Amiodarone-induced thyroid dysfunction: clinical guidelines

List of Abbreviations

Terms and Definitions

Amiodarone** (Am**) – a Class III antiarrhythmic drug that exhibits electrophysiological effects characteristic of all four classes of antiarrhythmics (C01: Cardiac therapy), with a predominant Class III effect (prolongation of the cardiomyocyte action potential).

Desethylamiodarone (DEA) – an active metabolite of Am**, which exerts a direct dose-dependent cytotoxic effect on the follicular cells of the thyroid gland (TG).

Amiodarone-induced thyroid dysfunction – thyroid dysfunction developing during Am** therapy.

Amiodarone-induced hypothyroidism (AIH) – reduced production of thyroid hormones developing during Am** therapy.

Overt hypothyroidism – hypothyroidism confirmed by an elevated thyroid-stimulating hormone (TSH) level (typically above 10 mIU/L) and free thyroxine (FT4) levels below the reference range.

Subclinical hypothyroidism – hypothyroidism confirmed by an elevated TSH level and a normal FT4 level.

Amiodarone-induced thyrotoxicosis (AIT) – excess thyroid hormones (thyrotoxicosis) developing during Am** therapy.

Amiodarone-induced thyrotoxicosis type 1 (AIT1) – thyrotoxicosis resulting from excessive, uncontrolled synthesis of thyroid hormones due to a large iodine load in patients who typically already have one or more thyroid nodules larger than 1.5–2 cm or latent Graves' disease (GD).

Amiodarone-induced thyrotoxicosis type 2 (AIT2) – thyrotoxicosis resulting from iodine- and/or Am-associated thyroid destruction and the release of preformed thyroid hormones into the systemic circulation.

Mixed amiodarone-induced thyrotoxicosis – thyrotoxicosis caused by a combination of follicular epithelial destruction and thyroid hormone hyperproduction.

Overt thyrotoxicosis – thyrotoxicosis characterized by a suppressed TSH level and elevated serum concentrations of FT4 and/or free triiodothyronine (FT3).

Subclinical thyrotoxicosis – thyrotoxicosis characterized by a suppressed TSH level and serum concentrations of FT4 and FT3 within the reference range.

Acute Wolff-Chaikoff effect – inhibition of thyroid iodine organification in response to an excessive iodine load, accompanied by a decrease in thyroxine (T4) and triiodothyronine (T3) production and an increase in TSH levels.

Thyroid ultrasound (US) – a diagnostic imaging method utilizing ultrasound waves to assess the size and structure of the thyroid gland.

Color Doppler interrogation (CDI) – an ultrasound blood flow visualization technique based on the Doppler effect.

Thyroid scintigraphy – a radioisotope imaging procedure based on detecting the uptake of a radiopharmaceutical (V09F: Thyroid therapy and diagnostics) by thyroid tissue and visualizing the emitted radiation using specialized equipment (gamma camera).

Glucocorticoids (GC) – a class of medicinal products structurally similar to natural steroid hormones.

Antithyroid drugs – a class of medicinal products that inhibit the synthesis of thyroid hormones.

Thyroidectomy (TE) – a surgical procedure aimed at the complete removal of the thyroid gland.

Radioiodine therapy – a treatment method using Sodium iodide [131I].

Plasmapheresis – a mechanical blood filtration procedure aimed at separating specific blood components, such as plasma, erythrocytes, leukocytes, platelets, and other constituents.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Amiodarone-induced thyroid dysfunction – thyroid dysfunction developing during Am** therapy.

Amiodarone-induced hypothyroidism – reduced thyroid function (hypothyroidism) developing during Am** therapy.

Amiodarone-induced thyrotoxicosis – an elevated serum concentration of thyroid hormones and their excessive effect on organs and tissues (thyrotoxicosis) developing as a result of amiodarone** therapy.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiological factor for amiodarone-induced thyroid dysfunction is the administration of Am**, a widely used Class III antiarrhythmic drug. Am** exhibits electrophysiological effects characteristic of all four classes of antiarrhythmics (C01: Cardiac therapy), with a predominant Class III effect (prolongation of the cardiomyocyte action potential). Am** was approved by the FDA in 1985 for the treatment of recurrent life-threatening ventricular arrhythmias [1]. Currently, Am** is used to treat various supraventricular and ventricular arrhythmias [2,3]. Am** is a benzofuran derivative whose molecular structure resembles that of the primary thyroid hormone, thyroxine (Fig. 1). Each Am** molecule contains 2 iodine atoms, which account for approximately 37% of its molecular weight [4–6]. Administration of 200–600 mg of Am** daily delivers 7 to 21 mg of free iodine into the circulation, which exceeds the daily iodine requirement (150–250 mcg) by 40 to 140 times. Am** and, to a greater extent, its active metabolite DEA exert a direct, dose-dependent cytotoxic effect on thyroid follicular cells [7]. Furthermore, both Am** and DEA tend to accumulate in various tissues and organs: primarily in adipose tissue, liver, and lungs, and to a lesser extent in the heart, kidneys, muscles, and thyroid gland [8]. Both Am** and DEA persist in the body for a long time (with a mean half-life of 52.6±23.7 and 61.2±31.2 days, respectively) [8,9]. Clearance is further reduced by 22% in obesity and by 46% in individuals over 65 years of age [10]. These pharmacokinetic properties result in both Am** and its metabolite DEA persisting in the circulation long after discontinuation of treatment [4,11]. Some researchers suggest that the DEA/Am** ratio can serve as a predictor of specific thyroid dysfunction patterns. Specifically, an increased DEA/Am ratio is characteristic of AIT, whereas a decreased ratio is associated with AIH [12]. In the majority of individuals (approximately 80%) receiving Am**, thyroid dysfunction does not develop throughout the treatment period [13]. However, Am** therapy can lead to the development of both AIH and AIT [5,14–18].

