07 - Thyroid Hormones and Anti-Thyroid Drugs

signs and symptoms of thyroid disease

• hypothyroidism:

  • salivary gland enlargment, compromised periodontium, macroglossia, glossitis, dysguesia, delayed dental eruption, enamel hypoplasia in primary and permanent dentition, micrognathia, thick lips, mouth breathing, anterior open bite, xerostomia

  • too little thyroid slows development

• hyperthryoidism:

  • increased caries risk, increased periodontal disease risk, enlargement of extraglandular thyroid tissu, burning mouth syndrome, Sjogren’s syndrome, systemic lupus erythematosus, maxillary and mandibular osteoporosis

  • too much thyroid speeds metabolism and bone turnover

T3 and T4

T3 ( triiodothyronine) and T4 (thyroxine) are major active hormones

• T3 is the active form of thyroid hormone, while T4 provides circulating depot that is eventually converted to T3 by 5’ deidodinases

  • D1, D2 → convert T4 into T3 in peripheral tissues

  • D3 → converts T4 into inactive reverse T3 (rT3) or inactivates T3 by converting it to T2

• T3 and T4 are highly protein-bound in blood, particularly with thyroxine-binding globulin (TBG)

  • binding creates circulating reservoir that slows hormone elimination and helps maintain stable hormone levels

  • estrogen can increase TBG

• thyroid hormone synthesis —

  1. iodine enters cell via Na⁺/I^- symporter (NIS) on basolateral membrane

  2. iodide is transported to colloid through pendrin apical transporter

  3. iodide oxidation to iodine via thyroid peroxidase

  4. iodine is attached to tyrosine residues in thyroglobulin

  5. iodinated tyrosines are coupled, creating T3 and T4 precursors

  6. thyroglobulin endocytosis into thyroid follicular cells, entering lysosomes

  7. proteolysis breaks thyroglobulin, releasing T3 and T4 into bloodstream

  8. dehalogenases recycle iodine in DIT/MIT that are not converted into T3/T4

thyroid hormone drug interactions

patients taking exogenous T4 are more likely to exhibit changes in thyroid status due to drug interactions

• exogenous hormones affect feedback on hypothalamic-pituitary axis, and patients may require dose adjustments

• estrogen → increases thyroxine-binding protein (TBG)

• lithium → inhibits T3 and T4 synthesis

thyroid hormone receptors

thyroid hormones act through nuclear thyroid hormone receptors, which form heterodimers with retinoid X receptors (RXR)

• required for normal growth and development of all organ systems

• in absence of T3:

  • TR-RXR heterodimer binds corepressor complexes that repress gene expression via HDAC enzymes to stabilize nucleosomes

  • prevents formation of transcription complexes

• in presence of T3:

  • TR-RXR binding causes release of corepressor complexes and binding of coactivator complexes that stimulate gene expression via HAT and other enzymes

  • destabilizes nucleosomes and triggers assembly of transcription complexes

hypothyroidism

caused by Hashimoto’s thyroiditis or iodine deficiency

• symptoms — lethargy, constipation, mild weight gain, putty face, cold intolerance, inhibition of growth, mental retardation

• Hashimoto thyroiditis — autoimmune destruction of thyroid gland

• treatment — T4

  • T4 is preferred because peripheral tissues can convert T4 into T3 as needed

  • full oral dose immediately in young patients or mild disease; slow titration oral dose in elderly patients

• myxedema coma — severe end-stage hypothyroidism; medical emergency

  • symptoms include severe hypothermia, respiratory impairment

  • treatment with IV T4 loading dose + IV corticosteroids

hypothyroidism treatment

main treatment is levothyroxine, or T4, because peripheral tissues can convert T4 to T3 as needed

• preferred over T3 because T4 has longer half-life, daily dosing, stable blood levels, body regulation to active T3

  • lower potency than T3

• monitor TSH for thyroid hormone replacement because it reflects whether the pituitary thinks thyroid hormone levels are appropriate

  • very high TSH → body thinks thyroid hormone too low

  • very low TSH → body thinks thyroid hormone too high

• for young patients, mild disease → full replacement immediately

• for elderly, cardiac disease → dose titrated slowly

  • too much thyroid hormone can increase heart rate, contractility, oxygen demand, arrhythmia risk, ischemia risk

hyperthyroidism

caused by Graves disease, toxic nodular goiter, post-partum thyroiditis

• symptoms — chronic osteoporosis, weight loss, lack of energy, heat intolerance, anxiety, sweating, increased thirst, palpitations

• Graves disease — autoimmune disease

  • thyroid-stimulating immunoglobulins (TSI) / TSH receptor antibodies (TRAb) mimic TSH action on TSH receptors

  • results in TSH receptor activation and increased thyroid hormone synthesis

  • treatment — radioactive iodine, anti-thyroid drugs, surgical thyroidectomy

  • Graves ophthalmoapthy invovles inflammatory and proliferative changes behind the eyes

    • fibroblasts expressing TSH receptors to promote hyaluronan production, inflammatory cytokines, hyperplastic orbital changes, causing exophthalmos

