6.2 Thyroid & Parathyroid Hormones

Thyroid Hormone Synthesis

The thyroid gland is composed of spherical follicles lined by follicular cells surrounding a colloid core filled with thyroglobulin. Thyroid hormone synthesis is a multi-step process requiring iodine and thyroid peroxidase (TPO):

1. Iodide trapping — follicular cells actively take up iodide from blood via the Na+/I- symporter (NIS) on the basolateral membrane.
2. Oxidation and organification — TPO oxidizes iodide to iodine and iodinates tyrosine residues on thyroglobulin, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT).
3. Coupling — TPO couples one MIT + one DIT to form triiodothyronine (T3), or two DIT to form thyroxine (T4).
4. Storage and release — iodinated thyroglobulin is stored in colloid; on stimulation by TSH, follicular cells endocytose colloid, lysosomal proteases cleave T3/T4 from thyroglobulin, and free hormone is secreted into blood.

Approximately 90% of thyroid secretion is T4, but T3 is roughly 4× more biologically active. Peripheral tissues convert T4 to T3 via 5'-deiodinase (D1/D2). Reverse T3 (rT3) is an inactive byproduct made by 5-deiodinase (D3) and is elevated in illness.

In circulation, >99% of T3/T4 is bound to thyroxine-binding globulin (TBG), transthyretin, and albumin; only the free fraction is active. TSH binds the TSH receptor (a Gs-protein–coupled receptor) on follicular cells, raising cAMP and stimulating both synthesis and release.

Thyroid Hormone Effects

Thyroid hormones act on nuclear T3 receptors (TR-alpha, TR-beta) that bind thyroid-response elements and alter gene transcription. Major effects:

• Increase basal metabolic rate by upregulating Na+/K+-ATPase and mitochondrial uncoupling.
• Increase heart rate and contractility (upregulate beta-1 adrenergic receptors).
• Essential for CNS development in infancy; congenital hypothyroidism causes cretinism.
• Promote skeletal growth and gut motility.
• Increase glycogenolysis, gluconeogenesis, and lipolysis.

Calcitonin

Parafollicular C cells of the thyroid secrete calcitonin in response to elevated serum calcium. Calcitonin lowers calcium by inhibiting osteoclast bone resorption and (weakly) increasing renal calcium excretion. In humans, calcitonin is a minor calcium regulator; PTH and vitamin D dominate. Medullary thyroid carcinoma arises from C cells and secretes calcitonin, a useful tumor marker.

Parathyroid Hormone and Calcium Homeostasis

The four parathyroid glands contain chief cells that secrete Parathyroid Hormone (PTH), an 84-amino-acid peptide. PTH secretion is controlled by the calcium-sensing receptor (CaSR) on chief cells — low serum calcium triggers PTH release, high calcium suppresses it.

PTH raises serum calcium through three coordinated actions:

1. Bone — stimulates osteoblasts to express RANKL, which activates osteoclast precursors, increasing bone resorption and releasing calcium and phosphate.
2. Kidney — increases calcium reabsorption in the distal convoluted tubule while decreasing phosphate reabsorption in the proximal tubule (phosphaturic effect). PTH also stimulates 1-alpha-hydroxylase in proximal tubular cells.
3. Intestine — indirectly increases calcium absorption by increasing activation of vitamin D, which upregulates intestinal TRPV6 and calbindin.

Vitamin D Activation

Vitamin D3 (cholecalciferol) is synthesized in skin by UV light or obtained in diet. Activation requires two hydroxylations:

• 25-hydroxylation in the liver (constitutive) → 25-hydroxycholecalciferol (calcidiol) — the main circulating form measured clinically.
• 1-alpha-hydroxylation in the kidney (regulated by PTH) → 1,25-dihydroxycholecalciferol (calcitriol) — the active hormone.

Active vitamin D acts through the vitamin D receptor (VDR, a nuclear receptor) to upregulate synthesis of calbindin-D9k and TRPV6, increasing intestinal absorption of calcium and phosphate. It also facilitates PTH-mediated bone mineralization.

