Amiodarone-induced Thyrotoxicosis Patients Research Articles

Real-life Data on the Effect of Medical Therapy for Amiodarone-induced Thyrotoxicosis on CV Events and Hospitalizations.

Patients with amiodarone-induced thyrotoxicosis (AIT) often receive initial therapy for thyrotoxicosis in several different medical settings before admission to a referral center. This work aimed to determine whether first-line medical therapy (ie, therapies for thyrotoxicosis at first diagnosis of AIT) affects the outcome of AIT patients. A single-center historical-prospective cohort study was conducted on 313 AIT patients. Clinical and biochemical data were collected at first diagnosis, at a referral center, and during the course of AIT. Primary outcomes were cardiovascular (CV) events and hospitalizations. First-line therapies were considered appropriate when they included glucocorticoids for type 2 AIT and methimazole for type 1 AIT at the approved dose, either alone (optimal medical therapy, OMT) or in combination (right-dose combination therapy, RCT). Other therapies were considered not appropriate, including no therapy. Duration of exposure to thyrotoxicosis was the time from first diagnosis of AIT to its remission. A total of 34.5% patients received appropriate therapies (28.1% OMT, 6.4% RCT), whereas the remaining (65.5%) received inappropriate therapies. CV events and hospitalizations were more frequent in patients who received inappropriate therapies (33.2% vs 4.5%, and 24.9% vs 6.5%, respectively; P < .0001 for both). Appropriate therapies reduced serum thyroid hormone concentrations (P = .018) from first diagnosis to referral, unlike the inappropriate therapies. The duration of exposure to thyrotoxicosis was longer in patients receiving inappropriate therapies and was a risk factor for arrhythmias (hazard ratio [HR] 1.004; P = .0008), major acute CV events (HR 1.004; P = .020), and hospitalizations (HR 1.006; P < .0001). The first medical therapy of AIT influences the exposure time to thyrotoxicosis and the occurrence of CV events and hospitalizations.

Identification of Two Different Phenotypes of Patients with Amiodarone-Induced Thyrotoxicosis and Positive Thyrotropin Receptor Antibody Tests.

Introduction: Serum thyrotropin (TSH) receptor antibodies (TRAbs) are occasionally found in patients with amiodarone-induced thyrotoxicosis (AIT), and usually point to a diagnosis of type 1 AIT (AIT1) due to Graves' disease (GD). However, the TRAb role and function in AIT have not been clarified. Methods: A retrospective cohort study of 309 AIT patients followed at a single academic center over a 30-year period. AIT TRAb-positive patients (n = 21, 7% of all cases) constituted the study group; control groups consisted of type 2 AIT (AIT2) TRAb-negative patients (n = 233), and 100 non-AIT patients with GD. Clinical and biochemical data at diagnosis and during the course of disease were compared. Histological samples of patients who had total thyroidectomy were reviewed. Stored serum samples were used for a functional assay of TRAb class G immunoglobulins (IgGs) in Chinese hamster ovary (CHO) cells stably transfected with complementary DNA encoding for the TSH receptor. Results: TRAb-positive patients were grouped according to color flow Doppler sonography, radioactive iodine thyroid uptake, and duration of amiodarone therapy before thyrotoxicosis in type 1 (n = 9, 43%; TRAb1) or type 2 (n = 12, 57%; TRAb2) AIT. TRAb1 patients had clinical and biochemical features indistinguishable from GD controls, and were responsive to methimazole. Conversely, TRAb2 patients had clinical features similar to AIT2 controls, and were responsive to glucocorticoids, but not to methimazole. The CHO cell functional assay demonstrated that TRAb1 IgGs had a stimulatory effect on cyclic AMP production, which was absent in TRAb2 IgGs. Pathology in TRAb1 showed hyperplastic thyroid follicles and mild lymphocyte infiltration, reflecting thyroid stimulation. On the contrary, TRAb2 samples revealed follicle destruction, macrophage infiltration, and sometimes fibrosis, consistent with a destructive process. Conclusions: Almost 60% of TRAb-positive AIT patients had a destructive thyroiditis. TRAb-positive tests in AIT patients do thus not necessarily imply a diagnosis of GD and AIT1, and should be evaluated in the clinical and biochemical setting of each AIT patient and confirmed by measuring thyroid-stimulating immunoglobulins.

