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4MODERN VIEWS ON THE PROBLEM OF AMIODARONE-INDUCED THYROID
DYSFUNCTION
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Abdikadirova T.Sh., Nasirova H.K., Trigulova R.X.
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, , Tashkent Pediatric Medical Institute https://doi.org/10.5281/zenodo.8368269
Abstract. This review presents various perspectives of scientists regarding the effectiveness of Amiodarone as a preferred antiarrhythmic drug commonly used for the treatment of ventricular arrhythmias and atrial fibrillation (AF). However, due to the high toxicity of Amiodarone, there is a risk of potential damage to various organs, including the liver, lungs, cornea, skin, and thyroid gland. According to the scientific literature, the most commonly observed disorders associated with Amiodarone use are subclinical hypothyroidism (18%) and overt thyrotoxicosis (15.8%), with less frequent occurrences of overt hypothyroidism (1.5%) and subclinical thyrotoxicosis (1.5%). Continuous research in this field has led to a change in the understanding of the problem and the development of new approaches to the diagnosis and treatment of these disorders.
Keywords: Amiodarone, arrhythmia, Amiodarone-induced thyrotoxicosis, Amiodarone-induced hypothyroidism.
Аннотация. В данном обзоре представлены различные взгляды ученых относительно эффективности Амиодарона в качестве приоритетного антиаритмического препарата, который обычно используется для лечения желудочковых аритмий и фибрилляции предсердий (ФП). Однако, из-за высокой токсичности Амиодарона, существует риск потенциального повреждения различных органов, включая печень, легкие, роговицу, кожу и щитовидную железу. Согласно научной литературе, наиболее часто обнаруживаемыми нарушениями при приеме Амиодарона являются субклинический гипотиреоз (18%) и манифестный тиреотоксикоз (15,8%), реже - явный гипотиреоз (1,5%) и субклинический тиреотоксикоз (1,5%). Непрерывные исследования в этой области позволили изменить взгляд на проблему и разработать новые подходы к диагностике и лечению этих расстройств.
Ключевые слова: амиодарон, аритмия, амиодарон-индуцированный тиреотоксикоз, амиодарон-индуцированный гипотиреоз.
Relevance. Amiodarone is a sufficiently effective antiarrhythmic drug with a proven impact on long-term prognosis, as confirmed by numerous clinical studies such as EMIAT, CIDS, AVID, and others [7]. In addition to its antiarrhythmic action, the drug also influences the function of the thyroid gland in some patients [2, 5]. Amiodarone contains 37% iodine. When a patient takes 200-400 mg of Amiodarone per day, they receive 75-150 mg of organic iodine or 612 mg of inorganic iodine daily (the daily requirement for iodide is 150-200 mcg). As a result, patients receive high doses of Amiodarone, which affects the synthesis and metabolism of thyroid hormones. The high iodine content in Amiodarone increases the plasma concentration of inorganic iodide 40-fold and leads to urinary excretion of iodide up to 15,000 mcg per day. Although most patients taking Amiodarone maintain a euthyroid state, some may develop hypothyroidism or thyrotoxicosis [12].
For several years, changes in thyroid gland function have been one of the reasons for discontinuing the drug or refusing its use. Ongoing research in this area has led to a change in
perspective on the problem and the development of new approaches to the diagnosis and treatment of these disorders [6, 14].
According to international authors, the frequency of thyroid dysfunction varies from 1% to 23%, with the majority of cases falling between 14% and 18% [3]. The type of Amiodarone-induced thyroid dysfunction largely depends on the region's iodine supply [2, 4, 10]. Therefore, patients residing in areas with high iodine consumption are more likely to develop Amiodarone-induced hypothyroidism (AIH), while those in regions with low iodine consumption are more prone to Amiodarone-induced thyrotoxicosis (AIT).
Amiodarone accumulates in various tissues, including adipose tissue, myocardium, liver, and lungs. Its long half-life can reach up to 100 days, primarily due to its accumulation in adipose tissue [9]. Thyroid dysfunction was observed in 14-18% of patients who took amiodarone [11]. The onset of symptoms of amiodarone-induced thyrotoxicosis may occur from 2 to 47 months after discontinuation of amiodarone therapy [9]. A study by R. Rao et al. [1] investigated the kinetics of iodine during 6 months of drug administration. During this time, urinary iodine excretion increased from 0.25 to 7 pmol/mmol creatinine. Thyroidal iodine clearance decreased from 5.93 to 0.25 mL/min, while plasma levels of inorganic iodine increased 40-fold. Thyroidal iodine uptake decreased by 3-fold compared to the baseline. In addition to the aforementioned effects, amiodarone and its metabolite DEA exert cytotoxic effects on the thyroid gland, causing destruction of thyrocytes and non-thyroidal tissue, particularly when there is a high amount of iodine in the molecule [6, 13].
The question of the influence of amiodarone on autoimmune processes in the thyroid gland is controversial [3]. Amiodarone-induced hypothyroidism (AIH) and amiodarone-induced thyrotoxicosis (AIT) are distinguished, which are further classified into types 1 and 2, as well as a mixed form. Type 1 AIT (AIT 1) represents a form of iodine-induced hyperthyroidism that occurs in the presence of nodular goiter or latent Graves' disease, while type 2 AIT (AIT 2) arises from destructive thyroiditis in a normal thyroid gland. Mixed (indeterminate) forms of AIT occur due to a combination of both pathological mechanisms [14]. Amiodarone significantly reduces overall mortality by 13% and arrhythmia-related mortality by 29% [7]. The type of thyroid dysfunction partially depends on the level of iodine consumption, as AIH is relatively more common in areas with high iodine content, while AIT is more prevalent in geographic regions with iodine deficiency [1, 15].
