calcium metabolism and its clinical significance
TRANSCRIPT
CalciumMetabolismanditsclinicalsignificanceDr.Rohini CSane
Calciummetabolism99%bone
qBodycontent=(1.0-1.5kg)1%ECF
qSources:milk(cow-100mg/100ml,humanmilk-300mg/100ml),cerealsàmajorsource
qDailyrequirement–
Individual DailyrequirementAdult 500mgChildren 1200mgPregnancy 1500mgOldage 1500mg/daycalcium+20microgram/dayvitaminD
Calciummetabolism-AbsorptionofCalcium
First&secondpartofduodeneum
Activetransport
Carrierprotein–calciumdependentATPase
Factors affecting CalciumAbsorption
Increasecalciumabsorption1.VitaminDà increaseinCalbindinà Calciumabsorption2.ParathyroidHormone3.acidity-favorscalciumabsorption4.Aminoacids(Lysine&Arginine)à Calciumabsorption
Decreasecalciumabsorption1.Phyticacid(hexa phosphateInositol)àfermentationdecreasePhytate content2.Oxlateà presentinleafyvegetables3.Steatorrhoeaà fattyacidnotabsorbedCalciumfattyacidcomplexnotabsorbed4.Highphosphatecontentà calciumphosphateisnotprecipitates,notabsorbed
Calciummetabolismq optimumRatioformaximumabsorption:Calcium:phosphorousà (1:2to2:1)
Dailyintake(500mg)
lossofcalcium:stool(400mg)urine(100mg)
CalciummetabolismqDistributionofCalciuminhumanbodyqIntracellularconcentration:10micromole/ltqExtracellularconcentration:2.5mmol/ltqInflux :1. Na⁺/Ca²⁺exchange–lowaffinityforcalcium2. Ca²⁺ /H⁺ATPaseexchange
1.2.Ca²⁺ Ca²⁺ECFNa⁺H⁺
ICF
Calciumbalanceinahumanbody
Functions ofCalciumq1.Activationofenzymes(1)through“Calmodulin”
qCalcium+Calmodulinà Calcium- Calmodulin
KinaseActivekinase
EnzymePhosphorylatedenzyme
Biologicaleffect
Indirectactivation(throughCalmodulin)
Indirectactivation(throughCalmodulin)
Functions ofCalciumq1.ActivationofAdenylate Cyclase :Indirectactivation(throughCalmodulin)
Indirectactivation(throughCalmodulin )
Directactivation(withoutCalmodulin)
Functions ofCalciumv2.Secretionofhormones:Ca²⁺mediatedhormoneseg Insulin,Parathyroidhormone,Calcitonin,Vasopressin
Functions ofCalcium- Insulinsecretion
Functions ofCalciumv3.Secondmessengerofhormones:Ca²⁺mediatedhormoneseg Parathyroidhormones,ADH
HORMONESàCAmpà Ca²⁺à Effect
FunctionsofCalcium:Calciummediatedphosphorylationofmyosinv4.Excitation&contractionofmusclefiberv Dephosphorylatedmyosinlightchainkinase
phosphorylatedinactivemyosinlightchainkinase
Calcium–Calmodulinmyosinlightchainkinase
Myosinrelaxed+ATPà myosinphosphorylated(contraction)+ADP
PHOSPHTASE
ATPADPCAmpactivatedproteinkinase
(+)Ca²⁺-Calmodulin
FUNCTIONSOFCALCIUM
• B.Calsequestrin:(1)Calciumbindingprotein(2)ActivetransportofCa²⁺Calciumdecreases“neuromuscularirritability”Calciumdeficiencycauses“Tetany”
RoleofCalsequestrin inCalciumMetabolism
FUNCTIONSOFCALCIUM
• 5.Microfilamentregulatedprocesses• Cellmobility• EndocytosisRegulatedbyCalciumCalmodulincomplex• Secretoryvesicle• Degranulation
