Thyroid Gland Anatomy and Function

Thyroid Hormone Synthesis, Transport, and Cellular Mechanism

• Learning Outcomes:
  • Describe the structure and location of the thyroid
  • Describe the origin of the thyroid gland and its functional relationships
  • Explain the mechanisms and control of thyroid hormone synthesis
  • Outline the biochemical and clinical functions of thyroid hormones

Thyroid Gland: Location and Structure

• Location: Situated below the thyroid cartilage, behind the strap muscles.
• Structure: Comprises two lobes joined by an isthmus, located below the cricoid cartilage.
• Additional finding: Pyramidal lobe in approximately 50% of adults; non-palpable; enlarges with disease.

Thyroid Gland & Follicles

• Functional unit: Thyroid follicle or acinus
• Follicle components: Follicular (epithelial) cells and a lumen filled with colloid.
• Capillaries: Deliver nutrients and transport hormones
• Sympathetic Innervation: Influences hormone synthesis/secretion
• Lymphatics: Drain excess fluid
• C-Cells (Parafollicular Cells): Produce calcitonin

Thyroid Gland: Blood Supply & Innervation

• Arterial Supply:
  • Superior thyroid artery (from external carotid)
  • Inferior thyroid artery (from thyrocervical trunk)
• Venous Drainage:
  • Superior and middle thyroid veins
  • Inferior thyroid vein → internal jugular vein
  • Brachiocephalic vein
• Innervation:
  • Recurrent laryngeal nerve (branch of vagus)
  • Damage to the recurrent laryngeal nerve may cause vocal cord paralysis
• Emergency Airway: Cricothyrotomy through the cricothyroid membrane.

Thyroid Gland Origin - Embryology

• The thyroid is the first endocrine gland to develop, appearing around the 24th day of gestation (3rd week of gestation).
• Origin: From the first pharyngeal arch's thyroglossal duct, a diverticulum that arises in the floor of the pharynx.
• Descent and Development: Grows and descends in the neck as an initially hollow structure, eventually solidifying and becoming bilobed with an isthmus.
• Initial descent: Initially anterior to the pharyngeal gut, still connected to the tongue by a thyroglossal duct; eventually bifurcates into two lobes

Thyroid Gland Origin - Embryology (Continuing)

• 7th week: As the gland descends, it takes on its mature shape, positioned anterior to the trachea.
• Complete Obliteration: The thyroglossal duct completely obliterates by 7-10 weeks.
• Remnants: Remnants of the duct may persist.
• Ectopic thyroid tissue: Can arise along this path.

Ectopic Thyroid Gland

• Example: A 4-year-old girl with slowed growth.
• Possible causes: Thyrotropin (TSH) 55 ulU/ml (nl 0.5-4.5), Total Throxine (T4) 3.5 mcg/dl (nl 5-12)

Thyroid Hormone: An Overview

• Synthesis: Thyroid hormones (T3 and T4) are synthesized from iodide (I) and tyrosine residues of thyroglobulin
• 'Reverse T3' (rT3): May be found in significant amounts; biologically inactive.

What Is Thyroid Hormone?

• Critical function: For brain development, skeletal function, and growth in infants
• Metabolic regulation: Regulates metabolic activity in all tissues except brain, spleen, and testes
• Basal metabolic rate and oxygen consumption: Increases these via Na+-K+ ATPase stimulation
• Tissue function: Affects virtually all tissues.

Thyroid Hormone Synthesis - Building Blocks

• Components: Iodine, thyroglobulin, tyrosine

Iodine

• Micronutrient: Crucial for thyroid hormone synthesis
• Dietary sources: Seafood, dairy products, grains, and vegetables grown in iodine-rich soil.

Recommended Daily Intake (IOM) - Iodine

• Kids: About 90-130 mcg
• Adults: About 150 mcg
• Pregnant women: 220 mcg
• Lactating women: 290 mcg

Endemic Goiter

• Cause: Deficiency of iodine in the soil leads to hypothyroidism, with the thyroid gland enlarging (forming a goiter) to produce more thyroid hormone.
• Prevention: Worldwide, table salt (NaCl) is enriched with iodine (iodized salt).

