Reintroduction of amiodarone in patients with a history of amiodarone-induced thyrotoxicosis (AIT) is rarely used. To date, the risk of AIT recurrence after amiodarone reintroduction is unpredicted. The aim of the study was to evaluate the risk of AIT recurrence. Retrospectively, from 2000 to 2011, all euthyroid patients with a history of AIT with amiodarone reintroduction were included. Type and severity of the first AIT, amiodarone chronology, and thyroid function evolution after reintroduction of amiodarone were investigated: 46 of 172 patients with AIT history needed amiodarone reintroduction. At first AIT episode, the mean age was 62.2 ± 16 years with male gender predominance; 65% of patients were classified as type 1 AIT. AIT recurred in 14 patients (30%), 12 patients developed hypothyroidism (26%), and 20 patients remained euthyroid (44%). Characteristics of type 1 AIT during the first episode, namely briefer exposure period to amiodarone and longer duration of treatment to normalize thyroid hormones, were predictive of AIT recurrence; 73% of patients (8 of 11) with previous episode of type 1 AIT, who did not receive a preventive thioamide treatment, developed a second episode of AIT. Thioamide preventive treatment could be useful to prevent type 1 AIT recurrence. In conclusion, AIT recurrence after amiodarone reintroduction is 4 times more frequent in patients with type 1 AIT history. Thyroid ablation before amiodarone reintroduction in patients with a history of type 1 AIT is preferred. Preventive thioamide treatment could be suggested in patients with type 1 AIT history pending for surgery.
Reintroduction of amiodarone in patients with a history of amiodarone-induced thyrotoxicosis (AIT) is rarely used. To date, the risk of AIT recurrence after amiodarone reintroduction in patients with a history of AIT is unpredicted. The aim of this retrospective study was to evaluate the risk of AIT recurrence after amiodarone reintroduction in euthyroid patients with a history of AIT. Furthermore, we tried to identify the predictive factors for recurrence of AIT after amiodarone reintroduction.
Methods
This is a retrospective study carried out in the departments of cardiology and endocrinology at the University Hospital of Clermont-Ferrand. The regional ethics committee approved the study.
Data concerning patients with an episode of AIT referred to the departments of endocrinology and cardiology were explored. From January 2000 to December 2011, we included patients having the following criteria: (1) amiodarone was interrupted as part of management of the first AIT, (2) thyroid function was subsequently normalized, (3) no preventive thyroid ablation was accomplished, and (4) amiodarone was later on reintroduced.
Thyroid function tests were collected, and their evolution was assessed during the following periods: amiodarone therapy, first AIT episode, antithyroid treatment, and during reintroduction of amiodarone. The diagnosis of AIT was based on the clinical evidence of hyperthyroidism with elevated free thyroxin (FT4) and/or free triiodothyronine (FT3) levels and undetectable serum thyroid-stimulating hormone (TSH) levels in patients treated with amiodarone. Amiodarone-induced hypothyroidism (AIH) was considered permanent when serum TSH concentrations were elevated (TSH >10 UI/L) with concomitant decrease of FT4 levels (FT4 <10 pmol/L).
Characteristics of patients with types 1 and 2 AIT during the first episode were compared. AIT type was documented for the first episode according to thyroid volume, echo structure, vascularity, and autoantibodies as reported previously ( Supplementary Table 1 ).
After amiodarone reintroduction, the patients (1) remained euthyroid, (2) developed a second episode of AIT, or (3) developed AIH. We compared the clinical and biologic data concerning patients who developed a second AIT or AIH with those who remained euthyroid.
Patients with type 1 or type 2 AIT history received low doses with a thioamide preventive therapy in parallel with amiodarone reintroduction (24 patients). They were compared with another group (22 patients without prevention). It was used only in patients who either firmly refused surgery or when the surgery-related mortality was very high. The risk of AIT recurrence with the presence or absence of thioamides was examined.
Data were expressed as mean ± SD or percentage. For quantitative parameters, a Mann-Whitney U test was used to test the differences between the 2 groups. For a correlation between 2 quantitative continuous variables, a nonparametric correlation test of Spearman was used. For qualitative parameters, Fisher’s exact and chi-square tests were used for differences between the 2 groups. Kaplan-Meier method was used to estimate the survival without recurrence. Statistical analyses were done using the SAS, version 8, statistical package; p values <0.05 were considered statistically significant.
Results
One hundred seventy-two patients were diagnosed to have an AIT. Of them, 46 patients needed amiodarone reintroduction and met the inclusion criteria ( Figure 1 ).
