Are you sure the thyroid function tests are influenced by medications/drugs?

Drug-induced thyroid dysfunction should be considered when thyroid function test results are inconsistent with the clinical scenario or when a patient is taking a medication known to commonly disrupt thyroid function. Pseudo-abnormalities in thyroid function tests should be differentiated from true thyroid dysfunction. Certain drugs or agents can cause either or both of these abnormalities and understanding their potential thyroidal effects will help the clinician to appropriately manage the patient.

The use of certain drugs or agents have the potential to interfere with various steps of thyroid hormone metabolism which results in hypothyroidism or hyperthyroidism:

  • thyroid hormone absorption (in patients already taking levothyroxine [LT4] therapy)

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  • hypothalamic and pituitary regulation of thyroid hormone production

  • thyroid hormone synthesis and production

  • binding of T4 and T3 (triiodothyronine) to serum carrier proteins, mainly thyroxine binding globulin (TBG)

  • thyroid hormone pharmacokinetics

  • thyroid hormone pharmacodynamics (e.g. interference with the conversion of T4 to T3 in peripheral target organs)

Thyroid dysfunction can be transient or permanent, depending on the specific drug or agent, status of iodine nutrition, and presence of absence of any pre-existing autonomous thyroid nodules, subclinical thyroid dysfunction, and thyroid autoantibodies.

Because primary hypothyroidism (e.g. Hashimoto’s disease) or hyperthyroidism (e.g. Graves’ disease, toxic multinodular goiter, silent thyroiditis) are common, the distinction between drug-induced and primary thyroid dysfunction cannot always be easily made. Clinical judgment should dictate whether the suspected drug should be withdrawn and how the thyroid dysfunction should be further investigated and treated.

Table I lists the drugs and agents most frequently associated with thyroid dysfunction:

Table In

General considerations regarding drug-induced hypothyroidism

The clinical presentation of drug-induced hypothyroidism is indistinguishable from other causes of hypothyroidism. The types of drug-induced hypothyroidism are:

  • Impaired levothyroxine absorption arising from use of calcium, iron, bile acid sequestrants, coffee, sulcralfate, aluminum hydroxide, and sevelamer (to minimize this, patients should be encouraged to take their levothyroxine in the morning on an empty stomach to reduce the risk of interaction)

  • Transient hypothyroidism, similar to the hypothyroid phase of painless thyroiditis (silent lymphocytic thyroiditis), which normalizes after withdrawal of the drug or agent

  • Permanent hypothyroidism (with or without detectable thyroid autoantibodies)

General considerations regarding drug-induced hyperthyroidism

Similarly, symptoms and signs resulting from drug-induced hyperthyroidism are indistinguishable from causes of spontaneous hyperthyroidism. The types of drug-induced hyperthyroidism are:

  • Transient hyperthyroidism, similar to the hyperthyroid phase of painless thyroiditis (silent lymphocytic thyroiditis)

  • Hyperthyroidism due to Graves’ disease (with or without positive TSH receptor antibodies)

  • Hyperthyroidism arising from an iodine load in a patient with thyroid nodules

Which drugs can modify thyroid hormone metabolism?

Use of certain drugs may result in altered thyroid hormone metabolism and require higher doses of replacement LT4 to achieve a normal TSH.

  • Increased hepatic enzymes from certain antiepileptic medications (phenobarbital, carbamazepine or phenytoin) and the antibiotic, rifampicin, may reduce the half-lives of T4 and T3

  • Imatinib (a tyrosine kinase inhibitor used to treat certain cancers) is thought to increase the hepatic metabolism of thyroid hormone

  • Drugs that increase thyroxine binding globulin (TBG) levels (e.g. estrogens) will reduce the availability of FT4

  • Amiodarone impairs the peripheral de-iodination of T4, and therefore, the conversion of T4 to T3

  • Glucocorticoids and some beta blockers at high doses can also inhibit T4 toT3 de-iodination, although these changes are not usually clinically relevant

What else could the patient have?

