Thyroid Hormone Synthesis

• The thyroid gland is below the jawbone and above the clavicle bones.
• The thyroid gland affects virtually all organ systems and is crucial for normal growth and development, helping maintain metabolic stability.
• The thyroid gland serves as a reservoir for thyroid hormones, maintaining consistent blood levels.
• The hypothalamic-pituitary-thyroid axis controls thyroid hormone release.
• Patients seek medical attention for symptoms of hormone imbalance, thyroid enlargement, or palpable nodules.

Hypothalamic-Pituitary-Thyroid Axis

• The hypothalamus releases thyrotropin-releasing hormone (TRH).
• TRH signals the anterior pituitary to release thyroid-stimulating hormone (TSH).
• TSH stimulates thyroid follicular cells to produce thyroglobulin, leading to T3 and T4 production.

Thyroid Hormone Synthesis

• Follicular cells synthesize thyroglobulin, secreting it into the follicle lumen for iodination and storage.
• Thyroglobulin is inactive until iodination.
• Thyroid hormones are synthesized in the colloid of thyroid follicle cells and removed into circulation via capillaries.
• Thyroid hormones are made by attaching iodide (iodine) to a tyrosine molecule.

Affecting Factors

• Bromine, fluorine, and lithium can block iodide transport, inhibiting hormone production.
• Sulfonylureas and sulfonamides can impair the organification and coupling of thyroid hormones.
• Large doses of iodide or lithium can inhibit thyroid hormone secretion.

Thyroid Hormone Production Steps

• The sodium-iodide symporter brings iodide into the cell.
• The Pedrin transporter moves iodide into the colloid of the gland.
• Follicular cells synthesize enzymes and thyroglobulin for the colloid.
• Thyroid peroxidase adds iodine to tyrosine on thyroglobulin to make T3 and T4.
• T4 (thyroxine) and T3 (triiodothyronine) are the active thyroid hormones.
• Thyroglobulin is taken back into follicular cells into vesicles.
• Intracellular enzymes separate T3 and T4 from thyroglobulin.
• T3 and T4 enter circulation via capillaries.

Coupling Reactions

• Tyrosine iodination forms monoiodotyrosine (MIT) or diiodotyrosine (DIT).
• Combining MIT and DIT forms triiodothyronine (T3).
• Combining two DIT molecules forms thyroxine (T4).
• Reverse T3 (RT3) is a metabolically inactive form of thyroid hormone, generated from T4 by deiodinase enzymes.

Thyroid Hormone Formation

• T4 and T3 are formed within thyroglobulin (TG).
• Iodide is transported into thyroid cells using a symporter.
• Pederin transports iodide into the follicular lumen.
• Thyroid oxidase oxidizes iodide and binds it to tyrosine to form MITs and DITs, which then form T3 and T4.

Thyroid Hormone Transport

• Released thyroid hormones bind to thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin.
• T3 and T4 have the strongest affinity for TBG, also binding to albumin due to its abundance.
• Transthyretin has a higher affinity for T4 than T3.
• Unbound T3 and T4 are the active forms.
• Free T4 has a half-life of 6-7 days, and T3 has a half-life of 6-24 hours.
• 99% of T3 and T4 are bound to proteins.

Binding Affecting Factors

• Steroid use or liver cirrhosis can decrease albumin production, increasing free hormone levels.
• During pregnancy, the liver produces more TBG, decreasing free hormone levels.

Hypothalamic-Pituitary-Thyroid Axis Feedback Loop

• Cold temperatures affect the hypothalamus, impacting TRH production.
• T3 has a negative feedback loop on the hypothalamus, reducing TRH production when levels are high.
• The anterior pituitary is stimulated to release TSH from the hypothalamus.
• T3 and T4 have a negative feedback loop on the anterior pituitary, reducing TSH production when levels are high.
• The thyroid gland is affected by iodine levels.
• Physiological or emotional stress can affect the entire process.

Comparing T3 and T4

• T3 is produced in smaller amounts with higher biological activity, acting as the active hormone.
• T4 is produced in higher amounts with lower biological activity, acting as a reservoir for T3, and can be converted to inactive reverse T3 (RT3).
• Deiodinase enzymes convert T4 to T3 in peripheral tissues
• T3 is formed by one MIT and one DIT, while T4 is formed by two DITs.

Physiological Effects

• T3/T4 increases basal metabolic rate (BMR), heat generation, and oxygen consumption.
• T3/T4 increases gluconeogenesis, glycolysis, glucose absorption, lipolysis, and protein turnover.
• T3/T4 stimulates bone maturation and growth, and increases cardiac output by increasing heart rate and contractility.

Thyroid Function Tests (TFTs)

• TFTs measure thyroid hormone components, with the most common being TSH, free T3, and free T4.
• TSH is very sensitive due to negative feedback loops.