The effects of amiodarone on thyroid function in pediatric and young adult patients

Context Amiodarone is used in patients with arrhythmias, but thyroid dysfunction [amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH)] is a common adverse effect. As the onset of AIT and AIH has not been studied in children, the timing of dysfunction and long-term monitoring are not known in this population. Objective To describe the incidence and timing of amiodarone-induced thyroid dysfunction in children and adolescents, with a secondary aim to identify risk factors for amiodarone-induced thyroid dysfunction, and to identify variance in thyroid hormone surveillance and treatment. Design Retrospective review of thyroid dysfunction in children and young adults treated with amiodarone between 2007 and 2018. Setting Children's Hospital of Philadelphia. Patients Children and young adults treated with amiodarone. Main outcome measures Prevalence of amiodarone-induced thyroid dysfunction. Results Of 484 patients, 190 had thyroid-function testing; 17.3% were found to have subclinical hypothyroidism, and 13.7% testing developed hypothyroidism. Hyperthyroidism occurred in 2.1%. In patients with subclinical hypothyroidism, 63% returned to normal thyroid function without thyroid hormone replacement. Only 26% of patients with hypothyroidism had spontaneous normalization of thyroid function. Twenty-five percent of AIT patients had spontaneous normalization of thyroid function. Conclusions This study looks at a pediatric and young-adult population in an effort to describe the natural history of amiodarone-induced thyroid dysfunction. Based on our data, we recommend that a complete thyroid-function panel be obtained within the first week and then at weekly intervals for the first 5 weeks after initiation. The majority of thyroid dysfunction was noted within the first 35 days of treatment.

Duration of Exposure to Thyrotoxicosis Increases Mortality of Compromised AIT Patients: the Role of Early Thyroidectomy.

Patients with amiodarone-induced thyrotoxicosis (AIT) and severely reduced left ventricular ejection fraction (LVEF) have a high mortality rate that may be reduced by total thyroidectomy. Whether in this subset of patients thyroidectomy should be performed early during thyrotoxicosis or later after restoration of euthyroidism has not yet been settled. Mortality rates, including peritreatment mortality and 5-year cardiovascular mortality, and predictors of death, evaluated by Cox regression analysis. Retrospective cohort study of 64 consecutive patients with AIT selected for total thyroidectomy from 1997 to 2019. Four groups of patients were identified according to serum thyroid hormone concentrations and LVEF: Group 1 (thyrotoxic, LVEF <40%), Group 2 (thyrotoxic, LVEF ≥40%), Group 3 (euthyroid, LVEF < 40%), Group 4 (euthyroid, LVEF ≥40%). Among patients with low LVEF (Groups 1 and 3), mortality was higher in patients undergoing thyroidectomy after restoration of euthyroidism (Group 3) than in those submitted to surgery when still thyrotoxic (Group 1): peritreatment mortality rates were 40% versus 0%, respectively (P = .048), whereas 5-year cardiovascular mortality rates were 53.3% versus 12.3%, respectively (P = .081). Exposure to thyrotoxicosis was longer in Group 3 than in Group 1 (112 days, interquartile range [IQR] 82.5-140, vs 76 days, IQR 24.8-88.5, P = .021). Survival did not differ in patients with LVEF ≥40% submitted to thyroidectomy irrespective of being thyrotoxic (Group 2) or euthyroid (Group 4): in this setting, peritreatment mortality rates were 6.3% versus 4% (P = .741) and 5-year cardiovascular mortality rates were 12.5% and 20% (P = .685), respectively. Age (hazard ratio [HR] 1.104, P = .029) and duration of exposure to thyrotoxicosis (HR 1.004, P = .039), but not presurgical serum thyroid hormone concentrations (P = .577 for free thyroxine, P = .217 for free triiodothyronine), were independent predictors of death. A prolonged exposure to thyrotoxicosis resulted in increased mortality in patients with reduced LVEF, which may be reduced by early thyroidectomy.

