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Calcium homeostasis

Calcium plays a very IMPORTANT role in metabolic processes of almost all body cells

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CalciumCalciumCalciumCalcium HomeostasisHomeostasisHomeostasisHomeostasis
Dr Dharmendra
Dept of Physiology
AFMC
2
Sequence of PresentationSequence of PresentationSequence of PresentationSequence of Presentation
Introduction
History & Comparative Physiology
Calcium: Metabolism & Role
Regulation of Ca++ Levels:
Parathyroid Hormone (PTH)
Vitamin D
Calcitonin
Applied Aspects
Conclusion
3
IntroductionIntroductionIntroductionIntroduction
•Ca++ is a chemical element, an alkaline earth metal
•5th most abundant element
•An essential dietary element for human life
•As an electrolyte, Ca++ plays vital role in the
physiological and biological processes
•Both Intracellular and Extracellular functions
4
•Ca++ outside cells are important for maintaining the
potential difference across excitable CM as well
proper bone formation.
•Regulation of Ca++ in blood occurs within narrow
limit
•Organ Ca homeostasis
•Target organs : bones, kidneys, intestines
•Endocrine Ca homeostasis
•Three hormones primarily regulate Ca++
metabolism
5
•Primary process for release of Ca into circulation
• Ca GI absorption and bone resorption
•Primary process for removal of Ca from blood
• Ca Renal excretion and bone formation
•Phosphate metabolism is closely linked
•Multiple disorders
6
Historical AspectsHistorical AspectsHistorical AspectsHistorical Aspects
• 1808- Humphry devy
• Isolated from oxide and named it
• 1883- Sydney Ringer:
• Ist to reveal importance of Ca++
1888- Role in cellular Adhesion
• 1888- Alexis Hartmann
• Ringer solution- modified to ‘Ringer Lactate Solution’ or
‘Hartmann's solution’
• 1927- Heilbrum- roll in clotting
1940 1970 1993
NT Ca channels CaSR

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Calcium homeostasis

  • 2. 2 Sequence of PresentationSequence of PresentationSequence of PresentationSequence of Presentation Introduction History & Comparative Physiology Calcium: Metabolism & Role Regulation of Ca++ Levels: Parathyroid Hormone (PTH) Vitamin D Calcitonin Applied Aspects Conclusion
  • 3. 3 IntroductionIntroductionIntroductionIntroduction •Ca++ is a chemical element, an alkaline earth metal •5th most abundant element •An essential dietary element for human life •As an electrolyte, Ca++ plays vital role in the physiological and biological processes •Both Intracellular and Extracellular functions
  • 4. 4 •Ca++ outside cells are important for maintaining the potential difference across excitable CM as well proper bone formation. •Regulation of Ca++ in blood occurs within narrow limit •Organ Ca homeostasis •Target organs : bones, kidneys, intestines •Endocrine Ca homeostasis •Three hormones primarily regulate Ca++ metabolism
  • 5. 5 •Primary process for release of Ca into circulation • Ca GI absorption and bone resorption •Primary process for removal of Ca from blood • Ca Renal excretion and bone formation •Phosphate metabolism is closely linked •Multiple disorders
  • 6. 6 Historical AspectsHistorical AspectsHistorical AspectsHistorical Aspects • 1808- Humphry devy • Isolated from oxide and named it • 1883- Sydney Ringer: • Ist to reveal importance of Ca++ 1888- Role in cellular Adhesion • 1888- Alexis Hartmann • Ringer solution- modified to ‘Ringer Lactate Solution’ or ‘Hartmann's solution’ • 1927- Heilbrum- roll in clotting 1940 1970 1993 NT Ca channels CaSR
  • 7. 7 Comparative PhysiologyComparative PhysiologyComparative PhysiologyComparative Physiology •Calcitonin/ PTH/ Vitamin D: • Fish, Reptiles, Birds and Mammals • Same functions as in humans • Fish rich source of Vit D • Salmon Calcitonin