The clinical and biochemical findings for all patients during the first episode of AIT are summarized in Tables 1 and 2 . Data concerning thyroid morphology and pathology for each patient are summarized in Supplementary Table 2 . Analyses according to AIT type revealed that type 1 AIT needed shorter exposure to amiodarone and longer time to normalize FT4 and FT3 levels (more resistant). Type 2 AIT was more severe with higher FT4/FT3 ( Table 2 ).
| Variable | All (n=46) |
|---|---|
| Male | 75% |
| Age (years) | 62±16 |
| Duration of amiodarone exposure (months) | 27±26 |
| Cumulative amiodarone dose (grams) | 154±145 |
| TSH (mUI/l) | 0.04±0.02 |
| Free thyroxin (FT4: pmol/l) | 52±33 |
| Free triiodothyronin (FT3: pmol/l) | 9.3±5.7 |
| Ratio FT4/FT3 | 6.1±2.9 |
| Type 1 AIT | 65% |
| Duration to normalize FT4 (days) | 96±66 |
| Duration to normalize FT3 (days) | 91±63 |
| Variables | AIT Type | p | |
|---|---|---|---|
| 1 (n=30) | 2 (n=16) | ||
| Male | 73% | 81% | ns |
| Age (years) | 62 | 62±17 | ns |
| Duration of amiodarone exposure (months) | 20±17 | 40±13 | <0.01 |
| Cumulative amiodarone dose (grams) | 125±88 | 212±213 | <0.05 |
| Thyroid stimulating hormone (TSH: mUI/l) | 0.03±0.05 | 0.03±0.02 | ns |
| Free thyroxin (FT4: pmol/l) | 41±21 | 69±28 | <0.01 |
| Free triiodothyronin (FT3: pmol/l) | 8.7±4.7 | 13.2±7.8 | <0.05 |
| Duration to normalize FT4 (days) | 124±72 | 92±63 | 0.08 |
| Duration to normalize FT3 (days) | 132±82 | 79±54 | <0.01 |
Once first AIT was confirmed, amiodarone therapy was stopped for a mean duration of 2 years. The cardiovascular characteristics of our cohort are summarized in Table 3 . The mean duration of follow-up after amiodarone reintroduction was 6 years. After amiodarone reintroduction, 14 patients developed a second episode of AIT, whereas 12 patients developed AIH. Meanwhile, 20 patients remained euthyroid after amiodarone reintroduction ( Figure 1 ).
| Variable | All (n=46) |
|---|---|
| Ischemic heart disease | 58% |
| Congenital heart disease | 12% |
| Hypertrophic cardiomyopathy | 6% |
| Dilated cardiomyopathy | 20% |
| Pulmonary hypertension | 4% |
| Associated valvular heart disease | 34% |
| Mean left ventricular diameter | 60±12mm |
| Left ventricular ejection fraction | 38±16% |
| Indications of amiodarone | |
| Atrial fibrillation | 40% |
| Atrial flutter | 12% |
| Supraventricular tachycardia | 2% |
| Ventricular tachycardia | 40% |
| Ventricular fibrillation | 6% |
| Defibrillator | 36% |
| Ablation trials (definitive success) | 0.2(0)% |
Of the 14 patients with a recurrent AIT, 11 had type 1 (79%) ( Table 4 ). Patients who developed a second AIT were more resistant to antithyroid treatment. It is worth noting that the duration of exposure of amiodarone before developing the first AIT tended to be shorter in the recurrent AIT group. No other differences between recurrent AIT group and euthyroid patients were elucidated ( Table 4 and Supplementary Table 3 ). Other than AIT or AIH, 2 patients developed interstitial lung diseases, one with neuropathy and another with skin photo toxicity, secondary to amiodarone treatment.
| Variable | Euthyroid (n=20) | recurrence (n=14) | AIH (n=12) | p 1 | p 2 |
|---|---|---|---|---|---|
| Male | 75% | 71% | 83% | ns | ns |
| Age (years) | 61±14 | 57±21 | 58±18 | ns | ns |
| Duration of amiodarone exposure | 31±26 | 20±25 | 32±20 | 0.07 | ns |
| TSH (mUI/l) | 0.04±0.02 | 0.05±0.03 | 0.03±0.03 | ns | ns |
| Free thyroxin (FT4: pmol/l) | 53±38 | 50±32 | 73±27 | ns | 0.07 |
| Free triiodothyronin (FT3: pmol/l) | 8.4±4.3 | 11±7.8 | 12±8.2 | ns | ns |
| Type 1 AIT | 65% | 79% | 50% | ns | ns |
| Duration to normalize FT4 (days) | 86±48 | 130±103 | 104±41 | <0.05 | ns |
| Duration to normalize FT3 (days) | 75±42 | 136±97 | 84±34 | <0.01 | ns |
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