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Glucocorticoid Response in Amiodarone-Induced Thyrotoxicosis Resulting from Destructive Thyroiditis Is Predicted by Thyroid Volume and Serum Free Thyroid Hormone Concentrations

Department of Endocrinology and Metabolism (F.B., L.T., E.D., F.A.-L., E.M.), University of Pisa, 56124 Pisa, Italy; Department of Clinical Medicine (L.B., M.L.T.), University of Insubria, 21100 Varese, Italy; and the Unit of Epidemiology and Biostatistics (G.R.), Institute of Clinical Physiology, National Research Council (CNR), 56100 Pisa, Italy

Address all correspondence and requests for reprints to: Dr. Fausto Bogazzi, Department of Endocrinology, University of Pisa, Ospedale Cisanello, Via Paradisa, 2, 56124 Pisa, Italy. E-mail: f.bogazzi{at}endoc.med.unipi.it or fbogazzi{at}hotmail.com.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Amiodarone-induced thyrotoxicosis (AIT) resulting from destructive thyroiditis (type 2) is commonly treated with glucocorticoids, but time needed to restore euthyroidism may be unacceptable for patients with underlying cardiac disorders.

Objective: The objective of this prospective study was to identify factors affecting the response to glucocorticoids in a large cohort of patients with type 2 AIT followed prospectively.

Setting: This study was conducted at university centers.

Patients: Sixty-six untreated patients with type 2 AIT were enrolled in the study.

Intervention: All patients were treated with prednisone (initial dose, 0.5 mg/kg·d) as long as needed to restore euthyroidism, defined as cure of AIT.

Main Outcome Measure: The main outcome measure was cure time.

Results: The median cure time was 30 d (95% confidence interval, 23–37 d). Serum free T₄ concentration (picograms per milliliter) and thyroid volume (milliliters per square meter) (and, to a lesser extent, serum free T₃ concentration) at diagnosis were the main determinants of response to glucocorticoids, with a cure hazard ratio of 0.97 (95% confidence interval, 0.95–0.99; P = 0.005) and 0.84 (95% confidence interval, 0.77–0.91; P = 0.000) for unit of increment, respectively. AIT was cured in all patients with a complete follow-up; euthyroidism was reached in 30 d or less in 60% of patients but in more than 90 d in 16%. A prompt control of thyrotoxicosis (30 d of treatment) was more frequent (77%) in patients with serum basal free T₄ concentration no greater than 50 pg/ml and thyroid volume (normalized for body surface area) no greater than 12 ml/m². The cure probability and the mean cure time in an individual patient can be obtained using a formula generated by multiple regression models.

Conclusions: Baseline serum thyroid hormone concentrations and thyroid volume help identify patients with type 2 AIT at risk of a delayed response to glucocorticoids.

	Introduction

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THE IODINE-RICH DRUG amiodarone is a very effective antiarrhythmic drug, but it causes thyroid dysfunction in approximately 15% of patients receiving long-term treatment (1, 2). The type of thyroid dysfunction is partly dependent on iodine intake because amiodarone-induced hypothyroidism is relatively more frequent in iodine-sufficient areas, whereas amiodarone-induced thyrotoxicosis (AIT) develops more frequently in iodine-deficient areas (3, 4). Amiodarone-induced hypothyroidism is not a major therapeutic problem, being in most cases easily corrected by levothyroxine replacement without mandatory amiodarone withdrawal. At variance, AIT management is a difficult task (5, 6, 7, 8, 9), also because amiodarone therapy may be essential for the underlying heart disorder. Basically, there are two main forms of AIT, type 1 and type 2 (1, 2, 5). Type 1 AIT is a true form of iodine-induced thyrotoxicosis developing in abnormal thyroid glands (usually nodular goiter or latent Graves’ disease), whereas type 2 AIT is a form of amiodarone-induced destructive thyroiditis occurring in a substantially normal thyroid gland (1, 5). Mixed forms, as a result of both pathogenic mechanisms (excessive thyroid hormone production and thyroid destruction), appear to be more frequent than previously recognized (8, 9).