Fig. 1 Chemical structure of amiodarone**, desethylamiodarone, and thyroid hormones [5]

The most well-known pathomechanism of AIH development is that a thyroid gland affected by an autoimmune process, under conditions of chronic high iodine intake, fails to escape from the Wolff-Chaikoff effect. Consequently, thyroid hormone production decreases, leading to hypothyroidism. Moreover, evidence indicates that a significant iodine load may impair iodine organification even in a normal thyroid gland [19]. In addition to the above, risk factors for iodine-induced hypothyroidism include a history of hemithyroidectomy for nodular non-toxic goiter, hyperthyroidism treatment, thalassemia (thyroid hemosiderosis), and chronic kidney disease [20]. The onset of AIH following the initiation of Am** therapy ranges from several weeks to 39 months [21]. Although AIH can be detected in patients with a previously normal thyroid gland, the presence of pre-existing chronic autoimmune thyroiditis significantly increases the risk of its development. Furthermore, AIH is more common in women and older adults. The combination of female sex and the presence of antithyroid antibodies increases the relative risk of AIH by 13.5-fold compared to antibody-negative men [11].

There are two types of amiodarone-induced thyrotoxicosis (AIT). AIT1 typically develops in patients with nodular goiter or latent Graves' disease. In cases of nodular goiter (node size or total nodular volume usually greater than 1.5–2 cm), the intake of iodine—the primary substrate for thyroid hormone synthesis—leads to uncontrolled production of the latter. As a result, autonomous thyrotoxicosis develops (multinodular toxic goiter or toxic thyroid adenoma). In the presence of latent (or undiagnosed) Graves' disease, an influx of a large amount of iodine also leads to increased biosynthesis of thyroid hormones and the development of thyrotoxicosis. AIT2, or destructive thyroiditis, is a consequence of iodine- and/or amiodarone**-associated inflammation and destruction of the thyroid gland, resulting in the release of pre-synthesized thyroid hormones into the circulation. There is also a mixed type of AIT, caused by a combination of follicular epithelial destruction and thyroid hormone hyperproduction [22].

1.3 Epidemiology of the Disease or Condition

The prevalence of overt amiodarone-induced hypothyroidism (AIH) ranges from 5 to 11% [23–25]. Subclinical hypothyroidism, according to the same studies, is detected in 20–26% of patients receiving chronic amiodarone** therapy [26]. In residents of Saint Petersburg who received long-term amiodarone** treatment, the prevalence of overt AIH was comparable to the European population at 9% [27].

AIH develops more frequently in iodine-deficient regions. Furthermore, unlike AIT, it occurs 3 times more often in men than in women. As a rule, AIH is detected several months after amiodarone** treatment is initiated, though it can develop at any time from the start of therapy and even months after its discontinuation [5, 11].

1.4 Features of Coding the Disease or Condition

Hypothyroidism due to medications and other exogenous substances (E03.2)

Other forms of thyrotoxicosis (E05.8)

1.5 Classification of the disease or condition

Amiodarone-induced thyroid dysfunction is divided into amiodarone-induced hypothyroidism and amiodarone-induced thyrotoxicosis.

Amiodarone-induced thyrotoxicosis is classified into AIT1, AIT2, and mixed-type amiodarone-induced thyrotoxicosis.

1.6 Clinical presentation of the disease or condition

The symptoms of AIH are similar to those of hypothyroidism of any other etiology. It should be borne in mind, however, that amiodarone** is prescribed to patients who already have impaired left ventricular function, and certain manifestations of hypothyroidism (decreased exercise tolerance, dyspnea, etc.) mimic the symptoms of congestive heart failure and may therefore be misdiagnosed as its progression. Both amiodarone** and thyroid hormone deficiency are capable of prolonging the QT interval and leading to torsades de pointes polymorphic ventricular tachycardia, though to a lesser extent than antiarrhythmic drugs such as sotalol** [1].

The clinical manifestations of AIT are diverse and generally similar to symptoms of thyrotoxicosis caused by any other etiology. However, one must account for the beta-blocking effect of amiodarone**, which may mask symptoms of thyrotoxicosis driven by sympathetic nervous system activation (tremor, sweating, tachycardia) [28]. Weight loss is detected more frequently than other symptoms, especially in older individuals. A typical feature of AIT is also the deterioration of a previously stable cardiovascular condition—specifically, cardiac arrhythmias—or the emergence of new arrhythmias, particularly supraventricular ones [24, 29, 30]. In patients receiving warfarin**, AIT can lead to hypersensitivity to the drug, requiring a reduction in its dose [31]. Another feature of AIT is a very high level of thyroid hormones in the presence of moderately severe clinical manifestations. The course of AIT may be asymptomatic, meaning the disease is discovered incidentally during routine examination.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition: the following criteria must be used when diagnosing overt amiodarone-induced hypothyroidism [26, 32]:

1. Elevated blood TSH levels (usually above 10 mIU/L)

2. Low serum free thyroxine (fT4) levels.

The following criteria must be used when diagnosing subclinical amiodarone-induced hypothyroidism [26, 32]:

1. Elevated blood TSH above the normal range (usually ranging from the upper limit of normal to 10 mIU/L),

2. Serum fT4 levels within the reference range.

The following criteria must be used when diagnosing overt amiodarone-induced thyrotoxicosis [reference]:

1. Suppressed blood TSH levels

2. High serum concentrations of fT4 and/or free triiodothyronine (fT3) in the blood.

The following criteria must be used when diagnosing subclinical amiodarone-induced thyrotoxicosis [26]:

1. Suppressed blood TSH levels

2. Normal serum concentrations of fT4 and fT3 in the blood

2.1 Complaints and Anamnesis

Symptoms of amiodarone-induced hypothyroidism: severe fatigue, drowsiness, dry skin, hair loss, slowed speech, puffiness of the face, fingers, and toes, constipation, memory impairment, feeling cold, hoarseness, depressed mood, exertional dyspnea, and reduced exercise tolerance. History of amiodarone** intake.

