Drugs that affect thyroid function
1 Amiodarone
Amiodarone is an effective antiarrhythmic drug, especially in patients with persistent ventricular tachycardia, ventricular fibrillation, and atrial fibrillation. Amiodarone use often causes potential systemic multi-organ damage such as pulmonary fibrosis, gastrointestinal discomfort, eye and skin disorders, neurological disturbances, and thyroid involvement. Soon after it was introduced, amiodarone received attention for causing abnormal thyroid function. Abnormalities in thyroid function often cause a range of clinical signs and symptoms, but the most characteristic are its effects on the heart and cardiovascular system. Although hyperthyroidism (hyperthyroidism) causes more pronounced changes in systemic signs and symptoms than hypothyroidism (hypothyroidism), both can lead to abnormal cardiac function if left untreated for a long time.
1.1 Amiodarone induced hypothyroidism (AIH)
The risk of AIH is significantly higher in patients with combined thyroid nodules and positive thyroid autoantibodies, with more female than male patients (1.5:1 female:male). It has been reported that the risk of AIH in female patients with positive thyroid autoantibodies is 14 times higher than that in male patients with positive thyroid autoantibodies. During thyroid hormone biosynthesis, iodine is taken up by thyroid follicular epithelial cells then oxidized by thyroid peroxidase to active iodine, which is subsequently organicized by tyrosine. Amiodarone causes an increase in iodine in the thyroid follicular epithelium, which inhibits the polyiodine action of the thyroid gland and the synthesis and release of thyroid hormones, i.e., the Wollf-Chaikoff effect, which generally lasts for 2 to 14 d. The iodine uptake by the thyroid follicular epithelium then returns to normal, i.e., the escape phenomenon of the Wollf-Chaikoff effect. In patients with underlying thyroid disease, amiodarone interferes with the escape of the wollf-Chaikoff effect, resulting in a decrease in thyroid hormone synthesis and release, a persistent increase in TSH levels, and a compensatory increase in thyroid volume, leading to the development of AIH. The clinical symptoms of AIH are similar to those of primary hypothyroidism and include fatigue, mental fatigue, and fear of cold. The treatment of AIH is similar to that of typical hypothyroidism, but requires starting with a small dose of L-T4 (25-50 μg/d) and monitoring the TSH level every 6-12 weeks to adjust the L-T4 dose to control the TSH within the normal range. In addition, L-T4 replacement therapy does not affect the antiarrhythmic efficacy of amiodarone.
1.2 Amiodarone induced hyperthyroidism (AIT)
The incidence of AIT fluctuates from 5% to 47% depending on the population and the underlying disease. Unlike AIH, AIT is relatively more frequent in male patients (3:1 male:female). AIT is usually more likely to occur in areas with relative iodine deficiency, whereas AIH tends to occur in areas with sufficient iodine. AIT occurs in patients with a normal thyroid or thyroiditis that destroys thyroid tissue, both of which are caused by the drug effects of amiodarone itself. However, because many patients have a mixed form of AIT, there are many difficulties in the typing of AIT. However, it is still clinically necessary to distinguish between these two types of AIT because of the different treatment modalities.
Type 1 AIT is a form of Jod-Basedow effect, iodine-induced hyperthyroidism, which can be caused by the ingestion of iodine-containing contrast media or oral iodine-containing medications (amiodarone) or supplements. T4).
The pathogenesis of type 2 AIT is similar to that of subacute thyroiditis, and thyrotoxicosis occurs due to a large amount of thyroid hormones entering the bloodstream through broken thyroid follicular epithelial cells.
The 24h thyroid uptake rate can help to differentiate between these two types of AIT, and is generally low in patients treated with amiodarone due to the increased amount of “cold iodine” (i.e., no radioactive iodine) in the body. The process of thyroid destruction in type 2 AIT is associated with thyroid follicular damage, fibrosis, lymphocytic infiltration, and the inflammatory factor interleukin-6. Patients with type 2 AIT often have a self-limiting course and do not require special treatment after discontinuation of the drug as long as the symptoms are mild and the cardiovascular status is good. As with Graves’ disease, patients with type 1 AIT require thioureas (methimazole 10-30 mg/d) to inhibit thyroid hormone synthesis. For patients who fail to respond to thiourea therapy, surgery or isotope therapy is an option, while for secondary hypothyroidism after treatment, L-T4 replacement therapy can be started at the same time. However, because of the coexistence of thyroid hormone over-synthesis and thyroid destruction, the diagnosis and treatment of mixed AIT is a great challenge.
2.Allan monoclonal antibody (monoclonal antibody)
Alemtuzumab is a humanized monomer against CD52 cell surface antigen. Researchers found that among 216 patients with multiple sclerosis treated with alemtuzumab, 48 patients developed abnormal thyroid function and 15 patients developed autoimmune hypothyroidism. Alemtuzumab can cause Graves’ disease, but the mechanism remains unclear and may be related to massive T-cell apoptosis and cell cycle. Graves’ disease has also been shown to be associated with genetic polymorphisms, such as human leukocyte antigen and cytotoxic T lymphocyte-associated antigen-4, but has not been confirmed by large-scale theoretical studies.
