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Thyroid Gland - Complete Guide for MUHS PG Medicine Theory Exam

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PART 1: ANATOMY & HISTOLOGY - Quick Recap

• Flat/cuboidal = inactive (high colloid)
• Tall columnar = active (little colloid, scalloped edges = resorption lacunae)

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PART 2: THYROID HORMONE PHYSIOLOGY

The HPT Axis (Hypothalamic-Pituitary-Thyroid)

Hypothalamus → TRH (thyrotropin-releasing hormone)
    ↓
Anterior Pituitary → TSH (thyroid-stimulating hormone)
    ↓
Thyroid Gland → T4 (80 µg/day) + T3 (4 µg/day)
    ↓
NEGATIVE FEEDBACK: T3/T4 inhibit both hypothalamus and pituitary

• TRH is a tripeptide; acts via Gq/IP3/DAG → increases TSH
• TSH acts via Gs/cAMP → stimulates ALL steps of thyroid hormone synthesis
• TSH receptor (TSH-R) is also stimulated by TSI (thyroid-stimulating immunoglobulin) in Graves' disease
• T3 is 3-4x more potent than T4 and provides the main feedback signal (TSH secretion is inhibited by intrapituitary T3 generated by type 2 deiodinase from circulating T4)

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PART 3: STEPS IN THYROID HORMONE SYNTHESIS

Step-by-Step (Ganong + Katzung)

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• Iodide (I⁻) is actively transported from blood into the follicular cell against a concentration gradient via the NIS (Sodium-Iodide Symporter) at the basolateral membrane
• NIS co-transports 2 Na⁺ with each I⁻ (secondary active transport)
• Normal gradient is 20:1 (thyroid:plasma); in Graves' disease it rises to 70-90:1
• Inhibited by: thiocyanate (SCN⁻), perchlorate (ClO₄⁻), pertechnetate (TcO₄⁻) - these are competitive anion inhibitors
• TSH upregulates NIS expression

• Pendrin mutation → Pendred syndrome (goiter + sensorineural deafness)

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• Iodide (I⁻) is oxidized to iodine (I⁰) by thyroid peroxidase (TPO) using H₂O₂
• H₂O₂ is generated by NADPH oxidase (Dual oxidase/DUOX)
• TPO is a membrane-bound enzyme on the apical surface

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• Iodine (I⁰) reacts with tyrosine residues on thyroglobulin (Tg) in the colloid
• Thyroglobulin is a large glycoprotein (660 kDa) with 123 tyrosine residues - only 4-8 are actually iodinated
• Products formed:
  • Iodination of 1 tyrosine → MIT (monoiodotyrosine)
  • Iodination of 2 positions → DIT (diiodotyrosine)
• This step is also catalyzed by TPO
• Also blocked by thioamides and high iodide (Wolff-Chaikoff effect)

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• Two iodotyrosines are coupled (still on thyroglobulin) by TPO via an oxidative condensation reaction:
  • DIT + DIT → T4 (thyroxine, 3,5,3',5'-tetraiodothyronine)
  • MIT + DIT → T3 (3,5,3'-triiodothyronine)
  • MIT + MIT → rT3 (reverse T3, biologically inactive) - minor pathway
• The ratio of T4:T3 in thyroglobulin is approximately 5:1
• MIT and DIT that are not used in coupling remain stored in thyroglobulin

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• Thyroglobulin (containing MIT, DIT, T3, T4) is stored in the colloid
• Humans can go up to 2 months without dietary iodine before hormone levels fall - this is the largest hormone store in the body

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• TSH stimulates endocytosis of colloid back into the follicular cell
• Lysosomes fuse with the endosomes → proteolytic cleavage of Tg by cathepsins
• Free T4 and T3 are released into the cytosol and then into capillaries
• MIT and DIT are deiodinated by iodotyrosine deiodinase (microsomal enzyme) within the gland → iodide is recycled back for new synthesis
  • Congenital absence of this enzyme → MIT/DIT in urine → iodine deficiency symptoms

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Summary Table: Drugs and Their Blockade Points

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PART 4: PERIPHERAL CONVERSION OF T4 → T3

The Key Concept

• ~80 µg T4/day (major secretory product - a "prohormone")
• ~4 µg T3/day
• ~2 µg rT3/day

The Three Deiodinase Enzymes (Medical Physiology - Boron & Boulpaep)

