A New Perspective on Hypocalcemia

Taipei Veterans General Hospital, Hsin-Chu branch

Director of Nephrology

Steve Chen

Ca

CalciumCalcium

Reference Range:8.8 – 10.3 mg/L

CalciumCalcium

Hypocalcemia is total calcium < 8.5 mg/dl

CalciumCalcium

Hypocalcemia is ionized calcium < 2.125 mmol/L

Pseudo-hypocalcemiaPseudo-hypocalcemia

Transfer sample from tubes containing K-EDTA

Sample stored at RT for extended time Vasovagal episode Usually accompanied with

pseudohyperkalemia

Etiology of Etiology of Hypocalcemia(1)Hypocalcemia(1)

– Common CausesCommon CausesSShockhockSSepsisepsisRRenal failureenal failurePPancreatitisancreatitis

Etiology of Etiology of Hypocalcemia(2)Hypocalcemia(2)– MalignancyMalignancy– Endocrine Endocrine

HypoparathyroidismHypoparathyroidism Vitamin D deficiency Vitamin D deficiency

– DrugsDrugs Cimetidine, Phosphates, Dilantin, Phenobarbital,

Glucagon, Aminoglycosides, Cisplatin, Heparin, Theophylline, Protamine, Norepinephrine, Loop diuretics, Glucocorticoids, Magnesium Sulfate, Nitroprusside

Symptoms & signs of Symptoms & signs of Hypocalcemia Hypocalcemia

Clinical Features(1)Clinical Features(1)– NeurologicalNeurological

Circumoral & digital paresthesiasCircumoral & digital paresthesias TetanyTetany Chvostek signChvostek sign Trousseau signTrousseau sign Impaired memory, confusionImpaired memory, confusion HallucinationsHallucinations, dementia, seizures, dementia, seizures

Symptoms & signs of Symptoms & signs of HypocalcemiaHypocalcemia

Clinical Features (3) Clinical Features (3) - - GI: steatorrheaGI: steatorrhea– MuscularMuscular

Spasms, cramps, weaknessSpasms, cramps, weakness– DermatologicDermatologic

HyperpigmentationHyperpigmentation Coarse, brittle hairCoarse, brittle hair Dry, scaly skinDry, scaly skin

Symptoms & signs of Symptoms & signs of HypocalcemiaHypocalcemia

Clinical Features (4)Clinical Features (4)– CardiovascularCardiovascular

Heart failure; HypotentionHeart failure; Hypotention VasoconstrictionVasoconstriction EKG abnormalitiesEKG abnormalities

– Prolonged QTProlonged QT– SkeletalSkeletal

OsteodystrophyOsteodystrophy RicketsRickets OsteomalaciaOsteomalacia

SCa < 8.5 mg/dl

SPi < 3.5 mg/dl SPi > 3.5 mg/dl

FECa

Renal loss25(OH)D↓ VD deficiency25(OH)D: N/1,25(OH)2D↓ VD dependent rickets: Type I25(OH)D: N/1,25(OH)2D↑ VD dependent rickets: Type II

HighLow

GFR

PTH

Mg

Low

Low N/↑

Pseudo-hypo-parathyroidism

Low N

Primary/Secondary hypoparathyroidism

Mg related hypoparathyroidims

CRF

FE of electolyteFE of electolyteFE of K >6.5%→ renal K wasting in hypoKFE of Pi >5.0% → renal Pi wasting in hypoPiFE of Mg>2.5%→ renal Mg wasting

in hypoMgFE of Na> 1.0% → renal Na wasting

in hypoNaFE of Ca>3.0% → renal Ca wasting

in hypoCa

Hypocalcemia: causesHypocalcemia: causesLoss of circulating free calcium:

extravascular deposition: hyperphosphatemia; renal failure; acute pancreatitis; osteoblastic metastasis; hyngry bones syndrome intravascular binding: citrate, lactate, foscarnet, EDTA, acute respiratory alkalosis(↑Ca-albumin)

Hypoparathyroidism: S/P PTX, thyroidectomy, or radical neck surgery pseudohypoparathyroidism; idiopathic Hypomagnesemia; severe hypermagnesemia

Vitamin D deficiency

Hungry bones syndromeHungry bones syndrome Severe form:

Profound hypocalcemia+↓Mg+↓Pi : S/P PTX for severe osteodystrophy

Mild form: S/P thyrotoxicosis accelerated bone formation in leukemia osteoblastic metastasis early healing of rickets or osteomalacia

