Unit+5+Lecture+2+Thyroid+Endocrinology+Narrative

Lecture Objectives (Unit 5 – Lecture 2)

  • Anatomical location: thyroid sits anterior/lateral to trachea; bilobed “butterfly” gland

  • 4 primary functions:

    • Conserve iodine for hormone synthesis

    • Regulate metabolic rate/oxygen consumption → heat production

    • Support somatic growth

    • Direct tissue differentiation

  • Early detection of congenital thyroid deficiency (cretinism) → prevents irreversible mental retardation

  • Cell types & products:

    • Follicular (acinar) cells → Tg, T3,,T4

    • Parafollicular (C) cells → Calcitonin ↓ Ca2+Ca^{2+} & PO43−PO_4^{3-}

  • Synthesis/release pathway for T3 & T4 with TSH influence on:

    1. Tg formation

    2. Iodide trapping (active, ATP-dependent)

    3. Iodination/organification (TPO-catalysed)

    4. Coupling & release of hormone from Tg

    5. Recycling of iodide & amino-acids

  • Compare T3vsvsT4:secretionrate(≈: secretion rate (≈7\,\mu gvsvs80!–!100\,\mu g/day),potency(), potency (T_3 ≈3–4×), peripheral conversion, half-life

  • Reverse T3T_3 (rT3) production ↑ in stress, illness, certain drugs (propylthiouracil, propranolol, amiodarone, glucocorticoids)

  • 3 major transport proteins + % carriage

    • TBG: 70!–!75%70!–!75\% T4,,60\%T3

    • TBPA/Transthyretin: 15!–!20%15!–!20\% T4(doesnotbind(does not bindT3)

    • Albumin: ≈10%\approx10\% T4,,40\%T3

    • Free fraction: <0.3%<0.3\% T3,,<0.05\%T4

  • Negative feedback: Free T3//T4 ↓↑ TRH & TSH via HPT axis

  • Nomenclature: primary (thyroid), secondary (pituitary/TSH), tertiary (hypothalamus/TRH) hyper- & hypothyroidism

  • Lab procedures list: TSH, total/free T4,total/free, total/freeT3, rT3, Tg, TBG, auto-antibodies (TPO-Ab, Tg-Ab, TRAb/TSI, TSH-R-Ab)

  • Clinical syndromes: overt & subclinical hyper/hypothyroidism, euthyroid sick syndrome (NTI)

  • Data interpretation correlations

Thyroid Anatomy & Histology

  • Bilobed, highly vascular, sits below larynx wrapping anterior trachea

  • Follicle: single layer epithelium around colloid lumen storing Tg

  • Parafollicular C-cells in interstitium → calcitonin

  • Rich capillary & venous network for swift hormone export

Four Primary Functions (Detailed)

  • Iodine economy: Unique among organs in active iodide trapping (Na⁺/I⁻ symporter)

  • Whole-body metabolic “thermostat”:

    • ↑ basal metabolic rate

    • ↑ mitochondrial number, Na⁺/K⁺-ATPase pump activity → heat

  • Growth facilitation: necessary cofactor for GH actions; lack → dwarfism, delayed bone age

  • Differentiation: CNS myelination, skeletal maturation; deficiency in fetus/neonate → cretinism (mental & physical impairment)

Cretinism (Congenital Hypothyroidism)

  • Absent/ectopic thyroid or dyshormonogenesis → low hormones at birth

  • Screening: heel-stick TSH/T4 48–72 h postpartum

  • Irreversible IQ loss if therapy delayed beyond first months

Hormone Biosynthesis (within Follicular Cell)

  1. Iodide Trapping

    • Active transport I−I^- vs serum (20–40× gradient)

    • Inhibited by perchlorate, thiocyanate; stimulated by TSH

  2. Tg Synthesis & Export

    • Rough ER → Golgi → exocytosed into colloid

    • Tg: 330 kDa glycoprotein rich in tyrosyl residues

  3. Oxidation/Organification

    • At apical membrane TPO + H2O2oxidisesoxidisesI^-→I^{+}

    • I⁺ iodinates Tg tyrosines → MIT (1I) & DIT (2I)

    • Blocked by thioamide drugs (propylthiouracil, methimazole)

  4. Coupling

    • TPO catalyses ether linkage: MIT+DIT→T3,DIT+DIT→, DIT+DIT→T4

    • Yields trace rT3 (inner-ring coupling)

  5. Storage

    • Iodinated Tg in colloid ≈ several weeks reserve

  6. Endocytosis & Proteolysis

    • TSH triggers pinocytosis; lysosomal proteases liberate T3,,T4

  7. Secretion & Recycling

    • T3/T4 diffuse to blood

    • MIT/DIT deiodinated by intrathyroidal deiodinase → iodine reuse

Low Iodine Intake

  • Sequence: ↓ intrathyroidal iodine → ↓ hormone → ↑TSH → follicular hyperplasia → goiter

