Endocrinology
Thyroid Function
T3, T4, TSH — hypothalamic-pituitary-thyroid axis controlling metabolism, growth, and thermogenesis
The thyroid gland synthesizes thyroxine (T4) and triiodothyronine (T3) by iodinating tyrosine residues on thyroglobulin. T4 is the major circulating form (~90% of secretion); T3 is the active form, generated peripherally by deiodinases (~80%) and at low levels by the thyroid (~20%). Hypothalamic TRH stimulates pituitary TSH, which drives thyroid synthesis; T3/T4 negatively feed back. Thyroid hormones bind nuclear receptors to regulate basal metabolic rate, cardiac output, thermogenesis, lipid and carbohydrate metabolism, growth, and CNS development. Hypothyroidism (high TSH, low T4) most commonly from Hashimoto's autoimmune thyroiditis. Hyperthyroidism (low TSH, high T4/T3) usually from Graves disease (TSH receptor antibodies) or toxic nodules. Treatment: levothyroxine, methimazole/PTU, radioactive iodine, surgery.
- Major secretionT4 (90%); active form is T3
- Iodine requirement150 µg/day (250 µg in pregnancy)
- TSH normal range~0.4-4.0 mIU/L
- Most common hypothyroidism causeHashimoto autoimmune thyroiditis
- Most common hyperthyroidism causeGraves disease (TSH receptor antibodies)
- Half-life of T4~7 days; T3 ~1 day
Interactive visualization
Press play, or step through manually. The visualization is yours to drive — try it before reading on.
Watch the 60-second explainer
A condensed visual walkthrough — narrated, captioned, under a minute.
Why thyroid function matters
- Common disease. ~5% of US adults have hypothyroidism; women 5-8x more often than men.
- Pregnancy. Maternal thyroid status affects fetal neurodevelopment; screening and replacement are critical.
- Cardiac disease. Hyperthyroidism causes atrial fibrillation; hypothyroidism worsens heart failure and lipids.
- Mental health. Hypothyroidism mimics depression; hyperthyroidism mimics anxiety — TSH is part of psychiatric workup.
- Newborn screening. Universal congenital hypothyroidism screen prevents irreversible cretinism with early levothyroxine.
- Drug interactions. Amiodarone, lithium, immune checkpoint inhibitors, and tyrosine kinase inhibitors all cause thyroid dysfunction.
- Cancer surveillance. Differentiated thyroid cancer has excellent prognosis with proper surgical and radioiodine management.
Common misconceptions
- T3 testing routinely needed. TSH and free T4 suffice for most diagnoses; T3 mainly in suspected T3-toxicosis.
- Subclinical means asymptomatic and benign. Subclinical hyper-/hypothyroidism still affect cardiovascular and bone health and may need treatment.
- All goiters are cancerous. Most are benign multinodular or autoimmune; cancer represents <10% of palpable nodules.
- Iodine deficiency is rare in developed countries. US iodine intake declined and pregnancy needs are often unmet without supplementation.
- Levothyroxine cures Hashimoto's. It replaces hormone but does not stop autoimmune destruction; goiter and antibodies persist.
- Eating goitrogens (soy, cabbage) causes hypothyroidism. Effect is negligible at normal dietary intake with adequate iodine.
Frequently asked questions
How is thyroid hormone synthesized?
Iodide is actively pumped into thyroid follicular cells by the sodium-iodide symporter (NIS), then transported into colloid where thyroid peroxidase (TPO) oxidizes it and iodinates tyrosines on thyroglobulin (organification). Coupling of mono- and diiodotyrosine residues forms T3 and T4 stored in colloid. TSH stimulates pinocytosis of colloid back into the cell, where lysosomal proteases release T3/T4 into circulation. Methimazole and PTU inhibit TPO, blocking new synthesis.
Why is TSH the best screening test?
TSH responds logarithmically to small changes in T4 because hypothalamic-pituitary feedback is exquisitely sensitive — TSH varies ~10-fold for a 2-fold change in free T4. So mild thyroid dysfunction shows abnormal TSH while T4 is still in normal range (subclinical hypo- or hyperthyroidism). TSH is the first-line screen; free T4 confirms primary thyroid disease. Central (pituitary) hypothyroidism is rare and presents with low TSH and low T4.
What are the clinical features of hypothyroidism?
Cold intolerance, fatigue, weight gain (despite poor appetite), constipation, dry skin, hair loss, depression, bradycardia, hypercholesterolemia, menstrual irregularities, delayed deep tendon reflex relaxation, periorbital edema, hoarseness. Severe untreated: myxedema coma — hypothermia, hypoventilation, hyponatremia, altered mental status, mortality ~25%. Treatment: levothyroxine 1.6 µg/kg/day; titrate every 6-8 weeks to TSH target. In elderly with cardiac disease, start low to avoid precipitating angina.
What are the features of hyperthyroidism?
Heat intolerance, weight loss with increased appetite, palpitations, atrial fibrillation, tremor, anxiety, insomnia, diarrhea, proximal muscle weakness, hyperreflexia, oligomenorrhea, warm moist skin. Graves adds ophthalmopathy (proptosis, diplopia from extraocular muscle inflammation) and pretibial myxedema. Thyroid storm: extreme tachycardia, hyperthermia, agitation, multiorgan failure, mortality ~10-30%. Treatment: methimazole/PTU (block synthesis), beta-blockers (symptom control), radioactive iodine ablation, or thyroidectomy.
How does pregnancy affect thyroid?
hCG cross-reacts with TSH receptor, mildly stimulating thyroid in first trimester (lower TSH). Estrogen increases TBG, raising total T4 but free T4 is roughly preserved. Thyroid hormone requirement rises ~30% — pregnant women on levothyroxine need dose increase as soon as pregnancy is confirmed. Fetal thyroid begins functioning by week 12; before this fetus relies on maternal T4. Maternal hypothyroidism impairs fetal neurodevelopment — TSH targets <2.5 in first trimester. Postpartum thyroiditis affects ~5%.
What's a thyroid nodule workup?
Palpable or incidentally detected nodules are common (~5% palpable, ~50% on ultrasound in elderly). Most are benign; ~5-10% are malignant. Ultrasound assesses size and risk features (TI-RADS): hypoechoic, microcalcifications, taller-than-wide, irregular margins. TSH first; if low, scintigraphy to check for hot (autonomously functioning, almost always benign) versus cold nodule. Cold nodules >1 cm with suspicious features get fine-needle aspiration. Bethesda system grades cytology and guides surgery.
What types of thyroid cancer exist?
Papillary (~80%): well-differentiated, slow-growing, lymphatic spread, excellent prognosis (~98% 5-year survival). Follicular (~10%): hematogenous spread to lung/bone, requires definitive surgery to distinguish from adenoma. Medullary (~3%): from parafollicular C cells, secretes calcitonin, can be familial (MEN2 syndromes from RET mutations). Anaplastic (<2%): undifferentiated, aggressive, mortality near 100% within months. Treatment: thyroidectomy, radioactive iodine for differentiated tumors, levothyroxine TSH suppression, targeted therapies (lenvatinib, selpercatinib).