Thyroid gland

What it normally does

• The follicular cell traps iodide from blood against a steep gradient using the sodium-iodide symporter (NIS) on its basolateral membrane, powered by the sodium gradient from the Na/K ATPase. Iodide moves to the apical membrane (pendrin and other channels), where thyroid peroxidase (TPO) — a membrane-bound enzyme sitting on the apical surface and facing the colloid — uses hydrogen peroxide to oxidise it and attach it to tyrosine residues on thyroglobulin (organification), then couples the iodinated tyrosines together: DIT + DIT gives T4, MIT + DIT gives T3. The finished hormone stays stuck to thyroglobulin in the colloid, outside the cell, and is only chopped free when the cell endocytoses colloid and digests it. The store is large: roughly two to three months of hormone sits in the colloid at any time.

  the gland is the only tissue that both concentrates iodine and organifies it — salivary gland, gastric mucosa and lactating breast express the same symporter but cannot fix iodine into hormone — which is why iodine isotopes can be used both to photograph it (uptake scan) and to destroy it (iodine-131), and why iodine intake in the food supply sets the size of the gland. It also explains the two great time lags on this page. A drug that blocks TPO cannot touch the hormone already in the colloid, so it takes weeks to work; and a gland that is inflamed and leaking its store can flood the patient with hormone while making none at all.

• The gland secretes mostly T4 — around 85 to 100 micrograms a day against only about 5 micrograms of T3. T4 is a prohormone. Deiodinase enzymes in liver, kidney, muscle, pituitary and elsewhere strip an outer-ring iodine to make T3, the form that actually binds the nuclear receptor with roughly ten times the affinity; stripping an inner-ring iodine instead makes inactive reverse T3. Most circulating T3 is made this way in the tissues, not secreted. Over 99% of circulating hormone is bound to thyroxine-binding globulin, transthyretin and albumin, so only the tiny free fraction is active. T4 has a half-life near seven days, T3 about one day.

  the long T4 half-life is why levothyroxine is a once-daily tablet, why a single missed dose does not produce an abrupt swing (the tablet is still a daily one), and why you wait about six weeks after a dose change before rechecking. It also explains why total T4 is a poor test: anything that raises binding globulin — pregnancy, the oestrogen-containing pill — raises total hormone while the free fraction and the patient stay normal. And it explains why illness or drugs that inhibit deiodinase (amiodarone, high-dose propranolol, glucocorticoids) drop T3 without any thyroid disease at all.

• The pituitary thyrotroph releases TSH under hypothalamic TRH drive. TSH binds a Gs-coupled receptor on the follicular cell and raises cAMP, which turns up iodide trapping, hormone synthesis, colloid uptake and release — and also makes the cells grow and divide. T3 generated inside the pituitary from T4 by type 2 deiodinase feeds back and shuts TSH off. The relationship is log-linear: a small movement in free T4 produces a large, inverse movement in TSH.

  TSH is the single most sensitive thyroid test, and reading the pair tells you where the fault is. High TSH with low free T4 means the gland has failed and the pituitary is shouting at it; low TSH with high free T4 means too much hormone is being made or released; low TSH with low free T4 means the pituitary itself is the problem. Because TSH is also a growth signal, anything that keeps it high for years — iodine deficiency, autoimmune destruction, a TPO blocker pushed too far — produces a goitre. That same fact is used deliberately after surgery for differentiated thyroid cancer, where levothyroxine is dosed to hold TSH down in patients whose recurrence risk justifies it, so residual tumour is not fed.

• T3 enters the target cell (MCT8 transporter), binds a nuclear receptor and changes transcription. Basal metabolic rate, Na/K ATPase activity and heat production rise; gut transit speeds up; bone turnover increases; and beta-1 adrenoceptor density in the heart goes up, so the same circulating catecholamines produce more rate and more force. In infants it is required for myelination and normal growth. Two neighbours matter as much as the gland itself: the recurrent laryngeal nerves run in the tracheo-oesophageal grooves behind it, and the parathyroid glands (usually four) sit on its posterior surface. Scattered between the follicles are parafollicular C cells, which make calcitonin — of little consequence in adult humans, but a tumour marker.

  you can derive the whole clinical picture in both directions rather than memorising two symptom lists — fast, hot, hungry, loose, tremulous and in atrial fibrillation at one end; slow, cold, constipated, dry and bradycardic at the other. The adrenergic upregulation is why a beta blocker fixes the thyrotoxic patient's symptoms without touching their thyroid. The neighbours explain thyroidectomy: a hoarse voice means the recurrent laryngeal nerve, and tingling fingers with a positive Chvostek sign the next morning means the parathyroids. And calcitonin is why medullary carcinoma has a blood marker when the other thyroid cancers use thyroglobulin.

