Hyperthyroidism case
scenerio

CASE HISTORY:
An 11-year-old female with no significant past medical history presented with
symptoms suggestive of hyperthyroidism (weight loss, heat intolerance). She has
also experienced a decline in grades at school. Family history is significant for
thyroid disease in both grandmothers (both on thyroid replacement therapies). The
clinician ordered thyroid function tests including Free T4, T3, TSH, anti-TSH
receptor antibodies, antithyroglobulin and antithyroid peroxidase antibodies

The results for the tests follow:
Free thyroxine (FT4) 2.87 ng/dL (Prepubertal 0.73-1.77 Pubertal/Adult 0.73-1.84)
Total triiodothyronine pediatric (T3) 374.00 ng/dL (123-211)
Thyroid-stimulating hormone (TSH) <0.018 uU/ml
Thyroxine (T4) 18.2 ug/dL (5.0-12.0)
Antithyroglobulin antibodies >3000 IU/ml (Negative <60 IU/mL Equivocal 60-100IU/mL Positive >100 IU/mL)
Antithyroid peroxidase antibodies 2667 IU/mL (<60) Anti-TSH receptor antibodies 69.6 % Inhibit. (<=16.0
Unit: %)
The laboratory findings confirmed the clinical impression and a diagnosis of Graves's disease (hyperthyr

The patient was started on methimazole right away but after approximately two
weeks of treatment she developed severe adverse reaction to it with significant
joint pain and swelling over her upper and lower extremities with hives;
Methimazole was stopped immediately and she was started on Benadryl and Advil
; her symptoms improved after few days, although she did have some residual
intermittent hives that were transient.
She has been given some brief course of Prednisone as well, and Atenolol 50 mg
twice a day was also started.

After approximately two weeks, due to the fact that the medical management for
hyperthyroidism failed, the patient was considered to have radioiodine ablation of her
thyroid next day and for that she underwent a thyroid imaging with uptake showing
enlarged thyroid gland, with homogeneous increased uptake, consistent with Graves
disease with 24-hour uptake equaling 86%.
The patient underwent radio-iodine ablation as scheduled and she was stable on
Atenolol 50 mg twice a day. She was discharged home.
At her next follow-up appointment in 2 weeks her thyroid functions tests lab values
were as follows:

her next follow-up appointment in 2 weeks her thyroid functions tests lab values
were as follows:
T4, Free, >12.00 ng/dl (Prepubertal 0.73-1.77 Pubertal/Adult 0.73-1.84)
T3, 1173.00 ng/dL (123-211 ng/dL)
TSH, <0.018 uIU/mL
DISCUSSION:

We present the case of a 65-year-old woman who was referred urgently from primary
care with worsening breathlessness for 3 weeks, associated with tachycardia and left
bundle branch block (LBBB). She had a background of type 2 diabetes, asthma and
hypertension. Initial ECG revealed atrial fibrillation with the fast ventricular rate on the
background of LBBB. ECHO findings were consistent with systolic impairment. Initial
testing including checking thyroid function test revealed hyperthyroidism. It became
evident that this patient had thyrotoxic cardiomyopathy. Early advice from the
endocrine team was sought and the patient was treated with a combination of
carbimazole and ivabradine. After a hospital stay, she made a remarkable recovery.
Keywords: arrhythmias

Heart failure is a clinical syndrome, not pathological entity.1 Causes of heart failure (HF) should be carefully looked for. Though most
cases of HF are caused by issues within the heart itself (pathology within the coronaries, valves, electrical pathways or myocardium),
rarely HF can be caused by a non-cardiac pathology.1
In this case report, we describe a patient who presented for urgent care with worsening shortness of breath and was found to have
congestive HF secondary to hyperthyroidism.
Although thyroid disorders are not uncommon, they remain a challenge to diagnose and treat effectively. In the context of cardiac
disease caused by thyroid disorders, hyperthyroidism should not be missed—without proper treatment of the underlying cause,
outcomes are inevitably poor. The consequences of excess thyroid hormones on the myocardium have been well described. There is a
predictable increase in heart rate and contractility which leads to increased cardiac output,2 ultimately resulting in undue strain on the
heart. Thus, hyperthyroidism, if left untreated, significantly increases the risk of atrial fibrillation (AF) and HF. The importance of
detecting hyperthyroidism in these patients when they first present cannot be overstated. When the patient is restored to a euthyroid
state and the ventricular rate is slowed the outcomes are always excellent.3 4

65-years-old woman was referred urgently from primary care with a history of progressively increasing shortness
of breath and cough for the last 3 weeks. Her breathlessness initially started on exertion which had now
progressed to being present even at rest. This was associated with a cough which was productive and contained
the scanty amount of whitish sputum without any diurnal variation. She also complained of three pillow
orthopnoea (she normally used one pillow to sleep) and paroxysmal nocturnal dyspnoea.
On systemic review, she revealed three stone weight loss over a period of 4 months but there was an intentional
element to it. She admitted to more frequent bowel opening for the last 4–6 weeks.
She was known to have type II diabetes mellitus and occupational asthma. She was postmenopausal, a social
drinker and was an ex-smoker. She was independent, fit and well, recently back from a holiday in Australia. She
was not known to have any drug allergies and was on metformin, steroid inhalers and valsartan although admitted
to poor medication compliance. She denied any previous hospitalisation and there was no history of exposure to
asbestosis. Her family history was significant for ischaemic heart disease (father had myocardial infarction).

On examination she was alert, pale but not icteric, and was struggling to finish
sentences due to shortness of breath, her respiratory rate being 24
breaths/minute. She was apyrexial, tachycardiac at 120 beats per minute, the
pulse being irregularly irregular with a blood pressure of 140/100 mm Hg. Her
oxygen saturation was 97% on room air. She had bibasal crackles in her lungs.
The remaining clinical examinations remained unremarkable.
Her ECG showed AF with a fast ventricular rate of 116 beats with a left bundle
branch block morphology (figure

Investigations
Her initial investigations were as follow.
Complete blood count: haemoglobin: 134 g/L (♀ 115–165 g/L), white cell count: 7.6×109/L (3.6–11.0×109/L), platelets 203×109/L (140–400×109/L).
Electrolytes: sodium: 138 mmol/L (133–146 mmol/L), potassium: 4.2 mmol/L (3.5–5.3 mmol/L), urea: 9.0 mmol/L (2.5–7.8 mmol/L), creatinine: 77 μmol/L (♀ 45–84 μmol/L).
Liver panel: bilirubin: 40 μmol/L (<21 μmol/L), alkaline phosphatase: 118 U/L (30–130 U/L), alanine aminotransferase: 61 U/L (♀<33 U/L), albumin: 33 g/L (♀<33 U/L).
Troponins: 20.10 ng/L and 21.60 (0 to 15.6 ng/L).
C reactive protein: 11 mg/L (<5 mg/L).
Blood glucose: 12.6 mmol (below 11.1 mmol/L).
Haemoglobin A1C: 55 mmol/mol (below 42 mmol/mol).
Lipid profile: total cholesterol 2.9 mmol/L (3.6–5 mmol/L), HDL-cholesterol: 0.6 mmol/L (1.2–9999 mmol/L).

Investigations
Her initial investigations were as follow.
Complete blood count: haemoglobin: 134 g/L (♀ 115–165 g/L), white cell count: 7.6×109/L (3.6–11.0×109/L), platelets 203×109/L (140–400×109/L).
Electrolytes: sodium: 138 mmol/L (133–146 mmol/L), potassium: 4.2 mmol/L (3.5–5.3 mmol/L), urea: 9.0 mmol/L (2.5–7.8 mmol/L), creatinine: 77 μmol/L (♀ 45–84
μmol/L).
Liver panel: bilirubin: 40 μmol/L (<21 μmol/L), alkaline phosphatase: 118 U/L (30–130 U/L), alanine aminotransferase: 61 U/L (♀<33 U/L), albumin: 33 g/L (♀<33 U/L).
Troponins: 20.10 ng/L and 21.60 (0 to 15.6 ng/L).
C reactive protein: 11 mg/L (<5 mg/L).

Blood glucose: 12.6 mmol (below 11.1 mmol/L).
Haemoglobin A1C: 55 mmol/mol (below 42 mmol/mol).
Lipid profile: total cholesterol 2.9 mmol/L (3.6–5 mmol/L), HDL-cholesterol: 0.6 mmol/L
(1.2–9999 mmol/L).
Chest x-ray: cardiomegaly, left-sided pleural effusion, prominent pulmonary hila,
appearance suggestive of early pulmonary oedema (figure 2)

Echocardiogram: showed severely dilated left atrium with severe impairment to
overall left ventricle systolic contractility (left ventricle internal diameter
(LVIDd)=5.5 cm (3.9–5.3 cm) with a severe increase in left ventricle end systolic
volume and left ventricle end diastolic volume). Ejection fraction was 14% (biplane
Simpson method). Moderate tricuspid regurgitation and mild mitral regurgitation
(video 1).
Video 1

Differential diagnosis
This case is significant because it demonstrates a relatively rare clinical entity with
common clinical cardiac symptoms. Initial differential diagnosis were
Silent myocardial infarction resulting in acute ischaemic cardiomyopathy.
Dilated cardiomyopathy.
Tachycardia-induced cardiomyopathy.
Hypertensive HF.

Treatment
The patient was initially treated with diuretics and transferred to cardiology ward for further management. As the patient had a new diagnosis of HF
and AF, screening for wider causes of cardiomyopathy was requested including thyroid function test, serum ACE and ferritin levels.
The thyroid function test revealed:
Thyroid-simulating hormone (TSH): <0.01 (0.35–3.50 mU/L)
Thyroxine (free T4): 28.5 (7.5–21.1 pmol/L)
Triiodothyronine(free T3): 8 (3.8–6.0 pmol/L).

Thyrotoxic cardiomyopathy was diagnosed. Her Burch and Warthofsky’s Score was 40 (15 points for pulmonary oedema, 10 points
each for AF and rate around 110 and 5 points for temperature) suggesting of impending thyroid storm, therefore early consultation with
endocrine team was made. The patient was started on antithyroid medications (carbimazole 20 mg × once daily) beta-blocker
(bisoprolol 2.5 mg × once daily), ramipril 2.5 mg × once daily and intravenous furosemide 80 mg × twice daily.
As the patient developed bronchospasm, bisoprolol was later switched to ivabradine 2.5 mg × twice daily which slowly uptitrated to
7.5 mg × twice daily. The dose of intravenous furosemide was decreased and switched to bumetanide 1 mg × once daily.
In the further course of hospitalisation, the patient’s condition improved over the next 3–4 days, with complete resolution of fluid
overload and heart rate slowed down to 70 beats per minute.
Later on, further testing found to have antithyroid peroxidase antibody: 147.7 kU/L (0–34) and thyroid-stimulating antibody: 3.52 IU/L
(<0.56).

Outcome and follow-up
She was followed by both cardiology and endocrinology in an outpatient clinic after 3
months and was found to have considerable improvement in her symptoms.
She was back in sinus rhythm, maintaining her heart around 50–60 beats per minute.
Her repeat echocardiogram showed moderate to severe left ventricular (LV)
impairment with a decrease in tricuspid and mitral regurgitation. Her ejection fraction
was improved to 37% (biplane Simpson method) (video 2).

