calcium & phosphorus anish

8/7/2019 CALCIUM & PHOSPHORUS ANISH

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Disorders of Calcium andDisorders of Calcium and

Phosphate MetabolismPhosphate Metabolism

ANISH JOSHIANISH JOSHI


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Major Mediators of Calcium andMajor Mediators of Calcium andPhosphate BalancePhosphate Balance

Parathyroid hormone (PTH)Parathyroid hormone (PTH)

Calcitriol (active form of vitamin DCalcitriol (active form of vitamin D33))


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Role of PTHRole of PTH

StimulatesStimulates renal reabsorption ofrenal reabsorption ofcalciumcalcium

InhibitsInhibits renal reabsorption ofrenal reabsorption ofphosphatephosphate

Stimulates bone resorptionStimulates bone resorption Inhibits bone formation and mineralizationInhibits bone formation and mineralization

Stimulates synthesis of calcitriolStimulates synthesis of calcitriol

Net effect of PTHNet effect of PTH serum calcium serum calcium

serum phosphate serum phosphate


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Regulation of PTHRegulation of PTH

LowLow serum [Caserum [Ca+2+2]] IncreasedIncreased PTH secretionPTH secretion

High serum [CaHigh serum [Ca+2+2]] Decreased PTH secretionDecreased PTH secretion


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Role of CalcitriolRole of Calcitriol

StimulatesStimulates GI absorptionGI absorption of both calciumof both calciumand phosphateand phosphate

StimulatesStimulates renal reabsorptionrenal reabsorption of bothof bothcalcium and phosphatecalcium and phosphate

StimulatesStimulates bone resorptionbone resorption

Net effect of calcitriolNet effect of calcitriol serum calcium serum calcium

serum phosphate serum phosphate


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Regulation of CalcitriolRegulation of Calcitriol


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Overview of CalciumOverview of Calcium--Phosphate RegulationPhosphate Regulation


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CaCa++++

Most abundant cationMost abundant cation

1.2 to 1.4 kg of calcium1.2 to 1.4 kg of calcium

99 % in bone, 1% in cells of soft tissue,99 % in bone, 1% in cells of soft tissue,0.15 % in ECF0.15 % in ECF


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Different Forms of CalciumDifferent Forms of Calcium

At any one time, most of the calcium in the body exists as theAt any one time, most of the calcium in the body exists as themineralmineral hydroxyapatitehydroxyapatite, Ca, Ca1010(PO(PO44))66(OH)(OH)22..

Calcium in the plasma:Calcium in the plasma:

45% in ionized form (the physiologically active form)45% in ionized form (the physiologically active form)45% bound to proteins (predominantly albumin)45% bound to proteins (predominantly albumin)

10% complexed with anions (citrate, sulfate,10% complexed with anions (citrate, sulfate,phosphate)phosphate)

To estimate the physiologic levels of ionized calcium in statesTo estimate the physiologic levels of ionized calcium in statesof hypoalbuminemia:of hypoalbuminemia:

[Ca[Ca+2+2]]CorrectedCorrected = [Ca= [Ca+2+2]]MeasuredMeasured + [ 0.8 (4+ [ 0.8 (4 Albumin) ]Albumin) ]


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ValuesValues

Normal serum calcium levels areNormal serum calcium levels are 8 to 108 to 10mg/dLmg/dL ((2.0 to 2.52.0 to 2.5 mmol/L)mmol/L)

NormalNormal ionizedionizedcalcium levels arecalcium levels are 4 to 5.64 to 5.6

mg /dLmg /dL ((1 to 1.41 to 1.4 mmol per L)mmol per L)

HypercalcemiaHypercalcemia is defined as total serumis defined as total serum

calciumcalcium >> 10.510.5 mg/dlmg/dl(>(>2.52.5 m mol/L ) orm mol/L ) or

ionized serum calciumionized serum calcium >> 5.65.6 mg/dlmg/dl ( >( >1.41.4 mmmol/L )mol/L )


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Values..Values..

