Drugs That Can Alter Thyroid Hormone Secretion

A number of medications available either over the counter, or through a doctors prescription, may affect thyroid function and cause hyper or hypothyroidism 1)www.mythyroid.com/drugs.html. This article discusses medications that can alter thyroid hormone secretion, thus leading to either hypothyroidism or hyperthyroidism.

THIONAMIDES: METHIMAZOLE (MMI), CARBIMAZOLE, PROPYLTHIOURACIL (PTU) 

Methimazole, propyltiouracil and carbimazole are antithyroid agents that belong to a class of drugs called the thionamides or thioamides 2)www.gdatf.org/about/about-graves-disease/patient-education/tapazole-and-propylthiouracil-in-graves-disease/. Antithyroid medications are a common treatment for hyperthyroidism, particularly an ongoing form of hyperthyroidism caused by Grave’s disease or a goiter 3)www.endocrineweb.com/conditions/hyperthyroidism/antithyroid-medications-hyperthyroidism.

Thionamides are compounds that are actively transported into the thyroid, where they inhibit both the organification of iodine (the second step of hormone synthesis) and coupling of iodotyrosine residues, leading to a fall in serum thyroxine (T4) and triiodothyronine (T3) levels. Propylthiouracil (PTU) and methimazole (MMI) are the thionamides available in the United States. Carbimazole, which has an additional carboxy side chain that, when cleaved, converts it to MMI, is also available in Europe. Thyroid hormone levels are reduced within a few weeks in 90% of patients, making the thionamides effective treatment for patients with Graves’ disease and other forms of hyperthyroidism 4)Thyroid Function Testing, Gregory A. Brent.

Thionamides are drugs that have effects on Thyroid Function Tests. They can effect tests, such as Serum T4, Resin T3 Uptake, Free T4, free T3, Serum T3, and Serum TSH. TSH may increase, while Serum T4, Serum T3, Free T4, free T3, and Resin T3 Uptake may decrease if patient becomes hypothyroid while on thionamides.

Thionamides-induced hypothyroidism may occur once hyperthyroidism resolves and patient is on maintenance dosage of thionamides. If this happens and serum TSH is elevated, maintenance dosage of thionamides needs to be decreased. Because an increased risk of hypothyroidism while on thionamides, routine monitoring of TSH and free T4 concentrations with dosage adjustments to maintain a euthyroid state is necessary 5)www.drugs.com/monograph/methimazole.html. Before initiating thioamide therapy, some clinicians recommend obtaining baseline free T4 and TSH concentrations. Monitoring of thyroid function (e.g., serum free T4, serum free or total triiodothyronine [T3], TSH) is required periodically (e.g., every 4–8 weeks [with subsequent dosage adjustments as needed] until thyroid function is stable or patient is euthyroid); once euthyroidism is achieved, monitor thyroid function every 2–3 months is required. Serum TSH is not a reliable parameter to monitor early in therapy because it may remain suppressed for several months after initiation of therapy despite normalization of free T4 concentrations. A suppressed TSH concentration during this period does not indicate a need for dosage increase. Monitoring serum T3 concentrations may sometimes be useful for dosage adjustment; if total or free T3 concentrations remain elevated despite low, normal, or reduced free T4 concentrations, may need to increase antithyroid dosage. When methimazole is discontinued in patients with Graves’ disease, monitor thyroid function every 1–3 months for 6–12 months is necessary to diagnose relapse early 6)www.drugs.com/monograph/methimazole.html.

LITHIUM

Lithium is commonly used to treat bipolar disorder and conduct disorder. Historically, patients on long-term therapy with lithium were noted to develop hypothyroidism and goiter. Lithium has multiple effects on thyroid function 7)Gregory A. Brent. Thyroid Function Testing. 2010;13: 253.

Lithium is concentrated by the thyroid and inhibits thyroidal iodine uptake 8)www.ncbi.nlm.nih.gov/pubmed/9827658 which may enhance a development of lithium-induced hypothyroidism. Low thyroid iodine uptake could be due to lithium induced iodide retention and competition for the iodide transport within the thyroid gland 9)www.thyroidresearchjournal.com/content/6/1/3. Lithium administration is also associated with reduced hepatic deiodination and clearance of free thyroxine (T4). The latter induces a decrease in the activity of type I 5’ de-iodinase enzyme 10)www.thyroidresearchjournal.com/content/6/1/3.