Cretinism in Endemic Severe Iodine Deficiency

• Fetal and postnatal development: Thyroid hormone is vital for fetal and postnatal brain and skeletal development.
• Iodine deficiency during pregnancy and infancy can result in coarse facial features, umbilical hernia, large fontanelles, macroglossia, etc.
• Consequences: Continued iodine deficiency postnatally leads to stunted physical and cognitive/neurologic development.

Thyroid Hormone Synthesis-Building Blocks (Continuing)

• Thyroglobulin: A large glycoprotein, created by the rough ER of thyroid follicular epithelial cells; stored in vesicles and exocytosed into colloid
• Composed of two subunits, containing tyrosine residues sterically oriented for thyroid hormone production

Synthesis of Thyroid Hormones

• Steps: Iodine trapping, oxidation/organification, coupling, endocytosis, proteolysis, transport, action on receptors

Synthesis of Thyroid Hormones (details)

• Iodide trapping: Active transport across the basal membrane of follicular cells against a gradient, involving a sodium-iodide symporter (Na+/K+ ATPase). Stimulated by TSH. Perchlorate anions (CIO4) inhibit uptake.
• Oxidation:Conversion of I− to I2, essential for its incorporation into thyroglobulin, catalyzed by thyroid peroxidase (TPO), requires H2O2

Synthesis of Thyroid Hormones (details 2)

• Coupling: Formation of T4 and T3, through the combination of MIT and DIT molecules within thyroglobulin,catalyzed by TPO
• Endocytosis: Colloid uptake by follicular cells.
• Proteolysis: Lysosomal proteases digest thyroglobulin, releasing free T3 and T4

Transport of Thyroid Hormones

• Hydrophobic nature: Thyroid hormones are hydrophobic and require carrier proteins to be transported in the bloodstream.
• Binding proteins. T4 binds more tightly to three significant serum binding proteins (TBG>TBPA>albumin)

Thyroid Hormone Circulates Bound to Serum Proteins

• Majority bound: T4 and T3 are primarily bound to serum proteins (>99%).
• Free hormone: A small percentage of T4 (0.04%) and T3 (0.5%) is unbound and biologically active.

Conversion of Iodothyronines

• T4 to T3: Peripheral tissues, particularly the liver and kidneys, convert T4 to T3 through deiodination.
• Biological activity T3: T3 is considerably more bio-active than T4.
• Half-life: T4 has a longer half-life than T3.
• Prohormone: T4 is a prohormone for T3.

Thyroid is Under Hypothalamic/Pituitary Control - Negative Feedback Loop

• Hypothalamic-pituitary-thyroid axis: A negative feedback loop involving TRH, TSH, and thyroid hormones.
• Regulation: Thyroid hormone levels regulate the release of TRH and TSH.

Regulation of Thyroid Hormone Synthesis

• Factors: Hypothalamus (TRH), Anterior pituitary gland (TSH), Availability of iodine, Thyroid gland integrity, Tissue conversion (T4 to T3).

Thyroid Stimulating Hormone (TSH)

• Glycoprotein: Created in the anterior pituitary, with slight increased levels at night.
• Effects: Stimulates thyroid hormone synthesis and increases thyroid gland size/vascularity.
• Feedback: Increased thyroid hormone levels decrease TSH release. Decreased levels increase TSH release; Crucial for iodine deficiency goiter.

Thyroid Response to TSH

• Effects: Increased cAMP, Ca2 +, protein kinase activity, colloid uptake, T3 and T4 liberation, thyroglobulin production, iodine uptake, thyroglobulin iodination. Thyroid size and activity increase.

Inhibitors of Thyroid Hormone Synthesis

• Inhibitors: Drugs and goitrogens. These substances hinder steps in thyroid hormone synthesis

Biochemical and Clinical Functions of Thyroid Hormones (Mechanism of Action)

• Mechanism: T4 converts to T3, binds to thyroid receptor, complexes with RXR, and binds to the thyroid response element in DNA. Protein synthesis then mediates the cellular responses.

