Thyroid Disorders and Treatments Quiz

Thyroid and Anti-Thyroid Drugs

• Thyroid gland produces two types of hormones:
  • Iodothyronines from thyroid follicles (thyroxine (T4) and 3,5,3'-triiodothyronine (T3))
  • Calcitonin from parafollicular cells (C-cells)
• Thyroid hormones are synthesized and stored as amino acid residues of thyroglobulin, a glycoprotein.
• T3 is 3-4 times more potent than T4.
• T3 has a half-life of 1 day, while T4 has a half-life of 7 days.
• T4 is secreted by the gland solely, whereas T3 is produced via thyroid and peripheral conversion.
• The thyroid gland produces 80% of T4 and 20% of T3.
• The major carrier of thyroid hormones is thyroxine-binding globulin (TBG), a glycoprotein.

Major Steps in Synthesis, Storage, Release, and Interconversion of Thyroid Hormones

• Uptake of iodide ion (I−) by the gland.
• Oxidation of iodide and iodination of tyrosyl groups of thyroglobulin.
• Coupling of iodotyrosine residues to generate iodothyronines.
• Resorption of thyroglobulin colloid from the lumen into the cell.
• Proteolysis of thyroglobulin, releasing thyroxine and triiodothyronine into the blood.
• Recycling of iodine within the thyroid cell via deiodination of mono- and diiodotyrosines, and reuse of the I−.
• Conversion of thyroxine (T4) to triiodothyronine (T3) in peripheral tissues and in the thyroid.

Uptake of Iodide

• Dairy products and fish are relatively high in iodine.
• Iodine in the diet reaches circulation as iodide ion (I−).
• The thyroid actively transports I− via sodium iodide symporter (NIS).
• NIS is inhibited by thiocyanate and perchlorate.

Oxidation and Iodination

• Iodination of tyrosine requires iodinating species to be in a higher state of oxidation.
• Thyroid peroxidase accomplishes the oxidation of iodide to its active form.
• Iodination leads to the formation of monoiodotyrosyl and diiodotyrosyl residues in thyroglobulin.
• Thyroglobulin is stored in the thyroid follicle lumen.

Formation of Thyroxine and Triiodothyronine from lodotyrosines

• Coupling of two diiodotyrosyl residues forms thyroxine (T4).
• Coupling of monoiodotyrosyl and diiodotyrosyl residues forms triiodothyronine (T3).
• The same thyroid peroxidase catalyzes these couplings.
• The rates of synthesis depend on TSH concentration and iodide availability.

Resorption, Proteolysis, and Secretion

• Endocytosis of colloid from the thyroid follicle lumen.
• Within the cell, thyroglobulin appears as intracellular colloid droplets, fusing with lysosomes containing proteolytic enzymes.
• TSH increases the degradation of thyroglobulin.
• Liberated hormones (T3 and T4) exit the cell.
• Monoiodotyrosine and diiodotyrosine are selectively metabolized, and iodine is reincorporated into protein.

Thyroid Hormone Metabolism and Conversion (T4 to T3)

• Normal daily thyroxine production is ~ 80-100 μg.
• Normal daily triiodothyronine production is ~ 30-40 μg.
• Peripheral deiodination of T4 in tissues accounts for ~ 80% of circulating triiodothyronine.

Transport of Thyroid Hormones in the Blood

• Thyroid hormones are transported in the blood in strong but non-covalent association with plasma proteins (TBG).
• TBG is the major carrier of thyroid hormones.
• T4, but not T3, is also bound by transthyretin (thyroid-binding prealbumin).
• Albumin can bind T4 when carrier proteins are saturated.
• Only unbound hormone has metabolic activity.

Factors that Alter Binding to TBG

• Drugs that increase binding include estrogens, methadone, and clofibrate.
• Drugs that decrease binding include glucocorticoids, androgens, L-asparaginase, salicylates, and mefenamic acid.
• Systemic factors, like liver disease and acute/chronic illness might influence binding.

Degradation and Excretion

• The liver is the major site of non-deiodinative degradation of thyroid hormones.
• T4 and T3 are conjugated with glucuronic and sulfuric acids via their phenolic hydroxyl groups.
• The conjugated hormones are excreted in bile.

