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Drugs and Other Substances Interfering with Thyroid Function

  • Lucia MontanelliEmail author
  • Salvatore Benvenga
  • Laszlo Hegedüs
  • Paolo Vitti
  • Francesco Latrofa
  • Leonidas H. Duntas
Reference work entry
Part of the Endocrinology book series (ENDOCR)

Abstract

Several drugs and supplements may interfere, at different levels, with regulation of thyroid function. Some drugs may also cause thyroid autoimmunity. This chapter reviews drugs that significantly affect thyroid function. Glucocorticoids, dopamine agonists, somatostatin analogs, and retinoids inhibit TSH secretion. Lithium, tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), antiepileptics, rifampin, metformin, and amiodarone mainly affect directly thyroid function. Interferon-α and antiretroviral drugs may have several effects, including inducing thyroid autoimmunity. The heterogeneous adverse effects induced by antineoplastic agents (cytotoxic and novel anticancer agents, tyrosine kinase inhibitors, bexarotene- and iodine-based cancer therapies, and radioimmunotherapies) will be highlighted. Immunoregulatory drugs (IL-2, denileukin diftitox, thalidomide and lenalidomide, IFN-α, alemtuzumab) and immune checkpoint inhibitors (anti-CTLA4 and anti-PD-1 monoclonal antibodies) mainly promote thyroid autoimmunity. The effects of endocrine disruptors and nutraceuticals and over-the-counter products (selenium, L-carnitine, thyroid hormones, iodine, and biotin) will also be discussed. The last part of the chapter concerns drugs that interfere with levothyroxine (LT4) absorption.

Keywords

Alemtuzumab Amiodarone Anti-CTLA4 monoclonal antibodies Anti-PD-1 monoclonal antibodies Bexarotene Cytotoxic agents Denileukin diftitox Dopamine Endocrine disruptors Glucocorticoids IFN-α IL-2 Immune checkpoint inhibitors Inositol Interferons L-carnitine Lenalidomide Levothyroxine sodium Lithium Metformin Nutraceuticals Rexinoids Rifampin Selective serotonin reuptake inhibitors Selenium Somatostatin Thalidomide Tricyclic antidepressants Tyrosine kinase inhibitors 

Drugs that Interfere with Hypothalamic-Pituitary-Thyroid Regulation

Glucocorticoids

Corticosteroids are involved in the regulation of diurnal variation of TSH secretion, and high levels of glucocorticoids inhibit TSH secretion (Haugen 2009). The decrease of TSH secretion is due to TRH inhibition in the paraventricular nucleus of the hypothalamus. A single low dose (0.5 mg) of dexamethasone is sufficient to alter TSH levels, while long-term high-dose glucocorticoids (30 mg prednisone/day for 1 week) or endogenous hypercortisolism (Cushing’s syndrome) does not result in central hypothyroidism (Brabant et al. 1989; Haugen 2009). Large doses of glucocorticoids, for example, 4 mg of dexamethasone per day, cause a 30 percent decrease in serum T3 concentrations within several days due to inhibition of type 1 deiodinase (Surks and Sievert 1995) (Table 1) (Fig. 1A, C).
Table 1

Drugs and other substances interfering with thyroid function

1. Drugs interfering with hypothalamic-pituitary-thyroid function

 (a) Glucocorticoids

 (b) Dopamine, dopamine agonists and dopamine antagonists

 (c) Somatostatin and somatostatinanalogues

 (d) Retinoids

2. Drugs interfering with thyroid function

 (a) Lithium

 (b) Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs)

 (c) Antiepileptics

 (d) Rifampin

 (e) Metformin

 (f) Amiodarone

3. Interferon and other anti-viral drugs

 (a) Interferon-α

 (b) Highly active antiretroviral therapy (HAART)

4. Antineoplastic agents

 (a) Cytotoxic and novel anticancer agents

 (b) Tyrosine kinase inhibitors

 (c) Bexarotene

 (d) Iodine-based cancer therapies and radioimmunotherapies

5. Immunoregulatory drugs

 (a) IL-2

 (b) Denileukindiftitox

 (c) Thalidomide and lenalidomide

 (d) IFN-α

 (e) Alemtuzumab

 (e) Immune checkpoint inhibitors

  I Anti-CTLA4 monoclonal antibodies

  II Anti-PD-1 monoclonal antibodies

6. Other substances interfering with thyroid function

 (a) Endocrine disruptors

 (b) Nutraceuticals and over-the-counter products.

  (1) Selenium and inositol

  (2) L-carnitine

  (3) Thyroid hormones and iodine

  (4) Biotin

7. Comorbidities and drugs interfering with L-thyroxine absorption (Table 6)

Fig. 1

(A, B, C, D, Ea, Eb) Drugs and conditions that affect thyroid hormone function or affect the intestinal absorption or orally taken thyroid hormone

Dopamine, Dopamine Agonists, and Dopamine Antagonists

Dopamine is a major regulator of the HPT axis. This is achieved by activating D2 receptors, thereby slightly stimulating hypothalamic TRH secretion and potently inhibiting TSH secretion (Haugen 2009). Dopamine administered intravenously at doses of ≥1 μg/kg/min and dopamine agonists administered orally, such as bromocriptine and L-dopa, inhibit TSH secretion. Conversely, the dopamine antagonist metoclopramide increases TSH secretion (Sarne 2016). However, prolonged treatment with bromocriptine does not induce central hypothyroidism (Haugen 2009) (Fig. 1A, B).

Somatostatin

Somatostatinergic pathways are involved in the regulation of pituitary function. Administration of somatostatin decreases both pulse amplitude and pulse frequency of TSH secretion by exerting a direct inhibition on TSH secretion and blunting TRH-stimulated TSH levels in healthy volunteers (Haugen 2009). Somatostatin and long-acting analogs bind to five different extracellular receptors in the pituitary and, via adenylate cyclase signaling, inhibit hormone secretion (Haugen 2009), though not sustainedly. Depending on dose, somatostatin and its analogs may induce a transient subclinical central hypothyroidism (Fig. 1A).

Retinoids

Rexinoids are a group of derivatives of vitamin A (retinol) that regulate complex gene networks involved in vision and in cell differentiation, proliferation, and apoptosis (Haugen 2009). The retinoid X receptor (RXR) is a member of the nuclear receptor superfamily, which forms heterodimers with other nuclear receptors, such as peroxisome proliferator-activated receptor (PPAR), liver X receptor, and farnesoid X receptor (Lefebvre et al. 2010). Rexinoids are selective agonists of nuclear hormone receptors that enable the formation of the heterodimers to regulate gene expression and inhibit proliferation (Wagner et al. 2017). In normal rats, vitamin A deficiency induces central hyperthyroidism by increasing TSHβ mRNA in the pituitary and consequently increasing serum T4 and T3 levels; treatment with retinoic acid normalizes TSHβ mRNA levels (Graeppi-Dulac et al. 2014). Accordingly, retinoids can induce central hypothyroidism by suppressing TSH at the pituitary or the hypothalamic level. Thyroid effects of bexarotene are reported in the section on Antineoplastic Agents (Fig. 1A).

