A New Perspective on Hypercalcemia

Taipei Veterans General Hospital, Hsin-Chu branch

Director of Nephrologist

Steve Chen

Ca

CalciumCalcium

Reference Range:8.8 – 10.2 mg/L

CalciumCalcium

Hypercalcemia is total calcium > 10.5 mg/dl

CalciumCalcium

Hypercalcemia is ionized calcium > 2.7 mmol/L

HypercalcemiaHypercalcemia

Mild: S-Ca >10.5 mg/dlModerate: S-Ca >12 mg/dl Severe: S-Ca >14 mg/dl 1g/dl albumin binds about 0.8mg/dl Ca

( 4 – S-albumin ) x 0.8 + Measured S-Ca = Corrected S-Ca

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

Etiology of HypercalcemiaEtiology of Hypercalcemia

– MMalignancyalignancy– EEndocrinopathiesndocrinopathies

HyperparathyroidismHyperparathyroidism HyperthyroidismHyperthyroidism Adrenal insufficiencyAdrenal insufficiency

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

– IImmobilizationmmobilization

(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, Wide T-waveShort QT, Wide T-wave

ECG changesECG changes

Pronged PR interval

Widened QRS complex

Shortened QT + 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

ELECTROLYTE ELECTROLYTE DISORDERSDISORDERS

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

Hypercalcemia

DD

iPTH↑ in hypercalcemiaiPTH↑ in hypercalcemia

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

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

Adynamic renal Adynamic renal osteodystrophy(ARO)osteodystrophy(ARO)

JASN 12: 1978-1985,2001JASN 12: 1978-1985,2001 Sustained Reversible

ParathyroidectomyDMOsteoporosis aging estrogen deficiencyOsteopenia steroid-induced

Aluminum toxicityCalcitriol therapyExogenous Ca loads oral/dietary dialysateImmobilizationIron overload(?)

Predictor of AROPredictor of ARO

PTH <200 pg/ml plus S-Ca >10mg/dl: positive predictive value(PPV): 60%

PTH <150 pg/ml plus S-Ca >10mg/dl: positive predictive value(PPV): >82% Salusky et al, KI 45: 253-258, 1994

K/DOKI: i-PTH 150K/DOKI: i-PTH 150 ～～ 300/LT300/LTBarreto et al: KI 2008(Federal University of Sao Paulo, Brazil)Barreto et al: KI 2008(Federal University of Sao Paulo, Brazil)

N=97 Sensitivity Specificity PPV

LT(ARD and OM) 0.5 0.85 0.83cut-off < 150HT(PHBD and MUO) 0.69 0.75 0.62cut-off >300ARD: adynamic bone disease; OM: osteomalaciaPHBD: predominant hyperprathyroid bone diseaseMUO: mixed uremic osteodystrophy

Long-term consequences of Long-term consequences of AROARO

HypercalcemiaSoft tissue and vascular calcification

Mawad et al, Clin Nephrol 52: 160-166, 1999

Vertebral fracture Atsumi et al, AJKD 33: 287-293, 1999

Hip fracture Coco et al, AJKD 36: 1115-1121, 2001

Linear growth↓ Kuizon et al, KI 53: 205-211, 1998

Secondary hyperparathyroidism

Regulation and action of FGF-23Regulation and action of FGF-23KI, 2008 ( Baylor University Medical Center, Dallas, Texas, USA)KI, 2008 ( Baylor University Medical Center, Dallas, Texas, USA)

FGF 23

Pi pool Bone

Kidney

↓Parathyroid ?

Pi

PiPi

1,25(OH)2D3

↓1σ hydroxylase

Principles of treatmentPrinciples of treatment

IV N/S until ECF volume restored Loop diuretics: Lasix 40-100 mg IV q2-4HrsUrine output > 3 L/dayMonitor for ↓K+ and ↓Mg+HemodialysisDecrease 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 primaryprimary hyperparathyroidismhyperparathyroidism

Variables 1990 Guidelines 2002 Guidelines

S-Ca24-Hr U-Ca↓ in C-CrBMD

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-Ca24 Hr U-CaS-CrC-CrBMDAbdominal sono

Every 6M Annual Annual Annual Annual Annual

Every 6M -- Annual --Annual at 3 sites --

Stepped Approach for Management of Secondary Hyperparathyroidism

Step Drugs Goals

I •Low-phosphorus diet•Phosphate binders•Ergocalciferol (stages III and IV)

•Calcium and phosphorus within normal ranges •25-hydroxyvitamin D> 30 pg/mL

II •Cinacalcet•Vitamin D sterols (calcitriol, paricalcitol, and doxecalciferol)

•PTH within normal ranges

III •Adjust doses •Calcium, phosphorus, and PTH within K/DOQI recommendations

Secondary Secondary hyperparathyroidism hyperparathyroidism K/DOQIK/DOQI

CKD GFR Pi (mg/dl)

Ca (mg/dl)

Ca x Pi i PTH (pg/ml)

III 30-59 2.7-4.6q12M

8.4-10.2q12M

30-70(Level B) q12M

IV 15-29 2.7-4.6q3M

8.4-10.2q3M

70-110(Level B) q3M

V <15 3.5-5.5q1M

8.4-9.5q1M

<55 150-300(Level A) q3M

Outcome of Outcome of BP BP ↓ after subtotal PTXafter subtotal PTXRostaing et al, CN 47: 248-54, 1997Rostaing et al, CN 47: 248-54, 1997

N=34Cadaveric RT Pts

Pre-PTX ～ 1M S/P PTX

1～ 6M S/P PTX

P<0.05

SBP 140 134↓﹡ 138↓ P=0.046

DBP 85 81↓﹡ 82↓ p=0.03

MBP 103.5 99.5↓﹡ 100↓ p=0.03

Outcome of BP after subtotal PTXOutcome of BP after subtotal PTX

Primary HPT: ↓BP

HD with Secondary HPT: ↓BP: delayed (～ 9M) Goldsmith et al, AJKD 27: 819-25, 1996

RT with persistent hyperparathyroidism: ↓BP: significant but transient Rostaing et al, CN 47: 248-54, 1997

Hungry bones syndromeHungry bones syndrome Severe form Profound hypocalcemia+↓Mg+↓Pi:

S/P PTX for severe osteodystrophy 1～ 2 M

Mild form: S/P thyrotoxicosis early healing of rickets or osteomalacia

Calcitriol: 2～ 4 μg/D (initial dose) with rapid reduction after normocalcemia: 8.5～ 10.5 mg/dl

Calcium: IV calcium: 1G calcium chloride for 1G tissue/24Hours x2 Oral calcium: ～ 10 G/D

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

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