  • Persistent deficiency may still maintain euthyroid state until stores exhausted; prolonged leads to hypothyroidism with goiter

Quantitative Secretion & Potency

  • Daily secretion: ≈80!–!100 μg\approx80!–!100\,\mu g T4,,6!–!7\,\mu gT3

  • Relative potency: T3≈3–4×≈3–4×T4 on nuclear receptor affinity

  • Half-life: T4≈7days;≈7 days;T3≈1 day (less protein-bound)

Peripheral Conversion & Reverse T3

  • Type 1 & 2 deiodinases remove 5’ outer-ring iodine → active T3(≈80(≈80 % of circulatingT3)

  • Type 3 deiodinase (fetal, severe illness) removes inner-ring iodine → rT3 (inactive)

  • Stress/illness/glucocorticoids/β-blockers shift balance to rT3 → “low T3 syndrome”

Plasma Transport

  • Binding affinity: TBG > TBPA > Albumin

  • Equilibrium cushions acute swings; only free hormone crosses membranes

  • Protein anomalies: e.g., ↑TBG in pregnancy, OCP → ↑total T4/T3 but euthyroid (normal FT4, TSH)

Metabolic Fate

  • Deiodination (80–85 %)

  • Conjugation with glucuronide/sulfate → bile, urine

  • Small free hormone lost directly in urine/bile

Regulation – HPT Axis

  • Hypothalamus secretes TRH → portal vessels → pituitary

  • Pituitary thyrotropes release TSH (glycoprotein, αβ\alpha\beta subunits)

  • TSH effects (marked ‘Ꚛ’ on diagram): stimulates every synthetic step + trophic growth

  • Negative feedback: free T3T_3 at pituitary & hypothalamus

  • Circadian TSH: peak 02–04h, nadir 17–18h

Classification of Disorders

  • Primary: thyroid malfunction (↑ or ↓ hormone, reciprocal TSH)

  • Secondary: pituitary TSH defect (both hormones & TSH ↓ or inappropriate)

  • Tertiary: hypothalamic TRH deficiency (rare; labs mimic secondary)

Laboratory Patterns (overview)

Disorder

TSH

FT4

Total/FT3

Primary hyperthyroid

↓↓

↑

↑ (esp T3)

T3 toxicosis

↓

→

↑

Subclinical hyper

↓

→

→

Primary hypothyroid

↑↑

↓

N/↓

Subclinical hypo

↑

→

→

Secondary/Tertiary hypo

↓

↓

↓

Euthyroid Sick (NTI)

→/↓

→

↓ (↑rT3)

Hyperthyroidism (Thyrotoxicosis)

  • Clinical: anxiety, heat intolerance, weight loss, tachycardia, moist skin, tremor

  • Lab hallmark: suppressed TSH + elevated FT4/FT3

  • Shift toward T3T_3 → 10!–!15%10!–!15\% pts: T3-toxicosis (normal T4)

  • Major etiologies:

    1. Graves’ disease (≈80 %)

    • TRAb/TSI stimulate TSH-R

    • Diffuse goiter, ophthalmopathy, ↑RAIU

    • Labs: ↓TSH, ↑FT3/4; antibodies: TRAb +, TPOAb in 75 %

    1. Thyroiditis (silent, subacute, postpartum)

    • Damaged follicles leak hormone → transient thyrotoxicosis

    • Low RAIU, normal/↑ESR, +TPOAb

    1. Toxic multinodular goiter / autonomous nodules (elderly)

    • Patchy uptake on scan; antibodies absent

    1. Exogenous hormone (factitious), hCG-mediated (pregnancy, trophoblastic)

  • Subclinical hyperthyroidism: ↓TSH, normal FT4/FT3; risk atrial fibrillation, bone loss

Hypothyroidism

  • Clinical: fatigue, cold intolerance, bradycardia, weight gain, myxedema facies, constipation

  • Primary overt pattern: ↑TSH, ↓FT4

  • Causes:

    1. Hashimoto’s thyroiditis (autoimmune, anti-TPO 80–99 %, anti-Tg 20–50 %)

    2. Iatrogenic: thyroidectomy, radio-iodine, antithyroid drugs

    3. Post-partum or subacute thyroiditis (transient)

    4. Secondary (pituitary) or tertiary (hypothalamus) failure

    5. Congenital agenesis/dysgenesis (1:3000–4000 births)

  • Myxedema coma: end-stage severe hypo-; high mortality >60 %

  • Subclinical hypo: ↑TSH (often <10 mIU/L), normal FT4; non-specific symptoms; progression risk correlates with TSH >20 or high TPOAb

  • Therapy: Levothyroxine; monitor TSH q6–8 wk (not