Pure type 2 AIT is diagnosed on the basis of low thyroidal radioactive iodine uptake (RAIU) values (at least in regions with moderate iodine deficiency) (3), absent hypervascularity at color flow Doppler sonography (CFDS), absence of goiter (or small goiter), and absence of circulating thyroid-directed autoantibodies. Serum IL-6 concentrations cannot always differentiate type 1 and type 2 AIT as previously reported (10). Type 2 AIT, as a result of its pathogenesis, is unresponsive to antithyroid drug treatment but often responds dramatically to glucocorticoids (1, 6); however, correction of thyrotoxicosis may be slow in some instances.

This delayed response can represent a problem in patients whose cardiac conditions, usually not so good to start with, are worsened by exposure to thyroid hormone excess. It would be of great help to identify factors that may negatively affect the effectiveness of glucocorticoid treatment, because in these cases, as a result of the urgent need to restore euthyroidism, other therapeutic approaches such as thyroidectomy after short-term preparation with iopanoic acid (11, 12, 13) might become the first-line option.

The aim of this prospective study of a large series of consecutive patients with type 2 AIT treated with glucocorticoids was to identify such risk factors. Our results demonstrate that baseline thyroid volume and serum free T₄ (FT4) [and, to a lesser extent, free T₃ (FT3)] concentrations may predict the response to glucocorticoids and the time required to achieve euthyroidism.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

The study included 66 consecutive, untreated patients with type 2 AIT [53 men, 13 women; age (mean ± SD), 67 ± 12 yr; range, 37–84 yr] seen at the Department of Endocrinology, University of Pisa and Department of Clinical Medicine, University of Insubria at Varese from January 2000 to June 2004 not included in previous studies. During the same period, 11 patients with type 1 AIT were referred to our departments but were not included in the analysis. All patients gave their informed consent to the study, which was approved by the Institutional Ethical Committees.

Diagnosis of AIT was based on clinical grounds (signs and symptoms of thyrotoxicosis) and laboratory findings, including increased serum FT3 and/or FT4 concentrations, undetectable serum TSH levels, and increased urinary iodine excretion in patients chronically treated with amiodarone. Diagnosis of type 2 AIT was based on the following criteria (1): absent hypervascularity at CFDS, absence of circulating thyroid-directed autoantibodies [antithyroglobulin (TgAb), antithyroid peroxidase (TPOAb), anti-TSH receptor (TRAb)], thyroid of normal or slightly increased volume without relevant nodules (1 cm) at conventional ultrasonography, and low/undetectable RAIU values (<5% at 24 h). Duration of amiodarone therapy ranged from 2 to 149 months (mean ± SD, 26 ± 22 months), and the cumulative dose of amiodarone ranged from 9 to 616 g (mean ± SD, 132 ± 106 g; median, 115 g).

Conventional and color-flow Doppler sonography

Thyroid volume was measured by ultrasonography and calculated by the ellipsoid model (width x length x thickness x 0.52 for each lobe) as previously described (14).

Thyroid volume was normalized by body surface area (BSA) using the following formula: BSA (m²) = height (m) x weight (kg)/3600 (15) because, as previously reported (16, 17, 18), body surface area accounts for the main variations in thyroid volumes, including gender-related differences; normal values in our areas are 3.5 to 13 ml/m². CFDS was performed as previously reported (10, 19, 20).

Assays

Serum FT4, FT3 (Vitros Immunodiagnostics, The Broadway, Amersham, Buckinghamshire, UK), TSH (Immulite 2000, Third Generation TSH, Diagnostic Products Corp., Los Angeles, CA), triglycerides (Immulite 2000; Diagnostic Products Corp.), TRAb (TRAK human; Brahms, Hennigsdorf, Germany), TgAb (AIA-Pack TgAb; Tosoh, Tokyo, Japan), and TPOAb (AIA-Pack TPOAb; Tosoh) were assayed by commercial kits. Normal values in our laboratories are as follows: FT4, 7 to 17 pg/ml (9.0–22.0 pmol/liter); FT3, 2.7 to 4.5 pg/ml (4.2–7.0 pmol/liter); triglycerides, 3 to 30 µg/liter; TSH, 0.4 to 3.4 mU/liter; TRAb, <1 U/liter; TgAb, <1 U/ml; and TPOAb, <1 U/ml.

