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

2. CalciumCalcium
Reference Range:
8.8 – 10.2 mg/L

3. CalciumCalcium
Hypercalcemia is total calcium > 10.5
mg/dl

4. CalciumCalcium
Hypercalcemia is ionized calcium > 2.7
mmol/L

5. HypercalcemiaHypercalcemia
Mild: S-Ca >10.5 mg/dl
Moderate: 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

6. 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

8. Etiology of HypercalcemiaEtiology of Hypercalcemia
– MMalignancyalignancy
– EEndocrinopathiesndocrinopathies
 HyperparathyroidismHyperparathyroidism
 HyperthyroidismHyperthyroidism
 Adrenal insufficiencyAdrenal insufficiency
– DDrugsrugs
 Hypervitaminosis D/AHypervitaminosis D/A
 Thiazides, LithiumThiazides, Lithium
– IImmobilizationmmobilization
(90%)

9. Symptoms & signs ofSymptoms & 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

10. ECG changesECG changes
Pronged PR interval
Widened QRS complex
Shortened QT + wide T

12. Symptoms & signs ofSymptoms & 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

13. ELECTROLYTEELECTROLYTE
DISORDERSDISORDERS
 Memory AidMemory Aid
– StonesStones -------- Renal CalculiRenal Calculi
– BonesBones -------- OsteolysisOsteolysis
– MoansMoans -------- Psychiatric disordersPsychiatric disorders
– Groans ----Groans ---- Abdominal (PUD, Pancreatitis)Abdominal (PUD, Pancreatitis)
Hypercalcemia

15. DD

16. iPTH↑ in hypercalcemiaiPTH↑ in hypercalcemia
pHPT
Tertiary HPT: CRF history
Ectopic HPT: rare
Familial Hypocalciuria Hypercalcemia(FHH)
UCa/Cr < 0.01
Lithium-induced, long-term

19. Adynamic renalAdynamic renal
osteodystrophy(ARO)osteodystrophy(ARO)
JASN 12: 1978-1985,2001JASN 12: 1978-1985,2001
Sustained Reversible
Parathyroidectomy
DM
Osteoporosis
aging
estrogen deficiency
Osteopenia
steroid-induced
Aluminum toxicity
Calcitriol therapy
Exogenous Ca loads
oral/dietary
dialysate
Immobilization
Iron overload(?)

20. 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

21. K/DOKI: i-PTH 150K/DOKI: i-PTH 150 ～～ 300/LT300/LT
Barreto 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 0.83
cut-off < 150
HT(PHBD and MUO) 0.69 0.75 0.62
cut-off >300
ARD: adynamic bone disease; OM: osteomalacia
PHBD: predominant hyperprathyroid bone disease
MUO: mixed uremic osteodystrophy

22. Long-term consequences ofLong-term consequences of
AROARO
Hypercalcemia
Soft 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

24. Secondary hyperparathyroidism

25. Regulation and action of FGF-23Regulation and action of FGF-23
KI, 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
Pi
Pi
1,25(OH)2D3
↓1σ hydroxylase

28. Principles of treatmentPrinciples of treatment
IV N/S until ECF volume restored
Loop diuretics: Lasix 40-100 mg IV q2-4Hrs
Urine output > 3 L/day
Monitor for ↓K+ and ↓Mg+
Hemodialysis
Decrease bone resorption in severe cases
bisphosphonates:
pamindronate 60- 80 mg iv over 4 Hrs
calcitonin: 2- 8 U SC
Hydrocortisone

29. 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

31. Surgery forSurgery for asymptomaticasymptomatic primaryprimary
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

32. Monitoring for asymptomatic primaryMonitoring for asymptomatic primary
hyperparathyroidismhyperparathyroidism
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
--

33. 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

34. SecondarySecondary hyperparathyroidismhyperparathyroidism
K/DOQIK/DOQI
CKD GFR Pi
(mg/dl)
Ca
(mg/dl)
Ca x Pi i PTH
(pg/ml)
III 30-59 2.7-4.6
q12M
8.4-10.2
q12M
30-70
(Level B)
q12M
IV 15-29 2.7-4.6
q3M
8.4-10.2
q3M
70-110
(Level B) q3M
V <15 3.5-5.5
q1M
8.4-9.5
q1M
<55 150-300
(Level A) q3M

35. Outcome ofOutcome of BPBP ↓ after subtotal PTXafter subtotal PTX
Rostaing et al, CN 47: 248-54, 1997Rostaing et al, CN 47: 248-54, 1997
N=34
Cadaveric
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

36. 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

37. 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

39. 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

40. PTH-related peptide: pathologicalPTH-related peptide: pathological
GR 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 ↑

42. PTHrP related tumor syndromesPTHrP 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

44. Milk alkali syndrome from Sippy dietMilk alkali syndrome from Sippy diet
Lin 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

45. Calcium(>4G/D) Alkali syndromeCalcium(>4G/D) Alkali syndrome
Post-menopausal women: CaCO3(+VD3)
Pregnant women: hyperemesis→ ECV→
Calcium via gut
Transplant recipients/HD patients: CaCO3
Patients with bulimia(anorexia nervosa):
food fetishes in Calcium
Betel nuts chewers: a lime paste from
ground oyster: CaO + Ca(OH)2
Thiazide users

46. Calcium Alkali syndromeCalcium Alkali syndrome
THAL
NKCC
ROMK
Na K ATP ase
Ca, Mg pH
Na/K
K
2Cl
CaSR
Negative
Positive

47. Calcium Alkali syndromeCalcium Alkali syndrome
DCT
NCC
TRPV5
Na K ATP ase
pH pH
Na
Ca
Calcium
flow
2Cl
CaSR
Positive
PositiveCaSR
CaATPase
NCX