Symptoms of amiodarone-induced thyrotoxicosis: palpitations, weight loss, onset or increased frequency of atrial fibrillation paroxysms, increased shocks from an implanted cardioverter-defibrillator, worsening weakness, fatigue, decreased exercise tolerance, muscle weakness, and increased frequency of angina attacks in patients with coronary artery disease. In some cases, symptoms associated with sympathoadrenal system activation may be absent due to the beta-blocking effect of amiodarone**. Patients may also note a significant reduction in warfarin** requirements. History of amiodarone** intake at the time of diagnosis or within the year preceding the onset of thyrotoxicosis symptoms. AIT is known to develop not only during amiodarone therapy but also for a prolonged period (18 months or more) after amiodarone discontinuation [11]. Differentiating AIT in a patient with latent Graves' disease (AIT1) from destructive thyroiditis (AIT2) in the absence of clinical syndromes such as ophthalmopathy (sometimes pretibial myxedema and, even more rarely, acropachy) is extremely difficult, as the symptoms of thyrotoxicosis itself are identical. To a certain extent, differential diagnosis is aided by the fact that AIT1, unlike AIT2, develops within a shorter time frame after starting amiodarone therapy [34].

2.2 Physical Examination

Physical examination for amiodarone-induced hypothyroidism in patients with severe and prolonged thyroid hormone deficiency may reveal characteristic external features: dry and pale skin, generalized and periorbital edema, a pale-yellowish puffy face, and diminished facial expressions. Upon palpation, the thyroid gland is of normal size or enlarged, soft to elastic in consistency, painless, and nodules may be palpable.

Physical examination of a patient with AIT1 frequently reveals goiter, a vascular bruit may be auscultated over the thyroid gland, and there may be signs of infiltrative ophthalmopathy, rarely pretibial myxedema, and even more rarely acropachy; if type 1 AIT is caused by autonomous thyrotoxicosis, palpation will reveal one or more nodules.

Physical examination of a patient with type 2 AIT generally reveals a normally sized thyroid gland with a soft-elastic consistency, no vascular bruit upon auscultation, and no signs of infiltrative ophthalmopathy.

2.3 Laboratory Diagnostics

• In patients receiving amiodarone** therapy who present with symptoms and syndromes suspicious for AIH, it is recommended to perform blood TSH and serum fT4 tests to confirm the diagnosis [26]. The diagnosis of overt AIH is confirmed by a TSH level exceeding the upper limit of normal (typically above 10 mIU/L) and low fT4 levels. Subclinical AIH is diagnosed when TSH is above normal (usually ranging from the upper limit of normal to 10 mIU/L) and fT4 remains within reference limits [26, 32].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• In patients receiving amiodarone** therapy who present with symptoms and syndromes suspicious for AIT (described in sections 2.6 and 2.7), it is recommended to perform blood TSH, serum fT4, and serum fT3 tests to confirm the diagnosis. The diagnosis of overt AIT is confirmed by a low TSH level alongside high fT4 and/or fT3 values. Subclinical AIT is diagnosed when TSH is below normal while fT4 and fT3 remain within reference limits [35, 36].

GCR CLEL 3Grade of Recommendation — C (Level of Evidence — 3)

• In patients with confirmed AIT, it is recommended to determine blood levels of TSH receptor antibodies (anti-TSHR). The presence of high anti-TSHR levels or typical clinical manifestations—specifically infiltrative ophthalmopathy and/or pretibial myxedema—confirms the diagnosis of Graves' disease and, consequently, AIT1 [37–39].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• For patients with amiodarone-induced thyrotoxicosis (AIT) who require differential diagnosis between AIT1 and AIT2, it is recommended to calculate the ratio of serum free thyroxine (fT4) to free triiodothyronine (fT3) (fT4/fT3) as an additional method [4, 40, 41]. An fT4/fT3 ratio (measured in pmol/L) of less than 3.1 indicates AIT1, whereas an fT4/fT3 ratio (measured in pmol/L) greater than 3.65 indicates AIT2 [42].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comments: The diagnosis of overt AIT is confirmed by a suppressed TSH level and high serum concentrations of fT4 and fT3. Subclinical AIT (low TSH levels and normal blood concentrations of fT4 and fT3) is not always a precursor to overt AIT. For instance, according to Benjamens S. et al., overt thyrotoxicosis developed in only 16 (24.6%) out of 65 individuals with subclinical AIT, while in the remaining 49, thyroid function remained unchanged over a 3.4 (0–16) year follow-up period [24].

The presence of TSH receptor antibodies (TRAb) generally indicates that AIT1 is underlyingly caused by Graves' disease (GD), although a slight elevation in these antibodies does not rule out AIT2. Conversely, the absence of elevated TRAb levels does not rule out AIT1. As for thyroid peroxidase antibodies (TPOAb) and/or thyroglobulin antibodies (TgAb) in the blood, they are detected in both type 1 and type 2 AIT [40, 43].

It is known that AIT2, as a variant of destructive thyroiditis, is characterized by a predominant increase in fT4, whereas in AIT1 (as in GD), the production of fT3 increases to a greater extent [44]. Some researchers have demonstrated that the fT4 level, as well as the fT4/fT3 ratio, is significantly higher in individuals with AIT2 than in those with AIT1, although the difference was generally not statistically significant [40, 41]. According to data obtained in another study, in 75% of patients with AIT1, the fT4/fT3 ratio (in pmol/L) was less than 3.10, whereas in 75% of patients with AIT2, the fT4/fT3 ratio (in pmol/L) was greater than 3.65 [42].

Determination of serum interleukin-6 concentration is rarely used in clinical practice today; however, it is known to be significantly elevated in patients with AIT2, while it is typically normal or only mildly elevated in AIT1 [45].

2.4 Instrumental Diagnostics

The diagnosis of amiodarone-induced goiter (AIG) does not strictly require instrumental imaging methods; however, instrumental diagnostic studies may be performed for the differential diagnosis of AIT1 and AIT2, as well as to detect thyroid nodules.

