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MEDICINE REVIEW ARTICLE Amiodarone Induced Thyroid Dsyfunction George J. Kahaly, Markus Dietlein, Roland Gärtner, Klaus Mann, Henning Dralle SUMMARY Introduction: Amiodarone, an iodine containing antiarrhythmic, induces functional thyroid dysfunction in circa 40% of patients receiving it.These disorders can be iodine-induced, or due to immunotoxic effects on thyrocytes. Methods: Selective literature review. Results: 2 types of amiodarone-induced hyperthyroidism are recognized. Type 1 is caused by unregulated hormonal synthesis; type 2 is due to the release of preformed hormone by inflammatory destruction of the gland. Color-flow doppler sonography is a helpful diagnostic tool. In type 1, amiodarone should be discontinued where possible, although this will not immediately restore normal thyroid function. Thionamides, potassium perchlorate, and lithium can be used to treat type 1, and steroids to treat type 2. Patients with mixed forms should be managed with combination therapy. Thyroidectomy is advisable for patients with severe type 1. Amiodarone need not be discontinued in amiodarone-induced hypothyroidism. Discussion: Amiodaroneinduced thyroid complications are best prevented through accurate monitoring of thyroid morphology and function both before and during amiodarone treatment. Dtsch Arztebl 2007; 104(51–52): A 3550–5 Key words: amiodarone, thyroid, thyroid function, interdisciplinary, evidence based R esults of randomized trials have confirmed the superiority of amiodarone in the management of atrial and ventricular arrhythmias (1). The problem with amiodarone therapy, however, is its organotoxicity. Complications that give grounds for concern include therapy refractory thyroid dysfunction (2, 3). Based on recent findings relating to the diagnosis and therapy of thyroid abnormalities associated with amiodarone, up-to-date, evidence based and interdisciplinary recommendations for prophylaxis and practical procedure are offered below. So far, there is a lack of standards approved by all members of the Thyroid Section of the German Society for Endocrinology. This survey article is based on a selective literature review by George J. Kahaly and his co-authors. Prevalence and predisposing factors The prevalence and incidence of amiodarone related thyroid dysfunction are geographically variable and correlate with iodine supply (2). Hypothyroidism tends to be more prevalent in countries with a sufficient iodine supply, such as the USA (22% versus 2% hyperthyroidism), while it is rarer in countries with lower iodine uptake, such as Italy (5%) or the Netherlands (6%) (versus 12% to 13% hyperthyroidism). Worldwide, hyperthyroidism has been described in 1% to 23% and hypothyroidism in 1% to 36% of patients treated with amiodarone (3). The main predisposing factors for amiodarone induced hyperthyroidism are high iodine intake and/or nodular goiter with low basal thyroid stimulating hormone (TSH) (functional autonomy) due to years of iodine deficiency. Genetic factors (such as HLA anti-gens as risk markers for the development of immunothyropathy) are also implicated but are not responsible for a large proportion of the explained variance (see box). The presence of thyroid antibodies and subclinical hypothyroidism predispose individuals with simultaneously elevated iodine intake to develop amiodarone induced hypothyroidism (4). I. Medizinische Univ.-Klinik und Poliklinik, Mainz: Prof. Dr. med. Kahaly; Klinik und Poliklinik für Nuklearmedizin, Universität zu Köln: Prof. Dr. med. Dietlein; Medizinische Univ.-Klinik, Klinikum Innenstadt, LMU München: Prof. Dr. med. Gärtner; Klinik für Endokrinologie, Universitätsklinikum Essen: Prof. Dr. med. Mann; Klinik und Poliklinik für Allgemein-, Viszeral- und Gefäßchirurgie, MLU Halle: Prof. Dr. med. Dralle Dtsch Arztebl 2007; 104(51–52): A 3550–5 ⏐ www.aerzteblatt.de 1 MEDICINE Pharmacology and molecular activity Amiodarone (2-n-butyl-3-[3, 5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran) is a structural congener of the thyroid hormones (diagram 1) and contains 39% parts by weight of iodine. With every tablet (200 mg amiodarone) about 75 mg bound iodine is ingested, with the free portion (9 mg) selectively entering the thyroid gland. This high iodine intake leads to a 40 fold rise in ioduria. The high iodine levels persist for 6 months after discontinuing the medication because amiodarone as a lipophilic substance is stored in fatty tissue (5). The main metabolite is desethylamiodarone, which in most tissues is present in a higher concentration than the parent compound. The half-life of amiodarone is 20 to 100 days. Amiodarone has a wide range of effects on the thyroid gland (table 1): Acute, transient changes in thyroid function Hypothyroidism in patients susceptible to the inhibitory effect of large amounts of iodine Hyperthyroidism due to – iodine induced hyperthyroidism in nodular goiter – an inflammatory destructive condition – immune hyperthyroidism. Amiodarone and its dealkylated metabolites competitively inhibit the extrathyroid conversion of T4 to the active T3 (6). Because of their structural similarity to iodothyronines they continue to be active deiodase inhibitors. Type I 5'-deiodase is preferentially inhibited. Amiodarone and its metabolites also bind to nuclear T3 receptors and change their interaction with co-activators or co-repressors of the transcription T3 regulated genes. Laboratory parameter changes during amiodarone therapy The initial phase of amiodarone therapy is accompanied by a temporary decrease in the fT4 levels and a usually transient TSH elevation due to the inhibitory effect of iodine on the thyroid gland (Wolff-Chaikoff effect). During the course of amiodarone therapy the inhibitory effect of the drug on deiodase activity and the thyroid hormone receptor predominates (6). This leads to increased fT4, reduced fT3, elevated reverse T3, and a temporary rise in TSH (up to 20 mU/L). During the further course the TSH levels normalize or remain slightly suppressed, with the result that the commonest laboratory parameter constellation during long term therapy is as follows: fT4 increase by 20% to 30%, fT3 decrease into the lower range of normal, basal TSH in the lower range of normal or suppressed (7). The case history of a 68-year-old patient presents the findings observed during amiodarone therapy. Thyroid examinations before and during amiodarone therapy Because of the impairments of thyroid function commonly caused by amiodarone, basal TSH, serum-fT3/ -fT4 and thyroid peroxidase (TPO) antibodies should be determined and a thyroid sonographic examination performed before commencing therapy to ensure timely identification of pre-disposed patients and to allow possible subsequent changes in thyroid BOX Predisposing factors for amiodarone induced thyroid dysfunction Hyperthyroidism Nodular goiter Functional autonomy Years of iodine deficiency Subclinical hyperthyroidism Genetic risk factors Hypothyroidism Thyroperoxidase (TPO) antibodies Subclinical hypothyroidism Dtsch Arztebl 2007; 104(51–52): A 3550–5 ⏐ www.aerzteblatt.de 2 MEDICINE Structural similarity between amiodarone and T3/T4 DIAGRAM 1 TABLE 1 Relative risk of amiodarone induced side effects, especially thyroid dysfunction* Total patient years: amiodarone 2580, placebo 2545 Odds Ratio P= Hypothyroidism 7.3 0.00005 Hyperthyroidism 2.5 0.0043 Pulmonary fibrosis 3.1 0.0003 Neuropathy 2.8 0.071 Hepatopathy 2.7 0.0072 Bradycardia 2.6 0.0003 *based on a meta-analysis of a large patient and control population. Reference 1 function to be conclusively attributed to the amiodarone therapy (5, 8). If thyroid nodules with a diameter >1 cm are present or if there is nodular goiter, thyroid scintigraphy is additionally valuable, because hyperfunctional nodules can also be present when TSH values are normal. As a general principle, radioiodide therapy cannot be performed in amiodarone treated patients for up to 1 year after discontinuing the medication (9). The protracted release of iodine from amiodarone prevents the uptake of the radioiodide into the thyroid in therapeutically relevant levels. If TPO antibodies are present, there is an increased risk of developing either clinically overt hypothyroidism or immunogenic hyperthyroidism. Close functional monitoring of the thyroid is required in such cases (diagram 2). During long term amiodarone therapy, regular monitoring of thyroid (fT3/ fT4, TSH and once annually TOP antibodies) and hepatic function is necessary, even in patients with initially normal thyroid function. After the cumulative total dose is reached, these tests should be performed after 3 months and then every 6 months. In several studies, concentrations of amiodarone and its metabolites in plasma showed no clinically relevant correlation with the antiarrhythmic action of the substance. Plasma level concentrations are also without evidential value in regard to tolerability. Side effects and interactions Side effects of amiodarone – depending on the dose and duration of treatment – include not only thyroid dysfunction but also corneal deposits, photosensitization and hyperpigmentation of the skin, pulmonary and hepatic toxicity, and optic neuropathies (table 2). Clinically relevant interactions are an increase in digitalis levels and a potentially increased bleeding Dtsch Arztebl 2007; 104(51–52): A 3550–5 ⏐ www.aerzteblatt.de 3 MEDICINE Diagnosis before and during amiodarone therapy DIAGRAM 2 TABLE 2 Prevalence of side effects of amiodarone* (dose/time dependent) Cases (in percent) Corneal deposits > 90 Photosensitivity 50–75 Thyroid dysfunction 30–40 Toxic hepatitis 20–50 Gastrointestinal complaints 20–30 Neuropathy, tremor 5–30 Interstitial pneumonia 5–20 *based on Reference 10 tendency in anticoagulated patients (10). In digitalized patients it is recommended to reduce the dose by half. If the patient is anticoagulated, the international normalized ratio (INR) value should be checked twice weekly and the dose reduction determined with reference to the target INR. The simultaneous use of drugs metabolized by cytochrome P4503A4 (ciclosporin, statins) and amiodarone – an inhibitor of CYP3A4 – can result in higher plasma levels. If severe complications develop on amiodarone therapy, the administration of colestyramine (3 × 4 to 8 g) or sucralfate (2 × 2 g) can accelerate biodegradation (3). Colestyramine and sucralfate significantly reduce the enterohepatic circulation and therefore accelerate elimination both in acute and long term treatment. Differential diagnosis of AIH The diagnosis of amiodarone induced hyperthyroidism (AIH) requires the determination of basal TSH and fT3 (11). A suppressed TSH (<0.1 mU/L) and elevated fT3 values are decisive for the diagnosis of AIH. Two forms of AIH are distinguished (table 3). Type I is characterized by previous thyroid conditions such as Basedow's disease and nodular goiter as well as increased production of thyroid hormones. The excess thyroid hormone synthesis is the consequence of increased iodine exposure. Since a thyroid diagnostic program is routinely performed prior to initiating elective amiodarone therapy, type I is now rarely observed. Type II usually develops without prior thyroid disease. In this case the mechanism is either an inflammatory destructive effect on the thyroid with increased release of thyroid hormones or the result of drug induced lysosomal activation which leads to destructive thyroiditis with accumulation of histiocytes in the thyroid gland (12). The development of type II AIH cannot be ruled out in advance. Mild forms of Type II can remit spontaneously or lead to hypothyroidism. Color Doppler sonography Dtsch Arztebl 2007; 104(51–52): A 3550–5 ⏐ www.aerzteblatt.de 4 MEDICINE CASE A 68-year-old patient attended our thyroid outpatient department for clarification of de novo thyroid dysfunction. There was a 3 year history of absolute arrhythmia successfully treated with amiodarone (200 mg/day). The patient reported effort dyspnea, sleep problems and digital tremor. Inspection and palpatory examinations revealed no neck abnormalities. Ultrasonographic thyroid volume was 17 mL with echo-deficient, inhomogeneous internal structure and duplex sonography showed slightly increased vascularization. Laboratory tests showed overt hyperthyroidism: TSH < 0.01 mU/L, fT3 6.8 pg/mL, fT4 3.9 ng/dL, thyroperoxidase and thyroglobulin antibodies were elevated, IL-6 also increased at 10 pg/mL (reference value < 6). From these findings we concluded the presence of amiodarone induced immunothyropathy with hyperthyroid metabolic situation (Type II AIH). Prednisolone (initially 50 mg/ day) was therefore prescribed. The amiodarone dose was retained. Control tests soon thereafter showed decreasing but still abnormal peripheral thyroid values and symptoms and we therefore recommended 20 mg/day metamizole. 2 weeks later, fT3 and fT4 were in the normal range. of the thyroid shows increased vascularization in type I and reduced to absent vascularization in type II (13–14). Interleukin 6 levels may be elevated in type II (15) but, like serum thyroglobulin, are unreliable differentiation markers. The thyroid scintigram is characterized by absent technetium storage (11) because the high endogenous iodine levels reduce the uptake of technetium pertechnate. Normal or increased uptake is a rarity and suggests type I. Thyroid scintigraphy is not usually helpful in the differential diagnosis of AIH. Treatment of type I AIH The treatment of AIH is impeded by the fact that the usual thionamides act competitively against iodine in the thyroid, which means that very high doses are needed. Moreover, the side effects of the thionamides on the liver and bone marrow must be considered. Radioiodide therapy is generally ruled out because of the reduced uptake of radioactive iodine. In type I AIH, amiodarone should be discontinued if an alternative antiarrhythmic therapy (beta blockers, flecainide, propafenone) is available. However, amiodarone inhibits the peripheral conversion of T4 to T3, i.e. also exerts thyrostatic action, so that discontinuation can aggravate the hyperthyroidism. Prospective, controlled studies (16–17) and a recent European survey (11) have underlined the role of thionamides in type I AIH (table 4) (18) and that of glucocorticoids in type II AIH. Thionamides Thionamides inhibit thyroperoxidase and the synthesis of thyroid hormones competitively to iodine. In AIH, thionamides have to be highly dosed (metamizole beginning with 40 to 60 mg daily by the oral route, carbimazole 60 to 90 mg daily, propylthiouracil 400 to 600 mg daily). Despite the long half-life of metamizole, a 2 to 3 times daily divided dose schedule is recommended (as for propylthiouracil) with a night interval of about 8 hours. The onset of action is observed after several days (diagram 3). Perchlorate Potassium perchlorate blocks thyroid iodine uptake by directly inhibiting the sodium iodide symporter and hence active thyroid iodine transport (19). The combination of perchlorate and thionamides is more effective. 600 to 1000 mg perchlorate is administered orally in 2 daily doses to reduce the intrathyroid iodine content. Dtsch Arztebl 2007; 104(51–52): A 3550–5 ⏐ www.aerzteblatt.de 5 MEDICINE TABLE 3 Features of amiodarone induced hyperthyroidism (AIH) Characteristics Type I AIH Type II AIH Pre-existing thyroid disease Common No Diffuse/nodular goiter Common No Onset Early (weeks) Late (months) Mechanism (thyroid hormones) Production increased Release Color Doppler sonography Blood flow increased Blood flow decreased Tc uptake (thyroid scan) Unchanged Lowered Serum interleukin-6 levels Unchanged Slightly increased Serum thyroglobulin level Greatly increased Slightly increased Thyroid antibodies (Increased) Normal to elevated Course Severe Mild to severe Histology Inflammatory Destructive Discontinuation of amiodarone Yes No Response to therapy Poor Good Definitive therapy necessary Yes No Transition to hypothyroidism No Possible Risk in later iodine exposure Hyperthyroidism Hypothyroidism Lithium Lithium reduces the release both of the thyroid hormones and iodine and additionally inhibits T4 deiodination (2). In type I, combination therapy with thionamides and lithium normalizes the thy-roid metabolic situation more rapidly (about 4 weeks) than thionamide monotherapy (about 10 weeks). An evening dose of 600 to 900 mg (86 to 130 mmol) and weekly monitoring of blood lithium levels (therapeutic range 0.4 to 1.3 mmol/L) are recommended. Lithium therapy is contraindicated in patients with severe heart failure. Thyroidectomy If thyroid autonomy is causally responsible for type I AIH, it cannot be permanently treated pharmacologically. Only surgical removal of the thyroid tissue remains, provided the patient can be safely subjected to this procedure. The main advantage of surgical management of AIH is the immediate elimination of the hyperthyroidism combined with the possibility of continuing the amiodarone therapy. Although subtotal thyroidectomy can save patients the necessity for lifelong LT4 substitution therapy, there is a risk of relapse. Almost total thyroidectomy is therefore preferable. Perioperative mortality and morbidity are increased in emergency hyperthyroidism, which is why thyroid operations should whenever possible be performed at a center specializing in thyroid surgery (21). Management of type II AIH Glucocorticoids have proved effective in type II AIH because of their anti-inflammatory effects on the destructive inflammatory process and their inhibition of proteolytic lysosomal enzyme activities (22). The additional action of the steroids resulting from inhibition of 5'-deiodase is less decisive, because amiodarone itself is a potent deiodase inhibitor. An initial weight related dose of 1 mg/kg bodyweight prednisolone for 2 weeks is recommended, followed by gradual dose reduction every 2 weeks over a total period of 20 weeks. Steroid therapy is also superior to the oral contrast medium iopanoic acid with a blocking property of T4/T3 conversion. The more pronounced the inflammatory destruction of the organ, the more self limiting is type II AIH. Renewed administration of amiodarone after achieving euthyroid status in type II AIH is therefore justifiable (23). Dtsch Arztebl 2007; 104(51–52): A 3550–5 ⏐ www.aerzteblatt.de 6 MEDICINE TABLE 4 Evidence based recommendations for diagnosis and treatment of type I and II amiodarone induced hyperthyroidism* Evidence grade Recommendation Diagnosis Color Doppler sonography 1a A Interleukin-6 (serum) 2a C Thyroid antibodies (serum) 3a B Tc uptake (scan) 3b C Thyroglobulin (serum) 4 D Treatment Methimazole (in type I) 1a A Perchlorate (in type I) 1b A Steroids (in type II) 1b A Thyroidectomy (in type I) 3a B * These recommendations correspond to those of the Thyroid Section of the German Society for Endocrinology. Evidence grade and grades of recommendation based on Reference 18. Evidence grade: 1a) several randomized prospective studies and meta-analyses with positive detection; 1b) No meta-analysis; 2a) Individual prospective controlled studies with positive detection; 3a) Positive expert opinion with recommendation; 3b) Neutral expert opinion; 4) Individual case reports. Recommendations: A) highly recommended, B) recommended, C) neutral or possible, D) not recommended Management of mixed forms If the differential diagnosis of AIH is not conclusive or if a mixed form is suspected, combined therapy with thionamides and glucocorticoids is recommended (for example metamizole and prednisolone, each beginning with 40 mg daily or 0.5 mg/kg body weight/day [2–3, 10]). Since mixed forms are on the increase, some research groups recommend treating all 3 forms of AIH immediately with the combination therapy (8). Management of amiodarone induced hypothyroidism The transient TSH elevation at the start of treatment is physiological and only needs to be treated if hypothyroidism develops during the course. If amiodarone is indicated, intake need not be discontinued in amiodarone induced hypothyroidism (8, 10). Because of the underlying cardiomyopathy, it is generally recommended to initiate thyroxine substitution of the overt hyperthyroidism with a low initial dose and not to exceed the maintenance dose of 1.5 µg LT4/kg body weight/day. On LT4 therapy, basal serum TSH should be in the upper range of normal. Amiodarone induced subclinical hypothyroidism can be controlled rather by adopting a temporizing approach if clinical symptoms are absent (diagram 4). Amiodarone therapy in pregnancy and lactation Amiodarone crosses the placenta and is excreted in breast milk. The main risks for the fetus are bradycardia, QT interval prolongation and hypothyroidism with goiter. The treatment of 64 pregnant women with amiodarone, however, resulted in the development of goiter in only 3% and transient hypothyroidism in 17% of newborns (24). Mild, scarcely symptomatic neurological retardation and slight speech disorders were observed in a small number of newborns. Otherwise, despite measured high concentrations of amiodarone and desethylamiodarone in breast milk, transient hypothyroidism was observed in only one infant, whose thyroid function normalized after the medication was discontinued. In consideration of these data and the low rate of side effects, the administration of amiodarone appears justified in pregnant women with life threatening cardiac arrhythmias and in the absence of effective alternative medications. Dtsch Arztebl 2007; 104(51–52): A 3550–5 ⏐ www.aerzteblatt.de 7 MEDICINE Procedure for amiodarone induced hypothyroidism DIAGRAM 3 Procedure for amiodarone induced hypothyroidism DIAGRAM 4 Prospects A substance with effective and similar electrophysiological and arrhythmogenic actions and which is iodine-free (dronedarone) is currently in the clinical trials stage. Dronedarone is less lipophilic and has a shorter half-life than amiodarone. Clinical studies suggest that there may well soon be a successor compound for amiodarone (25). Acknowledgement The authors express their very sincere thanks to all the members of the Interdisciplinary Thyroid Section of the German Society for Endocrinology for their critical review of the manuscript and constructive comments. Conflict of Interest Statement The authors declare that no conflict of interest exists according to the guidelines of the International Committee of Medical Journal Editors. 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