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Calcium Homeostasis (5 Marks)
Introduction
Calcium homeostasis refers to the physiological mechanisms that maintain plasma calcium concentration within a narrow normal range of 8.5-10.5 mg/dL (ionized fraction: 4.5-5.5 mg/dL). This is achieved by the coordinated action of three hormones acting on three target organs.
Normal Distribution of Calcium in Blood
Total plasma calcium exists in three forms:
- Protein-bound (mainly albumin) - ~40%
- Complexed (with phosphate, citrate) - ~10%
- Free ionized Ca²+ - ~50% (biologically active form)
Note: Ionized Ca²+ is what the parathyroid glands actually sense and regulate.
Three Hormones Involved
| Hormone | Source | Effect on Ca²+ |
|---|
| PTH (Parathyroid Hormone) | Chief cells of parathyroid glands | Raises Ca²+ |
| 1,25-(OH)₂ Vitamin D (Calcitriol) | Kidney (activated form) | Raises Ca²+ |
| Calcitonin | Parafollicular C-cells of thyroid | Lowers Ca²+ |
Mechanism 1: Parathyroid Hormone (PTH)
Stimulus: Fall in plasma ionized Ca²+ below 10 mg/dL detected by Calcium-Sensing Receptors (CaSR) on chief cells.
Synthesis: Preformed as PreproPTH (115 aa) → ProPTH (90 aa) → PTH (84 aa). Biologic activity lies in N-terminal 34 amino acids.
Actions (all via cAMP as second messenger):
- Bone - Stimulates osteoclast-mediated bone resorption → releases Ca²+ and phosphate into blood
- Kidney (direct):
- Increases Ca²+ reabsorption in distal tubule
- Decreases phosphate reabsorption (phosphaturia) - prevents Ca-phosphate precipitation
- Stimulates 1α-hydroxylase enzyme to activate Vitamin D
- Intestine (indirect) - via activation of Vitamin D → increased Ca²+ absorption
Net result: Plasma Ca²+ rises back to normal.
Mechanism 2: Vitamin D (1,25-Dihydroxycholecalciferol)
Activation pathway:
Diet/Skin (UV light) → Cholecalciferol (Vit D₃)
↓ 25-hydroxylase (Liver)
25-OH Cholecalciferol
↓ 1α-hydroxylase (Kidney) ← stimulated by PTH
1,25-(OH)₂ Cholecalciferol (Active form)
Actions:
- Primary action: Stimulates intestinal absorption of Ca²+ by inducing synthesis of Ca²+-binding proteins (calbindins)
- Supports PTH in bone resorption
- Increases renal Ca²+ reabsorption
Mechanism 3: Calcitonin
Stimulus: Rise in plasma Ca²+ above normal.
Source: Parafollicular (C) cells of the thyroid gland.
Actions:
- Inhibits osteoclast activity → reduces bone resorption
- Increases renal excretion of Ca²+
Net result: Plasma Ca²+ decreases back to normal.
In clinical practice, calcitonin plays a minor role in day-to-day calcium homeostasis compared to PTH and Vitamin D. Its importance is greater during growth, pregnancy, and as a pharmacological agent.
Feedback Loop Summary
Low Ca²+ → PTH ↑ → Bone resorption ↑, Renal reabsorption ↑, Vit D activation ↑
↓
Intestinal absorption ↑
↓
Plasma Ca²+ normalized
↓
PTH secretion suppressed (negative feedback)
High Ca²+ → Calcitonin ↑ → Bone resorption ↓, Renal Ca²+ excretion ↑
↓
Plasma Ca²+ normalized
Clinical Correlation
| Disorder | Cause | Effect |
|---|
| Hypercalcemia | PTH-secreting adenoma (Primary hyperparathyroidism) | Weakness, polyuria, kidney stones, bone pain |
| Hypocalcemia | Post-thyroidectomy (parathyroid removed) | Tetany, Chvostek's sign, Trousseau's sign |
| Rickets/Osteomalacia | Vitamin D deficiency | Defective bone mineralization |
Sources: Costanzo Physiology, 7th ed.; Guyton & Hall Medical Physiology; Harrison's Principles of Internal Medicine, 22nd ed.