Thyroid Agents

TSH binds its Gs-coupled receptor on the follicular cell; cAMP and protein kinase A switch on iodide uptake and thyroid peroxidase. The basolateral sodium-iodide symporter (NIS), driven by the Na⁺/K⁺-ATPase, traps iodide from the blood; pendrin moves it into the colloid. Thyroid peroxidase (TPO) then oxidizes iodide, attaches it to tyrosines on thyroglobulin (organification → MIT and DIT) and couples them: MIT + DIT = T3, DIT + DIT = T4. Hormone is stored on thyroglobulin until the cell takes it back up and lysosomal proteolysis releases it — about 80% T4 and 20% T3.

Thyroid hormone receptors bind T3 with much higher affinity than T4, so T4 is relatively inactive: type I and II deiodinases convert T4 to active T3, and type III converts it to inactive reverse T3. About 80% of circulating T3 comes from peripheral deiodination of T4 rather than from the gland.

Both are competitive inhibitors of TPO, so they block iodination and coupling, but they do not inactivate hormone already stored in the gland or circulating — reaching euthyroidism therefore typically takes several months. PTU also blocks the peripheral conversion of T4 to T3, the reason it may be effective in thyroid storm. Methimazole is the preferred first-line drug: it is equally effective, is taken once daily and has a better safety profile.

Their dangers differ. PTU carries a boxed warning for severe liver injury and acute liver failure, so it is reserved for patients who cannot take methimazole and for whom radioiodine or surgery is unsuitable — except that it may be the drug of choice just before or during the first trimester, because methimazole taken then is linked to aplasia cutis, choanal atresia and esophageal atresia. Methimazole is generally used in the second and third trimesters, when PTU’s liver risk counts for more. Methimazole’s liver injury is mainly cholestatic, in contrast to the allergic hepatitis of PTU. Agranulocytosis (usually in the first 3 months) and ANCA-associated vasculitis occur with both; agranulocytosis is idiosyncratic and cross-reacts between the two, so fever or sore throat means stopping the drug and checking a white count.

Pharmacologic iodide acts fastest by decreasing thyroglobulin proteolysis, so less hormone is secreted within hours to days. It also transiently inhibits organification — the Wolff–Chaikoff effect — but within 2 to 4 weeks of continued excess, NIS expression falls, less iodide enters the cell, and synthesis resumes (escape). Graves glands are more sensitive than normal ones to this inhibition. Before thyroidectomy for Graves disease or toxic multinodular goiter, saturated potassium iodide (SSKI) or Lugol’s iodine also decreases gland vascularity and intraoperative blood loss. (These are uses from clinical references; the FDA-approved potassium iodide tablets are labeled only for radiation emergencies, where stable iodide floods the gland so radioactive iodine cannot enter.)

When autoregulation fails, excess iodide does the opposite. In the Jod-Basedow phenomenon — typically after contrast media or amiodarone, in people from iodine-deficient regions or with nodular or occult Graves disease — hyperthyroidism develops weeks after the iodine load. Iodide is also raw material for hormone, so when it is combined with a thionamide it is given at least an hour after the thionamide: given first, the new iodine becomes substrate for more hormone.

Sodium iodide I-131 follows the dietary-iodide pathway: NIS concentrates it in follicular cells and TPO binds it into thyroglobulin, which traps it in the gland, and its beta emission destroys the cells that took it up. It therefore works only where tissue is iodine-avid — preferred definitive therapy for Graves disease, toxic multinodular goiter and toxic adenoma, and for papillary and follicular cancers — but not in medullary or anaplastic cancer, which lack NIS, or in thyroiditis, where uptake is low or absent. The usual long-term result is hypothyroidism.

It is contraindicated in pregnancy (it crosses the placenta, the fetal thyroid concentrates iodide from weeks 10 to 12, and neonatal hypothyroidism can be severe and irreversible) and in lactation (NIS is upregulated in the lactating breast). Anything that saturates or suppresses uptake — stable iodide, amiodarone, contrast, thyroid hormone, a thionamide — is stopped beforehand. In the days afterward, radiation thyroiditis releases preformed hormone and can worsen hyperthyroidism, even to thyroid storm, so a β-blocker may be used around treatment. Damaged tissue can also release thyroid antigens and boost TSH-receptor antibodies that worsen Graves ophthalmopathy.

Levothyroxine is synthetic T4; tissues deiodinate it to T3. Because T4 is more than 99% protein-bound with a half-life of about 6–7 days (9–10 days in hypothyroidism), a dose change takes weeks to reach a new steady state — the TSH is rechecked 6–8 weeks later — and it has a narrow therapeutic index: too little leaves hypothyroidism, too much causes iatrogenic hyperthyroidism, arrhythmias and bone loss.

Its absorption (40–80%, from the jejunum and upper ileum) is easy to disturb. Gastric acidity is required, so proton pump inhibitors, sucralfate and antacids reduce it; calcium carbonate, iron and sevelamer bind it, as do bile acid sequestrants; soy, fiber and grapefruit juice reduce it; fasting increases it. Rifampin, phenobarbital and carbamazepine speed its metabolism, and estrogen raises TBG and the TSH in treated women. Thyroid hormone also speeds glucocorticoid clearance, so in adrenal insufficiency glucocorticoids are replaced first — starting thyroid hormone first can precipitate adrenal crisis. Liothyronine (T3) acts within hours, peaks in 2–3 days and has a half-life of 2 days or less.

The most severe form of hypothyroidism — altered mental status and hypothermia, with bradycardia, hypotension, hypoventilation (blunted hypoxic and hypercapnic drive) and hyponatremia — is usually precipitated by infection, cold, surgery or drugs, and its mortality is high. Treatment is intensive care: airway and ventilation, cautious fluids, and slow rewarming, because rapid rewarming causes vasodilation and worsens hypotension.

Thyroid hormone is started promptly and intravenously — oral thyroid hormone is not recommended for myxedema coma — and hydrocortisone is given first, after cortisol is drawn, because levothyroxine increases cortisol metabolism and hypothyroidism can mask adrenal insufficiency. Liothyronine is considered only when there is no response, with caution, because high T3 levels have been linked to higher mortality and aggressive replacement can precipitate myocardial infarction.

Thyroid storm is life-threatening thyrotoxicosis set off by a precipitant (infection, surgery, iodinated contrast, stopping an antithyroid drug, radioiodine). Supportive care (fluids, oxygen, cooling, acetaminophen) comes with a fixed sequence of specific steps:

1. A β-blocker for the adrenergic surge (propranolol also reduces T4 → T3 conversion; Beta-Blockers page). 2. A thionamide to stop new synthesis — PTU is often chosen first for its extra peripheral block, then switched to methimazole once the patient is stable. 3. Iodine (SSKI) at least an hour after the thionamide, to stop release. 4. A glucocorticoid (hydrocortisone; Corticosteroids page), which also reduces T4 → T3 conversion. Cholestyramine can cut enterohepatic recycling in severe cases. Aspirin is avoided, because it can raise free hormone by displacing it from binding proteins.