Amiodarone and thyroid dysfunction.

Amiodarone is a potent antiarrhythmic drug associated with thyroid dysfunction. Its high iodine content causes inhibition of 5'-deiodinase activity. Most patients remain euthyroid. Amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH) may occur depending on the iodine status of individuals and prior thyroid disease. AIT is caused by excess iodine-induced thyroid hormone synthesis (type I AIT) or by destructive thyroiditis (type II AIT). If the medical condition allows it, discontinuation of the drug is recommended in type I AIT. Otherwise, large doses of thioamides are required. Type II AIT is treated with corticosteroids. Mixed cases require a combination of both drugs. Potassium perchlorate has been used to treat resistant cases of type I AIT but use is limited by toxicity. Thyroidectomy, plasmapheresis, lithium, and radioiodine are used in select cases of AIT. AIH is successfully treated with levothyroxine. Screening for thyroid disease before starting amiodarone and periodic monitoring of thyroid function tests are advocated.

Issues in amiodarone-induced thyrotoxicosis: Update and review of the literature.

Amiodarone, a benzofuranic iodine-rich pan-anti-arrhythmic drug, induces amiodarone-induced thyrotoxicosis (AIT) in 7-15% of patients. AIT is a major issue due to its typical severity and resistance to anti-thyroid measures, and to its negative impact on cardiac status. Classically, AIT is either an iodine-induced thyrotoxicosis in patients with abnormal thyroid (type 1), or due to acute thyroiditis in a "healthy" thyroid (type 2). Determination of the type of AIT is a diagnostic dilemma, as characteristics of both types may be present in some patients. As it is the main etiological factor in AIT, it is recommended that amiodarone treatment should be stopped; however, it may be the only anti-arrhythmic option, needing to be either continued or re-introduced to improve cardiovascular survival. Recently, a few studies demonstrated that amiodarone could be continued or re-introduced in patients with history of type-2 AIT. However, in the other patients, it is recommended that amiodarone treatment be interrupted, to improve response to thioamides and to alleviate the risk of AIT recurrence. In such patients, thyroidectomy is recommended once AIT is under control, allowing safe re-introduction of amiodarone.

Amiodarone-induced thyrotoxicosis. A review.

Amiodarone (AM), a potent class III anti-arrhythmic drug, is an iodine-rich compound with a structural resemblance to thyroid hormones triiodothyronine (T3) and thyroxine (T4). At the commonly employed doses, AM causes iodine overload up to 50-100 times the optimal daily intake, which may be responsible of a spectrum of effects on thyroid function often counterbalancing its heart benefits. Although most patients on chronic AM treatment remain euthyroid, a consistent proportion may develop thyrotoxicosis (AM-induced thyrotoxicosis, AIT) or hypothyroidism. AIT is more prevalent in iodine-deficient areas and is currently subdivided in two different clinico-pathological forms (AIT I and AIT II). AIT I develops in subjects with underlying thyroid disease, and is caused by an exacerbation by iodine load of thyroid autonomous function; AIT II occurs in patients with no underlying thyroid disease and is probably consequent to a drug-induced destructive thyroiditis. Mixed or indeterminate forms of AIT encompassing several features of both AIT I and AIT II may be also observed. The differential diagnosis between AIT I and AIT II (which is important for the choice of the appropriate therapy) is currently made on radioiodine uptake (RAIU), which may be high, normal or low but detectable in AIT I, while is consistently very low or undetectable in AIT II and on colour-flow Doppler sonography (CFDS) showing normal or increased vascularity in AIT I and absent vascularity in AIT II. Quite recently, studies carried out in our Units at the University of Cagliari (Italy) showed that sestaMIBI thyroid scintigraphy may represent the best single test to differentiate AIT I (showing increased MIBI retention) from AIT II (displaying no significant uptake). Treatment of AIT is dependent from its etiology. AIT usually responds to combined thionamides and potassium perchlorate (KClO4) therapy, AIT II generally responds to glucocorticoids, while indeterminate forms may require both therapeutic approaches. In patients with AIT I definitive treatment of hyperthyroidism by administration of (131)I, initially not feasible for the low RAIU and/or the risk of thyrotoxicosis exacerbation, is advised after normalization of iodine overload. To control severe AIT additional treatment with lithium carbonate, the use of short course of iopanoic acid and plasmapheresis have been also proposed. In cases resistant to medical treatment and/or in patients with severe cardiac diseases who cannot interrupt AM or require quick AM reintroduction, total thyroidectomy (possibly carried out by minimally invasive video-assisted technique) may be proposed after rapid correction of thyrotoxicosis with combination of thionamides, KClO4, corticosteroids and a short course of iopanoic acid.