Definition
Thyrotoxicosis is a condition characterized by the classic physiologic manifestations of
excess
thyroid hormones
regardless of the cause or hormonal source. If the excessive
hormones
are produced and released by the
thyroid
gland, the condition is called hyperthyroidism.

Epidemiology
Thyrotoxicosis due to hyperthyroidism:
De novo
synthesis
of hormone, with normal or high radioactive
iodine
uptake
Much more common in women than in men (5:1)
Prevalence
: approximately 1.3% overall in the United States; 0.8% in Europe
4%–5% in older women
Graves’ disease:
Most common cause of thyrotoxicosis (80%) in iodine-sufficient areas
More common in younger women, with
incidence
of 4.6 per 1000 women per 10 years of observation
Toxic multinodular

Epidemiology
Thyrotoxicosis due to hyperthyroidism:
De novo
synthesis
of hormone, with normal or high radioactive
iodine
uptake
Much more common in women than in men (5:1)

Prevalence
: approximately 1.3% overall in the United States; 0.8% in Europe
4%–5% in older women
Graves’ disease:
Most common cause of thyrotoxicosis (80%) in iodine-sufficient areas
More common in younger women, with
incidence
of 4.6 per 1000 women per 10 years of observation
Toxic multinodular
goiter
(15% of cases) and toxic adenoma (approximately 5% of cases):
Higher in iodine-deficient areas
More common in elderly people
More common in smokers
Pituitary
adenoma (< 1% of cases)

Thyrotoxicosis without hyperthyroidism:
Less common, generally transient
No new
synthesis
of hormone in
thyroid
and, therefore, low radioactive
iodine
uptake
3 major categories:
Inflammation
and release of stored hormone, most commonly:
Initial phase
or exacerbations of Hashimoto’s
thyroiditis
(
incidence

Thyrotoxicosis without hyperthyroidism:
Less common, generally transient
No new
synthesis
of hormone in
thyroid
and, therefore, low radioactive
iodine
uptake
3 major categories:
Inflammation
and release of stored hormone, most commonly:
Initial phase
or exacerbations of Hashimoto’s
thyroiditis
(
incidence
: 3.5/1000/year in women and 0.8/1000/year in men)
Subacute
thyroiditis

Treatment of heart failure in thyrotoxicosis
HF secondary to thyrotoxicosis is predominantly resolved by lowering peripheral
thyroid hormone levels, which aids in the reversal of systemic decompensation [44].
The main goals of treatment and management of thyrotoxicosis are to reduce
circulating thyroid hormone levels and block peripheral effects of circulating thyroid
hormone [44]. Gazzana et al. conducted a study to evaluate the effects of
hyperthyroidism and the possibility of reversing the effects on cardiovascular structure
and function using Doppler echocardiography. It was concluded that patients with
hyperthyroidism developed cardiovascular changes, increased cardiac chamber size,
cardiac output, left ventricular ejection fraction (LVEF), and pulmonary artery systolic
pressure. These changes were evidenced to be reversible after lowering the levels of
FT4 back to normal in patients without the pre-existing cardiovascular disease (Table
4) [46].

Additionally, Shuvy et al. conducted a study observing the heart rate variability (HRV) in thyroxine
suppressive therapy, as HRV is a sensitive marker of cardiac sympathetic activity. The 1-minute
HRV was calculated from the difference in beats per minute between the shortest and the longest
heart rate interval during six cycles of deep breathing measured by electrocardiography. Results
showed that the 1-minute HRV was significantly lower in thyroxine-treated patients than healthy
controls, concluding that thyroxine suppressive therapy decreases HRV by way of autonomic
dysregulation (Table 4) [47]. Another study conducted by Tomisti et al. over a period of 3 years at
the University of Pisa observed the effect of a total thyroidectomy on cardiac function and overall
survival of patients with amiodarone-induced thyrotoxicosis with severe left ventricular systolic
dysfunction. After undergoing thyroidectomy and receiving levothyroxine replacement therapy, the
LVEF improved in patients with LV systolic dysfunction. It was concluded that by restoring
euthyroidism, cardiac function and the risk of mortality are significantly diminished (Table 4) [

Blocking the synthesis of thyroid hormone is the action of agents known as the thionamides, also
known as anti-thyroid drugs, including PTU and MMI [49]. These drugs are commonly associated
with liver dysfunction, but PTU is the first-line drug used for hyperthyroidism, as it has the least risk
of hepatotoxicity [50]. As thyrotoxicosis is primarily seen in middle-aged women, it is essential to
know that PTU is also recommended in the first trimester of pregnancy due to decreased
teratogenic effects over MMI, which is used during the second trimester of pregnancy [50]. In a
study conducted by Takata et al. over 5 years in a sample population of 134 untreated patients
with Graves’ disease, who compared the effect of MMI treatment with MMI and potassium iodide
(KI) treatment in rapid normalization of thyroid hormones during the early phase of thyrotoxicosis.
They also monitored disease remission after 5 years. It was concluded that combined therapy with
MMI and KI improved the short-term control of Graves’ hyperthyroidism by normalizing FT3 levels
and was not associated with worsening hyperthyroidism or drug resistance (Table 4) [

Another option is to block to release of preformed thyroid hormone using lithium carbonate or
inorganic iodine components, like Lugol’s solution or potassium iodide [49]. These are commonly
used in combination with beta-adrenergic blockers, specifically propranolol, for significant
improvement in thyroid hormone levels [52]. To block the effects of thyroid hormone against
peripheral tissues, specifically the hyperadrenergic symptoms, beta-blockade using propranolol or
esmolol can be used [49]. Palmieri et al. conducted a study observing the effects of acute beta-1
adrenergic blockade (bisoprolol) on myocardial contractility and total arterial stiffness in patients
with thyrotoxicosis. It was observed that in a hyperthyroid state, there is a sustained increase in
preload with enhanced LV diastolic function. In patients treated with bisoprolol, there was
decreased cardiovascular hyperkinesia, which manifested as a lowered heart rate. It was
concluded that specific beta-1 adrenergic blockade using bisoprolol leads to the normalization of
total arterial stiffness, which attenuates the high-output state commonly seen in thyrotoxicosis
patients

Beta-blockade can be used as sole therapy to provide symptomatic relief in the
short term [54]. However, beta-blockers are used in combination with radioactive
iodine or anti-thyroid drugs for long-term treatment [54]. Tagami et al. conducted a
study over a period of 1 month with beta-blockers in a sample population of 28
adults to observe its effects on new-onset thyrotoxicosis caused by Graves’
disease. It was found that symptoms of shortness of breath and fatigability in
addition to heart rate all improved with adjunctive beta-blocker therapy than with
MMI therapy alone (Table 4) [

Peripheral conversion from T4 to T3 can be inhibited using PTU, propranolol,
glucocorticoids such as dexamethasone or hydrocortisone, or oral contrast agents
like iopanoic acid [49]. Glucocorticoid administration results in inhibition of TSH
release, which allows the thyroid hormone level to reduce, controlling the
symptoms of thyrotoxicosis [56]. An exploratory study conducted with a sample
population of three patients was observed for seven days for the effects of high-
dose IV glucocorticoids compared to standard-dose oral glucocorticoids in
amiodarone-induced thyrotoxicosis. It was concluded that high-dose IV
glucocorticoid therapy does not offer advantages over standard-dose oral
glucocorticoid therapy in the rapid, short-term period (Table 4) [57

Rarely, medications like lithium, hemodialysis, charcoal hemoperfusion, and cholestyramine can
also be used to treat symptoms of thyrotoxicosis [58]. Hemodialysis and charcoal hemoperfusion
clarify the blood by increasing the excretion of thyroid hormone [58]. Cholestyramine is effective
because it will bind the thyroid hormone, usually reabsorbed in the distal small intestine, reducing
the effective amount of circulating thyroid hormone [59]. A study conducted by Kaykhaei et al.
studied the effects of low-dose cholestyramine on serum total triiodothyronine and free thyroxine.
They concluded that cholestyramine when compared to methimazole and propranolol, is more
effective in decreasing serum levels of thyroid hormones (Table 4) [60]. Another study conducted
over a period of 5 weeks in a sample population of 15 patients with thyrotoxicosis observed the
effects of cholestyramine, an anion exchange resin that binds iodothyronines, in adjunction with
thionamides and atenolol, a beta-blocker. After weekly monitoring FT4, FT3, TSH, and thyrotropin-
binding inhibitory immunoglobulin, it was concluded that cholestyramine is most effective in
treating thyrotoxicosis during the first few weeks of treatment [59].

23-year-old previously healthy male presented after the onset of generalized weakness and
inability to rise from bed in the setting of 35 kg of unintentional weight loss, and was found to have
profound hypokalaemia, elevated thyroid hormone, and suppressed thyroid-stimulating hormone
consistent with thyrotoxicosis secondary to Grave’s disease. Following hospital admission, he
developed worsening tachycardia with dynamic anteroseptal ST-segment elevations and elevated
cardiac biomarkers concerning for MI. He was treated with aspirin, ticagrelor, and a heparin
infusion, but was unable to tolerate beta-blockade acutely due to hypotension. Echocardiography
demonstrated a severely dilated left ventricle (left ventricular end-diastolic volume index
114 mL/m2) and severely reduced systolic function (ejection fraction 23%) with global hypokinesis.
Following initiation of propylthiouracil, iodine solution, and stress-dosed steroids his tachycardia
and ST-elevations resolved. Computed tomography (CT) coronary angiography demonstrated no
evidence of coronary stenosis. He was discharged on methimazole, metoprolol, and lisinopril and
found to have recovered left ventricular systolic function at 2-month follow-up.

Discussion
Thyrotoxicosis can rarely cause coronary vasospasm, stress cardiomyopathy, and
autoimmune myocarditis. These conditions should be suspected in hyperthyroid
patients with features of MI and normal coronary arteries. Workup should include
laboratory evaluation, electrocardiography (ECG), echocardiography, and non-
invasive or invasive ischaemic evaluation.

Learning points
Thyrotoxicosis can be associated with cardiovascular manifestations, including stress
cardiomyopathy, coronary vasospasm, and autoimmune myocarditis, all of which can
mimic ST-segment elevation myocardial infarction (STEMI).
Workup of thyrotoxicosis-induced STEMI should include laboratory evaluation, ECG,
echocardiography, and non-invasive or invasive ischaemic evaluation.
Management should include anti-thyroid agents for thyrotoxicosis and guideline-
directed medical therapy for heart failure.

Introduction
Thyroid storm is a rare, life-threatening condition that can have a variety of
cardiovascular manifestations including tachycardia, atrial fibrillation, and
congestive heart failure.1 In this case, we present a patient with thyrotoxicosis
found to have dynamic ST-elevations, elevated cardiac biomarkers, and acute
systolic dysfunction initially concerning for acute myocardial infarction (MI) with
heart failure but who was later found to have normal coronary arteries. Here we
discuss possible explanations that may inform future care of cardiovascular
complications in hyperthyroid patients.