Drugs that Interfere with Thyroid Function

Lithium

Lithium is an effective treatment for bipolar disorder, but long-term lithium treatment has been associated with hypothyroidism (approximately 20%) and goiter (approximately 40%) (Fig. 1C).

In rats lithium decreases the release of thyroid iodine without affecting its uptake, resulting in an increase of intrathyroidal iodine (Berens et al. 1970). It also inhibits thyroid hormone release in both euthyroid and hyperthyroid patients (Spaulding et al. 1972). However, T4 levels do not change as an effect of the prolonged half-life of T4 due to the adaptive reduction of type 1 5′ deiodinase activity (Berens et al. 1970).

Goiter is the most common thyroidal side effect of lithium therapy, with a highly variable incidence (0–60%), depending on gender, geographical area, methods for diagnosing goiter, and duration of therapy (Fig. 2) (Perrild et al. 1984; Lazarus (2009). Goiter is probably due to the inhibition of thyroid hormone secretion rate and the consequent rise in TSH levels and a likely direct proliferative effect. There is no evidence that thyroid enlargement is associated with an increased incidence of thyroid nodules (Bocchetta and Loviselli 2006). A small study reported that LT4 treatment for hypothyroidism or goiter can prevent further lithium-induced enlargement of the goiter (Bauer et al. 2007).
Fig. 2

Thyroid volume (median and range) before, during (day 14 and 28) and after (day 56) treatment with lithium carbonate in 8 males and 8 females. *P<0.01 denotes significant difference between day 0 and 28 (paired t-test) (From Perrild et al. 1984)

The incidence of lithium-induced hypothyroidism is variable, depending on the population under evaluation, gender, and the methods for detection. In one study, the annual rate of developing hypothyroidism during lithium therapy was 1.5%, with 6.4% in thyroid antibody-positive and 0.8% in thyroid antibody-negative individuals (Bocchetta et al. 2007), although lithium treatment has not been associated with an increase in thyroid autoimmunity (Lazarus et al. 1986). Lithium-induced hypothyroidism requires prompt treatment with LT4, taking into account that hypothyroidism can worsen symptoms of depression, but does not require withdrawal of the drug.

Thyrotoxicosis is less commonly observed during treatment with lithium. Although some cases of autoimmune hyperthyroidism have been reported, thyrotoxicosis due to destructive thyroiditis is more common. Such cases are self-limiting and the symptoms can be treated with β-blockers. As a consequence of its action on thyroid hormone release, lithium has been used in the treatment of primary hyperthyroidism, although with less efficacy than that of thionamide therapy (Lazarus 2009). Lithium has been shown, by some authors, to increase the efficacy of 131I treatment for hyperthyroidism and to reduce the increase in thyroid hormone concentrations occurring after treatment (Bogazzi et al. 1999, 2002), but others have failed to demonstrate this effect (Bal et al. 2002). Lithium alters thyroglobulin structure, inhibits iodotyrosine coupling, and inhibits thyroid hormone secretion (Lazarus 2009). In a retrospective cross-sectional study, conducted to determine the risk factors associated with development of thyroid disease in patients receiving lithium, women younger than 60 years were at greatest risk (Kirov et al. 2005). Indeed, women were more prone than men to develop overt or subclinical hypothyroidism (25.8% vs. 8.7%), with prevalence among females exceeding 50% by the age of 65 years (Lazarus 2009). If overt hypothyroidism appears, LT4 therapy should be started, but lithium therapy may be continued (Shine et al. 2015).

Tricyclic and Selective Serotonin Reuptake Inhibitors (SSRIs)

Tricyclic antidepressants may variably interfere with the hypothalamic-pituitary-thyroid axis. The classical antipsychotics, phenothiazines, may alter iodine uptake, though it is unknown whether they can inhibit the sodium/iodide symporter (NIS). Tricyclic antidepressants can decrease TSH response to TRH via the noradrenergic or serotonergic systems (Sauvage et al. 1998). In addition, tricyclic antidepressants may promote autoimmunity, and favor appearance of thyroid autoantibodies, by enhancing the expression of major histocompatibility complex antigens (Sauvage et al. 1998). In a randomized controlled study, fluoxetine or sertraline induced a significant reduction of both serum T3 and T4 levels, albeit within their normal ranges and only in patients without preexisting thyroid disease (de Carvalho et al. 2009). On the other hand, in an open-label study of 62 patients with major depression, running over a period of 11 weeks, and treated with reboxetine, sertraline, or venlafaxine, the reboxetine group showed a significant reduction in serum TSH and increase in T4 (Eker et al. 2008), whereas the sertraline group had increased serum TSH and decreased T4 levels. Moreover, in the sertraline group, baseline TSH levels correlated with response to treatment. These observations support the safety of treatment with SSRIs, as they induce only minor changes in thyroid hormone economy. The different mechanisms of action of the various antidepressants might explain the variability of their actions on the HPT (Fig. 1A, C).

Antiepileptics

Antiepileptic drugs (AEDs) are a heterogeneous group of compounds, widely used in children and adults (Yılmaz et al. 2014). Their use has been associated with various adverse effects, some of which concern the thyroid (Verrotti et al. 2008). Alterations in thyroid hormone serum levels and occurrence of subclinical hypothyroidism have been reported particularly for phenytoin, valproate, and carbamazepine (Verrotti et al. 2008). Recent data from both cross-sectional and prospective studies have documented subclinical hypothyroidism and reduced T4, T3, FT4, FT3, and thyroid-binding globulin (TBG) concentrations with phenobarbital, phenytoin, carbamazepine, valproic acid, and oxcarbazepine, but not with the more recently developed lamotrigine, levetiracetam, tiagabine, and vigabatrin (Hamed 2015). Of note, carbamazepine, oxcarbemazepine, and valproic acid increase metabolism of thyroid hormones through the hepatic P450 system but may also influence the pituitary feedback and thereby induce central hypothyroidism (Hamed 2015). Carbamazepine and phenytoin have been also associated with an increased frequency of goiter. The increased hepatic degradation of thyroid hormones could in part be the explanation for the goitrogenic effect, as a compensatory mechanism (Hegedüs et al. 1985) (Fig. 1C).

