Case Report

Management of Amiodarone Induced Thyrotoxicosis - Not An Easy Task

Koutroumpi Stavroula1, Herrmann Markus2, Stratigou Theodora1, Vlassopoulou Varvara1, Tsagarakis Stylianos1
1Department of Endocrinology, Diabetes and Metabolism, "Evangelismos" Hospital, 45-47 Ipsilantou Street, 10676, Athens, Greece
22Clinical Institiute for Medical and Chemical Laboratory Diagnostics Medical University of Graz, Auenbruggerplatz 15/18036 Graz, Austria
*Corresponding author:

Koutroumpi Stavroula, Department of Endocrinology, Diabetes and Metabolism, "Evangelismos" Hospital, 45-47 Ipsilantou Street, 10676, Athens, Greece, Email: koutroumpi.lina@gmail.com

Keywords:

Amiodarone, Amiodarone-induced thyrotoxicosis, Color flow doppler sonography, Corticosteroids

Background:Amiodarone Induced Thyrotoxicosis (AIT) is a condition of thyroid hyper function due to amiodarone’s pharmacological and toxic actions. Two different forms can be distinguished: Type I is characterized by latent thyroid autonomy unmasked by exposure to excess iodine, type II is a destructive thyroiditis due to direct cytotoxic effects of the drug and its metabolites targeting thyrocytes.

Objectives: To highlight the impact of correct distinction between the two types on treatment management and the need of long-term follow up after euthyroidism restoration. Methods: We present the case of an 81 year old woman with AIT type II who was on long term treatment with amiodarone for ventricular arrhythmia. The diagnosis was established by clinical history, symptoms and color flow doppler sonography (CFDS). The patient has been treated with glucocorticoids. Amiodarone therapy was continued because of severe ventricular arrhythmia.

Results: Glucocortioid treatment restored euthyroidism within 4 weeks and at one year of follow up the patient was stable and did neither show signs of a relapse of AIT nor progression to clinical hypothyroidism.

Conclusions: AIT represents a diagnostic and therapeutic challenge that requires collaboration between the cardiologist and the endocrinologist.

Amiodarone is a type-III anti-arrhythmic drug for atrial and ventricular arrhythmias that cannot be controlled sufficiently with other anti arrhythmic agents [1]. Due to its high iodine content (37% of its weight) and its long half-life (approximately 100 days) with deposits mainly in adipose tissue, amiodarone may induce thyroid dysfunction shortly after commencement, during therapy or even months after its discontinuation [2].

Amiodarone induced hypothyroidism (AIH), seen more frequently in iodine sufficient areas, is typically not a matter of concern as it can easily be managed by thyroxine replacement therapy [3]. Amiodarone induced thyrotoxicosis (AIT) instead is more commonly observed in iodine deficient regions and represents a real diagnostic and therapeutic challenge. There are two types of AIT: AIT type I is defined as iodine-induced hyperthyroidism and affects individuals with pre-existing thyroid illness, AIT Type II is a drug-induced destructive thyroiditis that develops in an apparently healthy thyroid gland [3,4].

Distinction of the two forms of AIT is crucial for the management of affected patients. Whereas AIT type I is managed with anti-thyroid drugs, AIT type II is treated by glucocorticoids [3,4]. Inappropriate pharmacotherapy due to misclassification of AIT patients harbors a high risk of ineffective treatment response and unnecessary side effects. Table 1 summarizes characteristic features that may help to distinguish the two AIT forms.4In the diagnostic workup of AIT patients it is important to consider also mixed forms usually not responsive to monotherapy. In such cases anti-thyroid agents and glucocorticoids are often used simultaneously with close monitoring of thyroid function and drug doses titration based on the patient’s response.

Factor

Type I

Type II

Goiter

Often present

Usually absent

Duration of amiodarone Therapy

Shorter (1-2 years)

Longer (>2 years)

RAIU

Low, normal or high

Low/suppressed

Thyroid ultrasound-color flow doppler sonography (CFDS)

Increased parenchymal blood flow

Normal or decreased blood flow

Therapy

Thionamides, perchlorate

Oral Glucocorticoids

Subsequent hypothyroidism

No

Possible

Table 1. Comparison of AIT type I and II (Adapted from Ref 4)


Here we present a case of AIT type II where diagnosis was mainly based onthe assessment of thyroid vascularization by color flow doppler sonography (CFDS). The patient was treated with glucocorticoids leading to a rapid restoration of euthyroidism that remained stable during the first year of follow up. Amiodarone therapy was continued because of the patient’s underlying cardiac arrhythmia.