Case presentation
A 23-year-old previously healthy male was transferred to our hospital after the onset of diaphoresis, generalized weakness, and
inability to rise from bed. He endorsed 35 kg of weight loss over the prior 3 months and having had a high-carbohydrate meal the
evening prior to presentation. The patient was not on medications prior to presentation and denied palpitations, heat intolerance,
tremor, dyspnoea, oedema, anxiety, vision change, and change in bowel habit prior to presentation.
On exam, he was in moderate distress with a heart rate of 152 b.p.m., blood pressure of 89/56 mmHg, respiratory rate of 28 breaths
per minute, oxygen saturation of 98% on room air, and temperature of 37.8°C. The patient had an otherwise unremarkable
cardiovascular examination, including the absence of abnormal heart sounds, jugular venous distention, and lower extremity oedema.
His lungs were clear to auscultation. The patient had moist mucous membranes and an enlarged thyroid but no evidence of
exophthalmos, tremor, or ophthalmoplegia. He was found to have generalized weakness, predominantly in the lower extremities.
Laboratory studies were notable for a potassium of 1.9 mEq/L (normal 3.7–5.2 mEq/L), an undetectable thyroid-stimulating hormone,
and free T4 of 3.2 ng/dL (normal 0.6–1.2 ng/dL). Initial ECG demonstrated sinus tachycardia with prolonged QT interval (QTc 652 ms)
and minimal ST-elevations in V1–V3 (Figure 1, top panel). He was admitted to the medical intensive care unit (ICU).

12-lead ECG upon transfer to our hospital (top panel) demonstrating sinus tachycardia with minimal ST-elevations in V1–V3. Second ECG following admission to the medical intensive care unit (bottom panel)
demonstrating worsening sinus tachycardia with increasing ST-elevations in leads V1–V4 (arrows). Note the lack of reciprocal ST-depressions.
His weakness improved following potassium repletion and fluid resuscitation, but his tachycardia persisted. A second ECG was obtained and notable for anteroseptal (V1–V4) ST-elevations and resolution of QT
prolongation (QTc 401 ms) (Figure 1, bottom panel). He denied chest pain or pressure. Troponin-I was elevated to 7.97 ng/mL (normal <0.04 ng/mL), trending upwards to 18.98 ng/mL.
Treatment was initiated with aspirin, ticagrelor, and unfractionated heparin infusion. He was unable to acutely tolerate beta-blockade due to hypotension. Urgent echocardiogram (Supplementary material online,
Video S1) revealed a severely dilated left ventricle [left ventricular end-diastolic volume index (LVEDVi) 114 mL/m2] with severely reduced systolic function [ejection fraction (EF) 23%] and global hypokinesis. No
focal wall-motion abnormalities were present.
Following initiation of propylthiouracil, potassium iodine solution, and stress-dosed steroids, his tachycardia and ST-elevations improved. Computed tomography (CT) coronary angiography (Figure 2) 2 days after
presentation demonstrated no evidence of coronary artery atherosclerosis or stenosis. Additionally, cine cardiac CT images of the heart showed normal left ventricular systolic function (Supplementary material
online, Videos S2–S4). Aspirin, ticagrelor, and heparin were stopped at this time due to a low concern for type I MI. Thyrotropin receptor antibodies returned positive, consistent with Graves’ disease. Ultrasound of
the thyroid gland showed thyromegaly (right lobe volume 32 cc, left lobe volume 26 cc) with heterogenous parenchyma and increased vascularity, also consistent with Graves’ disease. Prior to discharge, the
patient endorsed improved but persistent fatigue and dyspnoea with exertion. He continued to be free of chest pain and remained normotensive throughout the remainder of his hospital stay. The patient was
discharged on methimazole in addition to guideline-directed medical therapy for heart failure, including lisinopril 2.5 mg daily and metoprolol succinate 25 mg daily. Up-titration of his lisinopril and metoprolol
dosages were limited by borderline-low blood pressures. He appeared euvolemic throughout the hospitalization, so diuretics were not initiated. Mineralocorticoid receptor antagonists were not prescribed upon
discharge due to borderline hypotension, as well.

3D-reconstructed image from CT coronary angiography showing the left main, proximal left
anterior descending, and proximal left circumflex coronary arteries. Full linear reconstructions of
the right and left coronary arteries were unable to be obtained due to significant artefact. Following
radiologist review of several cardiac phases, there was no evidence of atherosclerosis, stenosis, or
thrombosis.
At 2-month follow-up, the patient’s left ventricle remained severely dilated (LVEDVi 126 mL/m2)
but with recovered systolic function (EF 65%) (Supplementary material online, Video S5). He had
returned to normal activities without functional limitations. He was initially continued on lisinopril
and metoprolol, but both were eventually discontinued over the course of several months given the
patient’s recovered left ventricular systolic function and successful treatment of his
hyperthyroidism. He remained on methimazole and was clinically euthyroid on follow-up visits.

Discussion
There is a well-defined association between hyperthyroidism and cardiac disease, most commonly atrial fibrillation and tachycardia-induced cardiomyopathy.1
Excess thyroid hormone levels have also been independently associated with coronary events at hospital admission and over a 3-year follow-up.2 In our case, we
were concerned that the patient’s transient ST-elevations were indicative of more rare complications including acute MI due to vasospasm, myocarditis, or stress
cardiomyopathy.
The association between thyrotoxicosis and acute MI has been described in the literature, summarized in one case series of 21 patients presenting with acute MI
and thyrotoxicosis from 2002 to 2014.3 The authors found that among these patients, angiographically normal coronary arteries were the most common finding
(13/21 patients), but vasospasm without thrombosis was occasionally found (3/21). Coronary vasospasm should be suspected among patients presenting with signs
and symptoms of acute MI in the setting of a hyperthyroid state, but with normal coronary arteries on angiography.4,5
Myocarditis represents an even more uncommon complication of Graves’ disease but has been described in several case reports. One 46-year-old woman ultimately
died of refractory heart failure in the setting of thyrotoxicosis found to have lymphocytic myocarditis on autopsy.6 Another study evaluated 50 patients via cardiac
magnetic resonance imaging (CMRI) who had persistently high anti-microsomal and anti-thyroglobulin antibodies as well as chest pain, dyspnoea, and palpitations.7
Among them, 15 had CMRI findings consistent with myocarditis. Lymphocytic infiltration was found on endomyocardial biopsy in three of the five patients who had a
reduced left ventricular ejection fraction (LVEF). The pathophysiology of myocarditis associated with Graves’ disease is unclear, but the presence of thyrotropin
receptor in cardiac tissue has been demonstrated by reverse transcriptase polymerase chain reaction, suggesting a possible mechanism for stimulation by
thyrotropin receptor antibodies.8 Concurrent viral infection with coxsackievirus B type 4 and autoimmune diseases such as Takayasu’s arteritis, systemic lupus
erythematosus, and rheumatoid arthritis have also been described to be associated with myocarditis in hyperthyroid patients.9,10

Thyrotoxicosis is additionally associated with takotsubo cardiomyopathy, also known as stress cardiomyopathy, as described in several case reports.11 Takotsubo
cardiomyopathy can mimic ST-segment elevation MI with similar electrocardiographic findings, though it is typically characterized by transient focal wall-motion
abnormalities leading to apical-ballooning of the left ventricle.12 Our patient did not have these characteristic wall-motion abnormalities, but his ST-segment
elevation, transient systolic dysfunction, and elevated cardiac enzymes were consistent with acute stress cardiomyopathy. Furthermore, thyrotoxicosis causes
excessive sympathetic stimulation which is thought to be the underlying pathophysiologic mechanism of takotsubo cardiomyopathy.12
In this case, the patient had localized ST-elevations that may have been due to coronary vasospasm, autoimmune myocarditis, or an acute stress cardiomyopathy.
The absence of both reciprocal ST-depressions on ECG and focal wall-motion abnormalities on echocardiography suggest an alternative process to acute coronary
thrombus formation. Additionally, his CT coronary angiography reassuringly found no evidence of coronary stenosis, though transient vasospasm could not be ruled
out. If vasospasm had been definitively diagnosed or if the patient’s hyperthyroidism had not rapidly stabilized, calcium channel blocker therapy would have been
considered upon discharge. The patient was discharged on a beta-blocker, given its effects in both ameliorating symptoms in patients with hyperthyroidism and
slowing progression of ventricular remodelling in patients with heart failure. Metoprolol was selected rather than propranolol, because our patient’s borderline
hypotension prevented the initiation of a non-selective beta-blocker such as propranolol, which is more commonly used in the management of uncomplicated
hyperthyroidism. Additionally, CMRI would have been reasonable to accurately identify the presence of myocarditis and may be considered in other cases with
diagnostic uncertainty. His global systolic dysfunction is characteristic of tachycardia-mediated cardiomyopathy but may also have been a sign of underlying
myocarditis or stress cardiomyopathy. Additionally, concomitant viral infection leading to myocarditis should be considered.
Conclusion

Antithyroid Medications. Antithyroid medications are thionamides; they inhibit thyroid peroxidase, blocking the synthesis of T3 and T4.
Thionamides can serve as a long-term therapy or as a bridge to I-131 ablation or thyroidectomy, with the goal of normalizing thyroid
function and preventing exacerbation of hyperthyroidism after I-131 ablation or avoiding surgical risks associated with uncontrolled
hyperthyroidism. Because Graves disease remits in up to 30% of patients treated with thionamides, these medications can be used as
the initial treatment, with ablation or thyroidectomy performed if remission does not occur.25,26 Once medical therapy is discontinued,
relapse occurs in 30% to 70% of patients, mostly within the first year.27 After discontinuation, thyroid function should be monitored
every one to three months for six to 12 months, and the patient should be instructed to contact the physician if symptoms recur.
Because use of propylthiouracil has a higher risk of causing severe liver injury, as highlighted in the U.S. Food and Drug
Administration's boxed warning, methimazole is preferred except during the first trimester of pregnancy (can cause birth defects) and in
patients with an adverse reaction to methimazole.28,29 For patients using methimazole, the prevalence of agranulocytosis is 0.17%,
the incidence of hepatitis is 3.17 per 1,000 person-years, and the incidence of acute hepatic failure is 0.32 per 1,000 person-
years.30,31 Patients should be instructed to discontinue medication use and contact their physician if they develop jaundice, acholic
stools, dark urine, arthralgias, abdominal pain, nausea, vomiting, fever, or sore throat. A baseline complete blood count (CBC) with
differential and a hepatic panel should be obtained before initiating an antithyroid medication. Subsequent routine monitoring of CBC is
unnecessary, but CBC with differential should be obtained if fever and/or pharyngitis develop.

