Parathyroid Anatomy

HISTOLOGY OF THE NORMAL PARATHYROID GLANDS

Embryology and Number
- Derived from branchial pouches III and IV.
- Typically four parathyroid glands, though can range from two to six.
- Lower glands are generally larger than the upper glands.
Gross Anatomy
- Ovoid (bean-shaped) glands measuring about 4–6 mm × 2–4 mm × 0.5–2 mm.
- Weigh approximately 30 mg each.
- Color varies from yellow to tan, depending on vascularity and proportion of oxyphil cells and stromal fat.
Childhood Gland Composition
- Sheets of closely packed chief cells, with little stroma.
- Oxyphil (oncocytic) cells appear at puberty.
- Fat cells appear in the stroma in late childhood and increase with age.
Adult Gland Composition
- Composed of cords, sheets, and acini of chief cells in a loose areolar stroma containing many mature fat cells.
- Chief cells may be in:
  - Active (dark) phase: prominent endoplasmic reticulum (ER) and Golgi
  - Resting (light) phase: less developed ER
- Oxyphil cells are scattered individually or in groups among the chief cells.
Chief Cells
- ~8 μm in diameter.
- Well-defined cell membrane, centrally located nucleus (~4–5 μm).
- Nuclei: either densely packed chromatin (almost pyknotic) or finely fibrillar with peripheral margination; nucleoli are rare.
- Cytoplasm is clear and amphophilic with H&E stain.
- Periodic acid–Schiff (PAS): abundant glycogen.
- Also contain abundant neutral lipid droplets (demonstrable by azure B, Erie garnet A, oil red O, or Sudan IV).
- Immunohistochemistry: stronger parathyroid hormone (PTH) staining than oxyphil cells.
Oxyphil (Oncocytic) Cells
- Larger than chief cells (12–20 μm diameter), polygonal shape.
- Cell membranes usually clear.
- Nucleus similar to chief cell nucleus.
- Cytoplasm: highly eosinophilic, fine granules (stain carmine with Bensley acid aniline fuchsin [BAAF], dark blue with phosphotungstic acid hematoxylin).
- Packed with mitochondria (hence “oncocytic”).
- Little intracytoplasmic lipid or glycogen.
- Transitional oxyphilic cells: smaller, less eosinophilic.
Ultrastructure of Chief Cells
- Chief cells arranged in cords and nests, separated by a basal lamina from the interstitium.
- Plasma membranes: straight, with desmosomes linking adjacent cells.
- Active phase:
  - Enlarged Golgi apparatus, numerous vacuoles and vesicles in Golgi region.
  - Many mature secretory granules (50–300 nm).
  - Granules are oval/dumbbell-shaped, with a single membrane, a thin clear space inside, and a dense area of short rodlike profiles.
- Secretion pathway:
  - Granules move from cell → basement membrane → pericapillary space → capillary basement membrane → fenestrated endothelium → bloodstream (liberating PTH).

PHYSIOLOGY OF THE PARATHYROID GLANDS

Primary Function: Regulate and maintain normal serum ionized calcium levels (8.9–10.1 mg/dL).
Hormone: Parathyroid hormone (PTH).
Regulation:
- Ionized calcium in blood modulates PTH secretion.
- Low Ca²⁺ → ↑PTH release; high Ca²⁺ → ↓PTH.
- Calcium-sensing receptors (CaSRs) on parathyroid glands sense serum Ca²⁺.
- CaSRs in kidneys also adjust tubular Ca²⁺ reabsorption.
Importance of Calcium
- Critical for neuromuscular function, bone structure, signal transduction (e.g., cytosolic free calcium as second messenger).
- Hypercalcemia can cause muscle weakness, anorexia, constipation, confusion, coma.
- Hypocalcemia can cause anxiety, muscle twitching, carpopedal spasm, seizures, stridor, bronchospasm.
Calcium Balance
- Daily dietary Ca²⁺: 300–1500 mg; net GI absorption ~200 mg/day.
- Urinary Ca²⁺ excretion ~200 mg/day (about 2% of filtered load).
- Stool Ca²⁺ excretion varies greatly with body needs/diet (normally 500–700 mg/day).
Phosphate Metabolism
- Dietary phosphate: ~800–900 mg/day.
- GI absorption enhanced by 1,25-dihydroxyvitamin D.
- Fecal excretion ~30% dietary intake; renal excretion varies inversely with PTH.
Homeostatic Mechanisms
- Low serum Ca²⁺ → parathyroid releases PTH → increased renal 1α-hydroxylation of 25(OH)D → forms 1,25(OH)₂D (calcitriol) → ↑intestinal Ca²⁺ absorption.
- PTH enhances renal tubule Ca²⁺ reabsorption & bone resorption → net rise in serum Ca²⁺.
- High serum Ca²⁺ → suppressed PTH secretion → less 1α-hydroxylation → less Ca²⁺ absorption; also more renal Ca²⁺ excretion & reduced bone resorption.
Hypoparathyroidism
- If parathyroids are absent or nonfunctional:
  - Serum Ca²⁺ can fall to ~7 mg/dL, but seldom below 5 mg/dL (body’s skeletal reservoir stabilizes).
Effects of Excess PTH
- Osteoclast activation → bone matrix resorption → mobilization of Ca²⁺ and phosphate.
- Bone turnover response: osteoclasts & subsequent osteoblastic repair → raised serum alkaline phosphatase.
- PTH-induced bone resorption is also linked to GI absorption of calcium & phosphate (via upregulated 1,25(OH)₂D).

BONE REMODELING UNIT

Overview
- Bone = collagen matrix + hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂).
- Modeling (childhood): changes in bone size/shape.
- Remodeling (lifelong): maintenance/repair via coordinated osteoclast & osteoblast cycles.
Bone Cells
- Osteoblasts: form bone, derived from mesenchymal stem cells.
  - Respond to PTH, 1,25(OH)₂D, estrogen, etc.
  - Secrete collagen & osteoid; become osteocytes or line bone surface or undergo apoptosis.
- Osteoclasts: multinucleated, large cells from monocyte/macrophage lineage; resorb bone via acid & enzymes.
Remodeling Cycle
1. Resorption (∼2 weeks)
  - Osteoblasts release cytokines (RANK ligand, M-CSF) → osteoclast differentiation → degrade bone mineral & collagen.
  - Self-limited by local factors (high Ca²⁺, TGF-β, etc.).
2. Reversal (∼4 weeks)
  - Mononuclear cells deposit a cement line & recruit osteoblast precursors.
3. Formation (∼16 weeks)
  - Osteoblasts lay osteoid until resorbed cavity is refilled.
  - Osteoid → mineralized.
  - Cycle returns to quiescent state.
Defective Remodeling
- Excessive osteoclastic resorption or incomplete osteoblastic refilling → net bone loss.
  - Found in osteoporosis, hyperparathyroidism, etc.
- Impaired osteoclast function → overly dense bones (osteopetrosis).