THYROID

HORMONES
 Synthesis of
thyroxine
 Metabolic effects of
thyroid hormones
 Thyroid function
assessment
 Hyperthyroidism &
Hypothyroidism
Thyroid >--- follicular cells-------> 3 principle
hormones

 T3
 T4
 R T3
Biosynthesis of thyroid hormones requires 2 raw materials (substrates)

I. THYROGLOBULIN
II. IODINE

A)THYROGLOBULIN

Thyroid hormones are synthesised by iodination of tyrosine

residues of thyroglobulin (large protein)

CHEMISTRY

 Dimer glycoprotein
 19s type(macroglobulin)
 Mol wt – 6,60,000
 Receptor tyrosine molecules ------> present in
thyroglobulin------> each receptor contain 115 tyrosine
Carbs-----> 8-10% of weight of TGB
Iodide -----> 0.2 – 1.0% depend on diet intake
>70% above -----> iodide in TBG exists in inactive
precursors
MIT ( MONO-IODO-
TYROSINE)
DIT (DI-IODO-TYROSINE)
30% ------> IODOTHYRONYL RESIDUES

IODINE SUPPLY ---> SUFFICIENT RATIO -------> T4:T3 = 7:1

IODINE DEFICIENCY ----> Decrease in T4:T3 ALSO
B) Iodine

•Daily requirement: 150–200 mcg/day (sources: water, fish, cereals, veg,

iodised salt)
•Body iodine pool: 25-30 mg (80% in thyroid gland)
•Blood iodine level: 5–10 mcg/dl

• Fact: Himalayan regions = “goiterous belts” due to iodine-poor soil!

•Commercial source: Seaweeds

•Goitrogens: Block iodine use (present in cassava, maize, millet,
cabbage, bamboo shoots, etc.)
• Cabbage/tapioca: contains thiocyanate (blocks iodine uptake)
• Mustard seed: contains thiourea (blocks iodination)
•Only biological role: Iodine is used to make T4 (thyroxine) & T3
(triiodothyronine)
•Research Fact: Universal salt iodisation has slashed global goitre rates
[Link] Uptake
1. Iodide ion (I⁻) from the blood enters the
thyroid follicle cell.
2. This process needs energy (ATP).
[Link] Synthesis
1. Inside the follicle cell, thyroglobulin (a big
protein) is synthesized.
[Link] to Colloid
1. Iodide (I⁻) and thyroglobulin are both
transported to the colloid (the yellow area,
center).
[Link] Formation
1. In the colloid, iodide binds to thyroglobulin—
forming iodinated thyroglobulin.
2. Enzymes then help form the hormones T3 and
T4 attached to thyroglobulin.
[Link] & Release
1. The thyroglobulin with T3 and T4 is taken
back up into the follicle cell.
2. Enzymes in the cell cut (cleave) T3 and T4
away from thyroglobulin.
[Link] into Blood
1. The free hormones T3 and T4 are then
released into the blood.
Synthesis & Secretion of Thyroxine

Step 1: Iodine Uptake

•Thyroid actively concentrates iodine—stimulated by TSH, inhibited by
thiocyanate, perchlorate.
Step 2: Oxidation of Iodine
•Only thyroid can oxidize iodide (needs thyroperoxidase, H2O2, NADPH from
HMP shunt)
•Blocked by anti-thyroid drugs: thiourea, thiouracil, methimazole.

Step 3: Iodination
•Thyroglobulin made by follicular cells (huge: 5000 AA, 10% carbs, 115
tyrosines/35 can be iodinated)
•MIT (mono-iodotyrosine) and DIT (di-iodotyrosine) produced.
Step 4: Coupling
•2 DIT → T4
•DIT + MIT → T3 (deiodination of T4 as alternative in periphery)
•99% of thyroid hormone produced = T4
Step 5: Storage
•Unique! Thyroid stores large hormone quantities in colloid (8
T4 per Tgb molecule)
Step 6: Utilization
•When needed, thyroglobulin is absorbed by pinocytosis.
Step 7: Hydrolysis
•T4 released by specific proteases; process ↑ by TSH, ↓ by
iodide (note: KI helps hyperthyroidism)
•Genetic defects → abnormal Tgb, low thyroxine.
Step 8: Release
•T4/T3 released to blood. T3: mostly made by peripheral
deiodination of T4.
•Reverse T3 (inactive) produced by de-iodination at 5-
position.
Step 9: Iodine Salvage
•Unused MIT/DIT are salvaged—deiodinized for reuse.
•Failure (deiodinase defect) → DIT/MIT excreted in urine; iodine
lost.
Step 10: Transport
•Mostly bound to plasma proteins:
• TBG (80% T4, 60% T3)
• Transthyretin (TTR), albumin (rest)
•PBI about 10 mcg/dl; 8 is T4.
Step 11: Catabolism
•T4 half-life 4–7 days, T3 ~1 day.
•T4 is prohormone (→ T3 by deiodinase, a selenium enzyme).
•Catabolized via glucuronidation (bile, urine), or deaminated
(forms Tetrac/Triac: low activity).

