What are best practices for treating hypothyroidism

Summary
Introduction: Amiodarone as an iodine-containing antiarrhythmic causes functional disorders of the thyroid gland (SD) in around 40% of cases. These are caused by the high iodine content or immune-related cytotoxic effects. Methods: Review based on a selective review of the literature by the authors. Results: Amiodarone-induced hyperthyroidism is a disease that is difficult to influence therapeutically. A distinction is made between 2 forms. Type I is characterized by an increased production of SD hormones. Type II results from an inflammatory-destructive effect on the organ with increased hormone release. The SD color Doppler sonography serves to differentiate between the two forms. In type I amiodarone should be discontinued sooner. Thionamides, perchlorate and lithium are available for type I, glucocorticoids for type II. Thyroidectomy is the therapeutic option for severe forms of type I. The drug does not have to be discontinued in amiodarone-induced hypothyroidism. Discussion: An extensive investigation of the morphology and function of the SD before the administration of amiodarone effectively prevents the complications described. Pathological SD changes are detected and eliminated at an early stage.
Dtsch Arztebl 2007; 104 (51-52): A 3550-5
Keywords: amiodarone, thyroid, thyroid function, interdisciplinary, evidence-based

Summary
Amiodarone-Induced Thyroid Dysfunction
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: Amiodarone-induced 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


