Hypercalcemia
Heidi Chamberlain Shea, MD
Endocrine Associates of Dallas
Goals of Discussion




Review Calcium metabolism
Differential Diagnosis of Hypercalcemia
Treatment options
Calcium case presentations
Calcium Physiology







An essential intracellular and extracellular cation
Extracellular calcium is required to maintain
normal biological function of nervous system, the
musculoskeletal system, and blood coagulation
Intracellular calcium is needed for normal activity
of many enzymes
Preservation of the integrity of cellular membrane
Regulation of endocrine and exocrine secretory
activities
Activation of compliment system
Bone metabolism
Role of Calcium


Bone mineralization
Muscle contraction
Skeletal
 Cardiac
 Smooth muscle



Blood clotting
Nerve impulse transmission

Bone metabolism
 Parathyroid
hormone (PTH)
 Calcium
 Phosphorus
 Vitamin D
 Calcitonin
Calcium

41% combined with plasma proteins



9% combined with anionic substances




Not diffusible
One gram per deciliter of albumin binds
approximately 0.8 mg/dl of calcium
Citrate and phosphate
Not ionized
Diffusible
50% is diffusible and ionized

Most important in bodily functions
Effects of Calcium
Hypocalcemia


Increased neuronal
membrane permeability
to sodium ions facilitates
action potentials
When calcium levels
< 6mg/dl




Tetany
Chvostek’s sign
Trousseau’s sign
Calcium <4mg/dl =
Death
Effects of
Hypercalcemia

Calcium >12 mg/dl






Nervous system
depressed
Fatigue
Depression
Constipation
Anorexia
Polyuria

Most common nocturia

Parathyroid
poisoning


Calcium > 17mg/dl
Calcium phosphate
crystals precipitate
Findings with Hypercalcemia




Bony tenderness
Hyperactive tendon reflexes
Tongue fasciculations
Hypercalcemia in pregnancy

May cause hypocalcemia in the neonate


Suppressing the fetal parathyroid
Hypercalcemia

Small decrease in GFR

Hemodynamic effects & hyposthenuria (a loss of renal
concentrating abilities)
Findings with Hypercalcemia
Band Keratopathy

Deposition of Calcium






Corneal opacities
Long standing hypercalcemia
Associated with primary
hyperparathyroidism
Calcium deposition begins near
the limbus at the 3 & 9 o’clock
position
Less friction from the lids near
the limbus
Tear film is most alkaline in the
most exposed area, band
running across the cornea from
the 3 to 9 o’clock position
Complications of Hypercalcemia

Sinus bradycardia

Increase in the degree of a heart block
Cardiac arrhythmia
Hypertension
Pancreatitis
Peptic ulcer disease
Nephrolithiasis
Accelerated vascular calcification






Calcium Homeostasis

Hormones
PTH
 Vitamin D
 Calcitonin


Organs
Bone
 Kidney
 Small intestine

1,25-OH Vitamin D
Calcium Physiology
Target Organs

Small intestine :

Kidney :
approx. 40% absorbed, 50% of that excreted into bile and other intestinal secretions. So only 20% of
the total amount of Ca ingested daily is available to circulate
between bone and extracellular fluid.
Glomerulus filters out the Ca that is not bound to protein.
 Proximal tubule - approx. 50% to 70% is reabsorbed, Ca
reabsorption mirrors Na reabsorption.
 Ascending limb of the loop of henle - approx. 30% to 40%
reabsorbed
 Distal nephron - about 10% reabsorbed. PTH and activated Vit D
increases Ca absorption during Ca deficient states.
Normally kidney excretes approx. 200 mg /day of Ca to maintain
homeostasis. During states of severe Ca depletion, the Kidney
can decrease urinary excretion to 50mg /day or less.
CALCIUM
REGULATION
PTH
_
+
_
+
1,25(OH)2 D3
+
+
GI Tract
+
CALCITONIN
_
ECF Pool
of Calcium
URINE
BONE
Parathyroid






Four glands located
behind the thyroid
Length 6 millimeters
Width 3 millimeters
Thickness 2
millimeters
Often accidentally
removed
Normal function with
at least 2 glands
Parathyroid

Composed

Chief cells


Oxyphil cells


Synthesize, secrete
and store PTH
? function
Responsible for
calcium homeostasis


Kidney
Bone
Parathyroid Actions

Increases calcium

Regulates intestinal absorption

25-OH vitamin D
1,25-OH vitamin D
Renal absorption of calcium/excretion of
phosphorus
 Bone reabsorption


Osteolysis
Parathyroid and Bone


Osteoblasts + Osteocytes = Osteocytic
membrane system
Osteocytic pumps
Pump calcium from bone to ECF
 To maintain calcium concentration in bone
fluid, osteolysis occurs and calcium
phosphate is resorbed from bone
 Fibrous and gel matrix remain intact

Parathyroid and Bone

PTH stimulates osteocytic pump


Increases permeability of osteocytic membrane
allowing calcium to diffuse
Osteoblasts,cytes and clasts do not have
PTH receptors



PTH stimulates osteoblasts and cytes, which then
activate osteoclasts via “signaling” system
PTH indirectly stimulates formation of new
osteoclasts
Both cell lines are activated but clastic activity >
blastic
Calcitonin





Secreted by
Parafollicular (C cells)
in the thyroid
Temporarily lowers
calcium levels
Decreases osteoclastic
activity
Stimulated by high
calcium levels
Stimulating a distal
tubular - mediated
calciuresis
Calcium Caveats

Respiratory alkalosis and elevated pH



Decrease in pH has the opposite effect.