Free T4 and total T3 should be obtained four weeks after starting a thionamide and every four to eight weeks thereafter with the
dosage adjusted based on results. Once free T4 and total T3 levels normalize, they should be monitored every three months. Serum
TSH is of limited value early in the treatment course because levels may remain suppressed for several months after treatment is
started. An antithyroid medication should be continued for 12 to 18 months, then tapered or discontinued if the TSH level is normal at
the time. Elevated or above-normal TSH levels (greater than 4.0 mIU per mL) at antithyroid drug discontinuation is associated with an
increased likelihood of permanent remission.27
Radioactive Iodine Ablation. Radioactive iodine ablation of the thyroid gland is the most common treatment of Graves disease in the
United States. It is contraindicated in pregnancy. Moderate to severe Graves orbitopathy is a relative contraindication, especially in
patients who smoke, because radioactive iodine may exacerbate the eye disease.32,33 In mild cases of Graves orbitopathy,
radioactive iodine ablation can be performed with concomitant glucocorticoid therapy. Nonradioactive iodine impedes radioactive
iodine uptake by iodide transporter; therefore, exposure to large amounts of nonradioactive iodine (e.g., iodinated contrast,
amiodarone) should be avoided within three months before radioactive iodine ablation. Pregnancy should be ruled out within 48 hours
before radioactive iodine ablation and avoided for six months thereafter.1 A thionamide should be discontinued at least five days before
the treatment but can be restarted three to five days after to maintain control of thyroid function, because it may take up to 12 weeks to
achieve the full effect of radioactive iodine.

Most patients develop permanent hypothyroidism between two and six months after
radioactive iodine ablation and require thyroid hormone supplementation.1,33 Free T4
and total T3 should be measured four to eight weeks after ablation; if hyperthyroidism
persists, these indices should be monitored every four to six weeks and thyroid
hormone replacement started in the early stages of hypothyroidism.1
Thyroidectomy. This treatment option is preferred in patients with goiter-induced
compressive symptoms and in patients with contraindications to radioactive iodine
ablation or thionamides. Besides general anesthesia risk, thyroidectomy carries a risk
of inadvertently injuring parathyroid glands and recurrent laryngeal nerves.34

TOXIC ADENOMA OR TOXIC MULTINODULAR GOITER
Antithyroid medications can control hyperthyroidism, but do not induce remission of hyperthyroidism
associated with toxic adenoma or toxic multinodular goiter. Therefore, radioactive iodine ablation and
thyroidectomy are the main treatment options for these conditions. Thyroidectomy is favored if a nodule or
goiter causes compressive symptoms. Antithyroid medications may be used for long-term treatment in
select patients who refuse ablation or who have a contraindication to thyroidectomy.35,36
THYROIDITIS
Painless thyroiditis and subacute thyroiditis are self-limiting conditions that usually resolve spontaneously
within six months. There is no role for antithyroid medications or radioactive iodine ablation in the
treatment of thyroiditis. Beta blockers may be used if needed to control adrenergic symptoms. Pain
associated with subacute thyroiditis may be relieved with a nonsteroidal anti-inflammatory drug.5

Graves disease, toxic adenoma, and toxic multinodular goiter can sometimes
cause severe hyperthyroidism, which is termed a thyroid storm. The Burch-
Wartofsky score is a helpful tool for diagnosing thyroid storm37 (eTable B).
Treatment of thyroid storm is summarized in eTable C.

DRUG-ASSOCIATED HYPERTHYROIDISM
Amiodarone-induced thyrotoxicosis can be classified as type 1 (thyroid hormone
overproduction, treated with antithyroid medications) or type 2 (thyroid tissue
destruction, treated with steroids). Amiodarone should not be discontinued unless it
can be stopped safely, without triggering cardiac complications.38,39
Hyperthyroidism associated with use of other medications (e.g., lithium, interferon alfa,
tyrosine kinase inhibitors, highly active antiretroviral therapy) is usually self-limited. The
physician should determine whether the medication may be discontinued safely or
replaced with a different medication

Periodic paralysis
Periodic paralysis is a group of muscular of different etiologies, characterized by
episodic, short-lived, and hyporeflexic skeletal muscle weakness. They may present
with or without myotonia. The absence of sensory deficits or loss of consciousness is
the norm. Periodic paralysis can be inherited or acquired.[2]
The primary (familial) periodic paralysis is an autosomal dominant disease due to a
single gene mutation resulting in abnormalities of calcium, sodium, potassium, and
chloride channels on the muscle cell membrane. These defects lead to changes in the
serum potassium level at the time of the paralysis.

Three types:
Hypokalemic periodic paralysis (calcium channel disorder)
Hyperkalemic periodic paralysis (sodium channel disorder)
Andersen–Tawil syndrome (potassium channel subunit disorder).
Compared to hyperkalemic periodic paralysis (estimated prevalence of 1:200,000), familial hypokalemic
periodic paralysis is much more common (prevalence: 1 in 100,000). It is also more common in men (3–
4:1).[3]

35-year-old male patient awoke with bilateral paralysis of his extremities. He presented to the emergency
department of the hospital 6 h later. He had no associated difficulty in swallowing or breathing, weakness
of facial muscles, sphincter disturbances, pain, sensory symptoms, or alteration in mental state. He had
no similar episodes in the past. The patient gave a history of experiencing palpitations for several months,
heat intolerance, and loss of weight despite a good appetite. He had no known comorbidities. He denied
alcohol or illicit drug use and was not on any medication. There was no similar history in the family
members.
At the time of presentation, his blood pressure was 122/84 mmHg. His pulse rate was 101/min, regular,
and hyperdynamic. He had a diffuse thyroid swelling. He was oriented and cooperative during
examination. His higher mental faculties were normal, and the cranial nerve examination was
unremarkable. He demonstrated flaccid symmetrical proximal and distal muscle weakness of the arms
and legs (power arm: 2/5 and leg: 2/5). Deep tendon reflexes were depressed bilaterally. Sensation was
intact. The rest of the systemic examinations were normal

Blood tests showed serum K + of 2.1 mEq/L. Creatine phosphokinase (CPK) was
elevated to 421 IU/L. The rest of his biochemical parameters were within the
normal limits. The thyroid profile showed decreased thyroid-stimulating hormone
(TSH) (0.013 mIU/L) and increased free T3 and T4. The electrocardiography
(ECG) showed sinus tachycardia with 100 beats/min. The presence of U-wave
fused with P-waves [Figure 1]. The results of electromyography and nerve
conduction study were normal.

Treatment given
All the patients with hypokalemic paralysis received an intravenous (IV) potassium correction at the rate of
20 mEq/h for the first 6 h. This was done to reduce the possibility of rebound hyperkalemia. Subsequently,
they were switched over to oral potassium chloride supplementation of approximately 80 mEq/day dose
divided into 3–4 times. Serum potassium levels were measured serially in all the patients till their
potassium levels normalized. Average time to achieving was 6 h. Bed rest and oral hydration were
encouraged.
The patients diagnosed with thyrotoxicosis were also given tablet propranolol at 10 mg twice a day.
Carbimazole was started at 30 mg/day in three divided doses and titrated to achieve euthyroid levels. Oral
potassium was supplemented as necessary.

cases, there was a predominance of marked lower extremity weakness, with proximal muscles being more
affected than distal. The upper limbs were the last to get affected. The limbs were hypotonic. Deep tendon
reflexes were universally depressed. Sensation and higher mental functions were intact. There was no
correlation between the serum potassium levels and the severity of weakness. During recovery, the upper
limb fingers were the first to recover and the deep tendon reflexes were the last. Only two of our patients
had signs of thyrotoxicosis-exophthalmos, lid lag, and fine tremor; the others did not show any signs on
physical examination except sinus tachycardia. All the patients had severe hypokalemia on presentation.
The cause [Figure 2] of hypokalemia TPP rests in the fact that thyroid hormone increases the tissue
responsiveness to beta-adrenergic stimulation and insulin, which increases the activity of sodium-
potassium ATPase. This drives potassium into cells. This causes paradoxical depolarization of the muscle
membrane, and this relative inexcitability of the muscle fibers in this state leads to paralysis.[6]

Pathophysiology
Graves’ disease is an autoimmune
disorder that can occur when the
immune system mistakenly attacks
healthy thyroid tissue, leading to
overactivity of the thyroid gland.
Normally, thyroid function is
regulated by a hormone released
by the pituitary gland. When
needed, the body’s immune system
produces antibodies designed to
target a specific virus, bacterium, or
other foreign substance. In Graves’
disease, the body produces an
antibody to some of the cells in the
thyroid gland. The antibody
associated with Graves’ disease,
thyrotropin receptor antibody,
mimics the regulatory pituitary
hormone and overrides the body’s
normal regulation of the thyroid,
causing an overproduction of
thyroid hormones.2,6,8,9

Pathophysiology
Graves’ disease is an autoimmune disorder that can occur when the immune system
mistakenly attacks healthy thyroid tissue, leading to overactivity of the thyroid gland.
Normally, thyroid function is regulated by a hormone released by the pituitary gland.
When needed, the body’s immune system produces antibodies designed to target a
specific virus, bacterium, or other foreign substance. In Graves’ disease, the body
produces an antibody to some of the cells in the thyroid gland. The antibody
associated with Graves’ disease, thyrotropin receptor antibody, mimics the regulatory
pituitary hormone and overrides the body’s normal regulation of the thyroid, causing an
overproduction of thyroid hormones.2,6,8,9

These antibodies, called thyroid-stimulating immunoglobulins (TSIs), cause the thyroid to grow and
make more thyroid hormone than the body needs. TSIs bind to thyroid cell receptors, which are
normally “docking stations” for thyroid-stimulating hormone (TSH). TSIs then trick the thyroid into
growing and producing too much thyroid hormone, leading to hyperthyroidism. The thyroid gland
can become enlarged when the patient’s diet is lacking sufficient iodine or when levels of TSH
become elevated in response to a defect in normal hormone synthesis by the thyroid gland. In
Graves’ disease, B- and T-lymphocyte–mediated autoimmunity is known to be directed at familiar
thyroid antigens—thyroglobulin, thyroid peroxidase, sodium-iodide symporter, and the thyrotropin
receptor. The thyrotropin receptor is the primary autoantigen of Graves’ disease and is responsible
for the manifestation of hyperthyroidism. Cardinal symptoms of hyperthyroidism include bulging
eyes (exophthalmos), heat intolerance, increased energy, tachycardia, difficulty sleeping, diarrhea,
and anxiety. Signs and symptoms specific to Graves’ disease are listed in TABLE 2.4,10,11 If left
untreated, Graves’ disease can cause severe thyrotoxicosis or thyroid storm.9,10,12,13

Complications of Graves’ Disease
There are many complications associated with Graves’ disease, including pregnancy issues, heart
disorders, osteoporosis, and thyroid storm. Possible complications during pregnancy include
miscarriage, preterm birth, fetal thyroid dysfunction, poor fetal growth, maternal heart failure, and
preeclampsia.4,5,8 If left untreated, Graves’ disease can lead to heart rhythm disorders, changes
in the structure and function of heart muscles, and the inability of the heart to pump enough blood
to the body.5,8,10 Untreated hyperthyroidism also can lead to weak, brittle bones.5,8
Thyroid storm is a rare, life-threatening complication also known as accelerated hyperthyroidism or
thyrotoxic crisis.2,9,13-16 It is more likely when severe hyperthyroidism is untreated or treated
inadequately. Serious adverse effects include fever, profuse sweating, vomiting, diarrhea, delirium,
severe weakness, seizures, markedly irregular heartbeat, jaundice, severe low blood pressure,
and coma. Thyroid storm often requires immediate emergency care.5,8,15