Calcitriol: 2 ～ 3μg/D(initial dose) with rapid reduction after normocalcemia

Hypocalcemia in acute Hypocalcemia in acute pancreatitis pancreatitis

Extravascular depositionGlucagon-stimulated calcitonin releaseInadequate PTH secretion

HypoparathyroidismHypoparathyroidism

S/P OP: permanent or intermittent Hypomagnesemia(SMg<1mg/dl) in

malabsorption or chronic alcoholism Severe hypermagnesemia in toxemia of

pregnancy( SMg> 6mg/dl) Pseudo type1: Ia(AD, G-protein) Ib(↓receptor)Pseudo type II: ↓cAMP-dependent PK

Vitamin D deficiencyVitamin D deficiencyReduced VD intake or production:

bedridden state(no sun exposure) steatorrhea or malabsorption

Reduced availability of calcifediol(hepatic): severe liver disease use of Dilantin/phenobarbital nephrotic syndrome(↓VD binding protein)

Reduced production of calcitriol(renal): chronic renal failure VD-dependent ricket

Hypocalcemia in sepsisHypocalcemia in sepsis

Inadequate PTH or end-organ resistanceInadequate VDHypomagnesemia Glucagon-induced calcitonin release

Principles of treatmentPrinciples of treatment Symptomatic hypocalcemia – emergency 10 ml of 10% calcium gluconate IV over 10

minutes. Iv calcium should not be given with

bicarbonate or phosphate containing solution

Serial calcium measurements

Correction of co-existing alkalosis

Calcium suppy in long term

IV calcium supplyIV calcium supplySymptomatic hypocalcemia (Sca<5.6mg/dl) :

heart failure, hypotention, bradycardia convulsions, tetany, paresthesias

1 ～ 2 ampules(90mg/A), 10% Ca gluconate in 5 ～10ml, 5% dextrose, IVF for 5 ～ 10minutes 10 ampules, Ca gluconate in 1L, 5% dextrose, IVF: 50ml/Hr ( 45mg,calcium/Hr)

Calcium dose: 15mg/Kg IVF for 6 hrCalcium space: 50 ～ 75%(?)

Adjuvant therapyAdjuvant therapy

Magnesium supply: Hypocalcemia+Normal renal function+Normal DTR

10% MgSo4, 2G, IVF for 10 minutes 10% MgSo4, 1G/100cc,fluid/Hr

Oral calcium and calcitriol( 0.5 ～ 1.0μg/D) should initiated early

PO calcium supply PO calcium supply Calcium: 2 ～ 4G/DVitamin D indicated if insufficient response

PO Calcium preparationPO Calcium preparation

mg/Tb Ca,mg/Tb

CaCO3 500 200( 40% )

Ca gluconate 1000 90( 8% )

Ca lactate 300 60( 12% )

Things to rememberThings to remember

– Treat the patient, not the lab valueTreat the patient, not the lab value– Rate of correction should mirror rate of Rate of correction should mirror rate of

changechange– Correct in orderly fashionCorrect in orderly fashion

1. Volume1. Volume 2. pH2. pH 3. Potassium, Calcium, Magnesium3. Potassium, Calcium, Magnesium 4. Sodium and Chloride4. Sodium and Chloride

– Consider impact of interventions overallConsider impact of interventions overall

Calcium handling in kidneyCalcium handling in kidney PCT: 60 ～ 65% of filtrate by para-cellular path THAL: 20% of filtrate by para-cellular path

paracellin-1 for Mg&Ca reabsortion Simon et al, Science 1999

DN: 10 ～ 15% by trans-cellular pathway ECaC1, apical: VD ↑; lower pH ↓ Calbindin-D 28k: VD ↑; estrogen↑; CsA↓ NCX1,basolateral: 70% PMCA1b,basolateral: 30%

Cl channel: PTH, Thiazide

TRPV5 cell surface abundance TRPV5 cell surface abundance

Factors Cell surface abundance Proposed mode of action Klotho + Modification channel glycosylation Tissue kallikrein + PKC mediated channel phosphorylation

Acid pH - Dynamic plasma membrane traffickingCa - Channel recycling

Mg ND NA

PIP2 ND NA

WNK4 + ND (familial hyperkalemic HTN/hypercalciuria)ND: not determined; NA: not applicable +, increase; -, decrease; =, no effect WNK, With-No-Lysine(K): serine/threonine protein kinases

TRPV5 single channel activityTRPV5 single channel activityFactors Single channel activity Proposed mode of action Klotho ND NA Tissue kallikrein ND NA

Acid pH - Proton binding to channel pH sensorsCa - Feedback inhibition via channel C tail

