Online Appendix for the following JACC article
TITLE: Risk of Potentially Life-Threatening Thyroid Dysfunction Due to Amiodarone in
Idiopathic Pulmonary Arterial Hypertension Patients
AUTHORS: Elaine Soon, MBBChir, Mark Toshner, MBBS, Marianna Mela, MBBS,
Andrew Grace, PhD, Karen Sheares, PhD, Nicholas Morrell, MD, Joanna Pepke-Zaba, PhD
APPENDIX
Thyroid function tests and interpretation
Thyroid function tests were performed by the biochemistry laboratory based at
Addenbrookes’ Hospital and also by the referring hospitals. Peripheral venous blood was
drawn and stored in serum gel tubes. This was analyzed using a standard sandwich
immunoassay (ADVIA Centaur TSH-3, Bayer) to quantify thyroid stimulating hormone
(TSH). The measuring range was 0.004 to 150 mIU/L. The assay did not have any significant
cross-reactions with human chorionic gonadotrophin, follicle stimulating hormone. or
luteinizing hormone. If the TSH level was abnormal, then quantification of free T4 and T3
levels was performed, also using the ADVIA Centaur system.
The ranges used for making a diagnosis in the patients are 0.1 to 5 mIU/L for TSH, 11 to 25
pmol/l for free T4, and 2.8 to 6.5 pmol/l for free T3. Hence, a diagnosis of thyrotoxicosis was
generally made with a TSH level of <0.1 mIU/L and a free T4 level of ≥25 pmol/l, and the
presence of clinical signs or symptoms. A diagnosis of hypothyroidism was made with a TSH
level of >5 mIU/L and a free T4 level of ≤11 pmol/l, and the presence of clinical signs or
symptoms. These diagnoses were made in conjunction with endocrinologists, and if there was
any doubt, input was sought from the thyroid specialists at Addenbrookes’ Hospital,
Cambridge.
Thyroid function results
The table below shows the thyroid function results for AITD patients.
Patient group
TSH (mIU/l)
Free T4
(pmol/l)
Free T3
(pmol/l)
Amiodarone-induced thyrotoxicosis
0.07 (0.03)*
48.2 (8.1)
8.3 (2.2)
Amiodarone-induced hypothyroidism
31.0 (10.1)
10.7 (1.9)
3.7 (0.7)
*Four patients had TSH levels below the limit of detection
The 2 patients who died from amiodarone-induced thyrotoxicosis both had TSH levels below
the limit of detection, and free T4 levels of 76.3 and 43.0 pmol/l respectively.
Amiodarone prescription and regimen
The indication for amiodarone prescription was the presence of a clinically significant
arrhythmia, and either the contraindication of other anti-arrhythmic agents due to negative
inotropic effects, or the failure of other agents to control the arrhythmia. In general, these
patients had either refused ablation or were considered unfit for or unable to tolerate ablation.
In the idiopathic pulmonary arterial hypertension (IPAH) cohort, the arrhythmia provoking
the use of amiodarone consisted of atrial fibrillation or flutter in 8 patients, supraventricular
tachycardia (SVT) other than atrial fibrillation/flutter in 6 patients, ventricular tachycardia
(VT) in 3 patients, and combinations of different arrhythmias in 4 patients. The patients with
SVTs other than atrial fibrillation/flutter principally had atrioventricular nodal re-entrant
tachycardias (5 of 6). One was diagnosed and treated in another hospital, with a referring
letter that described their arrhythmia as a “supraventricular tachycardia” with no additional
information. The leading cause for amiodarone use in chronic thromboembolic pulmonary
hypertension (CTEPH) was atrial fibrillation/flutter (16 patients). Other indications were
SVT (3 patients), VT (1 patient), and combinations of different arrhythmias (3 patients). For
the CHD cohort, reasons for amiodarone prescription were atrial fibrillation/flutter (4
patients), SVT (2 patients), VT (3 patients), and combinations of different arrhythmias (3
patients).
AITD outcome
The outcomes for all PAH patients with AITD are summarized in the table below.
Total
number
Number
Number
Patient outcomes
of AITD
thyrotoxic hypothyroid
Discontinued amiodarone, recovered
normal thyroid function after acute
intervention
6
6
0
Discontinued amiodarone, died
despite acute intervention
2
2
0
Discontinued amiodarone,
needed further intervention
3
1*
2
Continued amiodarone (reduced dose),
recovered
normal thyroid function after acute
1
1
0
intervention
Continued amiodarone (reduced dose),
needed further intervention
8
0
8
To further clarify the above, “further intervention” in all cases consisted of long-term
thyroxine replacement. The thyrotoxic patient in this group (*) required thyroidectomy. He
subsequently became hypothyroid and needed long-term thyroxine replacement.