Treatment
The primary goals of treatment for hyperthyroidism are to eliminate excess thyroid
hormone and minimize the long-term consequences.9 Treatments include radio-active
iodine, antithyroid medications (propylthiouracil [PTU], methimazole [MMI]), and
surgery.2,8-10 Beta-blockers are sometimes added to provide symptomatic
relief.9,13,15
Radioactive Iodine Therapy (RIT): The usual dose for RIT ranges from 5 to 15 mCi of
131I. In general, higher dosages are required for patients who have large goiters or
low radioiodine uptake, or who have been pretreated with antithyroid drugs.15,16

Because the thyroid needs iodine to produce hormones, the radioiodine goes into the thyroid cells
and, over time, overactive thyroid cells are destroyed. The thyroid gland shrinks, and in several
weeks to months, hyperthyroid symptoms gradually diminish.16 RIT may increase the risk of new
or worsened symptoms of Graves’ ophthalmopathy. This adverse effect is usually mild and
temporary, but the therapy may not be utilized if the person already has moderate-to-severe eye
problems. Other side effects of this therapy include tenderness in the neck and a temporary
increase in thyroid hormone levels. Because this treatment can cause overall thyroid function to
decline, RIT is not usually utilized in pregnant or nursing women. Other treatments to supply the
body with normal amounts of thyroid hormone may be needed. Patients currently taking antithyroid
drugs must discontinue the medication at least 2 days prior to taking the
radiopharmaceutical.11,16 With radioactive iodine, the goal of therapy is to cause a hypothyroid
state due to the destruction of the thyroid gland, which usually occurs 2 to 3 months after
administering the drug. The absolute contraindication for radioiodine is pregnancy.14,16,17

ATMs may be used before or after RIT as a supplemental treatment. Adverse effects of both drugs
include rash, joint pain, liver failure, and a decrease in disease-fighting white blood cells. Because
of the risk of birth defects, MMI is not usually used to treat pregnant women in the first trimester.
PTU may be considered the preferred drug of choice just before and during the first trimester of
pregnancy. The FDA has issued a black box warning on PTU indicating its ability to cause
potentially fatal or severe liver injury and acute liver failure in adults and pediatric patients.18
Beta-Blockers: These medications do not inhibit the production of thyroid hormones, but they do
block the effect of hormones on the body. They may be used to provide relief of irregular
heartbeats, tremors, anxiety or irritability, heat intolerance, sweating, diarrhea, and muscle
weakness. Beta-blockers commonly used include propranolol, atenolol, metoprolol, lopressor, and
nadolol. Because beta-blockers may complicate management of asthma and diabetes, those
patients should use these drugs with caution.5,11

Treatment of Graves’ Ophthalmopathy
Graves’ ophthalmopathy can be divided into two clinical phases: the inflammatory
stage and the fibrotic stage.5 The inflammatory stage is marked by edema and
deposition of glycosaminoglycan in the extraocular muscles. This results in the clinical
manifestations of orbital swelling, stare, diplopia, periorbital edema, and, at times, pain.
Graves’ ophthalmopathy does not always improve with treatment for Graves’ disease.
Symptoms of Graves’ ophthalmopathy (TABLE 3) may even worsen for 3 to 6 months.
After that, the signs and symptoms usually stabilize for a year or so and then begin to
get better, often on their own. Mild symptoms of Graves’ ophthalmopathy may be
managed by using OTC artificial tears during the day and lubricating gels at night.5

Amidrone
40-year-old man suffering from dilated cardiomyopathy had been prescribed amiodarone for 2.5 years. Seven weeks before the
consultation at our department, his serum-free T4 levels increased above the upper limit and thyrotoxicosis developed. His thyroid
status was as shown in Figure 1. An attending cardiologist consulted at our thyroid clinic about the patient’s thyrotoxicosis, but he had
no complaints. He did not show any tachycardia or finger tremor, despite the thyrotoxicosis. His thyroid gland was not swollen and
ultrasonic study revealed a slightly enlarged thyroid gland with almost monotonous echogenicity (Figure 2(a)). The Doppler flow rate
inside the thyroid gland was not increased (Figure 2(b)). To differentiate the diagnosis of thyrotoxicosis, we planned to investigate
thyroid iodine uptake. Ten days after the first visit, he showed symptoms of acute heart failure and was admitted to the intensive care
unit of our hospital. His thyrotoxicosis had worsened by the time of admission, with increased levels of thyroglobulin, suggesting
destructive thyroiditis (Table 1). Amiodarone administration was stopped and inorganic iodine administration (189 mg/day) was started
upon admission; however, his thyrotoxicosis was prolonged and worsened. His cardiac function also worsened, with the thyrotoxicosis
being exacerbated (Figure 3). On admission, his heart rate was over 180 bpm and systolic blood pressure was 220 mmHg. Oxygen
saturation rate was 70% under 10 L/min of oxygen administration with a venturi mask. Intra-arterial balloon pumping was performed to
maintain the circulation. On the day after admission, administration of 200 mg of hydrocortisone was started, in addition to inorganic
iodine. After the hydrocortisone administration, free T3 levels were somewhat improved, but free T4 levels remained high. To control
and suppress the destruction of the thyroid, 40 mg of PSL was administered instead of hydrocortisone. Subsequently, 60 mg of PSL
improved the serum-free T4 levels, so we tapered the dose of PSL gradually. However, at a dose of 20 mg of PSL, the thyrotoxicosis
relapsed. At this point, TSH receptor antibody (TRAb) became positive (Figure 1), so we decided to prescribe 15 mg of methimazole
(MMI) together with 40 mg of PSL. Two days after these prescriptions, his free T4 levels increased to above the normal range. Thirty
milligrams of MMI, 40 mg of PSL,

decided to prescribe 15 mg of methimazole (MMI) together with 40 mg of PSL. Two days after these prescriptions, his free T4 levels increased to
above the normal range. Thirty milligrams of MMI, 40 mg of PSL, and inorganic iodine (189 mg/day) did not suppress the destructive thyroiditis. On
the 17th day of admission, thyroid Tc uptake was investigated, but none was observed (Figure 2(c)). At this point, we made a final diagnosis of type 2
amiodarone-induced thyrotoxicosis (AIT). On the 23rd day of admission, MMI was discontinued and the administration of 80 mg of PSL was
maintained. Subsequently, we attempted to taper the dose of PSL, but under a dose of 80 mg of PSL, overt thyrotoxicosis was not controlled (Figure
1). Since over 2.5 months had passed since a high dose of PSL had been administered, we decided to perform total thyroidectomy. The
administration of 80 mg of PSL was continued until the operation. With informed consent from the patient and his wife, total thyroidectomy was
performed on the 78th day of admission. Intravenous administration of 40 mg of PSL and 200 mg of hydrocortisone was performed during the
operation. The operation was safely performed and 25.6 g of thyroid was resected. After the operation, PSL was discontinued and the dose of
hydrocortisone was carefully tapered. Two days after the thyroidectomy, hydrocortisone was tapered to 100 mg and administered orally. Then,
hydrocortisone was again gradually tapered to 15 mg eleven days after the surgery. Twenty-five days after the operation, hydrocortisone was tapered
to 5 mg, and it was discontinued on the forty-sixth day after the thyroidectomy. During the tapering of hydrocortisone and after its discontinuation, the
patient demonstrated no symptoms of adrenal insufficiency. Pathological findings of the excised thyroid gland are as shown in Figure 4. Grossly, the
lobes became firm in consistency but maintained their normal shape (Figure 4(a)). On microscopy, several sizes of follicles were regularly lined with
flattened follicular epithelium. The lumen was filled with colloid. Scattered disrupted follicles with enlarged epithelium and cytoplasmic vacuoles were
observed (Figure 4(b)). It is of note that macrophages had infiltrated and multinucleated giant cells were also found in the follicular lumen (Figure
4(c)). Immunostaining with anti-KP1 (CD68) and antithyroglobulin antibodies confirmed that the infiltrated cells were macrophages but not follicular
cells (Figures 4(d) and 4(e)). These findings characterized by scattered follicle disruption, vacuoles in epithelial cells, and macrophage infiltration are
compatible with amiodarone toxicity [10].

Abstract
Amiodarone is used commonly and effectively in the treatment of arrhythmia; however,
it may cause thyrotoxicosis categorized into two types: iodine-induced hyperthyroidism
(type 1 amiodarone-induced thyrotoxicosis (AIT)) and destructive thyroiditis (type 2
AIT). We experienced a case of type 2 AIT, in which high-dose steroid was
administered intravenously, and we finally decided to perform total thyroidectomy,
resulting in a complete cure of the AIT. Even though steroid had been administered to
the patient (maximum 80 mg of prednisolone), the operation was performed safely and
no acute adrenal crisis as steroid withdrawal syndrome was found after the operation.
Few cases of type 2 AIT that underwent total thyroidectomy with high-dose steroid
administration have been reported. The current case suggests that total thyroidectomy
should be taken into consideration for patients with AIT who cannot be controlled by
medical treatment and even in those under high-dose steroid administration.

Introduction
Amiodarone, a benzofuranic acid derivative, is a potent class III antiarrhythmic drug that is used in the treatment of paroxysmal supraventricular tachycardia,
malignant ventricular tachyarrhythmia, atrial flutter, and fibrillation [1]. It is an iodine-rich (37% of its weight) compound with a molecular structure similar to thyroxine
(T4) and triiodothyronine (T3). It is also a fat-soluble drug with a long half-life (107 days), which allows the effects to be seen months after discontinuation [2].
Conventional doses of 100 to 600 mg of amiodarone per day provide 37 to 222 mg of organic iodine, which is up to 50–100 times the optimal daily iodine intake, and
greatly expand the systemic and thyroidal iodine pools [3]. Although it may reduce cardiac-related mortality and improve survival rates, amiodarone can also cause
the development of serious thyroid dysfunction in patients with or without underlying thyroid disease [4, 5]. The rate of occurrence of thyroid dysfunction, either
thyrotoxicosis (amiodarone-induced thyrotoxicosis: AIT) or hypothyroidism, is 15–20% [6]. AIT is more prevalent in iodine-deficient areas and is currently known to be
catabolized by two mechanisms: iodine-induced hyperthyroidism (type 1 AIT) and destructive thyroiditis (type 2 AIT), caused by amiodarone itself and its high iodine
content. Type 1 AIT develops in subjects with underlying thyroid disease and is exacerbated by iodine loading of thyroid autonomous function; on the other hand,
type 2 AIT occurs in patients with no history of thyroid disease and is probably consequent to drug-induced destructive thyroiditis. Moreover, the two mechanisms
may occur in the same patient (mixed type) [4, 7]. AIT may develop early during amiodarone treatment or even several months after it has been discontinued. This is
due to the fact that amiodarone and its metabolites have a long half-life and are stored in various tissues, particularly in fat, from which they are released very slowly.
The onset of AIT is often sudden and explosive [8]. AIT worsens ventricular arrhythmia because of the hyperthyroid state. Medical management including steroid
administration against AIT may produce a temporary response but often fails to resolve the thyrotoxicosis [9]. Here, we experienced a case of type 2 AIT, in which
high-dose steroid was administered intravenously, and we finally decided to perform total thyroidectomy, resulting in complete cure of the AIT. Even though steroid
had been administered to the patient (maximum 80 mg of prednisolone: PSL), the operation was performed safely and no acute adrenal crisis as steroid withdrawal
syndrome was found after the operation. Few cases of AIT with steroid administration that underwent total thyroidectomy have been reported. The current case
suggests that total thyroidectomy should be taken into consideration for patients with AIT who cannot be controlled by medical treatment and even in those under
steroid administration.
2. Case Presentation

Discussion
We have experienced a severe case of type 2 AIT, which was uncontrollable with high-dose PSL.
The final diagnosis was difficult since TRAb was positive at one time in the clinical course, which
led us to consider that this case may be type 1 and type 2 mixed AIT. Therefore, we administered
MMI to the patient at some points in the clinical course. However, taken together with the findings
from a thyroid scan and laboratory data, this case should be classified as type 2 AIT, even though
it has been reported that the features of hyperthyroidism and destructive thyroiditis may
concomitantly be present. Thionamides such as methimazole and propylthiouracil are not effective
in type 2 AIT [7]. It was a very difficult decision to perform the total thyroidectomy since a maximum
of 80 mg of PSL had been administered. However, considering the side effects, including infection,
of long-term use of high-dose steroid, we did not have an alternative approach other than
thyroidectomy. Moreover, in view of his cardiac status, implantation of a left ventricular epicardial
lead needed to be performed as soon as possible.