3. Lithium
Lithium is the most effective drug for the treatment of bipolar disorder and can counteract depression and mania thus reducing the risk of suicide and short-term mortality. The thyroid gland is able to concentrate lithium, and lithium can cause hypothyroidism and goiter. It affects thyroid function mainly through the following mechanisms: inhibition of iodine uptake and tyrosine coupling, alteration of thyroglobulin structure, and inhibition of thyroid hormone secretion. Although lithium-associated thyrotoxicosis is uncommon, long-term lithium use can significantly increase the risk of its development. Lithium carbonate can also induce subclinical hypothyroidism, which occurs mainly in patients with autoimmune thyroiditis. However, whether lithium can induce thyroid autoimmunity is still a controversial topic. For treatment, L-T4 therapy should be used promptly. Although lithium can have an effect on thyroid function, lithium therapy should be continued if necessary based on the patient’s actual condition.
4.Tyrosine kinase inhibitors
Thyroid function abnormalities caused by tyrosine kinase inhibitors were first reported in 2006, when sunitinib induced hypothyroidism in the course of treatment of patients with imatinib-resistant gastrointestinal questionable tumors. Some studies have confirmed that tyrosine kinase inhibitors, namely sorafenib, pazopanib, and axitinib, can cause abnormalities in thyroid function.
5.Interferon
Cytokines caused thyroid dysfunction during the treatment of a breast cancer patient was first reported in 1985. Interferon instrument combined with ribavirin in the treatment of chronic hepatitis C can cause various common thyroid function abnormalities, such as hyperthyroidism, hypothyroidism and biphasic thyroiditis. The mechanism of action is still not clearly elaborated, but it has been reported that hypothyroidism is due to autoimmune response, and biphasic thyroiditis is due to the toxic effect of the drug itself. In addition, biphasic thyroiditis in hyperthyroidism and hypothyroidism accounts for the majority of thyroid function abnormalities caused by interferon only. Close monitoring of thyroid function in female patients with TSH at critical values during interferon instrumentation for hepatitis C leads to rapid intervention and improved prognosis.
Medications that affect thyroid function testing
Many medications have been found to affect thyroid function testing. T4 and T3 are known to be transported by three carrier proteins in the blood, with only 0.3% of T3 and 0.03% of T4 present in free or unbound form, yet it is the free thyroid hormone that is biologically active. Clinical thyroid function tests are primarily designed to measure total plasma T3 and T4, basal plasma TSH concentrations, and free T4 concentrations. Clinicians must be aware that some medications can affect thyroid function testing to avoid misdiagnosis and the physiological and financial burden of inappropriate treatment.
1. Estrogen
Thyroid-binding globulin is an acidic glycoprotein composed of four subunits, which is synthesized in the liver, while estrogen can increase the synthesis of hepatic Tg. At the same time, estrogen-induced glycosylation of Tg can slow down its metabolic clearance rate and prolong its half-life. Plasma thyroid-binding globulin levels may increase in pregnant women, oral contraceptives and patients with acute hepatitis, thereby increasing the concentration of total T4, and the effect is positively correlated with estrogen dose.
2. Glucocorticoids
Glucocorticoids are end products of hypothalamic-pituitary-adrenal axis activation and are strongly influenced by the effects of stress. Glucocorticoids can inhibit hypothalamic-pituitary-thyroid axis function at the hypothalamic and pituitary levels during stress, resulting in a decrease in TSH secretion. In patients treated with glucocorticoids, the secretory response of TSH to thyrotropin-releasing hormone is reduced, leading to a decrease in thyroid hormone secretion, a decrease in the basal metabolic rate of the body exposed to cold, and a consequent decrease in the ability to protect against cold, but generally not causing central hypothyroidism. Some studies have also reported that glucocorticoids can also elevate TSH.
3.Anti-epileptic drugs and rifampin
Some anti-epileptic drugs with liver enzyme-inducing activity, such as carbamazepine and phenytoin sodium, can induce liver P450 oxidase and accelerate the metabolism of thyroid hormone, thus reducing the level of thyroid hormone. The anti-tuberculosis drug rifampicin has a similar effect. Carbamazepine can also interfere with the binding of thyroid hormones to thyroid binding globulin by affecting hormone synthesis in the hypothalamic-pituitary-thyroid axis, or cause hypothyroidism due to increased glucuronide binding.
4.NSAIDs and furosemide
NSAIDs and high doses of furosemide (>80 mg) can inhibit the binding of T3 and T4 to thyroid binding globulin, resulting in a transient increase in plasma T4 and alum levels, but long-term use of the drug will result in a decrease in total T4 levels.
5.Heparin
Heparin causes a transient rise in plasma FT4 due to the activation of lipoprotein lipase by heparin, which inhibits the conversion of triglycerides to free fatty acids and ultimately inhibits the binding of T4 to thyroid binding globulin in vitro.
In conclusion, in clinical practice, medical professionals need to pay sufficient attention to these drugs and perform regular thyroid function monitoring in order to correctly diagnose and reasonably treat drug-induced thyroid disorders in a timely manner. Also, by understanding the drugs that may affect thyroid function testing, clinicians can improve their diagnosis and avoid the occurrence of mistreatment.