Results of randomized studies confirm the superiority of amiodarone in the treatment of atrial and ventricular arrhythmias (1). The problem with amiodarone therapy, however, is its organ toxicity. Dreaded complications include therapy-resistant thyroid (SD) dysfunction (2, 3).
Based on more recent findings on the diagnosis and treatment of SD changes under amiodarone, current, evidence-based and interdisciplinary recommendations on prophylaxis and practical procedures are to be formulated below. So far, there has been a lack of standards that are supported by all members of the Thyroid Section of the German Society for Endocrinology. The following review article is based on a selective selection of literature by George J. Kahaly and his co-authors.
Prevalence and Predisposing Factors
The prevalence and incidence of amiodarone-related SD dysfunction vary geographically and correlate with iodine intake (2). Hypothyroidism is more likely to occur in countries with adequate iodine intake, such as the USA (22 versus 2% hyperthyroidism), while it is less common in areas with lower iodine intake, such as Italy (5%) or Holland (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). Predisposing factors for amiodarone-induced hyperthyroidism are above all a high iodine intake and / or nodular goiter with low basal TSH (functional autonomy) as a result of long-term iodine deficiency. Genetic factors (e.g. HLA antigens as risk markers for the development of immune thyroid disease) also play a role, but are not responsible for a large part of the explanation of variance (box). The presence of SD antibodies and subclinical hypothyroidism with a simultaneous increase in iodine intake predispose to the development of amiodarone-induced hypothyroidism (4).
Pharmacology and Molecular Action
Amiodarone (2-N-butyl-3- [3,5-diiodo-4-diethylaminoethoxybenzoyl] benzofuran) is structurally related to the SD hormones (Figure 1) and contains 39% by weight of iodine. Each tablet (200 mg amiodarone) absorbs about 75 mg bound iodine, with the free portion (9 mg) selectively entering the SD. This high iodine intake leads to a 40-fold increase in ioduria. The high iodine levels persist for 6 months after stopping the medication because amiodarone is stored as a lipophilic substance in adipose tissue (5). The main metabolite is desethyl-amiodarone, which in most tissues has a higher concentration than the parent substance. The half-life of amiodarone is 20 to 100 days. Amiodarone has a variety of effects on SD (Table 1):
- acute, temporary changes to the SD function
- Hypothyroidism in patients susceptible to the inhibitory effects of large amounts of iodine
- hyperthyroidism, through
- iodine-induced hyperthyroidism in case of nodular goiter
- an inflammatory-destructive condition
- an immune hyperthyroidism.
Amiodarone and its dealkylated metabolites competitively inhibit the extrathyroidal conversion of T4 to active T3 (6). Because of their structural similarity to iodothyronines, they are still effective deiodase inhibitors. Type I 5’-deiodase is preferably inhibited. Amiodarone and the metabolites also bind to nuclear T3 receptors and change their interaction with co-activators or co-repressors of the transcription of T3-regulated genes.
Laboratory changes under
Amiodarone therapy
The start of amiodarone treatment is accompanied by a temporary drop in fT4 levels and a mostly transient increase in TSH, due to the inhibitory effect of iodine on SD (the so-called Wolff-Chaikoff effect). In the course of amiodarone therapy, the inhibitory effect of the drug on deiodase activity and the SD hormone receptor predominates (6). This leads to increased fT4, decreased fT3, increased reverse T3 and a temporary increase in TSH (up to 20 mU / L). Over the course of time, the TSH levels normalize or remain slightly suppressed, so that the most common laboratory constellation under long-term therapy in euthyroid patients is as follows: fT4 increase by 20 to 30%, fT3 decrease in the lower normal range, basal TSH in the lower normal range, respectively suppressed (7). The case report of a 68-year-old patient represents a finding under amiodarone therapy.
Thyroid examination before and during amiodarone therapy
Because of the frequent impairment of the SD function by amiodarone, basal TSH, serum fT3 / -fT4 and SD peroxidase (TPO) antibodies should be determined and an SD sonography performed in order to identify predisposed patients in good time or to detect any later ones Changes in SD function can be clearly assigned to amiodarone therapy (5, 8). If there are SD nodules> 1 cm in diameter or if there is nodular goiter, SD scintigraphy is also useful, because hyperfunctional nodules can also be present with normal TSH. In principle, radioiodine therapy cannot be carried out during treatment with amiodarone for up to one year after discontinuation (9). The protracted release of iodine from amiodarone prevents the radioiodine from being absorbed into the SD in a therapeutically useful manner. If TPO antibodies are present, there is an increased risk of developing either overt hypothyroidism or immunogenic hyperthyroidism. In these cases, a close-meshed functional check of the SD is necessary (Figure 2).