Type 2 AIT may be self-limiting, and some reports recommend continuation of amiodarone for the cardiac effect [11]. Steroid is the best
treatment for type 2 AIT [12]. As other treatments, the use of lithium, potassium perchlorate, and iopanoic acid has been proposed for
type 2 AIT, but the evidence is too limited to support their effectiveness [7]. Plasmapheresis can provide acute relief from type 2 AIT but
is not generally used because of its transient effects, its cost, and the impossibility of maintaining its use over the long term [5, 7]. In
addition, radioactive iodine therapy is in principle not feasible in type 2 AIT patients because iodine uptake is usually suppressed, as
shown in this case [5, 7]. The initial PSL dose is about 0.5–0.7 mg/kg body weight per day and the treatment is usually continued for 3
months [6]. The current case can be considered rare because a maximum of 80 mg per day of PSL was required to control the
thyrotoxicosis. Therefore, we were very careful to taper the dose of steroid after the total thyroidectomy and the tapering was
performed successfully. Total thyroidectomy with general anesthesia is not the first-line treatment for type 2 AIT, since there may be
potential risks, such as severe arrhythmia, in the perioperative period in these patients with underlying cardiac disorders [7]. However,
this approach may be required in patients who are resistant to medical treatments [5, 9, 13, 14]. Minimally invasive thyroidectomy with
local anesthesia may further reduce the risk [15]; however, its use has not yet spread widely.
Thyroidectomy is an efficacious approach for type 2 AIT patients who are resistant to high-dose PSL to control thyrotoxicosis.
Physicians should not be reluctant to make a decision to perform the surgery and total thyroidectomy can be performed more safely
than expected, even if high-dose PSL has been administered to the patients

BETA BLOCKERS
Beta blockers offer prompt relief of the adrenergic symptoms of hyperthyroidism such as tremor, palpitations, heat intolerance, and
nervousness. Propranolol (Inderal) has been used most widely, but other beta blockers can be used. Nonselective beta blockers such
as propranolol, are preferred because they have a more direct effect on hypermetabolism.25 Therapy with propranolol should be
initiated at 10 to 20 mg every six hours. The dose should be increased progressively until symptoms are controlled. In most cases, a
dosage of 80 to 320 mg per day is sufficient.5 Calcium channel blockers such as diltiazem (Cardizem) can be used to reduce heart rate
in patients who cannot tolerate beta blockers.17
IODIDES
Iodides block the peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and inhibit hormone release. Iodides also are used as
adjunctive therapy before emergency nonthyroid surgery, if beta blockers are unable to control the hyperthyroidism, and to reduce
gland vascularity before surgery for Graves’ disease.9 Iodides are not used in the routine treatment of hyperthyroidism because of
paradoxical increases in hormone release that can occur with prolonged use. Organic iodide radiographic contrast agents (e.g.,
iopanoic acid or ipodate sodium) are used more commonly than the inorganic iodides (e.g., potassium iodide). The dosage of either
agent is 1 g per day for up to 12 weeks.26
ANTITHYROID DRUGS

ANTITHYROID DRUGS
Antithyroid drugs act principally by interfering with the organification of iodine, thereby suppressing thyroid hormone levels.
Methimazole (Tapazole) and propylthiouracil (PTU) are the two agents available in the United States. Remission rates vary with the
length of treatment, but rates of 60 percent have been reported when therapy is continued for two years.15 Relapse can occur in up to
50 percent of patients who respond initially, regardless of the regimen used. A recent randomized trial27 indicated that relapse was
more likely in patients who smoked, had large goiters, or had elevated thyroid-stimulating antibody levels at the end of therapy.
Methimazole
Methimazole usually is the drug of choice in nonpregnant patients because of its lower cost, longer half-life, and lower incidence of
hematologic side effects. The starting dosage is 15 to 30 mg per day, and it can be given in conjunction with a beta blocker.28 The
beta blockade can be tapered after four to eight weeks and the methimazole adjusted, according to clinical status and monthly free T4
or free T3 levels, toward an eventual euthyroid (i.e., normal T3 and T4 levels) maintenance dosage of 5 to 10 mg per day.9,17 TSH
levels may remain undetectable for months after the patient becomes euthyroid and should not be used to monitor the effects of
therapy. At one year, if the patient is clinically and biochemically euthyroid and a thyroid-stimulating antibody level is not detectable,
therapy can be discontinued. If the thyroid-stimulating antibody level is elevated, continuation of therapy for another year should be
considered. Once antithyroid drug therapy is discontinued, the patient should be monitored every three months for the first year,
because relapse is more likely to occur during this time, and then annually, because relapse can occur years later. If relapse occurs,
radioactive iodine or surgery generally is recommended, although antithyroid drug therapy can be restarted.9

Propylthiouracil
PTU is preferred for pregnant women because methimazole has been associated with rare congenital
abnormalities. The starting dosage of PTU is 100 mg three times per day with a maintenance dosage of 100 to
200 mg daily.28 The goal is to keep the freeT4 level at the upper level of normal.9
Complications
Agranulocytosis is the most serious complication of antithyroid drug therapy and is estimated to occur in 0.1 to 0.5
percent of patients treated with these drugs.28 The risk is higher in the first several months of therapy and may be
higher with PTU than methimazole.5,9,15 It is extremely rare in patients taking less than 30 mg per day of
methimazole.9 The onset of agranulocytosis is sometimes abrupt, so patients should be warned to stop taking the
drug immediately if they develop a sudden fever or sore throat. Routine monitoring of white cell counts remains
controversial, but results of one study29 showed that close monitoring of white cell counts allowed for earlier
detection of agranulocytosis. In this study, patients had white cell counts every two weeks for the first two months,
then monthly. In most cases, agranulocytosis is reversible with supportive treatment.15,25 Minor side effects
(e.g., rash, fever, gastrointestinal symptoms) sometimes can be treated symptomatically without discontinuation
of the antithyroid drug; however, if symptoms of arthralgia occur, antithyroid drugs should be discontinued
because arthralgia can be a precursor of a more serious polyarthritis syndrome.28

RADIOACTIVE IODINE
In the United States, radioactive iodine is the treatment of choice for most patients with Graves’ disease and toxic nodular goiter. It is
inexpensive, highly effective, easy to administer, and safe. There has been reluctance to use radioactive iodine in women of
childbearing years because of the theoretical risk of cancer of the thyroid, leukemia, or genetic damage in future offspring. Long-term
follow-up of patients has not validated these concerns.14,15 The treatment of hyperthyroidism in children remains controversial, but
radioactive iodine is becoming more acceptable in this group.30
Dosage
The treatment dosage of radioactive iodine has been a topic of much debate. A gland-specific dosage based on the estimated weight
of the gland and the 24-hour uptake may allow a lower dosage and result in a lower incidence of hypothyroidism but may have a higher
recurrence rate.15 Higher-dose ablative therapy increases the chance of successful treatment and allows the early hypothyroidism that
results from this regimen to be diagnosed and treated while the patient is undergoing close monitoring. Some studies8,18 have shown
that the eventual incidence of hypothyroidism is similar regardless of the radioactive iodine dosage. The high-dose regimen is clearly
favored in older patients, those with cardiac disease, and other groups who need prompt control of hyperthyroidism to avoid
complications. Patients with toxic nodular goiter or toxic adenomas are more radio resistant and generally need high-dose therapy to
achieve remission. They have a lower incidence of eventual hypothyroidism because the rest of the gland has been suppressed by the
toxic nodules and protected from the effects of radioactive iodine.18,30

Graves’ Disease
In 15 percent of patients, Graves’ ophthalmopathy can develop or be worsened by the use of radioactive
iodine.17,19 The use of prednisone, 40 to 80 mg per day tapered over at least three months, can prevent or
improve severe eye disease in two thirds of patients.19 Lower-dose radioactive iodine sometimes is used in
patients with ophthalmopathy because posttreatment hypothyroidism may be associated with exacerbation of eye
disease. Cigarette smoking is a risk factor for the development and progression of Graves’ ophthalmopathy.14,19
Use with OtherTreatments
Using antithyroid drugs to achieve a euthyroid state before treatment with radioactive iodine is not recommended
for most patients, but it may improve safety for patients with severe or complicated hyperthyroidism. Limited
evidence supports this approach.8,14,17 It is unclear whether antithyroid drugs increase radioactive iodine failure
rates.20,31,32 If used, they should be withdrawn at least three days before radioactive iodine and can be
restarted two to three days later. The antithyroid drug is continued for three months after radioactive iodine, then
tapered. Beta blockers are used to control symptoms before radioactive iodine and can be continued throughout
treatment if needed. Iodine-containing medications need to be discontinued several weeks before therapy.21
Safety Precautions

Safety Precautions
Most of the radioactive iodine is eliminated from the body in urine, saliva, and feces within 48 hours;
however, double flushing of the toilet and frequent hand washing are recommended for several weeks.
Close contact with others, especially children and pregnant women, should be avoided for 24 to 72
hours.21 Additional treatments with radioactive iodine can be initiated as early as three months, if
indicated.33
SURGERY
Gradually, radioactive iodine has replaced surgery for the treatment of hyperthyroidism, but it still may be
indicated in some patients and is considered underused by some researchers. A subtotal thyroidectomy is
performed most commonly. This surgery preserves some of the thyroid tissue and reduces the incidence
of hypothyroidism to 25 percent, but persistent or recurrent hyperthyroidism occurs in 8 percent of
patients.22 Total thyroidectomy is reserved for patients with severe disease or large goiters in whom
recurrences would be highly problematic, but carries an increased risk of hyperparathyroidism and
laryngeal nerve damage.22,23

