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A New Perspective on Hypercalcemia
Taipei Veterans General Hospital, Hsin-Chu branch
Director of Nephrologist
Steve Chen
Ca
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
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
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
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