Rifampin

Rifampin, a rifamycin antibiotic possessing germicide and bacteriostatic properties, induced hypothyroidism in three out of 25 Hashimoto’s thyroiditis patients and in none of 42 patients with no autoimmune thyroid disease. When rifampin was discontinued, the hypothyroidism resolved (Takasu et al. 2006). Rifampin enhances T4 clearance, via increased hepatic T4 metabolism along with biliary excretion of iodothyronine conjugates. Meanwhile, studies in healthy individuals have suggested that rifampin appears to diminish circulating thyroid hormone levels without changing TSH levels while inducing hypothyroidism in Hashimoto’s thyroiditis (Takasu et al. 2005). After administering rifampin, an increased LT4 dose was required for 50% of patients in the TSH suppression group for thyroid cancer and 26% of patients in the replacement group for hypothyroidism (Kim et al. 2017). Treatment with rifampin can also induce a rapid increase of thyroid size (Christensen et al. 1989) (Fig. 1C).

Metformin

Metformin is widely used in the treatment of type 2 diabetes mellitus and insulin resistance. Recently, it was reported that treatment with metformin suppresses TSH in patients with hypothyroidism, subclinical hypothyroidism, and diabetes but not in normal individuals (Cappelli et al. 2014; Lupoli et al. 2014). TSH suppression is not accompanied by altered T4 or T3 levels. In a study evaluating thyroxine absorption, when L-T4 was concomitantly ingested with metformin, L-T4 absorption remained unchanged, suggesting that other mechanisms may be involved in the TSH suppression (Al-Alusi et al. 2015). Treatment with metformin in euthyroid patients with type 2 diabetes did not induce goiter (Díez and Iglesias 2014) (Fig. 1C).

Amiodarone

Amiodarone is an iodine-rich drug used for the treatment of tachyarrhythmias and other cardiac conditions. Since its structure resembles that of thyroid hormones, it may interact with thyroid hormone receptors, inducing some antagonist effects. Its half-life is 40–60 days (Holt et al. 1983). After deiodination a daily dose of 300 mg of amiodarone provides 11 mg of inorganic iodine, which is 30–100 times the required daily dose (Rao et al. 1986). In addition, amiodarone inhibits the activity of type 1 deiodinase, inducing low T3 levels, high T4 levels, and high reverse T3 levels (Amico et al. 1984). TSH levels usually increase during the early months of treatment (Martino et al. 2001). Clinically significant thyroid dysfunction (thyrotoxicosis and hypothyroidism) occurs in a minority of patients treated with amiodarone. Amiodarone-induced thyrotoxicosis (AIT) and amiodarone-induced hypothyroidism (AIH) can develop in normal thyroids or in glands with preexisting disease, with a prevalence of 2–10% and 5–22%, respectively (Martino et al. 2001) (Fig. 1C, D). AIT has been reported to be more frequent in iodine-deficient areas, while AIH is more common in iodine-sufficient areas (Martino et al. 2001). AIT can develop from a few weeks until many years after treatment and even many months after its withdrawal (Martino et al. 1987a). Two forms of AIT have been described: type 1 AIT ensues in preexisting thyroid disease (pretoxic multinodular goiter or Graves’ disease) and type 2 AIT develops in apparently normal thyroid glands (Table 2). The possible mechanism underlying type 1 AIT is the excess synthesis of thyroid hormone induced by the iodine load. This is supported by the finding of low to normal iodine uptake, pointing toward failure of the thyroid gland to adapt normally to the iodine load. Conversely, in type 2 AIT, iodine uptake is very low, indicating the presence of thyroid destruction. Diagnosing the type of AIT may be cumbersome and mixed forms are common (Martino et al. 2001). Flow by color Doppler sonography is a useful tool in differentiating the two forms of AIT, vascularity being increased in type 1 and absent in type 2 (Bogazzi et al. 1997). The main therapy of type 1 AIT consists of large doses of thionamides and perchlorate, while in type 2 AIT, glucocorticoids are effective. Mixed forms require the combination of the three drugs. In patients resistant to medical therapy, thyroidectomy is indicated, while radioiodine therapy is only effective when uptake is adequate. Withdrawal of amiodarone is usually recommended but is not mandatory (Barbesino 2010; Eskes and Wiersinga 2009). AIH is more common in females and in subjects with thyroid autoimmunity. Patients with elevated TPOAb levels have a 7.3 times increased risk of developing autoimmune thyroid disease as compared to individuals without these antibodies (Trip et al. 1991). The inability of patients with Hashimoto’s thyroiditis to escape from the Wolff-Chaikoff effect (i.e., the inability to restore the normal thyroid hormone production during an iodine load) is the likely cause of AIH. Withdrawal of amiodarone is followed by restoration of euthyroidism, with the exception of patients with thyroid antibodies in whom it could be permanent (Martino et al. 1987b). AIH can easily be treated with LT4 replacement when the discontinuation of amiodarone is not feasible because of the underlying cardiac disease (Martino et al. 2001). Patients can be treated with perchlorate to accelerate resolution of AIH (Bogazzi et al. 2008).
Table 2

Clinical and pathogenetic features of the two main forms of AIT

 

Type 1 AIT

Type 2 AIT

Preexisting thyroid disease

Yes

No

 

(latent Graves’ disease, single or multinodulargoiter)

 

FT4/FT3 ratio

Often> 4

<4

Spontaneous remission

No

Possible

Thyroid CFDS

Increased vascularity

Absent vascularity

Thyroidal RAIU

Low-to-normal uptake

Low-to-absent uptake

Thyroid autoantibodies

Sometimes present

Usually absent

Abbreviations: CFDS color flow Doppler Sonography, RAIU radioactive iodine uptake

Modified from Bogazzi et al. (2014)

Interferon and Other Antiviral Drugs

Interferon-α

Interferons (IFN) are a family (α, β, γ) of small molecules that are produced by cells in response to viral infections and other synthetic and biological inducers. They reduce tumor growth and modulate immune response and are employed in the treatment of viral, autoimmune, and neoplastic diseases. For a long period, the mainstay in the treatment of hepatitis C (HCV) has been the combination of IFN-α (in the form or recombinant IFN-α1 or long-acting pegylated IFN-α) with ribavirin (RBV), a synthetic analog of guanoside. HCV affects nearly 3% of the global population, leads to chronic disease in more than 60% of the affected subjects, and results in cirrhosis in 16% of patients after 20 years (Nair Kesavachandran et al. 2013). In the early studies, treatment with IFN-α and RBV was associated with thyroid diseases in the form of positive thyroid autoantibodies, autoimmune hypothyroidism, destructive thyroiditis, and Graves’ disease (Prummel and Laurberg 2003). The frequency of thyroid dysfunction and thyroid autoantibodies following IFN-α therapy varies considerably in available reports. Reasons include heterogeneity in the definition of thyroid disorders and differences in the control populations (Nair Kesavachandran et al. 2013). Several aspects of the correlation between IFN-α plus RBV treatment for HCV and thyroid side effects have been discussed for some time, and many remain unsettled. The first point is whether HCV infection per se increases the incidence of thyroid diseases. While some epidemiological studies report a higher incidence of thyroid dysfunction in untreated HCV patients, as compared to the normal population or patients with hepatitis B, others do not (Antonelli et al. 2004; Huang et al. 1999; Ganne-Carrie et al. 2000; Loviselli et al. 1999; Fontaine et al. 2001). Several mechanisms have been proposed to explain the induction of thyroid autoimmunity in HCV infection: (i) a generalized autoimmunity induced by the infection with increased production of endogenous IFN-γ and consequent expression of HLA-DR antigens on thyrocytes, (ii) the infection of thyrocytes by HCV with production of IFN-γ and expression of HLA-DR antigens, and (iii) the binding of HCV E2 proteins to CD81 molecules on thyroid cells, followed by activation of interleukin-8 (Menconi et al. 2011).

