DRUG-INDUCED HYPOTHYROIDISM

previously normal thyroid function, interruption of the drug promotes recovery within 2-4 months in 60% of the cases. In the remaining 40%, it may persist for 5-8 months more.

In patients with previous thyroid dysfunction, hypothyroidism will persist even after discontinuation of amiodarone, requiring chronic levothyroxine therapy15.

In any of these scenarios, it is not necessary to interrupt amiodarone administration in the presence of hypothyroidism.

The decision about whether to treat amiodarone-induced hypothyroidism or not depends on the degree of dysfunction, the patient’s age and, in particular, on the underlying cardiac condition15, 18. In the presence of mild subclinical hypothyroidism (TSH < 10 uUI/ml), control without treatment may be sufficient. Low-dose levothyroxine (LT4) therapy can be initiated, starting with 25 mcg/day if treatment is required. Serum TSH levels should be assessed after 4-6 weeks, and the LT4 dose increased slowly every 4 or more weeks according to tolerance and cardiovascular controls, maintaining higher TSH levels than in other cases of hypothyroidism13.

At the other end of the amiodarone-induced hypothyroidism spectrum is myxedema coma. This condition is extremely severe and reinforces the concept of regular examinations of thyroid function in patients treated with amiodarone23. Amiodarone may also induce destructive thyroiditis due to direct cytotoxic damage of thyroid follicular cells causing thyrotoxicosis. About 15% of the cases subsequently develop hypothyroidism13.

In summary, monitoring of thyroid function is necessary in every patient that may need amiodarone treatment and should conveniently be performed before the beginning of treatment, requiring subsequent assessments after the first month, the third month, and every six months thereafter13.

3. Lithium

Lithium carbonate (Li2CO3) is an alkali cation of widespread use in neuropsychiatry. It is estimated that around 1 in 200 people receives lithium to treat bipolar disorder24. Lithium is concentrated in the thyroid in a ratio 3-4 times higher than in plasma24. It increases intrathyroidal iodine content, inhibits iodotyrosine coupling and blocks the release of thyroid hormones24. In vitro, it decreases colloid droplet formation within thyroid cells, a reflection of lower colloid pinocytosis from the follicular lumen. The inhibition of thyroid hormone secretion promotes a higher TSH secretion, which results in an increased thyroid volume. Additionally, it might induce signaling alterations in IGF-1, in other tyrosine kinases and in Wnt/beta-catenin signaling, favoring cell proliferation and the resulting goitrogenesis25. Cross-sectional studies have revealed the presence of diffuse goiter in 40-50% of patients treated with lithium within the first 5-10 years26.

The prevalence of lithium-induced hypothyroidism varies between 6 and 52% according to several series, and it is usually subclinical26, though severe hypothyroidism and also myxedema coma has been reported27. Lithium-induced hypothyroidism is more frequent among women and in the first two years of treatment24. In many cases, there is an underlying component of autoimmune thyroiditis26, 28. Treatment of hypothyroidism does not require withdrawal of lithium and is carried out with levothyroxine in usual doses. Before starting treatment with lithium, a thyroid test should be obtained and it should be repeated every 6-12 months24.

4. Minocycline

It is an antibiotic of the tetracycline group used to treat acne vulgaris. Benitz et al. initially described minocycline-induced black thyroid in 196729. Over the following decades, about 125 cases were reported in the literature30. Even though the black pigmentation of the thyroid has been considered pathognomonic of chronic minocycline intake, other tetracyclines such as doxycycline may induce it in just 12-day long treatments31. This pigmentation may also affect other tissues such as skin, sclera, bone, teeth, gingiva and nails32. The insoluble black pigment results from minocycline oxidation by thyroid peroxidase30. Minocycline may also inhibit thyroid function and may have goitrogenic effects33, which might be due to a blocking of the peroxidase activity on the coupling reaction32.

