View source for Medicine:Amiodarone induced thyrotoxicosis

{{Short description|Form of hyperthyroidism}}
'''Amiodarone induced thyrotoxicosis (AIT)''' is a form of [[Medicine:Hyperthyroidism|hyperthyroidism]] due to treatment with [[Chemistry:Antiarrhythmic agent|antiarrhythmic]] drug, [[Chemistry:Amiodarone|amiodarone]]. 

Amiodarone induced thyroid dysfunction more commonly results in [[Medicine:Hypothyroidism|hypothyroidism]], estimated to occur in 6-32% of patients, whereas hyperthyroidism from amiodarone use is estimated at 1-12%. <ref name="Goundan_2020">{{cite journal | vauthors = Goundan PN, Lee SL | title = Thyroid effects of amiodarone: clinical update | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 27 | issue = 5 | pages = 329–334 | date = October 2020 | pmid = 32773570 | doi = 10.1097/MED.0000000000000562 | s2cid = 221098785 }}</ref> However, the [[Prevalence|prevalence]] of AIT varies based on geographical region, and is more common in areas with low dietary [[Chemistry:Iodine|iodine]] intake, where it occurs in 10-12% of patients. In the {{wipe|United States}}, clinical manifestations of AIT occur in 3-5% of patients.<ref name="Ross_2022">{{Cite web | vauthors = Ross DS | date = 25 January 2022 | veditors = Cooper DS, Mulder JE |title=Amiodarone and thyroid dysfunction | work = UpToDate |url=https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction?search=amiodarone%20thyroid&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H23 |access-date=2023-01-04 }}</ref>

AIT may present clinically early after initiation of amiodarone or can be delayed even up several years.<ref name="Danzi_2015">{{cite journal | vauthors = Danzi S, Klein I | title = Amiodarone-induced thyroid dysfunction | journal = Journal of Intensive Care Medicine | volume = 30 | issue = 4 | pages = 179–185 | date = May 2015 | pmid = 24067547 | doi = 10.1177/0885066613503278 | s2cid = 21019957 }}</ref> Symptoms associated with AIT are similar to those of other forms of hyperthyroidism, including new-onset or recurrence of [[Medicine:Arrhythmia|arrhythmias]], worsening of pre-existing heart conditions such as ischemic heart disease or [[Medicine:Heart failure|heart failure]], unattributed weight loss, and fever. <ref name="Ross_2022" /><ref name="Danzi_2015" /> Development of AIT is associated with an increased risk for major adverse cardiovascular events, and increased mortality specifically in patients with AIT and underlying [[Medicine:Heart failure|heart failure]].<ref name="Danzi_2015" /><ref name="Bartalena_2018">{{cite journal | vauthors = Bartalena L, Bogazzi F, Chiovato L, Hubalewska-Dydejczyk A, Links TP, Vanderpump M | title = 2018 European Thyroid Association (ETA) Guidelines for the Management of Amiodarone-Associated Thyroid Dysfunction | journal = European Thyroid Journal | volume = 7 | issue = 2 | pages = 55–66 | date = March 2018 | pmid = 29594056 | pmc = 5869486 | doi = 10.1159/000486957 }}</ref>

== Pathophysiology ==
Amiodarone has both direct and indirect effects on thyroid function. The most notable indirect thyroid altering property is that the drug is approximately one-third [[Chemistry:Iodine|iodine]] by weight. As a result, amiodarone therapy elevates free circulating iodine levels up to 40 times greater than the iodine intake from the average American diet.<ref name="Ross_2022" /> Iodine plays a role in thyroid production, and excess iodine levels within the body can result in overproduction of thyroid hormone. Initially, the thyroid reacts according to the [[Biology:Autoregulation|auto-regulatory]] [[Biology:Wolff–Chaikoff effect|Wolff-Chaikoff effect]] to prevent an excess of thyroid hormone production.<ref name="Rose_2022">{{cite book | vauthors = Rose HR, Zulfiqar H | chapter = Jod Basedow Syndrome |date=2022 | chapter-url  =http://www.ncbi.nlm.nih.gov/books/NBK544277/ | title = StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31334997 |access-date=2023-01-04 }}</ref> Usually, the thyroid normalizes within 24-48 hours. In some cases, the thyroid responds with an alternative "escape" mechanism from the [[Biology:Wolff–Chaikoff effect|Wolff-Chaikoff]] [[Biology:Autoregulation|auto-regulatory]] effect called the [[Medicine:Jod-Basedow phenomenon|Jod-Basedow phenomenon]]. This usually occurs in response to exogenous iodine, and they develop hyperthyroidism instead. This Jod-Basedow phenomenon is considered one of the contributing factors for AIT.<ref name="Danzi_2015" /><ref name="Rose_2022" /><ref name="Ylli_2021" />  