The Effects of Amiodarone on Thyroid Function in Pediatric and Young Adult Patients

Amiodarone is used in patients with arrhythmias, but thyroid dysfunction [amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH)] is a common adverse effect. As the onset of AIT and AIH has not been studied in children, the timing of dysfunction and long-term monitoring are not known in this population. To describe the incidence and timing of amiodarone-induced thyroid dysfunction in children and adolescents, with a secondary aim to identify risk factors for amiodarone-induced thyroid dysfunction, and to identify variance in thyroid hormone surveillance and treatment. Retrospective review of thyroid dysfunction in children and young adults treated with amiodarone between 2007 and 2018. Children's Hospital of Philadelphia. Children and young adults treated with amiodarone. Prevalence of amiodarone-induced thyroid dysfunction. Of 484 patients, 190 had thyroid-function testing; 17.3% were found to have subclinical hypothyroidism, and 13.7% testing developed hypothyroidism. Hyperthyroidism occurred in 2.1%. In patients with subclinical hypothyroidism, 63% returned to normal thyroid function without thyroid hormone replacement. Only 26% of patients with hypothyroidism had spontaneous normalization of thyroid function. Twenty-five percent of AIT patients had spontaneous normalization of thyroid function. This study looks at a pediatric and young-adult population in an effort to describe the natural history of amiodarone-induced thyroid dysfunction. Based on our data, we recommend that a complete thyroid-function panel be obtained within the first week and then at weekly intervals for the first 5 weeks after initiation. The majority of thyroid dysfunction was noted within the first 35 days of treatment.

Increased Risk of Antithyroid Drug Agranulocytosis Associated with Amiodarone-Induced Thyrotoxicosis: A Population-Based Cohort Study.

Agranulocytosis occurs in 0.2-0.5% of patients treated with the antithyroid drugs (ATDs) methimazole and propylthiouracil. The objectives of this study were to evaluate the risk of ATD-related agranulocytosis in patients with amiodarone-induced thyrotoxicosis (AIT), and to compare it with the agranulocytosis risk in patients with thyrotoxicosis due to other etiologies treated with ATDs. This was a retrospective cohort study. Participants were 14,781 adult patients with thyrotoxicosis, newly treated with an ATD between January 1, 2002, and December 31, 2015. Among them were 593 patients treated by ATDs due to AIT. The main outcome measures were incidence rates and crude and adjusted hazard ratios using univariate and multivariable Cox regression models for ATD-related agranulocytosis within one year of treatment initiation, in association with AIT. Agranulocytosis occurred in 28 (0.19%) of patients newly treated with methimazole or propylthiouracil during the first year of follow-up. Of these 28 patients, 8/593 (1.35%) were AIT patients and 20/14,188 (0.14%) were thyrotoxic patients that was not AIT related (p < 0.001). Incidence rates were 22 (9.47-43.36) cases/1000 person-years of follow-up in AIT, and 1.79 (1.09-2.76)/1000 person-years of follow-up in non-AIT thyrotoxicosis (p < 0.0001). In univariate Cox regression analysis, risk for ATD agranulocytosis associated with AIT was 9.71 (4.28-22.05) compared to the risk in non-AIT thyrotoxicosis. In a multivariable model, adjusting for age, sex, body mass index, smoking history, year of cohort entry, diabetes mellitus, hypertension, renal failure, beta blockers, calcium channel blockers, anti-aggregants, and dose of ATDs, the risk associated with AIT was 5.70 (2.14-15.21). In a model adjusted for a propensity score to receive amiodarone, risk for ATD agranulocytosis associated with AIT was 6.32 (1.22-32.70). ATD use is associated with a higher risk for agranulocytosis in patients with AIT.

Amiodarone-Induced Thyrotoxicosis: Differential Diagnosis Using 99mTc-SestaMIBI and Target-to-Background Ratio (TBR).

Distinguishing between amiodarone-induced thyrotoxicosis (AIT) caused by excessive hormone synthesis (AIT-1) or by a destructive process (AIT-2) has important therapeutic implications, but is still difficult and debated. Tc-sestaMIBI thyroid scintigraphy (99m-STS) has been proposed as a tool for classifying the two forms. 30 AIT patients (11 females and 19 males) who underwent 99m-STS were retrospectively assessed for the present study. For each patient, a target-to-background ratio (TBR) was obtained on planar images. The TBR was then correlated with the qualitative assessment of the scans and the final clinical diagnosis. Considering clinical response to treatment as the gold standard for differential diagnosis, 14 cases of AIT-1, 12 of AIT-2, and 4 mixed forms were identified. 99m-STS was able to qualitatively identify all the mixed forms, while 1/14 AIT-1 and 6/12 AIT-2 cases were misdiagnosed as mixed forms. When the quantitative index (the TBR) was compared with the final clinical diagnosis, ROC curve analysis enabled us to identify an IBR of 0.482 during 99m-STS as a cut-off capable of discriminating between AIT-1 and AIT-2, with 100% specificity and 91.7% sensitivity (P < 0.0001, area under the curve: 0.982). Taking the TBR into consideration, 99m-STS proved a very useful tool for distinguishing AIT-1 from AIT-2, and thus offering patients appropriate treatment as of their diagnosis. This approach can avoid pointless and potentially dangerous combined overtreatments, and may speed up the return to normal thyroid function, which is crucial in AIT patients suffering from heart disease.

