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