iodine content per** 

Terry Naturally® (Europharma) Tri-Iodine® 25000, 12500, 6250,

Natural Living Iodine Plus-2® 12500 8333

Oradix StemDetox™ 5000 3333

Dr. Mercola Iodine 1500, 500 1000, 333 Life Extension® sea iodine 1000 667

(1500–2000 mOsm/kg) or nonionic ICM with low and iso-osmolarity

their molecular properties can be found in **Table 2**.

by 5.2 weeks following ICM administration [37].

(see **Table 3**) [31, 33–35].

Iodinated contrast media (ICM) is given for computed tomography (CT), angiography, myelography, and arthrogram. The route of administration could be systemic as i.v, i.a., oral, rectal, and local. The pharmacokinetics of all currently available ICMs is similar. The half-life of ICM in normal renal function subjects is approximately 2 hours. Thus, approximately 20 hours are required for the total excretion of the administered ICM [31]. Referring to their iodine content and osmolarity, the contrast media are divided into ionic ICM with high osmolarity

(600–1000 mOsm/kg). A list of iodinated contrast agents available in Romania and

The safety profile of the systemic administered nonionic low- or iso-osmolar contrast currently in use is 5- to 10-fold better than the ionic high-osmolar agents [32, 33]. The ratio of iodine atoms to the number of contrast particles in lowosmolar solution is higher than compared with high osmolar ICM and hence have a greater concentration of iodine than the high osmolar [32]. In both low and high osmolar ICM, the iodine content is far greater than the recommended daily allowance. Patients generally are given 50 and 100 mL of contrast per CT scan; however, it is essential to know that not all CT scans require contrast media administration

Higher doses of ICM may be required for invasive procedures such as cardiac catheterization. Typical doses for CT scans provide 2500–5000 μg of bioavailable free iodine and 15–37 g of total iodine [36]. Nonbioavailable iodine may be liberated to free iodide, particularly with increased half-times in the body (i.e., impaired kidney function) [35, 36]. After ICM administration, iodine deposits remain elevated for up to 4–8 weeks in patients with healthy thyroid. The urinary iodine excretion increased by 300–400% from baseline to peak levels after 1.1 week and normalized

After exposure to the iodine-containing contrast agent, the most rapid (hours to days) effect of pharmacologic doses of iodine is the Wolff-Chaikoff effect. The

**3.3 Iodine-containing contrast media**

*by WHO (RDA—recommended daily allowances).*

**62**

*The iodine content of nonionic iodinated contrast media (ICM) and their molecular properties.*


#### **Table 3.**

*Indications of contrast enhancement in CT imaging.*

mechanism for this acute effect is partially explained by the generation of iodolactones, iodoaldehydes, and/or iodolipids, which inhibit thyroid peroxidase activity, necessary for thyroid hormone synthesis [37]. The decrease of thyroglobulin proteolysis resulting in reduced thyroid hormone secretion also may be contributing to the ICM-induced Wolff-Chaikoff effect. The diminished serum T4 and T3 concentrations temporarily increased the serum concentrations of TSH, in some cases above the normal range. The phenomenon is transient in euthyroid adult patients and does not typically determine permanent hypothyroidism [38].

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

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 may develop 2.1 years after ICM exposure.

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.

#### **3.4 Amiodarone**

#### *3.4.1 Amiodarone pharmacology*

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

**65**

peroxidase titer.

*3.4.3 Risk of thyrotoxicosis after amiodarone administration*

*Prevention and Treatment of Iodine-Induced Thyrotoxicosis*

correlate well with efficacy or with adverse effects [45, 48–50].

metabolite, DEA, contributes to his toxicity. For a therapeutic effect, a plasma concentration between 0.5 and 2.5 μg/mL is required; however, serum levels do not

that are due to iodine and those effects that are intrinsic properties of the drug.

The effects of amiodarone on thyroid function can be divided into those effects

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].

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

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

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

*3.4.2 Amiodarone and the thyroid*

*3.4.2.1 Effects due to iodine*

*3.4.2.2 Intrinsic drug effects*

metabolite, DEA, contributes to his toxicity. For a therapeutic effect, a plasma concentration between 0.5 and 2.5 μg/mL is required; however, serum levels do not correlate well with efficacy or with adverse effects [45, 48–50].