• toxic multinodular goiter / toxic adenomas — autonomous hormone secretion

  • treatment — radioactive iodine, surgical thyroidectomy

• thyroid inflammation (thyroiditis) — self-limited inflammation post-partum

  • treatment — supportive care with beta-blockers, NSAIDs, corticosteroids

• thyrotoxicosis / thyroid storm — severe acute hyperthyroidism

  • treatment — stabilize patient and rapidly reduce T3/T4 with anti-thyroid drugs

thioamines

anti-thyroid drugs like METHIMAZOLE and PROPYLTHIOURACIL (PTU) that reduce thyroid hormone synthesis via thyroid peroxidase inhibition

• slow effects → 3-4 weeks because preformed stores in thyroid must be first depleted

• PTU — more quickly absorbed; also inhibits 5’-deiodinase (D1)

  • reduces conversion of T4 into T3

  • requires BID dosing

  • black-box warning for hepatotoxicity / liver failure

• METHIMAZOLE — produces faster return to euthyroid state

  • does not inhibit D1

  • requires daily dosing

  • preferred over PTU

• during pregnancy:

  • PTU preferred in first trimester due to lower birth defects; methimazole used after first trimester to reduce hepatotoxicity risk

• adverse effects — agranulocytosis (failure to develop WBCs)

  • stop taking if sore throat or fever develops

  • may experience rash, nausea, GI discomfort

• most useful in young patients with mild disease

radioactive iodine (RAI)

¹³¹I isotope used as an anti-thyroid drug that is taken up by thyroid tissue for destruction of thyroid follicular cells

• beta emitter with 5 day half-life and 2mm tissue penetration

  • administered orally as sodium iodide salt in a capsule or as a liquid

• most common definitive treatment for Graves disease to reduce T3/T4

  • selective uptake by thyroid follicular cells

  • most patients become hypothyroid in 2-6 months and require lifelong T4 replacement

• used to ablate residual/metastatic thyroid cancer cells in patients after surgical thyroidectomy

  • thyroid cancer patients pretreated to increase TSH and RAI uptake

  • does not increase risk of thyroid or other cancers

• contraindicated in pregnant women

• may increase progression of Graves ophthalmopathy

  • due to increased TSH receptor antibodies (TRAb)

  • thioamide therapy may be preferred in active disease

iodides

POTASSIUM IODIDE rapidly inhibits thyroglobulin organification and proteolysis in high doses

• results in rapid inhibition of thyroid hormone release, decreasing T3/T4 levels within 1-7 days

  • not used for chronic hyperthyroidism treatment; useful for only 2-8 weeks due to escape from inhibitory effects

• decreases vascularity and fragility of hyperplastic thyroid gland

  • reduces bleeding and thyroid hormone release during thyroidectomy

• disadvantages — increases store of iodine and thyroid hormone precursors in thyroid if used alone

  • delays onset of thioamide effects

  • prevents use of radioactive iodine (RAI) to destroy hyperactive thyroid tissues

• used in severe thyrotoxicosis when rapid hormone reduction is needed

  • administer at least one hour after dosing with methimazole or PTU to prevent increased synthesis of thyroid hormones

• can be used to protect workers and public from radioactive iodine released in the event of a nuclear accident

  • saturates thyroid and prevents uptake of radioactive iodine

• toxicity — reversible rash resembling allergic reaction, anaphylactic reaction

severe thyrotoxicosis / thyroid storm

medical emergency, where patient should be hospitalized

• reflects systemic decompensation due to chronic severe thyrotoxicosis

• symptoms — fever, tachycardia, arrhythmias, agitation, psychosis, seizures

• treatment — combinations of thioamine, beta-blockers, iodide after thioamine, glucocorticoids, cooling/supportive measures

  • iodides mainly used for rapid hormone reduction

beta-blockers

thyroid hormone increases beta-adrenergic receptor activity/expression, so beta-blockers are used in all hyperthyroid states for symptomatic control

• helps control of tachycardia, palpitations, arrhythmias, anxiety, tumor-related sympathetic symptoms

• diltiazem / verapamil → CCBs that can be used in patients who cannot tolerate beta-blockers

other drugs in hyperthyroidism management

• glucocorticoids → use to treat adrenal insufficiency complicating severe hyperthyroidism

  • also useful in some cases of Graves ophthalmopathy

• acetaminophen → used to control fever in cases

• iodinated radiocontrast media (ipodate) → inhibit deiodination of T4 to T3

  • not FDA approved, but has been used off-label

hyperthyroidism treatment considerations for Grves Orbitopathy

• radioactive iodine (RAI) → can increase risk of GO progression in patients with active GO

  • may be related to increases in TSH receptor antibody (TRAb) levels post-RAI

• thiomide anti-thyroid drugs → do not increase TRAb levels, producing less risk of GO progression

• glucocorticoids → low to moderate dose after RAI therapy may reduce risk of GO development or progression

• smoking increases risk of GO and should be discontinued