Some drugs or agents can directly lower TSH secretion without altering thyroid gland function (i.e. TT4 and FT4 remain normal). This effect is transient and has been reported primarily with high doses of glucocorticoids and intravenous dopamine or dobutamine. However, a sustained decrease in TSH production leading to a decrease of FT4 (central hypothyroidism) has rarely been reported during prolonged use of somatostatin analogs.

In subclinical hyperthyroidism, the TSH is low and FT4 is normal. A small increase in FT4 (even within the normal range) is usually detected by the hypothalamus and the pituitary to result in decreased TSH secretion. One may suspect subclinical hyperthyroidism if the FT4 is in the upper part of the normal range.

In patients with acute illness, including infection, heart failure, or respiratory failure, non-thyroidal illness may be associated with thyroid dysfunction. In these scenarios, serum TSH and T3 levels may be initially decreased and followed by a later decrease of the serum FT4 level. Clinical judgement and repeat thyroid function tests should be carried out after the illness is resolved.

Key laboratory and imaging tests

TSH is the most sensitive test to detect thyroid dysfunction. A low TSH is most frequently diagnostic of spontaneous hyperthyroidism. In addition to some types of drug-induced thyroid dysfunction, the differential diagnoses for a low TSH are:

  • Graves’ disease

  • Toxic multinodular goiter

  • Toxic adenoma

  • Thyroiditis (silent, painful, de Quervain)

  • Exogenous sources of thyroid hormone ingestion

  • Non-thyroidal illness (euthyroid sick syndrome)

  • Central hypothyroidism

  • Recovery phase after treatment for hyperthyroidism

  • Laboratory artifact (analytical interference)

  • Rare genetic conditions

When the TSH is abnormal, the next test in the evaluation of thyroid dysfunction is the measurement of TT4 and FT4 and/or TT3. While alterations in serum T4 and T3 levels are parallel to each other, there are some conditions associated with discrepancies in these tests, including non-thyroidal illness, amiodarone therapy, T3-toxicosis, hypothyroidism, and some rare conditions of impaired de-iodination.

Thyroid autoantibodies may be of some use in the evaluation of hypothyroidism, although they are not particularly specific and sensitive. For example, transient hypothyroidism after painless thyroiditis is not easily differentiated from permanent Hashimoto’s hypothyroidism because autoantibodies are present in both conditions. Furthermore, up to 20% of the general euthyroid population may have positive thyroid antibodies (anti-thyroglobulin or/and anti-TPO antibodies), although these individuals may progress over many years to hypothyroidism.

However, in suspected spontaneous hyperthyroidism, the measurement of TSH-receptor antibodies can prove useful because they are highly specific to Graves’ disease, although they can be absent in 10-20% of individuals. In patients with preexisting thyroid autoantibodies, there is a higher risk of developing thyroid dysfunction during treatment with interferon. In summary, the occurrence of drug-induced thyroid dysfunction cannot be accurately predicted, but pretreatment autoantibody screening may be helpful.

Which drugs can lower TSH without inducing true thyroid dysfunction?

  • Glucocorticoids in high doses during initial treatment; in contrast, prolonged exposure to glucocorticoid therapy or endogenous hypercortisolism (Cushing’s syndrome) do not result in thyroid dysfunction

  • Dopamine or dobutamine

  • Octreotide

These drugs do not generally cause clinically significant central hypothyroidism, and their suppressant effect on TSH production is transient. An exception is bexarotene, in which the associated central hypothyroidism that is occasionally seen normalizes after the discontinuation of the medication.

Which drugs can cause thyroid dysfunction and should this be treated?


Amiodarone can cause transient alterations of thyroid function tests, as well as overt hypothyroidism or hyperthyroidism. The incidence of amiodarone-induced thyroid dysfunction varies with iodine nutrition. In iodine-sufficient populations, hypothyroidism is more common, whereas in iodine-deficient populations, hyperthyroidism is more common. In most cases of hyperthyroidism, amiodarone should be withdrawn if agreed upon by the cardiologist. Amiodarone impairs the peripheral de-iodination of T4 to generate T3.

Following amiodarone administration, TSH levels transiently increase with a subsequent increase of T4. A new steady state is achieved, and TSH returns to normal. In euthyroid amiodarone-treated patients, the T4 and FT4 concentrations are high normal or slightly increased and the T3 and FT3 concentrations are in the lower range of normal. The half-life of amiodarone is extremely long, and elimination from adipose tissue may take several months.