Urinary iodine excretion

Morning random urinary samples were collected for iodine measurements using an autoanalyzer apparatus (Technicon, Rome, Italy). Median urinary iodine excretion in our areas is 110 µg/liter.

Thyroidal RAIU

Thyroidal RAIU values were measured 3 and 24 h after the administration of a tracer dose (5 µCi) of ¹³¹I. Normal 3-h and 24-h RAIU values in our areas are 10 to 20% and 30 to 45%, respectively.

Treatment

Amiodarone treatment was withdrawn in all patients at booking. All patients were treated with oral prednisone (starting dose 0.5 mg/kg·d). The drug was gradually tapered (0.1 mg/kg every 7–15 d) and withdrawn after reaching euthyroidism.

Study period and definition of cure

Serum FT4, FT3, and TSH concentrations were measured at 1-wk intervals until euthyroidism was restored and then every month in the absence of symptoms or signs of recurrent thyrotoxicosis. Cure of thyrotoxicosis was defined by normalization of both serum FT4 and FT3 as previously reported (21, 22) and confirmed during glucocorticoid tapering and in three subsequent determinations at 1-month intervals after glucocorticoid withdrawal. Hypothyroidism was considered permanent when serum TSH concentrations remained higher than normal (with a concomitant decrease in serum free thyroid hormone concentrations) in three subsequent determinations at least 6 months after glucocorticoid withdrawal. Follow-up lasted at least 2 yr, including treatment period. Six patients had a rebound of thyrotoxicosis (i.e. an increase in serum thyroid hormone concentrations above the normal range) during glucocorticoid treatment.

Statistical analysis

Results were expressed as mean ± SD. The cure time was analyzed by the Kaplan-Maier survival curve and the Cox regression model. Risk factors for a delayed response to glucocorticoids were evaluated by multivariate analysis using the Cox regression model. The model initially included all variables that resulted statistically significant in the univariate analysis. A backward elimination procedure was used; variables with a P value > 0.05 were removed from the model step by step according to their P value.

To estimate the cure probability within 30 d, a multivariate analysis was performed through the logistic regression model. The performance of the final model was evaluated by the area under the receiver operating characteristic (ROC) curve and by its ability to correctly classify patients as cured or noncured. The classification of patients was performed defining cured patients as those with a predicted probability of recovery > 0.5.

Performance indexes used were sensitivity, specificity, positive predictive value, negative predictive value, true prevalence, apparent prevalence, Youden’s J index, and concordance index. Youden’s J combines information about sensitivity and specificity into a single value (sensitivity + specificity – 1), ranging from –1 for a worthless test to 1 for a perfect test. index expresses the proportion agreement beyond chance. A of 0 indicates no agreement beyond chance, whereas a of 1 indicates perfect agreement.

Multiple linear regression model was used to predict the mean cure time by the risk factors independently associated with the natural logarithm of the time needed for achieving euthyroidism. The performance of the final model was evaluated by the intraclass and Linn correlation coefficients calculated by using observed and predicted cure time.

All 66 patients were included in the survival analysis. The patients lost to follow-up and the patients submitted to total thyroidectomy before reaching cure of thyrotoxicosis were considered as censored. When included in the analysis, the four patients submitted to total thyroidectomy did not substantially modify the logistic regression coefficients (constant, 4.222; FT4, –0.059; normalized thyroid volume, –0.180). Multiple logistic and linear regression analyses were performed in the 57 patients having a complete follow-up.

