A New Perspective on Hypercalcemia

Taipei Veterans General Hospital, Hsin-Chu branch

Director of Nephrologist

Steve Chen

Ca

CalciumCalcium

Reference Range:8.8 – 10.3 mg/L

CalciumCalcium

Hypercalcemia is total calcium > 10.5 mg/dl

HypercalcemiaHypercalcemia

Mild: S-Ca >10.5 mg/dlModerate: S-Ca >12 mg/dl Severe: S-Ca >14 mg/dl 1 mmol/L ＝ 4mg/dlpH ↓0.1 ＝ free Ca↑0.05mmol/L 1g/dl albumin binds about 0.8mg/dl Ca

CalciumCalcium

Hypercalcemia is ionized calcium > 2.7 mmol/L

Etiology of Etiology of HypercalcemiaHypercalcemia

– MMalignancyalignancy– EEndocrinopathiesndocrinopathies

HyperparathyroidismHyperparathyroidism HyperthyroidismHyperthyroidism Adrenal insufficiencyAdrenal insufficiency

– DrugsDrugs Hypervitaminosis D/AHypervitaminosis D/A Thiazides, LithiumThiazides, Lithium

– ImmobilizationImmobilization

(90%)

Symptoms & signs of Symptoms & signs of HypercalcemiaHypercalcemia

Clinical Features(1)Clinical Features(1)– GeneralGeneral

Malaise, weakness, dehydration, polydipsiaMalaise, weakness, dehydration, polydipsia

– NeurologicNeurologic Confusion, apathy, decreased memory, irritabilityConfusion, apathy, decreased memory, irritability HallucinationsHallucinations, headache, ataxia, headache, ataxia Hyporeflexia, hypotoniaHyporeflexia, hypotonia

– CardiovascularCardiovascular HTN, dysrhythmiasHTN, dysrhythmias EKG abnormalitiesEKG abnormalities

– Short QT & ST, Wide T-waveShort QT & ST, Wide T-wave

ECG changesECG changes

Pronged PR interval

Widened QRS complex

Shortened QT & ST + wide T

Symptoms & signs of Symptoms & signs of HypercalcemiaHypercalcemia

Clinical Features (2)Clinical Features (2)– GastrointestinalGastrointestinal

N/V, anorexia, weight lossN/V, anorexia, weight loss Constipation, abdominal painConstipation, abdominal pain PUD, PancreatitisPUD, Pancreatitis

– SkeletalSkeletal Fractures, bone pain, deformitiesFractures, bone pain, deformities

– UrologicUrologic PolyuriaPolyuria Renal insufficiencyRenal insufficiency NephrolithiasisNephrolithiasis

Renal failure in Renal failure in hypercalcemiahypercalcemia

ECV↓: Bartter-like effect Arterial vasoconstrictionKUf↓GFR↓ATNNephrocalcinosisTubulointerstitial fibrosis

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

Memory AidMemory Aid– StonesStones ---- ---- Renal CalculiRenal Calculi– BonesBones ---- ---- OsteolysisOsteolysis– MoansMoans ---- ---- Psychiatric disordersPsychiatric disorders– Groans ----Groans ---- Abdominal (PUD, Abdominal (PUD,

Pancreatitis)Pancreatitis)

Hypercalcemia

Hypercalcemic crisis: >15mg/dlHypercalcemic crisis: >15mg/dl

De-compensated hypercalcemia: Fatal! myocardial calcinosis: cardiac arrest hypercalcemic renal failure CNS (coma) gradual or sudden onset mostly from pHPT

Compensated hypercalcemia: 70%: malignancy 20%: primary hyperparathyroidism (pHPT) 10%: others

DD

iPTH↑ in hypercalcemiaiPTH↑ in hypercalcemia

pHPTTertiary HPT: CRF history Ectopic HPT: rareFamilial Hypocalciuria Hypercalcemia(FHH)

UCa/Cr < 0.01 Lithium-induced, long-term

Principles of treatmentPrinciples of treatment

IV N/S until ECF volume restored Loop diuretics: Lasix 40-100 mg IV q2-4HrsHemodialysisUrine output > 3 L/dayMonitor for ↓K+ and ↓Mg+Decrease bone resorption in severe cases

bisphosphonates: pamindronate 60- 80 mg iv over 4 Hrs

calcitonin: 2- 8 U SC Hydrocortisone

Measures Dosage Side effects

IV saline 4～ 6 L/D K ↓ Mg ↓

Furosemide 40～ 500 mg/D K ↓ Mg ↓

Clodronate 300mg IV,

6 ～ 8Hr,

for 2 ～ 6D

Renal insufficiency

Calcitonin 200～ 500IU/D Escape

Prednisone 40～ 100/D Cushing

HD Ca-free Dialysis-related

Surgery for Surgery for asymptomaticasymptomatic primary primary hyperparathyroidismhyperparathyroidism

Variables 1990 Guidelines 2002 Guidelines

S-Ca

24-Hr U-Ca

↓ in C-Cr

BMD

Age

1~1.6 mg/dl +UNL

> 400mg

30%

Z score < -2.0, forearm

<50 Y/O

1.0mg/dl + UNL

> 400mg

30%

Z score < -2.5 at any site

< 50 Y/O

Monitoring for asymptomatic primary Monitoring for asymptomatic primary hyperparathyroidism hyperparathyroidism

Bilezikian et al, J Bone Miner Res 17, 2002Bilezikian et al, J Bone Miner Res 17, 2002 Variables 1990 Guidelines 2002 Guidelines