As for the effect of treatment of HCV on thyroid dysfunction, monotherapy with IFN-α has been shown to induce thyroid autoantibodies in 20.6% and thyroid dysfunction in 2.7% of patients, while the combined treatment (IFN-α plus RBV) caused development of thyroid autoantibodies in 5.0% and thyroid dysfunction in 12.8% of patients (Nair Kesavachandran et al. 2013). Fifty percent of patients, with positive TPOAb before treatment, developed thyroid dysfunction in comparison with 5.4% of autoantibody-negative patients (Koh et al. 1997). Other predisposing factors for thyroid dysfunction are gender (female to male ratio, 4.4:1) ethnicity (the importance of Asian origin is debated), and genetic background (HLA-A2 and DRB1*11 alleles are associated with IFN-α-induced thyroid dysfunction). IFN-α interacts with specific cell surface receptors and activates several signaling pathways that lead to the expression of adhesion molecule and cytokine genes, such as IL-6, that are associated with autoimmune thyroiditis and upregulate the expression of MHC class I proteins, which again lead to the activation of cytotoxic T-cells. In addition, IFN-α induces the switching of the immune response to the Th1 pattern and the activation of several cells, including lymphocytes, macrophages, and dendritic cells. In conclusion, IFN-α triggers an autoimmune response in genetically predisposed individuals. In addition, direct effects of IFN-α on thyrocytes, with an initial increase in the levels of TSH, TPO, Tg, and sodium/iodide symporter, and subsequently apoptosis have been reported (Menconi et al. 2011).

The most common abnormality is the induction of thyroid autoantibodies in the absence of thyroid dysfunction, which occurs in about 10–40% of subjects. Thyroid autoantibodies remain positive after the end of treatment in the majority of patients and can be associated with subsequent development of autoimmune hypothyroidism (Fig. 1C). Subclinical or overt hypothyroidism is seen in 2.4–19.0% of patients (Carella et al. 2004). Hypothyroidism can be the expression of an autoimmune disease or a destructive process. In the latter case, it is usually preceded by a transient (and sometimes overlooked) phase of thyrotoxicosis and is not associated with the development of thyroid autoantibodies (Fig. 1D). Thyrotoxicosis is usually a destructive process, presents with a mild or subclinical course, and is transient, lasting just a few weeks or months. With rare exceptions, Graves’ disease is reported to be an uncommon phenotype in IFN-α-induced thyrotoxicosis (Menconi et al. 2011).

Because of the high frequency of thyroid disorders, clinical examination, detection of TPOAb and TgAb, and measurement of serum TSH are recommended. Clinical disorders can occur after a few or many months of treatment. Hypothyroidism can easily be corrected with levothyroxine treatment and does not require IFN-α withdrawal. After discontinuation of IFN-α, hypothyroidism may remit or persist. The latter occurs particularly in patients who initially had positive thyroid autoantibodies. Destructive thyroiditis occurs in 5% of patients treated with IFN-α and can lead to permanent hypothyroidism. Low radioactive iodine uptake (RAIU) and negative TSH-R autoantibodies (TRAb) are its characteristic features. This thyroiditis can be treated with beta-blockers, while corticosteroids are contraindicated in HCV. Graves’ hyperthyroidism is characterized by positive TRAb and high RAIU and can be treated with antithyroid drugs and, when severe, with radioiodine or thyroidectomy (Smith and Hegedüs 2016). Serum TSH should be measured every 2–3 months during IFN-α treatment and 6 months after its discontinuation. Patients with positive thyroid autoantibodies are prone to develop permanent thyroid dysfunction (Carella et al. 2004; Menconi et al. 2011).

The recently introduced direct-acting antiviral drugs have significantly changed the treatment of HCV infection. They have replaced regimens based on IFN-α, while RBV is still employed in selected patients (D’Ambrosio et al. 2017).

Highly Active Antiretroviral Therapy (HAART)

Autoimmune phenomena, including AITD, after immune recovery due to HAART have been reported. Patients infected with HIV have a higher prevalence of thyroid dysfunction when compared with the general population, with euthyroid sick syndrome, Graves’ disease, and subclinical hypothyroidism being the most common (Abelleira et al. 2014) (Fig. 1C, D). Several studies have suggested an association between hypothyroidism and treatment with nucleoside reverse transcriptase inhibitors, particularly stavudine and non-nucleoside reverse transcriptase inhibitors such as efavirenz (Abelleira et al. 2014). Vos et al. described three patients who developed Graves’ disease after starting HAART. They also refer to 13 patients reported in the literature (Vos et al. 2006). In a Brazilian study of 153 ambulatory HIV-infected women (Carvalho et al. 2013), the frequency of thyroid disorders was 7.8% (12/153 patients), and all were on HAART at the time of diagnosis, yielding a prevalence of 9.3% in patients receiving HAART compared with 0% in patients not on HAART. AITD, hyperthyroidism, and hypothyroidism were detected in 4.6%, 3.1%, and 4.1% of HAART patients, compared to none in untreated patients.

Antineoplastic Agents

Cytotoxic and Novel Anticancer Agents

Traditional cytotoxic agents rarely induce thyroid abnormalities but can sensitize the thyroid to the effects of radiation therapy, thereby increasing the risk of hypothyroidism. However, few studies have evaluated, prospectively, thyroid function in adult patients receiving cytotoxic agents. Mitotane, an agent used against adrenocortical cancer, induces a reduction in serum FT4 but not in FT3 and TSH levels (Daffara et al. 2008).