Severe hypercalemiaSevere hypercalemia is defined as total serumis defined as total serumcalciumcalcium > 14 mg/dl> 14 mg/dl (> 3.5 mmol/L)(> 3.5 mmol/L)

HypercalcemiccrisesHypercalcemiccrises is present whenis present when severesevere

neurologicalsymptomsneurologicalsymptoms oror cardiaccardiacarrhythmiasarrhythmias are present in a patientare present in a patientwith awith aserum calcium > 14 mg/dlserum calcium > 14 mg/dl (> 3.5 mmol/L)(> 3.5 mmol/L) ororwhen thewhen the serum calcium is > 16 mg/dlserum calcium is > 16 mg/dl (> 4(> 4mmol/L)mmol/L)


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Overview of Calcium BalanceOverview of Calcium Balance


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Etiologies ofEtiologies ofHypercalcemiaHypercalcemia

Increased GI AbsorptionIncreased GI AbsorptionMilkMilk--alkali syndromealkali syndromeElevated calcitriolElevated calcitriol

Vitamin D excessVitamin D excessExcessive dietary intakeExcessive dietary intakeGranuomatous diseasesGranuomatous diseases

Elevated PTHElevated PTHHypophosphatemiaHypophosphatemia

Increased Loss From BoneIncreased Loss From BoneIncreased net bone resorptionIncreased net bone resorption

Elevated PTHElevated PTHHyperparathyroidism( 1Hyperparathyroidism( 1OO 22OO))

MalignancyMalignancyOsteolytic metastasesOsteolytic metastasesPTHrP secreting tumorPTHrP secreting tumor

Increased bone turnoverIncreased bone turnoverPagets disease of bonePagets disease of boneHyperthyroidismHyperthyroidism

Decreased Bone Mineralization

Elevated PTH

Aluminum toxicity

Decreased Urinary Excretion

Thiazide diuretics

Elevated calcitriol

Elevated PTH

Familial Hypocalciurichypercalcemia

Acure Adrenal

insufficiency

Li, Vitamin A


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DifferentialDiagnosisDifferentialDiagnosis

HyperparathyroidismHyperparathyroidism : most common: most common

MalignancyMalignancy : second most common: second most common ,,((severe hypercalcemia and hypercalcemic crises)severe hypercalcemia and hypercalcemic crises)

squamous carcinoma of the lungsquamous carcinoma of the lung breastbreast

cancercancer renal cell cancer ,head and neckrenal cell cancer ,head and necksquamous cancersquamous cancer multiplemultiplemyeloma ,hematogenous and lymphomatousmyeloma ,hematogenous and lymphomatous

malignanciesmalignancies Together they account forTogether they account for > 90%> 90% of casesof cases


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Primary hyperparathyroidism is usuallyPrimary hyperparathyroidism is usuallysecondary to a parathyroidsecondary to a parathyroid adenoma (85%),adenoma (85%),parathyroidparathyroid hyperplasia (15%)hyperplasia (15%) and rarely dueand rarely due

to a parathyroidto a parathyroid carcinoma (< 1%)carcinoma (< 1%) Primary hyperparathyroidismPrimary hyperparathyroidism rarelyrarely

produces severe hypercalcemia and/or aproduces severe hypercalcemia and/or ahypercalcemic criseshypercalcemic crises, unless renal insufficiency, unless renal insufficiency+/+/-- dehydration is superimposed on thedehydration is superimposed on theunderlying hyperparathyroidismunderlying hyperparathyroidism


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MalignancyMalignancy accounts for theaccounts for the majority ofmajority ofcasescases of severe hypercalcemia andof severe hypercalcemia andhypercalcemic criseshypercalcemic crises