• Fact: Selenium deficiency can worsen hypothyroid

symptoms!
Mechanism of
Action
•Binds nuclear receptor
→ DNA (Thyroid
Responsive Element)
•T3 action: increases
mRNA transcription,
protein synthesis.
Mechanism of Action of Thyroid Hormones
•Thyroid hormones enter cells: via carrier-mediated active transport.
•Target organs: Liver, kidney, fat, heart, brain, lymphocytes, etc.
[Link] Action:
1. T4 & T3 enter nucleus, bind to "nuclear receptors" (high-affinity, non-histone
proteins).
2. This binding triggers nuclear DNA-dependent RNA polymerase.
3. Result: ↑ gene transcription, ↑ mRNA synthesis, ↑ specific proteins &
enzymes.

[Link]⁺-K⁺ ATPase Pump:

1. Thyroid hormones ↑ O₂ consumption, drive Na⁺-K⁺ ATPase pump in cells.
2. They ↑ the number of pump units in almost all cells.

[Link] of Proteins:
1. Thyroid hormones also directly ↑ translation of proteins.
2. They ↑ binding of aminoacyl-tRNA to ribosomes.
3. They ↑ activity of peptidyl transferase or translocase enzymes.
Metabolic Effects

•Calorigenic/thermogenic: 1 mg T4 releases 1000 kcal (heat

production ↑)
•Raises BMR (Basal Metabolic Rate)
•↑ Protein synthesis (at first!), at high T3: catabolism & negative
nitrogen balance
•Weight loss in hyperthyroidism
•↑ Gluconeogenesis, glucose uptake, carbohydrate oxidation
•↑ Fatty acid metabolism, cholesterol degradation (hyperthyroid:
low cholesterol)
Thyroid Function Tests

[Link] assays: T4, T3 (by RIA/ELISA, now also

chemiluminescence)
[Link]: T3/T4 ↑; TSH ↓ (feedback)
[Link]: T3/T4 ↓; TSH ↑
[Link] hormones: best indicator (not affected by carrier proteins)
[Link] proteins: now less important due to direct free hormone
measurement
[Link]: ↑ in primary hypo, ↓ in primary hyper; all low in secondary
hypo
[Link] response: differentiate primary/secondary/tertiary disorders
[Link]: ↑ in hypothyroid (not diagnostic, but useful for
monitoring therapy)
[Link] Iodine Uptake (RAIU): diagnostic, not in pregnancy/kids.
[Link] antibodies:
[Link]: TSIg/LATS binds TSH receptor (autoimmune hyper
NORMAL RANGES

T3 :120-190 ng/dl
r T3 : 10-25 ng/dl
T4 : 5-12 µg/dl
Thyroglobulin:3-5 µg/dl
TRH :5-60 ng/L
TSH :0.5-5 µU/ L
Thyroxine binding globulin :1-2 mg/dl
1. TSH (Thyroid Stimulating Hormone) Test
•Measures: TSH level in blood (from anterior pituitary).
•Why: TSH controls thyroid gland activity. It's the main screening test.
•Interpretation:
• High TSH: Primary hypothyroidism (thyroid isn't making enough
hormones, so pituitary shouts "work harder!").
• Low TSH: Hyperthyroidism or secondary hypothyroidism (pituitary
doesn’t signal; could be pituitary problem or thyroid is already
overactive).
•Quiz tip: TSH is the "master regulator" signal — always consider its
2. T4 and T3 Tests (Total & Free)
•Measures: Total & free levels of T4 (thyroxine) and T3
(triiodothyronine).
•Why: These are the main thyroid hormones controlling your
body’s metabolism.
•Free T4 (FT4): Not bound to proteins, directly active.
•Interpretation:
• High T3/T4 or FT4 = Hyperthyroidism
• Low T3/T4 or FT4 = Hypothyroidism
•Total vs. Free: Total can be affected by protein levels, while
free reflects true active hormone.
 4. Radioactive Iodine
3. Thyroid Antibodies
Uptake (RAIU)
•Measures: Autoantibodies in
blood that attack thyroid tissue. Measures: How much iodine
•Why: Diagnosing autoimmune the thyroid gland absorbs from
thyroid disease. blood.
• Graves' disease: TSH Why: To check gland activity
receptor or stimulating and the cause of
antibodies (TSI/LATS) hyperthyroidism.
• Hashimoto's: Anti- Interpretation:
thyroglobulin, anti- High uptake: Graves’
microsomal antibodies disease, toxic adenoma
•Interpretation: (overactive gland)
• Positive antibodies = Low uptake: Thyroiditis or
Autoimmune disorder (can hormone intake (thyroid not
explain abnormal working hard)
Safety: Not done in pregnant
5. Cholesterol Level
•Why: Hypothyroidism raises cholesterol (metabolism slows
down).
•Interpretation:
• High cholesterol: May suggest hypothyroidism (not
diagnostic, but helps in clinical context).

