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REVIEW ARTICLE
Year : 2012  |  Volume : 9  |  Issue : 1  |  Page : 3-6

Effects of drugs on thyroid function


1 Excel Center (Unit of Excelcare Hospitals), Ulubari, Guwahati, India
2 Bicon Limited, Bangaluru, India

Date of Web Publication28-Jan-2012

Correspondence Address:
Manash P Baruah
Excel Center (Unit of Excelcare Hospitals), Ulubari, Guwahati, Assam-781 007
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-0354.92387

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  Abstract 

A good number of drugs used in different indications in wide variety of clinical fields may influence the thyroid function tests (TFT), the use of which has seen a substantial increase in various clinical fields. Therefore, it is important to consider the possible effect of these drugs both on the results of TFT. Although two classical examples, i.e., amidarone and lithium are discussed in details, some special drugs classes like cytokines, tyrosine kinase inhibitors, and highly active antiretroviral therapy are also highlighted.

Keywords: Amiodarone, drugs and thyroid, lithium, thyroid function tests


How to cite this article:
Baruah MP, Singh RJ. Effects of drugs on thyroid function. Thyroid Res Pract 2012;9:3-6

How to cite this URL:
Baruah MP, Singh RJ. Effects of drugs on thyroid function. Thyroid Res Pract [serial online] 2012 [cited 2017 May 22];9:3-6. Available from: http://www.thetrp.net/text.asp?2012/9/1/3/92387


  Introduction Top


In clinical practice, testing of thyroid function is common. Many patients who are tested take medications that may affect thyroid function. Therefore, it is important to consider the possible effect of these drugs both on the results of thyroid function tests (TFT) and on the effectiveness of treatment. [1],[2]

Triiodothyronine (T3) and thyroxine (T4) inhibit the secretion of thyrotropin (the thyroid-stimulating hormone, TSH) both directly and indirectly, by inhibiting the secretion of thyrotropin-releasing hormone. TSH stimulates the synthesis and secretion of T4 and T3 by the thyroid gland. This is known as the Hypothalamic-Pituitary-Thyroid Axis. T4 is converted to T3 in the liver (and many other tissues) by the action of T4 monodeiodinases. Some of the T4 and T3 is conjugated with glucuronide and sulfate in the liver, excreted in the bile, and partially hydrolyzed in the intestine; the T4 and T3 formed there may be reabsorbed. Drug interactions can occur at any of these sites. Drugs that can alter TSH secretion are of clinical relevance only in interpretation of TFT, whereas drugs that can alter peripheral dynamics of T3 and T4 are of clinical relevance only in hypothyroid patients taking levothyroxine and subclinical thyroid disease. [1]


  Drugs Directly Affecting Synthesis/Secretion of Thyroid Hormones Top


The first step in the synthesis of thyroid hormones is the organification of iodine. Iodide is taken up, converted to iodine, and then condensed onto tyrosine residues which reside along the polypeptide backbone of a protein molecule called thyroglobulin. This reaction results in either a mono-iodinated tyrosine or di-iodinated tyrosine that is being incorporated into thyroglobulin. This newly formed iodothyroglobulin forms one of the most important constituents of the colloid material present in the follicle of the thyroid unit.

The other synthetic reaction that is closely linked to organification is a coupling reaction, where iodotyrosine molecules are coupled together. If two di-iodotyrosine molecules couple together, the result is the formation of T4. If a di-iodotyrosine and a mono-iodotyrosine are coupled together, the result is the formation of T3. [1],[2]

The major general mechanisms of action by which drugs may affect the synthesis of TH are elucidated in Box 1.



Drug-induced thyroid dysfunction are more likely to occur in a gland compromised by preexisting TAI, i.e., positive anti-thyroid peroxidase (anti-TPO) antibodies, preexisting nodules, prior radiation or surgery. It may or may not be reversible. [3]


  Amiodarone Top


Amiodarone is an iodine-rich drug widely used as type-III anti-arrhythmic agent. It often causes changes in TFT mainly related to the inhibition of 5'-deiodinase activity, resulting in a decrease in the generation of T3 from T4 with a consequent increase in serum reverse T3 production and a decrease in its clearance. Although the majority of the adverse effects of amiodarone on several organs are due to deposition of the drug in the parenchyma, its effects on the thyroid gland can be divided in two groups: intrinsic effects resulting from the inherent properties of the compound and iodine-induced effects due solely to the pharmacologic effects of a large iodine load [Table 1]. [4],[5]
Table 1: Effects of amiodarone on the thyroid gland[4],[5]