MalignancyMalignancy increases osteoclastic activityincreases osteoclastic activity bybytwo mechanismstwo mechanisms -- production ofproduction ofa PTHa PTH--likelikesubstance called PTHsubstance called PTH--related protein =related protein = PTHrPPTHrP((humoral hypercalcemia ofmalignancyhumoral hypercalcemia ofmalignancy --HHMHHM -- 80%80% of cases) and due to localof cases) and due to local

osteoclastic activityosteoclastic activity secondary to bonesecondary to bonemetastasis (metastasis (local osteolytic hypercalcemialocal osteolytic hypercalcemiaofmalignancyofmalignancy -- 20%20% of cases)of cases)


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Granulomatousdisease :Granulomatousdisease :

sarcoidosissarcoidosistuberculosistuberculosisleprosyleprosy berylliosisberylliosis

histoplasmosis/coccidiomycosishistoplasmosis/coccidiomycosis

disseminated candidiasis/cryptococcosisdisseminated candidiasis/cryptococcosis

NonNon--parathyroidendocrinedisordersparathyroidendocrinedisorders ::

HyperthyroidismHyperthyroidism

adrenal insufficiencyadrenal insufficiencypheochromocytomapheochromocytoma


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ClinicalManifestationsClinicalManifestations

Hypercalcemia leads toHypercalcemia leads to hyperpolarizationhyperpolarization ofofcell membranescell membranes

Patients with levels of calciumPatients with levels of calcium between 10.5between 10.5

and 12 mg /dl can be asymptomaticand 12 mg /dl can be asymptomatic..

When the serum calcium level rises above thisWhen the serum calcium level rises above thisstage, multisystem manifestations becomestage, multisystem manifestations becomeapparentapparent


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TreatmentTreatment

IncreaserenalcalciumexcretionIncreaserenalcalciumexcretion

Saline/fluid hydration :Saline/fluid hydration :

4 to 6 L IV 0.9 % NS daily for 1 to 3 days4 to 6 L IV 0.9 % NS daily for 1 to 3 days

Diuretics: Frusemide. Avoid thiazidesDiuretics: Frusemide. Avoid thiazides

Inhibition ofboneresorptionInhibition ofboneresorption

Biphosphonates :Biphosphonates :

Pamidronate (Aredia), 60 to 90 mg IVPamidronate (Aredia), 60 to 90 mg IV over 4 hours.over 4 hours.

Maximal effect at2Maximal effect at2--3 days. Lasts for several weeks3 days. Lasts for several weeks


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TreatmentTreatment

Gallium nitrate :Gallium nitrate :

100 to 200 mg per m100 to 200 mg per m22 IV over 24 hours for 5 daysIV over 24 hours for 5 days

Not used due to nephrotoxicityNot used due to nephrotoxicity Inh

ibitsabs

orp

tion &

vitami

n Dcon

version toInh

ibitsabs

orp

tion &

vitami

n Dcon

version to

calcitriolcalcitriol

GlucocorticoidsGlucocorticoids ::

Hydrocortisone, 200 mg IV daily for 3 daysHydrocortisone, 200 mg IV daily for 3 days Ketoconazole & Hydroxyl chloroquineKetoconazole & Hydroxyl chloroquine

Oral phosphatesOral phosphates

HemodialysisHemodialysis ::

usedin patients with renalfailureusedin patients with renalfailure


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TreatmentTreatment

ClinicalindicationsforClinicalindicationsforsurgerysurgeryin patientsin patientswith primary hyperparathyroidismwith primary hyperparathyroidism ::

1. S1. Significant symptoms of life threatening hypercalcemiaignificant symptoms of life threatening hypercalcemia2. Nephrolithiasis2. Nephrolithiasis3. Decreased bone mass (> 2 standard deviations below3. Decreased bone mass (> 2 standard deviations belowmean for age)mean for age)