  • 8. 8 Calcium:Calcium:Calcium:Calcium: MetabolismMetabolismMetabolismMetabolism Distribution of Ca: • Average human body – 1000 to 1100 gm • 99% - skeleton • 0.9% - intracellular • 0.1%- ECF (one gram) • Three forms in plasma: • Normal value – 9.4 mg/dl (2.4 mmol/l) • Total diffusible (ionic)- 5.3 mg/dl • Total nondiffusible (protein-bound)- 4.6 mg/dl • Ca estimation: Corrected Ca (mg/dl)= measured total Ca+.8 (4-Albumin)
  • 9. 9 Calcium: MetabolismCalcium: MetabolismCalcium: MetabolismCalcium: Metabolism • Overview of calcium exchange between different tissue compartments (90%) Rapid exchange Exchangable & Stable form (10%) (98–99%)
  • 10. 10 Calcium:Calcium:Calcium:Calcium: MetabolismMetabolismMetabolismMetabolism---- OrganOrganOrganOrgan CaCaCaCa homeostasishomeostasishomeostasishomeostasis Target organs: 1. Intestine- Ca absorption 2. Kidney- Ca excretion 3. Bone- uptake & release of Ca •Plasma Ca conc depends on net effect of these organ physiology
  • 11. 11 OrganOrganOrganOrgan CaCaCaCa homeostasis: GI Absorptionhomeostasis: GI Absorptionhomeostasis: GI Absorptionhomeostasis: GI Absorption • Mainly Small intestine- duodenum /proximal jejunum • Absorption and fecal excretion • Fractional absorption stimulated by- 1,25 DHCC • Brush border : active, carrier mediated energy dependent • Active transport transcellular route • Passive & bulk flow paracellular route
  • 12. 12 OrganOrganOrganOrgan CaCaCaCa homeostasis: GI Absorptionhomeostasis: GI Absorptionhomeostasis: GI Absorptionhomeostasis: GI Absorption • TRPV5/6- ‘Transient Receptor Potential Vanilloid Type 5/6 ’ • 1,25-DHCC- increases the expression of all these proteins • PTH- 1 α hydroxylase enzyme /NCX1
  • 13. 13 OrganOrganOrganOrgan CaCaCaCa homeostasis: Renal excretionhomeostasis: Renal excretionhomeostasis: Renal excretionhomeostasis: Renal excretion (98–99%)
  • 14. 14 Renal Ca reabsorption PCT- Passive paracellular pathway TAL- Both paracellular & transcellular pathway
  • 15. 15 OrganOrganOrganOrgan CaCaCaCa homeostasishomeostasishomeostasishomeostasis: Bone: Bone: Bone: Bone • Accretion & resorption are in balance • Bone remodeling can be modulated • Chronic Ca & Pi dysregulation or H dysregulation • Pathological changes • Chemical Composition: • Mineral salts - 35% (Ca++ & phosphates, Ratio: 1.3 to 2) • Organic matrix - 20% • Water – 45% • Amorphous(CaHPo4) compounds –loosely bound-1% of bone Ca++ - easily exchangeable – First line of Defense
  • 16. 16 OrganOrganOrganOrgan CaCaCaCa homeostasis: Bonehomeostasis: Bonehomeostasis: Bonehomeostasis: Bone Structure: Two types • Compact or Cortical (75%) • Outer layer • Nutrients by Canaliculi/Haversian Canals • Low surface to volume ratio • Collagen arranged in circles -Osteons • Trabecular or Spongy (25%) • Lie inside the compact bone • Made up of spicules • High surface to volume ratio • Nutrients diffuse through ECF
  • 17. 17 OrganOrganOrganOrgan CaCaCaCa homeostasis: Bonehomeostasis: Bonehomeostasis: Bonehomeostasis: Bone In adult- Bone remodeling involve: 1. Destruction of preformed bone with release of Ca, Pi & hydrolysed fragments of protein metrix (osteoid) into blood. 2. New systhesis of osteoid at the site of resorption with subsequent calcification Cell types: 02 major class •Osteoblasts •Osteoclasts
  • 18. 18 OrganOrganOrganOrgan CaCaCaCa homeostasis: Bonehomeostasis: Bonehomeostasis: Bonehomeostasis: Bone •Osteoblast regulation of osteoclast differentiation and function. After 2 wks
  • 19. 19 •osteoid (eg. Osteocalcin & ALP)- promote calcification Calcium phosphate Hydroxyappetite crystals Lamellae Haversian Lacunae Haversian system (osteon)
  • 20. 20 PTH PTH/PTHrP Sustained PTH- bone turnover & resorption Intermittent low dose PTH- promote OB survival & bone anabolic function OB