b) Immune mechanisms

The first descriptions associating thyroid dysfunction with interferon-alpha therapy (IFN alpha) date back to 198634. Its use has noticeably increased over the last few years in the treatment of diverse neoplastic and infectious entities such as leukemia, condyloma acuminatum, Kaposi’s sarcoma and, particularly, hepatitis B and C35. IFN-alpha activates a series of intracellular signals including JAK-STAT, CRK, IRS, and MAP-kinase pathways, stimulating transcription of the specific proteins responsible for mediating their antitumor immunomodulating effects34. Thus, the expression of class I proteins from the major histocompatibility complex increases and this may lead to higher exposure of autoantigens promoting thyroid damage. The mechanisms through which IFN-alpha induces thyroid dysfunction are still not clear. The recruitment of immune cells (natural killer cells) capable of damaging the thyroid or even a direct cytotoxic effect has been suggested36. One of the most common side effects of IFN-alpha is thyroiditis, described in 20-40% of cases, of which 5-20% develop thyroid dysfunction34, 37. Such complications may arise at any stage of treatment, even 6 months after discontinuation and are more common in female patients34. Persistent hypothyroidism is frequent after discontinuation of IFN-alpha38. It should be highlighted that both the presence of thyroid autoimmunity prior to treatment as well as an underlying genetic predisposition enhance the risk of developing IFN-alpha-induced autoimmune thyroiditis36, 38.

Considering the frequency of thyroid complications in patients treated with IFN-alpha, it would be advisable to request an antithyroid antibody test before starting treatment. Patients with hepatitis C are more prone to develop autoimmune and non-autoimmune thyroiditis induced by IFN-alpha since there might be a molecular mimicry phenomenon between the virus and thyroid antigens39.

Since the symptoms of hypothyroidism, such as fatigue and weight gain, may be attributed to hepatitis C or to IFN-alpha treatment, its diagnosis is usually delayed34. Treatment of INF-alpha-induced hypothyroidism should be regularly monitored (every 2-3 months) as dysfunction may be progressive requiring adjustments of the replacement dose. If treatment with INF-alpha is interrupted, it is necessary to evaluate the possibility of decreasing or even discontinuing hormone therapy34.

Other cytokines that may induce or exacerbate autoimmune thyroiditis are interferon beta40 and interleukin-241.

c) Drug-induced thyroiditis

Drug-induced thyroiditis can be the result of several mechanisms, the most common being an inflammatory/destructive process induced by drugs. These alterations start with an initial thyrotoxicosis phase due to the massive release of thyroid hormones into the circulation. After this, hypothyroidism is observed, which can be transient if full restoration of the thyroid tissue occurs42, or permanent. In other cases, thyroiditis is caused by the induction of immune mechanisms or by the blocking of the vascular endothelial growth factor receptor (VEGFR), as occurs with tyrosine kinase inhibitors42. The mechanisms of drug-induced thyroiditis may be summarized as follows:

– Cytotoxic

– Immune dysregulation

– Ischemic, by blocking the vascular endothelial growth factor receptor

Table 5 provides a list of the drugs that may induce thyroiditis.

d) Mixed: tyrosine kinase inhibitors

Tyrosine kinase inhibitors may induce hypothyroidism by different or mixed mechanisms over thyroid economy42.

The first description of tyrosine kinase inhibitor-induced hypothyroidism dates back to 2005, in patients with medullary thyroid cancer treated with imatinib43. Other tyrosine kinase inhibitors responsible for inducing hypothyroidism, as seen in several published cases, are sunitinib, sorafenib, cabozantinib, vandetanib, lenvatinib, etc. Although the use of these drugs initially focused on the treatment of gastrointestinal stromal tumors and renal

carcinoma, some of them are currently approved for the treatment of metastatic differentiated thyroid cancer (lenvatinib, sorafenib) and medullary thyroid cancer (vandetanib and cabozantinib). Currently, the incidence of tyrosine kinase inhibitor-induced hypothyroidism is estimated to be present in more than 50% of cases44.