Successful treatment of amiodarone-induced thyrotoxicosis.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is a difficult management problem about which there are little published data. We examined whether continuing amiodarone or differentiating AIT into 2 subtypes affected outcome. METHODS AND RESULTS: The type and duration of antithyroid treatment and response were recorded in a consecutive series of 28 cases. Comparisons were made between those in whom amiodarone either was continued or stopped and between those with either possible type 1 or type 2 AIT. Of the 28 cases, 5 had spontaneous resolution of AIT; 23 received carbimazole (CBZ) alone as first-line therapy. Eleven achieved long-term euthyroidism off CBZ or on a maintenance dose. Five became hypothyroid and required long-term thyroxine. Five relapsed after stopping CBZ treatment and were rendered euthyroid with either long-term CBZ (n=3) or radioiodine (n=2). Four were intolerant of CBZ and received propylthiouracil (PTU), with good effect in 3. One was resistant to thionamide alone (CBZ then PTU) and responded to adjunctive steroids. No difference in presentation or outcome was noted between those in whom amiodarone was continued or stopped or between possible type 1 or type 2 AIT. CONCLUSIONS: Continuing amiodarone has no adverse influence on response to treatment of AIT. First-line therapy with a thionamide alone is appropriate in iodine-replete areas, thus avoiding potential complications of other drugs. Differentiating between 2 possible types of AIT does not influence management or outcome.

Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study.

Amiodarone-induced thyrotoxicosis (AIT) occurs in both abnormal (type I) and apparently normal (type II) thyroid glands due to iodine-induced excessive thyroid hormone synthesis in patients with nodular goiter or latent Graves' disease (type I) or to a thyroid-destructive process caused by amiodarone or iodine (type II). Twenty-four consecutive AIT patients, 12 type I and 12 type II, were evaluated prospectively. Sex, age, severity of thyrotoxicosis, and cumulative amiodarone dose were similar. Type II patients had higher serum interleukin-6 (IL-6; median, 440 vs. 173 fmol/L; P < 0.001), but lower serum thyroglobulin levels. Several weeks of thionamide therapy in eight type II or prolonged glucocorticoid administration in two type I patients had previously failed to control hyperthyroidism. Type II patients were given prednisone (initial dose, 40 mg/day) for 3 months and achieved normal free T3 and IL-6 after an average of 8 and 6 days, respectively. Exacerbation of thyrotoxicosis with increased serum IL-6 values, observed in 4 patients while tapering steroid, was promptly corrected by increasing it. Type I patients, given methimazole (30 mg/day) and potassium perchlorate (1 g/day), achieved normal free T3 and IL-6 concentrations after an average of 4 weeks. Exacerbation of thyrotoxicosis with markedly increased IL-6 was controlled by prednisone in 3 of 4 cases. Distinction of different forms of AIT is essential for its successful management. Type II AIT should be treated with glucocorticoids; type I AIT should be treated with methimazole and potassium perchlorate. Exacerbation of thyrotoxicosis, which may occur in both forms and is probably related to destructive processes, should be controlled by the addition/increase in glucocorticoids.

Syndromes of thyrotoxicosis with low radioactive iodine uptake.

It is very important to diagnose correctly the etiology of thyrotoxicosis, because the course and treatment of thyrotoxicosis with low radioactive iodine uptake differ significantly from that of hyperthyroidism due to Graves' disease or toxic nodular goiter. Many causes of subacute thyroiditis have been identified producing a characteristic course of transient hyperthyroidism, followed by hypothyroidism, and usually recovery. Ectopic hyperthyroidism includes factitious thyroid hormone ingestion, struma ovarii, and, rarely, large deposits of functioning thyroid cancer metastases. Iodine-induced hyperthyroidism may be associated with low radioiodine uptakes. Amiodarone-associated hyperthyroidism may be the result of subacute thyroiditis or iodine-induced hyperthyroidism; assessment and treatment can be quite challenging.

The prevalence of elevated serum C-reactive protein levels in inflammatory and noninflammatory thyroid disease.

C-reactive protein (CRP) levels have not been routinely used to diagnose thyroid disease, although many thyroid conditions involve inflammation. This study was intended to determine whether CRP levels could differentiate between inflammatory and noninflammatory thyroid conditions, especially between type II inflammatory amiodarone-induced thyrotoxicosis (AIT) and type I iodine-induced AIT. Serum high-sensitivity CRP levels were measured in 100 euthyroid controls (7 taking amiodarone) and 353 patients with one of the following thyroid conditions: AIT, subacute thyroiditis, toxic diffuse goiter, nodular goiter, Hashimoto's thyroiditis, shortterm hypothyroidism, or postpartum thyroiditis. No patients with nontoxic multinodular goiter (n = 34), toxic nodular goiter (n = 23), or toxic diffuse goiter, either untreated (n = 49) or euthyroid while taking methimazole (n = 33), had positive CRP levels (>10 mg/L). The occurrence of positive CRP levels among patients with Hashimoto's thyroiditis (n = 35), short-term hypothyroidism (n = 38), and postpartum thyroiditis (n = 70) did not differ significantly from controls. The occurrence of positive CRP values did not differ significantly between patients with type I and type II AIT and controls. Six of 7 patients (86%) with untreated subacute thyroiditis had positive CRP levels (p < 0.00001). These results indicate that there is only a limited role for measurement of CRP levels in the diagnosis of thyroid diseases other than subacute thyroiditis.

Thyroidectomy for selected patients with thyrotoxicosis.

OBJECTIVE: To examine the indications for operation and the frequency, efficacy, and outcome of surgical therapy for thyrotoxicosis. METHODS: The medical records of all patients who underwent thyroidectomy between 1990 and 1998 were reviewed. Operative indications, laboratory evaluations, extent of thyroidectomy, pathologic findings, and morbidity and mortality were determined for patients with thyrotoxicosis. RESULTS: Of the 347 patients who underwent thyroidectomy, 54 (16%) had thyrotoxicosis, secondary to Graves' disease (32 patients), toxic multinodular goiter (18 patients), thyroiditis (2 patients), or amiodarone (2 patients). The indications for operation were compressive symptoms or substernal extension or both (35 patients), patient preference (12 patients), thyrotoxicosis (4 patients), or a dominant nodule (3 patients). Most patients received pharmacological preparation, followed by total (32 patients), near-total (13 patients), subtotal (8 patients), or unilateral (1 patient) thyroidectomy. The initial 8 patients with Graves' disease underwent subtotal thyroidectomy, and after a mean 28-month follow-up, 1 was euthyroid; 2, hyperthyroid; and 5, hypothyroid. Associated carcinoma was present in 4 (7%) of the 54 patients. Symptomatic hypocalcemia occurred in 10 patients (19%), with a mean free thyroxine level of 60.49 +/- 16.09 pmol/L vs 40.41 +/- 19.56 pmol/L (4.70 +/- 1.25 ng/dL vs 3.14 +/- 1.52 ng/dL) in 25 patients (46%) with asymptomatic hypocalcemia (P<.05). Vocal cord paresis and a hematoma requiring operative evacuation occurred in 1 patient each. There was 1 mortality in a patient with amiodarone-induced thyrotoxicosis. CONCLUSIONS: Massive thyroid enlargement with compressive symptoms, a dominant nodule, and patient preference are indications for surgical treatment of thyrotoxicosis. Near-total or total thyroidectomy is safe and more effective than subtotal thyroidectomy in preventing recurrence and should be considered in most patients referred for surgical treatment of thyrotoxicosis. Transient postoperative hypocalcemia is common and is related to the severity of thyrotoxicosis.

[Hyperthyroidism and heart]. / Hyperthyreose und Herz.

This review discusses the clinically relevant effects of thyroid hormone excess on the heart. Tachycardia and atrial fibrillation are usually reversible after euthyroidism is restored. Atrial fibrillation may, however, take several months to return to sinus rhythm. The increase in contractility leads to an increase of cardiac output. The development of a relative myocardial hypertrophy following long-term high-dose therapy with thyroid hormones is controversial. Cardiac failure at stress in spite of an increased cardiac output at rest is a phenomenon typical for thyrotoxicosis. Reports of dilated cardiomyopathy associated with Graves' disease and evidence for TSH-receptors in the human myocardium suggest a relationship between these two diseases. Endomyocardial biopsy studies have, however, failed to prove this hypothesis. Mitral valve prolapse is more frequent in hyperthyroid patients than in normals. Thyroid hormone excess as well as the autoimmune origin of the disease are suggested as etiology for this phenomenon. The frequently observed angina pectoris seems to be a consequence of the increase in consumption of oxygen in the presence of an unchanged oxygen supply rather than of obstruction of coronary circulation. Well documented cases of myocardial infarction patients with thyroid hormone excess and normal coronary arteries in angiography substantiate this theory. Finally diagnostic and therapeutic options of the two forms of thyrotoxicosis induced by the antiarrhythmic drug amiodarone are presented.

Thyrotoxicosis in childhood.

Evidence supports the presence of a genetic predisposition to an abnormality in immune surveillance, with environmental factors precipitating the development of Graves' disease.

The onset time of amiodarone-induced thyrotoxicosis (AIT) depends on AIT type.

OBJECTIVE: Considering the different pathogenic mechanisms of the two main forms of amiodarone-induced thyrotoxicosis (AIT), we ascertained whether this results in a different onset time as well. DESIGN AND METHODS: We retrospectively analyzed the clinical records of 200 consecutive AIT patients (157 men and 43 women; mean age 62.2±12.6 years) referred to our Department from 1987 to 2012. The onset time of AIT was defined as the time elapsed from the beginning of amiodarone therapy and the first diagnosis of thyrotoxicosis, expressed in months. Factors associated with the onset time of AIT were evaluated by univariate and multivariate analyses. RESULTS: The median onset time of thyrotoxicosis was 3.5 months (95% CI 2-6 months) in patients with type 1 AIT (AIT1) and 30 months (95% CI 27-32 months, P<0.001) in those with type 2 AIT (AIT2). Of the total number of patients, 5% with AIT1 and 23% with AIT2 (P=0.007) developed thyrotoxicosis after amiodarone withdrawal. Factors affecting the onset time of thyrotoxicosis were the type of AIT and thyroid volume (TV). CONCLUSIONS: The different pathogenic mechanisms of the two forms of AIT account for different onset times of thyrotoxicosis in the two groups. Patients with preexisting thyroid abnormalities (candidate to develop AIT1) may require a stricter follow-up during amiodarone therapy than those usually recommended. In AIT1, the onset of thyrotoxicosis after amiodarone withdrawal is rare, while AIT2 patients may require periodic tests for thyroid function longer after withdrawing amiodarone.

Determinants of serum T4 and T3 at the time of diagnosis in nosological types of thyrotoxicosis: a population-based study.

OBJECTIVE: To characterize thyroid hormone levels at the time of diagnosis in the nosological types of thyrotoxicosis diagnosed in the population and to analyze determinants for serum thyroxine (T4) and tri-iodothyronine (T3). DESIGN: Population-based study of thyrotoxicosis at disease onset. METHODS: In the period 1997-2000, we prospectively identified all patients diagnosed with incident primary overt thyrotoxicosis in a Danish population cohort and classified patients into ten well-defined nosological types of disease (n=1082). Untreated levels of serum T3, T4, and T3:T4 ratio were compared and related to sex, age, level of iodine deficiency, smoking status, alcohol intake, iodine supplement use, co-morbidity, and TSH receptor antibodies (TRAbs) in multivariate models. RESULTS: Graves' disease (GD) patients had much higher levels of T3 and higher T3:T4 ratio at diagnosis compared with other thyrotoxic patients, but with a profound negative association between hormone levels and age. In GD, patients diagnosed in the area with more severe iodine deficiency had lower levels of T3 and T4. TRAb-negative GD patients had biochemically mild thyrotoxicosis. Higher age was also associated with lower degree of biochemical thyrotoxicosis in nodular toxic goiter. We found no association between serum T3 and T4 and sex, smoking habits, iodine supplements, alcohol intake, or co-morbidity in any type of thyrotoxicosis. CONCLUSIONS: The study gives new insight into the hormonal presentation of thyrotoxicosis and showed that young age, positive TRAb levels, but also residency in the area with higher iodine intake was positively associated with biochemical disruption in GD.