Regulation of Thyroid Function

• Thyrotropin-releasing hormone (TRH) is synthesized by the hypothalamus.
• TRH stimulates the release of preformed TSH from the anterior pituitary.
• TSH secretion is controlled by TRH and thyroid hormone concentration via feedback mechanisms.

Actions of Thyroid-Stimulating Hormone (TSH)

• TSH stimulates all the phases of hormone synthesis & release (hormone synthesis, iodide uptake, organification, endocytosis, proteolysis of colloid).
• TSH results in increased vascularity of the gland and hypertrophy and hyperplasia of thyroid cells.
• In response to TSH, the thyroid produces and secretes T4, which is then converted to T3.

Actions of Thyroid Hormones

• Thyroid hormones act primarily through binding to nuclear thyroid hormone receptors (TRs) and modulating specific genes.
• Thyroid hormones have diverse effects; for instance, the body's development, thermoregulation, and cardiovascular function.

Major Clinical Effects of Thyroid Hormones

• Effects on growth and development, including brain development.
• Effects on thermogenesis
• Cardiovascular effects, including positive chronotropic/inotropic effects, cardiac hypertrophy, and decreased peripheral vascular resistance.
• Metabolic effects, including increased glucose absorption from the gut, metabolism of cholesterol to bile acids, and insulin resistance.

Levothyroxine

• A synthetic T4 hormone used to treat hypothyroidism.
• Levothyroxine can be used with surgery or radioiodine therapy to manage thyrotropin-dependent well-differentiated thyroid cancer.

Absorption of Oral T4

• Absorption from the gastrointestinal tract is 40-80% primarily in the jejunum and upper ileum.
• Absorption increases with fasting and decreases with malabsorption syndromes and some foods (soybeans, milk, etc.).
• Many drugs affect absorption (bile acid sequestrants, sucralfate, proton pump inhibitors, various minerals).
• For optimal absorption, levothyroxine should be taken on an empty stomach, 2-4 hours before meals and any interacting drugs.

Liver Degradation and Excretion

• The liver is the major site of non-deiodinative degradation of thyroid hormones.
• Thyroid hormones are conjugated with glucuronic and sulfuric acids.
• Conjugated hormones are excreted in the bile.

TSH Suppression Therapy

• TSH suppression therapy in patients with thyroid nodules or thyroid cancer involves administering levothyroxine to suppress TSH.
• It decreases nodule volume.
• TSH suppression should not be routinely recommended as a general practice but may be appropriate in cases of elevated TSH.

Anti-Thyroid Drugs and Other Thyroid Inhibitors

• Anti-thyroid drugs interfere directly with thyroid hormone synthesis.
• Ionic inhibitors block iodide transport.
• High iodide concentrations decrease thyroid hormone release and synthesis.
• Radioactive iodine damages the gland with ionizing radiation.

Adjuvant Therapy

• Adjuvant therapy with drugs that have no specific effects on thyroid hormone synthesis but useful for controlling peripheral manifestations of thyrotoxicosis.
• These include inhibitors of peripheral thyroxine deiodination (e.g., dexamethasone).
• Also, beta-adrenergic receptor antagonists (e.g., propranolol, atenolol).

Three General Categories of Antithyroid Drugs

• Thioureylenes (e.g., propylthiouracil, methimazole, carbimazole)
• Aniline derivatives (e.g., sulfonamides)
• Polyhydric phenols (e.g., resorcinol).

Propylthiouracil (PTU)

• A thiourea antithyroid agent.
• PTU binds to thyroid peroxidase and inhibits iodide to iodine conversion.
• PTU interferes with iodine incorporation into tyrosyl residues of thyroglobulin and inhibits coupling of iodotyrosyl residues to form iodothyronines.
• In addition to blocking hormone synthesis, PTU partially inhibits the peripheral deiodination of T4 to T3.

Propylthiouracil (PTU) Administration and Dosage

• PTU is administered orally, initially in three divided doses (300 mg/day).
• After the initial treatment, the dosage is adjusted to 100-150 mg/day.

