Thyroid Physiology
Physiology · Endocrine · lean revision notes
Thyroid Physiology
The thyroid gland is the only endocrine organ that stores its hormone extracellularly (in colloid) and the only one that requires a trace element (iodine) as an obligatory substrate. For NEET PG, the synthesis cascade, peripheral conversion, regulatory feedback, and TFT interpretation are perennial high-yield zones.
Functional anatomy and hormone overview
The thyroid follicle is the functional unit: a single layer of cuboidal follicular cells surrounding a central lumen filled with colloid. Colloid is essentially a reservoir of thyroglobulin (Tg), a large glycoprotein on which thyroid hormone is built and stored. Parafollicular C-cells lie between follicles and secrete calcitonin (a separate axis, not part of thyroid hormone physiology).
The gland secretes two iodothyronines:
- T4 (thyroxine, tetra-iodothyronine): the major secretory product (~90%); a prohormone with low intrinsic activity but long half-life (~7 days).
- T3 (tri-iodothyronine): the metabolically active hormone; ~10% secreted directly, but ~80% generated in peripheral tissues by deiodination of T4. Half-life ~1 day. T3 binds the nuclear receptor with ~10–15× the affinity of T4.
High-yield: Most circulating T3 is NOT secreted by the thyroid — it is produced in peripheral tissues (chiefly liver, kidney, muscle) by 5'-monodeiodination (outer-ring) of T4.
Hormone synthesis — the stepwise cascade
Synthesis occurs at the apical (luminal) membrane and within the colloid. The classic sequence tested in exams:
Iodide trapping → Oxidation → Organification → Coupling → Storage → Endocytosis → Proteolysis → Secretion
- Iodide trapping (uptake): The basolateral Na⁺/I⁻ symporter (NIS) actively co-transports iodide into the cell against a gradient, powered secondarily by the Na⁺/K⁺-ATPase. This concentrates iodide ~30–40× plasma. NIS is the target of competitive anions.
- Transport to lumen: Iodide crosses the apical membrane into colloid via pendrin (an I⁻/Cl⁻ exchanger; mutated in Pendred syndrome → goitre + sensorineural deafness).
- Oxidation: Thyroid peroxidase (TPO), using H₂O₂ (generated by DUOX2), oxidises iodide (I⁻) to an active iodinating species.
- Organification (iodination): TPO attaches iodine to tyrosyl residues on thyroglobulin → MIT (mono-iodotyrosine) and DIT (di-iodotyrosine).
- Coupling: TPO couples iodotyrosines —
- DIT + DIT → T4
- DIT + MIT → T3 (and a small amount of reverse T3).
- Storage: Iodinated Tg is stored in colloid — a reserve sufficient for ~2–3 months even if synthesis stops.
- Endocytosis & proteolysis: Under TSH stimulation, follicular cells endocytose colloid; lysosomal proteases cleave Tg, liberating T4 and T3 into the circulation.
- Deiodination of MIT/DIT: Leftover MIT/DIT are deiodinated intracellularly by iodotyrosine deiodinase (DEHAL1), recycling iodide. (This iodide is salvaged — important in iodine economy.)
High-yield: TPO catalyses three steps — oxidation, organification, AND coupling. It is the target of the thioamide antithyroid drugs (carbimazole/methimazole, propylthiouracil).
Drug/anion interference at each step
| Agent | Step blocked | Note |
|---|---|---|
| Perchlorate, pertechnetate, thiocyanate | Iodide trapping (NIS) | Competitive; perchlorate used in discharge test |
| Lithium | Hormone release | Causes hypothyroidism/goitre |
| Thioamides (carbimazole, methimazole, PTU) | Organification & coupling (TPO) | PTU also blocks peripheral T4→T3 |
| High-dose iodide (Lugol's) | Release + organification (Wolff–Chaikoff) | Used pre-thyroidectomy |
| Amiodarone | Multiple (iodine load + deiodinase block) | Both hypo- and hyperthyroidism |
Peripheral conversion — the deiodinases
T4 is converted in tissues by selenium-dependent deiodinases. This is heavily examined:
| Deiodinase | Site | Action | Product | Clinical relevance |
|---|---|---|---|---|
| D1 | Liver, kidney, thyroid | Outer + inner ring | T3 (and rT3) | Main source of plasma T3; inhibited by PTU |
| D2 | Brain, pituitary, BAT, muscle | Outer ring (5') | T3 (local, intracellular) | Local T3 for pituitary feedback; ↑ in hypothyroidism |
| D3 | Placenta, brain, fetal tissues | Inner ring (5) | rT3 & T2 (inactivating) | Protects fetus/brain from excess T3 |
- Outer-ring (5') deiodination of T4 → T3 = activation.