• Thyroid ultrasound (US) is recommended in the presence of palpable nodules and/or palpable thyroid enlargement to confirm or rule out thyroid enlargement and/or nodules [26, 33].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• For AIT patients with one or more thyroid nodules measuring 1.5 cm or larger, it is recommended to perform thyroid scintigraphy using diagnostic radiopharmaceuticals such as Sodium iodide [123I] or Sodium pertechnetate [99mTc]. If one or more "hot" nodules are identified on thyroid scintigraphy with Sodium iodide [123I] or Sodium pertechnetate [99mTc], a diagnosis of AIT1 is established [26, 46–49].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• For patients who require a differential diagnosis between AIT1 and AIT2, it is recommended to perform duplex scanning of the thyroid blood vessels combined with color Doppler flow imaging (CDFI) [4, 43]. The presence of "pattern 0" on CDFI generally indicates AIT2, whereas the presence of "patterns I–III" more likely points to AIT1 [50–56].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

• A diagnosis of mixed-type AIT is recommended for AIT patients who exhibit features of both AIT1 and AIT2 based on laboratory and/or instrumental examination results [26].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: The diagnosis of autonomous thyrotoxicosis (autonomous AIT1) associated with excessive iodine intake and subsequent increased thyroid hormone synthesis usually does not present difficulties. It is characterized by the presence of one or more thyroid nodules (often known prior to the initiation of amiodarone therapy), which are "hot" on thyroid scintigraphy with Sodium pertechnetate [99mTc] or hypervascular on CDFI. In autonomous thyrotoxicosis, antithyroid antibody levels are usually not elevated.

The differential diagnosis between AIT1 and AIT2 should be based on multiple methods, as none of them allows for the identification of strictly specific changes. Thyroid scintigraphy using Sodium iodide [123I], a classic test for differentiating thyrotoxicosis caused by increased thyroid hormone production from that caused by hormone leakage from a damaged thyroid gland, is uninformative in regions with adequate and high iodine intake. In AIT1 patients residing in such regions, iodine uptake by the thyroid is always reduced [57, 26]. In iodine-deficient regions, thyroid iodine uptake in AIT1 may be increased, normal, or even reduced [26]. Low or absent iodine uptake in a patient living in an iodine-deficient region strongly suggests AIT2 [4, 5, 24]. It should also be borne in mind that reduced Sodium iodide [123I] uptake in regions with moderate iodine deficiency may be a manifestation of mixed-etiology AIT [50].

In the differential diagnosis of AIT, thyroid scintigraphy with Sodium pertechnetate [99mTc] is also used, as well as two-day protocol thyroid scintigraphy using two radiopharmaceuticals: 99mTc-pertechnetate and 99mTc-sestamibi. Thyroid scintigraphy with Sodium pertechnetate [99mTc] has low sensitivity and specificity [51,52] in the differential diagnosis of AIT1 and AIT2. Two-day protocol thyroid scintigraphy is considered more promising. The method not only allows for a differential diagnosis between the two types of AIT, but also helps identify a mixed variant. In 2008, Piga M. et al. demonstrated that in patients with AIT1, 99mTc-sestamibi uptake was normal or increased, and was absent in all patients with AIT2. The study results in patients with the mixed variant of AIT differed from the data obtained in both AIT1 and AIT2: there was either weak persistent uptake of 99mTc-sestamibi or rapid washout of the radiopharmaceutical (V09F: Diagnostic radiopharmaceuticals for thyroid disorders) [52]. Similar results were published by other researchers [58–60]. According to Wang J. et al., thyroid scintigraphy with 99mTc-sestamibi was the only method that accurately determined the type of AIT [59]. It should be noted that studies evaluating the efficacy of thyroid scintigraphy with and 99mTc-sestamibi in patients with AIT included a small number of patients (slightly over 100), which limits recommendations for the widespread use of this technique [52,58–62].

The primary test used for the differential diagnosis of AIT1 and AIT2 is CDFI [4, 26]. Classical thyroid ultrasound helps clarify its size, as well as the presence and size of nodules. However, it has low diagnostic value in the differential diagnosis of AIT [51], since the presence of diffuse goiter or nodules does not rule out AIT2 [52, 53]. To differentiate between AIT types, CDFI is used to assess thyroid vascularity. In 1997, Bogazzi F. et al. described various vascular patterns of the thyroid obtained via CDFI and proposed using them for the differential diagnosis of AIT. The authors defined "pattern 0" as the absence of intraparenchymal thyroid vascularity or solitary punctate blood flow spots; "pattern I"—as the presence of glandular parenchymal blood flow with uneven focal distribution or vascular foci within a nodule; "pattern II"—as a slight increase in Doppler signal with uneven distribution or well-defined blood flow along the periphery of a thyroid nodule; and "pattern III"—as a marked increase in Doppler signal with a diffuse homogeneous distribution, or pronounced hypervascularity throughout the entire nodule. Analyzing CDFI results in AIT patients, they found "pattern 0" in all patients with AIT2, and patterns I–III—in all patients with AIT1 [54]. These findings were subsequently confirmed in a larger population of AIT individuals. It should be noted that this classification does not allow for the identification of mixed-type AIT. Nevertheless, the assessment of thyroid vascularity using CDFI is recognized as the most effective method for differential diagnosis of AIT. According to six different studies, the sensitivity and specificity of this method for diagnosing AIT1 were 96.8% and 94.1%, and for AIT2 93.6% and 90.1%, respectively [50–56]. It should be noted that the success of this method largely depends on the experience and qualification of the operator performing the examination [50].

Thus, despite the lack of highly informative methods for the differential diagnosis of type 1 and type 2 AIT, the combination of the diagnostic features discussed above allows for a reasonably accurate determination of the AIT type.

2.5 Other Procedures

Not applicable.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative treatment of amiodarone-induced hypothyroidism

• Administration of levothyroxine sodium** is recommended for all patients with overt amiodarone-induced hypothyroidism (AIH) to relieve its manifestations. Recommended TSH level during therapy: in the range of the upper third of normal values or slightly above normal (below 10 mIU/L) [21,26].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: Levothyroxine sodium** replacement therapy is prescribed for all patients with overt hypothyroidism, aiming for a TSH level in the upper third of normal values, or even slightly above normal (but below 10 mIU/L). It should be noted that patients with AIH often require higher doses of levothyroxine sodium** to normalize serum TSH concentration. This phenomenon is associated with the ability of amiodarone** to inhibit the conversion of T4 to T3 in peripheral tissues; therefore, slightly elevated free T4 (FT4) values are acceptable during levothyroxine sodium** replacement therapy provided that TSH values are normal [26].

