Isaacs, Sedick

Levitt, Naomi Sharlene

Marshall, David

Okreglicki, Andrzej

Ross, Ian Louis

South African Medical Journal (SAMJ)

March 2005, Vol. 95, No. 3  SAMJORIGINAL ARTICLESAmiodarone is a widely used anti-arrhythmic drug withconsiderable potential to cause thyroid dysfunction (TD)because of its 35% iodine content.1 Indeed, each 200 mg tablet(the usual daily maintenance dose) contains 75 mg of organiciodide with approximately 7.5 mg free iodide being releaseddaily. This greatly exceeds the daily dietary iodine requirementof 0.2 - 0.8 mg.2The frequency of reported TD with amiodarone therapy hasranged from 2% to 24%.3 It is generally accepted that thefrequency of hypothyroidism and hyperthyroidism isaccounted for by differing levels of iodine intake.Hyperthyroidism is therefore most likely to occur in patientsfrom areas with low environmental iodine in contrast tohypothyroidism where patients hail from iodine-replete orexcess areas. The mechanism of amiodarone-inducedhypothyroidism may be mediated by excess iodide. The largeamount of iodide released by metabolism of amiodaroneinhibits thyroid hormone biosynthesis (the Wolff-Chaikoffeffect).  Escape from the Wolff-Chaikoff effect usually occurs,yet there is persistence of the hypothyroid state in patientswith amiodarone-induced hypothyroidism. This is attributed toa subtle defect in thyroid hormonogenesis that results inenhanced susceptibility to the inhibitory effect of iodine onhormone synthesis.4,5 A disturbance of intrinsic thyroid iodineautoregulation is thought to account for amiodarone-inducedthyrotoxicosis, but these mechanisms are incompletelyunderstood.2,4,6,7Hyperthyroid states associated with amiodarone havetraditionally been categorised into two main classes.  Type 1refers to patients with an underlying thyroid disorder such asmultinodular disease or Graves’ disease, who on exposure toan excessive amount of iodine develop thyrotoxicosis.  Type 2hyperthyroidism is characterised by an absence of eitherGraves’ disease or multinodular disease, but the thyroid isvulnerable to inflammatory attack.8,9In addition to the abovementioned forms of TD, amiodaronemay also induce minor derangements of thyroid function tests.These are not clinically significant, should be recognised as theeffect of amiodarone, and do not require any specific therapy.Amiodarone is a potent inhibitor of type 1 and type 2 5’-deiodinase of thyroxine, the enzymes that convert T4 to T3.This inhibition may result in an elevated thyroid-stimulatinghormone (TSH) level, together with a mildly elevated ornormal T4 and a low T3 level.10 In addition, amiodarone affects180Amiodarone-induced thyroid dysfunctionIan Louis Ross, David Marshall, Andrzej Okreglicki, Sedick Isaacs, Naomi Sharlene LevittBackground.  Little is known about the frequency of thyroiddysfunction (TD) associated with amiodarone therapy insouthern Africa.Objectives.  To determine the incidence of TD in a cohort ofpatients initiated on amiodarone therapy at a cardiac clinic inCape Town, South Africa, believed to be an iodine-repletearea.Patients.  Pharmacy records were used to obtain the names ofpatients who received amiodarone between November 1999and December 2002.Results.  The sample size was 194, but data analysis waslimited to the 163 patients for whom there were completedata. The mean age ± standard deviation (SD) was 59.0 ± 15.0years (range 22 - 89 years). There were 67 female and 96 malepatients.  The indications for amiodarone therapy weresupraventricular tachycardias (N = 102, 62.6%), ventriculartachycardia (N = 55, 33.7%), and prophylaxis againsttachycardias (N = 3, 1.8%).  The indication was uncertain in 3patients (1.8%).  The median duration of amiodaronetreatment was 679.0 days (quartile deviation (QD) 1 172 days,range 3 - 6 425 days) in the whole cohort. The medianduration of amiodarone therapy until new TD was 943 days(QD 1 185 days), significantly longer than in patients whoremained euthyroid (547 days, QD 1 135 days) (P = 0.05).There were 45 new TD cases (27.6%): 11 patients (6.7%) werethyrotoxic, 1(0.6%) transient thyrotoxicosis, 1 (0.6%)subclinical hyperthyroidism, 13 (8.0%) had subclinicalhypothyroidism, 12 (7.4%) hypothyroidism and 7 (4.3%) hadminor changes in thyroid function.Conclusions.  We found a high incidence of new-onset TD,similar to the highest rates reported internationally.  Localfactors responsible for this need to be investigated.S Afr Med J 2005; 95: 180-183.Divisions of Endocrinology and Cardiology and Medical Informatics, GrooteSchuur Hospital and University of Cape TownIan Louis Ross, MB ChB, FCP (SA), Cert Endocrinology and Metabolism(SA)David Marshall, MB ChB, FCP (SA)Andrzej Okreglicki, MB ChB, FCP (SA)Sedick Isaacs, PhDNaomi Sharlene Levitt, MB ChB, MDCorresponding author: I L Ross (iross@uctgsh1.uct.ac.za)ORIGINAL ARTICLES181March 2005, Vol. 95, No. 3  SAMJpituitary release of TSH and may therefore cause theinappropriate TSH syndrome.3,4,10Little is known about the frequency of TD related toamiodarone use in southern Africa, as the reported studiesemanate from Europe and the USA.  We therefore examinedthe incidence of TD in a cohort of patients started onamiodarone therapy at the cardiac clinic, Groote SchuurHospital in Cape Town.  Groote Schuur Hospital is theteaching hospital of the University of Cape Town and is areferral centre for patients with cardiac arrythmias resident inCape Town and surrounding areas.  As Cape Town is believedto be an iodine-replete area, it was assumed thathypothyroidism would be the most common form of TDassociated with amiodarone use.5,11,12Materials and methodsThe names of all patients who received amiodarone betweenNovember 1999 and December 2002 were obtained from thehospital pharmacy records. Only patients with either cardiacnotes or hospital folders were included in the study.Demographic and medical details were extracted from thenotes. The medical data included the indication for amiodaronetherapy and results of thyroid function tests. TD wascategorised by two board-certified specialist endocrinologists(Table I). The serum samples for TSH, fT4 and fT3 weremeasured using the automated chemiluminescence assaysmanufactured by Bayer Corporation, New York, USA. Theinterassay co-efficient of variation for TSH was 5.48%, for  fT44.6%, and for fT3 2.3%.  All thyroid function tests were assessedat baseline and at 3 - 6 monthly intervals.The statistical analyses were performed using Student’s t-test. All values were expressed using either the mean ±standard deviation (SD) or median ± quartile deviation (QD),except when noted.  p-values ≤ 0.05 were consideredstatistically significant.ResultsOne hundred and ninety-four patients received amiodaroneduring the study period, but the analysis was limited to 163patients for whom the data were complete.  The 31 participantswith incomplete data did not differ statistically from theremaining subjects in terms of gender and age, but the medianduration of exposure to amiodarone was 219 days in theformer versus 1 008 days in the cohort with complete data(p < 0.01).  The study participants were 59 ± 15 years of age.There were 67 women and 96 men. TD antedating amiodaronetherapy was present in 13 patients (8%). The indications foramiodarone therapy are shown in Table II.New-onset TD occurred in 45 patients (27.6%).  Elevenpatients (6.7%) were thyrotoxic, 1 (0.6%) had transientthyrotoxicosis, 1 (0.6%) subclinical hyperthyroidism, 13 (8.0%)had subclinical hypothyroidism, 12 (7.4%) hypothyroidism and7 (4.3%) developed minor changes in thyroid function.  Sevenof the patients with hypothyroidism and 1 with subclinicalhypothyroidism were managed with thyroxine.  Thecardiologists adopted a protocol whereby they chose tomanage hypothyroidism secondary to amiodarone in thefollowing way:  if the patients were found to be hypothyroid,the need for amiodarone was reviewed. If an arrhythmianecessitated continued use, thyroxine was added.  Ifamiodarone could be stopped the thyroid function tests werereviewed 3-monthly.  Thyroxine was introduced if thehypothyroidism persisted beyond 3 months.  Subclinicalhypothyroid cases were observed for the evolution ofhypothyroidism.Amiodarone was stopped in 6 of the 12 patients withthyrotoxicosis.  One patient with subclinical hyperthyroidismwas managed with a reduced dose of amiodarone.  Therapy forthe thyrotoxic patients consisted of amiodarone withdrawalwhere the cardiovascular status permitted this, radioactiveiodine if a sufficient period had elapsed since the withdrawalof amiodarone to permit adequate iodine uptake by the thyroidgland, and neomercazole or prednisone or a combination ofTable I. Thyroid diagnoses by thyroid function testingDiagnosis DefinitionEuthyroidism TSH 3.5 - 5.5 µIU/mlfT4 11.5 - 22.7 pmol/lfT3 3.5 - 6.5 pmol/lThyrotoxicosis TSH < 0.01 µIU/mlfT4 > 22.7 pmol/lfT3 > 6.5 pmol/lSubclinical hypothyroidism TSH >5.5 µIU/mlfT4 11.5 - 22.7 pmol/lfT3 3.5 - 6.5 pmol/lHypothyroidism TSH > 5.5 µIU/mlfT4 < 11.5 pmol/lfT3 < 3.5 pmol/lMinor changes in thyroid function TSH > 5.5 µIU/mlfT4 11.5 - 22.7 pmol/l orfT3 ≥ 3.5 pmol/lSubclinicial hyperthyroidism TSH < 0.01 µIU/mlfT4 11.5 - 22.7 pmol/lfT3 3.5 - 6.5 pmol/lf = free.Table II. Indications for amiodarone therapyIndications Number of patients (%)Supraventricular tachycardia 102 (62.2)Ventricular tachycardia 55 (33.7)Prophylaxis against tachycardia 3 (1.8)Uncertain 3 (1.8)March 2005, Vol. 95, No. 3  SAMJORIGINAL ARTICLES182both neomercazole and prednisone.  The treatment ofamiodarone-induced thyrotoxicosis was not uniform asdifferent attending physicians offered a variety of expertopinions.Mortality for the cohort of 163 patients was 12.6%(confidence interval (CI) 7.9 - 18.8%).  There was no associationbetween mortality and TD (r = 0.04, p > 0.8).  The medianduration of amiodarone treatment was 679.0 days (range 3 - 6 425).  Three-quarters of the cohort received amiodarone forless than 1 172 days.  As seen in Table III, the subjects withnew-onset thyroid dysfunction had significantly longerduration of amiodarone therapy than those who remainedeuthyroid (p = 0.05).  In a life-table analysis, using a Kaplan-Meier curve, it was shown that the first 1 000 days representedthe period in which patients were most likely to develop TD.Thereafter the likelihood of developing TD plateaued (Fig. 1).DiscussionThis report represents one of the largest retrospective analysesof TD associated with amiodarone therapy, with a higherfrequency of TD demonstrated than in previous studies.13Environmental iodine content has had a major impact on thedistribution of the various forms of thyroid dysfunction.Therefore, in other settings in which iodine is replete,hypothyroidism has been the most common abnormality,ranging from 1% to 32%.4,11 Hypothyroidism was the mostcommon TD in our study, conducted in the iodine-replete CapeTown area, yet it still constituted a much smaller proportion ofTD than in previous studies.4,13 The reason for this observationis unclear.  In many parts of the world TD is not uncommon inpeople over the age of 60 years.  We have previously foundthat 11.2% of residents in old-age homes in Cape Town hadsome degree of TD.14 This is similar to the prevalence of TDantedating the initiation of amiodarone therapy in the currentcohort.  