a new perspective on hypocalcemia
TRANSCRIPT
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