Anatomy and Physiology of the Thyroid Gland and Parathyroid Gland

PART A: THYROID GLAND

1. Embryology

2. Gross Anatomy

• Two lateral lobes (right and left)
• An isthmus connecting them anteriorly across the 2nd and 3rd tracheal rings
• A pyramidal lobe extending superiorly from the isthmus in ~50% of individuals (a remnant of the thyroglossal duct)

• Each lobe: ~5 cm long, 3 cm wide, 2 cm thick
• Weight: approximately 20-30 g in adults
• Isthmus: ~1.25 cm wide, ~1.25 cm tall

3. Anatomical Relations

4. Blood Supply

• Superior thyroid artery: First branch of the external carotid artery; enters the superior pole
• Inferior thyroid artery: Branch of the thyrocervical trunk (from subclavian artery); enters the posterior aspect near the middle of each lobe; most important blood supply - also supplies the parathyroid glands
• Thyroidea ima artery (inconstant): Arises from brachiocephalic or aortic arch, enters at the isthmus (~1-3% of people)
• Blood flow is approximately 5 times the weight of the gland per minute, one of the highest blood flows per gram of any tissue in the body (Guyton & Hall)

• Superior thyroid vein drains into the internal jugular vein
• Middle thyroid vein drains into the internal jugular vein
• Inferior thyroid vein(s) drain into the brachiocephalic veins

• Superior part drains to upper deep cervical nodes
• Inferior part and isthmus drain to pretracheal and paratracheal (Level VI) nodes
• Important in thyroid cancer staging

5. Nerve Supply

• Adrenergic fibers from the middle cervical ganglion (sympathetic) and parasympathetic from the vagus nerve control blood flow and modulate hormone secretion
• The gland is NOT innervated by motor fibers; secretion is primarily under hormonal control (TSH)

6. Histology / Microanatomy

1. Follicles: The functional unit. Each follicle is a closed sphere (100-300 µm diameter) lined by a single layer of cuboidal to columnar follicular epithelial cells. The lumen is filled with gelatinous colloid (mainly thyroglobulin).

• When the gland is active: follicular cells become tall (columnar), colloid is reduced
• When the gland is inactive: cells are flat (squamous), colloid is abundant

1. Follicular cells (thyrocytes): Synthesize thyroglobulin and produce T3/T4. They have a well-developed rough ER, Golgi apparatus, and abundant mitochondria.
2. Parafollicular cells (C cells): Located in the interfollicular stroma and between follicular cells, but do not border the follicular lumen. They secrete calcitonin, which lowers serum calcium. They are derived from neural crest cells.

7. Physiology of the Thyroid Gland

A. Thyroid Hormones

• Thyroxine (T4): 93% of secreted hormone; tetraiodothyronine; prohormone; half-life ~6-7 days
• Triiodothyronine (T3): ~7% secreted; 3-4x more potent than T4; most active form; half-life ~1 day
• Calcitonin: from C cells

B. Hormone Synthesis (Step-by-Step)

• Iodide (I⁻) from blood is actively transported into follicular cells by the Sodium-Iodide Symporter (NIS) on the basolateral membrane - co-transports 2 Na⁺ with 1 I⁻ against concentration gradient
• Energy comes from Na⁺-K⁺-ATPase
• Normal gland: intracellular I⁻ = 30 × plasma concentration; active gland: up to 250 ×
• Stimulated by TSH

• Follicular cells synthesize thyroglobulin (MW ~335,000 Da; contains ~70 tyrosine residues) in the RER and Golgi
• Secreted by exocytosis into the follicular lumen

• I⁻ exits the apical membrane via pendrin (chloride-iodide counter-transporter) into the lumen
• Thyroid peroxidase (TPO) + H₂O₂ oxidizes I⁻ → I₂ (active iodine) at the apical membrane

• Active iodine binds tyrosine residues on thyroglobulin:
• 1 iodine + tyrosine → Monoiodotyrosine (MIT)
• 2 iodines + tyrosine → Diiodotyrosine (DIT)

• TPO catalyzes coupling:
• MIT + DIT → T3 (triiodothyronine)
• DIT + DIT → T4 (thyroxine)
• The hormones remain stored within the thyroglobulin molecule as colloid (enough for ~2-3 months supply)

• TSH stimulates follicular cells to engulf colloid by pinocytosis/endocytosis
• Lysosomes fuse with endosomes → proteases cleave thyroglobulin → releases MIT, DIT, T3, T4
• MIT and DIT are deiodinated intracellularly (iodine recycled); T3 and T4 enter the bloodstream
• In blood: T3 and T4 are bound to thyroxine-binding globulin (TBG, ~70%), albumin, and transthyretin

• ~80% of circulating T3 is produced by peripheral deiodination of T4 by deiodinase enzymes (mainly in liver and kidney)

C. Actions of Thyroid Hormones

D. Regulation of Thyroid Secretion (HPT Axis)

1. TRH (thyrotropin-releasing hormone): Released from the paraventricular nucleus of the hypothalamus → travels via portal blood to anterior pituitary
2. TSH (thyroid-stimulating hormone / thyrotropin): Released from thyrotrophs of the anterior pituitary (MW ~28,000; glycoprotein)

• Stimulates all steps of thyroid hormone synthesis and release
• Mechanism: TSH binds G-protein coupled receptor → adenylyl cyclase → cAMP → protein kinase A → multiple phosphorylations
• Effects: increased iodide trapping, thyroglobulin proteolysis, iodination, cell growth, columnar transformation