In iodine-sufficient areas, the occurrence of amiodarone-induced hypothyroidism is approximately 5-15%. Hypothyroidism continues as long as amiodarone is given. The mechanism is thought to be the failure to escape from the acute Wolff-Chaikoff phenomenon. Permanent hypothyroidism may result, especially in individuals with pre-existing thyroid autoimmunity. Treatment for amiodarone-induced hypothyroidism is LT4. The dose of LT4 required to achieve euthyroidism may be higher than usual because of the decrease in T4 de-iodination to T3.

Amiodarone-induced thyrotoxicosis (AIT) is categorized as type 1 (iodine-induced thyroid autonomy) versus type 2 (thyroiditis) AIT. In type 1 AIT, thionamides are the treatment of choice, whereas type 2 AIT will improve with high-dose glucocorticoids given approximately for 3-6 months. Use of amiodarone is associated with a large iodine load (200 mg contains approximately 70 mg of iodide, of which 10% [7 mg] is bioavailable; this is almost 50 times the daily recommended intake of 0.150 mg). This iodine load is the presumed mechanism of type 1 AIT, which is most commonly seen in patients with an underlying nodular goiter. Type 2 AIT is a painless thyroiditis due to amiodarone-induced inflammatory changes in the thyroid, which is also seen in other tissues.

Color-flow Doppler thyroid ultrasound may demonstrate increased blood flow in an enlarged, frequently nodular goiter (type 1 AIT) or decreased blood flow in a normal or small-sized thyroid (type 2 AIT). Treatment of type 1 AIT with large doses of methimazole and beta-blockers is recommended, and if a poor response is seen, the addition of 200 mg perchlorate (a competitive inhibitor of the sodium/iodide symporter on the basolateral surface of the thyroid epithelial cell) every 8 hours.

Corticosteroids are extremely efficacious in type 2 AIT. Some patients have a combination of the two types of AIT and require both methimazole and corticosteroids. Thyroidectomy is reserved for refractory cases. Regular monitoring (every 6 months) of TSH is recommended for patients on amiodarone therapy, since the incidence of hyperthyroidism is reported in 2-10% of patients, with higher incidences seen with longer durations of treatment. Baseline thyroid function tests prior to amiodarone administration are recommended.


Hypothyroidism is the most common thyroid complication of lithium therapy and may be confused with the depressive phase in bipolar patients. Lithium-induced hypothyroidism most commonly occurs in patients with positive thyroid peroxidase (TPO) antibodies. Replacement LT4 is indicated if the hypothyroidism is permanent.

Lithium-induced hyperthyroidism is transient and similar to silent thyroiditis. As lithium is primarily used in the treatment of bipolar disorder, hyperthyroidism should be considered in the differential diagnosis during manic or anxious episodes. The hyperthyroidism is usually self-limited. Only symptomatic treatment with beta blockers may be required, although cases of lithium-associated Graves’ disease have been reported. Thionamides (e.g. methimazole) are not indicated, as the underlying mechanism is not increased thyroid hormone synthesis, but rather the release of thyroid hormones arising from a destructive thyroiditis. Unless an alternative psychiatric medication is available, withdrawal of lithium is not required.

Lithium therapy has also been used as an adjunctive treatment for hyperthyroidism with 131I since it enhances the retention of 131I in the thyroid, a factor which also supports its use in the treatment of thyroid cancer with 131I. Among other endocrine abnormalities, lithium may induce primary hyperparathyroidism and diabetes insipidus by decreasing the action of antidiuretic hormone (ADH) on the kidney tubules; hence, regular monitoring of TSH, calcium, and fluid intake is recommended during lithium use.

Interferons (IFN)

IFN-α, used in the treatment of hepatitis C, can cause both hypothyroidism and hyperthyroidism, with hypothyroidism being far more common. Symptoms of IFN-induced hypothyroidism or hyperthyroidism may be difficult to distinguish from the side-effects of IFN therapy. Regular monitoring of TSH is recommended during IFN use.