An 81 year-old female presented with a two- month history of worsening arrhythmia, agitation and weight loss of 3 kilograms. No other symptoms were referred. Two years ago, ventricular tachycardia and heart failure were diagnosed and her cardiologist started treatment with 200 mg of amiodarone daily. In addition, she was on anti-hypertensive (metoprolol, furosemide/amiloride), lipid-lowering (atorvastatin), anti-platelet (aspirin) and anti-osteoporotic (alendronate, calcium/vitamin D) treatment. She did neither report a previous thyroid illness nor a family history of thyroid dysfunction. Thyroid function tests before commencement of amiodarone therapyand six months prior to presentation in our clinic while on amiodarone treatment were unremarkable. At presentation she had a small goiter that was painless at palpation. There was no bruit over the gland and no other signs of thyroid dysfunction. Blood pressure was 130/80 with irregular pulse and a heart rate of 90 bpm. Thyroid function tests and measurement of thyroid antibodies showed mild hyperthyroidism (TSH 0.04 mIU/l; Ft4 2.45 ng/dl; T3 2ng/ml) with increased anti-thyroglobulin antibodies (anti-TG 254 IU/ml)), while thyroid peroxidase antibodies (anti-TPO) and thyroid stimulating immunoglobulin (TSI) were both negative. Thyroid ultrasound performed by an experienced radiologist showed hypoechogenicity and irregularity of the parenchyma with two small mixed nodules of 13 and 12.5 mm at the right lobe. Assessment of the thyroid with CFDS revealed absent vascularization-pattern 0.Based on the CFDS result and the clinical pattern AIT type II was diagnosed. Glucocorticoid treatment (prednisone 30mg/day gradually tapered within 2 months) was commenced with close follow-up of thyroid function until restoration of euthyroidism and at regular intervals thereafter. Table 2 shows hormonal and biochemical parameters at diagnosis and during follow-up.

 

 

-9 (m)

Baseline

+15 (d)

+45 (d)

+3 (m)

+6 (m)

+ 9 (m)

+12 (m)

Parameters

Reference range

 

 

 

 

 

 

 

 

TSH (mIU/ml)

0.3-4.5

3.36

0.04

0.2

6.15

5.44

4.67

4.59

6.5

FT4 (ng/dl)

0.8-1.76

-

2.45

1.78

1.4

1.61

1.42

-

1.46

T3 (ng/ml)

0.8-1.9

-

2

1.91

1.52

1.39

1.21

-

1.02

AntiTG (IU/ml)

<60

-

254

-

-

175

-

-

67

Anti TPO (IU/ml)

<50

-

10

-

-

13

-

-

11

TSI U/l

<2

-

0.35

-

-

-

-

-

-

RBCs (106/mm3 )

4.1-5.5

5

5.02

5.52

5.56

-

5.06

-

-

HGB (gr/dl)

12-15

15

15

16

16

-

14.9

-

-

HCT (%)

37-45

45

45

47

45

-

45

-

-

SGOT (U/l)

6-31

31

36

20

26

40

-

-

-

SGPT (U/l)

6-31

31

36

28

27

25

-

-

-

γGT (U/l)

7-32

-

44

39

41

52

-

-

-

Creat  (mg/dl)

0.5-1.4

1.1

1.16

1.21

1.1

-

0.99

-

-

BUN (mg/dl)

10-50

42

36

56

-

-

25

-

-

BG (mg/dl)

70-110

106

103

82

90

114

99

-

-

HbA1c (%)

<6.5

-

-

5.9

5.5

5.8

5.5

-

-

(m), months; (d), days; RBCs, Red Blood Cells; HGB, Hemoglobin; HCT, hematocrit; SGOT, Serum Glutamic Oxaloacetic Transaminase; SGPT, Serum Glutamic-Pyruvic Transaminase; γGT, Gamma-Glutamyl Transferase; Creat, creatinine; BUN, Blood Urea Nitrogen; BG, Blood Glucose, HbA1C, Hemoglobin A1c

 


Table 2. Biochemical parameters before, at diagnosis and at one-year follow-up

Thyroid dysfunction is often suspected when a previously well-controlled arrhythmia deteriorates or recurs. In anti coagulated patients an unexpected increase of the International Normalized Ration (INR) may also give rise to suspect a developing AIT [5,6]. In the patient presented here symptoms of hyperthyroidism developed after two years of amiodarone treatment and were confirmed by blood tests. Interestingly, patients with AIT usually show only mild or moderate symptoms either because of their old age or because of amiodarone’s protective effect on the heart [7]. The guidelines of the American Association of Clinical Endocrinologists (AACE) andthe American Thyroid Association (ATA) recommend performing thyroid evaluation before, at 1 and 3 months after the initiation of amiodarone treatment and at 3-6 months intervals thereafter [7-9]. However, due to the unpredictable onset of thyroid dysfunction mainly in AIT type II, the usefulness of regular monitoring during amiodarone treatment is questioned by others [7]. In the present case the patient’s cardiologist monitored thyroid function regularly during amiodarone therapy with unremarkable results. Discrimination between the two types of AIT is challenging and several aspects should be taken into consideration. In the present patient AIT type II was suspected because of long term therapy with amiodarone before the occurrence of thyrotoxicosis, the unremarkable thyroid function tests before the occurrence of symptoms and the absence of clinical signs of either toxic diffuse (Graves’ disease) or nodular goiter. The presence of increased concentration of anti-TG does not exclude AIT type II. The diagnosis was further strengthened by the results of CFDS that showed a pattern 0 of thyroid vascularization.

