DRUG INDUCED THYROID PROBLEMS

Diseases of thyroid induced by drugs.

1. PERM STATE MEDICAL UNIVERSITY DRUG INDUCE D THYROID PROBLEMS -JOISY ALOOR 6 TH YEAR

2. INTRODUCTION 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.

3. 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 ). 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 ).

4. 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 Clinical judgment should dictate whether the suspected drug should be withdrawn and how the thyroid dysfunction should be further investigated and treated.

5. Various drugs may cause thyroid dysfunction. The drugs which may cause thyrotoxicosis include interferon, molecular-targeted agents, amiodarone, thyroid hormone itself and so on. Those which cause hypothyroidism include anti-thyroid drugs, lithium and iodine etc. which inhibit thyroid hormone synthesis and secretion, and dopamine etc. which block TSH secretion. Those drugs which alter the thyroid hormone metabolism or the binding to TBG or those inhibit thyroid hormone absorption may cause hypothyroidism or deteriorate it in patients with hypothyroidism treated with thyroid hormone or those with diminished reserved capacity. When thyroid dysfunction occurred, it is better to discontinue the causative drug, but in many cases, the patients are forced to be treated with the drug being continued.

6. DEFINITION Induced thyroid disorders (ITD) are conditions that occur when certain medicines or treatments change the amount of hormone the thyroid produces. Thyroid hormones regulate body temperature, heart rate, and weight gain or loss.

7. SOME CAUSES Amiodarone is used to treat arrhythmia . Its high iodine content is primarily responsible for producing a hyperthyroid state, though the medication may itself induce autoimmune thyroid disease . Interferon is used to treat tumors and other diseases, such as hepatitis C. This medicine directly attacks thyrocytes. This may lead to high or low amounts of thyroid hormones in the blood. Lithium treats mental disorders. It can increase the production of antibodies against thyroid cells and cause hypothyroidism. Radiotherapy uses radiation as treatment for head and neck tumors. Radiation may cause damage to the thyroid cells and may decrease the production of thyroid hormones.

8. Iodine-induced - Occurs after administration of either supplemental iodine to those with prior iodine deficiency or pharmacologic doses of iodine (contrast media, medications) in those with underlying nodular goiter Antineoplastic agents - Agents may cause thyroid dysfunction in 20-50% of patients. Symptoms of thyrotoxicosis may be mistaken for sepsis or an adverse drug effect, so monitoring of thyroid function must be considered.

9. Lithium therapy causes overt hypothyroidism in 5 to 15% of patients, and goitre in up to 37%. Thyroid function tests should be performed prior to initiating lithium therapy, and at 6-monthly intervals thereafter. Iodine and iodine-containing drugs ( e.g radiographic contrast media, iodinated glycerol and amiodarone) can have profound and variable effects on thyroid function . Glucocorticoids also lead to thyroid dysfunction.

10. DRUG INDUCED HYPO/HYPERTHYROIDISM Drug-induced hypothyroidism is an under active thyroid gland caused by certain medications. The medications that can cause hypothyroidism may be drugs normally used to treat hyperthyroidism or that are related to thyroid function and a group of non-thyroid related drugs. The drugs used to treat hyperthyroidism or are related to thyroid function that can result in drug-induced hypothyroidism are propylthiouracil , radioactive iodine, potassium iodide, and methimazole . Iodides, in general, alter thyroid function. Total T3 and total T4 are 3 and 4 iodinated tyrosines . Even iodide containing solutions used for sterilization or iodides used in dyes and contrast media can cause hypothyroidism. Iodide can also causes hyperthyroidism.

11. Drug-induced hypothyroidism presents with the same signs and symptoms as are seen with other hypothyroid conditions (i.e., fatigue, cold intolerance, weight gain, depression, and dry skin ). The same is with hyperthyroidism. Drugs and iodine can cause hyperthyroidism. Drugs include amiodarone, interferon-alpha, programmed death receptor-1 (PD-1) inhibitors (such as nivolumab and pembrolizumab ), alemtuzumab , and, rarely, lithium. Excess iodine, as may occur in people taking certain expectorants, or in those given iodine-containing contrast agents for x-ray studies, may cause hyperthyroidism. Taking too much thyroid hormone orally can also cause hyperthyroidism.