The incidence of IFN-induced hypothyroidism is increased with combined ribavirine treatment and in subjects with preexisting thyroid autoantibodies. Furthermore, hepatitis C virus has been directly linked to an increased risk of thyroid dysfunction in the absence of IFN treatment. Hypothyroidism has also been reported with interferon-β treatment for multiple sclerosis, but the thyroid dysfunction is usually subclinical and transient, with LT4 replacement usually not required.

IFN-α-induced hyperthyroidism can occur as typical Graves’ disease (sometimes with ophthalmopathy) or transiently as the hyperthyroid phase of thyroiditis. Both interferon-α or pegylated interferon-α can induce thyroid dysfunction. The incidence is approximately 10-20%. A thyroid nuclear study may be helpful and demonstrates decreased uptake in IFN-induced hyperthyroidism. Monitoring of thyroid function will allow the clinician to assess whether the hyperthyroidism is transient or more permanent.

Tyrosine Kinase Inhibitors (TKIs)

TKIs have been associated with both hypothyroidism and hyperthyroidism. Sunitinib has been shown to be associated with hypothyroidism in 30-50% of patients taking this medication. In some cases, thyroid gland atrophy is seen. There have been some reports of a correlation between cancer response to sunitinib and the occurrence of hypothyroidism. Hypothyroidism has also been reported with sorafenib and imatinib treatments. Similar to other causes of hypothyroidism, LT4 replacement may be indicated. Transient hyperthyroidism associated with a destructive thyroiditis and possible subsequent hypothyroidism (transient or permanent) has been described.


Alemtuzumab, used in the treatment of multiple sclerosis, has been associated with new-onset Graves’ disease that is confirmed with positive serum TSH-receptor antibodies.

Iodine-containing medications and agents

Exogenous iodine administration (from topical disinfectants, radiologic contrast agents, amiodarone, and other sources) can induce hyperthyroidism or hypothyroidism. In certain individuals (including those with Hashimoto’s thyroiditis), hypothyroidism may develop due to a failure to escape from the acute Wolff-Chaikoff phenomenon following an iodine load. In iodine-deficient areas, iodine supplementation (used to prevent endemic goiter) has been associated with an increase in the incidence of hyperthyroidism. This is more likely in susceptible individuals (those with euthyroid nodular goiter, toxic thyroid nodules, or euthyroid Graves’ disease), in which iodine administration may unmask latent hyperthyroidism.

Although screening for thyroid dysfunction before administration of radiologic contrast agents is not routinely recommended, if previous thyroid function tests suggest a borderline low serum TSH, prophylactic treatment with methimazole or 200 mg potassium perchlorate every 8 hours (not available in the U.S., but can be compounded using reagent grade sodium or potassium perchlorate) may help block thyroidal iodine uptake and prevent hyperthyroidism.

What’s the Evidence?/References

Surks, MI, Ross, DS. “Drug interactions with thyroid hormones”. 2011. (An authoritative review.)

Surks, MI, Sievert, R. “Drugs and thyroid function”. N Engl J Med.. vol. 333. 1995. pp. 1688-94. (An authoritative review.)

Barbesino, G. “Drugs affecting thyroid function”. Thyroid. vol. 20. 2010. pp. 763-70. (Excellent review with recent evidence.)

Sarne, D, De Groot, LJ. “Chapter 5a. Effects of the environment, chemicals and drugs on thyroid function”. thyroid disease manager . 2010. (Extensive review with more than 400 references.)

Basaria, S, Cooper, DS. “Amiodarone and the thyroid”. Am J Med. vol. 118. 2005. pp. 706-14. (Excellent concise review.)

Singh, N, Hershman, J. “Interference with the absorption of levothyroxine”. Curr Opin Endocrinol Diabetes. vol. 10. 2003. pp. 347-352. (Review of medications which affect levothyroxine absorption.)

Carella, C, Mazziotti, G, Amato, G, Braverman, LE, Roti, E. “Clinical Review 169. Interferon-α-related thyroid disease: pathophysiological, epidemiological and clinical aspects”. J Clin Endocrinol Metab.. vol. 89. 2004. pp. 3656-61. (Review of potential thyroid dysfunction associated with interferon-α use.)