1. Negative feedback: Rising T3/T4 inhibits both TRH release (hypothalamus) and TSH secretion (pituitary)
2. Cold/stress can stimulate TRH release, increasing thyroid output

E. Calcitonin

• Secreted by C cells in response to hypercalcemia
• Lowers serum calcium by inhibiting osteoclast activity (decreasing bone resorption)
• Physiologically less important in adults; more relevant in children during bone formation

PART B: PARATHYROID GLANDS

1. Embryology

• Superior parathyroid glands (parathyroid IV): Derived from the 4th pharyngeal pouch, along with the thyroid C cells
• Inferior parathyroid glands (parathyroid III): Derived from the 3rd pharyngeal pouch along with the thymus; they descend with the thymus and may therefore be found anywhere from the angle of the jaw to the anterior mediastinum (ectopic locations common)
• This crossed origin explains why the inferior glands have more variable locations than the superior glands

2. Gross Anatomy

• 84-87% of people have all 4 glands
• 3% to 6% have only 3
• Supernumerary (5th or more) glands occur in a small percentage; can be found in the mediastinum (Cummings Otolaryngology)

• Weight: 30-50 mg each
• Shape: Oval or bean-shaped
• Color: Yellow to brown (darker in young, more yellow in elderly due to increasing fat content)
• Dimensions: approximately 5 mm × 3 mm × 1 mm

• Superior parathyroid (PT IV): Located above the level where the RLN crosses the inferior thyroid artery; typically at the level of the cricoid cartilage or upper thyroid lobe, posterior surface; more consistent in position
• Inferior parathyroid (PT III): Located below the RLN-inferior thyroid artery crossing; near the inferior pole of the thyroid or in the thyrothymic ligament; more variable in location and may be in the anterior mediastinum

3. Vascular Anatomy (Clinically Critical)

• Both superior and inferior parathyroid glands receive their primary blood supply from the inferior thyroid artery (branch of thyrocervical trunk from subclavian artery)
• 10% of inferior parathyroid glands derive dominant supply from a branch of the superior thyroid artery
• Rich anastomoses exist with arteries of the larynx, pharynx, esophagus, and trachea, so ligation of the inferior thyroid artery does not always devascularize the parathyroid glands (Cummings Otolaryngology)

4. Histology of the Parathyroid Gland

1. Chief cells (principal cells): Most abundant; small, polygonal cells with pale cytoplasm; synthesize and secrete PTH; arranged in cords and nests with a rich capillary network
2. Oxyphil cells: Larger than chief cells; deeply eosinophilic (more mitochondria - take up Tc-99m in nuclear scans); fewer in number; function uncertain; increase in number with age
3. Fat cells (stromal adipocytes): Increase with age (up to 50% of gland by middle age); serve as an indicator of gland activity (decreased fat = hyperactive gland)

5. Physiology of Parathyroid Glands

A. Parathyroid Hormone (PTH)

• An 84-amino acid polypeptide; the most important regulator of calcium homeostasis
• Synthesized by chief cells as pre-pro-PTH → pro-PTH → PTH (active 1-84 peptide)
• Half-life: ~4 minutes in blood
• Secretion triggered by: low plasma Ca²⁺ (hypocalcemia); also mildly stimulated by hypomagnesemia
• Secretion suppressed by: high plasma Ca²⁺ (hypercalcemia), detected via the Calcium-Sensing Receptor (CaSR) on chief cell surface

B. Actions of PTH (Three Target Organs)

• Rapid phase (minutes to hours): Activates existing osteocytes via the osteocytic membrane system → osteolysis, releasing calcium and phosphate from bone fluid into ECF
• Slow phase (days to weeks): Proliferation and activation of osteoclasts → bone resorption → release of Ca²⁺ and phosphate into blood
• PTH acts on osteoblasts (which have PTH receptors) → they release RANKL → stimulates osteoclast differentiation and activity
• Result: ↑ serum Ca²⁺ and ↑ serum phosphate from bone

• Increases calcium reabsorption in the distal convoluted tubule
• Decreases phosphate reabsorption in the proximal tubule → phosphaturia (phosphate excretion in urine; prevents precipitation of Ca²⁺-phosphate)
• Stimulates 1-alpha-hydroxylase enzyme → converts 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (active Vitamin D / calcitriol)
• Net renal effect: ↑ serum Ca²⁺, ↓ serum phosphate

• PTH stimulates renal activation of Vitamin D (calcitriol)
• Calcitriol acts on intestinal epithelial cells → increases synthesis of calbindin (calcium-binding protein) → promotes intestinal absorption of Ca²⁺ and phosphate
• This effect takes 1-2 days to develop

C. Regulation of PTH Secretion (Calcium Sensing)

• Normal serum calcium: 8.5-10.5 mg/dL (2.1-2.6 mmol/L)
• Hypocalcemia → CaSR less activated → PTH secretion increases → Ca²⁺ rises back to normal
• Hypercalcemia (>9-10 mg/dL) → CaSR activated → PTH secretion suppressed
• Hypermagnesemia also suppresses PTH; severe hypomagnesemia paradoxically impairs PTH secretion (by depleting G-protein signaling)
• Vitamin D (calcitriol) also inhibits PTH gene transcription (long-loop feedback)

D. Clinical Correlations

Summary Table

• Cummings Otolaryngology Head and Neck Surgery (Chapters 8, 123, 124) - primary ENT reference
• Scott-Brown's Otorhinolaryngology Head & Neck Surgery Vol. 1 (Chapters 5, 6)
• Guyton and Hall Textbook of Medical Physiology (Chapters 77, 80) - thyroid and parathyroid physiology