6. TRH Stimulation Test (Specialist Use)

•Why: Assesses feedback loop (hypothalamus–pituitary–thyroid
axis).
•Interpretation:
How To Tie These Together

•Screening: Start with TSH. If

abnormal, check FT4/T3.

•Autoimmune suspected: Order

antibody tests.

•Hyperthyroidism cause unclear: Do

RAIU.

•Odd cholesterol levels: May prompt

checking thyroid, especially if
symptoms fit.
Test Best For
Most thyroid evaluations, altered protein
states, pregnancy, sick patients,
FT4/FT3
medication effects, suspected thyroid
dysfunction
Basic screening, population surveys,
healthy people, resource-limited settings,
Total T3/T4
when binding protein changes are NOT
suspected
Abnormalities of Thyroid Function

•History fun fact: Graves (Ireland, 1835) & Basedow (Germany,

1840) described hyperthyroidism; Kocher performed first
thyroidectomy (1883, Nobel 1909).
•Diseases: Most common endocrine problems! (Hyper, Hypo,
Goiter)
• Goiter: may or may not affect function; may be diffuse,
nodular, or due to iodine deficiency.
Hyperthyroidism

•Causes:
• ↑ binding protein or affinity
• Autoantibodies (Graves)
• Excess hormone intake
• Rare: TSH-secreting pituitary adenoma, hormone
resistance syndrome, gestational thyrotoxicosis
• Iodine excess, TSH receptor mutation, struma
ovarii (ovarian teratoma)
•Findings: High metabolism, weight loss, tachycardia,
tremor, sweating, emotional symptoms, heat
intolerance.
•Lab: T3/T4 ↑, TSH ↓, TRH: nil response
Hypothyroidism

•Primary: disease of thyroid (e.g., Hashimoto, thyroidectomy, drugs:

lithium, antithyroid, PAS); congenital (iodine def, agenesis,
dyshormonogenesis)
•Secondary: pituitary or hypothalamic failure (tumors, surgery,
sheehan’s, trauma).
• Diagnosis: high TSH (primary), all low (secondary/tertiary), use
TSH/TRH tests.
•Symptoms: myxedema (adults, more in women), lethargy, cold
intolerance, bradycardia, weight gain, slow everything.
•Cretinism: congenital, physical & mental retardation (needs prompt
treatment!).
•Fun Fact: Hypothyroidism in pregnancy can cause cretinism in
newborn—early diagnosis is crucial.
Other Clinical Notes

•Euthyroid goiter: Iodine deficiency, enlarged gland

but hormones normal; TSH always raised.
•Non-thyroidal illness: acute illness can lower
T3/T4/TSH—don’t test thyroid during critical illness
unless necessary.
•Cross-talk with other hormones: insulin (Ch. 24),
adrenaline (Ch. 17), PTH/calcitonin/vitamin D axis.
Research/Fun Facts

•Thyroid disorders affect women 5–10x more than men.

•Seaweed supplements can cause accidental thyrotoxicosis
in some populations!
•Modern labs use “third-generation" TSH assays, which can
detect subclinical disease.
•The world’s largest goitre removed weighed 5.8 kg
(recorded in 2004).
•90% of thyroid hormone in blood is T4, but only T3 is active
—"T4 = suitcase, T3 = actual clothes you wear!"
Regulation of Thyroid Hormone Secretion

•Controlled by: Hypothalamus + Anterior pituitary (via feedback)

Pituitary Role
•TSH (Thyroid Stimulating Hormone) from anterior pituitary is the main
regulator (peptide hormone, α & β chains, half-life: 60 min, norm: 2
U/mL).
•TSH increases:
• Follicular cell number/size
• Formation of thyroid follicles (cuboidal → columnar)
• Iodide uptake & pump activity
• Thyroglobulin secretion
• Iodination/coupling
• Proteolysis of thyroglobulin (releases hormone, shrinks colloid)
•Immediate effect: TSH triggers proteolysis & thyroxine release (in
~30m)
•Other effects: Occur over hours to weeks
Hypothalamus Role
•Produces TRH (Thyrotropin-releasing hormone) → triggers TSH from anterior
pituitary (via portal vessels)
Feedback Control
•Negative feedback: Thyroid hormones inhibit TRH (hypothalamus) & TSH (pituitary)
release
Iodide Role
•Essential for hormone synthesis

•Wolff-Chaikoff effect: Excess iodide inhibits hormone synthesis enzymes

Other Factors
•Increase secretion:
• Low BMR, Leptin (from fat), α-MSH (pituitary), low body temp (infants)
•Decrease secretion: Excess iodide, stress, somatostatin, glucocorticoids, dopamine
(all inhibit TRH release)

Hyperthyroidism Causes
•Graves’ disease (TSAbs mimic TSH, long action, TSH low)
•Thyroid adenoma
Stimulates Secretion Inhibits Secretion

TSH, TRH, Low BMR,

Excess iodide, stress,
Leptin,
somatostatin,
α-MSH, Low temp
glucocorticoids,
(infants)
dopamine