12. DRUG-INDUCED THYROIDITIS Drug-induced thyroiditis can be the result of several mechanisms , the most common being an inflammatory/ destructive process induced by drugs. The mechanisms of drug-induced thyroiditis may be summarized as follows: Cytotoxic Immune dysregulation Ischemic , by blocking the vascular endothelial growth factor receptor

13. Patients with positive thyroperoxidase antibodies (TPOAbs) are at an increased risk of developing drug-induced hypothyroidism with several of the non-thyroid related drugs. Patients with positive TPOAbs are at particular risk when a preexisting Hashimoto’s thyroiditis is present or when taking amiodarone. Amiodarone is an iodine containing antiarrhythmic . The National Academy of Clinical Biochemistry has specific guidelines for patients taking amiodarone. These guidelines recommend : if TSH is abnormal, a complete physical examination with baseline TSH, TPOAb, free T4, and free T3 should be undertaken prior to amiodarone therapy initiation thyroid status should be monitored every 6 months via TSH after amiodarone initiation.

14. TPOAb is a risk factor for developing drug-induced hypothyroidism at any time during amiodarone therapy Amiodarone induced hyperthyroidism (AIH) can also occur . Symptoms of hypothyroidism may include brittle fingernails, coarsening and thinning of hair, puffy eyes, weakness, and constipation. Symptoms expressing themselves later in the course of the disease are hoarseness; menstrual disorders; puffy hands, face, and feet; thickening of the skin; thinning of eyebrows; increased cholesterol levels; muscle and/or joint aches and stiffness; slowed speech; and decreased hearing.

15. The predisposing factors for ITD are: Autoimmune thyroiditis Post-treatment of hyperthyroidism Previous hemithyroidectomy for the treatment of nodular goiter A history of postpartum thyroiditis, subacute thyroiditis, drug-induced thyroiditis Thalassemia major (thyroid hemosiderosis ) Chronic renal disease

16. The National Academy of Clinical Biochemistry guidelines for testing of hospitalized patients with non-thyroid illness recommendations indicate : Acute or chronic non-thyroid illness has complex effects on thyroid function testing. Whenever possible, diagnostic testing should be deferred until the illness has resolved, except in cases in which there is a suggestion of presence of thyroid dysfunction . Physicians should be aware that some thyroid tests are inherently not interpretable in severely ill patients or patients receiving multiple medications . TSH in the absence of dopamine or glucocorticoid therapy is the more reliable test . TSH testing in the hospitalized patient should have a functional sensitivity of less than 0.02 mIU /L; otherwise, sick, hyperthyroid patients with profoundly low TSH cannot be differentiated from patients with mild transient TSH suppression caused by non-thyroid illness .

17. An abnormal free T4 in the presence of serious somatic disease is unreliable. In hospitalized patients, abnormal free T4 testing should reflex to total T4. If both free T4 and total T4 are abnormal in the same direction, a thyroid condition may exist. Discordant free T4 and total T4 abnormalities are more likely the result of illness, medication, or a testing artifact. Total T4 abnormalities should be considered in conjunction with the severity of the patient illness. A low T4 in patients not in intensive care is suspicious of hypothyroidism, since low total T4 levels in non-thyroid illness in hospitalized patients are most often seen in sepsis. If a low total T4 is not associated with an elevated TSH and the patient is not profoundly sick, hypothyroidism secondary to pituitary or hypothalamic deficiency should be considered. Reverse T3 formed by the loss of an iodine group from T4 where the position of the iodine atoms on the aromatic ring is reversed is rarely helpful in the hospital setting, because paradoxically normal or low values can result from impaired renal function and low binding protein concentrations.

18. HOW IS ITD DIAGNOSED? Thyroid function tests. An ultrasound. A thyroid scan. Fine needle biopsy.

19. Exposure to iodine-based compounds is also reflected in alterations of laboratory tests: TSH increase Decrease in thyroid hormones levels Increase in the amount of urinary iodine excretion over 24 hours

20. TREATMENT Pregnancy: Prenatal vitamins contain iron and calcium that can impair the absorption of thyroid hormone from the gastrointestinal tract. Consequently, levothyroxine and prenatal vitamins should not be taken at the same time and should be separated by at least 4 hours . Beta-blockers such as propranolol or metoprolol help control many of the symptoms of hyperthyroidism. These drugs can slow a fast heart rate, reduce tremors, and control anxiety. Doctors therefore find beta-blockers particularly useful to control symptoms of hyperthyroidism until the person responds to other treatments. However, beta-blockers do not reduce excess thyroid hormone production. Therefore, other treatments are added to bring hormone production to normal levels.

21. Methimazole and propylthiouracil are the drugs most commonly used to treat hyperthyroidism. They work by decreasing the gland’s production of thyroid hormones. Each drug is taken by mouth, beginning with high doses that are later adjusted according to blood test results. These drugs can usually control thyroid function within 6 to 12 weeks. Larger doses of these drugs may work more quickly but increase the risk of side effects.