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Thyroid Gland — Anatomy & Physiology

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1. Introduction

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2. Embryology

• Median thyroid anlage — a midline endodermal outgrowth from the floor of the pharynx at the level of the foramen cecum (between the 1st and 2nd pharyngeal pouches), which descends along the thyroglossal duct.
• Lateral thyroid anlage — derivatives of the 4th/5th pharyngeal pouches that contribute the parafollicular C cells (from neural crest origin).

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3. Gross Anatomy

Relations

• Anteriorly: Strap muscles (sternohyoid, sternothyroid, thyrohyoid)
• Posteriorly: Trachea, oesophagus, recurrent laryngeal nerves (in the tracheoesophageal groove)
• Superiorly: Larynx (thyroid cartilage)
• Posterolaterally: Carotid sheath contents
• Posterior surface: Four parathyroid glands embedded within (or close to) the gland

Blood Supply

Nerve Supply

• Vasomotor supply from the superior and inferior cervical sympathetic ganglia.
• The external branch of the superior laryngeal nerve runs near the superior pole vessels (risk during thyroidectomy).
• The recurrent laryngeal nerve (branch of vagus) ascends in the tracheoesophageal groove and is at risk during lower-pole dissection.

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4. Histology

a) Follicular cells (Thyrocytes)

• Cuboidal to columnar epithelium lining spherical follicles (100–300 µm diameter)
• Synthesize, store, and secrete T3 and T4
• Active gland: tall columnar cells, scanty colloid
• Inactive gland: flat cells, abundant colloid

b) Parafollicular C cells

• Located in the interfollicular stroma, mainly in the lateral mid-to-upper lobes
• Secrete calcitonin — involved in calcium regulation
• Neural crest origin

Colloid

• Fills the follicular lumen
• Composed chiefly of thyroglobulin (Tg) — a large glycoprotein (MW ~660,000 Da) that serves as the precursor and storage form of thyroid hormones
• Acts as a reservoir; iodine can be stored for 2–3 months' hormone supply

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5. Thyroid Hormone Synthesis — Step-by-Step

Iodine Requirement

Steps

• The Na⁺/I⁻ symporter (NIS) on the basolateral membrane of thyrocytes co-transports 1 I⁻ with 2 Na⁺ into the cell, driven by the Na⁺-K⁺-ATPase pump.
• Normal intracellular iodide concentration is ~30× plasma; rises to 250× when maximally stimulated by TSH.

• Iodide crosses the apical membrane into the follicular lumen via pendrin (a Cl⁻/I⁻ counter-transporter).

• Thyrocytes synthesise Tg in the endoplasmic reticulum and Golgi apparatus, then secrete it into the follicular lumen by exocytosis. Each Tg molecule has ~70 tyrosine residues (Ganong's says 123 residues; ~4–8 are actually incorporated into hormones).

• Thyroid peroxidase (TPO) at the apical membrane oxidises I⁻ → I₂ (nascent iodine) using H₂O₂.
• Iodine attaches to tyrosine residues on Tg:
  • 1 iodine + tyrosine → Monoiodotyrosine (MIT)
  • 2 iodines + tyrosine → Diiodotyrosine (DIT)

• Also catalysed by TPO:
  • DIT + DIT → T4 (tetraiodothyronine, thyroxine) + alanine
  • MIT + DIT → T3 (triiodothyronine) + alanine
  • DIT + MIT → rT3 (reverse T3, biologically inactive)
• In normal thyroid: ~3% MIT, 33% DIT, 35% T4, 7% T3

• Hormones remain covalently bound within Tg in the colloid.

• On TSH stimulation, thyrocytes endocytose colloid droplets by pinocytosis/endocytosis.
• Lysosomes fuse with colloid droplets; proteases hydrolyse Tg to release free T4, T3, MIT, and DIT.
• Free T4 and T3 diffuse into capillaries.
• MIT and DIT are deiodinated intracellularly by iodotyrosine deiodinase, recycling the iodine.

Key enzyme: Thyroid peroxidase (TPO) is essential for both organification and coupling. Blocked by propylthiouracil (PTU) and carbimazole/methimazole.

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6. Daily Secretion

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7. Transport in Blood

• 99.98% of T4 is protein-bound; free T4 = only ~2 ng/dL
• 99.8% of T3 is protein-bound (less than T4 → T3 acts faster and has shorter half-life)
• Only free (unbound) hormone is biologically active and exerts negative feedback

Factors altering TBG

Important: Changes in TBG alter total T4/T3 but not free hormone levels (compensatory TSH adjusts output). The patient remains euthyroid.

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8. Peripheral Conversion (Metabolism)

• ~80% of circulating T3 is derived from peripheral deiodination of T4 (not direct thyroid secretion)
• Three deiodinase enzymes (all contain selenocysteine):

• D1 and D2 remove the 5' iodine (outer ring) → active T3
• D3 removes the 5 iodine (inner ring) → inactive rT3
• In illness, starvation, and surgery: D1 is decreased → more rT3, less T3 (Euthyroid Sick Syndrome / Low T3 syndrome)

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9. Mechanism of Action

Nongenomic actions also exist (rapid effects within minutes): regulation of ion channels, mitochondrial oxidative phosphorylation, activation of cAMP/protein kinase pathways.