Models for predicting the mean cure time and the cure probability within 30 d were cross-validated to check for overfitting of the data by using a control group of 17 patients (validation set) that were not used for estimating the models.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Clinical and biochemical features of the study group at baseline are shown in Table 1. There was a predominance of men (males:females, 4:1). All 66 patients had, in addition to suppressed serum TSH, increased serum FT3, whereas serum FT4 was increased in 63 of 66 (95%) and high-normal in three of 66 (5%) subjects (Table 1). No patient had detectable TgAb, TPOAb, or TRAb. Mean thyroidal 3-h and 24-h RAIU values were 1.7 ± 1.4% and 1.2 ± 1.1%, respectively (5% in all cases). Mean thyroid volume was normal, but eight patients (12%) had a small goiter with (1 cm) or without nodules at conventional thyroid ultrasonography (Table 1). All patients had absent hypervascularization (pattern 0) at CFDS (Table 1). The median concentration of serum thyroglobulin was 61 ng/ml; seven patients (approximately 10%) had serum thyroglobulin less than 10 ng/ml; these data suggest that most patients with type 2 AIT had a moderate discharge of thyroglobulin at variance with those with other forms of destructive thyroiditis like subacute thyroiditis.

The median cure time, i.e. the time needed to cure thyrotoxicosis in 50% of patients during glucocorticoid therapy was 30 d (95% confidence interval, 23–37 d); the median cure time, as expected, was longer (90 d; 95% confidence interval, 77–103 d) when normalization of serum TSH was taken into consideration (Fig. 1).

View larger version (8K): [in this window] [in a new window]   FIG. 1. Proportion of patients remaining thyrotoxic during the follow-up period considering either the normalization of both T4 and T3 (continuous line) or that of TSH (dotted line). The median cure time was 30 d (95% confidence interval, 23–37 d) in the former and 90 d (95% confidence interval, 77–103 d) in the latter.

In the univariate analysis, the delayed response to glucocorticoids was related to baseline serum FT4 concentration (P = 0.005), normalized thyroid volume (P = 0.001), and, to a lesser extent, serum FT3 concentration (P = 0.031) (Table 2). In the multivariate analysis, baseline serum FT4 concentration (picograms per milliliter) and normalized thyroid volume (milliliters per square meter) were the main independent determinants of the delayed response to glucocorticoids with a cure hazard ratio of 0.97 (95% confidence interval, 0.95–0.99, P = 0.005) and 0.84 (95% confidence interval, 0.77–0.91, P = 0.000) for unit of increment, respectively. Sixty percent of the 57 patients with a complete follow-up had a prompt response to glucocorticoids (euthyroidism after 30 d), but 16% of patients required a prolonged treatment lasting at least 3 months. Baseline serum FT4 concentration greater than 50 pg/ml and normalized thyroid volume greater than 12 ml/m² greatly increased the time needed for achieving euthyroidism. The percentage of cured patients within 30 d was: 1) 77% when serum FT4 concentration was 50 pg/ml or less and normalized thyroid volume was 12 ml/m² or less; 2) 50% when serum FT4 concentration was 50 pg/ml or less and thyroid volume was greater than 12 ml/m²; and 3) 42% when serum FT4 concentration was greater than 50 pg/ml and thyroid volume 12 ml/m² or less. No patient with serum FT4 concentration above 50 pg/ml and thyroid volume above 12 ml/m² achieved euthyroidism within 30 d.

The performance of the logistic regression model, including basal serum FT4 concentrations and normalized thyroid volume, to correctly predict the cure of thyrotoxicosis within 30 d was as follows: specificity, 61% (95% confidence interval, 41–81); sensitivity, 82% (95% confidence interval, 68–95); crude correct classification, 73%; Youden’s J, 0.43; and , 0.43. The area under the ROC curve for the model was 0.80.

The cure probability within 30 d in an individual patient, based on initial serum FT4 concentration and normalized thyroid volume, can be obtained applying the formula (or the figure) reported in Appendix 1 (published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org), which shows the relation between the sum of regression coefficients multiplied by the value of relating variables and the predicted cure probability.

The cure probability predicted by the logistic regression model was divided into four categories: low (25%), intermediate (>25% and 50%), high (>50% and 75%), and very high (>75%). The actual proportion of cured patients in each probability category is reported in Table 3. The actual percentage of cure was in agreement with the probability predicted by the model. When the probability of cure increased, the actual percentage of cured patients was higher, and the cure mean time decreased.

