How the thyroid is tested on Step 1

Start with synthesis and the drugs that block each step.

Iodide trappingNa⁺/I⁻ symporter; blocked by perchlorate andpertechnetateOxidationTPO oxidizes and attaches iodine to thyroglobulin;methimazole, PTU blockCouplingTPO joins MIT and DIT to form T3 and T4ReleaseThyroglobulin is digested; mostly T4 released; highiodine briefly blocks (Wolff-Chaikoff)Activation5′-deiodinase converts T4 → T3; PTU, propranolol,steroids reduce it
Thyroid hormone synthesis. Most T4 circulates bound to thyroxine-binding globulin; estrogen raises TBG and total T4.
PatternTSHFree T4Example
Primary hypothyroidism↑↓Hashimoto thyroiditis
Subclinical hypothyroidism↑NormalEarly Hashimoto
Primary hyperthyroidism↓↑Graves disease, toxic nodule
Central hypothyroidism↓ or normal↓Pituitary disease
TSH-secreting adenoma↑ or normal↑Rare pituitary tumor

TSH is the best screening test in most patients.

Hyperthyroidism and hypothyroidism

Autoimmunity causes most of both.

Graves diseaseTSH-receptor stimulating antibodiesHyperthyroid; diffuse goiterExophthalmos, pretibial myxedemaDiffuse ↑ radioiodine uptakeMethimazole, radioiodine, surgeryHashimoto thyroiditisAnti-TPO, anti-thyroglobulinHypothyroid (may start hyper)Painless, firm goiterLymphoid follicles, Hürthle cellsLevothyroxinevs
Graves vs Hashimoto. Graves eye disease comes from fibroblasts and fat behind the eye that also carry TSH receptors.
  • Subacute granulomatous (de Quervain) thyroiditis: painful, tender thyroid after a viral illness; high ESR; transient hyperthyroidism, then hypothyroidism; low uptake.
  • Painless and postpartum thyroiditis: lymphocytic, transient, low uptake.
  • Toxic multinodular goiter and toxic adenoma: TSH-independent nodules; patchy or focal uptake.
  • Congenital hypothyroidism: lethargy, poor feeding, big tongue, umbilical hernia, prolonged jaundice; detected by newborn screening.
  • Drugs: lithium and amiodarone can cause hypothyroidism; amiodarone can also cause hyperthyroidism.

Thyroid storm and treatment

Block the effects, synthesis, release, and conversion.

  • Thyroid storm: fever, tachycardia or atrial fibrillation, agitation, and vomiting after a trigger (surgery, infection, iodine load). Treat with propranolol, PTU (or methimazole), then iodine solution, and corticosteroids.
  • Antithyroid drugs: methimazole is preferred except in the first trimester (teratogenic) and storm; PTU can cause liver failure; both can cause agranulocytosis.
  • Levothyroxine: treats hypothyroidism; overtreatment causes atrial fibrillation and bone loss.
  • Myxedema coma: severe hypothyroidism with hypothermia, low sodium, and confusion; IV levothyroxine and steroids.

Thyroid cancers

Histology, spread, and genetic associations.

CancerKey featuresSpread and associations
Papillary (most common)Ground-glass "Orphan Annie" nuclei, nuclear grooves, psammoma bodiesLymphatic; radiation exposure; RET/PTC, BRAF; excellent prognosis
FollicularInvades the capsule or vesselsBloodstream (bone, lung); RAS
MedullaryC cells; calcitonin; amyloid stromaMEN2A and 2B (RET)
AnaplasticUndifferentiated; older adultsRapid local invasion; very poor prognosis; TP53
LymphomaB-cell; rapidly enlarging glandHashimoto thyroiditis

Thyroid nodules are evaluated with TSH, ultrasound, and fine-needle aspiration.

Worked example

Find the antibody.

functions Worked example — palpitations and bulging eyes

A 32-year-old has weight loss, heat intolerance, palpitations, a diffuse non-tender goiter, protruding eyes, and thickened skin over the shins. TSH is low and free T4 high. What mechanism causes the disease?

  1. Low TSH with high T4 means primary hyperthyroidism.
  2. Exophthalmos and pretibial myxedema are specific to Graves disease.
  3. Antibodies stimulate the TSH receptor on thyroid cells, orbital fibroblasts, and dermal fibroblasts.
  4. This is a type II hypersensitivity in which the antibody activates rather than destroys its target.

Answer. Graves disease from TSH receptor–stimulating antibodies.