5.Microfilamentregulatedprocesses
Roleofcalciuminendocytosis
RoleOfCalciuminMicro-tubularFunction
FunctionsofCalcium• 7.permeabilityofserumthroughcapillaryisdecreasedbyCa²⁺Thereforeusedtoreduceallergicexudates
FunctionsofCalcium• 8.bloodcoagulation(CALCIUM=FACTORIV)
FunctionsofCalcium• 9.Prolongedsystoleinmyocardium:thereforeintravenousadministrationshouldbeslow
FunctionsofCalcium• 10.bone&teethformationOsteoblast:bonedepositionOsteoclastà demineralization
Ionizedform5mg/dl
Metabolicallyactive
Diffusible
ComplexesWithanion1mg/dl
ComplexeswithPO₄⁻³&
bicarbonateHCO₃⁻
Diffusible
Boundtoprotein4mg/dl
BOUNDTOAlbumin(3mg)&Globulin(1mg)
Nondiffusible
TotalserumCalcium:9-11mg/dl=5mequ/lt=2.5mmol/lt
ColorimetricMethodforestimationofTotalserumCalcium:usingNaphthal hydroxamic acid,OrthocresolthaleinMethodofestimationofIONIZEDFORM:IONSELECTIVEELECTRODES
SERUMCALCIUM=9-11mg/dl
SALKOWITCHTEST
Finecloudyppt
Physiological
SERUMCALCIUM=7.5mg/dl
SALKOWITCHTESTNoppt
Hypocalcaemia
SERUMCALCIUM>11mg/dl
SALKOWITCHTEST
Heavywhiteppt
Hypercalciuria
SALKOWITCHTESTESTIMATIONOFURINARYCALCIUMUSINGTURBIDOMETRICMETHHOD(AMMONIUMOXLATE)
Factorsregulatingbloodcalciumlevels
1. VITAMIND2. PTH3. CALCITONINMajorfactors4. PHOSPHOROUSLEVELS5. SERUMPROTEIN6. ACIDOSIS/ALKALOSIS7. KIDNEYFUNCTIONMinorfactors8. AGE
RoleofThyroidandparathyroidhormonesinCalciumbalance
Factorsregulatingbloodcalciumlevels1. VITAMIND
TargetorgansBone
Intestine
Kidney
↑activityalkalinephosphatase,NO&osteoblasts
AbsorptiondietaryCalcium
ReabsorptionCalciumfromfiltrate
VitaminDà increasesynthesiscalciumbinding proteinà increaseabsorptionofCalciumHypervitaminosis à Hyper-calcemia
Factorsregulatingbloodcalciumlevels2.SERUMPTH(Parathyroidhormone):10-60mg/dl(normallevel)FOURParathyroidglandsà chiefcellssynthesizePTH(ionicCa²⁺controlssecretionbynegativefeedback)
115AMINOACIDSPREPROPTH❶
90AMINOACIDSPROPTH❷
84AMINOACIDSPTH(ACTIVE)❸↑PTHà↑Calcium
SITEOFACTIONà BONE,KIDNEY,INTESTINESTORAGEOFPTHFORSEVERALHOURSNOTDAYS
Factorsregulatingbloodcalciumlevels2A.SERUMPTH(Parathyroidhormone—100ng/l)&Calcium:inbones
↑PTHànumberofosteoblast↑
↑Activityofpyrophosphatase
↑demineralization
↑Calciumlevels
Factorsregulatingbloodcalciumlevels2B.SERUMPTH(Parathyroidhormone)&Calcium:bone
↑PTHà↑LACTATE
↑solubiIization ofCalciumintosurroundingmedium
Factorsregulatingbloodcalciumlevels
Factorsregulatingbloodcalciumlevels2C.SERUMPTH(Parathyroidhormone)&Calcium:bone
↑PTHà↑secretionofCollagenase
Lossofmatrix&bonereabsorption
Mucopolysaccharide &HydroxyProlineinUrine
FactorsregulatingbloodcalciumlevelsSERUMPTH(Parathyroidhormone)&Calcium:Kidney
①↓RenalexcretionofCalcium(↑Ca²⁺Hypercalcemia )
②↑RenalabsorptionofCalcium(↑Ca²⁺- Hypercalcemia )
③↑Excretionofphosphorous(↓phosphorus)