What goes wrong

• Graves disease← from “The pituitary thyrotroph releases TSH under hy…”

  An IgG autoantibody binds the TSH receptor and switches it on (TSH receptor antibody, TRAb). It behaves like TSH that never stops: cAMP is driven continuously, so the gland traps iodine hard, makes hormone hard and grows — but the antibody is not subject to negative feedback, so the rising T4 shuts off pituitary TSH without touching the drive. The same receptor, with IGF-1 receptor signalling, sits on orbital fibroblasts, which respond by laying down glycosaminoglycans and fat behind the eye; that is a separate disease process in a separate tissue driven by the same antibody, which is why the eyes can worsen while the blood tests are normal. Smoking is the strongest modifiable risk factor for the eye disease.

  Stimulating TSH receptor antibody. Diffuse goitre, high and uniform isotope uptake, positive TRAb, orbitopathy. Commonest cause of hyperthyroidism in Australia; Graves affects roughly 0.5% of the population, with a lifetime risk near 3% in women and 0.5% in men. Thyroid storm — fever, delirium, tachyarrhythmia, often precipitated by infection, surgery or iodine load — is the emergency at the far end.

  You would find: A woman in her twenties to fifties — female to male roughly 5 to 10 to 1 — with weight loss despite a good appetite, heat intolerance, sweating, palpitations, fine tremor, anxiety and frequent loose stools. The gland is diffusely enlarged, smooth and may have a bruit. Look for lid retraction and proptosis. TSH is suppressed with raised free T4 and free T3, and TRAb is positive. If a scan is needed the uptake is high and diffuse across both lobes. In an older patient the presentation can be almost silent apart from new atrial fibrillation or unexplained weight loss (apathetic thyrotoxicosis).

• Hashimoto thyroiditis and primary hypothyroidism← from “T3 enters the target cell (MCT8 transporter), …”

  Autoreactive T cells infiltrate and gradually destroy follicles; anti-thyroid peroxidase antibodies are the marker of that autoimmunity more than its main effector. Output falls, so less T3 reaches the nuclear receptor and transcription across every tissue slows. The pituitary detects the fall and TSH climbs, which is why TSH rises before free T4 has left the reference range (subclinical hypothyroidism) — and the high TSH, acting as a growth signal on surviving tissue, adds to the lymphocytic infiltrate to produce the firm goitre. Late in the disease the gland shrinks and fibroses instead. The same clinical picture follows anything that removes the gland or suppresses its output: thyroidectomy, radioiodine, iodine excess including amiodarone, lithium (which blocks hormone release), and dietary iodine deficiency where it still exists.

  Commonest cause of hypothyroidism where iodine is sufficient. High TSH with low free T4, anti-TPO positive. TSH rises first — subclinical hypothyroidism is a TSH diagnosis. Clusters with other autoimmune disease: type 1 diabetes, coeliac, vitiligo, Addison disease.

  You would find: Tiredness, cold intolerance, weight gain of a few kilograms, constipation, dry coarse skin, hair thinning, heavy periods, low mood and slowed thinking — all creeping in over months, which is why it is often missed. Bradycardia and a delayed relaxation phase of the ankle jerk are the two physical signs worth practising. TSH is high, free T4 low or low-normal, anti-TPO antibodies positive. Newborns are picked up on the heel prick screen before symptoms appear, because untreated congenital hypothyroidism costs irreversible IQ.

• Destructive thyroiditis← from “The follicular cell traps iodide from blood ag…”

  The follicles are damaged and spill their colloid store into the blood. Nothing is being synthesised — the gland is simply leaking a two to three month reservoir of preformed hormone. So the patient is thyrotoxic for typically two to eight weeks, then becomes hypothyroid while the store is empty and the cells recover, and most return to normal within six to twelve months. The causes to know are subacute (de Quervain) thyroiditis after a viral illness, painless postpartum thyroiditis in the months after delivery, and amiodarone-induced thyrotoxicosis type 2.

  Thyrotoxicosis with LOW uptake means the hormone is leaking, not being made. Thionamides do nothing here — there is no synthesis to block. Treat symptoms: beta blocker, and NSAIDs or corticosteroids for the pain of de Quervain. Expect a hypothyroid phase before recovery; a proportion of postpartum cases stay hypothyroid permanently, so recheck TSH.