Amiodarone-induced thyrotoxicosis

Amiodarone-induced thyroid dysfunction occurs in about 15-20% of patients under amiodarone therapy. Amiodarone-induced hypothyroidism (AIH) can develop in patients with an apparently normal thyroid gland or in those with an underlying chronic autoimmune thyroiditis. On a clinical ground, AIH is not challenging and can be easily treated with L-thyroxine therapy. Amiodarone-induced thyrotoxicosis (AIT) can occur in patients with (AIT 1) or without (AIT 2) an underlying thyroid disease. AIT 1 is a true iodine-induced hyperthyroidism occurring in patients with an underlying thyroid autonomy while AIT 2 is a drug-induced destructive thyroiditis. According to the different pathogenetic mechanism, AIT 2 is treated with glucocorticoids while AIT 1 usually responds to thionamides. Thyroidectomy should be considered when AIT represents an imminent risk for cardiac conditions, when patients require a prompt resolution of thyrotoxicosis or when they do not respond to the medical therapy. An effective collaboration between cardiologists and endocrinologists is crucial in each part of the management of AIT patients, including the evaluation of cardiological conditions with regard to thyroid hormone excess and whether, or not, it is necessary to continue amiodarone therapy.

Plasma exchange in the treatment of thyroid storm secondary to type II amiodarone-induced thyrotoxicosis.

SummaryType II amiodarone-induced thyrotoxicosis (AIT) is an uncommon cause of thyroid storm. Due to the rarity of the condition, little is known about the role of plasma exchange in the treatment of severe AIT. A 56-year-old male presented with thyroid storm 2months following cessation of amiodarone. Despite conventional treatment, his condition deteriorated. He underwent two cycles of plasma exchange, which successfully controlled the severe hyperthyroidism. The thyroid hormone levels continued to fall up to 10h following plasma exchange. He subsequently underwent emergency total thyroidectomy and the histology of thyroid gland confirmed type II AIT. Management of thyroid storm secondary to type II AIT can be challenging as patients may not respond to conventional treatments, and thyroid storm may be more harmful in AIT patients owing to the underlying cardiac disease. If used appropriately, plasma exchange can effectively reduce circulating hormones, to allow stabilisation of patients in preparation for emergency thyroidectomy.Learning pointsType II AIT is an uncommon cause of thyroid storm and may not respond well to conventional thyroid storm treatment.Prompt diagnosis and therapy are important, as patients may deteriorate rapidly.Plasma exchange can be used as an effective bridging therapy to emergency thyroidectomy.This case shows that in type II AIT, each cycle of plasma exchange can potentially lower free triiodothyronine levels for 10h.Important factors to consider when planning plasma exchange as a treatment for thyroid storm include timing of each session, type of exchange fluid to be used and timing of surgery.

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

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. 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. 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). 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.

Effects of Amiodarone, Thyroid Hormones and CYP2C9 and VKORC1 Polymorphisms on Warfarin Metabolism: A Review of the Literature

ObjectiveTo review the literature regarding the interaction among amiodarone therapy, thyroid hormone levels, and warfarin metabolism. Methods73-year-old male with type 2 after describing an unusual case of amiodarone-induced thyrotoxicosis (AIT) who experienced a severe rise in international normalized ratio (INR) values after initiating warfarin therapy due to an unusual combination of excessive thyroid hormones, amiodarone therapy, and a genetic abnormality affecting warfarin metabolism. ResultsGenetic analysis revealed that the patient was CYP2C9*2 wild-type, CYP2C9*3/*3 homozygous mutant, and VKORC1*3/*3 homozygous mutant. A review of the literature revealed that both mutations can independently affect warfarin metabolism. In addition, amiodarone therapy and the presence of thyrotoxicosis per se can affect warfarin metabolism and reduce the dose needed to maintain INR in the therapeutic range. The association of the 2 genetic polymorphisms in a patient with AIT is extremely rare and strongly impairs warfarin metabolism, exposing the patient to a high risk of overtreatment. ConclusionsIn patients with AIT, warfarin therapy should be gradually introduced, starting with a very low dose, because of the significant risk of warfarin overtreatment. Whether the genetic analysis of CYP2C9 and VKORC1 polymorphisms should be routinely performed in AIT patients remains conjectural. (Endocr Pract. 2013; 19:1043-1049)