④Hydroxylationof25hydroxyCalciferol (Indirectabsorption)
Hyperparathyroidismà Hyper-calcemiaà decreasephosphorous
FactorsregulatingbloodcalciumlevelsSERUMPTH(Parathyroidhormone)&Calcium:intestine
①↑PTHà↑Hydroxylationof25hydroxycalciferol
②↑DHCC(DIHYDROXYCHOLECALCIFEROL)
③↑CALCIUMBINDINGPROTEIN
④↑CALCIUMABSORPTIONFROMDIETARYSOURCES
Hyper-parathyroidismà Hyper-calcemiaà decreasephosphorous
FactorsregulatingbloodcalciumlevelsCalcitonin:byparafollicularcellsofthyroidgland
①32-34aminoacids(dependingspecies)
②CalcitoninsecretionisstimulatedbyserumCalciumGastrin,Glucagon.biologicalamines
③↓SERUMCALCIUMLEVELS
4a.↓calciumreabsorptionofbone4b.↓activityofosteoblast 4c.Activityofosteoblast4d.↓PTH(PTH&CALCIUMareantagonist)
5.Kidney:↑phosphorousexcretionthroughurine
6.Promotebonegrowth
FactorsregulatingbloodcalciumlevelsIVSeruminorganicphosphorous:“reciprocalrelationship”withCALCIUMCaXP=40(adult)Rickets:CaXP<40Children:CaXP=50Renalinsufficiency:calciumdecreases(calciumexcretionincreases)&phosphorousincreases( phosphorousexcretiondecreases)
FactorsregulatingbloodcalciumlevelsVSERUMPROTEIN:Nephritis,malnutritionà Hypo-albuminemiaà serumcalciumdecreasesDecreaseinAlbuminby1gà decreaseinserumcalciumby0.8mg/dl(calciumboundtoAlbumin)Metabolicactive:ionizedformisnormal.Thereforenodeficiencymanifestation.VIAlkalosis&Acidosis:Alkalosisà favorsCalcium+protein:decreaseionizedformAcidosisàFavorsionizationofCalciumVIIKidneyThreshold:Kidneythreshold:10mg/dlCalciumintravenousinjectionà urinaryexcretionCalcium(Ca²⁺) ,Magnesium(Mg ²⁺) ,proton(H ⁺) preventstetany.
SerumcalciumlevelsHypercalcemia :>11mg/dl(NormalserumCalcium:9-11mg/dl)Causes:a) Hyperparathyroidism-MAJORCAUSEb) Metastaticcarcinomaofbonec) Hypervitaminosis D(VitaminDtoxicity)d) Lithiumtherapye) ThiazidediureticsMINORCAUSESf) Pagetdiseaseg) Multiplemyeloma
Kidneystones:acauseofrenaldysfunction
HyperparathyroidismMAJORCAUSEofHypercalcemia :>11mg/dl(NormalserumCalcium:9-11mg/dl)Causes :a) Parathyroid–Adenomab)EctopicsecretingtumorsSigns&Symptoms:1. Osteoporosis2. Punchoutareasofbonereabsorption3. Calciumexcretioninurine(Calciuria )4. Calciumprecipitateinurineà urinarycalculi5. Retentionofchlorideà Hyperchloremic acidosisà polyuria(increasedsolutes
inurine)6. Anorxia ,mucle weakness,shortQ-TintervalininECG7. Ectopiccalciumineal tissue,pancreas,arterialwall,muscletissue,ossificans )
Serumcalciumlevelsv Hypocalcemia :<8.8mg/dl(NormalserumCalcium:9-11mg/dl)Tetany:<7.5mg/dlMildtremors:8.5mg/dlqCauses1.Tetany:2.Fanconi’s syndrome3.Pseudohypothyroididism4.Renaltubularacidosis5.Renaltubularavidosis
Tetany-1q CausesofTetany:1. DecreaseinDietaryintake2. Surgicalremovalofparathyroidgland3. AutoimmunediseaseqSigns&symptoms:a) Neuro- muscularirritabilityb) Carppedalspasmc) Laryngismusà DEATHd) Chvostek’ssignà tappingof5th cranialnerve,facialcontractione) Trousseau’ssignà inflammationofbloodpressurecausescarpopedal