Amiodarone additionally alters the thyroid pathway through acting as a thyroid hormone analog and subsequently affecting the other enzymes involved in thyroid hormone production.<ref name="Danzi_2015" /> It also causes direct cytotoxicity and damages thyroid tissues.<ref name="Ylli_2021" /><ref name="Macchia_2022">{{cite book | vauthors = Macchia PE, Feingold KR | chapter = Amiodarone Induced Thyrotoxicosis | veditors = Feingold KR, Anawalt B, Boyce A, Chrousos G |date=2022 | chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK279030/ |title = Endotext |place=South Dartmouth (MA) |publisher=MDText.com, Inc. |pmid=25905259 |access-date=2023-01-04 }}</ref><ref name="Trohman_2019">{{cite journal | vauthors = Trohman RG, Sharma PS, McAninch EA, Bianco AC | title = Amiodarone and thyroid physiology, pathophysiology, diagnosis and management | journal = Trends in Cardiovascular Medicine | volume = 29 | issue = 5 | pages = 285–295 | date = July 2019 | pmid = 30309693 | pmc = 6661016 | doi = 10.1016/j.tcm.2018.09.005 }}</ref> 

AIT often has a delayed clinical presentation, and studies have shown that the average delayed presentation is 2 years.<ref name="Schubert_2021" /> The pharmacology of the drug results in a prolonged [[Physics:Half-life|half-life]] within the body as a result of its [[Chemistry:Lipid|lipid]] [[Chemistry:Solubility|solubility]] and distribution into tissues. This leads to a slow clearance of amiodarone from the body and a prolonged toxicity.<ref name="Danzi_2015" /><ref name="Trohman_2019" /> Other factors affecting AIT include pre-existing heart conditions such as [[Medicine:Dilated cardiomyopathy|dilated cardiomyopathy]] and [[Medicine:Sarcoidosis|cardiac sarcoidosis]], and both have been suggested to be predictive factors for developing AIT.<ref name="Schubert_2021">{{cite journal | vauthors = Schubert L, Bricaire L, Groussin L | title = Amiodarone-induced thyrotoxicosis | journal = Annales d'Endocrinologie | volume = 82 | issue = 3–4 | pages = 163–166 | date = June 2021 | pmid = 32409004 | doi = 10.1016/j.ando.2020.04.009 | s2cid = 218647824 }}</ref>

=== Subtypes ===
'''AIT type 1''' results from the [[Medicine:Jod-Basedow phenomenon|Jod-Basedow phenomenon]], in which the [[Chemistry:Iodine|iodine]] contained in amiodarone is used by the thyroid gland for excess production of thyroid hormones. It primarily occurs in patients with pre-existing thyroid disease such as nodular [[Medicine:Goitre|goiter]] or latent autoimmune [[Medicine:Graves' disease|Graves' disease]].<ref name="Bartalena_2018" />  These pre-existing thyroid diseases involve thyroid tissue which have lost their auto-regulation and function independently in the presence of excess iodine from amiodarone.<ref name="Trohman_2019" /> AIT type 1 commonly occurs in iodine-deficient regions, and usually appears within weeks-months after patients start amiodarone. 

'''AIT type 2''' is a form of an immune system response to the [[Biology:Cytotoxicity|cytotoxic]] properties of amiodarone and results in a destructive [[Medicine:Thyroiditis|thyroiditis]] ([[Medicine:Inflammation|inflammation]] in the thyroid).<ref name="Macchia_2022" /><ref name="Schubert_2021" /> This causes pre-existing thyroid hormones to spill out from damaged cells into the [[Biology:Circulatory system|circulation]] and a resultant immunologic reaction. AIT type 2 usually occurs in patients with a normal thyroid gland and could appear even several years after starting amiodarone. 