POSSIBILITIES
Newer treatment options under investigation include endoscopic subtotal
thyroidectomy,34 embolization of the thyroid arteries,35 plasmapheresis,36 and
percutaneous ethanol injection of toxic thyroid nodules.37 Autotransplantation of
cryopreserved thyroid tissue may become a treatment option for postoperative
hypothyroidism.38 Nutritional supplementation with L-carnitine39 has been shown
to have a beneficial effect on the symptoms of hyperthyroidism, andl-carnitine may
help prevent bone demineralization caused by the disease.
Prognosis and Follow-up

There are two antithyroid drugs that are used to treat hyperthyroidism and Graves’ disease: carbimazole and propylthiouracil. These
drugs reduce the amount of thyroid hormone released into the circulation. They are the first choice for treating children with over-active
thyroids. Your child will usually be given carbimazole. If they cannot tolerate carbimazole, they will be given propylthiouracil. Usually, a
course of antithyroid drugs will last 18 months to three years.
Carbimazole is available in 5mg and 20mg tablets. Propylthiouracil comes in 50mg tablets only. The amount given depends on the
child’s weight. Usually, the daily dose is:
0.5-1mg of carbimazole for every kilogram (kg) of their bodyweight, or
5-10mg of propylthiouracil for every kilogram of their bodyweight.
So a child who weighs 40 kg (about 6 st 2lb) could be given 20-40 mg of carbimazole every day or 200-400mg of propylthiouracil every
day.
Antithyroid drugs can be used as part of a block and replace (BR) regimen: the anti-thyroid drug blocks the thyroid gland from
producing any thyroxine. Levothyroxine is then given to your child to replace their natural thyroxine.
Side effects
If children are taking

Side effects
If children are taking too much carbimazole, they may get some of the symptoms of an under-active thyroid. This
is why it is important to have regular blood tests to check the thyroid hormone levels.
Some people experience minor side effects to antithyroid drugs, such as nausea or a rash.
There is a very rare side effect of both antithyroid drugs called agranulocytosis that causes the number of white
blood cells to drop. This affects the immune system so the body can’t fight infection properly. If your child
develops a sore throat, mouth ulcers, or an unexplained fever, stop giving them the tablets immediately. Get their
blood count checked urgently either through your GP or your local Accident and Emergency department. It will
usually be a false alarm and your child will be able to re-start their medication.
Very rarely serious liver injury has been reported as a side effect of propylthiouracil, especially during the first six
months. If you notice any yellowing of the eyes or skin you should take your child to see their doctor immediately.
Top tips:

FUNCTION OF ANTITHYROID DRUGS
Antithyroid drugs decrease the levels of the two hormones produced by the thyroid, thyroxine (T4) and
triiodothyronine (T3). (See "Patient education: Hyperthyroidism (overactive thyroid) (Beyond the Basics)".)
Antithyroid drugs may be used:
●As a short-term treatment in people with Graves' hyperthyroidism, to prepare for thyroid surgery or radioiodine.
●As initial treatment in Graves' disease for one to two years to see if the disease resolves. Approximately 30
percent of people with Graves' disease will have a remission after one to two years. Antithyroid drugs can be used
to control hyperthyroidism while waiting to see if remission occurs.
●To treat hyperthyroidism associated with toxic multinodular goiter or a toxic adenoma ("hot nodule"), usually to
prepare for thyroid surgery or radioiodine. (See "Patient education: Thyroid nodules (Beyond the Basics)".)
●To treat hyperthyroidism during pregnancy.

For long-term treatment of hyperthyroidism due to Graves' disease, toxic multinodular
goiter, or toxic adenoma when the person prefers to avoid definitive therapy with
radioiodine or surgery. Approximately 80 percent of people with Graves' disease will
have a remission after 10 years.
You will need to take antithyroid drugs for at least three weeks (usually six to eight
weeks or longer) before your thyroid hormone levels are lowered to normal. This is
because the drugs only block formation of new thyroid hormone; they do not remove
thyroid hormones that are already in the thyroid and the blood stream. Antithyroid
drugs need to be continued to prevent formation of new thyroid hormone, which may
result in recurrent hyperthyroidism. If you frequently miss taking your antithyroid drug,
thyroid hormone production may resume quickly and replenish thyroid gland stores,
preventing adequate control of the hyperthyroidism.

For long-term treatment of hyperthyroidism due to Graves' disease, toxic multinodular
goiter, or toxic adenoma when the person prefers to avoid definitive therapy with
radioiodine or surgery. Approximately 80 percent of people with Graves' disease will
have a remission after 10 years.
You will need to take antithyroid drugs for at least three weeks (usually six to eight
weeks or longer) before your thyroid hormone levels are lowered to normal. This is
because the drugs only block formation of new thyroid hormone; they do not remove
thyroid hormones that are already in the thyroid and the blood stream. Antithyroid
drugs need to be continued to prevent formation of new thyroid hormone, which may
result in recurrent hyperthyroidism. If you frequently miss taking your antithyroid drug,
thyroid hormone production may resume quickly and replenish thyroid gland stores,
preventing adequate control of the hyperthyroidism.

TYPES OF ANTITHYROID DRUGS
Two antithyroid drugs are currently available in the United States: propylthiouracil and methimazole (brand
name: Tapazole). Carbimazole (which is converted into methimazole in the body) is available in Europe
and parts of Asia but not in the United States.
Methimazole — Methimazole is usually preferred over propylthiouracil because it reverses
hyperthyroidism more quickly and has fewer side effects. Methimazole requires an average of six weeks
to lower T4 levels to normal; it is often given before radioiodine treatment and usually before thyroid
surgery. Methimazole can be taken once per day.
Propylthiouracil — Propylthiouracil does not correct hyperthyroidism as rapidly as methimazole, and it has
more side effects. Because of its potential for liver damage, it is used only when methimazole or
carbimazole are not appropriate. Propylthiouracil must be taken two to three times per day.

Antithyroid drugs during pregnancy — Propylthiouracil is the drug of choice during the first
trimester of pregnancy because it causes less severe birth defects than methimazole. Because
there have been rare cases of liver damage in people taking propylthiouracil, some health care
providers will suggest switching to methimazole after the first trimester, while others may continue
propylthiouracil.
For people who are breastfeeding, methimazole is probably a better choice than propylthiouracil
(to avoid liver side effects).
If you take antithyroid drugs and are considering future pregnancy, you should discuss your
treatment with your health care provider before trying to get pregnant. Having radioiodine
treatment or surgery at least six months before becoming pregnant can eliminate the need for
antithyroid treatment during pregnancy. (See "Patient education: Hyperthyroidism (overactive
thyroid) (Beyond the Basics)".)

Antithyroid drug side effects — Most of the side effects of antithyroid drugs are minor, but major side
effects can occur. Because there is no way to predict who will experience side effects, it is important to
discuss all possible side effects before starting treatment.
If you cannot tolerate antithyroid treatments, you can consider radioiodine treatment or surgery. (See
"Patient education: Hyperthyroidism (overactive thyroid) (Beyond the Basics)", section on
'Hyperthyroidism treatment'.)
Minor side effects — Up to 15 percent of people who take an antithyroid drug have minor side effects.
Both methimazole and propylthiouracil can cause itching, rash, hives, joint pain and swelling, fever,
changes in taste, nausea, and vomiting.
If one antithyroid drug causes side effects, switching to the other drug may be helpful. However,
approximately one-half of people who have side effects with one drug will have similar side effects with the
other. Nausea and vomiting may depend on the dose; spreading large doses out through the day can
reduce side effects.

Major side effects — Fortunately, the major side effects of antithyroid drugs are very rare. They include:
●Agranulocytosis – This is a term used to describe a severe decrease in the production of white blood cells. This
condition is extremely serious but affects only 1 out of every 200 to 500 people who take an antithyroid drug.
Older people taking propylthiouracil and those who take high doses of methimazole may be at higher risk of this
side effect.
Agranulocytosis more commonly occurs within the first three months of starting treatment with an antithyroid drug
but rarely can occur later. If you develop a sore throat, fever, or other signs or symptoms of infection, you should
stop your medicine and immediately call your health care provider to have a complete blood count (CBC with
differential). Serious and potentially life-threatening infections, or even death, can occur before agranulocytosis
resolves. However, once the antithyroid drug is stopped, agranulocytosis usually resolves within a week.
●Other – There are other very rare complications of antithyroid drugs, including liver damage (more common with
propylthiouracil), pancreatitis with methimazole, aplastic anemia (failure of the bone marrow to produce blood
cells), and vasculitis (inflammation of blood vessels associated with propylthiouracil).

MONITORING THYROID HORMONES DURING TREATMENT
During treatment, your blood thyroid hormone levels will be monitored periodically.
Antithyroid drugs typically reduce levels of both triiodothyronine (T3) and thyroxine
(T4), but levels of T3 may take longer to return to normal. Thyroid-stimulating hormone
(TSH) levels usually take the longest to return to normal.
Approximately 30 percent of people who take an antithyroid drug for one to two years
will have prolonged remission of Graves' disease. It is not known if the antithyroid drug
plays an active role in this remission or if it simply controls thyroid hormone levels until
Graves' disease resolves on its own.

Checking for remission and recurrence — No test can reliably predict remission of Graves' disease. While imperfect, the measurement
of TSH-receptor antibodies (TRAb) is widely used in the United States and Europe to determine if a person is in remission. Other
names for TRAb are TSI (thyroid stimulating immunoglobulins) or TBII (thyrotropin-binding inhibiting immunoglobulins).
Usually, after one to two years of treatment, TRAb is measured, and if low, your health care provider will recommend stopping the
antithyroid drug, and the chance of a remission is 80 percent. However, if TRAb remains high, the chance of a remission is under 20
percent, and it is appropriate to reconsider definitive therapy with radioiodine or surgery or continue antithyroid drugs.
If antithyroid drugs are stopped, thyroid blood tests are usually performed four to eight weeks later. The blood tests are periodically
repeated over 12 months to determine if hormone levels remain normal or increase over time (this is called a recurrence).
If your levels of T3, T4, and TSH remain normal for 12 months, the long-term prognosis is good. Recurrence after this time occurs in
only 8 to 10 percent of people.
WHERE TO GET MORE

Baseline thyroid hormone levels were positively associated with TSH receptor antibody
titres (P < 0.0001). Baseline free triiodothyronine (fT3) were linearly related to free
thyroxine (fT4) levels in the hyperthyroid state (fT3 = fT4*0.97–11), and fell
proportionately with carbimazole. The percentage falls in fT4 and fT3 per day were
associated with carbimazole dose (P < 0.0001). The magnitude of fall in thyroid
hormones after the same dose of carbimazole was lower during follow up than at the
initiation visit. The fall in thyroid hormone levels approximated to a linear response if
assessed at least 3 weeks after commencement of carbimazole. Following withdrawal
of antithyroid drug treatment, the risk of relapse was greater in patients with higher
initial fT4, initial TSH receptor antibody titre, males, smokers, and British Caucasian
ethnicity.
Conclusion: We identify a dose-response relationship for fall in thyroid hormones in
response to carbimazole to aid in the selection of dose for Graves' hyperthyroidism.