spasmf) IncreasesQ-TintervalinECG
SignsandSymptomsofTETANY
Trousseau’ssignindicatecalciumdeficiency
Chvostek’s sign indicatecalciumdeficiency
Tetany-2q LABORATORYTESTS/FINDINGS:1. Serumcalcium↓2. Seruminorganicphosphorous↑3. UrinaryexcretionofCalcium&inorganicphosphorous↓qTreatment:IntravenousinjectionofCalciumsalt
Hypocalcemiaq Fanconi’s syndrome1. Glycosuria2. Aminoaciduria3. DecreaseSERUMCalcium&increaseinorganicphosphorous4. Hypercalciuria
Hypocalcemiaq.Pseudohypothyroidisma) Xlinkeddominantconditionb) PTHlevelsnormalc) LackofendorganresponsetoPTHd) Hypocalcemia,Hypophosphatemiae) Shorteningof4th &5th metacarpal&metatarsalbones
HypocalcemiaqRenaltubularacidosisa. Inheritedabnormalityb. H⁺productiondeficient(urinarypH>5)c. Lossofbicarbonate,SodiumPotassium,Calcium,Magnesium(↓Serum
levelsofHCO₃⁻,Na⁺,K⁺ ,Ca ⁺ ²,Mg⁺² )d. RenalRicketsà Bonesimillar toRickets
HypocalcemiaqVitaminDdeficiency(notTetany)-Rickets–marginaldecreaseinserumCalciumlevels,MedullaryThyroidcarcinoma,dietarydeficiency,Malabsorption,SerumCalcitoninincreases
qMilddecreaseinserumCalciumobservedinrenaldiseases(decreaseCalcitoninformation)
LongQT
ComparisonofCalcitonin&Calcitriol
Calcitonin
Peptidehormone
Synthesis-bythyroidgland
Action—decreaseserumcalciumlevel
Calcitriol
Steroidhormone
Synthesisbyskin,Liver,Kidney
Action–increaseserum
levels
Factorsregulatingbloodcalciumlevels
DecreaseinSerumCALCIUMCalcitonin inhibited,PTHstimulated
Bonedemineralization(influxofCALCIUMinbone
IncreaseinSerumCALCIUMIncreasedCalcitoninsecretion,
PTHinhibitedBonemineralization(outfluxof
CALCIUMfrombone)
Bonemineralization&demineralization• Bonemineralization&demineralizationneed
Calcium
Phosphorous
Proteins
Vitamins:A,D,C
Enzyme:Alkalinephosphatase
Hormones:PTH,Calcitonin,sexhormones
Normalrenalfunction(forsynthesisofCalcitriol)
Osteoblast(formineralization)/&osteoclast(fordemineralization)
ProcessofBonemineralizationVitaminDà activityofAlkalinephosphataseincreases
Calcium&Phosphorousliberationfromsubstrate
Ionicconcentrationof(calciumxphosphorous)increased
Calcium&phosphorousgetdeposited
Hydroxyapatiteformation
Dynamicequilibriumwithserumcalcium
Bonereservoir&matrixoftriplestrandedCollagenmoleculeparticipate
Osteoporosisa) Age30yearsàMaximumcalciumcontentinboneb) Age45-50yearsà Calciumabsorptiondecreases,calciumexcretion
increases(negativebalance)à demineralization(OSTEOPENIA )c) Age60years à
AbsorptionofvitaminD↓
Androgen&Estrogen↓
SerumCalcium↓
Reducedbonestregth
Repeatedbonefracturesà OSTEOPOROSIS
OSTEOPOROSIS :WOMEN>MEN,INDIANS>WESTERNERS
Osteoporosis-bonedemineralization
Osteoporosis-bonedemineralization
RoleofCalmodulin kinaseinCalciumMetabolism