'''Mixed/indefinite AIT''' (or '''AIT type 3''') is used when subtype classification is unclear or when both AIT types occur at once.

== Diagnosis ==
The effects of AIT as mentioned above can be especially dangerous for those with heart disease. Some cases can spontaneously improve, but AIT should generally be diagnosed and treated until normal levels of hormone have been reached, otherwise known as the euthyroid state.

Differentiating AIT sub-types can be difficult and multiple diagnostics are usually used including: thyroid hormone levels, radionucleotide scans such as [[Medicine:Radioactive iodine uptake test|radioactive iodine]] or [[Chemistry:Technetium (99mTc) sestamibi|sestamibi]],<ref>{{cite journal | vauthors = Itzkovich D, Ben-Haim S, Godefroy J, Stokar J | title = <sup>99m</sup>Tc MIBI Scintigraphy for Classification of Amiodarone-induced Thyrotoxicosis | journal = JCEM Case Reports | volume = 1 | issue = 1 | pages = luac011 | date = January 2023 | pmid = 37908259 | pmc = 10578384 | doi = 10.1210/jcemcr/luac011 }}</ref> thyroid ultrasonography with [[Medicine:Doppler ultrasonography|color-flow-doppler]] and levels of circulating interleukin-6 or [[Biology:Beta-glucuronidase|beta-glucoronidase]], though none are considered the single [[Medicine:Gold standard (test)|gold-standard.]]<ref name="Ylli_2021">{{cite journal | vauthors = Ylli D, Wartofsky L, Burman KD | title = Evaluation and Treatment of Amiodarone-Induced Thyroid Disorders | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 106 | issue = 1 | pages = 226–236 | date = January 2021 | pmid = 33159436 | doi = 10.1210/clinem/dgaa686 | doi-access = free }}</ref> Imaging studies can demonstrate the presence of pre-existing thyroid disease and examine the activity levels of the thyroid gland.<ref name="Bartalena_2018" /><ref name="Macchia_2022" /> 

== Treatment ==
Due to the underlying differences in pathophysiology, there will be different treatment options according to the subtype of AIT.

'''AIT type 1''' is initially treated with [[Chemistry:Thioamide|thionamides]] and [[Chemistry:Sodium perchlorate|sodium perchlorate]] to reduce production of thyroid hormones. Definitive treatment with radioiodine or [[Medicine:Thyroidectomy|thyroidectomy]] can be initiated after thyroid hormones levels are stabilized and returned to a euthyroid state. <ref name="Ylli_2021" /><ref name="Schubert_2021" />

'''AIT type 2''' is treated with a different regime due to its immunologic pathophysiology. The thyrotoxic phase in AIT type 2 is usually self-limited but treatment with glucocorticoids can reduce its length through their [[Chemistry:Anti-inflammatory|anti-inflammatory]] and [[Chemistry:Immunosuppressive drug|immunosuppressive]] effect.<ref name="Goundan_2020" /><ref name="Danzi_2015" /> 

'''AIT type 3''' treatment usually combines both modalities with subsequent revaluation based on the response to treatment. <ref name="Goundan_2020" /><ref name="Macchia_2022" />

Persistent AIT that does not respond to treatment regardless of the subtype will likely have to consider alternatives such as [[Medicine:Plasmapheresis|plasmapheresis]] or surgery.<ref name="Macchia_2022" /><ref name="Trohman_2019" />

Monitoring is highly recommended for patients taking amiodarone, and thyroid function should be regularly evaluated during treatment and for at least one year following drug cessation.<ref name="Ross_2022" />

== Further reading   ==

* [https://www.karger.com/Article/Pdf/486957 2018 European Thyroid Association (ETA) Guidelines for the Management of Amiodarone-Associated Thyroid Dysfunction, Eur Thyroid J 2018;7:55–66]
* [https://www.liebertpub.com/doi/full/10.1089/thy.2016.0229 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis, Thyroid. Oct 2016.1343-1421.]

== References ==
{{Reflist}}

[[Category:Drug-induced diseases]]

{{Sourceattribution|Amiodarone induced thyrotoxicosis}}