Compared to AIT type I the lag time between commencement of amiodarone therapy and onset of symptoms may be several months longer in AIT type II [10]. It has been speculated that amiodarone’s high iodine content induces a rapid decompensation of a latent thyroid dysfunction leading to AIT type I while the direct thyrotoxic effects of amiodarone in AIT type II take longer to become apparent [10]. The positivity of anti-TG at the time of diagnosis in AIT type II does not necessarily imply the presence of underlying thyroid autoimmunity as it can be encountered in about 8% of such cases and could be due to the destructive process as seen in other types of destructive thyroiditis (subacute thyroiditis) [11]. On the contrary, the occurrence of AIT type II in an underlying chronic lymphocytic thyroiditis cannot be excluded in patients with features of destructive thyroiditis and high titers of anti-TG and anti-TPO [12]. At present the majority of European and North American endocrinologists consider CFDS the diagnostic tool of choice in AIT. However, a skilled radiologist with expertise in thyroid diseases is mandatory [13,14]. In the present case CFDS played indeed a key role in establishing the diagnosis of AIT type II. Iodine uptake (RAIU) was not performed as it is typically flawed in patients with long term amiodarone use [14]. Recently there is a growing interest in using thyroid [99mTc] 2-methoxy-isobutyl-isonitrile (MIBI) scintigraphy. However, more and larger studies are needed to confirm its usefulness particularly in mixed forms [2,14].

In the present case the mild thyroid dysfunction, the patient’s age and the underlying cardiac abnormalities raised the question if the patient should be treated or not. Glucocorticoids are the first line treatment in AIT type II but their use is associated with substantial side effects. Most patients with AIT type II show a rapid response to glucocorticoid treatment (approximately within 30 days) that mainly depends on the severity of the underlying hyperthyroidism and the volume of the thyroid gland [15]. However, many cases of mild AIT type II are self-limited and require no treatment [9,16] On the other hand, patients with poor cardiac function, characterized by a low ejection fraction, have a high risk of death [17]. In these patients glucocorticoid treatment may be important in order to rapidly restore euthyroidism. In our patient prednisone 30 mg/day was commenced with gradual tapering over a two month period. Biochemical tests were performed every 2-4 weeks until restoration of euthyroidism and every 3-4 months thereafter. The only adverse event noted was an asymptomatic increase of hematocrit that normalized after discontinuation of the glucocorticoid therapy.

The decision of whether or not amiodarone should be discontinued should involve a cardiologist and an endocrinologist. While the anti-arrhythmic effect of amiodarone is beneficial for the heart, thyrotoxicosis causes cardiac stress. It is important to consider that amiodarone has a very long half-life and thus its effect on the thyroid gland may last for several months after discontinuation of the drug. Therefore, suspension of amiodarone therapy may not influence the immediate response to medical therapy [2]. In most cases of AIT type I amiodarone is discontinued whereas in type II withdrawal is considered less important. However, it has been suggested that continuing amiodarone in AIT type II could be a risk factor for a relapse of hyperthyroidism, even years later [18]. In the patient presented here amiodarone was not suspended mainly as it was the only suitable antiarrhythmic agent and discontinuation would not have affected thyroid function immediately. Once euthyroidism was restored, thyroid function was tested at regular intervals and until today neither relapse of hyperthyroidism nor progression to clinical hypothyroidism has occurred. Nevertheless active surveillance of thyroid function is mandatory as the incidence of hypothyroidism after cure of AIT type II is rather high, especially in the presence of thyroid antibodies as in our patient [11,12].

Amiodarone Induced Thyrotoxicosis

There is no conflict of interest. None of the authors has received any kind of financial assistance from any commercial organizations in preparing the manuscript.

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Citation: Stavroula MS, Markus H, Theodora S, Varvara V, Stylianos T (2017) Management of Amiodarone Induced Thyrotoxicosis - Not An Easy Task. J Diabetes Care Endocrinolo 1:005

Published: 04 December 2017

Reviewed By : Dr. Oguz Ugur Aydin,

Copyright:

© 2017 Stavroula et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.