Mg - Conformational change channel via Mg bindingPIP2 + Stabilization channel open conformation

WNK4 = ND: not determined; NA: not applicable Kloth: anti-aging hormone

Modes of TRPV5 regulationModes of TRPV5 regulation

ECaC1 homologuesECaC1 homologuesMuller et al, NDT 2001Muller et al, NDT 2001

Sequence similarities

tissue distribution

Chromosome 7q35

hECaC1 80% Kidney>GI Evolution gene duplication

hCaT1 80% GI>kidney hECaC2

TRP V 5 knockout mice modelTRP V 5 knockout mice model

Transient receptor potential channels (TRP): Gate-keeper proteins

TRP V5 in kidney: ECaC 1 TRP V6 Hypercalciuria Diuresis: CaSR, apical in principal cells + Ca in lumen ﹡

→AQP2 Acid urine: CaSR, apical in intercalated cells + Ca in

lumen → H+APTase Hyperphosphaturia

Rene Bindels: Radboud University Nijmegen Medical Center, Netherlands

Hypercalciuric stone disease: XLHypercalciuric stone disease: XLO Devuyst and Y Prison: KI 2008(Belgium)O Devuyst and Y Prison: KI 2008(Belgium)

Dent’s disease: CLCN5/CLC-5/ Cl/H exchanger PT/TAL/IC α

Renal:Trafficking defect: endocytosisPT dysfunction: Fanconi syndromeNephrocalcinosis, stones Impaired urine acidificationRenal failure

Extra-renal:Rickets

Lowe’s diseaseOCRL/OCRL1/ Phosphatidylinositol 4,5-biphosphate 5-phosphatasePTRenal:PT dysfunction: Fanconi syndrome Proximal RTANephrocalcinosis, stonesExtra-renal:Mental retardation, growth delayCataract, rickets, cryptorchidism Neuromuscular/behavior abnormality

Hypercalciuric stone disease: ADHypercalciuric stone disease: ADO Devuyst and Y Prison: KI 2008(Belgium)O Devuyst and Y Prison: KI 2008(Belgium)

AD Hypocalcemia ( Bartter syndrome V)CASR/CaSR/ calcium sensing receptorPT/TAL/DCT/CDRenal: gain-of-function Low serum PTHHypocalcemia, Hypercalciuria Nephrocalcinosis, stones Salt-losing nephropathy; Hypokalemia (CaSR→ ROMK↓)Extra-renal: basal ganglia calcifications, seizures

Distal RTA (RTA I)SLC4A1/ AE1/ Cl/HCO3 exchangerICα Renal:Impaired anion exchange in IC αMetabolic acidosisHypercalciuriaNephrocalcinosis, stonesExtra-renal:Osteomalacia, rickets Growth retardation

Hypercalciuric stone disease; ARHypercalciuric stone disease; ARO Devuyst and Y Prison: KI 2008(Belgium)O Devuyst and Y Prison: KI 2008(Belgium)

Ante-natal Bartter’s syndrome I: NKCC2/ Na-K-2Cl cotransporter 2 Hyperprostaglandin E syndrome

Ante-nasal Bartter’s syndrome II: ROML/ K channel Hyperpostagladin E syndrome 2

Bartter’s syndrome III: CLC-Kb/ Cl channel Familial hypomagnesemia with hypercalciuria and

nephrocalcinosis: FHHNC Distal RTA with progressive nerve deafness: ATP6V1B1/

B1 subunits of proton pump Distal RTA with preserved hearing/late onset hearing loss:

ATP6V0A4 / A4 subunits of proton pump

FHHNCFHHNC CLND 16/ Claudin-16/ paracellin-1 tight junction

protein TAL, DCT Renal:

Impaired paracellular transport of Ca/Mg: calcium and magnesium wasting Nephrocalcinosis, stones Renal failure

Extra-renal: Convulsions, tetany, chondrocalcinosis, neuro-muscluar manifestations

Function of CIC 5: Cl/H exchangerFunction of CIC 5: Cl/H exchanger

PT cell

Coated vesicle

Recycling endosome

LMW

H+ Cl/H

CLLate endosome

Lysosome

Functional loss of ClC-5Functional loss of ClC-5

Trafficking defect in PT cells Generalized PT cell dysfunction-Renal

Fanconi syndromeLMW proteinuria: DBP-25(OH)D3; PTHInternalization of NaPi-IIa: phosphaturia↑1 α hydroxylase: ↑1,25(OH)2D3Hypercalciuria, nephrocalcinosis, stones