In the presence of subclinical hypothyroidism, levothyroxine sodium** is usually not prescribed (except in isolated cases), but serum TSH and FT4 concentrations are monitored every 4–6 months due to the risk of developing overt hypothyroidism. On the other hand, euthyroidism is known to recover after discontinuation of amiodarone** in some patients who previously had no thyroid disorders [63].

In general, replacement therapy for AIH does not differ from the therapy of hypothyroidism caused by other etiologies. Amiodarone** is not discontinued if it effectively controls the rhythm disorders for which it was prescribed [21]. If amiodarone** therapy is stopped, levothyroxine sodium** may be discontinued or its dose reduced, since 50% of patients recover euthyroidism within the next 2–3 months [24].

3.2 Conservative treatment of amiodarone-induced thyrotoxicosis

• For patients with amiodarone-induced thyrotoxicosis (AIT), it is recommended to discontinue amiodarone**, except in cases where it effectively controls the rhythm disorders for which it was prescribed [26,64].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• Treatment with drugs that block thyroid hormone synthesis, i.e., antithyroid drugs (H03BB02 Thiamazole** and H03BA02 #Propylthiouracil), is recommended for patients with AIT type 1 (AIT1):

  thiamazole** – the daily dose of thiamazole** is 40–60* mg (*off-label) or

  #propylthiouracil – a daily dose of 300–600 mg divided into 4–6 single doses. The dose of the drug should be reduced after normalization of blood FT4 and FT3 levels.

If antithyroid drugs have an insufficient effect or if signs of destructive thyroiditis appear, thyrotoxicosis should be regarded as mixed, and #prednisolone** should be added to the therapy [26,91].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: AIT1 is treated with antithyroid drugs, which block the synthesis of thyroid hormones. It should be taken into account that standard drug doses are insufficiently effective due to the large amount of intrathyroidal iodine. Usually, #thiamazole** is used at a daily dose of 40–60* mg (*off-label) or #propylthiouracil at a daily dose of 300–600 mg per day, divided into 4–6 single doses [26,91]. Although the dose can be reduced after 6–12 weeks, long-term treatment with high doses of the drug is often required. If there is no doubt that this is type 1 rather than a mixed variant of AIT, glucocorticoids (GCs) should not be added [45].

• For rapid normalization of thyroid function (especially in severe thyrotoxicosis when a decision is made to perform thyroidectomy for life-saving indications), administration of #lithium carbonate is recommended. It inhibits proteolysis and reduces the release of already synthesized thyroid hormones from the thyroid gland [68–70]. #Lithium carbonate is prescribed at a dose of 300 mg every 6–8 hours. The effect is achieved by the end of the first to the beginning of the second week. It should be remembered that treatment of thyrotoxicosis with lithium carbonate is an off-label treatment, and the prescription of this drug is possible only by decision of the Medical Commission and after the patient signs an informed consent. The drug is used with extreme caution in patients with myocardial dysfunction, maintaining its serum concentration in the range of 0.4–1.2 mEq/L [70].

GCR CLEL 3Grade of Recommendation — C (Level of Evidence — 3)

• After achieving euthyroidism in patients with AIT1, it is recommended to perform thyroid ablation, thyroidectomy (TE), or radioiodine therapy. Radioiodine therapy is recommended to be prescribed 6–12 months after amiodarone** discontinuation [26].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• For patients with AIT type 2 (AIT2), oral administration of #prednisolone** at a dose of 30 [26–40] [45] mg daily in 3 doses is recommended. The duration of therapy can range from 8–12 to 24 weeks. After normalization of peripheral thyroid hormones, it is recommended to reduce the dose of #prednisolone** until complete withdrawal slowly, taking into account the possible recurrence of thyrotoxicosis. If #prednisolone** is insufficiently effective or if signs of thyroid hormone hyperproduction appear, the addition of antithyroid drugs to the therapy is recommended [26].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: Although spontaneous remission is possible in AIT2, it should be treated, as the development of thyrotoxicosis is often accompanied by the worsening of the patient's existing cardiovascular pathology. Preference is given to #prednisolone**, the dose of which is usually 30 [26] to 40 [45] mg daily; the duration of treatment is usually 8–12 weeks. The dose of #prednisolone** is reduced very slowly after normalization of peripheral thyroid hormones to avoid recurrence of thyrotoxicosis [45,65]. In recent years, isolated papers have appeared on the efficacy of high doses of parenteral GCs for the treatment of AIT2 [71,72]. The inconsistency of the results obtained in these studies may be due to the small number of enrolled patients, as well as differences in doses and administration regimens of parenteral GCs [71,72], which necessitates further research in this area. After discontinuation of #prednisolone**, the outcome of AIT2 may be the restoration of euthyroidism, but sometimes hypothyroidism may develop, requiring monitoring of blood TSH.

• Patients with mixed AIT are recommended to start therapy with antithyroid drugs (H03BB02 Thiamazole** and H03BA02 #Propylthiouracil). #Prednisolone** is prescribed either simultaneously with antithyroid drugs (H03BB02 Thiamazole** and H03BA02 #Propylthiouracil) or when they are ineffective; no later than 4–6 weeks from the start of therapy (for dosing regimens, see above) [26].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: The development of AIT significantly worsens the course of underlying cardiovascular pathology and increases the risk of adverse outcomes, including patient death. For this reason, treatment of thyrotoxic syndrome is initiated immediately after its detection. Amiodarone** is usually discontinued unless there is evidence that it effectively controls the rhythm disorders for which it was prescribed. To select adequate treatment for AIT, it is necessary to correctly determine its type: AIT1 caused by thyroid hormone hyperproduction, or AIT2 caused by thyroid epithelial destruction and thyroid hormone leakage, as well as the mixed variant of AIT. The treatment tactics for AIT1 and AIT2 differ.