Overt hyperthyroidism affects 1.3% of people in iodine-replete populations (1) and if untreated is
associated with a catabolic state characterized by weight loss, reduced bone mineral density, atrial
fibrillation, and thromboembolic events (2, 3). Graves' disease is the commonest cause of hyperthyroidism
accounting for up to 80% of cases (4–6), with a lifetime prevalence of 3% in women and 0.5% in men (1,
7).
Recent evidence suggests that rapid control of hyperthyroidism in Graves' disease, whilst avoiding over-
treatment, is desirable. A low thyroid stimulating hormone (TSH) level at 1 year following diagnosis of
Graves' disease was associated with a 55% increase in cardiovascular mortality independent of treatment
modality (8). Similarly, every 6 months' duration with suppressed TSH levels in patients with
hyperthyroidism was associated with a 11–13% increase in total mortality (9). Conversely, even transient
hypothyroidism during treatment has been associated with greater weight-gain than those without over-
treatment following anti-thyroid medications (10). Moreover, avoidance of hypothyroidism is recommended
to prevent exacerbation of thyroid eye disease (11). Thus, the prompt and sustained normalization of
thyroid hormone levels is of foremost importance in the management of patients diagnosed with Graves'
disease (7).

Treatment modalities for the management of Graves' hyperthyroidism include anti-thyroid drugs (ATD), radioactive iodine (RAI)
therapy, or total thyroidectomy. ATD is favored as first line therapy in Europe, with remission achieved in approximately half of patients
after a 12–18 month duration of treatment (6, 12, 13). Traditionally, radioactive iodine has been preferred in USA (7), although recent
American Thyroid Association (ATA) guidelines have suggested that ATD can also be considered as first line (14). However, a
pharmacodynamic relationship between ATD and thyroid hormone levels has yet to be clearly described.
Thionamides inhibit the thyroid peroxidase enzyme to reduce thyroid hormone synthesis (15). In the UK, the two predominant ATDs
used are carbimazole (which is entirely metabolized to methimazole), and propylthiouracil (PTU). Methimazole has a longer half-life
(t1/2 4–6 h) than PTU (t1/2 75 min), enabling once-daily administration, whereas PTU is given as multiple doses over a day (15, 16).
Blood levels of both drugs peak 1–2 h following ingestion, with inhibition of thyroid hormone synthesis lasting for 12–24 h following
PTU (17) and >24 h following methimazole (15, 18). ATDs may be given either via a “dose titration” regimen whereby initial higher
doses are reduced over time, or as a “block and replace” regimen using fully inhibitory doses of ATDs with concomitant thyroxine
replacement to maintain euthyroidism. Neither approach has been reliably demonstrated as superior in achieving remission (19).
However, the dose-titration regimen is associated with lower doses of ATDs, and thus a potentially reduced risk of dose-related side-
effects such as agranulocytosis (20). Likewise, rates of discontinuation due to side-effects from ATDs are lower following the “dose-
titration” method compared to “block and replace” (19–22).

To date, there is a paucity of evidence to describe the pharmacodynamic response between the dose of
ATD and the resultant reduction of thyroid hormone levels. Consequently, many clinicians adopt
experience-based strategies to prescribe ATDs. For example, Abraham and colleagues recommend
initiating carbimazole/methimazole with a dose of 10–20 mg once daily if fT4 is <40 pmol/l and 40 mg
once daily if fT4 is >40 pmol/l and then halving the dose following 1 month of treatment (23).
In summary, Graves' disease is one of the most common endocrine pathologies encountered by the
endocrinologist, and whilst medical therapy with ATD is often adopted as the first line treatment modality,
there is scarce data to support physicians in selecting the dose of carbimazole for initiation and
subsequent dose-titration. In the present study, we aimed to determine the pharmacodynamic relationship
between dose of carbimazole and resultant change in thyroid hormone levels. We also investigated
baseline factors that could predict the chance of spontaneous remission following ATDs in a UK
population to inform the likely success of medical therapy.
Materials and Methods

Time to Achieve Euthyroid Status and Risk of Overtreatment
In patients with at least 2 months' duration of treatment (n = 422), the majority (95%)
achieved normal fT4 and fT3 levels (95 and 74%, respectively). Euthyroid status,
defined as having TSH, fT4, and fT3 all within range, was achieved by 28% of patients
at a median time of 192 days (range 84–407 days). Similarly, 29% (n = 98) of patients
were over-treated and rendered hypothyroid as indicated by either a TSH >4.2 mU/l, or
fT4 <9 pmol/l. Greater initial carbimazole dose (P = 0.04) and higher initial fT4 level (P
= 0.04) increased the risk of over-treatment when assessed by univariate logistic
regression, whereas initial TPO antibody titre (P = 0.09), TSH receptor antibody titre (P
= 0.79), sex (P = 0.23), ethnicity (P = 0.40), age (P = 0.86), and smoking status (P =
0.36) were not significant predictors.

Risk Factors for Relapse
Of the study cohort, 120 patients had completed 18 months' of antithyroid treatment and had a trial off treatment
with carbimazole. Of these, 19% (n = 23) had evidence of relapse/persistent disease at the first clinical
assessment following cessation of antithyroid medication, and a further 16% (n = 19) had relapse at subsequent
assessments with median time to relapse being 85 days (range 25–335 days). Thus, 35% (n = 42) in total had
relapse following cessation of medical therapy.
An increased frequency of relapse was observed in males (Figure 4A), white British ethnic origin (Figure 4B), and
current or previous smoking (Figure 4C) (Table 2). Those with an initial fT4 >45 pmol/l had an increased odds of
relapse compared to those with a fT4 <28 pmol/l (OR 7.5, 95% CI 1.69–33.27) (Figure 4D). Patients with a
greater TSH receptor antibody titre at diagnosis also had an increased odds of relapse (OR 3.69 if TSHrAb >9 vs.
<3 mU/L, 95% CI 1.32–10.29) (Figure 4E) (Table 2). Similarly, patients with a higher fT4 at the final visit prior to
withdrawal of carbimazole had an increased odds of relapse (Figure 4F; OR 3.41 if fT4 >15 pmol/l vs. <12 pmol/l,
95% CI 1.07–10.87) (Table 2). In an adjusted multivariable logistic regression model (r2 = 0.09, P = 0.04)
including ethnicity, gender, age, smoking status, TSHR and TPO antibody titre, and initial fT4 measurement, only
initial fT4 significantly predicted risk of relapse (P

In general, antithyroid drugs are used in two ways: as the primary treatment for
hyperthyroidism or as preparative therapy before radiotherapy or surgery (Figure 4).
Antithyroid drugs are most often used as the primary treatment for persons with
Graves' disease, in whom “remission,” which is usually defined as remaining
biochemically euthyroid for one year after cessation of drug treatment, is possible. In
contrast, antithyroid drugs are not generally considered to be primary therapy for
patients with toxic multinodular goiters and solitary autonomous nodules, because
spontaneous remissions rarely occur. Antithyroid drugs are also the preferred primary
treatment in pregnant patients and in most children and adolescents. The decision to
use antithyroid drugs as primary treatment must be weighed against the risks and
benefits of the more definitive therapy that radioiodine and surgery provide. For
example, antithyroid drugs might be preferable in patients with severe Graves' eye
disease, in whom radioiodine therapy has been associated with worsening
ophthalmopathy.33

The preference of the patient is paramount in the decision process. A prospective
randomized trial comparing antithyroid drugs, radioiodine, and surgery showed that
patient satisfaction was more than 90 percent for all three,34 but medical costs were
lowest for antithyroid drug treatment.35 Antithyroid drugs are also used to normalize
thyroid function before the administration of radioiodine, because their administration
may attenuate potential exacerbations following ablative radioiodine therapy,36 which
are likely caused by a rise in stimulating antithyrotropin-receptor antibodies following
radioiodine therapy.37 Pretreatment with antithyroid drugs is therefore recommended
for patients with underlying cardiac disease or for the elderly,38 two groups that may
be more vulnerable to worsening thyrotoxicosis.

The preference of the patient is paramount in the decision process. A prospective randomized trial comparing antithyroid drugs,
radioiodine, and surgery showed that patient satisfaction was more than 90 percent for all three,34 but medical costs were lowest for
antithyroid drug treatment.35 Antithyroid drugs are also used to normalize thyroid function before the administration of radioiodine,
because their administration may attenuate potential exacerbations following ablative radioiodine therapy,36 which are likely caused by
a rise in stimulating antithyrotropin-receptor antibodies following radioiodine therapy.37 Pretreatment with antithyroid drugs is therefore
recommended for patients with underlying cardiac disease or for the elderly,38 two groups that may be more vulnerable to worsening
thyrotoxicosis.
CHOICE OF DRUGS
The choice between the drugs available in the United States, methimazole and propylthiouracil, has traditionally been a matter of
personal preference. Nevertheless, methimazole, with its once-daily schedule, has decided advantages over propylthiouracil, including
better adherence27 and more rapid improvement in serum concentrations of thyroxine and triiodothyronine.27,39-41 The cost of low-
dose generic methimazole is similar to that of propylthiouracil. In a recent search of Internet pharmacies,42 a one-year supply of
propylthiouracil (300 mg daily) was approximately $408, as compared with a one-year supply of methimazole (15 mg daily, $360; or 30
mg daily, $720). Finally, differences in the side-effect profiles of the two drugs favor methimazole. As discussed below, propylthiouracil
is preferred during pregnancy.

PRACTICAL CONSIDERATIONS
The usual starting dose of methimazole is 15 to 30 mg per day as a single daily dose, and the usual starting dose of propylthiouracil is
300 mg daily in three divided doses. However, the disease of many patients can be controlled with smaller doses of methimazole,
suggesting that the accepted potency ratio of 10:1 for methimazole as compared with propylthiouracil is an underestimate. In one
randomized trial, 85 percent of patients had normal levels of thyroxine and triiodothyronine after six weeks of treatment with 10 mg of
methimazole daily, as compared with 92 percent of patients receiving 40 mg daily.43 Indeed, iatrogenic hypothyroidism may develop in
patients with relatively mild hyperthyroidism if methimazole dosing is overly aggressive.44 On the other hand, inadequate dosing will
lead to continuing unmitigated hyperthyroidism.
Once a patient has been started on an antithyroid drug, follow-up testing of thyroid function every four to six weeks is recommended, at
least until thyroid function is stable or the patient becomes euthyroid. After 4 to 12 weeks, most patients have improved considerably or
have achieved normal thyroid function, after which the drug dose can often be decreased while maintaining normal thyroid function.
The disease of many patients can be ultimately controlled with a relatively low dose — for example, 5 to 10 mg of methimazole or 100
to 200 mg of propylthiouracil daily. Indeed, hypothyroidism or goiter can develop if the dose is not decreased appropriately. After the
first three to six months, follow-up intervals can be increased to every two to three months and then every four to six months. Serum
thyrotropin levels remain suppressed for weeks or even months, despite a normalization of thyroid hormone levels, so a test of
thyrotropin levels is a poor early measure. Furthermore, patients sometimes continue to have elevated serum triiodothyronine levels
despite normal or even low thyroxine or free thyroxine levels, indicating the need to increase, not decrease, the antithyroid drug
dose.45