During long-term therapy with amiodarone, checks of the SD (fT3 / fT4, TSH and once a year TPO antibodies) and liver function are necessary at regular intervals, even if the SD function is initially normal. These should be carried out after 3 months after the total cumulative dose has been reached and then every 6 months. Concentrations of amiodarone and its metabolites in plasma showed no clinically relevant correlation with the antiarrhythmic effect of the substance in several studies. The level of the plasma level is also of no significance with regard to tolerability.
Side effects and interactions
Side effects of amiodarone are - depending on the dose and duration of therapy - in addition to SD dysfunction, corneal deposits, photosensitization and hyperpigmentation of the skin, lung and liver toxicity and optic neuropathies (Table 2). Clinically relevant interactions are the increase in digitalis levels and the potentially increased tendency to bleed in anticoagulated patients (10). For digitalis, it is recommended to reduce the dose by half. If the patient is anticoagulated, the INR value should be checked twice a week and the dose reduction should be determined on the basis of the desired INR. Concomitant use of drugs that are metabolised by cytochrome P4503A4 (ciclosporin, statins) and amiodarone - an inhibitor of CYP3A4 - can lead to higher plasma levels. If serious complications occur with amiodarone, administration of cholestyramine (3 × 4 to 8 g) or sucralfate (2 × 2 g) can accelerate the breakdown (3). With both acute and long-term application of amiodarone, colestyramine and sucralfate significantly reduce the enterohepatic circulation and thus accelerate the elimination.
Differential diagnosis of the AIH
For the diagnosis of amiodarone-induced hyperthyroidism (AIH), it is necessary to determine the basal TSH and fT3 (11). A suppressed TSH (< 0,1="" mu/l)="" und="" erhöhte="" ft3-werte.="" 2="" formen="" einer="" aih="" werden="" unterschieden="" (tabelle="" 3).="" der="" typ="" i="" ist="" durch="" sd-vorerkrankungen="" wie="" morbus="" basedow="" und="" knotenstruma="" sowie="" durch="" eine="" gesteigerte="" bildung="" von="" sd-hormonen="" gekennzeichnet.="" die="" überschüssige="" sd-hormonsynthese="" ist="" folge="" der="" erhöhten="" jodbelastung.="" da="" vor="" einem="" elektiven="" behandlungsbeginn="" mit="" amiodaron="" eine="" sd-diagnostik="" obligat="" durchgeführt="" wird,="" ist="" der="" typ="" i="" heute="" selten="" geworden.="" der="" typ="" ii="" entsteht="" in="" der="" regel="" ohne="" vorerkrankung="" der="" sd.="" der="" mechanismus="" ist="" hier="" entweder="" eine="" inflammatorisch-destruierende="" einwirkung="" auf="" die="" sd="" mit="" gesteigerter="" freisetzung="" von="" sd-hormonen="" oder="" das="" ergebnis="" einer="" arzneimittelinduzierten="" lysosomalen="" aktivierung,="" die="" zu="" einer="" destruktiven="" thyreoiditis="" mit="" anreicherung="" von="" histiozyten="" in="" der="" sd="" führt="" (12).="" die="" entwicklung="" einer="" typ="" ii-aih="" kann="" nicht="" im="" vorfeld="" ausgeschlossen="" werden.="" milde="" formen="" des="" typs="" ii="" können="" sich="" spontan="" wieder="" zurückbilden="" oder="" zu="" einer="" hypothyreose="" führen.="" die="" farbdopplersonografie="" der="" sd="" zeigt="" eine="" vermehrte="" vaskularisierung="" beim="" typ="" i="" und="" eine="" verminderte="" bis="" fehlende="" vaskularisierung="" beim="" typ="" ii="" (13–14).="" die="" interleukin-6-spiegel="" können="" beim="" typ="" ii="" erhöht="" sein="" (15),="" sind="" allerdings,="" wie="" das="" serum-thyreoglobulin,="" unzuverlässige="" differenzierungsmarker.="" das="" sd-szintigramm="" ist="" durch="" eine="" fehlende="" technetium-speicherung="" charakterisiert="" (11),="" weil="" die="" hohen="" endogenen="" jodspiegel="" die="" aufnahme="" von="" technetiumpertechnat="" vermindern.="" ein="" normaler="" oder="" erhöhter="" uptake="" ist="" eine="" rarität="" und="" spricht="" für="" einen="" typ="" i.="" in="" der="" regel="" ist="" die="" sd-szintigrafie="" bei="" der="" differenzialdiagnose="" der="" aih="" nicht="">
Therapy of AIH type I
The treatment of AIH is made more difficult by the fact that the usual thionamides act competitively with iodine in the SD, which means that very high doses are necessary. In addition, the side effects of thionamides on both the liver and the bone marrow must be taken into account. Radioiodine therapy is usually not possible because of the reduced absorption of radioactive iodine. In AIH type I, amiodarone should be discontinued if an alternative antiarrhythmic therapy (b-blocker, flecainide, propafenone) is available. However, amiodarone inhibits the peripheral conversion of T4 to T3, so it also has a thyrostatic effect, so that stopping it can worsen the hyperthyroidism. Prospective controlled studies (16-17) and a recent European survey (11) have underlined the role of thionamides for AIH type I (Table 4) (18) and that of glucocorticoids for AIH II.