A mixed variant of AIT, representing a combination of a destructive process in the thyroid gland with increased production of thyroid hormones, should be suspected in the presence of diagnostic tests indicating both AIT1 and AIT2. In this case, combination therapy with antithyroid drugs and #prednisolone** in standard doses for AIT treatment is prescribed. According to Bogazzi et al., such therapy also helps, to a certain extent, to differentiate between AIT types. Thus, if after 2 weeks of combination treatment the FT3 level decreases by more than 50% from baseline, the patient should be considered to have type 2 AIT, and it is advisable to discontinue antithyroid drugs and continue therapy with #prednisolone**. If there is no decrease in the serum concentration of FT3, type 1 AIT is considered more likely, which leads to the discontinuation of #prednisolone** and the continuation of therapy with antithyroid drugs [40,65].

3.3 Surgical treatment of amiodarone-induced thyrotoxicosis

• For patients with AIT with progressive worsening of cardiovascular pathology who do not respond to drug therapy, as well as in case of side effects during drug therapy, thyroidectomy (TE) is recommended as soon as possible [26,73,74,75–78].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

• Performing TE without achieving euthyroidism in emergency cases is recommended only in highly specialized medical organizations by a team of specialists with sufficient experience in treating such patients [26].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: The duration of medical therapy until achieving an euthyroid state in patients with AIT can range from several weeks to several months [26,73]. The excess of thyroid hormones persisting during this time can significantly worsen the course of the underlying cardiovascular pathology. In addition, in some cases, discontinuation of Am** is undesirable even in patients with AIT1, as it may be the only effective drug for treating cardiac arrhythmias [26,64]. It is known that Am**, due to blocking the peripheral conversion of T4 to T3, is able to reduce the manifestations of thyrotoxicosis, and its withdrawal, therefore, can lead to an increase in T3 levels, worsening of the underlying disease, and the development of dangerous arrhythmias [73,74,79]. Also, the prescription of antithyroid drugs is often associated with the development of side effects (e.g., hepatotoxicity and myelotoxicity), which is an obstacle to continuing treatment [45,80]. In all these cases, rapid relief of thyrotoxicosis can improve the course of cardiovascular disease and reduce the risk of mortality. TT is the optimal and effective way to achieve this goal. According to several studies involving a total of 99 patients with AIT, TT under general anesthesia was successful and safe [73,74,75-77], and in one – mortality was 9% (3 patients out of 34) [79]. In 2019, D. Cappellani et al. showed that among patients with severe left ventricular systolic dysfunction and AIT, the mortality rate was lower in those who underwent TT compared to those who received medical therapy [78]. With a normal left ventricular ejection fraction or mildly reduced systolic function, no such difference was found. The authors concluded that TT may be the method of choice in the treatment of AIT in patients with severe systolic dysfunction [78].

Thus, TT is indicated in cases of ineffectiveness and/or the development of serious adverse drug reactions from medical therapy for thyrotoxic syndrome and worsening of cardiovascular symptoms. Surgical treatment in such cases is performed despite the presence of thyrotoxicosis in the patient; the decision on the necessity of such treatment is made by a multidisciplinary team consisting of an endocrinologist, cardiologist, surgeon, and anesthesiologist-resuscitator. Since the surgery is associated with a high risk, it must be performed in a facility with experience in treating such patients.

Plasmapheresis can be used for preoperative preparation, however, according to the literature, experience with its use in patients with AIT is limited to isolated cases, and it is not effective in all patients [74,81-83].

3.4 Other treatment

Not applicable.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific methods of spa and resort treatment have not been developed.

Nonspecific methods of spa and resort treatment are contraindicated.

Methods of medical rehabilitation have not been developed.

5. Prevention and Dispensary Observation

• Blood TSH level testing and determination of thyroid peroxidase antibody levels are recommended for all patients prior to initiating Am** therapy to rule out thyroid dysfunction. Subsequently, if there is no clinical suspicion of thyroid dysfunction during Am** treatment, blood TSH testing (and FT4 and FT3 testing if clinically indicated) should be repeated no earlier than 3 months after starting treatment, and then every 6 months [84-86].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: Effects of Am** on thyroid function tests. The effect of Am** on the thyroid gland is due both to the presence of a large amount of iodine in its molecule and to the specific effects of the molecule itself. Patients receiving Am** usually exhibit changes in thyroid hormone and TSH levels. Early effects (within the first three months of Am** treatment) and chronic effects (during treatment for more than 3 months) of Am** are distinguished.

Effects associated with iodine intake into the thyroid gland. In response to the large amount of iodine contained in Am**, the thyroid gland blocks its organification (the so-called acute Wolff-Chaikoff effect), which leads to a decrease in thyroid hormone production and an increase in TSH [87]. Subsequently, the thyroid gland adapts to the excess iodine: iodine transport is inhibited, and escape from the Wolff-Chaikoff effect occurs. As a result, the intrathyroidal iodine concentration drops below the inhibition threshold, which allows organification to be restored. Serum T4 and TSH concentrations normalize in the process [88].

Effects due to Am** itself. Am** and its main metabolite DEA have a significant effect on type 1 (D1) and type 2 (D2) deiodinases, which are responsible for thyroid hormone metabolism. Inhibition of D1 activity in tissues (mainly the liver) and D2 in the anterior pituitary by Am** leads to a decrease in serum and pituitary T3 concentration, an increase in reverse T3 (rT3), which, in turn, causes an increase in T4 and TSH secretion [89]. It should be noted that for Am**, this effect has only been described in vitro; it is believed that in vivo deiodinase inhibition is carried out by DEA [7,89]. Am** is also able to block the uptake of T4 into the liver and thus reduce its metabolism.

It is believed that the early effects of Am__, the main one of which is a slight increase in TSH, are primarily due to the response of the thyroid gland to the intake of large amounts of iodine. Changes in thyroid hormones during long-term treatment are caused by the action of Am** itself. Long-term Am** administration is accompanied by a slight increase in total T4, FT4, and rT3. The serum concentration of total T3 and FT3 decreases, remaining at the lower limit of normal. As for TSH, its concentration usually remains within normal limits, with a tendency to decrease with prolonged treatment and/or a large cumulative dose of Am** [63]. Such biochemical changes in patients receiving Am** are regarded as euthyroidism [26], or as euthyroid hyperthyroxinemia [13,90]. Thyroid function test results in euthyroid individuals receiving Am** are presented in Table 1.

