Hormonal control of Calcium Metabolism

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Hormonal control of Calcium Metabolism

  1. 1. HORMONAL CONTROL OFCALCIUM METABOLISM Dr. M. Anbarasi, MD (Physiology)
  2. 2. HORMONES INVOLVED…1,25 DihydrocholecalciferolParathyroid hormoneCalcitonoinParathyroid hormone related protein{ PTHrP}Miscellaneous hormones : Glucocorticoids, Growth hormone,Estrogen
  3. 3. CALCIUM & PHOSPHATE METABOLISM
  4. 4. NORMAL VALUESTotal body calcium – 1100 g {27.5 mol / L} 99 % in bonesPlasma calcium : 9 – 11 mg / dL {5 m Eq / L or 2.5 mmol / L} Ionized calcium – 50 % {1.2 mmol / L} Protein bound – 41 % {1.0 mmol / L} Complexed with anions – 9 % {0.2 mmol / L}
  5. 5. FUNCTIONS OF CALCIUMFREE IONIZED CALCIUM Blood coagulation Muscle contraction Transmission of nerve impulses Formation of skeleton ,etc.
  6. 6. EFFECTS OF ALTERED CALCIUM HYPOCALCEMIA• Nerve and muscle cells becomes hyperexcitable. increased neuronal membrane permeability to Na + channels HYPOCALCEMIC TETANY – latent or manifest Calcium at 6 mg / dL --- TETANY at 4 mg / dL --- LETHAL Alkaline pH – tetany at higher values.
  7. 7. SIGNS OF MANIFEST TETANY CARPOPEDAL SPAM• Laryngeal stridor• Convulsions• Visceral features like intestinal spasm, bronchospasm and profuse sweating. Obstetric hand /
  8. 8. LATENT TETANY• CHVOSTEK’S SIGN• TROUSSEAU’S SIGN
  9. 9. HYPERCALCEMIACALCIUM LEVEL > 12 mg / dL • Nervous system is depressed • Reflex activities are sluggish • Decreased QT interval • Lack of appetite
  10. 10. CALCIUM IN BONETwo types1. Readily exchangeable reservoir {500 mmol of Ca2+ is exchanged}2. Stable calcium {7.5 mmol of Ca2+ is exchanged}
  11. 11. CALCIUM IN KIDNEYS• 98 % - 99 % is reabsorbed 60 % in PCT 40 % in Ascending limb of LOH Distal tubule PARATHYROID HORMONE
  12. 12. CALCIUM IN GIT• 30 – 80 % of ingested calcium is absorbed• Actively transported out of the intestinal cells with the help of Ca 2+ dependent ATPase 1,25 Vitamin D3• Increased plasma calcium – decreased absorption from the gut• Decreased by phosphates and oxalates and alkalis• Increased by high protein diet
  13. 13. DIET25mmol (1000 mg) BONE RAPID ABSORPTION EXCHANGE EXCHANGEABLE GIT 100 mmol 15 mmol 500 mmol ECF SECRETION 35 mmol STABLE REABSORPTION 27,200 mmol 12.5 mmol 7.5 mmol REABSORPTION 247.5 mmol GLOMERULARFECES FILTRATE22.5mmol 250 mmol URINE 2.5 mmol
  14. 14. PHOSPHATE METABOLISM
  15. 15. NORMAL VALUES• Total body phosphate – 500 to 800 g.• 85 – 90 % in skeleton• Plasma phosphate – 12 mg / dL 2/3rd – organic 1/3rd – inorganic {Pi} ex. PO43- , HPO42-, H2PO42-FUNCTIONS ATPase , c AMP , 2-3, DPG Phosphorylation and Dephosphorylation
  16. 16. BONE: 3 mg of PO4 enters and is again reabsorbed.KIDNEYS: 85 % - 90 % of filtered Pi is reabsorbed by Active Transport in PCT Overflow mechanism PTH
  17. 17. GIT• Absorbed in duodenum and small intestine by Active transport and passive diffusion.• Absorption is linear to dietary intake.• All PO4 excreted in urine.
  18. 18. BONE PHYSIOLOGY
  19. 19. Made up of organic matrix and salts ORGANIC MATRIXCOLLAGEN FIBERS GROUND• 90 – 95 % SUBSTANCES• Type 1 collagen made • Gelatinous substances up of triple helix (ECF + proteoglycans) Chondroitin sulphate Hyaluranic acid
  20. 20. BONE SALTS• Salts of calcium and phosphate. HYDROXYAPATITE Ca10(PO4)6. (OH)2400 Å long10 – 30 Å thick100 Å wideCa / P ratio – 1.3 to 2.0Other salts: Mg2+, Na+ , K+ ions conjugated to bone crystals.
  21. 21. STRUCTURE OF BONE2 types of bonesCompact or Cortical bone – 80 %• surface to volume ratio is low• receive nutrients by canaliculiTrabecular or Spongy bone – 20 %• made up of spicules or plates with high surface to volume ratio• receive nutrients from the ECF through Haversian canal
  22. 22. BONE GROWTHFetus to adults – ENCHONDRAL BONE FORMATIONException: clavicles, mandibles and certain skull bones. INTRAMEMBRANOUS BONE FORMATION
  23. 23. EPIHYSEAL PLATE – bone increases in lengthWidth is proportionate to growth and influenced by GH. EPIPHYSEAL CLOSURE Cartillage cells hypertropied Release VEGF Vascularization and ossification
  24. 24. BONE FORMATION & RESORPTION• Bone formation by OSTEOBLASTS• Bone resorption by OSTEOCLASTS
  25. 25. CELLS OF BONE• OSTEOPROGENITOR CELLS• OSTEOBLASTS• OSTEOCYTES• OSTEOCLASTS
  26. 26. OSTEOBLASTS• Modified fibroblasts developed from mesenchymal cells• Secrete collagen monomers and ground substances• Finally forms an ‘OSTEOID’• Calcium salts are deposited in the collagen fibers and forms hydroxyapatite crystals.
  27. 27. OSTEOCYTES• Mature bone cells – imprisoned osteoblasts in the lacunae of osteon.• Sends processes throughout bone matrix• Maintains the metabolic activity of bone• Opens the channels for distribution of nutrients• Exchanges calcium between bone and ECF.
  28. 28. OSTEOCLASTS• MEMBER OF MONOCYTE FAMILY• Attach its ruffled border to bone via integrins in the “sealing zone”• Proton pumps secrete acid and acidify the isolated area• Proteolytic enzymes breaks down the organic matrix• Eats away the bone in 3 wks - tunnel• Osteoblasts are activated - forms a new Haversian canal.
  29. 29. CONTINUAL BONE FORMATION : strength shape for mechanical support replace old brittle bone.BONE STRESS:• Compressional load – bone in cast• Shape of the bone
  30. 30. FRACTURE:• Activates periosteal and intraosseous osteoblasts• Stimulates osteoprogenitor cells.• Formation of “ CALLUS ”
  31. 31. VITAMIN D 3
  32. 32. FORMATION OF VITAMIN D3
  33. 33. 7 DEHYDROCHOLESTEROLSUNLIGHT PREVITAMIN D3 VITAMIN D3 CHOLECACIFEEROL 25 HYDROXYLASE LIVER 25- HYDROXY CHOLECALCIFEROL 24 α HYDROXYLASE 1 α HYDROXYLASE KIDNEY 24, 25 DIHYDROXY CHOLECALCIFEROL 1, 25 DIHYDROXY CHOLECALCIFEROL
  34. 34. MECHANISM OF ACTION• 1,25 – dihydroxycholecalciferol is a steroid compound (secosteroid)• Acts via the steroid receptor superfamily• Exposes the DNA – binding domain and results in increased transcription of some mRNAs.
  35. 35. ACTIONS OF VITAMIN D31. Promotes intestinal calcium absorptionBY 1. Formation of calcium binding protein (calbindin) 2. Formation of calcium stimulated ATPase 3. Formation of alkaline phosphatase
  36. 36. 25-HYDROXYLASE
  37. 37. 2. Promotes phosphate absorption by the intestines• As a direct effect• Calcium acts as a transport mediator for phosphate.3. Decreases renal excretion of calcium & phosphate• Increases reabsorption of Ca and PO4 by the renal tubules
  38. 38. 4. Increases both bone resorption and bone mineralizationBONE RESORPTION – by stimulating PTH.Calcitriol receptors are present in osteobastsReceptor – calcitriol complex – stimulate osteoblasts --- activation & differentiation of osteoclasts.BONE MINERALIZATION – by stimulation osteoblasts and alkaline phosphatase secretion
  39. 39. REGULATION OF SYNTHESIS PTH Ca 25 –OH D3 1,25 (OH)2 D3 BONE & INTESTINES24,25- (OH)2 D3 PO4
  40. 40. RICKETS & OSTEOMALACIAVITAMIN D deficiency in children and adults - defective bone mineralization and calcification - failure to deliver adequate Ca and PO4FEATURES: Weakness and bowing of weight bearing bones, dental defects and hypocalcemia. Responsive to Vitamin D therapy.VITAMIN D RESISTANT RICKETS: mutations in the gene coding for the enzyme 1 α HYDROXYLASE
  41. 41. Rickety rosary
  42. 42. STRUCTURE• FOUR parathyroid glands located behind the thyroid gland• 6 x 3 x 2 mm• Two types of cells 1. Chief cells 2. Oxyphil cells
  43. 43. CHEMISTRYPre pro PTH ( 115 aa)Pro PTH ( 90 aa )PTH ( 84 aa )Normal plasma PTH 10 -55 pg / mLHalf life – 10 mins