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Although amiodarone-induced thyroid dysfunction represents an important clinical problem, the majority of patients receiving amiodarone remain euthyroid. The alterations in serum TFT can be divided into acute, chronic phases that follow amiodarone exposure during the pharmacologic therapy [Table 2]. [4],[5] Amiodarone-induced Thyrotoxicosis (AIT) is primarily related to excess iodine-induced thyroid hormone synthesis in an abnormal thyroid gland (type 1 AIT) or to amiodarone-related destructive thyroiditis (type 2 AIT). [4] The pathogenesis of Amiodarone-induced hypothyroidism (AIH) is related to a failure to escape from the acute Wolff-Chaikoff effect due to defects in thyroid hormonogenesis, or in patients with positive thyroid autoantibody test, to concomitant Hashimoto's thyroiditis. Both AIT and AIH may develop either in apparently normal thyroid glands or in glands with preexisting, clinically silent abnormalities. AIT is more common in iodine-deficient regions of the world, whereas AIH is usually seen in iodine sufficient areas. In contrast to AIH, AIT is a difficult condition to diagnose and treat, and discontinuation of amiodarone is usually recommended. [4],[5] Treatment protocol for both these conditions (AIT and AIH) are elucidated in Box 2.
Table 2: Effects of amiodarone on thyroid function tests in euthyroid subjects[4],[5]

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  Lithium-Induced Thyroid Disease Top


Lithium interference with thyroid function occurs mainly at the level of hormone secretion and may lead to goitrogenesis, hypothyroidism, or rarely thyrotoxicosis (hyperthyroidism). Long-term lithium treatment results in goiter in up to 50% of patients, subclinical hypothyroidism in up to 34%, and overt hypothyroidism in up to 15%. This can appear abruptly even after many years of treatment which makes it mandatory to test thyroid function once or twice a year in these patients. Presence of thyroid autoantibody increases the risk of development of hypothyroidism; 50% of those with autoantibody and 15% of those without antibodies have subclinical hypothyroidism. The inhibitory effect of lithium on thyroid hormone secretion has been utilized in treatment of thyrotoxicosis in selected situations. Lithium treatment is also associated rarely with thyrotoxicosis. It is not common and occurs mainly after long-term use. Mechanism is unclear but is thought to involve either autoimmune or destructive thyroiditis. Transient euthyroid hyperthyroxinemia has been reported after discontinuation of lithium treatment. [2],[3]


  Cytokine-Induced Thyroid Disease Top


Patients with chronic inflammatory disorders or tumors who receive long-term treatment with cytokines may develop thyroid dysfunction. Therapy with interferon alfa is associated with the development of anti-TPO antibodies in 20% of patients, and some have transient hyperthyroidism, hypothyroidism, or both. Patients who have anti-thyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Thyroid dysfunction has not been reported during treatment with interferon beta or gamma. Therapy with interleukin-2 was associated with transient painless thyroiditis in about 20% of patients. [1],[2]


  Novel Therapies Affecting Thyroid Top


Over the years, several drugs used in the treatment of non-thyroidal conditions have been shown to affect thyroid function. Here, we will discuss about a few of the novel drugs used for non-thyroidal conditions that are recently showing clinically relevant thyroidal side effects. [6]


  Recombinant Human Growth Hormone Top


Administration of recombinant human GH (rhGH) to adults with severe Growth Hormone (GH) deficiency leads to clinically relevant central hypothyroidism, which manifest as a decline in serum concentration of T4 or FT4 values. GH deficiency masks a state of central hypothyroidism in a significant portion of hypopituitary patients that become manifest only during GH therapy. [7],[8]


  Tyrosine Kinase Inhibitors Top


Tyrosine kinase inhibitors are novel drugs used in the treatment of several neoplasias, including thyroid cancer. Examples include sunitinib, sorafenib, and imatinib. Thyroidal side effects are being increasingly detected with these drugs. Some drugs in this category affect thyroid hormone metabolism and therefore only affect patients on thyroid replacement. Others affect the thyroid directly profoundly, causing primary hypothyroidism. [6]


  Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus Top


A few and controversial data have been reported on thyroid function in human immunodeficiency virus patients on highly active antiretroviral therapy (HAART). HAART, particularly stavudine, is associated with a high prevalence of subclinical hypothyroidism. Hypotheses are made regarding responsible mechanisms and risk factors. Thyroid function should be tested and sequentially rechecked in HAART patients. [9]