Tyrosine kinase inhibitors promote hypothyroidism through several mechanisms, the most relevant of which are:

– Ischemic thyroiditis due to a marked capillary regression caused by blocking the vascular endothelial growth factor45.

– Higher thyroid hormone metabolism due to hepatic microsomal and DIII induction4.

Further effects of tyrosine kinase inhibitors on the thyroid include: inhibition of iodine organification, inhibition of peroxidase46, blocking of iodine uptake, thyroid autoimmunity47 and alteration of the intestinal absorption and of the enterohepatic reabsorption of levothyroxine42. Around 30-35% of patients treated with tyrosine kinase inhibitors present transient increase of TSH levels which requires no treatment48. Consequently, it is advisable to perform an initial thyroid examination, followed by assessments every 4 weeks during 4 months, and finally every 2-3 months during treatment with tyrosine kinase inhibitors 49.

Mechanisms of secondary/central

drug-induced hypothyroidism

a) Inhibition of TSH synthesis

1. Bexarotene

Bexarotene is a synthetic compound that represents a new subgroup of retinoids that activate retinoid X receptors (RXRs), which can therefore be defined as a rexinoid agent. It is used in the treatment of cutaneous T-cell lymphoma and induces central hypothyroidism due to TSH suppression in 90% of cases50. Bexarotene, like T3 and 9-cis-retinoic acid, produces about 50% in vitro suppression of the gene promoter of TSH beta-subunit. It also stimulates the peripheral metabolism of thyroid hormones by induction of glucuronyl transferases and sulfotransferases51. Thus, patients with bexarotene-induced hypothyroidism usually require higher hormone replacement doses (up to two times higher)52. Hypothyroidism appears a few days after treatment is started and all patients recover thyroid axis function after discontinuation. This effect is not observed with 13-cis-retinoic acid (isotretinoin), which is used for severe acne.

2. Somatostatin analogues

With respect to thyroid axis, somatostatin analogues have demonstrated therapeutic effectiveness in patients with the syndrome of pituitary resistance to thyroid hormones and with thyrotropinomas53. Administration of somatostatin to healthy volunteers decreases both TSH pulse frequency and amplitude54. Colao et al. stated that prolonged use of somatostatin analogues reduces TSH and its response to stimulus with thyrotropin-releasing hormone without affecting serum levels of thyroid hormone55. In a review of somatostatin analogues in acromegaly, an incidence of 2% of central hypothyroidism is described56. However, it is estimated that, although somatostatin analogues suppress TSH through direct action on thyrotropes, these effects are mainly temporary and generally do not promote the appearance of central hypothyroidism57.

3. Glucocorticoids and dopamine

The influence of glucocorticoids on TSH secretion has been long acknowledged58. At physiological levels, hydrocortisone plays an important role in the diurnal variation of TSH, showing lower levels in the morning and higher levels at night54. This explains why TSH levels are high in patients with untreated adrenal insufficiency. Glucocorticoids in high doses suppress TSH in both normal and in hypothyroid subjects. A prolonged administration of glucocorticoids in high doses does not usually cause central hypothyroidism. Recent publications suggest the presence of central hypothyroidism in patients with corticotroph microadenomas produced by the suppression of the hypothalamic-pituitary-thyroid axis induced by an excess of cortisol58.

