Chapter 3 of 5 - Endocrine System Course
The thyroid and parathyroid glands sit in the anterior neck and work together to regulate metabolic rate, growth, development, and calcium homeostasis - two of the most clinically tested topics in endocrinology.
The thyroid is a butterfly-shaped gland located in the anterior neck, just inferior to the larynx and anterior to the trachea (at the level of C5-T1 vertebrae). It is the largest purely endocrine gland in the body, weighing approximately 15-20 g in adults.
Left Lobe
Isthmus
Right Lobe
Butterfly-shaped gland - two lateral lobes connected by a central isthmus
Structurally, the thyroid consists of two key cell types organized into functional units:
The gland receives rich blood supply from the superior and inferior thyroid arteries and is innervated by sympathetic fibers from the cervical ganglia. Its close relationship with the recurrent laryngeal nerve makes thyroid surgery a high-risk procedure for voice changes.
The thyroid gland produces two iodine-containing hormones derived from the amino acid tyrosine. T4 (thyroxine) has four iodine atoms and is the major secretory product. T3 (triiodothyronine) has three iodine atoms and is 3-5 times more biologically potent, though most circulating T3 arises from peripheral conversion of T4.
1. Iodine Trapping (NIS)
Na+/I- symporter actively transports iodide into follicular cells against a concentration gradient
2. Thyroglobulin Synthesis
Follicular cells produce thyroglobulin (Tg) and secrete it into the colloid
3. Oxidation & Organification (TPO)
Thyroid peroxidase (TPO) oxidizes iodide to iodine and attaches it to tyrosine residues on Tg - forming MIT and DIT
4. Coupling
MIT + DIT = T3 | DIT + DIT = T4 (also catalyzed by TPO)
5. Endocytosis & Proteolysis
Colloid is reabsorbed, Tg is cleaved by lysosomes, releasing T3 and T4 into blood
Clinical Pearl
Anti-TPO antibodies are the hallmark of Hashimoto thyroiditis - they block organification and coupling, leading to hypothyroidism. Propylthiouracil (PTU) and methimazole also work by inhibiting TPO.
T3 and T4 are lipophilic hormones that enter target cells, bind nuclear receptors, and regulate gene transcription. They affect virtually every organ system:
| System | Effect |
|---|---|
| Metabolic rate | Increase basal metabolic rate (BMR) and oxygen consumption in all tissues |
| Cardiovascular | Increase heart rate, cardiac output, and systolic blood pressure; decrease SVR |
| Growth & development | Essential for normal brain development in fetuses/neonates and linear bone growth (synergize with GH) |
| Nervous system | Promote neuronal myelination, alertness, and rapid reflexes |
| Thermogenesis | Increase heat production via uncoupling oxidative phosphorylation |
| GI | Increase gut motility and carbohydrate absorption |
Quick Check
A 3-month-old infant presents with poor feeding, constipation, a large fontanelle, and hypotonia. Newborn screening reveals elevated TSH and low free T4. What is the most likely diagnosis?
Thyroid hormone secretion is tightly regulated through a classic negative-feedback loop involving three levels:
Hypothalamus
Releases TRH (thyrotropin-releasing hormone)
Anterior Pituitary
TRH stimulates thyrotrophs to secrete TSH (thyroid-stimulating hormone)
Thyroid Gland
TSH stimulates follicular cells to synthesize and release T3 & T4
Negative Feedback
Elevated T3/T4 inhibit TRH and TSH release, completing the loop
Diagnostic Patterns
| Condition | TSH | Free T4 | Origin |
|---|---|---|---|
| Primary hypothyroidism | ↑ High | ↓ Low | Thyroid gland failure |
| Primary hyperthyroidism | ↓ Low | ↑ High | Thyroid overproduction |
| Secondary hypothyroidism | ↓ Low | ↓ Low | Pituitary failure (low TSH) |
| TSH-secreting adenoma | ↑ High | ↑ High | Pituitary tumor |
Fill in the Blank
In primary hypothyroidism, TSH is elevated because the________loop from T3/T4 is reduced, so the anterior pituitary increases TSH output to compensate.
Calcitonin is a 32-amino-acid peptide hormone produced by the parafollicular C cells of the thyroid. Its primary role is to lower blood calcium when levels rise above normal (hypercalcemia).
Clinical Pearl
Serum calcitonin is a tumor marker for medullary thyroid carcinoma (MTC), a malignancy of C cells. MTC may occur sporadically or as part of MEN 2A/2B (multiple endocrine neoplasia) syndromes.