Thionamides
Thionamides compete with iodide and inhibit thyroid peroxidase and the synthesis of SD hormones. In the case of AIH, the thionamides must be administered in high doses (methimazole starting with 40 to 60 mg daily per os, carbimazole 60 to 90 mg daily, propylthiouracil 400 to 600 mg daily). Despite the long half-life of methimazole, a distribution of 2 to 3 doses per day (as with propylthiouracil) with an overnight interval of around 8 hours is recommended. You have to wait a few days for the response (Figure 3).
Perchlorate
Potassium perchlorate blocks thyroid iodine uptake by directly inhibiting the sodium iodide symporter and thus the active iodine transport of the SD (19). The combination of perchlorate and thionamides is more effective. To reduce the intrathyroid iodine content, 600 to 1,000 mg perchlorate per os, divided into 2 doses, are administered daily.

lithium
Lithium reduces the release of both SD hormones and iodine and also inhibits T4 dejodination (20). In type I, the combination therapy of thionamides and lithium normalizes the SD metabolism more quickly (approx. 4 weeks) than the thionamide monotherapy (approx. 10 weeks) or the waiver of thionamides. An evening dose of 600 to 900 mg (86 to 130 mmol) and weekly monitoring of the lithium blood level (therapeutic range 0.4 to 1.3 mmol / L) are recommended. Lithium therapy is contraindicated in severe heart failure.
Thyroidectomy
If SD autonomy is the cause of AIH type I, it cannot be treated permanently with medication. All that remains is the surgical removal of the SD tissue, provided that the patient can safely undergo this procedure. The main advantage of surgical rehabilitation of the AIH is the immediate elimination of the hyperthyroidism combined with the possibility of continuing the amiodarone therapy. Although subtotal thyroidectomy can protect against lifelong substitution therapy with LT4, it carries the risk of recurrence. Therefore, an almost total thyroidectomy is preferable. Perioperative mortality and morbidity are increased in emergency hyperthyroidism, which is why in such cases the SD operation should be performed in an operative SD center if possible (21).
Therapy of AIH type II
Glucocorticoids have proven to be effective in AIH type II through their anti-inflammatory effects on the destructive inflammatory process and through their inhibition of proteolytic lysosomal enzyme activities (22). The additional effect of the steroids by inhibiting 5’-deiodase is less important because amiodarone itself is a potent deiodase inhibitor. An introductory weight-related dose of 1 mg / kg body weight prednisolone is recommended for 2 weeks, followed by a gradual dose reduction every 2 weeks for a total of 20 weeks. The steroid therapy is also superior to the oral contrast agent iopanoic acid with blocking property of the T4 / T3 conversion.
The more pronounced the inflammatory destruction of the organ, the more self-limiting the AIH type II becomes. Therefore, repeated administration of amiodarone after reaching euthyroidism in AIH type II is justifiable (23).
Therapy of mixed forms
If the differential diagnosis of AIH is not clear or if a mixed form is suspected, a combined therapy of thionamides and glucocorticoids is recommended (for example methimazole and prednisolone, each starting with 40 mg daily or 0.5 mg / kg body weight / day [ 2-3, 10]). Because mixed forms are increasing, some working groups recommend treating all 3 forms of AIH immediately with combination therapy (8).
Therapy of the amiodarone-induced
Hypothyroidism
The TSH increase transient at the start of therapy is physiological and only needs to be treated if hypothyroidism develops over time. If amiodarone is indicated, it does not have to be discontinued in amiodarone-induced hypothyroidism (8, 10). Because of the underlying cardiopathy, it is generally recommended to start thyroxine substitution in manifest hypothyroidism gradually and not to exceed the maintenance dose of 1.5 µg LT4 / kg body weight / day. During LT4 therapy, the basal serum TSH should be in the upper normal range. Amiodarone-induced subclinical hypothyroidism can be checked on wait if there is no clinical picture (Figure 4).
Amiodarone therapy in the
pregnancy and breast feeding period
Amiodarone crosses the placenta and passes into breast milk. The main threats to the fetus are bradycardia, a prolonged QT interval, and hypothyroidism with goiter. However, treatment of 64 pregnant women with amiodarone only led to goiter in 3% of cases and to temporary hypothyroidism in the newborns in 17% (24). Mild, symptom-free neurological retardation and slight speech disorders were found in a few newborns. In addition, despite the high concentration of amiodarone and desethyl-amiodarone measured in breast milk, transient hypothyroidism has only been reported in a single infant. After discontinuation of the preparation, the child's SD function normalized. In view of these data and the low rate of side effects, the administration of amiodarone to pregnant women with life-threatening cardiac arrhythmias and a lack of effective alternative preparations appears to be justifiable.
outlook
A substance with effective and comparable electrophysiological and arrhythmogenic effects that is iodine-free (dronedarone) is currently being tested. Compared to amiodarone, dronedarone is less lipophilic and has a shorter half-life. Clinical studies suggest that amiodarone may soon be replaced (25).

thanksgiving
The authors would like to thank all members of the interdisciplinary Thyroid Section of the German Society for Endocrinology for the critical review of the manuscript and the constructive comments.

Conflict of interest
The authors declare that there is no conflict of interest within the meaning of the guidelines of
International Committee of Medical Journal Editors.

Manuscript dates
submitted: November 30, 2006; Revised version accepted on August 8, 2007


Address for the authors
Prof. Dr. med. George J. Kahaly
I. University Medical Clinic and Polyclinic
55101 Mainz
Email: [email protected]