Table 1*. Thyroid function test results in euthyroid individuals receiving amiodarone**

TSH – thyroid-stimulating hormone, T3 – triiodothyronine, T4 – thyroxine,

*adapted from Bartalena LA, et al. 2018 European Thyroid Association (ETA) Guidelines for the Management of Amiodarone-Associated Thyroid Dysfunction. Eur Thyroid J 2018; 7: 55–66

Am** is one of the most frequently prescribed drugs for the long-term treatment of cardiac arrhythmias [84]. Thyroid dysfunction is an infrequent but significant side effect developing during Am** treatment [63]. Therefore, thyroid function should be evaluated before and throughout Am** treatment [90]. Determination of TSH is recommended before initiating Am** therapy. Determination of thyroid peroxidase antibody levels in the blood helps assess the risk of hypothyroidism. If the patient's TSH is above normal, primary hypothyroidism should be ruled out. If hypothyroidism is confirmed, it is treated according to existing standards. Am** may be prescribed to a patient receiving thyroxine replacement therapy. If TSH is below normal, the patient should be screened for thyrotoxicosis, which (including subclinical) may be the cause of cardiac arrhythmias.

Patients with normal TSH values can be prescribed Am** therapy without delay. After initiating Am** therapy, if there is no clinical suspicion of thyroid dysfunction, TSH (and FT4, FT3 if necessary) should be reassessed no earlier than 3 months later, and then every 6 months [84-86].

It is known that AIT can develop not only during Am** therapy, but also for a long time (18 months or more) after Am** withdrawal [11]. Thus, if symptoms of thyrotoxicosis appear in a patient who previously received Am**, thyroid function should be evaluated and, if thyrotoxicosis is confirmed, it should be regarded as AIT, and diagnosis and treatment should be carried out according to existing guidelines.

6. Organization of Medical Care

Outpatient treatment of mild forms of AIG and AIT, in the absence of deterioration of cardiovascular disease.

Planned hospitalization. Care: inpatient/day care.

Indications for elective hospitalization in a medical organization (inpatient facility):

• thyroid dysfunction that cannot be corrected in an outpatient setting;

• combination of thyroid dysfunction with cardiovascular pathology that cannot be corrected in an outpatient setting.

Indications for emergency hospitalization:

• thyroid dysfunction accompanied by life-threatening complications.

Indications for discharge from the medical organization (hospital):

• stable improvement in the patient's condition, allowing them to continue treatment safely in an outpatient clinic or at home.

7. Additional Information

The prognosis is determined by the presence of severe comorbid conditions in the patient, primarily cardiovascular pathology.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

LEADERS:

Shlyakhto E.V., MD, Professor, Academician of the Russian Academy of Sciences, Saint Petersburg, President of the Russian Society of Cardiology

Grineva E.N., MD, Professor, Corresponding Member of the Russian Academy of Sciences, Saint Petersburg, Member of the Russian Association of Endocrinologists

AUTHORS OF THE TEXT:

Grineva E.N., MD, Professor, Saint Petersburg, Member of the Russian Association of Endocrinologists

Tsoy U.A., PhD, Saint Petersburg, Member of the Russian Association of Endocrinologists

Karonova T.L., MD, Saint Petersburg, Member of the Russian Association of Endocrinologists

Mikhailov E.N., MD, Associate Professor, Saint Petersburg, Member of the Russian Society of Cardiology

WORKING GROUP MEMBERS:

Vanushko V.E., MD, Moscow, Member of the Association of Endocrine Surgeons

Danilov I.N., PhD, Saint Petersburg

Ivanikha E.V., PhD, Saint Petersburg

Lebedev D.S., MD, Professor of the Russian Academy of Sciences, Saint Petersburg, Member of the Russian Society of Cardiology

Troshina E.A., MD, Corresponding Member of the Russian Academy of Sciences, Professor, Member of the Russian Association of Endocrinologists

Fadeev V.V., MD, Corresponding Member of the Russian Academy of Sciences, Professor, Member of the Russian Association of Endocrinologists

Frolov M.Yu., PhD, Chief Freelance Clinical Pharmacologist of the Russian Ministry of Health for the Southern Federal District

Conflict of interest:

The authors of the clinical guidelines declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. endocrinologist;

2. general practitioner (family physician);

3. general practitioner

4. cardiologist

Literature search

Methods used for evidence collection/selection: electronic database search.

Description of methods used for evidence collection/selection: the evidence base for the recommendations includes publications from the Cochrane Library, EMBASE, MEDLINE, and RSCI databases. The search depth was 30 years.

Levels of recommendations

To evaluate the recommendations, the scales of levels of evidence validity (LEV) and levels of recommendation credibility (LRC) were used. The scales are presented in Tables 2–4.

Table 2. Scale for grading levels of evidence validity (LEV) for diagnostic methods (diagnostic interventions)

Table 3. Scale for grading levels of evidence validity (LEV) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitation interventions)

Table 4. Scale for grading levels of recommendation credibility (LRC) for prevention, diagnostic, therapeutic, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision — at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Procedure for providing medical care to the adult population in the profile "endocrinology" (Order of the Ministry of Health of the Russian Federation No. 104n dated March 13, 2023) https://normativ.kontur.ru/document?moduleId=1&documentId=446549.

2. Nomenclature of positions of medical workers and pharmaceutical workers (Order of the Ministry of Health of Russia No. 205n dated May 2, 2023 (as amended on August 1, 2014)) https://normativ.kontur.ru/document?moduleId=1&documentId=464264.

3. Nomenclature of medical services (Order of the Ministry of Health of Russia No. 804n dated October 13, 2017) https://minjust.consultant.ru/documents/37309?items=1&page=1.