The Outer Ring vs Inner Ring Concept

• Outer ring (phenolic/distal ring) - iodine at 3' and 5' positions
• Inner ring (tyrosyl/proximal ring) - iodine at 3 and 5 positions

Sick Euthyroid Syndrome (Low T3 Syndrome) - Exam High Yield

• D1 activity decreases → less T4→T3 conversion → low T3
• D3 activity increases → more T4→rT3 → high rT3
• D2 (pituitary) is UNAFFECTED → local T3 in pituitary remains normal → TSH does not rise (no compensatory rise)
• Pattern: Low T3, high rT3, normal/low TSH, normal/low T4

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PART 5: TRANSPORT OF THYROID HORMONES IN BLOOD

• Free T4: ~0.02-0.04% of total T4
• Free T3: ~0.2-0.4% of total T3
• Only free hormones are biologically active and provide feedback

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PART 6: THYROID FUNCTION TESTS (TFTs)

Test Hierarchy: "TSH First" Policy

Step 1: TSH (best initial screening test)
    → Normal TSH = essentially excludes thyroid dysfunction
    → Abnormal TSH → Add Free T4
    → If hyperthyroid and T4 normal → Add Free T3 (rule out T3-toxicosis)

Interpretation Table (Quick Compendium of Clinical Pathology)

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Individual Tests Explained

• Best single test; third-generation immunometric assay can detect down to 0.01 mIU/L
• Pitfalls: Do not use TSH alone when:
  • Central hypothyroidism suspected (pituitary/hypothalamic disease - TSH is low/normal but T4 is low)
  • Critically ill patients (sick euthyroid)
  • Early in treatment (TSH lags - takes 6-8 weeks to normalize after treatment)
  • Dopamine infusion, high-dose steroids (suppress TSH spuriously)

• Reflects biologically active hormone unaffected by TBG changes
• Second-line test when TSH is abnormal
• Preferred over total T4 in pregnancy and states altering binding proteins

• Used to diagnose T3-toxicosis (elevated T3 with normal T4)
• Useful in monitoring hyperthyroid treatment

• Affected by TBG levels - less reliable
• Still used in some settings

• Elevated in sick euthyroid syndrome
• Helps distinguish sick euthyroid from true hypothyroidism

• Tumor marker after total thyroidectomy for differentiated thyroid cancer
• Rising Tg = recurrence

• Present in ~95% Hashimoto's thyroiditis, ~80% Graves' disease
• Best test for autoimmune thyroid disease

• Pathognomonic for Graves' disease
• Useful in pregnancy to predict neonatal Graves'

• Radiolabeled T3 added to patient serum → binds unoccupied TBG sites
• Low T3RU = more TBG sites available = low T3 state (hypothyroidism/elevated TBG)
• High T3RU = fewer TBG sites = high T3 state (hyperthyroidism/low TBG)
• Free Thyroxine Index (FTI) = Total T4 × T3RU (corrects for TBG changes)

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When TSH-First Policy Should Be Abandoned

1. Critically ill patients - sick euthyroid distorts all parameters
2. Central hypothyroidism - TSH is low/normal despite T4 deficiency
3. Early treatment monitoring - TSH lags weeks behind clinical response; use free T4
4. Dopamine or high-dose steroids - suppress TSH independently

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PART 7: ACTIONS OF THYROID HORMONES (Brief - for completeness)

• Without T3: TR binds co-repressors → gene silencing
• With T3: co-repressors released → co-activators recruited → gene transcription

• Increases BMR, O₂ consumption (calorigenesis)
• Increases heart rate and cardiac output (upregulates beta-adrenergic receptors)
• Promotes growth and CNS development (critical in fetal/neonatal life)
• Promotes protein synthesis and gluconeogenesis
• Essential for normal bone maturation

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EXAM MEMORY AIDS

• D1/D2 = outer ring removal = T3 (active)
• D3 = inner ring removal = rT3 (inactive)
• PTU blocks D1 (not D2, not D3) - clinically useful in thyroid storm

• Low TSH + High T4 = Hyperthyroid (primary)
• High TSH + Low T4 = Hypothyroid (primary)
• Low TSH + Low T4 = Central hypothyroidism or sick euthyroid
• Normal TSH + Low T4 = Check TBG (TBG deficiency or sick euthyroid)

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