269-278/Art. 1.1457   16-10-2006    15:24   Pagina 269

             European Review for Medical and Pharmacological Sc...
269-278/Art. 1.1457     16-10-2006       15:24    Pagina 270

                                             S. Ursella, ...
269-278/Art. 1.1457    16-10-2006      15:24    Pagina 271

                                      Amiodarone-induced th...
269-278/Art. 1.1457   16-10-2006   15:24   Pagina 272

                                       S. Ursella, A. Testa, M. ...
269-278/Art. 1.1457   16-10-2006      15:24     Pagina 273

                                     Amiodarone-induced thy...
269-278/Art. 1.1457   16-10-2006    15:24   Pagina 274

                                        S. Ursella, A. Testa, M...
269-278/Art. 1.1457   16-10-2006   15:24   Pagina 275

                                   Amiodarone-induced thyroid dy...
269-278/Art. 1.1457   16-10-2006    15:24    Pagina 276

                                        S. Ursella, A. Testa, ...
269-278/Art. 1.1457   16-10-2006    15:24    Pagina 277

                                    Amiodarone-induced thyroid...
269-278/Art. 1.1457   16-10-2006    15:24   Pagina 278

                                        S. Ursella, A. Testa, M...
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Amiodarone-induced thyroid dysfunction in clinical practice

  1. 1. 269-278/Art. 1.1457 16-10-2006 15:24 Pagina 269 European Review for Medical and Pharmacological Sciences 2005; 10: 269-278 Amiodarone-induced thyroid dysfunction in clinical practice S. URSELLA, A. TESTA, M. MAZZONE, N. GENTILONI SILVERI Department of Emergency Medicine, Catholic University of the Sacred Heart, Policlinico “A. Gemelli” – Rome (Italy) Abstract. – Amiodarone is a potent class III ment of ventricular arrhythmias, paroxysmal anti-arrhythmic drug used in clinical practice for supraventicular tachycardia, atrial fibrillation and the prophylaxis and treatment of many cardiac flutter1. rhythm disturbances, ranging from paroxismal As a category type-III anti-arrhythmic drug, its atrial fibrillation to life threatening ventricular tachyarrhythmias. Amiodarone often causes main mechanism of action is to block myocardial changes in thyroid function tests mainly related to potassium channels, but it also possesses some the inhibition of 5’-deiodinase activity resulting in beta-blocking properties2. a decrease in the generation of T3 from T4 with a Although highly effective in patients with ar- consequent increase in rT3 production and a de- rhythmias, its use in clinical practice is associat- crease in its clearance. In a group of amiodarone- ed with a wide array of adverse effects. With the treated patients there is overt thyroid dysfunction, cornea, the lungs, the liver, and the skin, the thy- either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH). AIT is roid is one of the major organs affected. primarily related to excess iodine-induced thyroid The aim of this review is to analyse the diag- hormone synthesis in an abnormal thyroid gland nostic and therapeutic aspects of amiodarone-in- (type I AIT) or to amiodarone-related destructive duced thyroid dysfunction according to recent lit- thyroiditis (type II AIT). The pathogenesis of AIH is erature. related to a failure to escape from the acute Wolff- All English language articles related to amio- Chaikoff effect due to defects in thyroid hormono- genesis, or, in patients with positive thyroid au- darone and the thyroid were searched in MED- toantibody test, to concomitant Hashimoto’s thy- LINE from 1966 to 2006. The keywords includ- roiditis. Both AIT and AIH may develop either in ed amiodarone and thyroid. The selection criteria apparently normal thyroid glands or in glands included all prospective and retrospective stud- with preexisting, clinically silent abnormalities. ies, all clinical and basic reviews and basic sci- AIT is more common in iodine-deficient regions of ence papers involving the pathophysiology of the world, whereas AIH is usually seen in iodine- amiodarone. sufficient areas. In contrast to AIH, AIT is a diffi- cult condition to diagnose and treat, and discon- tinuation of amiodarone is usually recommended. In this review we analyse, according to data from Pharmacology of Amiodarone current literature, the