4. Instructions for medical use of prednisolone**

5. Instructions for medical use of levothyroxine sodium**

6. Instructions for medical use of thiamazole**

7. Instructions for medical use of propylthiouracil**

8. Instructions for medical use of lithium carbonate

Appendix B. Physician Action Algorithms

Management algorithm for suspected amiodarone-induced hypothyroidism

Differential diagnostic features of amiodarone-induced thyrotoxicosis types 1 and 2

AIT1 – amiodarone-induced thyrotoxicosis type 1, AIT2 – amiodarone-induced thyrotoxicosis type 2, thyroid – thyroid gland, TSHr – thyrotropin receptor, fT4 – free T4, fT3 – free T3, ultrasound – ultrasonography, CDM – color Doppler mapping

Treatment algorithm for amiodarone-induced thyrotoxicosis

Appendix C. Patient Information

What is amiodarone?

Amiodarone is an antiarrhythmic drug used to treat rhythm disorders in patients with coronary artery disease and/or left ventricular dysfunction.

How does amiodarone affect the thyroid gland?

The effect of amiodarone on the thyroid gland is due to the presence of a large amount of iodine in its molecular structure. Patients receiving amiodarone usually exhibit changes in thyroid hormone and pituitary thyroid-stimulating hormone (TSH) levels. In response to the excess iodine delivered by amiodarone, the thyroid gland blocks its organification (the so-called acute Wolff-Chaikoff effect); the production of thyroxine (T4) and triiodothyronine (T3) decreases, while TSH levels increase. Subsequently, thyroid adaptation occurs, consisting of the inhibition of iodine transport and escape from the Wolff-Chaikoff effect: the intrathyroidal iodine concentration drops below the inhibition threshold, allowing the resumption of iodine organification. As a result, serum concentrations of T4 and TSH normalize.

In some patients, amiodarone therapy may lead to the development of amiodarone-induced thyroid dysfunction: amiodarone-induced hypothyroidism, characterized by decreased thyroid function occurring during amiodarone intake, and amiodarone-induced thyrotoxicosis, characterized by excess thyroid hormones occurring during amiodarone intake.

How does amiodarone-induced hypothyroidism manifest?

Symptoms of amiodarone-induced hypothyroidism are similar to those of hypothyroidism from any other cause. Manifestations include weakness, increased fatigue, reduced exercise tolerance, worsening dyspnea, dry skin, increased hair loss and brittle nails, constipation, and the appearance or worsening of edema.

How does amiodarone-induced thyrotoxicosis manifest?

Amiodarone-induced thyrotoxicosis presents with symptoms typical of thyrotoxicosis caused by any other etiology. However, it should be noted that symptoms such as hand tremors and sweating may be absent during amiodarone therapy. Weight loss is observed more frequently than other symptoms, especially in older individuals. A typical feature of amiodarone-induced thyrotoxicosis is the worsening of a previously stable cardiovascular condition, in particular an increased frequency of atrial fibrillation episodes, the onset of new rhythm disorders, and a potential increase in heart failure manifestations. In patients receiving warfarin, the development of amiodarone-induced thyrotoxicosis may reduce their requirement for the drug, leading to a dose reduction.

How is amiodarone-induced hypothyroidism diagnosed?

The diagnosis of overt amiodarone-induced hypothyroidism is confirmed by an elevated TSH level (usually above 10 mIU/L) and low free T4 values. Subclinical amiodarone-induced hypothyroidism is diagnosed when TSH is above normal while free T4 remains within the normal range.

How is amiodarone-induced thyrotoxicosis diagnosed?

The diagnosis of overt amiodarone-induced thyrotoxicosis is confirmed by a decreased TSH level and elevated serum concentrations of free T4 and/or free T3. Subclinical amiodarone-induced thyrotoxicosis is diagnosed when TSH is suppressed, while serum free T4 and free T3 levels remain within normal limits.

How is amiodarone-induced hypothyroidism treated?

Amiodarone-induced hypothyroidism does not require mandatory discontinuation of amiodarone. All patients with overt amiodarone-induced hypothyroidism are prescribed thyroid hormone replacement therapy. Treatment is monitored by measuring TSH levels, and in some cases, the assessment of free T4 is also required. Patients with subclinical hypothyroidism are not prescribed drug therapy (except for certain categories of patients); however, due to the potential progression from subclinical to overt hypothyroidism, thyroid function is assessed every 4–6 months.

How long does hormone replacement therapy need to be taken?

If amiodarone therapy is discontinued, thyroid hormone replacement can be stopped or its dose reduced, as normal thyroid function recovers in 50% of patients within 2–3 months following amiodarone withdrawal.

How is amiodarone-induced thyrotoxicosis treated?

If amiodarone-induced thyrotoxicosis is caused by excessive hormone production by thyroid cells (amiodarone-induced thyrotoxicosis type 1), patients are indicated for anti-thyroid drugs (thionamides). If amiodarone-induced thyrotoxicosis develops due to thyroid destruction caused by high iodine loads and the toxic effects of amiodarone and its metabolite on thyroid cells (amiodarone-induced thyrotoxicosis type 2), treatment is initiated with glucocorticoids. A combination of anti-thyroid drugs and glucocorticoids is used for mixed forms of AIT. Patients with amiodarone-induced thyrotoxicosis and progressive worsening of cardiovascular disease unresponsive to medical therapy, or experiencing adverse drug reactions, are recommended to undergo surgery—total thyroidectomy—as soon as possible.

In what cases should TSH, free T4, and free T3 levels be evaluated during amiodarone therapy?

TSH levels and thyroid peroxidase antibody titers (anti-TPO titers) are assessed prior to initiating amiodarone therapy. If there is no clinical suspicion of thyroid dysfunction, TSH (and free T4, free T3 if necessary) should be re-evaluated no earlier than 3 months after starting treatment, and every 6 months thereafter. Additionally, evaluations of TSH, free T4, and free T3 should be performed upon the appearance of complaints and symptoms that may be attributable to amiodarone-induced hypothyroidism (see section "How does amiodarone-induced hypothyroidism manifest?") or amiodarone-induced thyrotoxicosis (see section "How does amiodarone-induced thyrotoxicosis manifest?").

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable