Calcium

Calcium

1. Hypocalcaemia

   • increase in nerve excitability
     • cause tetany
       • spasms
       • if severe can cause death by asphyxiation

2. hypercalcaemia

   • reduces neuromuscular excitability
     • lead to cardiac arrhythmias, lethargy and death
   • causes
     • 54% primary hyperparathyroidism
     • 34% malignancy associated
     • 12% other

3. location

   • 99% bones and teeth
   • intercellular
     • soluble in cytosol and nucleus.  insoluble in PM, ER and mitochondria  
   • extracellular
     • extracellular fluid for  Blood clotting,  exocytosis and contraction   

4. PTH

   • parathyroid hormone 
   • produced by chief cells of the parathyroid gland
   • 88a
   • synthesised as prep-pro PTH (115aa)
     • cleaved to proPTH
       • cleaved again to PTH
         • cleaved in the liver 88aa half life 20mins  
   • secretion is inversely proportional to serum Ca
   • effects
     • increases bone resorption
     • increase renal Ca reabsorption
     • increase Pi excretion
     • increase production of Vit D
   • PTHrP
     • PTH related peptide
     • 141,139,173aa
       • alternate splicing 
     • secreted in certain cancers causing humoral hypercalcaemia of malignancy
     • similar to PTH
     • widely expressed under normal conditions
     • essential for normal skeletal development
       • identified from KO studies 
   • evolution

5. Vitamin D

   • biosynthesis
     • PTH increases transcription of 1 alpha hydroxalase gene in the renal proximal tubule
     • in the skin UVB forms preVitD3
   • carried in the plasma bound to specific globulin VitD binding protein (DBP)
     • VitD is lipid soluble 
   • source
     • oily fish
       • salmon 
     • milk
   • Deficiency
     • Rickets
     • secondary hyperparathyroidism
     • osteomalacia
   • actions
     • increase net intestinal Ca2+ uptake
     • increases calbindin expression
     • increase bone resorption
     • increases renal Ca reabsorption

6. Calcitonin

   • Parafollicular thyroidal “C cells''
   • 32 aa peptide (from pro-calcitonin)
   • reduces Ca plasma levels after a meal
   • reduces osteoclast activity- reduces bone resorption
   • Secretion inhibited by low Ca2+ levels in the blood

7. plasma calcium

   • total ~ 2.5 mM (10mg/dl)
     • 35-40% bound to macromolecular proteins
       • especially albumin
     • 5% complexed as salts
       •    Ca2+ salts of bicarbonate, phosphate, sulphate & citrate.   
     • free ionised Ca2+ concentration is ~ 1.2 mM
   • Calcium sensing mechanism only senses free ionised Ca
     • The Ca2+-sensing mechanisms that oversee Ca2+ homeostasis sense changes in free, ionised Ca2+ levels rather than total Ca2+ levels

8. renal failure

9. Factors affecting bone formation / Ca2+ metabolism

   • Calciotropic hormones
     • affect calcium
     • PTH
     • Vit D3
     • calcitonin
   • Non-calciotropic hormones
     • affect bone formation but not calcium 
     • Glucocorticoids
     • Growth hormone
     • thyroid hormones
     • estrogen
     • insulin
     • EGF, FGF, PDGF
     • PGE2, osteoclast activating factor