Total Thyroidectomy in Patients with Amiodarone-Induced Thyrotoxicosis and Severe Left Ventricular Systolic Dysfunction

Patients with amiodarone-induced thyrotoxicosis (AIT) and left ventricular (LV) systolic dysfunction have a high mortality rate. Usually, medical therapy is the first choice for AIT patients, whereas the role of the thyroidectomy is unsettled. The objective of the study was to evaluate the effect of a total thyroidectomy on cardiac function and survival of AIT patients with severe LV systolic dysfunction. This was a retrospective cohort study. The study was conducted at a tertiary university center. All AIT patients (n=24; nine patients with type 1 AIT, 15 patients with type 2 AIT) referred to the Department of Endocrinology and submitted to a total thyroidectomy at the Department of Surgery, both at the University of Pisa, during the years 1997-2010. The intervention was a total thyroidectomy. LV ejection fraction (EF) after the thyroidectomy and survival in December 2011 were measured. All enrolled patients had previously undergone to medical treatment for AIT, as appropriate, without achieving euthyroidism. Patients with moderate to severe LV systolic dysfunction (EF<40%, group 1, n=9) or with mild systolic dysfunction (40%≤EF≤50%, group 2, n=5) were compared with patients with normal systolic function (EF>50%, group 3, n=10). Two months after thyroidectomy, under levothyroxine replacement therapy, LVEF improved in patients with LV systolic dysfunction, particularly in those of group 1, in whom it increased from 28.2±7.2 to 38.3±6% (P=0.007). On the contrary, LVEF did not significantly change in group 3 (from 57.1±3.0 to 59.8±6.6%, P=0.242). The mean follow-up was 67±42 months. No death occurred during and 2 months after surgery. One death occurred in one patient of group 1, 30 months after the thyroidectomy, due to acute myocardial infarction. No patient had relevant complications of thyroidectomy. Total thyroidectomy, by rapidly restoring euthyroidism, may improve cardiac function and reduce the risk of mortality in AIT patients with severe LV dysfunction.

Continuation of Amiodarone Delays Restoration of Euthyroidism in Patients with Type 2 Amiodarone-Induced Thyrotoxicosis Treated with Prednisone: A Pilot Study

Type 2 amiodarone-induced thyrotoxicosis (AIT) is a destructive thyroiditis usually responsive to glucocorticoids. Whether continuation of amiodarone affects treatment outcome is unsettled. The objective of the study was to compare the outcome of glucocorticoid treatment in type 2 AIT patients who continued or withdrew amiodarone. This was a matched retrospective cohort study. The study was conducted at a university center. Eighty-three consecutive patients with untreated type 2 AIT participated in the study. After matching with patients continuing amiodarone (AMIO-ON, n = 8), patients interrupting amiodarone were randomly selected in a 4:1 ratio (AMIO-OFF, n = 32). All patients were treated with oral prednisone. Patients whose thyrotoxicosis recurred after glucocorticoid withdrawal were treated with a second course of prednisone. Time and rate of cure were measured. Median time to the first normalization of serum thyroid hormone levels did not significantly differ in AMIO-ON and AMIO-OFF patients (24 and 31 d, respectively; P = 0.326). Conversely, median time for stably restoring euthyroidism was 140 d in AMIO-ON patients and 47 d in AMIO-OFF patients (log rank, P = 0.011). In fact, AIT recurred in five of seven AMIO-ON patients (71.4%) and in only three of 32 AMIO-OFF patients (9.4%, P = 0.002), requiring readministration of prednisone. One AMIO-ON patient never reached thyroid hormone normalization during the study period. Factors associated with glucocorticoid failure were thyroid volume and amiodarone continuation. Prednisone restores euthyroidism in most type 2 AIT patients, irrespective of amiodarone continuation or withdrawal. However, continuing amiodarone increases the recurrence rate of thyrotoxicosis, causing a delay in the stable restoration of euthyroidism and a longer exposure of the heart to thyroid hormone excess.