S-Ca

24 Hr U-Ca

S-Cr

C-Cr

BMD

Abdominal sono

Every 6M

Annual

Annual

Annual

Annual

Annual

Every 6M

--

Annual

--

Annual at 3 sites

--

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

U(electrolyte)/UcrU(electrolyte)/Ucr

Uca/Ucr(UCACR) > 0.2 mg/mg Hypercalciuria

Urine Albumin-Creatinine Ratio(UACR) > 30 mg/G Albuminuria

Urine Protein-Creatinine Ratio(UPCR) > 20 mg/G Proteinuria

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: endocytosis

PT dysfunction: Fanconi syndrome

Nephrocalcinosis, stones

Impaired urine acidification

Renal failure

Extra-renal:

Rickets

Lowe’s diseaseOCRL/OCRL1/ Phosphatidylinositol 4,5-biphosphate 5-phosphatase

PT

Renal:

PT dysfunction: Fanconi syndrome

Proximal RTA

Nephrocalcinosis, stones

Extra-renal:

Mental retardation, growth delay

Cataract, 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 receptor

PT/TAL/DCT/CD

Renal: gain-of-function

Low serum PTH

Hypocalcemia, Hypercalciuria

Nephrocalcinosis, stones

Salt-losing nephropathy; Hypokalemia (CaSR→ ROMK↓)

Extra-renal: basal ganglia calcifications, seizures

Distal RTA (RTA I)SLC4A1/ AE1/ Cl/HCO3 exchanger

ICα

Renal:

Impaired anion exchange in IC α

Metabolic acidosis

Hypercalciuria

Nephrocalcinosis, stones

Extra-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 para-cellular transport of Ca/Mg: calcium and magnesium wasting Nephrocalcinosis, stones Renal failure

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

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

Nonparathyroidal hypercalcemiaNonparathyroidal hypercalcemia

Malignancy: 50% PTHrP↑ Calcitriol IL-1, IL-6, IL-11, TGF-β, INF, GM-CSF, PGs

Mechanical(immobilization): fracture, AIP Hyperthyroidism Adrenal insufficiency Granulomatous(Infectious): TB, Histoplasmosis,

Sarcoidosis, AIDS

PTH-related peptide: pathologicalPTH-related peptide: pathologicalGR Mundy et al: JASN 2008(Vanderbilt University, Tennessee)GR Mundy et al: JASN 2008(Vanderbilt University, Tennessee)

Tumor cellsPTHrP

Kidney

Osteoclast

Bone

Ca↑ TGF β

Ca re-absorption ↑

PTHrP related tumor syndromes PTHrP related tumor syndromes GR Mundy et al: JASN 2008(Vanderbilt University, Tennessee)GR Mundy et al: JASN 2008(Vanderbilt University, Tennessee)

Humoral hypercalcemia of malignancy Hypercalcemia Plasma PTHrP ↑ Nephrogenous cAMP↑ Metabolic alkalosis ; 1,25(OH)2 VD↓ (Hyperchloremic acidosis ; VD ↑in primary hyperparathyroidism)

Localized osteolysis ±Hypercalcemia No increase in PTHrP and cAMP

Hypercalcemia: Hypercalcemia: nonparathyroidal and nonmalignantnonparathyroidal and nonmalignant

Iatrogenic hypercalcemia Munchausen syndrome( Vitamin D user) Vitamin A intoxification Thiazides Tamoxifen Theophylline Salicylic acid intoxification

Milk alkali syndrome from Sippy dietMilk alkali syndrome from Sippy dietLin et al, NDT 17: 708-14, 2002Lin et al, NDT 17: 708-14, 2002

Absorption of free Ca in upper intestinal tract: CaCO3+H (gastric secretion)→free Ca via trans-cellular pathway→CaCO3 by NaHCO3 in duodenum

Absorption of free Ca in downstream intestinal tract: CaCO3+H →free Ca via para-cellular pathway only if HPO4 deficiency→ Ca(PO4)2

Potential HCO3 load: CHO→H (bacterial fermentation)+ OA( non oxalate)

Triads: Hypercalcemia + Metabolic alkalosis + CKD; 1,25(OH)2VD low or low normal

Calcium(>4G/D) Alkali syndrome Calcium(>4G/D) Alkali syndrome Post-menopausal women: CaCO3(+VD3) Pregnant women: hyperemesis→ ECV→

Calcium via gut Transplant recipients/HD patients: CaCO3Patients with bulimia(anorexia nervosa):

food fetishes in Calcium Betel nuts chewers: a lime paste from

ground oyster: CaO + Ca(OH)2Thiazide users

Calcium Alkali syndrome Calcium Alkali syndrome

THAL

NKCC

ROMK

Na K ATP ase

Ca, Mg pH

Na/K

K

2Cl

CaSRNegative

Positive

Calcium Alkali syndrome Calcium Alkali syndrome

DCT

NCC

TRPV5

Na K ATP ase

pH pH

Na

Ca

Calcium flow

2Cl

CaSRPositive

PositiveCaSR

CaATPase

NCX

Betel nut chewing Betel nut chewing

pH= 7.47; HCO3 36meq/L; pCO2 50mmHg Na 137meq/L; K 3.2meq/L; Cl 91meq/L BUN/Cr 47/9.7 mg/dl Ca/Pi 12.8/5.7 mg/dl; Salb 3.9g/dl

FEk= 6.5% ; TTKG 7.0 Ca/Cr=0.64 (mmol/mmol) Calcium load=1.4mmol/sample x 40=52mmol/D

saliva Ca= 12mmol/L x (0,5ml/min x 12hr)=4 ～5mmol/D typical diet Ca=20mmol/D

Primary HPT plus Primary HPT plus

SarcoidosisThyrotoxicosisPaget’s disease

Schmaldienst et al, NDT 16: 2423-25, 2001

Primary HPT: novel patternPrimary HPT: novel pattern

Hypercalcemia with low-normal i-PTH in serum Hollenberg et al, AJM 91: 547-548, 1991