alterations in thyroid labora- tory tests seen in euthyroid patients under treat- Amiodarone is a benzofuranic derivative ment with amiodarone and the epidemiology and whose structural formula closely resembles that treatment options available of amiodarone-in- duced thyroid dysfunctions (AIT and AIH). of human thyroid hormone T4. It contains ap- proximately 37% iodine by weight. The mainte- Key words: nance daily dose of the drug in clinical practice Amiodarone, Thyroid dysfunction, Thyrotoxicosis, Hy- ranges from 200 to 600 mg and, because approx- pothyroidism. imately 10% of the molecule is deiodinated daily, approximately 7-21 mg iodide are made avail- able each day, resulting in a marked increase in Introduction urinary iodide excretion3. If one considers that the optimal daily iodine Amiodarone is a potent anti-arrhythmic drug intake is 150-200 µg, amiodarone treatment re- used in clinical practice for the acute manage- lease 50- to 100-fold excess iodine daily4. Corresponding Author: Stefano Ursella, MD; e-mail: steura@hotmail.com. 269
  2. 2. 269-278/Art. 1.1457 16-10-2006 15:24 Pagina 270 S. Ursella, A. Testa, M. Mazzone, N. Gentiloni Silveri Furthermore, amiodarone is distributed in sev- significant variations, even during the first day eral tissues, including adipose tissue, liver, lung, of therapy9,10. and, to a lesser extent, kidneys, heart, skeletal • Amiodarone may induce a hypothyroid-like muscle, thyroid, and brain from which it is slow- condition at the tissue level partly related to a ly released5. reduction in the number of catecholamine re- The elimination half-lives averaged 52 ± 23.7 ceptors and to a decrease in the effect of T3 on days for amiodarone and 61.2 ± 31.2 days for its beta-adrenoreceptors11. metabolite desethylamiodarone (DEA) after cessa- • Direct toxic effect of the drug on thyroidal tion of long term amiodarone therapy5. Those con- cells12. siderations explain why, after amiodarone with- • Failure to escape from Wolff-Chaikoff effect13. drawal, the drug and its metabolites remain avail- • In susceptible individuals amiodarone may able for long period. Amiodarone is metabolised precipitate or exacerbate preexisting organ- through dealkylation, which leads to formation of specific autoimmunity14. DEA and approximately 66-75% of amiodarone is • Unregulated hormone synthesis (Jod-Basedow eliminated through bile and feces3. effect)15. Amiodarone and the Thyroid Effects of Amiodarone in Euthyroid Patients Although the majority of the adverse effects of amiodarone on several organs are due to deposi- Although amiodarone-induced thyroid dys- tion of the drug in the parenchyma, its effects on function represents an important clinical problem, the thyroid gland can be divided in two groups: the majority of patients receiving amiodarone re- intrinsic effects resulting from the inherent prop- main euthyroid. Because the thyroid gland is ex- erties of the compound and iodine-induced ef- posed to an extraordinary load of iodine with fects due solely to the pharmacologic effects of a amiodarone, important adjustments are made in large iodine load (Table I). thyroidal iodine handling and hormone metabo- Amiodarone acts on thyroid function through lism in order to maintain normal function16, the several mechanisms: reflection of which is seen in serum thyroid hor- mone levels. Those alterations in serum thyroid • Inhibits thyroid hormone entry into peripheral function tests can be divided into acute (less than tissues6. 3 months) and chronic (more than 3 months) • Inhibition of type I 5’-deiodinase activity phases that follow amiodarone exposure during which removes an atom of iodine from the the pharmacologic therapy17 (Table II). outer ring of T4 to generate T3 and from the outer ring of rT3 to produce 3,3’-diiodothyro- nine (T2). This inhibition may persist for sev- Acute Effects eral months after amiodarone withdrawal7,8. • Inhibition of type II 5’-deiodinase which con- Serum T4 and T3 verts T4 to T3 in the pituitary. Indeed, after a The pharmacological concentrations of iodide loading dose of amiodarone by intravenous in- associated with amiodarone treatment lead to a fusion, TSH is the first hormone to undergo protective inhibition of thyroidal T4 and T3 syn- Table I. Effects of amiodarone on the thyroid gland. Intrinsic drug effect Iodine-induced effects • Blockade of thyroid hormone entry into cells • Failure to escape from Wolff-Chaikoff effect • Inhibition of type I and type II 5’-deiodinase • Iodine-induced potentiation of thyroid autoimmunity • Decreased T3 binding to its receptor • Unregulated hormone synthesis (Jod-Basedow effect) • Thyroid cytotoxicity Modified from: Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005;118: 706-714. 270
  3. 3. 269-278/Art. 1.1457 16-10-2006 15:24 Pagina 271 Amiodarone-induced thyroid dysfunction in clinical practice Table II. Effects of amiodarone on thyroid function tests in euthyroid subjects. Thyroid Hormone Acute effects (up to 3 months) Chronic effects (> 3 months) Total and free T4 ↑ 50% Remains ↑ 20-40% of baseline Total and free T3 ↓ 15-20%, remains in low-normal range Remains ↓ 20%, remains in low-normal range rT3 ↑ > 200% Remains ↑ > 150% TSH ↑ 20-50%, transient, generally remains Normal < 20 mU/L Modified from: Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005;118: 706-714. thesis and release by thyroid tissue (called the lin, changes in FT4 and FT3 concentrations re- Wolff-Chaikoff effect) within the first two weeks flect those for total T4 and T320. of treatment18. Amiodarone also inhibits the 5’-deiodination Serum Reverse T3 (rT3) of T4 to T3 in the peripheral tissues, especially The reduction of peripheral metabolism leads to the liver and this inhibition persists during and increased rT3 levels with amiodarone treatment. for several months after the amiodarone treat- ment. The result is that serum T4 rises from pre- Serum Thyroid Stimulating Hormone (TSH) treatment concentrations by an average of 40% Serum TSH concentration rises transiently after two months and remains at this higher level within a few days of starting amiodarone (Table thereafter19,20,21. III), but rarely reaches greater than 20 mU/l (ref- The absolute serum T4 in patients on moderate erence range 0.35-4.3 mU/l)21,25. doses of amiodarone (200 mg/day) is usually to- TSH then gradually return to baseline concen- wards the upper limit of the reference range (71- trations, or even slightly below, over the next one 166 nmol/l). A group of clinically euthyroid pa- to three month21,25,26. tients will have serum T4 concentrations greater The early rise in plasma TSH occurs largely in than 166 nmol/l and this increases with higher response to falling intrapituitary T3 concentra- daily doses of amiodarone19. tions consequent on reduced 5’-deiodination of Serum T3 concentrations fall during amio- T4 to T3, especially within the pituitary. Further- darone treatment, initially in part due to reduced more, desethylamiodarone (DEA), the principal thyroid synthesis and secretion, but principally metabolite of amiodarone, binds to intracellular because of reduced 5’-deiodination of T4 to T3 T3 receptors and acts as a T3 antagonist27. in peripheral tissues. T3 concentration usually re- main within the reference range (1.3-3.0 nmol/l), but occasionally fall below 1.3 nmol/l22-24. Chronic Effects Free T4 (FT4) and Free T3 (FT3) After 3 months of amiodarone administering, a As amiodarone has no effect on the serum steady state is reached, with some hormonal concentration of thyroid hormone binding globu- changes persisting indefinitely. Total and free T4 Table III. Reference ranges for serum thyroid hormones and TSH concentrations in euthyroid untreated subjects and in euthyroid pa- tients receiving long-term amiodarone therapy. Test Untreated patients Patients on amiodarone treatment Free T4 (pmol/l) 11-20 12-24.7 Free T3 (pmol/l) 3-5.6 2.5-5.1 TSH (mU/l) 0.35-4.3 0.35-4.3 Modified from: Newman CM, Price A, Davies DW, Gray TA, Weetman AP. Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy. Heart 1998; 79: 121-127. 271
  4. 4. 269-278/Art. 1.1457 16-10-2006 15:24 Pagina 272 S. Ursella, A. Testa, M. Mazzone, N. Gentiloni Silveri and rT3 remain at the upper end of normal or treatment before the occurrence of AIT is about 3 slightly elevated, and serum T3 levels remain in years. That fact may be partially due to tissue the low normal range. In contrast, serum TSH lev- storage of the drug and its metabolites and to their els return to normal after 12 weeks of therapy25. slow release in blood flow so that the effect of The cause for TSH normalization is presumed amiodarone can persist for a long period of time. to be an increase in the T4 production rate, possi- A relative predominance of AIT among men, bly the result of increased intrathyroidal iodine with a M:F ratio of 3:1, has been reported35,36. stores and escape from the Wolff-Chaikoff effect AIT may develop both in a normal thyroid that partially overcomes the blockade of T3 gen- gland or in a gland with pre-existing abnormali- eration and raising serum T3 levels into the low- ties. Humoral thyroid autoimmunity seems to play normal range4,18,28,29. little role in the development of thyrotoxicosis in Despite having high total and free T4 levels, patients without underlying thyroid disorders37. amiodarone-treated patients are considered to be A possible pathogenic hypothesis suggests that euthyroid because the serum concentration of T3, thyrotoxicosis is due to excessive thyroid hormone the major hormone responsible for end-organ ef- synthesis induced by the iodine load. In those pa- fects, is in the low-normal range18. tients with underlying thyroid disorder and resid- In summary, chronic amiodarone treatment for ing in a mildly iodine deficient area, the thyroid more than three months in clinically euthyroid gland may fail to adapt normally to the excess io- patients is usually associated with high-normal or dine load during amiodarone therapy, maybe be- raised T4 and FT4, low-normal T3 and FT3, low- cause of the presence of autonomously function- normal TSH, and high rT3 plasma concentrations ing nodules resulting in unappropriately elevated (see Table II). radioiodine uptake values. That subgroup of AIT Using 99mTc thyroid scintigraphy the visualiza- patients usually have normal or slightly elevated tion of the gland appear very difficult and the 131I serum interleukine-6 (IL-6) levels38. uptake remains constantly depressed30 in euthy- The form of AIT with an underlying thyroid roid patients treated with amiodarone. disease, normal/elevated radioactive iodine up- take (RAIU) values, normal/slightly elevated serum IL-6 levels, color flow Doppler sonogra- Amiodarone-Induced phy patterns (patterns I-III) associated with a hy- Thyroid Dysfunction perfunctioning gland with hypervascularity and due to excessive thyroid hormone synthesis has Although the majority of patients given amio- been defined as type I AIT. darone remain euthyroid, some develop thyroid dys- In patients with apparently normal thyroid function like thyrotoxicosis and hypothyroidism30,31. glands the pathogenetic mechanism is related to Amiodarone-induced thyrotoxicosis (AIT) a thyroid-destructive process with swelling of appears to occur more frequently in geograph- follicular cells, vacuolisation of the cytoplasm ical areas with low iodine intake, whereas and fibrosis at the hystopathological examination amiodarone-induced hypothyroidism (AIH) is and associated leakage of preformed hormones more frequent in iodine-sufficient areas32,33. from damaged follicles. That form of thyroid In general the various published studies reported dysfunction following amiodarone therapy has in overall incidence of AIT ranging from 1% to been defined as type II AIT38. 23% and of AIH ranging from 1% to 32%8. Signif- Type I AIT is more common in iodine-deficient icant risk factors for the occurrence of amiodarone- parts of the world like Europe while type II AIT is associated thyroid dysfunction are recognized. more frequent in iodine-sufficient area of the Those risk factors are female sex, complex cyanot- world like United States and United Kingdom39. ic heart disease, previous Fontan-type surgery, and Nevertheless definitions of AIT may not be so a dose of amiodarone > 200 mg/day34. absolute and in fact mixed forms often exist, in which different features of type I and type II AIT may be present38. Amiodarone-Induced Thyrotoxicosis (AIT) Clinical Manifestations AIT may develop early or after many years of In patients presenting AIT the classical symp- amiodarone treatment and the average length of toms of thyrotoxicosis may be absent, due to an- 272
  5. 5. 269-278/Art. 1.1457 16-10-2006 15:24 Pagina 273 Amiodarone-induced thyroid dysfunction in clinical practice tiadrenergic action of amiodarone and its impair- Treatment ment of conversion of T4 to T3. Goiter my be present or absent, with or without pain in the cer- Type I AIT. In type I AIT the goal of therapy vical region; ophtalmopathy is often absent, un- should be to block further organification of iodine less AIT occurs in a patient with Graves’ and thus to block the synthesis of thyroid hor- disease40. mones. Since the iodine rich thyroid during amio- Physicians can suspect an AIT condition by a darone assumption is more resistant to thionamides, worsening of the underlying cardiac disorder larger than usual daily doses of methimazole (40-60 with tachyarrhythmias or angina during amio- mg) or propylthiouracil (600-800 mg) are often darone treatment. necessary. Another target of the therapeutic strategy The occurrence or recurrence of tachycardia or is also to decrease the entrance of iodine into thy- atrial fibrillation in a patient treated with amio- roid and deplete intrathyroidal iodine stores. The darone should be considered a good reason to in- latter effect can be achieved by potassium perchlo- vestigate thyroid function41. rate (1 g daily) that inhibits thyroid iodine uptake44. Physicians should make efforts to differentiate Simultaneous administration of potassium between the two types of AIT because those two perchlorate and methimazole is associated with a types of AIT will be treated differently. However shorter period of time for the attainment of eu- this may result very difficult in clinical practice thyroidism than in patients responsive to conven- because in general laboratory studies of thyroid tional thionamide treatment45,46. function do not discriminate type II AIT from Nevertheless the use of potassium perchlorate type II AIT: serum free T4 levels are elevated, is limited by its toxicity particularly agranulocy- TSH levels are suppressed, and serum T3 levels tosis, aplastic anemia and renal side effects. A may be normal or elevated17 (Table IV). complete blood count should be done every few Serum thyroglobulin (TG) may markedly in- weeks in patients receiving thionamide and per- crese in AIT patients for increased production chlorate to detect haematological alterations. and for amiodarone-induced follicular damage30. Type II AIT. In type II AIT thionamide and Otherwise, few elements may drive physicians potassium perchlorate are not considered an ap- to differential diagnosis between type I and type propriate therapy. Because of their membrane- II type of AIT: antithyroid antibodies are more stabilizing, anti-inflammatory effects and inhibi- often positive in type I AIT than in type II; the tion of 5’-deiodinase, steroids are a good and ef- levels of serum IL-6 has been reported to be nor- fective therapeutic strategy47. mal or only minimally elevated in AIT type II Steroids have been used in type II AIT at dif- whereas it is reputed to be elevated in the AIT ferent doses (15-80 mg prednisone or 3-6 mg type 2 (an inflammatory process)38. dexamethasone daily) and with different time Color flow Doppler sonography may help to schedules (7-12 weeks)40. discriminate type I AIT that is associated with a For the subgroup of patients with mixed forms high thyroidal blood flow, from type II AIT char- of AIT, a combination of methimazole, potassi- acterized by a destructive thyroiditis with a low um perchlorate, and steroids is probably the most internal thyroidal blood flow39,42,43. beneficial therapeutic regimen48. Table IV. Different features of type I and II amiodarone-induced thyrotoxicosis (AIT). Type I Type II Underlying thyroid abnormality Yes No Pathogenesis Excessive hormone synthesis Destructive thyroiditis Thyroidal radioiodine uptake Normal/raised Low/absent Serum IL-6 Normal/Slightly raised Profoundly raised Thyroid ultrasound Nodular, hypoechoic, volume Normal Color flow Doppler sonography High thyroidal blood flow Low thyroidal blood flow Modified from: Newman CM, Price A, Davies DW, Gray TA, and Weetman AP. Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy. Heart 1998; 79:121-127. 273
  6. 6. 269-278/Art. 1.1457 16-10-2006 15:24 Pagina 274 S. Ursella, A. Testa, M. Mazzone, N. Gentiloni Silveri Thyroidectomy may represent a valid option synthesis and the inability to escape from the for AIT patients in which withdrawal of amio- acute Wolff-Chaikoff effect33. darone is not feasible and in those patients resis- In AIH patients without underlying thyroid ab- tant to medical treatment, although the underly- normalities and with negative thyroid autoanti- ing cardiac conditions and the thyrotoxic state body tests, subtle defects in iodine organification may increase the surgical risk or even exclude and thyroid hormone synthesis are likely the best surgery in some patients49. explanation for the occurrence of AIH. It has In patients with a history of AIT in whom been reported that AIH may spontaneously remit amiodarone becomes necessary after it has been after discontinuation of amiodarone treatment discontinued, ablation of the thyroid with ra- within 2-4 months26,33. dioiodine before resuming amiodarone should be strongly considered48. Plasmapheresis aimed at removing the excess of Clinical Manifestations thyroid hormone from the circulation, has been re- ported to be efficacious but the effect is often tran- AIH typically occurs between 6-12 months of sient and followed by an exacerbation of AIT50. treatment with amiodarone51 and AIH patients frequently have vague symptoms and signs like fatigue, lethargy, cold intolerance, mental slug- gishness, and dry skin52. Myxedema coma has Amiodarone-Induced Hypothyroidism been reported in a patient taking amiodarone56. (AIH) In patients already on L-T4 replacement thera- py, the dose of L-T4 may need to be increased Amiodarone-induced hypothyroidism (AIT) due to the inhibition of the generation of T3 from occurs more frequently than AIT in iodine-suffi- T4 induced by amiodarone57. cient areas32. In contrast to AIT, AIH is slightly Laboratory tests show decreased serum free more frequent in females, with a M:F ratio of T4, increased serum TSH concentrations and in- 1:1.551. AIH patients are older than AIT ones and creased serum thyroglobulin because of the en- AIH usually develops earlier than AIT both in hanced thyroid stimulation by TSH8,33. patients with preexisting thyroid abnormalities52. Serum thyroglobulin is often increased, proba- In the study of Trip et al, female sex or the bly because of the enhanced thyroid stimulation presence of circulating anti-thyroid peroxidase by TSH30,33. (TPO) antibodies represented a relative risk of 7.9 and 7.3 respectively for the occurrence of AIH and the combination of female sex and an- Treatment tithyroid antibodies increased the risk to 13.551. Baseline elevation of TSH before starting If amiodarone can’t be discontinued for un- amiodarone has also been shown to be a risk fac- derlying cardiac disorder, it can be continued in tor for the development of AIH, probably reflect- association with L-T4 replacement which re- ing underlying autoimmune thyroid disease53. quires once-daily administration. The serum Furthermore there was no difference in the TSH concentration is the most important para- daily amiodarone dose or its serum concentra- meter to monitor therapy and adjusting the tions between euthyroid patients and those who dosage of L-T4. developed hypothyroidism51. Low-dose L-T4 therapy can be initiated, start- The most likely pathogenic mechanism is that ing with 25-50 µg/die. Serum TSH levels should the thyroid gland of these patients damaged by be assessed after 4-6 weeks, and the LT4 dose in- preexisting Hashimoto’s thyroiditis, is unable to creased slowly until the serum TSH has returned escape from the acute Wolff-Chaikoff effect after to normal values. The dose of L-T4 needed to an iodine load54 and to resume normal thyroid normalize serum TSH may be higher in amio- hormone synthesis48. An endemic iodine-induced darone-treated patients compared with conven- goiter has been described in adults in Okkaido, tional hypothyroid patients, possibly the result of Japan55. decreased intrapituitary T3 production due to in- A subtle defect in thyroid hormonogenesis hibition of pituitary type II 5’-deiodinase57. may explain the enhanced susceptibility to the If discontinuation of amiodarone is feasible, inhibitory effect of iodine on thyroid hormone spontaneous remission of hypothyroidism often 274