Epoprostenol

In a review of the thyroid function in patients with pulmonary arterial hypertension who were treated with epoprostenol (prostaglandin I2 or PGI2) cases of seronegative thyrotoxicosis, diffuse goiter and homogeneous uptake on thyroid scintigraphy were noted. Therefore, patients receiving this drug need to undergo close follow-up for the development of thyrotoxicosis and goiter. [10]

Bexarotene

Bexarotene is a retinoid X receptor agonist used in the treatment of cutaneous T-cell lymphoma. Increased peripheral degradation of thyroid hormones (T3 and T4) in addition to decreased TSH secretion contributes to bexarotene-induced hypothyroidism. In patients who develop hypothyroidism during bexarotene therapy, it should be realized that TSH measurements are unreliable to monitor L-T4 substitution therapy and that higher levothyroxine dosages may be required than expected because of the enhanced degradation of thyroid hormones. [11]


  Conclusion Top


The accurate interpretation of abnormal TFT results may be complicated by the concomitant presence of non-thyroidal illnesses and medications with known history of inducing thyroid disease like amiodarone, lithium, interferon, etc. Any "funny" (unusual) TFT reports like mismatch with clinical picture or discordance between T3-T4-TSH and an altered TFT in patient stable on T4 are a suspect of drug effect. It is important that clinicians recognize the effects of drugs on laboratory interpretation, drug-induced thyroid illnesses, and exogenous thyroid requirements to prevent medical treatments that may be dangerous or that inappropriately increase the cost of caring for patients.

 
  References Top

1.Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995;333:1688-95.  Back to cited text no. 1
[PUBMED]  [FULLTEXT]  
2.George J, Joshi SR. Drugs and thyroid. J Assoc Physicians India 2007;55:215-23.  Back to cited text no. 2
[PUBMED]    
3.Dong BJ. How medications affect thyroid function. West J Med 2000;172:102-6.  Back to cited text no. 3
[PUBMED]  [FULLTEXT]  
4.Martino E, Bartalena L, Bogazzi F, Braverman LE. The effects of Amiodarone on the thyroid. Endocr Rev 2001;22:240-54.  Back to cited text no. 4
[PUBMED]  [FULLTEXT]  
5.Ursella S, Testa A, Mazzone M, Silveri N. Amiodarone-induced thyroid dysfunction in clinical practice. Eur Rev Med Pharmacol Sci 2005;10:269-78.  Back to cited text no. 5
    
6.Barbesino G. Drugs affecting thyroid function. Thyroid 2010;20:763-70.  Back to cited text no. 6
[PUBMED]  [FULLTEXT]  
7.Moayeri H, Hemati A, Bidad K, Dalili H. Effects of growth hormone replacement therapy on thyroid function tests in growth hormone deficient children. Acta Med Iran 2008;46:473-6.  Back to cited text no. 7
    
8.Losa M, Scavini M, Gatti E, Rossini A, Madaschi S, Formenti I, et al. Long-term effects of growth hormone replacement therapy on thyroid function in adults with growth hormone deficiency. Thyroid 2008;18:1249-54.  Back to cited text no. 8
[PUBMED]  [FULLTEXT]  
9.Madeddu G, Spanu A, Chessa F, Calia GM, Lovigu C, Solinas P, et al. Thyroid function in human immunodeficiency virus patients treated with highly active antiretroviral therapy (HAART): A longitudinal study. Clin Endocrinol (Oxf) 2006;64:375-83.  Back to cited text no. 9
[PUBMED]  [FULLTEXT]  
10.Chadha C, Pritzker M, Mariash CN. Effect of epoprostenol on the thyroid gland: enlargement and secretion of thyroid hormone. Endocr Pract 2009;15:116-21.  Back to cited text no. 10
[PUBMED]  [FULLTEXT]  
11.Smit JW, Stokkel MP, Pereira AM, Romijn JA, Visser TJ. Bexarotene-inducedhypothyroidism: bexarotenestimulates the peripheralmetabolism of thyroidhormones. J Clin Endocrinol Metab 2007;92:2496-9.  Back to cited text no. 11
[PUBMED]  [FULLTEXT]  



 
 
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  In this article
Abstract
Introduction
Drugs Directly A...
Amiodarone
Lithium-Induced ...
Cytokine-Induced...
Novel Therapies ...
Recombinant Huma...
Tyrosine Kinase ...
Highly Active An...
Conclusion
References
Article Tables

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