TFT Values Interpretation

• Central Hypothyroidism: Low TSH, Low Free T3/T4, caused by primary pituitary failure
• Primary Hypothyroidism: High TSH, Low Free T3/T4, caused by primary thyroid failure
• Primary Hyperthyroidism: Low TSH, High Free T3/T4, caused by overproduction of thyroid hormones
• Secondary Hyperthyroidism: High TSH, High Free T3/T4, caused by TSH over production

Affecting Factors

• Non-thyroidal conditions, acquired pituitary dysfunction, altered thyroid-binding globulin levels, increased circulating free fatty acids, decreased peripheral conversion of T4 to T3, and altered ratio of T3 to reverse T3 can affect TFTs.

Reference Ranges

• TSH: 0.5 - 4.7 mU/L
• Total T4: 5 - 12 mcg/dL

TFT Interpretation Summary

• High TSH, Normal Free T4/T3 indicates Mild/Subclinical Hypothyroidism.
• High TSH, Low Free T4/T3 indicates Definite Hypothyroidism.
• Low TSH, Normal Free T4/T3 indicates Mild/Subclinical Hyperthyroidism.
• Low TSH, High Free T4/T3 indicates Hyperthyroidism.
• Low TSH, Low Free T4/T3 indicates Non-thyroidal illness or rare pituitary hypothyroidism.

Half-Lives

• Free T4 has a half-life of about 6-7 days.
• T3 has a half-life of about 6-24 hours.
• Normal T4, normal T3, low TSH indicates subclinical hyperthyroidism.

Hypothyroidism

• Symptoms: Fatigue, cold intolerance, loss of eyebrow hair, sleep problems, muscle aches, infertility, slow heartbeat, weight gain, constipation, headaches.
• Causes: Iodine deficiency is the most common cause worldwide, with spontaneous hypothyroidism more common in older women and 10 times more common in women than men.
• Primary causes: Hashimoto's thyroiditis, surgery, radiation therapy, postpartum thyroiditis, post-inflammatory thyroiditis, iodine deficiency, medications.
• Secondary causes: Pituitary or hypothalamic disorders.
• Treatment Goals: Normalize thyroid hormone levels, provide symptomatic relief, and prevent deficits in children.

Hyperthyroidism

• Symptoms: Heat intolerance, fine hair, bulging eyes, tachycardia, increased systolic blood pressure, weight loss, muscle wasting, tremors, diarrhea, menstrual changes.
• Is exposure of tissues to excessive T4 and T3, or an overactive thyroid, occurring in about 1.2% of the population, peaking between 20-39 years of age.
• Most common causes: Grave's disease, toxic multinodular goiter, toxic solitary nodules, thyroiditis, thyroid hormone excess.
• Grave's disease is the most common cause, an autoimmune disease caused by antibodies to the TSH.
• Grave's Disease: Autoimmune disease, more common in women, with an enlarged thyroid gland, bulging eyes, and TSH is low due to feedback by T3 and T4.
• Other Causes: Thyroid or pituitary tumor, and thyroid toxicosis (accidental or deliberate ingestion of thyroxine).
• Treatment Goals: Eliminate excess hormone, minimize symptoms, and avoid long-term consequences, through medications, radioactive iodine, or surgery/thyroidectomy.

Thyroid Hormones on Organ Systems

• Heart: Increases beta receptors, leading to increased/decreased heart rate, atrial fibrillation.
• Adipose Tissue: Stimulates lipolysis, leading to anorexia/obesity.
• GI Tract: Increases GI tone and motility, leading to constipation/diarrhea.
• Nervous System: Affects development, leading to mental retardation/ slowing/ irritability.
• Skeletal System: Stimulates bone maturation and growth, leading to muscle weakness/excessive bone loss.

Therapy Evaluation

• Evaluate patients monthly until levels are within reference ranges.
• Document signs and symptoms of hyper/hypothyroidism.

Key Points

• The hypothalamus secretes TRH, stimulating the pituitary to secrete TSH, which stimulates the thyroid to secrete thyroid hormones.
• The thyroid gland transports iodide and binds it to tyrosine to make T4 and T3.
• T4 is formed by 2 DITs, T3 is formed by 1 MIT and 1 DIT.
• T3 is biologically more active, while T4 is more abundant.
• Thyroid hormones are mostly bound, with free hormone being the active form.
• Thyroid affects the heart, metabolism, nervous system, etc., and disease occurs from under or overactive thyroid hormone.

Explore the key steps in thyroid hormone production, from the roles of the hypothalamic-pituitary-thyroid axis and thyroglobulin iodination to the impact of deficiencies in pendrin transporter protein. Learn how substances like sulfonylureas and sulfonamides interfere with synthesis, and understand the critical interventions for neonates born without a thyroid gland.