calcium homeostasis and the regulation of PTH, calcitonin and vitamin D

1. Calcium Homeostasis
Faez Baherin MBBS
MMed (Emergency) Training Programme USM
Supervised by Dr Hashairi

2. Outline
• Introduction
• Calcium metabolism
- PTH, Calcitonin, Vitamin d
• Functions of calcium
• Disorders of calcium
• Summary

3. Introduction
Body Bone intracellular extracellular
content
Calcium 1300 gms 99% 1% 0.1%
• Total plasma [Ca++] = 2.5mmol/L
• Range is 2.0 to 2.5 mmol/L
• Very tightly controlled

4. Introduction

5. Factors affecting calcium
concentration
1) Changes in plasma protein concentration
- Increased [protein] – increased total [Ca2+]
2) Changes in anion concentration
- Increased [anion] – increased fraction of Ca2+
that is complexed – decrease ionized [Ca2+]
3)Acid base abnormality

6. Acid Base Abnormality

7. Functions of Calcium
• 1. Nerve and muscle functions
- Decreased extracellular calcium – increase
excitability of excitable cells and lowers the
threshold potential – less inward current is
required to depolarize the threshold potential
– less inward current is required to fire AP
- Hence causing tingling ad numbness (sensory)
and spontaneous muscle twitches (motor
neurons and muscles)

8. Functions of Calcium
Cross
bridge
cycling

9. • Increase in intracellular Ca2+ concentration
 Ca2+ binds to troponin C  conformational
change in the troponin complex  moves
tropomyosin out of the way  permitting the
binding of actin to the myosin heads leading
cross-bridge formation and the muscle
contracts as a whole

10. Functions of Calcium
• 2. Homeostasis
-activation of clotting enzyme is the plasma

11. Functions of Calcium
• 3. Preserving bone density
- construction, formation and maintenance of
bone and teeth. This function helps reduce
the occurrence of osteoporosis

12. Functions of Calcium
• 4. Neurotransmitter release
- Directly proportional to the calcium level
- Arrival of action potential to axonal terminal
opening of voltage gated calcium channels
calcium influx into the terminal  transmitter
vesicle fuse with the release sites 
exocytosis-release of transmitters into the
cleft

13. Functions of Calcium
• 5. Calcium assists in maintaining all cells and
connective tissues in the body and regulating
mitotic transition and cell division.
• 6. Essential component in the production of
enzyme and hormones that regulate
digestion, energy, and fat metabolism.

14. Calcium Homeostasis
• Blood calcium is tightly regulated by:
1) Principle organ systems:
Intestine
Bone
Kidney
2) Hormones:
Parathyroid hormone (PTH)
Vitamin D
Calcitonin

15. Calcium Homeostasis

16. Parathyroid Hormone (PTH)
• There are 4 parathyroids glands, located on
the dorsal side of the thyroid
• The blood supply to the parathyroid glands is
from the thyroid arteries.

17. Parathyroid Hormone (PTH)
• Chief cells secrete PTH
• Oxyphil cells – function unknown. Probably
degenerated chief cells

18. Parathyroid Hormone (PTH)
• Regulation of PTH by plasma calcium
concentration

19. Parathyroid Hormone (PTH)
• Mechanism
Increase in extracellular calcium concentration
 Ca2+ binds to the receptor and activates
phospholipase C  increased levels of
IP3/Ca2+  which inhibits PTH secretion.
When extracellular Ca2+ is decreased, there is
decreased Ca2+ binding to the receptor, which
stimulates PTH secretion.

20. Parathyroid Hormone (PTH)
• Actions of PTH on bone, kidney and small intestine
• Direct vs indirect
1) Actions on bone
- PTH receptors on osteoblasts – initial bone formation
(direct action)
- Later on – bone resorption (indirect action) via
cytokines from osteoblast
- Overall effect : promote bone resorption and increase
calcium concentration

21. Parathyroid Hormone (PTH)
• 2. Actions on kidneys

22. Parathyroid Hormone (PTH)
a) Inhibits PO4 reabsorption (inhibits Na-PO4
cotransport in PCT) – phosphaturia – less
complexed Ca-PO4 – increase plasma calcium
b) Stimulates calcium reabsorption (on DCT)
Phosphaturia + Ca2+ reabsorption = increase in
Ca2+ concentration

23. Parathyroid Hormone (PTH)
• 3. Actions on small intestine (indirect)
- Stimulates Ca2+ reabsorption via activation of
vitamin D.
- PTH stimulates renal 1 alpha hydroxylase 
converts 25-hydroxycholecalciferol to 1.25
dihydroxycholecalciferol  stimulates intestinal
Ca2+ absorption

