Calcium homeostasis

BIOCHEMISTRY

1. Calcium Homeostasis Prakash Pokhrel

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

3. Introduction Total plasma [ Ca ++] = 2.5mmol/L Range is 2.1 to 2.6 mmol /L Very tightly controlled Body content Bone intracellular extracellular Calcium 1300 gm 99% 1% 0.1%

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 and numbness (sensory) and spontaneous muscle twitches (motor neurons and muscles)

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

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

10. Functions of Calcium 4. Neurotransmitter release Directly proportional to the calcium level Arrival of action potential to axonal terminal o pening of voltage gated calcium channels calcium influx into the terminal  t ransmitter vesicle fuse with the release sites  e xocytosis-release of transmitters into the cleft

11. 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.

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

13. Calcium Homeostasis

14. 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.

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

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

17. Parathyroid Hormone (PTH) Mechanism Increase in extracellular calcium concentration  Ca 2+ binds to the receptor and activates phospholipase C  increased levels of IP 04 /Ca 2+  which inhibits PTH secretion. When extracellular Ca 2+ is decreased, there is decreased Ca 2+ binding to the receptor, which stimulates PTH secretion.

18. Parathyroid Hormone (PTH) Actions of PTH on bone, kidney and small intestine Direct vs indirect 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

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

20. 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

21. Parathyroid Hormone (PTH)

22. Vitamin D

23. Vitamin D Actions of vitamin D

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

25. 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 Ca 2+ concentration The major action of calcitonin is to inhibit osteoclastic bone resorption , which decreases the plasma Ca 2+ concentration. calcitonin does not participate in the minute-to-minute regulation of the plasma Ca 2+ 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 Ca 2+ metabolism, as would be expected if calcitonin had important regulatory functions.

26. Calcium handling in the nephron

27. Calcium handling in the nephron - 67% of the filtered load is reabsorbed @ PCT - Ca 2+ reabsorption is tightly coupled to Na + reabsorption in the proximal tubule

28. Calcium handling in the nephron - @ ALH , 25% of the filtered load of Ca 2+ 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 Ca 2+ reabsorption to the same extent that they inhibit Na + reabsorption.

29. Calcium handling in the nephron @ DT 8% of the filtered load of Ca 2 the site of regulation of Ca 2+ reabsorption. the distal tubule is the only nephron segment in which Ca 2+ reabsorption is not coupled directly to Na + reabsorption. it has its own regulatory hormone, PTH. Thiazide diuretics increase Ca 2+ reabsorption, while the other classes of diuretics decrease it.

30. Hypocalcaemia 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

31. Hypercalcemia Causes

32. 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)

33. 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)

34. Summary A decrease in calcium level – stimulate PTH release – increase bone reabsorption, increase Ca2+ reabsorption from kidney (DCT), decrease PO4 reabsorption 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.

35. Reference Physiology by Linda S. Costanzo 3 rd edition