The model was estimated excluding an outlier patient with a very high value of normalized thyroid volume (31.4 ml/m²), a short cure time (21 d), and a basal FT4 value of 23.3 pg/ml. Therefore, the model applies to basal FT4 values up to 71 pg/ml and to normalized thyroid volumes up to 20 ml/m².

The intraclass correlation and the Linn correlation, used to evaluate the ability of the model to correctly predict the cure time, were 0.58 and 0.58, respectively.

To obtain a crossvalidation of the logistic and the linear regression model, the prediction equations developed from the study sample were applied to the validation set. In the validation set, the percentage of cured patients within 30 d was 53%. There was a very close agreement between the probability of cure or the cure time predicted by the logistic model and the actual percentage of cure or the actual cure time, respectively. Performance indices were as follows: specificity, 75%; sensitivity, 100%; crude correct classification, 88%; Youden’s J, 0.75; , 0.76; area under the ROC curve, 0.89 for the logistic model; and intraclass correlation, 0.88; Linn correlation, 0.87, for the linear regression model. The mean dose of glucocorticoids administered to the patients is reported in Table 4.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Type 1 AIT and mixed forms are very difficult to manage because the iodine load makes the thyroid gland resistant to thioamides, and radioiodine therapy is not feasible owing to usually low/suppressed RAIU values. At variance, type 2 AIT, as well as other forms of amiodarone-unrelated destructive thyroiditis, frequently responds dramatically to moderate doses of oral glucocorticoids (5). The latter form of AIT, as a result of its nature, often does not require further treatment; on the contrary, patients should be followed for development of hypothyroidism (23). However, this prompt response is not the rule. In a previous study, we showed that the median cure time was 43 d, and approximately 20% of glucocorticoid-treated patients with type 2 AIT still were thyrotoxic after 2 months of therapy (22). This is confirmed by the present study showing that 16% of patients required a prolonged glucocorticoid treatment lasting for 3 months or longer to restore euthyroidism. A rapid correction of thyrotoxicosis is crucial in patients with AIT, who usually have underlying cardiac problems (tachyarrhythmias, heart failure), which may be severe and life-threatening. For these reasons, it would be fundamental to predict the probability to cure thyrotoxicosis quickly and to identify factors affecting the short-term outcome of glucocorticoid therapy.

An open question is whether amiodarone should be withdrawn. Remission of thyrotoxicosis while amiodarone was continued has been reported either spontaneously (24) or during antithyroid treatment (25, 26, 27, 28). However, 80% of responders to the European Thyroid Association or Latin-American Thyroid Association questionnaire proposed amiodarone withdrawal in the case of type 2 AIT (9, 29). Amiodarone and its main metabolite desethylamiodarone may persist long after drug withdrawal and, therefore, amiodarone withdrawal may not have immediate effects. However, at the molecular level, desethylamiodarone is a weak thyroid hormone receptor agonist when, in large excess, reducing the effects of thyroid hormones and causing a hypothyroid-like status in the heart (30, 31); removal (or reduction) of this effect might exacerbate cardiac effects of thyroid hormone excess; in other words, amiodarone might have a protective effect on the heart. However, in the absence of controlled trials, both issues remain speculative.

Our results showed that baseline serum FT4 concentration and normalized thyroid volume are the main and independent determinants of the response to glucocorticoids.

This seems logical to us; if a patient has a severe destructive phenomenon occurring in a relatively large thyroid gland, the likelihood of a delayed response greatly increases, which is to say that euthyroidism cannot be restored within 1 month of treatment. The relationship that we found among baseline serum FT4 (and, to a lesser extent, FT3), thyroid volume, and the response time to glucocorticoids allowed us to develop of two formulas (reported in supplemental Appendices 1 and 2) leading us to define, on one hand, the probability that euthyroidism be restored within 1 month, and, on the other hand, the time required to achieve this goal. Because thyroid volume of patients included in the study ranged from normal to a moderately large goiter, the formulas could be used for the majority of patients with type 2 AIT. Our patients live in iodine-sufficient to slightly iodine-deficient areas; their clinical and biochemical findings were superimposable to those of patients with type 2 AIT residing in iodine-sufficient geographic regions (10); these findings suggest that formulas developed using the present series of patients likely apply to most type 2 AIT subjects residing in other regions.