24. Parathyroid Hormone (PTH)

25. PTH Active Bone Urine Serum Serum
Disorder Vit.D Calcium Phosphate
Primary ↑* ↑ ↑ Resorption ↑phosphate ↑ ↓
Hyperparathyroidism ↑ Ca2
↑ cAMP
Surgical ↓* ↓ ↓ Resorption ↓phosphate ↓ ↑
Hypoparathyroidism ↓ cAMP
Pseudohypo- ↑ ↓ ↓ Resorption ↓phosphate ↓ ↑
parathyroidism ↓ cAMP
defective Gs
Humoral ↓ ↑ ↑ Resorption ↑phosphate ↑ ↓
Hypercalcemia of ↑ Ca2
Malignancy ↑ cAMP
(↑ PTH-rp*)
Chronic Renal Failure ↑ ↓* Osteomalacia ↓ Urine ↓ ↑ (due to
↑ Resorption phosphate ↓1,25- ↓ urine
(due to ↓ dihydroxych phosphate)
GFR)* olecalciferol

26. Vitamin D

27. Vitamin D
• Actions of vitamin D

28. Vitamin D
• Common diseases related to vitamin D
1) Rickets - insufficient amounts of calcium and
phosphate to mineralize the growing bones
 growth failure and skeletal deformities
2) Osteomalacia – new bone fails to mineralize
 bending and softening of weight bearing
bones

29. Calcitonin
• a straight-chain peptide with 32 amino acids.
• synthesized and secreted by the parafollicular cells of the thyroid
gland.
• major stimulus for calcitonin secretion is increased plasma Ca2+
concentration
• The major action of calcitonin is to inhibit osteoclastic bone
resorption, which decreases the plasma Ca2+ concentration.
• calcitonin does not participate in the minute-to-minute regulation
of the plasma Ca2+ concentration in humans.
• a physiologic role for calcitonin in humans is uncertain because
neither thyroidectomy (with decreased calcitonin levels) nor thyroid
tumors (with increased calcitonin levels) cause a derangement of
Ca2+ metabolism, as would be expected if calcitonin had important
regulatory functions.

30. Calcium handling in the nephron

31. Calcium handling in the nephron
- 67% of the filtered load is reabsorbed @ PCT
- Ca2+ reabsorption is tightly coupled to Na+
reabsorption in the proximal tubule

32. Calcium handling in the nephron
- @ ALH , 25% of the filtered load of Ca2+ is reabsorbed
- The mechanism of coupling in the thick ascending limb
depends on the lumen-positive potential difference,
which is generated by the Na+-K+-2Cl- cotransporter.
- Loop diuretics such as furosemide inhibit Ca2+
reabsorption to the same extent that they inhibit Na+
reabsorption.

33. Calcium handling in the nephron
• @ DT 8% of the filtered load of Ca2
• the site of regulation of Ca2+ reabsorption.
• the distal tubule is the only nephron segment in which Ca2+
reabsorption is not coupled directly to Na+ reabsorption.
• it has its own regulatory hormone, PTH.
• Thiazide diuretics increase Ca2+ reabsorption, while the other
classes of diuretics decrease it.

34. Hypocalcemia
• Causes

35. Hypocalcemia
Symptoms and signs
• "CATS go numb"- Convulsions, Arrythmias,
Tetany and numbness/parasthesias in hands,
feet, around mouth and lips.
• Trousseau sign of latent tetany (eliciting carpal
spasm by inflating the blood pressure cuff and
maintaining the cuff pressure above systolic)
• Chvostek's sign (tapping of the inferior portion
of the zygoma will produce facial spasms

36. Hypercalcemia
• Causes

37. Hypercalcemia
"Stones, Bones, Groans, Thrones and Psychiatric Overtones“
-Stones (renal or biliary)
-Bones (bone pain)
-Groans (abdominal pain, nausea and vomiting)
-Thrones (sit on throne - polyuria)
-Psychiatric overtones (Depression 30-40%, anxiety, cognitive dysfunction, insomnia,
coma)

38. Calcium Imbalance

39. Summary
• Calcium is crucial for body physiological
function
• It must be tightly regulated to maintain
physiological stability, by the interaction
between the major organs (Intestine, kidney,
bone) and hormones ( PTH, Calcitonin,
Vitamin D)

40. Summary
• A decrease in calcium level – stimulate PTH
release – increase bone resorption, increase Ca2+
reabsorption from kidney (DCT), decrease PO4
reasbsorption from kidney (PCT), and increase
calcium uptake from GI (indirect)
• Vitamin D – same action but increase PO4
reabsorption from kidney
• Calcium imbalance must be recognized and
treated early to prevent any catastrophe.

41. Reference
• Physiology by Linda S. Costanzo 3rd edition