  7. 7. 269-278/Art. 1.1457 16-10-2006 15:24 Pagina 275 Amiodarone-induced thyroid dysfunction in clinical practice occurs within 2-4 months, particularly in patients ly to permit the identification of hypothyroidism without underlying thyroid abnormalities, while (see Figure 1). If equivocal biochemical results this outcome is less likely to occur in patients are obtained in clinically euthyroid patients, sug- with Hashimoto’s thyroiditis33. gestive of subclinical hypothyroidism or thyro- Thyroxine therapy can be administered if toxicosis, then further testing in six weeks is rec- the patient is symptomatic but, because hy- ommended. The presence of thyroid antibodies pothyroidism may resolve in patients without in patients with a moderately raised TSH is a underlying thyroid autoimmunity, patients strong supportive evidence of hypothyroidism should be re-evaluated after 6-12 months of and probably merits treatment with T4 without therapy to determine the continuing need for further delay. LT4 therapy17. Type II AIT has an explosive onset, and is difficult to predict, while type I AIT can occur months or even years after discontinuation of Amiodarone in Pregnancy amiodarone therapy. Some patients with treated type II AIT will eventually become hypothy- Mild mental retardation and impaired speech roid due to extensive damage to thyroid tissue, and language skills were reported in only a few as will some type I AIT patients treated with children exposed to amiodarone in utero58. radioiodine61. Hence, amiodarone can reasonably be admin- Careful and prolonged monitoring of thyroid istered to pregnant women if they have life- function in all patients with history of thyrotoxi- threatening or refractory arrhythmias that are re- cosis is therefore mandatory, even after amio- sistant to other anti-arrhythmics. Serial sono- darone is withdrawn. grams should be performed to detect fetal goiter. Patients should be counseled regarding the Iodine-induced goiter, with or without hypothy- symptoms of hyperthyroidism and hypothy- roidism, can cause severe dyspnoea in new- roidism and, once thyroid dysfunction is detect- borns55,59. ed, the patients should be referred to an endocri- If a goiter is seen, intra-amniotic LT4 therapy nologist for evaluation17. should be considered because it has been shown to be effective60. If a mother decides to breast feed while on Follow-up in patients receiving amiodarone amiodarone, serial evaluation of thyroid function tests should be performed in the infant, and ap- Baseline Thyroid tests: TPO Antibodies, propriate treatment promptly initiated if hypothy- TSH, FT4, FT3 roidism develops. Every 6 months Thyroid tests: TSH, FT4, FT3 Serum TSH ↑ Serum TSH ↓ Monitoring Thyroid Function in Patients Taking Amiodarone Baseline thyroid function testing should be un- dertaken before starting treatment and should in- Increased FT4, No change FT3 vs previous clude thyroid ultrasonography, serum TSH and FT4, FT3 values thyroid antibodies. Patients with pre-treatment normal-high levels of serum TSH and/or thyroid antibodies and thyroid ultrasound pattern of Hashimoto’s thyroditis are at increased risk of developing hypothyroidism and require close fol- Frequent low-up. Those patients with nodular goiter seen AIT AIH observations at thyroid ultrasound and/or with low TSH con- centrations are probably at increased risk of de- Figure 1. Flow chart for the follow-up of patients receiv- veloping type I AIT. ing amiodarone therapy. Modified from: Martino E, Bartale- Serum TSH concentrations should be mea- na L, Bogazzi F, Braverman LE. The effects of amiodarone sured every six months during treatment primari- on the thyroid. Endocrin Rev 2001;22(2):240-254. 275
  8. 8. 269-278/Art. 1.1457 16-10-2006 15:24 Pagina 276 S. Ursella, A. Testa, M. Mazzone, N. Gentiloni Silveri Conclusions 10) IERVASI G, CLERICO A, BONINI R, MANFREDI C, BERTI S, RAVANI M, PALMIERI C, CARPI A, BIAGINI A, CHOPRA IJ. Acute effects of amiodarone administration on Amiodarone is a very effective antiarrhythmic thyroid function in patients with cardiac arrhyth- drug, widely used in clinical practice for tach- mia. J Clin Endocrinol Metab 1997; 82: 275-280. yarrhytmias. Physician should know that its use 11) D ISATNIK MH, S HAINBERG A. Regulation of beta- is associated with variations in thyroid function adrenoceptors by thyroid hormone and amio- tests that don’t reflect true changes in thyroid darone in