  • 21. 21 EndocrineEndocrineEndocrineEndocrine CaCaCaCa homeostasishomeostasishomeostasishomeostasis: PTH: PTH: PTH: PTH •PTH & 1,25 DHCC = calciotropic Hormone Synthesis: •Two distinct cells: • Chief Cells- prominent ER, golgi appt – secrete PTH • Oxyphil Cells •Target organs •Net effect- S. Ca, S. Pi
  • 22. 22 EndocrineEndocrineEndocrineEndocrine CaCaCaCa homeostasis: PTHhomeostasis: PTHhomeostasis: PTHhomeostasis: PTH Actions of PTH: >Bone: • Increased resorption of bone, Growth & development of cartilage • Rapid and slow phase >Kidney: 1. Ca resorption & Pi resorption 2. Hyperphosphaturia 3. Increased urinary excretion of Hydroxyproline 4. Increased conversion of 25-HCC to 1,25 DHCC >Intestine: indirect action >Other actions: • Activation of Adenyl Cyclase in target tissues • Brain , placenta , Teeth
  • 23. 23 EndocrineEndocrineEndocrineEndocrine CaCaCaCa homeostasis: PTHhomeostasis: PTHhomeostasis: PTHhomeostasis: PTH Mechanism of Action : • 3 different receptors • PTH1 (PTHrP receptor) • PTH2: brain,placenta, kidney • CPTH • CPTH – acts at carboxyl terminal • PTHrP: • Produced by many tissues • Marked homology bw PTH & PTHrP • Similar receptors • On Osteoblast & PCT, DCT- for PTH
  • 24. 24 EndocrineEndocrineEndocrineEndocrine CaCaCaCa homeostasis: PTHhomeostasis: PTHhomeostasis: PTHhomeostasis: PTH Regulation; Major regulator: • Ca++ ion concentration Minor regulator: • Vit D •Decreased Ca++/Increased PTH •Increased Ca++/Decreased PTH CaSR- PLC-IP3/DAG- IC Ca CaSR
  • 25. 25 EndocrineEndocrineEndocrineEndocrine CaCaCaCa homeostasis:homeostasis:homeostasis:homeostasis: VitVitVitVit DDDD Synthesis: •Vit D3- by UV irradiation of 7-dehydrocholesterol in skin •Indirect inhibition by Ca++ •Target organ: intestine, bone, kidney parathyroid gland
  • 26. 26 Vitamin DVitamin DVitamin DVitamin D metabolismmetabolismmetabolismmetabolism PCT PCT Ca
  • 27. 27 Effect of plasma calciumEffect of plasma calciumEffect of plasma calciumEffect of plasma calcium concconcconcconc onononon 1,25 DHCC1,25 DHCC1,25 DHCC1,25 DHCC Effect ofEffect ofEffect ofEffect of VitVitVitVit D3 intake on 1,25 DHCCD3 intake on 1,25 DHCCD3 intake on 1,25 DHCCD3 intake on 1,25 DHCC
  • 28. 28 EndocrineEndocrineEndocrineEndocrine CaCaCaCa homeostasis:homeostasis:homeostasis:homeostasis: VitVitVitVit DDDD Mechanism of Action: Intestine: 1. 1,25 DHCC affects Ca++ absorption and transport 2. Act via Calbindin- D proteins 3. Intestinal epithelium – Calbindin D 9k 4. Also increases number of Ca++-ATPase/TRPV6 Kidney: Facilitates Ca++ resorption in kidneys via TRPV5 • Ca++ acts as transport mediator for phosphate Bone: • Increases synthetic activity of Osteoblasts • Stimulate termination of OC differentiation • Necessary for normal calcification of matrix
  • 29. 29 GI AbsorptionGI AbsorptionGI AbsorptionGI Absorption • TRPV5/6- ‘Transient Receptor Potential Vanilloid Type 5/6 ’ • 1,25-DHCC- increases the expression of all these proteins • PTH- 1 α hydroxylase enzyme /NCX1
  • 30. 30 EndocrineEndocrineEndocrineEndocrine CaCaCaCa homeostasis:homeostasis:homeostasis:homeostasis: VitVitVitVit DDDD Regulation: •PTH •Feedback - Ca++ and PO4 3+ levels •High levels Ca- • inhibit 1,25 DHCC production • More 24,25 DHCC produced (Inactive form) •Promotes mineral precipitation on collagen fibrils •Low levels Ca- • stimulates more PTH – more 1α hydroxylase
  • 31. 31 • Regulation: • A new protein called – α Klotho : • Important role in calcium and phosphate homeostasis • Stabilizes membrane proteins TRPV5/NaK ATPase. • Enhances activity of, Fibroblast Growth Factor 23 (FGF23) • FGF23 decreases renal NaPi-IIa and NaPi-IIc expression • Inhibits the production of 1 -hydroxylase, reducing 1,25- DHCC