  You would find: Thyrotoxic symptoms with a low or absent isotope uptake — this is the test that separates it from Graves disease, and the distinction changes the treatment completely. In de Quervain the gland is exquisitely tender, the patient reports a recent sore throat, and ESR and CRP are high. Postpartum thyroiditis is painless and easily mistaken for postnatal exhaustion or anxiety. Thyroglobulin is raised because the gland is being emptied (it is low in factitious thyrotoxicosis, the other low-uptake cause).

• Thyroid nodules and thyroid cancer← from “The pituitary thyrotroph releases TSH under hy…”

  Follicular cells retain the ability to divide under cAMP drive, and clones accumulate. A somatic activating mutation in the TSH receptor or its Gs protein makes one clone signal without TSH at all: it grows, makes hormone autonomously, suppresses pituitary TSH and so switches off the rest of the gland — a toxic (hot) nodule. Nodules that are cold on scan have lost that differentiated function, and it is these that carry the malignant risk. Papillary carcinoma is about 80 to 85% of thyroid cancer, spreads to cervical lymph nodes and has an excellent prognosis; follicular carcinoma spreads by blood to bone and lung; medullary carcinoma arises from the parafollicular C cells, secretes calcitonin and may be part of MEN 2 through RET mutation; anaplastic carcinoma is a rapidly enlarging, fixed mass in an older patient and is rarely survivable.

  TSH first, then ultrasound, then FNA — and never needle a hot nodule. Papillary: lymph nodes, best prognosis. Follicular: haematogenous, and cytology cannot call it because the diagnosis needs capsular or vascular invasion. Medullary: C cells, calcitonin, MEN 2. Anaplastic: elderly, fast, fatal.

  You would find: Most nodules are benign and most are found by accident on imaging of something else — thyroid cancer incidence in Australia has risen several-fold largely because we scan more necks, and much of that is small papillary cancer that would never have declared itself. The red flags are a hard fixed nodule, rapid growth, hoarseness (recurrent laryngeal nerve), cervical lymphadenopathy, and childhood neck irradiation. Work-up order matters: TSH first. If TSH is suppressed, scan for a hot nodule, which is almost never malignant and does not need a needle. If TSH is normal, ultrasound and, when features warrant, fine needle aspiration for cytology.

• Iodine supply, pregnancy and the thyroid← from “The follicular cell traps iodide from blood ag…”

  Hormone cannot be made without iodine. Too little and the gland hypertrophies under TSH drive to trap what there is — the classic goitre — and in the fetus the shortfall costs neurodevelopment. Pregnancy raises demand about 50%: oestrogen roughly doubles thyroxine-binding globulin so more total hormone is needed, the placenta deiodinates maternal hormone, and hCG weakly cross-stimulates the TSH receptor, which is why TSH dips in the first trimester and hyperemesis gravidarum can present with transient biochemical thyrotoxicosis. At the other extreme a sudden iodine load has two opposite effects: in a normal gland it transiently blocks organification (Wolff-Chaikoff) and, by a separate acute action, blocks release of stored hormone — the combination exploited therapeutically with potassium iodide before thyroidectomy and in storm — but in an autonomous nodule it supplies substrate for unrestrained synthesis (Jod-Basedow).

  Pregnancy raises thyroid hormone requirement by about 50% — increase levothyroxine early and check TSH. hCG stimulates the TSH receptor, so first-trimester TSH is normally low. Iodine load: Wolff-Chaikoff blocks a normal gland, Jod-Basedow ignites an autonomous one. Amiodarone is 37% iodine by weight and can do either.

  You would find: Australia had drifted back into mild iodine deficiency by the early 2000s; mandatory iodised salt in bread since 2009 corrected it at population level, and NHMRC advises a 150 microgram iodine supplement in pregnancy and breastfeeding. Fetal brain development in the first trimester depends entirely on maternal hormone, so a woman on levothyroxine typically needs a dose increase of around 25 to 30% as soon as pregnancy is confirmed, with TSH checked early. Thyroid disease is not one of the conditions with a documented large excess in Aboriginal and Torres Strait Islander communities, but iodine intake follows the food supply — remote communities depending on freighted bread and on tank or bore water have less reliable access to fortified staples, and the same access gaps affect antenatal testing and newborn screening follow-up.

What we give, and how it works

Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.