Dopamine and its agonists, such as bromocriptine, suppress TSH secretion by activating its D2 receptors57. Although the administration of dopamine or its derivatives dobutamine and dopexamine may cause difficulty in the interpretation of TSH serum levels, it does not induce central hypothyroidism. If ultrasensitive methods detecting TSH levels within the range of 0.01 mUI/ml are used, TSH values during treatment with these drugs are usually between 0.08 and 0.4 mUI/ml. These values are clearly different from those commonly observed in hyperthyroidism (TSH lower than 0.01 mUI/ml)59.

b) Immune mechanisms

1. Anti-Cytotoxic T lymphocyte associated antigen 4 (anti-CTLA-4) antibodies

Monoclonal anti-CTLA-4 antibodies are used in the treatment of several neoplasias, such as metastatic renal carcinoma and melanoma among others. The administration of ipilimumab or tremelimumab may induce the development of acute lymphocytic hypophysitis with panhypopituitarism; central hypothyroidism being the most frequent deficiency (90% of cases)60. Hypophysitis is observed in 7-13% of the patients treated with ipilimumab, who present with headache as the most frequent symptom61. It is more common in male patients with an average age of 60 and usually appears after 2 -4 months of treatment, typically after the third cycle60. The differential diagnosis is with metastatic melanoma and other pituitary tumors. A nuclear magnetic resonance can help diagnose hypophysitis by revealing pituitary enlargement with an increased longitudinal diameter, thickening of the stalk, suprasellar convexity and a hyperintense heterogeneous signal62. Ipilimumab-induced hypophysitis is generally characterized by the absence of diabetes insipidus unlike postpartum or gestational autoimmune hypophysitis62. Ipilimumab can also affect the thyroid function (though less commonly) and has been associated with primary adrenal insufficiency as well63.

2. Anti-Programmed cell death-1 receptor (anti-PD-1) antibodies

Hypophysitis induced by anti-PD-1 such as pembrolizumab and nivolumab is far more unusual, with few cases described64. On the other hand, the incidence of thyroid disorders induced by anti-PD-1 particularly silent thyroiditis is more common and occurs in 5-10% of patients64.

Interactions in the treatment of

hypothyroidism

Some drugs may reduce the intestinal absorption of levothyroxine by altering its transport and/or metabolism.

Drugs that decrease levothyroxine absorption

The gastrointestinal tract is of great importance in thyroid physiology, since conjugated iodothyronines are excreted in bile and are partially unconjugated in the intestine by bacterial enzymes, liberating a small amount of free hormones which are absorbed into portal circulation65. Less than 10% of the daily production of thyroid hormones is excreted in feces. Approximately 62-82% of orally administered levothyroxine is absorbed within the first three hours after intake, mainly in the jejunum and the ileum66. This absorption is higher when the drug is administered on an empty stomach, which shows the importance of gastric acidity in this process67. In hypothyroid patients receiving levothyroxine treatment, a wide range of drugs and dietary substances alter its absorption, preventing an adequate metabolic control68.

Colestyramine, colestipol and colesevelam are bile acid binding resins used in hyperlipidemia which significantly inhibit absorption of thyroid hormones69. Because of its potent action, colestyramine is used in the treatment of exogenous hyperthyroidism and it is sometimes recommended, combined with methimazole, for a faster control of hyperthyroidism in Graves’ disease70. Other drugs that can alter intestinal absorption of levothyroxine are sucralfate71, aluminum hydroxide72, proton-pump inhibitors73, iron salts74, calcium carbonate75, and laxatives and antacids containing magnesium76.

A reduced absorption of levothyroxine has been described when administered concomitantly with sodium sulfate polyestyrene (an ion-exchange resin used in hyperkalemia), sevelamer and lanthanum carbonate (phosphate binders), chromium77, raloxifene78, orlistat66 and tyrosine kinase inhibitors42.

The interaction of some dietary substances with thyroid hormone has become increasingly relevant due to the high consumption of bran and fiber for breakfast. Bran significantly inhibits intestinal absorption of levothyroxine79, which makes it convenient to separate bran intake from hormone intake by a few hours. Soy-containing nutritional preparations also affect intestinal absorption of thyroid hormones80. A reduced absorption of levothyroxine has been described when consumed concomitantly with herbal remedies81, prunes81 and espresso coffee82.