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10. Physiological Effects of Thyroid Hormones

A. Metabolic Effects

• Calorigenic effect: Increases BMR by 60–100% when excess; decreases ~50% in absence
• Stimulates Na⁺-K⁺-ATPase → increased oxygen consumption and heat production
• Increases carbohydrate metabolism: enhanced glycolysis, gluconeogenesis, GI glucose absorption, insulin secretion
• Increases fat metabolism: lipid mobilisation, free fatty acid oxidation
• Decreases plasma cholesterol, triglycerides, phospholipids (by upregulating hepatic LDL receptors and increasing biliary cholesterol excretion) — hence hypothyroidism → hypercholesterolaemia

B. Cardiovascular Effects

• Increased cardiac output, heart rate, stroke volume
• Decreased peripheral vascular resistance (due to heat production and vasodilation)
• Thyroid hormones have direct positive chronotropic and inotropic effects on the heart (upregulate β-adrenergic receptors)

C. CNS and Development

• Essential for brain development in fetal life and first 2–3 years of life
• Deficiency → cretinism (mental retardation, short stature, deaf-mutism, coarse features)
• In adults: hypothyroidism → slow mentation, depression; hyperthyroidism → anxiety, tremor

D. Growth

• Promotes linear growth and bone maturation (synergistic with GH and IGF-1)
• Hypothyroidism in children → growth retardation, delayed bone age
• Hyperthyroidism → accelerated bone maturation → premature epiphyseal closure → short final height

E. Reproductive System

• Required for normal menstrual cycles and fertility
• Hypothyroidism → menorrhagia or oligomenorrhoea; hyperthyroidism → oligomenorrhoea or amenorrhoea

F. Neuromuscular

• Excess → muscle weakness, tremor, hyperreflexia
• Deficiency → slowness of movements, delayed relaxation of deep tendon reflexes (Woltman's sign)

G. GI Tract

• Increase motility → hyperthyroidism causes diarrhoea
• Decrease motility → hypothyroidism causes constipation

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11. Regulation of Thyroid Hormone Secretion — HPT Axis

Hypothalamus
    ↓ TRH (thyrotropin-releasing hormone)
Anterior Pituitary
    ↓ TSH (thyroid-stimulating hormone)
Thyroid Gland
    ↓ T3 & T4
       ↑ Negative feedback on both hypothalamus and pituitary

TRH

• Tripeptide (pyro-Glu–His–Pro–NH₂) secreted from the paraventricular nucleus
• Stimulates TSH synthesis and secretion (acts via IP₃/DAG pathway)
• Stimulated by cold (especially in neonates); inhibited by stress and glucocorticoids

TSH

• Glycoprotein (α + β subunits); α subunit shared with LH, FSH, hCG
• Acts via G-protein-coupled receptor → activates adenylyl cyclase (cAMP) and phospholipase C
• Effects on thyroid: ↑ iodide trapping, ↑ Tg synthesis, ↑ organification, ↑ endocytosis of colloid, ↑ T3/T4 release, ↑ vascularity → goitre with prolonged excess
• Normal TSH: 0.4–4.0 mIU/L
• TSH is the best single test for thyroid function (log-linear relationship with free T4)

Negative Feedback

• Free T3 and T4 inhibit TSH and TRH secretion
• The pituitary expresses high levels of D2 deiodinase → converts T4 → T3 locally → the pituitary is largely regulated by T3
• This feedback is exquisitely sensitive; small changes in free T4 cause large, log-linear changes in TSH

Autoregulation (Intrinsic)

• High iodide load initially increases hormone synthesis, but with prolonged excess, organification is blocked — Wolff-Chaikoff effect
• Normal glands escape from this block within ~1–2 weeks
• Diseased glands (e.g., Hashimoto's) may fail to escape → hypothyroidism

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12. Calcitonin

• Secreted by parafollicular C cells
• 32-amino acid polypeptide
• Secreted in response to hypercalcaemia
• Actions:
  • Inhibits osteoclast activity → decreases bone resorption
  • Increases renal calcium and phosphate excretion
• In humans, calcitonin plays a minor role in calcium homeostasis (hyperparathyroidism causes more significant hypercalcaemia than calcitonin deficiency causes hypocalcaemia)
• Clinical importance: Calcitonin is a tumour marker for medullary thyroid carcinoma (MTC)

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13. Thyroid Hormone in Pregnancy

• TBG increases due to oestrogen → total T4 and T3 rise
• Free T4 and T3 remain normal → mother is euthyroid
• hCG (peak at 10–12 weeks) has weak TSH-like activity → TSH transiently suppressed in first trimester
• Maternal thyroid hormones cross the placenta and are critical for fetal brain development until the fetal thyroid matures (~12–16 weeks)
• Iodine requirements increase in pregnancy; deficiency → cretinism

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14. Euthyroid Sick Syndrome

• Low T3: Decreased D1 activity → less peripheral T4-to-T3 conversion
• Elevated rT3: D3 shunts T4 → rT3 (inactive)
• TSH: Normal or slightly low
• No clinical thyroid dysfunction; T4 supplementation is NOT indicated
• Resolves when the underlying illness resolves

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15. Summary Table

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References

• Guyton and Hall Textbook of Medical Physiology, 14th Ed., Ch. 77
• Ganong's Review of Medical Physiology, 26th Ed., Ch. 20
• Sabiston Textbook of Surgery, 21st Ed., Ch. 73