On the other hand, it could be argued that some of the less responsive patients had a mixed form of AIT (32); however, this is unlikely in patients residing in moderate iodine deficient areas with low-undetectable thyroid RAIU, absence of autonomous area at thyroid scan, and absent hypervascularization at CFDS (1, 4).

We believe that these results are of importance in directing the therapeutic approach in patients with type 2 AIT 2, whose thyrotoxicosis, as we mentioned previously, must be corrected as soon as possible in view of the, often critical, underlying cardiac conditions.

As a matter of fact, four patients with type 2 AIT with severe underlying cardiac diseases required total thyroidectomy during the first 30 d (three of four patients) or the 90 d (one of four patients) of glucocorticoid treatment as a result of the worsening of cardiocirculatory conditions. Patients, whose heart conditions worsened during glucocorticoids, were safely operated within 30 d, thus reinforcing the concept that prompt control of thyrotoxicosis should be obtained in this period. The practical suggestions of our study may be the following: 1) if the patient has satisfactory and stable cardiac conditions, glucocorticoids likely represent the treatment of choice, independently of the predicted cure time; and 2) if glucocorticoids, in unstable cardiac conditions, are highly unlikely, based on calculation of cure probability and cure time, to cause a prompt control of thyrotoxicosis within 1 month, other therapeutic approaches, particularly thyroidectomy after a short course of iopanoic acid, when available, (11) and possibly under local anesthesia (33) could be considered. Iopanoic acid, albeit very effective in reducing T₃ concentrations in particular situations (34), is no longer available on the market in several countries, making even more difficult the management of patients with AIT. Alternatively, other iodinated contrast agents might be substituted for iopanoic acid, although whether they are superimposable to iopanoic acid in the management of thioamide- or glucocorticoid-resistant AIT remains to be established.

All four patients submitted to total thyroidectomy had a predicted cure time greater than 30 d; however, surgery was the result of the worsening of cardiac conditions and not the probability of cure within 30 d. Thus, glucocorticoids might be the first-line therapy of patients with type 2 AIT, provided that the predicted cure time is very short. In this condition, a strict and careful control of the heart condition of the patient is necessary. However, as a result of the small number of patients with type 2 AIT with severe heart conditions, submitted to total thyroidectomy, our proposals should be confirmed in a larger population.

	Acknowledgments

 
We thank Professor Aldo Pinchera (University of Pisa) for his continuous encouragement and advice.

	Footnotes

 
This work was partially supported by grants from the University of Pisa (Fondi d’Ateneo) and the Ministry of Education, University and Research (MIUR, Rome; to E.M.); from the University of Insubria at Varese (Fondi d’Ateneo per la Ricerca) and from MIUR, Rome (to L.B.).

Disclosure Statement: The authors have nothing to disclose.

First Published Online December 5, 2006

Abbreviations: AIT, Amiodarone-induced thyrotoxicosis; CFDS, color flow Doppler sonography; FT3, free T₃; FT4, free T₄; RAIU, radioactive iodine uptake; ROC, receiver operating characteristic; TgAb, antithyroglobulin; TPOAb, antithyroid peroxidase; TRAb, anti-TSH receptor.

Received September 20, 2006.