- Inner-ring (5) deiodination of T4 → reverse T3 (rT3) = inactivation (rT3 is metabolically inert).
High-yield: In sick euthyroid syndrome (non-thyroidal illness), peripheral conversion shifts away from T3 toward rT3 → low T3, normal/low TSH, raised rT3. Do not treat; it is an adaptive response.
High-yield: PTU is the only thioamide that also inhibits peripheral D1 (T4→T3) — hence preferred in thyroid storm and the first trimester of pregnancy.
Transport in blood
High-yield: ~99.97% of T4 and ~99.7% of T3 are protein-bound; only the free fraction is biologically active and feedback-regulated.
Binding proteins (in order of affinity/contribution):
- Thyroxine-binding globulin (TBG): carries ~70% of T4 — the dominant carrier.
- Transthyretin (TBPA/prealbumin): ~10–15%.
- Albumin: large capacity, low affinity.
TBG changes alter TOTAL hormone but free levels (and thus clinical status) stay normal:
| TBG increased → ↑ total T4/T3 | TBG decreased → ↓ total T4/T3 |
|---|---|
| Pregnancy, oestrogen/OCPs | Androgens, glucocorticoids |
| Acute hepatitis | Nephrotic syndrome (urinary loss) |
| Hereditary excess | Chronic liver disease, severe illness |
Mnemonic for TBG increase: "POPE" — Pregnancy, Oestrogen (OCP), Porphyria/acute hepatitis, Estrogen states.
Regulation — the HPT axis
Hypothalamus (TRH) → Anterior pituitary (TSH) → Thyroid (T4/T3) → negative feedback on pituitary & hypothalamus
- TRH (tripeptide) from the hypothalamus stimulates thyrotrophs.
- TSH (glycoprotein, α-subunit shared with FSH/LH/hCG; β-subunit specific) acts on a Gs-coupled receptor → ↑ cAMP → stimulates all steps of synthesis plus follicular hypertrophy/hyperplasia.
- Negative feedback: Free T3/T4 suppress TSH and TRH. The pituitary senses T3 generated locally by D2 — this is why TSH is an exquisitely sensitive marker.
High-yield: TSH and free T4 have a log–linear (inverse) relationship — a small change in free T4 produces a large change in TSH. This makes TSH the single best screening test for primary thyroid dysfunction.
Other influences:
- Cold stimulates TRH (thermogenesis) — prominent in neonates.
- Somatostatin, dopamine, glucocorticoids suppress TSH.
- hCG (structurally TSH-like) mildly stimulates the thyroid → physiological first-trimester TSH dip; pathological in molar pregnancy/hyperemesis.
Autoregulation: Wolff–Chaikoff and Jod–Basedow
These paired effects are almost guaranteed exam material.
| Effect | Trigger | Mechanism | Net result |
|---|---|---|---|
| Wolff–Chaikoff | Sudden iodide excess | Transient block of organification (TPO) | Transient ↓ hormone synthesis; "escape" in ~48 h via NIS downregulation |
| Jod–Basedow | Iodide load in iodine-deficient / nodular gland | Substrate flooding of autonomous tissue | Iodine-induced hyperthyroidism |
High-yield: Wolff–Chaikoff (iodide → less hormone) underlies the use of Lugol's iodine / SSKI pre-thyroidectomy to reduce gland vascularity. Failure to "escape" (e.g., in autoimmune thyroiditis) can cause iodine-induced hypothyroidism — relevant to amiodarone and neonates exposed to iodine antiseptics.