Effects-Metabolic

• Carbohydrate metabolism effects: Increased glucose uptake, enhanced glycolysis, enhanced gluconeogenesis, and increased insulin secretion.
• Lipid metabolism effects: Increased lipolysis, decrease fatty acid and fat stores, increased B-oxidation, decreased plasma cholesterol phospholipids & TAG levels.
• Other metabolic functions: Increased mitochondria count, Na+/K+ ATPase activity, 02 consumption, and protein synthesis, and an increase in the metabolic rate.

Effects-Systemic

• Cardiovascular effects: Increased blood flow, cardiac output, heart rate, and heart strength.
• Respiratory effects: Increased respiration.
• Central nervous system effects: Essential for normal CNS neuronal development, enhances wakefulness, alertness, memory, learning, and emotional tone; increases speed/amplitude of peripheral nerve reflexes.

Effects-Growth & Development

• Growth effects: Growth and maturation of bone, teeth, and skin; increase in hair, follicles, and nails.
• Skeletal muscle: Increased rate and force of skeletal muscle contraction, and fetal CNS development.
• General child growth.

Summary of Actions

• Development: Inhibits nerve cell replication, enhances nerve cell body growth, branches of dendrites, and axon myelinization rate.
• Body Growth: Stimulates gene expression for growth hormone, increased structural and enzymatic protein synthesis, and bone calcification.
• Basal Energy: Regulates basal metabolic rates of oxidative phosphorylation, body heat production, and O2 consumption ("thermogenic effect")
• Metabolism: Stimulates the synthesis and degradation pathways of carbohydrates, lipids, and proteins
• TSH secretion: Inhibits TSH secretion by decreasing sensitivity of thyrotrophs to TRH.

Tests of Thyroid Function

• Thyroid Stimulating Hormone (TSH): Measures pituitary secretion of TSH in response to T4 feedback. Normal range = 0.5 – 4.5mU/L
• Free Thyroxine (FT4): Measures unbound T4. Normal range = 0.8 – 1.8ng/dL
• Free Triiodothyronine (FT3): Measures unbound T3. Normal range = 2.3 – 4.2pg/mL
• Total Thyroxine (T4): Measures bound plus free T4. Normal range = 5–12mcg/dL
• Total Triiodothyronine (T3): Measures bound plus free T3. Normal range = 60–180ng/dL

Log-Linear Inverse Relationship between TSH and T4

• Wide variation in individual "set points"
• Specific TSH:T4 set-point for each individual.

TSH Assay as Screening Test

• Optimal screening test for ambulatory healthy patients. Low TSH (<0.5 mU/L) suggests hyperthyroidism. Normal TSH (0.5–4.5 mU/L) means euthyroidism. High TSH (>4.5 mU/L) suggests hypothyroidism.

Thyroid Disorders (TSH, T4, T3, FT4)

• Primary hypothyroidism: Elevated TSH, decreased T4, T3, and FT4.
• Graves' Disease: Increased TSH, decreased T4 and T3, and increased FT4 and FT3.
• TSH deficiency (secondary hypothyroidism): Decreased TSH causing decreased T4 and T3.

MCQ (Multiple Choice Questions)

• MCQ 1 (Iodine activation): Thyroid peroxidase (TPO).
• MCQ 2 (Primary hypothyroidism): High TRH, high TSH, low T4.

Case Presentations

• Case presentations highlight clinical conditions and associated laboratory findings. Examples include primary hyperthyroidism in a 46-year-old woman, with elevated total/free T4 and suppressed TSH, presenting with weight loss and diarrhea;
• Case presentation for Primary Hypothyroidism, in a 72 year old man, presenting with decreased total/free T4 and elevated TSH, and vague symptoms/ reduced cognition. .

Explore the anatomy and function of the thyroid gland, including the pyramidal lobe, anatomical boundaries, and surgical considerations during thyroidectomy. Also covers the thyroid hormone receptor (TR) complex and its role in initiating transcription.