In all the above cases, interactions can be avoided if the administration of the hormone is separated from the intake of the above-mentioned drugs and foods by 4-6 hours66. Finally, it is worth pointing out that vitamin C may increase absorption of levothyroxine, therefore, in special cases such as gastritis, the concomitant intake of both may be convenient83.

Drugs that alter levothyroxine transport and metabolism

More than 99% of thyroid hormones circulate bound to transport proteins: thyroxine-binding globulin, transthyretin (originally called ‘thyroxine-binding prealbumin’) and albumin84. Thyroxine-binding globulin transports about 70–75% of circulating T4 and the rest is bound to transthyretin and/or albumin, while the circulating free form is lower than 0.001%85. Thus, thyroxine-binding globulin constitutes the main transport protein and the one most frequently affected by drugs86, being able to modify total serum concentrations of thyroid hormones without compromising the patient’s euthyroid state, since the free fractions are not modified85.

Estrogens increase hepatic synthesis of thyroxine-binding globulin as well as its glycosylation, delaying its clearance and increasing its serum concentration86. This increase is dose-dependent and total T4 levels rise by 20-35%84. On occasion, it could be necessary to increase the thyroid replacement dose in hypothyroid postmenopausal women undergoing estrogen therapy87. The same can be observed about the administration of oral contraceptives. These changes are usually seen within the first six weeks after starting estrogen therapy and the maximum effect is reached by week 1287. Evaluating the thyroid function 6-8 weeks after the start of oral estrogen therapy is recommended in order to adjust the levothyroxine dose. These changes are not observed in the case of transdermal estrogen therapy, due to the absence of the first hepatic stage. In short, in hypothyroid women who might require estrogen replacement therapy, transdermal delivery would be more advisable.

The interruption of estrogen therapy or the drop in estrogen levels during menopause produces the opposite effect in hypothyroid women receiving levothyroxine, thus requiring a decrease in the dose of thyroid hormone85. In hypothyroid patients who become pregnant, estrogens induce a higher levothyroxine requirement of about 40-50% above the pre-pregnancy replacement dose88. Due to their estrogenic agonist effect at hepatic level, tamoxifen and other selective estrogen receptor modulators modify the thyroid profile of hypothyroid women who may therefore, also require an adjustment of the levothyroxine dosage89.

A wide variety of drugs affect thyroid hormones metabolism, especially through intrahepatic deiodination, increased activity of CYP3A4, and conjugation with sulfate and glucoronic acid (enzyme induction). The main drugs involved are phenobarbital, carbamazepine, rifampicin and phenytoin90-92. In healthy subjects, the hypothalamic-pituitary-thyroid axis compensates for this situation increasing the production and secretion of thyroid hormones, and T4, T3 and TSH remain normal. In hypothyroid patients, this compensatory mechanism fails and it may be necessary to increase levothyroxine replacement doses.

In conclusion, the aim of this review is to draw attention to some major aspects of clinical practice that may go unnoticed. For example, when drugs such as amiodarone, lithium or immunomodulators are to be prescribed, the thyroid function should be previously assessed and regularly monitored thereafter.

It is also necessary to bear in mind that the intake of levothyroxine should be separated from that of drugs or foods that may impair its absorption. Similarly, those drugs that interfere with the transport and metabolism of the exogenous hormone should be taken into account and the corresponding dose adjustments should be made in hypothyroid patients.

Further consideration should be given to those drugs that alter thyroid function tests leading to false diagnoses and unnecessary therapies.

Finally, the new biological immunomodulating and antineoplastic therapies enlarge the battery of drugs which substantially interact with thyroid function and endocrine activity in general.

Acknowledgements: The authors wish to express their gratitude to Professor Leonard Wartofsky, MD, MACP, Georgetown University School of Medicine, Department of Medicine, Washington Hospital Center, for the revision of this article.

Conflict of interests: Leonardo F. L. Rizzo, is Medical Director of Química Montpellier S.A. Daniela Mana and Hector Serra, are Medical Consultants for Química Montpellier S.A.