Mechanism of action and physiological effects
T3 enters cells (via MCT8 transporter — mutated in Allan–Herndon–Dudley syndrome) and binds nuclear thyroid hormone receptors (TRα, TRβ) on thyroid response elements → modulates gene transcription. Some effects are non-genomic (membrane/mitochondrial).
Calorigenic / metabolic actions (most tested):
- ↑ Basal metabolic rate (BMR) — increases Na⁺/K⁺-ATPase activity and O₂ consumption in almost all tissues (except brain, gonads, spleen).
- ↑ Heat production; ↑ appetite.
- Carbohydrate: ↑ gut glucose absorption, glycogenolysis, gluconeogenesis.
- Lipid: ↑ lipolysis, ↑ LDL-receptor expression → lowers cholesterol (hypothyroidism → hypercholesterolaemia).
- Protein: physiological levels anabolic; excess catabolic → muscle wasting.
Cardiovascular ("permissive" sympathetic action):
- ↑ β-adrenergic receptor number → ↑ heart rate, contractility, cardiac output, widened pulse pressure. Explains tachycardia of thyrotoxicosis and the use of propranolol symptomatically.
Growth & CNS development:
- Essential for brain maturation and skeletal growth in fetus/infant. Deficiency → cretinism (irreversible intellectual disability if untreated) — basis of newborn TSH screening.
- Potentiates growth hormone effects on bone.
High-yield: Thyroid hormone effect on the heart is permissive to catecholamines (upregulates β-receptors); BMR is raised in all tissues except adult brain, gonads, uterus, lymph nodes and spleen.
Clinical correlation — hypo vs hyperthyroidism physiology
| Parameter | Hyperthyroidism | Hypothyroidism |
|---|---|---|
| BMR / weight | ↑ BMR, weight loss with ↑ appetite | ↓ BMR, weight gain |
| Heat tolerance | Heat intolerance, sweating | Cold intolerance |
| Cardiovascular | Tachycardia, AF, wide pulse pressure | Bradycardia, narrow pulse pressure, pericardial effusion |
| GI | Hyperdefecation/diarrhoea | Constipation |
| Neuro | Tremor, anxiety, hyperreflexia, lid lag | Lethargy, delayed relaxation of ankle jerk |
| Skin | Warm, moist; pretibial myxoedema (Graves) | Dry, coarse; non-pitting myxoedema |
| Lipids | Low cholesterol | High cholesterol, ↑ CK |
| Reflexes | Brisk | Hung-up / delayed relaxation |
TFT interpretation — the exam clincher
The pattern of TSH vs free T4 localises the lesion.
| TSH | Free T4 | Free T3 | Interpretation |
|---|---|---|---|
| ↓ | ↑ | ↑ | Primary hyperthyroidism (Graves, toxic nodule) |
| ↑ | ↓ | ↓/N | Primary hypothyroidism (Hashimoto, iodine deficiency) |
| ↓ | ↓ | ↓ | Central (secondary) hypothyroidism (pituitary/hypothalamic) |
| ↑ | ↑ | ↑ | TSH-secreting adenoma or thyroid hormone resistance |
| ↑ | N | N | Subclinical hypothyroidism |
| ↓ | N | N | Subclinical hyperthyroidism |
| ↓/N | ↓ | ↓ (↑ rT3) | Sick euthyroid syndrome |
High-yield: In primary disease, TSH and free T4 move in opposite directions. When they move in the same direction, suspect a central lesion or a TSH-oma / resistance.
Approach to a screening abnormality:
- Start with TSH. Normal → euthyroid (in nearly all outpatient settings).
- Abnormal TSH → add free T4.
- Discordant/central picture → assess pituitary, consider TSH-oma, repeat to exclude assay artefact.
Special / pregnancy physiology
- Oestrogen ↑ TBG → total T4/T3 rise; free levels stay normal.
- hCG cross-stimulates the TSH receptor → first-trimester TSH falls (lower trimester-specific reference range).