The parathyroid glands are four small, lentil-sized glands (each approximately 6 x 3 x 2 mm) embedded in the posterior surface of the thyroid gland - two superior and two inferior. They contain two cell types:
PTH is an 84-amino-acid peptide hormone and the most important regulator of blood calcium. It is released in response to low ionized calcium detected by calcium-sensing receptors (CaSR) on chief cells. PTH raises blood calcium through three target organs:
| Target | Action | Net Effect |
|---|---|---|
| Bone | Stimulates osteoclasts (indirectly via RANKL on osteoblasts) to resorb bone | Releases Ca2+ and PO43- into blood |
| Kidneys | Increases Ca2+ reabsorption in DCT; decreases PO43- reabsorption in PCT; activates 1-alpha hydroxylase | Retains Ca2+, excretes phosphate, produces active vitamin D |
| Intestines (indirect) | Active vitamin D (1,25-dihydroxycholecalciferol) increases intestinal Ca2+ and PO43- absorption | Absorbs more dietary calcium |
High-Yield Mnemonic
"PTH = Phosphate Trashing Hormone" - PTH raises calcium but lowers serum phosphate by promoting phosphaturia (renal phosphate excretion). This distinguishes PTH excess from other causes of hypercalcemia.
Normal serum calcium is maintained within a narrow range of approximately 8.5-10.5 mg/dL (2.1-2.6 mmol/L). PTH and calcitonin act as antagonists to maintain this balance, though PTH is by far the dominant regulator.
Normal Blood Calcium - 8.5-10.5 mg/dL
Low Ca2+ (Hypocalcemia)
PTH Released
Bone resorption + renal reabsorption + vitamin D activation
Blood Ca2+ rises
High Ca2+ (Hypercalcemia)
Calcitonin Released
Inhibits osteoclasts + promotes renal excretion
Blood Ca2+ falls
Clinically, calcitonin plays a relatively minor role in adult calcium homeostasis. Patients who have had a total thyroidectomy (and therefore produce no calcitonin) do not develop significant hypercalcemia - confirming that PTH is the primary regulator.
Quick Check
A patient with primary hyperparathyroidism would be expected to have which of the following lab findings?
| Condition | Mechanism | Key Features |
|---|---|---|
| Graves disease | Thyroid-stimulating immunoglobulins (TSI) - autoantibodies that mimic TSH and continuously activate TSH receptors | Diffuse goiter, exophthalmos (proptosis), pretibial myxedema, heat intolerance, weight loss, tremor, tachycardia |
| Toxic multinodular goiter | Multiple autonomously functioning thyroid nodules | Irregular, enlarged thyroid; common in elderly; no exophthalmos |
| Thyroid storm | Life-threatening exacerbation of hyperthyroidism - often triggered by surgery, infection, or trauma | Fever >40 C, severe tachycardia, delirium, vomiting, cardiovascular collapse - mortality up to 20-30% |
| Condition | Mechanism | Key Features |
|---|---|---|
| Hashimoto thyroiditis | Autoimmune destruction by anti-TPO and anti-thyroglobulin antibodies; lymphocytic infiltration with germinal centers | Most common cause of hypothyroidism in iodine-sufficient areas; painless goiter; fatigue, weight gain, cold intolerance, constipation |
| Congenital hypothyroidism | Thyroid agenesis, dysgenesis, or defective hormone synthesis during fetal development | Formerly called cretinism - intellectual disability, short stature, coarse facial features, protruding tongue if untreated |
| Myxedema | Severe, prolonged hypothyroidism - accumulation of glycosaminoglycans in the dermis | Generalized non-pitting edema, periorbital puffiness, altered mental status; myxedema coma is a medical emergency with hypothermia and bradycardia |
| Condition | Ca2+ | PO4 | Features |
|---|---|---|---|
| Primary hyperparathyroidism | ↑ | ↓ | Usually parathyroid adenoma (80%); "bones, stones, abdominal groans, and psychic moans" - osteitis fibrosa cystica, kidney stones, constipation, depression |
| Secondary hyperparathyroidism | ↓ or normal | ↑ | Compensatory PTH elevation due to chronic hypocalcemia - commonly from chronic kidney disease or vitamin D deficiency |
| Hypoparathyroidism | ↓ | ↑ | Most commonly iatrogenic (accidental removal during thyroid surgery); presents with tetany, Chvostek sign, Trousseau sign, perioral numbness, seizures |
Clinical Pearl
Chvostek sign - tapping the facial nerve anterior to the ear causes ipsilateral facial muscle twitching. Trousseau sign - inflating a blood pressure cuff above systolic pressure for 3 minutes triggers carpal spasm. Both indicate hypocalcemia-induced neuromuscular excitability.
Fill in the Blank
In Graves disease, thyroid-stimulating________bind to TSH receptors and continuously activate the thyroid gland, causing hyperthyroidism with a characteristically low serum TSH.
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