Accepted November 28, 2006.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Martino E, Bartalena L, Bogazzi F, Braverman LE 2001 Amiodarone and the thyroid. Endocr Rev 22:240–254[Abstract/Free Full Text]
2. Bogazzi F, Bartalena L, Gasperi M, Braverman LE, Martino E 2001 The various effects of amiodarone on thyroid function. Thyroid 11:511–519[CrossRef][Medline]
3. Martino E, Safran M, Aghini-Lombardi F, Rajatanavin R, Lenziardi M, Fay M, Pacchiarotti A, Aronin N, Macchia E, Haffajee C 1984 Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 101:28–34[Abstract/Free Full Text]
4. Pearce EN, Farwell AP, Braverman LE 2003 Thyroiditis. N Engl J Med 348:2646–2651[Free Full Text]
5. Bartalena L, Brogioni S, Grasso L, Bogazzi F, Burelli A, Martino E 1996 Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results from a prospective study. J Clin Endocrinol Metab 81:2930–2933[Abstract/Free Full Text]
6. Wiersinga WM 1997 Amiodarone and the thyroid. In: Weetman AP, Grossman A, eds. Pharmacotherapeutics of the thyroid gland. Berlin: Springer Verlag; 225–287
7. Iudica-Souza C, Burch HB 1999 Amiodarone-induced thyroid dysfunction. Endocrinologist 9:216–227
8. Bartalena L, Bogazzi F, Martino E 2002 Amiodarone-induced thyrotoxicosis: a difficult diagnostic and therapeutic challenge. Clin Endocrinol (Oxf) 56:23–24[Medline]
9. Bartalena L, Wiersinga WM, Tanda ML, Bogazzi F, Piantanida E, Lai A, Martino E 2004 Diagnosis and management of amiodarone-induced thyrotoxicosis in Europe: results of an international survey among members of the European Thyroid Association. Clin Endocrinol (Oxf) 61:494–502[CrossRef][Medline]
10. Eaton SEM, Euinton HA, Newman CM, Weetman AP, Bennet WM 2002 Clinical experience of amiodarone-induced thyrotoxicosis over a 3-year period: role of colour-flow Doppler sonography. Clin Endocrinol (Oxf) 56:33–38[Medline]
11. Farwell AP, Abend SL, Huang SK, Patwardhan NA, Braverman LE 1990 Thyroidectomy for amiodarone-induced thyrotoxicosis. JAMA 263:1526–1528[Abstract/Free Full Text]
12. Bogazzi F, Miccoli P, Berti P, Cosci C, Brogioni S, Aghini-Lombardi F, Materazzi G, Bartalena L, Pinchera A, Braverman LE, Martino E 2002 Preparation with iopanoic acid rapidly controls thyrotoxicosis in patients with amiodarone induced thyrotoxicosis. Surgery 132:1114–1118[CrossRef][Medline]
13. Franzese CB, Fan CY, Stack Jr BC 2003 Surgical management of amiodarone-induced thyrotoxicosis. Otolaryngol Head Neck Surg 129:565–570[CrossRef][Medline]
14. Rago T, Bencivelli W, Scutari M, Di Cosmo C, Rizzo C, Berti P, Miccoli P, Pinchera A, Vitti P 2006 The newly developed three-dimensional (3D) and two-dimensional (2D) thyroid ultrasound are strongly correlated, but 2D overestimates thyroid volume in the presence of nodules. J Endocrinol Invest 29:423–426[Medline]
15. Mosteller RD 1987 Simplified calculation of body surface area. N Engl J Med 317:1098
16. Gomez JM, Maravall FJ, Gomez N, Guma A, Soler J 2000 Determinants of thyroid volume as measured by ultrasonography in healthy adults randomly selected. Clin Endocrinol (Oxf) 53:629–634[Medline]
17. Hegedus L, Perrild H, Poulsen LR, Andersen JR, Holm B, Schnohr P, Jensen G, Hansen JM 1983 The determination of thyroid volume by ultrasound and its relationship to body weight, age, and sex in normal subjects. J Clin Endocrinol Metab 56:260–263[Abstract/Free Full Text]
18. Berghout A, Wiersinga WM, Smits NJ, Touber JL 1987 Determinants of thyroid volume as measured by ultrasonography in healthy adults in a non-iodine deficient area. Clin Endocrinol (Oxf) 26:273–280[Medline]