4. Serum calcium > 12mg/dl4. Serum calcium > 12mg/dl5. Age < 50 years5. Age < 50 years

6. Infeasibility of long6. Infeasibility of long--term followterm follow--upup7. Reduced creatinine clearance ( 400 mg)


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TreatmentTreatment

MedicalmanagementMedicalmanagement ofprimaryofprimaryhyperparathyroidismhyperparathyroidism ::

------medical therapy with drugs have not been shown tomedical therapy with drugs have not been shown to

affect the eventual outcomeaffect the eventual outcome------Oestrogens (premarin 1.25mg/day)Oestrogens (premarin 1.25mg/day) preserve bone masspreserve bone massin postin post--menopausal femalesmenopausal females

------WellWell--hydratedhydrated by drinking 2by drinking 2 -- 3 litres of fluid, and 83 litres of fluid, and 8 -- 1010g of salt dailyg of salt daily

---- Dietary restrictionDietary restriction of calcium isof calcium is not necessarynot necessary , thiazide, thiazidediuretics must not be useddiuretics must not be used

------Oral phosphateOral phosphate should only be used if symptomaticshould only be used if symptomatichypercalcemia cannot be corrected surgicallyhypercalcemia cannot be corrected surgically


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TreatmentTreatment

MedicalmanagementMedicalmanagement ofofhypercalcemiainhypercalcemiain cancercancer patientspatients ::

------ 22 -- 3 litres per day + 83 litres per day + 8 -- 10g of salt/day10g of salt/day

------ Pamridonate can be used every few weeks toPamridonate can be used every few weeks tokeep the serum calcium in the normal rangekeep the serum calcium in the normal range

------ Prednisone (20Prednisone (20 -- 50 mg bid) is only useful in50 mg bid) is only useful in

certain malignancies eg. multiple myeloma andcertain malignancies eg. multiple myeloma andcertain lymphomascertain lymphomas


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TreatmentTreatment

Medicalmanagement ofMedicalmanagement ofotherotherdisordersdisorders ::

----prednisone and lowprednisone and low--calcium diet ( < 400calcium diet ( < 400mg/day )mg/day )

Medicalmanagement ofMedicalmanagement of

hypercalcemiainhypercalcemiain sarcoidosissarcoidosis ::

----a low dose of prednisone (10a low dose of prednisone (10 -- 20 mg/day) is20 mg/day) isusually adequateusually adequate


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HypocalcemiaHypocalcemia


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Etiologies ofEtiologies ofHypocalcemiaHypocalcemia

Decreased GI AbsorptionDecreased GI Absorption

Poor dietary intake of calciumPoor dietary intake of calcium

Impaired absorption of calciumImpaired absorption of calcium

Vitamin D deficiencyVitamin D deficiency

Poor dietary intake of vitaminPoor dietary intake of vitaminDD

Vit D dependent ricketsVit D dependent ricketsMalabsorption syndromesMalabsorption syndromes

Decreased conversion of vit. D toDecreased conversion of vit. D tocalcitriolcalcitriol

Liver failureLiver failure

Renal failureRenal failure

Low PTHLow PTH

HyperphosphatemiaHyperphosphatemia

Decreased Bone Resorption/IncreasedDecreased Bone Resorption/IncreasedMineralizationMineralization

Low PTH (hypoparathyroidism)Low PTH (hypoparathyroidism)

PTH resistance (pseudohypoparathyroidism)PTH resistance (pseudohypoparathyroidism)