Another effects of lithium on thyroid gland functioning occur at the level of hormone synthesis and release. Lithium inhibits synthesis and release of thyroid hormones 11)www.thyroidresearchjournal.com/content/6/1/3. The latter effect is critical to the development of hypothyroidism and goiter 12)www.ncbi.nlm.nih.gov/pubmed/9827658. The inhibition of thyroid hormones release is due to the alteration in the microtubulin polymerisation 13)www.thyroidresearchjournal.com/content/6/1/3. Since microtubules are known to be involved in the secretory process, it is possible that the lithium interaction with these organelles may be important in initiating the decrease of secretion 14)J. H. Lazarus,Keith J. Collard. Endocrine and Metabolic Effects of Lithium; J. H. Lazarus,Keith J. Collard. 1986;5:102. Lithium also alters the structure of thyroglobulin thereby affecting protein conformation and function with subsequent iodotyrosine coupling defects 15)www.thyroidresearchjournal.com/content/6/1/3, leading to a decrease in synthesis of thyroid hormones. The coupling of iodothyrosines (monoidothyrosines MIT, and diiothyrosines DIT) is a process the iodothyrosines triiodothyronine (T3) and thyroxine (T4) are formed by (43)16)Nordic Council of Ministers. The influence of chemicals in the food and environment on the thyroid gland function. 2002; page 23. The initial inhibition of thyroid hormone release by lithium may result in decreased serum levels of total T4 and T3 that in turn leads to an elevation of TSH concentration. The elevated serum levels of TSH in turns leads to a restoration of normal thyroid hormone values in the circulation at the expense of an enlarged thyroid gland 17)J. H. Lazarus,Keith J. Collard. Endocrine and Metabolic Effects of Lithium; J. H. Lazarus,Keith J. Collard. 1986;5:102. Goiter, due to increased thyrotropin (TSH) after inhibition of thyroid hormone release 18)www.ncbi.nlm.nih.gov/pubmed/9827658 can be found in up to 50% of patients within the first 2 years after starting lithium therapy 19)Gregory A. Brent. Thyroid Function Testing. 2010;13: 253. Thyroid ultrasonography has been demonstrated to be a simple, cheap and sensitive method for screening for goitre and thyroid abnormalities among patients on lithium therapy 20)www.thyroidresearchjournal.com/content/6/1/3. Hypothyroidism occurs in up to 34% of patients. This typically occurs within the first 2 years of lithium use, but has been documented even after years of therapy. Lithium-induced subclinical hypothyroidism, with an elevated serum TSH and normal free T4 and T3 values, is more common than overt hypothyroidism 21)Gregory A. Brent. Thyroid Function Testing. 2010;13: 253]. The risk of developing lithium induced hypothyroidism has been shown to be significantly higher among females, with increasing age (>50 years), presence of family history of thyroid disease and thyroid auto-antibodies 22)www.thyroidresearchjournal.com/content/6/1/3. Lithium affects many aspects of cellular and humoral immunity. This accounts for a rise in antithyroid antibody titer in patients having these antibodies before lithium administration whereas there is no induction of thyroid antibody synthesis de novo 23)www.ncbi.nlm.nih.gov/pubmed/9827658. Patients who develop hypothyroidism while taking lithium have been noted to have a higher prevalence of pretreatment thyroid autoantibodies when compared to patients who remain euthyroid 24)Gregory A. Brent. Thyroid Function Testing. 2010;13: 253.

Due to the high frequency of hypothyroidism, it is clinically plausible to assess the thyroid function status, thyroid size and presence of thyroid auto-antibodies in all patients prior to initiation of lithium therapy and later annually. More frequent assessment of thyroid function tests (at least every 3–4 months) is recommended among middle aged females (>50 years) who are thyroid auto-antibody positive with family history of thyroid disease. Levothyroxine replacement therapy concurrently with lithium administration especially in the presence of clinically overt hypothyroidism, significantly enlarged thyroid glands, subclinical hypothyroidism and in rapidly cycling or treatment resistant cases is recommended in the management of lithium induced hypothyroidism 25)www.thyroidresearchjournal.com/content/6/1/3.

Lithium effects on thyroid hormone secretion have led to its occasional therapeutic use in hyperthyroidism and for increasing radioiodine retention in the treatment of Graves’ disease or thyroid cancer 26)Gregory A. Brent. Thyroid Function Testing. 2010;13: 253.

Rarely, lithium use has been associated with thyrotoxicosis (decreased TSH and increased serum total T4 and T3 levels). Cases of Graves’ disease, toxic nodular goiter, and thyroiditis have all been reported to be more frequent in lithium-treated patients than in the general population (13)27)Gregory A. Brent. Thyroid Function Testing. 2010;13: 253.

IODIDES

Medications or foods containing excess iodine may cause either hypothyroidism or hyperthyroidism in susceptible individuals with underlying thyroid diseases 28)www.mythyroid.com/drugs.html.