- Iodine and thyroid hormone requirements rise ~30–50%; placental D3 and fetal dependence on maternal T4 (early gestation) make maternal hypothyroidism a cause of poor fetal neurodevelopment.
- Levothyroxine dose typically increased by ~30% in known hypothyroid pregnant women.
Key differentials / look-alike concepts
- Low total T4 with normal free T4 & TSH → think TBG deficiency (androgens, nephrotic syndrome), not true hypothyroidism.
- Low T3, raised rT3, normal TSH in an ICU patient → sick euthyroid, not central hypothyroidism — avoid thyroxine.
- Goitre + deafness → Pendred syndrome (pendrin defect, organification trap).
- Tall stature/learning issues + high T4 + non-suppressed TSH → thyroid hormone resistance (TRβ mutation) vs TSH-oma (use α-subunit, MRI).
Investigations / functional tests
- Radioiodine (RAIU) uptake: ↑ in Graves/toxic nodular; low/absent in thyroiditis (de Quervain, silent), factitious thyrotoxicosis, and iodine load. Useful to differentiate causes of thyrotoxicosis.
- Perchlorate discharge test: positive (release of trapped iodide) in organification defects (e.g., Pendred, TPO defect).
- Anti-TPO antibodies: Hashimoto. TSH-receptor antibody (TRAb/TSI): Graves.
- Thyroglobulin: tumour marker for differentiated thyroid cancer follow-up (post-thyroidectomy).
Recently asked / exam angle
- "Most active form of thyroid hormone" → T3; "main secreted/circulating form" → T4; "main source of circulating T3" → peripheral D1 deiodination.
- Enzyme blocked by carbimazole/PTU → thyroid peroxidase (TPO); drug additionally blocking peripheral conversion → PTU.
- Iodide-induced ↓ synthesis = Wolff–Chaikoff; iodide-induced thyrotoxicosis = Jod–Basedow — direction questions are common.
- Transporter for iodide uptake = NIS (basolateral); apical transporter = pendrin.
- TFT vignette: TSH ↑ with free T4 ↑ → TSH-oma / resistance (same-direction trick).
- Sick euthyroid: low T3, high rT3, normal TSH — "do not start thyroxine."
- Reverse T3 produced by inner-ring (D3) deiodination — inactive.
- TBG ↑ in pregnancy/oestrogen, ↓ in nephrotic syndrome/androgens — total changes, free normal.
- Deiodinases are selenium-dependent; cofactor for TPO reaction is H₂O₂ (DUOX2).
- Delayed relaxation of ankle jerk → hypothyroidism; lid lag → hyperthyroidism.
Rapid revision
- Synthesis order: trap → oxidise → organify → couple → store → endocytose → proteolyse → secrete.
- TPO does oxidation + organification + coupling; needs H₂O₂.
- NIS traps iodide (basolateral); pendrin moves it to colloid (apical); defect → Pendred (goitre + deafness).
- DIT+DIT = T4; DIT+MIT = T3.
- T4 = prohormone (t½ ~7 d); T3 = active (t½ ~1 d); ~80% of T3 made peripherally.
- Outer ring = activation (T3); inner ring = inactivation (rT3). D1 liver/kidney, D2 brain/pituitary, D3 placenta/fetus.
- PTU uniquely blocks peripheral T4→T3 → drug of choice in storm and 1st-trimester pregnancy.
- Wolff–Chaikoff: iodide excess → transient ↓ synthesis (basis of Lugol's pre-op). Jod–Basedow: iodide → hyperthyroidism in nodular/deficient gland.
- TBG ↑ (pregnancy/oestrogen) raises total T4/T3; free stays normal — patient euthyroid.
- TSH–free T4 = log-linear inverse; TSH is the best screening test for primary disease.
- Primary disease: TSH and T4 move opposite; same direction → central/TSH-oma/resistance.
- Sick euthyroid: low T3, raised rT3, normal/low TSH — don't treat.
- Thyroid hormone is permissive to catecholamines (↑ β-receptors) and raises BMR in all tissues except brain, gonads, spleen, uterus, lymph nodes.
- Deficiency in infancy → cretinism (irreversible) → basis of newborn TSH screening.