Increase in the binding of calcium
Lowers ionized calcium.
As a general rule a shift of 0.1 pH unit produces a
change in ionized calcium of 0.04 to 0.05 mmol/L
Chelators such as citrate may transiently
decrease ionized calcium

Blood transfussions
Formulas for Correction







0.8 for each gm of Albumin
0.16mg/dl for each gm of globulin.
FEca= (uCA x sCR)/(sCA x uCR)
 FEca <1% - Familial hypocalciuric hypercalcemia,
 FEca >2% - primary hyperparathyroidism
 in pH will  protein bound Ca by 0.12mg/dl
80-90% of protein bound Ca is bound to Albumin.
Increase in serum pH of 0.1 may cause decrease in
ionized Ca of 0.16mg/dl
Calcium : Protein bound - 40%; Complexed - 13%;
Ionized fraction - 47%
Etiology of Hypercalcemia
Approx. 80% of all cases are caused by
Malignancy or Primary Hyperpathyroidism








V Vitamins
I
Immobilization
T Thyrotoxicosis
A Addison’s disease
M Milk-alkali
syndrome
I Inflammatory
disorders
N Neoplastic related
disease
S Sarcoidosis




T
Thiazide,
other drugs - Lithium
R Rabdomyolysis
A AIDS
P Paget’s disease,
Parental nutrition,
Pheochromocytoma,
Parathyroid disease
HYPERCALCEMIA
SERUM CALCIUM
> 10.6
Determine wheather hypercalcemia is real, measure ionized Ca
adjust for change in serum albumin level, careful drug hx Li, Vit D or A,
Measure PTH
PTH high
Hyperparathroidism
PTH - N or Low
Malig- prim. or mets
If cause remain unclear
measure Vit D
Vit high
consider Sarcoidosis
CXR
Consider other
*Hyperthyroidism
*Milk-alkali syndrome
*Familial hypocalciuric hypercalcemia
Hyperparathyroidism

Stones

Bones

Groans

Moans
Normal bone
Hyperparathyroid
Hyperparathyroidism
PTH
Calcium
normal / 

Secondary

 / normal
Tertiary


Primary
Intact PTH
PTHrP
1,25 -D
Ca++
Prim. HPT




PTHrP malignency




Non-PTHrP malig




Hyperparathyroidism
Surgical Management



Serum calcium > 12mg/dl
Hypercalciuria > 400mg/day
 Normal <200 mg/day
Presence of signs and
symptoms
 Nephrolithiasis
 Osteitis fibrosa Cystica
 Neuromuscular
symptoms

Markedly reduced cortical
bone density





Most common
Long bones
Decreased creatinine
clearance
Patient age < 50 years
Markedly reduced
cancellous bone density

Spine
Silverberg et al., JCEM:1996
Hyperparathyroidism
Medical Management


Alendronate therapy
37 patients
>50% female
 53 to 80 years
 Primary Hyperparathyroidism


Cross over
24 months Alendronate
 12 placebo and 12 treatment

Khan et. al., JCEM 2004
Hyperparathyroidism
Medical Management
Khan et. al., JCEM 2004
Treatment for Hypercalemia
Hydration
 Furosemide
 Bisphosphonate
 Calcitonin
 Mithramycin

Gallium nitrate
 Steroids
 IV Phosphate
 Dialysis
 Others

Treatment for Hypercalemia
Hydration




First step in the management of severe
hypercalcemia. --isotonic saline
Usually reduces - 1.6-2.4mg/dl
Hydration alone rarely leads to
normalization in severe hypercalcemia
Rate of IV saline based on severity of
hypercalcemia and tolerance of volume
expansion
Treatment for Hypercalemia
Loop Diuretics

Facilitate urinary excretion of calcium


Inhibits calcium reabsorption in the thick
ascending limb of the loop of Henle
Guard against volume overload

Volume expansion must precede the
administration of furosemide
Drug’s effect depends on delivery of calcium to
the ascending limb.
 Needs frequent measurement of lytes and urine
output

Treatment for Hypercalemia

Calcitonin


Not as effective as
bisphosphonate,
tachyphylaxis quickly
occurs and limits
therapeutic efficacy
Toxic effect limits it’s use,
reserved for difficult cases
of hypercalcemia that are
related to malignancy
Gallium Nitrate