The German version of this article is available online:
www.aerzteblatt.de/english
Amiodarone Trials Meta-Analysis Investigators: Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6 500 patients in randomized trials. Lancet 1997; 350: 1417-24. MEDLINE
Trip MD, Wiersinga WM, Plomp TA: Incidence, predictability, and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism. Am J Med 1991; 91: 507-11. MEDLINE
Martino E, Bartalena L, Bogazzi F, Braverman LE: The effect of amiodarone on the thyroid. Endocrine Rev 2001; 22: 240-54. MEDLINE
Basaria S, Cooper DS: Amiodarone and the thyroid. On J Med 2005; 118: 706-14. MEDLINE
Harjai KJ, Licata AA: Effects of amiodarone on thyroid function. Ann Intern Med 1997; 126: 63-73. MEDLINE
Kahaly GJ, Dillmann WH: Thyroid hormone action in the heart. Endocrine Reviews 2005; 26: 704-28. MEDLINE
Brabant G, Kahaly GJ, Schicha H, Reiners C: Mild forms of thyroid dysfunction. Dtsch Arztebl 2006; 103 (31-32): A 2110-5. FULL TEXT
Dietlein M, Schicha H: Amiodarone-induced thyrotoxicosis due to destructive thyroiditis. Therapeutic recommendations. Exp Clin Endocrinol Diab 2005; 113: 145-51. MEDLINE
Hermida JS, Jarry G, Tcheng E et al .: Radioiodine ablation of the thyroid to allow the reintroduction of amiodarone treatment in patients with a prior history of amiodarone-induced thyrotoxicosis. On J Med 2004; 116: 345-8. MEDLINE
Goldschlager N, Epstein AE, Naccarelli G, Olshansky B, Singh B: Practical guidelines for clinicians who treat patients with amiodarone. Arch Intern Med 2000; 160: 1741-8. MEDLINE
Bartalena L, Wiersinga WM, Tanda ML, Bogazzi F, Piantanida E, Lai A, Martino E: Diagnosis and management of amiodarone-induced thyrotoxicosis in Europe: results of an international survey among members of the European Thyroid Association. Clin Endocrinol 2004; 61: 494-502. MEDLINE
Brennan MD, Erickson DZ, Carney JA: Nongoitrous (type I) amiodarone-associated thyrotoxicosis: evidence of follicular disruption in vitro and in vivo. Thyroid 1995; 5: 177-83. MEDLINE
Bogazzi F, Bartalena L, Brogioni S et al .: Color flow doppler sonography rapidly differentiates type I and type II amiodarone-induced thyrotoxicosis. Thyroid 1997; 7: 541-5. MEDLINE
Eaton SEM, Euinton HA, Newman CM, Weetman AP, Bennet WM: Clinical experience of amiodarone-induced thyrotoxicosis over a 3-year period: role of color-flow Doppler sonography. Clin Endocrinol 2002; 56: 33-8. MEDLINE
Bartalena L, Grasso L, Brogioni S, Aghini-Lombardi F, Braverman LE, Martino E: Serum Interleukin-6 in amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 1994; 78: 423-7. MEDLINE
O'Sullivan AJ, Lewis M, Diamond T: Amiodarone-induced thyrotoxicosis: left ventricular dysfunction is associated with increased mortality. Eur J Endocrinol 2006; 154: 533-6. MEDLINE
Bartalena L, Brogioni S, Grasso L, Bogazzi F, Burelli A, Martino E: Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metab 1996; 81: 2930-3. MEDLINE
Woolf SH, Sox HC: The expert panel on preventive services: continuing the work of the USPSTF. Am J Prev Med 1991; 7: 326-30. MEDLINE
Wolff J: Perchlorate and the thyroid gland. Pharmacol Rev 1998; 50: 33-8. MEDLINE
Dickstein G, Shechner C, Adawi F, Kaplan J, Baron E, Ish-Shalom S: Lithium treatment in amiodarone-induced thyrotoxicosis. Am J Med 1997; 102: 454-8. MEDLINE
Hamoir E, Meurisse M, Defechereux T, Joris J, Vivario J, Hennen G: Surgical management of amiodarone-associated thyrotoxicosis: too risky or too effective? World J Surg 1998; 22: 537-42. MEDLINE
Bogazzi F, Bartalena L, Cosci C et al .: Treatment of type II amiodarone-induced thyrotoxicosis by either iopanoic acid or glucocorticoids: a prospective, randomized study. J Clin Endocrinol Metab 2003; 88: 1999-2002. MEDLINE
Ryan LE, Braverman LE, Cooper DS, Ladenson PW, Kloos RT: Can amiodarone be restarted after amiodarone-induced thyrotoxicosis? Thyroid 2004; 14: 149-53. MEDLINE
Bartalena L, Bogazzi F, Braverman LE, Martino E: Effects of amiodarone administration during pregnancy on neonatal thyroid function and subsequent neurodevelopment. J Endocrinol Invest 2001; 24: 116-30. MEDLINE
Kathofer S, Thomas D, Karle CA: The novel antiarrhythmic drug dronedarone: comparison with amiodarone. Cardiovasc Drugs Rev 2005; 217-30. MEDLINE