rat myocardiac cells in culture. function. However a group of amiodarone treated Biochem Pharmacol 1991; 41: 1039-1044. patients develop either hypothyroidism or thyro- 12) CHIOVATO L, MARTINO E, TONACCHERA M, SANTINI F , toxicosis in apparent normal glands or in glands LAPI P MAMMOLI C, BRAVERMAN LE, PINCHERA A. Stud- , with preexisting abnormalities. ies on the in vitro cytotoxic effect of amiodarone. The follow-up and clinical monitoring of thy- Endocrinology 1994;134:2277-2282. roid status in patients undergoing chronic treat- 13) BRAVERMAN LE, INGBAR SH, VAGENAKIS AG, ADAMS L, ment with amiodarone is mandatory in order to M ALOOF F. Enhanced susceptibility to iodine diagnose as soon as possible a starting amio- myxedema in patients with Hashimoto’s disease. J Clin Endocrinol Metab 1971; 32: 515-521. darone-induced thyroid dysfunction. 14) RABINOWE SL, LARSEN PR, ANTMAN EM, GEORGE KL, FRIEDMAN PL, JACKSON RA, EISENBARTH GS. Amio- darone therapy and autoimmune thyroid disease. References Increase in a new monoclonal antibody-defined T cell subset. Am J Med 1986; 81: 53-57. 1) TESTA A, OJETTI V, MIGNECO A, SERRA M, ANCONA C, DE LORENZO A, GENTILONI SILVERI N. Use of amio- 15) STANBURY JB, ERMANS AE, BOURDOUX P TODD C, OKEN , darone in emergency. Eur Rev Med Pharmacol E, TONGLET R, VIDOR G, BRAVERMAN LE, MEDEIROS-NE- Sci 2005; 9: 183-190. TO G. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 1998; 8: 83-100. 2) HARTONG R, WIERSINGA WM, PLOMP TA. Amiodarone reduces the effect of T3 on beta adrenergic re- 16) HALMI NS. Regulation of rat thyroid in short-term ceptor density in rat heart. Horm Metab Res iodine deficiency. Endocrinology 1954; 54: 216. 1990; 22: 85-89. 17) BASARIA S, COOPER DS. Amiodarone and the thyroid. 3) RAO RH, MCREADY VR, SPATHIS GS. Iodine kinetic Am J Med 2005; 118: 706-714. studies during amiodarone treatment. J Clin En- 18) LAMBERT MJ, BURGER AG, GALEAZZI RL, ENGLER D. Are docrinol Metab 1986; 62: 563-567. selective increases in serum thyroxine (T4) due 4) D ELANGE FM, E RMANS AM, I ODINE DEFICIENCY. In: to iodinated inhibitors of T4 monodeiodination in- Braverman LE, Utiger RD (eds) Werner and Ing- dicative of hyperthyroidism? J Clin Endocrinol bar’s The Thyroid–A clinical and fundamental Metab 1982; 55: 1058-1065. text, ed 8. Philadelphia: Lippincott-Raven; 2000: 19) AMICO JA, RICHARDSON V, ALPERT B, KLEIN I. Clinical 295-315. and chemical assessment of thyroid function dur- 5) H OLT DW, T UCKER GT, J ACKSON PR, S TOREY GCA. ing therapy with amiodarone. Arch Intern Med Amiodarone pharmacokinetics. Am Heart J 1983; 1984; 144: 487-490. 106: 843-847. 20) FRANKLYN JA, DAVIS JR, GAMMAGE MD, LITTLER WA, 6) KRENNING EP DOCTER R, BERNARD B, VISSER T, HENNE- , RAMSDEN DB, SHEPPARD MC. Amiodarone and thy- MANN G. Decreased transport of thyroxine (T4), roid hormone action. Clin Endocrinol (Oxf) 1985; 3,3',5-triiodothyronine (T3) and 3,3',5'-triiodothy- 22: 257-264. ronine (rT3) into rat hepatocytes in primary cul- 21) NADEMANEE K, SINGH BN, CALLAHAN B, HENDRICKSON ture due to a decrease of cellular ATP content JA, HERSHMAN JM. Amiodarone, thyroid hormone and various drugs. FEBS Lett 1982; 140: 229- indexes, and altered thyroid function: long-term 233. serial effects in patients with cardiac arrhythmias. 7) A ANDERAUD S, S UNDSFJORD J, A ARBOKKE J. Amio- Am J Cardiol 1986; 58: 981-986. darone inhibits the conversion of thyroxine to tri- 22) BURGER A, DINICHERT D, NICOD P JENNY M, LEMARC- , iodothyronine in isolated rat hepatocytes. En- HAND -B ERAUD T, VALLOTTON MB. Effect of amio- docrinology 1984; 115: 1605-1608. darone on serum triiodothyronine, reverse tri- 8) HARJAI KJ, LICATA AA. Effects of amiodarone on thy- iodothyronine, thyroxin, and thyrotropin. J Clin In- roid function. Ann Intern Med 1997; 126: 63-73. vest 1976; 58: 255-259. 9) SAFRAN M, FANG S-L, BAMBINI G, PINCHERA A, MARTINO 23) S OGOL PB, H ERSHMAN JM, R EED AW, D ILLMANN E, BRAVERMAN LE. Effects of amiodarone and de- WH. The effects of amiodarone on serum thy- sethylamiodarone on pituitary deiodinase activity roid hormones and hepatic thyroxine 5'-mon- and thyrotropin secretion in the rat. Am J Med Sci odeiodination in rats. Endocrinology 1983; 113: 1986; 29: 136-141. 1464-1469. 276
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