Parathyroid gland

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parathyroid gland anatomy physiology hormones 2024

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Here is a comprehensive overview of the parathyroid gland, drawing from Harrison's Principles of Internal Medicine 22E, Medical Physiology (Boron & Boulpaep), and Histology: A Text and Atlas.

Parathyroid Gland

Anatomy & Location

There are four parathyroid glands (two superior, two inferior), located on the posterior, medial aspect of each thyroid lobe. They are supplied by the inferior thyroid artery in most individuals, though vascular supply may arise from anastomoses between the superior and inferior thyroid arteries.

Weight: ~30–40 mg each
Size: ~3–4 mm (pea-sized)
Embryology: Superior glands derive from 4th pharyngeal pouch; inferior glands from the 3rd pharyngeal pouch (along with the thymus — which explains why inferior glands can be ectopic, sometimes found in the mediastinum)

Histology

The parenchyma is arranged as cords or sheets of cells separated by capillaries and delicate connective tissue septa. Two cell types are identifiable on H&E:

Cell Type	Features	Function
Chief cells (principal cells)	Most numerous; small round nucleus, scant cytoplasm	Synthesize and secrete PTH
Oxyphil cells	Larger, fewer; eosinophilic cytoplasm, smaller darker nucleus; appear in clusters	Function uncertain; appear at end of first decade, increase around puberty

Blood vessels and adipose tissue are associated with connective tissue trabeculae.

Parathyroid gland H&E histology showing chief cells (CC), oxyphil cells (OC), blood vessels (BV), and adipose (A)

H&E ×320 — Chief cells (CC) predominate; oxyphil cells (OC) appear in clusters; blood vessels (BV) and adipose tissue (A) visible. — Histology: A Text and Atlas

PTH — Structure & Biosynthesis

84-amino acid single-chain peptide
The amino-terminal PTH(1–34) fragment is biologically active and highly conserved
Synthesized as pre-pro-PTH → signal sequence cleaved in ER lumen → pro-PTH → pro-sequence cleaved in Golgi → mature PTH stored in secretory granules

Actions of PTH

PTH is the primary regulator of calcium homeostasis in the extracellular fluid (ECF).

Bone

Stimulates osteoclast-mediated bone resorption → releases Ca²⁺ and phosphate into blood
Chronically high PTH → increased bone turnover, osteoporosis

Kidney

Distal tubule: Increases Ca²⁺ reabsorption (↑ serum Ca²⁺)
Proximal tubule: Inhibits phosphate reabsorption → phosphaturia (↓ serum phosphate)
Proximal tubule: Stimulates 1α-hydroxylase → converts 25-OH vitamin D → 1,25(OH)₂D (calcitriol)

Intestine (indirect)

Via calcitriol → increases intestinal Ca²⁺ and phosphate absorption

Net effect: ↑ serum Ca²⁺, ↓ serum phosphate

Regulation of PTH Secretion

PTH secretion is controlled by a tight negative feedback loop:

Stimulus	Effect on PTH
↓ Serum Ca²⁺	↑ PTH secretion (major stimulus)
↑ Serum Ca²⁺	↓ PTH via calcium-sensing receptor (CaSR)
↑ 1,25(OH)₂D	↓ PTH synthesis and release
↑ FGF23	↓ PTH secretion
Hypomagnesemia	Impairs PTH secretion (paradoxically)

Calcium-Sensing Receptor (CaSR) Mechanism

Ca²⁺ binds the CaSR on chief cells → activates Gαx → PLC activation → IP₃ + DAG → ↑ intracellular Ca²⁺ + PKC activation → inhibition of PTH granule release (counterintuitive: most secretory cells are stimulated, not inhibited, by this pathway).

PTH secretion rate vs plasma calcium — normal curve and FHH (right-shifted) curve

Small decreases in free plasma Ca²⁺ greatly amplify PTH secretion. In familial hypocalciuric hypercalcemia (FHH), the CaSR set-point is shifted right. — Medical Physiology

PTH Receptor

PTH1R (primary receptor): G protein-coupled receptor, couples to adenylyl cyclase (↑ cAMP) and phospholipase C; most abundant in kidney (proximal and distal convoluted tubules) and bone
PTH2R: Identified but role in calcium homeostasis unclear
PTH and PTHrP (parathyroid hormone-related peptide) act through the same PTH1R receptor

Disorders

Hypercalcemia

Cause	Mechanism
Primary hyperparathyroidism	Adenoma (most common ~80%), hyperplasia, carcinoma; autonomous PTH excess
Humoral hypercalcemia of malignancy (HHM)	PTHrP overproduction by tumor cells (squamous cell carcinoma of lung, kidney, breast)
Familial hypocalciuric hypercalcemia (FHH)	Inactivating CaSR mutation → set-point shift right → PTH unsuppressed at normal Ca²⁺ levels
Vitamin D toxicity, granulomatous disease (sarcoidosis), lymphoma	Excess 1,25(OH)₂D

Symptoms of hypercalcemia: Fatigue, depression, mental confusion, anorexia, nausea/vomiting, constipation, polyuria, nephrolithiasis, short QT on ECG, arrhythmias (typically symptomatic at Ca²⁺ >11.6–12.0 mg/dL)

Hypocalcemia

Cause	Mechanism
Hypoparathyroidism	PTH deficiency (post-surgical, autoimmune, DiGeorge syndrome)
Pseudohypoparathyroidism (PHP)	PTH resistance at proximal renal tubule
Hypomagnesemia	Impairs PTH secretion and end-organ response

Clinical Pearls

Surgery for primary hyperparathyroidism is highly effective and reverses bone density loss
Calcimimetics (e.g., cinacalcet) activate CaSR → suppress PTH → used in secondary/tertiary hyperparathyroidism
Calcilytics (CaSR negative allosteric modulators) show promise in autosomal dominant hypocalcemia type 1
PTH(1–34) (teriparatide) is used therapeutically for postmenopausal osteoporosis and as hormone replacement in hypoparathyroidism
About 50% of total plasma Ca²⁺ is ionized (free); PTH responds to the ionized fraction, not total calcium

Sources: Harrison's Principles of Internal Medicine 22E, p. 3315–3318; Medical Physiology (Boron & Boulpaep), p. 1554–1555; Histology: A Text and Atlas, p. 2067–2069

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