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HORMONES THAT REGULATE CALCIUM METABOLISM

HORMONES THAT REGULATE CALCIUM METABOLISM

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HORMONES THAT REGULATE CALCIUM METABOLISM

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  1. HORMONES THAT REGULATE CALCIUM METABOLISM Prof.Dr.Arzu SEVEN

  2. Incalciumhomeostasis, bonesserve as thereservior • There is ~ 1 kg of calcium in thehuman body • Theskeletoncontains 99% of calcium as hydroxyapatitecrystals, theremainder is distributed in thesofttissues, teethand ECF

  3. Bone is a dynamictissue, it undergoesconstantremodeling • Inthesteadystatecondition, there is a balancebetweennew bone formationand bone resorption • About 1% of skeletalCa+2 is in a freelyexchangeablepool

  4. Yenıkıtap p 68 fıg 1

  5. Total serum calcium is maintainedbetween 8.8-10.4 mg/dl • Calciumexists in thecirculation in 3 forms

  6. Mb p339 fıg 25.2

  7. Yeni katap p 69 fıg 3

  8. If serum protein concentrations (dehydration, afterprolongedvenousstasis) protein_boundcalciumand total serum calcium

  9. Inconditions of reduced serum proteins (liverdisease, nephroticsyndrome, malnutrition) protein _boundcalcium is reduced, decreasing total calcium (ionizedcalcium is withinthereferencerange)

  10. Inclinicalsituations, it is importanttocalculatetheadjustedcalcium(total serum calcium, adjustedforthepatient’sprevailingalbuminconcentration) • AdjustedCa =measuredCa (mmol/L) + 0.02 (40_ albumin g/L)

  11. Ionızedcalcium is maintainedwithin a narrowrangethrough an extracellularcalciımsensingreceptor(Ca SR) that is a cellsurface G_protein coupledreceptorpresent in thechiefcells of parathyroidgland, thyroidal_C cellsandalongkidneytubules

  12. Minutechanges in ionizedcalciummodulatecellularfunctiontomaintainnormocalcemia

  13. Hormonalcontrol of calciumhomesotasis • PTH • PTH is an 84_amino acidsinglechainpeptidehormone, secretedbythechiefcells of parathyroidglads • preproPTH: 115 amino acidwithhydrophobic amino terminal extension of 25_amino acids (leader/signalsequence) • proPTH: 90 amino acid, havinghighlybasicdexapeptideextension

  14. P341 fıg 25 4 MB

  15. No biologicfunctionforthecarboxy terminal segment of PTH has beendefined • Cathepsin B cleaves PTH into 2 fragments : PTH1-34and PTH35-84 (biologicalactive ( inactivecarboxy terminal ) amino terminal )

  16. Pro_PTH has neverbeenfound in circulation • Theliver(Kupffercells) andkidneyareinvolved in peripheralmetabolism of secreted PTH • secretion is inverselyrelatedtoambientconcentrations of ionizedcalcium

  17. A decrease in extracellularionizedcalciumor an increase in serum phosphateconcentrationstimulates PTH secretion • Chronic severe Mg deficiency can inhibititsreleasefromsecretoryvasicles • Lowconcentrations of 1,25(OH)2 cholecalciferolinterferewithitssynthesis

  18. P340 MB fıg 25 3

  19. PTH actsvia a membranereceptor • Thehormone_receptorinteractioninitiates a typicalcascade

  20. Activation of adenylylcyclase intracellularcAMP intracellularCa phosphorylation of specificintracellularproteinsbykinases Activation of specificgenesandintracellularenzymesthatmediatethebiologicactions of PTH

  21. The PTH responsesystem is subjectto DOWN_REGULATION of receptornumberandto DESENSITIZATION, whichmayinvolve a post_cAMPmechanism

  22. PTH restores normal extracellularfluidcalciumconcentrationbyacting DIRECTLY on kidneyand bone andbyacting INDIRECTLY on theintestinalmucosa(throughstimulation of 1,25(OH)2cholecalciferolsynthesis)

  23. Themostrapidchangesoccurthroughtheaction on thekidney but thelargesteffect is from bone • Phosphate is releasedwithcalciumfrom bone whenever PTH increasesdissolution of mineral matrix

  24. PTH increasesrenalphosphateclearance, thus, net effect of PTH on bone andkidney is toincreasethe ECF calciumconcentrationanddecrease ECF phosphateconcentration

  25. Yeni kit68 fıg 2

  26. Pathophysiology • Insufficientamounts of PTH result in hypoparathyroidism • Thebiochemicalhallmarks: serum ionizedCaand serum phosphate • Symptoms: neuromuscularirritability, which, whenmild, causesmusclecrampsandtetany

  27. Severe acutehypocalcemiaresults in tetanicparalyses of therespiratorymuscles,laryngospasm,severe convulsionsanddeath • Long_standinghypocalcemiaresults in cutaneouschanges, cataractandcalcification of thebasalganglia of thebrain

