Thyroid hormones

Synthesis, step by step

• About 90% of the hormone released is T4 (thyroxine); most circulating T3 is made outside the thyroid by deiodination.
• T3 is the active hormone because it binds the nuclear thyroid receptor about ten times more strongly than T4; T4 is largely a prohormone. Reverse T3 is inactive and rises in severe illness (sick euthyroid state).
• Inactivation is by deiodination (to reverse T3 and other inactive forms) and, in the liver, conjugation with glucuronide and sulphate followed by biliary excretion.

Transport

Over 99% of T4 and T3 is protein bound, mainly to thyroxine-binding globulin (TBG), also transthyretin and albumin. Only the free hormone acts. Pregnancy and oestrogen raise TBG, so total T4 rises while free T4 and TSH stay normal.

Actions

• Metabolism: raises basal metabolic rate, O₂ consumption and heat (more Na⁺/K⁺-ATPase), gut glucose absorption, gluconeogenesis and lipolysis. It increases hepatic LDL receptor numbers, so hypothyroidism raises LDL cholesterol, which normalises on levothyroxine alone (treating with a statin first raises myopathy risk). It also speeds the catabolism of vitamin K-dependent clotting factors, so thyrotoxicosis raises the INR in a patient on warfarin; the INR falls again as the patient becomes euthyroid.
• Heart: increases heart rate, contractility and beta-1 adrenergic receptor number and sensitivity, so thyrotoxic patients behave as if they had excess catecholamines. This is why propranolol rapidly relieves tremor, palpitations and anxiety (and slightly reduces T4 to T3 conversion). Tachycardia in hyperthyroidism is due to increased sensitivity to catecholamines plus a direct effect on the SA node.
• Bone: increases turnover with net resorption. Long-term over-replacement (TSH suppressed below 0.05 on levothyroxine) causes osteoporosis and atrial fibrillation.
• Growth and brain development: essential for fetal and infant brain maturation and for bone maturation.
• Nervous system: reflex speed; slow-relaxing reflexes in hypothyroidism.

Development and cretinism

• The fetus depends on maternal T4 until its own thyroid works (about 12 weeks) and partly afterwards. In endemic cretinism (iodine-deficient valleys), low maternal T4 during fetal brain development causes intellectual disability, deafness and spastic gait; the child may be euthyroid when seen.
• Congenital hypothyroidism is screened at birth by heel-prick TSH because early levothyroxine prevents intellectual disability, and babies look normal at first.

Control and testing

TRH from the hypothalamus releases TSH, which stimulates the thyroid; free T4 and T3 feed back on both. TSH is the best single test of thyroid function when the pituitary is normal; confirm hypothyroidism with TSH plus free T4.

• TRH test: in pituitary (secondary) disease TSH fails to rise; in hypothalamic (tertiary) disease the low TSH rises markedly after TRH, because the pituitary is intact but unstimulated.
• Thyroglobulin: after total thyroidectomy and radioiodine for papillary or follicular carcinoma, any thyroglobulin means thyroid tissue: it is the marker of recurrence. It is useless while a normal gland remains.
• Low uptake thyrotoxicosis: thyroiditis (hormone leaks out, thyroglobulin high) versus factitious thyrotoxicosis from taking thyroxine tablets (gland suppressed, small and non-tender, thyroglobulin low), as in a health worker trying to lose weight.

Hyperthyroidism

• Graves disease: TSH-receptor stimulating antibodies (TSI) raise T3 and T4 and suppress TSH; diffuse goitre and diffuse uptake. Exophthalmos and pretibial myxoedema are specific to Graves. In active eye disease, swollen orbital muscles can compress the optic nerve: colour vision falls before acuity, an emergency for steroids or decompression.
• Toxic multinodular goitre / toxic adenoma: patchy or single hot nodule. Iodine load (iodinated contrast, amiodarone) fuels autonomous nodules (Jod–Basedow), causing thyrotoxicosis weeks later.
• Thyroiditis (painful subacute de Quervain; painless postpartum): transient, low uptake.
• Features: weight loss with good appetite, heat intolerance, diarrhoea, anxiety, tremor, tachycardia, AF, lid lag, proximal myopathy, osteoporosis.
• Treatment: beta-blocker for symptoms; carbimazole (agranulocytosis: stop if sore throat) or PTU (first trimester, thyroid storm; liver failure); radioiodine; surgery. Tetany on the first day after thyroidectomy means hypocalcaemia from parathyroid damage.

Hypothyroidism

• Hashimoto thyroiditis (anti-TPO antibodies; lymphocytic infiltrate with germinal centres and Hürthle cells) is commonest where iodine is adequate; iodine deficiency worldwide.
• Features: weight gain, cold intolerance, constipation, dry skin, hoarse voice, bradycardia, slow-relaxing reflexes, menorrhagia, macrocytosis, hyponatraemia, carpal tunnel syndrome, raised TSH, cholesterol, CK and prolactin.
• Non-pitting oedema (myxoedema): glycosaminoglycans (hyaluronic acid) accumulate in the dermis and bind water, so the fluid cannot be displaced by pressure.
• Myxoedema coma (hypothermia 33 °C, bradycardia, hyponatraemia, hypoventilation, drowsiness): give IV hydrocortisone with or before thyroxine, because thyroxine raises cortisol demand and can precipitate adrenal crisis.
• Treatment: levothyroxine titrated by TSH; start low in the elderly and in ischaemic heart disease. If symptoms return on a stable dose, check TSH, adherence and absorption (taking it with food, iron, calcium or PPIs), then adjust the dose.

Drugs affecting the thyroid

• Amiodarone (iodine-rich): hypo- or hyperthyroidism; blocks T4 to T3 conversion.
• Lithium: hypothyroidism and goitre (blocks release).
• Iodinated contrast: Jod–Basedow in nodular glands or transient hypothyroidism.

Remember Trap, oxidise, organify, couple, store, release, convert: the gland makes T4, the tissues make T3.

Exam trap PTU blocks both TPO and peripheral conversion; carbimazole blocks only TPO.

Exam trap In myxoedema coma give hydrocortisone before or with thyroxine.

How FCPS asks about this

• Hormone mostly released by the gland: T4; active hormone T3, made mostly peripherally and binding receptors more strongly.
• Tachycardia in hyperthyroidism: more beta-1 receptors and catecholamine sensitivity; propranolol gives rapid relief.
• Low TSH rising markedly after TRH: hypothalamic (tertiary) hypothyroidism; low TSH with low T4 means pituitary or hypothalamus.
• Why myxoedema is non-pitting: glycosaminoglycans binding water.
• Recurrence marker after thyroidectomy for papillary cancer: serum thyroglobulin; low thyroglobulin also identifies factitious thyrotoxicosis.
• Thyrotoxicosis after contrast in multinodular goitre: extra iodine fuels autonomous nodules.
• Heel-prick TSH screening: early treatment prevents intellectual disability.