Thyroid Hormone Action & Function-Test Patterns
From deiodinases to lab patterns: reading TSH and T4 like a physiologist
Deiodination: activating and inactivating thyroid hormone
T4 is a prohormone. The thyroid secretes mostly T4, and about 80% of circulating T3 is made in peripheral tissues by removing an outer-ring (5′) iodine. T3 binds the thyroid hormone receptor with roughly 10-fold higher affinity than T4 and is about 3 to 5 times more potent, so it is the active hormone. All three deiodinases are selenocysteine-containing enzymes, and severe selenium deficiency impairs conversion.
| Enzyme | Main sites | Reaction | Key point |
|---|---|---|---|
| D1 | Liver, kidney, thyroid | T4 → T3 (outer ring) | Supplies plasma T3; inhibited by PTU |
| D2 | Pituitary, brain, brown fat, muscle | T4 → T3 (outer ring) | Makes intracellular T3; lets the pituitary sense T4 |
| D3 | Placenta, fetal tissues, brain | T4 → reverse T3; T3 → T2 (inner ring) | Shields the fetus; rises in critical illness |
Blocking conversion. PTU (D1), high-dose propranolol, glucocorticoids, amiodarone and iodinated contrast agents inhibit T4 → T3 conversion, as do fasting and acute illness. In thyroid storm, PTU, propranolol and hydrocortisone therefore each lower active T3 beyond their main action; methimazole, by contrast, blocks only thyroid peroxidase.
How T3 acts
Nuclear receptors. T3 enters cells and binds TRα or TRβ, which sit on thyroid response elements in DNA as heterodimers with RXR. Without hormone, the receptor recruits corepressors; T3 binding swaps them for coactivators and turns on transcription, so effects appear over hours to days. Unlike glucocorticoid receptors, thyroid receptors are nuclear rather than held in the cytoplasm by heat-shock proteins.
Metabolic rate and heat. T3 induces Na+/K+-ATPase in most tissues, raising ATP turnover, O2 consumption and basal metabolic rate, and it boosts thermogenesis, including UCP1 in brown fat. Excess causes heat intolerance, sweating and weight loss despite good appetite; deficiency causes cold intolerance, weight gain and fatigue.
Heart. T3 increases β1-adrenergic receptor number, α-myosin heavy chain and SERCA2 and lowers phospholamban, producing tachycardia, stronger contraction, faster relaxation and higher cardiac output. Peripheral vasodilation lowers systemic vascular resistance and widens pulse pressure. Catecholamine levels are normal or low in hyperthyroidism; the heart is simply more sensitive, which is why β-blockers relieve symptoms. Atrial fibrillation and high-output heart failure are the complications.
Growth, brain and fuel. T3 is needed for bone growth and epiphyseal maturation, synergizing with GH, and for fetal and neonatal CNS maturation; untreated congenital hypothyroidism causes intellectual disability, the reason for newborn screening. T3 drives glycogenolysis, gluconeogenesis and lipolysis and increases hepatic LDL-receptor expression, so hypothyroidism raises LDL cholesterol.
Check TSH in new hypercholesterolemia before starting a statin: hypothyroidism is a reversible cause and raises the risk of statin myopathy.
Reading thyroid function tests
TSH first. TSH varies log-linearly with free T4, so small changes in free T4 move TSH greatly, making TSH the most sensitive screen for primary thyroid disease. Free T4 is added when TSH is abnormal or pituitary disease is suspected.
| Pattern | TSH | Free T4 | Think of |
|---|---|---|---|
| Primary hypothyroidism | ↑ | ↓ | Hashimoto, post-ablation, lithium |
| Subclinical hypothyroidism | ↑ | Normal | Early Hashimoto |
| Primary hyperthyroidism | ↓ | ↑ (or only T3 ↑) | Graves, toxic nodule, thyroiditis |
| Subclinical hyperthyroidism | ↓ | Normal (T3 normal) | Mild excess, too much levothyroxine |
| Central hypothyroidism | ↓ or normal | ↓ | Pituitary or hypothalamic disease |
| TSH-oma or hormone resistance | ↑ or normal | ↑ | α-subunit, MRI, family history |
| TBG excess or deficiency | Normal | Normal | Total T4 ↑ (estrogen) or ↓ (nephrotic) |
| Nonthyroidal illness | Normal or ↓ | Normal (↓ if severe) | T3 ↓, reverse T3 ↑ |
Central hypothyroidism. Low free T4 with a low or inappropriately normal TSH is missed by a TSH-only screen. The other pituitary axes are evaluated and the sella imaged, and treatment is monitored by free T4 rather than TSH.
If ACTH may also be deficient, give glucocorticoid before levothyroxine; thyroid hormone speeds cortisol clearance and can provoke adrenal crisis.
High TSH with high T4. A TSH-secreting pituitary adenoma causes thyrotoxic symptoms, goiter, elevated α-subunit and a sellar mass. Resistance to thyroid hormone, usually a dominant THRβ mutation, gives the same labs with normal α-subunit, no tumor, affected relatives and often few symptoms, although tachycardia can occur through intact cardiac TRα. Graves disease, by contrast, suppresses TSH.
Binding proteins. Pregnancy and estrogen raise TBG, lifting total T4 and T3 while free T4 and TSH stay normal; androgens, glucocorticoids, nephrotic syndrome and liver failure lower TBG and total T4. A patient without a working thyroid cannot compensate, so starting estrogen or becoming pregnant raises the levothyroxine requirement; in pregnancy the dose is typically raised by roughly 25–30% once pregnancy is confirmed, because placental D3 and a larger distribution volume add to the TBG effect.
Illness and pregnancy
Nonthyroidal illness (sick euthyroid). Sepsis, surgery, starvation and other acute illness, through cytokines and cortisol, lower D1 and D2 and raise D3 activity: T3 falls, reverse T3 rises and TSH is normal or low. Very severe illness lowers T4 as well, which predicts mortality. The change is adaptive, thyroid hormone is not given, and TSH may overshoot transiently during recovery.
First-trimester hCG. hCG shares its α subunit with TSH, LH and FSH and, at high concentrations, weakly activates the TSH receptor. Near its late-first-trimester peak it slightly raises free T4 and lowers TSH, so trimester-specific reference ranges are used. Very high hCG in hyperemesis gravidarum, molar pregnancy or choriocarcinoma can cause overt hyperthyroidism.
Drug effects
Amiodarone. About 37% iodine by weight, amiodarone also blocks D1 and D2, so early on T4 and reverse T3 rise, T3 falls and TSH rises transiently. Its iodine load can cause hypothyroidism when the gland fails to escape the Wolff-Chaikoff effect, especially with underlying Hashimoto thyroiditis, or thyrotoxicosis:
- Type 1: iodine-fueled hormone synthesis (Jod-Basedow) in a nodular goiter or latent Graves gland, with normal or increased Doppler vascularity; treated with methimazole.
- Type 2: destructive thyroiditis of a previously normal gland that releases preformed hormone, with low vascularity and very low radioiodine uptake; treated with glucocorticoids such as prednisone. Radioiodine is useless in an iodine-saturated gland.
Lithium. Concentrated in the thyroid, lithium inhibits hormone release, causing goiter and hypothyroidism, especially in women with anti-TPO antibodies, so TSH is monitored during therapy.
TSH suppressors. Dopamine, high-dose glucocorticoids and somatostatin analogs such as octreotide lower pituitary TSH and can mimic central hypothyroidism in hospitalized patients.
High-dose biotin interferes with streptavidin-based immunoassays, producing falsely low TSH and falsely high T4 and T3 that mimic Graves disease; hold biotin before testing.