Vitamin D deficiency / low calcitriolVitamin D deficiency / low calcitriol

Hungry bones syndromeHungry bones syndrome

Osteoblastic metastasesOsteoblastic metastasesHypomagnesemiaHypomagnesemia

Increased Urinary Excretion

Low PTH

Thyroidectomy

I131 treatment

Autoimmune hypoparathyroidism

PTH resistance

Vitamin D deficiency / low calcitriol

Hypoalbuminemia

Misc Fat embolism, Cardiopul. bypass

Met or resp. alkalosis

Sepsis, Toxic shock syndrome

Ac. Pancreatitis, Burns

Massive citrated BT

Severe Acute hyperphosphatemia

Tumorlysis synd

ARF

Rhabdomyolysis


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HYPOCALCEMIA: SIGNS ANDHYPOCALCEMIA: SIGNS ANDSYMPTOMSSYMPTOMS

NEUROMUSCULARNEUROMUSCULAR:: INVOLUNTARY MUSCLE CONTRACTIONINVOLUNTARY MUSCLE CONTRACTION(TETANY), 7(TETANY), 7THTH CRANIAL NERVE EXCITABILITY (CHVOSTEKS SIGN),CRANIAL NERVE EXCITABILITY (CHVOSTEKS SIGN),NUMBNESS AND TINGLING IN FACE, HANDS, AND FEET,NUMBNESS AND TINGLING IN FACE, HANDS, AND FEET,TROUSSEAUS SIGN, LARYNGOSPASM.TROUSSEAUS SIGN, LARYNGOSPASM.

CNSCNS:: IRRITABILITY, SEIZURES, PERSONALITY CHANGE,IRRITABILITY, SEIZURES, PERSONALITY CHANGE,IMPAIRED COGNITION, CALCIFICATION OF BASAL GANGLIA.IMPAIRED COGNITION, CALCIFICATION OF BASAL GANGLIA.

CARDIOVASCULARCARDIOVASCULAR:: QT PROLONGATION ON ECG, IN THEQT PROLONGATION ON ECG, IN THEEXTREME, ELECTROMECHANICAL DISSOCIATION MAY OCCUR,EXTREME, ELECTROMECHANICAL DISSOCIATION MAY OCCUR,

REVERSIBLE HEART FAILURE, HYPOTENSION, VASODILATATION.REVERSIBLE HEART FAILURE, HYPOTENSION, VASODILATATION.


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Mild hypocalcaemia

No treatment (investigate PTH, PO4, 25-OHD,Mg, ttg, ALP) Treat underlying causes Oral Calcium 500 mg 2 to 6 tabs daily

Oral Calcium and Vitamin D3(Calcitriol) 1000mg and 800 iu daily

Fastest onset,shortest duration of actionDisadvantage- higher cost

Vitamin D(ergocalciferol) Low cost, long half life and storage in fat Disadvantage- vitamin D intoxication

several weeks to achieve full

effect


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Severe hypocalcaemia

Calcium gluconate 10% (90 mg/10 ml)- 10 ml slow i.v.bolus

Calcium gluconate 10% - 60 ml infusion in 500 ml ofD5 over 24 hours

If iv Ca does not relieve tetany rule out and correct

hypomagnesemia. Start oral alfacalcidol 1- 2 mcg daily

Monitor calcium at least daily and adjust / await Ix


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PHOSPHATE HOMEOSTASISPHOSPHATE HOMEOSTASIS

Essential element.Essential element.

Pi containing compounds have imp. roles in,Pi containing compounds have imp. roles in,

1.1. Cell structureCell structure(cell membrane and nucleic(cell membrane and nucleic

acids),acids),

2.2. Cellular metabolismCellular metabolism(generation of ATP),(generation of ATP),

3.3. Regulation of subcellular processesRegulation of subcellular processes

((phosphorylation of key enzymesphosphorylation of key enzymes),),4.4. Maintenance of acidMaintenance of acidbase homeostasisbase homeostasis

((urinary bufferingurinary buffering).).


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Normal ValuesNormal Values

In the average adult, total body phosphorusIn the average adult, total body phosphorus

content iscontent is 700 g700 g,,

Distribution:Distribution:

1.1. Bone and teethBone and teeth 85% , 14%85% , 14%2.2. Soft tissuesSoft tissues 14%,14%,

3.3. ECFECF -- 1%.1%.

Daily IntakeDaily Intake -- 8008001,400 mg/day1,400 mg/day..