Calcium and Phosphate Homeostasis Summary

Clinical Disorders

• Primary hypothyroidism (Hashimoto thyroiditis) — low T4, high TSH; fatigue, cold intolerance, bradycardia, weight gain.
• Graves disease — TSH-receptor stimulating antibodies → high T4, low TSH, diffuse goiter, exophthalmos.
• Primary hyperparathyroidism (parathyroid adenoma) — high PTH, hypercalcemia, hypophosphatemia, stones, bone pain, constipation ('stones, bones, groans, moans').
• Hypoparathyroidism — low PTH, hypocalcemia, hyperphosphatemia, tetany, Chvostek/Trousseau signs.
• Vitamin D deficiency — rickets in children (soft bones), osteomalacia in adults; low calcium, low phosphate, high PTH (secondary hyperparathyroidism).
• Pseudohypoparathyroidism — PTH resistance (GNAS mutation); low calcium, high phosphate, high PTH.

Iodine Handling, Deiodination, and Calcium Integration

Iodine handling has two autoregulatory phenomena that PA-CAT items target. The Wolff-Chaikoff effect is an acute protective response: a large iodine load transiently inhibits thyroid hormone synthesis (within 24–48 hours) by downregulating NIS, TPO organification, and hormone release, preventing iodine-induced hyperthyroidism. The Jod-Basedow phenomenon is the opposite — an iodine load triggers hyperthyroidism in an autonomous nodule (Graves or toxic nodule) that has escaped normal regulatory control; this is why amiodarone (rich iodine load) can produce either thyrotoxicosis or hypothyroidism depending on the underlying gland. After several weeks of iodine excess, most glands escape the Wolff-Chaikoff block and resume synthesis, but some patients (especially with underlying autoimmune disease) fail to escape and develop iodine-induced hypothyroidism.

Peripheral conversion of T4 to T3 explains common lab patterns. Roughly 80% of circulating T3 comes from extrathyroidal 5'-deiodinase (D1 in liver/kidney, D2 in pituitary/CNS), which removes the 5'-iodine from T4 to yield active T3. The alternate 5-deiodinase (D3) produces reverse T3 (rT3), biologically inactive. In systemic illness, fasting, and glucocorticoid excess, D1 falls and D3 rises, so T4 is shunted toward rT3 rather than T3 — producing the euthyroid sick syndrome pattern: low T3, low free T4 (late), normal or low TSH, and elevated rT3. Treatment of the underlying illness, not thyroid replacement, is correct. The same enzyme logic explains why liothyronine (T3) rather than levothyroxine is used in myxedema coma: critically low deiodinase activity cannot reliably convert T4 to T3, so giving the active form bypasses the bottleneck.

Thyroid storm and myxedema coma are the two extremes that test recognition of decompensated thyroid disease. Storm is precipitated by surgery, infection, trauma, or iodine load in untreated hyperthyroidism; features include hyperthermia (often >40°C), tachycardia out of proportion to fever, agitation, heart failure, and a high T4 with suppressed TSH. Treatment order is beta-blocker (propranolol blocks adrenergic effects and T4→T3 conversion), then thionamide (PTU or methimazole), then iodine (given at least one hour after thionamide to avoid fueling synthesis), then glucocorticoids (blocks T4→T3 and treats relative adrenal insufficiency). Myxedema coma is severe decompensated hypothyroidism, precipitated by cold exposure, infection, or sedatives in elderly women; hallmarks are hypothermia, bradycardia, hypoventilation, hyponatremia, and altered mental status, with a high TSH and low T4. Treatment is IV levothyroxine plus liothyronine and hydrocortisone (until coexisting adrenal insufficiency is excluded) with passive warming.

A worked calcium regulation example ties the three regulators together. A parathyroid adenoma raises PTH, which (1) increases osteoclast bone resorption releasing Ca2+ and PO4, (2) increases distal tubular Ca2+ reabsorption while dropping proximal phosphate reabsorption via NaPi-IIa downregulation, and (3) upregulates renal 1-alpha-hydroxylase to raise calcitriol, increasing gut Ca2+ and PO4 absorption. Net serum result: high Ca2+, low PO4. The PA-CAT trap is pseudohypoparathyroidism vs hypoparathyroidism: both present with hypocalcemia and hyperphosphatemia, but pseudohypoparathyroidism (GNAS mutation causing PTH receptor resistance) shows high PTH, while true hypoparathyroidism (gland damage, DiGeorge) shows low PTH. Albright hereditary osteodystrophy (short fourth/fifth metacarpals, round facies) is the phenotypic clue to the resistance form.