Glucocorticoids Are Preferable to Thionamides as First-Line Treatment for Amiodarone-Induced Thyrotoxicosis due to Destructive Thyroiditis: A Matched Retrospective Cohort Study

Type 2 amiodarone-induced thyrotoxicosis (AIT) is a destructive thyroiditis usually responsive to glucocorticoids; however, recent surveys showed that many expert thyroidologists worldwide use thionamides for type 2 AIT patients. The objective of the study was to compare the effectiveness of methimazole (MMI) or prednisone (GLU) in type 2 AIT patients who had a short cure time according to a published predictive model. This was a matched retrospective cohort study. The study was conducted at a university center. Forty-two untreated type 2 AIT patients with a predicted cure time < or = 40 d were divided into two groups (MMI and GLU groups). After matching for the predicted cure time, patients in the GLU group were selected in a 1:1 ratio to patients in the MMI group. Patients were treated with GLU or MMI for 40 d. Patients still thyrotoxic after 40 d continued glucocorticoids if in the GLU group or were switched to prednisone (MMI-GLU group) if in the MMI group. Time and rate of cure (healing) at 40 d were measured. Patients still thyrotoxic after 40 d were 23.8 +/- 9.3% in the GLU group and 85.7 +/- 7.6% in the MMI group (P = 0.000). The GLU and MMI-GLU groups did not significantly differ in the nonhealing rate at 40 d (P = 0.730). When patients in the MMI group were treated with glucocorticoids, 94.1% patients achieved euthyroidism within 40 d. However, the global median cure time (MMI period + prednisone period) was longer (60 d, 95% confidence interval 53.5-66.5 d) in the MMI-GLU group than the GLU group (21 d, 95% confidence interval 15.1-26.9 d). Glucocorticoids are the first-line treatment in type 2 AIT, whereas thionamides play no role in this destructive thyroiditis.

Amiodarone-Induced Thyrotoxicosis Is a Predictor of Adverse Cardiovascular Outcome

Amiodarone-induced thyrotoxicosis (AIT) is a clinical condition that is notoriously difficult to manage; the relative risk of adverse cardiovascular events in these patients compared with euthyroid patients is largely unknown. We compared the clinical characteristics and major adverse cardiovascular events (MACE) in AIT and euthyroid patients. Patients at a tertiary referral center who had been prescribed amiodarone for at least 3 months were retrospectively analyzed. Baseline clinical characteristics, laboratory parameters, and outcome events were evaluated. MACE was defined as cardiovascular mortality, myocardial infarction, stroke and heart failure, or ventricular arrhythmias that required hospitalization. A total of 354 patients (61.8 +/- 14.1 yr; 64.7% male) with a mean follow-up of 48.6 +/- 26.7 months were studied. AIT, euthyroid status, and amiodarone-induced hypothyroidism were identified in 57 (16.1%), 224 (63.3%), and 73 (20.6%) patients, respectively. No differences in baseline clinical characteristics were observed between AIT and euthyroid patients. Nonetheless AIT patients demonstrated a higher MACE rate (31.6 vs. 10.7%, P < 0.01), mostly driven by a higher rate of ventricular arrhythmias that required admission (7.0 vs. 1.3%, P = 0.03). Cox-regression multivariate analysis revealed that AIT (hazard ratio 2.68; confidence interval 1.53-4.68; P < 0.01) and left ventricular ejection fraction less than 45% (hazard ratio 2.52; confidence interval 1.43-4.42; P < 0.01) were independent predictors of MACE. In patients prescribed long-term amiodarone therapy, occurrence of AIT is associated with a 2.7-fold increased risk of MACE. Regular and close biochemical surveillance is thus advisable to identify and treat this high-risk group of patients.