Treatment of amiodarone-induced thyrotoxicosis type 2: a randomized clinical trial.

CONTEXT: Amiodarone-induced thyrotoxicosis (AIT) type 2 is self-limiting in nature, but most physicians are reluctant to continue amiodarone. When prednisone fails to restore euthyroidism, possibly due to mixed cases of AIT type 1 and 2, perchlorate (ClO(4)) might be useful because ClO(4) reduces the cytotoxic effect of amiodarone on thyrocytes. OBJECTIVES: Our objectives were to demonstrate the feasibility of continuation of amiodarone in AIT type 2 and to evaluate the usefulness of ClO(4) (given alone or in combination with prednisone) in AIT type 2. DESIGN AND SETTING: A randomized multicenter study was conducted in 10 Dutch hospitals. METHODS: Patients with AIT type 2 were randomized to receive prednisone 30 mg/d (group A, n = 12), sodium perchlorate 500 mg twice daily (group B, n = 14), or prednisone plus perchlorate (group C, n = 10); all patients continued amiodarone and were also treated with methimazole 30 mg/d. Follow-up was 2 yr. MAIN OUTCOME MEASURES: Treatment efficacy (defined as TSH values ≥ 0.4 mU/liter under continuation of amiodarone) and recurrent thyrotoxicosis were evaluated. RESULTS: Initial therapy was efficacious in 100, 71, and 100% of groups A, B, and C, respectively (P = 0.03). The 29% failures in group B became euthyroid after addition of prednisone. Neither the time to reach TSH of 0.4 mU/liter or higher [8 wk (4-20), 14 wk (4-32), and 12 wk (4-28) in groups A, B, and C respectively] nor the time to reach free T(4) of 25 pmol/liter or below [4 wk (4-20), 12 wk (4-20), and 8 wk (4-20) in groups A, B, and C) were significantly different between groups (values as median with range). Recurrent thyrotoxicosis occurred in 8.3%. CONCLUSION: Euthyroidism was reached despite continuation of amiodarone in all patients. Prednisone remains the preferred treatment modality of AIT type 2, because perchlorate given alone or in combination with prednisone had no better outcomes.

Amiodarone-induced thyrotoxicosis: a review.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) develops in 3% of amiodarone-treated patients in North America. AIT is classified as type 1 or type 2. Type 1 AIT occurs in patients with underlying thyroid pathology such as autonomous nodular goiter or Graves' disease. Type 2 AIT is a result of amiodarone causing a subacute thyroiditis with release of preformed thyroid hormones into the circulation. OBJECTIVES: To review the literature and present an overview of the differentiation between and management of type 1 and type 2 AIT. METHODS: PubMed, the Cumulative Index to Nursing and Allied Health Literature and Medscape searches of all available English language articles from 1983 to 2006 were performed. Search terms included 'amiodarone -induced thyrotoxicosis', 'complications', 'management', 'treatment' and 'colour flow Dopper sonography'. RESULTS: There is evidence to suggest that to differentiate between type 1 and type 2 AIT, a careful history and physical examination should be performed to identify pre-existing thyroid disease. An iodine-131 uptake test and colour flow Doppler sonography should be performed. Patients with type 2 AIT should receive a trial of glucocorticoids, whereas those with type 1 should receive antithyroid therapy. For patients in whom the mechanism of the thyrotoxicosis is unclear, a combination of prednisone and antithyroid therapy may be considered.