Thyroid abnormalities are more commonly observed in patients treated with novel antineoplastic agents, namely, targeted therapies and immunotherapies. Data from such studies are often discordant because of heterogeneity in the definition of thyroid abnormalities and whether clinical and subclinical abnormalities or only clinical dysfunction is included. Some publications suggest that patients experiencing thyroid dysfunction have an increased likelihood of response to therapy (Hamnvik et al. 2011) (Table 3).
Table 3

Antineoplastic agents interfering with thyroid function

Drug

Effect

Mechanism of action

Cytotoxic and novel anticancer agents

All

Hypothyroidism

Sensitization to radiotherapy

Mitotane

↓ FT4

Tyrosine kinase inhibitors

Thyrotoxicosis

Destructive thyroiditis

Hypothyroidism

Inhibition of VEGF receptor

 

Impaired iodine uptake

↑ LT4 requirement

Modification in LT4 metabolism

Interference with TSH clearance,

Hypothalamic pituitary loopand

 

Thyroid hormone metabolism

Inhibition of MCT8

Bexarotene

Central hypothyroidism

Selective agonist of RXR

Iodine based cancer therapies and radioimmunotherapies

Hypothyroidism

Destructive thyroiditis

Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) are employed for the treatment of several tumors, including renal cell carcinomas, gastrointestinal stromal tumors, medullary and differentiated follicular thyroid tumors, pancreatic endocrine tumors, and non-small cell lung cancers. TKIs are small molecules that directly block the ATP-binding site of tyrosine kinase and thereby interfere with cell proliferation, angiogenesis, and the potential to metastasize.

These molecules may induce transient thyrotoxicosis and primary hypothyroidism in patients with normal thyroid function and may increase the required dose in hypothyroid patients on LT4 therapy (Fig. 1C, D). While thyroid destruction has been involved in thyrotoxicosis (Grossmann et al. 2008), several mechanisms have been proposed for the onset of hypothyroidism in euthyroid subjects starting on TKIs. One possible mechanism is capillary dysfunction due to inhibition of VEGF receptors (Makita and Iiri 2013). Indeed, the thyroid gland has the highest blood flow rates per weight unit of any tissue in man (Wang et al. 1998). This mechanism is relevant for TKI inhibitors such as sunitinib, which specifically target VEGF receptors. In addition, capillary dysfunction may directly lead to thyroid destruction (Makita and Iiri 2013). An impaired iodine uptake has been reported to play a role in sunitinib-induced hypothyroidism in vivo but not in vitro (Mannavola et al. 2007; Salem et al. 2008). The role of autoimmunity in inducing hypothyroidism has been excluded by some authors (Mannavola et al. 2007), while the appearance of TPOAb following a longer period of treatment was recently reported (Pani et al. 2015).

Many evidences suggest that TKIs may interfere with metabolism of thyroid hormones and their feedback. The fact that TKI treatment increases LT4 requirement in athyreotic patients can be related to a modification in LT4 metabolism or to the interference with TSH clearance (Verloop et al. 2013) or the hypothalamic-pituitary loop (Makita and Iiri 2013). In addition, TKIs inhibit, non-competitively, thyroid hormone membrane transport by MCT8 (Braun et al. 2012). Influence of TKIs on thyroid hormone metabolism is suggested by data in humans (increased serum TSH) and rats (decreased serum T3 and T4 and increased activity of hepatic type 3 deiodinase) (Kappers et al. 2011).

Hypothyroidism is commonly observed during treatment with sorafenib, sunitinib, and imatinib, but less frequently with vandetanib, axitinib, and cabozantinib. In clinical trials with sunitinib, the incidence of thyroid dysfunction ranges between 7% and 85%, and about 90% of patients start on LT4 treatment. Serum TSH levels rise during the on-periods and decrease during the off-periods (Illouz et al. 2014).

Before starting TKI treatment, evaluation of thyroid function and thyroid morphology by ultrasound is recommended. Careful monitoring of thyroid function is advised 4–6 weeks after starting treatment and – in the absence of thyroid dysfunction – approximately every three drug cycles hereafter (Illouz et al. 2014). During treatment with sunitinib, it has been proposed to postpone levothyroxine therapy until a rise in TSH levels during the treatment with TKI is confirmed at the end of an off-phase. This approach aims at avoiding thyrotoxicosis (Wolter et al. 2008; Illouz et al. 2014).

Bexarotene

Bexarotene is the only rexinoid currently approved for clinical use, primarily as second-line treatment for early- and late-stage refractory cutaneous T-cell lymphomas (Willemze et al. 2005). Because of its action as selective agonist of the RXR, it induces central hypothyroidism (low levels of serum FT4 with low-normal TSH) in 4–8 h in 40–100% of patients (Torino et al. 2013). Replacement L-T4 therapy and regular monitoring of FT4 are required during bexarotene treatment (Sherman 2003). The effect of bexarotene reverts in a few days after its discontinuation. In thyroidectomized patients who start bexarotene, a dramatic fall in FT4 levels without an appropriate rise in TSH levels has been observed. Most probably this is an effect on peripheral thyroid metabolism, via non-deiodinase mechanisms (Smit et al. 2007) (Fig. 1A).

Iodine-Based Cancer Therapies and Radioimmunotherapie s

Several antineoplastic agents act by delivering 131I to target cells. Tositumomab is a cluster of anti-CD20 antibodies combined with 131I, which is approved for treatment of non-Hodgkin lymphoma (Hamnvik et al. 2011) (Fig. 1C). 131Imetaiodobenzylguanidine and 131I iodobenguane target 131I into neuroendocrine tissue. Thyroid cells concentrate 131I from these agents leading to hypothyroidism in 10–65% of patients (Hamnvik et al. 2011). A saturated solution of potassium iodide (SSKI) (four drops three times daily) or Lugol’s solution (24 drops three times daily), starting 24 h before and ending 2 weeks after administration of the medication, can prevent hypothyroidism (Hamnvik et al. 2011).

Immunoregulatory Drugs

IL-2

IL-2 is a cytokine that activates natural killer cells and antigen-specific T-cells and is approved for treatment of advanced melanoma and renal cell cancer. Thyroid diseases have been reported in 10–50% of patients treated with IL-2, alone or in combination with other immunotherapies (Atkins et al. 1988; Weijl et al. 1993; Krouse et al. 1995). Hypothyroidism, thyrotoxicosis, and hypothyroidism after a phase of thyrotoxicosis have been reported. Hypothyroidism is more common in patients with preexisting thyroid autoantibodies and may remit after discontinuation of IL-2. Activation of autoreactive T lymphocytes is the likely mechanism involved in thyroid toxicity (Fig. 1C, D).

Denileukin Diftitox

In denileukin diftitox, the ligand-binding domain of IL-2 is fused to diphtheria toxin. It binds to IL-2 receptors on lymphocytes and macrophages, leading to their death. It is approved in cutaneous T-cell lymphoma and graft-versus-host disease after allogenic stem cell transplantation. It can induce thyrotoxicosis (Ghori et al. 2006) (Fig. 1D). Destructive thyroiditis or triggering of autoimmunity in predisposed individuals is the proposed mechanism (Hamnvik et al. 2011).