As the patients in this study were not examined for anunderlying cause of TD, it was attributed to amiodarone.  It isconceivable, however, that new thyroid dysfunction related toamiodarone use may have been overestimated.The total thyrotoxicosis prevalence was 7.3% in our study,compared with previous reports of 1 - 23%.3,8 Amiodarone-induced thyrotoxicosis prevails in areas with low iodine intake;therefore thyrotoxicosis is more common among Italian thanAmerican patients (10% compared with 2%), buthypothyroidism is less common (2% compared with 22%).4,11Despite the normal environmental iodine exposure in CapeTown, we found a relatively high incidence ofhyperthyroidism.  It is therefore plausible that a factor otherthan iodine exposure may be responsible for the wide variationin frequency of TD.  In this retrospective study it was notpossible to determine whether the thyrotoxicosis in ourpatients was as a result of type 1 or type 2 amiodarone-inducedthyrotoxicosis or a combination of both.  These patients werenot investigated and managed according to a specific protocolas none was in place in our hospital.Management of amiodarone-induced thyrotoxicosis isdifficult and withdrawal of amiodarone may not be possible,particularly when used for treatment of ventriculararrhythmias. Moreover even if withdrawal is permitted,thyrotoxicosis may take as long as 8 months to subside byvirtue of the prolonged half-life of amiodarone.4 Amiodarone-induced thyrotoxicosis often responds to antithyroid drugs.Prednisone has proved beneficial in some circumstances,especially in type 2 amiodarone-induced thyrotoxicosis.4,8Thyroidectomy is reserved for intractable thyrotoxicosisunresposive to medical therapy.  However, none of our patientsrequired this intervention.  There are a number of options fortreating amiodarone-induced hypothyroidism.  These includediscontinuing amiodarone therapy, decreasing the dose, orTable III. Clinical characteristics of new-onset thyroid dysfunctionversus euthyroidism in patients treated with amiodaroneNew thyroiddysfunction Euthyroidism(N = 45) (N = 105) Clinical characteristicsAge (yrs) (mean ± SD) 60 ± 15.2 57.7 ± 15.3 Gender (%) Males 66.7 Males 58.1 Duration of treatment (median (QD)) days 943 (QD = 1 185) 547 (QD = 1 135)*Mortality (%) 13.9 16.4 Indications for treatment (%)Supraventricular tachycardias 51 68.6†Ventricular tachycardia 44 28.6†Prophylaxis 0.0 1.9 Uncertain 4.4 1.0* p = 0.05.† p = 0.04.Fig. 1. Kaplan-Meier curve of cumulative risk for development ofthyroid dysfunction.ORIGINAL ARTICLES183March 2005, Vol. 95, No. 3  SAMJadministering replacement therapy with thyroxine.4,5,9Previous life-table analysis has indicated that 49% of patientsreceiving amiodarone develop TD by 36 months of follow-up.3We have shown that the first 1 000 days represents the mostlikely period in which patients will develop thyroiddysfunction.  Nevertheless, the longer an individual is exposedto amiodarone the higher the likelihood of developing TD.This suggests that amiodarone-induced TD is the result ofprolonged exposure, warranting continued surveillance ofthyroid function in patients on amiodarone therapy.Our study has some limitations. Although it represents oneof the largest data collections, the analysis was restricted to 163patients (84% of the total) with complete data. Demographiccharacteristics of the 31 patients excluded from data analysisdid not differ from those of the remaining patients.  Howeverthose with incomplete data had a shorter exposure toamiodarone, possibly because of the omission of thyroidfunction testing in patients given a short course of therapy.This may have introduced a degree of bias.  