  28. Themostcommoncause of hypoparatyhroidism is accidentalremovalordamage of theglandsduringnecksurgery (pharyngealorlaryngealtm, thyroidorparathyroiddisease)secondaryhypoprathyroidsm • Autoimmunedestruction of theglandsresults inprimaryhypoparathyroidsim

  29. Pseudohypoparathyroidism(PHP) • An inheriteddisorder,characterizedbyhypocalcemia, hyperphosphatemia, increased PTH concentrations • Theclassictype of PHP is duetoend_organ resistanceto PTH, causedby a geneticdefectresulting in an abnormalregulatorysubunıt of G_protein of adenylatecyclasecomplex

  30. Developmentanomaliessuch as shortstature, shortmetacarpalormetatarsalbonesandmentalretardation • Confirmation of diagnosis : lack of increase in plasma/urinarycAMP in responseto PTH infusion

  31. Hyperparathyroidism • Theexcessiveproduction of PTH, may be dueto • Parathyroid adenoma • Parathyroidhyperplasia • Ectopicproduction of PTH orPTHrP

  32. Thebiochemicalhallmarks: • Elevated serum ionizedCaand PTH anddepressed serum phosphatelevels • Inlong_standinghyperparathyrodism ; extensiveresorption of bone andrenaleffects ( kidneystones, nephrocalcinosis, frequenturinarytractinfections, in severe casesdecreasedrenalfunction)

  33. Secondaryhyperparathyroidism • Characterizedbyhyperplasia of theglandsand PTH hypersecretion, may be seen in patientswithprogressiverenalfailure

  34. Parathyroid_hormonerelated protein(PTHrP) • Synthesized as 3 isoformscontaining 139, 141 and 173 amino acids, as a result of alternativedifferentialsplicing of RNA • Structurallyandfunctionallysimiliarto PTH, especially in amino terminal region

  35. İmportant in regulatingfetalcalciumhomeostasisandskeletaldevelopment • Has an important role in thehypercalcemiaassociatedwithmalignancy(HCM)

  36. Vitamin D • Is synthesized in the skin by UV radiation • Vitamin D2(ergocalciferol) is synthesized in the skin by UV radiation of ergesterol • Vitmain D3 (cholecalciferol) is derivedalsoby UV radiationfrom 7_hydro_cholesterol in the skin of animals (nonenzymaticphotolysisreaction)

  37. Vitamin D3 anditsmetabolitesaretransported in theplasma, boundto a specificglobulin, vitamin D_binding protein(DBP)

  38. 25-hydroxylationoccurs in theendoplasmicreticulum of liver • Itrequires Mg, NADPH, molecularoxygenand an uncharacterisedcytoplasmicfactor • NADPH_dependentcytocrome P450 reductaseandcytocrome P450 areinvolved (hepaticmicrosomalenzyme)

  39. Rate limiting step in theconversion of vitamin D3 toitsactivemetabolite • 25(OH)D3 is themainliverstorage form of vitamin D • Itslevels in thecirculationreflecthepaticstores

  40. A significantproportion of 25(OH)D3 is subjecttoenterohepaticcirculationbilereabsorbed in thesmallbowel • Secondhydroxylation at position C1 occurs at therenaltubulesby a mitochondrialenzyme, requiring • NADPH, Mg andmolecularoxygen

  41. 3 componentmonooxygenasereactionrequires : renalferredoxinreductase, cytocrome P450 andrenalferrodoxin(ironsulfur protein) • Theproduct 1,25 (OH)2D3 = calcitriol is themostpotentnaturallyoccuringmetabolite of vitamin D3

  42. Mb p342 fıg 25.5

  43. 1 αhydroxylaseactivity is stimulatedby PTH, low serum concentrations of phosphateorcalcium, vitamin D deficiency, calcitonin, growthhormone, prolactinandestrogen

  44. Herper p 573 table 47,1

  45. Therenaltubules, cartilage, intestineand plasenta contain 24_hydroxylase, producingtheinactive 24,25(OH)2D3 • The 24,25(OH)2D3 in circulation is reciprocallyrelatedto 1,25(OH)2D3

  46. Vitamin D may be described as a hormone • Intheintestinalepithelialcells, it bindsto a cytoplasmicreceptorlikeothersteroidhormones • Thisligand_protein complex is transportedtothenucleus 1,25(OH)2D3 induces gene expressionaffectingCametabolism

  47. Calcitriol • Increasescalciumandphosphateabsorptionfromthe gut viaactive transport bycalciumbindingproteins • Togetherwith PTH, it stimulates bone resorptionbyosteoclasts • Theseeffectsincrease serum calciumandphosphateconcentrations

  48. Pathophysiology • Rickets: a childhooddisordercharacterizedbylowplasmacalciumandphosphoruslevelsandbypoorlymineralized bone withassociatedskeletaldeformites • Mostcomonlydueto vitamin D deficiency