Color-flow Doppler sonography in the differential diagnosis and management of amiodarone-induced thyrotoxicosis

Amiodarone-induced thyrotoxicosis (AIT) may be caused by excessive thyroidal hormone synthesis and release (type 1) or by a destructive process (type 2). This differentiation is considered essential for therapeutic choice. To evaluate the utility of color-flow Doppler sonography (CFDS) in the differential diagnosis and management of AIT. The clinical and laboratory data, thyroid sonography (grayscale sonography [GSS], CFDS), thyroid radioiodine uptake (RAIU) and thyroid scintigraphy, treatment, and clinical outcome were retrospectively reviewed in 21 AIT patients. The CFDS pattern of thyroid nodules was separately described from that of the perinodular parenchyma, and AIT was classified as type 1 (increased blood flow) or type 2 (low/no blood flow). Type 1 AIT patients were treated with methimazole (alone or associated with potassium perchlorate), while type 2 patients were treated with prednisone or amiodarone withdrawal alone. Eleven patients with increased blood flow were considered as type 1, and 10 with low/no blood flow as type 2. Ten of the 11 patients in the first group showed a hypervascular nodular pattern, while one showed a hypervascular parenchymal pattern. Clinical diagnoses were toxic nodular goiter and Graves' disease, respectively. Of the 10 patients with low/no blood flow, six had normal thyroid volume, three small diffuse goiter, and one small multinodular goiter. The clinical outcome showed that 20 of the 21 patients were treatment responsive. CFDS is a useful tool in the differential diagnosis of AIT. This differentiation appeared to be of clinical relevance as regards therapeutic choice. Separate evaluation of parenchymal blood flow from that of nodules may prove beneficial in the diagnosis of underlying thyroid diseases in patients with type 1 AIT.

Proportion of type 1 and type 2 amiodarone‐induced thyrotoxicosis has changed over a 27‐year period in Italy

Two main forms of amiodarone-induced thyrotoxicosis (AIT) exist. Type 1 AIT is a form of iodine-induced hyperthyroidism. Its management is complex and includes thionamides, potassium perchlorate and, occasionally, thyroidectomy. Type 2 AIT is a destructive thyroiditis, responds to glucocorticoids, and usually does not require further thyroid treatment once euthyroidism has been restored. To assess retrospectively the prevalence and relative proportion of type 1 and type 2 AIT over a 27-year period at a tertiary referral centre in Italy. Consecutive AIT patients (n = 215) seen at the department of endocrinology of the University of Pisa between 1980 and 2006. Type 1 AIT constituted the most frequent AIT form (60%) during the first years covered by this study. The annual mean number of type 1 AIT patients was 3.6 at the beginning of the study period, and 2.5 during the later years. In contrast, the mean annual number of new cases of type 2 AIT progressively increased from 2.4 to 12.5. Likewise, the proportion of type 2 AIT increased in a significant linear manner (P < 0.0001), currently accounting for 89% of AIT cases. Type 2 AIT patients showed a male preponderance, higher serum FT4/FT3 ratio (P < 0.002), lower 3-h and 24-h thyroidal radioactive iodine uptake values (P < 0.0001), and received a higher cumulative dose of amiodarone (P < 0.0001) than type 1 AIT patients. Over a 27-year period, the epidemiology of AIT changed, as the prevalence of type 2 AIT progressively increased and that of type 1 remained constant. Thus, under most circumstances, endocrinologists nowadays deal with type 2 AIT, which is a destructive thyroiditis, generally treated successfully with glucocorticoids. Although no additional treatment is usually required after the destructive process subsides, periodic assessment of thyroid function is warranted, because of the occurrence of hypothyroidism (up to 17%) during long-term follow-up of these patients.

Long-term outcome of thyroid function after amiodarone-induced thyrotoxicosis, as compared to subacute thyroiditis

