Pathophysiology
I-28. Hormonal regulation of calcium & phosphate metabolism
カルシウム・リン代謝のホルモン調節
Calcium Overview
- Plasma total Ca²⁺: 2.2–2.6 mmol/L.
- Needed for: bone structure, neurotransmitter release, muscle contraction, cardiac conduction, clotting.
Key Regulating Hormones
- PTH (parathyroid glands), Calcitriol/vitamin D (skin-liver-kidney axis), FGF23 (bone), Calcitonin (thyroid, mostly childhood).
Parathyroid Hormone (PTH)
- Serum 10–65 pg/ml; regulated by serum Ca²⁺ (Ca²⁺ binds parathyroid → inhibits PTH; ↓Ca²⁺ → ↑PTH).
- Functions (↑serum Ca²⁺): osteoblasts express RANKL → osteoclast differentiation; ↑renal Ca²⁺ reabsorption; ↑renal vitamin D activation; inhibits osteogenesis.
- Continuous high PTH → cardiac (LV) hypertrophy.
Calcitriol (Vitamin D)
- Regulates gene expression via VDR.
- Intestine: ↑Ca²⁺ uptake. Kidney: limits its own activation (24-hydroxylase), ↓renin (protective vs kidney fibrosis). Parathyroid: ↓PTH. Bone: activates osteoclasts + osteoblasts → remodels weak → stronger bone.
FGF23
- From osteocytes; regulates PO₄³⁻ (stimulated by hyperphosphatemia).
- Kidney: → phosphaturia (normalizes phosphate); inhibits calcitriol synthesis.
- Also: inhibits PTH secretion, induces cardiac hypertrophy.
Hyperparathyroidism
Primary
- PTH made independent of Ca²⁺; most common cause of outpatient hypercalcemia (1:500, females 3×).
- Causes: parathyroid adenoma, PTH-producing tumor.
- Labs: ↑Ca²⁺, ↓PO₄³⁻ (hypercalcemia).
- Symptoms: often asymptomatic; bone fractures (osteoporosis), kidney stones, gastritis/constipation/abdominal cramps, ectopic calcifications (lung, heart, pancreas → pancreatitis). (“Stones, bones, groans.”)
Secondary
- PTH overproduction responding to chronic hypocalcemia.
- Causes:
- Vitamin D deficiency (↓sunlight/diet) → ↓intestinal Ca²⁺, ↓PTH-gene inhibition.
- Chronic kidney disease: ↓phosphate excretion → phosphate binds Ca²⁺ (↓free Ca²⁺); ↓vitamin D activation → ↓Ca²⁺ absorption → hypocalcemia → ↑PTH.
- Labs: ↑Ca²⁺ and ↑PO₄³⁻. Symptoms: ↓intestinal Ca²⁺, bone resorption, vascular/soft-tissue calcification.
Hypo- vs Hypercalcemia
Hypocalcemia
- ↓threshold potential → ↑excitability: muscle spasms, longer QT (arrhythmogenic), tremor/tetany (~1.5 mM), laryngospasm → suffocation (~1 mM); general weakness.
Hypercalcemia
- Muscle weakness; very high Ca²⁺ blocks voltage-gated Na⁺ channels → ↓depolarization → cardiac arrest.
一問一答
▶How is PTH secretion regulated by calcium?
Serum Ca²⁺ binds the parathyroid calcium-sensing receptor and inhibits PTH; a fall in Ca²⁺ increases PTH release.
▶What is the normal plasma total calcium range, and why is calcium essential?
2.2–2.6 mmol/L; needed for bone structure, neurotransmitter release, muscle contraction, cardiac conduction, and clotting.
▶What are the actions of calcitriol (active vitamin D)?
Intestine: ↑Ca²⁺ uptake. Kidney: limits its own activation and ↓renin. Parathyroid: ↓PTH. Bone: activates osteoclasts + osteoblasts to remodel weak into stronger bone.
▶What are the four key hormones regulating calcium/phosphate, and their sources?
PTH (parathyroid glands), calcitriol/vitamin D (skin-liver-kidney axis), FGF23 (bone osteocytes), and calcitonin (thyroid, mainly in childhood).
▶How does PTH raise serum calcium?
Osteoblasts express RANKL → osteoclast differentiation/bone resorption; ↑renal Ca²⁺ reabsorption; ↑renal vitamin D activation; and inhibition of osteogenesis.
▶What is the role of FGF23?
Secreted by osteocytes and stimulated by hyperphosphatemia, it promotes renal phosphate excretion (phosphaturia), inhibits calcitriol synthesis and PTH secretion, and induces cardiac hypertrophy.
▶What is primary hyperparathyroidism and its biochemistry?
PTH produced independently of calcium (e.g., parathyroid adenoma); the most common cause of outpatient hypercalcemia, with ↑Ca²⁺ and ↓PO₄³⁻.
▶What is secondary hyperparathyroidism?
PTH overproduction responding to chronic hypocalcemia (e.g., vitamin D deficiency or chronic kidney disease), characterized by ↑Ca²⁺ effort but ↑PO₄³⁻.
▶What are the classic symptoms of primary hyperparathyroidism?
"Stones, bones, groans": kidney stones, bone fractures/osteoporosis, gastritis/constipation/abdominal cramps, and ectopic calcifications (lung, heart, pancreas → pancreatitis); often asymptomatic.
▶How does chronic kidney disease cause secondary hyperparathyroidism?
↓Phosphate excretion → phosphate binds Ca²⁺ (↓free Ca²⁺), and ↓vitamin D activation → ↓Ca²⁺ absorption → hypocalcemia → ↑PTH.
▶Why does hypocalcemia increase neuromuscular excitability?
Low Ca²⁺ lowers the threshold potential, raising excitability → muscle spasms, prolonged QT (arrhythmias), tremor/tetany (~1.5 mM), and laryngospasm (~1 mM).
▶What are the effects of hypercalcemia?
Muscle weakness; very high Ca²⁺ blocks voltage-gated Na⁺ channels → ↓depolarization → cardiac arrest.
▶How does FGF23 regulate phosphate in the kidney?
It promotes renal phosphate excretion (phosphaturia) to normalize phosphate and inhibits calcitriol synthesis.
▶How does vitamin D deficiency lead to secondary hyperparathyroidism?
↓Intestinal Ca²⁺ absorption and reduced inhibition of the PTH gene → hypocalcemia → compensatory ↑PTH.
▶Why does continuous high PTH cause cardiac hypertrophy?
Persistently elevated PTH has direct effects promoting left ventricular hypertrophy.
▶What labs distinguish primary from secondary hyperparathyroidism?
Primary: ↑Ca²⁺, ↓PO₄³⁻. Secondary: ↑PO₄³⁻ with low/normal Ca²⁺ driving ↑PTH.
▶How does calcitriol act at the cellular level?
It binds the vitamin D receptor (VDR) and regulates gene expression in target tissues.
▶Why is renin reduced by calcitriol clinically relevant?
Calcitriol's suppression of renin is protective against kidney fibrosis.
▶Why does primary hyperparathyroidism cause kidney stones?
Excess bone resorption raises serum and filtered calcium, leading to hypercalciuria and calcium stone formation.
▶How does PTH increase active vitamin D?
PTH stimulates renal 1α-hydroxylase, increasing conversion of vitamin D to active calcitriol → ↑intestinal Ca²⁺ absorption.