  44. 44. ACTIONS OF PTHI. Increases calcium and phosphate absorption from the bonesII. Decreases excretion of calcium by the kidneysIII. Increases the excretion of phosphate by the kidneysIV. Increases intestinal absorption of calcium and phosphate. INCREASED PLASMA CALCIUM
  45. 45. I. Ca & PO4 absorption from the bone Two phases1. Rapid phase – osteolysis by osteocytes2. Slow phase – by osteoclasts
  46. 46. RAPID PHASE - OSTEOLYSIS OCTEOCYTES OSTEOCYTIC MEMBRANE BONE FLUID ECF BONEECF O.M B.FL B
  47. 47. ECF OSTEOCYTIC BONE FLUID BONE MEMBRANEPTH Ca Ca Ca Ca Ca Ca Ca Ca Ca
  48. 48. SLOW PHASEDone by OSTEOCLASTS… immediate activation of existing cells formation of new cells Excess bone resorption Stimulates osteoblastic activity
  49. 49. II. Excretion of calcium and phosphate... • Decreases excretion of calcium increases reabsorption in CD, DT and Ascending limb of LOH • Increases excretion of phosphate PHOSPHATURIC ACTION dimishes absorption in PCT
  50. 50. III. Absorption of Ca & PO4 in GIT… Enhances absorption of both calcium and phosphate by stimulating 1,25 – dihydroxycholecalciferol. • cAMP mediated. • cAMP is in plenty in osteoblasts and osteocytes
  51. 51. MECHANISM OF ACTION• Binds to PTH receptors – 3 types.• REGULATION: stimulus : plasma calcium level.
  52. 52. • Produced by the parafollicular cells / C cells of thyroid gland.• Remnants of ultimobrachial body.STRUCTURE: Molecular weight – 3500 and has 32 aminoacids. In brain “Calcitonin gene related polypeptide ( CGrP)” is formed.
  53. 53. • STIMULUS : Increased plasma calcium Others: β adrenergic agonists, dopamine and estrogen, GASTRIN, CCK, glucagon..• ACTIONS: Decreases absorptive action of osteoclasts Deposits exchangeable Ca in bone salts Decreases the formation of osteoclasts• CLINICAL USE: Used in the treatment of PAGET’S DISEASE.
  54. 54. DISORDERS OF PTH• HYPOPARATHYROIDISM• HYPERPARATHYROIDISM primary and secondary• PSEUDOHYPOPARATHYROIDISM
  55. 55. HYPOPARATHYROIDISM• Body calcium level decreases• Osteoclasts are inactive• Sudden removal – signs of tetany appears• Responds to treatment with PTH or Vitamin D3 PSEUDOHYPOPARATHYROIDISM PTH is normal Defect is in PTH receptors Not responsive to hormone therapy
  56. 56. PRIMARY HYPERPARATHYROIDISM• Tumors – adenoma of parathyroid glands• More common in women.• Extreme osteolytic resorption - calcium and phosphate levels.Bone :Punched out cystic areas in the bone filled by osteoclasts – osteoclast tumors ‘ osteitis fibrosa cystica’Serum Alkaline phosphatase is elevated.
  57. 57. Hypercalcemia: P. Calcium – 12 – 15 mg / dL CNS depression, muscle weakness, constipation, abdominal pain, peptic ulcer, lack of appetite etc…Metastatic calcification: CaHPO4 crystals are deposited in renal tubules, lung alveoli, thyroid glands etc…Renal stones: Calcium phosphate and also calcium oxalate stones
  58. 58. SECONDARY HYPERPARATHYROIDISM• Increased levels of PTH is the result of compensatory mechanism to hypocalcemia• Due to chronic renal disease or deficiency of Vitamin D 3
  59. 59. OSTEOPOROSISDiminished bone matrix due to poor oeteoblastic activityCauses:1. Lack of physical stress2. Malnutrition3. Postmenopausal lack of estrogen4. Old age5. Lack of Vitamin C6. Cushing’s syndrome
  60. 60. OTHER HORMONESPARATHYROID HORMONE RELATED PROTEIN( PTHrP)• Produced by different tissues of our body• Binds to PTH receptors• Marked effect on growth and development of cartilage in utero.• Cartilage growth is stimulated by a protein called “Indian hedgehog”• Other uses : Brain – prevents excitotoxic damage Placenta – transports calcium• Defect in PTHrP – severe skeletal deformities.
  61. 61. GLUCOCORTICOIDSLowers plasma calcium by inhibiting osteoclasts.Over Long periods – osteoporosisInhibit protein synthesis in osteoblasts,thereby synthesis of organic matrixInhibit absorption of Ca and Po4 from the gut and facilitate its excretion in the kidneys.
  62. 62. GROWTH HORMONE Increases intestinal absorption of Calcium “Positive calcium balance”IGF – I Stimulates protein synthesis in bone.THYROID HORMONE Hypercalcemia, Hypercalciuria and Osteoporosis.ESTROGENS Prevents osteoporosis by inhibiting certain cytokinesINSULIN Increases bone formation

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