Two main forms of amiodarone- induced thyrotoxicosis (AIT) exist: type 1 AIT is a condition of true hyperthyroidism developing in patients with pre-existing thyroid disorders, and usually requires thyroid ablative treatment. On the other hand, type 2 AIT is a form of destructive thyroiditis occurring in normal thyroids, the management of which usually consists in glucocorticoid treatment. To assess the long-term outcome of thyroid function in a prospective study of type 2 AIT patients, as compared to patients with De Quervain's subacute thyroiditis (SAT). Sixty consecutive patients with type 2 AIT were evaluated during oral glucocorticoid treatment (oral prednisone 30 mg/day, gradually tapered and withdrawn over a 3-month period) and followed for 38+/-4 months (range 6-72) thereafter. Sixty consecutive patients with SAT, referred to our Institutes during the same period and treated with the same therapeutic schedule, served as controls. Type 2 AIT patients were older (p<0.0001) and showed a larger male preponderance (M:F 3.6:1 vs 0.5:1, p<0.0001) than SAT patients. Mean serum free T4 (FT4) and free T3 (FT3) concentrations at diagnosis were increased in both conditions, but higher in type 2 AIT than in SAT (FT4 47.6+/-18.8 and 29.6+/-8.3 pmol/l, respectively, p<0.0001; FT3 15.4+/-7.0 and 11.2+/-3.0 pmol/l, respectively, p<0.001). Correction of thyrotoxicosis was obtained in all patients in both groups, but restoration of euthyroidism occurred earlier in SAT than in type 2 AIT (p=0.006). Ten type 2 AIT patients (17%) and 3 SAT patients (5%, p<0.03) became permanently hypothyroid after glucocorticoid withdrawal and required levothyroxine replacement. A relevant proportion of type 2 AIT patients develop permanent hypothyroidism after correction of thyrotoxicosis. Thus, periodic surveillance of thyroid status is required after type 2 AIT.

Mild and Short Recurrence of Type II Amiodarone-induced Thyrotoxicosis in Three Patients Receiving Amiodarone Continuously for More Than 10 Years

Although there are two types of amiodarone-induced thyrotoxicosis (AIT), only type II AIT has been seen at our institution in Japan so far. There have been few case reports of AIT recurrence, probably because of the fact that amiodarone is immediately discontinued once AIT has developed. Our own policy is not to discontinue amiodarone in all AIT patients, unless severe adverse effects such as pulmonary fibrosis develop. Among more than 50 patients with type II AIT we have encountered, three with arrhythmogenic right ventricular cardiomyopathy showed AIT recurrence. In these patients, the first episode of AIT developed 3, 4, and 2 years after the start of amiodarone administration, and recurrence was observed 5, 6, and 8 years after the first episode, respectively. The AIT resolved spontaneously in all cases while the patients continued to take amiodarone. In comparison with the first AIT episode, the second was milder and resolved within a shorter period. These three cases suggest that recurrence of type II AIT may not be rare in iodine-sufficient areas, and that it is relatively mild and may resolve spontaneously. Furthermore, at least in Japan, it may be possible for patients with recurrent type II AIT to continue taking amiodarone.

Clinical characteristics of amiodarone-induced thyrotoxicosis and hypothyroidism in Japan.

Since amiodarone was introduced in Japan in 1992, the incidence of the drug-induced thyroid dysfunction has been increasing. We studied the thyroid function of 13 patients with amiodarone-induced thyrotoxicosis (AIT) and 11 patients with amiodarone-associated hypothyroidism (AAH) who had been referred to our Institute in the last 6 years. AIT and AAH developed after 39+/-21 and 20+/-16 months of amiodarone treatment, respectively. One patient developed AAH followed by AIT. The AIT ranged from subclinical to overt thyrotoxicosis. Four patients with moderate to marked AIT were treated with methimazole. Their thyrotoxicosis persisted for 3 to 9 months, despite administration of antithyroid agents. One patient with mild thyrotoxicosis was treated with prednisolone, resulting in a euthyroid state in a few months. Eight patients with asymptomatic to moderate thyrotoxicosis resolved spontaneously without any treatment. In four asymptomatic patients with AIT, serum levels of T3 and T4 were in the upper normal range or slightly high (< 12 microg/dl), accompanied by suppressed TSH (<0.1 microU/ml) and high thyroglobulin levels, suggesting destruction-induced thyrotoxicosis. Such a subclinical thyrotoxicosis developed repeatedly in one patient. Ultrasonographic studies revealed no nodular lesion in the thyroid, and color flow Doppler sonography demonstrated no hypervascularity in the thyroid gland in any AIT patient. Although it is postulated in Europe that there are two types of AIT, namely type I, which develops in patients with latent Graves' disease or toxic multinodular goiter, and type II, which develops in an apparently normal thyroid as destructive thyroiditis, all AIT patients we have seen so far had developed destructive type AIT. Sufficient intake of iodide and a very low incidence of toxic multinodular goiter may account for the rare incidence of type I AIT in our country. Mild to moderate AIT resolved spontaneously without discontinuing amiodarone, but it was discontinued in two of 13 AIT patients because of extrathyroidal adverse reactions.