Need to infuse it over 5
days, nephrotoxity limits it’s
use, not used frequently
Corticosteroids



Mithramycin





For myeloma, lymphoma,
Sarcoidosis, or vit D toxicity
Decreases GI absorption
200-300mg hydrocortisone
for up to 5 days
Slow response limits it’s
use
Hemodialysis

Zero or low calcium bath,
In selected condition,
eg-hypercalcemia
complicated by renal failure
Treatment for Hypercalemia
Bisphosphonate

Structurally related to pyrophosphate



P-C-P bound is a back bone that renders them resistant to
phosphates.
They bind to hydroxyapatite in bone and inhibit the
dissolution of crystals.
Their great affinity for bone and their resistance to
degradation account for their extremely long half life in bone.
Treatment for Hypercalemia
Bisphosphonate



Poor GI absorption- <10%
ETIDRONATE, PAMIDRONATE,CLODRONATE
Etidronate- 7.5mg/kg iv over 4 hr for 3-7 days





Serum calcium begins to decrease within 2 days after
first dose
Response better if patient is well hydrated
Oral bisphosphonate to prevent recurrent
hypercalcemia.
Adverse effect-increase creatinine, phosphate
Long term use-impair bone formation, osteomalacia
Treatment for Hypercalemia
Bisphosphonate

Pamidronate




Inhibits osteoclast function
The most potent bisphosphonate
60mg to 90 mg IV over 24hr
70% to 100% of patients



Adverse effect

Decreased calcium within 24 hr of treatment
2/3rd of this group had normal calcium within 7 days
Mild transient increase in temp(<2○ C), transient
leukopenia, small reduction in phosphate level
Excreted by kidney- dose adjustment
Treatment for Hypercalemia
Mithramycin




An inhibitor of RNA
synthesis in osteoclasts
IV 25 microgram/kg over
4-6 hr
Begins to decrease in
12hr, max in 48-72 hr
Duration of
normocalcemia ranges
from a few days to
several weeks

Depending on the extent of
ongoing bone resorption

Adverse effect





Nausea- Minimize with slow iv
Avoid extravasation-cellulitis
Hepatotoxic- in 20% patients
Nephrotoxic- increase in
creatinine, proteinuria
Thrombocytopenia
Contraindication-liver, kidney
dysfunction,
thrombocytopenia, or any
coagulopathy
Treatment for Hypercalemia
Gallium Nitrate



Inhibit bone resorption by adsorbing to
and reducing the solubility of
hydroxyapatite crystals
Adverse effect- Nephrotoxity,
hypophosphatemia, small reduction in
hemoglobin concentration
Clinical experience limited
Treatment for Hypercalemia

GLUCOCORTICOIDS

Inhibits the growth of neoplastic lymphoid tissue,
counteracting the effects of vitamin D
PHOSPHATE
Can lower calcium rapidly and profoundly,


Restricted to patient with extreme, life threatening
hypercalcemia


Very dangerous
Last resort
Contraindications-Hyperphosphatemia and
azotemia
Treatment for Hypercalemia
Choice of Agent

Mild (<12mg/dl)




Hydration with saline
Lasix
Saline + Calcitonin +
mithramycin
 Alternatively
bisphosphonate,
 Steroids if sensitive
Hypercalcemia secondary to
malignancy
Moderate (12-14 mg/dl)
with symptoms

Severe life threatening
(>14mg/dl)
Bisphosphonate



Survival after the appearance of
hypercalcemia is very poor
Median of 3 months.
What Is The Diagnosis?






52 yr old African
American female
presents with broken
hip
Poor light exposure
Fatigue
Constipation
Difficulty concentrating
History of kidney
stones
What Is The Diagnosis?




Calcium 13mg/dl (9-10.5)
Phosphorus 2mg/dl (3-4.5)
25-OH vitamin D 33 ng/ml (20-40)
PTH 90 pg/ml (10-80)
Diagnosis: Primary Hyperparathyroidism
What Is The Diagnosis?




10 day old infant presents to ER with
seizures
Calcium 5.5mg/dl (9-10.5)
Ionized calcium 3 mg/dl (4-5.6)
Phosphorus 10 mg/dl (3-4.5)
• PTH 5 pg/ml (10-80)
Diagnosis: Hypoparathyroidism
What Is The Diagnosis?






18 month old African American male
Presents with abnormal gait
Low sunlight exposure
Breast fed as infant with current poor dairy
intake
Calcium 8 mg/dl (9-10.5)
Phosphorus 4mg/dl (3-4.5)
• PTH 85 pg/dl (10-80)
• 25-OH Vitamin D 10 ng/ml (20-40)
Diagnosis

Vitamin D deficiency
with secondary
hyperparathyroidism

Tibial and femur
bowing

Treatment:
Ergocalciferol and
calcium