Thalidomide and Lenalidomide

Thalidomide and its derivative lenalidomide have many immunoregulatory actions, including stimulation and proliferation of T-cells and increasing the number and function of natural killer cells. These drugs also have antiangiogenic activity. Both drugs are approved for treatment of multiple myeloma, lenalidomide also for 5q myelodysplastic syndrome. Subclinical hypothyroidism, occurring 1–6 months after initiation of therapy, has been reported in 20% of patients treated with thalidomide (Badros et al. 2002). The reported rate of hypothyroidism after lenalidomide is 5–10% (List et al. 2006; Dispenzieri et al. 2007). Both hypothyroidism and thyrotoxicosis have been reported in another study (Figaro et al. 2011). Interference with thyroid hormone secretion, reduction of iodine uptake, destructive thyroiditis by ischemia, or immune-mediated mechanisms have been proposed as the potential causes of thyroid dysfunction induced by thalidomide and lenalidomide (Torino et al. 2013) (Fig. 1C, D).

IFN-α

IFN-α is approved for malignant melanoma, renal cell carcinoma, AIDS-related Kaposi’s sarcoma, and some hematologic malignancies. It is extensively discussed in the section “Interferon and Other Antiviral Drugs” (Fig. 1C).

Alemtuzumab

Alemtuzumab is a humanized monoclonal antibody that induces profound lymphopenia by binding to the CD20 receptors on lymphocytes and monocytes. It is used in B-cell chronic lymphocytic leukemia, stem cell transplants, graft-versus-host disease after allogeneic cell transplant, and in multiple sclerosis. Alemtuzumab causes thyroid dysfunction in 30% of patients, with onset ranging from 6 to 61 month, with the greatest risk 12–36 months after the first infusion (Coles et al. 2012; Cossburn et al. 2011). About half of the cases have been Graves’ disease with or without ophthalmopathy (Willis and Robertson 2014). Of patients with overt Graves’ hyperthyroidism, 23% spontaneously became euthyroid and an additional 15% spontaneously developed hypothyroidism (Daniels et al. 2014). The annual incidence of a first episode of thyroid dysfunction increased each year through year 3 and then decreased each subsequent year (Daniels et al. 2014). Management of alemtuzumab-induced Graves’ disease is similar to the management of classic Graves’ disease (Smith and Hegedüs 2016) (Fig. 1C, D).

Immune Checkpoint Inhibitors

Blocking of immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA4) and programmed death-1 (PD1), two co-inhibitor receptors that are expressed on activated T-cells, has emerged as an option for treatment of cancer. By activating T-cells, these drugs alter immune tolerance, inducing the control of neoplastic cells but also the breaking of immune tolerance, inducing “immune-related adverse effects” (IRAEs). Thyroid and other endocrine glands are often involved (González-Rodríguez and Rodríguez-Abreu 2016).

Anti-CTLA4 Monoclonal Antibodies

Ipilimumab and tremelimumab are mAbs directed against CTLA4. Ipilimumab is approved for use in advanced cutaneous malignant melanoma and tremelimumab for metastatic prostate cancer. Hypophysitis (which can cause central hypothyroidism) is the most severe and dose-limiting endocrine adverse effect, observed in 0–17.4% of patients treated with ipilimumab and 2.6% of those treated with tremelimumab (Torino et al. 2013; González-Rodríguez and Rodríguez-Abreu 2016). Thyroid disorders have been reported in 0%–7.4% of patients treated with ipilimumab, with an incidence of hypothyroidism of 0%–9% and of hyperthyroidism of 0%–2.8%. Thyroid disorders occur in 0.5–5.2% of patients treated with tremelimumab (Fig. 1C, D). The onset of thyroid dysfunction occurs after two to four infusions of anti-CTLA4 mAbs. Most cases are subclinical and transient; others evolve into permanent hypothyroidism (Di Giacomo et al. 2010). It is known that different CTLA4 polymorphisms have been associated with Graves’ orbitopathy. Of note, some patients developed euthyroid Graves’ orbitopathy following treatment with anti-CTLA4 mAbs (Min et al. 2011; McElnea et al. 2014).

Anti-PD-1 Monoclonal Antibodies

PD-1 is a negative regulatory receptor expressed on T and B lymphocytes and natural killer cells which limits their response. Nivolumab is an anti-PD-1 mAb approved for treatment of advanced malignant melanomas, renal cell carcinomas, and non-small cell lung cancer, while pembrolizumab is approved for treatment of advanced malignant melanoma and non-small cell lung cancer. Compared to standard treatment, these drugs showed a lower risk of adverse effects. Thyroid dysfunction has been observed in 9% of treated patients, with 3% developing hyperthyroidism and 6.5% developing hypothyroidism (Costa et al. 2017; González-Rodríguez and Rodríguez-Abreu 2016) (Fig. 1C, D) (Table 4).
Table 4

Immunoregulatory drugs interfering with thyroid function

Drug

Effect

Mechanism of action

IL-2

Hypothyroidism/thyrotoxicosis

Activation of autoreactive T lymphocytes

Denileukindiftitox

Thyrotoxicosis

Destructive thyroiditis, triggering of autoimmune thyroid disease

Thalidomide and lenalidomide

Hypothyroidism

Interference with thyroid hormone secretion reduction of iodine uptake,

 

Thyrotoxicosis

Destructivethyroiditis, immune mediated mechanisms

IFN-α

↑ AbTPO, AbTg, TSH

Triggering of autoimmune thyroid disease

Alemtuzumab

Graves’ disease

Triggering of autoimmune thyroid disease

Immune checkpoint inhibitors

I. anti-CTLA4 mAbs (ipilimumab, tremelimumab)

Central hypothyroidism

Hypothyroidism

Euthyroid Graves’ orbithopathy

Hypophysitis

II. anti-PD-1mAbs (nivolumab, pembrolizumab)

Hypothyroidism

Hyperthyroidism

Triggering of autoimmune thyroid disease

Other Substances Interfering with Thyroid Function

Endocrine Disruptors

Thyroid disruption can derive from occupational or environmental exposure (Diamanti-Kandarakis et al. 2009; Leung et al. 2014; Marini et al. 2012). A recent article (Benvenga et al. 2015) reviewed the studies investigating the onset of Hashimoto’s thyroiditis and/or thyroid nodules following occupational or environmental exposure to polluting substances. Among these pollutants, there are the polychlorinated biphenyls (PCB), polybrominated biphenyls (PBB), pesticides (the most studied being organochlorines, including dichlorodiphenyltrichloroethane [DDT], aldrin, heptachlor, chlordane, and lindane), and heavy metals.