In the early work of L. Bartalena et al. [11], a hypothesis was proposed regarding the elevated synthesis of thyroid hormone by autonomously functioning thyroid tissue in response to iodine. However, the epidemiology of AIT has changed over the past 25 years, as the prevalence of AIT caused by destructive thyroiditis has progressively increased [3]. The prevalence of amiodarone-induced thyroid dysfunction varies depending on the geographical region, the severity of iodine deficiency in the population, and the characteristics of the patient sample (age and gender of the study participants, presence of thyroid diseases). On average, this rate ranges from 14% to 20%. The incidence of AIT ranges from 0.6% to 21%, with a prevalence of 3% in the United States and 5.8% in Japan [8].
AIT type 1 is frequently observed in iodine-deficient regions and often leads to excessive and uncontrolled synthesis of thyroid hormone by autonomously functioning thyroid tissue in response to iodine [2, 14].
Type 2 AIT is most prevalent in regions of the world with sufficient iodine content. It can develop in apparently normal thyroid glands. In type 2 AIT, amiodarone has a direct cytotoxic effect on thyroid follicles and induces inflammation [3, 15].
According to studies conducted in the United Kingdom, men are more predisposed to the disease than women, with a male-to-female ratio of 3:1 [9, 12].
Clinically, the symptoms of AIH do not differ from those of hypothyroidism of other etiology, but severe hypothyroidism can contribute to an increased susceptibility to life-threatening arrhythmias. According to several studies, subclinical hypothyroidism can develop in 26% of patients receiving amiodarone, while manifest hypothyroidism occurs in 5% of patients.
According to the recommendations of the American Thyroid Association and the American Association of Clinical Endocrinologists in 2011 [6], it is stated that the decision to continue amiodarone therapy in the case of thyrotoxicosis should be made on an individual basis after consultation with a cardiologist. Russian experts, who have been studying the issue of amiodarone-induced thyroid dysfunction for many years, also consider it appropriate to perform compensation of thyrotoxicosis or substitute therapy for hypothyroidism while continuing amiodarone treatment if it was prescribed for primary or secondary prevention of fatal ventricular arrhythmias or if discontinuation of the drug is not possible for other reasons (any forms of arrhythmias with severe clinical symptoms that cannot be eliminated by other antiarrhythmic measures) [4]. As mentioned above, in severe cases requiring rapid restoration of thyroid function and in cases where medical therapy is ineffective, thyroidectomy may be performed.
The development of hypothyroidism is not accompanied by a deterioration in the antiarrhythmic efficacy of amiodarone and does not indicate its discontinuation, and substitute therapy with levothyroxine does not lead to a recurrence of cardiac rhythm disturbances [9]. Several small studies have shown the possibility of effectively treating thyrotoxicosis while continuing amiodarone therapy. For example, S.E. Serdyuk et al. [7] did not discontinue treatment with this drug in 87% of patients with amiodarone-induced thyrotoxicosis. In these patients, restoration of euthyroidism was accompanied by an increase in the antiarrhythmic efficacy of amiodarone. F. Osman et al. [14] noted comparable effectiveness in the treatment of amiodarone-induced thyrotoxicosis in patients who continued or discontinued antiarrhythmic therapy with this drug. According to S. Eskes et al. [13], euthyroidism was achieved in all 36 patients with type 2 thyrotoxicosis who received pathogenetic therapy while taking amiodarone. F. Bogazzi et al. [6], in a pilot study, showed that continuing amiodarone therapy may delay the restoration of euthyroidism in patients with type 2 thyrotoxicosis, although this finding needs confirmation in additional studies.
The question of the influence of amiodarone on the thyroid gland in children is rarely discussed in the medical literature, despite the considerable experience of using this antiarrhythmic drug in pediatric cardiology. Some authors have described that thyroid dysfunction induced by amiodarone develops in one out of every five children [8]. The likelihood of developing amiodarone-induced thyroid disorders in children is not dependent on the dose or duration of the antiarrhythmic drug administration [1, 5].
Studies have shown that the metabolism of amiodarone in children occurs faster than in adults, depending on the half-life of amiodarone and the volume of adipose tissue, resulting in an increased incidence of AIT with age [9].
Therefore, all patients who are planned to receive amiodarone should undergo an assessment of thyroid gland function and structure. This allows not only the detection of thyroid pathology but also the prediction of potential development of thyrotoxicosis or hypothyroidism after the initiation of therapy.
The diagnosis of AIT typically involves an increase in the levels of one or both free fractions of thyroid hormones and a decrease in TSH levels. Antithyroid antibodies, such as antibodies to antithyroid peroxidase, are usually positive in AIT type 1 and negative in AIT type 2, although their presence is not obligatory for establishing the diagnosis of AIT type 1.
Conclusion. Recent studies allow for the optimization of management strategies for patients with AIT. It is crucial to determine the type of AIT, as the treatment approach depends on it. Prior to initiating amiodarone therapy, it is necessary to assess thyroid gland function in all patients. Differential diagnosis of thyrotoxicosis syndrome is essential, as identifying the type of thyrotoxicosis is crucial due to the varying therapeutic approaches. Therefore, the investigation of both type 1 and type 2 AIT remains relevant due to conflicting data on the effectiveness of different treatment approaches (depending on the type of AIT) from various studies [10].
Thorough diagnostic evaluation of the thyroid gland's condition prior to amiodarone administration, as well as during follow-up in patients receiving long-term amiodarone treatment, especially at doses exceeding 200 mg/day, is highly necessary due to the potential development of serious complications during therapy.
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