Propylthiouracil (PTU) Absorption, Distribution, and Duration

• Absorption: ~75%
• Distribution: 80-85% bound to plasma proteins (lipoproteins, albumin).
• Duration: ~12-24 hours.

Propylthiouracil (PTU) Adverse Reactions

• Acute liver injury (common in pregnancy, adults, and children).
• Hypothyroidism.
• Vasculitis (symptoms include fever, weight loss, myalgia, arthralgia, and paresthesia; onset within weeks to years).
• Hypersensitivity reactions (Steven Johnson syndrome, toxic epidermal necrolysis, urticaria).
• Agranulocytosis (rare, potentially life-threatening, fever, sore throat, and granulocyte count less than 500/µL).

Methimazole

• A thionamide antithyroid agent, active metabolic product of carbimazole.
• 10 times more potent than PTU.
• Inhibits thyroid peroxidase actions—leading to reduced thyroid hormone synthesis.
• Does not affect the existing thyroxine (T4) and triiodothyronine (T3) in the circulation.

Methimazole Administration and Absorption

• Rapid and extensive absorption after oral administration.
• Little-to-no protein binding.
• Rapidly and extensively metabolized by the liver.
• Excreted mainly via the urine; fecal elimination is minimal.

Methimazole Adverse Effects

• Side effects are mostly dose-related (hives, itching).
• Serious adverse effects (most commonly):
  • Agranulocytosis
  • Hepatotoxicity
• Teratogenicity

Teratogenicity

• Methimazole may cross the placental membrane readily & causes immense fetal adverse effects, especially during the first trimester of pregnancy. This includes possible congenital disabilities such as goiter, cretinism, etc.
• Propylthiouracil (PTU) is generally preferred over methimazole for use during pregnancy, especially during the first trimester.

Ionic Inhibitors (thiocyanate, perchlorate, and fluoroborate)

• Substances that interfere with iodide concentration by the thyroid gland.
• Thiocyanate is produced by plant glycoside hydrolysis (e.g., cabbage and cigarette smoking; significantly increased concentration in blood and urine).
• Perchlorate is a strong inhibitor of iodide transport, and is associated with many effects such as GI irritation and skin rash.

Radioactive Iodine (Iodine-131)

• A radioactive isotope primarily used for thyroid diagnosis and treatment.
• Radioactive iodine (I-131) emits both gamma rays and beta particles, degrading within 56 days.
• Used to treat overactive or enlarged thyroids, as well as thyroid cancer.
• Treatment can cause hypothyroidism.
• Pregnancy is a major contraindication.

Iodine-Basedow Phenomenon

• Hyperthyroidism arising from iodine supplementation.
• May occur in those with pre-existing iodine deficiency.

Thyroid Storm

• Life-threatening complication of thyrotoxicosis.
• Symptoms: Fever, tachycardia, agitation, nausea, vomiting, diarrhea, and confusion; coma or death is possible.
• Treatment: supportive measures like intravenous fluids, cooling blankets, antipyretics; high doses of anti-thyroid drugs are important.

Plummer's Disease (Toxic Nodular Goiter)

• A form of hyperthyroidism due to abnormal nodules in the thyroid gland.
• Medical therapy less effective for Plummer's Disease compared to Graves' Disease.
• RAI is also effective, though results are delayed and it usually fails to resolve a goiter.
• Surgical treatment is preferred for Plummer's Disease.

Other Information

• Pediatric population: PTU is associated with liver injury in both adults and children.
• Renal impairment: dose adjustment is not required.
• Hepatobiliary disease: PTU should not be used in cases of liver impairment.
• Pregnancy: PTU can cross placenta and cause fetal cretinism and goiter; methimazole is preferred over PTU in pregnancy to lower the risk of adverse effects for the developing fetus.
• Breastfeeding: PTU is present in breast milk, but generally no clear-cut recommendations.
• Thyroid storm: life-threatening complication of thyrotoxicosis, characterized by severe hyperthyroidism.

Test your knowledge on the management of thyroid disorders, including treatment options for conditions such as Plummer's Disease and thyrotoxicosis. This quiz covers important considerations for medication use during pregnancy, operative risks, and symptom recognition in thyroid storms.