Recommended daily iodine intake is 150 μg in adults who are not pregnant or lactating 29)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976240/.

In healthy individuals, the thyroid gland has several intrinsic autoregulatory mechanisms to handle the iodine efficiently when the availability of iodine becomes scarce, as well as when iodine is available in excessive quantities 30)www.ncbi.nlm.nih.gov/pmc/articles/PMC1924637/. The sodium-iodide symporter system contributes most to this stability 31)www.ncbi.nlm.nih.gov/pubmed/20172475. Low iodine intake triggers thyroid stimulating hormone (TSH) secretion from the pituitary gland and increases the expression of the sodium/iodide symporter (NIS) to maximize the iodine uptake into the thyroid cell. The thyroid accumulates a larger percentage of ingested iodine (as iodide), reuses the iodine from the degradation of thyroid hormones more efficiently, and reduces the amount of iodine excreted in the urine. In chronic iodine deficiency, the thyroid uptake of iodine from the circulation can increase from 10 to 80% 32)Gregory A. Brent. Thyroid Function Testing. 2010;13:47. On the other side, faced with an iodine excess, the sodium/iodide symporter (NIS) throttles the transport of iodide into the thyroid cells, the rate-limiting step of hormone synthesis. Even before the iodine symporter reacts, a sudden iodine overload paradoxically blocks the second step of hormone synthesis, the organification of iodide. This so-called Wolff-Chaikoff effect is an effective means of rejecting the large quantities of iodide and therefore preventing the thyroid from synthesizing large quantities of thyroid hormones 33)www.ncbi.nlm.nih.gov/pubmed/11396709. The block does not last long (only few days), because after a while the sodium-iodide symporter shuts down; this allows intracellular iodide to drop, which allows the organification of intrathyroidal iodide to resume and the normal synthesis of thyroxine (T4) and triiodothyronine (T3) to return to normal 34)www.ncbi.nlm.nih.gov/pubmed/20172475,35)www.ncbi.nlm.nih.gov/pubmed/11396709. This is so-called “escape” phenomenon 36)www.ncbi.nlm.nih.gov/pubmed/11396709.

The pathologic consequences of iodine excess will ensue only when thyroid autoregulation is defective, in that escape from the Wolff-Chaikoff effect cannot occur, or when autoregulation is absent.

Defective autoregulation characterizes the fetal and neonatal thyroid, Hashimoto’s thyroiditis, radioiodine or surgically treated Graves’ hyperthyroidism, the thyroid of patients with cystic fibrosis, and the thyroid that has been exposed to weak inhibitors of the organic binding of iodine 37)www.ncbi.nlm.nih.gov/pubmed/1987441. Therefore, in a few apparently normal individuals, in newborns and fetuses, in some patients with chronic systemic diseases, euthyroid patients with autoimmune thyroiditis, and Graves’ disease patients previously treated with radioimmunoassay (RAI), surgery or antithyroid drugs, the escape from the inhibitory effect of large doses of iodides is not achieved because the sodium-iodide symporter fails to shut down, the intracellular concentration of iodide remains high after an ingestion of large quantities of inorganic iodide (typically greater than 1–2 mg/day) and chronic hypothyroidism ensues 38)Gregory A. Brent. Thyroid Function Testing. 2010;13:254,39)www.ncbi.nlm.nih.gov/pubmed/20172475,40)www.ncbi.nlm.nih.gov/pubmed/11396709. These patients may experience a reduction in serum free T4 and T3 concentrations and a resultant increase in serum concentration of TSH. Iodine-induced hypothyroidism typically resolves within 2–3 weeks of removing the source of excess iodine. If the iodine agent cannot be withdrawn, replacement levothyroxine therapy may be required 41)Gregory A. Brent. Thyroid Function Testing. 2010;13:254.

Lack of the Wolff-Chaikoff effect (absent autoregulation) is occasionally encountered in individuals with an underlying multinodular goiter, particularly those residing in endemically iodine-deficient areas 42)pubs.rsna.org/doi/full/10.1148/rg.234025716. It is presumed that such individuals harbor one or more autonomous areas (nodules) within the thyroid 43)pubs.rsna.org/doi/full/10.1148/rg.234025716. When large amounts of iodine are administered to patients with autonomously functioning thyroid tissue in whom the acute Wolff-Chaikoff effect does not take place (in the other words autoregulation is absent), iodine-induced hyperthyroidism, also known as Jod-basedow phenomenon, typically occurs 44)Gregory A. Brent. Thyroid Function Testing. 2010;13:254,45)www.thyroidmanager.org/chapter/multinodular-goiter/. The lack of the protective Wolff-Chaikoff effect causes that these autonomous nodules cannot adapt to an iodide load 46)Daniel Oertli, Robert Udelsman. Surgery of the Thyroid and Parathyroid Glands. 2012;page32. Moreover, autonomous nodules function independently of the normal pituitary-thyroid control mechanism 47)pubs.rsna.org/doi/full/10.1148/rg.234025716. Unlike in Graves disease, the mechanism of toxic autonomous nodule is not autoimmunity. Instead, it is presumed that the TSH receptors on the adenoma surface undergo gene mutation, resulting in their continuous activation 48)pubs.rsna.org/doi/full/10.1148/rg.234025716. If the patients with autonomous nodular goiters are given thyroid hormone, continued function of nodules can be demonstrated by radioiodine scanning techniques 49)www.thyroidmanager.org/chapter/multinodular-goiter/. Being no more under pituitary control 50)www.ncbi.nlm.nih.gov/pubmed/20172475 and missing the autoregulation (Wolff-Chaikoff effect), these nodules overproduce thyroid hormone and cause iodine-induced hyperthyroidism, when they are presented with sufficient iodine 51)www.ncbi.nlm.nih.gov/pubmed/20172475 (e.g. the introduction of iodine supplementation in regions of iodine deficiency, the administration of iodide-containing medications or when individuals move from an iodine-deficient region to a region with adequate iodine intake) 52)Gregory A. Brent. Thyroid Function Testing. 2010;13:254,53)www.thyroid.org/iodine-deficiency/. Autonomous (toxic) multinodular goiters that cause hyperthyroidism are usually very large. They grow from an existing simple goiter 54)www.nlm.nih.gov/medlineplus/ency/article/000317.htm. Risk factors include being female and over 60 years old. This disorder is almost never seen in children. Most patients who develop it have had a goiter with nodules for many years 55)www.nlm.nih.gov/medlineplus/ency/article/000317.htm. The longer the goiter had been present the greater is the tendency for thyrotoxicosis to develop. This condition appears to occur because with the passage of time, autonomous function of the nodules develops 56)www.thyroidmanager.org/chapter/multinodular-goiter/. In areas of iodine deficiency, goiter prevalence may be very high and especially in goiters of longstanding, multinodularity develops frequently 57)www.thyroidmanager.org/chapter/multinodular-goiter/. Therefore, iodine-induced hyperthyroidism is much more common in areas where dietary iodine is insufficient than in areas where the diet contains sufficient iodine 58)blogs.nejm.org/now/index.php/iodine-induced-hyperthyroidism/2011/12/02/. When dietary iodine intake falls below 100 μg/day, thyroid hormone synthesis is compromised. In the absence of sufficient iodine, TSH levels remain elevated, leading to goiter, an enlargement of the thyroid gland that reflects the body’s attempt to trap more iodine from the circulation and produce thyroid hormones 59)ods.od.nih.gov/factsheets/Iodine-HealthProfessional/. It is known that thyroid hormone synthesis goes along with increased H2O2 production and free radical formation witch may damage genomic DNA and cause mutations, thus resulting in development of autonomous nodules. In regions of iodine sufficiency, iodine-induced hyperthyroidism is less common overall, and may be seen in patients with latent Graves’ disease or autonomous nodules. The risk of iodine-induced thyrotoxicosis is higher in patients with subclinical hyperthyroidism at baseline. The elderly are at particular risk, given their increased prevalence of autonomous thyroid nodules and apathetic, or silent, Graves’ disease 60)Gregory A. Brent. Thyroid Function Testing. 2010;13:254. Excess iodide exposure from diet, drug therapy, or use of iodinated contrast agents in radiography leads to hyperthyroidism, with increased free T4, normal-to-elevated free T3, and suppressed TSH concentrations. The hyperthyroidism typically occurs 4–8 weeks after the introduction of the iodine source 61)Gregory A. Brent. Thyroid Function Testing. 2010;13:254. Many medications are sources of iodine including potassium iodine solutions, betadine vaginal douches, topical antiseptics, the antiamebic iodoquinol, radiographic contrast agents, and amiodarone 62)Gregory A. Brent. Thyroid Function Testing. 2010;13:254. Antithyroid drugs in high doses are the treatment of choice, with or without the addition of potassium perchlorate, which blocks further iodine uptake by the gland. If this regimen is unsuccessful, steroids are warranted 63)pubs.rsna.org/doi/full/10.1148/rg.234025716. Clinical symptoms requiring therapy with antithyroid agents may occur even after a single dose of iodide. The thyroid hormone changes can last for several months following iodine discontinuation 64)Gregory A. Brent. Thyroid Function Testing. 2010;13:254.

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