Two of the biggest Chinese cities, Beijing and Guangzhou, are heavily polluted. Beijing recently recorded the world’s highest level of sulfur dioxide, the third highest level of nitrogen dioxide, and one of the highest levels of particulates (Benvenga et al. 2015). In urban areas of Beijing, the incidence of differentiated thyroid cancer (DTC) has increased (or risen) sevenfold over the years 1995–2010, with an increase of 539%. Guangzhou has recently recorded a higher level of particulates in the air (Benvenga et al. 2015). Similar to Beijing, in the urban area of Guangzhou, the incidence of DTC increased three times over the time period 2000–2011 (Benvenga et al. 2015). Concerning occupational exposure, working as a mechanic and metal worker and having contact with solvents were identified as risk factors for developing thyroid cancer. Also, following the September 11, 2001, World Trade Center disaster and the subsequent release of toxic substances into the environment, thyroid cancer increased 2.3-fold over the years 2002–2012 in police officers who were in service on that day (Benvenga et al. 2015).

Turning to thyroid autoimmunity, smoke (and the related passive smoking), PCB, solvents, metals, and other anthropogenic compounds (see below) have been implicated in thyroid inflammation and autoimmunity. They might act by disrupting the immune tolerance with the subsequent triggering of AITD. Alternatively, thyroid disruptors can alter thyroglobulin structure by post-transductional modifications, thus increasing their immunogenicity (Benvenga et al. 2015). The rate of chronic lymphocytic thyroiditis at FNAC is higher in subjects living in the area of a large petrochemical complex (located in southeastern Sicily) compared with subjects from a control area located just 15 km away (32% vs 23%) (Arena et al. 2015). These two areas are environmentally distinct, because the concentrations in the atmosphere of four heavy metals (nickel, vanadium, chromium, and mercury) were higher in the petrochemical complex area compared with the control area. Also, the rate of suspiciously malignant or overtly malignant cytologies from thyroid nodules was twofold increased in patients living in the petrochemical complex area as in the control patients (Arena et al. 2015).

Slovakian workers who were exposed to PCB are an example of AITD resulting from occupational exposure. These workers had higher thyroid volume and higher frequency of thyroid antibody positivity compared with controls. Furthermore, the more these workers had worked in contact with PCB, the higher the prevalence of clinical and/or laboratory signs of thyroid diseases (Benvenga et al. 2015).

Food, in particular fish, is another important means of exposure. The west and south coasts of Newfoundland (Canada) are in contact with the Gulf of St. Lawrence, the outlet of St. Lawrence river. This river, its estuary, and its gulf are one of the most polluted water sources in the world. Hence, seafood consumed by the coastal communities of Newfoundland is contaminated with thyroid-disrupting chemicals. Indeed, the rate of hypothyroidism in the west and on the south coast is twice that of the east coast (Benvenga et al. 2015). The type of seafood consumed influences both the positivity rate and the serum levels of thyroid autoantibodies throughout pregnancy and postpartum (Benvenga et al. 2016 i). Indeed, the group of women who consumed swordfish, a top predator fish that concentrates pollutants (mainly, mercury), as the sole or predominant seafood, had the highest positivity rate of thyroid autoantibodies (25% at the first trimester and 12.5% at day 4 postpartum).

On the other hand, blood measurements for all metals and assessment of thyroid function showed that mercury was associated with reductions in T3 and T4 and cadmium was linked to decreased TSH (Duntas 2015). It is worth noting that endocrine disruptors (EDs) frequently exert nonlinear effects, i.e., acting in a U-shaped or inverted-U manner; thus, seemingly paradoxically, a minimal dose of EDs can cause more abnormalities than higher doses. The fact that even small amounts of EDs are capable of causing adverse effects, which however cannot be predicted by their effects at much higher doses, reintroduced what was first determined in the 1990s, namely, the “low-dose hypothesis,” together with the concept of non-monotonic dose response curves describing a nonlinear relationship between dose and effect (Köhrle 2008).

A variety of benzophenone UV screens (BP2), when applied for 5 days in adult ovariectomized rats, led to a significant reduction of T4 and T3 plasma levels. The suggested mechanism was the inhibition of thyroid peroxidase (Jarry et al. 2004). It is important to be aware that UV screens, besides being potent estrogen disruptors, may exert potential thyroid-disrupting activity within just a few days.

Nutraceuticals and Over-the-Counter Products

Selenium and Inositol

The effects of selenium on thyroid and other targets were recently reviewed (Duntas and Benvenga 2015; Winther et al. 2017). A large cross-sectional study in China showed a higher prevalence of Hashimoto’s thyroiditis and goiter in a low selenium area (median serum selenium concentration of 57.4 mcg/L) compared to an adequate selenium area (median serum selenium concentration of 103.6 mcg/L) (Wu et al. 2015). In an Italian study (Negro et al. 2007), 77 TPOAb-positive pregnant women were supplemented with 200 μg selenomethionine from the first trimester of gestation through month 12 postpartum. The average reduction in TPOAb, compared to baseline, was 62% during pregnancy and 48% during the 12 months postpartum. In the 74 TPOAb-positive pregnant women treated with placebo, the reduction in pregnancy and postpartum was significantly lower (44% and just 1%, respectively). The rate of thyroid hypoechogenicity was significantly lower in the selenomethionine-treated group compared to the placebo group. Postpartum thyroid dysfunction and permanent hypothyroidism were lower in the treated group compared with the placebo group (Negro et al. 2007).Other studies confirmed the reduction of TPOAb and TgAb in patients with chronic Hashimoto’s thyroiditis but no changes in quality of life and in thyroid function (Winther et al. 2017). Some small studies demonstrated the effectiveness of selenium supplementation in Graves’ disease and Graves’ orbitopathy. Some ongoing trials are investigating larger groups of patients. The available data do not support the routine use of selenium supplementation in patients with AITD with the exception of a 6-month trial of selenium in patients suffering from mild Graves’s orbitopathy suggested by the European Thyroid Association (Bartalena et al. 2016).

It is known that insulin resistance is correlated with serum TSH, that insulin enhances the effects of the inositols, and that inositols are involved in TSH signaling (Benvenga and Antonelli 2016). For these reasons, one study investigated the effect of myoinositol supplementation on subclinical hypothyroidism and thyroid autoantibody levels (Nordio and Pajalich 2013). The study was based on co-administration of myoinositol with selenomethionine in 48 women with subclinical autoimmune hypothyroidism and evaluated restoration of normal TSH levels, reduction of serum TPOAb and TgAb, and improvement of thyroid hypoechogenicity. Patients were randomized into two groups, one receiving orally 83 μg selenomethionine/day in a soft gel capsule and another a combined treatment, namely, 600 mg myoinositol contained in a 83 μg selenomethionine soft gel capsule. TSH concentrations decreased in the second but not in the first group, while TPOAb and TgAb significantly decreased in both groups. Changes in ultrasound echogenicity were more common in the second than in the first group (Nordio and Pajalich 2013). The association of myoinositol with selenomethionine was recently demonstrated to be more effective than each of them in reducing the H2O2-induced oxidative stress on peripheral mononuclear cells in vitro in both control and HT women (Benvenga et al. 2017).