In common withother retrospective analyses, clinical data were often deficientand therefore the clinical assessment of goitre size and testingfor thyroid antibodies were not performed routinely.  Wesuggest that the following be undertaken before initiatingamiodarone therapy: clinical examination of the thyroid glandand examination for features of Graves’ disease, and exclusionof thyroid-associated ophthalmopathy.  Thyroid function testsand thyroid antibody screening should be requested atbaseline.  This will help to identify patients at increased risk ofTD. Measurements of TSH, fT4 and fT3 should therefore bereassessed 3 months after commencing amioadarone.Thereafter TSH should be checked every 4 - 6 months.  Anelevated TSH, together with a low fT4, indicateshypothyroidism and necessitates treatment with thyroxine.  Anabnormally low TSH, or a drop in TSH, requires assessment offT3 and fT4.  A suppressed TSH with both an elevated fT4 andfT3 confirms hyperthyroidism and necessitates investigationand treatment.4Conclusion In conclusion, we found an overall high incidence ofamiodarone-induced TD in the Western Cape.  Local andenvironmental factors that may explain this high incidencerequire investigation.  Ideally amiodarone-induced TD shouldbe managed jointly by endocrinologists and cardiologists usingan evidence-based protocol.References1. Rosenbaum MB, Chiale PA, Halpern MS, et al.  Clinical efficacy of amiodarone as anantiarrhythmic agent. Am J Cardiol 1976; 38: 934-944.2. Fradkin JE, Wolff J.  Iodine induced thyrotoxicosis. Medicine 1983; 62: 1-20.3. Albert SG, Alves LE, Rose EP.  Thyroid dysfunction during chronic amiodarone therapy. J AmColl Cardiol 1987; 9: 175-183.4. Harjai KJ, Licata AA. Effects of amiodarone on thyroid function. Ann Intern Med 1997; 126:63-73.5. Martino E, Aghini-Lombardi F, Mariotti S, et al. Amiodarone  iodine-inducedhypothyroidism: risk factors and follow up in 28 cases. Clin Endocrinol (Oxf) 1987; 26: 227-237.6. Figge HL, Figge J. The effects of amiodarone on thyroid hormone function: a review ofphysiology and clinical manifestations. J Clin Pharmacol 1990; 30: 588-595.7. Ingbar SH. Autoregulation of the thyroid. Mayo Clin Proc 1972; 47: 814-823.8. Bartalena L, Brognioni S, Grasso L, Bogazzi F, Burelli A, Martino E. Treatment of amiodaroneinduced thyrotoxicosis, a difficult challenge: results of a retrospective study. J Clin EndocrinolMetab 1996; 81: 2930-2933.9. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001; 344:501-509.10. Burger A, Dinichert D, Nicod P, Jenny M, Lemarchand-Beraud T, Vallotton MB. Effect ofamiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin, and thyrotropin.A drug influencing peripheral metabolism of thyroid hormones. J Clin Invest 1976; 58: 255-259.11. Immelman R, Towindo T, Paiker J, et al. Report of the South African Institute for MedicalResearch on the iodine deficiency disorder survey of primary school learners for thedepartment of health, South Africa. Pretoria: Department of Health/SAIMR, 2000.12. Martino E, Safran M, Aghini-Lombardi F, et al. Environmental iodine intake and thyroiddysfunction during chronic amiodarone therapy. Ann Intern Med 1984; 101: 28-34. 13. Sanmarti A, Permanyer-Miralda G, Castellanos JM, Fos-Sala M, Galard RM, Soler-Soler J.Chronic administration of amiodarone and thyroid function: A follow-up study. Am Heart J1984; 108: 1262-1268.14. Muller GM, Levitt NS, Louw SJ. Thyroid dysfunction in the elderly. S Afr Med J 1997; 87:1119-1123.Accepted 24 December 2004.

Amiodarone-induced thyroid dysfunction

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Amiodarone-induced thyroid dysfunction

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