  • 32. 32 EndocrineEndocrineEndocrineEndocrine CaCaCaCa homeostasis:homeostasis:homeostasis:homeostasis: CalcitoninCalcitoninCalcitoninCalcitonin Synthesis: • Release in response of increase Ca Action: • Inhibits resorption of bones- Ca, Pi • Reduces levels of Calcium and Phosphates: • Inhibits activity of Osteoclasts • Increasing efflux of calcium from kidneys • Increased mitochondrial uptake of calcium • Overall Minor Role: • Post Thyroidectomy – Normal levels of Ca++ and bone density • Medullary Ca Thyroid-Very high calcitonin – No effect on Ca++
  • 33. 33 •In renal failure: • calcitonin •Regulation: Bone- • Ca • Same by CaSR • Similar PTH/PTHrP receptors • ECF Ca--- calcitonin • Act on Osteoclast •Kidney- inhibit reabsorption
  • 34. 34 Interplay ofInterplay ofInterplay ofInterplay of CaCaCaCa++++++++, PTH & Calcitonin, PTH & Calcitonin, PTH & Calcitonin, PTH & Calcitonin
  • 35. 35 Effect of other Hormones onEffect of other Hormones onEffect of other Hormones onEffect of other Hormones on CaCaCaCa++++++++ • Glucocorticoids : Bone: • inhibiting osteoclast formation and activity. • Osteoporosis - inhibits protein synthesis in osteoblasts. Intestine: • decrease the absorption of Ca2+ and PO4 3– Kidney: • Decrease reabsorption • Growth hormone: • increases intestinal absorption of Ca2+ • IGF-I stimulates protein synthesis in bone • Estrogens: • prevent osteoporosis - inhibits stimulation of osteoclasts • Increase Ca absorption & reabsorption • Insulin: increases bone formation - bone loss in untreated diabetes.
  • 36. 36 Role of CalciumRole of CalciumRole of CalciumRole of Calcium • Main component of Bony Skeleton (99%) • Excitation-Contraction coupling • Stabilization of Cell Membrane • Release of Neurotransmitters at synaptic vesicle • Secretion from Endocrine/Exocrine glands • Secondary massenger • Synthesis of Nucleic Acids • Activation/Regulation of enzymes • Blood Clotting • Teeth
  • 37. 37 Applied AspectsApplied AspectsApplied AspectsApplied Aspects 1. Hypercalcemia/Hyperpatathyroidism • GI absorption/Renal reabsorption/Bone resorption • Calcification in soft tissue • Bone demineralization • Osteoporosis • FBHH- CaSR mutation 2. Hypocalsemia/Hypoparathyroidism • Bone /kidney • Alkalosis • No bone demineralization • Teteny/carpopedal spasm/trousseau’s sign/chvostic sign • Laryngospasm • First degree HB
  • 38. 38 Integrated response to a hypocalcemic challenge.
  • 39. 39 Applied AspectsApplied AspectsApplied AspectsApplied Aspects 3. Vitamin D deficiency: • Defective bone mineralization • Ca– PTH • Child- Rickets • Adult- Osteomalasia 4. Osteoporosis: • Mutation OPG….. Highly overactive OC 5. Osteopetrosis: • Mutation in RANK/RANKL gene
  • 40. 40 Applied AspectsApplied AspectsApplied AspectsApplied Aspects 6. Hypervantilation: • Decrease PTH 7. Paget disease: • Increase bone resorption followed by new bone formation • Excessive bone turnover by increase OC actvity • Bone deformity • Raised ALP & Osteocalcin
  • 41. 41 Applied AspectsApplied AspectsApplied AspectsApplied Aspects 8. Renal osteodystrophy 9. Neuromuscular junction 10. Pseudohyperparathyroidism 11. Significant tissue damage 12. Drugs: loop diuretics/thiazides/CaSR modified & blocker 13. ECG changes 14. Effect of microgravity
  • 42. 42 ConclusionConclusionConclusionConclusion • Calcium plays a very IMPORTANT role in metabolic processes of almost all body cells • Necessary for normal Skeletal Bony Growth • Levels are maintained in a narrow range • Right conc. depends upon interplay of Ca absorption from intestine, bone uptake/ release and renal excretion • All the above are regulated in concert by PTH, Vit D & Calcitonin • Many disorders are linked with dysfunction
  • 43. 43