L-Carnitine

The naturally occurring quaternary amine L-carnitine is characterized as a modulator of thyroid hormone action in peripheral tissues, with a prevalent inhibitory effect of nuclear uptake (Benvenga et al. 2000). No modification of thyroid hormone or TSH levels have been observed. Studies in patients with spontaneous and iatrogenic thyrotoxicosis, including the most severe form (thyroid storm), showed that treatment with carnitine ameliorates symptoms of thyrotoxicosis (Benvenga et al. 2004, 2003).

Thyroid Hormones and Iodine

Thyrotoxicosis factitia from over-the-counter products containing one or both thyroid hormones or iodine is common (Hoang et al. 2013). Complementary medication and herbal medicine are commonly used, especially for purposes of weight loss, and an increasing number of patients consume herbal medicine without reporting their use to physicians (Johnston 1997). Use of kelp, large seaweeds belonging to the brown algae (Phaeophyceae) in the order Laminariales, has been associated with thyrotoxicosis (Müssig et al. 2006) (Fig. 1D).

Biotin

A low to medium dose of biotin (vitamin B7) is commonly present in multivitamin preparations, while high doses of biotin (10,000 times the recommended daily intake of approximately 30 μg) have been reported to improve clinical outcome and quality of life in patients with progressive multiple sclerosis (Elston et al. 2016). Many current immunoassays for determination of thyroid and other endocrine variables contain biotin, since they use a biotin-streptavidin detection system (Elston et al. 2016). Depending on the biotin assay used, thyroid hormone results can be falsely high or low. Temporary discontinuation of biotin treatment results in complete resolution of the biochemical abnormalities (Barbesino 2016) (Table 5).
Table 5

Other substances interfering with thyroid function

Drug

Effect

Mechanism of action

Endocrine Disruptors

Polychlorinated biphenyls (PCB)

Thyroid cancer

 

Polybrominated biphenyls (PBB)

Thyroid nodules

Pesticides [dichlorodiphenyltrichloroethane (DDT), aldrin, heptachlor, chlordane, lindane]

Induction of autoimmune thyroid disease

Disruption of immune tolerance

Heavy metals [nickel, vanadium, chromium, mercury]

Hypothyroidism

Smoke

  

Benzophenone UV-screens (BP2)

Reduction of T4 and T3

Inhibition of TPO

Nutraceuticals and over-the-counter products

Selenium and inositol

prevention of thyroid autoimmunity

 

L-carnitine

modulation of thyroid hormone action

Thyroid hormones and iodine (kelps)

thyrotoxicosis

Biotin

T4,T3, TSH alterations

interference with FT4, FT3, TSH measurement

Comorbidities and Drugs Interfering with LT4 Absorption

Levothyroxine sodium is among the most frequently prescribed drugs worldwide and continuously increases in tandem with the increasing incidence of thyroid disease over the last few decades. Based on community data of prescriptions for thyroid hormone in England, the amount of levothyroxine prescribed from 1998 to 2007 has nearly tripled, from 7 to almost 19 million prescriptions, while the duration of prescriptions has fallen by 25% over the same time (Mitchell et al. 2009). About 9% of patients of six general practitioner practices in Germany were taking thyroid hormones (Viniol et al. 2013). Levothyroxine tablets are most commonly taken in the fasting state, once a day, and lifelong for hypothyroidism. The safety of long-term administration of levothyroxine is well-known, although regular routine laboratory controls are required to ascertain that the proper dose has been prescribed. The absorption of levothyroxine compounds may be reduced by gastrointestinal comorbidities, such as gastritis, peptic ulcer, celiac disease, and irritable bowel disease, while in addition many other drugs can interfere with its absorption (Table 6) (Fig. 1Ea, Eb). Commonly prescribed drugs, such as anticoagulants, nonsteroidal anti-inflammatory drugs, antiepileptics, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, iodine-containing antiarrhythmics (amiodarone), β-blockers, also antibiotics, cytokines, and tyrosine kinase inhibitors (TKIs), among many more, interact with the absorption or peripheral metabolism of thyroxine or have an impact on the hypothalamic-pituitary-thyroid (HPT) axis, all of which potentially induce thyroid dysfunction (Liwanpo and Hershman 2009; Barbesino 2010; Colucci et al. 2013; Benvenga 2013; Haugen 2009; Trifirò et al. 2015) (Fig. 1). Novel formulations (soft gel capsules, oral liquid solution) of LT4 may enhance the absorption of LT4 (Vita et al. 2014; Virili et al. 2016) and reduce the frequency of TSH measurement (Ferrara et al. 2017).
Table 6

Factors and conditions that impair the intestinal absorption of thyroxine

A. Inappropriate modality of storing L-T4 tablets

B. Inappropriate modality of ingestion of the L-T4 tablet

 Involuntary noncompliance

 Voluntary noncompliance (pseudomalabsorption)

 Non-empty stomach (insufficient time elapsed between food and ingestion of the L-T4 tablet)

  L-T4 taken while eating or less than 60 min after having eaten

  Fiber-rich food (bread, bran, cereals, papaya)

 Improper liquid for taking the L-T4 tablet

  Coffee, grapefruit juice

C. Diseases or problems of the digestive system

 Lactose intolerance

 Gastritis (not necessarily associated with Helicobacter pylori)

 Celiac disease

Duodenitis, Enteritis, irritable bowel disease

 Intestinal parasitoses

 Interventions of bariatric surgery

 Chronic liver disease

 Pancreatic insufficiency

 Medications

Non absorbable antacids

  Absorbable antacids (proton-pump inhibitors, etc …)

  Iron salts

  Calcium salts

  Phosphate binders

  Bile acid sequestrants

  Ion resin exchangers

  Orlistat

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Lucia Montanelli
    • 1
    Email author
  • Salvatore Benvenga
    • 2
  • Laszlo Hegedüs
    • 3
  • Paolo Vitti
    • 5
  • Francesco Latrofa
    • 1
  • Leonidas H. Duntas
    • 4
  1. 1.Department of Clinical and Experimental Medicine, Endocrinology Unit 1University Hospital of PisaPisaItaly
  2. 2.Department of Clinical and Experimental Medicine, Master Program of Childhood, Adolescent and Women’s Endocrine Health, Interdepartmental Program of Molecular and Clinical Endocrinology, and Women’s Endocrine HealthUniversity of Messina and A.O.U. Policlinico G. MartinoMessinaItaly
  3. 3.Department of Endocrinology and MetabolismOdense University HospitalOdenseDenmark
  4. 4.Evgenideion Hospital, Unit of Endocrinology, Diabetes and MetabolismUniversity of AthensAthensGreece
  5. 5.Department of EndocrinologyUniversity of PisaPisaItaly

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