NormalNormal-- 2.52.54.5 mg/dl4.5 mg/dl


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Overview of Phosphate BalanceOverview of Phosphate Balance

High risk groups


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The serum assay measuresThe serum assay measures inorganicinorganic

orthophosphatesorthophosphates, of which 10% are bound to, of which 10% are bound to

protein, 5% are complexed with Ca & Mg, &protein, 5% are complexed with Ca & Mg, & 85%85%

are Hare H22POPO44 and HPOand HPO44 22.. In theory, there are potentially four species ofIn theory, there are potentially four species of

free orthophosphate that can be measuredfree orthophosphate that can be measured

((HH22POPO44 ,, HPOHPO44

22,, HH33POPO44and POand PO44

33),),

At physiologic pH, HAt physiologic pH, H33POPO44 and POand PO44

33

concentrations are negligible.concentrations are negligible.


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Circadian rhythmCircadian rhythm

1.1. Rapidly decreasingRapidly decreasing in thein the early morningearly morning, reaching a, reaching a

nadir of3.3nadir of3.3 0.3 mg/dl at 11a.m.,0.3 mg/dl at 11a.m.,

2.2. Increasing to aIncreasing to aplateau at 4 p.mplateau at 4 p.m., and., and3.3. Peaking atPeaking at4.64.6 0.2 mg/dl0.2 mg/dl between 1a.m.& 3 a.mbetween 1a.m.& 3 a.m..

So measured in fasting stateSo measured in fasting state


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In urine, Pi is an effective buffer, a function of itsIn urine, Pi is an effective buffer, a function of its

relatively high tubular conc.& pKa of 6.8, whichrelatively high tubular conc.& pKa of 6.8, which

is close to the pH of urine under normalis close to the pH of urine under normal

conditions.conditions. Maintaining normal phosphorus concentrationsMaintaining normal phosphorus concentrations

is essential for optimal cellular function.is essential for optimal cellular function.


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TheThe kidney & the small int.kidney & the small int. are the main organsare the main organsthat maintain Pi homeostasis.that maintain Pi homeostasis.

Intestinal phosphorus absorption occurs throughIntestinal phosphorus absorption occurs throughboth cellular and paracellular pathways.both cellular and paracellular pathways.

Transepithelial phosphate transport across intactTransepithelial phosphate transport across intactint. epithelium is driven by anint. epithelium is driven by an active Naactive Nadependent processdependent process..

In proximal tubule cells and enterocytes,In proximal tubule cells and enterocytes, type IItype II

sodiumsodiumphosphate cotransporters (NaPiphosphate cotransporters (NaPi--II)II) areareexpressed in the apical membrane;expressed in the apical membrane;

Their activity limits transepithelial phosphateTheir activity limits transepithelial phosphatetransport.transport.


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Clinical featuresClinical features

AcuteAcute Muscular: Rhabdomyolysis, Proximal muscleMuscular: Rhabdomyolysis, Proximal muscle

weakness, Impaired diaphramgatic function,weakness, Impaired diaphramgatic function,Respiratory failure, difficulty in weaning fromRespiratory failure, difficulty in weaning from

ventilatorventilator CVS: CHF, CardiomyopathyCVS: CHF, Cardiomyopathy

CNS: Paresthesias, Dysarthria, Confusion, SeizuresCNS: Paresthesias, Dysarthria, Confusion, Seizures& coma& coma

Haemat: Lt. shift of OHaemat: Lt. shift of O22 dissociation curve, haemolysisdissociation curve, haemolysis& tissue hypoxia, Impaired phagocytosis && tissue hypoxia, Impaired phagocytosis &opsonization leading to increased chance of bacterialopsonization leading to increased chance of bacterial& fungal infections& fungal infections

ChronicChronic Rickets (Children) & Osteomalacia (Adults)Rickets (Children) & Osteomalacia (Adults)


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Mod.(1

.0Mod.(1

.02.5 mg/dl) & severe (

calcium & phosphorus anish

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