19. Bogazzi F, Martino E, Dell’Unto E, Brogioni S, Cosci C, Aghini-Lombardi F, Ceccarelli C, Pinchera A, Bartalena L, Braverman LE 2003 Thyroid color flow Doppler sonography and radioiodine uptake in 51 consecutive patients with amiodarone-induced thyrotoxicosis. J Endocrinol Invest 26:635–640[Medline]
20. Bogazzi F, Bartalena L, Brogioni S, Mazzeo S, Vitti P, Burelli A, Bartolozzi C, Martino E 1997 Color flow Doppler sonography rapidly differentiates type I and type II amiodarone-induced thyrotoxicosis. Thyroid 7:541–545[Medline]
21. Chopra, IJ, Baber, K 2001 Use of oral cholecystographic agents in the treatment of amiodarone-induced hyperthyroidism. J Clin Endocrinol Metab 86:4707–4710[Abstract/Free Full Text]
22. Bogazzi F, Bartalena L, Cosci C, Brogioni S, Dell’Unto E, Grasso L, Aghini-Lombardi F, Rossi G, Pinchera A, Braverman LE, Martino E 2003 Treatment of type 2 amiodarone-induced thyrotoxicosis by either iopanoic acid or glucocorticoids: a prospective, randomized study. J Clin Endocrinol Metab 88:1999–2002[Abstract/Free Full Text]
23. Bogazzi F, Dell’Unto E, Tanda ML, Tomisti L, Cosci C, Aghini-Lombardi F, Sardella C, Pinchera A, Bartalena L, Martino E 2006 Long-term outcome of thyroid function after amiodarone-induced thyrotoxicosis, as compared to subacute thyroiditis. J Endocrinol Invest 29:694–699[Medline]
24. Bartalena L, Brogioni S, Grasso L, Martino E 1993 Increased serum interleukin-6 concentration in patients with subacute thyroiditis: relationship with concomitant changes in serum T4-binding globulin concentration. J Endocrinol Invest 16:213–218[Medline]
25. Davies PH, Franklyn JA, Sheppard MC 1992 Treatment of amiodarone induced thyrotoxicosis with carbimazole alone and continuation of amiodarone. BMJ 305:224–225[Free Full Text]
26. Trip MD, Duren DR, Wiersinga WM 1994 Two cases of amiodarone-induced thyrotoxicosis successfully treated with a short course of antithyroid drugs while amiodarone was continued. Br Heart J 72:266–268[Abstract/Free Full Text]
27. Newman CM, Price A, Davies DW, Gray TA, Weetman AP 1998 Amiodarone and the heart: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy. Heart 79:121–127[Free Full Text]
28. Daniels GH 2001 Amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 86:3–8[Free Full Text]
29. Diehl LA, Romaldini JH, Graf H, Bartalena L, Martino E, Albino CC, Wiersinga WM 2006 Management of amiodarone-induced thyrotoxicosis in Latin America: an electronic survey. Clin Endocrinol (Oxf) 65:433–438[CrossRef][Medline]
30. Wiegand V, Wagner G, Kreuzer H 1986 Hypothyroid-like effect of amiodarone in the ventricular myocardium of the rat. Basic Res Cardiol 81:482–488[CrossRef][Medline]
31. Bakker O, van Beeren HC, Wierrsinga WM 1994 Desethylamiodarone is a noncompetitive inhibitor of the binding of thyroid hormone to the thyroid hormone ß 1-receptor protein. Endocrinology 134:1665–1670[Abstract/Free Full Text]
32. Dietlein M, Schicha H 2005 Amiodarone-induced thyrotoxicosis due to destructive thyroiditis: therapeutic recommendations. Exp Clin Endocrinol Diabetes 113:145–151[CrossRef][Medline]
33. Williams M, Lo Gerfo P 2002 Thyroidectomy using local anesthesia in critically ill patients with amiodarone-induced thyrotoxicosis: a review and description of the technique. Thyroid 12:523–525[CrossRef][Medline]
34. Braga M, Cooper DS 2001 Clinical review 129: oral cholecystographic agents and the thyroid. J Clin Endocrinol Metab 86:1853–1860[Abstract/Free Full Text]

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